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NEURO- OPHTHALMOLOGY

Edited by DESMOND P. KIDD, MD, FRCP Consultant Neurologist Department of Clinical Neurosciences Royal Free Hospital and University College Medical School London, United Kingdom

NANCY J. NEWMAN, MD LeoDelle Jolley Professor of Ophthalmology Professor of Ophthalmology and Neurology Instructor in Neurological Surgery Emory University School of Medicine Atlanta, Georgia

VALE´RIE BIOUSSE, MD Cyrus H. Stoner Professor of Ophthalmology Professor of Ophthalmology and Neurology Emory University School of Medicine Atlanta, Georgia 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

NEURO-OPHTHALMOLOGY ISBN: 978-0-7506-7548-2

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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data

Neuro-ophthalmology / [edited by] Desmond P. Kidd, Nancy J. Newman, Vale´rie Biousse. – 1st ed. p. ; cm. – (Blue books of neurology series; v.32) Includes bibliographical references and index. ISBN 978-0-7506-7548-2 1. Neuroophthalmology. I. Kidd, Desmond P. II. Newman, Nancy J. III. Biousse, Vale´rie. IV. Series: Blue books of neurology; 32. [DNLM: 1. Eye Diseases. 2. Nervous System Diseases. W1 BU9749 v.32 2008 / WW 460 N4915 2008] RE725.N45682 2008 617.7032–dc22 2007040909

Acquisitions Editor: Adrianne Brigido Developmental Editor: Joan Ryan Project Manager: Mary Stermel Design Direction: Steven Stave Marketing Manager: Todd Liebel Printed in China

Lastdigitistheprintnumber:987654321 CONTRIBUTING AUTHORS

LAURA J. BALCER, MD, MSCE Associate Professor of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

VALE´RIE BIOUSSE, MD Cyrus H. Stoner Professor of Ophthalmology, Professor of Ophthalmology and Neurology, Emory University School of Medicine, Atlanta, Georgia

FION D. BREMNER, PhD, FRCOphth Consultant Neuro-Ophthalmic Surgeon, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

CHOTIPAT DANCHAIVIJITR, MD, MRCP (UK) Instructor in Neurology, Division of Neurology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

KATHLEEN DIGRE, MD Professor of Neurology and Ophthalmology, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah

STEVEN L. GALETTA, MD Van Meter Professor of Neurology and Ophthalmology; Director, Division of Neuro-Ophthalmology, Departments of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Scheie Eye Institute, and The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

CHRISTOPHER KENNARD, PhD, FRCP, FMedSci Professor of Clinical Neurology, Department of Clinical Neuroscience, Imperial College London, Charing Cross Campus, London, United Kingdom

DESMOND P. KIDD, MD, FRCP Consultant Neurologist, Department of Clinical Neurosciences, Royal Free Hospital and University College Medical School, London, United Kingdom

GRANT T. LIU, MD Professor of Neurology and Ophthalmology, Division of Neuro-Ophthalmology, Departments of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, and The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

ix x Contributing Authors

NEIL R. MILLER, MD, FACS Professor of Ophthalmology, Neurology and Neurosurgery and Frank B. Walsh Professor of Neuro-Ophthalmology, Johns Hopkins Medical Institutions, Baltimore, Maryland

NANCY J. NEWMAN, MD LeoDelle Jolley Professor of Ophthalmology, Professor of Ophthalmology and Neurology, Instructor in Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia

GORDON T. PLANT, MA, MD (Cantab), FRCP (UK), FRCOphth Consultant Neurologist, The National Hospital for Neurology and Neurosurgery, Moorfields Eye Hospital and St. Thomas’ Hospital, London, United Kingdom

MICHAEL POWELL, FRCS, FRCP Senior Consultant Neurosurgeon, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

GEOFFREY E. ROSE, BSc, MBBS, MS, DSc, MRCP, FRCOphth Consultant Orbital, Lacrimal, and Oculoplastic Surgeon, Moorfields Eye Hospital, London, United Kingdom

JANET C. RUCKER, MD Assistant Professor of Neurology and Ophthalmology, Rush University Medical Center, Chicago, Illinois

DAVID H. VERITY, MA, BM BCh, FRCOphth Consultant Orbital, Lacrimal, and Oculoplastic Surgeon, Moorfields Eye Hospital, London, United Kingdom CONTRIBUTING AUTHORS

LAURA J. BALCER, MD, MSCE Associate Professor of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

VALE´RIE BIOUSSE, MD Cyrus H. Stoner Professor of Ophthalmology, Professor of Ophthalmology and Neurology, Emory University School of Medicine, Atlanta, Georgia

FION D. BREMNER, PhD, FRCOphth Consultant Neuro-Ophthalmic Surgeon, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

CHOTIPAT DANCHAIVIJITR, MD, MRCP (UK) Instructor in Neurology, Division of Neurology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

KATHLEEN DIGRE, MD Professor of Neurology and Ophthalmology, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah

CHRISTOPHER KENNARD, PhD, FRCP, FMedSci Professor of Clinical Neurology, Department of Clinical Neuroscience, Imperial College London, Charing Cross Campus, London, United Kingdom

DESMOND P. KIDD, MD, FRCP Consultant Neurologist, Department of Clinical Neurosciences, Royal Free Hospital and University College Medical School, London, United Kingdom

ix x Contributing Authors

NEIL R. MILLER, MD, FACS Professor of Ophthalmology, Neurology and Neurosurgery and Frank B. Walsh Professor of Neuro-Ophthalmology, Johns Hopkins Medical Institutions, Baltimore, Maryland

NANCY J. NEWMAN, MD LeoDelle Jolley Professor of Ophthalmology, Professor of Ophthalmology and Neurology, Instructor in Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia

MICHAEL POWELL, FRCS, FRCP Senior Consultant Neurosurgeon, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

GEOFFREY E. ROSE, BSc, MBBS, MS, DSc, MRCP, FRCOphth Consultant Orbital, Lacrimal, and Oculoplastic Surgeon, Moorfields Eye Hospital, London, United Kingdom

JANET C. RUCKER, MD Assistant Professor of Neurology and Ophthalmology, Rush University Medical Center, Chicago, Illinois

DAVID H. VERITY, MA, BM BCh, FRCOphth Consultant Orbital, Lacrimal, and Oculoplastic Surgeon, Moorfields Eye Hospital, London, United Kingdom SERIES PREFACE

The Blue Books of Neurology have a long and distinguished lineage. Life began as the Modern Trends in Neurology series and continued with the monographs form- ing BIMR Neurology. The present series was first edited by David Marsden and Arthur Asbury, and saw the publication of 25 volumes over a period of 18 years. The guiding principle of each volume, the topic of which is selected by the Series Editors, was that each should cover an area where there had been significant advances in research and that such progress had been translated to new or improved patient management. This has been the guiding spirit behind each volume, and we expect it to continue. In effect, we emphasize basic, translational, and clinical research but principally to the extent that it changes our collective attitudes and practices in caring for those who are neurologically afflicted. Tony Schapira took over as joint editor in 1999 following David’s death, and together with Art oversaw the publication and preparation of a further 8 volumes. In 2005, Art Asbury ended his exceptional co-editorship after 25 years of distinguished contribution and Martin Samuels was asked to continue the co-editorship with Tony. The current volumes represent the beginning of the next stage in the development of the Blue Books. The editors intend to build upon the excellent reputa- tion established by the Series with a new and attractive visual style incorporating the same level of high-quality review. The ethos of the Series remains the same: up-to-date reviews of topic areas in which there have been important and excit- ing advances of relevance to the diagnosis and treatment of patients with neurological diseases. The intended audience remains those neurologists in training and those practicing clinicians in search of a contemporary, valuable, and interesting source of information.

ANTHONY H.V. SCHAPIRA MARTIN A. SAMUELS SERIES EDITORS

xi PREFACE

The practice of neurology is both interesting and challenging owing to the wide diversity of clinical problems and syndromes, and, oftentimes, the difficulty of establishing the pathology of the disease process without gaining access to tissue. Neuro-ophthalmology lies at the extreme of this; visual symptoms may arise as a result of disease anywhere within the eye and brain, and neuro-ophthalmologists, unlike many other subspecialists, have the added challenge of including all disease processes in their differential diagnosis of visual symptoms, including those of inflammatory, vascular, degenerative, neoplastic, toxic, traumatic, and metabolic origin. Although neurologists may find neuro-ophthalmologic problems somewhat daunting because of the need to gain an understanding of the ways of ophthalmologists and their equipment, neuro-ophthalmology is in essence the application of an understanding of neurological diseases and their pathophysiology to visual symptoms. This volume of the Blue Book series is the first to deal with neuro- ophthalmology and its practice; it is not intended as an exhaustive textbook on neuro-ophthalmology but is comprised of a series of chapters that deal in turn with each of the main and common conditions seen in neuro-ophthalmology, with an emphasis on modern methods of assessment and treatment. It is designed to interest neurologists, neurosurgeons, and ophthalmologists of any level of experience, with the hope that they will come to find neuro-ophthalmic cases as fascinating as we do. We would like to thank all our co-authors for their experience, expertise, clear writing, and attention to deadlines. We would also like to thank the staff at Elsevier for their help and professionalism in managing the volume, particularly Susan Pioli, whose calmness was especially helpful.

DESMOND P. KIDD NANCY J. NEWMAN VALE´ RIE BIOUSSE

xiii Dedication

To our families

xv 1 Neuro-Ophthalmologic Anatomy and Examination Techniques STEVEN L. GALETTA LAURA J. BALCER GRANT T. LIU

Introduction The Neuro-Ophthalmologic Examination The Afferent Visual Pathways Visual Acuity Anatomy of the Retina and Optic Near Vision Nerve Color Vision Disorders of the Retina Contrast Sensitivity and Low- Optic Nerve Disease Contrast Letter Acuity Anatomy of the Optic Chiasm Amsler Grid Testing Chiasmal Visual Loss Visual Field Testing Anatomy of the Retrochiasmal Tangent Screen Field Testing Visual Pathways Formal Perimetry Disorders of the Retrochiasmal Pupillary Examination Visual Pathways Eyelid Examination Ocular Motility The Ocular Motor System Ophthalmoscopy Anatomy of the Orbit and Extraocular Muscles Neuro-Ophthalmologic Anatomic Considerations of the Examination in Third, Fourth, and Sixth Comatose Patients Cranial Nerves Approach to the Comatose Orbital Apex and Cavernous Patient Sinus Syndromes Examination in Comatose Anatomy of the Supranuclear, Patients Internuclear, and Vestibulo- Pupillary Abnormalities in Coma Ocular Gaze Pathways Eye Movement Abnormalities Saccade System in Coma Vestibulo-Ocular System Abnormal Ocular Fundi in Coma Pursuit System Terson’s Syndrome

The Pupillary Pathways References Anatomy of the Pupillary Pathways

1 2 Neuro-Ophthalmology: Blue Books of Neurology

Key Points Certain visual field defects may have exquisite localizing value and may predict the underlying etiology of the lesion. The five hallmarks of an optic neuropathy are decreased acuity, impaired color vision, an afferent pupillary defect, abnormal visual field, and optic nerve head change. Vertical diplopia usually results from one of the following: third nerve palsy, fourth nerve palsy, skew deviation, myasthenia gravis, or thyroid eye disease. The presence of pain with an ocular motility disturbance, pupillary abnormality, or visual loss should raise the possibility of a neuro-ophthalmologic emergency.

Introduction

Neuro-ophthalmologic disorders, affecting the afferent and efferent visual pathways, are often encountered by neurologists in clinical practice. Combining an understanding of neuro-ophthalmologic anatomy with proper examination technique provides a powerful means to detect and localize lesions that involve the visual system. Furthermore, precise documentation of the extent of damage within the visual system is becoming an invaluable method to assess the effect of emerging neurologic therapies. Signs and symptoms of visual pathway dysfunction commonly occur as initial presenting features of potentially treatable neurologic disorders, including strokes, multiple sclerosis, tumors, aneurysms, central nervous system infections, and certain movement disorders. Visual loss and ocular motility disorders may also occur as manifestations of systemic disorders, such as cardiac disease, diabetes mellitus, hypertension, and drug toxicity. Prompt recognition and localization of neuro-ophthalmologic signs and symptoms are crucial to effective diagnosis and management. This chapter focuses on aspects of neuroanatomy and the neuro-ophthalmologic examination that are most important to the diagnosis of afferent and efferent visual pathway lesions.

The Afferent Visual Pathways

ANATOMY OF THE RETINA AND OPTIC NERVE The retina is the initial sensory structure encountered within the afferent visual pathways and has the distinction of being the only portion of the nervous system that can be directly examined by the clinician. Many neurologic and systemic disorders may be characterized by their retinal findings. The structures of the normal retina and fundus, including the optic disc, macular area, fovea, and retinal arterioles and veins, are shown in Figure 1–1A and B.1 The innermost cellular layer of the retina consists of ganglion cells. Ganglion cell axons travel within the retinal nerve fiber layer and are bundled in a distinct configuration as they approach the optic nerve head.2 Axons that directly enter the temporal aspect of the disc are called the papillomacular bundle and they are derived from the macula and serve central vision. Ganglion cell axons from the 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 3

Arteriole Fovea

Macula Vein

Optic disc A

B Figure 1–1 A, Schematic diagram of normal left fundus. B, Photograph of normal left fundus. (A, Reprinted with permission from Liu GT: Disorders of the eyes and eyelids. In Samuels MA, Feske S (eds): Office Practice of Neurology. New York, Churchill Livingstone, 1996, p 41.) peripheral field traverse around the papillomacular fibers to form the superior and inferior arcuate bundles. Finally, fibers subserving temporal vision coalesce in a radial pattern to enter the nasal aspect of the disc. Images fall on the retina in an “upside-down and backward” fashion. For example, in the left eye, the upper nasal retina receives information from the lower temporal portion of the visual field, whereas the lower temporal retina receives information from the upper nasal field. This retinotopic organization of visual information is also present within the optic nerve and is preserved throughout the afferent visual pathways. The blood supply to the retina and optic nerve originates primarily from the ophthalmic artery, the first major intracranial branch of the internal carotid artery. The inner two thirds of the retina is supplied by the central retinal artery (Fig. 1–2).3 This artery travels within the optic nerve for a short distance behind the disc and then branches out to supply the four main quadrants of the retina (Fig. 1–1A and B). The short and long posterior ciliary arteries are also branches of the ophthalmic artery; the long posterior ciliaries supply the ciliary body (responsible for lens accommodation), whereas the short posterior ciliary 4 Neuro-Ophthalmology: Blue Books of Neurology

Subarachnoid Central Central Optic space extends retinal retinal nerve forward to artery vein Dura just behind disc mater Posterior ciliary Sclera Retina artery

Cilioretinal artery

Anterior and posterior lamina cribrosa

Figure 1–2 Schematic diagram of the optic nerve head demonstrating circulation to the optic nerve head (posterior ciliary arteries) and retina (central retinal artery). (Reprinted with permission from Patten J: Vision, the visual fields and the olfactory nerve. In Neurological Differential Diag- nosis, ed 2. New York, Springer-Verlag, 1996, p 23.) arteries provide the main blood supply to the optic nerve head and the outer one third of the retina. Although the optic disc itself is supplied by a network fed mostly by the posterior ciliary arteries (the anastomotic circle of Zinn-Haller), the portion of the optic nerve directly behind the lamina cribrosa (intraorbital optic nerve) is supplied by perforating branches of the ophthalmic artery.

DISORDERS OF THE RETINA Visual field loss caused by retinal disorders is characterized by defects that may lack connection to the blind spot and typically do not show “respect” for (tend to extend beyond) the vertical or horizontal meridians. These meridians are important in the interpretation of visual fields; defects that occur in the setting of optic nerve disease tend to demonstrate “respect” for the horizontal meridian because the nerve fibers that enter the optic disc are segregated into superior and inferior arcuate bundles as they traverse the nerve fiber layer of the retina. Visual field defects that arise from chiasmal or retrochiasmal disease show respect for the vertical meridian; this is because of the segregation of nasal and temporal retinal fibers within and beyond the chiasm (Figs. 1–3 and 1–4).4,5

OPTIC NERVE DISEASE The optic nerve is vulnerable to injury resulting from increased intracranial pressure, which may cause swelling (papilledema) of both optic discs. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 5

3 5 4

L Location Field defect Left eye Right eye Comment

1 Right optic nerve No light perception right eye

2 Junction of right optic nerve Junctional syndrome and chiasm

Bitemporal hemianopsia 3 Chiasm (classic)

4 Posterior chiasm Central bitemporal hemianopic scotomas

5 Left optic tract Incongruous right homonymous hemianopia Figure 1–3 Lesions of the optic chiasm and their corresponding visual field defects. Note that fibers from the inferior nasal retina (corresponding to the superior temporal visual field) travel briefly within or very close to the contralateral optic nerve; this forward bend of fibers is termed Wilbrand’s knee. The term hemianopsia refers to a visual field defect that respects the vertical meridian; homonymous indicates that the defect involves the same side of the visual field in both eyes; an incongruous defect is that for which the extent of visual field loss is asymmetric between the two eyes. (From Liu GT: Disorders of the eyes and eyelids. In Samuels MA, Feske S (eds): Office Practice of Neurology. New York, Churchill Livingstone, 1996, p 46. Modified from Hoyt WF, Luis O: The primate chiasm. Arch Ophthalmol 1963; 70: 69-85.)

Optic nerve head ischemia, compression of the intraorbital optic nerve, infiltration by tumor, and inflammatory disease may produce optic disc swelling that may be difficult to distinguish from papilledema (swelling resulting from increased intracranial pressure) based on the disc appearance alone. However, although papilledema is most often bilateral, other mechanisms usually produce unilateral disc swelling. Optic atrophy, causing the optic disc to have a pale or white appearance (compared with the normal orange appearance seen in Fig. 1–1A), 6 Neuro-Ophthalmology: Blue Books of Neurology

5 2 3 4

6 7

9 8

Location Field defect Left eye Right eye Comment

1 Left optic nerve No light perception left eye

2 Chiasm Bitemporal hemianopsia

Incongruous left homonymous 3 Right optic tract hemianopsia Right homonymous 4 Left lateral geniculate nucleus sectoranopia (lateral choroidial artery) Incongruous right homonymous hemianopia

Right homonymous upper 5 Left temporal lobe quadrant defect ("pie in the sky")

Right homonymous defect, 6 Left parietal lobe denser inferiority

Right homonymous lower 7 Left occipital lobe (upper bank) quadrantanopsia (macular sparing)

Right homonymous upper 8 Left occipital lobe (lower bank) quadrantanopsia (macular sparing)

Left homonymous hemonymous 9 Right occipital lobe hemianopia (macular sparing) Figure 1–4 Lesions of the afferent visual pathway and their corresponding visual field defects. (Reprinted with permission from Liu GT: Disorders of the eyes and eyelids. In Samuels MA, Feske S (eds): Office Practice of Neurology. New York, Churchill Livingstone, 1996, p 43. Modified from Mason C, Kandel ER: Central visual pathways. In Kandel ER, Schwartz JH, Jessell T (eds): Principles of Neural Science, 3rd ed. Norwalk, CT, Appleton & Lange, 1991, p 437.) 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 7

may occur as a late finding in patients with visual loss resulting from untreated papilledema, optic nerve compression, ischemia, tumor infiltration, or inflammation. Visual field defects that are characteristic of early or developed papilledema include enlargement of the blind spot and generalized constriction. Central visual acuity and color vision are generally spared early on in the setting of papilledema. Ischemic, compressive, infiltrative, or inflammatory causes of optic nerve dysfunction, however, are often associated with altitudinal (involving selectively the upper or lower half of the visual field with respect for the horizontal meridian) or arcuate (radiating from the blind spot but not involving an entire half of the field) visual field defects. Other visual field defects characteristic of optic neuropathies include central scotomas (decreased central vision) and cecocentral scotomas (involving the central vision and blind spot). Patients with compressive, infiltrative, or ischemic optic neuropathies often present with reduced visual acuity; abnormal color vision; an afferent pupillary defect; and, in the case of chronic lesions, optic disc pallor.

ANATOMY OF THE OPTIC CHIASM Intracranially, the optic nerves join to form the optic chiasm. As shown in Figure 1–3, fibers from the temporal retina remain ipsilateral within the chiasm, whereas fibers from the nasal retina cross within the chiasm to enter the contralateral optic tracts (Fig. 1–5).6 Within the chiasm, the most inferior nasal fibers (representing the superior temporal visual field) travel briefly within or very close to the contralateral optic nerve after crossing over (Fig. 1–3). This forward bend of fibers from the contralateral eye at the anterior chiasm is termed Wilbrand’s knee. Although the existence of Wilbrand’s knee in living primates has been

8 mm X 4

15 mm 10 mm ON 45¡ C D

Figure 1–5 Relationships of the optic nerves (ON) and chiasm (X) to the sellar structures and third ventricle (3). C, anterior clinoid; D, dorsum sellae; P, pituitary gland in sella. (From Glaser JS, Sadun AA: Anatomy of the visual sensory system. In Glaser JS (ed): Neuro-Ophthalmology, 2nd ed. Philadelphia, JB Lippincott, 1990, p 68.) 8 Neuro-Ophthalmology: Blue Books of Neurology

questioned by some authors,7 the concept of this structure remains useful to the understanding of visual field defects that occur in the setting of anterior chiasmal lesions, such as the junctional scotoma (Fig. 1–3). In most individuals, the optic chiasm is located directly above the sella or pituitary fossa, anterior to the pituitary stalk, and directly inferior to the hypothalamus and third ventricle (Fig. 1–5). The position of the chiasm with respect to the pituitary fossa, however, may be variable, and occasional individuals may have a pre-fixed (main body of the chiasm located anteriorly above the sella) or post- fixed chiasm (body of the chiasm located posteriorly above the sella). The chiasm is situated at an upward 45-degree angle above the sella, as shown in Figure 1–5.6 The blood supply to the optic chiasm arises from two sources: (1) the superior hypophyseal arteries (inferiorly), which are fed by the internal carotid, posterior communicating, and posterior cerebral arteries, and (2) branches of the anterior cerebral arteries (superiorly). Because of this collateral blood supply, infarction of the chiasm is extremely rare.

CHIASMAL VISUAL LOSS Because of the cross-over of nasal retinal fibers within the body of the optic chiasm (Fig. 1–3), compressive and infiltrative lesions in this region usually cause temporal visual field defects in both eyes that respect the vertical meridian (a bitemporal hemianopsia). Common etiologies of chiasmal syndromes in adult patients include pituitary adenoma, craniopharyngioma, meningioma, and aneurysm. The exact characteristics of the visual field defect (Fig. 1–3) depend on the location and extent of chiasmal involvement, as well as the position of the chiasm (pre-fixed or post-fixed) with respect to the sella and third ventricle (Fig. 1–5). The most common defect related to chiasmal disease, the bitemporal hemianopsia, occurs in association with lesions affecting the body (central portion) of the chiasm (Fig. 1–3, visual field #3). Lesions of the anterior chiasm involve both the ipsilateral optic nerve and the crossing fibers derived from the contralateral temporal field; this results in a junctional scotoma, characterized by an ipsilateral central scotoma and a contralateral superior temporal defect (Fig. 1–3, visual field #2). Posterior chiasmal involvement may be associated with bitemporal central hemianopic scotomas (Fig. 1–3, visual field #4). Reduced visual acuity, color vision, and optic atrophy are also characteristic of chiasmal disorders. Because the optic chiasm is situated above the pituitary sella and below the third ventricle (Fig. 1–5), bitemporal defects affecting mainly the inferior visual fields suggest a lesion arising from the third ventricular region, whereas defects that break out superiorly and temporally usually indicate a lesion arising from the sella. The upward angle of the chiasm above the sella (Fig. 1–5) helps to explain why such field defects occur and why sellar masses, such as pituitary adenomas, must be large to produce chiasmal visual field loss.

ANATOMY OF THE RETROCHIASMAL VISUAL PATHWAYS The Optic Tracts Posterior to the chiasm, each optic tract contains fibers originating in the ipsilateral temporal retina and contralateral nasal retina. Fibers of the optic tracts travel 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 9

above and around the infundibulum and below the third ventricle (Fig. 1–4). The majority of the blood supply to the optic tracts derives from branches of the anterior choroidal artery, direct branches of the internal carotid artery, and the posterior communicating artery.2

The Lateral Geniculate Nuclei The lateral geniculate nuclei of the thalamus (LGN) contain the first post-retinal synapses within the afferent visual pathways. Most of the axons within the optic tracts synapse in the LGN; however, those that subserve the pupillary light reflex pathways branch off of the optic tracts before reaching the LGN, synapsing in the pretectal nuclei of the midbrain. Regions of the LGN are supplied by the anterior choroidal artery (lateral wedges of the LGN), by the posterior choroidal artery (medial wedge), or by an anastomosis of both (middle wedge supplying macular vision).8

The Optic Radiations After exiting the LGN, geniculocalcarine fibers destined for the calcarine (visual) cortex form the optic radiations. Fibers within the optic radiations separate into superior and inferior bundles, passing within the white matter of the parietal and temporal lobes, respectively (Fig. 1–4). The superior (parietal) fibers carry visual information from the contralateral inferior visual fields, whereas the inferior fibers, traversing forward within the temporal lobe to form Meyer’s loop, subserve the contralateral superior visual fields. The superior optic radiations receive their blood supply from branches of the middle cerebral arteries, whereas the inferior radiations are primarily supplied by branches of the posterior cerebral arteries.

The Occipital Lobes and Calcarine Cortex The superior (parietal) and inferior (temporal) bundles of the optic radiations project to the upper and lower banks of the calcarine (visual) cortex, respectively, within the occipital lobes. Thus, the upper bank of the calcarine cortex receives information from the contralateral inferior visual fields, whereas the lower bank receives information from the contralateral superior visual fields. This strict retinotopic organization of fibers to the upper and lower banks of the calcarine cortex explains why visual field defects related to occipital lobe lesions may be extremely congruous (symmetric defects in both eyes), respecting both the horizontal and vertical meridians (Fig. 1–4). The macular area is represented in the occipital poles; remarkably, this central 10 degrees of vision encompasses approximately one half of the surface area of the visual cortex.9 The fovea (Fig. 1–1A), or very center of vision, is represented within the tips of the occipital poles. Branches of the posterior cerebral arteries comprise the major blood supply to the calcarine cortex. The occipital poles have a dual blood supply consisting of branches of both the posterior and middle cerebral arteries, providing a basis for macular sparing in the setting of occipital lobe infarcts. Visual association areas, located in the occipito-temporal and occipito-parietal regions, subserve the functions of higher cortical visual processes, such as object 10 Neuro-Ophthalmology: Blue Books of Neurology

recognition (occipito-temporal area), color perception within the contralateral hemifield (lingual and fusiform gyri, area V4), facial recognition (mesial occipitotemporal regions), spatial orientation, and visual attention (parietal lobe).

DISORDERS OF THE RETROCHIASMAL VISUAL PATHWAYS Optic Tract Lesions Lesions of the optic tract in isolation are generally not associated with visual acuity loss. However, some optic tract lesions are large and may extend to affect the ipsilateral optic nerve. The characteristic visual field defect in the setting of an optic tract lesion is an incongruous (asymmetric extent of involvement between the two eyes) contralateral homonymous hemianopsia (Fig. 1–4, visual field #3). Patients with optic tract lesions also have an afferent pupillary defect in the eye with the greater extent of visual field loss (usually the eye contralateral to the lesion). A characteristic pattern of optic atrophy is also seen with optic tract disorders; this consists of temporal optic disc pallor ipsilateral to the lesion and “bow tie” atrophy of the contralateral optic disc.

Lateral Geniculate Nuclei Lesions Unilateral lesions of the LGN and beyond do not affect central visual acuity and are not associated with an afferent pupillary defect unless the optic tract is also involved. Incongruous contralateral homonymous hemianopsias, indistinguishable from those caused by tract lesions, may occur (Fig. 1–4, visual field #4). Given the LGN’s unique dual blood supply (lateral and anterior choroidal arteries), congruous contralateral sectoranopias affecting the lateral wedge in isolation or the upper and lower wedges of the visual field are also encountered (Fig. 1–4, visual field #4).8

Optic Radiation Lesions Because of the anatomic separation of the optic radiations into inferior (temporal) and superior (parietal) bundles, lesions in these areas cause homonymous hemianopsias affecting predominantly the upper (temporal lobe—“pie-in-the-sky”) or lower (parietal—more dense inferiorly) contralateral visual fields (Fig. 1–4, visual fields #5 and #6). Lesions involving the parietal radiations, or any other retrochiasmal structure, may also produce a dense, complete homonymous hemianopsia (affecting both the upper and lower quadrants). When this defect is encountered, the exact location of the lesion within the retrochiasmal pathways cannot be determined based on the visual field alone.

Occipital Lobe Lesions Macular sparing (lack of extension of the hemianopsia to the center of fixation) is a unique feature that may occur in the setting of occipital lobe lesions (Fig. 1–4, visual field #9). Occipital lobe-related homonymous hemianopsias, when incomplete, are generally congruous, unlike defects related to the optic tract or LGN. The occipital cortex is also retinotopically organized, such that lesions of the 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 11

lower bank of the calcarine cortex, for example, produce contralateral congruous superior visual field defects, respecting both the horizontal and vertical meridians (Fig. 1-4, visual fields #7 and #8). Bilateral occipital lobe lesions may produce cortical blindness. Such patients may deny that they are blind and may confabulate or “make-up” descriptions of what they see (Anton’s syndrome). Bilateral macular-sparing homonymous hemianopsias may cause a clinical picture of apparent “constriction” of the visual fields. This may be misinterpreted as functional, or nonphysiologic, visual loss because the pupillary responses in such patients are normal. Careful documentation of a vertical “step-off,” or a difference in size of the areas of macular sparing between the two eyes, should lead the examiner to suspect a bilateral occipital lobe process. Retrochiasmal visual field defects are often accompanied by other neurologic signs and symptoms, such as hemiparesis, hemisensory disturbance, aphasia, or neglect. Lesions involving the occipito-temporal area may produce palinopsia (persistent perception of an image after gaze has been shifted away from it). Patients may also perceive motion without being able to see details in the affected hemifield (Riddoch’s phenomenon). Complex visual hallucinations may also occur in the blind hemifield, either as release phenomena or as manifestations of partial seizure activity.

The Ocular Motor System

Disorders of the ocular motor system may occur secondarily to lesions in any of several locations, from the orbit to the cavernous sinus, subarachnoid space, brainstem, and involving supranuclear or vestibulo-ocular pathways. This section emphasizes the anatomic features that are important to the recognition and localization of eye movement disorders.

ANATOMY OF THE ORBIT AND EXTRAOCULAR MUSCLES There are six muscles that are responsible for eye movements; these are arranged about the eye as shown in Figure 1–6.10 The superior and inferior rectus muscles elevate and depress the eye, respectively, performing these functions best when the eye is abducted. The superior and inferior oblique muscles, however, work using a sling/pulley mechanism, with insertions of the muscles being located toward the posterior portion of the globe. The oblique muscles serve as rotators of the eye about the vertical axis as the eye is viewed (clockwise or counterclock- wise torsion) but also serve to elevate or depress the eye in adduction. The superior oblique primarily intorts the eye (rotates the superior aspect of the globe toward the nasal bridge about the vertical axis, clockwise in the case of the right eye as viewed by the examiner); this muscle also depresses the eye in adduction. The inferior oblique, in contrast, extorts the eye but also serves as an elevator in adduction. In the primary position of gaze, the superior and inferior oblique and rectus muscles all perform a combination of vertical and torsional actions. Adduction is performed by the medial rectus, whereas abduction is subserved by the lateral rectus muscle. The superior rectus, inferior rectus, inferior oblique, and medial rectus are innervated by the third cranial nerve (oculomotor nerve), whereas the superior 12 Neuro-Ophthalmology: Blue Books of Neurology

Superior Levator palpebrae oblique superioris Tendinous ring Superior rectus Optic nerve in sheath Superior transversing optic canal orbital fissure

Oculomotor Trochlear nerve nerve

Pons Inferior oblique Trigeminal ganglion Abducens Communicating Inferior nerve branches rectus Lateral Medial Ciliary rectus rectus ganglion Figure 1–6 Innervation of the muscles of the globe. The oculomotor (III), trochlear (IV), and abducens (VI) nerves enter the orbit through the orbital fissure. The trochlear nerve supplies the superior oblique, the abducens nerve supplies the lateral rectus, and the oculomotor nerve supplies the remaining five muscles. (From Moore KL: Clinically Oriented Anatomy, 4th ed. Baltimore, Lippincott and Wilkins, 1999, p 911.)

oblique and lateral rectus are supplied by the fourth (trochlear) and sixth (abducens) nerves, respectively (Fig. 1–6). The tendon origins of the four rectus muscles form the annulus of Zinn, a sheath through which the optic nerve, third nerve, and sixth nerve pass at the orbital apex.

ANATOMIC CONSIDERATIONS OF THE THIRD, FOURTH, AND SIXTH CRANIAL NERVES Third Nerve Originating in the dorsal midbrain as a cluster of subnuclei, the third nerve (oculomotor nerve) innervates the superior rectus, inferior rectus, inferior oblique, and medial rectus muscles. The pupillary sphincter and levator palpebrae (major eyelid elevator muscle) are also supplied by the third nerve. After traversing ventrally through the midbrain as the third nerve fascicle, the nerve itself exits the midbrain near the medial aspect of the cerebral peduncle. The nerve then enters the subarachnoid space (Fig. 1–6), where it travels medial to the posterior communicating artery and enters the cavernous sinus. Within the cavernous sinus, the third nerve travels within the lateral wall, superior to the fourth nerve (Fig. 1–7).11 Entering the orbit (Fig. 1–6), the nerve passes through the annulus of Zinn and then divides into a superior division (innervates levator, superior rectus) and inferior division (innervates pupillary sphincter, medial 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 13

Internal carotid artery

Chiasm

Anterior clinoid

III

Pituitary gland IV

Venous space

Sphenoid process V2

Figure 1–7 Schematic diagram of the left cavernous sinus, coronal view. Note that the sixth nerve lies freely within the cavernous sinus, whereas the third, fourth, and fifth (V1 and V2) nerves travel within the lateral wall. (From Galetta SL: Cavernous sinus syndromes. In Margo CE, Hamed LM, Mames RN (eds): Diagnostic Problems in Clinical Ophthalmology. Philadelphia, WB Saunders, 1994, p 610.) rectus, inferior rectus, inferior oblique). All of the structures innervated by the third nerve are located ipsilateral to their respective subnuclei, with the exception of the superior rectus, which receives axons from the contralateral superior rectus subnucleus. Lesions of the third (oculomotor) nerve or fascicle at any location distal to its nucleus in the midbrain are characterized by partial or complete ptosis, paresis of the superior rectus, medial rectus, inferior rectus, and inferior oblique (Fig. 1–8).12 In many cases, depending on the underlying etiology, there is pupillary dilation with decreased reaction to light and near stimuli. Patients describe varying degrees of binocular vertical, horizontal, or oblique diplopia, depending on the extent of the ptosis. The presence of an acute, painful, pupil-involving third nerve palsy often indicates the presence of an aneurysm at the junction of the ipsilateral internal carotid and posterior communicating arteries. Not infrequently, however, painful 14 Neuro-Ophthalmology: Blue Books of Neurology

Figure 1–8 Photographs of a patient with partial, pupil-involving right third nerve palsy. (From Balcer LJ, Galetta SL, Bagley LJ, et al: Localization of traumatic oculomotor nerve palsy to the midbrain exit site by magnetic resonance imaging. Am J Ophthalmol 1996;122:437.)

third nerve palsies may occur in the absence of pupillary dilation (pupil-sparing third nerve palsy), especially in older patients with diabetes or hypertension. Galetta and colleagues have presented a discussion of the recommendations for neuroimaging in adult patients with acute, isolated third nerve palsies.13,14 Table 1–1 summarizes their recommendations for evaluation based on the presence or absence of pupillary involvement and the complete versus incomplete extent of the ophthalmoparesis. In addition to compression by aneurysms, the third nerve within the subarachnoid space is also vulnerable to compression by uncal herniation because of supratentorial space-occupying lesions or edema. Such patients usually have altered mental status and may also have hemiparesis or other neurologic signs. At the level of the anterior cavernous sinus or superior orbital fissure, the third nerve divides into a superior and inferior division. Superior-division third nerve palsies, affecting the levator palpebrae and superior rectus only, may thus occur secondary to lesions within the cavernous sinus, orbital apex, or superior orbital fissure. Although there is an anatomic separation of the third nerve at the level

TABLE 1–1 Recommendations for Neuroimaging in Adult Patients with Acquired, Isolated Third Nerve Palsies

Degree of Ophthalmoparesis Status of Pupil Recommendations for Evaluation

Complete Involved CT or MRI, then conventional angiography Partial Involved CT or MRI, then conventional angiography Complete Spared Observation (þ/ MRI) MRI if no improvement within 8 weeks Partial Spared Serial observation of pupil for 1 week, MRI Repeat MRI in 8 weeks if no improvement

CT, computed tomography; MRI, magnetic resonance imaging. From Galetta SL, Liu GT, Volpe NJ: Diagnostic tests in neuro-ophthalmology. Neurol Clin 1996;14:201. Modified from Trobe JD: Third nerve palsy and the pupil. Footnotes to the rule. Arch Ophthalmol 1988;106:601. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 15

of the anterior cavernous sinus, divisional third nerve palsies may occur in the setting of more proximal lesions. Lesions of the third nerve nucleus are rare but may be manifested by the following findings: (1) unilateral third nerve palsy with contralateral superior rectus weakness and (2) bilateral partial ptosis.15 These findings are present because a single, central caudal nucleus is shared between the right and left third nerve nuclear complexes, and each superior rectus subnucleus innervates the contralateral superior rectus muscle. The presence of other neurologic signs and symptoms may also be helpful in localizing third nerve palsies to the brainstem, subarachnoid space, cavernous sinus, or orbital apex. For example, a hemiparesis contralateral to the side of the third nerve palsy would suggest a lesion in the anterior midbrain involving the third nerve fascicle and cerebral peduncle (Weber’s syndrome).16 Similarly, a lesion affecting the third nerve fascicle and red nucleus would produce a third nerve palsy and contralateral ataxia (Claude’s syndrome). The presence of other cranial neuropathies, particularly those involving contralateral or nonadjacent cranial nerves, would suggest a subarachnoid space process, such as an inflammatory, carcinomatous, or infectious meningitis. Cavernous sinus syndromes (see later section) may be characterized by dysfunction of the third nerve (superior division, inferior division, or both) along with the ipsilateral fourth, fifth (V1 and V2 divisions), and sixth nerves and the oculosympathetics (Fig. 1–7). Lesions located more distally at the orbital apex (Fig. 1–6) may also involve the third, fourth, and sixth nerves, as well as the ophthalmic (V1) division of the fifth nerve, oculosympathetics, and optic nerve. Proptosis or other orbital signs may be present.

Fourth Nerve Crossed innervation is also a unique characteristic of the superior oblique muscle, which is supplied by the contralateral fourth (trochlear) nerve nucleus in the midbrain. Exiting posteriorly, the fourth nerve crosses over to the contralateral side of the midbrain, then travels ventrally within the subarachnoid space. The fourth nerve subsequently follows a course similar to that of the third nerve, traveling within the lateral wall of the cavernous sinus (Fig. 1–7) to the orbital apex (Fig. 1–6). However, unlike the third nerve, which travels through the annulus of Zinn, the fourth nerve enters the superior orbit outside of the annulus to innervate the superior oblique muscle. The fourth (trochlear) nerve is unique in its dorsal exit from the midbrain (Fig. 1–6), posterior crossover within the subarachnoid space, and innervation of the superior oblique muscle contralateral to its nucleus. Because of these anatomic features and the resultant long course from midbrain to muscle, the fourth nerve is particularly vulnerable to injury in the setting of head trauma. Unilateral or bilateral fourth nerve palsies are indeed common in this setting. Lesions of the fourth nerve at any location from its nucleus to the orbit are manifested by weakness of the superior oblique muscle. This results in a tendency for the affected eye to rest higher than the other (a hypertropia). Patients note vertical double vision and, on questioning, may admit to a relative tilt of one image. Superior oblique weakness is particularly notable when the patient is asked to look downward with the affected eye in adduction (Fig. 1–9).17 Difficulty reading at near is thus a common complaint. The vertical diplopia generally 16 Neuro-Ophthalmology: Blue Books of Neurology

Figure 1–9 Photograph of patient with a left fourth nerve palsy. Because of weakness of the left superior oblique muscle, the patient has difficulty depressing the left eye in adduction.

becomes more pronounced when the patient looks in the direction contralateral to the side of the affected superior oblique (away from the side of the hypertropia) and when the head is tilted toward the side of the hypertropia. Thus, patients with fourth nerve palsies often manifest a head tilt away from the side of the affected superior oblique muscle. As is the case for third nerve palsies, the presence of other neurologic symptoms, cranial neuropathies, or oculosympathetic paresis (Horner’s syndrome) may be useful in localizing fourth nerve palsies to the midbrain, subarachnoid space, cavernous sinus, or orbital apex. For instance, the presence of an ipsilateral Horner’s syndrome and contralateral superior oblique weakness strongly suggests a nuclear fourth nerve lesion secondary to a midbrain process. How- ever, fourth nerve palsies (as well as third and sixth nerve palsies) may also occur in isolation as manifestations of intrinsic brainstem processes, including stroke, hemorrhage, or neoplasm.

Sixth Nerve The sixth cranial nerve (abducens nerve) has its nucleus at the medial dorsal pontomedullary junction, near the genu of the seventh (facial) nerve. This area within the dorsal pons is termed the facial colliculus. From the sixth nerve nucleus, motor neuron axons traverse anteriorly within the sixth nerve fascicle, whereas interneurons cross over to ascend within the contralateral medial longitudinal fasciculus (MLF) to the medial rectus subnucleus of the third nerve (Fig. 1–11). After exiting the pons, the sixth nerve ascends along the ventral aspect of the brainstem (Fig. 1–6), passes through Dorello’s canal beneath the petroclinoid (Gruber’s) ligament, and enters the cavernous sinus. Unlike the third and fourth nerves, which travel within the lateral wall of the cavernous sinus, the sixth nerve is freely situated within the cavernous sinus, lateral to the internal carotid artery (Fig. 1–7). Because the sixth nerve lies in close proximity to the cavernous carotid artery, it may be involved early in the setting of an expanding cavernous carotid artery aneurysm and may be associated with a Horner’s syndrome. The sixth nerve enters the orbit through the superior orbital fissure and annulus of Zinn (Fig. 1–6) to innervate the ipsilateral lateral rectus muscle. Lesions of the sixth nerve nucleus produce an ipsilateral horizontal conjugate gaze palsy, or inability to move both eyes toward the side of the affected sixth nerve nucleus. Because the genu of the seventh (facial) nerve passes posteriorly around the sixth nerve nucleus in the facial colliculus, lesions in this area may result in an ipsilateral peripheral seventh nerve palsy in addition to the conjugate gaze palsy (facial colliculus syndrome). In the setting of a sixth nerve nuclear lesion, 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 17

the inability to move the eyes past the midline horizontally cannot be overcome by the oculocephalic (Doll’s head) maneuver or caloric testing. Lesions involving the paramedian pontine reticular formation (PPRF) (Fig. 1–10) but sparing the sixth nerve nucleus also produce an ipsilateral horizontal conjugate gaze palsy.18 Gaze palsies that occur in this rare setting, however, can be overcome by the oculocephalic maneuver, although the patient cannot move the eyes voluntarily past the midline. In this manner, lesions of the PPRF that spare the sixth nerve nucleus may be distinguished from those affecting the sixth nerve nucleus. Because the sixth nerve lies freely within the cavernous sinus, rather than residing within the lateral wall (Fig. 1–7), it may be particularly susceptible to compression in this location by tumor or aneurysm. Unilateral or bilateral sixth

F E F P O T PC LR MR riMLF riMLF INC INC SC III III III IV IV IV PPRF MLF PPRF MLF VI VI VI VN VN

Figure 1–10 Summary of eye movement control. The center figure shows the supranuclear connections from the frontal eye fields (FEF) and the parieto-occipital-temporal junction region (POT) to the superior colliculus (SC), rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), and the paramedian pontine reticular formation (PPRF). The FEF and SC are involved in the production of saccades, whereas the POT is thought to be important in the production of pursuit. The schematic drawing on the left shows the brainstem pathways for horizontal gaze. Axons from the cell bodies located in the PPRF travel to the ipsilateral sixth nerve (abducens) nucleus (VI) where they synapse with abducens motoneurons whose axons travel to the ipsilateral lateral rectus muscle (LR) and with abducens internuclear neurons whose axons cross the midline and travel in the medial longitudinal fasciculus (MLF) to the portion(s) of the third nerve (oculomotor) nucleus (III) concerned with medial rectus (MR) function (in the contralateral eye). The schematic drawing on the right shows the brainstem pathways for vertical gaze. Important structures include the riMLF, PPRF, the interstitial nucleus of Cajal (INC), and the posterior commissure (PC). Note that axons from cell bodies located in the vestibular nuclei (VN) travel directly to the sixth nerve nuclei and, mostly via the MLF, to the third (III) and fourth (IV) nerve nuclei. (From Miller NR: Neural control of eye movements. In Miller NR (ed): Walsh and Hoyt’s Clinical Neuro-Ophthal- mology, 4th ed. Baltimore, Williams & Wilkins, 1985, p 627.) 18 Neuro-Ophthalmology: Blue Books of Neurology

nerve palsies also occur as false localizing signs of supratentorial mass lesions, edema, hemorrhage, or other causes of increased intracranial pressure. Within the subarachnoid space, the nerve is particularly vulnerable to downward pressure on the brainstem as it ascends the ventral aspect of the pons, passes beneath the petroclinoid ligament, and travels over the edge of the tentorium (Fig. 1–6). This appears to be the mechanism of sixth nerve palsies resulting from increased intracranial pressure.

ORBITAL APEX AND CAVERNOUS SINUS SYNDROMES Lesions at the superior orbital fissure and orbital apex (Fig. 1–6) are characterized by combinations of third, fourth, and sixth nerve palsies, as well as facial sensory loss in the V1 (ophthalmic) distribution, optic neuropathy, and oculosympathetic paresis. This syndrome is often difficult to distinguish from the cavernous sinus syndrome, which may involve a combination of cranial nerves three, four, six, the V1 and V2 distributions of the fifth nerve, and oculosympathetic paresis (Horner’s syndrome) (Fig. 1–7). Visual loss may also be present if the optic nerve or chiasm is involved, but lesions affecting the cavernous sinus in isolation, unlike orbital apex syndromes, do not produce optic neuropathy.

ANATOMY OF THE SUPRANUCLEAR, INTERNUCLEAR, AND VESTIBULO-OCULAR GAZE PATHWAYS The initiation of conjugate eye movements is controlled by pathways and centers above the third, fourth, and sixth nerve nuclei (supranuclear pathways) and by interconnections among these nuclei (internuclear pathways). Inputs from the vestibular system (vestibulo-ocular pathways) also play an important role in the maintenance of eye position with head movement. Pursuit eye movements are initiated and maintained through cortical and cerebellar inputs.

SACCADE SYSTEM Saccadic eye movements (fast conjugate eye movements to a fixed target) are initiated in the frontal eye fields (Fig. 1–10). The supplementary eye fields and parietal eye fields also play a role in saccade generation. The frontal eye fields send inputs to saccade-generating neurons within the superior colliculus, the contralateral PPRF, and rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) (Fig. 1–10). The horizontal saccade pathway (Fig. 1–10, left) involves axons that travel from cell bodies in the PPRF to the ipsilateral sixth nerve nucleus. From a synapse in the sixth nerve nucleus, axons of abducens motor neurons travel to the ipsilateral lateral rectus muscle, whereas axons of abducens internuclear neurons cross over and ascend in the contralateral MLF to the medial rectus subnucleus of the third nerve. It is this internuclear connection between the PPRF and contralateral third nerve nucleus via the MLF that is responsible for conjugate horizontal gaze. Each frontal eye field, therefore, generates a conjugate movement of the eyes toward the contralateral side of the body. Brainstem pathways for vertical saccades involve the riMLF, the PPRF, the posterior commissure (PC), and the interstitial nucleus of Cajal (INC) (Fig. 1–10, right). 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 19

VESTIBULO-OCULAR SYSTEM Conjugate gaze in both the vertical and horizontal planes is stabilized through inputs from the vestibular nuclei. From each vestibular nuclear complex, axons subserving horizontal gaze-holding connect to the contralateral sixth nerve nucleus; motor neurons from this nucleus innervate the lateral rectus, whereas interneurons cross back over to ascend in the MLF to the third nerve nucleus (Fig. 1–10, left). Stimulatory input from each vestibular nucleus, therefore, produces conjugate horizontal gaze toward the contralateral side of the body. Inputs from the vestibular nuclei also influence vertical gaze-holding through inputs to the contralateral fourth nerve nucleus, third nerve nucleus, INC, and riMLF (Fig. 1–10, right). The maintenance of ocular alignment in the vertical plane is controlled by the existence of balanced inputs from the vestibular nuclei to the fourth nerve nucleus (innervates contralateral superior oblique muscle), the superior rectus subnucleus (innervates contralateral superior rectus), and the inferior oblique and inferior rectus subnuclei (innervate ipsilateral inferior oblique and inferior rectus) (Fig. 1–11).19 An imbalance between these inputs to the various subnuclei results in skew deviation.

PURSUIT SYSTEM Smooth pursuit eye movements (conjugate maintenance of fixation of the eyes while following a moving target) are generated in higher cortical centers, especially the parieto-occipital-temporal (POT) junction (Fig. 1–10). Inputs are sent from each POT to the superior colliculi (SC), from which control of horizontal and vertical pursuit eye movements is mediated. Unlike the saccadic system, in which each hemisphere (frontal eye fields and other centers) produces conjugate horizontal eye movements toward the contralateral direction, the pursuit system is designed such that each hemisphere controls conjugate pursuit eye movements to the ipsilateral visual space.20

The Pupillary Pathways

ANATOMY OF THE PUPILLARY PATHWAYS Constriction of the Pupil—Parasympathetic Pathway Pupillary constriction to light and near stimuli is mediated via parasympathetic nerve fibers that travel along the third cranial nerve. The pupillary light reflex pathway (Fig. 1–12) is a four-neuron pathway consisting of three synapses.21 Light information from retinal ganglion cells travels through the optic nerves, chiasm (with decussation of the fibers from nasal retina), and tracts, synapsing in the pretectal nuclei of the dorsal midbrain. Note (Fig. 1–12) that both pretectal nuclei receive inputs from both eyes. In turn, each pretectal nucleus sends axons to both Edinger-Westphal nuclei. It is this duality of pathways that provides the anatomic basis for the consensual response of the pupils to light (i.e., the fact that both pupils, if normally innervated, constrict equally in response to a light stimulus in either eye). Parasympathetic fibers for pupillary constriction travel along the third nerve to the ipsilateral ciliary ganglion within the orbit (Fig. 1–12). 20 Neuro-Ophthalmology: Blue Books of Neurology

III

SCC

Figure 1–11 The main excitatory vestibulo-ocular connections from the vertical semicircular canals. The dashed line indicates the midline of the brainstem. The arrows indicate directions of eye movement when individual extraocular muscles are stimulated. Filled circles receive the anterior canal projection; open circles receive the posterior canal projection. Lesions occurring within these vestibulo-ocular pathways result in skew deviation. III, third nerve (oculomotor) subnuclei; IV, fourth nerve (trochlear) nucleus; IO, inferior oblique muscle; IR, inferior rectus muscle; SCC, semicircular canals; SO, superior oblique muscle; SR, superior rectus muscle; VN, vestibular nuclei. (From Zee DS: The organization of the brainstem ocular motor subnuclei. Ann Neurol 1978;4:384.) Distal to this synapse, the pupillary sphincter muscle (and ciliary muscle for lens accommodation) is innervated by the postganglionic parasympathetic fibers. The constriction of the pupils to near stimuli is also accomplished through the parasympathetic pathways. However, the near reflex pathway, thought to originate in higher cortical centers, bypasses the pretectal nuclei in the dorsal midbrain. Near inputs thus descend directly to the area of the Edinger-Westphal nuclei. This distinction between the light and near pathways forms the basis for some forms of pupillary light-near dissociation (pupils that react to near but not to light), in which the dorsal midbrain and pretectal nuclei are involved. Dilation of the Pupil—Oculosympathetic Pathway Dilation of the pupil is mediated through sympathetic pathways, which originate in the hypothalamus (Fig. 1–13).22 In this three-neuron pathway, the first-order 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 21

Edinger- Pretecto- Red Westphal oculomotor tract nucleus nucleus Posterior Optic tract commissure Oculomotor nerve (III)

Optic nerves

Pretectal Lateral geniculate nucleus Ciliary nucleus ganglion

Figure 1–12 Diagram of the pupillary light reflex pathway. (From Kardon RH: Anatomy and physiology of the autonomic nervous system. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clin- ical Neuro-Ophthalmology, 6th ed. Philadelphia, Lippincott, Williams & Wilkins, 2005, p 664.)

neuron descends caudally from the hypothalamus to the first synapse, which is located in the cervical spinal cord (levels C8-T2—ciliospinal center of Budge). The second-order neuron travels from the sympathetic trunk, through the bra- chial plexus, over the lung apex, and ascends to the superior cervical ganglion. This ganglion is located near the angle of the mandible and the bifurcation of the common carotid artery. Distal to the superior cervical ganglion (second synapse in pathway), the third-order neuron then ascends within the adventitia of the internal carotid artery and through the cavernous sinus. The oculosympathetic neuron then joins the ophthalmic (V1) division of the fifth cranial nerve (trigeminal nerve). In the eye and orbit, the oculosympathetic fibers innervate the iris dilator muscle as well as Mu¨ ller’s muscle, a small smooth muscle in the eyelid responsible for a minor portion of upper eyelid elevation and lower lid depression. Note (Fig. 1–13) that those sympathetic fibers responsible for facial sweating and vasodilation branch off at the superior cervical ganglion from the remainder of the oculosympathetic pathway, explaining why patients with 22 Neuro-Ophthalmology: Blue Books of Neurology

Trigeminal Ophthalmic Hypothalamus nerve artery

Sympathetic to eye

Pons

Medulla Long ciliary nerve Carotic plexus Internal carotid artery

External carotid artery Cervical spinal cord

Superior cervical ganglion

T1 Inferior cervical ganglion

Figure 1–13 The oculosympathetic pathways. Hypothalamic sympathetic fibers descend to the ciliospinal center of Budge (first-order neuron). The second-order neuron takes a circuitous course through the posterosuperior aspect of the chest and ascends in the neck in relationship with the carotid system. Third-order neurons originate in the superior cervical ganglion and are distributed to the face with branches of the external carotid artery and to the orbit via the ophthalmic artery and ophthalmic (V1) division of the fifth (trigeminal) nerve. (From Liu GT: Disorders of the eyes and eyelids: Disorders of the pupil. In Samuels MA, Feske S (eds): The Office Practice of Neurol- ogy. New York, Churchill Livingstone, 1996, p 62.)

third-order neuron Horner’s syndrome (oculosympathetic paresis) may not have anhidrosis. The signs of Horner’s syndrome, including mild ptosis, pupillary miosis, and, in some cases, anhidrosis, always occur ipsilateral to the side of the lesion, as there is no decussation or cross-over of the oculosympathetic pathway. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 23

The Neuro-Ophthalmologic Examination

In this section, we review the components of the neuro-ophthalmologic examination and the techniques necessary to assess the patient’s vision, pupillary function, ocular motility, and funduscopic findings.

VISUAL ACUITY The neuro-ophthalmologic examination should begin with an assessment of visual acuity. The standard method of testing visual acuity at distance uses the Snellen chart placed at 20 feet (6 meters).23 The patient is asked to cover one eye either by using a tissue or an occluding device. The patient should be wear- ing glasses or contact lenses because the examiner is most interested in the best corrected acuity. It is not uncommon for meaningless, subnormal acuities to be recorded while the patient’s glasses lie in a pocket or in a drawer. If the patient’s glasses are unavailable or subnormal acuity is obtained despite glasses, a pinhole test should be performed (Fig. 1–14). A pinhole device focuses a small point of light on the retina permitting a window of near optimal refraction. Most Snellen lines end with the numbers to let the examiner know what line is being tested. For example, the 20/30 line ends with a 3 and the 20/25 line ends with numbers 2–5. Acuity is recorded for the right eye first. The numerator represents the testing distance, which is 20 feet. The denominator denotes the size of the letter seen or denotes the distance at which an eye with normal vision sees the same letter. The 20/40 line contains letters twice the size of the 20/20 line. However, the ability to read the 20/40 line correlates with approximately 85% of normal visual function. If the patient cannot read the 20/400 E, then a 200 size E can be slowly brought toward the patient (Fig. 1–15). For instance, if the patient sees the E at 5 feet from their eye, vision is recorded as 5/200 E. More severe acuity loss may be recorded as count fingers, hand motion, light perception, or no light perception. Abnormal visual acuity may be the result of the following: 1. Refractive error (cornea, lens, vitreous) 2. Optic nerve or chiasmal disease and rarely from a bilateral cortical lesion 3. Macular dysfunction 4. Amblyopia 5. Functional visual loss

Figure 1–14 A pinhole device will focus a point of light on the retina correcting most refractive errors. 24 Neuro-Ophthalmology: Blue Books of Neurology

Figure 1–15 When the patient sees less than 20/200, but better than hand motions, a 200 sized E can be brought toward the patient. If the patient is able to see the E at 4 feet from the eye, visual acuity is recorded as “4/200.”

Once again, the importance of the pinhole examination cannot be overempha- sized in this differential diagnosis because it will correct most refractive errors. If acuity cannot be corrected by a pinhole device, then optic nerve disease, macular dysfunction, or amblyopia may be present. These entities are further distinguished by visual field, pupillary, and funduscopic examination. Amblyopic patients usually have a long-standing history of visual loss in one eye resulting from strabismus, asymmetric refractive error, or a media opacity.

NEAR VISION Despite the accuracy of a Snellen acuity,it is often necessary to assess acuity at near. Near vision may be tested using the Rosenbaum hand held card (Fig. 1–16). Because the test card has been designed to be held at 14 inches (3 5 cm) from the patient, any deviation of the testing distance profoundly affects the acuity equivalent seen. It is for this reason that most ophthalmologists prefer to use the Jaeger numbers. Thus, a near acuity of 20/25 may be written as J1 at 14 inches. Reading cards are also available and they provide an added benefit by testing for alexia. Once again, it must be emphasized that an uncorrected near acuity is virtually useless.

Figure 1–16 The Rosenbaum near card. Note near acuity is often recorded using the Jaeger numbers. For instance, “J1” is equivalent to a 20/25 near acuity. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 25

COLOR VISION Color vision may be assessed using the Ishihara or the Hardy-Rand-Rittler (HRR) color plates series (Fig. 1–17). We prefer the latter because it is designed to test both acquired and congenital color blindness (includes yellow-blue plates). The Ishihara series only tests for congenital color blindness (red-green plates only). The major utility of color plate testing is to detect the difference in color perception between the two eyes. Most color plates contain numbers or geometric shapes created by a series of colored dots. The examiner should record the number of plates correctly identified by each eye. Nearly 9% of males and 1% of females are congenitally color blind.21 When color plates are unavailable, difference in color perception between the two eyes may be identified using a color pen or bottle top (Fig. 1–18). Even with normal color plates testing, the patient may readily recognize a color difference in a red bottle top alternately presented to each eye. The patient may tell the examiner that one eye sees the bottle top as pink or orange. The patient may also be able to give the examiner

Figure 1–17 Pseudo-isochromatic color plates. A, In the Ishihara color series, the patient is asked to identify the number among the colored dots. B, In the Hardy Rand Rittler series, the patient is asked to identify the geometric shapes.

Figure 1–18 When color plates are unavailable, the examiner may use a color bottle top to detect a color difference between the two eyes. 26 Neuro-Ophthalmology: Blue Books of Neurology

a percentage of this desaturation. On occasion, green or blue bottle tops may detect a color difference not appreciated when the red tops were used. More extensive color vision testing can be carried out using the color sorting tests known as the Farnsworth-Munsell 100 hue test or the Farnsworth D-15 panel test.24 Acquired dyschromatopsia usually results from retinal or optic nerve lesions. In general, dyschromatopsia is more common with optic nerve lesions even if the visual acuity loss is mild. Dyschromatopsia secondary to retinal disease is typically associated with funduscopic abnormalities such as large macular scarring or diffuse pigmentary disturbances.

CONTRAST SENSITIVITY AND LOW-CONTRAST LETTER ACUITY Eye charts have been designed for maximal contrast (i.e., dark black letters on a white background). Contrast sensitivity testing uses shades of gray to better assess visual resolution problems. In some contrast sensitivity tests, the distance between the bars (thickness) can be altered to give various spatial frequencies; other types of contrast sensitivity testing capture minimum level of contrast perception using large sized letters (Pelli-Robson chart, as used in the Optic Neuritis Treatment Trial, has letters that correspond to 20/680 Snellen equivalent). How- ever, patients with neurologic disorders may have selective losses of contrast vision at small letter sizes (20/25 or 20/20 Snellen equivalent); low-contrast letter acuity charts (Sloan charts, Fig. 1–19) may have even greater sensitivity for capturing visual dysfunction in neuro-ophthalmologic patients. In addition to optic neuropathies, macular disease and media opacities such as cataracts may be associated with impaired contrast sensitivity and low-contrast acuity. Contrast sensitivity is only one measure of visual function and should not be substituted for all other measures.25

20M

16M

12M

10M

5M Figure 1–19 Low-contrast letter 4M 3M acuity charts (Sloan charts) mea- 2.5M 2M sure patients’ capacity to perceive 1.6M letters of progressively smaller size on a white background. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 27

Figure 1–20 The Amsler grid resembles graph paper and may be used to assess macula function or the central ten degrees of the visual field.

AMSLER GRID TESTING The Amsler grid, which resembles graph paper, is an extremely useful test to detect macular abnormalities as a cause for central acuity loss (Fig. 1–20). Each eye is tested separately. The patient should fixate on the central dot and determine whether all the lines on the paper are straight and whether all lines are present. The patient with a maculopathy will often see the straight lines as curved (metamorphopsia). Patients may also detect abnormal areas of the Amsler grid that correspond with their visual field loss. For documentation, the patient may draw the perceived field defect on the Amsler grid paper.

VISUAL FIELD TESTING The field of each eye is tested individually. The first step is to have the patient examine the examiner’s face. One should ask them to fixate on the examiner’s nose. If the nose is not clear to the patient, this implies a central scotoma. One should have the patient compare the examiner’s eyes and upper and lower face for any difference. Altitudinal or hemianopic defects may be readily detected by this method. The next step is to have the patient count fingers in the four quadrants (Fig. 1–21). Simultaneous presentations of fingers in two separate quadrants increase the yield of finding a field defect. The examiner should hold up both hands on each side of the vertical or horizontal meridian and have the patient compare them for clarity (Fig. 1–22). If a field defect is found, the hand is moved from the defective field to the normal one to establish the boundaries of the defect. Red bottle tops can also be used in a similar fashion. For example, when testing for a central scotoma, a red bottle top is placed in front of the examiner’s nose and another cap is held slightly off the midline. If the patient sees the cap held in the periphery as a better red, a central scotoma is suggested. Visual fields are recorded from the patient’s perspective (Fig. 1–23). 28 Neuro-Ophthalmology: Blue Books of Neurology

Figure 1–21 Confrontation visual field testing. Each eye is tested separately. The patient is asked to count the number of fingers that are flashed in crossed quadrants of the field.

Figure 1–22 When checking for a subtler hemianopia, the patient is asked to compare the clarity of two hands placed (A) on each side of the vertical meridian; (B) Two red bottle tops can be used in a similar fashion.

Patient’s view: Left homonymous inferior quadrantanopsia

CF CF CF CF

CF CF

Left eye Right eye Figure 1–23 Visual fields are recorded in the chart from the patient’s perspective. CF, counting fingers. In this diagram, the patient has a left inferior quadrantanopsia. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 29

Visual field defects may be associated with disorders of higher cortical function. Patients with neglect are usually able to perceive a single stimulus such as a finger. However, as soon as the examiner uses double simultaneous stimulation across the vertical meridian of the field, one of the stimuli will be neglected. Neglect is often seen with parietal lesions. Patients with visual agnosia have altered visual perception. For instance, patients with prosopagnosia are unable to recognize familiar faces. This might be tested by having the patient examine recognizable faces published in a newspaper or magazine. This is also a useful technique to examine for simultagnosia (the inability to interpret a complex visual scene). Central achromatopsia typically results from bilateral occipitotemporal lesions. Such patients are unable to sort isolumi- nent colored threads or discs. Cortical visual disorders are covered in Chapter 14.

TANGENT SCREEN FIELD TESTING The tangent screen is a black spider-web-like mural that hangs in many offices. This testing instrument can provide invaluable information about the central 30 degrees of the visual field. The patient is placed at 1 meter from the screen. In the traditional format, small white discs are presented kinetically and stati- cally (usually at least a 3- and 6-mm white disc are used). Alternatively, a projection light or laser pointer can be used from behind the patient (Fig. 1–24). The major advantage of the laser pointer technique is the patient will be unaware of the target origin. This technique is invaluable for the hospitalized patient who is unable to leave the inpatient floor. The wall of the patient’s room can also serve as a makeshift tangent screen. Tangent screen examination is also useful in evaluating functional visual disorders. The basic principle that the field should expand as the patient is moved away from the tangent screen is rarely appreciated by the functional patient. The patient is first tested at 1 meter using a 3-mm white target. The field is plotted and then the patient is retested at 2 m using a 6-mm white target (doubling the testing distance requires doubling the test target size to keep the testing conditions the same). Nonexpansion of the visual field at increasing testing distance is a nonphysiologic finding. In fact, it is not uncommon for the functional patient to further constrict the field at increasing distance (a reverse tunnel). The examiner may also do a similar but less accurate assessment of field expansion by using one finger at 1 foot and the entire hand at 5 feet from the patient.

Figure 1–24 Tangent screen testing with the patient placed at one meter from the screen. One eye is covered and the examiner is behind the patient using a laser pointer to map the visual field. 30 Neuro-Ophthalmology: Blue Books of Neurology

FORMAL PERIMETRY Automated (computer) perimetry has become the primary technique used to assess the visual field formally. Computerized perimetry is particularly useful to serially follow patients with glaucoma or papilledema. The introduction of the SITA fast programs has resulted in a 50% reduction in testing time, thereby permitting a larger cohort of patients who are able to tolerate the duration of this test. However, some patients are unable to concentrate well enough to perform computerized perimetry. In this case, Goldmann perimetry remains an excellent means to test for visual field defects in neuro-ophthalmic patients. It provides information about the central and peripheral field. The light used in the Gold- mann perimetry may be varied in size (I ¼ smallest target, V ¼ largest target) or illumination (2E is not as bright as 4E). Some helpful rules in localizing visual field defects are presented in Table 1–2.

PUPILLARY EXAMINATION Pupil size should be recorded in light and dark with the patient fixating at distance. The direct response to light is assessed in one eye and then in the other. The light is brought from below to avoid triggering a near reaction. Optimally, the light reaction of the pupil should be tested with the halogen transilluminator or indirect ophthalmoscope. A pupil gauge is conveniently located on the bottom of most near acuity cards. The direct response can be graded from 0 to 3þ: 0 ¼ no reaction 1þ¼sluggish 2þ¼slightly sluggish 3þ¼normal The near response is tested by having the patient look at his or her thumb as the examiner draws it closer. Again, the pupillary response is recorded on a scale of 0 to 3. One should remember the near response requires voluntary effort from the patient so one must encourage the patient vigorously. Light-near dissociation of the pupil is tested with a light directed at one pupil. The patient is then asked to look at his or her thumb, which is held at 14 inches. A much better pupillary response to near suggests light-near dissociation of the pupils. The afferent pupillary defect represents a sign of asymmetric optic nerve or severe retinal dysfunction (Fig. 1–25). To perform this test, one should have the patient fixate at distance and one should quickly shine the light in each eye to

TABLE 1–2 Visual Field Gems: Keys to Localization of Defects

Characteristic Localization

Vertical and horizontal meridians not respected Retina and choroid Horizontal meridian respected Optic nerve Vertical meridian respected Chiasm, retrochiasmal Vertical and horizontal respected in both eyes Occipital cortex Central scotoma and normal blind spot Macula, optic nerve Central scotoma and enlarged blind spot Optic nerve 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 31

LEFT AFFERENT PUPIL DEFECT

Figure 1–25 The swinging flashlight test is used to test the integrity of the afferent visual pathway. In this example, the left optic nerve is not functioning properly and there is a paradoxical dilation of the left pupil as the light is directed into it (left relative afferent pupillary defect). equally bleach both retinas. The swinging flashlight test is done rhythmically, holding the light on each eye for 1 to 2 seconds. It is important to cross the bridge of the nose quickly and equally stimulate both eyes. Some neuro-ophthalmologists use the following grading scheme for afferent pupillary defects: 1þ¼initial constriction followed by early release of the affected pupil 2þ¼no movement initially, followed by pupillary release 3þ¼immediate pupillary dilation 4þ¼amaurotic eye (no light perception vision) Because an afferent pupillary defect is established by comparing the light reaction of one pupil versus the other, there is no such entity as “a bilateral afferent pupillary defect.” The examiner must be careful of the physiologic phenomenon known as hippus. In the case of marked pupillary unrest (hippus), it is best to look primarily at the initial constriction response of each pupil. A bright light source should be used to assess the pupils, but occasionally a dim light will bring out an afferent defect not observed with a bright light.26,27 When one is unsure if an afferent pupillary defect exists, the examiner may try to gather supporting evidence by: 1. Having each eye compare the intensity of a bright light 2. Comparing red bottle tops 3. Performing contrast sensitivity testing 4. Comparing color plate performance 5. Placing a small (0.3 log filter) neutral density filter over the suspected eye to see if it magnifies or brings out an afferent pupillary defect The swinging flashlight test becomes a bit more difficult to interpret when one pupil is dilated as in a patient with a third nerve palsy. In this setting, one screens for an ipsilateral optic neuropathy by checking the response of the fellow pupil when light is directed into the dilated pupil. This is an indirect measure of the optic nerve function on the side of the dilated pupil. The term anisocoria refers to asymmetric pupil size. The most common form of anisocoria is physiologic or essential. Patients with physiologic anisocoria 32 Neuro-Ophthalmology: Blue Books of Neurology

should have normal pupillary responses to light and near. Most importantly, the amount of pupil inequality should be similar in light and dark conditions. Pathologic anisocoria results from damage to the efferent part of the pupillary pathway. It should be remembered that damage to the afferent part of the pupillary pathway does not produce anisocoria. Anisocoria that is greatest in light suggests parasympathetic dysfunction. In contrast, anisocoria greatest in dark is consistent with oculosympathetic paresis (Horner’s syndrome). In oculosympathetic paresis, the affected pupil fails to dilate or dilates very slowly when the lights are turned off. This is called dilation lag and the anisocoria is most evident in the first 5 seconds after the lights are turned off.28 Pupillary disorders are covered in Chapter 11.

EYELID EXAMINATION The examiner must be able to assess lid function. In normal individuals, the upper lid covers the superior 1 to 2 mm of the iris, and the lower lid borders the inferior aspect. The palpebral fissure is the opening that exists between the upper and lower lids and usually measures 9 to 12 mm in most normal individuals. Because lower lid position may vary, it may be best to measure the distance between the upper lid margin and pupillary light reflex. This measurement is known as the margin reflex distance and usually measures 4 to 5 mm.29 Measurement of lid function will help establish the cause of ptosis. Lid function is measured by manually neutralizing the ipsilateral brow with the hand while asking the patient to look downward30 (Fig. 1–26). A ruler is then placed at the lid margin and the number of millimeters of lid elevation is measured as the patient looks upward. Normal lid function exceeds 12 mm.29 Levator function is reduced in ptosis associated with myasthenia gravis, congenital ptosis, myopathic disorders such as myotonic dystrophy, chronic progressive ophthalmoparesis, and third nerve palsies. In contrast, levator function will be normal in patients with Horner’s syndrome and levator dehiscence. Pseudoptosis may be associated with blepharospasm. In this situation, the eyebrow will be dropped rather than elevated as seen in patients with true ptosis. A markedly hypotropic eye will also demonstrate pseudoptosis as the normal lid follows the globe downward. Lid retraction occurs when the upper lid rides too high. True lid retraction is usually obvious when the superior sclera becomes

Figure 1–26 A, To measure eyelid function a ruler is placed at the lid edge. B, The distance the lid travels to reach full upgaze is recorded as eyelid function. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 33

Figure 1–27 Patient with eyelid retraction from dorsal midbrain compression. Note that the superior sclera is exposed. exposed (Fig. 1–27). Common causes of eyelid retraction include thyroid eye disease, topically administered sympathomimetic drugs, and a dorsal midbrain syndrome.

OCULAR MOTILITY The objective of the motility examination is to assess the integrity of the supranuclear pathways, ocular motor nuclei, ocular motor nerves, and their muscles. Saccades or fast eye movements are tested by having the patient refixate between two targets. This can be easily accomplished by having the patient look at the examiner’s nose and then at an eccentrically placed finger (Fig. 1–28). Saccades may be recorded as follows: 1 ¼ normal, 2 ¼ hypometric when the patient under- shoots the target, 3 ¼ hypermetric when the patient overshoots the target, 4 ¼ slow when the examiner can observe the full trajectory. To test the pursuit system, one needs an object of regard. The examiner’s finger may be an adequate target provided that one does not exceed the limits of the pursuit system (40 degrees per second). Alternatively, one can swing a reflex hammer from side to side to induce pursuit eye movements (Fig. 1–29). Defective pursuit is “saccadic” because the fast eye system has to be activated to keep up with the target. The vestibular ocular reflex (VOR) can be tested in the awake patient by having the patient fixate on the examiner’s finger as the examiner rotates the patient’s head from side to side. Once again, a defective VOR results in catch up saccadic eye movements. Cancellation of the VOR usually requires an intact pursuit system. Failure to cancel the VOR properly may be detected when the patient is slowly rotated while focusing on the outstretched thumb. The patient with defective cancellation of the VOR shows catch up saccades.

Figure 1–28 Testing saccades may be accomplished by having the patient look quickly between two fingers. 34 Neuro-Ophthalmology: Blue Books of Neurology

Figure 1–29 Smooth pursuit may be tested by slowly oscillating a neurologic hammer across the midline.

When diplopia is binocular, it usually results from dysfunction of the ocular motor nerves, neuromuscular junction, or extraocular muscles. Monocular diplopia is usually caused by early cataract formation or astigmatism and is usually relieved by viewing through a pinhole device (Fig. 1–14). Monocular diplopia not alleviated by a pinhole suggests a functional etiology. The diplopia assessment is begun by finding out whether the double vision is vertical or horizontal. Is it worse at distance or near, and in what gaze is the double vision worse? For example, a patient with a right sixth nerve palsy might be able to discern that the diplopia is horizontal, worse at a distance (the eyes need to diverge at distance), and increased by right gaze. In the diplopia evaluation, review of old photographs is essential to check for an old strabismus, face turn, or a head tilt. For example, the patient with a long-standing right fourth nerve palsy will often have a left head tilt in old photographs. Chin depression to keep the eyes in upgaze and a left face turn to keep the eyes in right gaze may also be apparent. Before taking the patient through the cardinal positions of gaze, one should examine the lids carefully. Lid retraction might suggest thyroid eye disease or a dorsal midbrain syndrome depending on the associated findings. Fatigueable ptosis or Cogan’s lid twitch sign (transient improvement of lid function after sustained downgaze) suggests myasthenia gravis (Chapter 13). Next check the eyes in the cardinal positions of gaze. In most individuals, the sclera is covered by the lids in eccentric gaze. One should assess the ocular rotation by recording it as a percentage of normal (i.e., 70% of normal). This may be recorded in the chart from the examiner’s perspective (Fig. 1–30).

Examiner’s view: Right abduction deficit

100% 100%

Figure 1–30 Ductions are recorded from the examiner’s perspective as a percentage 80% 100% 100% 100% of a normal eye excursion. In the example provided, there is a right abduction deficit 100% 100% with an eye movement that is 80% of normal. Right eye Left eye 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 35

Although the appearance of sclera in end gaze is usually pathologic, some patients have shallow orbits and no true ocular deviation exists. In this instance, proof of an ocular deviation requires quantitation of the patient’s ocular misalignment. For example, when the examiner suspects an abduction deficit, confirmation comes from demonstrating an inward strabismus. When an eye is deviated inward, it is called an esotropia, outward deviation is called an exotropia, and vertical displacement is called a hypertropia. Regardless of which eye is vertically impaired, the hypertropia is denoted by the higher eye. Quantitation of the ocular deviation may be made using the cross-cover method, the Maddox rod, or red glass test. In the cross-cover method one eye is covered and the deviated eye will need to pick up the fixation target. For example, an eye that is exotropic will need to move inward to pick up the target when the fixating eye has been covered. The amount of ocular deviation can be neutralized by placing a prism over one eye. Each eye is then alternately covered as the amount of prism is slowly increased. When the eyes no longer move on alternate cover testing, the deviation has been neutralized and the amount of prism required can be read off of the prism bar. A Maddox rod can also be used to quantify the amount of ocular deviation. The Maddox rod is a series of red cylinders that create a bar of red light when a light is directed at it. By convention, the patient places the Maddox rod over the right eye (Fig. 1–31). Holding the bar with the cylinders horizontal provides a single vertical line. This is the orientation required to test horizontal deviations. The patient is then asked which side is the red bar on (relative to the white light). If the patient tells the examiner that the red bar is to the right of the white light, this is an esodeviation (Fig. 1–32). The patient is then taken into right and left gaze to see if the amount of separation increases in the field of action of either the right or left

Figure 1–31 A Maddox rod is placed over the right eye by convention. To test for a horizontal deviation of the eyes, the bars are placed horizontally as shown. This Maddox rod orientation generates a single red vertical line viewed by the patient. The examiner then asks the patient where the red bar lies in relationship to the white light that is viewed by the left eye.

Patient’s view: Esotropia

Red line

White light Figure 1–32 If the red bar lies to the right of the white light from the Primary position Right gaze: patient’s perspective, the patient has right 6th nerve palsy an esodeviation. 36 Neuro-Ophthalmology: Blue Books of Neurology

lateral rectus muscle. If prisms are unavailable, one can get a reasonable estimate of the ocular deviation by asking the patient to show the examiner the extent of separation by spreading his or her fingers apart. An esotropia, which increases in right gaze, is consistent with a right sixth nerve palsy. If the patient sees the red bar to the left of the white light, this represents an exodeviation (Fig. 1–33). This might be remembered by the statement “There is an “x” in exo.” This means that the red bar seen by the right eye crosses to the left of the white light (crossed diplopia). To examine a vertical deviation, the cylinders are placed over the right eye with a vertical orientation. This will give the patient a red horizontal bar when light is directed at him or her. In a right hypertropia (the right eye is higher than the left) the patient will see the red bar below the white light. The patient with a right hypertropia either has a problem with the depressors of the right eye (right inferior rectus or right superior oblique) or the elevators of the left eye (left superior rectus and left inferior oblique). When the red bar appears above the white light, the patient has a left hypertropia. The patient with a left hypertropia either has a problem with the depressors of the left eye or the elevators of the right eye. If the deviation or separation of the bar and light is greater in downgaze with a left hypertropia, then one of the depressors is implicated (left inferior rectus or left superior oblique). The patient is then taken into the cardinal fields of gaze to better localize the involved nerve or muscle. For example, a patient with a left fourth nerve palsy will have a left hypertropia that is worse in downgaze and in right gaze (Fig. 1–34). The deviation associated with a left fourth nerve palsy will increase with left head tilt and lessen with right head tilt. If a right hypertropia appears with right head tilt, this suggests a superimposed

Patient’s view: Exotropia

White light

Figure 1–33 If the red bar lies to the left of the white light from the patient’s Red perspective, the patient has an exodevia- line tion. In this example, the separation of the bar and light was greatest in right Primary position Right gaze: gaze consistent with a left internuclear left internuclear ophthalmoparesis. ophthalmoparesis

Patient’s view: Right fourth nerve palsy Figure 1–34 When testing for a vertical White separation of the eyes, the Maddox rod light bars are placed over the right eye in a vertical orientation. This orientation generates a horizontal red bar. In a patient with a right fourth nerve palsy, the red bar sits below the white light. In left and down gaze, the Red line separation between the red bar and white light should become even greater. Down and left Primary position 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 37

right fourth nerve palsy. Bilateral fourth nerve palsies (one which may be subtle or “masked”) are common with head trauma. In long-standing (congenital) fourth nerve palsies, there may be hypertrophy of the neck muscles contralateral to the head tilt. The diagnosis of a congenital fourth nerve palsy is suggested when the patient can fuse a very large amount of vertical deviation (a large fusional amplitude). Again, old photographs are extremely helpful to document the duration of a head tilt when a congenital fourth nerve palsy is suspected. A third nerve palsy is characterized by a hypertropia that changes sides in upgaze when compared with downgaze. For example, a right third nerve palsy will show a left hypertropia in upgaze (right superior rectus weakness) and a right in downgaze (right inferior rectus weakness). An ocular deviation may be concomitant, meaning that the deviation is the same in all fields of gaze. Concomitant deviations may be seen with the following: 1. Strabismus 2. Skew deviation 3. A long-standing nerve or muscle palsy 4. Convergence or divergence insufficiency 5. Myasthenia or thyroid eye disease In contrast, inconcomitant deviations have a variable ocular deviation depending on the position of gaze. Inconcomitant deviations are seen with the following: 1. Acute ocular motor palsy 2. Skew deviation 3. Myasthenia or thyroid eye disease 4. Internuclear ophthalmoplegia Because both thyroid eye disease and myasthenia gravis may mimic any ocular motor palsy, it is important to always consider these entities. A forced duction test can be easily carried out in the office or at the bedside (Fig. 1–35). The inability to move the eye passively with a cotton tip applicator (after topical anesthesia) suggests a restrictive process such as thyroid eye disease. A Tensilon test may be carried out when myasthenia is suspected. We use 2-mg increments (every 30 to 60 seconds) to avoid overmedicating the patient and occasionally missing the point of ocular recovery. The test can be terminated at any point or after the patient has received the full 10-mg dose if no response has occurred to that point. The red glass test is an analogous to the Maddox rod test except that the patient perceives a red circle rather than a red line in the red glass test. If a red glass or Maddox rod is unavailable, one could perform the cover-uncover

Figure 1–35 Forced duction testing. After topical anesthesia, one may assess the freedom of eye movement using a cotton tip applicator. The patient is instructed to look into one direction as the examiner gently pushes on the eye to determine restriction. 38 Neuro-Ophthalmology: Blue Books of Neurology

test with the hand or a paddle. The cover-uncover test is used to detect overt ocular misalignments (tropias). For instance, if the examiner covers the right eye and the left eye moves out, there is an esotropia, and, if acquired, an abduction deficit is suggested (i.e., sixth nerve palsy). On the other hand, inward movement of the uncovered eye is consistent with an exotropia (third nerve palsy, internuclear ophthalmoparesis, and strabismus). If the uncovered eye moves down, hypertropia is present (i.e., fourth nerve palsy, skew deviation, or myasthenia).

OPHTHALMOSCOPY In an undilated patient, the optic nerve and retina may be viewed with a direct ophthalmoscope. The examiner should make note of the color, contour, and the cup to disc ratio of the optic nerve. The retinal vasculature should be evaluated observing the caliber of the veins and arteries in all four quadrants. The macula can be viewed by moving the ophthalmoscope temporally from the disc or by having the patient directly look at the light of the ophthalmoscope. It is important for the examiner to recognize some of the early features of papilledema. They include (1) blurred disc margins particularly superiorly and inferiorly; (2) disc hyperemia; (3) nerve fiber layer hemorrhages; (4) venous distention; and (5) absence of the spontaneous venous pulse. It is the combination of these features that most convincingly establishes the presence of papilledema. Papilledema is also discussed in the coma section. Pharmacologic dilation of the pupil may be accomplished by topical administration of 1% tropicamide (an anticholinergic) and 2.5% phenylephrine (sympathomimetic). The dilating effect of tropicamide peaks at 20 to 40 minutes and lasts 2 to 6 hours, whereas phenylephrine works in 20 minutes and lasts 2 to 3 hours.

Neuro-Ophthalmologic Examination in Comatose Patients

Comatose patients are unresponsive to all external stimuli, noxious or otherwise. The eyes are closed, but there may be nonpurposeful movements or posturing of the limbs. Coma may be caused by a number of insults, including herniation, hydrocephalus, intracranial hemorrhage, hypoxic-ischemic injury, trauma, infection, and toxic or metabolic insult. The neuroanatomic correlates of coma include either (1) direct brainstem-diencephalic involvement disrupting the reticular formation or nuclei or (2) bilateral cerebral dysfunction.31 When physicians in the emergency department evaluate individuals with unexplained coma, the ability to differentiate between structural and toxic or metabolic causes heavily influences diagnostic and treatment considerations. The history often provides the most important clues, especially when trauma or drug ingestion are suspected. However, often the history is unavailable, and the examination findings may offer the initial clues. Furthermore, daily assessment of the comatose patients in the critical care setting requires a working knowledge of examination techniques and clinicoanatomic correlation. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 39

APPROACH TO THE COMATOSE PATIENT Plum and Posner31 emphasize the evaluation of breathing pattern, pupillary function, eye movements, and motor responses in the neurologic assessment of comatose patients, especially with regard to brainstem localization and diagnosis. Thus, neuro-ophthalmic techniques are paramount in this clinical setting. The ocular motility examination is especially important, because the pathways gov- erning ocular motility traverse the entire brainstem, so pathology in this region often produces recognizable eye movement abnormalities. Conversely, if the eye movements are all normal, it is likely that the entire brainstem is normal as well. This review concentrates on the pupillary, eye movement, and funduscopic abnormalities in coma. The examiner of a comatose patient should decide, in a rostral-caudal fashion, which neuroanatomic structures have been affected by the disease process. In general, if the brainstem is intact in a comatose patient, bilateral hemispheric or thalamic disease should be suspected. If the brainstem is injured, the dysfunction should be localized to the midbrain, pons, or medulla.

EXAMINATION IN COMATOSE PATIENTS In the neuro-ophthalmic assessment, pupillary size, shape, and reactivity to light should be evaluated first. If suspected, the absence of pupillary reaction to light should be confirmed with a magnifying lens. Next, eye position and spontaneous eye movements should be observed. Any overt misalignment, such as an esotropia, vertical or oblique misalignment, or conjugate eye deviation, should be noted. The examiner should also look for spontaneous roving or rhythmic, repetitive vertical movements.32 When spontaneous eye movements are absent, doll’s eye or oculocephalic eye movements can be elicited by turning the head horizontally then vertically. The eyes should deviate in the direction opposite to the head turn. Oculocephalic maneuvers should not be performed in trauma patients with possible cervical spine injury. If there are no oculocephalic eye movements, a stronger stimulus can be provided by applying ice cold water against the tympanic membranes, which pro- vokes the vestibulo-ocular reflex (cold caloric test). The patient’s head should be angled at 30 degrees to align the horizontal semicircular canals perpendicularly to the floor. After visual inspection to exclude rupture of the tympanic membrane, 30 to 60 ml of ice water can be irrigated into the external auditory canal using a large syringe and the tubing from a butterfly catheter or an Angiocath without the needle. A kidney basin should be placed under the ear to contain the overflow of ice water. The cold water creates convection currents in the endolymph of the horizontal semicircular canals and inhibits the ipsilateral vestibular system. In the normal caloric response, the eyes move slowly and conjugately toward the tested ear, followed by a fast corrective phase in the opposite direction to reset the eyes, then the cycle repeats. The slow phase is produced by vestibulo-ocular connections from the unopposed contralateral ear, whereas the fast phase is mediated by the frontal eye fields. Warm water stimulation produces a contralateral slow phase and ipsilateral fast phase. The direction of the caloric response is named after the fast phase, and normal responses can be summarized in the mnemonic 40 Neuro-Ophthalmology: Blue Books of Neurology

“COWS,” which stands for “cold-opposite, warm-same.” Caloric stimulation in the setting of a normal brainstem but bilateral hemispheric dysfunction would produce only an ipsilateral tonic slow phase. Complete brainstem injury would result in no slow or fast eye movements. The other ear can be tested after an interval of a few minutes. Bilateral caloric stimulation with cold water produces a downward slow phase, whereas stimulation with warm water bilaterally results in an upward slow phase. Other important neuro-ophthalmic observations in comatose patients include testing of the corneal reflexes and the funduscopic examination. The corneal reflexes can be evaluated with a sterile cotton swab. Bilateral eyelid closure should be observed, but asymmetric contracture of the orbicularis oculi may result if a facial nerve palsy is present. Completely absent corneal reflexes suggest pontine dysfunction. The funduscopic examination is often normal, but papilledema would indicate elevated intracranial pressure, for instance, whereas a vitreous hemorrhage (Terson’s syndrome) may signify an aneurysmal subarachnoid hemorrhage. Because frequent monitoring of the pupils is important in comatose patients, pharmacologic dilation of the pupils prior to funduscopic examination is not routinely recommended. The Glasgow Coma Scale assigns a number to the level of dysfunction in a patient following head injury. Patients can receive a score of 1 to 5 for level of their verbal response, 1 to 4 for spontaneity of eye opening (4 ¼ spontaneous, 3 ¼ to speech, 2 ¼ to pain, 1 ¼ none) and 1 to 6 for motor function. A total score of 3 to 8 is consistent with severe trauma, 9 to 13 indicates moderate trauma, and 14 or 15 reflects only mild trauma.33

PUPILLARY ABNORMALITIES IN COMA Hypothalamic lesions may cause small but reactive pupils because of oculosympathetic paresis, whereas thalamic and mesencephalic lesions may result in third nerve palsies; midposition or large pupils; or, less likely, pupillary corectopia. Destructive lesions of the pons may disrupt the descending oculosympathetic pathways and result in bilateral pinpoint pupils. Diffuse anoxic brain damage can cause midbrain dysfunction and dilated pupils. Initially in brain death, the pupils can be midposition or dilated and unreactive to light.34,35 With more time after death, however, all pupils become midposition, reflecting the equal parasympathetic and sympathetic dysfunction. As a rule, metabolic coma is more likely to be associated with normoreactive pupils than with coma resulting from a structural lesion, although there are exceptions.31

EYE MOVEMENT ABNORMALITIES IN COMA In comatose patients, any abnormality in the positions of the eyes and any spontaneous movements should be noted first. Conjugate lateral eye deviation may indicate a destructive lesion in the ipsilateral frontal lobe or contralateral pons or a seizure focus in the contralateral cerebral hemisphere. Rarely, a thalamic lesion causes “wrong-way eyes,” with contraversive horizontal eye deviation. Conjugate downward eye deviation implies a dorsal midbrain lesion or hydrocephalus. Dysconjugate eyes might suggest an extraocular muscle palsy,although depressed mentation often uncovers a latent esotropia or exotropia. A pupil involving third 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 41

nerve palsy might indicate uncal herniation or posterior communicating artery aneurysm. If ocular motor function in the brainstem is intact, there may be roving eye movements, characterized by conjugate or dysconjugate, slow ocular deviations in random directions. Periodic alternating or “ping-pong” gaze, refers to slow, repetitive, back and forth, horizontal conjugate eye movements. Spontaneous nystagmus is unusual in coma except in dorsal midbrain lesions associated with convergence-retraction nystagmus. Patients with ocular bobbing, usually comatose because of severely destructive pontine lesions, have a fast conjugate downward deviation followed by a slow upward correction to midposition. Ocular dipping, with a quick upward deviation followed by a slow downward movement, has the same neuroanatomical localization. Comatose patients exhibiting spontaneous, full, conjugate eye movements, as well as normal pupillary reactivity and eyelids, can be considered to have intact third, fourth, and sixth nerve function, as well as preserved internuclear connections. Individuals having absent or abnormal spontaneous eye movements should be tested using oculocephalic (head turning or doll’s head) or oculovestibular (ice-water caloric) maneuvers. In comatose patients with intact brainstem function but abnormal cortical influences, the oculocephalic response may be overly brisk (disinhibited), and ice-water stimulation in one ear may result in ipsiversive eye deviation without the contraversive corrective phase. These maneuvers may uncover a vertical gaze paresis, skew deviation, sixth nerve palsy, or internuclear ophthalmoplegia useful for brainstem localization. In early metabolic coma, the oculocephalic and oculovestibular reflexes are usually preserved. Absent oculocephalic and oculovestibular reflexes may indicate diffuse brainstem dysfunction and is seen in late transtentorial (rostral-caudal) herniation and brain death.32

ABNORMAL OCULAR FUNDI IN COMA Papilledema Papilledema refers to optic disc swelling resulting from increased intracranial pressure. Early papilledema occurs first in the superior-inferior axis and is associated with disc hyperemia. Opacification of the nerve fiber layer may cause obscuration of retinal vessels as they leave the disc. Hemorrhages, cotton wool spots, and exudates are common as papilledema progresses. Although an inconsistent finding, the presence of spontaneous pulsation of the retinal veins makes the presence of increased intracranial pressure less likely. Finally, the optic cup is preserved until papilledema is well developed. Papilledema is usually bilateral, although findings may occasionally be asymmetric.36 A history of other clinical features such as transient visual obscurations, morning headache, nausea, ataxia, or horizontal diplopia would also be compat- ible with increased intracranial pressure. Etiologies to consider would include mass lesions, hydrocephalus, venous thrombosis, and infectious meningitis.

TERSON’S SYNDROME Terson’s syndrome is vitreous, subhyaloid, or retinal bleeding in association with subarachnoid hemorrhage. The exact mechanism by which this occurs is 42 Neuro-Ophthalmology: Blue Books of Neurology

unclear, although it has been postulated that it may be because of subarachnoid blood tracking down the optic sheath or outflow obstruction resulting from the sudden rise in intracranial pressure causing venous engorgement and hemorrhage. Although Terson’s syndrome is most commonly seen in association with ruptured anterior communicating aneurysms, it may occur after subarachnoid hemorrhage from any etiology.36

REFERENCES 1. Liu GT: Disorders of the eyes and eyelids. In Samuels MA, Feske S (eds): Office Practice of Neurology. New York, Churchill Livingstone, 1996, p. 41. 2. Rizzo JF III: Embryology, anatomy and physiology of the retina. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2005, pp 3–24. 3. Patten J: Vision, the visual fields, and the olfactory nerve. Neurological Differential Diagnosis, 2nd ed. New York, Springer-Verlag, 1996, p 23. 4. Hoyt WF, Luis O: The primate chiasm. Arch Ophthalmol 1963;70:69–85. 5. Mason C, Kandel ER: Central visual pathways. In Kandel ER, Schwartz JH, Jessell T (eds): Principles of Neural Science, 3rd ed. Norwalk, CT, Appleton & Lange, 1991, p. 437. 6. Glaser JS, Sadun AA: Anatomy of the visual sensory system. In Glaser JS (ed): Neuro-Ophthalmology, 2nd ed. Philadelphia, Lippincott, 1990. 7. Horton JC: Wilbrand’s knee of the primate optic chiasm is an artifact of monocular enucleation. Trans Am Ophth Soc 1997;95:579–609. 8. Frisen L, Holmegaard L, Rosencrantz M: Sectoral atrophy and homonymous horizontal sectoranopia: A lateral choroidal artery syndrome. J Neurol Neurosurg Psychiatry 1978;41:374–380. 9. Horton JC, Hoyt WF: The representation of the visual field in human striate cortex. A revision of classic Holmes map. Arch Ophthalmol 1991;109:816–824. 10. Moore KL: Clinically Oriented Anatomy, 4th ed. Baltimore, Lippincott, Williams & Wilkins, 1999. 11. Galetta SL: Cavernous sinus syndromes. In Margo CE, Hamed LM, Mames RN (eds): Diagnostic Problems in Clinical Ophthalmology. Philadelphia, WB Saunders, 1994, p 610. 12. Balcer LJ, Galetta SL, Bagley LJ, et al: Localization of traumatic oculomotor nerve palsy to the midbrain exit site by magnetic resonance imaging. Am J Ophthalmol 1996;122:437–439. 13. Galetta SL, Liu GT, Volpe NJ: Diagnostic tests in neuro-ophthalmology. Neurol Clin 1996;14:201–222. 14. Trobe JD: Third nerve palsy and the pupil: Footnotes to the rule [editorial]. Arch Ophthalmol 1988;106:601–602. 15. Zee DS, Newman-Toker DE: Supranuclear and internuclear ocular motor disorders. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed. Philadelphia, Williams & Wilkins, 2005, pp 907–967. 16. Silverman IE, Liu GT, Volpe NJ, Galetta SL: The crossed paralyses: The original brain-stem syndromes of Millard-Gubler, Foville, Weber, and Raymond-Cestan. Arch Neurol 1995;52:635–638. 17. Galetta SL, Balcer LJ: Isolated fourth nerve palsy from midbrain hemorrhage: Case report. J Neuro-Ophthalmol 1998;18:204–205. 18. Miller NR: Neural control of eye movements. In Miller NR (ed): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 4th ed. Baltimore, Williams & Wilkins, 1985, pp 608–633. 19. Pierrot-Deseilligny C: Saccade and smooth-pursuit impairment after cerebral hemispheric lesions. Eur Neurol 1994;34:121–134. 20. Zee DS: The organization of the brainstem ocular motor subnuclei. Ann Neurol 1978;4:384–385. 21. Kardon RH: Anatomy and physiology of the autonomic nervous system. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed. Philadelphia, Lippincott, Williams & Wilkins, 2005, pp 649–714. 22. Slamovits TL, Glaser JS: The pupils and accommodation. In Glaser JS (ed): Neuro-Ophthalmology, 2nd ed. Philadelphia, JB Lippincott, 2005, p 464. 23. Frisen L: Visual acuity. In Clinical Tests of Vision. New York, Raven Press, 1990, pp 24–46. 24. Hart WM: Acquired dyschromatopsias. Surv Ophthalmol 1987;32:10–31. 25. Moseley MJ, Hill AR: Contrast sensitivity testing in clinical practice. Br J Ophthalmol 1994;78:795. 1 Neuro-Ophthalmologic Anatomy and Examination Techniques 43

26. Browning DJ, Tiedeman JS: The test light affects quantitation of the afferent pupillary defect. Ophthalmology 1987;94:53–55. 27. Johnson LN: The effect of light intensity on measurement of the relative afferent pupillary defect. Am J Ophthalmol 1990;109:481–482. 28. Pilley SF, Thompson HS: Pupillary “dilatation lag” in Horner’s syndrome. Br J Ophthalmol 1975;59:731–735. 29. Nunery WR, Cepela M: Levator function in the evaluation and measurement of blepharoptosis. Ophthalmol Clin 1991;4:1–16. 30. Sedwick LA: Ptosis. In Margo D, Hamed L, Mames R (eds): Diagnostic Problems in Clinical Oph- thalmology, Philadelphia, WB Saunders, 1994, pp 38–42. 31. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia, FA Davis, 1980, pp 1–86. 32. Liu GT: Disorders of the eyes and eyelids: Disorders of the eye movements. In Samuels MA, Feske S (eds): The Office Practice of Neurology, New York, Churchill-Livingstone, 1996, p 50. 33. Bleck TP: Levels of consciousness and attention. In Goetz CG, Pappert EJ (eds): Textbook of Clinical Neurology. Philadelphia, WB Saunders, 1998, pp 2–16. 34. Quality Standards Subcommittee of the American Academy of Neurology: Practice parameters for determining brain death in adults (summary statement). Neurology 1995;45:1012. 35. Wijdicks EFM: Determining brain death in adults. Neurology 1995;45:1003. 36. Laskowitz D, Liu GT, Galetta SL: Acute visual loss and other disorders of the eyes. Neurol Clin North Am 1998;16:323–353. 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) NANCY J. NEWMAN

Clinical Evaluation: Recognizing Retinovascular Occlusion and an Optic Neuropathy Retinal Detachment Retinal Degenerations Clinical Entities That are not Optic Neuropathies Investigations Ocular Media Abnormalities Abnormalities of the Macula and It is an Optic Neuropathy! Outer Retina References

Key Points The neurologist will see patients complaining of visual loss and should be able to evaluate the visual system and determine the location of the problem along the visual pathways from the eyes to the occipital lobes. The neurologist must be able to differentiate between visual loss from an optic neuropathy and visual loss from retinal and ocular causes. The classic features of an optic neuropathy are central visual loss, clear view through to the optic nerve, a relative afferent pupillary defect, and a swollen or pale optic nerve head. Ancillary testing, especially retinal electrophysiology, is often helpful, especially when differentiating bilateral optic neuropathies from subtle maculopathies and retinal degenerations. Essentially all categories of disease processes can cause an optic neuropathy.

The neurologist is not infrequently confronted with a patient complaining of visual loss. On some occasions, the patient has already been seen by an ophthalmologist or, more commonly, an optometrist. However, it is not unusual for the neurologist to be the first health care provider to examine the patient. As an expert on the central nervous system, of which the eye is a part, the neurologist is expected to be able to evaluate a patient’s complaint of visual loss and provide at least a cursory examination of the ocular apparatus and visual pathways. 44 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 45

Traditionally,the only part of the “eye” considered the domain of the neurologist is the optic nerve and its connections into the brain. At the very least, therefore, the neurologist should be able to recognize when visual loss is caused by an optic nerve problem and when it is not. The neurologist must know the classic defining features of an optic neuropathy. When these defining characteristics are not met, other abnormalities involving the ocular media and the retina should be considered. To localize the lesion within the eye and to generate a diagnosis, the neurologist must at least be aware of the other clinical entities that can cause visual loss, especially sudden visual loss, in addition to optic nerve damage. No one realistically expects the neurologist to be an expert on the eye. However, there are certain “red flags” on clinical evaluation that should make the neurologist think about these other diagnoses and seek prompt ophthalmologic referral. In some situations, it is the neurologist, with his or her particular knowledge of the brain and its adnexa, who makes the correct diagnosis and initiates the appropriate management, even when the problem is ocular and should have been the domain of the ophthalmologist.

Clinical Evaluation: Recognizing an Optic Neuropathy

It has been estimated that the optic nerves contain 38% of all the axons entering or leaving the brain.1 Not surprisingly, therefore, neurologists often find themselves confronted by patients with complaints of visual impairment. The neuro-ophthalmic evaluation has been detailed in Chapter 1. In this chapter, we emphasize the historical and clinical features that help differentiate an optic neuropathy from the more common ocular causes of visual loss. Optic neuropathies account for most instances of neurogenic visual loss. The classic features of an optic neuropathy are as follows: 1. Central visual loss 2. Clear view through to the optic nerve 3. Relative afferent pupillary defect 4. Swollen or pale appearing optic nerve (Fig. 2–1) If all these features are met, there is little question as to localization of the lesion. Of course, it is not always so clear-cut. Some optic neuropathies may spare central visual acuity. Glaucoma is a prime example. Furthermore, in up to 50% of patients with nonarteritic anterior ischemic optic neuropathy, for example, visual acuity is good despite altitudinal visual field loss. In other acute optic neuropathies, such as the majority of cases of retrobulbar idiopathic optic neuritis, the optic nerve appears normal for at least 4 to 6 weeks before optic nerve head pallor ensues. How- ever, in the last two examples, the presence of other features, especially a relative afferent pupillary defect, facilitates recognition of the optic nerve as the locus of pathology. A more difficult situation occurs when the optic neuropathy is bilateral and symmetrical, and, therefore, a relative afferent pupillary defect may not be present.

Clinical Entities That are not Optic Neuropathies

There are many causes of visual loss that are not optic neuropathies with which the neurologist should be familiar. In the remainder of this chapter, we consider those causes of visual loss that are not a result of primary optic nerve injury. 46 Neuro-Ophthalmology: Blue Books of Neurology

Figure 2–1 Appearance of the optic nerve on funduscopic examination. A, Normal-appearing optic nerve head. B, Swollen optic nerve head. C, Pale optic nerve head.

These entities are categorized by how many of the criteria for the classic diagnosis of an optic neuropathy they meet.

OCULAR MEDIA ABNORMALITIES Clinical entities that cause visual loss and do not allow a clear view back to the fundus are almost always problems with the ocular media: the cornea, the anterior chamber, the lens, or the vitreous.2,3 Many of these problems can be recognized with penlight observation or use of the direct ophthalmoscope focused on the more anterior eye (i.e., with more plus diopters dialed in). Corneal surface changes, scarring, edema, or structural abnormalities (such as keratoconus) will make the view in difficult. A hyphema (blood in the anterior chamber) may be visible to the naked eye. Cataracts will cause blurring, darkening, or an orange- brown discoloration of the fundus details, a glaring reflection of the ophthalmoscope’s light, or complete obscuration of view (Fig. 2–2). Vitreous hemorrhage, inflammation (uveitis), or debris may also completely obscure or blur the view of the optic nerve and retina. 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 47

Figure 2–2 Nuclear sclerotic and cortical cataract as it would look when viewed through a direct ophthalmoscope focused anterior to the fundus (more plus diopters).

Angle closure glaucoma is a sudden rise in intraocular pressure usually occurring in patients anatomically predisposed for a narrow drainage angle.2 Normally, the aqueous fluid of the eye is produced at the ciliary body (located just behind the peripheral circumference of the iris), passes through the pupil into the anterior chamber, and then drains from the eye mostly through Schlemm’s canal, which is located in the sclera near the junction of the cornea and the base of the iris. Elevation of the iris periphery, as can occur with pupillary dilation in some patients, narrows the path to Schlemm’s canal and can cause sudden, significant blockage of outflow and rise in intraocular pressure. The patient typically has nausea as part of the vagal reflex, a painful eye from the elevated pressure, a red eye from increased vascular congestion, a large and nonreactive pupil from ischemia to the iris, and subnormal vision from corneal haze. Cor- neal haze can be recognized with the direct ophthalmoscope looking for a reduction in the normal luster of the corneal surface, especially as compared with the fellow eye, and the view in will be hazy. The presence of a fixed dilated pupil and pain may mislead the physician to conclude that there is aneurysmal compression of the third nerve. However, the other ocular findings and the absence of ptosis or motility disturbances should lead to appropriate diagnosis and management. On rare occasions, angle closure may be intermittent, thereby causing transient blurring of vision (usually with associated eye pain or headache), mimicking so-called amaurosis fugax. If left untreated, optic nerve damage may ensue, contributing to visual loss and resulting in a relative afferent pupillary defect, potentially leading to further confusion in diagnosis. However, by the time optic nerve injury has occurred, the ocular media findings should be quite apparent. Vitreous hemorrhage (Fig. 2–3) most commonly occurs in the diabetic with diabetic retinopathy and neovascularization but also occurs after trauma and after subarachnoid hemorrhage (Terson’s syndrome). Smaller vitreal hemorrhages are usually described as large “floaters” that move when the eye is moved. Larger vitreal hemorrhages persistently disrupt central vision. Examination will reveal a diminished red reflex and the view of the fundus will be obscured on direct 48 Neuro-Ophthalmology: Blue Books of Neurology

Figure 2–3 Vitreous hemorrhage. A, Vitreous hemorrhage (green haze within the eye) obscuring the normal red reflex in a post-subarachnoid hemorrhage patient with Terson’s syndrome, as seen with a direct ophthalmoscope focused anterior to the fundus (more plus diopters). B, Fundu- scopic appearance of a different patient with vitreous hemorrhage obscuring visualization of the details of the left retina inferiorly.

ophthalmoscopy. The inpatient from the neurosurgery service who has visual loss on awakening after a subarachnoid hemorrhage almost always has unilateral or bilateral vitreous hemorrhage.

ABNORMALITIES OF THE MACULA AND OUTER RETINA The most common problem faced by the neurologist in the differential diagnosis of visual loss is deciding whether the visual loss is the result of a lesion of the optic nerve or a lesion of the macula.1,2,4 Both optic nerve lesions and macular lesions can reduce central acuity and both can cause central scotomas on visual fields. Both may also affect color vision, although the amount of color vision deficit for any given visual acuity deficit is usually much greater for an optic neuropathy than a maculopathy. Maculopathies are rarely painful, as opposed to some causes of optic neuropathy, especially idiopathic optic neuritis in which pain, particularly pain exacerbated by eye movement, is a common feature. Clas- sically, maculopathies cause visual distortions and vision is slow to recover after bright light, features not usually found among optic neuropathies. The visual field defects of an optic neuropathy may respect the horizontal meridian, whereas macular lesions will not. If the macula definitely looks abnormal, the answer is clear, but some retinal lesions are quite subtle and difficult to detect.4,5 However, it is the absence of a relative afferent pupillary defect that should lead the examiner to suspect a problem removed from the optic nerve. Very often, the retinal findings may be so subtle that examination by an ophthalmologist with slit lamp fundus biomicroscopy is essential, and more sophisticated electrophysiologic testing is required for diagnosis. Central serous retinopathy (CSR) (Fig. 2–4) is a relatively common cause of visual loss that occurs when serous fluid accumulates in the subretinal space underneath the macula causing a relative detachment of the layers of the retina. It makes the macula look like a blister. Presumably fluid has leaked from the choroid through a break in the retinal pigment epithelium. It occurs preferen- tially in males (male to female ratio of 10:1) in their fourth and fifth decades 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 49

Figure 2–4 Central serous retinopathy of the right eye macular region. Note the blister-like elevation of the inner retina from accumulation of fluid in the subretinal space. of life, especially so-called type A personalities under increased stress. The symptoms are fairly sudden in onset and consist of painless blurred and dim central vision and there is usually metamorphopsia. Most eyes improve spontaneously within 1 to 6 months. Fifty percent of patients experience recurrences. The clinical picture may be mistaken for optic neuritis, but the male gender, the metamorphopsia, the lack of pain, and the usual absence of a relative afferent pupillary defect should raise suspicion for CSR. Macular degeneration is typically a progressive, bilateral acquired degeneration of the outer retina in the region of the macula. With age, some patients develop chronic degenerative changes, so-called age-related macular degeneration (Fig. 2–5). An early sign of the process is the appearance of yellow-white deposits with irregular borders known as drusen (a completely different entity

Figure 2–5 Macular degeneration in the left eye with macular drusen deposits. 50 Neuro-Ophthalmology: Blue Books of Neurology

from the drusen found in optic nerves). These drusen result from thickening of Bruch’s membrane or from the retinal pigment epithelial cells’ inability to dispose of lipofuscin and other waste products. Hypopigmentation or hyperpigmentation of the retinal pigment epithelium may also be present. There are many other causes of maculopathy, many hereditary, occasionally toxic, almost always bilateral. A specific diagnosis depends on the location of the deposits, the results of fluorescein angiography, the age of the patient, and the family history. Most patients with severe visual loss from macular degenerations develop choroidal neovascularization, which places them at increased risk for subretinal hemorrhage, subretinal exudate, and macular edema. A macular hole is just that (Fig. 2–6). Idiopathic macular holes and cysts occur primarily in women in the sixth through eighth decades of life, probably as a result of progressive vitreoretinal traction. A fully formed hole is visible as a sharply deli- neated defect in the middle of the macula. The other eye may become similarly involved in up to 30% of patients. Acquired enlargement of the physiologic blind spot, both symptomatic and asymptomatic, is usually the result of swelling of the optic nerve head. Occa- sionally, however, blind spot enlargement may occur with a normal-appearing optic nerve and signify peripapillary outer retinal dysfunction, the so-called acute idiopathic blind spot enlargement (AIBSE) syndrome (Fig. 2–7). AIBSE is a syndrome characterized by the sudden onset of a monocular temporal blind area centered on the physiologic blind spot, often with associated photopsias in the sco- tomatous field. Women are affected at least twice as frequently as men, and most patients are between the ages of 20 and 40 years. Visual acuity and color vision are typically spared and there may or may not be a relative afferent pupillary defect (present less than 50% of the time). Ophthalmoscopic and fluoroangiographic findings are often normal or consist of nonspecific pigmentary changes or subtle grayish discoloration of the peripapillary retina. The electroretinogram (ERG)

Figure 2–6 Macular hole in a patient’s right eye. 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 51

Figure 2–7 Acute idiopathic blind spot enlargement syndrome (AIBSE). A, The right optic nerve head appearance in a patient with chronic AIBSE. Note the concentric deep pigmentary changes around the optic nerve head with preservation of the normal optic nerve color. B, Visual field of the right eye shows enlargement of the physiologic blind spot. is often abnormal, especially the multifocal ERG. AIBSE generally resolves over several weeks or months but occasionally will recur in the same or opposite eye. AIBSE may be one manifestation of a group of disorders designated as acute zonal occult outer retinopathy (AZOOR) and including AIBSE, the multiple evanescent white-dot syndrome (MEWDS), acute macular neuroretinopathy (AMN), and the pseudo-presumed ocular histoplasmosis syndrome (P-POHS). The group is linked because of a common involvement of the outer retinal layers, possibly by an autoimmune or viral etiology, especially in young women. Funduscopic changes may be minimal but the ERG is usually abnormal.

RETINOVASCULAR OCCLUSION AND RETINAL DETACHMENT The fibers that form the optic nerve originate in the ganglion cells, one of the most inner layers of the retina.1,2 The axons of the ganglion cells lie superficial to the ganglion cell layer and are designated as the nerve fiber layer before their coalescence into the optic nerve. Damage to the ganglion cell body or the nerve fiber layer is tantamount to damage to the optic nerve; there will be visual loss, a relative afferent pupillary defect if unilateral, and ultimately optic nerve atrophy. Because the central retinal arterial and venous circulations subserve the inner layers of the retina (including the ganglion cell and nerve fiber layers), retinal vascular occlusive events will result in inner retinal damage, visual loss, and a relative afferent pupillary defect. Acute vascular events involving the inner retina have a dramatic and distinct funduscopic appearance, allowing for immediate correct diagnosis. When a retinal artery becomes occluded the normally transparent retina supplied by that artery becomes white and edematous. There may be segmentation of the arteriolar blood column (boxcarring) and a reduction of the arteriolar lumen. A visible embolus 52 Neuro-Ophthalmology: Blue Books of Neurology

is present in 10% to 20% of patients with a central retinal artery occlusion and 60% to 70% of patients with a branch retinal artery occlusion. Occlusion of the central retinal artery (CRAO) (Fig. 2–8) is a medical emergency. Central and severe visual loss typically occurs painlessly and without warning. Occasionally, patients may experience episodes of transient monocular blindness before complete visual loss, especially in those cases related to ipsilateral carotid disease or giant cell arteritis. The classic funduscopic appearance of CRAO is central retinal whitening surrounding a cherry red spot in the macular region. This occurs because the retina is very thin at the level of the macula and the underlying choroidal circulation shows distinctly red against the white, swollen, ischemic surrounding retina. In the acute phase, the optic nerve head appears normal because its blood supply is not the central retinal artery but rather branches from the ciliary circulation. In time, however, with death of the inner retinal layers, including the ganglion cell layer and the nerve fiber layer, the optic nerve becomes pale. The retinal vessels ultimately become narrowed and sheathed. Most cases of CRAO are caused by an embolus obstructing either the central retinal artery or the ophthalmic artery. The standard of care if the patient is seen within a few hours of acute onset is to initiate a host of measures designed to improve circulation to the retina, including ocular massage to dislodge the embolus, breathing a mixture of 95% oxygen and 5% carbon dioxide to promote vasodilation, systemic administration of acetazolamide to reduce intraocular pressure, and anterior chamber paracentesis to dramatically reduce intraocular pressure. Unfortunately, only rarely is vision restored. The administration of selective arterial thrombolytics for this entity is controversial. In an ophthalmic artery occlusion, both the central retinal artery circulation and the ciliary circulation are compromised, resulting in ischemia to the inner and outer retina and the optic nerve. The funduscopic appearance is that of both retinal and optic nerve swelling, with no cherry red spot (the choroidal circulation is also compromised). In branch retinal artery occlusions (Fig. 2–9), the area of retinal whitening and edema, as well as the vision and visual field loss, is determined by the location and amount of retina subserved by that particular vessel.

Figure 2–8 Central retinal artery occlusion in the right eye. Note the overall whitening of the retina and the preservation of a cherry red spot at the fovea. 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 53

Figure 2–9 Superior branch retinal artery occlusion in the left eye. Note the small embolus at the origin of the involved branch artery at the top of the optic nerve head and the whitening of the involved superior inner retina.

Occlusion of the central retinal vein (CRVO) (Fig. 2–10) produces a dramatic funduscopic appearance, although visual loss may be minimal. The veins are markedly dilated with diffuse hemorrhage involving the superficial and deep layers of the retina. There are usually cotton wool spots (small infarctions of the nerve fiber layer) and swelling of the optic nerve head. Descriptions of CRVO include “blood and thunder” and “pizza pie.” Underlying hypertension and hypercoagulability need to be considered in these patients. A retinal detachment (Fig. 2–11) occurs when the connections between the overlying retina and the underlying retinal pigment epithelium (and the nourishing choroidal blood supply) are severed. If the detachment involves the retina centrally, this results in poor central vision and a relative afferent pupillary defect. Ophthalmoscopy will reveal the detached retina ballooning forward or simply a red reflex with an obscured view of the fundus. Myopic patients are especially vulnerable to retinal detachments, as are patients who have recently had intraocular surgery or ocular trauma, or who have a family history of retinal detachment.

Figure 2–10 Central retinal vein occlusion with optic nerve head swelling, diffuse hemorrhages, and cotton wool spots. 54 Neuro-Ophthalmology: Blue Books of Neurology

Figure 2–11 Superior retinal detachment of the left eye.

Detachments are often heralded by photopsias (flashes of light). If the detachment originates peripherally,there may first be a period of time when the patient notices a veil or shadow over a portion of the visual field before central visual involvement. Prompt evaluation by an ophthalmologist may preempt further detachment and allow for the appropriate reattachment surgery.

RETINAL DEGENERATIONS When optic neuropathies are bilateral and symmetric, all criteria for diagnosis of optic neuropathy may be met except for the presence of a relative afferent pupillary defect. These primary bilateral optic neuropathies may be difficult to distinguish from a group of retinal disorders, commonly designated retinal degenerations and dystrophies, in which secondary optic disc pallor occurs bilaterally.4,5 Retinal disorders that may “masquerade” as bilateral optic neuropathies include vitamin A deficiency retinopathies, toxic retinopathies, and carcinoma-associated and melanoma-associated paraneoplastic retinopathies.4 Clues to their diagnosis include photopsias (often considered the “agonal cry” of the dying photoreceptor), subtle retinal pigmentary changes, and retinal arterial attenuation or narrow- ing. Electrophysiologic testing, especially the ERG and multifocal ERG, are usually diagnostic. The cone dystrophies (Fig. 2–12) are characterized by bilateral loss of central vision, profound color vision deficits, and often a relatively normal-appearing fundus examination except for bilateral temporal disc pallor. The cone dystrophies are commonly sporadic, although inherited forms have been reported. Visual acuities typically deteriorate to the 20/200 to 20/400 level. Clues to suggest retinal cone dysfunction include the profound dyschromatopsia; photophobia; an inability to see as well in bright as in dim light (hemeralopia), retinal arterial attenuation; and, eventually, changes in the appearance of the macula, often resembling a bull’s-eye (Fig. 2–13). The ERG will show abnormalities of photopic function and is diagnostic. 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 55

Figure 2–12 Cone dystrophy masquerading as bilateral optic neuropathy. A, Funduscopic appearance with pale optic nerves bilaterally, but note the definite attenuation of the arteries and the subtle macular changes. B, Goldmann visual field in this patient showing relative central scotomas consistent with cone dysfunction but mimicking optic neuropathies.

Figure 2–13 Bull’s-eye maculopathy in a patient with cone dystrophy. 56 Neuro-Ophthalmology: Blue Books of Neurology

Some causes of toxic retinopathy that may masquerade as bilateral optic neuropathies include vigabatrin, chloroquine and hydroxychloroquine, deferoxamine, digoxin, quinine, and thioridazine. Vitamin A deficiency retinopathy occurs in the setting of protein-calorie malnutrition in developing countries, but in the developed world it is more likely to be encountered in patients with malabsorption from liver or gastrointestinal disease, including those patients who have had bariatric gastric bypass surgery. Two types of paraneoplastic retinopathy and multiple different antigens have been well-described. In carcinoma-associated retinopathy (CAR), there is a selective loss of photoreceptors, photopsias, hazy vision, and nyctalopia but often a normal funduscopic appearance except for retinal arterial attenuation. In melanoma-associated retinopathy, there is selective damage to the bipolar cells, prominent photopsias and nyctalopia, and also typically normal-appearing fundi, especially early in the course of visual loss. Paraneoplastic retinopathy classically has a much faster rate of progression than any of the inherited retinal dystrophies, but it may be the first manifestation of the malignancy. The ERG is diagnostic in these disorders.

Investigations

Because distinction of an optic neuropathy, especially a bilateral optic neuropathy, from a retinopathy can sometimes be difficult on the basis of clinical manifestations and retinal appearance alone, ancillary testing is commonly required.4 Fluorescein angiography can sometimes help in diagnosis, especially in regard to retinal vascular disease, central serous retinopathy, and some of the other maculopathies. Ocular coherence tomography (OCT) uses a laser slit beam projected onto the retina to obtain a cross-sectional image and is also particularly helpful in identifying subtle maculopathies. However, when the distinction between retinal disease and optic neuropathy is not obvious, the gold standard for evaluation is electrophysiology, in particular the full-field ERG and the multifocal ERG.4 The full-field ERG is the mass-electrical response of the retina to flash stimulation, using varied colored lights presented at different frequencies and in different illuminations. The standard ERG includes a scotopic rod response to a dim blue or white stimulus, a maximal response to bright white light in the dark-adapted eye (mixed rod and cone response), a photopic (cone) response, and a 30-Hz flicker (cone) response. The different wave forms reflect the responses from different parts of the retina, but the ganglion cell layer and the nerve fiber layer are not represented, allowing for differentiation of abnormalities of deeper layers of the retina. Unfortunately, however, disease limited to the macula does not cause full-field ERG changes (the contribution from the macula is overcome by the total retinal response). The multifocal ERG is a more recent technique in which focal ERGs from multiple locations are simultaneous recorded and mathematically extracted, generating a retinal response topography map. One can correlate focal retinal dysfunction with visual field abnormalities and funduscopic appearance, particularly allowing for the detection of subtle macular abnormalities. 2 Is It a Neuro-Ophthalmic Problem? (If Not, What Else Could It Be?) 57

It is an Optic Neuropathy!

Once one has determined by history and examination that a patient does indeed have an optic neuropathy, then a differential diagnosis as to the underlying cause of that optic neuropathy must follow.6 Essentially all categories of disease processes must be considered (Table 2–1). Unfortunately, the optic nerve has a very limited repertoire of how it can express itself when it is damaged or perturbed (Fig. 2–1). If the pathology involves the optic nerve head, one may see swelling of the nerve, so-called disc edema. If the locus of the pathology is behind the eyeball, termed retrobulbar, then it is likely that the optic nerve will appear normal at the time of acute visual loss. Ultimately, after 4 to 6 weeks, pallor will ensue if permanent damage has occurred. Important clues in establishing the etiology of an optic neuropathy include the age of the patient, the tempo of onset and progression of visual loss, the presence or absence of pain, the presence or absence of bilateral involvement, the level of visual acuity, the pattern of visual field loss, the appearance of the optic nerve head, and the presence or absence of associated signs.

Acknowledgments This work was supported in part by a departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, NY, and by core grant P30-EY06360 (Department of Ophthalmology) from the National Institutes of Health, Bethesda, Maryland. Dr. Newman is a recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award.

TABLE 2–1 Categories of Disease Processes That Can Cause an Optic Neuropathy

Inflammatory Infectious Noninfectious Vascular Compressive/Infiltrative Neoplastic Non-neoplastic Hereditary Toxic/metabolic Traumatic Mechanical Elevated intracranial pressure Elevated intraocular pressure 58 Neuro-Ophthalmology: Blue Books of Neurology

REFERENCES 1. Rizzo JF III: Embryology, anatomy and physiology of the afferent visual pathway. In Miller NR, Newman NJ, Biousse V, Kerrison JB (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 6th ed, vol 1. Baltimore, Lippincott Williams & Wilkins, 2005, pp 3–82. 2. Albert DM, Jakobiec FA: Principles and Practice of Ophthalmology, 2nd ed. Philadelphia, WB Saunders, 2000. 3. Spalton D, Hitchings R, Hunter PA: Atlas of Clinical Ophthalmology, 2nd ed. Philadelphia, JB Lippincott, 1992. 4. Sandbach JM, Newman NJ: Retinal masqueraders of optic nerve disease. Ophthalmol Clin North Am 2001;14:41–59. 5. Newman NJ: Optic disc pallor: A false localizing sign. Surv Ophthalmol 1993;37:273–282. 6. Van Stavern GP, Newman NJ: Optic neuropathies. An overview. Ophthalmol Clin North Am 2001;14:61–71. 3 Orbital Disease GEOFFREY E. ROSE DAVID H. VERITY

The Assessment of Orbital Ancillary Tests for Orbital Disease Disease Clinical History in Orbital Disease Common Orbital Diseases Clinical Examination for Orbital Benign Orbital Diseases Disease Malignant Orbital Diseases

Key Points An accurate clinical history and patient assessment are essential in the management of orbital disease. Orbital examination includes a full assessment of the following: optic nerve function (visual acuity, color vision, visual fields, pupil reactions, and disc assessment), axial and nonaxial globe position, ocular balance and motility, and intraocular and periorbital structures. Systemic examination is guided by the symptoms. The imaging of choice for orbital disease is CT. MRI may provide further detail of intrinsic optic nerve disease and orbital apical or intracranial pathology. Ultrasonography has higher resolution than CT and MRI and is valuable in assessing intraocular lesions and anterior orbital masses—in particular vascular lesions. Orbital inflammation is a not a diagnosis but a tissue response to a wide range of pathologies, and immunosuppression should not be instituted until an adequate biopsy has been obtained. The exceptions to this general principle are typical scleritis, myositis, thyroid eye disease, and characteristic orbital apex syndrome, in which delay in suppression of apical inflammation may jeopardize visual outcome. Similarly, the term “orbital pseudotumor” is not a diagnosis, has often led to inappropriate management, and is no longer in use. Thyroid eye disease is the most common cause of unilateral and bilateral proptosis. Management of aggressive disease consists of immunosuppression in the early, “active” phase, with nonresponsive patients requiring urgent decompression in the presence of optic neuropathy. Stable, inactive disease is managed by orbital decompression for exophthalmos, followed by correction of muscle imbalance and lid malposition. Subacute lacrimal gland inflammation, unresponsive to a few weeks of nonsteroidal treatment, may be due to underlying carcinoma and a specialist opinion should be sought without delay.

59 60 Neuro-Ophthalmology: Blue Books of Neurology

Although the orbit is affected by a broad spectrum of pathology—including structural, inflammatory, infectious, vascular, neoplastic and degenerative processes— the symptoms and signs of orbital disease are limited (Table 3–1). To the astute clinician, however, a thorough history and examination for both ocular and systemic disease usually leads to a concise differential diagnosis and can guide further investigation. The clinical assessment of orbital disease, radiologic interpretation, and an approach to diagnosis, investigation, and management of commoner benign and malignant orbital diseases are presented in this chapter.

The Assessment of Orbital Disease

Clinical history provides a good guide to likely orbital pathology, particularly taking into consideration the patient’s age, the presence and nature of pain, and the speed of onset of symptoms. Imaging, of which computed tomography (CT) remains the most useful primary modality for orbital conditions, tends to provide confirmatory evidence for the likely diagnosis and also helps define the extent of disease.

CLINICAL HISTORY IN ORBITAL DISEASE Pain The nature, intensity, location, and duration of orbital pain should be assessed: sharp, lancinating pains—often localized to “under the upper eyelid” and with bursts of profuse watering—come from ocular surface drying, typically resulting from incomplete lid closure because of proptosis; a history of sleeping with open eyelids (“nocturnal lagophthalmos”) should be sought. Inflammation from deep within the orbit, or raised intraorbital pressure, is often associated with relentless ache and may be due to malignancy, arteritic or sclerosing inflammations (such as Wegener’s granulomatosis), or thyroid orbitopathy. Factors influencing the pain should be elicited: distension of orbital varices give rise to a deep-seated ache after straining or bending forward, whereas the chronic pain of orbital myositis is markedly exacerbated by eye movements that relax (stretch) the affected muscle.

Position of the Globe Proptosis may be first noted by a friend or relative of the patient, and old photographs—preferably in which the patient is not smiling—may help establish the duration of ocular displacement. Progression in the degree of proptosis is relevant: the long globe of unilateral high myopia (refraction and ultrasound are confirmatory) may result in stable pseudoproptosis (Fig. 3–1); likewise, the patient with shallow orbits may have apparent, but unchanging, constitutional exophthalmos. Exophthalmos that increases on Valsalva maneuver—either deliberate or unintentional (as on bending)—is typically associated with distensible venous anomalies (Fig. 3–2). Pulsatile proptosis is due to transmission of either vascular pulsation or changes in cerebrospinal fluid (CSF) pressure, the latter occurs with sphenoid wing hypoplasia (neurofibromatosis), after surgical TABLE 3–1 Principal Orbital Symptoms and Their More Common Causes

Symptom of Orbital Disease Subclasses of Symptom Primary Causation Examples

Pain Deep, aching Inflammation Ocular or orbital inflammation Raised intraocular pressure Acute rise because of vascular shunt Stretching of tissues Distensible varices Sharp pain Corneal erosion Exposure keratopathy Visual loss Permanent Intrinsic optic nerve lesion Optic nerve tumors or infiltration Compressive optic neuropathy Thyroid eye disease or orbital mass Glaucoma Chronic vascular shunt or TED (thyroid eye disease) Exposure keratopathy Proptosis with incomplete lid closure Transient decrease nerve “Kinking” of optic nerve Optic nerve meningioma or large mass perfusion Raised intraorbital pressure “Hydraulic” thyroid eye disease Proptosis True proptosis Increased content, particularly Orbital mass postequatorial Pseudoproptosis Long axial length High myopia Contralateral enophthalmos Contralateral blowout fracture Shallow orbits Racial or cranial syndrome Upper lid retraction Thyroid eye disease Diplopia True binocular diplopia Restriction of globe movement Large orbital mass, or involving globe

Abnormal extraocular muscles Myositis, or thyroid eye disease 3

Entrapped ocular muscles or sheath Blowout fractures

Neurologic deficit Tumor infiltration or apex syndrome Disease Orbital Monocular diplopia Globe distortion causing refractive error Retrobulbar or parabulbar mass Blurring caused by superficial Exposure keratopathy keratopathy

Table continued on following page 61 62 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology:

TABLE 3–1 Principal Orbital Symptoms and Their More Common Causes (Continued)

Symptom of Orbital Disease Subclasses of Symptom Primary Causation Examples

Globe – Anterior mass causing displacement Lacrimal gland tumour displacement Outward bowing of orbital wall Imploding antrum syndrome Eyelid changes Swelling Forward displacement of orbital fat Retrobulbar mass or thyroid eye disease Infiltration of anterior tissues Lymphoma or inflammatory mass Redness Inflammatory vasodilatation Orbital inflammatory disease Retraction or Primary upper lid retraction Levator overaction in thyroid eye disease displacement Secondary upper lid retraction Inferior rectus fibrosis (TED) or inferior rectus tethering (blowout fracture) Lower lid displacement Caused by axial proptosis Contour defect Lid abnormality Eye lid tumors or neurofibroma Immediate postseptal mass Lacrimal gland inflammation or tumor Epiphora Bursts of lacrimation Ocular surface disease Exposure keratopathy Postradiation ocular surface disorders Lacrimal gland disorders Retention dacryoceles (intermittent) Failure of tear drainage Malposition of drainage puncta Proptosis or eyelid distortion Enophthalmos with loss of eyelid contact Nasolacrimal duct block Midfacial fractures or maxillary tumors Lacrimal sac occlusion Tumor of lacrimal sac (very rare) 3 Orbital Disease 63

Figure 3–1 Apparent right proptosis caused by an elongated, highly myopic globe—evident on computed tomography (CT) scan. removal of the orbital roof, or with post-traumatic orbito-cranial fistulae. Acquired arterial pulsation is generally associated with orbital arteriovenous malformations or carotico-cavernous fistulae but is rarely seen in tumors with a significant arterial supply. The direction of globe displacement is an important indication of the position of the lesion(s) within the orbit: posteriorly located masses cause axial proptosis, anterior lesions displace the globe away from the mass (Fig. 3–3). Enophthalmos occurs after blowout fractures of the orbital walls (Fig. 3–4), with scirrhous metastases (such as breast or bronchogenic carcinoma), with venous anomalies, with silent sinus syndrome, and with hemifacial atrophy.

Visual Loss Acute visual loss suggests a vascular cause and, if associated with acute nausea, is often due to orbital hemorrhage; periorbital or subconjunctival bruising may not become evident for several days. Multiple cranial nerve deficits, including sudden blindness, may occur with vaso-obliterative diseases such as mucormycosis and Wegener’s granulomatosis. Slowly growing retrobulbar masses tend 64 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–2 Patient with distensible orbital varices, with an enophthalmic globe showing marked proptosis after Valsalva maneuver.

to cause progressive visual failure because of optic nerve compression—in which case colors fade to give a “washed-out” quality to vision—or because of distortion of the globe causing induced hypermetropia or premature presbyopia (choroidal folds often are evident on funduscopy). Retrobulbar masses that stretch the optic nerve may result in gaze-evoked amaurosis. Regular assessment of visual development is mandatory in all children with periocular or orbital disease and amblyopia is managed actively, in conjunction with medical or surgical intervention. Visual acuity of each eye, ocular balance and movement, and refraction are all monitored and, when there is concern about raised intraocular pressure or adequate examination is not possible, examination under anesthesia should be performed.

Diplopia Loss of ocular muscle balance, with diplopia in many cases, is due to neurologic deficit, diseases of the neuromuscular junction or muscle, or distortion of orbital 3 Orbital Disease 65

30 mm 25 mm

Figure 3–3 Marked horizontal displacement of the left globe caused by sphenoidal wing meningioma.

Figure 3–4 Right enophthalmos and mild hypoglobus because of orbital floor blowout fracture, there is a notable “hollowing” of the right upper lid sulcus. tissues. Symptoms may be intermittent or constant, worse in different positions of gaze, and the images may be displaced horizontally, vertically, or obliquely. Orbital causes of diplopia include thyroid orbitopathy, trauma, and apical disease.

Sensory Disturbance Periorbital sensory loss is uncommon and rarely volunteered by the patient but may aid in localization of the lesion—occurring with orbital inflammation or with malignant infiltration, particularly perineural spread from orbital or periorbital tumors. 66 Neuro-Ophthalmology: Blue Books of Neurology

CLINICAL EXAMINATION FOR ORBITAL DISEASE Clinical signs are unlikely to be missed if a logical sequence of examination is followed.

Visual Functions The best-corrected visual acuity (Snellen or LogMAR chart) and color perception are recorded before pupillary examination. Although Ishihara color plates were designed to assess hereditary dyschromatopsia, their wide availability facilitates detection of subtle degrees of optic neuropathy, and the test speed and number of errors should be recorded. Pupillary reactions are tested last, and the presence of a relative afferent pupillary defect is noted, with a quantitative estimate of severity.

Evidence of a Mass Globe displacement is estimated in all three dimensions. When a manifest ocular deviation is present, the fellow eye should be covered to allow the index eye to take up fixation. Variation in position with arterial pulsation or Valsalva maneuver should also be sought, and the presence of a bruit or palpable thrill is recorded. An aspect of orbital examination, often overlooked, is the estimation of orbital tension—in which resistance of the globe to gentle retropulsion is recorded; this tension often is raised in thyroid orbitopathy. The size, shape, texture, and fixation to underlying structures may provide important clues to the likely pathology for a palpable anterior orbital mass. Tenderness—as, for example, with acute dacryoadenitis—indicates an acute inflammation. A dermoid cyst in the superotemporal quadrant is usually mobile, firm, and nontender, although it may give rise to acute inflammatory symptoms if ruptured or incompletely excised (Fig. 3–5); some dermoid cysts may, however, be tethered with a local periosteal attachment or may extend, through

Figure 3–5 Marked periorbital inflammation secondary to lipid leakage from an occult intraorbital dermoid within the lacrimal gland fossa. 3 Orbital Disease 67

Figure 3–6 Swelling and tenderness of the left upper eyelid caused by expansion of a frontal sinus mucocele. the lateral orbital wall, into the temporalis fossa. Although very rarely because of an anterior encephalocele, a fixed mass in the superomedial quadrant suggests an underlying frontal mucocele in adults (Fig. 3–6) or a dermoid cyst in children. Soft masses presenting with eyelid swelling should be regarded as infiltrative tumors or inflammation until proved otherwise, but in the neonate or young child orbital capillary hemangioma should also be considered and investigation directed accordingly.

Ocular Balance and Ductions Binocular patients should be examined for latent or manifest ocular deviation and the extent of uniocular ductions estimated in the four cardinal directions. Formal orthoptic examination provides valuable quantification when necessary—this includes Hess charting, assessment of field of binocular single vision, and, in rare cases, uniocular duction fields. Globe retraction during active duction, as often observed in chronic myositis, suggests fibrosis of the ipsilateral antagonist muscle. Neurologic and mechanical causes of restricted eye movements may be differentiated, under topical anesthesia, with a forced duction (“traction”) test. 68 Neuro-Ophthalmology: Blue Books of Neurology

Periorbital Signs Eyelid swelling is a common feature of orbital disease and may be due to the actual orbital mass, fat displacement by the mass, or venous congestion resulting from an apical orbital mass. Other eyelid signs include lid retraction, phase lag of the upper lid on slow down-gaze, and incomplete closure (“lagophthalmos”)—all of which are often observed in thyroid orbitopathy (Fig. 3–7). Lid retraction may be primary, resulting from primary levator muscle overaction, or secondary to fibrosis within the inferior rectus—the latter causes excessive co-contraction of the superior rectus and levator muscles. A persistent S-shaped upper lid contour is commonly seen with plexiform neurofibroma and, more rarely, with lacrimal gland infiltrative diseases; a similar, but transient, contour may be seen with dacryoadenitis, often with cutaneous erythema confined within the brow line. Anterior venous anomalies give a blue hue to eyelid skin and xanthomatous lesions may present as a yellow plaque. Episcleral vessels may indicate underlying pathology; fine corkscrew vessels suggest a low-flow dural arteriovenous shunt (Fig. 3–8), whereas marked conjunctival edema (“chemosis”) with large vessels suggests carotico-cavernous fistula. A high-flow fistula or orbital arteriovenous malformation may have a palpable thrill or audible bruit. Embarrassment of venous outflow leads to loss of spontaneous pulsation of the central retinal vein, and the presence or absence of pulsation should be noted in both fundi; this sign is not specific, however, as it is absent in a fifth of normal eyes. Corneal sensation should be checked before instilling drops into the conjunctival sac, and the periocular, cheek, and gum sensation should be assessed for localization of orbital disease along the various branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Examination of the nose and mouth can be contributory to orbital diagnosis: naso-sinus disease, such as lymphoma, carcinoma, or infections, readily spreads into the orbit through the thin bone of the ethmoidal lamina papyracea or the maxillary antral roof (orbital floor). Palatal necrosis may rarely be seen with sino-orbital tumor or infection (such as mucormycosis), and ipsilateral palatal varices (Fig. 3–9) support a putative diagnosis of orbital varices.

Figure 3–7 Marked left upper eyelid retraction caused by asymmetrical thyroid eye disease. 3 Orbital Disease 69

Figure 3–8 Dilated episcleral vasculature caused by a low-flow dural shunt.

Figure 3–9 Extensive palatal vessels in a patient with right hemifacial orbito-maxillary varices. Signs of Intraocular or Systemic Disease The ocular surface and the anterior and posterior segments of the eye should be examined by slit lamp biomicroscopy for tumor or inflammatory masses, vascular changes, iris pathology (such as the Lisch nodules of neurofibromatosis), and 70 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–10 Typical appearance of a slowly progressive subconjunctival lymphoma.

optic disc or retinal vascular anomalies. A “salmon patch” subconjunctival lesion is characteristic of lymphoma (Fig. 3–10). Scleritis presents as an intense, brick red, circumcorneal injection and may occur with severe idiopathic orbital inflammatory disease (such as myositis) or Wegener’s granulomatosis. Intraocular pressure is best measured by applanation tonometry and is typically raised with orbital arterial vascular anomalies (often with marked fluctua- tion during the cardiac cycle) and where there is tethering of a tight inferior rectus in thyroid orbitopathy, which causes a marked pressure rise on attempted up-gaze. Optic disc swelling or atrophy not only results from intrinsic optic nerve disease (such as meningioma, glioma, or infiltration) but also results from chronic orbital inflammation or a compressive orbital mass, especially small lesions jammed in the orbital apex. Cilio-retinal shunt vessels develop with long-standing optic nerve compression as, for example, with optic nerve meningioma. Choroidal folds, occasionally seen without an orbital mass, typically occur at the posterior pole, irrespective of the position of the orbital mass. The regional lymph nodes should be carefully palpated for evidence of enlargement or tenderness, and, in cases of hematologic malignancy, there may be associated splenomegaly. Other signs of systemic diseases that affect the orbit should be sought—such as clubbing (bronchogenic carcinoma) and acropachy or pretibial myxoedema (thyroid orbitopathy).

ANCILLARY TESTS FOR ORBITAL DISEASE Optic nerve function may be further examined, in a quantitative manner, with static (e.g., Humphrey) or kinetic (e.g., Goldmann) perimetry. In patients with orbital disease, hematologic tests are only rarely absolutely diagnostic (Table 3–2). A blood film may reflect orbital inflammation or hematologic malignancy, and serum angiotensin-converting enzyme levels may be elevated with orbital sarcoidosis. With orbital Wegener’s granuloma, antineutrophil cytoplasmic antibody (ANCA) titers are raised in less than a half of affected patients. Most patients with thyroid eye disease demonstrate raised free-T4 or 3 Orbital Disease 71

TABLE 3–2 Systemic Investigations to Be Considered for Various Orbital Conditions

Orbital Condition Tests for Associated Systemic Disease

Thyroid orbitopathy Ultra-sensitive TSH Free T3, Free T4 TSH receptor antibodies Anti-peroxidase antibodies Anti-thyroglobulin antibodies Orbital cellulitis Full blood count Blood cultures (if systemically toxic) (cultures of abscess contents) Orbital inflammatory Full blood count disease Erythrocyte sedimentation rate C-reactive protein Angiotensin-converting enzyme cANCA, pANCA Anti-nuclear antibody and extractable nuclear antigens Anti-double-stranded DNA Rheumatoid factor Ro and La antibodies (Sjo¨gren’s) Syphilis serology Sputum acid fast bacilli, Mantoux test Viral serology (EBV, Coxsackie) Bartonella henselae (cat scratch disease) Antiproteinase-3 Vascular endothelial growth factor Recurrent orbital Full blood count (film) hemorrhages Bleeding time Activated partial thromboplastin time Prothrombin time Thrombin time Fibrinogen Factor VIII Ristocetin Platelet desegregation time Orbital metastatic Carcinoembryonic antigen disease Prostate-specific antigen Vanillylmandelic acid Homovanillic acid

EBV, Epstein-Barr virus; TSH, thyroid-stimulating hormone. free-T3 (with concomitant suppression of thyroid-stimulating hormone [TSH]), but a minority with typical signs of this condition will be euthyroid or even hypothyroid at presentation. Ultrasonography has a higher resolution than CT or MRI and is particularly suited to the detection of intraocular lesions, scleritis, and periocular inflammation (manifest as fluid in the sub-Tenon’s space). Color-coded Doppler B-mode imaging is useful for sizing and assessing flow characteristics of vascular anomalies, such as arteriovenous malformations, low-flow dural shunts, and infantile 72 Neuro-Ophthalmology: Blue Books of Neurology

capillary hemangiomas. A low-flow dural arteriovenous shunt often causes an enlargement of the superior ophthalmic vein, with reversal of flow and the appearance of a detectable arterial wave-form; in contrast, dilation of the vein because of pressure at the orbital apex or superior orbital fissure causes reduced flow in the normal (anteroposterior) direction, without an arterial wave-form. As the orbital and periorbital structures have naturally high radiographic contrast, thin-slice CT is the most effective and economical method for orbital imaging. A single run of axial scans with intravenous contrast (unless contraindicated), with coronal reformatting, is usually adequate both to give a probable diagnosis and to plan subsequent management; contrast is not generally required for orbital fractures and thyroid orbitopathy. Parasagittal reformats along the plane of the vertical recti and optic nerve may provide greater detail of the relationship between orbital pathology and the course of the optic nerve. MRI should be used when detail of the optic nerve or intracerebral tissues is required (especially in areas of high bone content), or when a nonferromagnetic, nonradio-opaque foreign body is present. T1-weighted images identifying anatomical detail and T2-weighted images reflecting water content are useful in assessing inflammation or tumors with high internal vasculature. STIR (short tau inversion recovery) sequences have been used to monitor inflammatory edema in muscles in thyroid orbitopathy, although clinical examination is thought to be as sensitive. Because of the high T1 signal returned from orbital fat, administration of gadolinium-DTPA contrast without the use of fat suppression protocols tends to reduce the clarity of orbital lesions. Although various orbital structures give typical imaging, the signal characteristics are not specific enough to be able to differentiate inflammatory processes from tumors. Magnetic resonance angiography (MRA) demonstrates vascular flow in most orbital masses, although selective internal and external carotid contrast arteriography remains important in the exclusion of small aneurysms and low-flow dural arteriovenous fistulae and in the investigation of pulsatile proptosis not explained by other imaging modalities. MRA is also useful in the planning for surgery or preoperative embolization of high-flow tumors, such as hemangiopericytoma. Positron emission tomography (PET) and single photon emission CT (SPECT) do not yet play a significant role in orbital imaging but are currently used for staging some patients with non-small cell carcinoma of the lung, malignant melanoma, Hodgkin’s or non-Hodgkin’s lymphoma, colorectal carcinoma, or malignancies of the head and neck. PET scanning using fluorine-labeled deoxyglucose radiotracer has proved as reliable as conventional scanning for identifying primary or metastatic tumors and is superior to clinical examination (or other imaging) for detecting nodal metastases; unfortunately, the imaging technique presently lacks anatomic detail. A major current role, particularly in patients with lymphoma, is in the differentiation of tumor from fibrous tissue after radiotherapy. Following the discovery of somatostatin receptors on the activated lymphocytes associated with thyroid orbitopathy, radiolabeled octreotide (a somatostatin analogue) has been used as a semiobjective tool in the evaluation of the disease activity in this condition. The test is, however, extremely expensive and its use limited to a few research centers. Tissue biopsy is the gold standard for investigating most orbital infiltrative disease. With the exception of typical scleritis, myositis, or orbital apex syndrome, 3 Orbital Disease 73

the practice of initiating oral steroid treatment before orbital biopsy is likely to mislead the clinician and possibly jeopardize the patient’s health or life. As histologic diagnosis depends largely on structure—rather than just cell type—open biopsy provides the greatest diagnostic accuracy; in collaboration with an experienced cytologist, however, fine needle aspiration biopsy of anterior orbital lesions may have a role in the confirmation of a metastasis when there is known systemic malignancy. Postequatorial lesions are more safely and accurately accessed by open biopsy and enable a greater amount of biopsy material to be obtained for histologic analysis.

Common Orbital Diseases

The incidence of orbital disease is rare, the majority accounted for by thyroid eye disease. Knowledge of common orbital disease is, however, valuable because some will present to the neurologist with subtle orbital signs associated with periorbital pain or headache.

BENIGN ORBITAL DISEASES There is a wide spectrum of benign disease, from discrete developmental lesions—such as dermoid and epidermoid cysts (6% to 37% of benign lesions) or capillary hemangiomas (8% to 13%)—to inflammatory processes (especially thyroid eye disease or infections) or trauma (about 7% in some series). Tumors of the optic nerve within the orbit, either glioma or meningioma, are related to the management of their intracranial components and are not discussed here.

Structural Lesions of the Orbit and Paranasal Sinuses Epithelial cysts arise from squamous, conjunctival, or respiratory epithelia sequestered in the orbit along lines of fusion during embryologic development, by implantation after trauma, or from intraorbital expansion of the epithelial- lined paranasal sinuses. Superficial dermoid or epidermoid cysts commonly present in infancy, usually lie in the superotemporal quadrant (associated with the zygomatico-frontal suture; Fig. 3–11) but are sometimes located superonasally. Accumulation of desquamated epithelium, sebum, and hairs causes a slow enlargement of the cyst, and leakage of the contents may cause inflammation of the surrounding tissues—evident histologically in many cases; deep orbital cysts may be asymptomatic until inflammatory episodes occur in adulthood. Occasionally, a dermoid cyst communicates with the skin surface and presents as a chronically inflamed and discharging sinus (Fig. 3–12). Implantation cysts may behave in a similar fashion to congenital lesions but tend to occur at sites of previous periocular trauma. Dermoid cysts generally have a thin radio-opaque wall, which has ill-defined thickening when inflamed and a radiolucent center—the latter markedly so when filled with sebaceous oil rather than keratin. Bone scalloping, with intact cortex, resulting from pressure is commonly seen on CT and the dermoid cyst will, in many cases, extend up to or through clefts in the bone. Characteristic lesions presenting in childhood do not require radiologic 74 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–11 Right superotemporal dermoid attached to the zygomatico-frontal suture.

Figure 3–12 Small cutaneous sinus, containing hair follicles, in the upper lid—this sinus communicates with an anterior orbital dermoid.

investigation. All dermoid cysts should be excised intact, before inflammatory adhesions impair the function of surrounding orbital structures and complicate their surgical excision. Dermolipomas, although not cystic, also arise from dermis (epithelium and sub- dermal fat) sequestered on the surface of the globe—typically overlying temporal sclera (Fig. 3–13)—and occasionally are associated with Goldenhar’s syndrome. The abnormal epithelium may bear hairs and sebaceous glands that cause chronic conjunctivitis. Prolapsed subconjunctival fat, in which the conjunctiva is normal, usually occurs in obese adults and is the main differential diagnosis. If unsightly, or causing significant ocular irritation, the abnormal epithelium and associated fat should be excised by an experienced surgeon; injudicious excision of lesions 3 Orbital Disease 75

Figure 3–13 Hairy dermolipoma overlying the lateral sclera of the right eye; the hairs and squamous epithelium of the lesion tend to cause ocular irritation and discharge. in the superotemporal conjunctival fornix can be associated with major morbidity, such as dry eye or diplopia. Retention mucoceles most commonly arise from the ethmoidal and frontal paranasal sinuses and may expand into the orbit, causing slowly progressive proptosis or episodes of eyelid and orbital inflammation (Fig. 3–14). Maxillary sinus mucoceles may lead to collapse of the orbital floor and secondary enophthalmos, and retention mucoceles of the sphenoidal sinus may present with chronic headaches and visual failure, the latter because of the proximity with the optic canals. On CT, sinus mucoceles appear as a cystic cavity smoothly expanding and thinning the bones of the affected sinus and filled with moderately radio-opaque, often homogeneous, material; MRI appearances vary considerably because of changes in the mucus and water content of the mucocele. Management depends on the presentation: a severe acute sinusitis or orbital cellulitis requires intravenous antibiotics and surgical drainage if there is a threat to vision. Definitive ear-nose-throat (ENT) management is required once the acute phase has passed and may involve enhancing sinus drainage or removal of the mucosal lining of the affected sinuses. An infected mucocele may be complicated by orbital abscess formation, irreversible visual loss because of raised intraorbital pressure, or transcutaneous fistula. Microphthalmos with cyst arises from incomplete closure of the fissure in the optic vesicle, with the cyst sited below, or as part of, a microphthalmic globe (Fig. 3–15). Cysts show considerable variation between infants and typically grow slowly, with secondary expansion of the orbital bones; such cysts should be removed, often with the globe itself, before excessive orbital expansion occurs. Cephaloceles, which may be associated with neurofibromatosis, comprise a congenital herniation of intracranial contents through a skull defect and may contain meninges (meningoceles), cerebral tissue (encephaloceles), or both (meningoen- cephaloceles); anterior cephaloceles tend to lie in the paranasal region (Fig. 3–16) and impair lacrimal drainage, whereas posterior ones tend to occupy the midline. 76 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–14 Lateral displacement of the left globe caused by a large ethmoidal mucocele, a well-defined lesion associated with smooth expansion of the ethmoidal skeleton. CT delineates the bone defects associated with these anomalies, the treatment of which is neurosurgical and ophthalmic.

Vascular Anomalies of the Orbit Orbital capillary hemangioma, affecting 1% to 2% of infants, is the commonest vascular anomaly in childhood and is more prevalent in girls or in children of low birth weight. They may arise from tissue of placental origin and usually present as variable eyelid swelling within a few months of birth, the lesion shows growth for about 6 to 12 months before typically undergoing spontaneous decay, often with superimposed growth cycles that may occur over several years before eventual regression. Predominantly intradermal lesions are bright red and dimpled (so-called strawberry nevus), whereas the deeper orbital lesions have a blue coloration and spongy texture; both may increase slightly in size with crying or straining; larger hemangiomas may cause amblyopia because of mechanical ptosis or astigmatism. Doppler ultrasonography reveals numerous vessels with very high blood velocity (up to 1 m/sec) of arterial wave-form; this characteristic is useful in 3 Orbital Disease 77

Figure 3–15 Large cyst associated with a microphthalmic eye.

Figure 3–16 Infant with bilateral lacrimal drainage obstruction because of paranasal anterior encephaloceles. differentiating them from malignant rhabdomyosarcoma, which have a similarly rapid growth pattern in infancy. Management involves ophthalmic monitoring for amblyopia, refraction when old enough to wear spectacles, and intervention when there is a significant threat to visual development; intralesional or systemic steroids slow the growth of capillary hemangiomas and large lesions not involving the skin may occasionally be considered for surgical excision. Low-flow vascular lesions, such as varices or lymphangiomas, are probably developmental anomalies that only become evident in early adulthood. They are usually unilateral, may involve the orbit, face, and brain, and are typically composed of an admixture of venous channels, with (varices) or without (lym- phangioma) intravascular blood. The variceal component may have a variable degree of communication with the systemic circulation—leading, in some cases, 78 Neuro-Ophthalmology: Blue Books of Neurology

to saccular anomalies that are distensible on Valsalva maneuver (Fig. 3–2)— whereas lymphangiomas tend to show a greater cellular inflammatory infiltrate. Varices present with spontaneous painful hemorrhage in childhood that may be associated with marked vomiting or, in young adults, as an orbital ache with increasing tendency to painful proptosis on bending or straining. CT may show an enlarged orbit containing a serpiginous lesion (with calcified phleboliths in some) among otherwise normal orbital structures (Fig. 3–17). Lymphangiomas often manifest in the first decade with cystic lesions of the lid margin and conjunctiva, with globe displacement because of retrobulbar masses or with spontaneous hemorrhage (so-called chocolate cysts); the increase in size during respiratory tract infections may be due to lymphoid hypertrophy or vascular congestion. Imaging (CT or ultrasonography) may show an ill-defined mass with cystic spaces, sometimes with fluid levels (when hemorrhage has occurred) among the structures of an expanded orbit. Blood flow through these lesions is minimal. Drainage of a hemorrhage may be required when it causes optic neuropathy, and resection of large lymphangiomas may be indicated for aesthetic reasons, although amblyopia is common with large lymphangiomas, despite all efforts to maintain normal visual development. The commonest benign orbital mass in adults is cavernous hemangioma. Usu- ally lying in the retrobulbar space, they generally present in middle age with slowly progressive, painless axial proptosis, reduced extremes of eye movement, induced presbyopia, and choroidal folds or optic disc swelling. Cavernous hemangiomas may rarely be associated with persistent retrobulbar headaches, and small cavernous hemangiomas, wedged in the orbital apex, typically cause early and severe compressive optic neuropathy. They appear as a well-defined, ovoid intraconal lesion on imaging—often with optic nerve displacement—and show patchy contrast enhancement because of a very slow blood flow (Fig. 3–18); on MRI, the mass is hypointense to fat on T1-weighted images and isointense to vitreous and hyperintense to fat on T2 sequences. Although asymptomatic lesions may be

Figure 3–17 Abnormal ipsilateral ethmoidal and maxillary sinuses in association with an expanded orbit because of extensive intraorbital varices. 3 Orbital Disease 79

Figure 3–18 Intraconal cavernous hemangioma showing patchy contrast enhancement on computed tomography (CT). stable for many years, surgical removal should be undertaken when optic neuropathy, increasing proptosis, or diplopia is present (Fig. 3–19). High-pressure arteriovenous communications, either in the orbit or the anterior part of the intracranial circulation, may lead to pulsatile proptosis and orbital congestion because of raised venous pressure, the latter causes restriction of eye movements, optic disc congestion, conjunctival edema (“chemosis”), and raised intraocular pressure. Characteristic imaging includes mild proptosis with slightly enlarged extraocular muscles, widespread engorgement of orbital vessels, and, in some cases, slight enlargement of the ipsilateral cavernous sinus; orbital ultrasonography may demonstrate arterial waveforms within veins, with a reversal of flow (normally posteriorly directed) within the superior ophthalmic vein. Intra- orbital arteriovenous malformations are very rare, occur spontaneously or as a result of injury, and are commonly supplied by branches of both the internal or external carotid arteries. Management options include superselective embolization of supplying branches from the internal and external carotid arterial terri- tories or placement of thrombogenic coils within the orbital venous circulation (via the dilated superior ophthalmic vein). Dural shunts commonly present with persistence of a “red eye” of sudden onset (Fig. 3–8) and are due to a spontaneous fistula between a minor dural vessel and the cavernous venous sinus; most resolve spontaneously over a year, but ophthalmic care may be required for raised intraocular pressures. Arteriography (with occlusion of the shunt) is indicated in the presence of significant optic neuropathy or severe proptosis. Carotico-cavernous fistulae are high-pressure, high-flow communications that present with acute proptosis, lid swelling, and engorged episcleral vessels with chemosis and raised intraocular pressure; retinal hemorrhages, ocular ischemia, and third, fourth and sixth cranial nerve palsies may also occur. Such high-flow fistulae may occur spontaneously in atheromatous individuals, with intracavernous rupture of the internal carotid 80 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–19 Cavernous hemangioma during surgical removal from the intraconal orbital space, and a typical lesion after intact excision.

siphon, or may arise after severe head injury (Fig. 3–20). Imaging shows a more extreme version of the changes seen with low-flow dural shunts, and radiologically guided balloon occlusion of the fistula is effective in most cases, with low morbidity.

Inflammatory Diseases of the Orbit Acute or chronic inflammation may affect almost any orbital tissue and may be associated with systemic diseases, such as sarcoidosis, Sjo¨gren’s syndrome, Wegener’s granulomatosis, or rheumatoid arthritis. The commonest orbital condition—thyroid eye disease—is characterized by chronic inflammation of orbital fat and muscles with autoimmune thyroid gland disease (generally thyrotoxicosis). 3 Orbital Disease 81

Figure 3–20 Gross conjunctival chemosis and restriction of eye movements because of an atheromatous carotico-cavernous fistula.

Young women are typically affected by idiopathic orbital myositis, which presents with a severe prodromal retrobulbar ache before the onset of diplopia and limitation of eye movement. The pain is worse with stretching of the affected muscle(s), and slight ocular redness and episcleral edema are not uncommon. CT shows affected muscles to be enlarged along their entire length (Fig. 3–21), unlike the more localized, posterior muscular engorgement with thyroid eye disease. Treatment is with high-dose prednisolone (1 mg/kg/day). This provides almost immediate relief of pain and rapid improvement of eye movements, and the dosage is tapered down to 20 mg/day over a few days; steroid reduction below this dosage should be slower and the patient considered for steroid-sparing therapy or low-dose orbital radiotherapy if symptoms recur with reduction in treatment. Acute dacryoadenitis presents as headache, followed shortly by variable swelling and erythema of the upper lid and later with red eye or diplopia. The affected lacrimal gland may be palpable in the superotemporal quadrant and is generally exquisitely tender. In contrast, chronic dacryoadenitis is usually painless and may be associated with a nontender mass with dry eye (and dry mouth in Sjo¨gren’s syndrome) (Fig. 3–22). Imaging shows an enlarged gland, often bilateral and asymmetrical in sarcoidosis or other systemic conditions, that tends to mold to the globe and does not destroy bone; acute severe inflammation also will demonstrate spillage of changes into the preseptal upper lid tissues and overlying the temporalis fossa (Fig. 3–23). Acute dacryoadenitis should be treated with nonsteroidal anti-inflammatory drugs, with a rapid improvement of symptoms; failure to settle should raise a suspicion of underlying infection or some other source of inflammatory stimulus, such as a neighboring leaking dermoid or tumor. Any lacrimal mass persisting for more than 3 months should be regarded as possible malignancy and investigated with CT, with a view to incisional or excisional biopsy of the mass. With the exception of characteristic orbital apex syndrome, all patients with diffuse idiopathic inflammation of the orbit should undergo biopsy because the imaging changes are nonspecific and very similar to those seen with infective inflammation, lymphoma, or carcinoma. Inflammation is a tissue response and 82 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–21 Localized vascular dilatation and swelling overlying the lateral rectus muscle in a patient with idiopathic orbital myositis. Computed tomography (CT), for another patient, shows a uniform expansion of the left medial rectus; the expansion extending into the parabulbar muscle tendon unlike the muscular enlargement of thyroid eye disease.

not a diagnosis and may arise with many orbital diseases—for example, quite commonly with lacrimal gland malignancy. The term pseudotumor should be abandoned in favor of “idiopathic inflammatory disease,” the term idiopathic, which constantly reminds the clinician to search for an underlying cause for the inflammation. Likewise, the use of a trial of systemic steroids (with the exception of myositis, orbital apex inflammation, or thyroid eye disease) should be discontinued because almost all orbital processes—but especially hematologic malignancies, low-grade infections, and tumor-induced inflammation—show a gratifying response to this treatment modality.

Thyroid Eye Disease Thyroid eye disease is the most common adult cause of unilateral or bilateral proptosis. With an approximately sixfold female predominance, it commonly presents in the third and fourth decades with irritable and watering eyes, ocular redness, upper lid retraction, and puffiness of the lids (especially in the mornings); restriction of eye movements, with diplopia, and proptosis or optic 3 Orbital Disease 83

Figure 3–22 Bilateral chronic dacryoadenitis because of Sjo¨gren’s syndrome, with enlargement of the left lacrimal gland from secondary lymphoma.

Figure 3–23 Smooth enlargement of the left lacrimal gland, with molding around the globe because of mild dacryoadenitis. neuropathy are later manifestations of more severe disease. Both the eye and the vision may be jeopardized by corneal exposure (because of the incomplete blink cycle and incomplete lid closure), by gross proptosis, by uncontrolled ocular hypertension, or by optic nerve compression. Eye symptoms and signs (Table 3–3) occur in up to 40% of patients with hyperthyroidism (Graves’ disease) but in only a small minority of patients with Hashimoto’s thyroiditis or primary myxedema; the high incidence in Graves’ disease suggests a shared antigen between the thyroid and orbit; the prime candi- date is the TSH receptor. Circulating activated T lymphocytes infiltrate orbital tissues and release proinflammatory mediators, causing fibroblast activation and glycosaminoglycan (GAG) deposition, and this cellular infiltration and tissue edema results in proptosis because of expansion of orbital tissues during the active, inflammatory (“wet”) phase. With resolution of the inflammation, 84 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 3–3 Common Characteristics of Thyroid Eye Disease and Main Contributory Mechanisms

Clinical Feature of Thyroid Eye Disease Mechanisms

Irritable, watering, and Corneal drying caused by incomplete blink cycle and lid chronically red eyes closure Increased tear evaporation caused by eyelid retraction Poor lacrimal drainage because of punctal malposition Episcleral vascular engorgement Upper eyelid retraction Primary overaction of levator muscle and Mu¨ ller’s muscle Levator muscle overaction secondary to inferior rectus restriction Incomplete eyelid closure Moderate or marked proptosis with primary upper lid retraction Lid swelling, redness, Autoimmune orbital inflammation and inflammation Inflammation because of corneal and conjunctival exposure Proptosis Increased retrobulbar tissues (inflammatory infiltrate and, later in the disease, glycosaminoglycan deposition) Binocular diplopia Restriction of muscular relaxation resulting from congestion during active inflammatory phase and fibrosis during inactive disease Visual impairment Blurring of vision caused by corneal surface disease Optic neuropathy caused by optic nerve compression Visual field loss caused by chronic secondary glaucoma Raised intraocular Congestion of episcleral vascular outflow because of high pressure orbital pressure Compression of globe during upgaze because of tight inferior recti Retrobulbar ache Active orbital inflammation Chronically raised intraorbital pressure Subluxation of globe Eyelid retraction in the presence of marked proptosis

subsequent fibrosis of perimysial connective tissue during the inactive (“dry”) phase leads to muscular scarring and restriction of eye movements; unfortunately the accumulation of GAGs—and proptosis because of this tissue deposition—is largely irreversible. CT generally reveals bilateral enlargement of one or more extraocular muscles, with the inferior and medial recti are affected most often (Table 3–4); enlargement of the oblique muscles is distinctly rare. Other features include increased orbital fat, which often shows a “streaky” opacity, and outward bowing of the thin orbital walls with long-standing disease (Fig. 3–24). Optic neuropathy is associated with orbital apex crowding and less proptosis (rather than elongation of the optic nerve), and the posterior part of the medial rectus is often disproportionately enlarged (Fig. 3–25). Imaging is particularly important with unilateral disease (lymphoma or reactive lymphoid hyperplasia may masquerade as unilateral thyroid eye disease) and to exclude underlying sinus disease or craniofacial anomalies in patients being 3 Orbital Disease 85

TABLE 3–4 Orbital Computed Tomography (CT) Changes Commonly Seen in Patients with Thyroid Eye Disease

Orbital Tissue Changes Within Affected Tissue

Extraocular Enlargement, typically sparing the tendinous insertion muscles Most commonly affecting inferior and medial rectus Orbital apex crowding associated with optic neuropathy Orbital fat Increased quantity of fat, often prolapsing into upper and lower eyelids Diffuse “streakiness” and vascularity, especially during active inflammation Intracranial bulging of fat pad at superior orbital fissure, with high orbital pressure Orbital walls Outward bowing of the lamina papyracea with chronic muscle enlargement “Coca-Cola bottle” sign—configuration of the nasoethmoidal complex Lacrimal gland Commonly displaced anterior to the orbital rim with chronic proptosis Optic nerve Course of optic nerve becomes straighter with increasing proptosis Fixation of optic nerve and flattening of the globe creates the “Y” sign with grossly increased intraorbital pressures Superior Superior ophthalmic vein may be markedly enlarged with ophthalmic intraorbital vascular congestion, but cavernous sinus of normal vein size (distinguishing from dural shunts)

Figure 3–24 Chronic bilateral thyroid eye disease, with enlargement of the posterior half of multiple muscles, is associated with outward bowing of the ethmoidal lamina papyracea, which produces a “Coca-Cola bottle” configuration of the ethmoidal complex. 86 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–25 Orbital apex crowding in a patient with bilateral compressive optic neuropathy in thyroid eye disease.

considered for orbital decompression. MRI scanning, particularly STIR sequences, identifies inflammatory edema in the extraocular muscles, but the investigation is expensive and contributes little to clinical findings. Although most patients with thyroid eye disease have abnormal thyroid function, some appear to remain biochemically euthyroid and the only detectable abnormality may be raised serum levels of thyroid autoantibodies. Treatment of Graves’ thyrotoxicosis tends to improve eye signs, although medically induced under activity may also exacerbate ophthalmopathy and should be avoided by regular blood tests. Radioiodine treatment will cause a flare-up of ophthalmopathy in a minority, and this is best avoided by early thyroxine replacement. Smoking should be discouraged, as this carries a markedly (about sevenfold) greater risk of significant ophthalmopathy. There are several scales for assessing the activity of thyroid eye disease, but most patients have only mild symptoms and signs requiring, for example, ocular lubricants and sunglasses during control of their thyroid function; should upper lid retraction or incomplete lid closure persist, this can be dealt with surgically when eye signs are stable. When a patient has diplopia, increasing eyelid swelling, or proptosis, systemic immunosuppression should be instituted early in the active phase—before irreversible GAG deposition and fibrosis—and an objective deterioration in visual function, or a threat of corneal ulceration, is an indication for urgent ophthalmic intervention. Systemic immunosuppression, to reduce the degree of inflammation and secondary orbital congestion, is most likely to benefit patients with clear signs of clinical activity, or with muscular inflammatory edema shown on STIR-sequence MRI. High-dose systemic steroids (either intravenous methyl prednisolone [typically 1 g/day] or oral prednisolone [about 80 mg/day]) are given and the patient monitored for improvement over the first week: When there is a subjective and objective improvement, the steroid dosage is tapered gradually to 20 mg daily while the patient is referred for low- dose (2000 to 2400 cGy) lens-sparing radiotherapy to the posterior tissues of the orbit; such radiotherapy may, however, be contraindicated in diabetics because of the risk of exacerbating retinopathy. Steroids can normally be tailed off over about 6 to 8 weeks after completion of orbital radiotherapy. Gastric pro- tection and control of hyperglycemia or hypertension should be instituted as 3 Orbital Disease 87

necessary, and any patient on steroids for more than a few weeks should also have bone prophylaxis. Surgical rehabilitation should be considered when eye disease has been inactive for some months and eye signs are stable. Aesthetic orbital decompression usually involves removal of a combination of the lateral, medial, and inferior walls of the orbit, nowadays performed through a minimal incision (Fig. 3–26). Relief of optic neuropathy necessitates removal of the medial wall; floor removal adds significantly to reduction in proptosis, and lateral wall fenestration corrects prolapse of the lacrimal gland prolapse and counteracts the tendency to convergent squint after medial decompression. Orbital fat excision is associated with a rather unpredictable, and often poor, reduction in proptosis. Incorporation of a prism into glasses, or strabismus surgery, can be beneficial with troublesome squint or diplopia, and persistent upper eyelid retraction is managed by weakening the levator muscle (Fig. 3–27). Acute surgical intervention (before the disease is inactive) may be necessary as an adjunct to medical therapy when there is severe conjunctival prolapse preventing eye closure or threatened corneal perforation—this is treated by padding the eye closed for a few days—or when there is extremely severe proptosis causing persistent globe prolapse or corneal melting, in which

Figure 3–26 Right-sided orbital decompression for thyroid eye disease; the 11-mm reduction in proptosis is achievable through a small external incision at the outer canthus. 88 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–27 Patient after surgical correction of marked right upper retraction—the preoperative level is the same as that of the unoperated left side.

maximal decompression may be indicated. Acute orbital decompression is indicated if, despite high-dose systemic steroids, visual function deteriorates.

Orbital Osseous Disease There are many benign lesions of periorbital bone; most of these are very rare and cured by surgical excision. One tumor, meningioma of the greater wing of the sphenoid, is relatively common and may lead to proptosis, eyelid swelling, and progressive visual impairment; this visual loss is manifest as impaired color perception, a decreas- ing acuity, and loss of visual field sensitivity. Sphenoid wing meningioma, commonest in women in the fifth and sixth decades, is associated with hyperostosis of the sphenoid wing and soft tissue tumor extending into the lateral part of the orbit, the temporalis muscle fossa, or the anterior pole of the middle cranial fossa (Fig. 3–3). The tumor is probably driven by progestogens and affected patients should avoid progesterone-base hormone replacements. Surgical resection of these tumors is a major neurosurgical procedure, is incomplete in many cases (because of en-plaque involvement of the dura), and carries a significant risk of visual loss; there is also a belief that surgical manipulation of meningiomas may accelerate their growth pattern. Relief of progressive optic neuropathy may, however, be provided by medial orbital decompression; this may relieve compression of the optic nerve but not disturb the tumor itself. Radiotherapy is probably of benefit in slowing growth of meningiomas, but the high dosage required is likely to lead to later blindness from radiation optic neuropathy.

MALIGNANT ORBITAL DISEASES Primary and secondary orbital malignancy is rare, occurs at any age, and must be considered whenever there is a rapidly or relentlessly progressive disease, an inflammatory picture, or when an apparently benign disease displays atypical behavior. 3 Orbital Disease 89

Orbital Malignancy in Children and Young Adults The rare and aggressive malignancies of rhabdomyosarcoma and neuroblastoma typically present in children younger than 10 years, acute hematologic malignancies within the first 2 decades, and primary lacrimal gland malignancy has a peak incidence in the fourth decade. Rhabdomyosarcoma arises from pluripotent mesenchyme that normally dif- ferentiates into striated muscle cells and comprises three variants—embryonal (the commonest), alveolar (with the worst prognosis), and pleomorphic (best prognosis) forms. Rhabdomyosarcoma is the commonest primary orbital malignancy of childhood, with a peak incidence at age 7, and usually presents with a few weeks of proptosis and mild inflammation (Fig. 3–28). Imaging typically shows a well-defined, moderately contrast enhancing orbital mass that displaces orbital structures, flattens the globe, and does not arise from extraocular muscles (Fig. 3–29). Rhabdomyosarcomas require urgent biopsy, at which time the tumor can often be resected macroscopically and evaluation performed for systemic disease with whole-body CT scan and bone marrow biopsy. Adjuvant multiple drug

Figure 3–28 Child with rhabdomyosarcoma with symptoms and signs of inflammation and swelling for only 6 weeks.

Figure 3–29 Well-defined, rapidly growing mass of rhabdomyosarcoma—this tumor generally pushes neighboring orbital structures aside and does not arise from extraocular musculature. 90 Neuro-Ophthalmology: Blue Books of Neurology

chemotherapy, with or without orbital radiotherapy, has improved the 5-year survival for these tumors to greater than 90%; local resection of residual tumor or orbital exenteration may rarely be indicated. Complications of orbital radiotherapy include cataract; dry eye with secondary corneal scarring; loss of adnexal appendages (lashes and brow hair) orbital fat atrophy; and, in infants, impairment of orbital growth. Neuroblastoma presents in a similar way to rhabdomyosarcoma, with rapidly progressive metastasis within the orbital soft tissues or bone. Likewise, acute myeloid leukemia may also present with rapidly progressive orbital inflammatory signs, and Langerhans’ cell histiocytosis—typically eosinophilic granuloma within the orbital bones—can present with a relatively short history of proptosis or eyelid swelling. All of these lesions, once confirmed by biopsy, require timely systemic investigation and treatment with chemotherapy and/or radiotherapy. Overall prognosis depends, among other factors, on the extent of disease at the time of presentation. Features suggestive of lacrimal gland carcinoma include upper lid inflammation and swelling, progressive ocular displacement over a few months, and a nontender mass in the lacrimal gland fossa (Fig. 3–30); this picture may be shared by acute dacryoadenitis (although usually a tender mass) and malignancy should be considered wherever a subacute dacryoadenitis fails to resolve after a few weeks of anti-inflammatory drugs. Adenoid cystic carcinoma, the commonest lacrimal malignancy, accounts for about one third of all epithelial tumors and has a peak incidence in the fourth decade. Rarer carcinomas include primary adenocarcinoma, mucoepidermoid carcinoma, squamous carcinoma, and malignant mixed tumors, the last arising within a pre-existing pleomorphic adenoma. CT typically shows an enlarged lacrimal gland molding around the globe, extending posteriorly along the lateral orbital wall, and displacing the lateral rectus medially (Fig. 3–31), with more advanced cases showing erosion of cortical bone in the lacrimal gland fossa and flecks of tumor calcification. The nature of a persistent lacrimal gland mass should be determined by incisional biopsy, although it is imperative that benign pleomorphic adenomas are excised intact—incisional biopsy of these benign tumors risks late pervasive

Figure 3–30 Adenoid cystic carcinoma of the right lacrimal gland, presenting with a few month’s history of eyelid swelling, red eye, and chronic periocular ache. 3 Orbital Disease 91

Figure 3–31 Lacrimal gland carcinoma, showing flecks of calcification, molding around the right globe, and extending back along the lateral orbital wall and through the superior orbital fissure. recurrence, in some cases malignant. Definitive treatment for lacrimal gland carcinoma remains controversial, as recurrence of adenoid cystic carcinoma may occur after a long latency; current advice is tumor debulking (which may even be complete) and external beam irradiation of both the orbit and ipsilateral cavernous sinus. Implantation brachytherapy has been advocated as delivering a globe-sparing, high-radiation dosage to the lacrimal gland fossa, but this approach fails to treat the cavernous sinus or pterygopalatine fossa, which is commonly affected by perineural invasion. Although intracarotid chemotherapy may have a role as an adjunct to radiotherapy in advanced disease, there is no reliable evidence to suggest that the disfigurement of either exenteration or “super- exenteration” (with removal of the neighboring orbital bones) leads to a reduced tumor recurrence or improved survival. Sadly, most patients with adenoid cystic carcinoma will eventually suffer a painful and relentlessly progressive recurrence of the disease, either locally or with pulmonary metastasis.

Adult Orbital Malignancy Orbital malignancy presenting in adulthood tends to be secondary to systemic disease or arises by direct spread from the neighboring paranasal sinuses or intraocular tumors. Lymphoproliferative lesions show a spectrum of disease, from benign histology with well-organized follicular pattern (reactive lymphoid hyperplasia) to frank malignant lymphoma, and diagnosis of these lesions has improved greatly with immunohistochemical stains for lymphocytes and their precursors. Orbital lymphomas—effectively all B-cell non-Hodgkin’s lymphomas—account for about 10% of all orbital masses and generally present in patients aged older than 50 years as a slow-growing orbital mass causing eyelid swelling, proptosis, or diplopia; a pink subconjunctival mass will often be evident, providing an ideal site for biopsy (Fig. 3–10). Younger patients tend to develop more aggressive lymphomas; these often arise in the paranasal sinuses and secondarily invade 92 Neuro-Ophthalmology: Blue Books of Neurology

Figure 3–32 Proptosis and patchy infiltration of fat caused by bilateral orbital lymphoma; the tumor does not cause marked displacement of orbital structures or disruption of orbit functions.

the orbit. CT identifies a moderately well-defined soft tissue mass, pervading multiple tissues, molding to the globe, but usually without any widespread disruption of intraorbital structure or invasion of bone (Fig. 3–32); calcification is extraordinarily rare in lymphomas. All pervasive orbital masses should be biopsied and, if shown to be lymphoma, the patient should undergo investigation for systemic disease. If purely orbital disease exists, this tends to respond well to fractionated radiotherapy (24 to 35 cGy, dependent on the variant), whereas systemic involvement generally requires chemotherapy and, in some cases, adjunctive orbital radiotherapy. Although the visual prognosis is very good, the overall morbidity and mortality is variable, with systemic lymphoma becoming evident several years after the presentation of isolated orbital disease. In contrast to childhood, metastasis from systemic malignancy favors the uveal tract in adults, and metastatic disease represents only 2% to 3% of all orbital tumors in adulthood. Nevertheless, orbital signs are occasionally the first manifestation of an occult primary tumor; the commonest sites of origin are breast, prostate, lung, kidney, and gastrointestinal tract. Orbital metastases may present with painful proptosis and diplopia; these signs potentially mimic orbital inflammation or abscess (Fig. 3–33). Fractionated local radiotherapy is the mainstay of treatment, although, in certain cases, there may be a role for surgical debulking. Secondary orbital infiltration may occur from any of the neighboring structures, such as the eyelids or paranasal sinuses, or from the globe. Meibomian gland (sebaceous cell) carcinomas of the eyelid—or neglected basal cell and squamous carcinomas—tend to invade the orbit and cause diplopia because of mechanical restriction of eye movements. Perineural invasion, commonest with squamous carcinoma of the forehead, generally occurs along branches of the frontal nerve and is often associated with pain. Sebaceous carcinoma of the lid has a propensity for intraepithelial (Pagetoid) spread and, by this means, an apparently localized eyelid mass may involve the whole ocular surface and necessitate orbital exenteration. Squamous carcinoma is the commonest sinus malignancy to invade 3 Orbital Disease 93

Figure 3–33 Orbital cellulitis because of necrosis within a carcinomatous metastasis; the patient had undergone sinus exploration prior to referral. the orbit, generally by direct destruction of the intervening bone and periorbita, and, as this represents advanced disease, the prognosis tends to be poor. Manage- ment often involves diagnostic biopsy and later wide surgical clearance (including exenteration if there is direct orbital involvement) with radiotherapy. Other rare paranasal tumors that invade the orbit include adenocarcinoma, adenoid cystic carcinoma, esthesioneuroblastoma, and melanoma. Primary uveal melanoma is the commonest intraocular tumor of adulthood and may spread directly to the orbit through scleral emissary veins or, very rarely with more aggressive tumors, by direct invasion of the sclera or optic nerve. Uveal melanoma with orbital extension is treated with fractionated radiotherapy but carries a poor prognosis because there is often concurrent systemic disease. Other adulthood orbital malignancies are exceptionally rare: Malignant neuri- lemmoma may arise de novo or be associated with neurofibromatosis and management (after confirmatory biopsy) involves wide surgical clearance and possibly adjunctive radiotherapy or chemotherapy. Orbital hemangiopericytoma has a spectrum of invasiveness; the more benign lesions are cured by intact excision and the more malignant and pervasive tumors require wide clearance with orbital exenteration, although local or remote recurrence is common with malignant hemangiopericytoma. 4 Transient Monocular Visual Loss VALE´RIE BIOUSSE

Mechanisms of TMVL Diagnosis TMVL Caused by Ocular History Conditions (Other Than Ophthalmic Examination Arterial Diseases) Ancillary Studies TMVL Caused by Vascular Arterial Ischemia Treatment Carotid Endarterectomy Natural History of TMVL Other Measures Retinal Stroke Cerebral Hemispheric Stroke References Death

Key Points TMVL has numerous causes but most often results from transient retinal ischemia. TMVL may herald permanent visual loss or devastating stroke and patients with TMVL should be evaluated urgently. A practical approach to the evaluation of the patient with TMVL must be based on the patient’s age and the suspected underlying etiology. In the older patient, tests should be performed to investigate giant cell arteritis, atherosclerotic large vessel disease, and cardiac abnormalities. In the younger patient, TMVL is usually benign and the evaluation should be tailored to the particular clinical setting.

Transient monocular visual loss (TMVL) describes acute and temporary visual loss in one eye.1–3 As indicated in Table 4–1, there are numerous nonischemic causes of TMVL,1–4 which must be ruled out by a careful ocular examination before considering a vascular mechanism. This is why we prefer avoiding the term “amaurosis fugax,” usually referring exclusively to transient ischemia of the retina.3 The most important step in evaluating a patient with visual loss is to establish whether the visual loss is monocular or binocular.2,3 Monocular visual loss always results from lesions anterior to the chiasm (the eye or the optic nerve), whereas binocular visual loss results from lesions of both eyes or optic nerves, or, more likely, of the chiasm or retrochiasmal visual pathway. Deciding whether an episode of acute visual loss occurred in one eye or both is not always easy; very few patients realize that binocular hemifield (homonymous) visual field loss affects the fields of both eyes. They will usually localize it to the eye that lost 94 4 Transient Monocular Visual Loss 95

TABLE 4–1 Differential Diagnosis of Transient Monocular Visual Loss (TMVL)

Vascular Orbital ischemia (ophthalmic artery) Retinal ischemia (central retinal artery and its branches, central retinal vein) Optic nerve ischemia (short posterior ciliary arteries/ophthalmic artery) Choroidal ischemia (posterior ciliary arteries) Vasospastic TMVL (central retinal artery) Ocular Diseases Anterior segment: Dry eyes Keratoconus Hyphema Angle closure glaucoma Retinal detachment Optic Nerve Disorders Papilledema (transient visual obscurations) Optic disc drusen (transient visual obscurations) Congenitally anomalous optic disc (transient visual obscurations) Optic nerve compression (gaze-evoked TMVL) Uhthoff’s phenomenon (demyelination) its temporal field. The best clues to the fact that visual loss was actually binocular are reading impairment (monocular visual loss does not impair reading unless the unaffected eye had prior vision impairment) and visual loss confined to a hemifield (monocular visual loss does not usually cause visual loss respecting the vertical meridian).2

Mechanisms of TMVL

In most cases of TMVL, the underlying mechanism is arterial ischemia of the retina or optic nerve (Table 4–1). However, numerous other ocular disorders may produce episodes of reversible monocular visual loss and can be easily ruled out by a careful ophthalmologic examination.

TMVL CAUSED BY OCULAR CONDITIONS (OTHER THAN ARTERIAL DISEASES) Ocular disorders changing the patient’s refractive error (such as elevated blood sugar) and alterations in corneal properties (such as dry eyes or keratoconus) or in transparency of the anterior chamber (such as hyphema) often produce episodes of blurry vision that may last from a few seconds to a few hours. Sudden elevations in intraocular pressure (such as in episodic angle closure glaucoma) may also produce acute monocular visual loss, with or without ocular pain, often preceded or associated with halos around lights.2–4 Another important cause of TMVL is a swollen or congenitally anomalous optic disc (with or without optic disc drusen), which may pinch off its own 96 Neuro-Ophthalmology: Blue Books of Neurology

ciliary blood supply or the central retinal artery (Figs. 4–1, 4–2, and 4–3).2,3,5 In such cases, the episodes of TMVL last only seconds, occur frequently during the day, and are often provoked by changing gaze position or, more commonly, by assuming the upright posture (orthostatic TMVL). These brief episodes of visual loss are called “transient visual obscurations.”2,3,5 Orbital tumors may intermit- tently compress the ophthalmic or central retinal artery, thereby producing brief gaze-evoked TMVL (Fig. 4–4).3,4 Rarely, TMVL may arise from impending occlusion of the central retinal vein (Fig. 4–5).6

Figure 4–1 Congenitally crowded optic nerve (without true disc edema) responsible for brief episodes of transient visual obscurations.

Figure 4–2 Optic nerve head drusen in a patient with transient visual obscurations. 4 Transient Monocular Visual Loss 97

Figure 4–3 Disc edema in the setting of raised intracranial pressure (i.e., papilledema) presenting with episodes of transient visual obscurations.

Figure 4–4 Right orbital mass revealed by episodes of acute complete visual loss in the right eye triggered by eye movements. The patient lost the vision in her right eye each time she looked to the right. Her visual function was normal in primary position.

Figure 4–5 Impending central retinal vein occlusion in the left eye of a young man with hyperhomocysteinemia who presented with recurrent episodes of diffusely blurry vision in his left eye. He described seeing rain showers with increased brightness lasting approximately 30 minutes. Note the dilated and tortuous retinal veins associated with flame and dot-blot retinal hemorrhages consistent with central retinal vein occlusion. 98 Neuro-Ophthalmology: Blue Books of Neurology

TMVL CAUSED BY VASCULAR ARTERIAL ISCHEMIA TMVL most often results from impaired perfusion in the ophthalmic, retinal (central or branch retinal arteries), choroidal (posterior ciliary arteries), or optic nerve (posterior ciliary arteries) circulation (Figs. 4–6 and 4–7). There are three main mechanisms responsible for episodes of vascular arterial TMVL. They comprise (1) arterial emboli that originate in proximal arteries or the heart (usually to the ophthalmic artery, central retinal artery or its branches), (2) ocular hypoperfusion secondary to hemodynamic impairment (stenosis or occlusion of the aortic arch, carotid or ophthalmic arteries, reduced cardiac output or systemic hypotension), and (3) arterial vasospasm (usually involving the central retinal artery). Each of these mechanisms may occur separately or in association with each other. The characteristics of the episode of TMVL and the fundus appearance help characterize the mechanism (Figs. 4–8, 4–9, 4–10, 4–11, 4–12, and 4–13).1–3,7–9

Superficial temporal a. Reversal of Ophthalmic a. flow through ophthalmic artery Supraorbital a. Supratrochlear a. Anterior cerebral a. Medial palpebral a.

Middle cerebral a. Dorsal a. of nose Lateral palpebral a. Posterior Angular a. communicating a. Lacrimal a.

Transverse facial a. Maxillary a. Occipital a. Middle meningeal a. Internal carotid a. Facial a. (occluded) External carotid a. Common carotid a.

Figure 4–6 Blood supply to the orbit and potential collateral circulation following occlusion of the ipsilateral internal carotid artery. The ophthalmic artery, a branch of the internal carotid artery, provides most of the blood supply to the eye and orbit. It gives the central retinal artery and the posterior ciliary arteries. In case of occlusion of the internal carotid artery and a poorly functional circle of Willis, the flow within the ophthalmic artery may be reversed to protect the ipsilateral anterior cerebral hemisphere from ischemia. In this setting, the blood flow comes from branches of the external carotid artery (mostly the maxillary, facial, and middle meningeal arteries). This phenomenon is responsible for the rare observation of dilated episcleral arteries in patients with chronic internal carotid artery occlusion and for a relative ocular “steal phenomenon” that produces episodes of hemodynamic transient monocular visual loss (TMVL). (From Netter FH: Ner- vous system. The CIBA Collection of Medical Illustrations, vol 1, part II. CIBA Pharmaceutical Company, New York, NY, USA, 1986, Section III , Plate 7, p 57.) 4 Transient Monocular Visual Loss 99

Figure 4–7 Diagram demonstrating the ophthalmic artery and its branches (central retinal artery and posterior ciliary arteries). The central retinal artery penetrates the optic nerve and divides into superior and inferior branches at the level of the optic nerve head. It vascularizes the inner portion of the retina. The ciliary arteries are very small caliber arteries and provide the blood supply to the outer retina, the choroid, and the optic nerve head. Various degrees of ocular (or orbital) ischemia may result from lesions occurring at the level of the internal carotid artery, ophthalmic artery, central retinal artery or ciliary arteries. (From Zide BM, Jelks GW: Surgical Anatomy of the Orbit. New York, Raven Press, 1985.)

Figure 4–8 Funduscopy showing two yellow refractile retinal emboli characteristic of cholesterol emboli. This patient had recurrent episodes of transient monocular visual loss (TMVL) in his left eye secondary to a tight atheromatous stenosis of his left internal carotid artery.

Retinal Emboli TMVL was first linked to retinal arterial emboli 50 years ago when white frag- ments were observed by ophthalmoscopy to travel through the retinal arterial vessels during episodes of TMVL.3,7,8 These emboli originate most often from an atherosclerotic plaque at the carotid bifurcation (Fig. 4–14) and less commonly from the aortic arch or ophthalmic artery (Fig. 4–15). Patients with this symptom typically complain of TMVL that lasts a few minutes at most.3,10,11 100 Neuro-Ophthalmology: Blue Books of Neurology

Figure 4–9 Platelet-fibrin emboli in a branch of the inferior branch of the central retinal artery in a patient with ulcerated plaques of the aortic arch.

Figure 4–10 Multiple cholesterol and platelet-fibrin emboli responsible for recurrent episodes of right transient monocular visual loss (TMVL) and a small retinal infarction in a patient with diffuse atherosclerotic disease.

Anterior Circulation Stenosis Severe stenosis of the carotid or ophthalmic arteries or stenosis of the aortic arch (in severe aortic arch atherosclerosis or Takayasu arteritis) may cause TMVL by hypoperfusion rather than embolism.1–3,12

Hypotension Reduced cardiac output or systemic hypotension may also produce TMVL.3 Although TMVL is not typically an isolated symptom of systemic hypotension, 4 Transient Monocular Visual Loss 101

Figure 4–11 Venous stasis retinopathy (also called hypotensive retinopathy) in a patient with chronic left carotid artery occlusion and poor collateral circulation. Note the dilated retinal veins and multiple dot-blot hemorrhages in the retina midperiphery secondary to chronic poor perfusion of the eye.

Figure 4–12 Ocular ischemic syndrome with neovascularization of the iris and cataract. which generally also causes lightheadedness, confusion, and binocular visual loss, the combination of a drop in systemic blood pressure and asymmetric anterior circulation stenosis may cause TMVL alone, particularly orthostatically induced TMVL.2,3

Chronic Ocular Hypoperfusion Chronic ocular hypoperfusion of any mechanism may be associated with transient but prolonged visual loss (several minutes to hours) and positive visual phenomena.3,12–14 It may be induced by situations that further decrease perfusion pressure (postural change) or increase retinal oxygen demand (exposure to bright light).3,13 Borderline ocular perfusion may not be able to maintain retinal metabolic activity when blood flow is diverted to other tissues as after eating a meal or during exercise.3,14 Chronic hypoperfusion of the eye may also induce delay in the regeneration of visual pigments in the photoreceptor layer 102 Neuro-Ophthalmology: Blue Books of Neurology

Figure 4–13 Choroidal hypoperfusion demonstrated on a retinal fluorescein angiogram in a patient with multiple episodes of transient monocular visual loss (TMVL) from giant cell arteritis. The vasculitic process involves the posterior ciliary arteries vascu- larizing the choroid and the optic nerve head. Finding of delayed choroidal filling is highly suggestive of this disorder.

of the retina, resulting in blurred or absent vision that persists until regeneration of visual pigment occurs. Impaired dark adaptation may be a consequence of this phenomenon. In these cases, examination often shows venous stasis retinopathy or the ischemic ocular syndrome (dilated retinal veins, retinal hemorrhages, retinal or iris neovascularization, ocular hypotony or hypertony, anterior chamber cells and flare, cataract, and corneal edema) (Figs. 4–11 and 4–12).3,12–14

Other Causes Less common causes of TMVL are vasculitis and radiation toxicity.3 Giant cell arteritis commonly causes TMVL by compromising the optic nerve circulation, more commonly than the retinal arterial flow.3,9,15 TMVL from isolated choroidal ischemia is rare and should point to a vasculitic process such as giant cell arteritis (Fig. 4–13).3,15 TMVL is rarely a premonitory symptom of ischemic optic neuropathies. In those cases, arteritic (rather than nonarteritic) ischemic optic neuropathy should be suspected.3,9,15

Idiopathic TMVL in Young Individuals (Vasospasm?) Young people who have no evidence of vasculopathy may have episodes of TMVL secondary to reversible vasospasm of retinal arteries.2,3,16–18 Rare case reports have documented this phenomenon.17,18 Such vasospasm may be the basis for the TMVL of so-called retinal migraine, which remains a debated entity.3,19 In listening to the patient’s history, it is impossible to distinguish TMVL as an isolated symptom of vasospasm from TMVL of other causes.3 There- fore, vasospasm should remain a diagnosis of exclusion. 4 Transient Monocular Visual Loss 103

Figure 4–14 Carotid angiogram showing an atheromatous plaque responsible for a stenosis at the level of the origin of the internal carotid artery.

Natural History of TMVL

The natural history of patients with TMVL depends on the age of the patient and the etiology of the TMVL (Table 4–2).1–3,20–25

RETINAL STROKE A major adverse outcome is persistent visual loss, mostly resulting from branch or central retinal artery occlusion (Figs. 4–15 and 4–16). Based on several natural history studies, the aggregate risk of permanent ipsilateral visual loss is about 1% to 2% per year.3,22

CEREBRAL HEMISPHERIC STROKE TMVL may also herald a cerebral infarction (Fig. 4–17). When carotid occlusive disease is related to atherosclerosis, TMVL is a marker of systemic atheromatous disease and is associated with a higher risk of vascular death.1,3,20–22 104 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 4–2 Natural History of Transient Monocular Visual Loss (TMVL)—The Triple Threat

Irreversible visual loss (central retinal artery occlusion) Estimated to be around 1% per year in patients with internal carotid stenosis Cerebral infarction (prevalence varies depending on the cause of TMVL) Patients with ipsilateral atheromatous internal carotid stenosis 50% have a risk of 10% at 3 years (vs. 20.3% after cerebral transient ischemic attack) Correlation with degree of stenosis Vascular death (myocardial infarction) 4% per year

Figure 4–15 Embolic inferior branch retinal artery occlusion. The inferior half of the retina is ischemic (whitish and edematous).

The NASCET study showed a 25% 3-year risk of stroke in patients with hemo- dynamically significant carotid stenosis causing ipsilateral TMVL, cerebral hemispheric transient ischemic attack (TIA), or mild stroke.11,25 However, the risk of stroke doubles in patients presenting with a hemispheric TIA compared with those with an episode of TMVL (see later).25

DEATH The risk of death in patients with TMVL and atheromatous carotid stenosis is approximately 4% per year, mainly related to myocardial infarction.1,3,20–22 Patients with retinal and hemispheric TIAs are equally vulnerable. These data suggest that TMVL is a marker for systemic arteriosclerosis and should prompt immediate comprehensive patient evaluation. 4 Transient Monocular Visual Loss 105

Figure 4–16 Central retinal artery occlusion with severe visual loss. The entire retina is ischemic and edematous. The macula appears as a “cherry red spot” as the underlying choroid remains normal.

Figure 4–17 T2-weighted brain magnetic resonance imaging (MRI) showing a left middle cerebral artery infarction.

Diagnosis

HISTORY The patient’s description of the visual characteristics of an attack seldom allows the physician to determine its cause.2,3 Except for the transient visual obscurations of optic nerve abnormalities, which never last more than seconds, the duration of visual loss can vary from seconds to hours. TMVL lasts longer in cases of ocular hypoperfusion or venous congestion than in cases of embolism.2,3 106 Neuro-Ophthalmology: Blue Books of Neurology

The characteristics of the visual loss do not specify a particular mechanism. For example, an ascending or descending (“curtain-like”) spread of blindness, commonly held as specific for embolism, can occur in patients with hypotension or vasospasm.1 Positive visual phenomena are also nonspecific, signaling a lower degree of ischemia than is necessary to produce negative visual phenomena; however, positive visual phenomena may be associated more with nonembolic hypoperfusion than with emboli.2 It is classic in patients with venous congestion6 and may be more common in patients with acute carotid dissection.26 The following accompanying manifestations are generally helpful in determining a mechanism of TMVL: (1) zigzag (fortification) scintillations—visual cortex migraine; (2) headache, scalp tenderness, jaw claudication—impending ciliary artery occlusion in association with giant cell arteritis; (3) eye or brow pain—intermittent angle closure glaucoma or ischemia in association with giant cell arteritis; (4) headache, neck, jaw,or brow pain—cervical carotid dissection; and (5) presyncope—systemic hypotension or a hyperviscosity syndrome; 6) ipsilateral Horner’s syndrome—carotid disease such as dissection (Fig. 4–18).2,3,26

OPHTHALMIC EXAMINATION This is a critical step to rule out local ocular causes of TMVL (Table 4–1) and to detect retinal emboli, retinal ischemia, venous stasis retinopathy, or evidence of optic nerve ischemia.1–4 Although the neurologist is often consulted first when a patient presents with TMVL, a detailed ophthalmologic examination (with dilated funduscopic examination) should always be performed in emergency.

ANCILLARY STUDIES In older patients, complete blood count, erythrocyte sedimentation rate, C-reactive protein, and fibrinogen should be obtained emergently, looking for a biologic inflammatory syndrome that would suggest giant cell arteritis.1–3,9 Carotid and cardiac sources of emboli can usually be ruled out by ultrasonic examination. Two studies confirmed that retinal ischemia is caused more often by carotid stenosis than by cardiac-source emboli.27,28 Therefore, cervical carotid ultrasound should be obtained emergently, looking for carotid dissection or carotid atheroma. Evaluation of the intracranial circulation by transcranial Doppler in patients with severe carotid stenosis is helpful in predicting the risk of stroke.3,26 Doppler of the ophthalmic artery may show poor flow in some patients with normal carotid arteries, suggesting stenosis or occlusion of the ophthalmic artery.3,26 Computed tomography angiography (CTA) or magnetic resonance angiography (MRA) may be used when reliable ultrasound is not available. A conventional angiogram is only rarely indicated. A transthoracic echocardiogram may be helpful in some patients, but a transesophageal echocardiogram is required in most patients with a negative preliminary workup because cardiac sources of emboli and aortic arch atheroma are better evaluated with this method.2,3,29–31 In selected patients who lack conventional arteriosclerotic risk factors and whose vascular and cardiac evaluations are negative, hypercoagulable states should be ruled out.3 4 Transient Monocular Visual Loss 107

Figure 4–18 Transient monocular visual loss (TMVL) associated with Horner’s syndrome revealing an ipsilateral internal carotid artery dissection. A, Right Horner’s syndrome with only subtle ptosis but no anisocoria in the light (top) and marked anisocoria in the dark (bottom) secondary to a right oculosympathetic paresis with impaired dilation of the pupil in the dark. B, T1-weighted magnetic resonance imaging (MRI) showing a hypersignal within the wall of the right internal carotid artery characteristic of subacute dissection. C, MRI of the same patient demonstrating a hyposignal in the right middle cerebral artery, which suggests cerebral hypoperfusion.

Most individuals who have episodes of TMVL in youth will have no ophthalmologic or blood laboratory abnormalities, constitutional manifestations, or major arteriosclerotic risk factors.3,16,32 Their chance of future stroke is low.3,32 108 Neuro-Ophthalmology: Blue Books of Neurology

Treatment

If ocular causes are not found and there are no biologic markers of inflammation, the physician should be guided by the results of ultrasonic studies. If the carotid ultrasound is negative, attention centers on the aortic arch and the heart. All patients should be given antiplatelet agents acutely (such as aspirin, clopidogrel, or combination of aspirin and dipyridamole). Aggressive treatment of arteriosclerotic vascular risk factors is essential (see later) (Table 4–3).1,3,33 When vasospasm is suspected, the combination of antiplatelet agents and calcium-channel blocker treatment may reduce the frequency of TMVL attacks.18 Vasoconstrictors should be avoided.

CAROTID ENDARTERECTOMY A common question is whether patients with TMVL and high-grade (>70%) internal carotid stenosis should undergo carotid endarterectomy. Two large collaborative trials34,35 published in the early 1990s compared conventional medical therapy with carotid endarterectomy in patients with TMVL, hemispheric TIA, or hemispheric mild stroke. Both trials found that carotid

TABLE 4–3 Recommendations for the Prevention of Stroke and Cardiovascular Events in Patients with Transient Monocular Visual Loss (TMVL)

Risk Factor Management Blood pressure should be decreased in both hypertensive and nonhypertensive patients Cigarette smoking should be discontinued Coronary artery disease, cardiac arrhythmias, congestive heart failure, and valvular heart disease should be treated appropriately Excessive use of alcohol should be eliminated (limit to 1 or 2 drinks a day) Treatment of hyperlipemia is recommended Fasting blood glucose levels <126 mg/dl are recommended Physical activity is recommended Antiplatelet Agents Long-term antiplatelet agents should be given to every patient who has experienced a noncardioembolic TMVL and has no contraindication (aspirin 50 to 325 mg qd, combination of aspirin 25 mg and extended-release dipyridamole 200 mg bid, or clopidogrel 75 mg od are all acceptable options for initial therapy) Oral Anticoagulants Long-term anticoagulation (target INR 2.5) should be used for prevention of stroke in patients with atrial fibrillation with other high-risk cardiac sources of embolism and in some hypercoagulable states Carotid Endarterectomy Should be considered only in selected high-risk patients who are good surgical candidates and with an ipsilateral internal carotid stenosis of 70% to 99% (see Table 4–4)

bid, twice a day; INR, international normalized ratio; qd, once a day. 4 Transient Monocular Visual Loss 109

endarterectomy overall significantly reduced the future risk of ipsilateral stroke if carotid stenosis was greater than 70%. However, in 2001, Benavente and col- leagues25 compared the stroke rate among patients with 50% to 99% carotid stenosis who presented with TMVL with that of patients who presented with hemispheric TIA in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) completed in 1990. TMVL was the presenting symptom in 397 patients, and hemispheric TIA attack in 829 patients. In medically treated patients with TMVL, the 3-year risk of ipsilateral stroke was 10%; in medically treated patients with hemispheric TIA, the 3-year risk was 20%. Thus, the medically treated patients with TMVL were at substantially lower risk of subsequent hemispheric stroke than were those with hemispheric TIA.25 In the NASCET, there were six risk factors for stroke in the TMVL group (Table 4–4). Among those with one or fewer of these risk factors (“low-risk group”), the 3-year risk of ipsilateral stroke was 1.8% with medical treatment and 2.2% with endarterectomy. Nearly 80% of the patients fell into this low-risk group. The risk of stroke was higher in those with two or more risk factors (“moderate-risk group”), but endarterectomy was beneficial only in the group with three or more of the previously listed risk factors (“high-risk group”).25 With this information in mind, carotid endarterectomy does not appear to be indicated for most patients with TMVL. Only those few patients who fall into the high-risk group (three or more of the previously listed risk factors) would be candidates (Table 4–4).25,36

OTHER MEASURES Among noncandidates for carotid endarterectomy, those who do not have a car- diogenic source of emboli should be managed with antiplatelet agents and, more importantly, with aggressive treatment of arteriosclerotic risk factors.3,33,36 Indeed, specific prevention strategies are tailored to the most likely cause of

TABLE 4–4 Predictors of the 3-Year Risk of Ipsilateral Stroke Among Patients with Transient Monocular Visual Loss (TMVL) and Internal Carotid Artery Stenosis >50% (174 Medically Treated Patients)

Age 75 years Male sex History of hemispheric transient ischemic attack or stroke History of intermittent claudication Ipsilateral stenosis of 80% to 94% of internal carotid artery No collateral circulation on angiography Each of these six variables doubles the risk of stroke at 3 years. Patients with TMVL are considered at high risk of stroke if at least three of these risk factors are present. Only high-risk TMVL patients may be considered for a carotid endarterectomy in addition to medical treatment.

Modified from Benavente O, Eliasziw M, Streifler JY, et al. for the North American Symptomatic Carotid Endarterectomy Trial Collaborators: Prognosis after transient monocular blindness associated with carotid artery stenosis. N Engl J Med 2001;345:1084–1090. 110 Neuro-Ophthalmology: Blue Books of Neurology

the TMVL and the patient’s underlying risk factors. Numerous prospective studies and clinical trials have shown a decreased risk of stroke and other cardiovascular events with control of modifiable risk factors, especially hypertension and smoking (Table 4–3).3,33,36 Prevention of a future event should begin with education of the patient in the ophthalmologist’s or neurologist’s office.

REFERENCES 1. Bernstein EF: Amaurosis Fugax. New York, Springer-Verlag, 1987, pp 286–303. 2. Biousse V, Trobe JD: Transient monocular visual loss. Am J Ophthalmol 2005;140:717–721. 3. Biousse V: Cerebrovascular disease. In Miller NR, Newman NJ, Biousse V, Kerrison JB (eds): Clinical Neuro-Ophthalmology, 6th ed, vol 2. Baltimore, Williams & Wilkins, 2005, pp 1967–2168. 4. Shultz WT: Ocular causes of transient monocular visual loss other than emboli. Ophthalmol Clin North Am 1996;9:381–391. 5. Sadun A, Currie J, Lessell S: Transient visual obscurations with elevated optic discs. Ann Neurol 1984;16:489. 6. Shuler RK, Biousse V, Newman NJ: Transient visual loss from venous congestion. J Neuro- Ophthalmol 2005;25:152–154. 7. Fisher CM: Observations of the fundus oculi in transient monocular blindness. Neurology 1959;9:333–347. 8. Ross Russell RW: The source of retinal emboli. Lancet 1968;2:789–792. 9. Hayreh SS, Podhajsky PA, Zimmerman B: Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998;125:509–520. 10. Goodwin JA, Gorelick PB, Helgason CM: Symptoms of amaurosis fugax in atherosclerotic carotid artery disease. Neurology 1987;37:829–833. 11. Streifler JY, Eliasziw M, Benavente OR, et al: The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial. Arch Neurol 1995;52:246–249. 12. Ross Russell RW, Page NGR: Critical perfusion of brain and retina. Brain 1983;106:419–434. 13. Furlan A, Whisnant A, Kearns T: Unilateral visual loss in bright light: An unusual symptom of carotid artery occlusive diseases. Arch Neurol 1979;36:675. 14. Levin LA, Mootha VV: Postprandial transient visual loss. A symptom of critical carotid stenosis. Ophthalmology 1997;104:397–401. 15. Slavin ML, Barondes MJ: Visual loss caused by choroidal ischemia preceding anterior ischemic optic neuropathy in giant cell arteritis. Am J Ophthalmol 1994;117:81–86. 16. Tippin J, Corbett JJ, Kerber RE, Schroeder E, Thompson HS: Amaurosis fugax and ocular infarction in adolescents and young adults. Ann Neurol 1989;26:69–77. 17. Burger SK, Saul RE, Selhorst JB, Thurston SE: Transient monocular blindness caused by vasospasm. N Engl J Med 1991;325:870–873. 18. Winterkorn JMS, Kupersmith MJ, Wirtschafter JD, Forman S: Treatment of vasospastic amaurosis fugax with calcium-channel blockers. N Engl J Med 1993;329:396–398. 19. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain, 2nd ed. Cephalalgia 2004;(Suppl 1):1–160. 20. Poole CJM, Ross Russell RW: Mortality and stroke after amaurosis fugax. J Neurol Neurosurg Psychiatry 1985;48:902–905. 21. Hurwitz BJ, Heyman A, Wilkinson WE, et al: Comparison of amaurosis fugax and transient cerebral ischemia: a prospective clinical and arteriographic study. Ann Neurol 1985;18:698–704. 22. KIine LB: The natural history of patients with amaurosis fugax. Ophthalmol Clin North Am 1996;9:351–357. 23. Hankey GJ: The effect of treating people with reversible ischaemic attacks of the brain and eye on the incidence of stroke in Australia. Aust N Z J Med 1997;27:420–430. 24. Johnston SC: Transient ischemic attack. N Engl J Med 2002;21:1687–1692. 25. Benavente O, Eliasziw M, Streifler JY, Fox AJ, Barnett HJM, Meldrum H, for the North American Symptomatic Carotid Endarterectomy Trial Collaborators: Prognosis after transient monocular blindness associated with carotid artery stenosis. N Engl J Med 2001;345:1084–1090. 4 Transient Monocular Visual Loss 111

26. Biousse V, Touboul PJ, D’Anglejan-Chatillon J, Levy C, et al: Ophthalmic manifestations of internal carotid artery dissection. Am J Ophthalmol 1998;126:565–577. 27. Anderson DC, Kappelle LJ, Eliasziw M, et al: Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 2002;33:1963–1968. 28. Mead GE, Lewis SC, Wardlaw JM, Dennis MS: Comparison of risk factors in patients with transient and prolonged eye and brain ischemic syndromes. Stroke 2002;33:2383–2390. 29. Newman NJ: Evaluating the patient with transient monocular vision loss: the young versus the elderly. Ophthalmol Clin North Am 1996;9:455–466. 30. Kramer M, Goldenberg-Cohen N, Shapira Y, et al: Role of transesophageal echocardiography in the evaluation of patients with retinal artery occlusion. Ophthalmology 2001;108:1461–1464. 31. MacLeod MR, Amarenco P, Davis SM, Donnan GA: Atheroma of the aortic arch: An important and poorly recognised factor in the aetiology of stroke. Lancet Neurol 2004;3:408–414. 32. Poole CMJ, Ross Russell RW, Harrison P: Amaurosis fugax under the age of 40 years. J Neurol Neurosurg Psychiatry 1987;50:81–84. 33. Albers GW, Hart RG, Lutsep HL, et al: AHA Scientific Statement: Supplement to the guidelines for the management of transient ischemic attacks: a statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association. Stroke 1999;30:2502–2511. 34. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–453. 35. European Carotid Surgery Trialists Collaborative Group: European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 1991;337:1235–1243. 36. Rothwell PM, Eliasziw M, Gutnikov SA, et al: Carotid Endarterectomy Trialists Collaboration. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet 2004;363:915–924. 5 Ischemic Optic Neuropathies VALE´RIE BIOUSSE

Nonarteritic Anterior Ischemic Posterior Ischemic Optic Optic Neuropathy Neuropathy Diagnosis Risk Factors and Recurrence Perioperative Ischemic Optic Treatment Neuropathy

Arteritic Anterior Ischemic Radiation Optic Neuropathy Optic Neuropathy Diagnosis Diabetic Papillopathy and Pre- Diagnostic Tests AION Optic Disc Edema Treatment and Outcome References

Key Points Ischemic optic neuropathies include anterior ischemic optic neuropathy (always associated with disc edema), and posterior ischemic optic neuropathy (when the optic nerve appears normal acutely). Anterior ischemic optic neuropathies are categorized as nonarteritic anterior ischemic optic neuropathies and arteritic anterior ischemic optic neuropathies (usually in the setting of giant cell arteritis). Nonarteritic anterior ischemic optic neuropathies typically occur in the setting of a disc at risk (small crowded optic nerve with a small cup-to-disc ratio). In a patient with suspected ischemic optic neuropathy, the first step should always be to rule in or out giant cell arteritis.

Ischemic optic neuropathies (IONs) are the most common acute optic neuropathies in patients older than 50 years. The term ischemic optic neuropathy is used as a general term to refer to all presumed ischemic causes of optic neuropathy. Depending on the segment of optic nerve affected, they are divided into anterior and posterior IONs (Fig. 5–1). Optic disc edema from ischemia to the anterior nerve is, by definition, present in anterior ischemic optic neuropathy (AION) (Fig. 5–2) and absent in posterior ischemic optic neuropathy (PION) (Fig. 5–3).1 AION is much more common than PION, accounting for 90% of cases of optic nerve ischemia. IONs can also be divided into nonarteritic and arteritic etiologies (nonarteritic AION [NAION] and arteritic AION). Arteritic ION, classically resulting from 112 5 Ischemic Optic Neuropathies 113

Figure 5–1 Vascularization of the optic nerve. The eye has a dual vascular supply, with arterial contributions from the choroidal and central retinal circulations, both of which originate from the ophthalmic artery, a branch of the internal carotid artery. The choroidal circulation is comprised of choroidal arteries, which primarily supply the outer retina, and posterior ciliary arteries, which supply the optic nerve. The intraocular optic nerve is supplied by an anastomotic arterial circle (the circle of Zinn-Haller) or directly from short posterior ciliary arteries. Contributions to the circle of Zinn-Haller include short posterior ciliary arteries, branches from the nearby pial arterial network, and choroidal feeder vessels, with the most significant contribution from the short posterior ciliary arteries. The posterior optic nerve is supplied by the surrounding pial plexus. The central retinal artery supplies the inner retina. (From Zide BM, Jelks GW: Surgical Anatomy of the Orbit. New York, Raven Press, 1985.) giant cell arteritis, is an ophthalmologic emergency, requiring prompt recognition and treatment to prevent devastating blindness.1

Nonarteritic Anterior Ischemic Optic Neuropathy

NAION is presumably secondary to small vessel disease of the short posterior ciliary arteries, with resultant hypoperfusion and infarction of the anterior optic nerve.1 Diagnosis is primarily clinical, and, despite its high incidence, NAION remains largely untreatable. The Ischemic Optic Neuropathy Decompression Trial (IONDT), a large, multicenter, prospective treatment trial, has provided valuable information on the natural history of NAION.2–5

DIAGNOSIS NAION typically occurs after the age of 50 years, but cases in younger patients and even in children are well documented. Incidence is estimated at 2.3 to 10.2 cases per year per 100,000 persons 50 years and older, and 95% of cases occur in Caucasians.1 The typical presentation is of sudden, painless monocular visual loss that progresses over hours to weeks. Premonitory transient visual loss and ocular discomfort are infrequent in NAION.1,6 Examination in typical NAION reveals an 114 Neuro-Ophthalmology: Blue Books of Neurology

Figure 5–2 Anterior ischemic optic neuropathy. A, Optic nerve appearance at the acute phase (top) showing diffuse disc edema with peripapillary hemorrhages; 1 month later (middle), the disc edema has almost completely resolved; there is segmental superior pallor and persistent inferior disc edema with an adjacent hemorrhage; 2 months later (bottom), the disc edema has completely resolved and there is superior segmental optic nerve pallor corresponding to the inferior visual field defect shown in B. B, Humphrey visual field of the right eye showing an inferior arcuate defect in this patient with nonarteritic anterior ischemic optic neuropathy. Visual acuity is 20/25 and color vision is normal.

optic neuropathy, with decreased visual acuity and color vision, a relative afferent pupillary defect, visual field loss, and optic disc edema, often with peripapillary hemorrhages. Disc edema may be diffuse or segmental, involving only the superior or inferior portion of the optic disc (Figs. 5–2 and 5–4). This may correspond with the division of the circle of Zinn-Haller into distinct upper and lower halves.1 Similarly, the corresponding visual field defect is often an inferior (most common) or superior altitudinal or arcuate defect (Figs. 5–2 and 5–4). Initial visual acuity varies widely from 20/20 to no light perception. It is better than or equal to 20/60 in 31% to 52% of patients and worse than or equal to 20/200 in 34% to 54% of patients.1,6 Four to 6 weeks after visual loss, disc edema resolves and optic disc pallor develops, often in a sectoral pattern (Fig. 5–2).1 Although the onset of visual loss is classically sudden (as in all vascular events), progressive worsening of vision over a few days or weeks is common in NAION. The IONDT showed that up to 43% of patients spontaneously regained three lines of visual acuity at 6-month follow-up, with 31% sustaining that benefit at 24 months.2–5 An important examination finding, usually considered essential to diagnosis of NAION, is the presence of a small optic nerve with a small or absent physiologic cup (termed the disc at risk) in the unaffected eye (Figs. 5–5 and 5–6).1,7,8 5 Ischemic Optic Neuropathies 115

Figure 5–3 Bilateral posterior ischemic optic neuropathies. A, Normal-appearing optic nerves in a 35-year-old man who complained of profound visual loss in the right eye after spine surgery. His visual acuity was “hand motion” in the right eye and 20/25 in his left eye. He had a right relative afferent pupillary defect and his fundus examination was normal. B, Goldmann visual fields showed a central scotoma and inferior defect in his right eye as well as an inferonasal defect in his left eye (the right eye visual field is on the right and the left eye visual field is on the left). C, Two months later, his right optic nerve appears pale; his left optic nerve is only very mildly pale temporally (the right eye is on the left and the left eye is on the right). 116 Neuro-Ophthalmology: Blue Books of Neurology

Figure 5–4 Luxury perfusion in nonarteritic anterior ischemic optic neuropathy. A, Disc edema secondary to anterior ischemic optic neuropathy with telangiectatic, dilated small vessels superiorly corresponding to luxury perfusion. B, Humphrey visual field in the left eye of the same patient showing an inferior altitudinal defect.

Figure 5–5 Illustration of the cup-to-disc ratio. The physiologic cup of the optic nerve corresponds to the size of the scleral canal (the opening in the sclera through which the optic nerve exits the eye). The ratio of cup size to the diameter of the optic disc determines if the patient has a disc at risk for NAION. A, Middle, Normal cup with cup-to-disc ratio (0.5). Left, Large cup-to-disc ratio (0.8) such as in patients with glaucoma. Right, Small optic disc with cup-to-disc ratio (<0.1). This is the classic “disc at risk” in nonarteritic ischemic optic neuropathy (NAION). B, Corresponding fundus photos. 5 Ischemic Optic Neuropathies 117

Figure 5–6 Four weeks after nonarteritic anterior ischemic optic neuropathy in the right eye. Both optic nerves are small and crowded, the so-called disc at risk. There is mild residual disc edema and superior pallor in the right eye (left image) and the left eye (right image) is normally pink, without disc edema. Both optic nerves are lacking a physiologic cup.

It is widely thought that an anatomically small, crowded optic nerve predisposes patients to NAION by virtue of mechanical factors such as crowding with impaired axonal flow resulting in compromise of the laminar microcirculation.1,7,8 Caucasians tend to have small cup to disc ratios, which may explain why NAION predominates in this group.1,9 NAION must be differentiated from other causes of acute optic neuropathies, such as idiopathic optic neuritis, infectious optic neuritis, or compressive optic neuropathies.1,10,11 The absence of pain, rapid loss of vision, relatively good color vision and the finding of a disc at risk in the fellow eye support the diagnosis of NAION (Table 5–1). Occasionally, magnetic resonance imaging (MRI) of the optic nerve (with contrast) may be helpful, wherein the finding of enhancement of the optic nerve or optic nerve sheath should suggest an alternative diagnosis.1

RISK FACTORS AND RECURRENCE Although the pathophysiology of AION remains unknown, studies have reported the association of AION with optic nerve anomalies and systemic disorders (Table 5–2).1,7 As emphasized above, the main risk factor for NAION is the presence of an anomalous optic nerve. A disc at risk (small optic nerve with a small or absent physiologic cup) is usually present even in patients who may have another reason to develop NAION (such as perioperative AION or AION occurring in association with drugs). Other optic nerve anomalies such as papilledema or optic nerve head drusen can also be complicated by AION (Fig. 5–7), most likely because of impaired axonal flow and resultant compromise of the laminar microcirculation.1,7,12 Systemic diseases associated with increased risk of NAION include systemic hypertension (in about 50%) and diabetes (in about 25%).1,4,7,13,14 Ischemic heart disease, hypercholesterolemia, stroke, tobacco use, sleep apnea, and systemic atherosclerosis have also been associated,1,15,16 but few rigorous population-controlled studies have been performed. In patients younger than 50, 118 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology:

TABLE 5–1 Clinical Characteristics of Inflammatory Optic Neuritis, Nonarteritic Anterior Ischemic Optic Neuropathy (AION), and Arteritic Anterior Ischemic Optic Neuropathy

Optic Neuritis AION Nonarteritic AION Arteritic

Age of patients Younger Older (>50 years) Older (>65 years) Laterality Unilateral Unilateral Unilateral or bilateral Visual loss Rapidly progressive Acute Acute Acuity rarely spared Acuity variable Severe visual loss Pain Orbital pain frequent with eye movements Pain infrequent Headache common Color vision Commonly abnormal Commonly spared if vision good Correlates with visual acuity Visual field Central defects Altitudinal defect Any defect (severe) Optic disc Acute Normal (2/3) or disc edema (1/3) Disc edema, segmental Disc edema, pallid Small cup-to-disc ratio Retinal/choroidal infarction Late Temporal pallor Segmental pallor Diffuse pallor, cupping Visual prognosis Good Variable Poor 25% recurrence risk 15% second eye at 5 years 75% second eye within 2 weeks Systemic diseases Risk of multiple sclerosis HTN (51%), DM (24%) GCA GCA to be ruled out 25% have no GCA symptoms

DM, diabetes mellitus; GCA, giant cell arteritis; HTN, hypertension. 5 Ischemic Optic Neuropathies 119

TABLE 5–2 Disorders and Drugs Suggested Associated with the Occurrence of Anterior Ischemic Optic Neuropathies

Arteritic anterior ischemic optic neuropathy Giant cell arteritis þþþ Periarteritis nodosa Churg-Strauss syndrome Wegener’s granulomatosis Connective tissue diseases such as systemic lupus erythematosus Rheumatoid arthritis Relapsing polychondritis Nonarteritic anterior ischemic optic neuropathy Anomalous optic nerve: Disc-at-risk: small crowded optic nerve Papilledema Optic nerve head drusen Elevated intraocular pressure (acute glaucoma, ocular surgery) Radiation-induced optic neuropathy Diabetes mellitus Other vascular risk factors (atherosclerosis) Hypercoagulable states* Acute systemic hypotension/anemia Bleeding Cardiac arrest Perioperative (especially cardiac and spine surgeries) Dialysis Sleep apnea Drugs Amiodarone Interferon-alpha Vasoconstrictor agents (such as nasal decongestant) Erectile dysfunction drugs

*Hypercoagulable states are rarely responsible for anterior ischemic optic neuropathy (AION) and should only be tested in younger patients without other risk factors for AION.

Figure 5–7 Left nonarteritic anterior ischemic optic neuropathy in a patient with optic nerve head drusen. Both optic nerves are crowded because of drusen, which are easily seen in the right eye (left). There is visual loss and disc edema in the left eye (right), with peripapillary hemorrhages suggesting superimposed acute nonarteritic anterior ischemic optic neuropathy. 120 Neuro-Ophthalmology: Blue Books of Neurology

diabetes, hypertension, and hypercholesterolemia are more strongly associated with NAION than in older patients.4,15,16 In the IONDT, 60% of patients had one or more risk factors associated with cerebrovascular disease, including hypertension, diabetes, and cigarette use.4 NAION is a disease of the small vessels supplying the optic nerve head and is not associated with ipsilateral internal carotid artery stenosis; embolic AION is extremely rare.1,17 As with small vessel disease affecting the central nervous system, some association between carotid occlusive disease and acute AION has been suggested. However, in most cases of AION, the optic neuropathy is a sign of widespread atherosclerosis affecting both large and small vessels, reflecting shared risk factors such as hypertension, diabetes mellitus, or tobacco use, or is isolated and a reflection of the disc at risk. Rarely, optic nerve infarction results from reduced perfusion pressure secondary to severe carotid occlusive disease (especially dissections) and poor collateral blood supply.18 Thus, although most cases of AION are probably due to local vascular factors involving a small, cupless optic disc, rare cases are caused by ipsilateral carotid artery disease. It is not necessary to obtain a carotid ultrasound examination in all patients who develop AION. However, if the patient complains of visual symptoms suggestive of hypoperfusion of the eye (i.e., blurred vision with changes of posture, with bright light or during exercise), or if the AION was preceded by or associated with contralateral neurologic symptoms and signs, transient monocular visual loss, Horner’s syndrome, or orbital pain, noninvasive carotid imaging may be appropriate to identify patients at risk of further embolic or hemodynamic events.1,18 Rarely, hypercoagulable states have been associated with NAION; however, case-controlled studies have given various results. It is suggested that thrombotic factors, in particular homocysteine, be measured in patients younger than 45 years with NAION without vascular risk factors, in bilateral simultaneous NAION, in NAION recurrent in the same eye, in NAION in the absence of a small cup-to-disc ratio, and in familial NAION.1,19–23 Acute bleeding with anemia and systemic hypotension can result in unilateral or bilateral AION. Similarly, fluctuations in blood pressure, especially in anemic patients such as those with chronic renal insufficiency receiving dialysis, have been implicated as a precipitant of AION.1,7 Multiple medications have been implicated in the occurrence of NAION, such as amiodarone, interferon-alpha, nasal decongestants, various vasopressors or vasoconstricting drugs, and erectile dysfunction drugs.1,24–27 However, establishing a direct relationship between use of a specific medication and NAION is problematic because most patients have concurrent vascular risk factors and an underlying disc at risk. When possible, it is generally recommended to discontinue such medications in patients with AION. Acute elevation of intraocular pressure such as during ocular surgeries or during an attack of angle closure glaucoma may precipitate NAION.1,28–30 NAION recurs in the affected eye in less than 5% of patients.5 It is possible that atrophy of the nerve after NAION relieves crowding and reduces recurrence risk. Because patients often have a disc at risk in both eyes, it is not uncommon to observe bilateral NAION, usually sequentially rather than simultaneously. The risk of second eye involvement is 12% to 15% at 5 years and appears to be related to poor baseline visual acuity in the first eye and to diabetes but not to age, sex, 5 Ischemic Optic Neuropathies 121

smoking history, or aspirin use.1,5,7 There is a modest correlation of final visual acuities between eyes in bilateral, sequential NAION, with approximately 50% of patients having Snellen visual acuities within three lines of one another.5

TREATMENT There is no established treatment for NAION, although a number of medical and surgical treatments have been evaluated. The clinician’s primary role in managing patients with this disorder is exclusion of giant cell arteritis and detection and control of vascular risk factors.1 Phenylhydantoin, subtenon injection of vasodilators, intravenous intraocular pressure-lowering agents, vasopressors, stellate ganglion block, levodopa, anticoagulation, aspirin, oral corticosteroids, hyperbaric oxygen, transvitreal optic neurotomy (opening of the scleral canal), and optic nerve sheath decompression have not proven useful for the treatment of acute NAION (Table 5–3 summarizes the most recent studies).1,2,5,31–38 However, most studies were retrospective, nonrandomized, and small. Although it has been suggested that neuroprotective agents (especially those that can be administered topically or directly in the eye) may be efficacious in the acute treatment of NAION, this remains to be demonstrated in a controlled study. Although a few retrospective studies have suggested that aspirin may help prevent fellow eye involvement, this remains debated. However, because aspirin is beneficial in primary and secondary prevention of most atherosclerosis-related vascular diseases, it is reasonable to prescribe aspirin in NAION patients.1

Arteritic Anterior Ischemic Optic Neuropathy

AION is the most common ophthalmic manifestation of giant cell arteritis (Table 5–4).1 Arteritic AION is exceedingly important to recognize and differentiate from NAION to prevent further devastating visual loss. Although giant cell arteritis is the most common cause of arteritic AION, other vasculitides such as periarteritis nodosa should also be considered (Table 5–2).1

DIAGNOSIS Giant cell arteritis occurs predominantly in women and in Caucasians older than the age of 65. The annual incidence is approximately 20 per 100,000 persons aged 50 years or older.39,40 Up to 50% of patients with giant cell arteritis present with ocular symptoms; of those, 70% to 80% have arteritic AION (Table 5–4).1,39 The clinical presentation of arteritic AION is similar to that of NAION, but numerous red flags should raise clinical suspicion for arteritic AION rather than NAION (Table 5–1)1,6,41–43: (1) systemic symptoms such as jaw claudication, neck pain, headache, scalp tenderness, malaise, weight loss, and fever may precede visual loss by months; however, about 25% of patients with positive temporal artery biopsies do not exhibit these systemic symptoms42; (2) permanent visual loss from arteritic AION is sometimes preceded by episodes of transient visual loss (30%) or transient diplopia (5% to 10%) secondary to ischemia to the optic nerve head, extraocular muscles, or cranial nerves42,43; (3) the finding 122 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology: TABLE 5–3 Studies Evaluating the Treatment of Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Published Since 1996

Study Number of Author Year Treatment Type Patients Outcome Conclusions of the Study

Acute treatment of AION Arnold et al.31 1996 Hyperbaric P 22 treated/27 No significant difference Hyperbaric oxygen does oxygen untreated in final VA not improve visual outcome of affected eye Botelho et al.32 1996 Aspirin R 78 total No significant difference Aspirin does not improve 23 treated in final VA visual outcome of 55 untreated affected eye Johnson et al.33 2000 Levodopa R 37 total Improved VA at 6 Levodopa may improve 18 treated months: visual outcome of 19 untreated 76.9% of treated affected eye 30% of untreated No change in VF IONDT2 2002 ONSD P 258 total No difference in visual There is no role for 127 treated outcome; 24% of ONSF in acute NAION 131 untreated surgical patients treatment worsened Soheilian et al.34 2003 Transvitreal R 7 treated 6/7 patients had some Transvitreal optic optic improvement in VA neurotomy may be neurotomy helpful in AION with severe visual loss Fazzone et al.35 2003 Topical R 31 total The group treated with brimonidine 14 treated brimonidine had worse 17 untreated visual function at 8–12 weeks Secondary prevention of AION (prevention of fellow eye involvement) Kupersmith et al.36 1997 Aspirin R 100 total NAION in fellow eye: Aspirin may decrease risk 57 treated At 2 years: of AION in the fellow 43 untreated 17.5% of treated eye 53.5% of untreated Beck et al.37 1997 Aspirin R 431 total NAION in fellow eye: Aspirin does not decrease 153 treated At 2 years: risk of AION in the 278 untreated 7% of treated fellow eye 15% of untreated At 5 years: 17% of treated 20% of untreated Salomon et al.38 1999 Aspirin R 52 total NAION in fellow eye: Aspirin may decrease risk 36 treated 22.2% of treated of AION in the fellow 16 untreated 50% of untreated eye IONDT5 2002 Aspirin P* 326 total NAION in fellow eye: Aspirin does not decrease At baseline{: Aspirin at baseline: risk of AION in the 87 treated 20% of treated fellow eye 237 untreated 13% of untreated After baseline{: Aspirin after baseline:

86 treated 15% of treated 5 240 untreated 15% of untreated shmcOtcNeuropathies Optic Ischemic *Although the IONDT was a prospective trial to evaluate optic nerve sheath decompression, it was not a prospective trial to evaluate aspirin therapy. Aspirin data are observational only. {Reported starting regular aspirin use 1 month before onset of symptoms at baseline visit. {Responded positively to “started regular use” of aspirin on at least one study visit after baseline. IONDT, Ischemic Optic Neuropathy Decompression Trial; ONSF, optic nerve sheath fenestration; P, prospective; R, retrospective; VA, visual acuity; VF, visual field. 123 124 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 5–4 Ophthalmologic Manifestations of Giant Cell Arteritis

Ischemic optic neuropathy Anterior ischemic optic neuropathy Posterior ischemic optic neuropathy Choroidal infarction Central retinal artery occlusion Branch retinal artery occlusion Cilioretinal artery occlusion Central retinal vein occlusion Ophthalmic artery occlusion Ischemic ocular syndrome Corneal edema Anterior uveitis Cataract Ocular hypertony (neovascular glaucoma) Ocular hypotony Retinal hemorrhages (venous stasis retinopathy) Retinal neovascularization Orbital ischemia Orbital pain Diplopia (ischemia of the extraocular muscles) Proptosis Cranial nerve ischemia Diplopia (third, fourth, and sixth nerve ischemia) Cerebral ischemia Brainstem ischemia (diplopia) Occipital lobe infarction (cerebral blindness) Visual hallucinations Tonic pupil Horner’s syndrome

of peripapillary, retinal, or choroidal ischemia in addition to the AION is highly suspicious for giant cell arteritis (Figs. 5–8 and 5–9); (4) the degree of visual loss tends to be more severe in arteritic AION, with initial visual loss between count fingers and no light perception in 54% of patients, compared with 26% of NAION patients1,42; if untreated, arteritic AION becomes bilateral within days to weeks in at least 50% of cases1,42; (5) the affected swollen optic nerve is often pale acutely in giant cell arteritis (Fig. 5–10), whereas pallor is delayed in NAION; and (6) a disc at risk is not necessary for arteritic AION.1,6 There- fore, a thorough history and ocular examination evaluating the cup-to-disc ratio and looking for other signs of ocular ischemia are of paramount importance in the diagnosis of arteritic AION. In difficult cases, retinal fluorescein angiography can be very helpful at detecting choroidal hypoperfusion (Fig. 5–11).1

DIAGNOSTIC TESTS The erythrocyte sedimentation rate (ESR) is greater than 40 mm/hour in at least 77% of patients with active, untreated giant cell arteritis. An ESR greater than 50 mm/hour is one of the five diagnostic criteria used by the American College 5 Ischemic Optic Neuropathies 125

Figure 5–8 Acute arteritic anterior ischemic optic neuropathy in a patient with giant cell arteritis. In addition to the optic nerve head swelling which is already pallid, there are peripapillary changes suggesting extensive ischemia of the posterior pole of the eye (involving the retina and the choroid). Involvement of more than one vascular territory is highly suggestive of arteritic anterior ischemic optic neuropathy.

Figure 5–9 Acute bilateral visual loss in giant cell arteritis. The right optic nerve (left image) is swollen inferiorly, suggesting an anterior ischemic optic neuropathy; the left optic nerve (right image) is normal, suggesting a posterior ischemic optic neuropathy. In addition, the peripapillary areas in both eyes are abnormal secondary to choroidal ischemia, and there are cotton wool spots in the left eye related to inner retinal ischemia.

Figure 5–10 Acute arteritic anterior ischemic optic neuropathy in a patient with giant cell arteritis. The nerve is swollen and the arteries very attenuated. Although the visual loss is acute, the nerve is already pale with a chalky appearance. 126 Neuro-Ophthalmology: Blue Books of Neurology

Figure 5–11 Acute right arteritic anterior ischemic optic neuropathy, left retinal ischemia, and bilateral choroidal ischemia in a patient with giant cell arteritis. A, The right optic nerve is swollen (left image), suggesting an anterior ischemic optic neuropathy. Although the patient has no visual symptoms in her left eye (right image), there is a cotton wool spot below the optic nerve, suggesting an area of retinal ischemia. B, Retinal fluorescein angiography of the same patient showing delayed and patchy choroidal filling in both eyes; normal choroid should appear “white” (filled with fluorescein) approximately 30 seconds after injection. In this patient, filling is still patchy more than 1 minute after injection.

of Rheumatology. When the ESR is raised, the disease process correlates well with the ESR level and, hence, facilitates monitoring of the disease. However, the ESR is a nonspecific marker of a variety of inflammatory, infectious, and neoplastic disorders and may be normal in 7% to 20% of patients with giant cell arteritis before treatment. Therefore, a normal ESR does not rule out giant cell arteritis.39,40 In patients with clinical symptoms suggestive of giant cell arteritis and a normal ESR, the ESR should be repeated weekly because its elevation can be delayed. In addition, levels of other acute phase response markers, such as C-reactive protein or fibrinogen, should be obtained. Other laboratory tests such as complete blood count, platelet count, and hepatic alkaline phospha- tase may also be useful in this setting, because most patients have a mild-to- moderate anemia of chronic disease, and approximately one third of patients have mildly abnormal liver function tests. Thrombocytosis (elevated platelet count) is also common.39,40 They may also be used to monitor patients with giant cell arteritis. As emphasized previously, fluorescein angiography is often very useful in the diagnosis of giant cell arteritis (Fig. 5–11). It is a widely available, safe, and relatively inexpensive diagnostic tool for many retinal, choroidal, and optic nerve disorders. As opposed to NAION (which tends only to affect the posterior ciliary circulation), the multifocal nature of arteritic AION often leads to involvement of both the posterior ciliary and choroidal circulations; therefore, when extensive 5 Ischemic Optic Neuropathies 127

choroidal hypoperfusion is identified by fluorescein angiography (Fig. 5–11) in the setting of ION, an arteritic etiology is highly likely.1 Magnetic resonance imaging (MRI) is not a classic diagnostic test for AION. However, MRI is often obtained as a component of the diagnostic evaluation for a unilateral optic neuropathy. Although the MRI is normal in NAION, orbital fat enhancement and optic nerve and nerve sheath enhancement have been reported in arteritic AION.1 Temporal artery biopsy is the gold standard for definitive diagnosis. Although diagnosis of arteritic AION may be suspected on clinical grounds, biopsy confirmation of giant cell arteritis is essential, especially given the complication rate associated with the subsequent necessary long-term steroid therapy.1,39,40

TREATMENT AND OUTCOME Corticosteroid responsiveness and improved outcome with early treatment make immediate and aggressive initiation of therapy the goal to prevent permanent visual loss. The following treatment suggestions are those generally recommended by neuro-ophthalmologists confronted with patients with a significant danger of high visual morbidity. The aggressive treatment suggestions differ from those often recommended by rheumatologists, who may more regularly treat the systemic symptoms of giant cell arteritis in patients unaffected by visual loss. In a patient with arteritic ION, systemic corticosteroids should be promptly instituted on suspected diagnosis and should not be delayed for temporal artery biopsy. In the setting of visual loss, high-dose (1 to 2 g/day for 2 to 3 days) intravenous steroids followed by high-dose oral steroids are recommended, although no prospective studies evaluating this therapy have been performed.1,39–41,43–46 If oral prednisone alone is used, doses in the range of 1 to 2 mg/kg/day are suggested. Maintenance therapy in this dose range should be continued for at least 4 to 6 weeks, until normalization of laboratory inflammatory markers occurs, to be followed by a slow taper over the next 12 to 18 months, with careful follow-up of ESR and C-reactive protein. The rate of steroid taper is approximately 10 mg per month initially, then decreased to 5 mg per month, and even as low as 1 mg per month, once a dose of 10 or 15 mg per day is reached. A maintenance dose of 5 to 7.5 mg/day is generally adequate after the first 6 to 12 months of therapy. Alternate-day steroid regimens are not recommended, because rebound arteritis has been associated with this regimen. Response of systemic symptoms is usually rapid and dramatic, with relief of headache and malaise within 24 hours. Unfortunately, only 4% to 15% of patients with arteritic AION experience improvement in visual loss with therapy.1,41,44,45 Recent reports emphasize that, if improvement does occur, it usually consists of improvement in visual acuity in the presence of persistent, often severe, visual field defects.44,45 Steroid treatment also aims to prevent involvement of the unaffected eye; however, progression of visual loss or second eye involvement occasionally occurs despite high-dose systemic therapy. If this occurs, it tends to be within a few days of initiation of therapy.46 Recurrence of symptoms or relapse elevation of ESR and C-reactive protein occurs in more than half of patients as steroids are tapered.41,42,44 Immediate 128 Neuro-Ophthalmology: Blue Books of Neurology

elevation of the steroid dose to the last dose before relapse is suggested. Because of the high rate of steroid complications, especially in the elderly population, there is substantial interest in steroid-sparing agents; however, none has proven useful in randomized studies to date.40 The anti-inflammatory effects of aspirin have been suggested as potentially beneficial for visual outcome, but there are no prospective studies.1,40 Anticoagu- lation has also been tried, with no proven benefit.1

Posterior Ischemic Optic Neuropathy

PION is relatively uncommon compared with AION. The diagnosis of PION is usually made only after other causes of a retrobulbar optic neuropathy (e.g., inflammatory, toxic, compressive) have been excluded.1,47,48 Although both AION and PION are manifestations of vascular insufficiency to the optic nerve, they represent two very different pathophysiologic entities. This distinction is related primarily to the marked difference in vascular supply between the anterior and posterior segments of the optic nerve (see previous discussion) (Fig. 5–1). The posterior segment of the optic nerve is supplied only by the pial capillary plexus that surrounds it; only a small number of capillaries actually penetrate the nerve and extend to its central portion among the pial septae. As a result, the center of the posterior portion of the optic nerve is relatively poorly vascularized compared with its anterior portion.1,48 There is no known structural abnormality of the optic nerve that has been identified in patients with PION similar to the disc at risk seen with AION. However, the portion of the optic nerve affected in PION, by definition, is not visible during ocular funduscopic examination. Acutely, patients with PION have sudden vision loss in one eye, typically painless. Examination reveals decreased visual acuity, visual field loss, and a relative afferent pupillary defect but a normal-appearing optic disc (Fig. 5–3).1,47,48 The two main causes of PION are perioperative PION and giant cell arteritis, and the latter should be excluded in all patients older than 50 years.

Perioperative Ischemic Optic Neuropathy

Perioperative visual loss is a devastating injury that has been reported after various types of surgeries. AION may occur rarely after intraocular surgery such as cataract extraction or after intraocular injections. The presumed mechanism is optic nerve head ischemia secondary to fluctuations in intraocular pressure.28–30 IONs may also occur after nonocular surgeries and during procedures such as dialysis or even cardiac catheterization.1,49 Although this complication has been reported after many types of surgery, the two most classic are coronary artery bypass procedures (Fig. 5–12) and spine surgery (Fig. 5–3).1,50–52 During coronary artery bypass, AION is probably more common than PION, presumably related to fluctuations in blood pressure and blood loss.1,50 During the past decade, there has been a growing concern about ION in the setting of spine surgery performed in the prone position.52 Most of the reported cases are PION, are frequently bilateral, and typically have a poor visual prognosis. The etiology 5 Ischemic Optic Neuropathies 129

Figure 5–12 Bilateral anterior ischemic optic neuropathies after coronary artery bypass graft surgery. This 68-year-old man underwent an uncomplicated coronary artery bypass graft procedure. He awoke from anesthesia with visual loss in both eyes that worsened over a few days. Visual acuity was 20/400 in the right eye and 20/80 in the left eye. His vision did not improve. A, Bilateral optic nerve head edema suggesting bilateral anterior ischemic optic neuropathies. B, Goldmann visual fields show bilateral inferior altitudinal defects involving the central field in the right eye. C, Six weeks later, both optic nerves are pale. The disc edema has resolved and there are peripapillary changes consistent with previous disc edema. 130 Neuro-Ophthalmology: Blue Books of Neurology

remains debated and poorly understood. A recent review52 noted that these complications cannot be explained only by relative hypotension and anemia because these are common occurrences during spine surgery. The prone position, length of surgery, and amount of blood loss may be related, but no case-control study has yet determined any specific factor definitively associated with visual loss. Although direct pressure on the globes from the headrest has been postulated as a factor in a few cases, this would be an unlikely cause of PION (in which elevation of intraocular pressure by external compression should not affect retrobulbar blood flow) and even AION, but it accounts for the rare unilateral case of central retinal artery occlusion in this setting. Finally, there may be an anatomical “watershed” region involving the vascular supply of the posterior optic nerves in some individuals, rendering these patients susceptible to fluctuations in blood pressure and oxygen delivery that would not affect others.1,47,52 Further data are necessary to determine what factors are relevant, and the anesthesia commu- nity is currently acquiring such information. Until such data are available, both surgeons and anesthesiologists should be encouraged to discuss the small but significant potential risk for visual loss in patients undergoing prolonged spine surgery in the prone position, especially if the patient has underlying vascular risk factors and the surgery is expected to entail significant blood loss or hypotension, or both.

Radiation Optic Neuropathy

Radiation optic neuropathy is thought to be an ischemic disorder of the optic nerve that usually results in irreversible severe visual loss months to years after radiation therapy to the brain, skull base, paranasal sinuses, and orbits.1,53 It is most often a retrobulbar process. Patients typically present with rapidly progressive painless loss of vision in one eye, which often becomes bilateral within weeks or months. Characteristically there is marked enhancement of the affected optic nerve on MRI.1,53 There is currently no known effective treatment, although corticosteroids and hyperbaric oxygen are often prescribed.1,53,54

Diabetic Papillopathy and Pre-AION Optic Disc Edema

Patients may develop disc swelling from AION before they have any visual symptoms. 1,55 The asymptomatic disc swelling is often noted in the fellow eye of a patient with a previous history of AION. The mechanism of disc swelling in these cases is presumed to be ischemia.1,55 Similarly, young patients with diabetes mellitus may develop disc swelling in one eye with no or very mild visual loss; so-called diabetic papillopathy. The swelling may be unilateral or bilateral and the visual prognosis is usually excellent. In more than 80% of reported cases, diabetic retinopathy is present at the time of onset of diabetic papillopathy. The mechanism remains unknown, although ischemia of the optic nerve head is most likely. Another potential cause of optic nerve swelling is vitreal traction1,55 (Fig. 5–13). 5 Ischemic Optic Neuropathies 131

Figure 5–13 Diabetic papillopathy. Optic nerve head edema with some vitreous traction in a patient with proliferative diabetic retinopathy. The visual function is normal and there is no relative afferent pupillary defect.

REFERENCES 1. Arnold AC: Ischemic optic neuropathy. In Miller NR, Newman NJ, Biousse V, Kerrison JB, (eds): Clinical Neuro-Ophthalmology, 6th ed, vol 1. Baltimore, Williams & Wilkins, 2005, pp 349–384. 2. Ischemic Optic Neuropathy Decompression Trial (IONDT) Research Group: Optic nerve decompression surgery for non-arteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA 1995;273:625–632. 3. Ischemic Optic Neuropathy Decompression Trial (IONDT) Research Group: Ischemic optic neuropathy decompression trial: Twenty-four-month update. Arch Ophthalmol 2000;118:793–798. 4. Ischemic Optic Neuropathy Decompression Trial (IONDT) Research Group: Characteristics of patients with non-arteritic anterior ischemic optic neuropathy eligible for the ischemic optic neuropathy decompression trial. Arch Ophthalmol 1996;114:1366–1374. 5. Newman NJ, Scherer R, Langenberg P, et al: The fellow eye in NAION: Report from the ischemic optic neuropathy decompression trial follow-up study. Am J Ophthalmol 2002;134:317–328. 6. Hayreh SS: Anterior ischemic optic neuropathy: Differentiation of arteritic from non-arteritic type and its management. Eye 1990;4:25–41. 7. Arnold AC: Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuro-ophthalmol 2003;23:157–163. 8. Beck RW, Servais GE, Hayreh SS: Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 1987;94:1503–1508. 9. Chi T, Ritch R, Stickler D, et al: Racial differences in optic nerve head parameters. Arch Ophthal- mol 1989;107:836–839. 10. Rizzo JF, Lessell S: Optic neuritis and ischemic optic neuropathy: Overlapping clinical profiles. Arch Ophthalmol 1991;109:1668–1672. 11. Horton JC: Mistaken treatment of anterior ischemic optic neuropathy with interferon beta-1a. Ann Neurol 2002;52:129. 12. Purvin V, King R, Kawasaki A, Yee R: Anterior ischemic optic neuropathy in eyes with optic disc drusen. Arch Ophthalmol 2004;122:48–53. 13. Hayreh SS, Joos KM, Podhajsky PA, Long CR: Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1994;18:766–780. 14. Jacobson DM, Vierkant RA, Belongia EA: Nonarteritic anterior ischemic optic neuropathy. A case-control study of potential risk factors. Arch Ophthalmol 1997;115:1403–1407. 15. Mojon DS, Hedges TR, Ehrenberg B, et al: Association between sleep apnea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 2002;120:601–605. 16. Deramo VA, Sergott RC, Augsburger JJ, et al: Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients. Ophthalmology 2003;110:1041–1045. 132 Neuro-Ophthalmology: Blue Books of Neurology

17. Fry CL, Carter JE, Kanter MD, et al: Anterior ischemic optic neuropathy is not associated with carotid artery atherosclerosis. Stroke 1993;24:539–542. 18. Biousse V, Schaison M, Touboul PJ, D’Anglejan-Chatillon J, Bousser MG: Ischemic optic neuropathy associated with internal carotid artery dissection. Arch Neurol 1998;55:715–719. 19. Feldon SE: Anterior ischemic optic neuropathy: trouble waiting to happen. Ophthalmology 1999;4:651–652. 20. Salomon O, Huna-Baron R, Kurtz S, et al: Analysis of prothrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy. Ophthalmology 1999;106: 739–742. 21. Weger M, Stanger O, Deutschmann H, et al: Hyperhomocysteinemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy. Br J Ophthalmol 2001;85:803–806. 22. Lee AG: Prothrombotic and vascular risk factors in non-arteritic anterior ischemic optic neuropathy. Ophthalmology 2000;107:2231. 23. Biousse V: The coagulation system. J Neuro-ophthalmol 2003;23:50–62. 24. Murphy MA, Murphy JF: Amiodarone and optic neuropathy: The heart of the matter. J Neuro- ophthalmol 2005;25:232–326. 25. Chiari M, Manzoni GC, Van de Geijn EJ: Ischemic optic neuropathy after sumatriptan in a migraine with aura patient. Headache 1994;34:237–238. 26. Fivgas G, Newman NJ: Anterior ischemic optic neuropathy following the use of a nasal decongestant. Am J Ophthalmol 1999;127:104–106. 27. Lee AG, Newman NJ: Erectile dysfunction drugs and non-arteritic anterior ischemic optic neuropathy. Am J Ophthalmol 2005;140:707–708. 28. Lee AG, Kohnen T, Ebner R, et al: Optic neuropathy associated with laser in situ keratomileusis. J Cataract Refract Surg 2000;26:1581–1584. 29. McCulley TJ, Lam BL, Feuer WJ: Non-arteritic anterior ischemic optic neuropathy and surgery of the anterior segment: Temporal relationship analysis. Am J Ophthalmol 2003;136:1171–1172. 30. Slavin ML, Margulis M: Anterior ischemic optic neuropathy following acute angle-closure glaucoma. Arch Ophthalmol 2001;119:1215. 31. Arnold AC, Hepler RS, Lieber M, Alexander JM: Hyperbaric oxygen therapy for non-arteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1996;122:535–541. 32. Botelho PJ, Johnson LN, Arnold AC: The effect of aspirin on the visual outcome of non-arteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1996;121:450–451. 33. Johnson LN, Guy ME, Krohel GB, Madsen RW: Levodopa may improve vision loss in recent- onset, nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2000;107:521–526. 34. Soheilian M, Koocheck A, Yazdani S, Peyman GA: Transvitreal optic neurotomy for nonarteritic anterior ischemic optic neuropathy. Retina 2003;23:692–697. 35. Fazzone HE, Kupersmith MJ, Leibmann J: Does topical brimonidine tartrate help NAION? Br J Ophthalmol 2003;87:1193–1194. 36. Kupersmith M, Frohman L, Sanderson M, et al: Aspirin reduces the incidence of non-arteritic anterior ischemic neuropathy: A retrospective study. J Neuro-ophthalmol 1997;17:250–253. 37. Beck RW, Hayreh SS, Podhajsky PA, et al: Aspirin therapy in non-arteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1997;123:212–217. 38. Salomon O, Huna-Baron R, Steinberg DM, et al: Role of aspirin in reducing the frequency of second eye involvement in patients with non-arteritic ischaemic optic neuropathy. Eye 1999;13:357–359. 39. Salvarani C, Cantini F, Boiardi L, Hunder GG: Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347:261–271. 40. Weyand CM, Goronzy JJ: Medium and large vessel vasculitis. N Engl J Med 2003;349:160–169. 41. Hayreh SS, Zimmerman B: Management of giant cell arteritis: our 27-year clinical study: New light on old controversies. Ophthalmologica 2003;217:239–259. 42. Hayreh SS, Podhajsky PA, Zimmerman B: Occult giant cell arteritis: Ocular manifestations. Am J Ophthalmol 1998;125:521–526. 43. Liozan E, Herrmann F, Ly K, et al: Risk factors for visual loss in giant cell (temporal) arteritis: A prospective study of 174 patients. Am J Med 2001;111:211–217. 44. Hayreh SS, Zimmerman B, Kardon RH: Visual improvement with corticosteroid therapy in giant cell arteritis: Report of a large study and review of literature. Acta Ophthalmol Scand 2002;80:353–367. 45. Foroozan R, Deramo VA, Buono LM, et al: Recovery of visual function in patients with biopsy- proven giant cell arteritis. Ophthalmology 2003;110:539–542. 5 Ischemic Optic Neuropathies 133

46. Hayreh SS, Zimmerman B: Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy. Ophthalmology 2003;110:1204–1215. 47. Sadda SR, Nee M, Miller NR, et al: Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol 2001;132:743–750. 48. Hayreh SS: Posterior ischaemic optic neuropathy: Clinical features, pathogenesis, and management. Eye 2004;18:1188–1206. 49. Buono LM, Foroozan R, Savino PJ, et al: Posterior ischemic optic neuropathy after hemodialysis. Ophthalmology 2003;110:1216–1218. 50. Shapira OM, Kimmel WA, Lindsey PS, Shahian DM: Anterior ischemic optic neuropathy after open heart operations. Ann Thorac Surg 1996;61:660–666. 51. Cheng MA, Sigurdson W, Templehoff R, Lauryssen C: Visual loss after spine surgery: A survey. Neurosurgery 2000;46:625–631. 52. Ho VT, Newman NJ, Song S, Ksiazek S, Roth S: Ischemic optic neuropathy following spine surgery. J Neurosurg Anesthesiol 2005;17:38–44. 53. Lessell S: Friendly fire: Neurogenic visual loss from radiation therapy. J Neuro-ophthalmol 2004;24:243–250. 54. Miller NR: Radiation-induced optic neuropathy: Still no treatment. Clin Exp Ophthalmol 2004;32:233–235. 55. Almog Y, Goldstein M: Visual outcome in eyes with asymptomatic optic disc edema. J Neuro- ophthalmol 2003;23:204–207. 6 Optic Neuritis DESMOND P. KIDD GORDON T. PLANT

Introduction Cerebrospinal Fluid

Epidemiology The Natural History of Optic Neuritis Clinical Features: Symptoms Residual Visual Loss Following Orbital Pain and Headache Optic Neuritis Visual Loss Recurrent Optic Neuritis Positive Visual Phenomena Relationship to Multiple Clinical Features: Signs Sclerosis Visual Acuity Clinical Data The Pupillary Reactions Magnetic Resonance Imaging Visual Field Data Ophthalmoscopic Abnormalities Cerebrospinal Fluid Data Abnormalities in the Fellow Eye Treatment Diagnosis Blood Investigation Summary Visual Evoked Potential Magnetic Resonance Imaging References

Key Points Optic neuritis is a common neuro-ophthalmologic condition with an incidence of 1 to 5 per 100,000 people. It presents as a subacute, often painful optic neuropathy that usually starts to improve quickly after the symptoms reach their nadir. Recovery in general is excellent, with 75% of patients regaining satisfactory visual acuity, although residual neurologic symptoms and signs are common. MRI shows a high signal lesion within the affected nerve associated with enhancement in almost all cases. Often the nerve is seen to be swollen; after recovery it becomes smaller than normal, implying that atrophy has occurred. This correlates with thinning of the retina seen on OCT. The risk of developing multiple sclerosis after optic neuritis increases from 40% at 5 years to 60% at 40 years.

134 6 Optic Neuritis 135

Introduction

Optic neuritis is a subacute disorder caused by inflammation within the optic nerve that leads to visual impairment comprising loss of visual acuity, color vision, and contrast sensitivity. It may affect one or both eyes and may arise at any age, and many different disease processes may be associated with it. This chapter deals with the most common cause of the disorder, a primary demyelinating disease in which optic neuritis may develop as the first manifestation or during the course of multiple sclerosis (MS). The next chapter deals with similar disorders of different pathophysiology.

Epidemiology

The natural history of optic neuritis has been investigated in detail in several studies1–8 (Nettleship: 28 cases, Traquair: 160 cases, Carroll: 100 cases, Bagley: 133 cases, Bradley and Whitty: 73 cases, Nikoskelainen: 185 cases, Hutchinson: 144 cases, and Perkin and Rose: 170 cases) over the past 125 years. The most important recent study of optic neuritis has been the carefully planned and followed prospective study, the Optic Neuritis Treatment Trial (ONTT), in which 457 patients were enrolled over a 3-year period in 15 U.S. centers.9 These have shown that optic neuritis is a disorder of the young, with the majority of patients presenting at 20 to 50 years2,5–9 (mean 32 years). It is more common in females than in males (Table 6–1). Like MS, it is more common in Caucasians, in particular, in peoples of Northern European genetics.10 The incidence is highest in the spring months.7,11 There have been two formal epidemiologic studies; the first, from Mayo Clinic, identified 156 cases, and the annual age- and sex-adjusted incidence rate of optic neuritis between 1985 and 1991 was 5.1 per 100,000 person-years, with a prevalence of 115 105.12 This is a high prevalence, indeed similar to the prevalence of MS in the United Kingdom,13 but so too is the prevalence of MS in Minnesota.14 The second took place in Stockholm County, Sweden (population 1.6 M), between 1990 and 1995 and revealed 150 consecutive patients with mean age at onset of 31.7 8.4 years and a female-male ratio of 4.07. The crude mean annual incidence was 1.46 per 105 person-years,10,11 lower than that in Minnesota.

Clinical Features: Symptoms

ORBITAL PAIN AND HEADACHE Pain within and around the affected eye arises before or at the time of the onset of visual loss in about 90% of cases and has equal prevalence in those with and without optic disc swelling.5,7–9 Pain most often arises at the onset of visual symptoms, but in one series it preceded the symptoms by more than 1 week in 19% of cases.5 Characteristically the pain is experienced as a dull ache around the eye initially that worsens over hours or days and becomes sharp and stabbing within the eye. Most experience a worsening of this pain when the eye is moved in a certain TABLE 6–1 Summary of the Principle Results of the Large Studies Carried Out Over the Past 30 Years

CSF Pleocytosis (Oligoclonal Recovery Study Number % Female Age Acuity Papillitis Uveitis Bands) MRI (at 6 Months)

Bradley and 73 63 82% 20–50 6/9–NPL 17% Not stated 33% Not available 6/5–6/9 in 75% Whitty5 Nicoskelainen6 185 57 81% 20–50 0.8–NPL 23% 3 had Not stated Not available 6/5–6/9 in 56% vitreous cells 3 had periphlebitis 2 had neuroretinitis Hutchinson7 144 73 74% 20–50 6/9–NPL 17% Not stated 35% Not available 72% “good” 15% “fair” 13% “poor” Perkin and Rose8 170 65 33.5 (10–60) 6/6–NPL 58% 8 15% Not available 6/6–6/12 in 75% Jin et al.10 150 71 31.7 8.4 Not stated 19% Excluded 45% 55% >3 WML 6/5–6/12 in 93% (22% had (68%) poor acuity) Sandberg- 86 68/86 28 (14–55) Not stated 29% Not stated 54% 44% “abnormal” Not stated Wolheim et al.56 (41%) ONTT 457 77 32 6.7 20/20–NPL 35% 1.8% had retinal 36% 26.7% >2 WML 20/20–20/40 (18–46 only) exudates (50%) in 93% 3.3% had vitreous cells

NPL, no perception of light; WML, white matter lesion. 6 Optic Neuritis 137

or several directions; 51% of patients in the ONTT noted this feature and a further 35% experienced pain only on eye movement. Pain is presumably related to the trigeminal afferents arising from the inflamed and swollen optic nerve sheath.1,8 Lepore15 found that pain was less common in patients with disc swelling than without, although this was not seen in the ONTT.9 Pain is less common in anterior ischemic optic neuropathy (AION),16,17 but common, and often more severe, in other forms of optic neuritis such as that in CRION (chronic relapsing inflammatory optic neuropathy), sarcoid, infections, and that related to sinus mucoceles.

VISUAL LOSS Visual symptoms begin after the onset of pain, and pain itself tends to diminish as the visual loss develops. It begins in a subacute way and evolves over hours to, more typically, days. Patients often note a gray cloud or veil in front of the eye, particularly involving the central field; those with more severe visual loss note evolution from a veil to a scotoma in which severe blurring or nothing is seen in one part of the field. Although uncommon, visual loss may proceed to no perception of light.

POSITIVE VISUAL PHENOMENA Phosphenes or photopsias were noted by 30% of ONTT patients9; these are flashes of white or black shapes and showers of sparkles. Often spontaneous, they may also be stimulated by rubbing the eye; moving it; or, rarely, by auditory stimuli.18 Phosphenes or photopsias are more visible in the dark or with the eyes closed, and some patients notice them only under these conditions.

Clinical Features: Signs

These are the signs of an optic neuropathy with reduction in central acuity, color vision, and contrast sensitivity; an afferent pupillary abnormality; and a visual field defect. Ophthalmoscopic or slit lamp evidence for an inflammatory disorder is seen in only a small number of cases (see the section entitled “Ophthalmoscopic Abnormalities”).

VISUAL ACUITY Visual acuity deteriorates over 1 to 7 days to a nadir, which remains for only a short time before recovery begins; in the ONTT the mean visual acuity was 20/80 (6/24), with 162 patients having acuity of 20/40 (6/12) or better, 166 patients with 20/200 (6/60) or worse, and 129 in between; 3.1% had no perception of light. The mean pattern deviation of the visual field was –23.02 dB (–31.9 to –12.25 dB).9 Tests of color vision are important in cases in which central acuity is not or only slightly reduced; Ishihara or Hardy-Rand-Rittler pseudoisochromatic plates reveal often striking abnormalities of color vision even under these circumstances. Others less severely affected will note that the colors of the plates appear washed out or less distinct when compared with the asymptomatic eye. Clearly those with more profound visual loss, particularly those with central field defects, will be unable to perform the test. 138 Neuro-Ophthalmology: Blue Books of Neurology

Achromatic contrast sensitivity measures the minimum detectable spatial luminance change of vision. It is least likely of all measures to recover completely (see Residual Visual Loss Following Optic Neuritis). In the ONTT, contrast sensitivity thresholds were abnormal in 98% of cases.

THE PUPILLARY REACTIONS Providing the integrity of the fellow optic nerve is not impaired, the patient will show a relative afferent pupillary defect or Marcus Gunn phenomenon when tested carefully. This was noted in 76% of cases in Perkin and Rose’s study. Patients with previous symptomatic or asymptomatic optic neuritis in the other eye may not show this phenomenon.

VISUAL FIELD Previously it was considered that central defects alone accounted for the field defects seen in optic neuritis8; however, the ONTT data show that any possible kind of field defect may arise,19 including arcuate, altitudinal, quadrantic, and hemianopic defects as well as peripheral constrictions and multiple paracentral scotomas. In the ONTT, central or centrocecal scotomas were seen only in 8% of cases out of 415 patients tested (Fig. 6–1).

OPHTHALMOSCOPIC ABNORMALITIES Two percent to 35% of patients show evidence for disc swelling (Fig. 6–2, Table 6–1). The remainder, therefore, have “retrobulbar neuritis.” The degree to which the disc is swollen does not correlate with the degree of visual loss.8 Only a minority of patients show disc or peripapillary hemorrhages, in contrast to that which is seen in AION. The disc may therefore appear completely normal in the acute phase. Disc pallor at the onset of symptoms may indicate a previous asymptomatic episode but should also serve as a warning that an acute worsening of a more chronic compressive lesion (e.g., an aneurysm or a sinus mucocele) may be responsible. Vitreous cells may be seen but when they are numerous an alternative etiology, for example sarcoidosis, should be considered. Sheathing of retinal vessels (Fig. 6–3), or periphlebitis retinans, may occur, but this is also seen in sarcoidosis, Behc¸et’s syndrome, and other conditions (see next chapter). In one series of 50 consecutive patients with acute optic neuritis seen at Moorfields Eye Hospital, 14 were seen to have ocular abnormalities at the time of presentation; perivenous sheathing arose in 6, of whom 4 had evidence for fluorescein leakage and a further 6 had fluorescein leakage without clinically evident perivenous sheathing. Media cells were seen in a further 2 cases.20 In the ONTT, such abnormalities were less common; 3.3% had vitreous cells, 1.8% had retinal exudates, and 5.6% had peripapillary hemorrhages. Pars planitis and intermediate uveitis may also be seen and can precede the onset of the demyelinating disorder by many years.21 The prevalence in that study, however, was only 1% of 2628 patients attending MS and uveitis clinics in France. Pars planitis has a particular association with MS; of 36 patients followed up, 12 developed optic neuritis, MS or both, giving a 20.4% risk over 6 Optic Neuritis 139

Figure 6–1 A summary of the visual field defects seen in the optic neuritis treatment trial. (From Optic neuritis study group: Arch Ophthalmol 1993;111:231–234.) 140 Neuro-Ophthalmology: Blue Books of Neurology

Figure 6–2 Acute optic neuritis. A, Mild disc swelling. B, Temporal disc pallor.

5 years of developing either condition following the onset of the retinal disorder. The presence of perivenous sheathing increased the risk in that study.22

ABNORMALITIES IN THE FELLOW EYE Bilateral optic neuritis is more common than is realized; in Bradley and Whitty’s study of 72 cases, 5 were bilateral and simultaneous, and in 9 and 7 cases the second eye became involved less than and more than 3 months later, respectively. In Hutchinson’s study,19% of 144 cases were bilateral, and 30% of Nikoskelainen’s cohort of 185 cases was bilateral. The ONTT excluded bilateral optic neuritis. Asymptomatic abnormalities of visual function, however, are common; 43% of one series of 53 patients from Holland were found to have abnormalities of acuity, contrast sensitivity,or visual field in the unaffected eye.23 In the ONTT, 417 patients had had no prior history of optic neuritis in the fellow eye; of these 12.2% had abnormal acuity,18.4% abnormal color vision, 15.4% abnormal contrast sensitivity,and a striking 46.3% had abnormal static perimetry. Only 34.1% of fellow eyes had no

Figure 6–3 Perivenous sheathing in acute optic neuritis. 6 Optic Neuritis 141

measurable abnormalities on testing.24 These deficits were observed to regress over several months, suggesting that, rather than these reflecting a previous asymptomatic optic neuropathy, these deficits reflect a subclinical concurrent involvement of the other optic nerve. These patients were no more likely to have an abnormal brain magnetic resonance imaging (MRI) or progression to CDMS (clinically definite multiple sclerosis) than those without fellow eye abnormalities. In another study,25,26 34% showed a delayed cortical pattern visual evoked potential (VEP) in the asymptomatic eye. A recent Italian study27 of a small number of patients with clinically definite MS who had not had symptoms of any visual disturbance during the course of their disease showed abnormalities of VEP in 54%, visual field in 63%, and contrast sensitivity in 73%. Only 1 patient in their cohort of 11 showed no abnormalities on any of these tests.

Diagnosis

The diagnosis is a clinical one based on the history provided and clear evidence for at least one sign of an optic neuropathy on clinical testing. The laboratory investigations noted later help to confirm the diagnosis but more importantly to rule out an alternative explanation for the symptoms and signs.

BLOOD INVESTIGATION Some authorities consider that it is not important to undertake serologic tests in cases of presumed optic neuritis28; in the ONTT, an anti-nuclear antibody was found at low titer in 13% and at high titer in 3.4%, and only one was seen subsequently to develop other signs of lupus. Serologic tests for syphilis were positive in 6%, and none was found to have active infection or cerebrospinal fluid (CSF) abnormalities in keeping with neurosyphilis. Nonetheless it is customary to arrange blood testing for erythrocyte sedimentation rate (ESR), FBC, chemistry screening, angiotensin converting enzyme (ACE), anti-nuclear antibody (ANA), vitamin B12, and sometimes syphilis serology. In general, patients with an acute demyelinating optic neuritis will recover quickly; if there are atypical features, then other tests to attempt to identify infectious, vasculitic, or other inflammatory causes would be indicated.29 This is reviewed in the next chapter.

VISUAL EVOKED POTENTIAL VEP is unhelpful in differentiating between inflammatory and compressive optic neuropathies in the early stages,30 but the pattern electroretinogram (ERG) is helpful in differentiating macular and retinal disorders, in which the P50 and N95 components of the ERG are abnormal, and in optic neuropathy, in which the P50 tends to remain normal, with a reduction in the amplitude of the N95.31 In the acute phase of optic neuritis, the VEP amplitude diminishes and its latency becomes prolonged; with recovery, the amplitude increases but not to normal, and the latency remains prolonged in all but about 10% of cases.32 The principle use of VEP is in the identification of an asymptomatic previous optic neuropathy in patients with clinically isolated syndromes elsewhere in the 142 Neuro-Ophthalmology: Blue Books of Neurology

nervous system who therefore may have laboratory support for the diagnosis of MS.33 This has become less important since the advent of MRI.

MAGNETIC RESONANCE IMAGING In the majority of patients, the phenotype of MS-associated optic neuritis can be diagnosed clinically. Spontaneous recovery to some degree is universal, but if corticosteroids are used this information may not be available. The decision to carry out imaging will depend on the need to confirm the diagnosis but also to determine the risk of a future, MS-defining, episode of neurologic symptoms. It could be argued that imaging investigations are always performed and are seldom necessary; only two patients enrolled in the ONTT were found to have compressive lesions. Nonetheless, high-resolution contrast-enhanced computed tomography (CT) and, more helpfully, for reasons noted later, MRI are usually performed. Either investigation will rule out compressive optic neuropathies such as meningioma or glioma of the optic nerve, tumors, aneurysms, and inflammatory and infective lesions that arise in the parasellar region and paranasal air sinuses. CT, because of its ability to detect calcification more readily, will detect optic neuropathies resulting from disc drusen. Orbital sequence MRI using short tau inversion recovery and fat-saturated fast spin echo sequences will show high signal lesions within the affected nerve in almost all cases34,35 (Fig. 6–4). Enhanced orbital MRI is more likely than CT to be helpful in distinguishing non-MS inflammatory optic neuropathies, and only MRI will show evidence for preexisting or concurrent white matter lesions that are predictive of MS (see later). The lesion seen within the optic nerve may occupy the entire length of the nerve or just a short segment. In one study,35 a high signal lesion was seen in 59 of 66 eyes studied: The mean length of the lesion was 3.1 1.9 5-mm MRI slices at onset. The length of the lesion and its position along the nerve was associated neither with acuity at onset nor to prognosis for recovery. Lesion length on T2-weighted sequences increased in some patients between initial MRI and follow-up at 6 months. The likely explanation for this is that the early change represents edema, which soon resolves, whereas the late change is the result of gliosis. These changes are permanent. T1-weighted sequences following gadolinium-based contrast agents injection will show enhancement within the nerve in 95% to 100% of cases36,37 and may show up other abnormalities in alternative disorders, such as sarcoid, CRION, perineuritis, and compressive disorders. In an early study, enhancement was seen

Figure 6–4 Magnetic resonance imaging showing (A) high signal lesion within the right optic nerve on T2-weighted imaging and (B) enhancement in the same region on T1-weighted imaging. 6 Optic Neuritis 143

in all 13 symptomatic optic nerves studied and was seen to have resolved within 4 weeks. This correlated with a return of the amplitude of the VEP, implying that enhancement is associated with conduction block in optic neuritis. Following recovery, there was an association between lesion length and latency of VEP.36 In another study, 107 cases underwent MRI at 8.7 6.0 days after the onset of symptoms of optic neuritis. Optic nerve enhancement was seen in 101 cases; the mean length of enhancing lesion was 14.6 9.3 mm. The lesion was seen within the orbital segment of the nerve in 43.9% of cases and within the canal in 35.4%. The lesion was intracranial in only 5.6% of cases.37 Long lesions were associated with lower central acuity, color vision, and threshold perimetry at onset, but there was no correlation between lesion length or site and subsequent recovery of vision. More recently38 it has been shown that with the use of triple-dose gadolinium the median length of enhancement was longer at 30 mm (0 to 39 mm) and that the duration of enhancement was also longer at 63 days (0 to 113 days). In all but two cases, the intracanalicular portion of the nerve was involved. The median lesion length on T2-weighted imaging was 24 mm (9 to 39 mm). Again, the lesion length did not correlate with nadir acuity, with visual field mean deviation, or with the VEP.However, although these parameters were associated with duration of enhancement, providing confirmation that enhancement does correlate with inflammation and hence with the establishment of conduction block, they did not correlate with the amplitude or the latency of the VEP. These patients also underwent imaging of optic nerve cross-sectional area; 20% showed evidence for optic nerve swelling during the acute phase. This subsequently resolved, and over time there was a tendency for optic nerve area to reduce from a mean of 16.1 mm2 compared with 13.4 mm2 for the contralateral nerve and 13.6 mm2 for normal controls, to 11.3 mm2, 12.8 mm2, and 13.1 mm2, respectively, implying that optic nerve atrophy occurred and hence that during or subsequent to optic neuritis axons are lost.39

CEREBROSPINAL FLUID Abnormal CSF constituents arise in 50% to 80% of cases (Table 6-1) and include modest lymphocytosis and protein increases but not usually greater than 50 per cm3 and 0.9 g/dl, respectively. Elevated immunoglobulin G (IgG) indices and the presence of oligoclonal bands arise in around 70%; in the ONTT, for example, 131 patients underwent a CSF examination of whom 36% had a pleocytosis, myelin basic protein (MBP) was detected in 18%, increased IgG synthesis in 44%, the IgG ratio was increased in 22%, and oligoclonal bands were seen in 50%. Kappa light chains were seen in 27%.40 The number of patients with no CSF abnormality was not stated. As noted later, it seems superfluous to perform a spinal fluid examination nowadays to establish the diagnosis and to assess risk of subsequent development of MS, but it should still be performed if there is concern that an alternative explanation may exist.

The Natural History of Optic Neuritis

Once improvement begins after optic neuritis it usually does so rapidly; in the ONTT, a substantial visual recovery was seen to have occurred within 2 weeks after onset of symptoms, indeed even in the placebo group the median acuity 144 Neuro-Ophthalmology: Blue Books of Neurology

had improved from 20/60 (6/18) to 20/25 (6/9) within 15 days.41 In another study, those who subsequently went on to recover well did so by a mean of 4.60 dB of visual field per day against those with a poor recovery who did so by a mean of 0.99 dB per day.39 Over 6 months, patients in all three treatment groups of the ONTT improved to the same degree, although the rate of early improvement was significantly higher in those treated with the intravenous steroid preparation. At 6 months, the incidence of normal visual acuity and contrast sensitivity was 0.60 and that of normal visual field nearly 0.80.41 This corresponds well with previous studies; in Bradley and Whitty’s study,5 75% had normal acuities at 6 months, and Nikos- kelainen reported 56% of her patients to have good visual acuity at the same time point.42 Hutchinson divided his patients up into those whose acuity had returned to “good” (6/6 to 6/9) (72% of cases), “fair” (6/12 to 6/36) (15%), and “poor” (worse than 6/60) (13%).7 Perkin and Rose found that 75% of their patients had recovered to 6/6 to 6/12.8 In the Swedish study, 97% had acuities of better or equal to 6/12 at 6 months.11 In the ONTT, the mean acuity at 1 year was 20/15 (6/5), and 93% of patients had acuities of better than 20/40 (6/12). Only 3% had acuities of worse than 20/200 (6/60).43 At 5 years, visual acuity was 20/25 (6/7.5) or better in 87%, 20/25 to 20/ 40 (6/7.5 to 6/12) in 7%, 20/50 to 20/190 (6/12 to 6/36) in 3%, and worse in 3%.44 At 10 years, 319 out of the original cohort of 454 were re-evaluated; 74% had acuities of 20/20 (6/6) at 10 years, including 49% of those whose acuity at onset was CF or NPL, 18% had acuities of 20/25 to 20/40 (6/7.5 to 6/12), 5% had 20/ 40 to 20/200 (6/12 to 6/60), and only 3% had worse vision than 20/200 (6/60)45 (Table 6–2). It is disappointing that there are no clear data that define the clinical variables that exist at the onset of the disorder that forecast the degree to which the patient will eventually recover. Some studies have found an association between nadir acuity and outcome,5,46–47 another that older age presaged a worse outcome,48 but others have not.3,6–8,45,49,50 Indeed Slamovits and colleagues identified five

TABLE 6–2 The Relationship of Visual Acuity at 10 Years to That at Entry to the Optic Neuritis Treatment Trial

Visual Acuity at Study Entry

Visual Acuity at Follow-up >20/20 <20/20–>20/ <20/40–>20/ <20/200– CF–NLP Total Examination (n ¼ 57) 40 (n ¼ 82) 200 (n ¼ 73) CF (n ¼ 62) (n ¼ 45) (n ¼ 319)

>20/400 96% 98% 99% 97% 91% 97% >20/200 96% 98% 99% 97% 91% 97% >20/100 96% 98% 97% 94% 87% 96% >20/40 96% 93% 93% 84% 76% 91% >20/25 95% 90% 89% 84% 62% 86% >20/20 91% 77% 77% 68% 49% 74%

From Optic neuritis study group: Am J Ophthalmol 2004;137:77–83. 6 Optic Neuritis 145

patients in a series of 12 whose acuity at nadir was no perception of light who subsequently regained 20/20 vision.50 MRI studies have also failed to identify prognostic factors; early studies suggested an association between lesion length or the presence of an intracanalicular lesion and outcome, but this has been refuted by later, larger studies.37,38 Studies of the VEP during recovery from optic neuritis have shown that VEP latency shortens following recovery; the most marked reduction occurs between the third and sixth month following the attack, but further reduction occurs progressively over the course of the remainder of a year then continues over the course of the following year more slowly.26 Fellow eye abnormalities remained abnormal over the 2-year period. Contrast sensitivity tends to improve over 9 months then remain static, and fellow eye abnormalities tended not to change over 2 years. These data suggest that the major improvement in vision that occurs following an acute optic neuritis occurs as a result of restitution of conduction, which is blocked in the presence of inflammation and edema, but that further improvement occurs in vision because of remyelination, which takes place over a period of 2 years.

RESIDUAL VISUAL LOSS FOLLOWING OPTIC NEURITIS Many patients with normal visual acuity following recovery, particularly those whose occupation is visually demanding—artists, graphic designers, and the like—complain that their vision is not what it was. Color vision in particular remains abnormal in many following recovery to 20/20 or 6/6 vision; Perkin and Rose found color deficits in 50% of their 120 cases, and 72% showed residual visual field abnormalities. Fleishman and colleagues51 studied 27 patients over 6 months following optic neuritis and found 11% had color deficits on Ishihara and 57% on Farns- worth Munsell 100 Hue test results. Contrast sensitivity thresholds were subnormal in 72%, and field defects were seen in 26%. Not 1 patient in their series of 27 had normal results in each of the investigations after a median of 33 months of follow-up, although it should be noted that these patients were invited to attend and there may have been a selection bias in the study. In another study, patients were reassessed 1 year after optic neuritis, and a complete recovery of vision as measured by the graded visual impairment scale was seen in only 65%.49 In general, residual symptoms are noted as an alteration in clarity of visual acuity; visual field defects may be apparent and color vision is noticeably worse on the affected side. Many patients note that their vision appears “washed out” on that side. Uhthoff phenomenon (a deterioration in visual acuity in circumstances of increased body temperature, for example, after a hot bath or during exercise) is noted by many, particularly following recovery, although it is on occasion the presenting complaint, following, presumably, an asymptomatic acute episode. Similarly, the Pulfrich phenomenon, in which misperception of motion in depth occurs, may arise after recovery.52,53 Commonly, patients will report that they misjudge the trajectory of objects moving toward them, especially in ball sports such as tennis but also with cars. Loss of stereopsis was found in 89% of one study.51 146 Neuro-Ophthalmology: Blue Books of Neurology

Residual visual symptoms following recovery arise as a result of persisting demyelination, but axonal loss contributes to the overall deficit. This is shown by virtue of the development of optic disc pallor beginning 3 months or so after the attack and was seen in 60% to 77% of some studies.6,8,51 It is possible to see retinal nerve fiber layer defects in MS even in those with normal central acuities with red-free filter photography54,55 and more recently in studies of retinal nerve fiber layer thickness using optical coherence tomography (OCT),56,57 in which thinning has been seen to occur in the affected eye following optic neuritis, alongside secondary macular ganglion cell loss.58 Residual abnormal visual function is significantly associated with these abnormalities in optic neuritis56 and in patients with MS who have had optic neuritis57; those without a history of optic neuritis also show abnormalities, albeit less pronounced. Atrophy of the optic nerve is seen to develop following optic neuritis39 and furthermore the mean reduction in optic nerve cross-sectional area (an impres- sive 33% compared with controls) correlates with retinal nerve fiber layer loss, VEP amplitude, visual acuity, and visual field mean deviation.58

RECURRENT OPTIC NEURITIS Recurrence of optic neuritis is a common feature (16% to 42%) of most longitudinal studies.5,7,12,46,59 In the ONTT, the data appear to show that of the 319 re-evaluated, 112 (35%) patients had undergone a further episode of optic neuritis; 19% in the same eye and 17% for the other. This was more common in patients who had developed MS during the study but still arose in 41 (24%) of those without other symptoms to allow a diagnosis of MS to be made. Recurrent attacks do not lead to a worse visual impairment,45 although a progressive visual loss may arise in MS.60 Not all patients, however, who have recurrent optic neuritis develop MS; of 1274 patients who had attended Mayo Clinic in the 6 years to 2000 with a diagnosis of optic neuritis, 72 were found to have had a recurrence in the same eye over 3 months after the first attack. Of these patients, 20 were found to have developed MS and 8 neuromyelitis optica, but the majority, 44, had had no further symptoms. Regrettably there were little further data in this study, particularly MRI data were available in only 16 cases, but the authors were able to show that the annual relapse rate of recurrent optic neuritis was highest in the Devic group at two per year, one per year in the MS group, and only 0.6 per year in the “nonconverters.”61

Relationship to Multiple Sclerosis

CLINICAL DATA What is the risk that a patient with an optic neuritis will in time develop clinically definite MS? There is no clear consensus over what relationship exists among age, sex, race, or clinical characteristics of the optic neuritis and the subsequent development of MS,62 although the longest follow-up study63 has 6 Optic Neuritis 147

shown that age of onset, optic neuritis recurrence, and the presence of a CSF pleocytosis and oligoclonal bands at onset are significantly associated with subsequent development of MS. Longitudinal studies have shown that the risk increases progressively with time: over 3.9 years the incidence was 40% in one study,64 and this rose to 57% in the same cohort after 11.6 years.65 Cohen et al. found an incidence of 28% over 7.1 years,46 and Bradley and Whitty found a prevalence of transformation to probable or definite MS over a mean follow-up period of 10.2 years (0.5 to 20 years) of 51%.66 Hutchinson noted that the risk of developing MS was 73% to 79% at 15 years for unilateral, recurrent unilateral, and bilateral optic neuritis.7 Hely and colleagues67 calculated an early risk at 42% at seven years and found at 15 years that 52% had developed MS.68 Sandberg-Wolheim and colleagues,59 in the first prospective study, identified a risk of developing MS in a cohort of 86 patients with optic neuritis at 45% over 15 years. The risk was greatest in those with a young age of onset, an early recurrence of optic neuritis, and the presence of oligoclonal bands in the CSF. The Mayo Clinic series confirms an increasing incidence over time: 39% at 10 years, 49% at 20 years, 54% at 30 years, and 60% at 40 years following an isolated optic neuritis.12 The 10-year risk of MS in the optic neuritis treatment trial was 38%.69 The prevalence of MS following childhood optic neuritis is considerably lower70; in one series,71 the prevalence was only 13% over a 10-year period, rising to 26% by 40 years. A history of bilateral but sequential optic neuritis and of recurrent unilateral optic neuritis was associated with a greater risk.

MAGNETIC RESONANCE IMAGING DATA Using MRI as a marker for the subsequent development of MS, WI McDonald’s group at the Institute of Neurology has used the presence and absence of white matter lesions within the brain on MRI at the onset of first symptoms to forecast with reasonable accuracy the risk of development of MS over the ensuing years. The risk at 5 years in those with abnormal MRI was higher following optic neuritis (56%) compared with those with isolated cord and brainstem syndromes (39% and 47%, respectively).72 When the same cohort was reassessed at 10 years,73 the incidence of MS in the optic neuritis group had increased to 89% of those with an abnormal MRI at onset compared with only 7% of those whose MRI was normal at onset. Those with a normal MRI at onset who also developed MS over the 10-year period had a significantly smaller risk of having become disabled; indeed, none had developed a progressive phase. The most recent reassessment of this cohort, at 14 years,74 has revealed that 88% of those with abnormal MRI had developed MS, whereas 19% of those with normal MRI developed MS. The correlation between increase in lesion volume over the first 5 years and disability at 14 years was only 0.60, confirming that there is much more to the pathogenesis of neurologic impairment than the development of MRI-visible lesions. The reasons for this are becoming understood in the light of recent pathologic evidence,75 which has shown that the extent of involvement of the brain by the disease is very much more widespread. In the ONTT, the incidence of MS at 10 years was 56% of those with an abnormal brain MRI at onset and 22% in those with normal MRI.69 148 Neuro-Ophthalmology: Blue Books of Neurology

CEREBROSPINAL FLUID DATA Oligoclonal bands are found in the CSF in 97% of patients with MS,76 and it stands to reason that their presence in an isolated clinical syndrome in keeping with the first attack of MS should correlate well with the subsequent development of the disorder. Studies have not shown this to be the case, however. In the ONTT, for example, 76 of the patients who had undergone a CSF examination were re-evaluated at 5 years, and clinically definite MS was seen to have developed in 22 (29%); 16 had oligoclonal bands and 6 had not (odds ratio ¼ 3.88). The predictive value of the presence of oligoclonal bands at disease onset is not high, therefore, and less than that when the presence of MRI abnormalities is used on its own. However, in those whose MRI was normal, MS developed in 3 of 11 with bands and in only one of 28 without. In the case of MRI abnormal scans, MS was seen to have developed in 13 of 27 with bands and in 5 of 10 without.77 This lies in contrast to the results of other studies in which the relationship of oligoclonal bands to the subsequent development of MS is much more clear; in the Swedish cohort, the presence of bands strongly predicted the subsequent development of MS; the presence of oligoclonal bands and three or more MRI lesions was associated with the subsequent development of MS in 100%, and none of the 21 patients with neither bands nor abnormal MRI had developed MS at 5 years.78 However, more recently another Swedish study has shown that only 50% of those with oligoclonal bands were found to have developed MS at 30 years.63

Treatment

Early trials of steroids in optic neuritis did not show positive results.79–81 More recently, Kapoor et al.35 found that patients given intravenous methylprednisolone did not show an improved outcome over placebo, nor was there evidence that the use of steroids prevented a lengthening of the MRI lesion within the optic nerve. Orbital MRIs from the same cohort were later subjected to a measurement of optic nerve cross-sectional area; this did not show any difference between nerve areas in treated and placebo groups from the previous study.82 The optic neuritis treatment trial also failed to show any benefit. There were three treatment groups; one was randomized to receive intravenous methylprednisolone 250 mg four times a day for 3 days then oral prednisolone at 1 mg/kg for 11 days, the second group received oral prednisolone at 1 mg/kg for 14 days, and the third placebo for 14 days. As before, an earlier improvement was seen to occur, but no alteration to outcome was observed.83 A Japanese study also showed no benefit when megadose methylprednisolone was compared with 84 vitamin B12. A recent meta-analysis of steroid trials in optic neuritis and in MS also failed to show any benefit except for an acceleration of recovery in the short term.85 The Quality Standards subcommittee of the American Academy of Neurology stated that “oral prednisolone in doses of 1 mg/kg has no demonstrative efficacy in the recovery of visual function in acute monosymptomatic optic neuritis, and therefore is of no proven value in treating this disorder. Higher dose oral or parenteral methylprednisolone or adrenocorticotrophic hormone may hasten 6 Optic Neuritis 149

the speed and degree of recovery of visual function in persons with acute monosymptomatic optic neuritis. There is, however, no evidence of long-term benefit for visual function.”86

Summary

In conclusion, therefore, optic neuritis is a subacute, often painful, visual disorder in which visual impairment arises and worsens over several days but then improves quickly again in most cases. A further slower improvement occurs over the course of 2 years. Eighty percent to 90% of all cases will recover a substantial proportion of vision, although residual impairments, albeit mild, are common and noticeable. The clinical parameters that predict a good or poor recovery are not clearly understood, but patients with a good outcome have been observed to recover more quickly in the early stages than those with a poor outcome. Blood tests are in general normal, and a modest spinal fluid pleocytosis is observed in about 50%. Oligoclonal bands are seen in 70%. MRI scans of the optic nerve show a high signal lesion on T2-weighted imaging, which enhances in almost every case on T1-weighted imaging. The nerve is swollen and subsequently reduces in size, implying that atrophy of the nerve occurs. There is a clear relationship between the presence and severity of residual visual symptoms and signs and the presence of optic nerve atrophy and retinal nerve fiber layer defects measured on optic coherence tomography. Sixteen percent to 42% of patients undergo a recurrence of optic neuritis either in the same or the other eye. This is associated with the subsequent development of MS in some but not all patients. The incidence of MS in clinical studies of optic neuritis rises progressively from about 40% at 5 years to 60% at 40 years. The presence of four or more lesions on MRI scans of the brain is associated with a substantially increased risk of the subsequent development of MS, around 90% over 10 years. Treatment with oral or intravenous corticosteroids has been shown to hasten recovery of vision but not to influence the outcome or the subsequent development of MS in any way.

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38. Hickman SJ, Toosy AT, Mizkiel KA, et al: Visual recovery following optic neuritis: A clinical, electrophysiological and magnetic resonance imaging study. J Neurol 2004;251:996–1005. 39. Hickman SJ, Toosy AT, Jones SJ, et al: A serial MRI study following optic nerve mean area in acute optic neuritis. Brain 2004;127:2498–2505. 40. Optic neuritis study group: Cerebrospinal fluid in acute optic neuritis: Experience of the optic neuritis treatment trial. Arch Neurol 1996;46:368–372. 41. Optic neuritis study group: The course of visual recovery after optic neuritis. Experience of the optic neuritis study group. Ophthalmology 1993;101:1771–1778. 42. Nikoskelainen E: Later course and prognosis of optic neuritis. Acta Ophthalmol 1975;53: 273–291. 43. Optic neuritis study group: Optic neuritis treatment trial: One year follow-up results. Arch Ophthalmol 1993;111:773–775. 44. Optic neuritis study group: Visual function 5 years after optic neuritis. Experience of the optic neuritis treatment trial. Arch Ophthalmol 1997;115:1545–1552. 45. Optic neuritis study group: Visual function more than 10 years after optic neuritis. Experience of the optic neuritis treatment trial. Am J Ophthalmol 2004;137:77–83. 46. Cohen MM, Lessell S, Wolf PA: A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis. Neurology 1979;29:208–213. 47. Honan WP, Heron JR, Foster DH, et al: Visual loss in multiple sclerosis and its relation to previous optic neuritis, disease duration and clinical classification. Brain 1990;113:975–987. 48. Earl CJ, Martin B: Prognosis in optic neuritis related to age. Lancet 1967;i:74. 49. Celesia GG, Kaufman DI, Brigell M, et al: Optic neuritis: A prospective study. Neurology 1990;49:919–923. 50. Slamovits TL, Rosen CE, Cheng KP, Striph GG: Visual recovery in patients with optic neuritis and visual loss to no light perception. Am J Ophthalmol 1991;111:209–214. 51. Fleischman JA, Beck RW, Linares OA, Klein JW: Deficits in visual function after resolution of optic neuritis. Ophthalmology 1987;94:1029–1035. 52. Slagsvold JE: Pulfrich pendulum phenomenon in patients with a history of optic neuritis. Acta Ophthalmol 1978;56:817–826. 53. Diaper CJM: Pulfrich revisited. Surv Ophthalmol 1997;41:493–499. 54. Frisen L, Hoyt WF: Insidious atrophy of retinal nerve fibres in multiple sclerosis. Arch Ophthalmol 1974;92:91–97. 55. McFadyen DJ, Drance SM, Douglas GR, et al: The retinal nerve fibre layer, neuroretinal rim area, and visual evoked potentials in MS. Neurology 1988;38:1353–1358. 56. Trip SA, Schlottmann PG, Jones SJ, et al: Retinal nerve fibre layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005;58:383–391. 57. Fisher JB, Jacobs DA, Markowitz CE, et al: Relation of visual function to retinal nerve fibre layer thickness in multiple sclerosis. Ophthalmology 2006;113:324–332. 58. Trip SA, Schlottmann PG, Jones SJ, et al: Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: Evidence that axonal loss is a substrate of MRI-detected atrophy. NeuroImage 2006;31:286–291. 59. Sandberg-Wolheim M, Bynke H, Cronqvist S, et al: A long-term prospective study of optic neuritis: Evaluation of risk factors. Ann Neurol 1990;27:386–393. 60. Ormerod IE, McDonald WI: Multiple sclerosis presenting with progressive visual failure. J Neurol Neurosurg Psychiatry 1984;47:943–946. 61. Pirko I, Blauwet LK, Lesnick TG, Weinshenker BG: The natural history of recurrent optic neuritis. Arch Neurol 2004;61:1401–1405. 62. Smith CH: Optic neuritis. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro- ophthalmology, 6th ed. Baltimore, Williams & Wilkins, 2005, p 335. 63. Nilsson P, Larsson EM, Maly-Sundgren P, et al: Predicting the outcome of optic neuritis: Evalua- tion of risk factors after 30 years of follow-up. J Neurol 2005;252:396–402. 64. Compston DAS, Batchelor JR, Earl CJ, McDonald WI: Factors affecting the risk of multiple sclerosis developing in patients with optic neuritis. Brain 1978;101:495–511. 65. Francis DA, Compston DAS, Batchelor JR, McDonald WI: A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow up. J Neurol Neurosurg Psychiatry 1987;50:758–765. 66. Bradley WG, Whitty CWM: Acute optic neuritis: Prognosis for development of multiple sclerosis. J Neurol Neurosurg Psychiatry 1968;31:10–18. 152 Neuro-Ophthalmology: Blue Books of Neurology

67. Hely MA, McManis PG, Doran TJ, et al: Acute optic neuritis: A prospective study of risk factors for multiple sclerosis. J Neurol Neurosurg Psychiatry 1986;49:1125–1130. 68. Frith JA, McLeod JG, Hely M: Acute optic neuritis in Australia: A 13 year prospective study. J Neurol Neurosurg Psychiatry 2000;68:246. 69. Optic neuritis study group: High and low risk profiles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophthalmol 2003;121:944–949. 70. Meadows SP: Retrobulbar and optic neuritis in childhood and adolescence. Doyne memorial lecture. Trans Ophthalmol Soc UK 1969;89:603–639. 71. Luccinetti CF,Kiers L, O’Duffy A, et al: Risk factors for developing multiple sclerosis: after childhood optic neuritis. Neurology 1997;49:1413–1418. 72. Morrisey SP, Miller DH, Kendall BE, et al: The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndrome suggestive of multiple sclerosis: A five year follow up study. Brain 1993;116:135–146. 73. O’Riordan JI, Thompson AJ, Kingsley DPE, et al: The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A ten-year follow up. Brain 1998;121:495–503. 74. Brex PA, Ciccarelli O, O’Riordan JI, et al: A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;356:158–164. 75. Kutzelnigg A, Lucchinetti C, Stadelman C, et al: Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705–2712. 76. Zeman ASJ, Kidd D, McClean BN, et al: A study of oligoclonal band negative multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60:27–30. 77. Optic neuritis study group: The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. Neurology 1998;51:885–887. 78. Soderstrom M, Jin YP,Hillert J, Link H: Optic neuritis: Prognosis for multiple sclerosis from MRI, CSF and HLA findings. Neurology 1998;50:708–714. 79. Rawson MD, Liversedge LA, Goldfarb G: Treatment of acute retrobulbar neuritis with corticotrophin. Lancet 1966;ii:1044–1046. 80. Bowden AM, Bowden PMA, Friedman AI, et al: A trial of corticotrophin gelatine injection in acute optic neuritis. J Neurol Neurosurg Psychiatry 1974;37:869–873. 81. Gould ES, Bird AC, Leaver PK, McDonald WI: Treatment of optic neuritis by retrobulbar injection of triamcinolone. BMJ 1977;1:1495–1497. 82. Hickman SJ, Kapoor R, Jones SJ, et al: Corticosteroids do not prevent optic nerve atrophy following optic neuritis. J Neurol Neurosurg Psychiatry 2003;74:1139–1141. 83. Optic neuritis study group: A randomised controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992;326:581–588. 84. Wakakura M, Mashimo K, Oono S, et al: Multicenter clinical trial for evaluating methylprednisolone pulse treatment of idiopathic optic neuritis in Japan. Optic neuritis treatment trial multicenter cooperative research group (ONMRG). Jpn J Ophthalmol 1999;43:133–138. 85. Brusaferri F, Candelise L: Steroids for multiple sclerosis and optic neuritis: A meta-analysis of randomised controlled clinical trials. J Neurol 2000;247:435–442. 86. Kaufman DI, Trobe JD, Eggenberger ER, Whitaker JN: Practice parameter: The role of corticosteroids in the management of acute monosymptomatic optic neuritis: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:2039–2044. 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis DESMOND P. KIDD

Introduction Celiac Disease Inflammatory Bowel Disease Optic Neuritis Associated with Vogt-Koyanagi-Harada Infections Syndrome Viral Disorders Bacterial Disorders Connective Tissue Disorders and Fungal Disorders Systemic Vasculitis Neuroretinitis Lupus Optic Perineuritis Sjo¨gren’s Syndrome Sinus Mucocele and Pyocele Mixed Connective Tissue Disease Systemic Inflammatory Scleroderma Disorders Rheumatoid Arthritis Sarcoidosis Churg-Strauss Syndrome Chronic Relapsing Inflammatory Wegener’s Granulomatosis Optic Neuropathy Granulomatous Angiitis of the Optic Neuritis Associated with Central Nervous System Autoantibodies Polyarteritis Nodosa Optic Neuritis Following Giant Cell Arteritis Vaccination Devic’s Syndrome References Behc¸et’s Syndrome

Key Points Optic neuropathies indistinguishable on clinical grounds from a primary demyelinating optic neuritis may arise in systemic inflammatory, connective tissue, and vasculitic diseases. Early identification of such disorders, with prompt and aggressive treatment, enhances the likelihood of a satisfactory visual outcome. Delay often results in severe and permanent visual deficits. Optic neuritis in infectious disease, particularly that resulting from viruses, usually has a good prognosis. Recent advances in the understanding of the pathophysiology of systemic inflammatory disorders such as sarcoidosis, Devic’s syndrome, and systemic

153 154 Neuro-Ophthalmology: Blue Books of Neurology

lupus erythematosus has led to the availability of a greater range of therapies, particularly in severe cases. The syndromes of recurrent relapsing bilateral optic neuropathy, including CRION and autoimmune optic neuropathy, respond well to chronic immunosuppression.

Introduction

Subacute optic neuropathies that develop with and without pain may arise in a diverse and wide-ranging series of inflammatory disorders. This chapter makes note of all those disorders in which optic neuropathy may arise, however rare. It will be noted that vasculitic disorders are included. Some optic neuropathies arise as a consequence of ischemia following thrombotic occlusion of the ophthalmic artery or its branches, and it is clear that recovery of visual function under these circumstances may merely be a forlorn hope. Giant cell arteritis is an example. However, other vasculitic disorders may present with symptoms and signs of an optic neuropathy indistinguishable on clinical (and often too on imaging) grounds and prompt treatment of which leads often to a substantial improvement of visual function. Wegener’s granulomatosis, Churg-Strauss syndrome, and lupus are examples of this circumstance. It is important, therefore, to understand that vigorous and urgent investigation of such cases may lead to instigation of treatment sufficiently early to allow a recovery to take place. This is poorly understood and it is hoped that the information included leads to an improvement in the management of these uncommon but important disorders. The relationship between the ophthalmic and the neurologic complications of these disorders is also underlined; the use by neurologists of an ophthalmic consultation and vice versa as a mandatory collaboration rather than a test under these circumstances is an extremely important message to understand.

Optic Neuritis Associated with Infections

Optic neuritis may complicate a wide variety of infective disorders (Table 7–1). In general, the natural history of the disorder is the same as that of a primary demyelinating optic neuritis, although in the majority of cases a prodrome suggestive of an infective illness is apparent. The optic neuropathy may occur in isolation but may also complicate other neurologic or ophthalmic complications.

VIRAL DISORDERS More common in children than in adults and more often bilateral, the optic neuritis that complicates viral disorders usually follows a symptomatic infective prodrome some 1 to 3 weeks before. The clinical syndrome is the same as a primary demyelinating optic neuritis, and the disc appearances vary in the same way.Other neurologic 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 155

TABLE 7–1 Viral, Bacterial, and Fungal Infections Known to Have Caused Optic Neuritis

Viral Bacterial Fungal

Adenoviruses Bacillus anthracis Mucor Coxsackie b-hemolytic streptococcus Aspergillus HSV 1 and 2 Brucella Candida CMV Bartonella hensellae Coccidiodes EBV Meningococcus Cryptococcus HHV Mycobacterium tuberculosis VZV Bordetalla pertussis Rubella Salmonella typhi Mumps Mycoplasma pneumoniae Measles Hepatitis A and B

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpes virus; HSV, herpes simplex virus; VZV, varicella zoster virus. complications may arise simultaneously, such as ataxia and meningoencephalitis. Imaging reveals no abnormalities in the brain when the optic neuropathy occurs on its own but shows white matter lesions when meningoencephalitis occurs at the same time. The cerebrospinal fluid (CSF) shows a modest protein elevation and lymphocytosis in most cases. Recovery is usually good, although the discs are seen to become pale.1 Some advocate treatment with corticosteroids,2 although there is no evidence that recovery is enhanced were this to be undertaken. Table 7–2 summarizes the principle viral infections that are associated with neuro-ophthalmic complications. It is not an exhaustive summary, and interested readers are strongly urged to read the superb chapter by Paul Brazis and Neil Miller in Walsh and Hoyt’s Clinical Neuro-Ophthalmology3 for a comprehensive and clear account of all the known neurologic, neuro-ophthalmic, and ophthalmologic complications of viral infections.

Human Immunodeficiency Virus Infection Human immunodeficiency virus (HIV) infection may cause a range of ocular and neurologic complications by virtue of the resultant immunosuppression leading to the acquisition of infection. Primary complications in the eye include a retinal microangiopathy leading to cotton wool spots and microaneurysm formation leading to retinal hemorrhage. A retinopathy in which slowly progressive enlarging focal field defects associated with abnormalities of the pattern electroretinogram (ERG) may also occur. Optic neuropathy resulting from a direct toxic effect of HIV-1 on retinal ganglion cells and optic nerve axons is rare and associated with a progressive decline in visual function that is commonly unresponsive to treatment, although Newman and Lessell5 reported two patients in whom a diagnosis of HIV-associated optic neuropathy made an incomplete response to zidovudine (AZT) and Sweeney and colleagues6 reported a similar case in whom a unilateral optic neuropathy arose and enhancement of the optic nerve was seen at magnetic resonance 156 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology: TABLE 7–2 Neurologic and Ophthalmic Complications of Common Viral Infections

Virus Neurologic Optic Neuropathy Ophthalmic

DNA viruses Adenoviruses Encephalitis Optic neuritis APMPPE Meningitis Keratoconjunctivitis Myelitis HSV 1 and 2 Encephalitis Tends to occur along with Uveitis Meningitis (Mollaret’s) retinitis or chorioretinitis Retinitis (ARN, PORN) Myelitis Keratitis Radiculopathy Blepharitis Isolated cranial neuropathy (VII, VIII) VZV Varicella Cerebellar ataxia Occurs as an isolated syndrome Keratitis Meningoencephalitis or within ADEM or Retinal vasculitis ADEM and myelitis meningoencephalitis ARN Meningitis Iridocyclitis Polyradiculoneuropathy Focal or diffuse cerebral vasculitis III and VII have also been reported Zoster Encephalitis Uncommon* Herpes zoster Meningoencephalitis ophthalmicus Radiculopathy or plexopathy Conjunctivitis Any cranial neuropathy, especially VII, Scleritis V, VIII, and III Keratitis III often occurs alongside uveitis Uveitis Focal or diffuse cerebral vasculitis Retinal vasculitis Meningitis Orbital myositis ARN and PORN EBV Encephalitis Conjunctivitis Cerebellar and brainstem encephalitis Usually bilateral and not Blepharitis Meningitis associated with other Uveitis Cranial neuropathies neurologic complications Dacryocystitis Polyradiculoneuropathy Retinal vasculitis Radiculopathies

Myelitis 7

CMV{ Meningoencephalitis Retinitis

ADEM Sclerosis Multiple with Associated Not Neuropathies Optic Inflammatory Myelitis Radiculopathies and polyradiculoneuropathy Multifocal sensorimotor neuropathy HHV 6, 7, 8 Encephalitis Has not been reported Meningoencephalitis Myelitis Polyradiculoneuropathy Hepatitis B Meningitis Neuroretinitis APMPPE (after Encephalitis Optic neuritis vaccination) Cranial neuropathy Polyradiculoneuropathy Myelitis RNA viruses{ Influenza Encephalitis Neuroretinitis is rare Conjunctivitis Meningitis Keratitis Myelitis Iridocyclitis Cranial neuropathies are rare Retinopathy Measles Encephalitis Optic neuritis Pigmentary retinopathy SSPE Keratitis Mumps Encephalitis Optic neuritis Meningitis Neuroretinitis Polyradiculoneuropathy Poliomyelitis Pupillary dysfunction

Table continued on following page 157 158 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology: TABLE 7–2 Neurologic and Ophthalmic Complications of Common Viral Infections (Continued)

Virus Neurologic Optic Neuropathy Ophthalmic

Rubella Encephalitis Optic neuritis Follicular conjunctivitis Polyradiculoneuropathy Keratitis Poliomyelitis Panuveitis Myelitis Chorioretinitis Enteroviruses Coxsackie Meningitis Optic neuritis Acute hemorrhagic Encephalitis Neuroretinitis conjunctivitis Myelitis Keratoconjunctivitis Poliomyelitis Scleritis Polyradiculoneuropathy Panuveitis Isolated cranial neuropathy Chorioretinitis Myositis in children Echoviruses* West Nile Meningitis Rare, but often bilateral Iridocyclitis virus Encephalitis Uveitis Poliomyelitis syndrome Vitritis Choroiditis Filoviridae*

The list is not exhaustive. ADEM, acute disseminated encephalomyelitis; APMPPE, acute posterior multifocal placoid pigment epitheliopathy; ARN, acute retinal necrosis; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpes virus; HSV, herpes simplex virus; PORN, progressive outer retinal necrosis; SSPE, subacute sclerosing panencephalitis; VZV, varicella zoster virus. *An optic neuritis may develop in association with other neurologic syndromes or on its own. It is more commonly associated with herpes zoster ophthalmicus than zoster elsewhere and may be mild or severe. Neuroretinitis may also be seen. {Neurologic complications usually only in immunocompromised patients. An optic neuropathy tends to complicate CMV retinitis and is most uncommon on its own. {Although RNA viruses are so commonly associated with encephalitis, neuro-ophthalmic complications of these infections are uncommon. The exceptions are noted in the table. Optic neuritis when it does occur may do so on its own but is more commonly seen in association with more widespread neurologic involvement. }Echoviruses including hepatitis A, all produce the same neurologic and ophthalmic complications. Optic neuritis, when it occurs, may be bilateral or unilateral. kFiloviridae may be associated with a mild uveitis but most are not reported to be associated with neuro-ophthalmic complications. There is, however, a single report of neuroretinitis with Dengue fever.4 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 159

imaging (MRI). The patient made an incomplete recovery without treatment. Other cases in which a response to corticosteroids7 and to highly active antiretroviral treatment (HAART)8 occurred have also been reported. In a recent series from the Democratic Republic of Congo,9 optic neuropathy was seen in 52 of 166 patients studied, of whom 25 showed signs of neuroretinitis, 16 papillitis, and 11 retrobulbar optic neuropathy. In this series, the majority were found to have infective causes, including toxoplasmosis (17/25 cases of neuroretinitis were associated with this infection), cryptococcus, tuberculosis, and varicella. Seven cases showed no evidence for an alternative cause to HIV itself: 4% of the study population. Abnormalities of the visual evoked potential were seen in 42% of HIV infected patients without neurologic complications, suggesting that subclinical involvement of the anterior visual pathway is common. This may reflect axonal degeneration in optic nerve fibers resulting from viral proteins and to neurotoxic factors particularly tumor necrosis factor alpha (TNFa).10 There is also a relationship between the manifestation of Leber’s hereditary optic neuropathy and HIV infection,11,12 particularly presenting at the time of commencement of antiretroviral treatment (see Chapter 8).

BACTERIAL DISORDERS The optic neuropathy that may arise with bacterial and fungal disorders is a result of direct infection of the optic nerve during meningitis or during compression from an abscess, from compression itself, or from an infective endarteritis. In meningitis, an optic neuropathy may arise in the syndrome of optic perineuritis (see later). The development of hydrocephalus or raised intracranial pressure resulting from abscess formation or venous sinus thrombophlebitis may also lead to optic neuropathies. Many case reports exists in the literature that suggest that, although rare, many bacterial infections may be associated with isolated unilateral or bilateral optic neuritis, including Shigella, Salmonella, and Francisella tularensis (Table 7–1). Those more commonly associated with optic neuritis are noted later. Mycoplasma infection has been associated with a bilateral optic neuritis in a few published reports, usually in association with other neurologic complications, such as acute disseminated encephalomyelitis (ADEM), meningitis, brainstem encephalitis, and acute polyradiculoneuropathy.13,14 An optic perineuritis (see later) is more common than optic neuritis itself. Recovery tends to be good in time. Brucella infection of the nervous system can be associated with meningoencephalitis, radiculopathies, and cranial neuropathies, including an optic neuritis that appears to be similar to noninfectious optic neuropathies.15,16 Neurobrucellosis can also cause a syndrome of intracranial hypertension, so the optic neuropathy may arise as a result of this. Patients with syphilis may have a whole host of neuro-ophthalmologic complications, including an acute optic neuritis or perineuritis, neuroretinitis, and papilledema as a consequence of meningitis or choroidoretinitis.17 Symptoms tend to arise in the secondary stages of the disease and in children with congenital infection. The ophthalmic complications include a keratitis, iridocyclitis with pupillary abnormalities, uveitis, and chorioretinitis. Optic atrophy is commonly seen in the tertiary phase, both in tabes dorsalis and in general paresis. 160 Neuro-Ophthalmology: Blue Books of Neurology

Another spirochete, Borrelia burgdorferi, causes Lyme disease and is associated with neurologic complications in 5% of cases,18 including isolated cranial neuropathies, meningitis, and polyradiculopathies. Optic neuritis and neuroretinitis may occur but are rare.19 In tuberculosis an optic neuropathy may arise as a result of infiltration of the optic nerve or, more commonly, the chiasm by granulomatous inflammation,20 by compression from a tuberculoma21 or complicating uveitis, and during treatment with ethambutol, particularly in those with renal impairment. Neuroretini- tis has also been reported. The ocular manifestations consist of a chronic bilateral granulomatous uveitis, but posterior involvement leading to choroidoretinitis and choroidal tubercles may also occur.22 Leptospira has also been reported to be associated with the development of an isolated optic neuritis23 alongside meningitis, uveitis, and interstitial keratitis. These neuro-ophthalmic complications tend to occur only in conjunction with meningitis. Bartonella henselae causes cat scratch disease and is a common cause of neuroretinitis24; it may be associated with other ophthalmic complications such as pars planitis, branch arteriolar or venular occlusions, focal choroiditis, serous retinal detachments, focal retinal vasculitis, and white spot syndrome. Most patients with the infection develop a mild illness with regional lymphadenopathy, but the incidence of other complications is about 2%,25 including pneumo- nia, lytic bone lesions, organ enlargement, and the neurologic and ophthalmic complications. Meningitis, encephalitis, and isolated cranial neuropathies have all been reported.26 Although Whipple’s disease may present with neurologic symptoms resulting from meningoencephalitis and the distinctive oculomasticatory myorhythmia,27 optic neuritis has not been reported. Ocular manifestations include a chronic anterior uveitis, vitreous opacities, and choroidoretinitis.28

FUNGAL DISORDERS Optic neuropathy may complicate meningitis resulting from a variety of molds and yeasts whose prevalence varies throughout the world. The prevalence of these disorders increases in immunocompromised or immunosuppressed patients with diabetes, lymphoreticular disorders, or acquired immunodeficiency syndrome (AIDS). Many of the organisms can cause a meningitis or cerebral abscess, for example, mucormycosis, histoplasmosis, and candidiasis.

Aspergillus This organism is found throughout the world and is acquired by inhalation of airborne spores. Optic neuropathy may arise when an aspergilloma develop within a nasal sinusitis in which the infective material passes out of the ethmoid or sphenoid sinuses into the extradural space. Patients therefore present with an optic neuropathy that is either subacute or progressive, often painful with other signs of an orbital apex syndrome. Invasive aspergillosis can arise in severely immunocompromised patients with evidence for systemic disease, meningitis, and arteritis. It may occasionally arise in nonimmunocompromised patients, and the prognosis can be very poor.29 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 161

Cryptococcus Optic neuropathies that arise in cryptococcal infections of the nervous system occur as a result of meningitis; this is often indolent and subacute and may even wax and wane rather than deteriorating in a progressive way. Intracranial pressure rises, and papilledema develops. Sixth nerve pareses may arise as a false localizing sign. Later, as a basal meningitis develops, other cranial neuropathies arise. Optic neuropathy therefore may arise as a consequence of intracranial hypertension or a result of direct infection of the nerves from the meningitic process. The prognosis for recovery of vision is poor, and the mortality of the underlying disease is of the order of 30%.30

NEURORETINITIS Described first by Leber in 1916 and later further characterized by Gass in 1977,31 this condition shows disc swelling and the development of hard exudates around the macula in a stellate pattern. The disc swelling appears at the same time or just before the development of the maculopathy, then resolves leaving the retinal exudates (Fig. 7–1). It is a disorder of children or young adults; 50% have had antecedent viral-type symptoms. Most often there is no pain; occasionally patients feel a mild periorbital ache; visual blurring develops subacutely and worsens as the maculopathy develops. Acuity loss is usually not profound, although some may only perceive light. The visual field defect is often central, with central, centrocecal, and arcuate scotomas being the most common. Disc swelling varies and can be severe and associated with splinter hemorrhages. The macular star may be present at the time of the first examination but more often develops over the succeeding weeks, progressing as the disc swelling regresses. A mild vitritis and sometimes an anterior chamber cellular infiltrate may be seen, as well as small discrete choroidoretinal lesions and retinal perivenous sheathing. Most cases are unilateral; in some a mild cellular infiltrate may be seen

Figure 7–1 Neuroretinitis. A, Swollen disc at presentation with visual loss. B, Four weeks later the disc swelling has resolved and a macular star has developed. (Courtesy of Dr. Gordon Plant.) 162 Neuro-Ophthalmology: Blue Books of Neurology

in the nonaffected eye. At fluorescein angiography, there is leakage from the vessels on the surface of the disc but never leakage at the macula. Occasionally slight leakage from peripapillary vessels is seen. The disorder is self-limiting; the disc swelling resolves over 6 to 8 weeks, and the macular lesions evolve over 7 to 10 days then remain static for several weeks before receding slowly over 6 to 12 months. Most patients recover completely, whereas others are left with slight visual distortion from the macula, in association with defects of retinal pigment epithelium at that site. Rarely, patients exhibit a poor visual recovery and develop optic disc pallor. There is a subgroup of patients who have a relapsing condition. This is uncommon but associated with a less favorable visual outcome. Attacks may affect the same eye or both. Corticosteroids appear not to be helpful but immunosuppression may be so.32 Fifty percent of patients provide a history of antecedence viral-type symptoms. A modest CSF lymphocyte pleocytosis may be seen, but serologic evidence for viral infection is not often found in blood or in CSF.33,34 Other conditions may mimic neuroretinitis: a macular infiltrate may be seen in papilledema, and anterior ischemic optic neuropathy and disc infiltration by tumor. In these cases, the macular lesions would leak fluorescein, however, so these conditions can readily be thus distinguished from neuroretinitis. There is no association between neuroretinitis and the subsequent development of multiple sclerosis (MS),35 although a recent series of 25 cases included 3 who had already been diagnosed with MS, all of whom were taking interferon.36 Patients with bacterial pathogens noted previously almost invariably have symptoms of the underlying disorder (Table 7–3). Thus, those with cat scratch disease may have myalgia, malaise, fever, and lymphadenopathy, and those with Lyme disease may have arthritis, skin lesions such as erythema chronicum migrans, and the various other neurologic and ophthalmic manifestations of the infection (Table 7–3).

Treatment In general, those with viral or idiopathic disorders will recover well and spontaneously. There is no clear evidence that use of corticosteroids enhances or accel- erates recovery. Those with serologic evidence for a causative infection should have this treated. Patients with B. henselae have been treated with doxycycline,

TABLE 7–3 Infections Reported with Neuroretinitis

Viruses Bacteria Fungi and Parasites

Mumps Bartonella henselae Toxoplasmosis Hepatitis B Leptospira Toxocariasis Herpes simplex Borrelia burgdorferi Histoplasmosis Influenza Secondary and late tertiary syphilis Enteroviruses 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 163

ciprofloxacin, azithromycin, rifampicin, or gentamycin.37 Those with syphilis should be treated with penicillin or doxycycline, and those with B. burgdorferi infection should be treated with doxycycline, although ceftriaxone and penicillin may be more effective for neurologic complications.38

OPTIC PERINEURITIS Optic perineuritis is a disorder in which painful visual loss occurs progressively, often over weeks rather than days, in association with optic disc swelling. For- merly, it was seen in association with meningitic processes such as acute bacterial and viral meningitis, syphilis, and sarcoidosis. The pathologic process is seen to be an infiltration by inflammatory cells including polymorphs. A vitritis may be seen. More recently,39–41 it has been shown that the condition may arise without meningitis; patients present with headache, periorbital pain, and pain on eye movement associated with progressive visual loss that is rarely severe but extends, without treatment, over weeks or months. Visual field defects tend not to be central and in one series were often paracentral and arcuate.41 Patients are in general older than those with a primary demyelinating optic neuritis. Importantly, the MRI and CT findings show circumferential enhancement rather than enhancement of the nerve itself (Fig. 7–2). The nerve sheath may be enlarged and may therefore simulate an optic nerve sheath meningioma. Some show a streaky enhancement of the adjacent orbital fat and others show muscle involvement. There is usually a prompt and significant response to corticosteroid administration, although spontaneous improvement is also seen.42 Most cases are idiopathic, and it is assumed therefore that the condition is related to orbital pseudotumor syndrome. Others have been found in association with giant cell arteritis and Wegener’s granulomatosis.

Figure 7–2 Optic perineuritis. A, T2-weighted coronal magnetic resonance imaging showing enlargement of the optic nerve-sheath complex on the left. B, Enhancement of the optic nerve sheath on T1-weighted coronal images. (Courtesy of Dr. Neil Miller.) 164 Neuro-Ophthalmology: Blue Books of Neurology

A few cases that have been biopsied to investigate the possibility of an optic nerve sheath meningioma have shown a lymphocytic infiltration, in others granulomas are seen, and in others fibrous tissue, suggesting that the pathogenesis, although certainly inflammatory, is not consistent.

SINUS MUCOCELE AND PYOCELE A mucocele is a noninfective complication of sinusitis in which sinus mucosa containing mucus and other secretions pass through the thin bony wall of the sinus into the extra-axial space. When this arises from the ethmoid or sphenoid sinuses, neuro-ophthalmic syndromes may ensue. A pyocele or fungal infection of the sinuses may also cause an optic neuropathy and orbital apex syndrome in the same way.

Ethmoid Sinus Those arising from the anterior ethmoid air cells may erode into the orbit producing a painful proptosis and lateral rectus restriction. Those that arise form the posterior air cells may also produce proptosis, but if the lesion is more posteriorly placed it may compress the optic nerve at the orbital apex (Fig. 7–3) or through the orbital canal by erosion. The optic neuropathy that results may be painless and slowly progressive but may also present with a painful subacute or sudden visual loss, which is misconstrued as an acute optic neuritis. It may even relapse and remit and appear to be steroid-responsive. If even more posteriorly placed, the lesion may involve the cavernous sinus leading to ophthalmoparesis. Mucoceles that arise from the Onodi cells are particularly likely to be associated with an optic neuropathy in view of their close proximity to the orbital apex.43

Figure 7–3 Mucoceles of (A) the ethmoid and (B) the sphenoid sinuses causing optic nerve compression. 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 165

Sphenoid Sinus Those arising from the sphenoid sinus may spread upward to the cavernous sinus leading to ophthalmoparesis and trigeminal pain and sensory loss or to the parasellar region and even into the pituitary. The chiasm may be involved or one or both of the optic nerves or tracts. Just as with ethmoid sinus mucoceles or pyoceles, the optic neuropathy may be progressive or subacute. In two recent series of isolated sinus disease associated with acute bacterial sinusitis, aspergillus sinusitis, and sinus mucocele,44,45 optic neuropathy arose in 10 of 73 patients of one series, and ophthalmoparesis with or without trigeminal involvement arose in 10, in which a sixth nerve neuropathy was the most common. In the second series of 50 cases, 24 had “visual changes” and only one an eye movement disorder. The diagnosis is made with imaging (Fig. 7–3), and treatment is with surgery in which the mucocele is drained and removed. This may be carried out as an open procedure at craniotomy or as an endoscopic technique. The prognosis for visual recovery in general depends on the latency between onset of symptoms and treatment46; these authors contend that visual recovery from optic neuropathy is poor, whereas recovery from ocular motor palsies may occur even months after onset of symptoms.

Systemic Inflammatory Disorders

SARCOIDOSIS Sarcoidosis is an inflammatory disorder of unknown etiology in which there is inflammation accompanied by an infiltration of granulomatous tissues. The prevalence is 10 to 40 105 and is more common in African Americans than Caucasians. Most organs may be involved; those most often involved include the lungs, skin, joints, and eyes. The central nervous system is affected in 10% of cases, with the development of meningeal-based inflammatory lesions leading most commonly to cranial neuropathies, but mass lesions in the brain and spinal canal occur in around 20% of cases. Intraparenchymal masses may arise very rarely, and involvement of the muscles and peripheral nerves, although uncommon, has been noted.47

Ocular Complications Twenty-five percent to 80% of patients develop ocular complications at some point during the course of the disease, and oftentimes it is the presenting symptom of the disease. One series of 183 patients with sarcoidosis attending the Johns Hopkins Medical Institutions48 identified 47 patients (26%) who had developed ophthalmic complications attributable to the systemic disease. Seventy-four percent showed signs of uveitis, of whom the majority had an anterior involvement, 28% had involvement of the lacrimal glands, and 17% had conjunctival involvement. A band keratopathy was seen in three patients (6%), and there was one patient each with scleral involvement and an optic neuropathy. Uveitis was less common in a series from Finland49 in which 79 of 281 patients (28%) were 166 Neuro-Ophthalmology: Blue Books of Neurology

found to have ophthalmic complications. Half of the uveitis patients underwent a monophasic course, whereas the others underwent a relapsing or chronic course. Patients with involvement of orbital tissues present with lacrimal gland enlargement or orbital masses arising from the fat or muscles.50 Many patients with sarcoid develop a xerophthalmia. Small masses of granulomatous tissue may develop within the skin of the eyelids manifested as small papillae associated with mild edema. In the Finnish series, 37 (40%) showed conjunctival involvement49; this led to a vogue for blind conjunctival biopsies as a source of positive histologic confirmation of the diagnosis.51,52 Most patients show signs of a follicular conjunctivitis, whereas others show more diffuse opaque conjunctival masses. Corneal involvement is also common; band keratopathy and corneal calcification may arise in patients with pronounced hypercalcemia.48 An interstitial keratitis and corneal ulceration may arise rarely. Episcleritis, scleritis, and scleral plaques are also very rare.53 Uveitis is most commonly confined to the anterior chamber, but a vitritis or a panuveitis may develop.48,49,54 The anterior uveitis develops insidiously and is bilateral. Mutton fat keratic precipitates are seen on the corneal surface. Those with a chronic uveitis develop iris nodules composed of granulomatous infiltration; when situated near the pupil, they are known as Koeppe nodules, when more peripherally placed, Busacca nodules. A sarcoid vitritis is characterized by a “string of pearls” or “snowballs” composed of a series of gray-white globoid bodies. Retinal periphlebitis may be asymptomatic, although when the macula is involved, distortion of vision may arise. The rather striking appearance known as candle wax drippings or taches de bougie is highly suggestive of sarcoid, although not pathognomonic.54 Chor- ioretinitis may complicate retinal periphlebitis, leading to the development of cystoid macular edema and choroidal or retinal granulomata (Fig. 7–4). Venous occlusion may develop but is never prominent, unlike that seen in Behc¸et’s syndrome.54 Retinal ischemic syndromes with neovascularization occur infre- quently55 but most involve the optic disc. Neovascularization leads to vitreous hemorrhage, ischemia, and retinal detachment. Retinal pigment epithelial changes occur commonly when the posterior segment of the eye is involved and may evolve from choroidal granulomas. Although they are not associated

Figure 7–4 Sarcoidosis of the eye. A, The right disc is enlarged and lumpy because of the presence of granulomas within the disc. B, There are numerous choroidal granulomas and periphlebitis on the left side. (Courtesy of Dr. Elizabeth Graham.) 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 167

with substantial visual symptoms, their presence is helpful in differentiating a sarcoid uveitis from other causes. Most ophthalmic manifestations of sarcoid respond well and rapidly to topical or systemic steroid administration. The chronic insidious panuveitis, however, does not and is associated with posterior synechiae, cataract formation, and glaucoma, leading to persistent visual impairment in around 25% of cases. Immunosuppression with azathioprine, methotrexate, cyclosporine A, and mycophenolate alone or in combination works well; more recently TNFa antagonists have also been shown to work in cases refractory to immunosuppression.56

Optic Neuropathy Optic neuropathy in sarcoidosis arose in 5% of cases in one published series,57 although another series of 649 patients had only one case58 and a third had no cases in 285 patients with systemic sarcoidosis.59 A review of the early literature on optic nerve involvement by sarcoidosis revealed 57 published cases, the majority as single case reports or small series. Subsequent investigation revealed the cause of the optic neuropathy to be compression because of an intracerebral mass lesion in 9 cases and to hydrocephalus in 6 cases. In 6 cases, the optic neuropathy was attributed to complications of posterior uveitis. The remaining 35 cases showed evidence for a primary optic neuropathy; of these 11 presented as anterior involvement with disc granuloma (this was asymptomatic in 1 case), and in the remaining 24 cases, 9 were bilateral (4 were sequential involving the nerves, the remainder had chiasmal involvement), and 8 were associated with disc swelling in the acute phase. In only 4 of the 15 unilateral cases and none of the bilateral cases was pain a feature. In general, the clinical syndrome closely resembled that of other inflammatory optic neuropathies, because the condition developed subacutely, over days, with blurred vision and the appearance of a central scotoma. The nadir acuity was lower than that seen in demyelinating optic neuritis; 65% had an acuity in the worse affected eye of 6/60 (20/200) or lower. In 4 cases, it was NPL (no perception of light) (28%). In only 1 case did spontaneous improvement occur60; however, a recovery of function was observed to be appreciable in association with systemic corticosteroids in the majority of cases. Some patients may undergo a worsening in acuity after steroid withdrawal.61,62 In our own series of patients with optic nerve involvement, 24 cases have been seen, of whom 12 were female and 11 were Afro-Caribbean. The mean age was 41 (20 to 71) years. Four cases had previously been diagnosed as having systemic sarcoidosis, and a further 4 cases had had symptoms likely to represent an earlier manifestation of the disease. Half had unilateral optic neuropathies (6 were associated with periorbital pain or pain on eye movement); of the bilateral cases, 3 occurred simultaneously, in the remainder the second eye was usually involved within 3 months of the first. Six were painful. Thirteen cases showed disc swelling in the acute phase. The nadir acuity was lower than that of a demyelinating optic neuritis (57% had acuity in the worse affected eye of 6/60 [20/200] or lower, and 3 had no perception of light). The clinical syndrome was of a subacute optic neuropathy with a central field defect in the majority of cases. Two further cases had compressive optic neuropathies associated with 168 Neuro-Ophthalmology: Blue Books of Neurology

Figure 7–5 Sarcoidosis. A, T2-weighted coronal magnetic resonance imaging showing high signal within the right optic nerve. B, Enhancement on T1-weighted sequences in a patient with systemic sarcoidosis who developed a recurrent painful optic neuropathy on the right side.

neurosarcoid mass lesions. Nine had evidence of uveitis. Of 16 cases who had undergone MRI, 7 showed enhancement of the optic nerve or sheath (Fig. 7–5), 2 showed granulomatous masses in close relation to the optic nerve, and 9 showed no abnormality. MRI of the brain and spinal cord showed abnormalities other than the optic nerve involvement in 12 cases. Two cases improved spontaneously without steroid treatment. Twenty-two cases were treated with high-dose steroids, 9 of whom showed a worsening of acuity on stopping or reducing the steroid dose. Nine patients were treated additionally with azathioprine and two with methotrexate. Visual outcome was good in 11 patients given steroids within 1 week of visual loss, and a delay in treatment beyond 4 weeks was associated with a good response to treatment in only 3 out of 7 cases. Mean follow-up was 17 months (10 weeks to 70 months); 7 out of 36 eyes followed had a final acuity of worse than 6/12. In another recent series,63 24 cases were presented of whom 17 had not previously been diagnosed with systemic sarcoidosis. Sufficient paraclinical data to support a diagnosis were obtained in all cases with a raised serum angiotensin converting enzyme (ACE) (an isolated feature in only 1 case), chest x-ray (CXR), gallium scan, and urinary calcium excretion. In these 17 patients, the gallium scan was abnormal in all 10 cases in which it was performed, the serum ACE was elevated in 11 of 13 cases, and the CXR abnormal in 9 of 14 cases. Seventy-five percent had bilateral visual symptoms. The field defects included a wide range including central and paracentral scotomata, peripheral depression, arcuate defects, and chiasmal and tract defects. Forty-two percent showed evidence for current or previous uveitis. The discs were swollen only in 29% of cases, and periphlebitis and other fundal abnormalities were seen in around 15% of cases. Neuroimaging was abnormal in 70% and normal in those with isolated optic disc granulomata. Fourteen of 16 patients who underwent a spinal fluid examination showed abnormalities such as raised protein or lymphocytosis. Treatment and its response to it were not included in the report. Hence, sarcoidosis may affect the anterior visual pathways in a number of ways. First and most commonly, a primary inflammatory optic neuropathy may 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 169

Figure 7–6 Neurosarcoidosis. A, T2-weighted axial magnetic resonance imaging showing high signal around the fourth ventricle. B, Meningeal enhancement on T1-weighted sequences in a patient with systemic sarcoidosis who developed a subacute ataxia with nystagmus. arise in which pain occurs in about half the cases and optic disc swelling less often. In general, the acuity is worse than that seen in demyelinating optic neuropathies, although mild cases have been seen, and any type of field defect may be seen. Imaging may reveal optic nerve swelling with or without enhancement (Fig. 7–5), or optic nerve sheath enhancement, but can be normal in around half the cases. Uveitis or periphlebitis retinans occurs in around 20% of cases. Second, an optic neuropathy may arise in association with an adjacent inflammatory mass lesion. Meningeal masses arise commonly from the orbital apex, cavernous sinus, or sphenoid ridge, leading to involvement of adjacent structures including the optic nerve (Figs. 7–6 and 7–7). Less commonly, hydrocephalus and an intracranial hypertension syndrome occur infrequently but may also cause optic neuropathy through compression,

Figure 7–7 Neurosarcoidosis. Histologic section (hematoxylin & eosin) of a dural biopsy showing extensive infiltration of the dura by necrotizing granulomata and Langerhans giant cells. 170 Neuro-Ophthalmology: Blue Books of Neurology

and optic nerve granuloma and ischemic complications of uveitis may also be associated with signs of optic neuropathy.

CHRONIC RELAPSING INFLAMMATORY OPTIC NEUROPATHY From the neuro-ophthalmology departments of the National Hospital and St. Thomas’ Hospital we identified 15 patients in whom bilateral optic neuropathies (Fig. 7–8) arose that improved with corticosteroid administration but relapsed after cessation of treatment. These patients were not found to have an underlying systemic inflammatory or vasculitic disease or MS, and we felt that they formed a separate disease entity, which Dr. Elizabeth Graham called chronic relapsing inflammatory optic neuropathy (CRION).64 In the majority of cases, pain was a prominent feature before the onset of visual loss, even with relapse. The degree of visual loss is in general more severe than that seen in demyelinating optic neuritis, and the response to steroids is often dramatic, with restoration of vision from blindness within 2 to 3 days; furthermore, vision may improve with steroid administration even though months have elapsed since the onset of the optic neuropathy. On relapse, all but two cases showed further improvements in vision, and vision was subsequently maintained with immunosuppression, but in two cases relapse was associated with an irreversible visual loss. Investigations revealed high signal within optic nerves (Fig. 7–9), often associated with enhancement, and no brain lesion. Blood investigations were normal as noted earlier, and spinal fluid examinations revealed modest elevations of protein in four of the patients and no cellular response. Oligoclonal bands were not seen. We felt that the disorder was one of granulomatous inflammation for two reasons: first, the characteristics of the clinical syndrome with a painful subacute optic neuropathy that responded quickly to steroids, with relapse after steroid withdrawal,61,62 which is typical of that seen in sarcoidosis (it is known that in this condition symptoms may improve months after onset if steroids are withheld, and it is most uncommon for spontaneous improvement without treatment to take place60; and second, there are pathologic data from biopsied cases in which an optic nerve sheath meningioma was suspected, but a granulomatous

Figure 7–8 Chronic relapsing inflammatory optic neuropathy (CRION). Bilateral optic disc swelling in a patient with a subacute painful bilateral optic neuropathy that was steroid responsive and subsequently recurred. 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 171

Figure 7–9 Chronic relapsing inflammatory optic neuropathy (CRION). A, T2-weighted axial magnetic resonance imaging (MRI) showing high signal and pain particularly within the left optic nerve. B, T1-weighted coronal MRI showing enhancement of both nerves in the same patient, more prominent on the left.

mass was found.62,65–67 We searched for systemic disease in these patients and found no evidence for sarcoidosis or systemic lupus erythematosus in any patient, although one had a mildly raised antinuclear antibody (ANA). The disorder therefore appears to be a distinct one related to but separate from systemic sarcoidosis and sharing similarities to autoimmune optic neuropathy but without serologic evidence for lupus on investigation. These patients and others diagnosed since the report have been followed up, with no evidence to date for the development of MS, sarcoidosis, lupus, or indeed any other systemic disorder. The disorder shares clinical features with autoimmune optic neuropathy (see later), and may be treated effectively in the same way, but does not have the associated ANAs with which the other condition is linked.

Treatment We recommend prompt identification of the disease after investigation and intravenous steroids followed by a slow reduction of high-dose oral steroids over several months. With relapse, immunosuppression should be instituted with azathioprine, methotrexate, or mycophenolate, and close clinical observation should be made to preserve visual acuity. The prognosis for good recovery appears to be closely associated with the latency to commencement of treatment.

OPTIC NEURITIS ASSOCIATED WITH AUTOANTIBODIES The prevalence of autoantibodies in acute demyelinating optic neuritis is, as has been noted previously, low in all published series with ANA positive in 13% of 172 Neuro-Ophthalmology: Blue Books of Neurology

the optic neuritis treatment trial.68 The condition known as autoimmune optic neuropathy is discussed following lupus. Thyroid associated autoantibodies have been noted in some cases of optic neuritis and in the opticospinal form of MS in Japan69; these antibodies were found in 5 of 14 patients with the opticospinal form of MS and in 1 of 32 with the classical form of MS. The prevalence of thyroid antibodies in non-neurologic controls is not stated, and the report predates the recent controversy over the relevance of neuromyelitis optica IgG (NMO-IgG) in the optic-spinal form of MS in Japanese patients.70,71 Optic neuritis is not, however, noted in a series of Hashimoto encephalitis or steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT).72 The occurrence of an optic neuropathy associated with paraneoplastic antibodies seems to be rare with few cases in the literature; most are associated with small cell lung cancer. The pathology of one case revealed a widespread lymphocytic infiltration and fibrosis of the meninges extending to the optic nerves and chiasm as well as other cranial nerves.73 In one case the optic neuropathy presented with disc swelling and improved spontaneously,in the other two a progressive predominately central field loss developed with optic atrophy.74,75 All three cases have been associated with a cerebellar syndrome. More recently an association has been shown between optic neuritis and the paraneoplastic antibody collapsin response-mediated protein 5 (CRMP-5). A series of 15 patients has been reported by one center76 in which 18 previous case reports (including the 3 noted previously) are also referenced. All had developed a subacute visual loss with swollen optic discs. Five were seen to have coexisting retinitis, and 9 had vitritis. Fluorescein angiography revealed leakage from the swollen disc and also peripheral parts of the retina, and 4 who had had vitrectomy showed a reactive vitreous lymphocytosis. All had other neurologic signs during the disease course with white matter lesions on MRI. The optic neuropathy often became bilateral. The CSF was moderately active and all had oligoclonal bands; CRMP-5 was found in all CSF samples tested. Most patients had small cell lung carcinoma, others had thyroid and renal carcinoma. Although CRMP-5 is found in association with thymoma, no patient with this disorder has been shown to have a CRMP-5 associated optic neuritis.

OPTIC NEURITIS FOLLOWING VACCINATION The prevalence of this complication is difficult to ascertain because many cases are unlikely to be reported. There are case reports of optic neuritis following influenza vaccinations,77,78 measles, mumps, rubella (MMR),79 diphtheria, tetanus, pertussis (DTP),80 bacille Calmette-Guerin (BCG),81 and hepatitis B.82 Most cases are bilateral, and the prognosis with and without treatment with corticosteroids seems to be good.

DEVIC’S SYNDROME Devic described a neurologic syndrome comprising the association of an optic neuropathy with transverse myelitis. The clinical phenotype may be seen in conjunction with a variety of immune-mediated disorders such as systemic lupus erythematosus, Sjo¨gren’s syndrome, antiphospholipid antibodies and anti-neutrophil cytoplasmic 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 173

antigen (ANCA), toxins such as clioquinol, as well as various viruses and other infections such as tuberculosis and mycoplasma.83 Those that arise without such associations may be considered to have Devic’s syndrome. Devic’s syndrome is considerably more common in females84,85 and occurs at any age. The disease may arise as a monophasic illness, in which it is more common that both optic nerve and cord involvement arise synchronously, or a relapsing one, in which repeated attacks occur85,86 and in which the severity of the neurologic impairment at onset is on average less severe. The optic neuropathy may be unilateral and sequential or bilateral and synchronous and develops before or after the cord lesion with equal frequency. The majority of patients suffer optic neuropathies on both sides, although simultaneous involvement is most uncommon. Rather, the second eye would become involved hours or days after the first; very rarely would there be weeks or months apart. Characteristically, the loss of vision would be acute and severe, in contrast to Leber’s hereditary optic neuropathy, in which a slow progression of symptoms arises. Forty percent deteriorate to NPL. Pain occurs but is less common than in MS or in granulomatous optic neuropathies. The field defects tend to be central.83,86 Disc appearances also vary from normal appearances at onset to severe swelling with peripapillary hemorrhage. Over time, all cases exhibit a gradual atrophy. Most recover to some degree, often after the first week and continuing over several weeks, although some are left without light perception. With repeated attacks of optic neuritis, a permanent visual deficit accrues. The CSF is usually highly active with raised protein and often hundreds or even thousands of white cells. There may be a polymorph leucocytosis. Glucose levels are not reduced, and the prevalence of oligoclonal bands is low at around 30%.84,85 On repeated testing, oligoclonal bands tend to become absent. Recently,an antibody against central nervous system (CNS) endothelial tissues, NMO-IgG, has been associated with 73% of patients tested with a clinical diagnosis of Devic’s syndrome87 and 58% of patients with the opticospinal form of MS prevalent in Japan. NMO-IgG binds to the abluminal surface of microvessels, pia, subpia, and Virchow-Robin sheaths, at the aquaporin-4 (AQP4) water channel.88 MRI of the brain shows a lesion within one or both optic nerves that enhances, and the remainder of the brain is normal in the majority of cases. Those who have a relapsing disease course tend to acquire brain lesions that are typical of those seen in MS. Recently, it has been shown intriguingly that high signal abnormalities arise on fluid attenuated inversion recovery (FLAIR) sequences around the third and adjacent to the fourth ventricles without clinical accompaniment; these occur in regions of high density of aquaporin-4 channels89,90 (Fig. 7–10). The cord scans are without exception abnormal and show cord swelling in the acute phase (Fig. 7–10), with long and large cord lesions that extend over several cord segments. The pathology is one of diffuse swelling and softening over the affected segments, occasionally the entire cord or optic nerve.91 Histologic examination reveals extensive macrophage infiltration with myelin and axonal loss, necrosis, and cavitation. Both white and gray matter structures are affected. In chronic cases, there is extensive gliosis, cystic cavitation, and profound atrophy. The vessels show thickening and hyalinization. Immunopathologic studies show complement activation and a prominent neutrophil and eosinophil but sparse lymphocyte infiltration. Vascular changes with thickening and hyalinization occur in active and inactive lesions with 174 Neuro-Ophthalmology: Blue Books of Neurology

Figure 7–10 Devic’s syndrome. A, Axial FLAIR magnetic resonance imaging (MRI) showing high signal adjacent to the fourth ventricle. B, T2-weighted sagittal MRI of the cervical cord showing a long lesion extending between C3 and D1 with cord swelling.

prominent perivascular deposition of immunoglobulin. The pattern therefore is one of a humoral immune disorder with early involvement of the vessels. The diagnosis remains a clinical one with much overlap between classical descriptions of the disease and other inflammatory and immune-mediated disorders, and only patients with rather classical descriptions may be labeled thus 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 175

TABLE 7–4 New Diagnostic Criteria for Devic’s Syndrome

Definite NMO Optic neuritis Acute myelitis At least two of three supportive criteria Contiguous spinal cord MRI lesion extending over more than 3 vertebral segments Brain MRI not meeting diagnostic criteria for multiple sclerosis NMO-IgG seropositive status

MRI, magnetic resonance imaging; NMO, neuromyelitis optica. From Wingerchuck DM, et al: Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1466–1467. with confidence. This year new diagnostic criteria for Devic’s syndrome have been suggested92 (Table 7–4).

Treatment No randomized controlled trial of any treatment in this condition has been published. The literature points out that steroids often are used, and many authors use immunosuppression in an attempt to reduce number of attacks in the relapsing form. There is one report of a significant benefit over an 18-month treatment period with azathioprine93 and more recently also with mitoxantrone.94 Plasma exchange is also advocated.95 One paper used intravenous immunoglobulin (IVIG) in two patients whose attacks stopped during treatment,96 and another reported the use of rituximab in eight patients in whom the frequency of attacks was dramatically reduced.97

Prognosis The rate of relapse in the nonmonophasic form is on average high, with the majority of patients suffering attacks more than once per year,98 leading to a stepwise decline in neurologic function over a short time. Incomplete recovery both to vision and to spinal cord function usually means a high level of residual neurologic impairment and disability.

BEHC¸ET’S SYNDROME Behc¸et’s syndrome is an uncommon systemic disorder of unknown etiology characterized by recurrent oral and genital ulceration and panuveitis. Constitutional symptoms comprising malaise, fatigue, and loss of weight are common. Skin involvement, characterized by erythema nodosum, pustular eruptions, or pseudofolliculitis, occurs, and there is an oligoarthropathy of large joints such as the knees, ankles, and shoulders. Involvement of the lungs, gastrointestinal tract, and kidneys is rare. Thrombosis is common, and vasculitis may be associated with the development of arterial aneurysms. There is an association with HLA-B51, particularly in patients with Mediterranean and Japanese ancestry.Other genetic susceptibility factors, such as factor V Leiden gene mutations and mutations within the TNFa gene, are likely to allow the condition to develop in patients genetically susceptible, when the immune system is triggered by certain, presumed infective, antigenic stimuli.99 176 Neuro-Ophthalmology: Blue Books of Neurology

Figure 7–11 Behc¸et’s syndrome. Fundus photograph of a patient with an occlusive retinal vasculitis of the inferior quadrant. (Courtesy of Mr. Miles Stanford.)

The eyes are affected in around 70% of cases.100 The ophthalmic complications include an anterior uveitis (classically with the development of hypopyon) and a retinal vasculitis in which retinal vein occlusion may arise as a result of inflammation (Fig. 7–11), macular edema and optic disc ischemia may arise, and cataract, cystoid macular edema, glaucoma, and optic atrophy may eventually develop. Scleritis and vitritis may also occur.101 Optic neuropathy may arise as a consequence of retinal vasculitis in the condition, and the ocular complications are a much more common cause of visual impairment than neurologic complications. Neurologic complications arise in 5% to 10% of cases and involve either the development of inflammation within the brain, brainstem, spinal cord, roots, or muscle or as a consequence of a venous sinus thrombosis.102 Most complications arise as single events, others follow a relapsing-remitting course and less often a progressive course may be followed leading to severe neurologic impairment and disablement. Intracranial hypertension may develop not associated with discernible venous sinus thrombosis. Isolated optic neuropathy is extremely rare with only a handful of published case reports, although the prevalence of reports is increasing. The majority of cases have developed a subacute painless unilateral optic neuropathy of varying but often mild severity associated with a central field defect and optic disc swelling without hemorrhage or retinal vasculitis.102–108 There are three reports of bilateral synchronous optic neuropathy.109–111 As with other forms of neurologic Behc¸et’s syndrome, the initial manifestations may be neurologic.102,112 Imaging may be normal or associated with high signal lesions within the optic nerve on dedicated optic nerve imaging.106 CSF tends not to be active unless there is evidence for inflammation elsewhere within the nervous system. Oligoclonal bands are absent. Treatment with intravenous corticosteroids has resulted in improvements in visual acuity in most cases. There is no report of relapsing optic neuropathy, but in the case of neurologic complications elsewhere, patients treated with immune suppression do tend to have a less often relapsing disease course.

CELIAC DISEASE Celiac disease may be associated with neurologic complications, and the neurologic syndromes may be associated with anti-gliadin antibodies in the absence of the gastrointestinal disorder; peripheral neuropathy, myopathy, cerebellar ataxia, 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 177

brainstem encephalitis, and an encephalopathy with seizures and calcification have been reported. There is a recent report of two cases who presented with a Devic phenotype in whom optic neuropathy was seen: in the first case, the bilateral optic neuropathy occurred synchronous with the cord lesion, and in the second a unilateral optic neuropathy of poor recovery had arisen a year before the development of the cord lesion.113 There is another report of a patient with ANCA antibodies and celiac disease who presented with bilateral optic neuritis.114

INFLAMMATORY BOWEL DISEASE Case reports of optic neuropathy in ulcerative colitis and Crohn’s disease are rare.115–118 Patients present with signs of an optic neuropathy and disc swelling. Around half the cases have an associated pain, and a further half have signs of ocular inflammation, predominately an anterior granulomatous-type uveitis. Inflammatory ocular complications are said to arise in around 5% of patients with Crohn’s disease119 and include conjunctivitis, episcleritis, iridocyclitis, and retinal vasculitis. Two cases of neuroretinitis have been described.116,120

VOGT-KOYANAGI-HARADA SYNDROME Vogt-Koyanagi-Harada (VKH) is a rare disorder that is more common in dark- skinned people of African and Asian ancestry. It consists of a viral-type prodrome with an aseptic meningitis and hearing problems including tinnitus. This is a result of an immune-mediated attack of melanin-containing cells of the meninges and cochlea. An anterior granulomatous uveitis then develops, sometimes associated with a vitritis, disc swelling, and multiple serous retinal detachments. As the uveitis subsides, depigmentation develops leading to vitiligo, alopecia, and poliosis of the eyelids, eyebrows, and hair. This depigmentation also involves the choroid leading to a mottled “sunset glow” fundus in which can be seen multiple Dalen-Fuchs nodules in the inferior peripheral retina.121 Optic neuropathy is most uncommon; only three cases have been reported,122–124 and the authors of one point out correctly that it is uncertain whether the signs of the optic neuropathy reflect optic disc involvement or (perhaps more likely) ischemia of the disc as a consequence of choroidal involvement by the inflammatory disease.123

Connective Tissue Disorders and Systemic Vasculitis

LUPUS Systemic lupus erythematosus is an uncommon multisystem disease associated with ANA and anti-DNA antibody. The skin, joints, kidneys, lungs, nervous system, and eyes are all affected. The anti-phospholipid antibody arises commonly, although it may be no more prevalent than in other connective tissue diseases.125 Neurologic complications arise in around 20%126 and include encephalopathy with seizures and psychosis, vascular disorders, transverse 178 Neuro-Ophthalmology: Blue Books of Neurology

myelitis, including (quite commonly) a Devic’s syndrome phenotype, optic neuropathy, and headache disorders. There is a closer association between neurologic complications in lupus and the presence of anti-phospholipid antibodies.127 The ocular manifestations arise predominately in the retina, with the development of cotton wool spots, often associated with retinal arteriolar dilatation.128 Intraretinal hemorrhages may also occur.129 Retinal artery and vein occlusion may also occur. More rarely, a progressive arteriolar vaso-occlusive disease develops, in which extensive hemorrhage and neovascularization may follow. Involvement of anterior structures is less common; scleritis, episcleritis, and orbital involvement may occur, but an anterior uveitis is rare.130 The optic neuropathy that may arise in lupus may be acute or chronic and progressive. In the acute form, patients present in a manner typical of a demyelinating optic neuritis with periocular pain and pain on eye movement leading to a subacute visual loss. The disc may be swollen or normal. There appears not to be a relationship between the development of an optic neuropathy and the presence of retinal vasculitis,131,132 with only one published report in which the two conditions coexist.133 Generally, there is a central field defect that is sco- tomatous or arcuate, but altitudinal defects may also be seen. These patients seem more likely to have involvement of other areas of the nervous system at the same or other times,128,132,136 although other series do not show this.135,136 The simultaneous development of a bilateral optic neuritis has been seen in three cases, most of whom were children.137,138 Chiasmal involvement has also been seen.139,140 Imaging investigations show enlargement of the affected nerve or chiasm with gadolinium enhancement.136,140 Untreated, the patients are less likely to improve than those with a demyelinating optic neuritis. The pathology is one of infarction associated with arteriolar fibrinoid necrosis.138 More recently, however, it has been noted that patients often improve following administration of corticosteroids137,139 and immune suppression141 including oral methylprednisolone, methotrexate, chlorambucil, and azathioprine, but in refractory and steroid-unresponsive cases, pulsed IV cyclophosphamide has been shown to be beneficial.134 The seemingly separate condition of “auto-immune optic neuritis,” coined by Dutton and colleagues,142 in which subacute or progressive optic neuropathy develops in association with ANAs in the absence of systemic clinical evidence for lupus is not currently understood and may reflect a series of separate immune-mediated disorders in which autoantibodies are formed in a nonspecific way. The majority of the patients are female. In Dutton’s series of three cases, the condition was bilateral in two (although a previous optic neuropathy of undeter- mined etiology had arisen some years before), and all three showed ANAs. In one, there was an associated retinal vasculitis, in the second there was serologic evidence for mixed connective tissue disease with ANA and anti-RNP, and in the third both ANA and anti-DNA antibodies were present without systemic features of lupus, except that a polymyositis developed some time later. Each was treated with corticosteroids, and in general a reasonable visual recovery took place in each case. Following relapse of the disorder in each case, an immune-suppres- sive agent was added, and a short-term follow-up suggested that no further symptoms had arisen. A more comprehensive series published by Kupersmith and colleagues143 some time later reported 14 patients with recurrent optic 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 179

neuropathies in association with ANAs. In their series, 75% had bilateral optic neuropathies, although seldom had this occurred synchronously. Twenty-five percent of their cases also had other neurologic impairments. Patients had failed to improve following conventional corticosteroid therapy for a presumed demyelinating optic neuritis, but the majority improved when “megadose” intravenous methylprednisolone was given (5 to 14 g over 5 to 7 days). Around a third of these cases were seen to relapse on steroid withdrawal. This series was never followed to define what the risk of developing lupus or another connective tissue disorder was, and I am not certain how prevalent this disorder is. I personally have encountered only one such case. There is also an association between the antiphospholipid antibody syndrome without lupus and optic neuropathy. There are no comparative data, but it is my impression that optic neuropathy is more common in lupus without antiphospholipid antibodies than in that associated with antiphospholipid antibodies and in the primary antiphospholipid antibody syndrome. One recent review cites 10 cases, although there is a mixture of ischemic optic neuropathy and other forms, including a slowly progressive bilateral optic neuropathy.144 A vaso-occlusive ischemic retinopathy is common, with around 80% showing retinal venous tortuosity and 25% showing ischemic changes.145,146

SJO¨ GREN’S SYNDROME Sjo¨gren’s syndrome is an immune-mediated condition in which a lymphocytic infiltration of lacrimal and salivary glands leads to xerostomia and xerophthalmia. There is an association between the disorder and the autoantigens SS-A(Ro) and SS-B (La). The syndrome may occur as a primary disorder or in conjunction with other connective tissue diseases, particularly lupus, rheumatoid arthritis, and scleroderma. In patients with primary Sjo¨gren’s syndrome, a series of neurologic manifestations may arise, including peripheral neuropathy and ganglionopathy, isolated cranial neuropathy, myositis, transverse myelitis, and encephalomyelitis (which may be relapsing-remitting and mimic MS on imaging). Optic neuritis is uncommon with around 28 cases reported,147–149 although it arose in 13 of 82 cases reported recently from France.150 Two were associated with a Devic’s phenotype in this series. Treatment both for an optic neuritis and for the Devic phenotype involves corticosteroids and immunosuppression. The prognosis appears to be good with treatment, with a greater risk of residual visual impairment on relapse than after the first attack.

MIXED CONNECTIVE TISSUE DISEASE This disorder shows features of lupus, systemic sclerosis, polymyositis, and rheumatoid arthritis in association with the autoantibodies ANA, extractable nuclear antigens (ENA), and rheumatoid factor. Neurologic complications appear to be less common than in other connective tissue disorders, but there is a report of a relapsing bilateral optic neuropathy that was unresponsive to treatment with steroids and cyclophosphamide associated with anti-SS-A and anti-RNP antibodies.151 Optic neuropathy occurs more often in association with a Devic’s syndrome; in one case,152 high-dose steroids 180 Neuro-Ophthalmology: Blue Books of Neurology

were seen to be ineffective, but an improvement occurred in association with plasma exchange and azathioprine.

SCLERODERMA Calcinosis, Reynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia (CREST) syndrome and scleroderma may be associated with ocular complications although the prevalence appears to be rare. Keratitis, keratoconjunctivitis sicca, and eyelid telangiectasia have been reported, and vascular disorders within the retina causing retinal vein and arterial occlusions, cotton wool spots, and vitreous hemorrhage. No case of optic neuropathy has been published to date, although Ortiz and colleagues153 reported a case in which multiple intracranial aneurysms in a patient with CREST syndrome in which the internal carotid aneurysms had caused compressive optic neuropathies on both sides.

RHEUMATOID ARTHRITIS In rheumatoid arthritis, optic neuropathy appears to be much less common than in other connective tissue diseases. There are two reports of anterior ischemic optic neuropathy, the first of which showed pathologic evidence for a ciliary arteritis at autopsy.154,155 More common case reports deal with the complications of idiopathic hypertrophic pachymeningitis, which is known to arise in rheumatoid arthritis,156,157 with favorable reports of treatment with cytotoxic agents158(Fig. 7–12). The third potential cause for an optic neuropathy in rheumatoid arthritis is that associated with treatment. Reports show that an optic neuropathy may arise in conjunction with penicillamine,159 methotrexate,160,161 infliximab,162,163 and entanercept.164,165 There are also rare reports of unilateral or bilateral optic neuropathies in ankylosing spondylitis166–168 and Reiter’s syndrome.169

Figure 7–12 Hypertrophic pachymeningitis in a patient who developed chronic escalating headache. The symptoms and the magnetic resonance imaging abnormalities resolved with corticosteroids and methotrexate. 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 181

CHURG-STRAUSS SYNDROME Churg-Strauss syndrome is a small vessel vasculitis associated with p-ANCA, lung involvement associated with symptoms of airways obstruction, a peripheral blood hypereosinophilia, and vasculitis affecting various tissues, including the nervous system and muscle (Fig. 7–13). Ophthalmic involvement is not common but cases of conjunctivitis, keratitis, scleritis, and uveitis have been described, whereas retinal vasculitis appears to be rare.170,171 An optic neuropathy may arise but is most uncommon with only 10 cases published in the literature.170–178 It may be bilateral170,179 or symptomatic on one side only despite evidence for choroidal hypoperfusion on fluorescein angiography173 and may be seen as disc edema before the onset of visual loss.178 In a Mayo Clinic review of a series of 47 consecutive patients with Churg-Strauss syndrome, optic neuropathy was seen in only 1 case of 29 patients with neurologic complications.175

Treatment and Prognosis When associated with signs of central retinal artery occlusion, visual recovery seems not to occur despite reasonable treatment with corticosteroids and immunosuppression.170–173,175 In 2 of the 10 cases,174,176 it has been shown that visual recovery may occur provided treatment is prompt. Treatment with high-dose corticosteroids and cyclophosphamide appears to be optimal.

WEGENER’S GRANULOMATOSIS Wegener’s granulomatosis is small vessel vasculitis associated with antibodies to cytoplasmic-pattern ANCA (c-ANCA) in which a necrotizing vasculitis with granuloma formation develops in lung, upper airways, kidney, and other organs, including the nervous system.180 The ophthalmic manifestations are common and include conjunctivitis, dacryocystitis, keratitis, episcleritis, scleritis, uveitis, and retinal vasculitis. They may arise because of independent involvement by the vasculitis itself or by means of a spread of abnormal tissue from adjacent structures, usually the paranasal air sinuses. Hence, the development of an inflammatory tissue mass within the orbit is a common complication, leading

Figure 7–13 Temporal artery biopsy of a patient with Churg-Strauss syndrome presenting with a subacute painful optic neuropathy. There is an infiltration predominately of eosin- ophils around two small vessels. (Courtesy of Dr. Julie Crow.) 182 Neuro-Ophthalmology: Blue Books of Neurology

to orbital pain, evolving proptosis, and ophthalmoparesis. Adjacent structures become involved, leading to keratitis, uveitis, and scleritis.181 Limited forms of the disease have on occasion been seen to affect orbital structures alone. Similarly, involvement of the optic nerve may occur as an independent process or in consequence of compression by an inflammatory mass within the orbit. Patients may present with symptoms and signs suggestive of an anterior or posterior ischemic optic neuropathy in association with the presence of abnormal tissue within the orbit and adjacent paranasal air sinuses on MRI or, less commonly, with signs of an optic neuropathy with normal imaging. The optic neuropathy may be bilateral.182 Although a vasculitic disorder implies that the pathophysiology of the optic neuropathy is one of ischemia, most recent case reports suggest a favorable outcome provided prompt and aggressive treatment is made available. High-dose corticosteroids improve acuity, but the treatment of choice in Wegener’s granulomatosis is cyclophosphamide. A trial of etanercept failed to show benefit,183 but recent reports point to the effectiveness of the CD20 antagonist rituximab184 in cases refractory to cyclophosphamide.

GRANULOMATOUS ANGIITIS OF THE CENTRAL NERVOUS SYSTEM Granulomatous angiitis is a rare vasculitic disorder of the CNS in which small and medium-sized vessel vasculitis develops with a perivascular inflammatory infiltration involving lymphocytes, macrophages, and giant cells. Optic neuropathy has been reported only rarely and always in association with other manifestations of the disorder. It may complicate raised CSF pressure, and one case of optic perineuritis has been seen.185

POLYARTERITIS NODOSA Polyarteritis nodosa (PAN) is a systemic vasculitis affecting both small and medium-sized arteries, which can affect all tissues including the kidney, lungs, and nervous system. It is twice as common in men than women and presents at all ages but more commonly between 40 and 60 years. The eye is said to be involved in 10% to 20% of cases with an ischemic retinopathy associated with branch and central retinal artery occlusions, uveitis, exudative retinal detachment, scleritis, episcleritis, and keratitis.186,187 Optic neuropathies may arise with signs of anterior or posterior ischemic optic neuropathy with only 10 case reports in the literature; an early case showed inflammatory occlusion of the posterior ciliary arteries on both sides in a man with PAN who became blind shortly before death.188 Others presented as anterior ischemic optic neuropathies.189–193 Another case, which also came to autopsy, involved a man who reported unilateral transient visual loss194 in which a vasculitis of the small vessels of the orbit was seen without significant changes in the ciliary arteries. It was postulated that the visual loss arose as a result of choroidal ischemia rather than an optic neuropathy. Treatment involves systemic corticosteroids and cyclophosphamide; the prognosis for recovery of vision appears to be poor; presumably then the pathology of the optic neuropathy is one of thrombotic occlusion of vessels involved in vasculitis, rather than inflammation adjacent to it. 7 Inflammatory Optic Neuropathies Not Associated with Multiple Sclerosis 183

Figure 7–14 Temporal artery biopsy showing giant cell arteritis; high-power view showing a giant cell (arrow) and disruption of the internal elastic lamina. On the left, there is a mononuclear inflammatory cell infiltrate, on the right the thickened intima. (Courtesy of Prof. Tamas Revesz.)

GIANT CELL ARTERITIS Giant cell arteritis is much more common in older adults than in middle age. It is characterized by involvement of the large and medium-sized vessels of the branches of the arteries that arise from the aortic arch (Fig. 7–14). The prevalence increases from 2.3 105 in the sixth decade of life to 44.7 105 in the ninth decade195 and only very rarely in those younger than age 50. It is more frequent in Caucasian peoples than in Africans, and each sex is equally represented. The pathology is one of a severe granulomatous vasculitis with infiltration of lymphocytes, histiocytes, and giant cells; edema of the adventitia; and necrosis of the internal elastic lamina.196 The visual symptoms that arise are a result of thrombotic occlusion of the arteries and not to the direct affects of inflammation (see Chapter 5). An anterior ischemic optic neuropathy resulting from occlusion of the short ciliary arteries is the most common, when the disc is seen to be pale and swollen with flame- shaped hemorrhages and cotton wool spots in the adjacent retina. A posterior ischemic optic neuropathy may also arise, as may a central or branch retinal artery occlusion. Ophthalmoparesis and any neuro-ophthalmic manifestation of stroke may also arise, and mononeuropathies and peripheral polyneuropathies occur rarely.

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179. Vitali C, Genovesi-Ebert F, Romani A, et al: Ophthalmological and neuro-ophthalmological involvement in Churg-Strauss syndrome: A case report. Graefes Arch Clin Exp Ophthalmol 1996;234:404–408. 180. Nishino H, Rubino FA, DeRemee RA, et al: Neurologic involvement in Wegener’s granulomatosis: An analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 1993;33:34–39. 181. Perry SR, Rootman J, White VA: The clinical and pathological constellation of Wegener granulomatosis of the orbit. Ophthalmology 1997;104:683–694. 182. Monteiro MLR, Borges WIS, Ramos CVF,et al: Bilateral optic neuritis in Wegener granulomatosis. J Neuro-ophthalmol 2005;25:25–28. 183. Wegener’s Granulomatosis Etanercept trial (WGET) research group: Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 2005;352:251–361. 184. Stasi R, Stipa E, Poeta GD, et al: Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology 2006;45: 1432–1436. 185. Hassan AS, Trobe JD, McKeever PE, Gebarski SS: Linear magnetic resonance enhancement and optic neuropathy in primary angiitis of the central nervous system. J Neuro-Ophthalmol 2003;23:127–131. 186. Morgan CM, Foster CS, D’Amico DJ, Gragoudas ES: Retinal vasculitis in polyarteritis nodosa. Retina 1986;6:205–209. 187. Galetta S: Vasculitis. In Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuro-ophthalmology, 6th ed. Baltimore, Williams & Wilkins, 2005, pp 2342–2344. 188. Goldstein I, Wechsler D: Bilateral atrophy of the optic nerve in periarteritis nodosa. Arch Ophthalmol 1937;18:767–773. 189. Kimbell OC, Wheliss JA: Polyarteritis nodosa complicated by bilateral optic neuropathies. JAMA 1967;201:139–140. 190. Saraux H, Le Hoang P, Larache L: Anterior and posterior acute ischaemic optic neuropathy related to polyarteritis nodosa. J Fr d’ophtalmol 1982;5:55–61. 191. Hutchinson CH: Polyarteritis nodosa presenting as posterior ischaemic optic neuropathy. J R Soc Med 1984;77:1043–1046. 192. Hsu CT, Kerrison JB, Miller NR, Goldberg MF: Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa. Retina 2001;21:348–351. 193. Graf CM, Skare TL, Moreira CA: Anterior ischemic optic neuropathy and polyarteritis nodosa: Case report. Arg Bras Oftalmol 2006;69:107–109. 194. Newman NJ, Hoyt WF, Spencer WH: Macula sparing monocular blackouts: Clinical and pathological investigations of intermittent choroidal vascular insufficiency in a case of periarteritis nodosa. Arch Ophthalmol 1974;91:367–370. 195. Machado EB, Michet CJ, Ballard DJ, et al: Trends in incidence and clinical presentation of temporal arteritis in Olmsted County, Minnesota, 1950–1985. Arthritis Rheum 1988;31:745–749. 196. McDonnell PJ, Moore GW, Miller NR, et al: Temporal arteritis: A clinicopathologic study. Oph- thalmology 1986;93:518–530. 8 Hereditary Optic Neuropathies NANCY J. NEWMAN

Leber’s Hereditary Optic Optic Neuropathy in Other Neuropathy Hereditary Diseases

Dominant Optic Atrophy Therapeutic Implications References

Key Points The hereditary optic neuropathies are a group of disorders in which optic nerve dysfunction figures solely or prominently and direct inheritance is clinically or genetically proven. The most common hereditary optic neuropathies are autosomal dominant optic atrophy and maternally inherited Leber’s hereditary optic neuropathy. Other inherited neurologic and systemic syndromic disease will not uncommonly manifest optic neuropathy. A selective vulnerability of the optic nerve to perturbations in mitochondrial function may underlie a final common pathway among these disorders. The neurologist should be familiar with the clinical characteristics and diagnosis of the hereditary optic neuropathies.

The traditional classification of the hereditary optic neuropathies relies on the recognition of typical clinical characteristics and classic patterns of familial transmission, but genetic analysis now permits diagnosis of some of these disorders even in the absence of a family history or in the setting of unusual clinical presentations.1,2 As a result, the clinical phenotypes of each disease are broader, and it is easier to recognize unusual cases. Nearly all of the inherited optic neuropathies eventually have symmetric, bilateral, central visual loss. In many of these disorders, the papillomacular nerve fiber bundle is affected, with resultant central or cecocentral scotomas. Optic nerve damage is usually permanent and, in many diseases, progressive. In classifying the hereditary optic neuropathies, it is important to exclude the primary retinal degenerations that may masquerade as primary optic neuropathies because of the common finding of optic disc pallor. Retinal findings may be subtle, especially among the cone dystrophies, in which optic nerve pallor may be an early finding.1 It is essential in these cases to enlist the aid of your ophthalmology colleagues. Retinal arterial attenuation and abnormal electroretinography should help distinguish these diseases from the primary optic neuropathies. 191 192 Neuro-Ophthalmology: Blue Books of Neurology

Additionally, it is also customary to distinguish those disorders in which optic neuropathies feature prominently, with or without associated neurologic and systemic findings, from those primarily neurologic and systemic multisystem diseases in which there may be optic nerve involvement (Table 8–1). Obviously, this distinction is not always clear. The neurologist will often be the first one to see these patients and recognize optic nerve dysfunction.

Leber’s Hereditary Optic Neuropathy

The clinical characteristics of patients with Leber’s hereditary optic neuropathy (LHON) have been known for almost 150 years.1 Since the late 1980s, LHON

TABLE 8–1 Inherited Optic Neuropathies

Primary hereditary optic neuropathies Leber’s hereditary optic neuropathy Dominant optic atrophy Congenital recessive optic atrophy Sex-linked optic atrophy Inherited optic neuropathy with other neurologic or systemic signs Wolfram/DIDMOAD syndrome Autosomal dominant progressive optic atrophy and deafness Autosomal dominant progressive optic atrophy with progressive hearing loss and ataxia Hereditary optic atrophy with progressive hearing loss and polyneuropathy Opticocochleodentate degeneration Sex-linked recessive optic atrophy, ataxia, deafness, tetraplegia, and areflexia Opticoacoustic nerve atrophy with dementia Dominant optic atrophy, deafness, ophthalmoplegia, and myopathy PEHO syndrome Behr’s syndrome Optic neuropathy in other hereditary degenerative or developmental diseases Hereditary ataxias Friedreich’s ataxia Spinocerebellar ataxias Hereditary polyneuropathies Charcot-Marie-Tooth disease Familial dysautonomia (Riley-Day) Hereditary spastic paraplegias Hereditary muscular dystrophies Storage diseases and cerebral degenerations of childhood (see Table 8–2) Mitochondrial diseases Leigh syndrome MELAS syndrome MERFF syndrome CPEO/KSS syndrome

CPEO, chronic progressive external ophthalmoplegia; DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; KSS, Kearns-Sayre syndrome; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy and ragged red fibers; PEHO, progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy. 8 Hereditary Optic Neuropathies 193

has received notoriety as a maternally inherited disease linked to abnormalities in mitochondrial DNA.1–10 The actual prevalence and incidence of visual loss from this disorder worldwide remains unstudied, but among individuals in the northeast of England, there is a minimal prevalence of visual loss from LHON of 3.22 per 100,000 individuals and a prevalence for harboring a primary LHON-associated mtDNA mutation of 11.82 per 100,000 individuals.11 In Australia, the disease accounts for about 2% of legal blindness in individuals younger than 65 years and for about 11% of all patients with bilateral optic neuropathy of uncertain etiology.12 Men are affected with visual loss more often than women, with a male predominance of about 80% to 90% in most pedigrees.4,7–13 A minimum of 25% of men and 5% of women at risk for LHON experience visual loss.1,12,13 The onset of visual loss typically occurs between the ages of 15 and 35 years, but otherwise classic LHON has been reported in many individuals both younger and older,4,6–8,13 with a range of age at onset from 2 to 80 years. Visual loss typically begins painlessly and centrally in one eye. The second eye is usually affected weeks to months later. Reports of simultaneous onset are numerous and likely reflect both instances of true bilateral coincidence and those in which initial visual loss in the first eye went unrecognized. More than 97% of patients will have second eye involvement within 1 year.4,6 The duration of progression of visual loss in each eye also varies and may be difficult to document accurately. Usually, the course is acute or subacute, with deterioration of visual function stabilizing after months.4–8,13 Visual acuities at the point of maximum visual loss range from no light perception to 20/20, with most patients deteriorating to acuities worse than 20/200.4,6,8,13 Color vision is affected severely, often early in the course, but rarely before significant visual loss.8 Pupillary light responses may be relatively preserved when compared with the responses in patients with optic neuropathies from other causes, although others have not confirmed this finding.1 Visual field defects are typically central or cecocentral4,8,13 (Fig. 8–1).

Figure 8–1 Goldmann visual fields of a patient with visual loss from Leber’s hereditary optic neuropathy showing dense cecocentral defects (involving fixation and the physiologic blind spot), reflecting damage to the papillomacular retinal ganglion cell fibers in both eyes. 194 Neuro-Ophthalmology: Blue Books of Neurology

Figure 8–2 Funduscopic view of the right optic nerve of a patient acutely losing vision from Leber’s hereditary optic neuropathy. Note the hyperemia of the optic nerve head, the tortuosity of the retinal vessels just temporal to the disc, and the blurring of the disc margins and mild elevation of the disc from “pseudoedema.”

Funduscopic abnormalities, especially during the acute phase of visual loss (Fig. 8–2), include hyperemia of the optic nerve head and dilation and tortuosity of vessels and, less commonly, retinal and disc hemorrhages, macular edema, exudates, and retinal striations.1 A triad of signs has been proposed as pathognomonic for LHON: 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 (distinguishing the LHON nerve head from truly edematous discs).14 These findings can be found not only in patients in the acute phase of visual loss but also in “presymptomatic” eyes, as well as in the eyes of asymptomatic maternal relatives.8 Indeed, having abnormalities of the peripapillary nerve fiber layer does not necessarily predict visual loss. Furthermore, some patients with LHON never exhibit the characteristic ophthalmoscopic appearance, even if examined at the time of acute visual loss.4,6,7 Hence, the “classic” LHON ophthalmoscopic appearance may be helpful in suggesting the diagnosis if recognized in patients or their maternal relatives, but its absence—even during the period of acute visual loss—does not exclude the diagnosis of LHON. As the disease progresses, the telangiectatic vessels disappear and the pseudoedema of the disc resolves. Perhaps because of the initial hyperemia, the optic discs of patients with LHON may not appear pale for some time. This feature, coupled with the relatively preserved pupillary responses and the lack of pain, has led to the misdiagnosis of nonorganic visual loss in some LHON patients. Eventually, however, optic atrophy with nerve fiber layer dropout most pronounced in the papillomacular bundle supervenes (Fig. 8–3). Nonglaucomatous cupping of the optic discs may also be seen in patients with symptomatic LHON. In most patients with LHON, visual loss remains profound and permanent. However, recovery of excellent central vision may occur years after visual deterioration.4,6,8,13,15 It may take the form of a gradual clearing of central vision or be restricted to a few central degrees, resulting in a small island of vision within a large central scotoma.15 Recovery is usually bilateral but may be unilateral. 8 Hereditary Optic Neuropathies 195

Figure 8–3 Funduscopic view of the right (A) and left (B) optic nerves of a patient with Leber’s hereditary optic neuropathy who lost vision 6 months prior. Note the pallor of the discs, especially temporally, the latter indicating preferential damage to the papillomacular bundle. Those patients whose vision improves most substantially appear to have a lower mean age at the time of initial visual loss.6,8 Recurrences of visual failure are extremely rare among those patients both with and without visual recovery. In the majority of patients with LHON, visual dysfunction is the only significant manifestation of the disease. However, some pedigrees have members with associated cardiac conduction abnormalities, especially the pre-excitation syndromes.1 Minor neurologic abnormalities have been reported in patients with LHON.13,16 Less commonly, pedigrees have been described in which multiple maternal members demonstrate the clinical features of LHON in addition to more severe neurologic abnormalities, such as movement disorders, dystonia, encephalopathic episodes, and brainstem syndromes.1 Disease clinically indistinguishable from multiple sclerosis may occur in families with LHON.6,16–18 It is possible that this association between LHON and multiple sclerosis is no greater than the prevalence of the two diseases but that an underlying LHON mutation may worsen the prognosis of optic neuritis in patients with multiple sclerosis.18 Ancillary tests, aside from genetic analysis, are generally of limited usefulness in the evaluation of LHON. Computed tomography and magnetic resonance imaging of the brain are typically normal in patients with LHON.1,4 All pedigrees clinically designated as LHON have a maternal inheritance pattern.3,9,10,19–21 In maternal inheritance, all offspring of a woman carrying the trait will inherit the trait, but only the females can pass the trait on to the subsequent generation. Although both the father and the mother contribute to the nuclear portion of the zygote, the mother’s egg is virtually the sole provider of the zygote’s cytoplasmic contents. Because the intracytoplasmic mitochondria are the only source of extranuclear DNA, maternal inheritance indicates transmission of the abnormal trait via the mitochondrial DNA (mtDNA). Ironically, 196 Neuro-Ophthalmology: Blue Books of Neurology

the majority of proteins crucial to normal mitochondrial function are encoded on nuclear genes, manufactured in the cytoplasm, and transported into the mitochondria (Fig. 8–4). Hence a “mitochondrial disease” could conceivably result from genetic defects in either the nuclear or the mitochondrial genomes. Inheri- tance of mitochondrial diseases will be maternal if the genetic defect is an mtDNA point mutation or Mendelian if the genetic defect is on a nuclear gene involved in mitochondrial function. Three point mutations in the mtDNA, the so-called primary LHON mutations, are believed to account for about 90% of cases of LHON worldwide.1,9,19 They are located at mtDNA positions 11778 (69% of cases), 3460 (13% of cases), and 14484 (14% of cases). Several other mtDNA mutations may be “primary” but account individually for only a few pedigrees worldwide (Fig. 8–5). Screening for LHON in a patient with visual loss from optic neuropathy should begin with the three primary mutations.19 In those primary mutation-negative patients in whom suspicion remains high, testing for the other mtDNA mutations associated with LHON can be performed in specialized centers, especially for those mutations deemed likely causal in a few previous pedigrees. Alternatively, because

Nucleus

DOA Chromosomes 3q 18q LHON 11778 DNA 4p DIDMOAD 14484 3460

mRNA Mitochondrion

Oxphos Ribosomes mt DNA

mRNA Protein

Figure 8–4 Diagram of a proposed common pathophysiology of the hereditary optic neuropathies through mitochondrial dysfunction. This schematic diagram of a cell shows how proteins coded for in the nucleus and in the mitochondrion both contribute to mitochondrial function. The bold arrows indicate where the genetic defects underlying dominant optic atrophy (DOA), Leber’s hereditary topic neuropathy (LHON), and Wolfram syndrome (DIDMOAD) may cause mitochondrial dysfunction and optic atrophy. mRNA, messenger RNA; mtDNA, mitochondrial DNA; oxphos, oxidative phosphorylation. (From Newman NJ: Hereditary optic neuropathies: From the mitochondria to the optic nerve. Am J Ophthalmol 2005;140:517–523.) 8 Hereditary Optic Neuropathies 197

15812 15257 14831* 3275* 14596*d m OH 3376* 12s PH F T 14568 rRNA Cyt b 4136* D-loop region 14510* 3308 14498* V 14495* 4025* ^ 0/16569 P 14482* 3505 14459*d 3733* 16s P 14325* 3734 rRNA L E 14279* 3700* ND6 4171* 3497 L 14484 13730* ND5 3394 13708 3496 13637* ND1 3547 3460 Primary 13528* 3472 LHON 13051* 3398 I Q mutations L 13045*m 3316 M 11778 S 3635* H 12848* 4216 ND2 12811* A N OL ND4 4640* C 4917 W Y 5244* 11696* ND4L 11253* R 10663* S ND3 COI G COIII 10237* ATPase6 D COII K 9804* ATPase8 9738* 7444* 9438* 9101* 9016*

Complex I genes Complex III genes Transfer RNA genes (NADH (ubiquinol: dehydrogenase) cytochrome c oxidoreductase) Complex IV genes Complex V genes Ribosomal RNA genes (cytochrome c (ATP synthase) oxidase)

Figure 8–5 Mitochondrial genome showing the point mutations associated with Leber’s hereditary optic neuropathy (LHON). More than 90% of all cases of LHON are associated with the three primary mutations located inside the genome, and the other mutations are shown outside the genome. These other mutations vary markedly in their prevalence, degree of evolutionary conser- vation of the encoded amino acids altered, and frequency among controls. Mutations marked * may be primary, but they each account for only one or a few pedigrees worldwide. Mutations marked *d are primary mutations associated with LHON and dystonia. Mutations marked *m are primary mutations associated with LHON/MELAS overlap syndrome. (Modified from MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org, 2005. December 22, 2005.) the majority of these other mtDNA mutations reside in genes encoding subunits of complex I, complete sequencing of complex I might also be considered. Finally, sequencing the entire mitochondrial genome is possible, although labor intensive. This should be performed only in those cases of high suspicion and interpreted only by those versed in the complexities of mitochondrial genetics. 198 Neuro-Ophthalmology: Blue Books of Neurology

Genetic analysis allows a broader view of what constitutes the clinical profile of LHON.1 Most striking is the number of patients without a family history of visual loss. Some of these singleton cases are women, some outside the typical age range for LHON, and some without the classic ophthalmoscopic appearance. Clearly, the diagnosis of LHON should be considered in any case of unexplained bilateral optic neuropathy, regardless of age of onset, gender, family history, or funduscopic appearance. Many questions remain unanswered regarding the determinants of phenotypic expression in LHON. For instance, does the specific mtDNA mutation dictate particular clinical features? Although those pedigrees with LHON “plus” demonstrate that certain mtDNA mutations may result in specific disease patterns of Leber’s-like optic neuropathies with other neurologic abnormalities,1,9 few significant clinical differences have been demonstrated to date among those LHON patients positive for the 11778 mutation, those with other mtDNA mutations, and those as yet genetically unspecified. One major exception is the difference in spontaneous recovery rates among those patients with the 11778 mutation and those with the 14484 mutation. Among 136 patients with the 11778 mutation, only 5 (4%) reported spontaneous recovery,15 compared with 37% to 65% of 14484 patients.6,8 Furthermore, the ultimate visual acuities in patients with the 14484 mutation are significantly better than those with the 11778 and 3460 mutations.6 An mtDNA mutation will be present in all maternally related family members of patients with LHON, even though many will never become symptomatic. Hence, whereas the presence of an mtDNA mutation may be necessary for phenotypic expression, it may not be sufficient. Nuclear-encoded factors modifying mtDNA expression, mtDNA products, or mitochondrial metabolism may influence phenotypic expression of LHON. Although most studies have not been able to confirm X-linkage as an explanation of the male predominance of visual loss in LHON, the X-linkage hypothesis may still be viable.9 Environmental factors, both internal and external, may play a role. Systemic illnesses, nutritional defi- ciencies, medications, or toxins that stress or directly or indirectly inhibit mitochondrial metabolism have been suggested to initiate or increase phenotypic expression of the disease. Although some reports suggest a possible role for tobacco and excessive alcohol use as precipitants of visual loss,22 one large case-control study of sibships23 failed to confirm this. Other agents known to be toxic to the optic nerve, such as ethambutol, or to mitochondrial function, such as antiretroviral therapy, may have a heightened toxicity in patients with the LHON mutations and already compromised mitochondrial function.1 Theories on the pathogenesis of LHON must reconcile how multiple different mtDNA mutations located in different genes encoding different proteins result in an essentially identical clinical phenotype that is expressed only in the optic nerve, suddenly and bilaterally.10,19 Pathogenetic theories include reduction in ATP production and/or free-radical damage with resultant apoptosis of retinal ganglion cells. Selective involvement of the ganglion cell or its axon may be explained on a vascular, mechanical, or regional basis, with several studies suggesting a high degree of mitochondrial respiratory activity within the unmyelinated, prelaminar portion of the optic nerve.19 This portion of the visual system may be particularly vulnerable to mitochondrial dysfunction, especially abnormalities of complex I.24 8 Hereditary Optic Neuropathies 199

Dominant Optic Atrophy

Autosomal dominant optic atrophy (DOA), or Kjer’s disease, is believed to be the most common of the hereditary optic neuropathies, with an estimated disease prevalence of 1 in 50,000.25 The typical onset of visual loss is in the first or second decade of life, although most patients cannot identify a precise onset of reduced acuity.1,2 Indeed, optic atrophy is often discovered only as a consequence of examination of other affected family members, attesting to the usually impercep- tible onset in childhood, often mild degree of visual dysfunction, and absence of acute or subacute progression. Visual acuity is usually reduced to the same mild extent in both eyes, with more than 80% of patients retaining better than 20/200 vision, although there is considerable interfamilial and intrafamilial variation in acuities.26 In some patients, there is a mild, slow, insidious progression of visual dysfunction. The observation that some families have a marked decline in visual acuity with age, whereas others do not has important implications for counseling.26 Spontaneous recovery of vision is not a feature of this disorder. Although tritanopia was originally designated as the characteristic color vision defect in patients with DOA, subsequent studies suggest that a generalized dyschromatopsia, with both blue-yellow and red-green defects, is most common.1,26 Visual fields in patients with DOA characteristically show central, paracentral, or cecocentral scotomas. In patients with acuities of 20/50 or better, static perimetry is often necessary to identify the defects (Fig. 8–6). In one large study,26 66% of the visual field defects in 50 affected patients were predominantly in the superotemporal visual fields, mimicking the bitemporal visual field defects seen with lesions of the chiasm. The optic atrophy in patients with dominantly inherited optic neuropathy may be subtle, temporal with a triangular excavation, or diffuse, involving the entire optic disc2,26 (Fig. 8–7). Although there are dominantly inherited syndromes of optic atrophy associated with neurologic dysfunction, most of the patients with the syndrome of

Figure 8–6 Humphrey automated perimetry performed on a patient with visual loss from dominant optic atrophy. A, Visual field of the left eye. B, Visual field of the right eye. Note the bilateral cecocentral defects that appear to respect the vertical meridian, mimicking chiasmal damage. 200 Neuro-Ophthalmology: Blue Books of Neurology

A Figure 8–7 Funduscopic view of the right (A) and left (B) optic nerves of a patient with dominant optic atrophy. Note the pallor and excavation of the discs, especially temporally, the latter indicating preferential damage to the papillomacular bundle.

autosomal-dominant optic atrophy have no additional neurologic deficits. How- ever, sensorineural hearing loss is not uncommon and tends to cluster within families.1 The hearing loss may be severe and congenital, or subclinical, requiring audiology for detection. In most cases, it is unclear whether these pedigrees represent a phenotypic variant of DOA, a genetically distinct disorder, or a genetically heterogeneous group of disorders with a similar phenotype. In one remarkable family in which ophthalmoplegia and ptosis accompanied DOA and hearing loss,27 a chromosome 3 missense mutation was found, a mutation which in other pedigrees resulted solely in nonsyndromic optic atrophy. DOA is likely to be a primary degeneration of central retinal ganglion cells but not the exclusive result of either parvocellular or magnocellular cell loss.26,28 Although a linkage study of one large DOA pedigree localized the gene responsible for DOA with the Kidd blood group antigen, subsequently localized to a region on the long arm of chromosome 18 (18q12.2–12.3),29 most of the pedigrees with DOA have genetic homogeneity in their linkage to the telomeric portion of the long arm of chromosome 3 (3q28–29).1,25,28 Thirty percent to 90% of DOA families have been found to harbor more than 90 different missense and nonsense mutations, deletions, and insertions in a gene within this region that has been designated the OPA1 gene.28 The product of the OPA1 gene is targeted to the mitochondria and appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.28 Downregulation of the OPA1 leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential with cytochrome c release and caspase- dependent apoptosis.30 Interestingly, linkage analysis of patients with normal tension glaucoma has shown an association with polymorphisms of the OPA1 gene.31 These findings, coupled with the typical expression of both DOA and LHON 8 Hereditary Optic Neuropathies 201

as isolated optic neuropathies, emphasizes the crucial role of mitochondria in retinal ganglion cell pathophysiology.10,28

Optic Neuropathy in Other Hereditary Diseases

In some pedigrees with inherited optic neuropathies, certain neurologic or systemic manifestations are regularly observed.1 The most common of these syndromes is Wolfram’s syndrome, although still quite rare, with a prevalence of 1 in 770,000 in the United Kingdom.1,2,32–36 The hallmark of Wolfram’s syndrome is the association of juvenile diabetes mellitus and progressive visual loss with optic atrophy, almost always associated with diabetes insipidus and neurosensory hearing loss (also called DIDMOAD for diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Symptoms and signs of diabetes mellitus usually occur within the first or second decade of life and usually precede the development of optic atrophy. In later stages, visual loss becomes severe, usually worse than 20/200.33 Visual fields show both generalized constriction and central scotomas. Optic atrophy is uniformly severe, and there may be mild to moderate cupping of the disc. Hearing loss and diabetes insipidus may be quite severe. Atonia of the efferent urinary tract is present in about 50% of patients and is associated with recurrent urinary tract infections and even fatal complications.32 Other systemic and neurologic abnormalities are common.1,32,35 Median age at death is 30 years, most commonly resulting from central respiratory failure with brainstem atrophy.32 Many of the associated abnormalities reported in Wolfram’s syndrome are commonly encountered in patients with presumed mitochondrial diseases, especially those patients with the chronic progressive external ophthalmoplegia syndromes.21 This has led to speculation that the Wolfram’s phenotype may be nonspecific and reflect a wide array of underlying genetic defects in either the nuclear or mitochondrial genomes, with a unifying pathogenesis in underlying mitochondrial dysfunction1 (Fig. 8–4). In several families with presumed autosomal recessive inheritance, the Wolfram’s gene was localized to the short arm of chromosome 4 (4p16.1).37 However, this locus does not account for all DIDMOAD pedigrees. The gene responsible at this locus has been designated WFS1, in which multiple point mutations and deletions have been identified.38 Some of these mutations were subsequently found to be a common cause of inherited isolated low-frequency hearing loss. In one report, the locus on chromosome 4p16 was proposed as a predisposing factor for the formation of multiple mtDNA deletions.39 DIDMOAD patients were also found to concentrate on two major mtDNA haplotypes that are also over-represented among LHON patients.40 Other inherited diseases with primarily neurologic or systemic manifestations, such as the multisystem degenerations, can include optic atrophy among their signs, typically as a secondary and inconsistent finding. This category of disorders encompasses the hereditary ataxias, the hereditary polyneuropathies, the hereditary spastic paraplegias, the hereditary muscular dystrophies, storage diseases and other cerebral degenerations of childhood, and mitochondrial disorders other than LHON (Tables 8–1 and 8–2).1,2,41 Many of these disorders, despite Mendelian inheritance, may have a final common pathway in mitochondrial dysfunction and, hence, not surprisingly, will have optic nerve involvement. 202 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 8–2 Familial Storage Diseases and Cerebral Degenerations of Childhood That Can Manifest Optic Atrophy

Adrenoleukodystrophy Allgrove syndrome (“4A”) Canavan’s disease Cerebral palsy Cockayne syndrome COFS GAPO syndrome Hallervorden-Spatz disease Infantile neuroaxonal dystrophy Krabbe’s disease Lipidoses (infantile and juvenile GM1–1 and GM1–2, GM2, infantile Niemann-Pick disease) Menkes’ syndrome Metachromatic leukodystrophy Mucopolysaccharidoses (MPS IH, IS, IHS, IIA, IIB, IIIA, IIIB, IV, VI) Pelizaeus-Merzbacher disease Smith-Lemli-Opitz syndrome Zellweger syndrome

“4A,” alacrima, achalasia, autonomic disturbance, and ACTH insensitivity; COFS, cerebro-oculo- facio-skeletal syndrome; GAPO, growth retardation, alopecia, pseudoanodontia, and optic atrophy; GM1-gangliosidoses, GM1-1 and GM1-2; GM2-gangliosidoses, Tay-Sachs disease, Sandhoff disease, late infantile, juvenile and adult GM2-gangliosidose; MPS IH, Hurler; MPS IS, Scheie; MPS HIS, Hurler-Scheie; MPS IIA and IIB, Hunter; MPS IIIA and IIIB, Sanfilippo; MPS IV, Morquio; MPS VI, Maroteaux-Lamy.

In Friedreich’s ataxia, for example, evidence of optic neuropathy is present in up to two thirds of cases, although severe visual loss is uncommon.1,42 This is an autosomal recessive disorder linked to the long arm of chromosome 9 (9q13-q21) involving a GAA trinucleotide expansion in a gene coding for a protein called fra- taxin, which regulates iron levels in the mitochondria.41 Similarly, many patients with spinocerebellar ataxia (SCA) (especially SCA1 and SCA3)1,43 and Charcot- Marie-Tooth disease (CMT) (especially CMT type 6)1,44–46a also have optic atrophy. Whether all of these diseases will prove to have a final common pathophysiology via mitochondrial dysfunction remains unknown, but this appears to be the case for autosomal dominant CMT6.46a Given the relative selective involvement of the optic nerve in disorders in which the final common pathophysiology is proven to be via mitochondrial dysfunction, it is somewhat surprising that other mitochondrial disorders do not regularly manifest optic neuropathies. The subacute necrotizing encephalo- myelopathy of Leigh results from multiple different biochemical defects that all impair cerebral oxidative metabolism.1,10 This disorder may be inherited in an autosomal recessive, X-linked, or maternal pattern, depending on the genetic defect. The onset of symptoms is typically between the ages of 2 months and 6 years, and consists of progressive deterioration of brainstem functions, ataxia, seizures, peripheral neuropathy, intellectual deterioration, impaired hearing, and poor vision. Visual loss may be secondary to optic atrophy or retinal degeneration. The syndrome of Leigh is likely a nonspecific phenotypic response 8 Hereditary Optic Neuropathies 203

to certain abnormalities of mitochondrial energy production. Other presumed mitochondrial disorders of both nuclear and mitochondrial genomic origins may manifest optic atrophy as a secondary clinical feature, often a variable manifestation of the disease.1,10,21 Examples include cases of myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and chronic progressive external ophthalmoplegia, both with and without the full Kearns-Sayre phenotype. The other, more constant, phenotypic characteristics of all of these mitochondrial disorders distinguish them from diseases such as LHON in which visual loss from optic nerve dysfunction is the primary manifestation of the disorder.

Therapeutic Implications

In light of the possibility for spontaneous recovery in some patients with LHON, any anecdotal reports of treatment efficacy must be considered with caution. Some manifestations of other mitochondrial diseases, specifically the mitochondrial cytopathies, may respond to therapies designed to increase mitochondrial energy production.1,19 Most of the agents used are naturally occurring cofactors involved in mitochondrial metabolism, whereas others have antioxidant capabilities. Unfortunately, studies in LHON patients are few and not convincingly positive.47 Topical agents deemed neuroprotective or antiapoptotic for ganglion cells could be administered directly to the eye.48 It remains to be seen whether any of these agents alone or in combination will prove consistently useful in the treatment of acute visual loss in LHON, in the prevention of second eye involvement, or in the prophylactic therapy of asymptomatic family members at risk. A promising form of gene therapy known as allotypic expression may play a future role in the therapy of LHON and other mitochondrial diseases.49 In this approach, a nuclear-encoded version of a gene normally encoded by mtDNA (in this case, the ND4 gene containing nucleotide position 11778) is made synthet- ically, inserted via an adeno-associated viral vector, and codes for a protein expressed in the cytoplasm that is then imported into the mitochondria. This protein increased the survival of cybrids harboring the 11778 mutation three-fold and restored ATP synthesis to a level indistinguishable from that in cybrids containing normal mtDNA.49 Alternatively, additional copies of antioxidant genes can be inserted into the nucleus.50 Further elucidation of the genetic and environmental triggers of the pathologic cascade in susceptible individuals with the hereditary optic neuropathies will require more genetic, biochemical, physiologic, and pathologic studies. The relative accessibility of the eye and its ganglion cells may provide the ideal setting in which to test specific therapies. Additionally, LHON with its near universal involvement of the second eye once vision deteriorates in one eye, provides a unique opportunity for a potential therapeutic window. Success in the treatment or prevention of the hereditary optic neuropathies may have profound implications for the treatment of acquired optic nerve disorders.

Acknowledgments This work was supported in part by a departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, NY, and 204 Neuro-Ophthalmology: Blue Books of Neurology

by core grant P30-EY06360 (Department of Ophthalmology) from the National Institutes of Health, Bethesda, MD. Dr. Newman is a recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award. This study was adapted in part from Newman NJ: Hereditary optic neuropathies: From the mitochondria to the optic nerve. Am J Ophthalmol 2005140:517–523, with permission.

REFERENCES 1. Newman NJ: Hereditary optic neuropathies. In Miller NR, Newman NJ, Biousse V, Kerrison JB (eds): Walsh & Hoyt’s Clinical Neuro-Ophthalmology, vol 1, 6th ed. Baltimore, Lippincott, Williams & Wilkins, 2005, pp 465–501. 2. Newman NJ, Biousse V: Hereditary optic neuropathies. Eye 2004;18:1144–1160. 3. Wallace DC, Singh G, Lott MT, et al: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988;242:1427–1430. 4. Newman NJ, Lott MT, Wallace DC: The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991;111:750–762. 5. Mackey D, Buttery RG: Leber hereditary optic neuropathy in Australia. Aust N Z J Ophthalmol 1992;20:177–184. 6. Riordan-Eva P, Sanders MD, Govan GG, et al: The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995;118:319–337. 7. Hotta Y, Fujiki K, Hayakawa M, et al: Clinical features of Japanese Leber’s hereditary optic neuropathy with 11778 mutation of mitochondrial DNA. Jpn J Ophthalmol 1995;39:96–108. 8. Nikoskelainen EK, Huoponen K, Juvonen V, et al: Ophthalmologic findings in Leber hereditary optic neuropathy,with special reference to mtDNA mutations. Ophthalmology 1996;103:504–514. 9. Man PYW, Turnbull DM, Chinnery PF: Leber hereditary optic neuropathy. J Med Genet 2002;39:162–169. 10. Carelli V, Ross-Cisnros F, Sadun A: Mitochondrial dysfunction as a cause of optic neuropathies. Prog Ret Eye Res 2004;23:53–89. 11. Man PYW, Griffiths PG, Brown DT: The epidemiology of Leber hereditary optic neuropathy in the north east of England. Am J Hum Genet 2003;72:333–339. 12. Mackey DA: Epidemiology of Leber’s hereditary optic neuropathy in Australia. Clin Neurosci 1994;2:162–164. 13. Van Senus AHC: Leber’s disease in the Netherlands. Doc Ophthalmol 1963;17:1–163. 14. Smith JL, Hoyt WF, Susac JO: Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 1973;90:349–354. 15. Stone EM, Newman NJ, Miller NR, et al: Visual recovery in patients with Leber’s hereditary optic neuropathy and the 11778 mutation. J Neuroophthalmol 1992;12:10–14. 16. Nikoskelainen EK, Marttila RJ, Huoponen K, et al: Leber’s “plus”: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1995;59: 160–164. 17. Harding AE, Sweeney MG, Miller DH, et al: Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992;115:979–989. 18. Bhatti MT, Newman NJ: A multiple sclerosis-like illness in a man harboring the mtDNA 14484 mutation. J Neuroophthalmol 1999;19:28–33. 19. Newman NJ: From genotype to phenotype in Leber hereditary optic neuropathy: Still more questions than answers. J Neuroophthalmol 2002;22:257–261. 20. DiMauro S, Schon EA: Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348: 2656–2668. 21. Biousse V, Newman NJ: Neuro-ophthalmology of mitochondrial disorders. Curr Opin Neurol 2003;16:35–43. 22. Sadun AA, Carelli V, Salomao SR, et al: Extensive investigation of a large Brazilian pedigree with 11778 haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol 2003;136:231–238. 23. Kerrison JB, Miller NR, Hsu F-C, et al: A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000;130:803–812. 24. Qi X, Lewin AS, Hauswirth WW, et al: Suppression of complex I gene expression induces optic neuropathy. Ann Neurol 2003;53:198–205. 8 Hereditary Optic Neuropathies 205

25. Kjer B, Eiberg H, Kjer P, Rosenberg T: Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthal Scand 1996;74:3–7. 26. Votruba M, Fitzke FW, Holder GE, et al: Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy. Arch Ophthalmol 1998;116:351–358. 27. Payne M, Yang Z, Katz BJ, et al: Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: A syndrome caused by a missense mutation in OPA1. Am J Ophthalmol 2004;138:749–755. 28. Delettre C, Lenaers G, Pelloquin L, et al: OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab 2002;75:97–107. 29. Kerrison JB, Arnould VJ, Ferraz Sallum JM, et al: Genetic heterogeneity of dominant optic atrophy, Kjer type. Arch Ophthalmol 1999;117:805–810. 30. Olichon A, Baricault L, Gas N, et al: Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 2003;278:7743–7746. 31. Aung T, Okada K, Poinoosawmy D, et al: The phenotype of normal tension glaucoma patients with and without OPA1 polymorphisms. Br J Ophthalmol 2003;87:49–152. 32. Barrett TG, Bundley SE, Macleod AF: Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 1995;346:1458–1463. 33. Barrett TG, Bundey SE, Fielder AR, Good PA: Optic atrophy in Wolfram (DIDMOAD) syndrome. Eye 1997;11:882–888. 34. Barrett TG, Bundey SE: Wolfram (DIDMOAD) syndrome. J Med Genet 1997;34:838–841. 35. Castro FJ, Barrio J, Perena MF, et al: Uncommon ophthalmologic findings associated with Wolfram syndrome. Acta Ophthalmol Scand 2000;78:118–119. 36. Minton JA, Rainbow LA, Ricketts C, Barrett TG: Wolfram syndrome. Rev Endocr Metab Disord 2003;4:53–59. 37. Polymeropoulos MH, Swift RG, Swift M: Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4. Nat Genet 1994;8:95. 38. Van Den Ouweland JM, Cryns K, et al: Molecular characterization of WFS1 in patients with Wolfram syndrome. J Mol Diagn 2003;5:88–95. 39. Barrientos A, Volpini V, Casademont J, et al: A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome. J Clin Invest 1996;97:1570–1576. 40. Hofmann S, Bezold R, Jaksch M, et al: Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 1997;39:8–18. 41. Lynch DR, Farmer J: Practical approaches to neurogenetic disease. J Neuroophthalmol 2002;22:297–304. 42. Givre SJ, Wall M, Kardon RH: Visual loss and recovery in a patient with Friedreich ataxia. J Neuroophthalmology 2000;20:229–233. 43. Abe T, Abe K, Aoki M, Itoyama Y, Tamai M: Ocular changes in patients with spinocerebellar degeneration and repeated trinucleotide expansion of spinocerebellar ataxia type 1 gene. Arch Ophthalmol 1997;115:231–236. 44. Kuhlenbaumer G, Young P, Hunermund G, et al: Clinical features and molecular genetics of hereditary peripheral neuropathies. J Neurol 2002;249:1629–1650. 45. Chalmers RM, Bird AC, Harding AE: Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy. J Neurol Neurosurg Psychiatry 1996;60:195–196. 46. Chalmers RM, Riordan-Eva P, Wood NW: Autosomal recessive inheritance of hereditary motor and sensory neuropathy with optic atrophy. J Neurol Neurosurg Psychiatry 1997;62: 385–387. 46a.Zu¨ chner S, De Jonghe P, Jordanova A, et al: Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006;59:276–281. 47. Mashima Y, Kigasawa K, Wakakura M, et al: Do idebenon and vitamin therapy shorten the time to achieve visual recover in Leber hereditary optic neuropathy? J Neuroophthalmol 2000;20:166–170. 48. Newman NJ, Biousse V, David R, et al: Prophylaxis for second eye involvement in Leber’s hereditary optic neuropathy: An open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol 2005;140:407–415. 49. Guy J, Qi X, Pallotti F,et al: Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol 2002;52:534–542. 50. Qi X, Lewin AS, Sun L, et al: SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I. Ann Neurol 2004;56:182–191. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath NEIL R. MILLER

Primary Tumors of the Optic Schwannoma Nerve Hemangiopericytoma Optic Nerve Glioma (Benign) Malignant Optic Nerve Glioma Secondary Tumors Ganglioglioma Metastatic and Locally Invasive Medulloepitheliomas Tumors Hemangioblastoma Lymphoreticular Tumors

Primary Tumors of the Optic Summary Nerve Sheath Optic Nerve Sheath Meningioma References

Key Points Most primary tumors of the optic nerve and its sheath are benign and produce slowly progressive visual loss associated with evidence of an anterior or posterior optic neuropathy and variable proptosis. The diagnosis of the most common tumors—glioma and meningioma—can be made with neuroimaging. Most optic nerve gliomas are benign and do not need treatment unless they produce unacceptable proptosis or appear to be progressing on neuroimaging. Optic nerve gliomas that require treatment may be resected or treated with radiation therapy; the role of chemotherapy is controversial. The optimal treatment for optic nerve sheath meningiomas that require therapy is conformal 3D or stereotactic fractionated radiation therapy.

Tumors of the optic nerve can be classified as primary or secondary and as intrinsic nerve tumors and tumors of the sheath. In this chapter, I discuss each type of lesion.

Primary Tumors of the Optic Nerve

The most common tumor of the optic nerve is the optic nerve glioma. Most of these tumors are benign, but malignant gliomas of the optic nerve occur as do 206 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 207

other tumors, including gangliogliomas, medulloepitheliomas, and vascular tumors, such as hemangioblastomas and hemangiopericytomas.

OPTIC NERVE GLIOMA (BENIGN) Optic nerve gliomas comprise about 1% of all intracranial tumors.1 They are almost always unilateral and occur more often in females than in males. These tumors may occur at any age, but most become symptomatic in childhood. Indeed, according to Chutorian et al,2 75% of patients with optic nerve gliomas become symptomatic in the first decade of life, and 90% become symptomatic during the first 2 decades of life. In a series of 33 patients with optic nerve gliomas reported by Rush et al,3 the age range was 2 to 46 years, with a median age of 6.5 years and a mean age of 10.9 years. Optic nerve gliomas occurring in adults behave similarly to gliomas of the optic nerve in childhood. Most cases of optic nerve glioma are sporadic, but several reports describe these tumors in siblings, and others describe them in various generations of several families. In all of these reports, the affected patients have had evidence of neurofibromatosis type 1 (NF1). The symptoms and signs that occur in patients with optic nerve gliomas are well described, and include decreased visual function, proptosis (often associated with infradisplacement of the globe), optic disc swelling or pallor, and strabis- mus4 (Fig. 9–1). Neither orbital nor ocular pain is typically present. Because of chronic compression of the central retinal vein, some patients with optic nerve gliomas develop central retinal vein occlusion, venous stasis retinopathy, optocili- ary shunt vessels, or rubeosis iridis with neovascular glaucoma. Others experience acute loss of vision, usually associated with development or worsening of proptosis, from hemorrhage into the tumor.5 However, not all optic nerve gliomas are symptomatic. Some are found during general screening of children with NF1.4 In many of these patients, visual evoked potentials (VEPs) are mildly abnormal. A relationship between optic nerve glioma and NF1 is well established.6 The reported incidence of NF1 among patients with optic nerve or chiasmal gliomas

Figure 9–1 External appearance of a patient with an optic nerve glioma. 208 Neuro-Ophthalmology: Blue Books of Neurology

ranges from 10% to 70% in large series, probably reflecting the differing degrees of thoroughness with which investigators examine their patients for the stigmata of NF1, different institutional biases, and patterns of referral. Conversely, the incidence of optic nerve glioma in patients with NF1 varies from 8% to 31%.6 The diagnosis of an optic nerve glioma can be confirmed by either computed tomographic (CT) scanning or magnetic resonance imaging (MRI). The appearance depends on whether or not the patient has NF1. In patients without NF1, there is almost always a fusiform enlargement of the optic nerve with a clearcut margin produced by the intact dural sheath (Fig. 9–2A). In patients with NF1, the nerve is more irregular and tends to show both kinking and buckling as well as low-density areas within the nerve (Fig. 9–2B).7 MRI typically shows gliomas to be hypointense to isointense on T1-weighted images and mildly to strongly hyperintense on proton density- and T2-weighted images. After intravenous injection of a paramagnetic substance such as gadolinium, some gliomas enhance wholly or in part, and it is thought that such lesions are more metabol- ically active than those that do not enhance.8 MRI can also show extension of tumor and tumor-associated changes beyond the optic nerve into the chiasm, findings that may not be apparent on CT scanning (Fig. 9–3). Although the appearance of some optic nerve gliomas may be mistaken for that of an optic nerve sheath meningioma,9 the distinction between the two entities usually is easy to make by combining clinical and imaging findings. Some patients with optic nerve gliomas have an enlarged optic canal on the side of the lesion. The enlargement can be identified by both CT scanning and MRI. An enlarged optic canal does not indicate with certainty that the tumor extends intracranially, however. Arachnoid hyperplasia alone may be responsible for the enlargement. Conversely, a normal-sized optic canal does not indicate that the tumor is confined within the orbit.

A Figure 9–2 Imaging appearance of optic nerve gliomas. A, A patient without neurofibromatosis. B, A patient with neurofibromatosis. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 209

Figure 9–3 Magnetic resonance imaging of an optic nerve glioma showing intracranial extension of the tumor. The gross appearance of an optic nerve glioma is characteristic. In patients without NF1, the process consists of a diffuse expansion of the nerve that may extend the entire length of the nerve or occur along any portion of it (Fig. 9–4A). The expanded area may be solid or have areas with a gelatinous appearance. Hemorrhage may be present in some areas. In patients with NF1, the tumor not only expands the optic nerve parenchyma but often breaks through the pia-arachnoid to fill both the subarachnoid and subdural spaces10 (Fig. 9–4B). However, the tumor almost always remains within the confines of the dural sheath of the optic nerve as long as it stays within the confines of the orbit or optic canal. Once it extends intracranially, however, it may remain primarily intraneural or develop a sizable exophytic component that in rare cases compresses the opposite optic nerve, optic chiasm, or both. The natural history of optic nerve gliomas is almost always benign.4 Most grow slowly in a self-limited fashion, and some spontaneously regress.11 It

A Figure 9–4 Macroscopic appearance of optic nerve gliomas. A, A patient without neurofibromatosis. B, A patient with neurofibromatosis. 210 Neuro-Ophthalmology: Blue Books of Neurology

therefore is not surprising that long-term studies indicate that patients who are not treated usually retain excellent, or at least have stable, visual function. Unfortunately, in most large series, the tumors have been excised rather than observed because of the concern that the tumor will extend to the optic chiasm and damage visual function in the opposite eye. In fact, this rarely occurs. Thus, although most investigators agree that complete removal of the tumor, whether by an orbital or a transcranial approach, is associated with excellent long-term survival, I agree with other authors12 that such treatment is rarely necessary and reserve removal of the optic nerve for patients with severe cosmetic disfigurement or imaging evidence of progressive extension of the tumor. The value of radiotherapy and chemotherapy in the treatment of optic nerve gliomas is even less clear than the value of surgery.12,13 Individual case reports indicate that some patients with presumed optic nerve gliomas experience improvement in vision and reduction in the size of the lesion following conventional fractionated radiation therapy or chemotherapy, but the results may not be any better than the natural history of the lesion, and, in addition, the treatment may produce a variety of complications. There remain many unanswered questions pertaining to optic nerve gliomas: (a) What is the risk that the tumor will extend intracranially and place the patient at a higher risk of contralateral visual loss or death? (b) Are optic nerve gliomas that appear to grow really infiltrating a previously normal structure or have preexisting tumor cells in the area entered a more aggressive growth phase? (c) Does the presence or absence of NF1 correlate with the behavior of an optic nerve glioma? (d) What are the features of an optic nerve glioma that render it susceptible to radiotherapy, chemotherapy, or both? I believe that these questions and others can be answered only by following patients with gliomas confined to the optic nerve over extended periods with meticulous clinical examinations and MRI at regular intervals. In the meantime, I recommend that most patients with unilateral optic nerve gliomas, particularly those with NF1, be followed at regular intervals both clinically and with neuroimaging without intervention. Only if there is cosmetically unacceptable proptosis, progressive deterioration of visual function, evidence by MRI of definite tumor enlargement or extension but not to the optic chiasm, or a combination of these, should surgical excision of the lesion be considered. In some cases, surgical excision of a glioma confined to the orbital portion of the optic nerve is best performed by a craniotomy to ensure removal of the entire tumor. In most cases, however, an orbital approach may suffice to remove the involved nerve, particularly when the main reason for surgery is cosmetically unacceptable proptosis. Regardless of the operation that is used, the involved eye need not be enucleated. An eye whose optic nerve is removed to treat an optic nerve glioma or meningioma (see later) usually does not become phthisi- cal, particularly if care is taken to preserve the short posterior ciliary arteries, because there is an adequate collateral blood supply to the globe.

MALIGNANT OPTIC NERVE GLIOMA Although most gliomas that involve the optic nerve have a benign histologic appearance and a relatively benign prognosis, malignant astrocytomas occasionally involve the anterior visual system, producing a clinical course characterized 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 211

by rapidly progressive visual loss, neurologic deficits, and, eventually, death.14 Unlike low-grade gliomas of the anterior visual system that occur in children, malignant gliomas almost always occur in adults.14 The age range is broad, ranging from the second to the eighth decade of life. Some reports suggested that these tumors occur primarily in men, whereas others report an equal incidence in men and women. The specific pattern of visual loss that occurs in patients with malignant gliomas of the optic nerve appears to depend on the site of origin of the tumor. Tumors that originate in the proximal portion of the nerve produce a characteristic syndrome.14 The initial symptoms are monocular blurring of vision and retrobulbar pain simulating optic neuritis. The fundus of the affected eye initially may appear normal, but most patients rapidly develop evidence of occlusive vascular disease involving the optic disc, including venous stasis and edema (Fig. 9–5A). There may be extensive hemorrhage in the posterior pole, and the appearance of the fundus may thus resemble the ischemic form of central retinal vein occlusion (CRVO), and neovascular glaucoma may develop. This does not remain, however, a monocular disease. Within 5 to 6 weeks, both eyes become affected, and the patient soon becomes completely blind. Hypothalamic dysfunction, hemiparesis, and other neurologic deficits develop in the latter stages of the disease, and death usually occurs in less than 1 year.15 Malignant optic gliomas that originate in the distal portion of the optic nerve produce a similar syndrome of progressive unilateral visual loss, neurologic symptoms, and death; however, the visual loss in these patients is associated with a normal appearing optic disc that eventually becomes pale.15 The neuroimaging appearance of a malignant glioma of the optic nerve is nonspecific. In some cases, the optic nerve appears diffusely thickened, and MRI after intravenous injection of a paramagnetic contrast agent may show marked enhancement of the nerve with inhomogeneity and cystic-appearing areas15,16 (Fig. 9–5B). The pathologic features of a malignant optic nerve glioma are characteristic.14–16 The vascular and partially necrotic tumor occupies most of the nerve. In the orbit, it usually infiltrates the meninges of the nerve and the surrounding soft tissue, whereas intracranially, it eventually infiltrates the optic chiasm, hypothalamus, and adjacent parts of the brain. The histopathology of this tumor is completely different from that of the typical optic nerve glioma, being characterized by extreme cellular pleomorphism, nuclear hyperchromaticity,and scattered mitoses (Fig. 9–5C). There are often numerous areas of vascular endothelial proliferation, necrosis, and hemorrhage, similar to those seen in glioblastomas. There is no satisfactory treatment for a malignant optic nerve glioma, and death is the result in most cases. Short-term success occasionally follows treatment with combined radiotherapy and chemotherapy.

GANGLIOGLIOMA In rare instances, ganglion cell tumors originate within the substance of the optic nerve.17–19 Such a tumor may be thought to be an optic glioma until an exploration is performed and the nerve is removed or a biopsy of the lesion is obtained. The presentation of these tumors as well as their imaging characteristics are similar to those of optic nerve gliomas (Fig. 9–6A), although the visual 212 Neuro-Ophthalmology: Blue Books of Neurology

Figure 9–5 Malignant optic nerve glioma. A, Fundus showing appearance of a severe central retinal vein occlusion. B, Magnetic resonance imaging of lesion. C, Histopathology.

loss may be more rapidly progressive; however, their pathology is quite different. The tumor is composed of numerous ganglion cells, separated by connective tissue that is abundant in some areas and sparse in others.17–19 Microscopic findings show neoplastic astrocytic nuclei throughout a hypercellular nerve associated with small numbers of randomly distributed, well-differentiated ganglionic elements as well as binucleate ganglion cells (Fig. 9–6B). These tumors also show immunoreactivity to synaptophysin and neurofilament protein.19

MEDULLOEPITHELIOMAS Medulloepitheliomas most commonly arise in the brain and spinal cord; however, they also may arise from the optic nerve.20–22 This is not surprising when one considers that the embryonic neuroepithelium that lines the invaginated 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 213

Figure 9–6 Ganglioglioma of the optic nerve. A, Magnetic resonance imaging appearance. B, Histopathology. (Courtesy of Dr. Clinton D. McCord.) optic vesicle is continuous with that lining the cavities of the optic nerve and the forebrain early in embryonic development. A medulloepithelioma can thus arise from any point along this pathway. The presentation of an optic nerve medulloepithelioma depends on its location. When the tumor involves the orbital portion of the optic nerve, there is proptosis and optic disc swelling, similar to that produced by an optic nerve glioma. More posterior lesions produce a progressive retrobulbar optic neuropathy. The imaging appearance of these lesions may mimic that of an optic nerve glioma, consisting of a fusiform enlargement of the nerve (Fig. 9–7A).

Figure 9–7 Medulloepithelioma of the optic nerve. A, Computed tomography appearance. B, Histopathology. (Courtesy of Dr. W. Richard Green.) 214 Neuro-Ophthalmology: Blue Books of Neurology

Like its intracranial counterpart, the optic nerve medulloepithelioma is composed of multilaminar columnar cells that grow in tubes and cords, creating an elaborate interconnecting set of cellular strands that give the impression of a net (Fig. 9–7B). Mitoses may be rare or abundant, and the degree of cellular anaplasia varies considerably among tumors. A simple medulloepithelioma contains only elements that resemble medullary epithelium and structures derived from the optic vesicle, including retinal pigment epithelium, ciliary epithelium, vitreous, and neuroglia. There are also benign and malignant teratoid variants that contain one or more heteroplastic elements such as cartilage or striated muscle. The treatment of an optic nerve medulloepithelioma is complete excision of the nerve; however, recurrences can occur despite gross total removal of the lesion, and metastatic spread may occur.

HEMANGIOBLASTOMA Hemangioblastomas occasionally occur within the substance of the optic nerve.23 The neuroimaging appearance of such lesions is similar to that of optic nerve gliomas (Fig. 9–8A); however, they generally show much more enhancement, which tends to be diffuse. Some these patients have evidence of von Hippel-Lindau disease. In other cases, the tumor appears to be an isolated phenomenon. Hemangioblastomas are composed of two principal cellular components. One is the endothelial cell with accompanying pericytes. The other is an interstitial or stromal cell. The ratio of these two elements, the caliber of the interposed vascular channels, and the degree of lipidization of stromal cells contribute to the histologic heterogeneity of the tumor (Fig. 9–8B). Although the name “hemangioblastoma” implies a poorly differentiated lesion with malignant or at least invasive characteristics, hemangioblastomas are benign lesions with little tendency to seed, metastasize, or recur once they are removed. Their treatment is total removal whenever possible. This can usually be accomplished through adequate exposure of the tumor at surgery,microsurgical technique, and careful attention to hemostasis.

Figure 9–8 Hemangioblastoma of the optic nerve. A, Computed tomography appearance; B, Histopathology. (Courtesy of Dr. John Carter.) 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 215

Primary Tumors of the Optic Nerve Sheath

The most common tumor of the optic nerve sheath is the meningioma; however, a few rare tumors of the sheath have also been described, including one case of a hemangiopericytoma and several cases of schwannomas.

OPTIC NERVE SHEATH MENINGIOMA Primary optic nerve sheath meningiomas (ONSMs) account for one third of primary optic nerve tumors, are the second most common optic nerve tumors after glioma, and are the most common tumors of the optic nerve sheath.24 Although ONSMs are said to comprise 1% to 2% of all meningiomas, their reported incidence has increased since the development of more advanced neuroimaging techniques, which have also significantly contributed to earlier recognition of the disease. ONSMs may be primary or secondary. Secondary ONSMs arise intracranially from dura on or near the planum sphenoidale and spread anteriorly within the confines of the optic nerve sheath through the optic canal to surround the orbital portion of the nerve, whereas primary ONSMs arise from arachnoid cap cells within the dural sheath surrounding the orbital or, less commonly, the canalicular portion of the optic nerve.25,26 Independent of the primary site of origin, ONSMs usually spread around the optic nerve through the subdural and subarachnoid spaces, following pathways of least resistance such as vessels and dural septae.25,27 As they spread, they compromise the function of the nerve both by impairing blood supply to the nerve and by interfering with axon transport. The tumors thus are interposed between the nerve substance and its extradurally derived blood supply, making the majority of ONSMs not amenable to resection. Some ONSMs remain localized to a small segment of the optic nerve, whereas others spread to surround the entire length of the orbital and canalicular portions of the nerve. Rarely, the tumor infiltrates the dura and spreads beyond the confines of the nerve to infiltrate adjacent orbital structures, including fat, extraocular muscles, and bone. When the tumor spreads to adjacent bone, it may enter the haversian canal system, inciting hyperostosis and bone proliferation.28 In a meta-analysis by Dutton published in 1992,24 the mean age at presentation for primary ONSMs was 41 years (age range 3 to 80), with women being affected more often than men (3:2). Patients with neurofibromatosis had a higher incidence of ONSM compared with the general population. Almost all cases (95%) were unilateral. The majority of primary ONSMs were intraorbital, with 8% confined to the optic canal. Interestingly, canalicular meningiomas had a higher incidence of bilaterality (38%) than ONSMs within the orbit. In a subsequent series,29 half of the patients with bilateral ONSMs had tumor along the planum sphenoidale in continuity with the lesions in both optic canals. Thus, it would appear that some cases of apparently bilateral ONSMs are truly bilateral, whereas others represent either spread of a primary planum sphenoidale meningioma to both optic canals or of a unilateral ONSM across the planum to the contralateral optic canal. 216 Neuro-Ophthalmology: Blue Books of Neurology

Approximately 4% to 7% of ONSMs occur in childhood. Unlike ONSMs that occur in adults, there is no gender predilection, and they are often associated with neurofibromatosis type 2. In addition, ONSMs in children often behave in a more aggressive fashion characterized by faster growth, more frequent intracranial, and more frequent bilateral involvement than occurs in adults.29 The majority of primary ONSMs present with a slowly progressive optic neuropathy characterized by a variable loss of visual acuity.24,29–31 In the study performed by Dutton,24 45% of patients had vision of 20/40 or better, whereas fewer than 25% had counting fingers or worse. Even patients who do not have significant reduction in visual acuity often have disturbances of color vision and visual field defects. Less common symptoms in patients with ONSMs include pain or discomfort, double vision, and transient visual obscurations.24,29–31 The obscurations of vision are almost always associated with optic disc swelling and in some cases are exacerbated or induced by eye movement. Almost all patients with a unilateral ONSM have an ipsilateral relative afferent pupillary defect, and most have either swelling of the optic disc without hemorrhages or exudates or optic atrophy.24,29–31 Other ophthalmoscopic findings include macular swelling contiguous with a swollen optic disc, choroidal folds, and acquired retinochoroidal collateral vessels (Fig. 9–9). Indeed, the triad of visual loss, optic atrophy, and retinochoroidal collateral vessels is almost pathognomonic for ONSM, although this triad tends to occur relatively late in the course of the disorder.32 Orbital signs such as proptosis are present in 30% to 65% of patients with ONSMs, depending on the series.24,29 Mechanical restriction of ocular motility is found in 39% of patients29 but is usually asymptomatic. The diagnosis of an ONSM may be made by a variety of imaging studies, most often high-resolution CT scanning,33 thin-section MRI,34 or ultrasonography.35 These studies obviate the need for tissue biopsy in most cases, thus making an early diagnosis possible without potentially damaging the optic nerve during surgery.

Figure 9–9 Fundus of a patient with a left optic nerve sheath meningioma shows slightly swollen, superiorly pale optic disc with multiple retinochoroidal collateral vessels (arrowheads). 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 217

ONSMs have three main morphologic patterns on imaging: tubular, fusiform, and globular.29 CT scanning typically shows enlargement of the optic nerve with an increased density peripherally and decreased density centrally (the “tram- track” sign). These changes are particularly well seen after intravenous injection of iodinated contrast material (Fig. 9–10). In addition, in some cases of ONSM, calcifications surrounding the nerve are present on CT scanning, although they may be masked by contrast enhancement and thus are best identified on precon- trast soft tissue and bone-windowed images.36 The presence of such calcifications is thought to indicate slow growth.29 MRI provides somewhat better detail of ONSMs than does CT scanning34 (Fig. 9–11). In particular, the soft tissue component of the tumor is readily visible, particularly when T1-weighted are viewed after intravenous injection of a paramagnetic contrast agent and fat saturation techniques are used. The appearance of the optic nerve on coronal magnetic resonance (MR) images after gadolinium is most often that of a hypodense area (the nerve) surrounded by an

Figure 9–10 Axial non-contrast computed tomography scan demonstrates a hyperintense left optic nerve sheath with central lucency corresponding to the nerve (i.e., the “tram-track” sign).

Figure 9–11 Axial, non-contrast, T1-weighted magnetic resonance imaging in a patient with a right optic nerve sheath meningioma shows a fusiform mass surrounding the optic nerve with the lateral deviation of the nerve. Note extension of the tumor into the optic canal. 218 Neuro-Ophthalmology: Blue Books of Neurology

enhancing, thin, fusiform or globular peripheral ring of tissue (the tumor) (Fig. 9–12). In addition, on careful examination, rather than having a perfectly smooth outline, all forms of ONSMs can be seen to have very fine extensions into the orbit (Fig. 9–13). MRI also provides sufficient tissue detail that one can use it to assess intracranial extension24,29,34 (Figs. 9–11 and 9–13). Ultrasound of the orbit can also be helpful in the diagnosis of an ONSM but only if one has the services of a superb ultrasonographer. Echographic evaluation of an ONSM characteristically shows an enlargement in the diameter of the nerve, with predominantly medium-high reflectivity, and an irregular acous- tic structure. In addition, there may be shadowing from internal calcification.24

Figure 9–12 Coronal T1- weighted magnetic resonance imaging with gadolinium enhancement and fat suppression shows diffusely enhancing right optic nerve sheath surrounding the optic nerve. The nerve itself appears as a small hypodense central area.

Figure 9–13 Axial T1-weighted magnetic resonance imaging with gadolinium enhancement and fat suppression in two patients with right optic nerve sheath meningiomas. A, This scan demonstrates thin enhancement of the optic nerve sheath with irregular margins, suggesting orbital fat invasion. B, This scan shows a fusiform, enhancing mass surrounding the optic nerve. Again, note the irregular outline of the mass. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 219

In many cases, performance of a 30-degree test reveals solid thickening of the nerve, whereas in others, the tumor is located more posteriorly, and the anterior enlargement of the nerve is the result of cerebrospinal fluid that is trapped by the tumor.35 In rare cases, small tumors located within the optic canal are impossible to detect using current neuroimaging procedures. Such lesions usually are discovered during exploratory craniotomy. The lesions may be suspected, however, in any patient with slowly progressive, unilateral loss of vision associated with signs of optic neuropathy.36 In addition, the presence of enlarged, aerated, posterior ethmoid and sphenoid sinuses, a condition known as pneumosinus dilatans, is believed by some authors to be pathognomonic of an ONSM.37 Two histologic patterns are seen in primary ONSMs.38 In the meningothelial or syncytial pattern, polygonal cells are arranged in sheets separated by vascular trabeculae. Mitoses are uncommon. In the transitional pattern, spindle or oval cells are arranged in the whorls. Psammoma bodies are common in this form and develop from hyalinization and deposition of calcium salts in the degenerated centers of the whorls. Traditionally, ONSMs have either been observed without intervention or treated by excision of the tumor along with the nerve because of concern for intracranial extension. In such cases, the patient is blind following surgery,and disturbances of eyelid function and eye movements are often present.24 Attempts to excise these tumors while keeping the optic nerve itself intact are usually unsuccessful, and most patients are blind in the eye following such surgery.25,29,39–41 The only exceptions are ONSMs that are primarily extradural.24 In such cases, the bulk of the tumor can be excised, although rarely if ever can the entire tumor be removed,24,29,42 as at least some of the tumor remains behind in the subdural or subarachnoid space surrounding the nerve. In other cases, particularly those with acute visual loss, some authors recommend opening the optic nerve sheath to decompress the nerve.29,43 To date, trials of medical therapy for ONSM have not been successful. Because meningioma cells often express a variety of hormone receptors, most commonly estrogen and progesterone receptors,44 it might be expected that treatment with estrogen or progesterone antagonists would result in destruction of the tumor or at least reduction in its size and extent, but this does not seem to be the case. Similarly, although hydroxyurea has been said to be helpful in some cases of intracranial meningioma, we are aware of only one case report in which the treatment of an ONSM with hydroxyurea resulted in visual improvement.45 Radiotherapy for ONSM was initially used only as an adjuvant to surgery, as meningiomas in general were once considered to be completely radioresistant. In 1981, however, Smith et al46 reported the successful treatment of five patients with ONSMs using conventional fractionated radiotherapy. These authors documented improvement in visual acuity in two of the patients, an improvement in the visual field in three, and regression of retinochoroidal shunt vessels in two patients. Kennerdell et al40 subsequently treated six patients with fractionated radiation therapy and documented improvement in visual acuity and visual fields in five patients with stabilization in one. No complications were observed during a follow-up period that ranged from 3 to 7 years. In 2002, Turbin et al36 reported a retrospective series of 64 patients with primary ONSMs who had been managed with observation alone, surgery, surgery 220 Neuro-Ophthalmology: Blue Books of Neurology

with radiation, and radiation alone. The study included patients from the original paper by Kennerdell et al40 The follow-up in this study ranged from 51 to 516 months, with a mean follow-up of 150 months. Turbin et al concluded that treatment with radiation alone resulted in the best long-term visual outcome even though about one third of patients treated in this fashion developed complications from the radiation, including radiation retinopathy, retinal vascular occlusion, persistent iritis, and temporal lobe atrophy. The study does not describe which radiation technique was used, but given the era during which the study was conducted and the length of time the patients were followed, it is likely that the majority of the patients were treated with conventional treatment techniques. The major concern with radiotherapy for ONSMs is late toxicity. Not only can radiation damage the optic nerve itself but adjacent tissues can also be damaged, including the retina, pituitary gland, and the white-matter tracts of the brain.47 Retinal injury has been described with exposures of more than 50 Gy,48,49 but coexistence of diabetes mellitus may lower the threshold for retinal or optic nerve damage to 45 Gy.49,50 Late pituitary dysfunction is a rare complication of radiation as is small-vessel injury in the anterior temporal lobe after irradiation of ONSMs that extend intracranially.47,51 The threshold for radiation damage to the optic nerve, optic chiasm, or both has been estimated to be 8 to 10 Gy for a single dose.50 Because lower doses of radiation are thought to have a more uncertain effect on benign tumors such as ONSMs, and a large, single dose of radiation is associated with a high risk of tissue damage, single-dose stereotactic radiosurgery is not widely used to treat ONSMs; however, stereotactic fractionated radiotherapy (SFR) appears to offer the potential for delivering a sufficient amount of radiation to an ONSM in a manner more focused than that of conventional fractionated radiation therapy, thus minimizing the complications from exposure of the surrounding tissue to high doses of radiation. SFR requires complex planning, which is facilitated by sophisticated software and three-dimensional imaging. The pretreatment imaging (CT and/or MRI) and radiation delivery require the patient to be repeatedly immobilized, although the newest linear accelerator (LINAC) units such as the Cyberknife use a tracking system that eliminates the need for rigid immobilization during the treatment phase. Unlike conventional radiation therapy, the LINAC system delivers the radiation in non-coplanar fields that take into account the characteristics of the surrounding tissue. Every beam is size- and shape-adjusted by different devices, micro-leaf collimators being the most advanced way of achieving a high degree of conformality to the tumor, thus minimizing irradiation of the surrounding tissue.52 In 1996, the first case report appeared in the literature documenting improvement of vision after conformal irradiation of ONSM.53 Since then, at least seven series have been published that have documented either improvement or stabilization of vision after SFR. These series are discussed in detail later. The natural history of the ONSM is progressive loss of visual acuity.29–31,54 In one series,55 six of seven patients with initial visual acuity of 20/40 or better who were followed without intervention had nearly complete loss of vision over an average duration of 9 years. Nevertheless, observation is appropriate if there is no significant visual dysfunction, no significant progression of visual loss, 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 221

or no significant intracranial extension of the tumor. In such cases, a clinical examination, including assessment of visual acuity,color vision, and visual fields should be conducted twice a year for 2 to 3 years, then once a year if the patient’s visual function has remained stable. Patients should be counseled to contact their physician if they note any visual loss in the interim. Neuroimaging at 6-month intervals is appropriate for the first 1 to 2 years, then once a year for 2 to 3 years and then every 3 to 4 years, assuming that the clinical examination is stable.56,57 Because younger patients are more likely to have larger or more rapidly developing tumors, children and young adults with presumed ONSMs should be followed both clinically and with neuroimaging at more frequent intervals. Several series have been published describing SFR as a primary treatment option for ONSMs.29,51,55,58–61 The data from these studies, including visual outcomes, are summarized in Table 9–1. Summarizing the data from all seven series, the overall disease control in 75 patients was 94.6%. Improvement of visual function occurred within the first 3 months after treatment in 54.7% of the patients. None of the patients had neuroimaging evidence of tumor enlargement during the period of follow-up, and, in fact, a few patients had imaging evidence of a slight decrease in tumor volume. Acute effects of SFR included headache, nausea, local erythema, and focal alopecia. None of these complications were severe or permanent; however, radiation retinopathy was observed in two patients 4 years after treatment. The retinopathy was severe in one and was associated with vitreous hemorrhage,61 whereas the other patient had only retinal microaneurysms.55 This latter patient had a large tumor involving the proximal optic nerve adjacent to the globe, and portions of her retina received 54 Gy. Even so, her vision improved from 20/50 and remained stable at 20/25. In a more recent report,62 radiation retinopathy occurred 22 months after SFR, resulting in loss of vision from 20/25 to 20/200. The posterior retina in this patient had received 27 to 48 Gy. Other late ophthalmic complications of SFR included cataract in one patient, dry eye in one, and iritis in two. None of the patients developed radiation optic neuropathy; however, two patients continued to lose vision, thought to be from tumor progression. Late nonocular side effects reported in these studies included late pituitary dysfunction in three patients and radiologically evident cerebral punctate small- vessel fallout in one. Both are a potential concern after irradiation for posteriorly located ONSMs, particularly those with mild but definite intracranial extension. Interval monitoring of pituitary function in such patients thus is appropriate. As noted previously, in rare cases of anteriorly located, primarily exophytic tumors with focal involvement of the dural sheath, surgical excision is a potential treatment choice and can be performed without undue risk of iatrogenic visual loss.29,54 Optic nerve sheath decompression with release of trapped cerebrospinal fluid or removal of soft tumor followed by radiation therapy may also be beneficial in cases of acute visual loss63; however, extensive removal of ONSMs that extend for some distance within the optic nerve sheath or are located in the posterior orbit and/or optic canal is generally indicated only in rare cases in which there is aggressive tumor growth or disfiguring proptosis. Along with unavoidable and permanent blindness, such procedures may also cause temporary or permanent ophthalmoparesis, ptosis, or both. The main goals in the management of ONSMs are ensuring a favorable visual outcome, establishing local control of the tumor, and minimizing the risks of 222 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology:

TABLE 9–1 Summary of Primary Stereotactic Radiotherapy Series

Authors (Reference Mean Treatment Treatment Number) Eyes Period Follow-up Modality Regimen Stable Improved Worse Imaging Complications* Liu et al. (58) 5 1994–2001 1–7 years SFR 25–30 Â 1.8 1 4 0 0 0 Pitz et al. (59) 12 1989–2000 37 months SFR 28 Â 1.8 7 5 0 0 Hyperprolactinemia (2), partial hypophyseal insufficiency (1) Narayan et al. (55) 14 1986–2001 51.3 months 3D-CFR 28–31 Â 1.8 7 5 2 0 Dry eye (1), iritis (2), microaneurysms (1) Saeed et al. (29) 6 1976–1999 CSFR 0 5 1 0 Cataract (1) Andrews et al. (60) 11{ 1996–2001 20.7 months SFR 28–30 Â 1.8 10 1 0 0 0 Baumert et al. (61) 23 1996–2003 20 months CSFR 25–30 Â 5 16 2 0 Radiation retinopathy 1.8–2.0 4 years after treatment (vitreous hemorrhage) (1) Richards et al. (51) 4 1999–2002 2 years SFR 25–27 Â 0 5 0 0 Radiologically evident 1.7–1.75 cerebral punctuate small vessel fall out in the field of irradiation(1)

*Transient complications not listed. {The number of eyes with primary optic nerve sheath meningioma. Eyes: The subset of eyes with measurable vision (counting fingers and better). Treatment modality: SFR, stereotactic fractionated radiotherapy; 3D-CFR, 3-dimensional conformal fractionated radiotherapy; CFSR, highly conformal stereotactic radiotherapy. Treatment regime: The number of fractions times doses per fraction (Gy). Stable, improved, worse: The treatment effect on visual acuity and visual fields at the last follow-up, as defined by the author. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 223

treatment-related morbidity. Limitations for any treatment study of ONSMs include both the rarity and usually very slow course of the disease, the fact that there often is no tissue diagnosis so that some patients in a treatment trial could have lesions other than an ONSM (e.g., sarcoid of the optic nerve), the necessity of pooling of data from multiple different treatment centers, and the need for a long (>10 years) follow-up period to detect late recurrences and late side effects of the treatment. In the seven studies described previously, the short-term efficacy of SFR in preserving or improving vision appears to be excellent, with more than half of the patients having an improvement within 3 months following treatment. The results also suggest that earlier treatment might offer a better chance of preserving useful vision. Based on the results of published studies as well as our own experience, we believe that SFR is the best option for most cases of progressive or advanced disease. However, because of increasing early diagnosis, more and more patients with presumed ONSMs associated with mild progressive or stable visual loss are being diagnosed, and the decision as to whether to observe or treat is much less clear. Longer follow-up to establish the incidence of late toxicity following SFR will be needed to clarify the optimal management of these cases.

SCHWANNOMA Schwannomas are benign tumors that arise from Schwann cells in the peripheral nervous system. Although the most common sites are the vestibular division of the eighth cranial nerve and the trigeminal nerve root, schwannomas occasionally involve the optic nerve.64–66 Because optic nerve myelin is produced by oligodendrocytes rather than Schwann cells, these tumors probably arise from the Schwann cells that accompany the sympathetic nerves that are tightly adherent to the optic nerve sheath.67 The microscopic appearance of schwannomas of the optic nerve is the same as for all schwannomas of peripheral nerve origin, thus distinguishing them from similar appearing lesions, such as optic nerve gliomas or meningiomas; however, the clinical presentation of these lesions is nonspecific. They have been reported in both children and adults, all of whom have developed progressive visual loss associated with evidence of an optic neuropathy and variable proptosis. Optic nerve sheath schwannomas probably cannot be diagnosed on clinical grounds alone, and their neuroimaging appearance mimics that of the more common optic nerve gliomas (Fig. 9–14). Instead, in the reported cases, the diagnosis has been made at surgery. To date, surgery has been the treatment of choice, but in view of the increasing tendency to treat many intracranial schwannomas with stereotactic radiosurgery, this treatment option perhaps should be considered for schwannomas of the optic nerve.

HEMANGIOPERICYTOMA Hemangiopericytomas are composed of the pericytes of blood vessels (Fig. 9–15). They may develop in virtually any tissue in the body that has capillaries. It was once thought that hemangiopericytomas were actually a type of angioblastic 224 Neuro-Ophthalmology: Blue Books of Neurology

Figure 9–14 Optic nerve sheath schwannoma. A, Computed tomography appearance. B, Histopathology.

A Figure 9–15 Histopathology of optic nerve sheath hemangiopericytoma. A, Relationship of tumor to dural sheath. B, Higher power of tumor cells. (Courtesy of Dr. W. Richard Green.)

meningioma that arose from the vascular elements of the pia mater. Ultrastruc- tural studies, however, have led to a better understanding of the histogenesis of these tumors. By light microscopy, hemangiopericytomas are composed of a monomorphous proliferation of plump or spindle-shaped cells. Ultrastructurally, the pericytes show varying degrees of differentiation into smooth muscle cells, glomus cells, endothelial cells, and fibroblasts. Hemangiopericytomas, unlike meningiomas, have no sex predilection. They usually become symptomatic in the fifth decade of life and usually are painless and enlarge slowly. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 225

Figure 9–16 Computed tomography appearance of an optic nerve sheath hemangiopericytoma. (Courtesy of Dr. R.L. Font.)

I am aware of a single case of a hemangiopericytoma of the optic nerve sheath.68 The patient was a 61-year-old man who experienced progressive visual loss in the right eye following a systemic viral illness. He was thought to have optic neuritis, but the visual loss worsened considerably of the next few months and a CT scan showed a focal fusiform enlargement of the orbital portion of the right optic nerve thought to be consistent with an optic nerve sheath meningioma (Fig. 9–16). The patient subsequently underwent exploration of the right orbit at which time the abnormal portion of the optic nerve was excised. Pathologic examination of the specimen revealed an intradural hemangiopericytoma compressing an otherwise normal optic nerve. The treatment of choice for hemangiopericytomas is complete surgical excision. The roles of both radiation therapy and chemotherapy are controversial.

Secondary Tumors

The most common secondary tumors that infiltrate the optic nerve are metastatic and locally invasive carcinomas and various lymphoreticular malignancies, particularly lymphoma and leukemia.

METASTATIC AND LOCALLY INVASIVE TUMORS The optic nerve may be the site of metastasis from distant tumors or of spread of tumor from a contiguous structure. Metastases can reach the optic nerve by one of four routes: from the choroid, by vascular dissemination, by invasion from the orbit, and from the central nervous system (CNS).69–72 Regardless of the mode of spread, the substance of the nerve is affected more often than the sheath. In one large series, metastases to the optic disc occurred in 30 of 660 (4.5%) patients with ocular metastases.73 The disease occurs more often in women. Patients with metastases to the optic nerve usually have evidence of an optic neuropathy. The visual loss is usually severe, but relatively normal vision may be present in the early stages. Any type of field defect may be present. A relative 226 Neuro-Ophthalmology: Blue Books of Neurology

afferent pupillary defect is usually present unless the patient has bilateral optic nerve metastases or the opposite retina or optic nerve has previously been damaged by some other condition. When the metastasis is located in the prelaminar or immediately retrolaminar portion of the optic nerve, the optic disc is usually swollen; a yellow-white mass can be seen to protrude from the surface of the nerve (Fig. 9–17) and clumps of tumor cells can occasionally be seen in the vitreous overlying the disc.71,74–76 A juxtapapillary choroidal component is often seen. A central retinal occlusion occurs in up to 50% of eyes. When the metastasis is to the posterior aspect of the orbital portion of the optic nerve or to the intracanalicular or intracranial portions of the nerve, the optic disc initially appears normal. The most common metastatic tumors to the optic nerve are adenocarcinomas, primarily because these are the most common metastatic tumors to all parts of the body. In women, carcinomas of the breast and lung are the most common tumors, whereas carcinomas of the lung and bowel are most common in men.71,73,77–80 Other tumors that can metastasize to the optic nerve include carcinomas of the stomach,81 pancreas, uterus, ovary, prostate, kidney, larynx,82 and tonsillar fossa. Fine needle aspiration can occasionally be used to establish the diagnosis.73 Skin cancers, malignant melanoma, and mediastinal tumors also may metastasize to one or both optic nerves. Isolated metastases to the optic nerve of intracranial tumors, such as medulloblastomas, may rarely occur.83,84

Figure 9–17 Metastatic adenocarcinoma to the optic disc. A, The entire optic disc is infiltrated by a large mass of yellow-white tissue. Note loss of normal disc architecture. There were numerous malignant cells in the vitreous. B, In another case, histopathologic appearance of optic nerve shows extensive involvement of optic disc and optic nerve by metastatic carcinoma. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 227

Most patients with metastatic tumor to the optic nerve already have a known diagnosis of a primary carcinoma with other evidence of metastases at the time that visual loss occurs. This makes the diagnosis relatively straightforward, whereas most patients with a tumor that spreads contiguously to the optic nerve are not known to harbor a tumor when they first experience loss of vision. Nevertheless, any person with known cancer in another part of the body, with or without other evidence of metastases, who develops an optic neuropathy should be suspected of having cancer as the cause until proven otherwise. Simi- larly, any patient with a basal skull tumor who develops an optic neuropathy should be assumed to have spread of tumor to the optic nerve, unless there has been previous radiation therapy to the region, in which case the possibility of radiation-induced optic neuropathy must also be considered. Contiguous spread of primary tumors from the paranasal sinuses, nasopharynx, brain, and adjacent intraocular structures to the optic nerve occurs much less often than does metastasis to the nerve.85–89 In most cases, the tumor invades the posterior orbit or cavernous sinus, producing a syndrome that is characterized by loss of vision, diplopia, ophthalmoparesis, and trigeminal sensory neuropathy.87 Unusual examples of such occurrences include a case of an esthesioneuroblastoma presenting with unilateral blindness in an 11-year-old girl90 and a case of adenoid cystic carcinoma of the lacrimal gland producing a steroid-responsive optic neuropathy.91 Even less common than cases of metastatic or locally invasive tumors of the optic nerve, are cases of “tumor within a tumor” (“collision tumors”). Renal cell carcinoma seems to be the recipient or host tumor that most commonly “attracts” other cancers, with lung carcinoma being the most common primary tumor to metastasize to the site.92 Neuroimaging should be performed in all patients suspected of having infiltration of the optic nerve by cancer. CT scanning typically shows an enhancing nerve that may or may not be enlarged. On MRI, either a circumscribed area of optic nerve enlargement is identified93 or, more commonly, the nerve is usually diffusely enlarged similar to a meningioma74,80,94 (Fig. 9–18) and may show varying T1 and T2 values that are presumed to be related to associated hemorrhage or exudates. Tumors with a tendency to metastasize to bone, such as prostate and carcinoma, can present with optic canal involvement and a retrobulbar optic neuropathy.95

Figure 9–18 Magnetic resonance imaging appearance of infiltration of optic nerve by metastatic breast carcinoma in a 57-year-old woman. Axial view shows massive enlargement of the right optic nerve with flattening of the posterior pole of the right eye. 228 Neuro-Ophthalmology: Blue Books of Neurology

Most metastatic optic nerve tumors show at least temporary response to radiation therapy. Tumors that spread contiguously to the optic nerve from the base of the skull or paranasal sinuses are typically less radiosensitive than metastatic tumors and also tend to be less responsive to chemotherapy. Meningeal tumor cuffing or direct infiltration of the optic nerve can cause loss of vision in the setting of meningeal spread of carcinoma.96–98 This phenomenon is called meningeal carcinomatosis. The optic neuropathy that occurs in the setting of meningeal carcinomatosis is usually associated with a “diagnostic quartet” that consists of (a) headaches typical of raised intracranial pressure, (b) blindness, (c) sluggish or absent pupillary reflexes, and (d) normal-appearing optic discs.99 The frequency of optic nerve involvement in patients with carcinomatosis of the meninges varies from 15% to 40%.100–103 Patients who develop meningeal carcinomatosis with visual loss may do so after the primary lesion, usually in the lung or breast, has already been diagnosed. In other cases, visual loss may occur coincident with other signs of chronic meningitis104 or as an isolated finding as the first sign of disease.105 Although blindness may begin in one eye, both eyes are usually affected within a short time. In rare instances, visual loss remains strictly unilateral.106 A similar presentation has been described in patients with germinomas and vision loss resulting from secondary optic nerve seeding through the cerebrospinal fluid.107 Histopathologic examination of cases with meningeal carcinomatosis and blindness generally shows marked cuffing of the subarachnoid space of the optic nerve by sheets of malignant cells, with little invasion of the nerves themselves. Thus, in some cases, there is true infiltration, whereas in other cases, the lesion is more compressive than infiltrative.

LYMPHORETICULAR TUMORS Infiltration of the retrobulbar optic nerve, optic chiasm, or both can occur in patients with both Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL).108–120 In most of these cases, the infiltration occurs from spread of CNS tumor; however, in some cases, there is infiltration of the optic nerve, apparently from extension of tumor from the adjacent maxillary and sphenoid sinuses.121 In many cases of lymphomatous infiltration of the anterior visual sensory pathway, the patient is known to have NHL or Hodgkin’s disease at the time visual signs and symptoms develop, and the diagnosis is not in doubt.111 In other cases, however, the visual loss is the presenting sign of the disease108,110,113,122 or an isolated manifestation of disease recurrence.114 The symptoms and signs of patients with lymphomatous infiltration of the optic nerve depend on the location and extent of the lesion. In some cases, the visual loss is insidious in onset and slowly progressive.116 In other cases, the visual loss is acute and mimics optic neuritis or ischemic optic neuropathy.110,114,115 Secondary retinal vein and retinal artery occlusions have been described in conjunction with lymphomatous infiltration of the optic nerve.120,123 Successful treatment has been reported using steroids, chemotherapy, radiation therapy, or a combination of these modalities. The appearance of optic nerve infiltration by lymphoma is nonspecific. With CT scanning, the infiltrated nerve appears enlarged, has increased density, and enhances after intravenous injection of iodinated contrast material. With MRI, 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 229

A B Figure 9–19 Neuroimaging appearance of infiltration of the both optic nerves by a B-cell lymphoma. A, Noncontrast, T1-weighted, coronal magnetic resonance imaging (MRI) shows enlargement of intracranial portion of right optic nerve (arrowhead). B, After intravenous injection of gadolinium, T1-weighted, coronal MRI shows enhancement of both the right and left optic nerves (arrowheads).

the same structure can be isointense, hyperintense, or hypointense on T1- weighted images; is hyperintense on T2-weighted MR images; and enhances after intravenous injection of paramagnetic contrast material (Fig. 9–19). Angioimmunoblastic lymphadenopathy is a proliferative disease of the lymphoid system from which a malignant lymphoma may arise and for which the etiology is unknown. Matthews et al112 reported the case of a patient with this condition who developed a retrobulbar optic neuropathy from infiltration of the nerve by lymphoma cells. Multiple myeloma, lymphomatoid granulomatosis, and Langerhans cell histiocytosis can all produce an optic neuropathy.109,124–128 In some of these cases, the optic neuropathy, which may be of the anterior or retrobulbar variety, appears to be produced by infiltration of the nerve129 rather than from compression.130,131 Leukemia is a well-described cause of infiltrative optic neuropathy.132–141 In some of the patients, visual acuity is lost abruptly, whereas in others, there is a gradual progression of visual loss over days, weeks, or months. In still others, the disc appears swollen, but there is no evidence of visual dysfunction. Most patients with leukemic infiltration of the optic nerve are known to have leukemia at the time the visual loss occurs or the patient is found to have asymptomatic disc swelling; however, in some cases, as occurs in patients with lymphomatous infiltration of the optic nerve (see previous discussion), the optic neuropathy is the first evidence of the disease.133,142 There appear to be two distinct clinical patterns of optic nerve infiltration by leukemia: (a) infiltration of the optic disc and (b) infiltration of the immediate retrolaminar portion of the proximal optic nerve. In leukemic infiltration of the optic disc, the features of the disc are obscured by a whitish fluffy infiltrate that is often associated with true disc swelling and peripapillary hemorrhage143,144 230 Neuro-Ophthalmology: Blue Books of Neurology

(Fig. 9–20). On the other hand, infiltration of the proximal optic nerve just posterior to the lamina cribrosa usually produces markedly decreased visual acuity associated with true optic disc swelling (Fig. 9–21). Such patients have a variety of visual field defects, and a relative afferent pupillary defect is invariably present

Figure 9–20 Leukemic infiltration of the right optic disc in a child with acute lymphocytic leukemia. The child was thought to be in remission at the time the abnormality was discovered. The disc is whitish gray and markedly elevated with obscuration of vessels. Visual acuity was 20/25.

Figure 9–21 Leukemia infiltration of the orbital portion of the right optic nerve producing optic disc swelling in a child with acute leukemia. A, The disc is swollen and hyperemic. Visual acuity was 20/80, and there was a central scotoma. B, T1-weighted, contrast-enhanced, axial magnetic resonance image shows diffuse enlargement and enhancement of right optic nerve. 9 Primary and Secondary Tumors of the Optic Nerve and Its Sheath 231

unless the infiltration is bilateral and symmetric. In addition, there are often peripapillary and peripheral retinal hemorrhages.145 Neuroimaging in such cases typically reveals a diffusely enlarged optic nerve that usually enhances after intravenous injection of contrast material.146 In other patients there may be a paucity of findings on both ophthalmoscopy and MRI.136,141 The response of leukemic infiltration of the optic nerve to radiation therapy is usually rapid and dramatic. In almost all cases, visual function returns to normal or near normal, and the disc elevation, if present, resolves.145 Even though some patients do not respond to this treatment,146,147 radiation therapy is the treatment of choice for optic nerve infiltration in the setting of acute leukemia.135,137,148 In addition, Brown et al132 successfully treated a patient with an infiltrative optic neuropathy in the setting of acute promyelocytic leukemia with trans-retinoic acid. This form of acute leukemia results from a chromosome translocation that is associated with the retinoic acid receptor gene,149 and trans- retinoic acid works by stimulating the terminal differentiation of the malignant cells so that they become normal lymphoid cells. It must be emphasized that swelling of the optic disc can occur in patients with acute leukemia when CNS involvement by the disease results in increased intracranial pressure. Optic disc swelling and neovascularization also occur as a local phenomenon in the setting of the diffuse retinopathy of acute leukemia.145,150 Thus, one must consider a number of pathologic mechanisms in addition to infiltration in any patient with acute leukemia and apparent optic disc swelling. The acute leukemias are responsible for most of the reported cases of infiltrative optic neuropathies caused by lymphoreticular disorders; however, patients with chronic forms of leukemia, particularly chronic lymphocytic leukemia, may also develop optic nerve infiltration.151 Patients with optic nerve infiltration in the setting of CLL and other chronic leukemias have a more indolent clinical course than patients with the acute leukemias. Visual loss is less severe, and retinal changes of the type seen in acute leukemia are rare. Optic disc swelling, however, is indistinguishable from that which occurs in patients with infiltration in the setting of acute leukemia.

Summary

Most primary tumors of the optic nerve and its sheath are benign and produce slowly progressive visual loss associated with evidence of an anterior or posterior optic neuropathy and variable proptosis. The diagnosis of the most common tumors—glioma and meningioma—can be made with neuroimaging. However, in some cases, the diagnosis is not made until the orbit is explored and a biopsy of the nerve is obtained or the affected nerve is excised. The treatment of optic nerve tumors depends on the nature of the lesion. In some cases, excision of the nerve is appropriate; however, in most, observation, radiation, or chemotherapy is a better choice. The visual prognosis of primary optic nerve tumors depends on the nature of the lesion. Secondary tumors of the optic nerve are rare but much more serious, not only because of the poor visual prognosis but also because they are often associated with a poor systemic prognosis. 232 Neuro-Ophthalmology: Blue Books of Neurology

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Overview Craniopharyngiomas Other Tumors Clinical Presentation Endocrine Presentation and Cysts Investigation Arachnoid Cysts Visual Symptoms and Measurement Metastatic Tumors Headache and Symptoms of Raised Intracranial Pressure Infections and Inflammations Incidental Discovery Hypophysitis Langerhans Cell Histiocytosis Tumor Types Pituitary Adenomas Vascular Lesions Meningiomas References Rathke’s Cleft Cysts

Key Points The parasellar region may be host to a wide range of pathologies, from embryologic remnants and tumors to inflammatory, infective, and vascular disorders. Only one in 20 tumors in this region is not a pituitary adenoma. Patients present with endocrine symptoms or visual dysfunction because of pressure effects from a mass lesion and in an asymptomatic phase when the lesion is discovered on imaging for investigation for an unrelated problem.

Overview

The pituitary and parasellar region is host to a wide range of pathologies, as the tissues that are normally found there derive from every part of the embryo, from the Rathke’s cleft elements of the primitive stomatodeum through mesenchyme to neuroectodermal elements of the brain itself.1 Not only is there a vast number of tumors that are derived from these structures but inflammatory disorders, 238 10 Disorders of the Sella and Parasellar Region 239

infections, and aneurysms and other vascular malformations may cause symptoms in this region. Most lesions in the area are pituitary adenomas, in fact only 1 in 20 is not, and of the remaining 5%, most are planum sphenoidale meningiomas, craniopharyngiomas, or Rathke’s cleft cysts. For clinicians, the good news is that whatever the lesion, there are only four basic ways in which these tumors can be discovered. These are with endocrine dysfunction, visual symptoms, pressure symptoms of a mass lesion, and now, with the frequency of intracranial imaging for every imaginable symptom, by chance in the asymptomatic patient. These presentations are discussed in more detail in the following section.

Clinical Presentation

ENDOCRINE PRESENTATION AND INVESTIGATION Endocrine symptoms can be the result of both underproduction and overproduction of pituitary hormones.2 Pituitary function is vital to the normal body, and without two of the five anterior pituitary hormones, serious morbidity and even death can rapidly follow. These are adrenocorticotropin-stimulating hormone (ACTH) as the central part of the hypothalamic-pituitary-adrenal axis and thyroid-stimulating hormone (TSH). These are the two hormones that are responsible for the majority of symptoms in patients presenting with hypopituitarism: weight loss, lethargy, and general underperformance. Many patients will have suffered from decreased sexual function (libido, failed menses, etc.) for some time resulting from lack of the gonadotrophins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and on occasions from the symptoms of general lethargy from adult growth hormone (GH) deficiency. The fifth anterior pituitary hormone, prolactin, has a more complex role. In males, its existence has no known biologic function, and in women its only role is in lactation; however, when elevated, it has a powerful action in suppressing gonadotroph cell activity, resulting again in symptoms of lack of libido, sexuality, and menses. The lactotroph cells from which the hormone is secreted are, unusually, under mainly negative feedback control from the hypothalamus; dopamine inhibits hormone release. Therefore, any tumor upsetting the hypothalamus, median emi- nence, or stalk can have the effect of leading to a paradoxical rise in prolactin. The rise may be up to 5000 mU/L (upper limit of normal 500 to 700 mU/L); it is unwise, therefore, to treat all moderate hyperprolactinemias with dopamine agonists as they may restore gonadotroph function, allowing the tumor causing the hyperprolactinemia to continue to grow unrecognized. True macroprolactinomas have levels in excess of 5000 mU/L as a rule, although not always. Pituitary endocrine overfunction is well recognized in a number of diseases. Acromegaly (4 to 8 per million new cases per annum) from somatotroph cells, Cushing’s disease (2 to 4 per million per annum) from corticotroph cells, and prolactinomas all have well-recognized clinical syndromes and symptoms. Each of these has protocols for treatment. For some reason, TSH-secreting adenomas causing high TSH thyrotoxicosis are rare. Many of the so-called nonfunctioning tumors (or null cell tumors) contain LH, FSH, or both on careful study, although they never seem to express their hormones in a recognized clinical syndrome. 240 Neuro-Ophthalmology: Blue Books of Neurology

Figure 10–1 Coronal magnetic resonance imaging, T1 with enhancement. Thyrotroph hyperplasia in a 16-year-old girl who presented with delayed puberty. Two rarities of anterior function syndromes are also worth mentioning. Primary thyroid failure may lead to exuberant thyrotroph hyperplasia (Fig. 10–1), which because of its rarity is seldom thought of in the differential diagnosis. The patient is particularly vulnerable if thyroid function is not fully checked. Second, hypothalamic lesions in children, although usually presenting with reduced stature from lack of GH, can on occasions produce the opposite, precocious puberty. Posterior lobe function is equally important; the presence of diabetes insipidus from a lack of antidiuretic hormone (ADH) almost precludes the diagnosis of a pituitary adenoma. It is, however, not uncommon in craniopharyngioma and other lesions that involve the hypothalamus. Overproduction of ADH (syndrome of inappropriate antidiuretic hormone [SIADH]) usually occurs in the early postoperative period, but hyponatremia may on occasion be part of the presentation of other large pituitary-based lesions as part of hypopituitarism. Investigations for pituitary function should always include prolactin and thyroid function. Complex dynamic testing of the hypothalamic-pituitary axis is suggested by some, although for others a morning cortisol level of more than 300 nmol/L will suffice. Sex hormone levels are of interest, although a single level of FSH and LH in a young woman will only be of use if both are very low, and in men testosterone levels will be of more value than the gonadotroph levels. Both acromegaly and Cushing’s disease require complex investigation with a barrage of special endocrine tests. Posterior lobe function seldom requires investigation, but if diabetes insipidus is suspected, urine output, serum and urine osmolarity, and fluid restriction investigations may be required.

VISUAL SYMPTOMS AND MEASUREMENT Most of the patients seen with sella and parasellar pathology in a clinical neuroscience center have problems with their vision. Although visual symptoms are theoretically a less common presentation than those of hyperprolactinemia, compression of the optic chiasm with its attendant symptom of bitemporal visual field loss by a macroadenoma remains a regular problem leading to a neurosurgical admission. Although 1 in 20 macroadenomas are associated with acromegaly and even Cushing’s disease can present as a large tumor, the majority 10 Disorders of the Sella and Parasellar Region 241

do not express a hormone excess, and the patient is often either partially or completely panhypopituitary. The classic visual presentation is of a bitemporal field loss, which is often not symmetrical. Early compression leads to upper temporal field desaturation for red, and the mass may compress one side of the chiasm earlier than the other. The position of the optic nerves and chiasm in relation to the sella is variable and about 12% of the population has a pre-fixed chiasm and a lesser proportion post-fixed. Pre-fixed chiasmata present with optic tract signs, which is typical of some rarer parasellar pathology, particularly craniopharyngiomas. Lesions that affect the intracranial optic nerves obviously affect one eye alone. These may be lesions of the optic nerve itself, its sheath, or adjacent structures, typically adenomas with a post-fixed chiasm or planum or anterior clinoid meningiomas. It is worth noting that for compressive lesions, it is the field that is damaged first, and acuity loss occurs as a later event. Investigating the visual fields is in principle easy; confrontation with a red pin is fast, easy, and accurate. It is often skipped in busy clinics, particularly if other more common eye pathology is being investigated; pituitary patients who have been investigated in glaucoma and other clinics for a while before the diagnostic “penny dropping” are not unheard of, even in famous postgrad- uate institutions. Field testing is now more commonly carried out using Humphrey static perimetry. This is accurate and repeatable wherever the test is carried out but does require a permissive level of vision for accurate testing. In the severely damaged eye, the Goldmann kinetic perimeter carried out by an expert remains the most accurate assessment. This is also true when other ophthalmic pathology coexists. Visual acuity is usually preserved until late in the disease process. Its testing with the Snellen chart may give an impression of accuracy—records in the notes such as “6/24 left and 6/9 right” seem so precise—but lighting levels and distance from the chart are usually poorly understood by those using them, hence their accuracy should not be relied on, particularly in some surgical series. Parasellar pathology, which involves the cavernous sinus, commonly presents with ophthalmoplegia. Pituitary apoplexy, particularly, may present with a third nerve palsy rather than chiasmal compression, as does a cavernous sinus meningioma. Many other less common lesions also present in this fashion (Table 10–1). Fourth and sixth nerve palsies may also be the only physical sign.

HEADACHE AND SYMPTOMS OF RAISED INTRACRANIAL PRESSURE Headache is present at the diagnosis in 33% to 50% of most series of pituitary adenoma and is not uncommonly the only presenting symptom. However, because headache has in recent years become a symptom justifying a scan, the tumor may present earlier than it otherwise may have done. Why pituitary tumors cause headache appears unknown. Even a large pituitary tumor seldom causes true raised intracranial pressure in the same way as a malignant process or a large meningioma. However, stretching of the basal dura must occur and in particular distortion of the medial wall or position of the carotid in the cavernous sinus may be responsible. This was a frequent enough occurrence as to be used a diagnostic tool in carotid angiography for pituitary adenomas in the pre-computed tomography (CT) era. 242 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 10-1 Differential Diagnosis of Tumors and Other Lesions in the Sella Region

Tumors Adenohypophyseal origin: Pituitary adenomas and carcinomas1,2 Neurohypophyseal origin: Granular cell tumors,4–15 stalk and posterior lobe astrocytomas16–20 Neuroepithelial origin: Optic nerve and hypothalamic gliomas,21–28 hemangioblastoma,29–32 esthesioneuroblastoma,33–36 germ cell tumors,37–53 primary melanoma Other neural origin: Schwannoma54–57 Mesenchymal: Meningiomas,59–63 hemangiopericytomas, chordomas,64–68 chondromas, chondrosarcomas,69 post irradiation sarcomas,70 fibrous dysplasia,71–73 giant cell tumor of bone,74–75 glomangioma,76 lipoma77–78 Others: Craniopharyngiomas,79–95 primary lymphomas,96 paragangliomas97–104 Cysts, Hamartomas, and Malformations Rathke’s cleft cyst,105–112 arachnoid cyst,113–119 epidermoid cyst,120–121 dermoid cyst,122–123 gangliocytomas,124–131 empty sella syndrome132–138 Metastatic Tumors Carcinomas, plasmacytomas, lymphomas, leukemias139–144 Inflammatory Conditions Infections,145 abscesses,146–152 mucocoele,153–156 lymphocytic hypophysitis,157–164 sarcoidosis,165–172 Langerhan’s cell histiocytoses,173 giant cell granuloma, Wegener’s granulomatisis Vascular Lesions Aneurysms,174 cavernous angiomas175–177

Headache has recently been categorized by Levy and colleagues in Brain3;the majority of patients present with migraine-type headaches, including features of photophobia and improvement on lying still. It may be single sided and is often periorbital. It was constant in around half the patients, but 30% had a paroxysmal nature, and 5% showed features of short lasting unilateral neuralgiform headache (SUNCT). There does not appear to be a relationship with cavernous sinus invasion. Pituitary headache may have some of the features of raised intracranial pressure, which are more noticeable in the early morning. In this series headache improved in 49% of those treated surgically, and in 64% and 25% of patients with acromegaly and prolactinoma, respectively, treated with somatostatin analogues and cabergoline. Adenomas rarely cause blockage of the third ventricles and thus hydrocephalus. When they do so, they present both as chronic and acute raised intracranial pressure. They are particularly difficult surgical problems as the unfortunate patient may rapidly deteriorate following surgery. Other sella and parasellar tumors may present with hydrocephalus, pediatric craniopharyngiomas notoriously so.

INCIDENTAL DISCOVERY Because the use of imaging investigations for suspected neurologic and other disease is so commonplace, the incidence of discovery of asymptomatic tumors, particularly pituitary adenomas, has become surprisingly high. The problem for the 10 Disorders of the Sella and Parasellar Region 243

clinician is to decide what to do about them. Modern pituitary surgery is safe and effective, but there is nothing so depressing for a surgeon than to cause hypopituitarism or, worse, visual defects in a patient who had previously had no complaints. Although these complications are fortunately rare, the mantra of “if it works, don’t fix it” is one that the judicious surgeon should follow. If the patient has no complaints, surgery can only make him or her worse. Clearly, if vision is borderline normal or pituitary function is all at the bottom end of the normal range, a more interventional view can be taken. It is perfectly acceptable to monitor the patient for a time without treatment, with neuro-ophthalmic examinations, pituitary function, and magnetic resonance imaging (MRI) at twice yearly intervals.

Tumor Types

PITUITARY ADENOMAS The list of potential lesions in the fossa and parasella area is long. As mentioned previously, adenomas are much the most common, followed by meningiomas, Rathke’s cleft cyst, and craniopharyngiomas. These are discussed in some detail, the remaining lesions less so. Tumors may be small—microadenomas (Fig. 10–2) are defined as less than 1 cm, but in Cushing’s disease, adenomas may be even smaller, 3 mm is the limit of the best magnetic resonance (MR) images. Tumors greater than 1 cm but con- strained within the sella are described by many as mesoadenomas (Fig. 10–3). Macroadenomas are more than 1 cm and are those that typically affect vision. They can be further defined by shape and size. Huge multilobed tumors exist as well but are still termed macroademonas (Fig. 10–4).2 In postmortem studies, silent pituitary lesions are surprisingly common. Tumors arise from cell lines within the anterior lobe of the gland. It is simplistic to think only in terms of nonfunctioning and functioning adenomas, the latter group consisting of prolactinomas, somatotroph (GH-secreting) tumors, Cush- ing’s (ACTH-secreting) tumors, and the rare TSH-secreting tumor. Many

Figure 10–2 Coronal magnetic resonance imaging, T1 with enhancement. Typical microade- noma (growth hormone secreting). 244 Neuro-Ophthalmology: Blue Books of Neurology

Figure 10–3 Coronal magnetic resonance imaging, T1 with enhancement. Typical lateralized mesoadenoma.

Figure 10–4 A, Sagittal magnetic resonance imaging, T1 with enhancement. B, Huge multilob- ular prolactinoma with prolactin >1 million mU/L.

nonfunctioning tumors contain secretory granules, usually for LH and FSH but simply do not express them. Silent tumors that express ACTH, GH, and prolactin do exist, albeit infrequently, and there are dual secretors, typically prolactin and GH and also stem cell tumors. The most striking feature is their blandness; most tumors are extremely slow growing and do not change decade after decade. Malignant change is rare; when it does, it usually occurs in ACTH-expressing tumors.

Treatment The consistency and shape of these tumors makes them ideal for surgical management.2 Only prolactinomas are regularly treated medically, responding well to dopamine agonists; cabergoline at a dose of 0.5 to 1.0 mg/week leads to a response in greater than 85% by virtue both by ceasing production of the hormone and by tumor shrinkage, and bromocriptine works almost as well 10 Disorders of the Sella and Parasellar Region 245

(>75% response). Of the remainder, GH-secreting tumors do shrink, although seldom to any significant degree, with somatostatin analogues although GH production can be halted. A proportion also responds to cabergoline. Pretreatment of Cushing’s tumors by blocking the adrenal output of cortisol is sometimes offered using either metyrapone or ketoconazole. Surgery is carried out using the transsphenoidal route in the majority of cases. It is a very effective method for decompressing the chiasm and most surgical series report an improvement of more than 80% in visual fields with a reasonable proportion returning to normal. For hormone-secreting tumors, the results of surgery depend on both the size and shape of the tumor and the experience of the surgeon. For GH-secreting tumors, control is reported to be between 65% to 80þ%. For Cushing’s tumors, in which about one third do not have an MRI- visible tumor, the result is between 65% overall and more than 80% when a micro- adenoma is seen on MRI. Microprolactinomas are seldom operated on; however, when surgery is carried out by experts, control is achieved in more than 80%. Craniotomy is reserved for the giant tumors that have multiple lobes. The tumors also shrink well, if slowly, with radiotherapy. Safe regimens were devised long before surgery became safe. Modern techniques such as stereotactic conformal linear accelerators and gamma knife have further refined the results. Radio- therapy is mainly used for recurrences and for hormone-secreting tumors following failed surgery. Pituitary carcinomas are fortunately extremely rare. They often arise from ACTH-staining types (Fig. 10–5), with a long latent history, and patients may have had radiotherapy in the past. They seldom respond well either to radiotherapy or to surgery, although there is no other therapy except in the even rarer type that transform into a sarcoma.

MENINGIOMAS These common intracranial tumors occur anywhere within the skull dural lining but arise often in the sella area.59–63 More common in women by a ratio of 3:2, they are derived from the arachnoid villi and are usually benign. The World Health Organization grades them into three subtypes: I (benign, the vast majority), II (atypical), and III (carcinomatous). The majority, particularly in the sella area, are type I. Four sites require consideration:

Figure 10–5 Coronal magnetic resonance imaging, T1 with enhancement. Malignant transformation of Cushing’s tumor invading the cavernous sinus. 246 Neuro-Ophthalmology: Blue Books of Neurology

1. On the planum sphenoidale, they present with chiasmal compression (Fig. 10–6) but virtually never with pituitary hormone involvement. Slightly more lateral, but within the area, those arising from the clinoid are less frequent. 2. More extensive tumors of the sphenoid wing can also be considered in this group, although they only infrequently involve visual pathways. The hyperostotic type (Fig. 10–7) causes bony thickening leading to proptosis and ultimately reduction of the optic nerve canal. 3. Cavernous sinus and sinus-involving petroclival meningiomas may have extensive slow creeping spread by the time they present, usually with ophthalmoplegia (Fig. 10–8), although occasionally with the effects of hyperprolactinemia.

Figure 10–6 Sagittal magnetic resonance imaging, T1 with enhancement. Large planum meningioma lifting and compressing optic nerves and anterior cerebral arteries.

Figure 10–7 A, Computed tomography of hyperostotic left sphenoid wing meningioma with small intraorbital component presenting as disfiguring proptosis and early visual loss. The optic nerve canal is just starting to be involved. B, Axial magnetic resonance imaging, T1 with enhancement. Long-term results of partial resection of a similar tumor involving the left sphenoid wing twelve years previously, without progression. 10 Disorders of the Sella and Parasellar Region 247

Figure 10–8 Coronal magnetic resonance imaging, T1 with enhancement, of a cavernous meningioma presenting with severe trigeminal pain and ophthalmoplegia during pregnancy.

Figure 10–9 A, Axial magnetic resonance imaging (MRI), T1 with enhancement, of optic nerve sheath meningioma. The patient presented with rapid unilateral loss of vision. B, Coronal MRI, T1 with enhancement. The same tumor, just starting to erupt into cranial compartment on planum.

4. Optic nerve sheath meningiomas involve the orbit but sometimes extend cra- nially onto the planum to involve the other eye (Fig. 10–9). These tumors present with monocular progressive visual loss. The loss is painless as the tumor volume is small. These are discussed further in Chapter 9.

Treatment Although these tumors are in essence challenges for surgical technique, they do respond to radiotherapy, and many modern experts advocate limited decompres- sive surgery, followed by irradiation for the inaccessible parts. Surgery is usually carried out by craniotomy although endoscopy surgeons are now recommending 248 Neuro-Ophthalmology: Blue Books of Neurology

transnasal approaches for the planum tumors. The route of the craniotomy is a matter of intense surgical debate; mini-craniotomies to huge orbito-zygomatic procedures are variously advocated and all have their place, depending on the clinical signs and imaging appearances. For the planum meningioma, in which vision is affected early, the outlook for both vision and longevity is generally good with relatively simple cranial surgery. For the hyperostotic sphenoidal type, surgery is largely cosmetic but can be effective although very long histories with little tumor progression are expected. Cavernous sinus tumors are complex; I believe that they are best managed as conservatively as is possible. Optic nerve sheath meningiomas should only be treated surgically when spread occurs onto the planum.

RATHKE’S CLEFT CYSTS This nontumorous cyst, a relic of the migration of tissue from the primitive stomatodeum, was often misdiagnosed as a craniopharyngioma until more recent times. Immunohistochemical stains help to differentiate them. They usually contain fluid or creamy cyst contents secreted by a monolayer of ciliated epithelium. The presentation is with some or all of the classic triad of chiasmal compression, endocrine failure sometimes with diabetes insipidus, and headache (Fig. 10–10). A radiologic classification has been made depending on their signal intensity on MRI—Type 1 shows T1 hypointensity with T2 hyperintensity, type 2 is T1 hyperintense with T2 isointensity, and type 3 shows T1 and T2 hyperintensity. Each contains a different type of fluid, although this has no prognostic significance. Although they usually have an enlarged sella with smooth suprasellar extension, there are the occasional small lesions within the gland and some have hemorrhages or calcification to further complicate the picture. CT is not particularly useful in diagnosis except when calcification occurs, sometimes within the gland itself. Once diagnosed, their management is simple,105–112 as they usually respond well to simple transsphenoidal drainage and marsupialization. Complete excision of the wall is seldom necessary.

Figure 10–10 Coronal magnetic resonance imaging, T1 with enhancement, of large Rathke’s cleft cyst compressing chiasm with resultant visual loss. The normal gland is compressed downward with consequent hypopituitarism. 10 Disorders of the Sella and Parasellar Region 249

Figure 10–11 Sagittal magnetic resonance imaging, T1 with enhancement. Large cystic and solid craniopharyngioma compressing the grossly edematous chiasm from behind. The tumor projects into the third ventricle. Note the normal gland below. This patient presented with behavioral problems and severe visual loss.

CRANIOPHARYNGIOMAS Sharing their origin with the Rathke’s cleft cyst, craniopharyngiomas have a much less benign course despite their ostensibly benign nature (Fig. 10–11). The age of presentation is biphasic; it is one of the commonest supratentorial tumors in childhood, with a second peak in late adult life. In children, they often present with hydrocephalus, but otherwise present like the Rathke’s cleft cyst. There are two different types: the commonest, the adamantinomatous, which contains cysts of dark shimmering green “engine oil” appearance as well as solid clumps of almost caseous material, and the less common papillary, in which the lesion is predominately a simple cyst. This type has a better prognosis. It has been suggested that it is a variant of the Rathke’s cleft cyst, but it has a distinct difference in histologic terms; all contain stratified squamous epithelial elements with calcification and cholesterol clefts. Only 20% lie within the sella, many existing in and around the third ventricle and suprachiasmatic cistern. Some have their origin within the sphenoid and a few outside this defined line of the Rathke’s pouch.

Treatment Their management is controversial.79–95 Hydrocephalus is managed with shunts and carries a worse prognosis in children. Surgical series are full of “cures” from radical excision, but because many of these tumors involve vital structures such as the hypothalamus and optic nerves to which they are closely applied, complete separation is technically challenging and surgeons can easily be deluded into thinking they have achieved a total excision. Recurrences are common, although subtotal excision may lead to long remission. Furthermore, surgical damage, particularly to the hypothalamus, can wreck the patient whose subsequent life can be marred by hyperphagia, poikilothermia, and other hypothalamic problems. Most management regimens therefore concentrate on surgical excision of easily removable parts followed by radiotherapy. Many surgeons use cyst catheters to control volume expansion, particularly while radiotherapy controls the remnant tissue. Most patients need long-term endocrine, surgical, and neuro- ophthalmologic care because late recurrences can be seen. 250 Neuro-Ophthalmology: Blue Books of Neurology

OTHER TUMORS Other tumors are much less common; a few demand discussion.

Optic Nerve Gliomas Glial tumors of the optic nerves occur in childhood and in adults. In children, they may be extensive, extending into the base of the brain, but are considered slow growing to the point that some are considered hamartomas. Presenting in the prechiasmal optic nerves in adults with rapid monocular visual loss, the pressing question regards whether or not the chiasm is truly spared. If it is not seen to be spared on imaging, then resection may be considered via craniotomy.34–41 Others can be discovered comparatively late when they may have been present for decades (Fig. 10–12). My unit has experience of a few malignant optic nerve gliomas, which present in late adulthood. It is intriguing to wonder if this is a late-stage transformation of a previously undiagnosed slow-growing optic nerve glioma in the same way as cerebral grade II astrocytomas change.

Chondrosarcomas Despite their dread title, these lethargic lesions may present in the skull base, usually just off the midline, in the cavernous sinus or petrous tip. They present with ophthalmoplegia, involving cavernous structures, and the symptoms may have been present for some years. They have the appearance of chordomas, both in surgical behavior and in histology, because both are halcyon blue positive. However, they have distinct immunohistochemical characteristics. This group does well with surgery and may have very long remissions. Surgery is complex and involves extensive skull base procedures, which are well

Figure 10–12 Coronal magnetic resonance imaging, T1 with enhancement. Large, rather nonspecific, enhancing tumor extending from hypothalamus region into the third ventricle. A transcranial biopsy had previously confirmed this to be an optic nerve glioma with very low proliferative markers. The patient had presented with very slow onset of visual loss and ultimately developed hydrocephalus (note ventricular tube) over several decades. 10 Disorders of the Sella and Parasellar Region 251

Figure 10–13 Sagittal magnetic resonance imaging, T1 with enhancement. Clival chordoma compressing brainstem. The astute may notice the enlarged pituitary fossa; the patient had had surgery and radiotherapy for acromegaly 20 years previously. worth considering because of their benign behavior and radiation insensitivity.42 It is important, therefore, to resist the temptation to offer radiotherapy as it has no known benefit and makes further surgery extremely difficult.

Chordomas Intracranial chordomas occasionally involve the cavernous sinus and pituitary fossa at presentation (Fig. 10–13) but are found more commonly in the clivus where the lower cranial nerves are more likely to be affected. Unlike the chondrosarcoma, the behavior is usually far from benign, and relentless progression despite heroic surgery and radiotherapy is the norm.64–68 Fast neutrons and other hard to source forms of radiation are said to be worth considering.

Schwannomas Schwannomas of the trigeminal nerve arising in the cavernous sinus are uncommon. It might be expected that they would present with facial sensory loss or pain, but those seen at the National Hospital have all presented with ophthalmoplegia. Slow growing, they can be seen as bony scalloping on CT scans of the skull base but are as usual best imaged with gadolinium enhanced MRI (Fig. 10–14). These tumors are usually considered surgical challenges (access is along the skull base using extradural approaches)54–57 but may become a group of tumors, which when moderate to small, are best treated with single fraction radiotherapy stereotactic techniques such as gamma knife, like vestibular schwannomas.58

Germinomas The pituitary is a well-recognized if uncommon site for germinoma, a rare tumor; it presents with panhypopituitarism, often with diabetes insipidus. 252 Neuro-Ophthalmology: Blue Books of Neurology

Figure 10–14 Axial magnetic resonance imaging, T1 with enhancement. Temporal fossa trigeminal schwannoma presenting with double vision. Only a small component extends from the mouth of Meckel’s cave into the posterior fossa.

When found, their treatment is with minimal surgery, usually by the transsphenoidal route, followed by radiotherapy, to which they are exquisitely sensitive.37–53 Usually, however, by the time the histologic diagnosis is made, the surgery has been radical.

Cysts

Epidermoids and dermoids arise only rarely in the sella region. Their incidence is very low and, because these developmental anomalies grow insidiously and very slowly, they may be massive at discovery.120–123 The patient illustrated in Figure 10–15 had no visual problems but a mild hypothalamic syndrome and went on to develop seizures.

ARACHNOID CYSTS An incredible amount of surgical discussion time is given to arachnoid cysts without much clarity of resolve. Mostly these are incidental findings; occasionally they may present with hyperprolactinemia. What one does about them is another matter.113–119 They are probably best left alone; I have been persuaded to explore them and have been left with a dramatic cerebrospinal fluid leak as a consequence.

Metastatic Tumors

The pituitary fossa is not a common place for carcinomatous metastasis. Metas- tases from lung and breast carcinoma are more common. There may be neuroepithelial differentiation, and often many of the histologic features of a simple 10 Disorders of the Sella and Parasellar Region 253

Figure 10–15 Sagittal magnetic resonance imaging, T1 with enhancement. Large sella epidermoid presenting with variable headache and nonspecific symptoms, possibly epilepsy, in a 40-year-old woman. adenoma are seen. Although the imaging features are usually those of a typical benign adenoma, they almost always have headache and panhypopituitarism with diabetes insipidus, most uncommon in benign pituitary adenoma, and therefore a warning sign. Surgery and oncologic management, usually radiotherapy, is required.139–166 Other metastases may occur, for example, lymphoma and melanoma, but are very rare; I have also seen a choriocarcinoma in the pituitary.

Infections and Inflammations

Infection within the sphenoid is rare, even with extensive sinus disease. It is one of the fortunate coincidences of life that however potentially dirty the nose is, transsphenoidal surgery, at least when not complicated by cerebrospinal fluid leak, tends to have a very low prevalence of postoperative infection. Mucoceles in the sphenoid sinus do occur, however (Fig. 10–16), as well as sphenoid sinusitis.153–156 Usually there has been previous surgery. Infected trapped mucoceles can trigger pituitary apoplexy. Of primary infections of the pituitary, only tuberculosis has been seen in my practice (Fig. 10–17). It is painless but causes panhypopituitarism with diabetes insipidus.177–180 Pyogenic abscesses may occur,146–152 and fungal and parasitic infections have also been reported.180–185

HYPOPHYSITIS Hypophysitis is an autoimmune disease in which the pituitary, usually the ade- nohypophysis, is involved. It typically occurs in the last trimester of pregnancy or in the immediate postpartum period. Patients present with pituitary failure and visual loss from chiasmal compression. Prolactin should be extremely high in the postpartum period, so if this and other pituitary hormones are low, it is reasonable to make the diagnosis without histology. High-dose steroids cause a prompt resolution of the imaging abnormalities, and the visual loss usually recovers well.157–164 254 Neuro-Ophthalmology: Blue Books of Neurology

Figure 10–16 A, Sagittal magnetic resonance imaging (MRI), T1 with enhancement. Large prolactinoma with two entrapment mucoceles in the sphenoid sinus. Compare with Figure 10–16B. B, Sagittal MRI, T1 with enhancement. Florid enhancement in infected mucocele caused by large macroadenoma.

Figure 10–17 Sagittal magnetic resonance imaging, T1 with enhancement. Tuberculosis of the hypophysis. Note that the enhancing mass replaces the normal gland. There was pituitary failure, diabetes insipidus, and headache. The observer could be forgiven for thinking this looks like an adenoma. Compare with Figure 10–19.

The condition may, however, occur in postmenopausal women and even in men.161,162 It may involve the cavernous sinus and so present with pain and ophthalmoparesis. Although the majority needs only a relatively short period of high-dose steroids, some have a more relapsing course and may need plasma exchange or radiotherapy for control.

LANGERHANS CELL HISTIOCYTOSIS Langerhans cell histiocytosis, the most common variant of an extremely rare condition, is found in children usually presenting with diabetes insipidus pro- ceeding on to anterior pituitary failure. It usually involves the pituitary 10 Disorders of the Sella and Parasellar Region 255

Figure 10–18 Axial magnetic resonance imaging, T1 with enhancement. Langerhans cell histiocytosis. The patient had a 5-year history of diabetes insipidus progressing to anterior pituitary failure. infundibulum (Fig. 10–18) and can be managed on an imaging diagnosis, by hormone replacement and steroids. Biopsy, via a transsphenoidal route, can be achieved with care and some difficulty.173 Granular cell tumor (Fig. 10–19), sarcoidosis,165–171 Rosai-Dorfman disease,186 and Chester-Erdheim disease187 may also present with pituitary involvement.

Figure 10–19 Sagittal magnetic resonance imaging, T1 with enhancement. Granular cell tumor. Compare with Figure 10–17; similar story, although no diabetes insipidus. This image is indistinguishable from an adenoma. 256 Neuro-Ophthalmology: Blue Books of Neurology

Figure 10–20 A, Axial computed tomography. Aneurysm presenting with bitemporal visual failure. B, Carotid angiogram of the same lesion, anterior-posterior view.

Vascular Lesions

I have only seen one aneurysm presenting as a pituitary tumor, with bitemporal hemianopia. It was in the pre-MRI days. Luckily, there were some suspicious features on the CT and an angiogram was requested (Fig. 10–20). Horror stories of surgeons biopsying aneurysms through the transsphenoidal route do exist, but modern MR is so powerful a diagnostic tool, the stories are drifting into legend. Nowadays, such a lesion would probably be coiled.

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149. Martines F, Scarano P, Chiappetta F, Gigli R: Pituitary abscess. A case report and review of the literature. J Neurosurg Sci 1996;40(2):135–138. 150. Scanarini M, Cervellini P, Rigobello L, Mingrino S: Pituitary abscesses: Report of two cases and review of the literature. Acta Neurochir (Wien) 1980;51(3–4):209–217. 151. Somali MH, Anastasiou AL, Goulis DG, et al: Pituitary abscess presenting with cranial nerve paresis. Case report and review of literature. J Endocrinol Invest 2001;24(1):45–50. 152. Vates GE, Berger MS, Wilson CB: Diagnosis and management of pituitary abscess: A review of twenty-four cases. J Neurosurg 2001;95:233–241. 153. Delfini R, Missori P, Iannetti G, et al: Mucoceles of the paranasal sinuses with intracranial and intraorbital extension: Report of 28 cases. Neurosurgery 1993;32:901–906. 154. Abla A, Maroon J, Wilberger JJ, et al: Intrasellar mucocele simulating pituitary adenoma: case report. Neurosurgery 1986;xx:197–199. 155. Close N, O’Conner W: Sphenoethmoidal mucoceles with intracranial extension. Otolaryngol Head Neck Surg 1983;91:350–357. 156. Gore RM, Weinberg PE, Kim KS, Ramsey RG: Sphenoid sinus mucoceles presenting as intracranial masses on computed tomography. Surg Neurol 1980;13:375–379. 157. Asa SL, Bilbao JM, Kovacs K, et al: Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: A distinct clinicopathologic entity. Ann Intern Med 1981;95:166–171. 158. Thorner MO, Vance ML, Horvath E, Kovacs K: The anterior pituitary. In Foster DW (eds): Williams Textbook of Endocrinology, Philadelphia, WB Saunders, 1992, pp 221–310. 159. Cosman F, Post K, Holub DA, Wardkaw SL: Lymphocytic hypophysitis. Report of 3 new cases and review of the literature. Medicine (Baltimore) 1989;68:24–56. 160. Feigenbaum S, Martin M, Wilson C, Jaffe R: Lymphocytic adenohypophysitis: A pituitary mass lesion occurring in pregnancy. Proposal for medical treatment. Am J Obstet Gynecol 1991;164:1549–1555. 161. Lee JH, Laws ER Jr, Guthrie BL, et al: Lymphocytic hypophysitis: Occurrence in two men. Neu- rosurgery 1994;34:159–162; discussion 162–163. 162. Tubridy N, Saunders D, Thom M, et al: Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement. J Neurol Neurosurg Psychiatry 2001;71:798–801. 163. Reusch JE, Kleinschmidt-DeMasters BK, Lillehei KO, et al: Preoperative diagnosis of lymphocytic hypophysitis (adenohypophysitis) unresponsive to short course dexamethasone: case report. Neurosurgery 1992;30:268–272. 164. Kidd D, Wilson PL, Unwin B, Dorward N: Lymphocytic hypophysitis presenting in the first trimester of pregnancy. J Neurol 2003;250:1385–1387. 165. Scott IA, Stocks AE, Saines N: Hypothalamic/pituitary sarcoidosis. Aust N Z J Med 1987; 17(2):243–245. 166. Bakshi R, Fenstermaker RA, Bates VE, et al: Neurosarcoidosis presenting as a large suprasellar mass. Magnetic resonance imaging findings. Clin Imaging 1998;22:323–326. 167. Loh KC, Green A, Dillon WP Jr, et al: Diabetes insipidus from sarcoidosis confined to the posterior pituitary. Eur J Endocrinol 1997;137:514–519. 168. Guoth MS, Kim J, de Lotbiniere AC, Brines ML: Neurosarcoidosis presenting as hypopituitarism and a cystic pituitary mass. Am J Med Sci 1998;315:220–224. 169. Chevrette E, Morissette L, Gould P: Neurosarcoidosis presenting as an intrasellar pseudotu- moral mass: case report. Can Assoc Radiol J 1999;50:407–412. 170. Bullmann C, Faust M, Hoffmann A, et al: Five cases with central diabetes insipidus and hypo- gonadism as first presentation of neurosarcoidosis. Eur J Endocrinol 2000;142:365–372. 171. Konrad D, Gartenmann M, Martin E, Schoenle EJ: Central diabetes insipidus as the first manifestation of neurosarcoidosis in a 10-year-old girl. Horm Res 2000;54(2):98–100. 172. Grois NG, Favara BE, Mostbeck GH, Prayer D: Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998;12:287–305. 173. Weir B: Pituitary tumors and aneurysms: case report and review of the literature. Neurosurgery 1992;30:585–591. 174. Mohr G, Hardy J, Gauvin P: Chiasmal apoplexy due to ruptured cavernous hemangioma of the optic chaism. Surg Neurol 1985;24:636–640. 175. Sansone M, Liwnicz B, Mandybur T: Giant pituitary cavernous hemangioma. J Neurosurg 1980;53:124–126. 176. Buonaguidi R, Canapicci R, Mimassi N, Ferdeghini M: Intrasellar cavernous hemangioma. Neurosurgery 1984;14:732–734. 10 Disorders of the Sella and Parasellar Region 263

177. Paramo C, de L, Nodar A, Miramontes S, et al: Intrasellar tuberculoma—A difficult diagnosis. Infection 2002;30(1):35–37. 178. Patankar T, Patkar D, Bunting T, et al: Imaging in pituitary tuberculosis. Clin Imaging 2000; 24(2):89–92. 179. Sharma MC, Arora R, Mahapatra AK, et al: Intrasellar tuberculoma—An enigmatic pituitary infection: A series of 18 cases. Clin Neurol Neurosurg 2000;102(2):72–77. 180. Ramos-Gabatin A, Jordan RM: Primary pituitary aspergillosis responding to transsphenoidal surgery and combined therapy with amphotericin-B and 5-fluorocytosine: case report. J Neuro- surg 1981;54:839–841. 181. Endo T, Numagami Y, Jokura H, et al: Aspergillus parasellar abscess mimicking radiation- induced neuropathy. Case report. Surg Neurol 2001;56:195–200. 182. Heary RF, Maniker AH, Wolansky LJ: Candidal pituitary abscess: Case report. Neurosurgery 1995;36:1009–1012; discussion 1012–1013. 183. Del Brutto O, Guevara J, Sotelo J: Intrasellar cysticercosis. J Neurosurg 1988;69:58–60. 184. Osgen T, Bertan V, Kansu T, Akalin S: Intrasellar hydatid cyst. Case report. J Neurosurg 1984;60:647–648. 185. Sano T, Kovacs K, Scheithauer BW, et al: Pituitary pathology in acquired immunodeficiency syndrome. Arch Pathol Lab Med 1989;113:1066–1070. 186. Kidd D, Revesz TR, Miller NR: Neurological complications of Rosai-Dorfman disease. Neurol- ogy 2006;67:1551–1555. 187. Lachenal F,Cotton F, Desmurs-Clavel H, et al: Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: Report of six cases and systematic review of the literature. J Neurol 2006;253:1267–1277. 11 Pupillary Disorders FION D. BREMNER

The Normal Pupil Parasympathetic Lesions Lesions of the Visual Pathway The Abnormal Pupil Lesions in the Midbrain Lesions within the Eye Sympathetic Lesions References

Key Points Careful examination of the pupil is an invaluable exercise, potentially providing information about function in both sympathetic and parasympathetic branches of the autonomic nervous system, the anterior visual pathways, and the upper midbrain. Autonomic disturbances generally affect both the size and the responsiveness of the pupil and may be confirmed using simple pharmacologic tests. Damage to the retina or pregeniculate anterior visual pathways has little or no effect on resting pupil diameter but attenuates the pupillary response to light. Unilateral or asymmetric damage gives rise to a relative afferent pupillary defect (RAPD). When the pupil signs are not easily explained by the neurologic workup, it is advisable to seek the opinion of an ophthalmologist to look for a local cause within the eye.

The Normal Pupil

The pupil is the diaphragm in the eye through which light enters: It regulates retinal exposure and affects depth of field and optical artefact in much the same way as the aperture stop in a camera. The size of the pupil is determined by the tone in two opposing smooth muscles. The iris sphincter muscle has circular fibers, which lie close to the pupil margin: Activation of its muscarinic (mainly M3) cholinoceptors causes constriction or miosis of the pupil. The iris dilator muscle has radial fibers, which lie within the midperiphery of the iris stroma: Activation of its noradrenergic (mainly a-1) adrenoceptors causes dilation or mydriasis of the pupil. The fibers of both muscles express a number of other receptors on their surfaces including adrenoceptors on sphincter fibers and cholinoceptors on dilator fibers: These probably contribute to reciprocal inhibition but are not of any apparent clinical importance. 264 11 Pupillary Disorders 265

The sphincter muscle is innervated by parasympathetic neurones whose preganglionic fibers originate in the ipsilateral Edinger-Westphal nucleus of the upper midbrain. The fibers course anteriorly through the red nuclei, joining other fibers from the oculomotor nuclear complex to emerge in the interpedun- cular fossa as the third cranial nerve. The parasympathetic fibers lie superficially within the oculomotor nerve throughout its course in the subarachnoid space, rendering them susceptible to extrinsic compression but relatively safe from ischemic insults. Within the orbit, the fibers join the inferior division of the oculomotor nerve before terminating in the ciliary ganglion. Postganglionic parasympathetic fibers emerging from the ciliary ganglion pass through the sclera temporal to the optic nerve as the short posterior ciliary nerves and pass forward in the suprachoroidal space: Only 3% to 5% of these neurons terminate in the iris sphincter muscle; the remainder terminate in the ciliary muscle and control accommodation.1 The dilator muscle is innervated by sympathetic neurones using a polysynaptic pathway that originates in the hypothalamus. The first part of this journey is by convention termed the central neuron and descends uncrossed through the brainstem and upper spinal cord to terminate at the ciliospinal center of Budge and Waller at the level of C8-T1 (sometimes T2). The preganglionic sympathetic fibers then emerge from the spinal cord in the ventral roots (mainly T1) and join the cervical sympathetic chain, passing through the first thoracic (stellate) ganglion at the apex of the lung and ascending in the neck; the fibers pass uninterrupted through the inferior and middle cervical ganglia before terminating in the superior cervical ganglion at about the level of the angle of the jaw. The postganglionic fibers form a plexus in the adventitia of the internal carotid artery and ascend through the foramen lacerum into the middle cranial fossa where they lie in close relation to the trigeminal ganglion. They course forward in the cavernous sinus, hitchhiking for awhile with the abducens nerve before entering the orbit through the superior orbital fissure in the nasociliary nerve (a branch of the ophthalmic division of the trigeminal nerve). Fibers destined for the iris dilator muscle enter the eye with the long ciliary nerves and pass forward in the suprachoroidal space to the iris root. Under resting conditions, both pupils are normally round, central within the iris, and of similar size. Pupil size varies linearly with age (Fig. 11–1): The pupils are largest at the age of around 20 years and diminish in size thereafter at a rate of approximately 0.04 mm/year. Even within subjects of a similar age, pupil size varies widely, making detection of bilateral symmetrical changes in pupil size difficult unless the abnormality is extreme (i.e., both pupils either very small or very large). An abnormal pupil size is much easier to detect if the lesion is unilateral. In the healthy population, the difference between the sizes of the pupils in the two eyes (anisocoria) is normally less than 0.7 mm (95% limits), although in rare cases it can be more than 1.5 mm. This physiologic anisocoria is more apparent in the dark than in the light and may vary within the same individual from day to day, even reversing in direction.2 Careful examination reveals that the normal pupil at rest is never completely still but continuously changes its size. This pupillary unrest, or hippus, is most apparent in the light and is synchronous between the two eyes indicating its central rather than peripheral origin; it has no clinical significance. Light levels affect pupil size because of the retinotectal projections of some retinal ganglion cells (Fig. 11–2). The afferent fibers that contribute to this reflex 266 Neuro-Ophthalmology: Blue Books of Neurology

6 Dark diameter (mm) 4

2 Figure 11–1 Relationship between age and pupil 0 306090 diameter in healthy subjects (N ¼ 315). Age (yr)

T Light PT EW CG Pupil N N N

PT EW CG Pupil N N

Retina OC PC Figure 11–2 Diagram to illustrate the neural pathways underlying the pupil light reflex. Direct response (continuous arrows), consensual response (dashed arrows). CG, ciliary ganglion; EWN, Edinger-Westphal nucleus; N, nasal retina; OC, optic chiasm; PC, posterior commissure; PTN, pretectal nucleus; T, temporal retina.

arc have large receptive fields but small cell bodies and are distributed throughout the retina, with slightly greater density in the macula; it is not known if these cells form a separate population to those serving visual perception (i.e., the retino- geniculo-cortical projection). Their myelinated axons pass along the optic nerves, traverse the optic chiasm with decussation of the nasal fibers, and then continue along the optic tracts leaving just before the lateral geniculate nucleus to terminate in both ipsilateral and contralateral pretectal nuclei. Pretectal neurons emerging from these nuclei project to both the ipsilateral and, via a decussation in the posterior commissure, contralateral Edinger-Westphal nuclei and stimulate bilateral pupillary constriction. A bright light shone in one eye will therefore cause constriction of the ipsilateral pupil (direct response) and the contralateral pupil (consensual response) (Fig. 11–3); both direct and consensual responses occur relatively quickly (reflex latency lies in the range 200 to 500 milliseconds, 11 Pupillary Disorders 267

8.0

7.5

7.0

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Pupil diameter (mm) 6.0

5.5

5.0 Figure 11–3 Normal direct (solid 0231456line) and consensual (dashed line) pupil responses to a 1-second light Time (seconds) stimulus. varying inversely with light intensity), briskly (constriction should be rapid), and symmetrically (direct responses are often slightly greater in amplitude but this “contraction anisocoria”3 is rarely detectable on clinical examination of healthy subjects). The briskness and extent of the pupil response to a bright light varies considerably between healthy subjects and depends on a number of factors including the starting diameter (larger pupils show bigger responses) and alertness. It has been suggested that iris color and age4 are important, but this has not been established conclusively. If the light stimulus is rapidly alternated between the eyes (the “swinging flashlight test”5), both pupils remain maximally miosed with little or no “escape” as the light is moved from side to side. The observation of miosis on presenting the light stimulus to one eye but mydriasis when moving the stimulus to the other eye indicates less pupillomotor drive from the latter eye, that is, a relative afferent pupillary defect (RAPD). A false-positive RAPD may be seen in the absence of an anterior visual pathway lesion if the light stimulus is projected away from the macula in one but not both eyes (e.g., in cases of manifest strabismus) or if there is significant anisocoria (less light enters the eye with the smaller pupil). The execution of a swinging flashlight test and its interpretation therefore require considerable experience and are discussed later. In addition to ambient light levels, pupil size is determined by the accommodative state of the subject. When attempting to view a near object, the healthy subject uses a synergistic triad of convergence, miosis, and accommodation. The degree of pupillary miosis is related to the proximity of the object and the 268 Neuro-Ophthalmology: Blue Books of Neurology

degree of accommodative effort exerted by the subject. The near response can be elicited even in blind patients by asking them to look at the tip of their own finger held before their eyes. Healthy subjects with a myopic refraction, presby- opic individuals, or individuals with poor motivation may show little or no near response, and so failure to elicit a convincing pupillary constriction when the subject is made to look at a near target does not always indicate pathology. When present this near response is normally brisk but of smaller amplitude than the light response (Fig. 11–4), that is, light-near dissociation (greater miosis during a near effort than that achieved with the brightest light stimulus) is rarely seen in healthy subjects. The level of alertness of a subject has a profound influence on the pupil. When asleep, our pupils are miosed and show diminished responses to light; the more awake we are, the bigger and more responsive our pupils become. The relationship between pupil size and arousal has been known for centuries: Women in 16th century Venice used the extract of Atropa belladonna (atropine) to dilate the pupils and make them look youthful and more “interested” in their suitors, and in China jade dealers used to watch for pupillary dilation as a sign to raise the price when bartering a price for their goods. Reflex dilation of the pupil can be observed in normal subjects around 1 second after a sudden “wake-up” noise such as a loud bang: This “startle” response is generated mainly by central inhibition of the Edinger-Westphal nucleus and activation of the peripheral sympathetic supply, although circulating adrenaline may also contribute with more continuous stimulation. If instead, a subject is allowed to become

8.0

7.5

7.0

6.5

Pupil diameter (mm) 6.0

5.5 Figure 11–4 Normal pupil responses to a near effort. Gaze was transferred from a distant target (at 6 meters) to a near target 5.0 (at 0.3 meters) at the open arrow 5110 520 25 and transferred back again at the filled arrow. Time (seconds) 11 Pupillary Disorders 269

drowsy, for example, by placing him or her in a darkened, warm room, the pupils gradually miose over the course of 10 to 20 minutes, and superimposed on this progressive miosis the pupils are seen to oscillate in size. These so-called fatigue waves are very slow (frequency < 0.5 Hz) but of increasing amplitude (reaching several millimeters excursion from peak to trough in some individuals) and have been used as an objective and quantifiable index of fatigue in some experimental studies.6 An understanding of the pharmacology of the pupil is important in its clinical evaluation. Normal pupils respond symmetrically to topically applied receptor agonists such as phenylephrine 2.5% to 10% (producing mydriasis) or pilocarpine 1% to 4% (producing miosis) with maximum effect after 30 to 45 minutes. Supersensitivity, defined as an enhanced response to a receptor agonist at a concentration that has little or no effect on the size of a normal pupil (e.g., 1% phenylephrine, 0.5% to 1% apraclonidine, or 0.1% pilocarpine), indicates muscle denervation (e.g., Horner’s syndrome), muscle disuse atrophy (e.g., long-standing bilateral blindness), or increased drug penetration into the eye (e.g., dry eyes). In contrast, failure of the pupil to respond to a normal concentration of a receptor agonist indicates receptor blockade (e.g., inadvertent atropinization by jimson weed), although the clinician must be confident that the test drug got into the eye and was not “squeezed out” by an unwilling subject. A number of indirect sympathomimetic agents are also useful in evaluating Horner’s syndrome. Cocaine (4% to 10%) blocks the active reuptake process for noradrenaline at sympathetic neuroeffector junctions in the dilator muscle and so increases the concentration of endogenous agonist at the receptors causing dilation of the normal pupil; failure of the pupil to dilate following cocaine administration indicates oculosympathetic palsy (Horner’s syndrome), but the test has no localizing value. One percent hydroxyamphetamine, 0.5% pholedrine, or 2.5% tyramine all displace noradrenaline from its storage vesicles in the sympathetic nerve endings and so may be used to test the integrity of the postganglionic sympathetic neuron, dilating the normal pupil and the pupils of patients with preganglionic Horner’s syndrome but not those with postganglionic lesions. A number of caveats apply to correct interpretation of pharmacologic tests of the pupil. First, the effect and duration of action of many drugs depend on iris color because of melanin binding.7 For this reason it is advisable that the clinician allows at least 48 hours “wash-out” time between sequential drug tests to be certain the effects have worn off. Second, the sensitivity of pharmacologic tests in the detection of pupil abnormality is much greater when the lesion is unilateral; in conditions giving rise to bilateral symmetrical sympathetic or parasympathetic blockade (e.g., patients with generalized autonomic failure) it is sometimes not possible to use drug testing to make a diagnosis. Finally, drug responses depend critically on drug penetration; patients with dry eyes may give false-positive results following instillation of weak receptor agonists because of greater penetration of the drug into the eye.8

The Abnormal Pupil

There is a wide range of pupil abnormalities seen in clinical practice, reflecting the many parts of the central and peripheral nervous systems that influence the 270 Neuro-Ophthalmology: Blue Books of Neurology

pupil. These include an irregular shape or position within the iris, an abnormal size in the light or in the dark, anisocoria, an attenuated or absent response to light, an exaggerated, tonic or absent response to an accommodative effort, and abnormal responses to topically applied drugs. In many cases, the pupil abnormality is not isolated but associated with other clinical symptoms or signs that help to indicate the diagnosis. Few pupil abnormalities are symptomatic and even fewer warrant treatment, but their recognition can make an important contribution to the neurologist’s evaluation and in some cases save the patient unnecessary investigations. The following is a review of some of the commoner clinical abnormalities seen in the four main areas of influence over the pupil, namely the local environment within the eye, the autonomic supply to the iris muscles, the visual pathways, and the mesencephalon.

LESIONS WITHIN THE EYE It is worth reminding the reader that some apparently neurogenic pupil abnormalities have a local cause within the eye. Trauma to the anterior segment may lead to an unreactive pupil that is large (as a result of sphincter muscle rupture), misshapen, or small (from secondary uveitis). Active inflammatory eye disease causes pupillary miosis, whereas chronic inflammation may lead to the formation of posterior synechiae, an irregular pupil, and little or no response to light or near. Iris ischemia, with or without rubeosis, may occur in the context of herpes zoster, diabetes, or acute (angle-closure) glaucoma and gives rise to a stiff unresponsive pupil often with an irregular shape and iris transillumina- tion defects. Cysts or tumors of the anterior uveal tract, although rare, all cause pupil abnormalities and may be difficult to diagnose. Inadvertent exposure to drugs that affect the pupil (classic sources include fingers contaminated with jimson weed or belladonna from the garden, or ipratropium bromide inhalers in asthmatics) may not be apparent in the initial history from the patient or relatives. There is a long list of mostly rare congenital and hereditary conditions that affect pupil size,9 shape, position, and reactivity; in some but not all there are other developmental abnormalities present within the eye. As a rule of thumb, if the pupil abnormality does not fit any plausible neurologic condition, the opinion of an ophthalmologist should be sought.

SYMPATHETIC LESIONS Oculosympathetic palsy was first described in experimental dogs by Franc¸ois Pourfour du Petit (1727)10 and more than a century later by Claude Bernard in cats (1852).11 A student of Bernard’s, Silas Weir Mitchell, returned to America where he described the same clinical signs in a man with a through-and-through gunshot wound to the neck (1864),12 but it was Johann Friedrich Horner’s paper in 1869 that earned him the eponymous syndrome.13 The pupil in Horner’s syndrome is small (Fig. 11–5), and when the defect is unilateral it causes anisocoria that is most apparent in the dark. The pupil reacts briskly to a flash of light but then is slow to redilate, a sign known as redilatation lag (Fig. 11–6). The startle response is absent. The pupil shows denervation supersensitivity to dilute adrenoceptor agonists such as 1% phenylephrine or 0.5% apraclonidine but fails to dilate after instillation of 4% cocaine. Because 11 Pupillary Disorders 271

Figure 11–5 Left-sided Horner’s syndrome: There is pupillary miosis, ptosis of the upper lid, and elevation of the lower lid when compared with the normal side.

6.5

6.0

5.5

Pupil diameter (mm) 5.0

Figure 11–6 Unilateral postganglionic Horner’s syndrome in a 4.5 patient presenting with headache. The affected pupil (dashed line) has a smaller resting diameter in the dark and shows redilatation (arrow) 04286 10lag compared with the unaffected fellow eye (solid line). The Time (seconds) cause in this case was unknown. an intact sympathetic supply to the eye is required for normal melanization of the iris during development, sympathetic lesions that are congenital or occurred within the first few years of life lead to iris hypochromia (heterochromia iridis in unilateral cases). The sympathetic nerves that supply the eye and face include vasomotor, sudomotor, and vasodilator fibers as well as pupillary fibers. Involvement of some or all of these fibers in Horner’s syndrome may give rise to a number of nonpupillary signs, including ptosis of the upper lid and elevation of the lower lid (because of weakness of Mueller’s muscles), congestion of the conjunctival vessels and lowered intraocular pressure (vasomotor fibers), and anhydrosis (sudomotor fibers) either of the entire ipsilateral face (for preganglionic lesions) or of a small patch of supraorbital skin above the affected eye (for postganglionic lesions). In some cases, damage to sympathetic vasodilator fibers in the face and neck gives rise to ipsilateral failure to flush on heat, on exercise, or in response to curries and spicy food (harlequin syndrome14). The pattern of sympathetic deficits seen in each patient with Horner’s syndrome varies considerably depending 272 Neuro-Ophthalmology: Blue Books of Neurology

on the location, nature, and extent of the lesion, but in practice it is difficult to localize an isolated Horner’s on the basis of clinical examination alone. The causes of Horner’s syndrome are legion, reflecting the long course of the peripheral sympathetic pathway from hypothalamus to eye. Central lesions associated with brainstem (Wallenberg’s syndrome, tumors) or spinal cord (syringo- myelia, cervical spondylosis) pathology usually but not invariably produce long tract and other neurologic signs. A rare but easily missed sign is contralateral superior oblique paresis in an apparently isolated central Horner’s, which indicates a midbrain lesion of the ipsilateral trochlear nucleus through which the sympathetic fibers pass. Preganglionic lesions are most commonly associated with trauma to the chest or neck (including insertion of chest tubes, central lines, and pacemakers). However, occult malignancy must always be considered: Tumors at the apex of the lung (usually lung or breast) cause wasting of the small hand muscles and Horner’s syndrome (Pancoast’s syndrome), and neck tumors, both benign and malignant, may also interrupt the cervical sympathetic chain. The proportion of preganglionic Horner’s syndrome caused by malignancy has been estimated at up to 25%15 but in my experience the neuro-ophthalmic signs are rarely the presenting feature. Postganglionic lesions most often arise in the context of carotid, skull base, and cavernous pathology and may occur in association with visual loss, ophthalmoplegia, or accompanied only by trigeminal pain. The signs of a Horner’s syndrome may be masked if there is also an oculomotor nerve palsy. An important condition in the differential diagnosis of an isolated painful postganglionic Horner’s is internal carotid artery dissection: The eye signs may be the only abnormal examination finding, but if the diagnosis is missed there is a significant risk of subsequent stroke. Bilateral Horner’s syndrome is difficult to diagnose and rarely suspected by patient or clinician. There may be little or no anisocoria, the lid and other extra- pupillary signs are symmetrical, and pharmacologic tests are insensitive when there is no “control” eye for comparison (Fig. 11–7). The only reliable way to detect bilateral Horner’s syndrome is by measuring redilatation lag using formal pupillographic techniques.16 Bilateral Horner’s syndrome is most commonly seen in diabetes mellitus but is also found in other conditions associated with widespread autonomic neuropathy, for example, amyloidosis, pure autonomic failure, and the hereditary sensory and autonomic neuropathies.17 When the cause of an isolated Horner’s syndrome is not apparent, hydroxyamphetamine (or pholedrine, tyramine; see previous discussion) should be

Figure 11–7 Bilateral Horner’s syndrome. Both pupils are small with no anisocoria, and there is ptosis of both upper lids. Neither the patient nor the referring clinician were aware of the oculosympathetic paresis because the signs are bilateral and symmetrical. In the absence of a “control” eye, drug tests have poor sensitivity, and the diagnosis is best made using pupillography to demonstrate bilateral redilatation lag. 11 Pupillary Disorders 273

used to distinguish between preganglionic and postganglionic lesions: The affected pupil fails to dilate when the last order neuron is damaged. Subsequent investigation will depend on the clinical context and may include chest, neck, and head imaging, but the yield is low and the cause in many cases is never established. Excitation of sympathetic fibers by irritative lesions may lead to mydriasis (“springing pupil”) or, if affecting only one meridian, a “tadpole pupil” (Fig. 11–8).18 These pupil changes are invariably unilateral and transient lasting only a minute or two but often associated with blurring of vision and an odd sensation within the eye. The pupil shows brisk and normal light and near responses both during and between these “attacks” confirming that these changes occur as a result of sympathetic overactivity and not parasympathetic underactivity. It is interesting to note that in many cases pharmacologic and pupillographic tests reveal a degree of coexisting sympathetic block.19 The etiology of both springing pupils and tadpole pupils is unknown but appears to be benign and further investigations are not indicated.

PARASYMPATHETIC LESIONS In contrast to sympathetic lesions, damage to the parasympathetic supply to the eye produces different clinical signs depending on whether the lesion is preganglionic or postganglionic, and so clinical examination alone is required to make the distinction. The pupil in preganglionic lesions is dilated, with the anisocoria most apparent in the light, and its shape is round with no selective paresis of different meridians of the sphincter muscle. The light reflex is attenuated or absent to both direct and consensual stimuli, and there is no miosis during an accommodative effort although convergence may be preserved. Unaided near acuity will be reduced in nonpresbyopic patients because of the cycloplegia. Within days, the denervated sphincter muscle becomes supersensitive to weak receptor agonists such as 0.1% pilocarpine, and so (contrary to what is written in some older textbooks) this drug test has no localizing value. Preganglionic parasympathetic blockade usually occurs in the context of oculomotor nerve palsies and much has been written about the significance of pupil involvement or pupil “sparing.” In general, the rule suggested by Rucker20 still holds true: If the oculomotor nerve palsy is incomplete, then pupil involvement implies an extrinsic compressive lesion until proved otherwise

Figure 11–8 Example of a “tadpole” pupil. The pupil has a circular shape most of the time (left) but during an “attack,” it becomes elongated along the 7 o’clock meridian (center). Within 5 to 10 minutes, it has returned to its normal round shape (right). In many cases, a tadpole pupil occurs in the context of an underlying Horner’s syndrome. 274 Neuro-Ophthalmology: Blue Books of Neurology

(mostly aneurysms in his large case series). The anatomical studies of Kerr and Hollowell21 help to explain this clinical finding: The pupillomotor fibers travel superficially throughout much of the subarachnoid part of the nerve rendering them more susceptible to compressive lesions but less susceptible to ischemia. Some additional caveats are needed when applying this rule in clinical practice. First, the rule applies only to incomplete third nerve palsies—when all muscles supplied by the oculomotor nerve are denervated the fact there is pupil involvement contributes nothing to the differential diagnosis. Second, pupil sparing may be seen early in the evolution of compressive lesions and so patients with pupil-sparing incomplete third nerve palsies need careful monitoring to ensure that the pupil does not become involved days or weeks after initial presentation with external ophthalmoplegia. Third, any patient with progressive ophthalmoplegia requires neuroimaging regardless of the pupil signs because a surgical cause is very likely. Finally, whereas it is not uncommon to see patients with a pupil-sparing third nerve palsy, the opposite almost never occurs (i.e., internal ophthalmoplegia sparing all the extraocular muscles and levator): This clinical picture is most often seen as a result of receptor blockade, for example after inadvertent exposure to an atropine-like drug (see previous discussion). Postganglionic parasympathetic blockade occurs as a result of damage to the ciliary ganglion or the short posterior ciliary nerves and leads to a different clinical picture. The pupil is initially large and round showing little reaction to light or near, but with time the pupil becomes progressively smaller—eventually in some cases reversing the anisocoria—and irregular in shape. A magnified view of the pupil margin as seen using slitlamp biomicroscopy reveals “sector palsy” with bunching of the iris collarette in some meridians and stretching in other meridians (Fig. 11–9) leading to “vermiform” movements as light is moved across the pupil margin. The light reflex is slow and attenuated or may be completely absent to both direct and consensual stimuli. In contrast, the pupil shows an exaggerated miosis during accommodative efforts (i.e., there is light- near dissociation) and moreover the pupillary changes when transferring gaze from far to near and especially from near back to far again are greatly slowed (Fig. 11–10): This pupil behavior is termed “tonic” (the inability to relax following muscle contraction reminding one of myotonia elsewhere) and is pathognomonic of damage to the postganglionic parasympathetic fibers. At least some of these pupil features can be understood in terms of aberrant regeneration: More than 95% of postganglionic fibers emerging from the ciliary ganglion normally terminate in the ciliary muscle, but after injury many of these regenerating

Figure 11–9 Irregular pupil shape in Holmes-Adie syndrome. Sector palsy and aberrant regeneration lead to bunching of the collarette in some meridians but stretching in others. The result is an irregular pupil margin that shows vermiform movement when stimulated with the beam of a slit lamp. 11 Pupillary Disorders 275

7.5 7

7.0 6

6.5

6.0 Pupil diameter (mm) Pupil diameter (mm) 4 5.5

5.0 3 12 1614 18 20 10 1412 16 18 20 Time (seconds) Time (seconds) Figure 11–10 Pupil responses to a light stimulus (left graph) and a near effort (right graph— arrow indicates time when gaze moved from distance to near target). The tonic pupil (dashed line) shows little response to light but a slow, exaggerated response to near. The pupil in the fellow eye shows normal responses to both light and near. The patient had tendon areflexia and Holmes-Adie syndrome.

“accommodation” fibers mistakenly terminate in the sphincter muscle giving rise to exaggerated near but impaired pupil light responses.22 Since Holmes23 and his student Adie24 reported patients with tonic pupils and ipsilateral tendon areflexia, considerable confusion has been generated in the literature as a result of failing to distinguish between the nonspecific pupil signs described previously and their eponymous syndrome. Clarity is restored if the term “Adie’s pupil” is expunged and replaced by the more descriptive term “tonic pupil.” A tonic pupil results from damage to the postganglionic parasympathetic supply to the eye. If unilateral, it may be caused by local processes such as traumatic, neoplastic, or inflammatory orbital disease and even panretinal laser photocoagulation in the eye. If bilateral and symmetrical, the clinician should suspect a generalized autonomic neuropathy such as pure autonomic failure, amyloidosis, Sjo¨gren’s syndrome, or paraneoplastic states.17 In many patients, however, no cause can be identified: In some of these idiopathic cases, the pupil signs are associated with ipsilateral tendon areflexia in otherwise well young adults—this is properly called Holmes-Adie syndrome and occurs most commonly in females. The signs in Holmes-Adie syndrome are unilateral at presentation in 80% to 90%, but the risk of second eye involvement is estimated at 10% per decade thereafter. When bilateral, there is usually marked anisocoria and asymmetry between the eyes, reflecting perhaps the stag- gered involvement of the eyes over time in contrast to the symmetrical pupil signs found in generalized dysautonomias in which the insults are synchronized. Laboratory testing of autonomic function in patients with a clinical diagnosis of 276 Neuro-Ophthalmology: Blue Books of Neurology

Holmes-Adie syndrome reveals a significant prevalence of subclinical abnormalities in both sympathetic and parasympathetic arms of the autonomic nervous system, and the number of these abnormalities increases over time, implying that the unknown pathologic process is not only more widespread than initially thought but also progressive.25,26 However, the only extraocular symptom experienced by a small number of patients with Holmes-Adie syndrome is a patchy disturbance of sweating because of damage to the sympathetic sudomotor fibers (Ross syndrome27); in general, patients with Holmes-Adie syndrome complain only of the cycloplegia and anisocoria and the disease runs a benign course.

LESIONS OF THE VISUAL PATHWAY Use of the pupil to diagnose lesions of the anterior visual pathways has been practiced since the days of Galen of Pergamon in the second century.28 The pupil signs can, however, be subtle: Lesions that interrupt the afferent limb of the pupil light reflex attenuate or abolish the pupil response to light, but in most other respects the pupil examination in these patients appears normal. Both pupils are round, central, and seem to be of normal size even in patients with no perception of light in either eye (it is likely that both pupils have larger resting light diameters after such visual loss, but without premorbid measurements and with a wide range of “normal” diameters, this size increase is rarely apparent). The lesion does not cause anisocoria even when unilateral. Both pupils constrict briskly and normally to an accommodative effort (i.e., light-near dissociation) confirming integrity of the efferent limb of the light reflex. The pupil responds normally in all drug tests. The visual pathway damage becomes evident when a bright light is directed into the eye and the phasic pupil light response is observed. With unilateral lesions, the direct response is smaller or absent compared with the consensual response, and the swinging flashlight test confirms the presence of a relative afferent pupil defect (RAPD). In broad terms, an RAPD is seen only with lesions of the retina or optic nerve. Media opacities such as corneal scarring, cataract, or vitreous hemorrhage merely scatter the light degrading acuity but preserving the pupillomotor drive from retinal luminance receptors. It should be remembered that the swinging flashlight test is a comparative assessment, and the “good” eye is only shown to be better than the “bad” eye and not necessarily normal. With bilateral symmetrical lesions, both pupils respond poorly to light (reduced amplitude and “sluggish,” i.e., delayed latency and slowed constriction velocity), and there is no RAPD. Chiasmal lesions, which affect crossing fibers, symmetrically cause no clinically apparent abnormality in the pupil light reflex. Optic tract lesions theoretically should generate an RAPD because the temporal hemifield is larger than the nasal,29 but in practice this is extremely difficult to reproduce convincingly in a patient and the light responses usually look symmetrical. Retrogeniculate lesions were classically thought not to affect the pupil reflex arc,30 and so it should be possible to distinguish between tract and radiation hemianopias on the basis of the pupil reactions to light shone selectively into the blind and seeing hemifields. Pupil perimetry, however, shows that retrogeniculate lesions do cause significant attenuation of the pupil light response in the blind hemifield (pupillary “hemiakinesia”),31,32 presumably by interrupting a centrifugal connection 11 Pupillary Disorders 277

between striate cortex and pretectum/midbrain, and so pupil examination is not as useful as disc examination in making this distinction. Modern pupillographic techniques have similarly confirmed that the pupil response in dense amblyopia is mildly attenuated,33 but in clinical practice it is unwise to ever accept amblyopia as a cause of an RAPD. The safest clinical rule is to state that any convincing RAPD must indicate either retinal or optic nerve disease even if the fundus examination is unremarkable. The degree of attenuation of the pupil light response shows best correlation with the extent of visual field loss. In unilateral lesions, the RAPD measured using neutral density filters shows moderately good linear correlation with the mean visual defect measured using automated perimetry.34 With bilateral lesions, the RAPD correlates with the difference between the mean visual defects in the two eyes. The threshold for clinical detection of an RAPD appears to be an inter-eye difference in mean visual defects of at least 8 dB.35 In contrast, attenuation of the pupil light reflex shows little correlation with visual acuity (e.g., poor acuity from cataract but normal pupil light response, or sluggish pupil light response because of extensive visual field loss in advanced glaucoma but preserved acuity) or color vision. In some conditions, there appears to be an interesting mismatch between the extent of the visual defect and the degree of attenuation of the pupil light responses. Patients with Leber’s hereditary optic neuropathy36 or dominant optic atrophy37 have very poor vision but a relatively preserved pupil light reflex, whereas patients after recovery from optic neuritis may have an apparently complete recovery of vision but show a persistent RAPD.38 This mismatch has been called pupillovisual dissociation and may reflect the susceptibilities of different fiber subpopulations within the optic nerves to axonal compared with demyelinating pathologies.28

LESIONS IN THE MIDBRAIN Pretectal lesions, most commonly extrinsic compression from pineal region tumors or hydrocephalus, interrupt the light reflex pathway without affecting the near triad (which originates ventral to the aqueduct) or the geniculostriate projection. These patients therefore have the classic triad of Parinaud’s (or dorsal midbrain) syndrome: absent pupil light responses, preserved (and brisk rather than tonic) near responses, and normal vision. The pupil abnormalities are almost always bilateral but can be asymmetric; the pupils are large in diameter, normal in shape and position, and constrict to a near effort but not to a light stimulus (i.e., light-near dissociation) despite normal sight. Lesions causing Parinaud’s syndrome are usually large and affect a number of other structures in the upper midbrain. They are often associated with a vertical saccadic palsy (through damage to the rostral interstitial nucleus of Cajal) with convergence retraction nystagmus and Collier’s sign (lid retraction on attempted upgaze), and some patients also develop a skew deviation (from interruption to the otolith pathway to the oculomotor nuclear complex). Some patients particularly in the pediatric age range also develop papilledema. These signs are often reversible once surgical decompression of the dorsal midbrain has been achieved. A rare abnormality nowadays is the Argyll Robertson (AR) pupil seen in tertiary syphilis. First described in the mid-19th century before a cause for tabes dorsalis had been established,39 it rapidly became an ominous clinical sign in 278 Neuro-Ophthalmology: Blue Books of Neurology

the preantibiotic era indicating progression to central nervous system disease. AR pupils are small in both the light and the dark and are often misshapen (because of concurrent inflammatory eye disease rather than the central lesion). The light response is diminished or absent, but a brisk near response can be elicited despite the small resting pupil diameters. These pupils will respond normally to topically applied receptor agonists and antagonists unless there is local damage to the iris. Visual function is classically described as normal but may be poor if there is concurrent involvement of the eye or visual pathways in the tre- ponemal infection. It is not known where the abnormality lies in these patients and autopsy evidence has been inconclusive, but it is assumed that the lesion is ventral to the aqueduct in the upper midbrain. The origin of the pupillary miosis is also debated but may be because of interruption to the supranuclear inhibitory pathways that suppress the natural discharge rates of Edinger-Westphal neurons. The advent of penicillin has made this a rare diagnosis, but other conditions may produce pupils that have all the same features including metabolic (chronic alcoholism, diabetes mellitus), neuroinflammatory (multiple sclerosis, sarcoid), neurodegenerative (dementia), and neurogenetic (myotonic dystrophy) disease. A number of other unusual pupil findings may be found rarely in association with midbrain disease, including “spastic miosis” (small pupils that do not react to light or near) and “inverse-AR” pupils (small pupils that react to light but not to near). The pattern of deficits is determined by which of the light, near, and central inhibitory pathways have been damaged. All of these midbrain syndromes share in common the following features: The pupil abnormalities are bilateral and usually symmetrical, visual function is preserved, and the pupils respond normally to all pharmacologic tests (assuming no concurrent damage to the eye). An increasingly wide spectrum of etiology is now recognized as potentially causing these syndromes, but a good rule of thumb particularly now that syphilis incidence is rising is that any patient with “midbrain pupils” and normal neuroimaging should have their serum and cerebrospinal fluid tested for syphilis.

REFERENCES 1. Warwick R: The ocular parasympathetic nerve supply and its mesencephalic sources. J Anat 1954;88:71–93. 2. Bremner FD, Booth A, Smith SE: Benign alternating anisocoria. Neuro-ophthalmology 2004;28:129–135. 3. Smith SA, Ellis CJ, Smith SE: Inequality of the direct and consensual light reflexes in normal subjects. Br J Ophthalmol 1979;63:523–527. 4. Loewenfeld IE: Pupillary changes related to age. In Thompson HS, Daroff R, Frisen L, et al (eds): Topics in Neuro-Ophthalmology, Baltimore, Williams & Wilkins, 1979, pp 124–150. 5. Levatin P: Pupillary escape in diseases of the retina or optic nerve. Arch Ophthalmol 1959;62:768–779. 6. Wilhelm H, Lu¨ dtke H, Wilhelm B: Pupillographic sleepiness testing in hypersomniacs and nor- mals. Graefes Arch Clin Exp Ophthalmol 1998;236:725–729. 7. Salazar-Bookaman MM, Wainer I, Patil PN: Relevance of drug-melanin interactions to ocular pharmacology and toxicology. J Ocul Pharmacol 1994;10:217–239. 8. Kazakos DC, Smith SE, Bron AJ: The pupil response to pilocarpine (0.125%) in dry eye patients. Ophthalmol Res 2001;33(S1):108. 9. Bremner FD, Houlden H, Smith SE: Genotypic and phenotypic heterogeneity in familial micro- coria. Br J Ophthalmol 2004;88:469–473. 10. Pourfour du Petit D: Me`moires dans lequel il est de`montre` que les nerfs intercostaux fournissent des rameaux qui portent les esprits aux yeux. Hist Acad Roy Sci (Paris) 1727;1:1–19. 11 Pupillary Disorders 279

11. Bernard C: Expe`riences sur les function de la portion ce`phalique du grand sympathique. CR Soc Biol (Paris) 1852;155:168–170. 12. Mitchell SW, Morehouse G, Keen W: Gunshot Wounds and Other Injuries of Nerves, Philadel- phia, JP Lippincott, 1864, p. 164. 13. Horner F: U¨ ber eine form von ptosis. Klin Monatsbl Augenheilkd 1869;7:193–198. 14. Lance JW, Drummond PD, Gandevia SC, Morris JG: Harlequin syndrome: The sudden onset of unilateral flushing and sweating. J Neurol Neurosurg Psychiatry 1988;51:635–642. 15. Thompson H, Maxner C, Corbett J: Horner’s syndrome due to damage to the preganglionic neuron of the oculosympathetic pathway. In Huber A (eds): Sympathicus und Auge, Stuttgart, Ferdinand Enke, 1990, pp 99–104. 16. Smith SA, Smith SE: Bilateral Horner’s syndrome: Detection and occurrence. J Neurol Neurosurg Psychiatry 1999;66:48–51. 17. Bremner FD, Smith SE: Pupil findings in a consecutive series of 150 cases of generalised autonomic neuropathy. J Neurol Neurosurg Psychiatry 2006;77:1163–1168. 18. Thompson HS, Zackon DH, Czarnecki JSC: Tadpole-shaped pupils caused by segmental spasm of the iris dilator muscle. Am J Ophthalmol 1983;96:467–477. 19. Balaggan KS, Bremner FD, Hugkulstone CE: Episodic segmental iris dilator muscle spasm—the tadpole-shaped pupil. Arch Ophthalmol 2003;121:744–745. 20. Rucker CW: The causes of paralysis of the third, fourth and sixth cranial nerves. Am J Ophthalmol 1966;61:1293–1298. 21. Kerr FWL, Hollowell OW: Location of pupillomotor and accommodation fibers in the oculomotor nerve: Experimental observations on paralytic mydriasis. J Neurol Neurosurg Psychiatry 1964; 27:473–481. 22. Lowenfeld IE, Thompson HS: The tonic pupil: A reevaluation. Am J Ophthalmol 1967;63:46–87. 23. Holmes G: Partial iridoplegia with symptoms of other diseases of the nervous system. Trans Ophthalmol Soc UK 1931;51:209–228. 24. Adie WJ: Pseudo-Argyll Robertson pupils with absent tendon reflexes: Benign disorder simulating tabes dorsalis. Br Med J 1931;1:928–930. 25. Bacon PJ, Smith SE: Cardiovascular and sweating dysfunction in patients with Holmes-Adie syndrome. J Neurol Neurosurg Psychiatry 1993;56:1096–1102. 26. Jacobson DM, Hiner BC: Asymptomatic autonomic and sweat dysfunction in patients with Adie’s syndrome. J Neuro-Ophthalmol 1998;18:143–147. 27. Ross AT: Progressive selective sudomotor denervation. A case with coexisting Adie’s syndrome. Neurology 1958;8:809–817. 28. Bremner FD: Pupil assessment in optic nerve disorders. Eye 2004;18:1175–1181. 29. Bell RA, Thompson HS: Relative afferent pupillary defect in optic tract hemianopias. Am J Ophthalmol 1978;85:538–540. 30. Wernicke G: U¨ ber hemianopische pupillenreaction. Fortschr Med 1883;1:49–53. 31. Cibis GW, Campos EC, Aulhorn E: Pupillary hemiakinesia in suprageniculate lesions. Arch Ophthalmol 1975;93:1322–1327. 32. Barbur JL, Ruddock KH, Waterfield VA: Human visual responses in the absence of the geniculocalcarine projection. Brain 1980;103:905–928. 33. Greenwald MJ, Folk ER: Afferent pupillary defects in amblyopia. J Pediatr Ophthalmol Strabis 1983;20:63–67. 34. Kardon RH, Haupert CL, Thompson HS: The relationship between static perimetry and the relative afferent pupillary defect. Am J Ophthalmol 1993;115:351–356. 35. Johnson LN, Hill RA, Bartholomew MJ: Correlation of afferent pupillary defect with visual field loss on automated perimetry. Ophthalmology 1988;95:1649–1655. 36. Bremner FD, Shallo-Hoffmann J, Riordan-Eva P, et al: Comparing pupil function with visual function in patients with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 1999;40:2528–2534. 37. Bremner FD, Tomlin EA, Shallo-Hoffmann J, et al: The pupil in dominant optic atrophy. Invest Ophthalmol Vis Sci 2001;42:675–678. 38. Bremner FD, Tomlin EA, Shallo-Hoffmann J, et al: Poor recovery of the pupil light reflex following acute optic neuritis. Neuro-ophthalmology 2001;25:56. 39. Robertson DA: Four cases of spinal miosis: With remarks on the action of light on the pupil. Edinburgh Med J 1869;15:487–493. 12 Papilledema and Idiopathic Intracranial Hypertension KATHLEEN DIGRE

Papilledema Primary Intracranial What Is Papilledema and How Hypertension Do We Recognize It? Secondary Intracranial Ophthalmoscopic Features Hypertension Unusual Forms of Papilledema Diagnosing the Underlying References Cause of Papilledema Natural History and Visual Complications Treatment of Papilledema

Key Points Papilledema is a term reserved for disc swelling resulting from increased intracranial pressure. Evaluation for papilledema includes an imaging procedure that adequately excludes intracranial masses and venous thrombosis; if no mass or thrombosis is present, a lumbar puncture with accurate measurement of opening pressure and cerebrospinal fluid contents should be made. The most common cause of increased intracranial pressure is primary (or idiopathic) intracranial hypertension; it is associated with female gender and obesity. Visual loss is a disabling feature of papilledema. Careful evaluation of vision, including visual fields, is necessary; when vision is threatened despite maximum medical therapy, a surgical procedure should be considered.

Papilledema

Papilledema is one of the true neuro-ophthalmic emergencies. Not only can the sign signal an underlying brain tumor or acute neurologic process, but swelling of the disc can also mean visual loss for the patient.

WHAT IS PAPILLEDEMA AND HOW DO WE RECOGNIZE IT? Papilledema is the term used to denote disc swelling related to increased intracranial pressure (ICP). Other terms including “choked disc,” “papillitis,” and “disc 280 12 Papilledema and Idiopathic Intracranial Hypertension 281

edema” refer to generic disc swelling, whereas we reserve papilledema for swelling because of increased pressure in the brain. Experiments by Tso and Hayreh1 showed that “axoplasmic stasis” was the basic mechanism of any cause of disc swelling, whether it resulted from papilledema (inflated intracranial balloons and high-dose radiation to the brain) or from ocular hypotension (ciliary body destruction). They demonstrated that axoplasmic stasis occurred at the lamina cribrosa. Other researchers confirmed these findings and also observed that edema occurred after tying a ligature around the retrobulbar portion of the optic nerve.2,3 Therefore, swelling of the axons causes the nerve to swell. An atrophic nerve cannot swell; thus, a functional nerve must have axons. The features that we look for in papilledema are related to axonal swelling.

OPHTHALMOSCOPIC FEATURES (FIG. 12–1) To recognize true disc swelling, a review of specific characteristics is needed.4 Is the disc elevated? When viewing the disc monocularly through an ophthalmoscope, one should look for clues that elevation is present. Do the arteries and veins appear to drape over the top of the disc? In addition, one should focus the ophthalmoscope on the plane of the retina and then focus the ophthalmoscope at the top of the disc. Is there a change in the diopters that suggests an elevated optic disc? (Fig. 12–1A). Is a cup present? In true papilledema, the cup is preserved until very late in the swelling process, whereas a disc in which the cup is absent has a greater chance of being associated with pseudo-swelling (Fig. 12–1B). Is the disc hyperemic? Although this is one of the least useful signs of true disc swelling, it is present in most cases of papilledema. Hyperemia can occur because there are small dilated capillaries on the disc (Fig. 12–1C). Is the nerve fiber layer thickened and blurred? In true swelling, the vessels will be lost in the nerve fiber because of this thickened layer. In pseudo- swelling, the vessels appear to drape over the top of the disc (Fig. 12–1D). Is there anomalous branching? In papilledema, the vessels are usually normal, although anomalous discs can occasionally show papilledema. Most anomalous discs may have abnormal branching patterns such as trifurcations or tetrafurcations. Are the veins dilated? In papilledema, the venous structures are generally dilated. An older term for papilledema is “choke”: the vessels and the disc are squeezed, but the veins are not particularly swollen (Fig. 12–1E). Are there venous pulsations? One should view one of the large trunks of the veins at the disc margin. Hedges found that 70% of those with healthy eyes and brains, but no increased pressure, had venous pulsations.5 Venous pulsations can be viewed at http://medlib.med.utah.edu/NOVEL/Moran/ index3.html. One should be cautious in interpreting these findings: individuals with normal ICP may have no venous pulsations, and pulsations have been documented in patients with elevated ICP.4

Incidental Findings with True Disc Swelling Is there hemorrhage? In true disc swelling, hemorrhage can be present. However, this is not absolute, because a splinter hemorrhage can be present in some forms of pseudo-swelling (Fig. 12–1F). 282 Neuro-Ophthalmology: Blue Books of Neurology

Figure 12–1 True disc swelling. A, Elevation of disc. B, Cup is present. C, Hyperemia. D, Nerve fiber layer. E, Dilated veins. F, Hemorrhages on the disc. 12 Papilledema and Idiopathic Intracranial Hypertension 283

G H Figure 12–1 Cont’d—G, Retinal exudates. H, Retinal folds.

Are there exudates? Although exudates are not usually present until papilledema is fully established, their presence can signal an active process (Fig. 12–1G). Are there retinal folds? On occasion, retinal folds will accompany papilledema. Although this is not required for disc swelling, it is an incidental finding (Fig. 12–1H). Table 12–1 shows the Lars Frise´n staging scheme, which is used to classify papilledema.6 Knowing the classification of disc swelling enables the clinician to determine an improvement or worsening of the swelling and to communicate the findings to others.

What Kinds of Disc Abnormalities Can Be Mistaken for Papilledema? What Is Pseudopapilledema? (Fig. 12–2) Normal variations of the disc can be mistaken for papilledema or for what some have termed pseudopapilledema. Table 12–2 summarizes the diagnostic criteria of papilledema and pseudopapilledema. The most common cause of pseudopapilledema is a hyperemic, small, crowded disc. The “little red disc,” a term coined by Corbett and Thompson, is often seen in hyperopia and appears almost elevated because of crowding that occurs when axons are traveling through a very small lamina cribrosa (Fig. 12–2A).4 Other causes of pseudopapilledema include persistent membranes on the disc, tilted discs, and myelinated nerve fibers (Fig. 12–2B to D). Another common cause of pseudopapilledema is discs with drusen. Optic disc drusen are small hyaline bodies that are usually congenital, inherited, and refractile. They may be buried in the disc or visible with an ophthalmoscope by using the red-free light or shining the slit-beam at an oblique angle. Buried drusen pose more difficulty in diagnosis because they are often not visible because of elevation of the nerve. Orbital ultrasound, which often shows a special echo resulting from the calcium in these discs, or a computerized tomogram (CT scan) will generally correctly diagnose buried drusen. 284 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 12–1 Papilledema Staging Scheme by Lars Frise´n

Stage 0 is a normal disc with minimal swelling of nasal margin of the disc; nerve fiber layer is clear; no obscuration of the vessel is observed; and the cup (if present) is not obscured. This individual had a documented opening pressure of 350 mm cerebrospinal fluid (CSF). Stage 1 is a C-shaped swelling of the nasal, superior and inferior borders. Usually the temporal margin is normal with sharp disc margins. The cup is maintained. No vessel obscuration. Stage 2 involves elevation of the temporal margin and 360-degree swelling. There is a blur of the nerve fiber layer (NFL); some vessel obscuration may be present. The cup begins to fill in. Stage 3 involves elevation of the entire disc with obscuration of the retinal vessels at the disc margin. NFL is moderately opaque with 360-degree swelling, hyperemia, and vascular obscuration at disc margin. The cup may be totally obscured. In Stage 4 there is complete obliteration of the cup and obscuration of the vessels on the surface of the disc. NFL is opaque with 360-degree swelling and advanced hyperemia of the disc; vessels are largely obscured on the disc surface. In Stage 5 there is a dome-shaped appearance and all vessels are obscured.

Modified from Frise´n L: Swelling of the optic nerve head: A staging scheme. J Neurol Neurosurg Psychiatry 1982;45:13–18.

Figure 12–3 shows examples of buried (Fig. 12–3A) and visible (Fig. 12–3B) drusen as well as ultrasound (Fig. 12–3C) and CT (Fig. 12–3D) appearances.

How Long Does It Take True Papilledema to Develop? Most investigators have shown that it takes 1 to 7 days to develop papilledema after an acute increase in ICP.7,8 Not everyone with increased ICP develops papilledema.9 Reasons for this finding are thought to be related to differences in size of the optic canal.10 Laboratory investigations demonstrate that the first sign of papilledema is usually blurring of the disc margin by the swelling of the axons, followed by hyperemia of the disc. Swelling progresses from the upper and lower pole to the nasal margin, with the temporal margin being the last to swell.11,12

What Are the Symptoms of Papilledema? Similar symptoms characterize papilledema no matter what its cause. First, patients will often report transient visual obscurations. These are often described as a spontaneous dimming of the light in one or both eyes over seconds, often occurring without positional changes. Diplopia is another common visual complaint. Giuseffi et al.13 found that about 38% of patients with idiopathic intracranial hypertension (IIH) had diplopia. A sixth nerve palsy is the most common cause. Rarely, vertical diplopia and ophthalmoplegia have been reported.10 12 Papilledema and Idiopathic Intracranial Hypertension 285

D Figure 12–2 Common causes of pseudopapilledema. A, Crowded disc, sometimes called a “little red disc” or a hyperopic disc. B, Membranes on the disc. C, Tilted discs. D, Myelinated nerve fiber.

The most common nonvisual symptom of papilledema is headache, which is reported by more than 90% of patients with IIH. Headaches associated with high pressure are said to be holocranial, continuous, and worsened by Valsalva maneuver. Often, there may be superimposed migraine-like symptoms of photophobia, phonophobia, nausea, and vomiting. Pain can also be experienced behind the eyes as well as in the neck. Both these symptoms are thought to be caused by dilation of the dural sheath because of increased pressure.14 As noted later in the discussion of papilledema-associated headache, severity of the headache and height of the elevated ICP do not correlate.15,16 Intracranial noise, another common nonvisual symptom, may be overlooked unless the patient is queried specifically about it. On questioning by an otolar- yngologist, almost 90% of patients reported intracranial noise.17 Patients often describe the noise as whooshing, buzzing, or “wind-like.” In addition, pulsatility may be a component of the noise. On occasion, the pulsatile tinnitus can be auscultated.13 286 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 12–2 Differentiating Papilledema from Pseudopapilledema (Anomalous Discs)

Papilledema Pseudopapilledema

Symptoms Transient visual obscurations, Often none, although headache headache, tinnitus and anomalous nerves are a cause of misdiagnosis Signs Diplopia (usually sixth nerve None palsy) Family history Usually none May have family history of drusen, tilted discs, hyperopia Associated Increased intracranial pressure Maternal diabetes conditions from whatever cause Visible features Physiologic cup is usually Physiologic cup is absent present Vessels arise nasally in the disc Vessels arise from the center of the disc at the apex of the swelling Veins bifurcate normally Anomalous branching and venous trifurcations occur Peripapillary blurring of the Disc margin irregular, pigment nerve fiber layer (NFL) changes Hyperemia with capillary Absent capillary telangiectasia; dilation disc color varies from pale to hyperemic Diffuse elevation of the disc Elevation irregular; refractile bodies (drusen) Peripapillary NFL radial Occasionally see peripapillary hemorrhage subretinal hemorrhage or rare superficial hemorrhages Retinal veins dilated No retinal vein dilation Exudates if the papilledema is No exudates chronic Absent spontaneous venous SVP present pulsations (SVP)

Signs of Papilledema What signs besides the presence of disc swelling will convince the clinician that the swelling is the result of increased ICP rather than another process? First, the visual acuity is usually normal unless there has been very severe papilledema with fluid in the macula or infarction of the disc. Wall and George18 showed that only 13% of patients who presented with IIH had visual acuity worse than 20/20. In many of those cases, patients had severe visual field loss despite their normal visual acuity. If visual acuity loss is observed at presentation, and if causes for the visual loss are not readily identifiable, one should consider another cause of disc swelling such as optic neuritis. 12 Papilledema and Idiopathic Intracranial Hypertension 287

C D Figure 12–3 Disc drusen. A, Buried drusen. B, Visible drusen. C, Ultrasound of buried drusen. D, Computed tomography scan of drusen.

Looking for a relative afferent pupillary defect is important when papilledema is noted. In symmetrical papilledema without visual loss, an afferent defect should not be present. Optic neuritis or another process causing disc swelling may be the cause of an afferent defect. Assessment of visual fields is essential in the evaluation of any cause of papilledema. Because confrontational visual fields are of limited use, quantitative static perimetry (e.g., Humphrey visual field) or kinetic perimetry (Goldmann perimetry) are required. Wall and George’s18 prospective study of patients with IIH showed that more than 90% of patients with either type of perimetry had abnormalities at the time of presentation. Types of visual field abnormalities seen in papilledema, no matter what the cause, include enlarged blind spot because of a swollen disc. Other common findings include arcuate defects 288 Neuro-Ophthalmology: Blue Books of Neurology

because of loss of a nerve fiber bundle from pressure effects on the optic disc, inferior nasal constrictions, nasal steps, and nasal scotomata.19,20 The most serious defect associated with papilledema is generalized constriction and depression of the visual field. Care must be taken promptly to recognize and treat these findings to avoid permanent visual loss. Figure 12–4 shows a variety of visual field defects. Determining whether the disc swelling is the result of papilledema or another cause requires a history and full neuro-ophthalmic examination. Table 12–3 summarizes methods for differentiating papilledema from other causes of disc swelling.

How Can One Diagnose Papilledema When One Is Not Sure? Papilledema can be diagnosed purely on the appearance of the optic disc, along with the appropriate history of headache, transient visual obscurations, and/or pulsatile tinnitus. Although clinicians like to think that diagnosing papilledema is an easy matter, certain cases are not straightforward and require further testing. Sometimes the history is atypical or the disc does not have discernible swelling (stage 0-1 papilledema). In these cases, fluorescein angiography can sometimes be very helpful in making the correct diagnosis (Fig. 12–5). When looking for buried drusen and autofluorescence, papilledema is associated with “staining” and “leakage” of the disc. A “30-degree test” using standardized

Figure 12–4 A to C, Visual field testing in papilledema. 12 Papilledema and Idiopathic Intracranial Hypertension 289

TABLE 12–3 Differentiating Papilledema from Other Causes of Disc Swelling

Clinical Other Optic Disc Characteristic Papilledema Swelling

History Transient visual obscurations, Visual loss, blurred vision dimming Visual acuity Usually normal Almost always decreased Eyes Bilateral swelling Unilateral swelling Relative afferent pupillary No RAPD RAPD present if defect (RAPD) unilateral Visual field defect No defect except enlarged Visual field defect blind spot present After resolution Usually does not cause pallor Causes optic disc pallor

Figure 12–5 Fluorescein angiogram in papilledema.

A scan echography of the orbit has been shown to correlate with increased ICP.21 Ultrasound can also determine if buried drusen are present. Magnetic resonance imaging (MRI) and other techniques are often important if one suspects papilledema. Brain tumors and other space-occupying tumors can be seen. Other MRI findings can help diagnose elevated ICP; for example, one may be able to see an empty sella or dilated nerve sheaths on axial views. Magnetic resonance venography (MRV) helps exclude venous thrombosis.10 If imaging studies are normal, lumbar puncture (LP) is suggested with careful measurement of the opening pressure in the lateral decubitus position. Papilledema is usually associated with elevated pressures (>200 mm cerebrospinal fluid [CSF]). 290 Neuro-Ophthalmology: Blue Books of Neurology

Because processes such as meningitis can be associated with papilledema, CSF should be analyzed for protein, glucose, and cells.

UNUSUAL FORMS OF PAPILLEDEMA Unilateral papilledema can sometimes be difficult to diagnose because the examiner is often thinking of an optic nerve swelling process such as optic neuritis or ischemic optic neuropathy. However, clues to the diagnosis can be similar to those associated with bilateral papilledema. Transient visual obscurations in one eye only may occur. However, other symptoms such as headache and pulsatile tinnitus will be present. Acuity will usually be normal bilaterally. Visual field testing will show an enlarged blind spot in the appropriate visual field. Asym- metric papilledema is not common, nor is it rare. Wall and White22 found that 8% of IIH patients had papilledema with an asymmetry of more than two grades. Why only one disc would swell has been debated. One likely explanation is that if there is a larger subarachnoid communication from the intracranial optic nerve, papilledema is more likely to occur than if there is less communication and fluid and pressure cannot be transmitted through the optic canal. Sometimes ICP monitoring is necessary to make the diagnosis.23 Increased pressure without papilledema can occur. That a disc could be normal without swelling in the face of elevated ICP should not be surprising. When patients with documented brain tumors and increased ICP underwent intracranial monitoring, many of them did not have papilledema.24 In the laboratory Hayreh and Hayreh12 showed that despite increasing the ICP with a balloon, only 29/32 rhesus monkeys developed papilledema. He also noted that it did not suffice to have a space-occupying balloon in the enclosed cranium; to develop papilledema, the balloon had to be inflated for a long period and ICP had to be elevated to maintain intracranial hypertension and disc edema. Even in the face of documented increased ICP,papilledema can be rare. Selhorst and colleagues9 regularly examined patients with documented intracranial hypertension in an intensive care unit. They found that, despite elevated pressures documented by ICP monitoring, only 15/426 patients (3.5%) had documented papilledema. Of the 6 patients with very severely elevated ICP (>60 mm Hg), none developed papilledema even though they were observed for 3 days before they died. Similarly, Steffen and colleagues8 studied 37 continuously monitored patients with elevated ICP resulting from an acute intracranial process (trauma or hemorrhage). Despite elevated pressures and fundus examinations twice a day, no patient developed optic disc swelling if the pressure was mildly elevated at 20 to 30 mm Hg (i.e., 260 to 390 mm CSF). One out of seven patients with definitely elevated pressures of 30 to 70 mm Hg (i.e., 390 to 910 mm CSF) developed blurred disc margins, and none of 17 patients whose pressures were within normal limits for 3 days in a row developed papilledema. Steffen concluded that papilledema is actually quite rare in the setting of increased ICP. Sanders25 remarked that the highest pressure he had seen with no papilledema was 1000 mm water in a 30-year-old woman with venous sinus thrombosis. In twin peaks papilledema the swelling is mainly in the superior and inferior pole of the optic disc (Fig. 12–6). This rare, distinctive form of papilledema can be diagnostic. Gliomas involving the optic track and occasionally the chiasm can produce this type of swelling.4,26 12 Papilledema and Idiopathic Intracranial Hypertension 291

Figure 12–6 Twin peaks papilledema.

DIAGNOSING THE UNDERLYING CAUSE OF PAPILLEDEMA When papilledema is found, the next step is to make the correct diagnosis of the cause. Table 12–4 lists primary and secondary causes. An extensive history, neuro-ophthalmic examination, and testing are required. Usually MRI is the procedure of choice rather than CT because MRI visualizes the venous sinuses easily. Evaluation of a secondary cause of intracranial hypertension must include a search for venous sinus thrombosis, brain tumors, or other space-occupying lesions. As noted previously, MRI may also show signs of increased ICP (Fig. 12–7). Although ventricular size changes (“the slit ventricle”) were once thought to be associated with IIH, Jacobson and colleagues27 showed that ventricular size is similar to that of controls. Techniques, such as autotriggered elliptic centric-ordered (ATECO) MRV, help eliminate confusion about whether a sinus is truly or only artificially occluded by flow artifacts.28 Empty sella turcica, which can often be seen on sagittal and coronal MR views, has been reported to occur in up to 70% of patients with IIH.29 Conventional angiogram or venogram is occasionally necessary to exclude venous thrombosis as a cause of intracranial hypertension. Once a space-occupying mass has been excluded, diagnostic LP is essential. A relaxed patient in a lateral decubitus position with legs outstretched and the neck in a nonflexed position is crucial to measure opening pressure accurately. Fluid must be sent for routine chemistries including protein and glucose, as well as for white and red cell count. When protein is elevated, spinal cord tumor should be suspected. When glucose is abnormal, one should consider meningitis, infection, sarcoid, or vasculitis. Longer term monitoring is necessary if the diagnosis is unclear or opening pressures have been disparate. The clinician should monitor pressure with lumbar catheters or subarachnoid monitoring.30 Complications of LP, including tonsillar herniation, are rare.31 Laboratory studies may also be helpful. When conditions other than IIH are suspected, one should consider antinuclear antibody, Venereal Disease Research 292 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 12–4 Causes of Papilledema

Primary Idiopathic intracranial hypertension Secondary Nutritional Enzyme deficiency Galactokinase Antichymotrypsin 11 B hydroxylase galactosemia Cystic fibrosis Deprivational dwarfism Endocrine Corticosteroid deficiency Corticosteroid excess (Cushing’s) Thyroid disease (hypothyroid; thyroid) Replacement in hypothyroidism Pituitary disorder Adenoma (growth hormone) Acromegaly Parathyroid disease Idiopathic Hypoparathyroidism Pseudohypoparathyroidism Turner’s syndrome Adipsic hypernatremia Hematologic Anemia: iron deficiency, blood loss, pernicious anemia Polycythemia vera Paroxysmal nocturnal hemoglobinuria Idiopathic thrombocytopenia purpura Cryoglobulinemia Cryofibrinogenemia Monoclonal gammopathy Hypocomplementemic urticarial vasculitis Circulatory diseases Venous hypertension Congestive heart failure Pulmonary emphysema; chronic pulmonary hypoventilation Sleep apnea Superior vena cava obstruction Radical neck dissection Congenital cardiac disease Atrial septal defect repair Ligation of the patent ductus arteriosus Hypertensive encephalopathy Systemic lupus erythematosus Cerebrovascular malformation Subarachnoid hemorrhage Dural sinus thrombosis Spontaneous Tumor (glomus jugulare, cholesteatoma, sarcoid, metastatic, eosinophilic granuloma of the temporal bone) 12 Papilledema and Idiopathic Intracranial Hypertension 293

TABLE 12–4 Causes of Papilledema

Otogenic Hypercoaguable state Behc¸et’s syndrome Leiden factor V Protein C and S deficiency Antithrombin III deficiency Lupus anticoagulant Anticardiolipin antibody Thrombocythemia Systemic lupus erythematosus (SLE) Cryofibrinogenemia Oral contraceptive use Familial Mediterranean fever Pregnancy Infection Iatrogenic trauma Head injury Drugs Antibiotics Tetracycline Minocycline Nalidixic acid Nitrofurantoin Sulfamethoxazole Psychiatric drugs Lithium Chlorpromazine Steroids Oral contraceptives Vitamin A Vitamin D Amiodarone Etretinate Perhexiline maleate Indomethacin Phenytoin Infections Viral meningitis (Epstein-Barr, Coxsackie B) Upper respiratory infection Lyme disease Human immunodeficiency virus Poliomyelitis Acute lymphocytic meningitis Coxsackie B viral encephalitis Guillain-Barre´ syndrome Infectious mononucleosis Syphilis Dengue fever Brucella

Table continued on following page 294 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 12–4 Causes of Papilledema (Continued)

West Nile virus Cryptococcus Tuberculosis Bartonella Malaria Leptospirosis Coccidioidomycosis Parasitic disease Sandfly fever Trypanosomiasis Torulosis Neurocysticercosis Developmental disease Hydrocephalus Aqueductal stenosis Craniostenosis Neoplastic disease Leukemia Spinal cord tumors Brain tumors (gliomatosis cerebri) Lymphoproliferative disorders (Sweet’s syndrome; Castleman’s disease) Myeloma and POEMS syndrome Other Sarcoid Paget’s disease Renal—chronic uremia

POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Modified from Digre K, Corbett JJ: Idiopathic intracranial hypertension (pseudotumor cerebri: a reappraisal). Neurologist 2001;7:2–67. Johnston I, Hawke S, Halmagyi M, et al: The pseudotumor syndrome. Disorders of cerebrospinal fluid circulation causing intracranial hypertension without ventriculomegaly. Arch Neurol 1991;48:740–747.

Laboratory (VDRL), serum calcium, creatinine, cortisol testing (for Addison’s, or Cushing’s disease), parathyroid hormone testing, and thyroid testing.

NATURAL HISTORY AND VISUAL COMPLICATIONS When diagnosed properly and treated promptly, many patients with papilledema do well. Visual loss, however, is the major complication of papilledema. Corbett and colleagues32 found that in patients with IIH who were followed for 5 to 41 years, 14/57 (25%) had permanent severe visual loss. Other prospective studies have found similar results.18 Prognostic factors for papilledema-associated vision loss include long-standing disc swelling, visual field/acuity loss on the first examination, older age, African American race, male gender, systemic hypertension, increased intraocular pressures, and underlying optic disc disease such as drusen.10 In addition, higher grades of papilledema increase the risk of visual loss.22 12 Papilledema and Idiopathic Intracranial Hypertension 295

A B

C Figure 12–7 Magnetic resonance findings of increased intracranial pressure. A, The arrowhead points to the prolapse of the papilla into the globe while the arrow points to the patulous optic nerve sheath. B, An empty sella is seen most of the time in increased intracranial pressure (arrow). Excess CSF often outlines the optic nerve within the sheath in increased pressure axially (C, arrow ) and coronally (D). Several mechanisms, particularly ischemia, are responsible for visual loss. Orbital color flow Doppler studies have documented reduced blood flow in patients with papilledema.33 Vigorous treatment for systemic hypertension with papilledema can cause an ischemic insult.32 In addition, postrenal dialysis hypotension can lead to a precipitous decline. Other ischemic events such as central and branch retinal artery occlusions have complicated papilledema.34 296 Neuro-Ophthalmology: Blue Books of Neurology

Tso and Hayreh1 have proposed that pressure along the optic nerve in the subarachnoid space can also cause compressive axonal damage. An autopsy study validated this research in part; a man with visual loss from papilledema and constricted individual fields was found to have more axonal loss on the peripheral areas than on any central areas of the optic nerve.35 Genetic factors may also play a role in visual loss. A genetic contribution to the structure of the optic nerve may increase or reduce susceptibility to damage because of swelling. A smaller, crowded disc has less room to swell and may cause vision loss more easily, whereas a disc with a large cup to disc ratio has considerable room to swell and may in some way be protective. Other complications of papilledema will lead to visual loss. Subretinal neovascularization can occur with papilledema from whatever cause and lead to visual loss. This often presents with a sudden, abrupt loss of vision.36 Choroidal folds and macular edema can accompany papilledema and cause visual loss.37 Functional visual loss represents another cause of visual loss with papilledema. If this is suspected, a tangent screen at 1 and 3 m is recommended to demonstrate nonphysiologic response in the visual field.10

TREATMENT OF PAPILLEDEMA After correctly diagnosing and fully evaluating the patient, treatment of papilledema resulting from any cause is necessary. If the patient has no visual symptoms or signs, one could argue against any kind of treatment. However, if either is present, medical treatment with diuretics is usually initiated first. Their use is justified in that they reportedly reduce CSF production. Acetazolamide has been shown to treat papilledema successfully in IIH patients, with 50% to 60% reduction of CSF production.38,39 The dose required to lower pressure is between 1 to 4 g.40 Successful use of other carbonic anhydrase inhibitors such as methazolamide has been reported.10 Complications of carbonic anhydrase inhibitors include kidney stones, tingling extremities, aplastic anemia, and rashes. A sulfa allergy is not a contraindication for trying these medications.41 Other diuretics including furosemide (40 to 160 mg daily) and chlorthalidone (200 mg) have also been used with success.42,43 Other medications tried with variable success rates include glycerol, cardiac glycosides (digoxin), and octreotide (an inhibitor of growth hormone).10 Papilledema is often treated with corticosteroids, alone or in combination with diuretic therapy. Corticosteroids have been shown to be helpful in some patients with acute papilledema resulting from IIH. For many years, dexamethasone has been used to treat acute intracranial hypertension and papilledema resulting from brain tumors.44 How dexamethasone works is not completely clear; imaging studies suggest that the drug reduces the water content in the brain without changing blood flow to the tumor. Dexamethasone has been compared with high-dose methylprednisolone and found to be equally useful in reducing pressure, but methylprednisolone may have fewer side effects.45 Whichever corticosteroid is selected, it is important to keep the dose and duration to a minimum because of potentially severe pulmonary, cardiac, neurologic, and other side effects. Gradual withdrawal, or “tapering,” of corticosteroids is desirable but must be done carefully so as to minimize steroid withdrawal syndrome. Preventive measures may be successful for common steroid-associated problems such as constipation, insomnia, and appetite stimulation.44 12 Papilledema and Idiopathic Intracranial Hypertension 297

Management of papilledema-associated headache, which is the result of increased ICP,is a challenge. Many of these high-pressure headaches are bilateral (as opposed to unilateral), but the symptoms of throbbing, photophobia, phonophobia, nausea, and vomiting are indistinguishable from migraine symptoms.13 Features that help distinguish the headache include retrobulbar pain with eye movement. Stretching of the root sleeves of the dural sac causes radicular pain in the neck (48%) and shoulders, and because there is decreased CSF outflow in the intracranial cisterns, the CSF is diverted to arachnoid granulations in these sleeves. The height of the CSF pressure and the severity of the headache do not correlate with each other.15,16 The extent of headache relief following LP is sometimes used to determine if the increased pressure is the cause of the chronic headache. Some patients without elevated ICP experience relief after LP; others have a post-LP positional headache when the pressure is clearly elevated. Although these observations are consistent with International Headache Society criteria for IIH headache (Table 12–5), they are difficult to use as absolute clinical criteria. What treatment is recommended for headaches associated with intracranial hypertension? Few guidelines are currently available. Obviously, if there is an underlying cause to the increased ICP such as a brain tumor or venous thrombosis, treatment of the underlying condition is very helpful. IIH is one of the most common chronic conditions associated with increased ICP and headache. In these patients, treatment of the increased ICP with acetazolamide and

TABLE 12–5 International Headache Society Diagnostic Criteria for Headache Associated with Idiopathic Intracranial Hypertension

IHS criteria of high-pressure headache A. Progressive headache with at least one of the following characteristics and fulfills C and D: 1. Daily occurrence 2. Diffuse and/or constant (nonpulsating) pain 3. Aggravated by coughing or straining B. Intracranial hypertension fulfilling the following: 1. Alert patient with neurologic examination normal or has i. Papilledema ii. Enlarged blind spot iii. Visual field defect iv. Sixth nerve palsy 2. Increased cerebrospinal fluid (CSF) pressure (>200 mm CSF in nonobese, >250 mm CSF obese) 3. Normal CSF chemistry (low CSF protein acceptable) and cellularity 4. Intracranial disease including venous thrombosis ruled out 5. No metabolic, toxic, or hormonal cause C. Headache develops in close temporal relationship to the diagnosis of increased pressure D. Headache improves after removal of fluid to a pressure of 120 to 170 mm CSF and resolves after normalization of CSF pressure

International Headache Society. The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004;24(suppl 1):1–160. 298 Neuro-Ophthalmology: Blue Books of Neurology

furosemide has met with some success.46 Others have recommended treating the headache the same way migraine disorders are treated.14,47 Because many of these individuals have concurrent migraine, this approach does make some sense.48 Because weight gain is problematic for IIH patients, the clinician should use amitriptyline, divalproex sodium, cyproheptadine, and similar medications cautiously because of the known side effect of increased weight gain. Topiramate has been used in a few cases with success. This medication has carbonic anhydrase activity as well as an associated weight loss, a helpful side effect in IIH. Mathew and colleagues48 found that the combination of a migraine preventative and a diuretic seemed to be the best treatment of headache associated with IIH. Treatment of acute headache symptoms with nonsteroidal anti-inflammatories, aspirin, and other simple analgesics or even anti-migraine medications such as sumatriptan or ergotamine is sometimes useful.

What Is the Cause of the Headache in Intracranial Hypertension? Interestingly enough, no one knows for sure what is the cause of headache in intracranial hypertension. Researchers have artificially elevated the CSF pressure by infusing normal saline into the CSF. Frontal and temporal headaches occurred, but some study participants had no pain despite of the documented rise in CSF pressure.49 In 1943 Kunkle and colleagues50 also artificially elevated CSF pressure up to 850 mm for 2 minutes in four subjects and no headache resulted. Therefore, it is not clear if increased pressure alone can create head pain. Increased ICP associated with brain tumors may also be associated with compression of cranial nerves or innervated structures such as venous sinuses. Increased ICP associated with hydrocephalus often causes a positional headache, which is worse when lying down and better upright and which has many similarities to headaches associated with IIH.51 The cause of the headache in hydrocephalus is also not known but is thought to be stretching of the ventricles themselves. Frequent causes of chronic headache associated with ICP and normal MR imaging include IIH as discussed previously; venous thrombosis, which can look very similar to IIH but is diagnosed on MRV; and chronic meningitis. Other causes of increased pressure should be considered.

Surgical Therapy Should Be Considered When Vision Is Threatened On occasion surgical procedures are performed for increased ICP that has caused visual loss and headache. Subtemporal decompression, which was introduced in the late 19th century and early 20th century, was one of the first neurosurgical treatments for intracranial hypertension.52 Although it appeared to help headache and prevent visual loss in some patients, visual loss still occurred in up to one third.53,54 Complications from the procedure include seizure, stroke, hematoma, infection, and cosmetic changes.55 LP, although technically not a surgical therapy, has been used to treat high pressure.54,55,57 LP can be performed both to temporize the situation in visual loss and to reduce headaches. The high ICP sometimes resolves, which in fact “cures” the disorder. Occasionally, continuous lumbar drainage to lower CSF production is also helpful. Although lumbar drainage can be considered a 12 Papilledema and Idiopathic Intracranial Hypertension 299

temporary treatment, CSF pressures will return to previous levels within about 90 minutes.54 Lumboperitoneal and ventriculoperitoneal shunts, as well as other CSF diversion procedures, are used extensively to treat ICP resulting from hydrocephalus, IIH, posterior fossa meningoceles, and other causes. Shunts do succeed in treating papilledema, preventing visual loss and reducing headache in some patients. These procedures are performed by most neurosurgeons and therefore are readily available. Many reports document reduced papilledema when shunts are used to treat high pressure resulting from both IIH and venous thrombosis.10,56 In high pressures related to venous thrombosis and severe headache, placement of a shunt may be the optimal procedure.58 Although it is tempting to use these shunts for headache reduction, they have the disadvantage of frequent failures, and reoperations can be required. Burgett et al.59 reported in a series of 36 patients with IIH that more than 95% of patients had resolution of papilledema, more than 80% had resolution of headache, and almost 75% of those with visual loss experienced some improvement. However, although the majority of the shunt revisions occurred in four patients, the average number of shunts per patient was approximately 4.2. In addition to shunt failure, other complications include obstruction, which can lead to rapid visual loss; overdrain- age and intracranial hypotension; radiculopathies; infections; and acquired Chiari malformation.58,60–62 The possible consequence of a low-pressure headache replacing the high-pressure headache also must be considered.10 Optic nerve sheath fenestration was introduced by DeWecker in 1872 but really did not gain hold as a treatment for papilledema until Hayreh reintro- duced the procedure. The procedure involves making a window or slit in the optic nerve sheath to release pressure on the optic nerve head. In Hayreh’s7 original experiments in monkeys, a window made in one side relieved optic disc swelling in the other eye as well. Several large series of patients who had papilledema and underwent fenestration showed that no matter what type of surgical approach was used (lateral, medial, or superior lid crease), papilledema was relieved and headaches reduced in about 50%.63–66 This procedure is generally easy and safe to perform, the optic nerve is protected from pressure, the need for reoperation is rare, and the decompression may improve blood flow to the optic nerve head.33 However, complications do occur. Visual loss can ensue even if the procedure is successful, and visual loss from retinal artery occlusion is possible. Pupil abnormalities are common in the lateral approach. Motility disturbances often occur with the medial approach.10 Bariatric surgery has been purported to improve IIH by reducing weight. Although Sugerman et al.67 and others have documented successful treatment in their patients, these reports should not be construed as a recommended surgical procedure for papilledema. Successful weight reduction takes time, and treatment of progressive visual loss resulting from papilledema cannot be delayed. A more recently developed surgical technique, venous sinus stenting, has been reported to resolve or improve papilledema and other pressure-associated signs and symptoms in refractory cases. Potential complications of stenting include headache, hearing loss, acute subdural hematoma, and venous resteno- sis; these possible sequelae should be considered before offering this treatment option. Further studies will be needed to determine whether or not the risks of stenting outweigh the benefits.68–70 300 Neuro-Ophthalmology: Blue Books of Neurology

Primary Intracranial Hypertension

Primary intracranial hypertension, or IIH, is probably the most common cause of papilledema. Diagnostic criteria have been formulated to diagnose this condition and to separate it from secondary forms of increased ICP. Other causes must be ruled out in the primary form of this disorder. Table 12–6 provides a listing of the criteria for IIH diagnosis. IIH occurs in women of child-bearing age at a rate of about 1 in 100,000 in the general population but in almost 20 in 100,000 obese women.71 To put this prevalence rate into perspective, IIH is one third as common as multiple sclerosis, which occurs in 3 in 100,000 people in the general population,72 but in obese young women it is five times more common than multiple sclerosis. As the prevalence and incidence of obesity increases in many societies, the incidence of IIH may also be increasing.60,73 The mean age of onset is around 30 years of age.71 Although men can acquire the condition, IIH affects women eight times more often than men.71 Given the number of reports of inherited disease, there is clearly a genetic association; however, no studies have been done to date.10 The symptoms and signs of IIH are identical to those of papilledema. Although there has been no proven cause of IIH, there is speculation that the disorder is caused by decreased CSF egress through the Pacchionian granulations. Several IIH associations have been reviewed; obesity is the one that seems to appear in every study. Other associations have also been postulated and are listed in Table 12–7. Why obesity is associated with the condition is unclear; hypotheses include increased venous pressure,74 increased abdominal pressures,67 endocrine dysfunction,75 hypervitaminosis A causing interference with CSF absorption,10 and hypercoagulability.76 Clearly, obesity-related complications such as orthostatic edema and sleep apnea occur in patients with IIH.77,78 Weight loss is recommended as a vital component of treatment for this disorder in addition to the other medical and surgical options.67,79,80

TABLE 12–6 Modified Dandy Criteria for Idiopathic Intracranial Hypertension

If symptoms present, they may only reflect those of generalized intracranial hypertension or papilledema If signs present, they may only reflect those of generalized intracranial hypertension or papilledema Documented elevated intracranial pressure measured in the lateral decubitus position Normal cerebrospinal fluid composition No evidence of hydrocephalus, mass structural, or vascular lesion on magnetic resonance imaging (MRI) or contrast-enhanced computed tomography for typical patients and MRI and MR venography for all others No other cause of intracranial hypertension identified

From Friedman DI, Jacobson DM: Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002;59:1492–1495. 12 Papilledema and Idiopathic Intracranial Hypertension 301

TABLE 12–7 Associations with Idiopathic Intracranial Hypertension

1. Proven associations (meets all 4 criteria for association) Obesity, especially weight gain 2. Probable associations (meets 3 criteria but lacks case control studies) Chlordecone (Kepone) and lindane Hypervitaminosis A Uremia 3. Possible associations (meets 2 criteria) Steroid withdrawal in children Growth hormone—rapid brain growth Feeding in malnutrition Hypothyroid children receiving replacement Ketoprofen and indomethacin in Bartter’s syndrome Hypoparathyroidism Addison’s disease Uremia Tetracycline; minocycline Nalidixic acid Danazol Norplant Lithium Amiodarone Phenytoin Nitrofurantoin Ciprofloxacin Nitroglycerin Vitamin A deficiency (infants only) 4. Unsupported (meet only 1 criterion and no data to support) Menstrual irregularity Oral contraceptive use Iron deficiency anemia Vitamin A deficiency (adults) Minor head trauma Hyperthyroidism Steroid ingestion Immunization Pregnancy Menarche

Modified from Digre KB, Corbett JJ: Idiopathic intracranial hypertension (pseudotumor cerebri): A reappraisal. Neurologist 2001;7:2–67.

SECONDARY INTRACRANIAL HYPERTENSION Pseudotumor Syndrome Pseudotumor syndrome is a term introduced by Johnston in 1991 to denote the many conditions in which the symptoms, signs, and normal imaging resemble IIH.81 We suggest considering primary intracranial hypertension to be synony- mous with IIH and using the term secondary intracranial hypertension when the cause of the increased pressure is known. 302 Neuro-Ophthalmology: Blue Books of Neurology

Cerebrovenous Thrombosis Cerebrovenous thrombosis can present exactly like IIH in 37% of cases with dural venous thrombosis, with signs including papilledema, elevated ICP, and normal CSF.82 This leads us to recommend imaging of the venous sinuses to make the correct diagnosis. Usually MRV or CT venography is sufficient to exclude venous thrombosis. Occasionally, arteriography is required. If thrombosis is found, a search for the cause is necessary (Table 12–4). Because papilledema in venous thrombosis can often be severe, aggressive evaluation and treatment may be needed to prevent blindness.83 In addition to instituting therapeutic anticoagulation, treating the papilledema-related visual loss with diuretics may be helpful. Surgical procedures such as optic nerve sheath fenestration and/or ventriculo- lumbar-peritoneal shunting may be required.

Brain Tumor Any space-occupying lesion in the brain has the ability to increase ICP and cause papilledema. Thus, it is amazing that not all tumors in the brain cause papilledema. Only 50% to 60% of adults and 38% of children with documented brain tumors and increased ICP have been found to have papilledema.24,84 Hayreh and Hayreh12 documented similar findings in the laboratory. When papilledema is present, we insist on imaging to look for space-occupying lesions. Obviously, treating the underlying tumor by surgical excision, radiation, or other methods also treats the tumor-associated papilledema, but the same principles of following and treating papilledema associated with other conditions apply in this setting.

Other Malignancies In addition to causing space-occupying lesions, malignancies can be associated with papilledema in other ways. Carcinomatous and lymphomatous meningitis can present with signs and symptoms almost identical to those of primary intracranial hypertension.85,86 Leukemia may infiltrate the optic nerve and meninges to produce intracranial hypertension.87 Spinal tumors can also cause papilledema, although this is very difficult to diagnose unless the spinal canal is imaged. Many present identically to primary intracranial hypertension, although perhaps with slightly or greatly elevated CSF protein levels.88 Malig- nancy can also be associated with papilledema in gammopathies such as myeloma, or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes).89

Hydrocephalus Hydrocephalus especially in its acute form, behaves similarly to other space- occupying lesions. Hydrocephalus is generally defined as increased ICP caused by an increase of fluid within the brain. A variant is compensatory hydrocephalus, in which the fluid increase exists but there is no increased ICP. Hydrocephalus can develop by overproduction of CSF (e.g., by a choroid plexus papilloma), by aqueductal stenosis (one of the most common causes), and by decreased CSF absorption through arachnoid granulations (e.g., from subarachnoid hemorrhage 12 Papilledema and Idiopathic Intracranial Hypertension 303

or from spinal tumors that cause elevated CSF protein levels).51 Hydrocephalus can be either noncommunicating (caused by tumors or aqueductal stenosis) or communicating (where blockage is actually distal to the ventricular system, such as after subarachnoid hemorrhage). Usually, the communicating form has the slower rate of ventricular dilatation.90 In addition to papilledema, other neuro-ophthalmic and neurologic signs that can accompany hydrocephalus include sixth nerve palsy, midbrain compression by the third ventricle, gait instability,incontinence, and cognitive changes. Patients have been known to have chronic hydrocephalus without documented papilledema.51 The same general principles for following patients with papilledema pertain to hydrocephalus associated papilledema.

Medications Although no medication has unequivocally caused intracranial hypertension, there are many instances in which taking a medication was associated with intracranial hypertension and discontinuing it stopped the high pressure. Although some medications such as tetracycline and minocycline have often been associated with IIH,91 others have rarely if ever been reported, and the reporting may have preceded the era of modern imaging. In evaluating any medication for possible association with intracranial hypertension, one should consider whether the medication was associated with the condition and if stopping the medication brought remission. In addition, one should determine whether restarting the medication brought about signs of intracranial hypertension, and if a controlled trial demonstrates evidence of an association. Table 12–8 has a review of medications and proposed mechanisms for ICP.

Increased Venous Pressures and Cardiopulmonary Disease Increased venous pressures have long been known to cause intracranial hypertension. In 1934 Friedfeld and Fishberg92 reported a linear relationship between venous and CSF pressure. The cause-and-effect relationship between increased venous pressures and intracranial hypertension can manifest itself in development of papilledema associated with acute and chronic and respiratory failure, as well as with congestive heart failure.93,94 When the underlying disease is treated successfully, the venous pressures subside and the papilledema resolves.

Growth Disorders Achondroplasia is an example of a growth disorder associated with papilledema. This autosomal dominant condition results in short stature and an abnormally large head. Hydrocephalus, venous stenosis, and associated narrowed spinal cord and canal have been postulated as mechanisms for increased pressure.95 Treatment of growth disturbances with growth hormone has also resulted in intracranial hypertension.96

Nutritional Disorders Many cases of increased ICP in conjunction with papilledema have been reported as a consequence of hypervitaminosis A. Within 6 months of stopping 304 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology:

TABLE 12–8 Medications Reported to Cause Intracranial Hypertension

Strength of Medication Type of Association Proposed Mechanism Association* Reference

Vitamin A and its Elevated serum vitamin A and Alteration of egress through þþþ derivatives CSF related to increased ICP granulations Antibiotics The “cyclines” Use of the cyclines associated Alteration of absorption þþþ 91, 97–99 Tetracycline with increased ICP mechanism by affecting Minocycline cyclic adenosine Doxycycline monophosphate at the arachnoid granulation Nalidixic acid Use of drug associated with Unknown mechanism þþþ 99 increased ICP, mainly in children Fluoroquinolones Use of drug associated with ICP Drug is similar to nalidixic acid þþ 100 (e.g., ciprofloxacin) Sulfamethoxazole Drug associated with ICP Unknown mechanism þ 101 Nitrofurantoin Use of the drug associated with Unknown mechanism þþ 102 ICP Psychiatric drugs Lithium Use associated with ICP Adverse affect on Na-K pump þþþ 103 creating intracellular edema Chlorpromazine, Use associated with ICP Unknown þ 104 imipramine, thioridazine, phenothiazine Steroids Corticosteroids Withdrawal associated with Unknown effect, may have to þþ 105 ICP; rare reports of steroids do with fluid balance themselves associate with ICP Growth hormone Use associated with ICP; Associated with fluid retention; þþþ 106 also insulin-like perhaps more frequent in possible insulin-like growth growth factor children with renal disease factor affect on increasing

production in the choroid 12 plexus þ

Oral Use associated with increased Possibly related to increased 107 Hypertension Intracranial Idiopathic and Papilledema contraceptives ICP weight gain Levonorgestrel Use associated with ICP Weight gain þ 10 Danazol Use associated with ICP; both Weight gain; change in þ 10 IIH and venous thrombosis coagulation? Leuprorelin Associated with ICP Unknown þ 108 (Lupron) Stanazol and Associated with ICP Unknown—weight gain? þ 10 anabolic steroids Other drugs Oxytocin Associated with ICP Unknown þ 109 Amiodarone Associated with ICP but also Unknown þ 110 AION Perhexiline Associated with ICP; used for Unknown þ 111 maleate angina Phenytoin Associated with ICP Unknown þ 112 Nitroglycerin Associated with ICP Increased blood volume þ 113 þ 114

Table continued on following page 305 306 er-ptamlg:Bu ok fNeurology of Books Blue Neuro-Ophthalmology:

TABLE 12–8 Medications Reported to Cause Intracranial Hypertension (Continued)

Strength of Medication Type of Association Proposed Mechanism Association* Reference

Ketoprofen, Associated with ICP in Bartter’s Alteration in Na-K indomethacin syndrome ATPase pump Cyclosporine Associated with ICP Unknown þ 115 Cytosine Associated with ICP Unknown þ 116 arabinoside Toxins Chlordecone and Toxins associated with ICP Inhibition of the Na-K þþ 117, 118 lindane ATPase pump action

AION, anterior ischemic optic neuropathy; CSF, cerebrospinal fluid; ICP, intracranial pressure; IIH, idiopathic intracranial hypertension. *Strength: Medication associated with ICP (þ); withdrawing medication improves (þþ); restarting worsens (þþþ); clinical trial shows association (þþþþ). 12 Papilledema and Idiopathic Intracranial Hypertension 307

excess vitamin A ingestion, the papilledema resolves. Intracranial hypertension in association with papilledema has also been reported as a complication of parenteral hyperalimentation and during implementation of catch-up nutritional interventions instituted after diagnosis of nonorganic failure to thrive. Increased ICP and papilledema have been observed in patients with the eating disorder bulimia; nutritional deprivation could have been a contributing factor.10

Endocrine Disease Associations of endocrinologic factors with increased ICP have been studied, but they have not been as well characterized as have other, more conclusively documented associations. Increased ICP with concurrent papilledema has been observed in patients with hypoparathyroidism, although thus far, no mechanisms have been suggested for this observation. No studies have shown that hypothyroidism or hyperthyroidism causes increased ICP. Papilledema in association with both Addison’s disease and Cushing’s disease has been reported; but further evaluation is necessary to understand the possible links between these endocrine disorders and increased ICP.10

Infections Table 12–4 lists infections associated with ICP and papilledema. The mechanism by which these cause intracranial hypertension has been postulated to be meningitis; alternatively, infections can be associated with venous thrombosis and inflammation. Successful treatment of the infection is the key to papilledema resolution. However, many other causes of visual loss associated with infection will not respond to traditional therapy for papilledema. For example, inflammation around the nerve can lead to infarction or optic neuritis and visual loss. Treatment of such cases requires careful consideration.

Acknowledgment I acknowledge the assistance of Susan Schulman with the preparation of this chapter.

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63. Corbett JJ, Nerad JA, Tse DT, et al: Results of optic nerve sheath fenestration for pseudotumor cerebri. The lateral orbitotomy approach. Arch Ophthalmol 1988;106:1391–1397. 64. Goh KY, Schatz NJ, Glaser JS: Optic nerve sheath fenestration for pseudotumor cerebri. J Neuro-Ophthalmol 1997;17:86–91. 65. Sergott RC, Savino PJ, Bosley TM: Modified optic nerve sheath decompression provides long-term visual improvement for pseudotumor cerebri. Arch Ophthalmol 1988;106: 1384–1390. 66. Spoor TC, McHenry JG: Long-term effectiveness of optic nerve sheath decompression for pseudotumor cerebri. Arch Ophthalmol 1993;111:632–635. 67. Sugerman HJ, Felton WL 3rd, Salvant JB Jr, et al: Effects of surgically induced weight loss on idiopathic intracranial hypertension in morbid obesity. Neurology 1995;45:1655–1659. 68. Friedman DI: Cerebral venous pressure, intra-abdominal pressure, and dural venous sinus stenting in idiopathic intracranial hypertension. J Neuro-Ophthalmol 2006;26:61–64. 69. Owler BK, Parker G, Halmagyi GM, et al: Pseudotumor cerebri syndrome: Venous sinus obstruction and its treatment with stent placement. J Neurosurg 2003;98:1045–1055. 70. Brazis P: Pseudotumor cerebri. Curr Neurol Neurosci Rep 2004;4:111–116. 71. Durcan FJ, Corbett JJ, Wall M: The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana. Arch Neurol 1988;45:875–877. 72. Wynn D, Rodriguez M, O’Fallon M, et al: A reappraisal of the epidemiology of multiple sclerosis in Olmsted County, Minnesota. Neurology 1990;40:780–786. 73. Skau M, Brennum J, Gjerris F, et al: What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalalgia 2006;26:384–399. 74. Karahalios DG, Rekate HL, Khayata MH, et al: Elevated intracranial venous pressure as a universal mechanism in pseudotumor cerebri of varying etiologies. Neurology 1996;46:198–202. 75. Greer M: Benign intracranial hypertension. VI. Obesity. Neurology 1965;15:382–388. 76. Glueck C, Aregawi D, Goldenberg N, et al: Idiopathic intracranial hypertension, polycystic- ovary syndrome, and thrombophilia. J Lab Clin Med 2005;145:72–82. 77. Friedman D, Streeten D: Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis. Neurology 1998;50:1099–1104. 78. Marcus DM, Lynn J, Miller JJ, et al: Sleep disorders: A risk factor for pseudotumor cerebri? J Neuro-Ophthalmol 2001;21:121–123. 79. Kupersmith M, Gamell L, Turbin R, et al: Effects of weight loss on the course of idiopathic intracranial hypertension in women. Neurology 1998;50:1094–1098. 80. Johnson L, Krohel G, Madsen R, et al: The role of weight loss and acetazolamide in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Ophthalmology 1998;105:2313–2317. 81. Johnston I, Hawke S, Halmagyi M, et al: The pseudotumor syndrome. Disorders of cerebrospinal fluid circulation causing intracranial hypertension without ventriculomegaly. Arch Neurol 1991;48:740–747. 82. Biousse V, Ameri A, Bousser MG: Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology 1999;53:1537–1542. 83. Cunha LP, Goncalves AC, Moura FC, et al: [Severe bilateral visual loss as the presenting sign of cerebral venous sinus thrombosis: Case report]. Arq Bras Oftalmol 2005;68:533–537. 84. Wilne SH, Ferris RC, Nathwani A, et al: The presenting features of brain tumours: A review of 200 cases. Arch Dis Child 2006;91:502–506. 85. Allen RS, Sarma PR: Pseudotumor cerebri: Meningeal carcinomatosis presenting as benign intracranial hypertension. South Med J 1987;80:1182–1183. 86. Bruna J, Martinez-Yelamos S, Alonso E, et al: Meningeal lymphomatosis as the first manifestation of splenic marginal zone lymphoma. Int J Hematol 2005;82:63–65. 87. Reddy SC, Menon BS: A prospective study of ocular manifestations in childhood acute leukae- mia. Acta Ophthalmol Scand 1998;76:700–703. 88. Porter A, Lyons MK, Wingerchuk DM, Bosch EP: Spinal cord astrocytoma presenting as “idiopathic” intracranial hypertension. Clin Neurol Neurosurg 2006;108:787–789. 89. Wong VA, Wade NK: POEMS syndrome: An unusual cause of bilateral optic disk swelling. Am J Ophthalmol 1998;126:452–454. 90. Pollay M: Research into human hydrocephalus: A review. In Shapiro K, Marmarou A, Portnoy H (eds): Hydrocephalus. New York, Raven Press, 1984, pp 301–314. 91. Digre KB: Not so benign intracranial hypertension. BMJ 2003;326:613–614. 92. Friedfeld L, Fishberg A: The relation of the cerebrospinal and venous pressures in heart failure. J Clin Invest 1934;13:495–501. 12 Papilledema and Idiopathic Intracranial Hypertension 311

93. Stevens P, Austen K, Knowles J: Prognostic significance of papilledema in course of respiratory insufficiency. JAMA 1963;183:161–164. 94. Pye I, Blandford R: Papilloedema associated with respiratory failure. Postgrad Med J 1977;53: 704–709. 95. Landau K, Gloor BP: Therapy-resistant papilledema in achondroplasia. J Neuro-ophthalmol 1994;14:24–28. 96. Maneatis T, Baptista J, Connelly K, et al: Growth hormone safety update from the National Cooperative Growth Study. J Pediatr Endocrinol Metab 2000;13(suppl 2):1035–1044. 97. Chiu AM, Chuenkongkaew WL, Cornblath WT, et al: Minocycline treatment and pseudotumor cerebri syndrome. Am J Ophthalmol 1998;126:116–121. 98. Gardner K, Cox T, Digre KB: Idiopathic intracranial hypertension associated with tetracycline use in fraternal twins: Case reports and review. Neurology 1995;45:6–10. 99. Mukherjee A, Dutta P, Lahiri M, et al: Benign intracranial hypertension after nalidixic acid overdose in infants. Lancet 1990;335:1602. 100. Winrow AP, Supramaniam G: Benign intracranial hypertension after ciprofloxacin administration. Arch Dis Child 1990;65:1165–1166. 101. Jain N, Rosner F: Idiopathic intracranial hypertension: Report of seven cases. Am J Med 1992;93:391–395. 102. Griffin JP: A review of the literature on benign intracranial hypertension associated with medication. Adverse Drug React Toxicol Rev 1992;11:41–57. 103. Saul RF, Hamburger HA, Selhorst JB: Pseudotumor cerebri secondary to lithium carbonate. JAMA 1985;253:2869–2870. 104. Blumberg A, Klein D: Severe papilledema associated with drug therapy. Am J Psychiatry 1961;118:168–170. 105. Liu GT, Glaser JS, Schatz NJ: High-dose methylprednisolone and acetazolamide for visual loss in pseudotumor cerebri. Am J Ophthalmol 1994;118:88–96. 106. Malozowski S, Tanner LA, Wysowski D, et al: Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Engl J Med 1993;329:665–666. 107. Soysa ND: The oral contraceptive pill and benign intracranial hypertension. N Z Med J 1985;98:656. 108. Arber N, Shirin H, Fadila R, et al: Pseudotumor cerebri associated with leuprorelin acetate. Lan- cet 1990;335:668. 109. Mayer-Hubner B: Pseudotumour cerebri from intranasal oxytocin and excessive fluid intake. Lancet 1996;347:623. 110. Fikkers BG, Bogousslavsky J, Regli F, et al: Pseudotumor cerebri with amiodarone. J Neurol Neurosurg Psychiatry 1986;49:606. 111. Gibson JM, Fielder AR, Garner A, et al: Severe ocular side effects of perhexilene maleate: Case report. Br J Ophthalmol 1984;68:553–560. 112. Kalanie H, Niakan E, Harati Y, et al: Phenytoin-induced benign intracranial hypertension. Neurology 1986;36:443. 113. Ohar JM, Fowler AA, Selhorst JB, et al: Intravenous nitroglycerin-induced intracranial hypertension. Crit Care Med 1985;13:867–868. 114. Larizza D, Colombo A, Lorini R, et al: Ketoprofen causing pseudotumor cerebri in Bartter’s syndrome. N Engl J Med 1979;300:796. 115. Cruz OA, Fogg SG, Roper-Hall G: Pseudotumor cerebri associated with cyclosporine use. Am J Ophthalmol 1996;122:436–437. 116. Evers JP, Jacobson RJ, Pincus J, et al: Pseudotumour cerebri following high-dose cytosine arabinoside. Br J Haematol 1992;80:559–560. 117. Koch RB: Chlorinated hydrocarbon insecticides: Inhibition of rabbit brain ATPase activities. J Neurochem 1969;16:269–271. 118. Sanborn GE, Selhorst JB, Calabrese VP, et al: Pseudotumor cerebri and insecticide intoxication. Neurology 1979;29:1222–1227. 13 Acquired Ocular Motility Disorders and Nystagmus JANET C. RUCKER

Introduction Supranuclear Ocular Motility Control Clinical Approach and Diagnostic Tools Abnormal Spontaneous Eye Movements Ophthalmoparesis Nystagmus Extraocular Muscles Saccadic Intrusions The Neuromuscular Junction Cranial Nerve Palsies References Brainstem Disorders

Key Points Eye movement disorders may be considered in two categories: those that cause incomplete eye movements (ophthalmoparesis) and those that cause excessive eye movements (saccadic intrusions and nystagmus). Central to an understanding and correct diagnosis of abnormal eye movements is the evaluation of ocular alignment, ocular motility, and each functional class of eye movements: optokinetic, vestibular, vergence, smooth pursuit, and saccades. Ophthalmoparesis is caused by dysfunction of extraocular muscles, the neuromuscular junction, cranial nerves, cranial nerve nuclei, and internuclear and supranuclear connections. The initial pathologic eye movement in nystagmus is a slow drift of the eye away from the desired position, whereas the initial pathologic eye movement in saccadic intrusions is an inappropriate saccade that intrudes on fixation. Identification of the characteristics of nystagmus (physiologic versus pathologic, jerk versus pendular) is necessary for diagnostic evaluation and treatment.

Introduction

The goal of all normal eye movements is to place and maintain an object of visual interest on each fovea simultaneously to allow visualization of a stable, single object. Any deviation from normal eye movements may degrade vision. The spectrum of ocular motility disorders ranges from absent or inadequate 312 13 Acquired Ocular Motility Disorders and Nystagmus 313

ocular motor function (ophthalmoplegia or ophthalmoparesis) to excessive ocular motor function (spontaneous eye movements). This chapter is divided into three sections; the first details those aspects of the history and examination required for an accurate diagnosis of abnormal ocular motility, the second concerns acquired disorders of ophthalmoparesis, and the third concerns acquired abnormal spontaneous eye movements.

Clinical Approach and Diagnostic Tools

Ophthalmoparesis results in ocular misalignment; hence an object of visual interest falls on the fovea in one eye and on an extrafoveal location in the other eye, leading to the subjective appreciation of binocular diplopia (Fig. 13–1). When there are abnormal spontaneous eye movements, illusory motion of the visual world (oscillopsia) occurs if the subjective experience of retinal motion is in excess of that normally tolerated by the visual system (up to about 5 degrees per second for Snellen optotypes).1 An understanding of the nature and pathophysiology of these symptoms allows the correct identification and localization of an ocular motility disorder. Binocular diplopia may result from dysfunction of extraocular muscles, the neuromuscular junction, cranial nerves, cranial nerve nuclei, and internuclear and supranuclear connections. Oscillopsia may result from nystagmus and saccadic intrusions. When diplopia is present, it is essential to determine if the diplopia resolves with covering each eye in turn (binocular diplopia). If it persists with monocular covering (monocular diplopia), it is not attributable to ocular misalignment but rather to refractive error or other ocular causes.2–4 It should be determined if binocular diplopia is horizontal, vertical, or oblique; worse in a particular direction of gaze; and worse at distance or near. Horizontal diplopia is caused by impaired abduction or adduction and vertical diplopia by impaired elevation

Figure 13–1 Fixation with normal ocular alignment is represented by solid black lines. An image of the feather falls on each fovea simultaneously and a single object is seen. Binocular diplopia, which develops with an ocular misalignment (lateral deviation of the right eye as depicted by the dashed arrow), occurs because the image of the feather falls on an extrafoveal location in the deviated right eye (dashed lines). (Adapted from Leigh RJ, Zee DS: The Neurology of Eye Movements, 3rd ed. Oxford, Oxford University Press, 1999, p 337.) 314 Neuro-Ophthalmology: Blue Books of Neurology

or depression. Worsening diplopia in a particular gaze direction suggests that motility in that direction is impaired. The temporal course of the diplopia and any associated neurologic symptoms should be assessed; proximal muscle weakness, difficulty swallowing, and shortness of breath, for example, suggest neuromuscular dysfunction, and a deterioration of monocular vision and proptosis suggest an orbital process. These historical features are also important in the evaluation of patients with oscillopsia and spontaneous eye movements. The neurologic and visual systems should be carefully examined in all patients with diplopia, ophthalmoparesis, oscillopsia, or abnormal spontaneous eye movements.5 The eye movement examination should include an assessment of ocular alignment and motility, as described in Chapter 1 (Fig. 13–2). In addition, stability of gaze fixation should be assessed with the eyes close to central position, viewing near and far targets, and at eccentric gaze angles. Prolonged observation for up to 2 minutes is necessary, as some types of nystagmus periodically change direction. Observation of the effect of removal of fixation on eye stability is also important, as nystagmus caused by peripheral vestibular dysfunction may only be visible under this circumstance. This can be achieved by transient coverage of the fixating eye during ophthalmoscopy in a dark room. Each functional class of eye movements should be examined in both horizontal and vertical directions. Optokinetic nystagmus occurs reflexively during self- rotation and can be elicited at the bedside with visual tracking of an optokinetic drum or tape with alternating black-and-white vertical stripes. It consists of slow tracking, smooth pursuit movements alternating with quick resetting saccadic movements.6 Vestibular eye movements hold an image steady on the fovea by means of compensatory eye movements during brief, nonsustained head movements, such as during walking. These eye movements may be evaluated clinically with passive head thrusts during which the examiner applies a low- amplitude, high-acceleration head rotation while the patient fixates a target.7,8 If vestibular function is normal, the patient will maintain fixation of the target during and after the head movement. If vestibular function is impaired, the patient will not be able to maintain fixation and a corrective saccade back to the target is seen following the head rotation. Examiner-applied passive head thrusts are more sensitive than patient-initiated active head thrusts for identifying vestibular dysfunction.9 Vergence eye movements consist of disconjugate convergent and divergent eye movements that maintain stability of a visual image during near and far gaze shifts. Smooth pursuit is a slow eye movement

A Figure 13–2 Corneal light reflection test. A, Normal ocular alignment—a light shined in the center of one pupil B falls in the center of the other pupil. B, Exotropia—a light shined in the center of one pupil falls medial to the pupil C, center in the other eye. Esotropia—a light shined in C the center of one pupil falls lateral to the pupil center in the other eye. D, Right hypertropia—a light shined in the center of the pupil in the left eye falls below the pupil center in the right eye. D 13 Acquired Ocular Motility Disorders and Nystagmus 315

(velocity 20 to 50 degrees/second), which functions to hold the image of a moving target steady on the fovea and which can be assessed by having the patient follow a slowly moving target. Saccades are fast eye movements (velocity 300 to 500 degrees/second) that rapidly shift gaze to place an object of visual interest on the fovea.10 Saccades present a challenging task to the brain, as their execution requires a sudden, intense neural discharge to effect a high-velocity eye movement and to overcome the elastic, damping orbital pull of extraocular muscles and suspensory ligaments.10 This intense neural discharge is provided by brainstem neurons called burst neurons.

Ophthalmoparesis

EXTRAOCULAR MUSCLES Thyroid ophthalmopathy is typically painless and bilateral, although it may be asymmetric. It tends to affect the inferior and medial rectus muscles first, leading to restrictions of elevation and abduction. Although it is useful to obtain thyroid function studies (thyroid-stimulating hormone, triiodothyronine, and thyroxine), it may be associated with hyperthyroid, hypothyroid, or euthyroid states. Thyroid-stimulating antibodies correlate with the presence of thyroid eye disease and can be an important disease marker in the setting of a serologic euthyroid state.11–13 Orbital computed tomography (CT) or magnetic resonance imaging (MRI) scans demonstrate enlargement of involved extraocular muscle bodies with relative sparing of muscle tendon insertions at the globe (Fig. 13–3A). Coronal images are best, because muscle enlargement may be underestimated if only axial images are acquired. Treatment options include corticosteroids, radiation, and orbital decompression surgery, as discussed in Chapter 3. Discontinuation of smoking should be strongly advised, as smoking may worsen thyroid ophthalmopathy and lessen treatment effect.14,15 Orbital pseudotumor is typically painful and unilateral. Any extraocular muscle may be involved; orbital CT or MRI scans demonstrate enlargement of

Figure 13–3 A, Axial T1-weighted magnetic resonance imaging scan with gadolinium showing enlargement of the extraocular muscles from thyroid eye disease. Involvement is asymmetric, with greater muscle enlargement in the left orbit than in the right. Muscle tendon insertions at the globe are relatively spared. B, Contrast-enhanced computed tomography scan showing enlargement of the left medial rectus muscle body and muscle tendon insertion from orbital pseudotumor. 316 Neuro-Ophthalmology: Blue Books of Neurology

involved extraocular muscle bodies and muscle tendon insertions at the globe (Fig. 13–3B), in contrast to that seen in thyroid ophthalmopathy, in which there is sparing of the tendon insertions (Fig. 13–3A). The posterior sclera and orbital fat may also be radiographically abnormal. Spontaneous resolution is common. Nonsteroidal anti-inflammatory medications and steroids relieve pain, hasten recovery, and decrease the risk of recurrence.16 Infiltration by amyloid or infections and inflammation in sarcoidosis and Wegener’s granulomatosis may also cause this phenotype. Lymphoid malignancies are the most common orbital neoplasms.17 Metastasis of other neoplasms to extraocular muscles is rare. Orbital disease is covered in detail in Chapter 3. Chronic progressive external ophthalmoplegia (CPEO) causes a slowly progressive, bilateral, symmetric ocular immobility and bilateral ptosis. The pupils are not affected, but the orbicularis oculi typically is. Characteristically the saccadic velocities are reduced throughout the movement, making it more easily differentiated from neuromuscular junction disorders. The extraocular muscles are sometimes seen to be atrophic on orbital imaging. Patients are often asymptomatic because of the slowly progressive, bilateral nature of the disease. Mito- chondrial genetic defects are the most common etiology, in which deletions or duplications arise. The phenotype may occur on its own or with cardiac problems and retinitis pigmentosa and other disorders such as Kearns-Sayre syndrome. It may also arise within a myodonic epilepsy with ragged red fibers (MERFF) and a mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) disorder. A CPEO phenotype may also be seen in oculophar- yngeal dystrophy, myotonic dystrophy, congenital myopathies such as myotubu- lar myopathy, and in association with neuropathies such as Refsum’s and Stephen’s syndromes and abetalipoproteinemia.

THE NEUROMUSCULAR JUNCTION Myasthenia gravis (MG) is the most common disease of the neuromuscular junction. Ocular motility dysfunction in MG can mimic nearly any abnormal eye movement; it may resemble internuclear ophthalmoplegia, cranial nerve or nuclear palsies, but the pupil is only very rarely involved. Features strongly suggestive of neuromuscular junction impairment include moment to moment or visit to visit variability in ocular motility, eyelid or extraocular muscle fatigue with prolonged upgaze, Cogan’s lid twitch, the peek sign, orbicularis oculi weakness, ptosis, and enhanced ptosis.18–20 Upgaze should be maintained for at least 2 minutes to assess adequately the appearance or worsening of ptosis or impaired ability to maintain eye elevation. Cogan’s lid twitch may be seen with saccadic return of the eyes to the central position following a few seconds of sustained downgaze.18 The upper eyelid may elevate excessively, twitch, and become ptotic again. The peek sign is positive when prolonged eye closure allows orbicularis oculi weakness to cause lid separation and globe exposure, despite initial complete eye closure.19 Enhanced ptosis is seen when ptosis in a less or nonptotic eyelid increases on manual elevation of the more ptotic lid.20 This phenomenon is based on Hering’s law of equal neural innervation to both eyelids; when maximal innervation is applied to a severely ptotic lid in an attempt to hold it open, the same maximal innervation may minimize the appearance of ptosis in a contralateral less or nonptotic lid. Manual elevation of the more 13 Acquired Ocular Motility Disorders and Nystagmus 317

Figure 13–4 Enhanced ptosis. A, At rest, the left eyelid exhibits significant ptosis. B, Manual elevation of the left eyelid results in increased ptosis of the right eyelid. ptotic lid decreases the innervation of both lids, allowing the contralateral lid to become more ptotic (Fig. 13–4). Another phenomenon attributable to Hering’s law is that of lid retraction in the eye contralateral to a ptotic lid. Frontalis overactivity resulting from the attempt to hold ptotic lids open is often seen. A positive edrophonium chloride test (Fig. 13–5) provides diagnostic support for MG.21 It is most useful when there is a defined deficit such as significant ptosis or a fixed ocular motility defect that may be monitored for improvement. Edrophonium chloride is a reversible acetylcholinesterase inhibitor that decreases breakdown of acetylcholine in the synaptic cleft, thereby improving neuromuscular transmission. Sensitivity and specificity of the edrophonium test in the setting of ocular MG are 60% to 80% and 86%,22,23 respectively. Rare potential test risks include cardiac arrhythmias, syncope, respiratory failure, and seizures; however, this risk is approximately 0.16%.24 In one series a mean dose of only 3.3 mg edrophonium resulted in improvement of ptosis or an ocular motility defect, thereby minimizing test risk.25 The ice pack test is an alternative to the edrophonium test; an ice pack is lightly placed over a closed ptotic eye for 2 minutes, followed by observation for improvement of ptosis. The premise of this test is that neuromuscular transmission is improved by cold temperatures.26 Sensitivity is as high as 80% when partial ptosis is present but may be lower with complete ptosis.27 Acetylcholine receptor antibodies consist of three types: binding, blocking, and modulating. In generalized MG, binding and modulating antibodies have a prevalence of 89% and blocking antibodies of 52%28; in ocular MG it is lower at 50%. Although anti-muscle specific receptor tyrosine kinase (anti-MuSK) 318 Neuro-Ophthalmology: Blue Books of Neurology

EDROPHONIUM TEST METHOD 1. Identify an examination parameter to observe for improvement after edrophonium administration.

2. Establish IV access.

3. Prepare edrophonium (10 mg in 1 cc syringe), 1 mg atropine, saline flush (10 cc), blood pressure and heart rate monitoring equipment, video camera (optional).

4. Inject 1 mg edrophonium test dose, flush IV, observe for improvement or side effects for 1 minute.

5. Monitor blood pressure and heart rate.

6. Repeat steps 4 and 5 every 1–2 minutes until Figure 13–5 Edrophonium test improvement of chosen parameter, side effects, method for diagnosis in myasthenia or 10 mg of edrophonium administered. gravis.

antibodies are positive in some patients previously considered to have seronegative generalized MG, they are only rarely associated with ocular MG.29–32 A 20% or greater decrement of the compound muscle action potential with repetitive suprathreshold stimulation has a sensitivity of only 42% in ocular MG,33 but the diagnostic yield is increased with single-fiber electromyogram, with up to 100% sensitivity.33 Standard treatments for MG include the long-acting acetylcholinesterase inhibitor pyridostigmine, corticosteroids, and steroid-sparing immunosup- pressive agents such as azathioprine and mycophenolate mofetil.34,35 Pyridostig- mine is primarily used for symptom relief, whereas the others provide treatment of the underlying disease process. In ocular MG, pyridostigmine is more effective for ptosis than for diplopia.36 Corticosteroids are highly effective for both ptosis and diplopia and may successfully render the patient asymptomatic. There is some evidence that they may also diminish the risk of progression of ocular MG to generalized MG.25,36 Botulism results from exposure to an anticholinergic toxin produced by Clostridium botulinum. Exposure is acquired by ingestion of toxin in contaminated food; from wound infections; and, in infants, from gastrointestinal production of toxin. The clinical features are of a subacute ophthalmoparesis with pupillary involvement, particularly paralysis of accommodation, and muscle weakness without sensory loss elsewhere. It is said to be difficult to distinguish from ophthalmoplegia from MG; however, pupillary light-near dissociation and impaired accommodation are common with botulism. Ocular motility is rarely affected with the Lambert-Eaton myasthenic syndrome, a presynaptic neuromuscular junction disorder caused by voltage-gated calcium channel antibodies. The clinical features are of autonomic disturbances, ptosis, and pupillary light-near dissociation in association with weakness elsewhere.37 The disorder may be paraneoplastic but can also occur independently. 13 Acquired Ocular Motility Disorders and Nystagmus 319

CRANIAL NERVE PALSIES Third Nerve Palsy (Oculomotor Nerve) The oculomotor nerve innervates the medial, inferior, and superior recti muscles; the inferior oblique muscle; the levator palpebrae superioris; the pupillary sphincter muscle; and the ciliary body.38,39 Identification of a complete third nerve palsy is typically straightforward on examination, when there is ptosis, an eye that is deviated “down and out,” and a dilated pupil. Elevation, depression, and adduction of the eye are impaired. Identification of a partial third nerve palsy can be more challenging, especially if the pupil is spared. Although a lesion anywhere along the oculomotor nerve pathway may result in third nerve dysfunction, the two most common causes are compression of the nerve by a posterior communicating artery aneurysm within the subarachnoid space and microvascular ischemia. Lesions of the third nerve fascicle in the brainstem, cavernous sinus, and superior orbital apex are readily localized when nearby structures are also involved. Meningeal infiltration of the cavernous sinus or superior orbital apex by infectious, neoplastic, or autoimmune processes and compression of the third nerve by an internal carotid artery aneurysm within the cavernous sinus are common diagnostic considerations. Hemorrhage into a pituitary adenoma (pituitary apoplexy) may cause sudden onset unilateral or bilateral third nerve dysfunction, often accompanied by vision loss, nausea, or headache.40 Onset of a third nerve palsy following minor trauma should prompt investigation for an underlying posterior communicating artery aneurysm,41 although one may not always be found.42 Third nerve palsies may also arise in raised intracranial pressure, when the nerve is stretched as it passes across the tentorial edge. Elevation of the eyelid or constriction of the pupil during adduction or depression of the eye is suggestive of aberrant regeneration (anomalous axon innervation) (Fig. 13–6). When aberrant regeneration develops following an acute third nerve palsy, a compressive posterior communicating artery aneurysm or traumatic etiology should be considered.43 When aberrant regeneration occurs spontaneously, without a preexisting acute third nerve palsy, a cavernous sinus meningioma, or an internal carotid artery aneurysm is likely,44–46 although an unruptured posterior communicating artery aneurysm may also be responsible.47

Fourth Nerve Palsy (Trochlear Nerve) Cranial nerve IV innervates the superior oblique, which depresses the adducted eye and intorts the eye. Each trochlear nerve innervates the superior oblique contralateral to its nucleus. With a fourth nerve palsy, the affected eye is higher than the contralateral eye (hypertropia) and vertical diplopia increases with downgaze and adduction of the affected eye and reduces when a contralateral head tilt places the affected eye in an extorted position. There may be a resting head tilt in the direction away from the paretic eye. It is helpful to examine old photographs of the patient to determine if a head tilt is present, which suggests long-standing misalignment such as that seen with congenital fourth nerve dysfunction. Congenital fourth nerve palsies are relatively common and neuroimaging may not be necessary if a long-standing nature can be confirmed by history. 320 Neuro-Ophthalmology: Blue Books of Neurology

Figure 13–6 Aberrant regeneration following a traumatic left oculomotor nerve palsy. A, In central position, there is slight left ptosis and pupillary dilation. B, In right gaze, there is incomplete adduction of the left eye and increased elevation of the left eyelid.

The dorsal location of the brainstem exit near the tentorium makes the trochlear nerves particularly prone to traumatic injury, which may cause unilateral or bilateral trochlear dysfunction.48 Microvascular fourth nerve palsies are less common than microvascular third and sixth nerve palsies. Schwannomas of the fourth nerve, although very rare, are more common than those of the third and sixth nerves (Fig. 13–7).49

Figure 13–7 Axial T1-weighted magnetic resonance imaging with gadolinium showing a left fourth nerve schwannoma in the subarachnoid space. 13 Acquired Ocular Motility Disorders and Nystagmus 321

Sixth Nerve Palsy (Abducens Nerve) Cranial nerve VI innervates the lateral rectus. A sixth nerve palsy results in paresis of abduction of the ipsilateral eye and esotropia. The amount of esotropia is greatest in the direction of action of the weak muscle. The patient usually complains of binocular horizontal diplopia. As the nerve passes through Dorello’s canal,50,51 it is prone to become affected, often bilaterally, by elevations in intracranial pressure. Relatively minor head trauma may result in sixth nerve dysfunction.48 MG and restrictive medial rectus involvement in thyroid eye disease often mimic the sign of a sixth nerve palsy.

Investigation of Cranial Neuropathy Causing Diplopia Intracranial magnetic resonance angiography (MRA) or CT angiogram (CTA) is commonly obtained to evaluate for an intracranial aneurysm in the setting, for example, of an acute onset, pupil-involving third nerve palsy. Ninety-two percent of posterior communicating artery aneurysms causing third nerve palsies are larger than 5 mm.52 MRI detects aneurysms larger than 5 mm with 97% sensitivity and aneurysms smaller than 5 mm with 54% sensitivity. The rupture risk of an aneurysm less than 10 mm is 0.05% per year.53,54 Approximately 1.5% of third nerve palsy-causing aneurysms that eventually rupture may not be detected by MRA. It is often prudent to proceed with conventional intracranial angiogram to exclude an aneurysm definitively if MRA or CTA are equivocal. Gadolinium-enhanced MRI with high resolution, thin cuts through the brainstem increases diagnostic yield, especially after an aneurysm is excluded by MRA or CTA. If MRI is unremarkable, lumbar puncture may be required to assess for cerebrospinal fluid abnormalities. Acute onset of a painful, pupil- sparing third nerve palsy and sixth nerve palsy may represent microvascular ischemia to the nerve, especially in older patients with vascular risk factors.55 Spontaneous resolution over 8 to 12 weeks is typical. Investigation of the other causes noted in the table should also be undertaken.

Multiple Cranial Neuropathies Lesions at the cavernous sinus are associated with third, fourth, and sixth nerve pareses in combination with signs of involvement of the first and second divisions of the trigeminal nerve and sympathetic fibers. Primary tumors such as parasellar meningiomas, lymphoma, and pituitary adenomas and secondary tumors including nasopharyngeal carcinoma and myeloma; vascular disorders such as carotid-cavernous fistula and intracavernous internal carotid artery aneurysm; and inflammatory disorders such as Tolosa Hunt syndrome, Wegener’s granulomatosis, Rosai-Dorfman syndrome, and hypertrophic pachymeningitis may all cause cavernous sinus syndromes (Table 13-1). Lesions at the orbital apex may affect the oculomotor, trochlear, and abducens nerves in combination with the first division of the trigeminal nerve and the optic nerve. Proptosis, chemosis, and conjunctival injection are often present. Inflammation, including orbital pseudotumor and those noted previously, infection from the sphenoid and ethmoid sinuses, particularly aspergillosis and mucormycosis, and primary and secondary neoplastic disease may all cause orbital apex syndromes. 322 Neuro-Ophthalmology: Blue Books of Neurology

TABLE 13-1 Causes of Third, Fourth, and Sixth Cranial Nerve Paresis

Site Disorder

Brainstem Infarction Hemorrhage Demyelination Tumor Infection/abscess Subarachnoid Aneurysm course Meningitis, including carcinomatous and leukemic infiltration, infectious including bacteria, spirochetes, and aseptic meningitis Microvascular infarction Tumor Cavernous sinus/ Internal carotid aneurysm orbital apex Caroticocavernous fistula Pituitary lesions Meningioma Metastasis Microvascular Sphenoid and ethmoid mucoceles Tolosa-Hunt syndrome, Wegener’s granulomatosis and other inflammatory disorders Herpes zoster Orbit Trauma Infections Tumor

Multiple ocular motor nerves may be affected in Guillain-Barre´ syndrome or in the Miller-Fisher variant of Guillain-Barre´. The classic triad of Miller-Fisher syndrome is ophthalmoplegia, ataxia, and areflexia. In addition to ophthalmoplegia, pupillary light-near dissociation is common. Anti-GQ1b antibodies are present in greater than 90% of patients with Miller-Fisher syndrome and are associated with Campylobacter jejuni infections. Treatment if required is with plasma exchange or intravenous immunoglobulin, as for Guillain-Barre´ syndrome

BRAINSTEM DISORDERS Cranial Nerve Nuclei As has been noted in Chapter 1, nuclear lesions differ in clinical appearance from their corresponding cranial neuropathies. A third nerve nuclear lesion causes bilateral impairment of ocular elevation (resulting from contralateral innervation of the superior rectus) and bilateral ptosis (resulting from a single midline levator palpebrae subnucleus that innervates both levator muscles).56,57 Very rarely, a third nerve nuclear lesion may result in isolated weakness of a single muscle such as the inferior or superior rectus.58,59 A fourth nerve nuclear lesion causes a superior oblique palsy clinically similar to a fourth nerve lesion; however, the superior oblique weakness is contralateral to 13 Acquired Ocular Motility Disorders and Nystagmus 323

the nuclear lesion because of the fourth nerve decussation after dorsal emergence from the midbrain. In addition, a fourth nerve nuclear lesion is almost invariably accompanied by a Horner’s syndrome ipsilateral to the lesion because of the proximity of the preganglionic sympathetic fibers to the dorsally placed fourth nerve nucleus.60 A sixth nerve nuclear lesion causes an ipsilateral horizontal gaze palsy.61–63 Although rare cases of isolated horizontal gaze palsy are reported,63 it is nearly always accompanied by an ipsilateral seventh cranial nerve palsy with lower motor neuron facial weakness (because of the anatomic proximity of the seventh cranial nerve fascicle to the sixth nerve nucleus, which it wraps around).

SUPRANUCLEAR OCULAR MOTILITY CONTROL Supranuclear eye movement abnormalities result from dysfunctional cerebral, cerebellar, and brainstem afferent connections to the ocular motor cranial nerve nuclei. Because of the excessive demands that saccadic eye movements place on the neural network, a clinical hallmark of supranuclear eye movement disorders is disproportionate involvement of saccadic eye movements relative to smooth pursuit. Vestibular eye movements are typically intact. In contrast, a nuclear or infranuclear process impairs saccades, smooth pursuit, and vestibular eye movements to the same extent. Burst neurons in the brainstem provide the sudden, intense neural discharge required to initiate a high velocity saccade and to overcome dampening, orbital elastic forces. Burst neurons for horizontal saccades are located in the paramedian pontine reticular formation (PPRF) and, for vertical saccades, in the rostral interstitial medial longitudinal fasciculus (riMLF) in the midbrain (Chapter 1). A lesion of the PPRF causes slow or absent horizontal saccades and a lesion of the riMLF causes slow or absent vertical saccades. Burst neurons must be inhibited; otherwise constant saccades would occur and disrupt vision. This is provided to both the horizontal and vertical burst neurons by omnipause neurons located in the pons. Dysfunction of these neurons results in excessive back-to-back saccades in either the horizontal directions (ocular flutter) or in all directions (opsoclonus) (see later). The dorsal midbrain syndrome is comprised of a supranuclear upgaze palsy, convergence-retraction nystagmus, lid retraction (Collier’s sign), and pupillary light-near dissociation. The most common etiologies are a pineal gland cyst or hemorrhage and hydrocephalus. A supranuclear upgaze palsy with forced downward deviation of the eyes (“peering at the tip of the nose”) may result from a thalamic lesion that extends into the midbrain.64 Thalamic esotropia, in which the eyes are deviated medially on both sides, arises because of excessive convergence tone with compression or involvement of the dorsal midbrain.65 Gaze deviation is a common manifestation of a supranuclear disorder. The frontal eye fields (FEF) project to the contralateral PPRF; a destructive lesion of the FEF,for example, following cerebral infarction, results in ipsiversive bilateral gaze deviation; the patient “looks at the lesion.” With an irritative lesion, for example, seizure or hemorrhage, there is contraversive deviation; the patient “looks away from the lesion.” A thalamic lesion, however, may cause “wrong way eyes” in which the patient “looks away” from a destructive lesion.66 Degenerative brainstem diseases such as progressive supranuclear palsy, Parkinson’s disease, spinocerebellar degenerations, and Huntington’s disease 324 Neuro-Ophthalmology: Blue Books of Neurology

and metabolic disorders such as Wilson’s disease and lipid storage diseases may all show distinctive abnormalities of supranuclear ocular motility control. Internuclear ophthalmoparesis (INO) results from a lesion of the medial longitudinal fasciculus (MLF), which carries signals from the abducens nucleus to the contralateral medial rectus subnucleus of the oculomotor nucleus. These signals allow conjugate horizontal eye movements with co-contraction of the ipsilateral lateral rectus and contralateral medial rectus muscles. A unilateral INO leads to impaired adduction of the eye ipsilateral to the MLF lesion and dissociated nystagmus of the contralateral abducting eye. Despite adduction weakness on direct horizontal motility testing, adduction of the eye ipsilateral to the MLF lesion is intact with convergence eye movements because direct vergence signals to the medial rectus motor neurons do not pass through the MLF.67 The eye movements may appear normal with bedside smooth pursuit testing and the presence of an INO diagnosed only by the identification of a decreased velocity of the adduct- ing eye compared with the abducting eye during saccadic testing, known as adduction lag.68 Multiple sclerosis; vascular lesions such as infarction, hemorrhage, and arteriovenous malformations; and tumors are the most common causes of INO.69,70 Bilateral INO is usually because of multiple sclerosis and may be associated with a marked exotropia; the “walled eyed” bilateral INO. Because the PPRF and MLF lie in close proximity within the brainstem on each side, lesions in this region may affect both structures, leading to the “one and a half syndrome” coined by Miller-Fisher. The coexistence of an INO and an ipsilateral horizontal gaze palsy results in there being only abduction in the contralateral eye and no other horizontal eye movement. Skew deviation is a vertical misalignment of the visual axes. Patients have a hypertropia, which may be concomitant (the same in all directions of gaze), or incomitant. It may be difficult to differentiate incomitant skews from other ocular motility problems such as ophthalmoparesis because of dysfunction of cranial nerves III or IV, but there should be other signs of brainstem or cerebellar dysfunction. It occurs when a disorder causes a mismatch between inputs to the brainstem from the otoliths on both sides. Some patients may have an INO as well. Others may show the ocular tilt reaction (OTR), in which there is a tilt of the head to the side contralateral to the lesion. It is assumed that this reflects a compensation by the brainstem for the loss of vestibular input; the patient’s position of center of gravity has been shifted. The OTR may be paroxysmal or sustained. Skew deviation with or without the OTR may arise with lesions in the cerebellum, midbrain (particularly lesions of the dorsal midbrain which include the interstitial nucleus of Cahal), and pons.

Abnormal Spontaneous Eye Movements

NYSTAGMUS Nystagmus is a repetitive to-and-fro movement of the eyes that can be congenital or acquired, physiologic or pathologic. Physiologic nystagmus is sometimes evident at a bedside motility examination and consists of low-amplitude, high-frequency gaze-evoked nystagmus present only in extremes of horizontal gaze. The nystagmus will resolve when the eyes are moved to a slightly less eccentric gaze position. 13 Acquired Ocular Motility Disorders and Nystagmus 325

Pathologic acquired nystagmus is described as jerk or pendular; jerk nystagmus is characterized by a to-and-fro oscillation whose phases are of unequal velocity, termed the slow and fast phases, whereas in pendular nystagmus the phases have equal velocity. Although the direction of jerk nystagmus is named after the direction of the fast phase, the underlying mechanism generating the abnormal eye movement is the slow phase, or slow drift of the eyes away from the desired position. The fast phase is a rapid, corrective movement in the opposite direction. There are three primary mechanisms by which an image is maintained on the fovea: fixation, the vestibulo-ocular reflex, and eccentric gaze holding. Nystagmus may result from disruption of any one of these mechanisms.

Nystagmus Associated with Visual Loss Visual loss of any cause may disrupt fixation and be associated with nystagmus; that resulting from optic nerve disease is more commonly pendular and that resulting from retinal disease more commonly of jerk type. In the Heimann- Bielchowsky phenomenon, the nystagmus is more prominent in the eye with the greater visual loss71–74 or may arise when the visual loss is only in one eye. This is usually pendular and is more prominent in the vertical direction.

Acquired Pendular Nystagmus Acquired pendular nystagmus (APN) is one of the most visually disabling types of nystagmus. It is a pendular nystagmus that may have horizontal, vertical, or torsional components. APN may occur in the setting of visual loss because of optic neuritis, but it is more commonly seen in brainstem lesions, for example, because of multiple sclerosis;75 Pelizaeus-Merzbacher disease; lysosomal storage diseases; brainstem infarction; Whipple’s disease76 (when it is associated with oculomasticatory myorhythmia); spinocerebellar degenerations; toluene abuse;77 or as a component of oculopalatal myoclonus (oculopalatal tremor),78 in which pendular nystagmus with a prominent vertical component associated with a synchronous palatal tremor develops months after brainstem or cerebellar infarction. Others brainstem signs are invariably present, such as INO and skew deviation. Treatment of APN A double-blind, placebo-controlled, cross-over study comparing gabapentin and baclofen found gabapentin to be highly effective in minimizing oscillopsia and ocular oscillations in patients with APN.79 The known role of gamma- aminobutyric acid (GABA)-ergic neural transmission in control of the neural integrator, which functions to maintain stability of the eyes in eccentric gaze positions, suggests altered GABA transmission as a mechanism for APN. Meman- tine, clonazepam, valproate, and scopolamine may also be tried.80,81 Patients with oculopalatal tremor may respond to carbamazepine.82,83

Nystagmus from Vestibular Imbalance Nystagmus from vestibular imbalance may be caused by disease of peripheral or central vestibular pathways. With peripheral vestibular disease, asymmetric vestibular inputs result in jerk nystagmus because the unaffected and unopposed 326 Neuro-Ophthalmology: Blue Books of Neurology

contralateral vestibular nucleus drives the eyes slowly toward the side of the lesion, and hence the direction of the nystagmus is away from the lesion. An important feature of peripheral vestibular nystagmus is that it is accentuated by, and indeed may only be detected with, elimination of fixation, for example, with Frenzel goggles. The nystagmus is usually of mixed torsional and horizontal direction. Most nystagmus from acute peripheral vestibular impairment such as benign paroxysmal positional vertigo or acute labyrinthitis resolves spontaneously; however, if oscillopsia or vertigo are significantly debilitating, acute management with pharmacologic agents such as diphenhydramine or promethazine may be beneficial. Imbalance of central vestibular connections may result in vertical or torsional nystagmus. Elimination of fixation tends not to influence the severity of the nystagmus appreciably. Downbeat nystagmus, in which the slow phase is in an upward direction and which is accentuated looking down and to either side, may arise because calcium channel-rich cerebellar Purkinje cells inhibit the vestibular nucleus mediating downward, but not upward, eye movements. This causes a relative decrease in inhibition of upward eye movements, with a resultant slow drifting of the eyes upward and fast corrective downward eye movements.84 Other signs of cerebellar dysfunction, such as abnormal vestibulo-ocular reflex, are also seen. Upbeat nystagmus is usually present in the primary position of gaze and, like downbeat nystagmus, increases when the eye is moved in the direction of the nystagmus. It is not, however, accentuated by looking to either side. Vertical nystagmus is almost always associated with a central cause, although a peripheral vestibular lesion can occasionally be associated with upbeating nystagmus, usually with a torsional component. Either downbeat or upbeat nystagmus may result from a variety of other brainstem or cerebellar pathologies such as vascular disorders, tumors, encephalitis, inherited and acquired causes of cerebellar degeneration, multiple sclerosis and other inflammatory diseases, and metabolic states such as drug intoxication with lithium and anticonvulsants, Wernicke’s encephalopathy, and vitamin B12 deficiency. Downbeat nystagmus may also be caused by structural lesions of the craniocervical junction, such as Arnold-Chiari malformation (Fig. 13–8),85 Paget’s disease and basilar invagination, and foramen magnum lesions such as meningioma. Pure torsional nystagmus is rare and is associated with the brainstem diseases noted previously. Treatment The potassium channel blockers 3,4-diaminopyridine and 4 aminopyridine are effective treatments for downbeat nystagmus.86,87 Clonazepam, baclofen, and gabapentin may also be useful.88,89

Periodic Alternating Nystagmus Periodic alternating nystagmus (PAN) is a horizontal jerk nystagmus that spontaneously reverses direction every 60 to 90 seconds. It is often missed if the examiner does not watch the eyes for long enough. At the time of direction-reversal, there may be a transition period in which vertical nystagmus or a series of square wave jerks may arise, before the horizontal nystagmus changes direction and 13 Acquired Ocular Motility Disorders and Nystagmus 327

Figure 13–8 Sagittal T1-weighted magnetic resonance imaging with gadolinium showing an Arnold- Chiari type I malformation. continues. It may occur in multiple sclerosis, cerebellar degenerations or mass lesions, brainstem infarction, anticonvulsant toxicity, meningoencephalitis, and trauma. In an animal model, PAN results from ablation of the cerebellar nodulus and uvula, structures known to use GABA B inhibitory pathways to control rota- tionally induced nystagmus.90 Both experimental and clinical PAN respond well to the GABA B agonist baclofen.91

Seesaw Nystagmus This is a rare nystagmus in which one eye elevates and intorts while the other moves down and extorts, then the movement reverses. It occurs in patients with chiasmal visual loss due, for example, to pituitary and other parasellar lesions but may also arise in brainstem lesions that involve the interstitial nucleus of Cahal in the midbrain. Treatment of the parasellar lesion usually improves the condition, as do baclofen, clonazepam, and alcohol.

Gaze-Evoked Nystagmus Gaze-evoked nystagmus is the most common type of nystagmus, is absent in central position, and beats in the direction of eccentric gaze. It is the result of impairment in eccentric gaze holding mechanisms from a variety of causes, including anticonvulsant or sedative medications and brainstem lesions that have impaired the function of the diffuse gaze-holding neural network. Because it is absent in central position, it is generally not visually disabling and, therefore, does not require treatment.

SACCADIC INTRUSIONS In contrast to nystagmus, in which the initial abnormal movement is a slow drift of the eyes away from their desired position, the initial abnormal eye movement 328 Neuro-Ophthalmology: Blue Books of Neurology

with saccadic intrusions is a sudden saccadic movement that abolishes steady fixation. The spectrum of saccadic intrusions ranges from abnormal intrusive single saccades (macrosquare wave jerks) to sustained saccadic oscillations (ocular flutter and opsoclonus). Back-to-back saccades with no saccadic interval in the horizontal plane are termed ocular flutter, whereas similar saccadic intrusions in all directions are termed opsoclonus. Ocular flutter and opsoclonus arise because of disease of pontine omnipause neurons that normally inhibit saccadic burst neurons.92 Many causes of ocular flutter and opsoclonus, such as viral parainfectious encephalitis, meningitis, and medication toxicity, resolve spontaneously. Others, such as paraneoplastic syndromes, stroke, or tumor, may not and clonazepam or gabapentin may be tried but are not very effective.

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Anatomy and Physiology of Visual Illusions (Dysmetropsia) Vision Visual Hallucinations

Negative Visual Disorders Bedside Testing of a Patient V1 Lesions with Suspected Higher Disorders of Specific Visual Visual Disorder Attributes Clinical Course, Prognosis, and Positive Syndromes Therapeutic Options Palinopsia Cerebral Polyopia References

Key Points Beyond the striate cortex, the extrastriate cortex contains a large number of functionally interconnected visual areas specialized for analyzing and categorizing different stimulus features such as color, shape, and motion. The extrastriate visual cortex contains two visual processing streams—the dorsal stream (D) projecting into the parietal lobe, which is involved with spatial perception and visuomotor performance (the WHERE stream), and the ventral stream (V) projecting into the temporal lobe, which is involved in object discrimination and recognition (the WHAT stream). Lesions in area V1 (striate cortex), if unilateral, lead to a homonymous hemianopia and, if bilateral, to cortical blindness. Some patients exhibit visual function of which they are unaware in their blind fields called blindsight. Some patients with cortical blindness are unaware of their deficit and actively deny it—Anton’s syndrome. The color selective area—area V4—lies in the fusiform gyrus on the inferior occipital lobe. When damaged, the patient exhibits prosopagnosia—a loss of color perception with all other visual functions intact. The motion selective area—area V5 or MT (middle temporal)—is located at the lateral occipitotemporal junction. When damaged the patients exhibits akinetopsia—a loss of motion perception resulting from an acquired brain lesion. Visual object agnosia is characterized by a difficulty to recognize or identify familiar objects using visual information when this difficulty cannot be explained

332 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 333

by other cognitive impairments. There are two types—apperceptive and associative. The fusiform face area lies anterior to V4 in the fusiform gyrus and is involved in face recognition along with a complex neural network. Damage to this area leads to prosopagnosia—a failure of face recognition. Balint’s syndrome is a triad of visual deficits occurring in patients with bilateral occipitoparietal lesions. The deficits are simultanagnosia, ocular apraxia, and optic ataxia. Several positive visual phenomena occur as a result of destructive or irritative lesions of the visual system. Palinopsia refers to the perseveration of the visual image in time; cerebral polyopia refers to two or more copies of a visualized object seen simultaneously. Visual illusions occur when an object of interest is perceived differently from reality, usually in size, shape, and spatial orientation. Visual hallucinations are visual percepts without real external stimuli.

This chapter discusses disorders of vision related to damage of the primary visual cortex: hemianopic visual loss or, if bilateral, cortical blindness but in particular the visual disorders, such as achromatopsia, akinetopsia, and prosopagnosia, resulting from damage to the extrastriate visual cortex and other visually related temporoparietal areas. These disorders, or more properly termed “syndromes,” are often referred to as “higher visual disorders” or “cortical visual disorders,” although the latter term fails to recognize that sometimes they originate from damage to the white matter that connects the relevant areas together. Despite the fact that many of these disorders have been described for more than 100 years, the challenge to interpret their clinical aspects and their pathophysiology in the context of the rapid advances in visual neuroscience still remains.

Anatomy and Physiology of Vision

It is well recognized that the visual brain not only consists of the primary visual pathway from the retina to the primary visual cortex (Brodmann area 17, area V1, or striate cortex) but in addition many other areas are involved in vision, especially in the visual association cortex in the occipital lobe (Brodmann areas 18, 19), as well as areas of the parietal and temporal lobes. The occipital cortex contains an array of interconnected visual areas, many of which show evidence of a retinotopic map, and are relatively specialized for analyzing and categorizing different stimulus features, such as color, shape, and motion. Because these areas are closely located to each other anatomically, several of them may be damaged by the same pathology, such as cerebral infarction, so it is not uncommon to see combinations of visual dysfunctions that can give rise to a very complex clinical picture (Fig. 14–1). The neurophysiology of early vision is rather linear and better understood than in the rest of the visual brain. The visual information transmitted to the 334 Neuro-Ophthalmology: Blue Books of Neurology

Figure 14–1 An outline drawing of the lateral surface of the human brain showing the pathway of the two visual processing streams—the dorsal stream (D) projecting into the parietal lobe, which is involved with spatial perception and visuomotor performance (the WHERE stream) and the ventral stream (V) projecting into the temporal lobe, which is involved in object discrimination and recognition (the WHAT stream).

visual cortex appears to be segregated at an early stage into two streams, the parvocellular and magnocellular geniculostriate inputs. The former is characterized by color opponency and slow-conducting axons, whereas the latter is defined by large, fast-conducting axons that convey information about transient visual signals. Geniculostriate fibers input to the striate cortex (V1) where early vision is processed. Projections from V1 pass to the visual association areas (V2–8). The striate cortex (V1) is located around the calcarine sulcus and receives input from the lateral geniculate nucleus (LGN), which first projects to neurons in layer 4c. These neurons in the striate cortex, especially those in layer 2/3, 4B, and 5, are sensitive to the specific orientation and illumination of visual stimuli within their receptive field.1–7 Complex cells receive inputs from simple cells, have a larger receptive field, and respond to a specifically orientated stimulus. Neurons of common orientation for a particular region of the visual field are contained within a vertical column, and there are sets of such orientation columns (hypercolumns), which cover the full 360 degrees of orientations for each region of the visual field. Retinotopic organization is, therefore, still well maintained in area V1 (and also in V2), although there is significant magnification of the foveal projection, which results in much of the striate cortex representing the central 10 degrees of the visual field. A further role for area V1 is to combine visual formation from the two eyes, providing the substrate for binocular vision. Although a prevailing view has been that the visual brain is organized on the basis of a hierarchical model whereby visual inputs travel through the association cortex toward a more complex and integrated visual image, this appears to be only partly true. Indeed there is now considerable evidence for a nonhier- archical parallel model of visual processing because the visual association areas around V1 are operationally divided into two pathways (streams): the dorsal and ventral processing streams (Fig. 14–1), a concept that is helpful in interpreting cortical visual disorders. It has been argued that the ventral stream through the temporal lobe plays a role in interpreting “what” the object is in terms of 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 335

color, luminance, stereopsis, and form (i.e., object discrimination and recognition), whereas the dorsal stream through the parietal lobe is involved in the “where” (spatial perception and visuomotor performance). These two systems have extensive forward and backward connections, and it is important to understand that the two streams are interconnected so they do not function independently. It should be noted that there is a normal variation of human neuroanatomy and vascular anatomy. For instance, Watson and colleagues8 demonstrated that V5, a motion area, could vary up to 27 mm in location across subjects. The anatomy of the four main branches of the posterior cerebral artery (PCA), the anterior temporal, posterior temporal, parieto-occipital, and the calcarine arteries also varies considerably across subjects. Smith and Richardson9 demonstrated that the conventional description of striate cortex being supplied solely by the calcarine artery was found in only 8 out of 32 cases studied. In addition, it was also found that in 2 cases there was a significant contribution to the supply of the striate cortex from the middle cerebral artery (MCA). These normal variations in the vascular anatomy need to be taken into account when interpreting the findings of brain imaging. The physiology of vision is still incompletely understood. In the past, the specific function of one area of the human brain was hypothesized from the neurologic deficits that occurred secondary to a discrete lesion (e.g., a contralateral inferior homonymous quadrantanopia from a unilateral superior V1 lesion). High-resolution imaging techniques, computed tomography (CT) and magnetic resonance imaging (MRI), have greatly aided the determination of functional specialization in the extrastriate visual areas that occur in the lesioned brain of patients with specific visual deficits. The lesion approach to functional localization is still of considerable value, particularly when applied in association with functional imaging techniques. For example, functional MRI (fMRI) and positron emission tomography (PET) can be used to examine which areas of the brain are involved in different visual functions in the normal human brain, and this functional activation can be superimposed on the structural brain scan. Careful planning of the tasks in fMRI is crucial to ensure that the activation of a focal cortical area can be correctly correlated with performance of a specific visual function. In addition, a recent new technique, transcranial magnetic stimulation (TMS), may be used to stimulate or disable certain parts of the cortex involved in vision, by creating temporary “virtual functional lesions.” Recording from deep brain and surface electrodes, a technique that has been extensively used in animal models of behavior, is now being explored in humans as a by product of electrode implantation undertaken for other reasons, such as seizure focus localization. Cerebral lesions can cause visual disorders in several ways. First, they can produce negative visual phenomena including hemianopia, achromatopsia (an inability to see colors), visual agnosia (an inability to associate the seen object with knowledge of that object), akinetopsia (an inability to see movement), and visual neglect. Second, these lesions can also produce positive visual symptoms, for instance, visual illusions and hallucinations and palinopsia (the persistence of a seen image). In general, lesions of the striate cortex impair vision specific to the location of field defect but not the modality, whereas the reverse is true for association visual cortex. 336 Neuro-Ophthalmology: Blue Books of Neurology

The main complaint of patients with cortical visual disorders is usually rather nonspecific or they may not complain at all because, for example, they have visual neglect or fail to recognize the deficits (anosognosia). It must always be remembered that these patients may have coincidental language and memory disorders. For example, inability to describe seen color could be the result of cerebral achromatopsia (an inability to see color), color anomia (an inability to name color as part of expressive dysphasia), or amnesia (memory impairment). Comprehensive and extensive exploration of memory and language capabilities is sometimes required to isolate the exact pattern of functional deficits.

Negative Visual Disorders

V1 LESIONS Cortical blindness occurs as a result of bilateral occipital lobe lesions involving either the optic radiations or V1. The patient is totally blind, but there is preservation of pupillary light reflexes because of sparing of the direct pathway from the optic tract to the Edinger-Westphal pupillomotor nucleus in the midbrain. The usual cause for the sudden onset of cortical blindness is occlusion of the posterior arterial circulation. Other causes include tumors,10 cerebral hemorrhage,11,12 venous infarcts, cardiac bypass surgery, cardiopulmonary arrest,13,14 demyelination,15,16 uncal herniation, systemic lupus erythematosus,17 and the Heidenhain variant of Creutzfeldt-Jacob disease.18 Transient cortical blindness can occur as a result of cerebral or coronary angiography,19 migraine, traumatic brain injury,20–22 seizures,23 myelography,24 and drugs such as cyclosporine.25 Some recovery of vision usually occurs, which is most likely in younger patients with hypoxic insults and least likely in patients older than 40 years with stroke and vascular risk factors. In general, motion detection seems to be most tolerant to damage, whereas color perception and spatial sensitivity are the most vulnerable. As a consequence, Riddoch’s phenomenon26 (statokinetic dissociation) may be seen on rare occasions during recovery in which kinetic perimetry reveals significantly larger visual fields than the static technique. Some patients with cortical blindness are unaware of their deficit and actively deny it. This syndrome is called Anton’s syndrome27 or visual anosognosia. These patients may try and carry on normally, inevitably bumping into objects, and may confabulate about what it is they are “seeing.” These patients usually have a bilateral occipital lesion that extends anteriorly to involve the medial temporal or visual association areas. Blindsight is a term used to describe a phenomenon in which a patient with a V1 lesion fails consciously to perceive any visual information in their defective visual field, yet can still use some of the information presented. For instance, some patients can make accurate saccades or point to visual targets presented tachistoscopically in their blind hemifield using a forced choice paradigm, despite the fact that they believe that they are merely guessing.28 These patients tend to be able to discriminate brightness and movement and sometimes gross size and orientation. Some, when presented with pictures in the blind field, are able to guess the correct answers on multiple-choice questions at well above chance while not able to describe anything. It is believed that this phenomenon 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 337

represents activation of accessory visual pathways, either via the superior colliculus and pulvinar or directly from the LGN to V5 as demonstrated in monkey28; these pathways bypass the damaged area V1 and provide visual information for higher cortical areas. However, this does suggest that area V1 is important for the conscious awareness of visual stimuli.

DISORDERS OF SPECIFIC VISUAL ATTRIBUTES Color—Cerebral Achromatopsia Color vision is an important visual attribute that enhances object identification and recognition and form perception in low level illumination. Because objects are not “colored” and are not the different wavelengths of light that are reflected, color perception must be the result of sensations evoked in the visual brain. To make the task even more complex the wavelengths reflected from a particular object differ depending on the background illumination, yet we perceive the object as having the same color—a phenomenon known as color constancy. The perception of color, therefore, depends on a series of neural computations stemming from the trichromatic signals produced by the retinal cones. Although early electrophysiologic single cell recordings from the extrastriate cortex revealed one region V4, which appeared to predominantly contain color selective neurons, ablation of this area in the monkey does not abolish color vision but has a greater effect on form vision. However, functional imaging stud- ies29–31 and autopsy and structural scanning32 in patients with focal lesions have indicated that the human homologue for V4, the “color area,” is located in the fusiform gyrus on the ventromedial region of the occipital lobe33 (Fig. 14–2). Cerebral achromatopsia describes an acquired loss of color perception, with intact or relatively intact visual acuity, caused by damage to the visual cortex in an alert patient without any language disturbance. It was first described in the late 1800s,34 well before the physiology of vision was understood, and is usually associated with damage in the “color center.” Patients with achromatopsia usually describe the affected area as having a “loss of color,” “the colors look dull,” or “everything looks a muddy grey.” Although complete achromatopsia from bilateral lesions occurs most often, this phenomenon may affect only half of the visual field (hemiachromatopsia) or only one quadrant of the field if the lesion is limited to one side, and it may be accompanied by visual object agnosia or alexia.32 The most common etiology of cerebral achromatopsia is an embolic stroke in the territory of the PCA,35–42 affecting the ventral occipitotemporal area. Other conditions such as carbon monoxide poisoning43 and cerebral metastases44 have also been reported as causing cerebral achromatopsia. Hemiachromatopsia is usually, but not exclusively, associated with a superior quadrantanopia ipsilateral to the hemiachromatopsic field but any type of visual field loss can be seen (for a review see Bouvier and Engel45). In addition, prosopagnosia—an inability to recognize faces—seems to be commonly associated with achromatopsia, not surprising in view of the close proximity of the area specialized for face processing to V4. The effect of cerebral achromatopsia on activities of daily living is usually minimal because of the relatively unaffected visual acuity in the achromatopsic field. However, in one report there were devastating effects to an artist who 338 Neuro-Ophthalmology: Blue Books of Neurology

FFA V4

B Figure 14–2 An outline drawing of the lateral (A) and the medial (B) surfaces of the human brain showing some of the specialized visual areas in the extrastriate region around the primary visual area, striate cortex (V1): V4, the color area; V5, the motion area; FFA, the facial fusiform area.

encountered significant difficulty in painting with colors as a result of cerebral achromatopsia after a traumatic brain injury.46 He subsequently adapted to the deficit by painting in black and white, which fortunately was productive and successful. Some patients are unable to name colors or point to a color when given its name—a condition called color anomia (also called color agnosia and color- naming defect)—yet have normal color vision when assessed with color-matching tests and pseudoisochromatic plates (both of which are abnormally performed in cerebral achromatopsia) and are not aphasic. It is usually associated with a right- sided homonymous hemianopia and pure alexia. The lesion responsible for this condition is located in the left mesial occipitotemporal region, inferior to the sple- nium. Rarely, disorders of color association have been reported, when in the context of aphasia, patients are unable to color in correctly drawings of common objects.

Motion—Cerebral Akinetopsia Akinetopsia is the term used to describe loss of motion perception as a consequence of an acquired cerebral lesion. It was first reported in man by Zihl et al,47 after the discovery of an extrastriate region (area V5, also known as 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 339

the middle temporal area [MT]) in monkeys containing motion selective neurons, which suggested that a disorder of motion perception may occur in humans with damage to homologous areas. MT neurons are selective for detecting direction and speed33 but not for shape or color. Monkeys with lesions in area MT exhibit impaired perception of motion. Functional imaging studies in humans have located V5 to the posterior continuation of the middle temporal gyrus at the lateral occipitotemporal junction.8 In general, overt akinetopsia results from bilateral lesions to these regions, although subclinical deficits may be seen with unilateral lesions. This condition is considered to be very rare because only two clearly defined cases have been described. Both patients, LM47 and AF,48 have been well described and tested extensively, although similar symptoms have been described in two patients with transient akinetopsia resulting from nefazodone (a selective serotonin reuptake inhibitor) toxicity.49 LM and AF both suffered bilateral cerebral hemisphere damage because of cerebrovascular disease involving area V5 at the lateral occipitotemporal junction. Akinetopsics describe the deficit as an inability to appreciate the smooth movement of a moving target, for example, LM reported that when she poured tea “the fluid appeared to be frozen like a glacier,” and when crossing the road “when I’m looking at the car first, it seems far away. But then, when I want to cross the road, suddenly the car is very near.” In other words, the moving object appears to jump rather than move smoothly, as experienced by normal individuals when viewing moving objects under stroboscopic illumination, for example, at a disco. Hemiakinetopsia has also been described, and it is always contralateral to the lesioned side; however, it is not commonly detected because of the masking effect of the concurrent visual field loss.

Disorders of Stereopsis—Astereopsis The ability to perceive three-dimensional (3D) images (stereopsis) is one of the most fascinating visual phenomena but the least well understood. This visual function involves processing disparities between the two-dimensional images viewed and perceived from a slightly different angle by the left and right eye. The brain uses these retinal disparities to extrapolate the distance of the objects to guide our vergence eye movements and to provide our perception of stereoscopic depth. This process develops innately but may be impaired by ophthalmologic disturbances before the adult level of stereoacuity is achieved. As a result, approximately 5% to 10% of the population is unable to appreciate stereopsis, primarily as a result of uncorrected childhood strabismus or amblyopia, presumably because of disruption of the normal development of binocular cortical neurons. The physiology of stereopsis is rather complex because numerous cortical areas are involved. Much of the striate and extrastriate cortices have some role in stereopsis. Binocular visual interactions first occur in the V1 neurons, which respond selectively to retinal disparity. In addition, area V2 and V3 contain retinal disparity-sensitive neurons that act similarly to V1 neurons. The current evidence also suggests that both the dorsal and ventral streams are involved in stereopsis. The depth information from the dorsal stream is probably used to localize objects accurately in visual space and guide vergence eye movements, whereas the information from the ventral stream establishes a richer perceptual 340 Neuro-Ophthalmology: Blue Books of Neurology

representation, including detailed 3D representations. However, although several studies have suggested a dominant role of the right hemisphere in the perception of depth from stereopsis, a unilateral lesion does not abolish stereopsis.50,51 Some patients with astereopsis or stereoblindness complain of difficulty per- ceiving distance, perspective, depth, or thickness; however, the majority are unaware of any deficits. This could be the result of anosognosia, but the ability to use other cues such as motion and linear perspective to compensate for the lack of stereoacuity could explain this observation. Impaired stereopsis in an acquired form has been reported in Alzheimer’s disease,52 tumors,53 and strokes,54 following surgical excisions for the treatment of intractable epilepsy,55 and in traumatic head injuries.56

Visual Object Agnosia Visual object agnosia is characterized by a difficulty to recognize or identify familiar objects using visual information, when this difficulty cannot be explained by other cognitive impairments such as a disorder of intelligence, attention, and language or impaired peripheral visual processing (acuity, brightness discrimination, depth perception, visual field, and color vision). Generally, a diagnosis of visual object agnosia should be made when a patient misnames an object if he or she is unable to describe or mime the use of the object presented visually but is then able to do so correctly when he or she can feel or hear the object. Visual object agnosia was classified by Lissauer57 into two categories: apperceptive, in which higher order visual perception and therefore recognition is impaired, and associative, in which perception is largely intact but recognition is selectively impaired.However, the distinction between these two categories is not always clearcut and some perceptual disorders may exist in each. Despite this, Lissauer’s categorization remains a useful framework. In apperceptive visual agnosia, the patient is not able to recognize the shape of objects and, therefore, has difficulty recognizing, copying, matching, or discrim- inating simple visual stimuli and drawing an object. Although the visuopercep- tive disturbance has been likened to the image seen on a TV screen connected to a faulty aerial, it has been proposed that apperceptive visual agnosia is the result of damage to those components of object recognition that normally allow the construction, by recourse to stored representations, of an object-specific structural description.58 This was based on a small group of patients who had difficulty in object recognition only when the perspective was unusual or the lighting was uneven. Others have suggested that the major deficit is a more global deficit in the perceptual integration of shape elements into coherent wholes.59 The lesions causing apperceptive visual agnosia tend to be typically diffuse and posterior. The typical white matter lesions suggest that it results from some form of disconnection possibly of local intralaminar connections rather than neuronal loss. Apperceptive visual agnosia has been reported in carbon monoxide or mercury poisoning, anoxia, or bilateral PCA stroke.60 In contrast, associative visual agnosia is a condition in which the individual is able to see normally and appreciate the shape of an object, but as Teuber61 so succinctly described “the visual percept is stripped of its meaning.” Hence, such patients are able to copy, draw, and match objects62 but are unable to 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 341

recognize the object by the visual information—this includes the picture that they just drew or copied. Interestingly, patients with associative visual agnosia are usually capable of identifying the objects by the other means, for instance, by touch, hearing, or verbal description63—traditionally known as “optic aphasia.” For example, associative visual agnosics would fail to recognize a key when it is presented visually but are able to recognize it if allowed to touch it. It is important to discriminate this condition from anomic aphasia (inability to name) by using both verbal and nonverbal tests. The anomic patient will be able to recognize and explain the use or function of the object although being unable to name it, whereas the visual agnosic will be unable to state what the object is or its function. Associative visual object agnosia occurs as a result of lesions in the ventral stream, particularly at the inferior temporoparietal junction and adjacent white matter, either unilateral or bilateral, resulting from PCA infarction,64 tumor, hemorrhage, and demyelination. This may be the result of a disconnection of the visual association and the temporolim- bic memory areas or destruction of visual association cortices in the temporo- occipital region. In some patients, visual object agnosia may be category specific, and cases have been reported in which specific deficits in the identification of fruit and vegetables or animals have been observed. However, the most common dissociation reported in these patients is an impairment in the recognition of natural (living) objects relative to human-made (nonliving) objects. Posterior cortical atrophy, a term first proposed by Benson et al,65 usually gives rise to various cortical disorders, including visual object agnosia. The visual association cortex may store the neuronal templates that are required to match a visual stimulus with visual memory, and functional imaging studies, including fMRI and PET, have shown activation in the ventral stream during visual object recognition tasks.66 It is not surprising, therefore, that these patients may have partial visual field defects as well as achromatopsia and sometimes prosopagnosia.

Prosopagnosia Prosopagnosia derives from the Greek prosopon (face) and gnosis (knowledge). It is used to describe the inability to recognize the identity of familiar faces (retrograde defect) or, more rarely, to learn and recognize the identity of new faces (anterograde defect) and is arguably a restricted form of visual agnosia. These patients recognize the components of a face, the eyes, nose, mouth, and so forth, and know that together they represent a face, but they cannot tell whose face it is. However, these patients can usually identify their spouses by voice, perfume, or clothes although failing to recognize the face. Face recognition is one of the most complex tasks undertaken by the human brain because faces are composed of multiple, complex curved surfaces and in addition show subtle dynamic changes, both short term with emotional state and long term with aging. Despite this, we are still able to easily recognize faces with differing expressions and age. Therefore, because of its complexity, authorities in the past regarded prosopagnosia as a combination of a generalized mental impairment combined with visual disturbances. However, a complex neural network involved in face recognition has now been defined along with cortical 342 Neuro-Ophthalmology: Blue Books of Neurology

areas containing neurons that are face sensitive.67 These neurons, which respond to face stimuli regardless of identity and not other simple or complex stimuli, have been identified in the inferotemporal (IT) cortex and the superior temporal sulcus (STS) of monkeys. A smaller number are also found in the amygdala, ventral striatum, and inferior prefrontal cortex. These neurons show preferences for facial orientation, for example, frontal versus profile. Neurons in IT are involved in facial identification and in STS in perception of gaze and head orientation. In humans, the homologue for IT is the fusiform facial area (FFA) in the medial occipitotemporal cortex, anterior to the V4 color area.68 Models of the distributed human neural system for face perception propose that the core system consists of low-level visual processing of facial structure leading to a face percept.67,69,70 This takes place in the STS where recognition of changeable aspects of faces such as perception of eye gaze, expression, and lip movement is undertaken, and the FFA where invariant aspects of face recognition (i.e., the perception of unique identity) are performed. This face percept then moves into an extended system where, for example, in the anterior temporal region it is matched to “face recognition units,” which store memories of previously encountered faces. Once a match has been made, person identity nodes are activated providing information such as name and biographical information. Other areas may have more specific roles such as the amygdala for processing of facial emotion and emotional responses and the auditory cortex for prelexical speech perception. It has been proposed that depending on precisely where a lesion in this system occurs different disorders of face perception will arise. For example, at one level the face percept may not be formed (an apperceptive prosopagnosia) or at another it may not be possible to match with “face recognition units” (an associative prosopagnosia).71 There is still debate about prosopagnosia as to how specific it is for face recognition. As shown by the case of Bruyer et al72 who was able to recognize individual cows, dogs, houses, streets, and cars but not faces, even those on playing cards, prosopagnosia can be very specific and leave other categorical specific identification intact. However, some patients with prosopagnosia do show difficulty in identification within other specific categories. For example, a farmer was no longer able to recognize his own cattle or a bird-watcher was unable to identify different species of birds. It is, therefore, a possibility that face perception may represent the ultimate expression of a system for detecting subtle differences in shapes and features of objects of a similar category and may not have a unique anatomic substrate or dedicated visual system.70 Lesions in the inferior temporo-occipital cortex, especially the lingual and fusiform gyri, which are part of the ventral stream, are associated with prosopagnosia. In most cases, bilateral lesions have been reported73,74; however, isolated right-sided lesions resulting in prosopagnosia have also been reported.75,76 The lesions resulting in prosopagnosia may give rise to visual field defects (usually a left or bilateral upper quadrantanopia or left homonymous hemianopia), achromatopsia, and topographical disorientation. Although the most common etiology is PCA infarction, it has been reported, in relation to primary brain tumor,77 hematoma,78,79 brain abscess, and surgical resections.80 Although most cases of prosopagnosia are acquired, congenital cases of prosopagnosia are also recognized.81 These patients may not recognize their face recognition deficits until they encounter social difficulties later on in life. 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 343

Disorder of Visuospatial Function Balint’s syndrome, a triad of visual defects, was first described in 1890 by Rezso¨ Balint, an Austrian-Hungarian neurologist, in a patient with bilateral occipito- parietal lesions resulting from a stroke. The triad comprises simultanagnosia (an inability to perceive the components of a visual scene as a whole, with variable perception of isolated components), ocular apraxia (inability to voluntarily direct gaze toward a new object of interest), and optic ataxia (impaired target pointing under visual guidance despite normal limb function and joint positional sense). Gordon Holmes, a British neurologist, also reported a similar syndrome resulting from brain damage caused by gunshot injuries and considered the condition a “disturbance of visual orientation.” Most of the subsequent reported cases of Balint’s syndrome, either complete or incomplete, have been caused by hypotensive stroke associated with diffuse atherosclerosis or a cardiac bypass operation, multiple emboli or venous infarction,82 tumor (multiple metastases or a butterfly glioma), trauma, prion disease, human immunodeficiency virus infection,83–85 corticobasal ganglionic degeneration,86 adrenoleukodystrophy,87 and Alzheimer’s disease.88 As previously mentioned, patients described by Balint and Holmes had a rather widespread injury to the brain that was almost always bilateral. Recent evidence indicates that it is rather difficult to tie the triad to one single location in the brain. In addition, there have been cases of incomplete triads, for instance, optic ataxia alone without simultanagnosia or ocular apraxia, which certainly supports the idea of different locations responsible for the different components. In general, lesions at the parieto-occipital junction, often bilateral, are often found in patients with these visuospatial disorders. Patients with Balint’s syndrome are often severely disabled and appear almost blind, requiring assistance to avoid bumping into things. They are not able to direct their gaze toward the new stimuli and do not blink to threat.89 Although simultanagnosia contains the term agnosia, recent evidence suggests that it has nothing to do with agnosia. It is a disorder of visual perception in which the patient fails to appreciate all the visible items in a complex visual scene and has been termed “piecemeal vision.” For instance, when shown a picture of a spider on a hand, the patient might report only the spider and the hand is totally ignored. Such patients may be able to read, but only when they spell each letter out loud (single letter reading strategy). Patients with simultanagnosia appear to have defects in spatial integration and sustained attention but have relatively intact visual fields on formal testing. Patients with simultagnosia see only with macular vision, which restricts their overall perception of a visual scene, and they show unpredictable shifts of focus from region to region. Isolated simultanagnosia is caused by bilateral lesions of the superior occipital visual association cortex (Brodmann areas 18,19), with sparing of the parietal visuomotor control area. It may occur in Alzheimer’s disease and is a common finding in posterior cerebral atrophy. Ocular apraxia, first described as psychic paralysis of gaze by Balint, is not well described. The most significant feature is the inability to generate voluntary saccades toward a particular object of interest, although reflexive saccades (saccades toward a novel target) are intact. Gaze is therefore relatively random and targets are found by chance. Other features include saccadic dysmetria, a disturbance 344 Neuro-Ophthalmology: Blue Books of Neurology

in maintaining fixation, and impaired convergence and pursuit eye movements. Ocular apraxia is considered to be a disorder of visuospatial integration and generation of volitional saccades rather than a “true” apraxia. Isolated oculomotor apraxia is rare but can be seen in bilateral parietal lobe disorders and Gaucher’s disease. Optic ataxia (also called visuomotor ataxia or defective visual localization) describes a difficulty in reaching for an object by hand under visual guidance. However, patients with optic ataxia can reach to touch their own body parts relatively accurately with their eyes closed, which suggests that this disorder is not a primarily motoric dysfunction of the limbs or a feature of cerebellar dysfunction. Accuracies of pointing or grasping in patients with optic ataxia reduce as the object is moved further away from the central vision.90 Optic ataxia may result from lesions of the dorsal visual association areas (intraparietal sulcus and superior parietal lobe) or from a disconnection of the projections from the visuomotor centers in the parieto-occipital lobes to the frontal lobes, where reaching is programmed (before the movement is initiated). However, more recent studies (for review see reference 91) emphasized the importance of on- line processing (after the hand movement is initiated to reach a moved target), which is essential for reaching a peripheral target accurately. This could also explain why the pointing or grasping ability in patients with optic ataxia is less accurate in the peripheral field because foveal targets require less real-time processing than peripheral targets.

Positive Syndromes

As a result of either destructive or irritative lesions of the visual system, a variety of interesting positive visual phenomena can be observed. Visual illusions result from an alteration of the perceived visual image leading to its persistence (palinopsia), replication (polyopia), or distortion (dysmetropsia). Visual hallucinations are visual percepts generated internally, unrelated to the external visual world. They may be simple (spots of light, diffuse color) or complex (faces, objects, or visual scenes). They can be very distressing to the patient, particularly complex visual hallucinations, because they often lead to the patient privately questioning his or her sanity.

PALINOPSIA Palinopsia, Greek palin (again) opsis (vision), refers to the perseveration of the visual image in time.92 The images are usually of a real object that has recently been visualized and are superimposed on certain parts of the current visual scene. For instance, Meadows and Munro93 reported a palinopsic patient who after looking at someone dressed up as Santa Claus saw an image of Santa Claus’s face superimposed on the face of other people at the party. Patients with palinopsia may also describe the visual persistence as they turn their gaze away from the object, giving rise to a smeared image. Two types of palinopsia have been reported: an immediate and a delayed type. In the immediate type, the image persists after the disappearance of the actual object or scene and usually 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 345

persists for several minutes. Some authorities have argued that this type of palinopsia is simply part of the spectrum of retinal afterimages,94 but others have disagreed.95 In the delayed type, the perseverated image appears a few seconds after the object has disappeared or the patient’s gaze has been redirected away from it. Some patients may have both types of palinopsia.93 The persistent image can occupy any location in the visual field and it usually moves as the eyes move, resembling a retinal afterimage. In some cases, the persistent image multiplies across the entire visual field.96 In addition, the location of the persistent image can be contextually specific, for instance, one face is copied and pasted on to other persons’ faces.93 The mechanism of palinopsia is still unclear. It may result from an epileptic discharge or occur as a release phenomenon. The most common cause of palinopsia is parieto-occipital damage involving either hemisphere but more commonly the right hemisphere, which can also cause an associated homonymous hemianopia. The common etiologies include cerebrovascular disease,97,98 tumor,99 tuberculoma,100 trauma, epilepsy,101 hallucinogenic drugs (mescaline or lysergic acid diethylamide [LSD]102,103), therapeutic medications (e.g., mitrazapine,104 maprotiline,105 nafazodone,106 and trazodone),107 or paroxetine withdrawal.108 There have also been case reports of palinopsia occurring in optic nerve disease without cerebral lesions.

CEREBRAL POLYOPIA Cerebral polyopia is also a type of visual perseveration in space, when two or more copies of a visualized object are seen simultaneously.109,110 This condition usually occurs under monocular or binocular viewing conditions. If the former, ocular pathology such as a cataract or retinal detachment must be excluded. Cerebral diplopia is used to describe the condition in which two copies of the image are perceived, whereas cerebral polyopia signifies more than two copies. Occipital lesions may result in cerebral polyopia and an associated visual field defect, whereas migraine usually causes transient and reversible cerebral polyopia.

VISUAL ILLUSIONS (DYSMETROPSIA) A visual illusion describes a phenomenon when an object of interest is perceived differently from reality, usually in size, shape, and spatial orientation. Illusions of the spatial aspect can be divided into three categories: micropsia (objects are smaller than reality), macropsia (objects are perceived larger than reality), and metamorphopsia (objects are perceived as a distorted image). Among these, micropsia is probably the most common form of dysmetropsia. A survey of more than 3000 students111 revealed a surprisingly high incidence of dysmetropsia (9%)—the phenomenon being reported most often during high fever, fall- ing asleep, and migraine. Micropsia can occur as a physiologic phenomenon. One form of micropsia, convergence micropsia, is a condition in which the object is perceived as smaller when the person focuses at a point nearer that the object. The exact physiology remains uncertain, but it may be the result of a modification in the size of visual receptive fields that occurs during convergence. Pathologic micropsia has been reported 346 Neuro-Ophthalmology: Blue Books of Neurology

in cerebrovascular disease,112 psychogenic conditions, and most commonly migraine. Retinal conditions, especially with foveal involvement, such as macular edema,113 can also cause micropsia but are usually accompanied by metamorphopsia and are monocular. Hemimicropsia, a condition in which the perceived image is smaller in only one hemifield, has been reported in the hemifield contralateral to a cerebral lesion.114 Macropsia is much less common than micropsia. It can also occur as a feature of normal vision, similar to micropsia, when the object is viewed with the focusing point further away than the object. However, neither physiologic micropsia nor macropsia are likely to be a significant complaint. Pathologic macropsia has been reported in association with zolpidem,115 the scarring stage of macular edema. Hemimacropsia of cerebral in origin was reported in a patient with a left occipital lobe tumor.116 Metamorphopsia, when an object is perceived as being distorted in shape, usually occurs as a symptom of ocular disorders, especially retinal pathology such as macular edema, epiretinal membranes, and macular degeneration. As a consequence, it is usually monocular and is almost never symmetrical if the symptom exists binocularly. Cerebral metamorphopsia is extremely rare. It has mainly been reported in seizure disorders.117–119 Hemimetamorphopsia has been reported in left putaminal hemorrhage.120 Upside-down visual metamorphopsia, in which the object or complete visual scene is suddenly perceived as inverted by 180 degrees, is a rare form of metamorphopsia seen in brainstem and parieto-occipital pathology, usually resulting from a cerebrovascular acci- dent or migraine.121 The degree of reversal can sometimes be partial, with tilting of varying numbers of degrees.

VISUAL HALLUCINATIONS Visual hallucinations are visual percepts without real external stimuli. The object is perceived in the absence of an actual object(s), and, depending on the degree of alertness and pathology, the observer may or may not be able to appreciate that the seen object does not exist. The quality of the perceived image can range from a simple flash of light (phosphene) to a well-formed object, animal, or a person. Movement of the images is often perceived. Patients are often convinced that hallucinations are, in fact, genuine, and under these circumstances a history from relatives or carers refuting this belief is invaluable. Visual hallucinations are not specific to dysfunction in a particular brain region but have been observed in many neurologic conditions as well as functional or psychiatric disorders. Visual hallucinations, in the absence of hallucinations in other sensory modalities, are suggestive of an organic pathology. The common disorders include confusional states secondary to metabolic derange- ment (hypoglycemia, electrolyte imbalance), adverse drug reaction, alcohol withdrawal, and neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease). Release hallucinations (Charles Bonnet syndrome) are isolated visual hallucinations often occurring in the area of a visual field defect but have also been observed when there is severe generalized visual loss. Charles Bonnet first described the condition in 1796; the patient was actually his grandfather who became blind from bilateral cataracts but who remained cognitively intact. 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 347

These hallucinations are considered to be the result of a release of the visual system, secondary to a reduction of visual information, which allows the emergence into consciousness of endogenous visual activity. Any type of visual loss, including ocular and cerebral pathology, can cause such release hallucinations. Cataracts, senile macular degeneration,122 and diabetic retinopathy are most frequent among the ocular causes, and cerebrovascular disease123 is the commonest cause, secondary to a cerebral insult.124 They have also been observed to occur after brain resection,125,126 ocular enucleation,127 brimonidine eye drops,128 and multiple sclerosis.129,130 The onset of visual hallucinations can occur immediately after the onset of visual loss but can also be delayed for as long as 10 years. The duration and frequency of each episode of hallucination can also be extremely variable, ranging from a few episodes lasting 2 to 3 seconds in duration to being continuous for several hours. Although occurring almost exclusively in adults, especially the elderly, they have been reported in young children.131 The incidence of release hallucination ranges from 12%132 to 57%124 in different series of patients with ocular pathology but may be underestimated because many patients may be too embarrassed to admit to experiencing hallucinations. Patients with release hallucinations are usually cognitively intact and many realize that the observed scenes are not real,132 and some even enjoy them. Loneliness, intraversion, and shyness are risk factors for developing release hallucinations in the elderly.133 Release hallucinations can be simple or complex in quality. Simple forms, the commoner among the two, consist of flashes of lights, lines, shapes, or phosphenes.124 Complex hallucinations composed of recognizable objects (both living and nonliving) and fantasized objects (angels, dragons). One of the commoner items visualized in the complex form are deceased friends or relatives.132 The distinction between simple and complex visual hallucinations does not have any localizing value. Visual hallucinations can also be a feature of occipital lobe epilepsy. The distinction between epilepsy and the Charles Bonnet syndrome can be difficult, especially in the presence of brain lesions and visual field defects. As mentioned, the content of visual hallucinations does not help to differentiate between the two, but accompanying head or eye deviation and rapid blinking are suggestive of occipital lobe seizures. Other features in support of occipital lobe seizure include confusion, tonic-clonic limb movements, and automatisms. In addition to neuroimaging and electroencephalogram, single-photon emission computed tomography, and fluorodeoxyglucose positron emission tomography (FDG-PET) may help to confirm and localize occipital lobe epilepsy.134 Visual hallucinations are also a well-known feature of migraine with aura. The aura almost always precedes the headache by 20 to 30 minutes, but it can also occur in the absence of headache (acephalgic migraine). Enlarging scintillating scotoma, a scotoma surrounded by sparkling light, is almost pathognomonic of migrainous aura. The speed of enlargement increases as it expands because of the relative larger cortical representation of the central visual field than the peripheral. Other common features of the migrainous aura include spots, wavy or zigzag lines (fortification spectra), and shimmering effects in the visual scene. These can happen in the entire visual field, in a hemifield, or in only one quadrant of the visual fields and then progress to involve the whole visual field. 348 Neuro-Ophthalmology: Blue Books of Neurology

Bedside Testing of a Patient with Suspected Higher Visual Disorder

Standard neuro-ophthalmologic examination includes visual acuity, visual fields, pupil light reactions, and funduscopy; together, these provide important clues in making a diagnosis of a higher visual disorder. Visual field testing with a confrontation technique is an easy way to detect large visual field defects and it has the advantage of examining the most peripheral region of the visual field. Visual field defects detected by confrontation are usually a true deficit, although this technique lacks sensitivity. More detailed information, especially at large eccentricities, can be obtained by using the Bjerrum tangent screen visual field test. Static automated threshold perimetry provides many advantages, including more standardized testing procedures, and requires less technician skill. It also yields high reproducibility, which is very important for follow-up purposes, but the process is laborious. In general, kinetic perimetry requires less cooperation, can be done in cases of severe visual loss, and tests a wider area of the visual field, but it is very time consuming and dependent on technician skill and experience. Full-field achromatopsia can be formally tested by using standard tests, for example, color plates or color arrangement tests. It is useful to have some objects of different colors (i.e., bottle caps) in the clinic, which can be used to test for gross hue discrimination deficits (i.e., ask the patient to point to the red cap). Standard pseudoisochromatic plates, for instance Ishihara color plates, can be used. In addition, Ishihara color plates or Hand Rittler Round plates also offer additional advantages such as the ability to differentiate between generalized loss of color perception (as seen in achromatopsia) and congenital color blindness (usually red-green defect). In addition, in hemiachromatopsia, the patient might miss the number on the color-deficient side when using the two-numbered plates. Asking the patient to trace a perceived outline with a finger on these pseudoisochromatic plates is sometimes required because this does not require language skills that might be defective (alexia or aphasia), as may particularly occur in left-sided lesions. The standard tests for color vision such as the Farnsworth Munsell 100 Hue test (tests hue discrimination at a fixed luminance), the Lanthony New Colour Test (tests hue discrimination as well as which colors are confused with grays), and the Lightness Discrimination Test (tests the range of gray from light to dark)135 are required to make a firm diagnosis. Patients with cerebral achromatopsia usually have abnormal hue discrimination with preserved perception of brightness.136 Disorders of motion perception cannot easily be tested by bedside examination. The traditional testing for visual object agnosia is to ask the patient to name an object placed in front of him or her. Different objects, preferably real ones, may be used for the test, and they should be presented in the intact visual field where there is known reasonable acuity. The examiner should then check that the patient can actually see the object by asking the patient to give a verbal description (i.e., shape, color) or draw a copy. In associative visual agnosia, drawing and copying ability should be intact. The next step is to ask the patient to name the object. It must be noted at this stage that “naming” and “recognizing” are not the same. It is true that naming requires object recognition, but the reverse is not true. Intact recognition can be declared if the patient can express 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 349

an abstract aspect of the object (e.g., its use) even if he or she failed to name it (anomia). Prosopagnosia, when it occurs in isolation, can be very dramatic as the patient can recognize any object but cannot recognize pictures of famous faces or the face of family members. Pictures of famous faces (i.e., the presi- dents/prime ministers or famous celebrities) can be used to test face recognition; however, these pictures should not contain any significant cues (e.g., Elton John’s glasses or Abraham Lincoln’s beard) that might aid the patient recognition. It should be noted that these object recognition disorders, including prosopagnosia, rarely occur in isolation but are usually present with other cortical visual disorders, of which hemianopia and achromatopsia are the commonest. Simultanagnosia can be tested clinically relatively easily. Any pictures that contain more than one object can be used for the test. Typically, patients with simultanagnosia tend to attend and describe only one object and fail to report the others. Ideally, the picture should be well balanced in its four quadrants, for instance the famous “Cookie Theft Picture” from the Boston Diagnostic Aphasia Examination.

Clinical Course, Prognosis, and Therapeutic Options

The overall prognosis for cortical visual disorders is poor. Complete resolution of defective functions rarely happens except in the case of reversible causes such as migraine or epilepsy. Some patients with acquired homonymous hemianopia may not recognize the deficit especially when a right hemispheric lesion results in visuospatial neglect. However, most patients do eventually become aware of their defective fields. About 20% to 30% of all patients in neurologic rehabilitation centers have homonymous visual field disorders.137 Partial field recovery mainly occurs in the first 2 to 3 months in about 10% to 20% of patients, with the average visual field recovery of 5 degrees.138 After this, further recovery is rarely seen. Vision usually returns to the hemianopic field in stages, starting with the perception of light and followed by motion, form, color, and stereognosis in that order.139 Less than 10% of patients recover their full visual field. Poor recovery is particularly seen in elderly patients with a history of diabetes or hypertension, large lesions, and the presence of cognitive, language, or memory impairment. The quality of life is particularly affected in the case of hemianopia without macular sparing. Spontaneous recovery from visual agnosia resulting from carbon monoxide poisoning has been described in detail by Adler,140 but patients with visual agnosia generally do not show dramatic recovery because of the extensive damage to the visual cortices. Prosopagnosia also carries a poor prognosis. In an attempt to treat homonymous hemianopia, two approaches have been studied: first, to gain the ability to cope and compensate for such a defect, and second, to enhance recovery of the area of defective visual field (see reviews in references 141 and 142). Numerous treatments have been tried in the hope that the area of the visual field defect will become smaller by using appropriate training or therapy. Some studies have shown a reduction in the area of visual field defect,47,143 but this has not always been replicated.144–146 In most patients who improved with these techniques, the field enlargement does not exceed 5 degrees 350 Neuro-Ophthalmology: Blue Books of Neurology

of eccentricity, although there has been the occasional individual case with remarkable recovery. The more recent studies by Sabal and colleagues147–149 have shown some reduction in the area of visual field defect. However, fixation has not always been adequately controlled and a recent study in which this was achieved using a scanning laser ophthalmoscope (SLO) failed to replicate these results.150 Patients with a possible reversible area of field defect, as indicated by a poorly demarcated border on visual field testing, are more likely to recover than those with a sharply demarcated field defect. To improve visual function in hemianopia, optical aids may occasionally be helpful. Hemianopic spectacles work on the basis that they permit the patient to look at an adjustable mirror and see the reflection of objects in the hemianopic field. It is conventionally placed alongside the left eye in left hemianopia and the reverse is true for right hemianopia. Hemianopic prisms can be carefully incorporated into the existing lenses to displace the image of objects from the hemianopic field into the intact one. Conventionally, only one lens is fitted because bilateral placement usually affects the visual acuity, which could be more troublesome. In addition, the central area must be trimmed to avoid diplopia in primary gaze.151 Use of prisms improved vision in several domains including recognition152 and activity of daily living.153 The fitting requires skilled opticians and the process is rather laborious. Another strategy that may help to improve visual function in a hemianopic patient is to use visual search training to get the patient to increase exploration of their hemianopic field. It has been shown to successfully expand the visual search field (the perimetrically measured area that a patient can actively scan via eye movements without head movements154). Using a relatively simple visual search retraining program, which patients could use at home, it was found that reaction times to locate targets in the hemianopic field reduced and they improved in activities of daily living.155 Hemianopia also significantly impairs the ability to read. In a culture in which the reading is from left to right, patients with left hemianopia have great difficulty searching for the beginning of the next line. Right hemianopia, however, is generally accepted to cause more difficulty when reading as most people make a saccade toward the beginning or middle of the word, and as a result of the hemianopia the rest of the word is not seen. Hence, it is probably sensible for patients with a left hemianopia to try to read the word as a whole while focusing on the beginning of the word and for right hemianopes to make a saccade to the end of the word before reading it. Zihl and Kennard156 used this strategy to successfully train patients with hemianopia who by the end of the training were able to read faster with fewer errors by using larger saccadic jumps and shorter fixation periods. Wang157 reported a helpful trick used by his patient with right hemianopia; when reading an article, the patient rotated the article 90-degrees clockwise and read it up to down instead of left to right. Rehabilitation for other types of cortical visual disorders has not attracted much interest from researchers, possibly because of the rarity and the lesser effect on quality of life in comparison with hemianopia. In addition, patients with these disorders often have extensive bilateral lesions, which cause additional deficits that complicate the rehabilitation planning. Furthermore, the response to such rehabilitation is not readily quantifiable as it is in hemianopia. 14 Cortical Visual Disorders—Functional Localization and Pathophysiology 351

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Page numbers followed by ‘f’ indicate material found within a figure. Page numbers followed by ‘t’ indicate tabular material.

A Acute demyelinating optic neuritis, 171–172 Abducens nerve, 12f, 16, 321 Acute idiopathic blind spot enlargement Abnormal liver function tests, 126 syndrome (AIBSE), 50–51 Acetylcholine receptor antibody, 317–318 Acute inflammatory symptoms, 66–67 Achondroplasia, 303 Acute leukemia Achromatic contrast sensitivity, measures spatial form of, 231 luminance, 138 of infiltrative optic neuropathy, 231 Achromatopsia, central, from occipitotemporal Acute macular neuroretinopathy (AMN), 50–51 lesions, 29 Acute myeloid leukemia, 90 Acquired arterial pulsation, 60–63 Acute NAION, treatment of, 121 Acquired immunodeficiency syndrome (AIDS), Acute nausea, 63–64 160 Acute optic neuritis Acquired ocular motility disorders neuro-ophthalmologic complications, 159 abnormal spontaneous eye movements, perivenous sheathing in, 140f 327–328 Acute optic neuropathy, 45 nystagmus, 327 causes of, 117 saccadic intrusions, 327–328 ION, common, 112 clinical approach and diagnostic tools, Acute orbital decompression, 87–88 313–315 Acute sinusitis, 75 introduction, 312–313 Acute surgical intervention, 87–88 ophthalmoparesis, 323–324 Acute visual loss, with acute nausea, 63–64 brainstem disorders, 322–323 Acute zonal occult outer retinopathy (AZOOR), cranial nerve palsies, 321–322 50–51 extraocular muscles, 315–316 Adenoid cystic carcinoma neuromuscular junction, 316–318 common lacrimal malignancy, 90 supranuclear ocular motility control, of right lacrimal gland, 90f 323–324 Adenomas, 242, 243 Acquired pendular nystagmus (APN), 325 ADH. See Antidiuretic hormone in setting visual loss, 325 Adrenoceptors, cause dilation or mydriasis, 264 treatment of, 325 Adrenocorticotropin-stimulating hormone Acromegaly (ACTH), 239 and Cushing’s disease, 240–241 Age from somatotroph cells, 239 of presentation, 249 ACTH. See Adrenocorticotropin-stimulating and pupil diameter, relation between, 266f hormone Age-related macular degeneration, 49–50 ACTH-secreting tumors, 243–244 Aggressive disease, management of, 59 ACTH-staining types, 245 Agnosia Active duction, globe retraction during, 67 disorder of visual perception, 343 Active inflammatory eye disease, 270 visual object, 340–341 Acuity loss, 161 AIBSE syndrome. See Acute idiopathic blind Acute arteritic anterior ischemic optic spot enlargement syndrome neuropathy, with giant cell arteritis, 125f, AION. See Anterior ischemic optic neuropathy 126f Airborne spores, inhalation of, 160 Acute bacterial sinusitis, 165 Akinetopsia, 338–339 Acute bilateral visual loss, in giant cell arteritis, Alexia, testing for, 24 125f Allotypic expression, 203 Acute bleeding, with anemia, 120 Alzheimer’s disease, 346 Acute/chronic inflammation, with systemic Amaurosis fugax, 47 diseases, 80 American Academy of Neurology, Quality Acute dacryoadenitis Standards subcommittee of, 148–149 with nonsteroidal anti-inflammatory drugs, 81 Amsler grid testing, 27 with tenderness, 66–67 to assess macula function, 27f 357 358 Index

AMN. See Acute macular neuroretinopathy Artery occlusions ANA. See Antinuclear antibody branch retinal, 52 Anastomotic circle of Zinn-Haller, 3–4 central retinal, 52f ANCA. See Anti-neutrophil cytoplasmic antigen Aspergilloma, within nasal sinusitis, 160 Ancillary testing, 44 Aspergillus, 160, 165 Aneurysm Asymmetric pupil size, 31–32 with bitemporal visual failure, 256f Asymptomatic abnormalities, of visual function, presence of, 13–14 140–141 Angioimmunoblastic lymphadenopathy, 229 Ataxia and meningoencephalitis, 154–155 Angle closure glaucoma, 47 ATECO. See Autotriggered elliptic centric- Anisocoria, 31–32 ordered form of, 31–32 Atherosclerosis-related vascular diseases, 121 pathologic, 32 Atonia, of efferent urinary tract, 201 Annulus of Zinn, 11–12, 15, 16–17 Atropine, to dilate pupils, 268–269 Anoxic brain damage, diffuse, 40 Autoantibodies Anterior function syndromes, rarities of, 240 prevalence of, 171–172 Anterior ischemic optic neuropathy (AION), thyroid associated, 172 119t, 135–137 Autoimmune disease, 253 acute, 120 Autoimmune optic neuropathy, 171–172 disorders and drugs suggested with Automated perimetry, 30 occurrence of, 119t Autosomal-dominant optic atrophy, 191, embolic, 120 199–200 nonarteritic, 118t Autosomal recessive disorder, 201–202 Anterior uveitis, 166, 176 Autotriggered elliptic centric-ordered (ATECO) Anticholinergic toxin, 318 MRV, 291 Antidiuretic hormone (ADH), 240 Axonal swelling, 281 overproduction of, 240 Azathioprine, immunosuppression with, 167 Anti-GQ1b antibody, 322 AZOOR. See Acute zonal occult outer Anti-neutrophil cytoplasmic antigen (ANCA), retinopathy 70–71, 172–173 Antinuclear antibody (ANA), 170–171 and anti-DNA antibody, 177–178 B in ONTT, 141 Bacille Calmette-Guerin (BCG), 172 Antiphospholipid antibody syndrome, 172–173, Balint’s syndrome, 343 179 Bartonella henselae, causes cat scratch disease, Antiplatelet agents and calcium-channel blocker, 160 108 Basal dura, stretching of, 241 Antiretroviral therapy, mitochondrial function, Basilar invagination, 326 198 B-cell non-Hodgkin’s lymphomas, 91–92 Anton’s syndrome, 11, 336 BCG. See Bacille Calmette-Guerin Aortic arch atherosclerosis, 100 Behc¸et’s syndrome, 138, 166–167, 176, 176f Aphasia, 11 Benign orbital diseases, 88 APN. See Acquired pendular nystagmus B. henselae, treatment for, 162–163 Aquaporin-4 water channel, 173 Bilateral chronic dacryoadenitis, 83f Arachnoid hyperplasia, 208 Bilateral Horner’s syndrome, 272f Arcuate bundles Bilateral lacrimal drainage obstruction, infant inferior, 2–3 with, 77f superior, 2–3 Bilateral optic neuritis, development of, 178 Area V5, 338–339 Binocular diplopia, 313, 313f Argyll Robertson pupil, 277–278 Biopsy, 254–255 Arnold-Chiari malformation, 326 Bitemporal field loss, 241 Arteriosclerotic vascular risk factors, treatment Blindsight, 336–337 of, 108 Blood sugar, elevated, 95 Arteritic AION, 112–113, 118t, 121 Blood supply, for optic chiasm, 8 clinical presentation of, 121–124 Blood tests, 149 nature of, 126–127 Blowout fracture, 65f Arteritic ION, 112–113 Bone scalloping Artery biopsy, with Churg-Strauss syndrome, on CT scans, 251 181f with intact cortex, 73–74 Index 359

Botulism, 318 Central retinal vein occlusion (CRVO), 53, 211 Brachytherapy, implantation, 90–91 descriptions of, 53 Brain Central serous retinopathy (CSR), 48–49 CT of, 195 Centrocecal scotomas, in ONTT, 138 MRI of, 173 Cephaloceles, with neurofibromatosis, 75–76 Brainstem injury, complete, 39–40 Cerebral achromatopsia, 337–338 Brainstem pathways effect of, 337–338 for horizontal gaze, 17f etiology of, 337 for vertical saccades, 18 Cerebral akinetopsia, 338–339 Brain tumors, 302 Cerebral artery infarction, 105f and space-occupying tumors, 289 Cerebral infarction, 333 Breathing pattern, evaluation of, 39 Cerebral lesions, cause visual disorders, 335 Bright light, to assess pupils, 31 Cerebral polyopia, 345 Brucella infection, of nervous system, 159 Cerebrospinal fluid (CSF), 154–155 Bull’s-eye maculopathy, with cone abnormal, 143 dystrophy, 55f pressure, 60–63 Buried drusen, 287f Cerebrovenous thrombosis, 302 Burst neurons, in brainstem, 323 Cervical cord, sagittal MRI of, 174f Busacca nodules, 166 Charcot-Marie-Tooth disease (CMT), 201–202 Charles Bonnet syndrome, 346–347 C Chester-Erdheim disease, 255 Calcarine cortex Chiasmal disease, common defect of, 8 occipital lobes and, 9–10 Chiasmal lesions, 276–277 upper and lower bank of, 9 Chiasmal/retrochiasmal disease, visual field Campylobacter jejuni infections, 322 defects from, 4 Candle wax drippings, 166–167 Chiasmal syndrome, etiology of, 8 CAR. See Carcinoma-associated retinopathy Chiasmal visual loss, 8 Carbonic anhydrase inhibitors, complications Childhood, familial storage diseases and cerebral of, 296 degenerations of, manifest optic atrophy, Carcinoma-associated retinopathy (CAR), 56 202t Cardiac disease, as manifestations of systemic Chin depression, 34 disorders, 2 Chocolate cysts, 77–78 Carotico-cavernous fistula Choked disc, 280 with acute proptosis, 79–80 Cholesterol, multiple and platelet-fibrin emboli, atheromatous, 81f 100f Carotid angiogram, 103f, 256f Chondrosarcomas, 250–251 Cataracts, cause blurring, darkening, 46 Chordomas, 251 Cat scratch disease, 162 Chorioretinitis, retinal periphlebitis on, Cavernous hemangioma 166–167 adulthood benign orbital mass, 78–79 Choroidal circulation, 52 during surgical removal, 80f Choroidal folds Cavernous meningioma, 247f on funduscopy, 63–64 Cavernous sinus syndrome, 15, 18, 246, 321 and macular edema, 296 Cushing’s tumor invading, 245f Choroidal hypoperfusion, on retinal fluorescein diagram of, 13f angiogram, 102f with ophthalmoplegia, 241 Choroidal ischemia, TMVL from isolated, 102 orbital apex and, 18 Choroidoretinitis, 160 and pituitary fossa, 251 Choroid plexus papilloma, 302–303 Celiac disease, 176–177 Chronic anterior uveitis, 160 with anti-gliadin antibodies, 176–177 Chronic degenerative changes, 49–50 with neurologic complications, 176–177 Chronic headache, causes of, 298 Cellular anaplasia, degree of, 214 Chronic hypoperfusion, 101–102 Cellular components, 214 Chronic inflammation, 270 Central acuity loss, cause for, 27 Chronic insidious panuveitis, 167 Central nervous system (CNS), 225 Chronic ocular hypoperfusion, 101–102 Central retinal artery (CRA), 52 Chronic progressive external ophthalmoplegia occlusion of, 52 (CPEO), 316 cases of, 52 Chronic relapsing inflammatory optic funduscopic appearance of, 52 neuropathy (CRION), 170f, 171f 360 Index

Chronic uveitis, 166 Corneal sensation, 68 Churg-Strauss syndrome, 154, 181 Corneal surface, luster of, 47 Ciliary arteries, posterior, 3–4 Coronary artery bypass graft surgery, bilateral Ciliary ganglion, damage to, 274–275 anterior ischemic optic neuropathy after, Cilio-retinal shunt vessels, 70 129f Circle of Zinn-Haller, 113–114, 113f Cortical blindness, 11, 336 Circulation stenosis, anterior, 100 Cortical visual disorders Claude’s syndrome, 15 prognosis for, 349 Clioquinol, toxins, 172–173 types of, 350 Clival chordoma, compressing brainstem, 251f Corticosteroids, 154–155 CMT. See Charcot-Marie-Tooth disease with acute papilledema, 296 CNS. See Central nervous system with arteritic ION, 127 Cogan’s lid twitch sign, 34, 316 and cyclophosphamide, 182 Cold caloric test, 39–40 Cover-uncover test, 37–38 Color agnosia, 338 CPEO. See Chronic progressive external Color anomia, 338 ophthalmoplegia Color blindness, tests for congenital, 25–26 CRA. See Central retinal artery Color bottle top, to detect color difference, 25f Cranial nerve deficits, multiple, 63–64 Color-coded Doppler B-mode imaging, for Cranial nerve nuclei, 322–323 vascular anomalies, 71–72 Cranial nerve paresis, causes of third, fourth, Color-naming defect, 338 and sixth, 322t Color plate test, utility of, 25–26 Cranial nerves, anatomic considerations of third, Color selective area, 332 fourth, and sixth, 16–18 Color vision, 25–26, 193, 337 Cranial neuropathy, investigation of, causing abnormal, 145 diplopia, 321 assessed using Ishihara, 25–26 Craniopharyngiomas, 243, 249 tests of, 137 Craniotomy Coma for giant tumors, 245 abnormal ocular fundi in, 41 route of, 247–248 causes of, 38 CRAO. See Cental retinal artery (CRA), eye movement abnormalities in, 40–41 occlusion of neuroanatomic correlates of, 38 C-reactive protein pupillary abnormalities in, 40 ESR and, 127 unexplained, 38 and fibrinogen, 106, 126 Comatose patients CRION. See Chronic relapsing inflammatory approach to, 39 optic neuropathy examination in, 39–40 Crossed innervation, 15 Complex cells, 334 CRVO. See Central retinal vein occlusion Computed tomography angiography (CTA), 106 Cryptococcus, 161 Computed tomography, modality for orbital CSF. See Cerebrospinal Fluid conditions, 60 CSF absorption, interference with, 300 Computerized perimetry, with glaucoma or CSF lymphocyte pleocytosis, 162 papilledema, 30 CSR. See Central serous retinopathy Cone dystrophy CTA. See Computer tomography angiography bilateral loss of central vision, 54 Cup-to-disc ratio, illustration of, 116f as bilateral optic neuropathy, 55f Cushing’s disease, from corticotroph cells, 239 Congenital fourth nerve palsy, diagnosis of, Cushing’s tumors, pretreatment of, 244–245 36–37 Cyberknife, LINAC units, 220 Conjugate gaze, in vertical and horizontal Cytoplasmic-pattern ANCA (c-ANCA), 181–182 planes, 19 Conjunctival chemosis, gross, 81f Contrast sensitivity D and low-contrast letter acuity, 26 Dalen-Fuchs nodules, 177 measure of visual function, 26 Death, risk of, 104 types of, 26 Defective visual localization, 344 Corneal haze, 47 Degenerations, retinal, 54–56 Corneal light reflection test, 314f Degenerative brainstem diseases, 323–324 Corneal reflexes, testing of, 40 Demyelinating disease, primary, 135 Corneal scarring, 276 Dermoid cysts, 66–67, 73–74 Index 361

Dermolipomas, from dermis, 74–75 Duction testing, forced, 37f Desquamated epithelium, accumulation of, Dural biopsy, of dura, 170f 73–74 Dural shunts, 79–80 Deviations Dural venous thrombosis, 302 concomitant, 37 Dyschromatopsia inconcomitant, 37 acquired, 26 Devic’s syndrome, 153–154, 172, 174f, 176–177, with funduscopic abnormality, 26 177–178 with optic nerve lesions, 26 diagnostic criteria for, 175t Dysmetropsia, 345–346 Diabetes insipidus, presence of, 240 Diabetes mellitus bilateral Horner’s syndrome in, 272 E as manifestations of systemic disorders, 2 Edinger-Westphal nucleus, 19–20, 268–269, 336 symptoms and signs of, 201 contralateral, 265–267 Diabetic papillopathy, 131f Edrophonium chloride test, 317 DIDMOAD, (diabetes insipidus, diabetes Edrophonium test method, for diagnosis in mellitus, optic atrophy, and deafness), myasthenia gravis, 318f 201 Electrophysiology, 56 Dilation lag, 32 Electroretinogram (ERG), 50–51 Dilator muscle, by sympathetic neurones, 265 ENA. See Extractable nuclear antigens Diplopia Endocrine disease, 307 as binocular, 34 Endothelial cell, with pericytes, 214 causes of, 64–65 Enophthalmos and hypoglobus, 65f crossed, 35–36 Epidermoids and dermoids, 252 monocular, 34 Episcleral vasculature, dilated, of low-flow dural Disc abnormalities, for papilledema, 283–284 shunt, 69f Disc, at risk, 114–117, 117f Episcleral vessels, 68 Disc drusen, 287f Epithelial cysts, 73 Disc edema, 57, 280–281 ERG. See Electroretinogram diffuse/segmental, 113–114 Erythrocyte sedimentation rate (ESR), 124–126, in setting intracranial pressure, 97f 141 Disc pallor, 138 Esodeviation, 35f,36f temporal, 140f Esotropia, amount of, 321 Disc swelling, 161 ESR. See Erythrocyte sedimentation rate asymptomatic, 130 Ethambutol, toxic to optic nerve, 198 causes of, 288 Ethmoid air cells, anterior, 164 diabetes mellitus develop, 130 Ethmoidal mucocele, displacement of left globe, generic, 281 76f mechanism of, 130 Ethmoid and sphenoid sinus, mucoceles of, 164f mild, 140f Exophthalmos, 60–63 DNA, extranuclear, source of, 195–196 Extractable nuclear antigens (ENA), 179 DOA. See Dominant optic atrophy Eye charts, for maximal contrast, 26 Doll’s eye, 39 Eye deviation, conjugate lateral, 40 Doll’s head, 16–17, 41 Eyelid Dominant optic atrophy (DOA), 196f elevator muscle, 12–13 autosomal, 199 examination of, 32–33 with Kidd blood group antigen, 200–201 function, defined, 32f phenotypic variant of, 199–200 meibomian gland carcinomas of, 92–93 Dorello’s canal, 321 retraction beneath petroclinoid ligament, 16–17 causes of, 32–33 Dorsal midbrain syndrome, 323 from dorsal midbrain compression, 33f Downbeat nystagmus, 326 upper, 68f effective treatments for, 326 swelling, 68 Drug chemotherapy, with or without orbital tenderness of, 66f radiotherapy, 89–90 Eye movements Drugs, on iris color, 269 abnormality in coma, 40–41 Drug toxicity, as manifestations of systemic disorders, 312 disorders, 2 functional class of, 314–315 Drusen, computed tomography scan of, 287f initiation of conjugate, 18 362 Index

Eye movements—Cont’d Functional MRI (fMRI), 335 muscles responsible for, 11 Fundus restriction of, 81f photograph of normal left, 3f summary of, 17f schematic diagram of normal left, 3f vergence, 314–315 Fungal disorders, 161 vestibular, 314–315 Fusiform face area, 333 Eyes conjugate movement of, 18 dysconjugate, 40–41 G effect of removal of fixation on, 314 Gadolinium, showing Arnold-Chiari type I esotropia, 35 malformation, 327f exotropia, 35 GAG deposition, 83–84 hypertropia, 35 accumulation of, 83–84 inability to move, 37 Gamma aminobutyric acid (GABA)-ergic neural symptoms and signs of, 83–84 transmission, 325 test for horizontal deviation of, 35f Gamma knife, 245 testing for vertical separation of, 36f Ganglioglioma, of optic nerve, 213f Ganglion cells, 2–3, 51 axons of, 51 F damage to, 51 Face recognition, 341–342 involvement of, 198 Facial colliculus syndrome, 16–17 near mandible, 20–22 Farnsworth D-15 panel test, 25–26 Ganglion cell tumors, within optic nerve, Farnsworth-Munsell 100 hue test, 25–26 211–212 Fatigueable ptosis, 34 Gaze deviation, 323 Fatigue waves, 268–269 Gaze-evoked nystagmus, 327 Fat, proptosis and patchy infiltration of, 92f Gaze palsy, 16–17 Fat-saturated fast spin echo, 142 Gene therapy, form of, 203 FBC chemistry screening, blood test for, 141 Genetic analysis, 198 FEF. See Frontal eye fields Geniculocalcarine fibers, for calcarine cortex Fibers form, 9 destined for iris dilator muscle, 265 Germinoma, 251 form optic nerve, 51 GH-secreting tumors, 243–244, 244–245 Fibroblast activation and GAG deposition, Giant cell arteritis, 102, 121–124, 126, 128, 154, 83–84 183 Field testing, 241 artery biopsy showing, 183f Fine needle aspiration, to establish diagnosis, diagnosis of, 126–127 226 ophthalmologic manifestations of, 124t Fixation, with normal ocular alignment, Glasgow coma scale, 40 313f Glial tumors, of optic nerves, 250 Florid enhancement, in infected mucocele, Glioma, surgical excision of, 210 254f Globe displacement, 65f,66 Fluorescein angiography, 56, 126–127, 161–162, Goldmann kinetic perimeter, on damaged 172 eye, 241 FMRI. See Functional MRI Goldmann perimetry, 287–288 Follicle-stimulating hormone (FSH), 239 to test for visual field defects in neuro- Formal perimetry, 30 ophthalmic patients, 30 Fossa trigeminal Schwannoma with double Goldmann visual field, showing relative central vision, 252f scotomas, 55f Fourth nerve, 15–16 Granular cell tumor, 255, 255f Fourth nerve palsy, 16, 319–320 Granulomatous angiitis, 182 lesions of, 15–16 Granulomatous inflammation, 170–171 photograph of, 16f Granulomatous tissue, 166 Fovea, preservation of cherry red spot Graves’ disease, 83–84 at, 52f Graves’ thyrotoxicosis, treatment of, 86 Friedreich’s ataxia, 201–202 Growth disorders, 303 Frontal eye fields (FEF), 323 example of, 303 FSH. See Follicle-stimulating hormone Gruber’s ligament, 16–17 Full-field achromatopsia, 348 Guillain-Barre´ syndrome, 322 Index 363

H Horner’s syndrome, 16, 32, 120, 269 Hair follicles, cutaneous sinus containing, 74f bilateral, 272 Hairy dermolipoma, overlying lateral sclera, 75f causes of, 272 Hallucinations evaluating, 269 complex, 347 left-sided, 271f release, 347 preganglionic, 272 visual, 347 signs of, 20–22, 272 Hand Rittler Round plates, 348 unilateral postganglionic, 271f Hardy-Rand-Rittler (HRR) color plates series, HRR. See Hardy-Rand-Rittler 25–26, 25f, 137 Human brain Harlequin syndrome, 271–272 drawing of lateral surface of, 334f Headache drawing of medial surfaces of, 338f categorize of, 242 Humphrey static perimetry, 241 cause of, in hydrocephalus, 298 Humphrey visual field, 116f, 287–288 with high pressure, 285 Huntington’s disease, 323–324, 346 with idiopathic intracranial hypertension, Hydrocephalus, 169, 302–303 diagnostic criteria for, 297t development of, 159 relief, extent of, 297 with shunts, 249 symptom of papilledema, 285 Hypercoagulable, with NAION, 120 Head turning, 41 Hyperemia, of optic nerve head, 194 Hearing loss, severe and congenital, 199–200 Hyperglycemia/hypertension, control of, Heidenhain variant, of Creutzfeldt-Jacob disease, 86–87 336 Hyperopic disc, 285f Hemangioblastomas, composed of, 214 Hyperostotic sphenoidal type, 248 Hemangiopericytoma, 72 Hyperostotic sphenoid wing meningioma, 246f as symptomatic, 224 Hyperplasia, thyrotroph, 240f type of angioblastic meningioma, 223–224 Hypertension Hemianopsia defects, 5f and hypercoagulability, 53 Hemiparesis, 11 as manifestations of systemic disorders, 2 Hemorrhage systemic, treatment for, 295 drainage of, 77–78 Hypertrophic pachymeningitis, 321 and hydrocephalus, 323 Hypophysitis, 253–254 Hepatitis B, 172 Hypotension, 100–101 Hereditary optic neuropathy Hypotensive retinopathy, 101f classification of, 191 Hypothalamic lesions, 40 dominant optic atrophy, 199–201 hereditary diseases, 201–203 Leber’s, 192–198 I with mitochondrial dysfunction, 196f Ice pack test, 317 therapeutic implications, 203 ICP. See Intracranial pressure Hering’s law,on neural innervation to eyelids, 316 Idiopathic, 81–82 Hess charting, 67 Idiopathic hypertrophic pachymeningitis, High-dose steroids, 253 complications of, 180 Higher visual disorder, 348–349 Idiopathic intracranial hypertension (IIH) High-flow fistula, 68 associations with, 301t High-pressure arteriovenous communications, of and diplopia, 284 intraconal circulation, 79–80 modified Dandy criteria for, 300t High-pressure headaches symptoms and signs of, 300 bilateral, 297 Idiopathic TMVL, in young individuals, 102 unilateral, 297 IIH. See Idiopathic intracranial hypertension High-resolution imaging techniques, 335 Immunoglobulin G, elevated, 143 Hodgkin’s disease, and non-Hodgkin’s Implantation cysts, 73–74 lymphoma (NHL), 72, 228 INC. See Interstitial Nucleus of Cajal Holmes-Adie syndrome Inconcomitant deviations, 37 clinical diagnosis of, 275–276 Incongruous defects, 5f irregular pupil shape in, 274f Inferior temporo-occipital cortex, lesions in, 342 signs in, 275–276 Inflammatory diseases, of orbit, 80–82 Homonymous defects, 5f Inflammatory disorders, 321 Homonymous hemianopia, 349–350 Inflammatory edema, STIR sequences on, 84–86 364 Index

Inflammatory optic neuropathy Intracranial pressure (ICP)—Cont’d chronic relapsing, 171 magnetic resonance findings of, 295f clinical characteristics of, 118t and papilledema, 302 connective tissue disorders and systemic Intracytoplasmic mitochondria, 195–196 vasculitis, 183 Intraocular pressure Churg-Strauss syndrome, 181 acute elevation of, 120 giant cell arteritis, 165 measured by applanation tonometry, 70 granulomatous angiitis of central nervous Intraorbital dermoid, and lacrimal gland fossa, system, 182 66f lupus, 177–179 Intraorbital optic nerve, 3–4 mixed, 179–180 Intravenous corticosteroids, treatment with, 149 polyarteritis nodosa, 182 Intravenous immunoglobulin (IVIG), 175 rheumatoid arthritis, 180 ION. See Ischemic optic neuropathy scleroderma, 180 IONDT. See Ischemic optic neuropathy Sjo¨gren’s syndrome, 179 decompression trial Wegener’s granulomatosis, 181–182 Ipsilateral ethmoidal, abnormal and sinus, 78f with infections, 164–165 Ipsilateral Horner’s syndrome, presence of, 16 bacterial disorders, 159–160 Ipsilateral internal carotid artery,occlusion of, 98f fungal disorders, 161 Ipsilateral pupil, constriction of, 265–267 human immunodeficiency virus infection, Iris dilator muscle, 20–22 155–159 radial fibers in, 264 neuroretinitis, 162–163 Iris ischemia, with or without rubeosis, 270 treatment, 162–163 Iris nodules, develop, 166 viral disorders, 155–159 Iris periphery, elevation of, 47 introduction, 154 Iris sphincter muscle, 264 optic perineuritis, 163–164 Ischemia, for visual loss, 295 sinus mucocele and pyocele, 165 Ischemic disorder, 130 ethmoid sinus, 164 Ischemic optic neuropathy decompression trial sphenoid sinus, 165 (IONDT), 113 systemic inflammatory disorders, 177 with cerebrovascular disease, 117–120 with autoantibodies, 171–172 Ischemic optic neuropathy (ION), 112 Behc¸et’s syndrome, 175–176 after nonocular surgery, 128–130 celiac disease, 176–177 anterior, 112, 114f Devic’s syndrome, 175 arteritic, 127–128 with inflammatory bowel disease, 177 diagnosis, 121–124 sarcoidosis, 167–169 diagnostic tests, 124–127 vaccination, 172 treatment and outcome, 127–128 Vogt-Koyanagi-Harada syndrome, 177 bilateral posterior, 115f Inherited optic neuropathy, 201 diabetic papillopathy and pre-AION optic disc INO. See Internuclear ophthalmoparesis edema, 130 Interferon-alpha, 120 luxury perfusion in nonarteritic anterior, 116f Internuclear ophthalmoparesis (INO), 324 nonarteritic anterior, 117f, 121 bilateral, 324 diagnosis, 113–117 and skew deviation, 325 risk factors and recurrence, 117–121 unilateral, 324 treatment, 121 Interstitial Nucleus of Cajal (INC), 17f perioperative, 128–130 Interstitial/stromal cell, 214 posterior, 112, 128 Intraconal cavernous hemangioma, 79f radiation, 130 Intracranial hypertension, 169 Ishihara, color deficits on, 145 cause of headache in, 298 Ishihara color plates, 137, 348 medications reported to cause, 304t to assess hereditary dyschromatopsia, 66 with papilledema, 303–307 Isolated Horner’s syndrome, 272–273 primary, 301–299 IVIG. See Intravenous immunoglobulin secondary, 307–302 Intracranial noise, symptom of papilledema, 285 K Intracranial pressure (ICP), 280 Kappa light chains, 143 cause of increased, 280 Kearns-Sayre syndrome, 316 infections with, 307 Keratitis and corneal ulceration, 166 Index 365

Kidney basin, under ear, 39–40 LSD. See Lysergic acid diethylamide Kjer’s disease, 199 Lumbar puncture (LP) Koeppe nodules, 166 with opening pressure, 289–290 used to treat high pressure, 298–299 Lung and breast carcinoma, metastases from, L 252–253 Lacrimal gland carcinoma, 90, 91f Lupus erythematosus, 177–178 treatment for, 90–91 Luteinizing hormone (LH), 239 Lacrimal gland fossa, 90–91 Lyme disease, 160 Lacrimal gland inflammation, subacute, 59 Lymph nodes, regional, 70 Lacrimal gland, left, smooth enlargement of, 83f Lymphoid malignancies, 316 Lacrimal gland mass, nature of persistent, 90–91 Lysergic acid diethylamide (LSD), 345 Lactotroph cells, 239 Lambert-Eaton myasthenic syndrome, 318 Langerhans cell histiocytosis, 90, 255f M Lateral geniculate nuclei (LGN), 9 Macropsia, 346 unilateral lesions of, 10 Macula and outer retina, abnormality of, 48–51 Leber’s hereditary optic neuropathy (LHON), Macular abnormality, detection of, 27, 56 173, 191, 192–193, 195f, 196f, 197f Macular area, in occipital poles, 9 diagnosis of, 198 Macular degeneration, 49–50 and dystonia, 197f with macular drusen deposits, 49f manifestation of, 159 Macular hole, 50, 50f and multiple sclerosis, 195 Macular infiltrate, 162 phenotypic expression in, 198 Macular lesions, 162 screening for, 196–197 Macular sparing, in occipital lobe lesions, 10–11 theories on pathogenesis of, 198 Macular star, 161, 161f Lesions Maculopathy, causes of, 50 diagnosis of, 242t Maddox rod magnetic resonance imaging of, 212f over right eye, 35f of third nerve or fascicle, 13 to quantify ocular deviation, 35–36 unilateral, 265 Magnetic resonance angiography (MRA), 106 Leukemia Magnetic resonance imaging (MRI), 247f cause of infiltrative optic neuropathy, 229 demonstrate vascular flow, 72 infiltrate optic nerve, 302 with gadolinium enhancement and fat Leukemic infiltration suppression, 218f response of, of optic nerve, 231 for high-flow tumors, 72 of right optic disc with acute lymphocytic Magnetic resonance venography (MRV), 289 leukemia, 230f Malignancy, 302 of right optic nerve producing optic disc with papilledema, 302 swelling, 230f Marcus Gunn phenomenon, 138 Levator function, in ptosis, 32 MCA. See Middle cerebral artery LGN. See Lateral geniculate nuclei Medial longitudinal fasciculus (MLF), 16, 17f, LH. See Luteinizing hormone 324 LHON. See Leber’s hereditary optic neuropathy Media opacities, 26, 276 Lid function Medulloepitheliomas, in brain and spinal cord, assess, 32 212–213 measurement of, 32 Meningeal carcinomatosis, 228 Lid retraction Meningeal masses, from orbital apex, cavernous primary, 68 sinus, 169 secondary, 68 Meningeal tumor cuffing, 228 LINAC. See Linear accelerator units Meningioma, 215, 326 Linear accelerator units (LINAC), 220 MERRF. See Myclonic epilepsy with ragged red Lissauer’s categorization, 340 fibers Lithium and anticonvulsants, drug intoxication Mesoadenoma, lateral, 244f with, 326 Metabolic coma, with normoreactive pupils, 40 Lobe function, posterior, 240 Metamorphopsia, 346 LogMAR chart, 66 cerebral, 346 Low-contrast letter acuity charts, 26f upside-down visual, 346 LP. See Lumbar puncture Metastasis, from systemic malignancy, 92 366 Index

Metastatic optic nerve tumors, 228 Myasthenia gravis (MG), 316 Metastatic tumors, to optic nerve, 226 Mycoplasma infection, with bilateral optic MEWDS. See Multiple evanescent white-dot neuritis, 159 syndrome Myeloma, 302 Meyer’s loop, formation of, 9 Myoclonic epilepsy with ragged red fibers MG. See Myasthemia gravis (MERRF), 202–203 Microadenomas, 243, 243f Myopathic disorders, 32 Microphthalmic eye, large cyst associated with, 77f Microphthalmos, with cyst, 75–76 N Micropsia, 345–346 Nadir acuity, 144–145 form of, 345–346 NAION. See Nonarteritic anterior ischemic optic Midbrain syndrome, dorsal, 32–33 neuropathy Middle cerebral artery (MCA), 335 Nasal retinal fibers, cross-over of, 8 Middle temporal area, 338–339 NASCET. See North American Symptomatic Migraine-type headaches, 242 Carotid Endarterectomy Trial Migrainous aura, common features of, 347 Naso-sinus disease, 68 Mild vitritis, 161–162 Nausea, as part of vagal reflex, 47 Miller-Fisher syndrome, classic triad of, 322 Near vision, 24 Miller-Fisher variant, of Guillain-Barre, 322 tested using Rosenbaum hand held card, 24 Miosis, observation of, 267 Nerve fiber layer, opacification of, 41 Mitochondrial cytopathy, 203 Nerve, fusiform enlargement of, 213 Mitochondrial DNA (mtDNA), 195–196, 196–197 Nerve nuclear lesion expression, nuclear-encoded factors fourth, 322–323 modifying, 198 third, 322 mutation, 198 Nerve palsy Mitochondrial dysfunction, 202–203 fourth, 36–37 and optic atrophy, 196f sixth, 285 Mitochondrial encephalopathy lactic acidosis, 316 third, 32, 37 Mitoses, 214 with diabetes or hypertension, 13–14 MLF. See Medial longitudinal fasciculus pupil-involving right, 14f Monocular diplopia, 34 Nerve sheath, enlarged, 163 Motility examination, objective of, 33 Nerve, swelling of, 57 Motion selective area, 332 Neurobrucellosis, cause syndrome of MRA. See Magnetic resonance angiography intracranial hypertension, 159 MRI. See Magnetic resonance imaging Neurofibromatosis type 1 (NF1), evidence of, 207 MRV. See Magnetic resonance venography Neuroimaging, recommendations for, in adult MS. See Multiple sclerosis patients with acquired, isolated third MtDNA. See Mitochondrial DNA nerve palsy, 14t Mucocele, noninfective complication of Neuron sinusitis, 164 first-order, 20–22 Mucoceles, from Onodi cells, 164 oculosympathetic, 20–22 Mucormycosis, 63–64 second-order, 20–22, 22f Mueller’s muscles, 20–22, 271–272 third-order, 20–22, 22f Multilobed tumors, 243 Neuro-ophthalmic assessment, 39 Multiple cranial neuropathy, 321–322 Neuro-ophthalmic problem Multiple evanescent white-dot syndrome clinical entities, 54–56 (MEWDS), 50–51 clinical evaluation, 45 Multiple myeloma, 229 investigations, 56 Multiple ocular motor nerves, 322 Neuro-ophthalmic techniques, 39 Multiple sclerosis (MS), 162, 324 Neuro-ophthalmologic disorders, anatomy and development of, 147 examination techniques incidence of, 149 afferent visual pathways, 10–11 prevalence of, 147 examination, 38 risk of, 134 in comatose patients, 41–42 Multisystem degenerations, 201–202 components of, 23 Muscles introduction, 2 innervation, of globe, 12f ocular motor system, 19 responsible for eye movements, 11 pupillary pathways, 19–22 Index 367

Neuro-ophthalmologic examination, in Ocular motility, 33–38, 318 comatose patients, 41–42 Ocular motility disorders, spectrum of, 312–313 Neuroretinitis, 161f Ocular motor system, disorders of, 11 infections reported with, 162t Ocular muscle balance, loss of, 64–65 Neurosarcoidosis, 169f, 170f Ocular/neurologic complications, cause by HIV, Neutrophil and eosinophil, 173–174 155 NF1. See Neurofibromatosis type 1 Ocular tilt reaction (OTR), 324 NHL. See Hodgkin’s disease and non-Hodgkin’s Oculocephalic eye movements, 39 lymphoma Oculomotor nerve palsy, 11–12, 12–13, 12f, 265, Nonarteritic anterior ischemic optic neuropathy 273–274, 319, 320f (NAION), 112–113, 119f Oculomotor nerve pathway, 319 acute treatment of, 121 Oculosympathetic neuron, 20–22 in affected eye, 120–121 Oculosympathetic palsy, 270 disease of small vessels, 120 Oculosympathetic pathways, diagram of, 22f risk factor for, 117 Oligoclonal bands treatment of, 122t in CSF, 148 Nonfunctioning tumors, 239 predictive value of presence of, 148 Nonsteroidal anti-inflammatory drugs, 81 prevalence of, 173 Nontumorous cyst, 248 Onodi cells, 164 North American Symptomatic Carotid ONSM. See Optic nerve sheath meningiomas Endarterectomy Trial (NASCET), Ophthalmic artery 108–109 blood supply from, to retina, 3–4 Null cell tumors, 239 and branches, diagram of, 99f Nutritional disorders, 303–307 Ophthalmoparesis, 312, 313 Nystagmus, 324 Ophthalmoscopy, 38 from acute peripheral vestibular, 325–326 Optical coherence tomography (OCT), 146 associated with visual loss, 325 Optic ataxia, 344 downbeat, 326 Optic atrophy, 199 pathologic acquired, 325 causing optic disc, 4–7 physiologic, 324 dominantly inherited syndromes of, 199–200 type of, 327 with inherited optic neuropathy, 199 upbeat, 326 with nerve fiber layer, 194 vertical, 326 pattern of, 10 in tertiary phase of tabes dorsalis/paresis, 159 Optic chiasm, 220 O anatomy of, 7–8 Oblique muscles blood supply to, 8 characteristic of superior, 15 and visual field defects, lesions of, 5f as rotators, 11 Optic disc, 3–4, 225–226 superior and inferior, 11 infiltrated by yellow-white tissue, 226f Occipital lobe epilepsy, feature of, 347 metastatic adenocarcinoma to, 226f Occipital lobe lesions, bilateral, 11 and neovascularization, 231 Occipital lobes, and calcarine cortex, 9–10 with or without optic disc drusen, 95–96 Occipital poles, dual blood supply in, 9 swelling, 4–7, 41, 70, 231 Occipito-temporal area, lesions involving, 11 Optic disc drusen, 283–284 OCT. See Optical coherence tomography Optic disc edema, 112 Ocular alignment, maintenance of, 19 Optic nerve, 45, 213, 225 Ocular apraxia, 343–344 in acute phase, 52 Ocular coherence tomography (OCT), 56 anatomy of, 2–4 Ocular complications, 165–167 appearance of, 46f Ocular deviation, 37 artery within, 3–4 amount of, 35–36 atrophy of, 146 Maddox rod to quantify, 35–36 bilaterally, 55f quantitation of, 35–36 congenitally crowded, 96f Ocular dipping, 41 demonstrating circulation, 4f Ocular ischemic syndrome detail of, 72 degrees of, 99f disease of, 4–7 with neovascularization, 101f domain of neurologist, 45 Ocular media abnormality, 46–48 enlargement of, 217, 227f 368 Index

Optic nerve—Cont’d Optic nerve medulloepithelioma, 213 form optic chiasm, 7–8 composed of multilaminar columnar cells, frequency of, 228 214 funduscopic view of, 194f treatment of, 214 funduscopic view of right and left, Optic nerve myelin, by oligodendrocytes, 223 195f, 200f Optic nerve sheath hemangioblastoma of, 214f enhancement of, 163f hemangiopericytoma of, 225 primary tumors of, 223–225 infiltration of, 228, 229f hemangiopericytoma, 223–225 invasive tumors of, 227 meningioma, 215–223 involvement of, 182 Schwannoma, 223 malignant glioma of, 211 tumor of, 215 medulloepithelioma of, 213f Optic nerve sheath hemangiopericytoma metastatic tumor to, 227 computed tomography appearance of, 225f MRI scans of, 149, 168f, 227f histopathology of, 224f and optic chiasm, relationships of, 8 Optic nerve sheath meningiomas (ONSM), 163, orbital portion of, 210 215, 217, 247 pathologic features of, 211 in childhood, 216 position of, 241 diagnosis of, 216, 218–219 posterior segment of, 128 echographic evaluation of, 218–219 primary tumors of, 214 goals in management of, 221–223 ganglioglioma, 211–212 majority of primary, 216 hemangioblastoma, 214 natural history of, 220–221 malignant optic nerve glioma, 210–211 primary, 215, 219–220 medulloepitheliomas, 212–214 radiotherapy for, 219, 220 optic nerve glioma, 207–210 with retinochoroidal collateral vessels, 216f summary, 231 secondary, 215 and retina, 38 for small segment of optic nerve, 215 secondary tumors of, 206 treatment option for, 221 lymphoreticular tumors, 228–231 Optic nerve sheath Schwannoma, 223 metastatic and locally invasive tumors, computed tomography, 224f 225–228 histopathology, 224f with transient visual obscurations, 96f Optic neuritis, 135–137, 154, 179 tumors of, 73 acute, 140f vascularization of, 113f acute demyelinating, 141 Optic nerve dysfunction, causes of, 7 bilateral, 140 Optic nerve function, 70 causing disc swelling, 287 Optic nerve glioma, 206, 207, 207f, 250 clinical features, signs, 140–141 appearance of, 208f abnormalities in fellow eye, 140–141 common tumor of optic nerve, 206–207 ophthalmoscopic abnormalities, diagnosis of, 208 138–140 enlarged optic canal, 208 pupillary reactions, 138 gross appearance of, 209 visual acuity, 137–138 macroscopic appearance of, 209f visual field, 138 malignant, 212f clinical features, symptoms, 137 MRI of, 209f orbital pain and headache, 135–137 natural history of, 209–210 positive visual phenomena, 137 and NF1, 207–208 visual loss, 137 as sporadic, 207 development of, 160 symptoms and signs with, 207 diagnosis, 143 treatment for malignant, 211 blood investigation, 141 Optic nerve head cerebrospinal fluid, 143 normal-appearing, 46f magnetic resonance imaging, 142–143 pale, 46f visual evoked potential, 141–142 swollen, 46f disorder in females, 136t Optic nerve head ischemia, 4–7 epidemiology, 135 Optic nerve infiltration history of, 135 appearance of, by lymphoma, 228–229 in infectious disease, 153 clinical patterns of, 229–231 introduction, 135 Index 369

Optic neuritis—Cont’d Orbital apex crowding, with optic neuropathy, multiple sclerosis, relationship to, 148 86f cerebrospinal fluid data, 148 Orbital apex syndrome, 81–82 clinical data, 146–147 Orbital capillary hemangioma, 76–77 MRI data, 147 Orbital cellulitis, 93f natural history of, 146 Orbital disease recurrent, 146 ancillary tests for, 70–73 residual visual loss, 145–146 assessment of, 70–73 neuro-ophthalmologic condition, 134 diplopia, 64–65 and paraneoplastic antibody, 172 globe, position of, 60–63 with reduction in central acuity, 137 pain, 60 subacute disorder, 135 sensory disturbance, 65 subacute, visual disorder, 149 visual loss, 63–64 summary, 149 choice for, 59 treatment, 148–149 clinical examination for, 69–70 and visual loss, 307 evidence of mass, 66–67 Optic Neuritis Treatment Trial, 26, 135, 148 ocular balance and ductions, 67 Optic neuropathy, 57, 167–169, 181, 228 periorbital signs, 68 with adjacent inflammatory mass lesion, 169 signs of intraocular or systemic disease, bilateral, 56 69–70 and symmetric, 54 visual functions, 66 and synchronous, 173 clinical history in, 65 categories of disease processes cause, 57t common, 88–93 causes, 77–78 incidence of, 73 complicate meningitis, 160 malignant, 91–93 consequence of intracranial hypertension, 161 principal and causes of, 61t consequence of ischemia, 154 Orbital fat excision, 87–88 consequence of retinal vasculitis, 176 Orbital fissure and orbital apex, lesions on in cryptococcal infections, 161 superior, 18 from demyelinating optic neuritis, 153 Orbital infiltration, 92–93 with Devic’s syndrome, 179–180 Orbital malignancy diagnosis of, 54 adult, 91–93 differentiate, 45 in children and young adults, 89–91 from direct toxic effect of HIV, 155–159 Orbital mass, right, revealed by episodes of acute etiology of, 57 complete visual loss, 97f evidence of, 201–202 Orbital metastases, 92 features of, 44, 45 Orbital osseous disease, 88 inherited, 192t Orbital pseudotumor syndrome, 163, 315–316 isolated, 176 Orbital radiotherapy, complications of, 89–90 in isolation, 154 Orbital tissues, 166 in lupus, 178 Orbital varices, distensible, 64f of neurogenic visual loss, 45 Orbit and extraocular muscles, anatomy of, occurrence of, 172 11–12 with orbital apex, 84–86 Orbit and paranasal sinuses, structural lesions primary, 191 of, 73–76 primary bilateral, 54 OTR. See Ocular tilt reaction progressive or subacute, 165 recognizing, 45 spare visual acuity, 45 P subacute, 154, 167–168 Paget’s disease, 326 with transversemyelitis, 172–173 Pain in tuberculosis, 160 within affected eye, 135–137 unilateral, 167–168 as dull ache, 135–137 unilateral and sequential, 173 factors influencing, 60 Optic perineuritis, 163f in neck, 285–286 Optic radiations, anatomic separation of, 10 Palatal necrosis, 68 Optic tract lesions, 276–277 Palinopsia, 344–345 Optic tracts, fibers of, 8–9 mechanism of, 345 Orbital apex, and cavernous sinus syndromes, 18 types of, 344–345 370 Index

PAN. See Periodic alternating nystagmus Pituitary function, investigations for, 240 Pancoast’s syndrome, 272 Pituitary hormones, underproduction and Panhypopituitarism, with diabetes insipidus, overproduction of, 239 253 Pituitary lesions, silent, 243–244 Papilledema, 41, 298–299, 302 Pituitary sella, optic chiasm above, 8 with Addison’s disease and Cushing’s disease, Pituitary tumors, cause headache, 241 307 Planum meningioma and cerebral arteries, 246f causes of, 289t, 291–294, 292t, 300 Planum meningioma, vision in, 248 complications of, 296 Platelet-fibrin emboli, 100f with corticosteroids, 296 POEMS syndrome, 302 diagnosing, 288–290 Point mutations, mitochondrial genome evaluation for, 280 showing, 197f features of, 38 Polyarteritis nodosa (PAN), 182 fluorescein angiogram in, 289f Polygonal cells, 219 natural history and visual complications of, Positive syndromes, 346–347 294–296 Positron emission tomography (PET), 72, 335 nonvisual symptoms of, 285–286 Posterior cerebral artery (PCA), 335 signs of, 286–288 Posterior ischemic optic neuropathy (PION), symptoms of, 284–286 128 treatment of, 296–298 AION and, 128 unusual forms of, 290 causes of, 128 visual field testing in, 288f diagnosis of, 128 Papilledema-associated headache, management Postganglionic fibers form, 265 of, 297 POT. See Parieto-occipital-temporal Papilledema-associated vision loss, prognostic Potassium channel blockers, 326 factors for, 294 P-POHS. See Pseudo-presumed ocular Papilledema Staging Scheme, by Lars Frise´n, histoplasmosis syndrome 284t PPRF. See Paramedian pontine reticular Papilledema, with elevated pressures, 289–290 formation Papillitis, 280 Preganglionic parasympathetic blockade, Papillomacular bundle, 2–3 273–274 Paramedian pontine reticular formation (PPRF), Pressure symptoms, of mass lesion, 239 16–17, 323 Pretectal lesions, 277 and MLF, 324 Pretectal neurons, 265–267 Paraneoplastic retinopathy, 56 Primary LHON mutations, 196–197 Paraneoplastic syndromes, 327–328 Primary tumors, 321 Parieto-occipital-temporal (POT) junction, 19 contiguous spread of, 227 Parkinson’s disease, 323–324, 346 Prolactinoma Pars planitis and intermediate uveitis, 138–140 anterior pituitary hormone, 239 PCA. See Posterior cerebral artery with entrapment mucoceles, 254f Pelizaeus-Merzbacher disease, 325 with prolactin, 244f Pelli-Robson chart, 26 Proptosis, 60–63 Penicillin, advent of, 277–278 after Valsalva maneuver, 64f Pericytes, endothelial cell with, 214 apparent right, 63f Periodic alternating nystagmus (PAN), 326–327 cause of unilateral and bilateral, 59 Periorbital inflammation, marked, 66f and optic disc swelling, 213 Peripheral field, ganglion cell axons from, 2–3 orbital signs, 216 PET. See Positron emission tomography Prosopagnosia, 341–342 Petroclival meningiomas, sinus-involving, 246 Protein elevation and lymphocytosis, Phosphenes or photopsias, 137 154–155 Photoreceptors, loss of, 56 Pseudo-isochromatic color plates, 25f Pineal gland cyst, 323 Pseudopapilledema “ping-pong” gaze, 41 cause of, 283–284 Pinhole device, on retina, 23–24, 23f common cause of, 285f PION. See Posterior ischemic optic neuropathy differentiating papilledema from, 286t Pituitary carcinomas, 245 Pseudo-presumed ocular histoplasmosis Pituitary dysfunction, late, 220 syndrome (P-POHS), 50–51 Pituitary fossa, 252–253 Pseudoptosis, with blepharospasm, 32–33 chiasm, position of, 8 Pseudotumor syndrome, 81–82, 301 Index 371

Ptosis Rathke’s cleft cysts, 248 cause of, 32 sharing, 249 and diplopia, 318 variant of, 249 Pulfrich phenomenon, 145 with visual loss, 248f Pulsatile proptosis, 60–63 Rathke’s cleft elements, of primitive Pulsatile tinnitus, auscultated, 286 stomatodeum, 238–239 Pulsatility, 286 Reading cards, 24 Pupil Rectus muscle abnormal, 265, 269–270 superior and inferior, 11 with bilateral symmetrical lesions, 276 vascular dilatation and swelling overlying, 82f bright light to assess, 31 Red bottle tops, 27 briskness and extent of, 265–267 Red glass test, an analogous to Maddox rod test, constriction of, parasympathetic pathway, 37–38 19–20 Redilatation lag, 270–271 degree of attenuation of, 277 Refractive errors, 23f diaphragm in eye, 264 Refsum’s syndromes, 316 dilation of, oculosympathetic pathway, 20–22 Reiter’s syndrome, 180 examination of, 30–32 Relative afferent pupil defect (RAPD), 264, 267, failure of, 269 276 in Horner’s syndrome, 270–271 clinical detection of, 277 normal direct and consensual, 267f with lesions of retina or optic nerve, 276 pharmacologic dilation of, 38 Renal cell carcinoma, 227 pharmacology of, 269 Residual symptoms, 145 reflex dilation of, 268–269 Residual visual symptoms, 146 responses to light stimulus, 275f Retention mucoceles, from ethmoidal and under resting conditions, 265 frontal paranasal sinuses, 75 size of, 30, 264 Retina Pupillary abnormalities, in coma, 40 cellular layer of, 2–3 Pupillary disorders disorders of, 4 abnormal, 277–278 and fundus, structures of, 2 lesions in midbrain, 277–278 inner layers of, 51 lesions of visual pathway, 276–277 ocular manifestations in, 178 lesions within eye, 270 and optic nerve parasympathetic lesions, 273–276 anatomy of, 2–4 sympathetic lesions, 270–273 blood supply to, 3–4 afferent, 30–31 Retinal arterial attenuation, 191 grading scheme for afferent, 30–31 Retinal artery, and vein occlusion, 178 normal, 264–269 Retinal artery occlusion, 104t Pupillary miosis, 270 embolic inferior branch, 104f degree of, 267–268 superior branch, 53f origin of, 277–278 with visual loss, 105f, 299 Pupillary pathways, anatomy of, 20–22 Retinal bleeding, with subarachnoid Pupillary reflex pathways, diagram of, 21f hemorrhage, 41–42 Pupil light reflex, neural pathways underlying, Retinal degenerations, 54–56, 202–203 266f Retinal detachment, 53–54 Pupillovisual dissociation, 277 retinovascular occlusion and, 51–54 Pupil signs, with ipsilateral tendon, 275–276 Retinal dysfunction, with visual field Pupil size and arousal, relationship between, abnormality, 56 268–269 Retinal electrophysiology, 44 Pursuit eye movement, smooth, 34f Retinal emboli, 99 Pursuit system, 19 Retinal fluorescein angiography, 126f Pyogenic abscesses, 253 Retinal ischemic syndromes, with neovascularization, 166–167 Retinal migraine, 102 R Retinal vein occlusion Radiation, in non-coplanar fields, 220 central, 212f Radiation optic neuropathy, an ischemic impending central, 97f disorder of, 130 with optic nerve head swelling, 53f RAPD. See Relative afferent pupillary defect Retinal vessels, sheathing of, 138 372 Index

Retino-geniculo-cortical projection, 265–267 Sclera, appearance of, 35 Retinopathy, with vitreous hemorrhage, 221 Scleroderma, CREST syndrome and, 180 Retinovascular occlusion, and retinal Sebaceous carcinoma, 92–93 detachment, 51–54 Secondary tumors, 228–231 Retraction nystagmus and Collier’s sign, 277 Seesaw nystagmus, 327 Retrobulbar idiopathic optic neuritis, 45, 57 Sella and parasellar region, disorders of, 252 Retrobulbar masses, on gaze evoked amaurosis, arachnoid cysts, 252 63–64 diagnosis of tumors and lesions in, 242t Retrobulbar optic nerve, infiltration of, 228 endocrine presentation and investigation, Retrochiasmal visual pathways 239–240 anatomy of, 9–10 headache and intracranial pressure, 241–242 lateral geniculate nuclei (LGN), 9 incidental discovery, 242–243 occipital lobes and calcarine cortex, 9–10 infections and inflammations, 254–255 optic radiations, 9 hypophysitis, 253–254 optic tracts, 8–9 Langerhans cell histiocytosis, 254–255 disorders of, 10–11 metastatic tumors, 252–253 lateral geniculate nuclei lesions, 10 overview, 238–239 occipital lobe lesions, 10–11 tumor types, 250–252 optic radiation lesions, 10 chondrosarcomas, 250–251 optic tract, lesions of, 10 chordomas, 251 Retrogeniculate lesions, 276–277 craniopharyngiomas, 249 Reversible acetylcholinesterase inhibitor, 317 germinomas, 251–252 Rhabdomyosarcoma meningiomas, 247–248 and neuroblastoma, malignancies of, 89 optic nerve gliomas, 250 rapidly growing mass of, 89f pituitary adenomas, 244–245 with symptoms and signs of inflammation and Rathke’s cleft cysts, 248 swelling, 89f Schwannomas, 251 Rheumatoid arthritis, 80 vascular lesions, 256 optic neuropathy in, 180 visual symptoms and measurement, 240–241 Riddoch’s phenomenon, 11, 336 Sella epidermoid, with variable headache, 253f Right upper retraction, surgical correction of Sella/pituitary fossa, optic chiasm above, 8 marked, 88f SFR. See Stereotactic fractionated radiotherapy riMLF. See Rostral interstitial medial SIADH. See Syndrome of inappropriate longitudinal fasciculus antidiuretic hormone Rosai-Dorfman disease, 255, 321 Sinus mucocele, 165 Rosenbaum hand held card, 24, 24f Sixth nerve palsy, 16–18, 321 Ross syndrome, 275–276 within cavernous sinus, 13f, 17–18 Rostral interstitial medial longitudinal fasciculus Sjo¨gren’s syndrome, 80, 172–173, 179 (riMLF), 323 Skew deviation, 324 Ruler, to measure eyelid function, 32f Skin cancers, 226 Sloan charts, 26, 26f S Snellen acuity, accuracy of, 24 Saccade system, 18 Snellen chart, 66, 241 fast eye movements, 33 Snellen optotypes, 313 testing, 33f Soft masses, with eyelid swelling, 66–67 Saccadic eye movements, in frontal eye fields, 18 Soft tissue, component of tumor, 217–218 Saccadic intrusions, spectrum of, 327–328 Soft tissue mass, 91–92 Sarcoid, manifestations of, 167 Somatostatin receptors, discovery of, 72 Sarcoidosis Space-occupying lesions, 302 affect anterior visual pathways, 168–169 Sphenoidal wing meningioma, 65f of eye, 166f Sphenoid sinus, mucoceles in, 253 hypertrophic pachymeningitis with, 180f Sphenoid wing, extensive tumors of, 246 an inflammatory disorder, 165 Sphenoid wing meningioma Sarcoid vitritis, 166–167 with hyperostosis of sphenoid wing, 88 SCA. See Spinocerebellar ataxia soft tissue tumor, 88 Schwannoma, 251 Sphincter muscle, 265, 273 benign tumors, 223 Spinal fluid pleocytosis, 149 of fourth nerve, 320 Spinal tumors, cause papilledema, 302 of optic nerve, 223 Spinocerebellar ataxia (SCA), 201–202 Index 373

Spinocerebellar degenerations, 323–324 Temporal artery biopsy, for definitive diagnosis, Squamous carcinoma, 92–93 127 Standard tests, for color vision, 348 Tenderness, with acute dacryoadenitis, 66–67 Stephen’s syndromes, 316 Tensilon test, 37 Stereopsis Terson’s syndrome, 40, 41–42, 47–48 disorders of, 339–340 in with ruptured anterior communicating impaired, 340 aneurysms, 8 loss of, 145 Tetracycline and minocycline, 303 physiology of, 339–340 Thalamus, LGN of, 9 Stereotactic conformal linear accelerators, 245 Third cranial nerve, 11–12 Stereotactic fractionated radiotherapy (SFR), 220 Third nerve fascicle, lesions of, 319 acute effects of, 221 Third nerve nucleus complex planning, 220 lesions of, 15 ophthalmic complications of, 221 localizing, 15 Stereotactic radiotherapy series, summary of Third nerve palsy, 16, 319 primary, 222t acute, painful, pupil-involving, 13–14 Steroids, in optic neuritis, 148 Thrombocytosis, 126 Steroid taper, rate of, 127 Thyroid antibody, prevalence of, 172 Strawberry nevus, 76–77 Thyroid eye disease, 32–33, 59, 70–71, 80, 82–88 Stroke asymmetrical, 68f factors for, 109 characteristics of, 84t neuro-ophthalmic manifestation of, 183 CT changes with, 85t Stroke and cardiovascular events, prevention of, extraocular muscles from, 315f in patients with TMVL, 108t with multiple muscles, 85f STS. See Superior temporal salcus and myasthenia gravis, 37 Subacute ataxia with nystagmus, 169f right-sided orbital decompression for, 87f Subarachnoid space, third nerve within, 14–15 scales for assessing, 86–87 Subconjunctival lymphoma, appearance of, 70f Thyroid ophthalmopathy, 315 Subretinal neo-vascularization with papilledema, Thyroid-stimulating antibody, 315 296 Thyroid-stimulating hormone (TSH), 70–71, 239 Sub-Tenon’s space, 71–72 Tissue biopsy, orbital infiltrative disease, 72–73 Subtler hemianopia, checking for, 28f TMVL. See Transient monocular visual loss Sulfa allergy, 296 Tobacco and alcohol, possible role for, in visual Superior temporal sulcus (STS), 341–342 loss, 198 Supersensitivity, an enhanced response to Tolosa Hunt syndrome, 321 receptor agonist, 269 Tonic pupil Supranuclear eye movement, abnormalities, 323 bilateral and symmetrical, 275 Supranuclear, internuclear, and vestibulo-ocular unilateral, 275 gaze pathways, anatomy of, 18 Toxicity Supranuclear palsy, progressive, 323–324 late, 220 Surgery, for cavernous sinus tumors, 248 vasculitis and radiation, 102 Swelling, to nasal margin, 284 Toxic retinopathy, causes of, 56 Swinging flashlight test, 30–31, 31f Traditional testing, for visual object agnosia, Swollen disc, with visual loss, 161f 348–349 Syndrome of inappropriate antidiuretic hormone Transcranial magnetic stimulation (TMS), 335 (SIADH), 240 Transient ischemic attack (TIA), cerebral Syndrome of Leigh, 202–203 hemispheric, 103–104 Syphilis, serologic tests for, 141 Transient monocular visual loss (TMVL) Systemic diseases, with NAION, 117–120 with atheromatous stenosis, 99f Systemic lupus erythematosus, 172–173 carotid endarterectomy, 108–109 Systemic steroids, use of, 81–82 cause of, 95–96, 102 characteristics of, 98 diagnosis, 106–107 T ancillary studies, 106–107 Tabes dorsalis, cause for, 277–278 history, 105–106 Taches de bougie, 166–167 ophthalmic examination, 106 “tadpole” pupil, example of, 273f differential diagnosis of, 95t Takayasu arteritis, 100 with Horner’s syndrome, 107f Tangent screen testing, 29, 29f and Internal Carotid Artery Stenosis, 109t 374 Index

Transient monocular visual loss (TMVL)—Cont’d V mechanisms of, 98–102 V1 lesions, 336–337 ocular conditions, 95–97 Variation vascular arterial ischemia, 102 with arterial pulsation, 66 natural history of, 104, 104t with Valsalva maneuver, 66 cerebral hemispheric stroke, 103–104 Varices/lymphangiomas, low-flow vascular death, 104 lesions, 77–78 retinal stroke, 103 Vascular anomalies, of orbit, 76–80 orthostatic, 95–96 Vascular arterial TMVL, mechanisms responsible other measures, 109–110 for, 98 for systemic arteriosclerosis, 104 Vaso-obliterative diseases, 63–64 treatment, 109–110 Vaso-occlusive ischemic retinopathy, 179 Trauma, 38, 270 Vasospasm, 108 Triple-dose gadolinium, 143 Venous occlusion, 166–167 Tritanopia, 199 Venous pressures Trochlear nerve, 15, 319–320 and cardiopulmonary disease, 303 supply superior oblique, 12f and intracranial hypertension, 303 True disc swelling, 281 Venous sinus stenting, 299 diagram of, 282f Venous stasis retinopathy, 101f ophthalmoscopic features of, Venous thrombosis, excluding, 289 281–283 VEP. See Visual evoked potentials True papilledema, 284 Vertical deviation, examine, 36–37 TSH. See Thyroid-stimulating hormone Vertical semicircular canals, vestibulo-ocular TSH-secreting adenomas, causing high TSH connections from, 20f thyrotoxicosis, 239 Vestibular imbalance, nystagmus from, TSH-secreting tumor, 243–244 326 Tuberculosis, of hypophysis, 254f Vestibular ocular reflex (VOR), 33, 39–40 Tumor and tumor-associated changes, MRI on cancellation of, 33 extension of, beyond optic nerve, 208 defective, 33 Tumor cells, power of, 224f Vestibulo-ocular system, 19 Tumors Viral, bacterial, and fungal infections, caused composed of ganglion cells, 211–212 optic neuritis, 155t consistency of, 244–245 Viral disorders, 154–155 diagnosis of, 206, 242t Viral infections between nerve substance, 215 neurologic and ophthalmic complications of within optic canal, 219 common, 156t of optic nerve, 206 with neuro-ophthalmic complications, relationship of, to dural sheath, 224f 155 in siblings, 207 Virchow-Robin sheaths, 173 silent, 243–244 Visible drusen, 287f Twin peaks papilledema, 290, 291f Vision Type A personalities, 48–49 anatomy and physiology of, 333–336 neurophysiology of early, 333–334 obscurations of, 216 U physiology of, 335 Uhthoff phenomenon, 145 Vision loss, 128 Ulcerative colitis, and Crohn’s disease, 177 Visual acuity, 193, 199, 241 Ultrasonography, 71–72 abnormal, 23–24 Unilateral papilledema, 290 assessment of, 23–24, 220–221 Urinary calcium excretion, 168 and color vision, 50–51 Uveal melanoma method of testing, 23–24 with orbital extension, 92–93 relationship of, 144t primary, 92–93 Visual agnosia Uveal tract, anterior, cysts or tumors of, 270 apperceptive, 340 Uveitis associative, 340–341 anterior, 166 Visual association areas, in occipito-temporal chronic, 166 and occipito-parietal regions, 9–10 confined to anterior chamber, 166 Visual attributes, disorders of, 343–344 signs of, 165–166 Visual development, assessment of, 64 Index 375

Visual disorders Visual loss—Cont’d evaluating functional, 29 from Leber’s hereditary optic neuropathy, negative, 337–344 193f, 194–195 Visual distortions, maculopathy cause, 48 monocular or binocular, 94–95 Visual dysfunction, 195 and ocular motility disorders, 2 Visual evoked potentials (VEP), 141, 207 onset of, 114, 199 in asymptomatic eye, 141 from optic neuropathy, 44 principle use of, 141–142 pattern of, 211 Visual failure, recurrences of, 194–195 perioperative, 128 Visual field defects, 7, 161, 163, 193 setting of, 127 abnormality, types of, 287–288 Visual object agnosia, 332–333, 340 assess, 30 Visual pathway and visual field defects, lesions characteristics of, 8 of, 6f with disorders of cortical function, 29 Visual recovery, prognosis for, 165 inferior, 113–114 Visual search training, 350 nonexpansion of, 29 Visual system, anterior, low-grade gliomas of, of optic neuropathy, 48 210–211 retrochiasmal, 11 Visuomotor ataxia, 344 summary of, in optic neuritis treatment trial, Visuospatial function, disorder of, 343–344 139f Vitamin A deficiency retinopathy, 56 superior, 113–114 Vitamin B12 deficiency, 326 Visual field gems, 30t Vitreal hemorrhages, 47–48 Visual field loss, caused by retinal disorders, 4 Vitreous cells, 138 Visual fields Vitreous hemorrhage, 46, 47–48 assessment of, 287–288 with Terson’s syndrome, 48f with DOA, 199 Vitreous opacities, 160 investigating, 241 VKH. See Vogt-Koyanagi-Harada recorded in chart from patient’s perspective, Vogt-Koyanagi-Harada (VKH) syndrome, 177 28f Von Hippel-Lindau disease, evidence of, 214 Visual field testing, 27–29 VOR. See Vestibular ocular reflex with confrontation technique, 28f, 348 Visual function, 277–278 Visual hallucinations, 333, 346–347 W in blind hemifield, 11 Water stimulation, warm, 39–40 onset of, 347 Weber’s syndrome, 15 Visual illusions, 333, 345–346 Wegener’s granulomatosis, 60, 63–64, 69–70, 80, Visual impairment scale, graded, 145 154, 181–182, 321 Visual information, retinotopic organization of, giant cell arteritis and, 163 2–3 Wernicke’s encephalopathy, 326 Visual loss, 299 Whipple’s disease, 160, 325 acute and temporary, 94 Wilbrand’s knee, 5f, 7–8 in acute leukemia, 231 Wilson’s disease and lipid storage diseases, acute phase of, 194 323–324 in amblyopic patients, 24 Wolfram’s syndrome, 196f, 201 in arteritic AION, 121–124 hallmark of, 201 caused by optic nerve, 45 with mitochondrial diseases, 201 causes of, 45–46, 48–49 World Health Organization, subtypes, characteristics of, 106 245–247 complication of papilledema, 294 Worsening diplopia, 313–314 degree of, 169–170 differential diagnosis of, 48 X and disc edema, 119f Xerostomia and xerophthalmia, 179 duration of progression of, 193 feature of papilledema, 280 genetic factors role in, 296 Z history of, 198 Zygomatico-frontal suture, superotemporal and hydrocephalus, 250f dermoid with, 74f incidence of, 192–193 Zygote, nuclear portion of, 195–196