Continuum Neuro-Ophthalmology

OCTOBER 2019
VOL. 25 NO. 5 Neuro-ophthalmology

Guest Editor: Marc Dinkin, MD
1192 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
1194 The Pupil

Marc A. Bouffard, MD
1215 Ischemic Optic Neuropathy

Mark J. Morrow, MD, FAAN
1236 Optic Neuritis

Jeffrey L. Bennett, MD, PhD, FAAN
1265 Toxic-Metabolic and Hereditary Optic Neuropathies

Cristiano Oliveira, MD
1289 Idiopathic Intracranial Hypertension

Matthew J. Thurtell, MBBS, MSc, FRACP
1310 Chiasmal and Postchiasmal Disease

Heather E. Moss, MD, PhD, FAAN
1329 Higher Cortical Visual Disorders

Sashank Prasad, MD; Marc Dinkin, MD
1362 Approach to Diplopia

Christopher C. Glisson, DO, MS, FAAN
DENOTES CONTINUUM
AUDIO INTERVIEW
1376 Nystagmus and Saccadic Intrusions
DENOTES VIDEO Janet C. Rucker, MD
CONTENT
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1401 Paraneoplastic Syndromes in Neuro-ophthalmology
Lynn Gordon, MD, PhD; Marc Dinkin, MD
1422 Infectious Optic Neuropathies

Eric R. Eggenberger, DO, FAAN
1438 Imaging in Neuro-ophthalmology

Fiona Costello, MD, FRCPC; James N. Scott, MD, MSc
SELF-ASSESSMENT AND CME
1186 Learning Objectives and Core Competencies
1491 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
1493 Postreading Self-Assessment and CME Test
1507 Postreading Self-Assessment and CME Test—Preferred Responses
1517 Index
List of Abbreviations (Back Cover)

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives ◆ List the most common types of nystagmus and

saccadic intrusions, discuss the most common
Upon completion of this Continuum: Lifelong etiologies and mechanisms for abnormal spontaneous
Learning in Neurology Neuro-ophthalmology eye movements, and initiate the pharmacologic
issue, participants will be able to: management of oscillopsia
◆ Define the anatomy and physiology of the pupil and ◆ Recognize the wide range of neuro-ophthalmic clinical
its innervation, leveraging that knowledge of proper manifestations of paraneoplastic disease and discuss
function to comprehensively approach abnormal the diagnostic and therapeutic approaches to patients
pupillary function with these diseases
◆ Describe the diagnosis, treatment, and prognosis ◆ Describe the clinical features and management of
of anterior and posterior ischemic optic neuropathy infectious optic neuropathies
and identify giant cell arteritis as a cause of
these conditions ◆ Discuss how various imaging modalities can be used
to refine the diagnosis and management of neuro-
◆ Differentiate, diagnose, and treat inflammatory optic ophthalmic disorders
nerve injuries
◆ Discuss the features and underlying mechanism

of toxic-metabolic and hereditary optic Core Competencies
neuropathies This Continuum: Lifelong Learning in Neurology
Neuro-ophthalmology issue covers the following
◆ Discuss the diagnostic criteria, clinical features,
imaging findings, differential diagnosis, and core competencies:
management approach for idiopathic
intracranial hypertension ◆ Patient Care
◆ Describe the symptomatic, examination, and ◆ Medical Knowledge

evaluation implications of neurologic diseases
affecting the optic chiasm, optic tracts, optic ◆ Practice-Based Learning and Improvement
radiations, and occipital lobes
◆ Interpersonal and Communication Skills
◆ Describe the anatomic regions responsible for higher
visual processing and discuss the spectrum of ◆ Professionalism
symptoms that may accompany disorders of these
regions ◆ Systems-Based Practice
◆ Systematically use elements of the history and

examination to localize and develop a differential
diagnosis to guide further confirmatory testing in
patients with diplopia
1186 O C TO B ER 2 0 1 9

CONTRIBUTORS
Marc Dinkin, MD Jeffrey L. Bennett, MD, PhD,

Guest Editor FAAN
Associate Professor, Gertrude Gilden Professor
Departments of Neurology, for Neurodegenerative
Ophthalmology, and Disease Research, Professor
Neurosurgery; Director of Neurology, Ophthalmology,
of Neuro-ophthalmology, and Immunology Program
Weill Cornell Medical College, in Neuroscience, University
New York, New York of Colorado School of
Medicine, Aurora, Colorado
Relationship Disclosure: Dr Dinkin serves
as an associate editor for the Journal Relationship Disclosure: Dr Bennett serves
of Neuro-Ophthalmology and as an editor on the editorial boards of the Journal
for Practical Neurology and has received of Neuro-Ophthalmology, Multiple
compensation for travel for speaking Sclerosis, and Neurology: Neuroimmunology
engagements from The American Austrian & Neuroinflammation and as a consultant
Foundation and research/grant support for AbbVie Inc; Alexion; Chugai
from the Helen and Robert Apel Foundation. Pharmaceutical Co, Ltd; Clene
Dr Dinkin has provided depositions Nanomedicine; EMD Serono, Inc;
and expert testimony on medicolegal Equillium, Inc; Frequency Therapeutics;
cases involving idiopathic intracranial Genentech, Inc; MedImmune; and Sanofi
hypertension, ischemic optic neuropathy, Genzyme. Dr Bennett has received
and head trauma. research/grant support from EMD
Serono, Inc; the Guthy-Jackson Charitable
Unlabeled Use of Products/Investigational Foundation; Mallinckrodt Pharmaceuticals;
Use Disclosure: Dr Dinkin discusses the National Eye Institute (R01EY022936);
the unlabeled/investigational use the National Institute of Allergy
of azathioprine for cancer-associated and Infectious Diseases (UM1AI110498);
retinopathy; corticosteroids for bilateral and Novartis AG. Dr Bennett receives
diffuse uveal melanocytic proliferation, publishing royalties from UpToDate, Inc,
cancer-associated retinopathy, and has received personal compensation
melanoma-associated retinopathy, for serving as a medicolegal consultant on
opsoclonus-myoclonus syndrome, medical cases involving neuroinflammatory
and paraneoplastic optic neuropathy; and neuro-ophthalmologic disorders.
IV immunoglobulin (IVIg) for cancer-associated
retinopathy, melanoma-associated Unlabeled Use of Products/Investigational
retinopathy, and opsoclonus-myoclonus Use Disclosure: Dr Bennett discusses the
syndrome; lenalidomide for POEMS unlabeled/investigational use of plasma
(polyneuropathy, organomegaly, exchange and apheresis for the treatment
endocrinopathy, monoclonal plasma cell of optic neuritis.
disorder, and skin changes); mycophenolate
mofetil for cancer-associated retinopathy
and paraneoplastic optic neuropathy; and
rituximab for cancer-associated retinopathy.
Instructor in Neurology, Harvard
Medical School; Codirector
of Neuro-Ophthalmology, Beth
Israel Deaconess Medical Center,
Boston, Massachusetts
Relationship Disclosure: Dr Bouffard
serves as a consultant for the US
Department of Justice Vaccine Injury
Compensation Program.
Unlabeled Use of Products/Investigational

Use Disclosure: Dr Bouffard reports no
disclosure.
1188 O C TO B ER 2 0 1 9

Fiona Costello, MD, FRCPC Lynn Gordon, MD, PhD
Associate Professor, Professor of Ophthalmology,
Departments of Clinical Stein Eye Institute; Senior
Neurosciences and Surgery, Associate Dean, David
Cumming School of Medicine, Geffen School of Medicine
University of Calgary, Calgary, at University of California Los
Alberta, Canada Angeles, Los Angeles, California
Relationship Disclosure: Dr Costello Relationship Disclosure: Dr Gordon serves
has served on advisory boards for on the board of trustees of the American
Frequency Therapeutics and Alexion Academy of Ophthalmology and on the
Canada and receives research/grant editorial boards of Ophthalmology Retina,
support from the Hotchkiss Brain Institute Ocular Immunology and Inflammation,
and the MS Research Program. and the Journal of Neuro-Ophthalmology.
Dr Gordon receives licensing fees from
Unlabeled Use of Products/Investigational the University of California Los Angeles for
Use Disclosure: Dr Costello reports no epithelial membrane protein 2.
disclosure.
Use Disclosure: Dr Gordon discusses the
unlabeled/investigational use of azathioprine
Eric R. Eggenberger, DO, FAAN for cancer-associated retinopathy;
corticosteroids for bilateral diffuse
Professor of Ophthalmology,
uveal melanocytic proliferation,
Neurology, and Neurosurgery, cancer-associated retinopathy,
Mayo Clinic College melanoma-associated retinopathy,
opsoclonus-myoclonus syndrome,
of Medicine and Science, and paraneoplastic optic neuropathy; IV
Jacksonville, Florida immunoglobulin (IVIg) for cancer-associated
retinopathy, melanoma-associated retinopathy,
Relationship Disclosure: Dr Eggenberger and opsoclonus-myoclonus syndrome;
reports no disclosure. lenalidomide for POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal
Unlabeled Use of Products/Investigational plasma cell disorder, and skin changes);
Use Disclosure: Dr Eggenberger reports no mycophenolate mofetil for cancer-associated
disclosure. retinopathy and paraneoplastic optic
neuropathy; and rituximab for
cancer-associated retinopathy.
Christopher C. Glisson, DO, MS,

FAAN
Medical Director,
Neuro-Ophthalmology,
Mercy Health Hauenstein
Neurosciences, Grand Rapids,
Michigan; Assistant Professor,
Department of Neurology
and Ophthalmology,
Michigan State University,
East Lansing, Michigan
Relationship Disclosure: Dr Glisson reports
no disclosure.

Use Disclosure: Dr Glisson reports no
disclosure.
C O N T I N U U M J O U R N A L .C O M 1189

CONTRIBUTORS (CONTINUED)
Mark J. Morrow, MD, FAAN Cristiano Oliveira, MD

Chair, Department of Neurology, Assistant Professor
Harbor-University of California of Ophthalmology, Weill Cornell
Los Angeles Medical Center; Medicine, New York, New York
Clinical Professor of Neurology,
Relationship Disclosure: Dr Oliveira reports
David Geffen School of Medicine no disclosure.
at University of California Los
Angeles, Los Angeles, California Use Disclosure: Dr Oliveira discusses
the unlabeled/investigational use of gene
Relationship Disclosure: Dr Morrow reports
therapy and idebenone for Leber hereditary
no disclosure.
optic neuropathy.
Use Disclosure: Dr Morrow discusses
the unlabeled/investigational use of
medications for the treatment of ischemic Sashank Prasad, MD
optic neuropathy, none of which are Associate Professor of Neurology,
approved by the US Food and Drug Harvard Medical School; Director,
Administration.
Harvard Brigham and Women’s
Hospital–Massachusetts General
Hospital Neurology Residency;
Heather E. Moss, MD, PhD,
Chief, Division of Neuro-
FAAN
ophthalmology, Brigham
Assistant Professor
and Women’s Hospital,
of Ophthalmology, Byers Eye
Boston, Massachusetts
Institute, Stanford University,
Palo Alto, California; Assistant Relationship Disclosure: Dr Prasad serves
Professor of Neurology and as an associate editor for the Journal
of Neuro-Ophthalmology, receives
Neurological Sciences, Stanford publishing royalties from McGraw-Hill,
University, Stanford, California and has provided expert medicolegal
opinion on legal cases involving idiopathic
Relationship Disclosure: Relationship intracranial hypertension, ischemic optic
Disclosure: Dr Moss serves on the board neuropathy, and traumatic brain injury.
of directors of the North American
Neuro-Ophthalmology Society and as a Unlabeled/Investigational Use Disclosure:
review editor for Current Eye Research, Dr Prasad reports no disclosure.
an associate editor for Frontiers
in Neurology, a section editor
for the Journal of Neuro-Ophthalmology,
and a special section editor Janet C. Rucker, MD
for Neuro-Ophthalmology. Dr Moss receives Bernard A. and Charlotte
research/grant support from the Myelin
Repair Foundation, the National Institutes Marden Professor of Neurology;
of Health/National Eye Institute Professor of Ophthalmology,
(K23 EY024345, P30 EY 026877),
and Research to Prevent Blindness
New York University School
and publishing royalties from Elsevier. of Medicine, New York, New York
Dr Moss has served as a legal consultant
providing record review and deposition Relationship Disclosure: Dr Rucker reports
on neuro-ophthalmic diseases. no disclosure.
Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

Use Disclosure: Dr Moss reports no Use Disclosure: Dr Rucker discusses
disclosure. the unlabeled/investigational use
of medications for the management
of abnormal eye movements, none of which
are approved by the US Food and
Drug Administration.
1190 O C TO B ER 2 0 1 9

James N. Scott, MD, MSc Matthew J. Thurtell, MBBS,
Clinical Associate Professor, MSc, FRACP
Departments of Diagnostic Associate Professor
Imaging and Clinical of Ophthalmology and
Neurosciences, Cumming Neurology; Director of
School of Medicine, Neuro-ophthalmology,
University of Calgary, Calgary, University of Iowa, Iowa City, Iowa
Alberta, Canada
Relationship Disclosure: Dr Thurtell serves
Relationship Disclosure: Dr Scott reports on the editorial board of the Journal of
no disclosure. Neuro-Ophthalmology, receives research/
grant support from the National Eye Institute
Unlabeled Use of Products/Investigational (U10-EY025990), and receives book royalties
Use Disclosure: Dr Scott reports from Oxford University Press.
no disclosure.
Use Disclosure: Dr Thurtell discusses
the unlabeled/investigational use
of acetazolamide, furosemide,
methazolamide, and topiramate
for the treatment of idiopathic
intracranial hypertension.
Self-Assessment and CME Test Writers
Douglas J. Gelb, MD, PhD, James W. M. Owens Jr, MD, PhD

FAAN Associate Professor of Neurology,
Professor of Neurology, Adjunct Associate Professor
University of Michigan, of Pediatrics, University
Ann Arbor, Michigan of Washington School of
Medicine, Seattle, Washington
Relationship Disclosure: Dr Gelb receives
royalties from MedLink, Oxford University Relationship Disclosure: Dr Owens serves
Press, and UpToDate, Inc. as CME co-editor for Neurology and
receives publishing royalties from
Unlabeled Use of Products/Investigational UpToDate, Inc.
Use Disclosure: Dr Gelb reports
no disclosure. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Owens reports
no disclosure.

EDITOR’S PREFACE
Cicadic Intrusions
This issue of Continuum was created to inform us about the
recognition, diagnosis, and management of the conditions that can
present to the neurologist as disorders of vision, eye movement, or
pupillary function. As it is a noncore topic in the Continuum
curriculum, it has been 5 years since the last issue on neuro-
ophthalmology (unlike the usual 3-year cycle for core topics in Continuum). We
are privileged that Dr Marc Dinkin accepted my request to take on the challenge of
this important theme, and I extend my sincere thanks to him for bringing on such
expert neuro-ophthalmologists and educators as contributors to this issue.
The issue begins with the article by Dr Marc A. the characteristic signs and symptoms and
Bouffard, who reminds us of the important management of the disorders that can cause visual
neuroanatomic and physiologic concepts underlying dysfunction in these regions.
pupillary size and responses to light and near as well Drs Sashank Prasad and Marc Dinkin then present
as the disorders that affect those functions. Dr Mark an overview of the many higher cortical vision
J. Morrow then reviews the many causes of ischemic disorders, while also providing details about their
optic neuropathy, with particular emphasis on those initial discovery that place these disorders into their
conditions for which it is critical that neurologists historical context to further inform our current
maintain a high index of suspicion (eg, arteritic understanding of these fascinating, but also often
anterior ischemic optic neuropathy related to giant quite disabling, presentations.
cell arteritis). Dr Jeffrey L. Bennett then discusses The issue then includes two articles that discuss
the diagnosis and management of the many causes disorders affecting the movements of the eyes.
of inflammation of the optic nerve (optic neuritis), Regarding this—and please excuse this brief
including, but not limited to, idiopathic optic intrusion for clarification—readers will note that
neuritis and optic neuritis associated with multiple neuro-ophthalmologists uniquely use a specific term,
sclerosis, neuromyelitis optica (NMO) spectrum the efferent visual system, to refer to the pathways and
disorders, and myelin oligodendrocyte glycoprotein mechanisms that control eye movement. Although
(MOG) antibody–associated disease. Dr Cristiano evoking the implausible scenario of images being
Oliveira next reviews both toxic-metabolic and projected on the outside world through the pupils,
hereditary optic neuropathies, causes of optic nerve this term is used in this issue, as in common neuro-
dysfunction that share many pathophysiologic ophthalmologic parlance, to refer to the overall set
underpinnings. of pathways and mechanisms involved in eye
Dr Matthew J. Thurtell covers the current movements and their control. In fact, as this editorial
diagnosis and management of idiopathic intracranial is being written, I am keenly reminded of the need
hypertension, a disorder that commonly presents to for outstanding afferent and efferent visual pathway
neurologists and represents an important cause of function to avoid stepping on the cicadalike spotted
preventable visual loss. Next, Dr Heather E. Moss lanternfly that has invaded parts of Pennsylvania.
walks us through the visual pathway from the optic The first of the articles relating to disorders of eye
chiasm through the postchiasmal regions to review movement is written by Dr Christopher C. Glisson,
1192 OCTOBER 2019

who provides his approach to and management of After reading the issue and taking the Postreading
(binocular) diplopia, a symptom that occurs due to Self-Assessment and CME Test written by Drs
misalignment of the eyes and often has a neurologic Douglas J. Gelb and James W. M. Owens Jr, you may
cause. Next, Dr Janet C. Rucker demystifies the topic earn up to 20 AMA PRA Category 1 CreditsTM toward
of nystagmus and saccadic intrusions and the self-assessment and CME or, for Canadian
disorders that cause these abnormalities that affect participants, a maximum of 20 hours toward the
eye movements. Self-Assessment Program (Section 3) of the
In the subsequent article, Drs Lynn Gordon and Maintenance of Certification Program of the Royal
Marc Dinkin review the clinical features, diagnosis, College of Physicians and Surgeons of Canada.
and management of the paraneoplastic syndromes Additional credit can be obtained by listening to
that may present with neuro-ophthalmologic Continuum Audio interviews associated with this and
features. Dr Eric R. Eggenberger then describes the other Continuum issues, available to all subscribers,
clinical features and management of the most and completing tests on the Continuum Audio web
common infectious causes of optic neuropathies. platform or mobile app. Continuum Audio is also
In the final review article of the issue, Drs Fiona accredited by the Royal College of Physicians and
Costello and James N. Scott provide a well-illustrated Surgeons of Canada.
and encyclopedic review of the imaging features of I would like to give my sincere appreciation to
neuro-ophthalmologic disorders. Dr Dinkin for his expert and devoted guest editorship
of this remarkable issue. I would also like to thank
him for his meticulous and timely attention to all the
details and decisions that arise in such a complex
We are privileged that Dr Marc
issue and for enlisting such expert subspecialist
Dinkin accepted my request to take authors to assist us in the diagnosis and management
on the challenge of this important of the many patients who present to us with
theme, and I extend my sincere neuro-ophthalmologic clues to their underlying
disorders.
thanks to him for bringing on such
expert neuro-ophthalmologists —STEVEN L. LEWIS, MD, FAAN
EDITOR-IN-CHIEF
and educators as contributors to
this issue. © 2019 American Academy of Neurology.
CONTINUUMJOURNAL.COM 1193

REVIEW ARTICLE

The Pupil
C O N T I N UU M AUDIO By Marc A. Bouffard, MD
INTERVIEW AVAILABLE
ONLINE
ABSTRACT
PURPOSE OF REVIEW: Thegoal of this article is to review the anatomy and
physiology of pupillary function and then employ that information to
develop a comprehensive framework for understanding and diagnosing
pupillary disorders.
RECENT FINDINGS: The contribution of rods and cones to the pupillary light
reflex has long been known. A third photosensitive cell type, the
intrinsically photosensitive retinal ganglion cell, has recently been
discovered. This cell type employs melanopsin to mediate a portion of the
pupillary light reflex independent of rods and cones (the postillumination
pupillary response) and photic regulation of circadian rhythm.
SUMMARY: The autonomic nervous system regulates pupil size in response to

stimuli. The parasympathetic nervous system causes miosis in response to
light and near visual stimuli. These stimuli activate supranuclear pathways
that project to the Edinger-Westphal nuclei. The sympathetic nervous
system causes mydriasis in response to a variety of arousing factors, both
physiologic (wakefulness) and pathologic (pain). Abnormalities of
physiologic function cause disturbances of pupil size, shape, and response
to stimuli. The clinical approach to pupillary abnormalities should focus on
the clinical and pharmacologic assessment of the pupil’s expected
response to diverse stimuli.
CITE AS:
CONTINUUM (MINNEAP MINN) 2019;
25(5, NEURO-OPHTHALMOLOGY):
1194–1214.
INTRODUCTION
P
Address correspondence to upillary abnormalities are commonly encountered by neurologists in
Dr Marc A. Bouffard, Shapiro
Clinical Center, 5th Floor, Beth all practice settings. The presence of abnormal pupils is a frequent
Israel Deaconess Medical cause of consternation among clinicians, since a given finding, be it
Center, 330 Brookline Ave,
Boston, MA 02115, marc.a.
1 mm of anisocoria or a large poorly reactive pupil, could reflect
bouffard@gmail.com. anything from a completely benign process to an impending
neurologic emergency. Beyond the initial observation of abnormal pupil size,
RELATIONSHIP DISCLOSURE:
Dr Bouffard serves as a
shape, or response to stimulus, the examiner can interrogate the pupil’s function
consultant for the US in a number of ways, with both bedside examination techniques and
Department of Justice Vaccine pharmacologic agents, to localize the source of the pupillary abnormality
Injury Compensation Program.
(TABLE 1-1). Paired with an intimate understanding of the processes that
UNLABELED USE OF influence pupillary function at various neuroanatomic sites, diagnoses can
PRODUCTS/INVESTIGATIONAL
frequently be reached quickly and accurately.
USE DISCLOSURE:
Dr Bouffard reports no disclosure. Any didactic approach to pupillary abnormalities must begin with the
normal anatomy and physiology of the pupil. It is only once that fundamental
© 2019 American Academy
understanding of what regulates physiology has been established that
of Neurology. pathophysiology can be understood. As complex as pupillary physiology may be,
1194 OCTOBER 2019

each detail is worth touching upon as every major pupillary abnormality has a
logical explanation and can be connected to the dysfunction of an identifiable
neuroanatomic structure or pathway. To that end, the first two sections of this
article recount the anatomy of the pupil and the means by which it is dilated and
constricted to various stimuli. The third section outlines the mechanisms behind
and means by which one can diagnose common pupillary abnormalities:
anisocoria, bilaterally small and large pupils, irregular pupils, and pupils
exhibiting light-near dissociation.
ANATOMY OF THE PUPIL

The anterior surface of the iris is divided into two concentric zones: the
peripheral ciliary zone and the central pupillary zone. These are divided by a
ridge called the collarette. The stroma lies beneath the anterior epithelium, and
the organization of its vasculature is reflected in the radial furrows and ridges
of the overlying epithelium. The pupillary sphincter, responsible for constriction
of the pupil, is a muscle that surrounds the pupil concentrically; it is embedded
within the stroma adjacent to the pupil and is, at most, 1 mm wide. The pupillary
dilator is composed of fibers that are radially arranged around the pupil and run
along the entire underside of the stroma, separating it from the pigment
epithelium that comprises the posterior surface of the iris. It is this posterior
pigmented epithelium that comprises the pupillary ruff, the dark-colored ring
that is often seen separating the iris from the pupillary aperture itself. When the
pupil is dilated, the ruff may disappear. When the pupil is constricted, the
diameter of the ruff is maximized, as the pupil’s constriction results in the ruff
being pulled anteriorly into view from the posterior surface of the iris.
PHYSIOLOGIC FUNCTION OF THE PUPIL

The first step toward approaching pupillary disorders in clinical practice is to
understand pupillary physiology. This can be conceptualized by considering
the two main functions of the pupil: constriction and dilation. Physiologic
constriction of the pupil is mediated by the parasympathetic nervous system’s
cholinergic innervation of the pupillary sphincter and occurs either as a result of
stimulation by light or as a response to fixation on a target at near. Physiologic
dilation of the pupil is mediated by the sympathetic nervous system’s
catecholaminergic innervation of the pupillary dilator.
Pupil Examination TABLE 1-1
1 Examine the pupil for size, shape, and response to light and near stimuli
2 Avoid writing PERRL or PERRLA; whenever possible, measure the pupil sizes in dim light, bright
ambient light, and with direct light
3 Exercise care to not linger asymmetrically when testing for a relative afferent pupillary defect;
“photobleaching” of the retina asymmetrically can cause a transient relative afferent pupillary
defect
4 Obtain information regarding ocular trauma, surgery, and use of eye drops when evaluating
the patient with pupillary abnormalities
PERRL = pupils equal, round, reactive to light; PERRLA = pupils equal, round, reactive to light,
accommodation.

THE PUPIL
Pupillary Constriction (Miosis)

Constriction of the pupil is mediated by the parasympathetic nervous system.
The two major supranuclear drivers of physiologic pupillary constriction, the
near reflex and the pupillary light reflex, both activate the same two-neuron final
common pupillomotor pathway comprised of the Edinger-Westphal nucleus and
the ciliary ganglion (FIGURE 1-1).
THE FINAL COMMON PATHWAY (EDINGER-WESTPHAL NUCLEUS/CILIARY

GANGLION/PUPILLARY SPHINCTER). The first neuron of this final common
pupillomotor pathway is located in the Edinger-Westphal nucleus. The Edinger-
Westphal nuclei are paired
structures that lie in the dorsal
rostral midbrain. The axons
\of the cholinergic Edinger-
Westphal cell bodies form the
pupillomotor fibers that travel
with the third cranial nerve after
exiting the midbrain. In the
subarachnoid space, the
pupillomotor fibers lie on the
mediodorsal aspect of the third
nerve, in proximity to the
posterior communicating artery.
After entering the cavernous
sinus, the pupillomotor fibers
FIGURE 1-1 become more diffusely
Each eye responds to light by sending a signal down
the ipsilateral optic nerve (ON). Fibers subserving distributed around the periphery
the temporal retina (nasal visual field) do not cross of the third nerve. When the
in the optic chiasm (OC) and feed into the ipsilateral third nerve divides into its
optic tract, whereas fibers from the nasal retina superior and inferior divisions in
(temporal visual field) decussate in the chiasm and
contribute to the contralateral optic tract (OT).
the anterior cavernous sinus, the
Axons encoding visual information synapse in the pupillomotor fibers exclusively
lateral geniculate nucleus (LGN) with neurons that travel on the inferior division,
form the axons of the optic radiations (OR), which which also innervates the
project to the ipsilateral occipital cortex (OCC).
However, fibers governing pupillary reaction to
inferior rectus, inferior oblique,
light peel off the OT, enter the dorsal midbrain and medial rectus (the superior
through the brachium of the superior colliculus, and division innervates only the
synapse in the olivary pretectal nucleus (PTN). From levator palpebrae and superior
there, half the fibers synapse with the ipsilateral
rectus). This inferior division of
Edinger-Westphal nucleus (EW), a subnucleus of the
oculomotor nucleus, and half decussate in the the oculomotor nerve enters the
posterior commissure to reach the contralateral EW. orbit via the superior orbital
The neurons of the EW form the parasympathetic fibers fissure, where the pupillomotor
of the oculomotor nerve, which then synapse in the
axons synapse on the cell bodies
ciliary ganglion (CG) located within the orbit. The final
pathway is formed by neurons of the CG, whose axons that form the ciliary ganglion,
innervate the pupillary constrictors as well as the ciliary employing acetylcholine to
muscles, which govern changes in lens shape to allow activate nicotinic II receptors.
accommodation. Through this circuitry, light into either The ciliary ganglion is located
eye will cause constriction of both pupils. Note that
in the inferior orbit just posterior
output from the visual cortex down to the dorsal
midbrain helps govern the accommodation reflex. to the globe. The “final common
Figure courtesy of Marc Dinkin, MD. pathway” is common in an
1196 OCTOBER 2019

anatomic sense, but there are cell bodies within it that distinctly mediate pupil KEY POINTS
constriction in response to light or reflexive pupil constriction in response to the
● The pupillary sphincter
tracking of a target as it approaches the eye (as part of the near triad). This muscle is located
distinction gives rise to the observation that some pathologic processes affect the concentrically near the inner
pupil’s response to one stimulus but not the other, evidenced by the fact that margin of the iris and
96.5% of the cell bodies in the ciliary ganglion send their axons to innervate the mediates pupillary
constriction via cholinergic
ciliary body, which controls the shape of the lens (accommodation) and pupillary
stimulation from
sphincter in response to tracking a target as it approaches the subject. Only a parasympathetic neurons.
minority of cell bodies—approximately 3.5%—give rise to axons that innervate
the pupillary sphincter in response to the pupillary light reflex.1 The axons ● The pupillary dilator is
involved in pupillary constriction that exit the ciliary ganglion form the short composed of muscles
radially arranged around the
ciliary nerves, which then insert into the sclera and distribute diffusely until pupil that are stimulated by
reaching their targets, employing acetylcholine to activate muscarinic receptors the sympathetic nervous
on the pupillary sphincter and ciliary body. syndrome via adrenergic
input.
ACTIVATION OF THE FINAL COMMON PUPILLOMOTOR PATHWAY BY LIGHT. The ● The pupil constricts to
afferent limb of the pupillary light reflex begins in the retina. Each eye contains both light and viewing of a
approximately 60 million rods and 3 million cones.2 Rods subserve low-light near target. These two
vision, and cones, the peak concentration of which is found at the macula, reflexes share the same
anatomic efferent limb,
subserve high-resolution color vision. Until recently, it was assumed that rods
the first-order neuron of
and cones were the sole mediators of the pupillary light response and that the which is located in the
1.2 million retinal ganglion cells found in each eye did no more than transmit the parasympathetic Edinger-
signal received from rods and cones to the brain to mediate image formation in Westphal nucleus and the
second-order neuron of
the occipital lobe and to convey the pupillary light reflex to the midbrain.
which is located in the ciliary
However, a third photosensitive cell type has been recently discovered within the ganglion. However, the
ganglion cell layer. A minority (<5%) of retinal ganglion cells are intrinsically parasympathetic neurons
photosensitive. These intrinsically photosensitive retinal ganglion cells employ that mediate the near reflex
melanopsin to mediate direct depolarization by light in a manner completely outnumber those involved in
the pupillary light reflex by a
independent of rod- and cone-mediated photoactivation.3 Each of these three ratio of 30:1.
photoreceptor cell types has a distinct contribution to the pupillary light reflex.
To briefly summarize, rods and cones are responsible for rapid modulation in ● Rods, cones, and
pupillary size with changes in ambient light sensitivity, whereas intrinsically intrinsically photosensitive
retinal ganglion cells all
photosensitive retinal ganglion cells mediate a slower but more sustained contribute to the pupillary
pupillary response to light.4 The overlap of intrinsically photosensitive retinal light reflex.
ganglion cell function with rod and cone function is only partial; intrinsically
photosensitive retinal ganglion cells do not generate vision-forming signals as ● Retinal ganglion cells
stimulate the ipsilateral
rods and cones do, but they do project to the suprachiasmatic nucleus, serving
olivary pretectal nucleus in
as the sole retinal regulator of circadian rhythm.5 The net luminance-generated response to light. Each
signal from rods, cones, and intrinsically photosensitive retinal ganglion cells olivary pretectal nucleus
is relayed via retinal ganglion cells through the optic nerve, chiasm, and innervates the bilateral
tract until exiting the tract just anterior to the lateral geniculate nucleus and Edinger-Westphal nucleus,
although the contralateral
synapsing on the ipsilateral pretectal olivary nucleus. The axons originating from Edinger-Westphal nucleus is
each olivary pretectal nucleus innervate both the ipsilateral and contralateral more highly innervated.
Edinger-Westphal nucleus (the contralateral is reached through the posterior
commissure at the very dorsal midbrain), although the contralateral
Edinger-Westphal nucleus receives more innervation than the ipsilateral.
ACTIVATION OF THE FINAL COMMON PUPILLOMOTOR PATHWAY VIA THE NEAR

REFLEX. The near triad refers to the constellation of ocular adaptation that
must be achieved to maintain focus and single vision on an object at near.

THE PUPIL
The near triad consists of miosis, convergence, and accommodation. During

accommodation, the ciliary muscle relaxes the zonular fibers that connect it to
the lens, allowing the lens to relax into its default, more biconvex configuration
and thus maintaining focus at near. The near triad employs the same final
common pathway involving the cell bodies of the Edinger-Westphal nuclei and
ciliary bodies as described above.
Supranuclear control of the near triad should intuitively be mediated by a
combination of afferent and efferent structures, as one would expect for a
system required to initiate motor signals based on visual input. Animal studies
have demonstrated the role of the peristriate visual cortex (areas 19 and 22) and
the lateral suprasylvian areas,6,7 which seems to comport well with this
assumption. Several midbrain nuclei, including the raphe interpositus, superior
colliculus, and mesencephalic reticular formation, aid in the organization of
these cortical signals and their appropriate transmission to the neurons in the final
common pathway (the Edinger-Westphal nuclei for miosis and accommodation,
the medial rectus subnuclei of the third cranial nerve for convergence).7,8
Pupillary Dilation (Mydriasis)

Dilation of the pupil is accomplished by the stimulation of the pupillary dilator
by the sympathetic nervous system. The sympathetic pathway that innervates
the pupillary dilator is a three-neuron system. The majority of the first-order
neurons are located in the paraventricular and arcuate nuclei of the ipsilateral
hypothalamus and send axons caudally through the lateral brainstem and
cervical spinal cord to synapse on the second-order neurons that form the
ciliospinal nucleus of Budge.9 However, a number of other cell groups also
project onto the ciliospinal nucleus of Budge, including those that mediate
changes in sympathetic tone in response to wakefulness and pain.10
The ciliospinal nucleus of Budge extends from the C8 to T2 spinal cord levels.
The axons of these cell bodies exit the spinal cord and traverse the superior
thorax in the region of the lung apex and subclavian artery, where they adhere to
and ascend rostrally in proximity to the common carotid artery to synapse, via
acetylcholine and type II nicotinic acetylcholine receptors, on the third-order
neurons that form the superior cervical (stellate) ganglion.
The superior cervical ganglion is located adjacent to the carotid bulb. Its
third-order axons go on to innervate three distinct targets: the Müller tarsal
muscles (both superior and inferior), the pupillary dilator, and the sweat glands
of the face. Those axons destined to innervate the pupillary dilator and superior
and inferior tarsal muscles adhere to the internal carotid artery, accompanying it
through the cavernous sinus, where they are in proximity to the ipsilateral
abducens nerve, and then follow the ophthalmic artery toward the orbit. They
arrive in the orbit via the short ciliary nerves (which arise from the ciliary
ganglion) and via the long ciliary nerve (which arises from the ophthalmic
branch of the trigeminal nerve [V1]). These third-order neurons innervate their
target muscles using epinephrine and norepinephrine to stimulate β1-adrenergic
receptors. The third-order neurons in the superior cervical ganglion destined to innervate
the sweat glands of the face send their axons along the external carotid artery.
PATHOLOGIC PUPILLARY REACTIONS

The commonly encountered abnormalities of pupillary function in adults
logically originate from disruption of the physiologic pathways described
1198 OCTOBER 2019

above. The discussion that follows focuses on the main patterns of KEY POINTS
pupillary abnormalities, etiologies of each category of pupillary dysfunction,
● The near triad
key physical examination techniques, the use and interpretation of encompasses pupillary
pharmacologic tests for pupillary denervation, and considerations for miosis, convergence, and
diagnostic testing. accommodation.
Accommodation refers to
Pupils of Asymmetric Size (Anisocoria) relaxation of the ciliary body
and a resulting increase in
Asymmetry in pupil size is referred to as anisocoria. The sections that follow the concavity of the lens to
focus mainly on the characteristics of the pupils in the absence of the allow for focus on an object
appropriate sympathetic or parasympathetic influences; however, at each at near; accommodation
stage, it should be kept in mind that any evaluation of anisocoria should be does not refer to the miosis
that accompanies it as part
augmented by a careful examination of lid position, lid function, and of the near triad.
extraocular movement. Although versions (ie, eye movements with both eyes
open) are tested in all patients, more detailed motor function testing should ● Axons originating from
be considered (eg, cover-uncover testing to examine for ocular misalignment the third-order sympathetic
neurons in the superior
that might not be easily appreciated). Additionally, measurement of the
cervical ganglion that
margin-to-reflex distance 1 (MRD1) and margin-to-reflex distance 2 (MRD2) is innervate the superior and
encouraged. The MRD1 is tested by instructing the patient to look at a light held inferior Müller tarsal
directly in front of the face; the distance (using a ruler) between the lower muscles and the pupillary
dilator form a plexus around
margin of the upper lid and the light reflex on the cornea is the MRD1. The
the internal carotid artery.
MRD2 is the analogous measurement using the upper margin of the lower lid. Axons originating from
Measurement of levator excursion (maximal difference in position of the lid in third-order sympathetic
downgaze and upgaze) is also helpful and is abnormal in patients with third neurons in the superior
nerve palsy involving the levator palpebrae. This is also known as levator cervical ganglion that
innervate the sweat glands
function. of the face adhere to the
Much discussion of anisocoria revolves around the assessment and external carotid artery on
implications of pathologically mydriatic and miotic pupils, and within that route to their target.
context, it is critical to bear in mind what the acceptable range of “normal”
● Every examination of
is with reference to physiologic anisocoria. A small difference (1 mm or patients with anisocoria
less) in pupil size is commonly encountered in normal subjects. Because should include a detailed
damage to neither the sympathetic nor parasympathetic pathways is assessment of eye
present, the relative difference in pupil size should remain stable in bright movements (including
cover-uncover testing) and
and dim ambient lighting. The pupils should react well to both light and
of lid position and function.
near stimuli and exhibit no dilation lag. This is known as physiologic
anisocoria. ● Anisocoria resulting
from parasympathetic
denervation is maximized in
MONOCULAR MYDRIASIS. Monocular mydriasis results from disruption of
the light (when both pupils
parasympathetic input to the pupillary sphincter. The anisocoria should be should constrict maximally).
maximized in conditions of bright ambient light when the fellow eye
constricts and the affected eye fails to do so. Mydriasis may be due to
damage to the oculomotor nerve before synapsing on the ciliary ganglion,
damage to the ciliary ganglion or its axons on their route to the pupillary
sphincter, pharmacologic dilation of the pupil, or damage to the sphincter
itself.
The first step in assessing any patient with monocular mydriasis is to evaluate
for a third nerve palsy with a careful examination of levator palpebrae, inferior
rectus, medial rectus, superior rectus, and inferior oblique function (TABLE 1-2).
Chronic mydriasis in complete isolation of these findings is extraordinarily
unlikely to result from a third nerve palsy, but evolving third nerve palsies,
particularly compressive ones, may present with pupillary abnormalities before

THE PUPIL
other signs are discernible. Four questions should be answered when any third
nerve palsy is encountered:
u Is the third nerve palsy complete (every muscle profoundly affected)?
u Is the pupil involved?
u Is pain present?
u Are there signs of aberrant regeneration?
Common causes of third nerve palsies include compression (aneurysmal or

otherwise) and microvascular ischemia. It is important to note that most cases of
aneurysmal compression are painful, although slow-growing aneurysms may
present in a manner similar to compression from meningiomas or other
slow-growing tumors. The third nerve is more resilient to trauma than the fourth
and sixth cranial nerves. Traumatic third nerve palsies are thus unlikely to occur
with mild head trauma or in isolation without accompanying fourth and sixth
nerve palsies. Midbrain lesions (eg, infarction, hemorrhage) are encountered
frequently but rarely in neurologic isolation. Nuclear third nerve palsies involve
ipsilateral inferior rectus, inferior oblique, and medial rectus weakness; bilateral
levator palpebrae weakness; and contralateral or bilateral superior rectus
weakness (the nucleus is contralateral to the innervated eye but the fascicles
originating from each superior rectus nucleus decussate and pass through the
contralateral superior rectus nucleus). “Peripheral-appearing” third nerve palsies
may also result from more anterior midbrain damage wherein the fascicles rather
than nuclei are damaged.
Damage to the ciliary ganglion or its axons results in a mydriatic pupil referred
to as a tonic pupil owing to its slow constriction and sluggish redilation. The pupil
is often irregularly shaped with sectoral hypokinesis or vermiform writhing
movements that may not be seen with the naked eye but are often easily seen
with the aid of a slit lamp. These pupils constrict better to near visual stimuli
than to the light stimuli; this is presumably because of the 30:1 ratio of
parasympathetic fibers mediating the near reflex to those mediating the pupillary
light reflex and, therefore, their relative preservation in the face of injury.
Cholinergic hypersensitivity of the pupillary sphincter develops 1 to 2 weeks after
ciliary ganglion lesions. To test for hypersensitivity, dilute pilocarpine (a direct
cholinergic agonist) is used. Instillation of one drop of dilute pilocarpine
(0.125%) (typically compounded by the hospital pharmacy) into both eyes
should cause the affected mydriatic eye to become miotic after approximately
45 minutes; the fellow eye is generally unaffected. Thus, a positive test is clearly
seen when the anisocoria reverses. Less frequently, both pupils may constrict; the
test may still be interpreted as positive if the larger pupil constricts 0.5 mm or
more than the fellow pupil. Although it has been traditionally taught that a
TABLE 1-2 Approach to the Unilaterally Large Pupil
1 Assess for clinical evidence of third nerve palsy and note any light-near dissociation
2 Assess for irregular pupillary margin (if compatible with tonic pupil, should constrict to 0.125%
pilocarpine)
3 If no evidence of third nerve palsy or tonic pupil, administer two drops of 2% pilocarpine; if
no constriction, then the mydriasis is pharmacologic
1200 OCTOBER 2019

pilocarpine concentration of 1% is generally required to constrict mydriatic KEY POINTS
pupils in patients with third nerve palsies, care must be taken as this rule is not
● Chronic mydriasis in
absolute, and, on occasion, mydriatic pupils due to a third nerve palsy may also complete isolation is
constrict to dilute (0.125%) pilocarpine.11 The majority of tonic pupils are benign extraordinarily unlikely
and idiopathic, in which case it is called an Adie pupil, but the history and to result from a third
examination should take into account findings suggestive of giant cell arteritis,12 nerve palsy.
generalized dysautonomia,13,14 orbital inflammation (eg, sarcoid),15 neoplasm,16
● Tonic pupils are irregular,
Guillain-Barré syndrome,17 or trauma, since tonic pupils may infrequently result display sectoral hypokinesis
from any of these processes, among others. Adie pupils are generally monocular, (which may require the aid
seen in female patients, and isolated, though they may be accompanied by loss of a slit lamp to visualize),
of deep tendon reflexes of the lower extremity, in which case the term Holmes- are slow to redilate after
constriction (thus their
Adie syndrome is used. name), and demonstrate
Pharmacologic dilation of the pupils can result either from administration light-near dissociation
of sympathomimetics (eg, phenylephrine) or from anticholinergics (eg, (reacting better to near
tropicamide eye drops, ipratropium nebulizers, inadvertent transmission of stimuli than light). They may
be idiopathic, occur
scopolamine from retroauricular patches to the eye). Instillation of 1% to 2% frequently in young women,
pilocarpine should constrict any mydriatic pupil other than those that have been and are only rarely
pharmacologically dilated (more concentrated pilocarpine drops are not only associated with other
unnecessary but should be avoided given the risk for retinal detachment). The pathologic processes.
Ninety percent of cases
patient should also be queried about any source of iris trauma, either surgical or are monocular.
accidental, that might have resulted in a mydriatic irregular pupil.
● Constriction of a
MONOCULAR MIOSIS. Pathologic miosis typically results from denervation of the mydriatic pupil by dilute
pilocarpine (0.125%) was
sympathetic input to the pupillary dilator. Thus, the amount of anisocoria will
traditionally thought to be
be maximized under conditions of dim ambient light when the denervated eye specific to tonic pupils.
will fail to dilate and the fellow eye will dilate maximally. Careful observation However, this is incorrect;
may reveal slow dilation after a light stimulus is removed from the affected pupil; preganglionic third nerve
this is referred to as dilation lag. palsies resulting from
compression and trauma
The sympathetic fibers that subserve mydriasis do not travel in isolation; may result in a mydriatic
they are accompanied by the fibers that innervate the Müller tarsal muscles and, pupil responsive to 0.125%
until the carotid bifurcation, by the fibers that supply sudomotor function to pilocarpine.
the sweat glands of the face as described above. A complete Horner syndrome,
● Pilocarpine 2% will cause
which comprises ipsilateral mild ptosis, miosis, and facial anhidrosis, results constriction of any mydriatic
from damage to the sympathetic pathway proximal to the divergence of the pupil other than one that is
sympathetic fibers that supply the sweat glands of the face (adherent to the pharmacologically dilated.
external carotid artery) and those that innervate the pupillary sphincter and
● Anisocoria resulting from
tarsal muscles (both adherent to the internal carotid artery, with those
sympathetic denervation of
innervating the tarsi leaving the internal carotid most distally). Horner syndrome the pupil is maximized in the
may be incomplete, even if the lesion is proximal. The relative difference in dark (when both pupils
MRD1 between eyes usually does not exceed 1 mm to 2 mm in a patient with should dilate maximally).
Horner syndrome, although the interpalpebral distance (MRD1 + MRD2) may
be smaller by 2 cm to 4 cm and the lower lid often elevates in patients with
Horner syndrome, creating a “pseudoenophthalmos” or “inverse ptosis.” Some
patients with Horner syndrome have accompanying features that are absent
from the classic triad but may be helpful clues in cases of partial Horner
syndrome. Among the most prominent are conjunctival injection due to
vasodilation resulting from decreased sympathetic tone and decreased
intraocular pressure relative to the fellow eye resulting from a decrease in
aqueous humor production by the ciliary body, a process that is stimulated by
the sympathetic nervous system.

THE PUPIL
The detection of Horner syndrome should be followed by investigation as to

its cause:
u First-order Horner syndrome (accompanied by ipsilateral ptosis and anhidrosis of the

ipsilateral face and body)
u Second-order Horner syndrome (accompanied by ipsilateral ptosis and ipsilateral facial
anhidrosis)
u Third-order Horner syndrome (accompanied by ipsilateral ptosis of the upper and lower
eyelids without anhidrosis)
The first-order neurons originate in the hypothalamus, which is rarely the

site of injury. The most common location for first-order neuron injury is in the
dorsolateral medulla; this is a common component of Wallenberg syndrome but
may occur more rostrally. Spinal cord lesions rostral to the ciliospinal nucleus
of Budge are encountered, particularly in patients with a Brown-Séquard
syndrome. The second-order neuron is often injured by thoracic neoplastic
disease; the classic association is with the Pancoast tumor in the lung apex, but
any pathology in this location (eg, aneurysm, sarcoidosis) may be responsible.
The common carotid artery is a less frequent site of injury for the second-order
neuron. The third-order neuron ascending the carotid is prone to injury in the
setting of carotid dissection. Bearing this differential diagnosis in mind, a
targeted examination should be done in detail, both clinically and radiographically.
The typical radiographic profile includes MRI of the brain and cervical spine
with contrast (which may, at some institutions, be protocoled to image the lung
apex; a chest CT with contrast can be done otherwise) and a magnetic resonance
angiogram (MRA) of the head and neck (including the great vessels). The
workup for isolated, painless, incidentally discovered cases of Horner syndrome
is frequently unrevealing but must be performed given the potentially serious
etiologies above. Rare cases of Horner syndrome are associated with idiopathic
headache syndromes, including the family of trigeminal autonomic
cephalalgias, idiopathic Raeder paratrigeminal syndrome, and migraine with
autonomic features. Even transient Horner syndrome should not be attributed
to these entities without a careful clinical and radiographic investigation.
Eye drops may be used to rapidly determine whether miosis is pathologic or
simply reflects physiologic anisocoria. Traditionally, a combination of cocaine
and hydroxyamphetamine eye drops has been used to detect sympathetic
denervation of the pupil. Cocaine reduces presynaptic reuptake of
catecholamines secreted into the synaptic cleft. Thus, instillation of cocaine
drops into both eyes for approximately 45 minutes leads to accentuation of
anisocoria in patients with Horner syndrome; the normally innervated pupil
becomes excessively mydriatic, and the denervated pupil fails to dilate
commensurately. A postcocaine increase in anisocoria of 1 mm or greater is
interpreted as a positive test. On a subsequent date, hydroxyamphetamine
eye drops can be used to help differentiate third-order neuron lesions from first-
or second-order neuron lesions. Instillation of hydroxyamphetamine causes
third-order neurons to secrete catecholamines. Thus, a miotic pupil from a
third-order Horner syndrome will not dilate in response to hydroxyamphetamine
as the damaged neuron cannot respond to the secretagogue. If the Horner
syndrome is due to a first- or second-order neuron lesion, the third-order neuron
remains intact and will respond to a secretagogue, dilating the pupil.
1202 OCTOBER 2019

Because of issues surrounding substance control, cocaine and KEY POINTS
hydroxyamphetamine eye drops are difficult to obtain. This two-step test has
● The ptosis that results
largely been abandoned in favor of apraclonidine testing. Decreased stimulation from sympathetic
of the pupillary dilator from a lesion of any order neuron in the sympathetic denervation is often subtle
chain results in increased expression of catecholamine receptors on the pupillary (1 mm to 2 mm), and
dilator; this usually occurs within a few days of injury but may take up to a week frequently both the upper
and lower lids are affected
to occur. This phenomenon allows a weak α-2 agonist, such as apraclonidine
(as both the superior and
0.5%, to dilate the supersensitive pupil. Two drops of apraclonidine 0.5% into inferior tarsus receive
normal eyes should not result in sympathetic stimulation of a normal pupillary sympathetic innervation),
dilator. However, in pupillary dilator muscles that have been denervated long which sometimes results
in the optical illusion
enough to become hypersensitive, the abnormal pupil will dilate in response to
of enophthalmos
apraclonidine, whereas the unaffected fellow pupil generally does not change in (pseudoenophthalmos).
size (drops must be instilled into each eye as the nonmiotic pupil serves as a
control). A clearly positive test occurs when reversal of anisocoria is seen after 45 ● Apraclonidine, a weak
to 60 minutes (CASE 1-1). The benefits of apraclonidine over cocaine, other than α-2 agonist, has largely
supplanted cocaine and
its accessibility, include the fact that it is much easier to discern reversal of hydroxyamphetamine in
anisocoria than an exacerbation of anisocoria (the latter of which may require confirmation of sympathetic
careful measurements) and that the ptosis that typically accompanies miosis in denervation of the pupil.
Horner syndrome generally also responds to apraclonidine. The benefits of Denervation supersensitivity
may take up to 1 week to
cocaine over apraclonidine are that cocaine can be used immediately after the occur; apraclonidine testing
pupil becomes miotic and that it may be used in infants, in whom apraclonidine will not detect acute
may cause respiratory depression (its use in infants is strictly contraindicated; sympathetic denervation of
consultation with a pediatric ophthalmologist or neuro-ophthalmologist should the pupil. Apraclonidine
cannot be used in young
be sought before instillation of drops in children).
children because of the
Not all pathologically miotic pupils result from sympathetic denervation. The possibility of respiratory
main exception is the tonic pupil when it has been present chronically. As depression.
described above, tonic pupils are large and irregular at the outset. However,
within months to years, a tonic pupil may evolve into a miotic pupil. This ● Tonic pupils, which are
mydriatic at the outset, may
presumably reflects a reinnervation phenomenon. It is important to note that the eventually become miotic
light-near dissociation of the tonic pupil persists even after the pupil has and irregular.
progressed from abnormally large to abnormally small.
EPISODIC ANISOCORIA. Episodic anisocoria is an uncommon phenomenon with a

relatively short differential diagnosis:
u Benign episodic anisocoria

u Iatrogenic (eg, manual contamination with scopolamine patch, datura plant)
u Seizure
u Intermittent increase in sympathetic tone in patient with previously unnoticed unilateral
Horner syndrome
u Primary headache syndromes with intermittent Horner syndrome (eg, migraine, trigeminal
autonomic cephalalgias)
The syndrome of intermittent mydriasis with cholinergic supersensitivity has

been described and mainly occurs in young women, many of whom have
migraines (although this is distinct from the episodic anisocoria that can occur as a
feature of migraine or trigeminal autonomic cephalalgia); interestingly, a minority
may develop a generalized ganglionopathy.18 Although transient anisocoria is a
generally benign phenomenon, it may sometimes be a clue to more serious

THE PUPIL
processes. Transient mydriasis may be seen during and briefly after seizures.
Ictal anisocoria is poorly characterized and does not have clear localizing value.
Both pupils may dilate during seizures. Furthermore, the anisocoria of Horner
syndrome may be subtle, particularly when patients are in bright ambient
lighting (generally the only time at which nonphysicians ever make note of their
pupil size). When patients with Horner syndrome experience circumstances of
elevated sympathetic tone (eg, pain, fright), the fellow pupil may physiologically
CASE 1-1 A 52-year-old man was referred to the neuro-ophthalmology clinic for
evaluation of anisocoria detected by his optometrist during a routine
evaluation. The patient was unaware of any pupillary asymmetry and
denied any history of head or neck pain or trauma. He had no significant
past medical history, took no medications, and had quit smoking several
years before evaluation.
His examination demonstrated orbital fat atrophy with high lid creases
in both eyes, a margin-to-reflex distance 1 (MRD1) of 1.5 mm in the right
eye and 2 mm in the left eye (the lids were subsequently retracted for
photography) and a margin-to-reflex distance 2 (MRD2) of 4 mm in the
right eye and 4.5 mm in the left eye. He had normal afferent visual
function, and his pupils were 3 mm right eye/4.5 mm left eye (dark),
2.5 mm right eye/3 mm left eye (ambient light), and 2 mm right eye/
2.5 mm left eye (direct light). The ocular motor examination and general
neurologic examinations were normal.
His pupil size was measured before and after administration of 0.5%
apraclonidine. Preapraclonidine, his right pupil was smaller, a finding that
was accentuated in dim lighting (FIGURE 1-2A). Postapraclonidine, a reversal
of anisocoria in the same ambient lighting was noted, confirming the
presence of a partial Horner syndrome (FIGURE 1-2B).
COMMENT Apraclonidine is a rapid means by which a clear diagnosis of Horner

syndrome can be established, particularly in patients in whom another
cause exists for ptosis, which confounds the examination, as was the
case here (levator dehiscence with age-related orbital involutional
changes). Both the ptosis and anisocoria seen in Horner syndrome are
generally subtle. Patients with partial Horner syndrome (without the aid
of hydroxyamphetamine drops to aid in localization) should undergo MRI
from the midbrain to the upper thoracic spinal cord with and without
contrast, contrast-enhanced chest imaging to evaluate for neoplasm
and subclavian artery abnormalities, and angiography of the head and
neck. MRI of the orbits may also be useful to detect distal third-order
neuron lesions. This patient underwent magnetic resonance angiography
(MRA) of the head and neck and MRI of the brain, orbits, and cervical
spine with and without contrast, all of which were normal. The workup
for isolated, incidentally discovered, painless cases of Horner syndrome
is often unrevealing but must be undertaken nevertheless given the
potentially serious etiologies.
1204 OCTOBER 2019

dilate; the patient may only notice anisocoria under these circumstances, incorrectly
identifying the normal mydriatic eye as the abnormality. As such, patients reporting
episodic anisocoria must be closely inspected for a Horner syndrome. Patients
should also be questioned as to unintentional exposure to anticholinergics; patients
may scratch a scopolamine patch worn for nausea or touch plants that produce
anticholinergic compounds (eg, datura) and then touch the eye, causing
intermittent anisocoria. Some over-the-counter eye drops contain pheniramine, an
FIGURE 1-2
Testing for Horner syndrome in the patient in CASE 1-1 showing the pupils before apraclonidine
(A) and 1 hour after the administration of one drop of 0.5% apraclonidine in each eye (B).

THE PUPIL
anticholinergic that causes mydriasis, which can occasionally be asymmetric.

Aerosolized ipratropium, used for asthma, may cause dilation in one eye if the face
mask is ill fitting. Rarely, episodic sectoral spasm of the iris results in “tadpole”
pupils, which can herald an incipient Horner pupil.19
Bilaterally Small Pupils

Bilaterally small pupils may result from bilateral sympathetic denervation of the
pupillary dilator (as described earlier in the article), from factors causing
predominance of parasympathetic tone over sympathetic tone, or from chronic
reinnervation:
u Parasympathetic excess
◇ Sedating medications
◇ Cholinergic agonists (eg, pilocarpine)
u Sympatholysis
◇ Diencephalic lesions
◇ Pontine tegmentum lesions
◇ Bilateral peripheral Horner syndrome
u Chronic ganglionopathies
◇ Argyll Robertson pupils
◇ Chronic tonic pupils
Structural lesions may cause sympatholysis and bilaterally small pupils. The
most pronounced example is seen in cases of pontine tegmental damage, which
may not only cause deafferentation of the ciliospinal nucleus of Budge from
the hypothalamus (thus causing bilateral central Horner syndrome) but also
disruption of ascending afferent algesic stimuli that serve as drivers of
pupillodilation under normal circumstances. Thus, pontine tegmental damage can
cause pinpoint pupils in excess of what is seen in second- or third-order neuron
Horner syndromes. Diencephalic lesions may produce pupils that are small but
generally not to the extent seen with bilateral pontine tegmental damage.
Stimulation of the parasympathetic nervous system resulting in bilaterally
small pupils is often pharmacologic. The most common nonstructural causes of
bilaterally small pupils are medications and drugs of abuse belonging to the
opiate and barbiturate class, but any sedating medication can cause bilateral
miosis. Under circumstances of fatigue or sedation (wherein parasympathetic
tone predominates), the pupils become miotic (the Westphal-Piltz
phenomenon), even in dim conditions when one might expect the pupils to
dilate because of lack of input to the pupillary light response.
Chronic reinnervation may similarly cause bilaterally miotic pupils. The
most common scenario causing reinnervation is that of the ciliary
ganglionopathy in the chronic stage, yielding the chronic tonic pupil. Tonic
pupils are mydriatic in the acute and subacute setting. After several months to
years, however, tonic pupils generally become miotic while retaining their
features of light-near dissociation and irregularity with sectoral hypokinesis.
The exact mechanism by which the tonic pupil develops is not certain, but it is
clear that reinnervation can cause such changes because miosis has been seen
as a form of aberrant regeneration following third nerve palsies. Syphilis may
be another cause of ciliary ganglionopathy. The localization of the Argyll
1206 OCTOBER 2019

Robertson pupil (the eponym used to describe the small, irregular pupils KEY POINTS
exhibiting light-near dissociation that are seen in syphilis) has been a
● Bilaterally small pupils
long-standing subject of debate.20 Owing to the lack of sectoral hypokinesis in may result from bilateral
some reports (which would be expected to be seen in ciliary ganglion sympathetic denervation
damage), it has been hypothesized that syphilitic involvement of the dorsal of the pupillary dilator,
midbrain might account for the Argyll Robertson pupil. However, debate from factors causing
predominance of
continues as to whether the Argyll Robertson pupil localizes to the dorsal
parasympathetic tone over
midbrain or the ciliary ganglion.20 Pathologic evidence of syphilis sympathetic tone, or from
involvement in the dorsal midbrain is lacking; it is known that syphilis affects chronic reinnervation as
other ganglia (ie, the dorsal root ganglia), and neither small nor irregular seen with bilateral tonic
pupils.
pupils are classically seen in dorsal midbrain syndromes (which yield
midsized pupils). As such, identification of small irregular pupils with ● Bilaterally small irregular
light-near dissociation in both eyes should prompt the neurologist to consider pupils should prompt
both chronic idiopathic tonic pupils and Argyll Robertson pupils. consideration of chronic
tonic pupils and Argyll
Bilaterally Large Pupils Robertson pupils.
Treponemal syphilis
Bilaterally large pupils are seen when sympathetic input to the iris exceeds serologies should be
parasympathetic input. This is either through exaggerated sympathetic ordered.
stimulation of the pupillary dilator or decreased parasympathetic stimulation of
the pupillary sphincter:
u Increased sympathetic innervation of the pupillary dilator (eg, cocaine)
u Decreased parasympathetic innervation of the pupillary sphincter
◇ Loss of supranuclear input to both Edinger-Westphal nuclei
→ Severe bilateral blindness
◇ Defects of the final common pathway
→ Edinger-Westphal nucleus
→ Third nerve palsies
→ Ciliary ganglion (tonic pupils, 10% are bilateral)
→ Neuromuscular junction (anticholinergics, botulinum toxin)
→ Iris injury
Factors promoting excess sympathetic stimulation of the pupillary dilator,

such as drugs (either iatrogenic [such as phenylephrine and tricyclic
antidepressants] or recreational [such as cocaine]), may be the cause.
Physiologically large pupils (eg, from anxiety) are rarely prominent enough to
prompt medical attention. Decreased parasympathetic signaling to the pupil may
be a result of defective supranuclear input to the Edinger-Westphal nucleus or to
damage to the final common pathway itself. Commonly encountered
supranuclear defects resulting in large pupils include severe bilateral optic
neuropathy that prevents light signals from reaching the olivary pretectal
nucleus and tectal lesions disrupting the connection between the olivary
pretectal nucleus and the Edinger-Westphal nucleus. Commonly encountered
defects of the final common pathway (Edinger-Westphal nucleus/ciliary
ganglion/iris) include lesions affecting the third nerve, ciliary ganglionopathies
(the acute tonic pupil, Miller Fisher syndrome, diabetes mellitus), disorders of
the neuromuscular junction (mainly botulism, which prevents acetylcholine
release from the ciliary ganglion neuron, and never myasthenia gravis), and
iatrogenic anticholinergics (such as tropicamide drops used for dilation,

THE PUPIL
scopolamine contamination from antiemetic patches, or ipratropium blown into

the eye rather than airways) (CASE 1-2).
If the cause of large pupils is not ascertainable after checking the response
to light and the response to near, testing acuity, carefully assessing the
ocular motor examination (both for defects of supranuclear and final common
pathway function), and examining the iris in as much detail as possible for
sphincter rupture or surgical trauma, drops can be used to aid in localization.
The use of pilocarpine, both full strength and dilute, is discussed in the
section on anisocoria; this can just as easily be employed when both pupils are
large and do not react well to either light or near stimuli. Dilute pilocarpine
(0.125%) can be used to determine if the pupil is parasympathetically
denervated; this is most commonly seen in tonic pupils, which are bilateral
CASE 1-2 A 24-year-old man was referred to the neuro-ophthalmology clinic

for evaluation of photophobia. He reported sensitivity to bright light
requiring the aid of sunglasses for approximately 6 weeks. He denied
any eye pain under conditions of dim light, changes in his vision,
accompanying neurologic deficits, recent head or orbital trauma, or
symptoms suggestive of rheumatologic disease. He had no significant
past medical history.
Examination demonstrated normal visual acuity and color vision. The
pupils were large: 8 mm in both eyes in dim light, 7.5 mm in both eyes in
ambient light (FIGURE 1-3A), and reacted only to 6.5 mm in both eyes with
bright direct light (FIGURES 1-3B and 1-3C). The pupils constricted to 3 mm
when he was asked to follow a target as it approached the bridge of his
nose (FIGURE 1-3D). The slit-lamp examination demonstrated sectoral
hypokinesis of the iris in both eyes. No anterior chamber or vitreous cells
were seen. There was no ptosis or limitation of ductions. His general
neurologic examination was normal.
COMMENT The presence of bilaterally large pupils that react poorly to light but briskly
to the near reflex implicates an abnormality of the afferent or efferent limb
of the pupillary light reflex. This patient’s excellent acuity implicates the
efferent limb. The absence of any ocular motor abnormalities or ptosis
exonerates the third nerves, and the presence of sectoral hypokinesis
confirms bilateral tonic pupils as the diagnosis. Hemoglobin A1c was normal
and fluorescent treponemal antibody absorption (FTA-ABS) was
nonreactive. This patient’s idiopathic tonic pupils remained stable and
isolated at follow-up.
When in doubt as to the diagnosis of a tonic pupil, dilute pilocarpine
(0.125%) can be employed to test for denervation of large pupils consistent
with tonic pupils, bearing in mind that, rarely, constriction may occur in the
setting of third nerve palsies. Dilute pilocarpine may similarly aid in the
treatment of patients who are photophobic from their large pupils. Full-
strength pilocarpine should not generally be used as this may cause ocular
pain and, in rare cases, retinal detachment.
1208 OCTOBER 2019

in approximately 10% of cases. Pilocarpine 1% to 2% should constrict
all mydriatic pupils except in cases due to iatrogenesis (eg, tropicamide
or scopolamine).
Irregularly Shaped Pupils

Evaluation of pupillary shape can be difficult without high magnification,
making a slit-lamp examination optimal in characterizing and diagnosing
abnormally shaped pupils. Many neurologists encounter these scenarios, and an
overview of the possible causes may aid in knowing which questions to ask the
patient and when to seek the consultation of an ophthalmologist. Abnormally
shaped pupils can be due to congenital and acquired causes.
FIGURE 1-3
Light-near dissociation in the patient in CASE 10-2. A, Pupil size in normal ambient lighting. B, C,
Pupils show a lack of constriction to light. D, Pupillary constriction to fixation on a near target
is preserved.

THE PUPIL
CONGENITAL. The most common congenital abnormalities of pupil shape a

neurologist will encounter include coloboma, aniridia, and corectopia. A
confident diagnosis of congenital abnormality of the iris is best made by an
ophthalmologist because of the need for a slit-lamp examination.
Colobomas are focal areas of excavation of the iris. These are the result of
defective iris closure during its formation. Other structures may be similarly
affected, including the optic nerve. Colobomas may be sporadic or syndromic,
most notably in association with CHARGE syndrome (coloboma of the eye, heart
defects, atresia of the choanae, renal abnormalities and retardation of growth
CASE 1-3 A 46-year-old woman was referred to the neuro-ophthalmology clinic for
evaluation of irregular pupils by her optometrist, who followed her for
refractive error. She was a developmentally normal adult and was
unaware of any pupillary abnormalities; because of dark irides, it was
difficult to ascertain from old photographs whether this was long-
standing. She denied any history of eye surgery, ocular trauma, uveitis,
iritis, or accompanying neurologic symptoms. Her past medical history
was notable only for a history of systemic hypertension. She did not use
any eye drops.
Her afferent examination revealed normal visual acuities and color
vision in both eyes. The pupillary examination demonstrated slightly
irregular pupils bilaterally that measured 4 mm in both eyes in dim light
and 3.75 mm in both eyes in ambient light, 3.5 mm in both eyes to
direct light stimulation, and 2 mm in both eyes when tracking a target
approaching the bridge of her nose (FIGURE 1-4). The slit-lamp examination
demonstrated mild sectoral hypokinesis in both eyes, with no evidence
of synechiae or intraocular inflammation. The eyelids were normally
positioned (margin-to-reflex distance 1 was 4 mm in both eyes), and her
ocular motor examination was normal. The remainder of the general
neurologic examination was normal.
COMMENT This developmentally normal adult without ocular trauma or inflammation

referred for evaluation of abnormally shaped pupils was found to have
midsized irregular pupils with light-near dissociation in both eyes. This
constellation, particularly in the setting of an otherwise normal neurologic
examination, is suggestive of either bilateral tonic pupils or Argyll
Robertson pupils. Because Argyll Robertson pupils are seen in tertiary
syphilis and titers of nontreponemal tests (ie, Venereal Disease Research
Laboratory, rapid plasma reagin [RPR]) may decrease over time even in
patients who are not treated, treponemal testing (ie, fluorescent
treponemal antibody absorption [FTA-ABS] or Treponema pallidum particle
agglutination assay [TPPA]), which does not normalize even in late syphilis,
is mandatory. This patient’s treponemal and nontreponemal syphilis
serologies were negative, and a diagnosis of bilateral chronic tonic pupils
was made. The patients in CASE 1-2 and CASE 1-3 also illustrate the evolution in
pupil size over time as acute tonic pupils become chronic.
1210 OCTOBER 2019

and/or development, genital abnormalities, and ear abnormalities), which
arises from mutations in the CHD7 gene and is frequently encountered as a
new mutation.21
Patients with aniridia have hypoplastic irides resulting in a correspondingly
large pupil, caused by a mutation in the transcription factor PAX6. Frequently,
the iris is not the only defective structure, as the PAX6 gene acts as a transcription
factor for other structures as well (eg, cataracts and glaucoma frequently
accompany the condition).22 Two-thirds of cases are inherited in an autosomal
dominant manner.
FIGURE 1-4
Pupil irregularity in the patient in CASE 1-3. A, The
pupil in normal ambient lighting. B, The pupil has
an abnormal shape and shows lack of response to
light. C, The pupil shows brisk reaction to fixation
on a target at near.

THE PUPIL
Corectopia is an off-center pupil (beyond its slightly nasal position in the iris
that is often found in normal subjects) that may be congenital or acquired. When
congenital, corectopia is often present as a component of Axenfeld-Rieger
syndrome, which frequently involves pediatric glaucoma and hypertelorism and
is autosomal dominant. About 40% of patients have abnormalities in either the
PITX2 or FOXC1 genes.23
ACQUIRED. Trauma, surgical or accidental, is a common cause of acquired

pupillary irregularity. It is important to recall that disruption of the pupillary
sphincter at one location does not render the entire muscle unable to function.
Inflammation of the iris (iritis) may result in adhesions of the lens to iris called
posterior synechiae, in which this physical tethering may cause a misshapen
pupil. Tonic pupils and Argyll Robertson pupils tend to be irregular as well,
although sometimes appreciation of this feature requires the aid of the slit
lamp (CASE 1-3). The exact mechanism by which this occurs is not clear, but it
may reflect chronic reinnervation after ciliary ganglion injury. As mentioned,
not all cases of corectopia are congenital. Brainstem pathology may cause
corectopic pupils as well.
Pupils Exhibiting Light-Near Dissociation

Pupils that react poorly in response to the light reflex but well in response
to the near reflex (ie, light-near dissociation) are frequently encountered.
The converse, in which the pupil’s reaction to light is pristine but miosis
with a near pursuit target is impaired, is not expected. This is likely because
of two facts. First, more fibers mediate the near triad than the pupillary
light reflex, so the system is inherently less susceptible to damage. Second,
the anatomy of the pupillary light reflex’s reflex arc places it in more danger of
sustaining structural damage than that of the near triad’s supranuclear
components. Presumably patients with damage to the supranuclear circuits
mediating the near triad would be too neurologically devastated to be tested.
Light-near dissociation has three common localizations: the dorsal midbrain,
the ciliary ganglion, and the optic nerve:
u Dorsal midbrain syndrome

u Ciliary ganglionopathy
◇ Tonic pupil (in isolation or with hyporeflexia [Adie pupil])
◇ Syphilis (Argyll Robertson pupils)
◇ Diabetes mellitus
u Amaurotic pupil
In the dorsal midbrain, the majority of axons traveling from each pretectal
olivary nucleus, which decussate through the posterior commissure to synapse
on the Edinger-Westphal nuclei, are prone to mechanical injury as they are
superficially positioned. In addition to midsized pupils that react poorly to light
but briskly to near stimuli (as the pathways mediating the near triad lie more
anteriorly in the midbrain), the dorsal midbrain syndrome includes retraction
of the upper eyelids, supranuclear vertical gaze palsy (as the third nerve
nucleus is classically unaffected), and convergence-retraction movements in
attempted upgaze.
1212 OCTOBER 2019

The second localization of light-near dissociation is at the ciliary ganglion. KEY POINTS
Because of the disproportionately low number of cell bodies dedicated to
● When in doubt as to the
mediating pupillary constriction associated with the pupillary light reflex (as etiology of an irregularly
opposed to the high proportion mediating constriction as part of the near shaped pupil, enlist the aid
response), ganglionopathies often present with light-near dissociation. As of an ophthalmologist who
described earlier, tonic pupils and Argyll Robertson pupils are the most can employ a slit lamp to
look for important anatomic
common examples.
details and signs of
The third localization of light-near dissociation is at the optic nerve. A severe inflammation that are
optic neuropathy causes a sluggish reaction to light or, in severe cases in which difficult to observe with the
the eye is unable to perceive light at all, no reaction to light shined ipsilaterally naked eye.
(this is referred to as an amaurotic pupil). It should be noted that if light is shined
● The most common
into the unaffected fellow eye, the pupil of the eye with low vision should still congenital causes of
have a normal consensual response (the defect is afferent, not efferent). irregular pupils include
Similarly, pursuit of an approaching target that triggers the near response should coloboma, aniridia, and
cause pupillary constriction, even in an amaurotic pupil. It is reported that pupillary decentration,
referred to as corectopia.
patients with no light perception vision in both eyes can still trigger the near
response via proprioceptive cues (eg, “looking” at one’s own thumb). ● When evaluating irregular
pupils, consider trauma,
inflammation with synechiae
formation, tonic pupils, and
CONCLUSION
Argyll Robertson pupils.
Familiarity with the pupil’s function in health and disease is essential for every
neurologist. This knowledge enhances the bedside examination, prompts the ● Light-near dissociation
correct diagnostic tests, and aids in the rapid and accurate diagnosis of many typically localizes to the
neurologic disorders. ciliary ganglion, dorsal
midbrain, or bilateral
optic nerves.
ACKNOWLEDGMENT
The author would like to thank Nurhan Torun, MD, FRCS(C) for her critical
appraisal of this manuscript. The author has had the great luck to draw upon
Dr Torun’s expertise endlessly, and he remains her pupil.
REFERENCES
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THE PUPIL
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Paxinos G, editor. The rat nervous system. Barré syndrome with bilateral tonic pupils.
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19 Thompson HS, Zackon DH, Czarnecki JS.
12 Foroozan R, Buono LM, Savino PJ, et al. Tonic Tadpole-shaped pupils caused by segmental
pupils from giant cell arteritis. Br J Ophthalmol spasm of the iris dilator muscle. Am J Ophthalmol
2003;87(4):510–512. doi:10.1136/bjo.87.4.510. 1983;96(4):467–477. doi:10.1016/S0002-
9394(14)77910-3.
13 Toth C, Fletcher WA. Autonomic disorders and
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1214 OCTOBER 2019

Ischemic Optic REVIEW ARTICLE
Neuropathy

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Mark J. Morrow, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Visionis often threatened or lost by acute ischemic
damage to the optic nerves. Such pathology most often affects the
anterior portion of the nerve and is visible on funduscopic examination.
Ischemic optic neuropathy is associated with typical vascular risk factors
and with one systemic disease in particular: giant cell arteritis (GCA). This
article provides an overview of the three major classes of ischemic optic
neuropathy, including information on risk factors, differential diagnosis,
evaluation, and management.
RECENT FINDINGS: Optical coherence tomography provides precise anatomic

imaging in ischemic optic neuropathy, showing neural loss weeks before it
is visible on examination. Refinements of optical coherence tomography
reveal optic nerve microvasculature and may assist in understanding
pathogenesis and verifying diagnosis. New diagnostic algorithms and
cranial vascular imaging techniques help define the likelihood of GCA in
patients with ischemic optic neuropathy. Finally, intraocular drug and
biological agent delivery holds promise for nonarteritic ischemic optic
neuropathy, whereas newer immunologic agents may provide effective CITE AS:
steroid-sparing treatment for GCA. CONTINUUM (MINNEAP MINN) 2019;
1215–1235.
SUMMARY: It is essential to recognize ischemic optic neuropathy upon
presentation, especially to determine the likelihood of GCA and the need Address correspondence to
for immediate steroid therapy. A broad differential diagnosis should be Dr Mark J. Morrow, Department
of Neurology, Harbor-UCLA
considered so as not to miss alternative treatable pathology, especially in Medical Center, 1000 W Carson
cases with retrobulbar optic nerve involvement. St, Box 492, Torrance, CA 90509,
mmorrow@labiomed.org.
Dr Morrow reports no
INTRODUCTION disclosure.
T
he optic nerve may be damaged by ischemia anywhere from its visible
UNLABELED USE OF
portion at the back of the eye to its intracranial transition into the PRODUCTS/INVESTIGATIONAL
optic chiasm.1–4 Of conditions classified as ischemic optic neuropathy, USE DISCLOSURE:
involvement at the optic nerve head (anterior ischemic optic Dr Morrow discusses the
unlabeled/investigational use of
neuropathy [also known as AION]) is far more common than medications for the treatment
involvement behind the eye (posterior ischemic optic neuropathy [also known as of ischemic optic neuropathy,
PION]). Anterior ischemic optic neuropathy is traditionally divided into those none of which are approved
by the US Food and Drug
cases that are associated with vasculitis, usually giant cell arteritis (GCA), and Administration.
those that are not. Arteritic anterior ischemic optic neuropathy (also known as
AAION) comprises only 10% to 15% of all anterior ischemic optic neuropathy © 2019 American Academy
cases, but its early differentiation from nonarteritic anterior ischemic optic of Neurology.

ISCHEMIC OPTIC NEUROPATHY
neuropathy (also known as NAION) is critical for medical management. Arteritic

anterior ischemic optic neuropathy is a true medical emergency because GCA
can cause imminent ischemic damage to the fellow optic nerve, retina, brain,
and heart.
Anterior ischemic optic neuropathy is the most common cause of acute optic
nerve damage in persons older than 50 years of age, with an annual incidence of
2.3 cases per 100,000 to 10.2 cases per 100,000.5,6 It often leads to significant
permanent visual impairment in affected eyes. Whether associated with arteritis
or not, anterior ischemic optic neuropathy is typically painless. It begins
suddenly, sometimes first noted upon awakening, but may slowly progress to
peak visual loss over a week or more. Visual field impairment is usually
altitudinal, with the deficit usually worse below the visual horizon. Visual acuity
is variably affected and generally worse in arteritic anterior ischemic optic
neuropathy than in nonarteritic anterior ischemic optic neuropathy. Posterior
ischemic optic neuropathy is much less common and is most often seen in GCA
and in the postoperative setting after spinal procedures; one or both eyes may be
affected. Posterior ischemic optic neuropathy is always a diagnosis of exclusion,
because the characteristic funduscopic changes of anterior ischemic optic
neuropathy are not seen and the only objective examination finding, a relative
afferent pupillary defect (APD), is nonspecific.
The most common conditions in the differential diagnosis for ischemic optic
neuropathy are other vascular phenomena, such as retinal artery and vein
occlusions, optic neuritis, and acute optic nerve compression. These conditions
can almost always be distinguished by a thorough history and an examination
that includes visual and pupillary function and funduscopy. Imaging is not
usually needed to confirm a diagnosis of anterior ischemic optic neuropathy.
Advanced MRI and ultrasound techniques have been used to identify temporal
artery abnormalities and raise suspicion for GCA but are not yet widely available
nor sufficiently accurate. The mainstays of the arteritic anterior ischemic optic
neuropathy diagnosis are testing for signs and symptoms of GCA and blood
work, including complete blood cell count (CBC), erythrocyte sedimentation
rate (ESR), and C-reactive protein (CRP).
ANATOMY OF THE OPTIC NERVE

The optic nerve is composed largely of the axons of retinal ganglion cells,
segments of which occupy the three innermost layers of the retina (FIGURE 2-17).
Retinal ganglion cell dendrites synapse chiefly with retinal bipolar cells and lie
within the inner plexiform layer. Retinal ganglion cell somata lie closer to the
inner surface of the retina in the ganglion cell layer. Their axons project upward
to form the retinal nerve fiber layer, the innermost structure that abuts the
vitreous humor. Individual retinal ganglion cell axons stream toward the optic
nerve head from their positions all over the retinal surface and then make a turn
at the optic nerve head to traverse the orbit and optic canal, projecting through
the optic chiasm and tract to their synapse at the lateral geniculate nucleus. The
normal adult human eye has approximately 1.2 million retinal ganglion cell
axons, with an age-related decline in number beginning in middle age. Within
the retina and optic nerve head, retinal ganglion cell fibers are unmyelinated and
thus translucent. As they traverse the thickness of the eye, however, they each
gain a myelin sheath. This largely accounts for the difference in diameter
between the optic nerve head at the surface of the retina (1.5 mm to 2.0 mm) and
1216 OCTOBER 2019

KEY POINTS
● Anterior ischemic optic

neuropathy presents as
acute, painless monocular
visual loss that may progress
over several days.
● Anterior ischemic optic

neuropathy must be
distinguished from optic
neuritis, compressive
masses, and retinal artery
and vein occlusions. This
distinction is usually
clear-cut after a thorough
history and examination, but
imaging is occasionally
needed in equivocal cases.
Blood work for giant cell
arteritis and vascular risk
FIGURE 2-1
factors is indicated in
Layers of the human retina. A, illustrated representation; B, histologic section. Light enters
most cases.
through the refractive media (cornea, lens, and aqueous and vitreous humors) from the left,
traversing the depth of the retina to excite rod and cone photoreceptors just above its
outermost stratum, the pigment epithelium. The choroid and sclera lie external to the retina.
Retinal ganglion cell bodies occupy the second innermost layer, their dendritic synapses with
bipolar cells forming the inner plexiform layer. Retinal ganglion cell axons compose most of
the surface, or retinal nerve fiber layer, en route to forming the optic nerve.
Reprinted with permission from Ellis J, LabRoots.7 © 2016 LabRoots Inc.
the diameter of the retrobulbar optic nerve (2.5 mm to 4.0 mm). From the
perspective of anterior ischemic optic neuropathy, a critical feature of optic
nerve anatomy is the anatomic bottleneck as retinal ganglion cell axons cross the
plane of the sclera. Unlike the flexible retina and choroid, the sclera is a sphere of
tough, unyielding connective tissue. The vulnerable fibers of the optic nerve
must pass through a fixed circular orifice in this membrane in exiting the eye.
Spanning the optic nerve from one edge of the sclera to the other is the lamina
cribrosa, a mesh of connective tissue fibers that divide the axons into bundles.
The optic cup is a visible indentation on the surface of the nerve head (disc)
(FIGURE 2-28). The ratio of the diameters of the cup and disc is a standard
ophthalmic measure because increased cup size often signifies glaucoma. In
contrast, a small optic cup with cup to disc ratio of 0.2 or lower suggests crowding
of structures in the optic nerve head and is a well-established risk factor for
anterior ischemic optic neuropathy.9–11
The blood supply of the optic nerve derives from distal branches of the
ophthalmic artery, which is the first major branch of the internal carotid artery
after it traverses the cavernous sinus (FIGURE 2-3). The central retinal artery
pierces the nerve about 10 mm behind the globe and travels toward the eye,
supplying the anterior part of the retrobulbar nerve via centrifugal arterioles. The
ocular portion of the optic nerve, between the levels of the retina and sclera, is
supplied by a network of small vessels that derive from 6 to 12 short posterior
ciliary arteries at the back of the globe. A subset of these vessels forms a
circumferential network called the circle of Zinn-Haller, and these vessels perfuse
the optic nerve head in a centripetal and segmental fashion that explains the

characteristic altitudinal visual

field loss of anterior ischemic
optic neuropathy. Because of the
small size and rich anastomoses
of these vessels, anterior ischemic
optic neuropathy seldom, if ever,
arises from embolic disease.
NONARTERITIC ANTERIOR
Nonarteritic anterior ischemic
optic neuropathy comprises more
than 85% of all cases of anterior
ischemic optic neuropathy, with
FIGURE 2-2
an estimated 6000 new cases per
Diagram of the vascular supply of the eye, year in the United States.5,6 It is
showing the origin of the ophthalmic artery and more common in the white
its branches from the internal carotid. The central population and affects men
retinal artery supplies the distal retrobulbar optic
slightly more than women, with a
nerve, whereas branches of the short posterior
ciliary arteries supply the optic nerve head. mean age of onset around age 60.
Reprinted with permission from Abbatemarco JR, et al, A significant subpopulation has
Cleveland Clinic J Med.8 © 2017 Cleveland Clinic. onset younger than age 50.3 The
precise cause of nonarteritic
anterior ischemic optic
neuropathy is uncertain, but it is clear that congenital-variant anatomy of the optic
nerve head is a significant contributor. The vast majority of patients who develop
nonarteritic anterior ischemic optic neuropathy have relatively crowded nerve
heads with small optic cups, known as a “disc at risk.” It is thought that the blood
supply of such nerves is tenuous and that added stressors may impair autoregulation
and cause capillary-filling pressures to fall below critical levels. Identified risk factors
include hypertension; diabetes mellitus; obstructive sleep apnea12,13; and possibly
hyperlipidemia, anemia, and smoking (TABLE 2-1). Despite its links with typical
vascular risk factors, patients with nonarteritic anterior ischemic optic neuropathy
do not have significantly increased risks of carotid stenosis, cardiac disease, or
stroke.14,15 Migraine seems to be a risk factor in younger patients. Nocturnal
hypotension has been suggested as a contributor to nonarteritic anterior ischemic
optic neuropathy, explaining the common observation of symptoms upon
awakening.16 Blood pressure normally drops during sleep; this may be exacerbated
by antihypertensive therapy and other drugs.
The use of certain medications has been linked to nonarteritic anterior
ischemic optic neuropathy; the most widely reported of these have been
phosphodiesterase 5 (PDE 5) inhibitors and amiodarone. PDE 5 inhibitors, such
as sildenafil, are used widely for erectile dysfunction and could predispose
patients to nonarteritic anterior ischemic optic neuropathy by exacerbating
nocturnal hypotension. The literature includes more than 100 cases of PDE 5
inhibitor use and nonarteritic anterior ischemic optic neuropathy.2,3 Although a
causal association is not entirely clear, an approximately twofold risk of
nonarteritic anterior ischemic optic neuropathy exists within 5 half-lives of PDE 5
use,17,18 and recurrent visual symptoms have been reported after rechallenge
with these drugs.19 Amiodarone has been associated both with typical
1218 OCTOBER 2019

nonarteritic anterior ischemic KEY POINT
optic neuropathy, in which the
● Nonarteritic anterior
link is likely coincidental, and ischemic optic neuropathy is
with a more insidious bilateral the most common cause of
optic neuropathy associated acute optic neuropathy in
people older than age 50,
with disc swelling, in which a
peaking in incidence around
causal association is more age 60 and somewhat more
likely.20,21 common in men than
Although some patients with women. It is most strongly
nonarteritic anterior ischemic linked to congenitally
crowded optic discs. Other
optic neuropathy perceive their putative risk factors include
deficits to be of sudden onset hypertension, diabetes
and immediate peak severity, mellitus, and obstructive
others progress over days to sleep apnea.
weeks (CASE 2-1). Disc edema
may also worsen slowly and
may, in fact, precede measurable
FIGURE 2-3 visual loss, implying a preclinical
Small optic cups (ie, “crowded discs”) strongly phase of ischemia.22–24 These
correlate with nonarteritic anterior ischemic optic phenomena suggest a vicious
neuropathy. Funduscopic assessment traditionally cycle in which early ischemic
compares the diameter of the pale-colored
indentation near the center of the disc with that of
edema leads to microvascular
the disc itself. Normal optic disc (A) and normal compression, increasing
optic disc with periphery of disc and cup outlined ischemia and swelling until a
(B); the cup to disc ratio was measured as 0.35. zenith of damage is reached.1
Crowded optic disc (C) and crowded optic disc
with cup and disc outlined (D); the cup to disc ratio
Within as little as 2 weeks of
is 0.15. symptoms, evidence of retinal
ganglion cell damage appears as
loss of cell bodies on optical
coherence tomography (OCT), whereas initial nerve fiber layer thickening gives
way to atrophy over a month or more.25–27 Visible edema takes an average of
2 months to resolve. As atrophy develops, the optic cup enlarges and preexisting
optic nerve head crowding lessens. This probably explains why recurrence
of nonarteritic anterior ischemic optic neuropathy is rare in the same eye
(approximately 5%).28,29 On the other hand, the same risk factors usually apply
to the fellow eye as to the originally affected one, including small optic cups.30
The lifetime risk of nonarteritic anterior ischemic optic neuropathy in the
second eye has been estimated as high as 30% to 40%, with a 5-year rate of
15% to 20%.30,31
Diagnosis
Visual loss may have an acute, subacute, or stepwise onset in nonarteritic
anterior ischemic optic neuropathy and is not usually accompanied by pain.
About 40% of patients first become aware of their deficits soon after awakening.
Progression for over a month is atypical and should suggest an alternative
diagnosis. Visual acuity is usually decreased, although about half of patients see
20/64 or better at the peak of the deficit.32,33 Acuity of 20/200 or worse is seen
in about 30% of patients. Visual fields are usually abnormal on confrontation
tests (eg, finger counting) and virtually always abnormal when tested with
automated perimetry. When they fall into a clear pattern, abnormal fields usually

take the form of altitudinal defects that are greater above or below the visual
horizon (FIGURE 2-4 and FIGURE 2-5).34,35 Inferior altitudinal loss is more
common than superior loss. These deficits may be complete or partial (eg,
arcuate scotomas). Funduscopic examination in the acute stage shows a
moderately to markedly swollen optic disc on the affected side, typically with the
appearance of increased perfusion (hyperemia). Optic nerve head elevation is
often segmental, being worse either superiorly or inferiorly. Small hemorrhages
may be seen near the optic nerve head as a sign of focal ischemia. The fellow
eye will usually show a small or no cup (visual cup to disc ratio of 0.2 or less).
Despite the irreversible loss of retinal ganglion cell bodies and axons in the
aftermath of nonarteritic anterior ischemic optic neuropathy, most patients
eventually show some improvement. Visual acuity gained three lines or more
in 40% of control patients in one large study.36 Conventional OCT provides
precise anatomic imaging of the retina and optic nerve head, extending the
funduscopic examination and demonstrating the characteristic evolution of
anterior ischemic optic neuropathy.25–27 A newer technique, OCT angiography,
allows the quantitative analysis of capillaries and arterioles in and around the
optic disc. This technique can track the evolution of nonarteritic anterior
ischemic optic neuropathy from early capillary dilation to late capillary
attenuation; results correlate with visual fields and conventional OCT
changes.37–39 A relative APD should always be seen in the affected eye unless
there has been prior damage of a similar magnitude in the fellow eye.
Nonarteritic anterior ischemic optic neuropathy must be distinguished from
several conditions for which management and prognosis differ markedly. The
distinction from arteritic anterior ischemic optic neuropathy is particularly
TABLE 2-1 Potential Risk Factors for Nonarteritic Anterior Ischemic Optic
Neuropathya
◆ Congenitally crowded optic disc

◆ Hypertension
◆ Diabetes mellitus
◆ Obstructive sleep apnea
◆ Nocturnal hypotension
◆ Hyperlipidemia
◆ Anemia
◆ Smoking
◆ Migraine
◆ Hyperhomocysteinemia
◆ Hypercoagulopathies
◆ Optic nerve head drusen
◆ Cataract surgery
◆ Cardiac surgery
a
Data from Miller NR, Arnold AC, Eye (Lond).2
1220 OCTOBER 2019

crucial and is discussed in its own section later in this article. Optic neuritis can be
confused with nonarteritic anterior ischemic optic neuropathy because the
demographics of both conditions overlap. The mean age of onset is considerably
younger for optic neuritis (about age 32), with a strong sex bias toward women
(approximately 3:1).40 Nonarteritic anterior ischemic optic neuropathy and optic
neuritis can both progress over days. Pain is the chief symptomatic difference
between these conditions; it occurs in only about 10% of patients with
nonarteritic anterior ischemic optic neuropathy but in more than 90% of patients
with optic neuritis.40,41 Pain in optic neuritis may vary from mild to severe and is
perceived as originating in and behind the eye. Increased pain with eye
movement is particularly helpful in distinguishing optic neuritis from
nonarteritic anterior ischemic optic neuropathy. This symptom should be sought
specifically; patients may not report milder examples, which might comprise
only a dull aching sensation at the extremes of gaze. Visual field loss tends to be
purely central in optic neuritis rather than altitudinal as in nonarteritic anterior
ischemic optic neuropathy. About 35% of patients with acute optic neuritis
demonstrate disc swelling (anterior optic neuritis, or papillitis); the remainder
have initially normal optic discs and are designated retrobulbar. Disc swelling is
mild to moderate in optic neuritis and thus less pronounced than in nonarteritic
anterior ischemic optic neuropathy. It is usually vertically symmetric rather than
segmental, and hemorrhages near the disc are rare compared with nonarteritic
anterior ischemic optic neuropathy. In ambiguous cases, orbital contrast MRI
may help make this distinction; optic nerve enhancement is typical of optic
neuritis and uncommon in nonarteritic anterior ischemic optic neuropathy.42
A 58-year-old man noted painless visual loss in his right eye upon CASE 2-1
awakening in the morning, with gradual worsening over the following
24 hours. His central vision was somewhat blurry, but he was particularly
bothered by his inability to see objects below the center of his vision. His
past medical history was notable for hypertension and obesity.
On examination, acuity was 20/70 in the right eye and 20/20 in the left
eye with his current spectacles. He could not see hand motion in the
inferior field of the right eye but could count fingers in all other areas of
vision in each eye. He had an obvious right relative afferent pupillary
defect on the swinging-flashlight test. Funduscopic examination showed
significant hyperemic swelling of the right optic nerve head that was
somewhat worse superiorly than inferiorly, with two splinter
hemorrhages at the superior edge of the disc. The left disc appeared
healthy but had a small central cup (cup to disc ratio 0.1; normal 0.2 to 0.5).
Nonarteritic anterior ischemic optic neuropathy is characterized by COMMENT

painless visual loss that may progress over the first few days and is often
first noted upon awakening. Clues include moderate to severe disc
swelling and a crowded “disc at risk,” with reduced cup to disc ratio in the
fellow eye. Obstructive sleep apnea and nocturnal hypotension should be
considered as contributing factors.

KEY POINTS FIGURE 2-4

Visual field, fundus, and optical
● Examination in arteritic coherence tomography (OCT)
and nonarteritic anterior progression of nonarteritic anterior
ischemic optic neuropathy ischemic optic neuropathy from acute
shows visual field (left column, 2 weeks after onset) to
impairment, variable loss of chronic (right column, 2 months after
acuity, a swollen optic disc, onset) in a 48-year-old man with
and a relative afferent uncontrolled diabetes mellitus and
pupillary defect in the hypertension. The patient presented
affected eye. Visual loss after awakening with severe, painless
and optic disc swelling tend visual loss in his right eye. Examination
to be worse in the arteritic showed a marked right relative afferent
form (arteritic anterior pupillary defect and mild diabetic
ischemic optic neuropathy). retinopathic changes; the left optic
disc had a very small cup (cup to disc
● The optic disc in the ratio, 0.1). Initial visual acuity was count
unaffected eye almost fingers in the right eye; this improved
always shows a small cup in gradually to 20/200. Humphrey
nonarteritic anterior 30-2 fields show severe generalized
ischemic optic neuropathy. loss (A) improving to dense inferior
Over 1 to 3 months, optic altitudinal and superior arcuate defects
disc swelling resolves to a (B). Fundus photos show inferior-
flat, atrophic disc in all predominant optic disc swelling
cases of anterior ischemic acutely (C) that has resolved by the
optic neuropathy. Optical 2-month mark (D). Three-dimensional
coherence tomography OCT scans of the right optic nerve
shows evidence of retinal head, shown from the temporal
ganglion cell body loss after projection at 2 weeks (E) and 2 months
only a few weeks. (F) after onset. As in C and D, these
show initial inferior segmental disc
elevation (E, right side of image) with
later resolution (F). Peripapillary retinal
nerve fiber layer thickness plots from
OCT, showing acute, inferior more than
superior axon layer swelling (G)
followed by superior and temporal
atrophy (H). Macular ganglion cell layer
plots. At only 2 weeks after visual loss
(I), clear thinning of the superior
ganglion cell layer is seen (normal
thicknesses would be colored red,
orange, and yellow; see FIGURE 2-5 for
normal plot); by 2 months, severe
generalized loss is seen, in keeping
with poor visual outcome (J).
G = global mean; N = nasal; NI = nasal inferior;
NS = nasal superior; N/T = nasal/temporal
ratio; PMB = papillomacular bundle;
RNFLT = retinal nerve fiber layer thickness;
T = temporal; TI = temporal inferior;
TS = temporal superior.
1222 OCTOBER 2019

FIGURE 2-5
Visual field and optical coherence tomography data from the left eye of a 48-year-old
woman with onset of visual loss and segmental disc edema 1 year earlier consistent with
nonarteritic ischemic optic neuropathy. Outcome was more benign than for the patient in
FIGURE 2-4; final visual acuity was 20/30 in the affected eye. A, Humphrey 30-2 perimetry
showing dense but incomplete inferior altitudinal loss, with preserved superior field. B,
Peripapillary retinal nerve fiber layer plot, showing superior and temporal thinning of retinal
ganglion cell axons. Normal and affected eye macular ganglion cell layer plots, showing the
normal, vertically symmetric, toroidal distribution around the fovea (C) and severe thinning
superiorly corresponding to inferior visual field loss (D).
G = global mean; N = nasal; NI = nasal inferior; NS = nasal superior; N/T = nasal/temporal ratio;
PMB = papillomacular bundle; RNFLT = retinal nerve fiber layer thickness; T = temporal; TI = temporal
inferior; TS = temporal superior.
Nonarteritic anterior ischemic optic neuropathy presents similarly to retinal

artery and vein occlusions; all may cause acute, painless visual impairment with
altitudinal field loss. However, funduscopic examination readily distinguishes
these conditions; only nonarteritic anterior ischemic optic neuropathy causes
isolated, severe optic disc swelling. Within hours of onset, central and branch
retinal artery occlusions demonstrate superficial retinal edema—a milky,
translucent appearance of the ischemic area with no optic disc swelling.
Unaffected by superficial retinal swelling, the fovea at its center may stand out,
appearing “cherry red.” Unlike nonarteritic anterior ischemic optic neuropathy,
central and branch retinal artery occlusions are frequently associated with
atherosclerotic carotid disease and cardiogenic embolus and thus require an
evaluation similar to that for stroke.
Central and branch retinal vein occlusions are characterized by a “blood and
thunder” appearance, with numerous retinal hemorrhages and cotton wool
spots. Although retinal vein occlusion may cause optic nerve head swelling, these
dramatic retinal changes allow for a clear distinction. Central and branch retinal
vein occlusions are occasionally associated with hypercoagulable states, and an
appropriate workup should be considered. Finally, optic nerve compression
can occasionally mimic nonarteritic anterior ischemic optic neuropathy.
Compression from tumors and orbital inflammatory disease usually causes
slowly progressive visual loss and optic atrophy. Chronic compression near the
globe, as from optic nerve sheath meningioma, may produce initial disc swelling
rather than atrophy. Acute to subacute visual loss may arise from rapidly
expansile compressive lesions such as ophthalmic artery aneurysms, but these
would rarely produce optic disc edema. Contrast imaging of the entire length of
the optic nerve is appropriate when compression is a concern.

Given the high impact of a missed diagnosis of GCA-associated arteritic

anterior ischemic optic neuropathy, the review of systems inquiry should focus
on excluding this condition, as discussed later in this article. Screening laboratory
work for GCA is always reasonable, including CBC, ESR, and CRP. With the
diagnosis of nonarteritic anterior ischemic optic neuropathy, testing should focus
on vascular risk factors that might be unknown to the patient, including blood
pressure determination, fasting lipid profile, and assessment of blood glucose and
hemoglobin A1c. Screening questions for sleep apnea should be asked. The
patient’s medications should be reviewed, looking for those that might be
associated with nocturnal hypotension, including PDE 5 inhibitors. In
patients younger than age 50, additional testing should be considered.
Hyperhomocysteinemia is seen more often in young patients with nonarteritic
anterior ischemic optic neuropathy and is easily treated with B vitamins.
Hypercoagulable states have been associated with nonarteritic anterior ischemic
optic neuropathy43; laboratory screening might be considered if a personal or
family history suggesting thrombophilia is present.
Management
Many therapies have been proposed and tested for acute nonarteritic anterior
ischemic optic neuropathy over the years, but none has thus far withstood the
tests of rigorous controlled trials.2,3,44–46 The best and largest of these studies was
IONDT (Ischemic Optic Nerve Decompression Trial), which has yielded a
cornucopia of data on the natural history of nonarteritic anterior ischemic optic
neuropathy.36,47 This trial randomly assigned 258 patients with acute nonarteritic
anterior ischemic optic neuropathy, all older than 50 and with visual acuity of
20/64 or worse. Of these, 119 received retrobulbar optic nerve decompression
surgery. The rest were monitored without the procedure. Surgical patients had
worse outcomes than those managed conservatively. Of the nonsurgical group,
43% improved three lines or more of visual acuity over 6 months. In the surgical
group, only 33% did so. Conversely, 12% of conservatively treated patients lost
three lines or more of acuity over 6 months compared with 24% of surgically
treated patients. Several other surgical procedures have been tried for
TABLE 2-2 Systemic Features of Giant Cell Arteritisa
◆ Headache/neck pain
◆ Jaw claudication
◆ Scalp/temporal tenderness
◆ Polymyalgia
◆ Visual loss
◆ Fatigue/malaise
◆ Weight loss/anorexia
◆ Eye pain
◆ Diplopia
a
In approximate order of frequency, with most common at top.
1224 OCTOBER 2019

nonarteritic anterior ischemic optic neuropathy without clear benefit, including KEY POINTS
vitrectomy and radial optic neurotomy.
● Because no treatment has
Of medications, oral and injectable steroids have been studied the most been established for
extensively in acute nonarteritic anterior ischemic optic neuropathy but have nonarteritic cases, it is
shown no consistent effectiveness. The strongest evidence of benefit has been a especially important to
retrospective patient-choice study in which more than 600 patients were exclude giant cell arteritis as
a cause of anterior ischemic
followed, about half opting for a long, tapering course of prednisone starting at
optic neuropathy.
80 mg/d.48 Patients who received oral steroids showed improvement more often
than those who did not (70% versus 41% with better visual acuity at 6 months). ● Although most patients
However, this study was neither randomized nor blinded. Subsequent small with nonarteritic anterior
studies have failed to show benefit for high-dose oral or IV steroids, with ischemic optic neuropathy
will show some spontaneous
expected side effects.49,50 Based on the limited data and absence of any proven improvement, many are left
treatment option, some clinicians do offer a limited course of steroid treatment to with significant deficits. No
patients with severe visual loss.51 Interesting but limited data have suggested a therapy has been proven to
benefit for oral levodopa in nonarteritic anterior ischemic optic neuropathy, improve outcomes, although
several clinical trials are
although this has not been widely adopted.52 ongoing.
Intravitreal injections and sustained-release therapies likely hold greater
promise than medications given systemically. Much higher concentrations of ● Nonarteritic anterior
pharmaceutical and biological agents can be delivered directly into the eye than ischemic optic neuropathy
strikes the second eye in 15%
into the bloodstream, without needing to pass through the gastrointestinal
to 20% of patients over
mucosa, the liver, or other biological barriers. Direct ocular delivery of steroids, 5 years. Limited evidence
bevacizumab, erythropoietin, and other agents has been tried in small patient has shown that aspirin may
groups and in animal models, and several clinical trials are ongoing.3,46 One such reduce risk over the first
few years, but no clear
multicenter trial involves intravitreal injections of a small interfering RNA that
long-term benefit of aspirin
inhibits caspase-2, an enzyme that is involved in cellular apoptosis.53 or any other preventive
Prevention of fellow-eye involvement is a common concern after nonarteritic treatment has been proven.
anterior ischemic optic neuropathy, given a 5-year incidence of at least 15%. Vascular risk factors such as
However, no proof exists that any such intervention works. Daily aspirin has hypertension and diabetes
mellitus should be
been the most closely studied in this regard, with a suggestion of risk reduction at addressed as a matter of
2 years but not at 5 years.30,31,54 Nevertheless, many clinicians recommend daily general health maintenance.
aspirin for patients with nonarteritic anterior ischemic optic neuropathy based
on its common association with vascular risk factors. Routine health maintenance
calls for control of diabetes mellitus, hypertension, hyperlipidemia, and smoking,
and for optimal management of obstructive sleep apnea, notwithstanding the
absence of proven benefit in secondary prevention of nonarteritic anterior
ischemic optic neuropathy.
ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY

Anterior ischemic optic neuropathy is associated with systemic vasculitis in
10% to 15% of cases, with GCA being by far the most common diagnosis.
Several differences between nonarteritic anterior ischemic optic neuropathy
and arteritic anterior ischemic optic neuropathy help draw a relative
ophthalmologic distinction, chiefly in terms of more severe and widespread
ocular ischemia in arteritic anterior ischemic optic neuropathy.55–58 However,
no examination feature can rule out GCA, and the stakes for missing this
diagnosis are very high. Without treatment, about half of patients will have
arteritic anterior ischemic optic neuropathy in their fellow eye, sometimes
within a matter of days of the first eye. Stroke, aortic dissection, and
myocardial infarction are other potential life-threatening complications of
GCA. Clinicians must always inquire about symptoms of GCA (TABLE 2-2) and

should strongly consider screening laboratory workup in patients older than

50 years of age with anterior ischemic optic neuropathy, including CBC, ESR,
and CRP. The most pressing question a clinician faces after the diagnosis of
anterior ischemic optic neuropathy is which patients to treat presumptively for
GCA and refer for temporal artery biopsy.
GCA is a medium to large vessel vasculitis of uncertain origin.59 There has
been recent interest in occult varicella-zoster virus infection as a contributor,
although this has been tempered by failure to replicate early results.60 The
incidence of GCA increases with age. It is extremely rare in patients younger
than age 50 and has a mean age of onset of 75 to 80 years. It has a female
predominance of at least 2:1 and a predilection for whites of Northern
European descent.61,62 Although less common in African Americans, its
manifestations and age and sex demographics are similar in this population.63
Visual loss develops in 8% to 20% of patients with GCA, and arteritic anterior
ischemic optic neuropathy is by far the most common cause of the deficit. In
general, patients with arteritic anterior ischemic optic neuropathy present with
and persist with worse visual loss than patients with nonarteritic anterior
ischemic optic neuropathy. Initial visual acuity is worse than 20/200 in about
70% of patients with arteritic anterior ischemic optic neuropathy compared with
about 30% of patients with nonarteritic anterior ischemic optic neuropathy, and
more than 20% of patients with arteritic anterior ischemic optic neuropathy
show no light perception.55,57 Some patients with arteritic anterior ischemic optic
neuropathy improve from their peak deficit, although probably not as many as
those with nonarteritic anterior ischemic optic neuropathy; this proportion
CASE 2-2 A 75-year-old woman presented with painless, sudden loss of vision in
her left eye that began while watching television. She had recent weight
loss due to anorexia as well as worsening hip and shoulder pain. She
became fatigued easily when chewing solid foods. Her past medical
history was significant for hyperlipidemia and hypertension.
On examination, acuity was 20/20 in the right eye and 20/400 in the
left. She counted fingers with errors in the superior field of the left eye
and could not see hand motion inferiorly. She had a dramatic left relative
afferent pupillary defect. The left optic disc was pale and markedly
swollen, worse superiorly, with several peripapillary hemorrhages. The
right disc was normal, with a cup to disc ratio of 0.4. General examination
showed mild tenderness of the temporal fossa and scalp bilaterally.
COMMENT As in nonarteritic anterior ischemic optic neuropathy, anterior ischemic

optic neuropathy associated with giant cell arteritis presents as acute
visual loss, usually without pain in the affected eye. It is important to
recognize the increased incidence of giant cell arteritis in older patients
and to solicit relevant symptoms (polymyalgia and jaw claudication in this
patient) and findings such as temporal tenderness. A normal cup to disc
ratio in the unaffected eye suggests a diagnosis other than nonarteritic
anterior ischemic optic neuropathy.
1226 OCTOBER 2019

varies widely in the literature depending on the parameters used to measure KEY POINTS
vision (eg, acuity versus fields) and the rapidity with which steroid therapy
● Arteritic anterior ischemic
was initiated.64 optic neuropathy, like giant
Central retinal artery occlusion from GCA is about 20% as common as anterior cell arteritis itself, is more
ischemic optic neuropathy from GCA.55,56,61,63 Proximal involvement of the common with advancing age
ophthalmic artery may produce combined central retinal artery occlusion and (mean 70 to 75 years) and in
women by at least 2:1 over
arteritic anterior ischemic optic neuropathy, more widespread circulatory failure
men. Although most patients
that includes the anterior portion of the eye (ocular ischemic syndrome), or presenting with arteritic
ischemia within the orbital muscles that causes ocular motility deficits. Diplopia anterior ischemic optic
occurs in up to 10% of patients with GCA, typically resulting from ischemia to neuropathy have signs and
symptoms of giant cell
cranial nerves III, IV, or VI, occasionally as the presenting visual symptom.65
arteritis, about 20% present
with visual problems alone
Diagnosis and have no systemic
Like those with nonarteritic anterior ischemic optic neuropathy, patients with features; this has been
arteritic anterior ischemic optic neuropathy present with acute visual loss that described as occult giant
cell arteritis. Thus, a high
can progress over several days (CASE 2-2). More commonly than with level of suspicion is
nonarteritic anterior ischemic optic neuropathy, transient monocular visual loss essential.
may precede persistent deficits in patients with arteritic anterior ischemic optic
neuropathy (about 30% of cases).56 At presentation, visual acuity is usually at ● Erythrocyte
sedimentation rate and
or below the 20/200 level. Visual field deficits follow the same patterns as in C-reactive protein are the
nonarteritic anterior ischemic optic neuropathy, tending toward altitudinal loss. most sensitive tests for giant
Arteritic anterior ischemic optic neuropathy–associated optic disc edema is cell arteritis, each being
typically severe and takes on a pallid appearance in contrast to the hyperemic elevated in about 85% of
cases. These test results
color of nonarteritic anterior ischemic optic neuropathy. Small hemorrhages
are nonspecific, however,
near the disc margin are more common in arteritic anterior ischemic optic and both are negative in
neuropathy, and the fellow eye does not usually show the crowded nerve head about 10% of patients.
that is typical in nonarteritic anterior ischemic optic neuropathy. About 20% of Thrombocytosis and anemia
are also common in giant
patients with arteritic anterior ischemic optic neuropathy present with visual
cell arteritis and should
problems alone and have no systemic features; this has been described as increase diagnostic
occult GCA.58,63,66 suspicion if present.
Headache is the most common symptom of GCA, observed in about 70% of
patients (TABLE 2-2). It should be of particular concern if it is of recent onset or ● Temporal artery biopsy
remains the gold standard
reflects a change of a chronic pattern in location or severity. Jaw claudication is for the diagnosis of giant cell
probably the most specific symptom but occurs in only about half of cases.62,63 arteritis and should be
Elevated ESR and CRP are each about 85% sensitive for GCA but are no more arranged within the first few
than 30% specific in patients with anterior ischemic optic neuropathy. Only 10% days of a suspected
presentation. Although
of patients with GCA have normal values for both tests.67,68 Elevated platelet pathologic findings are
count and reduced hemoglobin values are less sensitive and no more specific. eventually altered by
The gold standard for GCA diagnosis is a positive temporal artery biopsy, therapy, these changes take
showing evidence of granulomatous inflammation with destruction of the weeks and are not a
consideration with regard to
vessel’s internal elastic lamina. The giant cells for which the condition is known
the immediate initiation of
actually appear in less than half of biopsies. A specimen of at least 2 cm in length corticosteroid treatment.
is desirable, with thin sectioning for microscopic examination. However, even
with optimal surgical technique and pathologic examination, an initial biopsy
result can be negative in 5% to 10% of patients who are later shown to have
GCA.59,69 Given the risk and inconvenience of temporal artery biopsy, some are
moving toward using noninvasive imaging techniques for diagnosis, including
MRI and ultrasonography of the scalp vessels. MRI can show enhancement of
arterial walls, whereas both MRI and ultrasonography can demonstrate scalp
artery thickening and focal stenosis.70,71 However, eschewing temporal artery

biopsy in favor of imaging carries the risk of false-negative and false-positive

interpretations and has not been endorsed by any North American group.60
Noninvasive imaging may at least improve the diagnostic yield of biopsy by
locating an area of likely abnormality. MRI of the orbit is not generally needed for
the diagnosis of arteritic anterior ischemic optic neuropathy but may occasionally
show helpful features, such as enhancement of the central optic nerve head,
nerve sheath, extraocular muscles, and other tissues.72,73 OCT angiography
shows similar changes in arteritic anterior ischemic optic neuropathy and
nonarteritic anterior ischemic optic neuropathy.74,75 In contrast, fluorescein
angiography shows delayed choroidal filling in arteritic anterior ischemic optic
neuropathy but not nonarteritic anterior ischemic optic neuropathy, and thus
might support a diagnosis of GCA.76,77
Various diagnostic schemes have been used to determine patients at highest
risk of GCA. The time-honored American College of Rheumatology criteria
(1990) were originally reported to be 94% sensitive and 91% specific; they
include a positive biopsy as one criterion (TABLE 2-3).78 A 2017 multicenter study
analyzed clinical and demographic characteristics associated with results of 530
temporal artery biopsies, of which 133 were positive.62 A predictive nomogram
was developed by using the highest-yield parameters: age, platelet count, CRP
value, and presence or absence of visual loss and jaw claudication. A cumulative
score for these five items yields a probability value of a positive biopsy and thus a
definitive diagnosis of GCA.62
Management
Patients with moderate to high suspicion for arteritic anterior ischemic optic
neuropathy should have laboratory tests drawn (CBC, ESR, and CRP) and be
started on steroids immediately to reduce the risk of damage to the fellow eye
and serious systemic consequences of GCA. In cases with sufficient clinical
evidence of GCA, completed blood work is not needed to initiate steroid
treatment. In less clear cases, CBC, ESR, and CRP results might be needed to
make this decision. These test results are available within a few hours in most
hospital and office settings. If immediate testing and treatment in the office are
not practical, patients should be referred to a local emergency department for
prompt care. Within the first 24 hours, patients who are at moderate to high
risk should be referred for a temporal artery biopsy. However, a wait of several
TABLE 2-3 American College of Rheumatology Criteria for Giant Cell Arteritis (1990)a
At least three of the following:

◆ Age at onset ≥50 years
◆ New headache or altered location/type of pain
◆ Temporal artery tenderness or decreased pulsation to palpation
◆ Elevated erythrocyte sedimentation rate (>50 mm/h, Westergren method)
◆ Biopsy evidence of vasculitis with predominance of mononuclear-cell infiltration or
granulomatous inflammation, usually with multinucleated giant cells
a
Data from Hunder GG, et al, Arthritis Rheum.78
1228 OCTOBER 2019

days to obtain a suitable tissue specimen should never delay the initiation of KEY POINTS
high-dose steroids. Pathologic changes in the temporal artery take weeks to
● For patients at moderate
months to respond to steroids, so a short delay will not obscure a to high risk of giant cell
positive diagnosis. arteritis who present with
Most experts treat patients with acute anterior ischemic optic neuropathy, anterior ischemic optic
arteritic central retinal artery occlusion, or recent spells of transient visual loss neuropathy or transient
visual loss, most experts
suspicious for GCA with at least 1 day and typically 3 days of high-dose IV
recommend immediate
methylprednisolone (approximately 1000 mg/d) or equivalent.64,79,80 An initiation of high-dose IV
excellent case can be made for admitting patients to the hospital for at steroids (eg, 1000 mg/d
least 1 night to monitor steroid side effects and organize ongoing care (eg, methylprednisolone)
followed by oral therapy,
rheumatology consultation, temporal artery biopsy, patient education). After the
typically prednisone 1 mg/kg
first IV dose, different approaches may be used regarding further IV versus or 80 mg/d. Many advocate
high-dose oral steroids. Modest evidence exists in favor of completing a 3-day initial hospital admission to
course of high-dose IV steroids before switching to the oral route, suggesting monitor for steroid side
benefit on visual recovery in the affected eye and prevention of involvement in effects, arrange temporal
artery biopsy, and provide
the fellow eye.64,81 After IV steroids, the consensus approach is to begin oral patient education.
treatment with a moderately high dose of prednisone (1 mg/kg, or about
80 mg/d) or equivalent. Tapering of the steroid dose is accomplished very slowly ● Corticosteroids are the
over 1 year or longer while closely monitoring symptoms and ESR and CRP mainstay of acute and
chronic therapy in giant cell
values. Most patients enjoy rapid improvement of systemic symptoms after arteritis. They have many
introduction of high-dose steroids. However, despite rapid treatment, a small side effects, especially in
number of patients progress relentlessly over the first few weeks, ultimately the elderly population at
losing vision in both eyes. highest risk for the
condition.
A positive temporal artery biopsy proves the diagnosis and the need for
long-term therapy for GCA. Given the false-negative rate of 4% to 10%, biopsy of ● In most patients, systemic
a second site should be considered in patients who are at high-risk and for whom manifestations of giant cell
the initial pathologic examination is negative or equivocal. The potential arteritis respond quickly to
consequences of chronic steroid use are substantial in the elderly population at treatment. Despite this,
steroids must be tapered
greatest risk of GCA, including peptic ulcers, osteoporosis with pathologic very slowly over 1 year or
fractures, hip necrosis, hyperglycemia, hypertension, weight gain, myopathy, more to avoid relapse, while
and increased susceptibility to infection. Most patients treated with long-term monitoring symptoms,
steroids should receive gastric-protective agents (eg, proton pump inhibitors) erythrocyte sedimentation
rate, and C-reactive protein.
and calcium and vitamin D supplementation. Bone density test and glucose and Various immune suppressant
blood pressure monitoring are also recommended. Side effects have driven the drugs have been used to
need for steroid-sparing agents, of which methotrexate has been the best augment steroids and
studied.79 In 2017, tocilizumab, an interleukin-6 inhibitor, became the first drug reduce their long-term risks.
to receive US Food and Drug Administration (FDA) approval for treating GCA.
● Tocilizumab recently
In its pivotal trial, subcutaneous injections of tocilizumab were given weekly or became the first US Food
biweekly along with tapering doses of oral corticosteroids.82 Tocilizumab was and Drug Administration–
shown to improve the rate of sustained steroid-free remission at 1 year. approved option for giant
cell arteritis.
Tocilizumab is FDA-approved for GCA as 162 mg subcutaneous injections given
every 1 to 2 weeks, initially in combination with oral steroids. It can be continued
after steroids are stopped.
In view of the frequent ischemic events in GCA, including myocardial
infarction and stroke, some support exists for the use of low-dose daily aspirin.79
It is reasonable to defer starting aspirin until after temporal artery biopsy to
minimize bleeding risks. Patients taking aspirin for GCA should be monitored for
gastrointestinal bleeding given the increased risk of peptic ulcer disease on
steroid therapy. The reader is referred to several excellent reviews for further
information on long-term treatment of GCA.59,60,79,80

POSTERIOR ISCHEMIC OPTIC NEUROPATHY

Posterior ischemic optic neuropathy comprises unilateral or bilateral optic
neuropathy of vascular origin that is unaccompanied by optic disc edema.83,84
As with retrobulbar optic neuritis, the optic disc appears normal during the acute
event and develops atrophy over the following 1 to 2 months in parallel with
any residual damage. Posterior ischemic optic neuropathy is much less common
than anterior ischemic optic neuropathy and chiefly occurs under three
circumstances: (1) in patients who have undergone prolonged spinal operations,
(2) as an uncommon complication of GCA, and (3) in a nonarteritic form that is
usually associated with vascular risk factors. Nonarteritic posterior ischemic
optic neuropathy cannot be explained by the same mechanical factors presumed
to affect the crowded nerve head in nonarteritic anterior ischemic optic
neuropathy. The diagnosis of posterior ischemic optic neuropathy requires
careful history, examination, and imaging to rule out optic neuritis and
compressive lesions in particular.
Both posterior ischemic optic neuropathy and anterior ischemic optic
neuropathy can present in the immediate postoperative period after major
nonophthalmic surgery. Posterior ischemic optic neuropathy predominates
in spinal operations and radical neck dissections, whereas anterior ischemic
optic neuropathy is seen more often after cardiac surgery, including coronary
artery bypass grafting.85–87 Post–spinal procedure posterior ischemic optic
neuropathy is typically painless and bilateral, with very poor initial acuity of
light perception or worse. Of affected individuals, about 70% are male; they
have a mean age of onset of about 50 years and often have a history of obesity,
hypertension, or diabetes mellitus. Visual improvement is usually limited,
with devastating residual loss. Ho and colleagues85 analyzed operative risk
factors for post–spinal surgery posterior ischemic optic neuropathy. These
included prone positioning with facial frame support; procedures lasting
longer than 7 hours; and intraoperative hypotension, blood loss, and fluid
administration.
CASE 2-3 A 56-year-old man reported blindness in both eyes immediately after
undergoing an 8-hour spinal fusion operation. Surgery was performed in
the prone position, and there were brief periods of hypotension, with
systolic blood pressure as low as 80 mm Hg. He received considerable
volumes of IV fluids and blood during the procedure.
On examination, he denied eye or head pain and reported no light
perception in either eye. His pupils did not react to light but did constrict
when he was asked to cross his eyes. Fundi were normal as was the
remainder of the neurologic examination.
COMMENT This patient had typical risk factors for perioperative posterior ischemic
optic neuropathy: prolonged surgery and intraoperative hypotension.
Normal funduscopic examination indicated that the problem was behind
the eyes. Absent pupillary reflexes implied bilateral optic nerve
dysfunction in this context.
1230 OCTOBER 2019

Posterior ischemic optic neuropathy is the presenting cause of visual loss in 6% KEY POINTS
to 7% of patients with GCA, in which it is about one-tenth as common as arteritic
● The diagnosis of posterior
anterior ischemic optic neuropathy and half as common as central retinal artery ischemic optic neuropathy
occlusion.56,63 Suspicion for posterior ischemic optic neuropathy should thus requires contrast imaging of
trigger a search for GCA in a nonsurgical setting. the brain and orbits to
exclude inflammatory and
compressive conditions.
Diagnosis Outside of the postoperative
Posterior ischemic optic neuropathy is always a diagnosis of exclusion, although setting, giant cell arteritis
it should be considered a strong possibility with recent surgery and known or should be suspected and
suspected GCA (CASE 2-3). Visual loss is generally painless and acute, with thoroughly excluded.
various reported patterns of field loss. By definition, the optic nerve should ● Posterior ischemic optic
appear normal acutely. When unilateral, posterior ischemic optic neuropathy is neuropathy is a diagnosis of
accompanied by a relative APD in parallel with the degree of visual impairment; exclusion because no
the only exception is in cases with significant preexisting fellow-eye damage. confirmatory funduscopic
findings are seen and many
When symmetric, bilateral posterior ischemic optic neuropathy does not
other processes may affect
produce a relative APD, although pupils should react more slowly or through a the retrobulbar optic nerve.
smaller amplitude than normal to bright light. Unilateral or bilateral posterior It is reasonable to anticipate
ischemic optic neuropathy can be mimicked by acute visual pathway an ischemic cause of acute,
fundus-negative optic
compression (eg, pituitary apoplexy) or inflammation (retrobulbar optic
neuropathy after major
neuritis). Bilateral posterior ischemic optic neuropathy can also be confused with surgery and in giant cell
cerebral visual loss (eg, bilateral posterior cerebral artery strokes or posterior arteritis.
reversible encephalopathy syndrome [PRES]). Thus, urgent, high-quality
contrast MRI of the brain and orbits is strongly recommended. MRI may ● No specific treatment for
posterior ischemic optic
show increased T2 intensity and diffusion-restriction in posterior ischemic neuropathy has been
optic neuropathy–affected nerves, the latter being the key clue to an established, other than in
ischemic origin.88 those cases presumed to be
of arteritic origin.
Management
No therapy has been shown to be effective for perioperative posterior ischemic
optic neuropathy. Correction of anemia and maintenance of normal blood
pressure seem logical after such an event. The key to this rare surgical
complication is limitation of risk factors, including intraoperative hypotension
and prolonged procedure time. The essence to managing GCA-related posterior
ischemic optic neuropathy is avoiding delays that might put the fellow eye, the
heart, and the brain at risk. As with anterior ischemic optic neuropathy,
suspicion of GCA should lead to prompt laboratory testing, steroid therapy, and
temporal artery biopsy. Finally, very limited data exist on the treatment of
idiopathic, nonarteritic posterior ischemic optic neuropathy. One small study
suggested a benefit of oral steroids.84
CONCLUSION
Ischemia is a common cause of optic nerve damage, especially in older
individuals. Its most serious implication is the potential of GCA, which can
be blinding, crippling, or fatal if not recognized and treated immediately.
Diagnosis of anterior ischemic optic neuropathy can usually be made on clinical
grounds, whereas the rarer posterior ischemic optic neuropathy is a diagnosis
of exclusion. The level of concern for arteritis as a cause for either anterior
ischemic optic neuropathy or posterior ischemic optic neuropathy is based
on history and examination, with the addition of a few simple laboratory tests.

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1061–1064. doi:10.1136/bjo.85.9.1061.

REVIEW ARTICLE

Optic Neuritis
C O N T I N UU M A UD I O By Jeffrey L. Bennett, MD, PhD, FAAN
I NT E R V I E W A V AI L A B L E
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article discusses the clinical presentation,
CITE AS: evaluation, and management of the patient with optic neuritis. Initial
CONTINUUM (MINNEAP MINN) 2019; emphasis is placed on clinical history, examination, diagnostic testing, and
1236–1264.
medical decision making, while subsequent focus is placed on examining
specific inflammatory optic neuropathies. Clinical clues, examination
Address correspondence to findings, neuroimaging, and laboratory testing that differentiate
Dr Jeffrey L. Bennett, Department autoimmune, granulomatous, demyelinating, infectious, and
of Neurology, 12700 E 19th Ave,
Box B-182, Aurora, CO 80045, paraneoplastic causes of optic neuritis are assessed, and current
Jeffrey.Bennett@ucdenver.edu. treatments are evaluated.
Dr Bennett serves on the editorial RECENT FINDINGS: Advances in technology and immunology have enhanced
boards of the Journal of our understanding of the pathologies driving inflammatory optic nerve
Neuro-ophthalmology, Multiple
Sclerosis, and Neurology:
injury. Clinicians are now able to interrogate optic nerve structure and
Neuroimmunology & function during inflammatory injury, rapidly identify disease-relevant
Neuroinflammation and as a autoimmune targets, and deliver timely therapeutics to improve visual
consultant for AbbVie Inc;
Alexion; Chugai Pharmaceutical outcomes.
Co, Ltd; Clene Nanomedicine;
EMD Serono, Inc; Equillium, Inc; SUMMARY: Optic neuritis is a common clinical manifestation of central
Frequency Therapeutics;
Genentech, Inc; MedImmune; nervous system inflammation. Depending on the etiology, visual prognosis
and Sanofi Genzyme. Dr Bennett and the risk for recurrent injury may vary. Rapid and accurate diagnosis of
has received research/grant
support from EMD Serono, Inc;
optic neuritis may be critical for limiting vision loss, future neurologic
the Guthy-Jackson Charitable disability, and organ damage. This article will aid neurologists in
Foundation; Mallinckrodt formulating a systematic approach to patients with optic neuritis.
Pharmaceuticals; the National
Eye Institute (R01EY022936); the
National Institute of Allergy
and Infectious Diseases
(UM1AI110498); and Novartis AG.
INTRODUCTION
Dr Bennett receives publishing
O
royalties from UpToDate, Inc, and ptic neuritis, or inflammation of the optic nerves, is a frequent
has received personal cause of acute optic nerve injury in children and adults. While
compensation for serving as a
medicolegal consultant on
optic neuritis is frequently associated with multiple sclerosis (MS),
medical cases involving the causes of optic neuritis are protean. As a result, the prognosis
neuroinflammatory and and treatment of optic neuritis will vary depending upon the
neuro-ophthalmologic disorders.
etiology, the duration and severity of vision loss, prior injury, and the success of
UNLABELED USE OF prior treatment. Optimal care of patients with optic neuritis therefore depends
on rapid recognition, appropriate diagnostic studies, and early institution of
USE DISCLOSURE:
Dr Bennett discusses the effective therapies.
unlabeled/investigational use Multiple causes of optic nerve inflammation exist: autoimmunity, infection,
of plasma exchange and
apheresis for the treatment of
granulomatous disease, paraneoplastic disorders, and demyelination. Rapid
optic neuritis. determination of the etiology of optic neuritis is important for implementing
timely and appropriate treatment. In addition, understanding the cause of optic
neuritis informs on visual prognosis, illuminates future health risks, and directs
of Neurology. additional evaluations and treatments. Differentiating between various causes of
1236 OCTOBER 2019

optic neuritis, however, often requires a multifaceted evaluation that extends KEY POINTS
beyond a clinical history and neuro-ophthalmologic examination. Visual field
● The classic presentation
perimetry, optical coherence tomography (OCT), MRI, serologic testing, and of optic neuritis associated
CSF analysis may help to focus the differential diagnosis or identify an with multiple sclerosis is
alternative diagnosis. Therefore, an initial overview of the clinical presentation, unilateral, moderate, painful
examination findings, evaluation, and treatment of the patient with optic neuritis vision loss with an afferent
pupillary defect and normal
is warranted.
fundus examination.
Bilateral vision loss, lack of
EVALUATING AND TREATING THE PATIENT WITH OPTIC NEURITIS pain, and severe loss of
The evaluation of the patient with optic neuritis begins with a careful history and vision should raise concern
for an alternative
examination that provides the framework for guiding and interpreting further
inflammatory optic
laboratory, imaging, and visual testing. The following sections provide a road neuropathy.
map for the evaluation of the patient with optic neuritis, highlighting how
history, examination, visual function, OCT, and neuroimaging may be used to ● Neuromyelitis optica
hone the differential diagnosis and focus therapy. spectrum disorder (NMOSD)
and myelin oligodendrocyte
glycoprotein (MOG)–IgG
Presentation and Examination optic neuritis cause severe
Optic neuritis characteristically presents as acute, unilateral, painful vision loss and are more
vision loss. In the Optic Neuritis Treatment Trial,1 95% of patients showed frequently bilateral.
MOG-IgG optic neuritis
unilateral vision loss and 92% had associated retroorbital pain that frequently frequently causes significant
worsened with eye movement. Some inflammatory and infectious causes optic disc edema.
of inflammatory optic neuropathy, however, present with subacute visual
decline and variable levels of eye discomfort (TABLE 3-1). Therefore, patients
with chronic vision loss and the absence of eye pain should raise suspicion
for an alternative cause of optic neuropathy or vision loss. Bilateral optic
neuritis is more common in children and in adults who are seropositive for
myelin oligodendrocyte glycoprotein IgG (MOG-IgG) or anti-aquaporin-4
(AQP4) IgG.2–4
Examination of the patient with optic neuritis typically reveals visual acuity
loss, visual field loss, color vision deficits, and an afferent pupillary defect in the
affected eye. The absence of an afferent pupillary defect should always raise
diagnostic concern unless the patient has bilateral involvement or a history of
optic neuropathy in the fellow eye. The extent of visual acuity loss may vary
significantly. In idiopathic optic neuritis and optic neuritis associated with MS,
high-contrast visual acuity loss is moderate, with the majority of patients having
acuity better than 20/200.5 Conversely, optic neuritis associated with
neuromyelitis optica spectrum disorder (NMOSD) or MOG-IgG often presents
with severe vision loss worse than 20/400.6,7 The severity of vision loss associated
with infectious, granulomatous, and paraneoplastic optic neuropathy varies
based on the extent and duration of disease. In idiopathic optic neuritis, the
funduscopic examination is typically normal, with less than 25% of patients
presenting with disc edema. Significant disc inflammation, disc hemorrhages, or
ocular inflammation should raise concern for infection, granulomatous inflammation,
or optic neuritis associated with MOG-IgG. TABLE 3-1 presents common clinical
symptoms and examination findings for inflammatory optic neuropathies.
Visual Testing: Perimetry, Evoked Potentials, Optical

Coherence Tomography
Visual evoked potentials provide a sensitive test of the axonal transmission along
the optic nerve. While an abnormal P100 latency on visual evoked potential

OPTIC NEURITIS
testing confirms the presence of an optic neuropathy, visual evoked potential

testing will not differentiate the cause of inflammation nor inform on visual
prognosis. Visual evoked potentials, however, may prove useful in confirming
subtle cases of optic neuritis. Furthermore, a significant increase in P100 latency
without a drop in amplitude is consistent with a demyelinating optic neuropathy,
while a drop in amplitude suggests concurrent axonal injury.
Visual field defects due to optic neuritis vary considerably. Therefore, the
pattern of visual field loss is not specific for any subtype of optic neuritis. Diffuse
or central visual field loss is the most frequent pattern observed in acute
idiopathic optic neuritis and MS optic neuritis8; altitudinal field loss may be more
frequent in NMOSD optic neuritis than MS optic neuritis.9,10
OCT is a noninvasive imaging technology capable of identifying subtle optic
nerve and retinal pathology. OCT frequently identifies peripapillary retinal nerve
TABLE 3-1 Demographics and Clinical Presentation of Optic Neuritis
Onset of Associated Systemic/

Diagnosis Demographics Vision Loss Pain Eye Findings Neurologic Disease
Multiple Young adults, female Acute or Yes Normal or mild disc edemaa Signs or symptoms of
sclerosis predominance subacute multiple sclerosis
Neuromyelitis Older adults, strong Acute or Yes Normal or mild disc edemaa Longitudinally extensive
optica (NMO) female predominance subacute transverse myelitis, area
spectrum postrema syndrome,
disorder SIADH
MOG-IgG Pediatric and adult, Acute or Yes Frequent disc edema; Myelitis, ADEM
no sex predilection subacute often moderate or severea
Seronegative Young adults, female Acute or Yes Normal or mild edema; rare Autoimmune serology,
(AON, RION, predominance subacute uveitisa steroid dependence
CRION)
Granulomatous All age groups, sarcoidosis Subacute Variable Normal or edematous disc Sarcoidosis: hilar
(sarcoidosis, more common in African adenopathy, lung
Sarcoid: uveitis, vitreitis,
granulomatosis and Caribbean ethnicity, fibrosis, cardiac
periphlebitis, episcleritis
with polyangiitis) granulomatosis with symptoms, erythema
polyangiitis peaks at Granulomatosis with nodosum
older age polyangiitis: scleritis,
Granulomatosis with
conjunctivitis, uveitis,
polyangiitis: sinus
vitreitis, vasculitis, orbital
disease, otitis, nasal
inflammation
ulcers,
glomerulonephritis,
systemic vasculitis,
pleural effusion
Autoimmune Young adults, strong Acute or Variable Normal or edematousa Sjögren syndrome:
(Sjögren female predominance subacute xerostomia, dental
Sjögren syndrome: dry eye
syndrome, disease, pancreatitis
systemic lupus
Systemic lupus
erythematosus)
erythematosus: malaise,
arthritis, malar rash, renal
disease, thrombosis
CONTINUED ON PAGE 1239
1238 OCTOBER 2019

fiber layer thickening in acute optic neuritis that evolves into focal retinal nerve
fiber layer and macular thinning.11 Unfortunately, initial studies have not
identified any correlation between acute retinal nerve fiber layer changes and
visual outcomes or treatment response. OCT angiography is a new adaptation of
OCT technology that provides high-resolution information on retinal blood
vessels and may provide novel diagnostic and prognostic information in patients
with optic neuritis. OCT angiography reveals decreased vessel density in the
peripapillary retina and macula following optic neuritis.12 In NMOSD, reduced
peripapillary and parafoveal vessel density is observed independent of a history
of optic neuritis and appears to correlate with visual function.13 In complex cases,
OCT may be helpful to document associated retinal abnormalities or identify
alternative diagnoses such as chorioretinitis, central serous chorioretinopathy,
and acute macular neuroretinopathy. TABLE 3-2 summarizes the results of
CONTINUED FROM PAGE 1238
Onset of Associated Systemic/

Diagnosis Demographics Vision Loss Pain Eye Findings Neurologic Disease
GFAP-IgG Early to late adulthood, Not No Disc edema, normal Encephalitis,
no sex predilection reported intracranial pressure meningoencephalitis,
myelitis, seizure
Paraneoplastic Older adults, no sex Subacute No Disc edema, vitreitis, retinal Malignancy
(CRMP-5) predilection vascular leak
Neuroretinitis No age predilection, Subacute No Disc edema with macular Viral prodrome,
no sex predilection star infection,
catscratch disease
Syphilis Concurrent HIV, Acute, Variable Frequent severe disc Meningitis, encephalitis,
high-risk behavior subacute edema, neuroretinitis, cranial nerve palsies
or chronic episcleritis, uveitis
Lyme disease Lyme-endemic region Acute or Rarely Disc edema, neuroretinitis Myalgia, arthralgia,
subacute reported erythema migrans
Tuberculosis Tuberculosis- Acute or Infrequent Normal or edema, uveitis, Pulmonary disease,

endemic region, subacute orbital apex syndrome meningitis,
Immunocompromise lymphadenopathy
Viral infection Viral-endemic regions, Acute or Variable Normal or edema, retinal Zoster, fever, rash,
zoster reactivation, subacute necrosis, chorioretinitis lymphadenopathy,
immunocompromise immunocompromise
ADEM = acute disseminated encephalomyelitis; AON = autoimmune optic neuropathy; CRION = chronic relapsing inflammatory optic neuropathy;
CRMP-5 = collapsin response mediator protein-5; GFAP-IgG = glial fibrillary acidic protein immunoglobulin G; HIV = human immunodeficiency
virus; MOG-IgG = myelin oligodendrocyte glycoprotein immunoglobulin G; RION = relapsing isolated optic neuritis; SIADH = syndrome of
inappropriate secretion of antidiuretic hormone.
a
Optic disc pallor if recurrent disease.

OPTIC NEURITIS
TABLE 3-2 Ophthalmic Diagnostics in Optic Neuritis
Diagnosis Visual Evoked Potentials Visual Fields Optical Coherence Tomography
Multiple sclerosis P100 latency prolonged with Diffuse field loss, central Acute peripapillary retinal nerve
normal or mildly reduced scotoma fiber layer (RNFL) thickening with
amplitude subsequent peripapillary RNFL and
GC+IPL thinning
Neuromyelitis optica P100 latency prolonged with mildly Total loss, central, Severe peripapillary RNFL thinning
(NMO) spectrum reduced amplitude, reduced quadrant, altitudinal
disorder amplitude with normal latency
absent response
MOG-IgG P100 latency prolonged with normal Not reported Peripapillary RNFL thinning and GC+IPL
or mildly reduced amplitude thinning, worsens with recurrence
Seronegative (AON, P100 latency prolonged with mildly Central scotoma, Severe peripapillary RNFL thinning
RION, CRION) reduced amplitude, reduced constriction, altitudinal worsening with recurrent disease,
amplitude with normal latency (CRION) microcystic macular edema
(CRION)
Granulomatous (sarcoid, P100 latency prolonged with Central scotomas, Peripapillary RNFL thickening,
granulomatosis with normal or mildly reduced occasional hemianopic retinal and subretinal fluid,
polyangiitis) amplitude and altitudinal defects choroidal nodules (sarcoid)
Autoimmune (Sjögren P100 latency prolonged with Variable Peripapillary RNFL thinning,
syndrome, systemic normal or mildly reduced choroidopathy (systemic lupus
lupus erythematosus) amplitude erythematosus)
GFAP-IgG Normal Arcuate defects, enlarged Peripapillary RNFL thickening

blind spot, diffuse loss
Paraneoplastic P100 latency prolonged; Arcuate defects, Peripapillary RNFL thickening,

(CRMP-5) electroretinogram may be constriction; enlarged retinal hyperreflective material
abnormal blind spot, paracentral
scotoma, diffuse loss
Neuroretinitis P100 latency normal or modestly Central or centrocecal Peripapillary RNFL thickening, outer
prolonged; electroretinogram scotoma retinal fluid or hyperreflective
normal material
Syphilis P100 latency prolonged Variable Peripapillary RNFL thickening,

choroidopathy, retinal or subretinal
fluid
Lyme disease P100 latency prolonged with normal Central or centrocecal Peripapillary RNFL thickening, outer
or mildly reduced amplitude; latency scotoma retinal fluid or hyperreflective
may be normal in neuroretinitis material if neuroretinitis
Tuberculosis Not reported Variable, but enlarged Peripapillary RNFL thickening if disc
blind spot and central edema, rare choroidal lesions
scotoma are most common
Viral infection Not reported Variable Retinal thinning, cystic fluid,

hyperreflective lesions with
retinitis and necrosis, outer and
inner retinal hyperreflective
material with chorioretinitis
AON = autoimmune optic neuropathy; CRION = chronic relapsing inflammatory optic neuropathy; CRMP-5 = collapsin response mediator protein-5;
GC+IPL = ganglion cell plus inner plexiform layer thickness; GFAP-IgG = glial fibrillary acidic protein immunoglobulin G; MOG-IgG = myelin
oligodendrocyte glycoprotein immunoglobulin G; RION = relapsing isolated optic neuritis.
1240 OCTOBER 2019

paraclinical testing that may impact the diagnosis of optic neuritis in the KEY POINTS
acute setting.
● Ophthalmic testing is not
generally helpful in
Magnetic Resonance Imaging differentiating acute optic
MRI is an exquisitely sensitive tool for the detection of optic neuritis. MRI of the neuropathies. Visual evoked
orbits with fat suppression and gadolinium enhancement detects acute optic potentials may help to
detect subtle optic nerve
neuritis lesions in 95% of affected individuals within 20 days of vision loss14;
injury when clinical
T2-weighted images with fat suppression and short tau inversion recovery examination findings
(STIR) detect lesions in up to 89% of acute optic neuritis cases with abnormalities are uncertain.
persisting for as long as 6 weeks in 92% of cases.15,16 In addition, the distribution
and appearance of optic nerve, orbital, brain, and meningeal inflammation ● Optical coherence
tomography may be useful
associated with acute optic neuritis may help to differentiate between autoimmune, in detecting subtle retinal
infectious, and granulomatous inflammation (TABLE 3-3). For example, bilateral pathology or documenting
optic neuritis is more common in NMOSD and MOG-IgG disease than in MS. the extent of prior injury in
Lesions involving the optic chiasm and optic tract are highly suggestive of cases of recurrent optic
neuritis.
optic neuritis associated with NMOSD. Longitudinally extensive lesions of the
retrobulbar optic nerve are commonly observed in both NMOSD and MOG-IgG ● MRI of the orbits is the
disease, more so with MOG-IgG disease (FIGURE 3-1).4,17 Perineural optic nerve most sensitive diagnostic
enhancement (optic perineuritis) is frequent with MOG-IgG–associated optic test (90%) for optic neuritis;
however, a normal orbital
neuritis (FIGURE 3-1)6; however, in certain clinical circumstances, syphilis,
MRI scan does not exclude
tuberculosis, sarcoidosis, and granulomatosis with polyangiitis (previously optic neuritis.
known as Wegener granulomatosis) should also be considered.
The presence and pattern of brain and spinal cord MRI lesions also may ● The pattern of
provide valuable diagnostic clues. T2-hyperintense and gadolinium-enhancing inflammation of the optic
nerve on MRI may provide
lesions in multiple regions of the brain and/or spinal cord may be highly diagnostic information.
suggestive or diagnostic of MS,18 whereas periependymal, fornix, and hypothalamic NMOSD optic neuritis more
lesions may favor NMOSD.19 Prior or concurrent longitudinally extensive often affects the optic chiasm,
spinal cord lesions would indicate a high likelihood of NMOSD or MOG-IgG intracranial optic nerve, and
optic tracts; MOG-IgG optic
encephalomyelitis; more frequent involvement of the lower cord and conus is neuritis frequently inflames
seen with MOG-IgG disease.20 Optic neuritis with glial fibrillary acidic protein the intraorbital optic nerve
autoantibodies (GFAP-IgG) may be with a unique pattern of linear perivascular and optic nerve sheath. Both
enhancement.21 Meningeal enhancement and thickening might focus the disorders may be bilateral
with longitudinally extensive
evaluation toward granulomatous disease or infection. lesions.
Serology and CSF Analysis ● Antinuclear

Autoimmune serology and CSF analysis may yield critical clues that either focus autoantibodies are observed
in many patients with optic
the differential diagnosis or clarify an underlying etiology. While not specific for
neuritis; however, they are
any cause of optic neuritis, antinuclear autoantibodies (ANA) are more common much less frequent in
in patients with NMOSD or MOG-IgG optic neuritis than in those with MS.22,23 multiple sclerosis–
Patients with optic neuritis with NMOSD and GFAP-IgG may demonstrate serum associated optic neuritis.
and CSF antineuronal autoantibodies that are commonly reported in autoimmune
encephalopathy panels.21,24 A mild CSF pleocytosis is frequently observed in
patients with acute optic neuritis; however, extensive pleocytosis (>100 cells/mm3)
is observed more often in patients with MOG-IgG. Typically, pleocytosis of less
than 50 cells/mm3 is noted in cases of MS-associated optic neuritis. Eosinophils
and polymorphonuclear cells in the CSF are suggestive of NMOSD. Oligoclonal
bands and intrathecal IgG synthesis, hallmarks of optic neuritis associated with
MS, are uncommon in NMOSD and MOG-IgG–related optic neuritis and rarely
persist.22,25 GFAP-IgG may be restricted to the CSF in affected patients.21 In
contrast, most AQP4-IgG is produced in the periphery, and testing for CSF

OPTIC NEURITIS
TABLE 3-3 MRI Findings in Optic Neuritis
Diagnosis Optic Nerve Imaging Orbital Imaging Brain and Spinal Cord Imaging
Multiple sclerosis Unilateral, retrobulbar and Negative Periventricular ovoid lesions,

canalicular, short anterior subcortical and juxtacortical lesions
segmental lesions, optic
nerve enhancement
Neuromyelitis optica May be bilateral, often Negative Longitudinally extensive transverse

(NMO) spectrum intracranial involving chiasm myelitis, posterior fossa and
disorder and optic tract, often periaqueductal gray lesions,
longitudinally extensive, optic hypothalamic lesions
nerve enhancement
MOG-IgG Frequently bilateral and Enhancement of Myelitis (thoracolumbar and conus

retrobulbar, often perineural orbital tissue predominance), lesions of deep gray
longitudinally extensive, optic nuclei
nerve and perineural sheath
enhancement
Seronegative (AON, Retrobulbar, optic nerve Normal Normal

RION, CRION) enhancement, occasional
nerve swelling
Granulomatous Commonly unilateral, Sarcoid: orbital apex Sarcoidosis: periventricular lesions,

(sarcoidosis, frequent combined optic inflammation leptomeningeal lesions, pituitary and
granulomatosis with nerve and sheath hypothalamic lesions
Granulomatosis with
polyangiitis) enhancement
polyangiitis: orbital Granulomatosis with polyangiitis:
cellulitis, orbital mass, pachymeningitis, nonspecific gray and
orbital pseudotumor white matter lesions due to vasculitis
Autoimmune (Sjögren Retrobulbar, optic nerve Normal Systemic lupus erythematosus: infarcts
syndrome, systemic enhancement and dural thrombosis
lupus erythematosus)
GFAP-IgG Normal Normal Linear radial perivascular enhancement,

meningitis, myelitis, leptomeningeal
and ependymal enhancement
Paraneoplastic Bilateral, optic nerve Normal Cerebellar atrophy, mesial temporal

(CRMP-5) enhancement lesions, cerebellar lesions, myelitis (may
be longitudinally extensive)
Neuroretinitis Normal, occasional high T2 Normal Normal

signal or enhancement in
proximal optic nerve
Syphilis Optic nerve and perineural Occasional enhancement Leptomeningeal enhancement,

sheath enhancement of orbital fat encephalitis, myelitis, infarct
Lyme disease Retrobulbar, optic nerve Normal Cranial nerve enhancement,

enhancement periventricular and subcortical lesions
Tuberculosis Retrobulbar, optic nerve and Orbital tuberculoma, Leptomeningeal enhancement,

sheath enhancement dacryoadenitis ependymitis, tuberculoma
Viral infection Retrobulbar, optic nerve Normal Variable depending on pathogen

enhancement
AON = autoimmune optic neuropathy; CRION = chronic relapsing inflammatory optic neuropathy; CRMP-5 = collapsin response mediator protein-5;
GFAP-IgG = glial fibrillary acidic protein immunoglobulin G; MOG-IgG = myelin oligodendrocyte glycoprotein immunoglobulin G; MRI = magnetic
resonance imaging; RION = relapsing isolated optic neuritis.
1242 OCTOBER 2019

KEY POINTS
● CSF pleocytosis may be

highest in MOG-IgG optic
neuritis, whereas CSF
eosinophils are suggestive
of NMOSD.
● Oligoclonal bands should

suggest multiple sclerosis–
associated optic neuritis,
especially if they persist.
● Aquaporin-4 IgG is rarely,

if ever, isolated to the CSF.
FIGURE 3-1
Fat-suppressed postcontrast T1-weighted orbital imaging of optic neuritis. A, Axial image
shows bilateral longitudinally extensive lesions involving the orbital and intracanalicular
optic nerves in a patient with myelin oligodendrocyte glycoprotein antibody (MOG-IgG) optic
neuritis. Note the enhancement of the optic discs suggestive of disc edema. B, Coronal image
of optic nerves in panel A showing both sheath (right eye) and nerve (left eye) enhancement.
Gadolinium contrast fills both superior orbital veins (arrows). C, Coronal image showing an
enlarged, enhancing optic chiasm in a patient with neuromyelitis optica (NMO) spectrum
disorder–associated optic neuritis. Additional cloudlike enhancement is seen in the left
thalamus/basal ganglia due to NMO inflammation. D, Bilateral enhancing lesions of the orbital
and intracanalicular optic nerves in a patient with chronic relapsing immune-mediated optic
neuropathy.
AQP4-IgG is neither sensitive or cost-effective.26 If suspicion exists for infection

or granulomatous disease, serum and CSF should be evaluated for syphilis,
Lyme bacillus, and angiotensin-converting enzyme (ACE). Additional serologic
testing for Bartonella henselae should be considered in cases of neuroretinitis in
which optic disc edema is accompanied by a macular star of exudates located in a
radial pattern around the fovea; serologic testing for cytoplasmic antineutrophil
cytoplasmic antibodies (c-ANCA) should be included in optic neuritis cases
under consideration for granulomatosis with polyangiitis (formerly known as
Wegener granulomatosis).
Treatment
Administration of high doses of corticosteroids is the standard treatment for
acute optic neuritis. In the Optic Neuritis Treatment Trial, IV methylprednisolone

OPTIC NEURITIS
(1000 mg/d for 3 days), followed by oral prednisone (1 mg/kg/d for 11 days)
accelerated visual recovery but failed to improve functional outcomes.1 Subsequent
studies in patients with relapsing MS or optic neuritis have demonstrated that
doses of corticosteroid equivalent to 1000 mg IV methylprednisolone,
administered IV or orally, provides an equivalent therapeutic effect of accelerated
recovery.27,28 IM or subcutaneous adrenocorticotropic hormone (ACTH) is also
approved for the treatment of acute optic neuritis and provides an alternative
option for enhancing corticosteroid signaling. Lower doses of oral prednisone
(1 mg/kg/d or less) should be avoided in cases of idiopathic optic neuritis as an
increased risk of relapse exists.1 Chronic treatment with low-dose oral prednisone,
however, is important for the treatment of sarcoid optic neuritis and recurrent
optic neuritis due to chronic relapsing inflammatory optic neuropathy.29,30 In
the Optic Neuritis Treatment Trial, treatment with IV methylprednisolone
was reported to delay conversion to MS in the first 2 years.31 A similar finding,
however, was not observed in the original Optic Neuritis Treatment Trial
dataset,1 likely resulting from the reclassification of study participants.32 Indeed,
independent studies evaluating the effects of IV methylprednisolone on relapse
rates in patients with MS have failed to observe a similar effect.33,34
IV immunoglobulin (IVIg) and plasma exchange have been evaluated in
patients with optic neuritis that is refractory to high-dose corticosteroid
treatment. IVIg (2 g/kg) failed to improve contrast sensitivity or visual function
in patients with acute optic neuritis or MS with refractory vision loss.35,36
Treatment response may have been limited because of the delayed
administration of IVIg in both studies. In contrast, plasma exchange has resulted
in improved visual outcomes in patients with corticosteroid-refractory optic
neuritis and NMOSD optic neuritis.7,37 While the frequency of responders
varied, the majority of patients with optic neuritis treated with plasma exchange
had improvement in their visual function. Increased response to plasma
exchange has been associated with male sex, lower baseline disability, rapid
initiation of treatment, and shorter relapse duration.38,39 While the optimal use
and timing of plasma exchange in patients with optic neuritis has yet to be
defined, the natural history of poor visual recovery in NMOSD and recurrent
optic neuritis argues that plasma exchange should be considered as a first-line
treatment in certain clinical circumstances, as discussed later in this article.
Therapeutic apheresis, using immunoadsorption, offers an alternative to plasma
exchange outside of the United States and has been reported to benefit
steroid-refractory optic neuritis.40
If infection is prominent in the differential diagnosis of a patient with optic
neuritis, it is prudent to begin appropriate antibiotic therapy as soon as possible.
Symptomatic therapy with corticosteroids may be initiated concurrently unless
otherwise contraindicated. Antibiotic or antiviral therapies may be tailored or
discontinued based on diagnostic imaging, serology, cultures, or CSF analysis.
For optic neuritis associated with Bartonella infection, the utility of antibiotic
therapy remains unclear; however, significant vision loss, systemic infection, and
immunocompromised status should bolster consideration for antibiotics.41
THE SPECTRUM OF OPTIC NEURITIS

The differential diagnosis of optic neuritis has undergone a significant
transformation over the past decade. An expanding spectrum of autoimmune,
paraneoplastic, and idiopathic inflammatory disorders have been associated with
1244 OCTOBER 2019

acute optic neuritis, and their visual prognosis, response to treatment, and risk KEY POINTS
for recurrence vary substantially. The following sections address the diagnosis
● High-dose IV
and treatment of specific inflammatory and infectious causes of optic neuritis. methylprednisolone
(1000 mg/d IV for 3 days) is
Optic Neuritis Associated With Multiple Sclerosis effective at improving the
Optic neuritis affects roughly 70% of patients with MS and is the presenting speed of recovery of optic
neuritis. Small studies have
symptom in approximately 25% of individuals. Women are affected twice as
demonstrated that the type
often as men, and whites dominate the racial distribution. Optic neuritis is of steroid and mode of
frequently unilateral and painful and progresses over 1 to 2 weeks; bilateral optic delivery (oral versus IV) are
neuritis and severe vision loss (count fingers or worse) are uncommon. Optic likely inconsequential.
Lower dosages of oral
disc edema is infrequent (35%) (FIGURE 3-2); hemorrhagic disc edema (5.6%),
prednisone (1 mg/kg) are
retinal exudates (1.8%), and vitreal cells (3.3%) are rare and impart a reduced risk contraindicated for acute
for MS.5,42 OCT of the peripapillary retinal nerve fiber layer has demonstrated optic neuritis treatment
that mild segmental swelling of the nerve fiber layer (>110% of normal thickness) because of a higher risk
is present in 82% of affected eyes and persists in 58% of eyes at 1 month.11 of relapse.
Peripapillary and macular OCT show relatively rapid and concurrent thinning of ● Plasma exchange may
the peripapillary retinal nerve fiber layer and macular ganglion cell plus inner be useful in treating
plexiform layer. The change in ganglion cell plus inner plexiform layer thickness steroid-resistant optic
in the first month may predict poor visual acuity after 6 months.43 At 1 month, neuritis, severe optic
neuritis due to NMOSD, and
visual acuity of 20/50 or less, contrast sensitivity less than 1.0 log units, and visual recurrent optic neuritis at
field mean deviation of –15 dB or lower also predict moderate to severe vision risk for poor recovery. Time
loss at 6 months.44 T1 gadolinium enhancement is evident in 95% of acute to administration of plasma
MS-associated optic neuritis lesions within 20 days of vision loss14; lesions are exchange may be critical to
treatment success.
typically short and anterior when compared to NMOSD- and MOG-associated
optic neuritis.4,45 The location and length of enhancement of the optic nerve ● Optic neuritis is the initial
lesion on MRI do not correlate with visual recovery. Brain MRI and CSF analysis presentation of multiple
are important for determining MS risk in patients with idiopathic optic neuritis sclerosis in 25% of
using the 2017 McDonald criteria.18 The presence and pattern of enhancing and individuals. The presence
of enhancing and
T2-weighted brain MRI lesions may be diagnostic of MS or provide dissemination nonenhancing brain MRI
in space criteria. In addition, the presence of CSF oligoclonal bands now fulfills lesions meeting
dissemination in time criteria for patients with optic neuritis who meet clinical or dissemination in space
MRI criteria for dissemination in space. criteria by the 2017
McDonald criteria is
Visual recovery from diagnostic of multiple
MS-associated optic neuritis is sclerosis. If no enhancing
generally good. In the Optic lesions are present,
Neuritis Treatment Trial, the oligoclonal bands may
provide dissemination in
median acuity at recovery was time criteria according to
20/16. Visual acuity returned to the 2017 McDonald criteria.
20/40 or better in 91% of subjects
with 20/200 or worse vision at
entry, independent of treatment
with corticosteroids. As noted
previously, treatment with IV
methylprednisolone hastened the
speed of visual recovery in the
Optic Neuritis Treatment Trial but
did not influence long-term
outcomes. Patients with FIGURE 3-2
MS-associated optic neuritis who Mild optic disc edema associated with multiple
have poor visual recovery following sclerosis.

OPTIC NEURITIS
treatment with high-dose corticosteroids often respond to plasma exchange.37

The optimal timing for institution of plasma exchange after IV
methylprednisolone, however, remains to be determined. A phase 2 clinical trial
recently evaluated phenytoin for neuroprotection in acute optic neuritis.
Phenytoin treatment significantly reduced peripapillary retinal nerve fiber layer
loss at 6 months but had no effect on visual outcomes.46
Optic Neuritis Associated With Neuromyelitis Optica Spectrum Disorder

NMOSD is a central nervous system (CNS) inflammatory disorder that
frequently involves the optic nerves and spinal cord. According to the
International Consensus criteria,47 NMOSD is classified as either seropositive or
seronegative based on the presence of serum AQP4-IgG. Approximately 80% of
affected individuals are seropositive for AQP4-IgG, and the presence of a core
clinical presentation (optic neuritis, acute myelitis, area postrema syndrome,
acute brainstem syndrome, symptomatic narcolepsy, or acute diencephalic
syndrome with NMOSD-typical MRI lesions, or symptomatic cerebral syndrome
with NMOSD-typical brain lesions) and serum AQP4-IgG is diagnostic of
disease.47 NMOSD-associated optic neuritis may also be diagnosed in AQP4-IgG
seronegative individuals who have concurrent or prior core clinical presentations
that meet additional criteria.47 Optic nerve MRI criteria for NMOSD-associated
optic neuritis requires a T2-hyperintense or T1-weighted gadolinium-enhancing
lesion extending over half of the optic nerve length or involving the optic chiasm.
Optic nerve head edema is rare, as with MS-associated optic neuritis. Optic
neuritis associated with NMOSD is seen more often in women and nonwhites.
It is typically severe (mean acuity ≤20/400),7 and bilateral optic neuritis occurs
in up to 20% of cases.48 Retinal nerve fiber layer loss is typically more severe
following NMOSD-associated optic neuritis.49,50
Complete response to high-dose corticosteroids is much less common than
in MS-associated optic neuritis, occurring in only 36%.48 Retrospective studies
comparing IV methylprednisolone to plasma exchange have documented
improved visual acuity and visual fields using plasma exchange (CASE 3-1).7,37
A short interval (≤5 days) between optic neuritis onset and the institution of
plasma exchange is associated with an increased probability of complete
improvement.39 Therefore, patients with acute optic neuritis suspicious for
NMOSD may benefit from initiation of plasma exchange before confirmation of
AQP4-IgG seropositivity. MRI and CSF findings raising concern for NMOSD
include longitudinally extensive or bilateral optic nerve lesions, inflammation
of the optic chiasm or optic tracts, periependymal brain lesions,
polymorphonuclear CSF pleocytosis, or CSF eosinophils. Patients with
seropositive NMOSD are at high risk for relapse, and initiation of
immunosuppressive therapy is therefore recommended.47 Differentiating
MS-associated optic neuritis from NMOSD-associated optic neuritis is critical
as some immunomodulatory therapies approved for MS may exacerbate
NMOSD disease activity.51–53
Optic Neuritis Associated With Myelin Oligodendrocyte

Glycoprotein Autoantibodies
Serum autoantibodies against MOG (MOG-IgG) identify a cohort of patients
with a strong predilection for isolated and recurrent optic neuritis.2,3 MOG-
IgG–associated optic neuritis is slightly more common in females (57%), displays
1246 OCTOBER 2019

no distinct ethnic predilection, and is frequently bilateral (37% to 44%) KEY POINTS
(CASE 3-2).3,6 The age of onset may vary considerably (range: 2 to 79 years);
● It is important to
adults with disease onset between 20 and 45 years of age commonly present with differentiate optic neuritis
unilateral optic neuritis, while older patients more often present with bilateral due to NMOSD from that
optic neuritis. Simultaneous optic neuritis and transverse myelitis mimicking due to multiple sclerosis.
NMOSD has been reported in up to 25% of cohorts.3,6 MOG-IgG disease The prognosis for visual
recovery is poorer for
commonly presents as acute disseminated encephalomyelitis (ADEM) or
NMOSD optic neuritis, and
recurrent optic neuritis in children.3,54 the risk for recurrence is
Vision loss due to MOG-IgG–associated optic neuritis is typically severe high.
(mean: count fingers vision), painful (86%), and associated with optic disc
edema (86%) (FIGURE 3-5).6 Common MRI findings include longitudinally ● NMOSD optic neuritis
should prompt
extensive (more than half the length) optic nerve lesions (80%) and perineural consideration for early
enhancement (50%). MOG-IgG optic neuritis is frequently steroid responsive plasma exchange.
and steroid dependent.55 Although severe vision loss has been reported, it is
typically due to repeated attacks of optic neuritis; the risk of severe visual ● Treatments for multiple
sclerosis, such as interferon
impairment from a single event of optic neuritis is low.6 IV methylprednisolone is beta, fingolimod, and
therefore the treatment of choice in cases of acute MOG-IgG optic neuritis. If IV natalizumab, have been
methylprednisolone has failed to improve vision with prior events or MOG-IgG documented to exacerbate
optic neuritis is recurring in a previously affected eye, then a combination of plasma NMOSD disease activity.
exchange and IV methylprednisolone should be considered. MOG-IgG optic neuritis
● MOG-IgG disease
frequently recurs; 80% of patients have two or more attacks over a median time frequently causes recurrent
of 2.9 years.6 Long-term immunosuppressants used to prevent MOG-IgG optic optic neuritis. Bilateral optic
neuritis include corticosteroids, azathioprine, mycophenolate mofetil, and neuritis, longitudinal optic
rituximab. The optimal preventive therapy, however, has yet to be determined.3,54 nerve lesions, optic nerve
sheath enhancement, and
steroid responsiveness are
Optic Neuritis Associated With Glial Fibrillary Acidic Protein important clinical and
Autoantibodies radiologic clues.
Serum and CSF autoantibodies against GFAP-IgG have been recently identified
● GFAP-IgG
in patients with inflammatory meningitis, encephalitis, and myelitis. Roughly encephalomyelitis is
40% of patients with GFAP-IgG meningoencephalitis demonstrated commonly associated with
inflammatory optic disc edema on examination.21,56 The optic disc edema was optic nerve papillitis. As a
bilateral and symmetric, and the CSF opening pressure was normal in result, disc edema is
prominent, but vision
all patients except for two individuals who showed a mildly elevated intracranial
loss is rare.
pressure (<300 mm H2O). Additional findings consistent with inflammatory
papillitis included mild vitreitis, venular leakage on fluorescein angiography, and ● Perivascular radial
resolution with high-dose corticosteroids. Inflammatory lesions of the enhancement on MRI is
retrobulbar optic nerve were not reported.21,56 Many affected individuals showed highly suggestive of
GFAP-IgG disease.
a characteristic radial perivascular enhancement on brain MRI. Visual acuity was GFAP-IgG may be isolated
minimally affected; however, some patients showed nerve fiber layer bundle to the CSF in a large
defects and optic disc atrophy after clinical resolution. The combination of fraction of patients.
meningoencephalitis, bilateral papillitis, and normal MRI of the optic nerves,
with or without radial perivascular enhancement on brain MRI, should prompt
testing for serum and CSF GFAP-IgG. Initial treatment of GFAP-IgG papillitis is
with IV methylprednisolone followed by high-dose oral corticosteroids.21,56
Recurrent Idiopathic Optic Neuritis

Autoimmune optic neuropathy, chronic relapsing inflammatory optic neuropathy,
and relapsing isolated optic neuritis are terms used in the literature to describe
cases of recurrent, seronegative optic neuritis. Autoimmune optic neuropathy
was initially described by Dutton and colleagues57 in patients with recurrent

OPTIC NEURITIS
events of steroid-responsive optic neuritis. Visual acuity loss may range from
mild to severe; pain is infrequent, and the fundus examination often reveals mild
edema. Laboratory and imaging tests are typically unrevealing, although positive
ANA and anticardiolipin antibodies have been reported in some series. Skin
biopsy has revealed evidence of histopathologic vasculitis in roughly 25% of
patients and immunoglobulin, immune complex, or complement deposition in
most others.58 Relapsing isolated optic neuritis is used to describe patients with
spontaneous and isolated attacks of nonprogressive, unilateral, or bilateral optic
neuritis.59 Patients with relapsing isolated optic neuritis are predominantly
female with moderate levels of vision loss (average: 20/80). Systemic illness is
infrequent (14%), and patients infrequently display ANA seropositivity (15%).
CSF pleocytosis is minimal, and oligoclonal bands are uncommon (19%).
CASE 3-1 A 35-year-old woman presented with acute painful loss of vision in the
right eye that began 1 month earlier. The vision loss progressed over
2 days and reached light perception. She received 3 days of high-dose IV
methylprednisolone 2 weeks earlier, and her vision improved but
remained very blurry. She denied any additional neurologic or ophthalmic
problems. She had experienced a similar episode of painful right eye
vision loss 5 years ago, from which she recovered after IV
methylprednisolone.
On examination, visual acuity was 20/500 right eye and 20/20 left eye
with a right afferent pupillary defect. There was central vision loss in the
right eye and dense visual field suppression. The right optic nerve was
pale; the left was normal. Optical coherence tomography (OCT) of the
peripapillary retinal nerve fiber layer showed severe thinning in the
right eye (FIGURE 3-3A). MRI of her orbits showed longitudinally extensive
T1 gadolinium enhancement of the intraorbital right optic nerve
(FIGURE 3-3B) and T2-hyperintense signal in the intracranial right optic
nerve (FIGURE 3-3C).
COMMENT Recurrent severe optic neuritis is concerning for neuromyelitis optica

spectrum disorder (NMOSD)–associated optic neuritis. Suspicion for
NMOSD optic neuritis is raised by the significant retinal nerve fiber layer
thinning in the previously affected right eye. The prognosis for visual
recovery is poor given the severe vision loss 1 month after disease onset
and the lack of response to IV steroids. Serologic testing returned positive
for aquaporin-4 antibodies (titer: 1:10,000). The patient was admitted to the
hospital and received 5 consecutive days of plasma exchange. Vision
returned to 20/30 in the right eye, and she was started on azathioprine
for prophylactic therapy.
1248 OCTOBER 2019

Generally, response to IV methylprednisolone is excellent, with 70% of patients
with relapsing isolated optic neuritis recovering to better than 20/25 acuity.
Relapse following steroid withdrawal is uncommon (10%) in patients with
relapsing isolated optic neuritis.
In contrast, chronic relapsing inflammatory optic neuropathy is used to
describe patients with recurrent episodes of isolated unilateral or bilateral optic
neuritis who demonstrate progressive vision loss between attacks.60 Chronic
relapsing inflammatory optic neuropathy was initially defined as a steroid-
dependent condition; however, later publications have noted only that patients
with chronic relapsing inflammatory optic neuropathy require immunosuppression
for prevention of optic neuritis relapses.30 Indeed, patients with chronic relapsing
inflammatory optic neuropathy demonstrate a threefold increase (31% versus
FIGURE 3-3
Findings of the patient in CASE 3-1. A, Spectral domain optical coherence tomography of the
peripapillary retinal nerve fiber layer showing severe thinning on the right (mean right:
51 microns; mean left: 104 microns). B, Axial fat-suppressed postcontrast T1-weighted MRI
showing a subtle longitudinally extensive enhancing lesion of right orbital nerve and sheath.
C, Axial T2-weighted MRI showing subtle signal abnormality (arrowhead) in the posterior
right optic nerve.

OPTIC NEURITIS
CASE 3-2 An 18-year-old man with a history of recurrent optic neuritis presented
with acute, painful bilateral vision loss. The eye pain worsened with
eye movement, and vision declined to its nadir over 5 days. He had
experienced his last episode of optic neuritis 6 months earlier and was
currently on B-cell depletion therapy with rituximab. He denied any prior
or concurrent neurologic problems.
On examination, visual acuity was 20/40 right eye and 20/30 left eye.
He had central field loss in both eyes, sluggish pupils, and no afferent
pupillary defect. Optic disc pallor was seen bilaterally.
Aquaporin-4 IgG, antinuclear antibodies, and antineutrophil
cytoplasmic antibodies were negative. MRI showed bilateral optic nerve
T2 signal hyperintensity and swelling (FIGURES 3-4A and 3-4B); optical
coherence tomography showed minimal peripapillary retinal nerve fiber
layer thinning in both eyes (FIGURE 3-4C).
FIGURE 3-4
Findings of the patient in CASE 3-2. A, Axial fat-saturated T2-weighted turbo inversion
recovery magnitude images showing enlarged optic nerves with long T2-hyperintense
orbital lesions. B, Coronal short tau inversion recovery (STIR) images showing
T2-hyperintense enlarged optic nerves. C, Spectral domain optical coherence tomography
of the peripapillary retinal nerve fiber layer showing normal mean thickness in both
eyes despite two prior episodes of optic neuritis. Mild segmental retinal nerve fiber
layer thickening is seen in the right eye due to edema as well as focal temporal thinning
due to prior episodes of optic neuritis, together leading to the normal mean thickness
(pseudo–normal mean thickness). The patient had no clinical evidence of disc edema
on examination.
COMMENT Recurrent bilateral optic neuritis in a young man with longitudinally

extensive optic nerve inflammation with sheath involvement is highly
suggestive of myelin oligodendrocyte glycoprotein (MOG)–IgG optic
neuritis. MOG-IgG testing by cell-binding assay was positive in this patient.
He was treated with 5 days of IV methylprednisolone and had prompt
return of normal vision. Because of recurrent disease activity on rituximab,
the patient was switched to mycophenolate mofetil and has remained
relapse-free.
1250 OCTOBER 2019

10%) in risk of relapse compared KEY POINT
to patients with relapsing isolated
● Autoimmune optic
optic neuritis following neuropathy, relapsing
discontinuation of corticosteroids.59 isolated optic neuritis, and
Patients with chronic relapsing chronic relapsing
inflammatory optic neuropathy inflammatory optic
neuropathy are idiopathic
are predominantly female and
seronegative optic
ethnically diverse. Visual acuity neuropathies characterized
loss is generally severe, and by their responsiveness to or
the average visual acuity on dependency on steroid
immunosuppression. They
recovery is worse than in
are currently a diagnosis of
relapsing isolated optic neuritis exclusion for patients with
FIGURE 3-5 (20/40 versus 20/25).30,59,60 recurrent optic neuritis
Optic disc edema and retinal inflammation in optic
neuritis. Optic disc edema with nerve fiber layer The reasons for worse visual seronegative for AQP4-IgG
and MOG-IgG.
(splinter) hemorrhages due to myelin oligodendrocyte outcome are likely multifactorial:
glycoprotein (MOG)–IgG optic neuritis. interattack progression, attack
frequency, and the timing of
acute treatment and chronic
immunosuppression. Similar to patients with relapsing isolated optic neuritis,
patients with chronic relapsing inflammatory optic neuropathy are rarely ANA
seropositive, lack concurrent systemic disease, and rarely produce CSF
oligoclonal bands.30,59,60 Acute attacks of chronic relapsing inflammatory optic
neuropathy are usually responsive to IV methylprednisolone; however, chronic
immunosuppression is generally required. Immunosuppressive agents include
prednisone, azathioprine, mycophenolate mofetil, cyclophosphamide, and IVIg.30
Since autoimmune optic neuropathy, relapsing isolated optic neuritis, and
chronic relapsing inflammatory optic neuropathy are diagnoses of exclusion, prior
evaluations should include MRI of the brain and optic nerves, lumbar puncture, and
serologic testing for AQP4-IgG and MOG-IgG. A single small case study reported a
low incidence (5%) of NMOSD among chronic relapsing inflammatory optic
neuropathy cases61; however, the incidence of MOG-IgG disease among chronic
relapsing inflammatory optic neuropathy cases remains unknown. It is likely that
advances in antigen identification will lead to more definitive categorization of
patients currently diagnosed with autoimmune optic neuropathy, relapsing isolated
optic neuritis, or chronic relapsing inflammatory optic neuropathy.
OPTIC NEURITIS ASSOCIATED WITH SYSTEMIC IMMUNE DISORDERS

Acute optic neuritis may occur in the background of systemic or neurologic
immune disorders. Occasionally, optic neuritis may be the presenting symptom
of a systemic immune process. The following sections review the features of optic
neuritis associated with Sjögren syndrome, systemic lupus erythematosus, and
paraneoplastic disease.
Sjögren Syndrome
Sjögren syndrome is a systemic immune disorder characterized by destructive
inflammation of salivary and lacrimal glands resulting in keratoconjunctivitis
and xerostomia (sicca syndrome). Sjögren syndrome may present in isolation with
sicca syndrome (primary Sjögren syndrome) or in association with other
autoimmune connective tissue disorders (secondary Sjögren syndrome). Primary
Sjögren syndrome is commonly diagnosed using the American-European

OPTIC NEURITIS
Consensus Group criteria, which include ocular and oral clinical symptoms and
signs, histopathology, and serology.62 A simpler classification proposed by the
American College of Rheumatology is based on serology, ocular surface staining,
and histopathology; it shows comparable sensitivity and specificity.63 Sjögren
syndrome commonly presents in middle age and predominantly affects women.
CNS involvement is infrequent (approximately 5%), and optic neuritis is present
in a small percentage (4%) of these cases.64 Affected individuals are commonly
treated with corticosteroids, and improvement in vision is variable; recurrent
optic neuritis may occur in one-third of patients. Sjögren syndrome has been
reported in conjunction with NMOSD; therefore, it is important to check for
AQP4 autoantibodies in patients with primary or secondary Sjögren syndrome and
optic neuritis, particularly if optic neuritis is associated with myelitis or brainstem
inflammation. Despite their association, Sjögren syndrome and NMOSD are
considered to be independent, overlapping autoimmune conditions; AQP4
autoantibodies are observed at a similar frequency in patients with NMOSD with
and without Sjögren syndrome, and the neurologic presentations of AQP4-IgG
seropositive patients with Sjögren syndrome are not distinct from those observed
in NMOSD.65
Systemic Lupus Erythematosus

Isolated optic neuritis is an infrequent manifestation of systemic lupus
erythematosus (SLE). In a 3-year prospective study of 370 patients with SLE
without a history of neurologic involvement, only 16 patients (4.3%) had CNS
events; optic neuritis comprised two of 23 events (8.7%).66 Optic neuritis in patients
with SLE is typically severe, and recovery is often incomplete. In a small series of
patients with SLE with optic neuritis, almost 40% had 20/200 or worse acuity at
recovery and 37.5% had a recurrent event.67 Some patients with acute SLE optic
neuritis respond to high-dose corticosteroids; the response to plasma exchange is
not reported. For patients with recurrent disease, successful control has been
reported with steroid-sparing immunosuppressants, such as cyclophosphamide,
azathioprine, methotrexate, and cyclosporine. As noted for Sjögren syndrome,
AQP4-IgG seropositivity is common in patients with SLE who present with
NMOSD, longitudinally extensive transverse myelitis, and recurrent optic neuritis.
Therefore, it is prudent to check patients with SLE with acute or recurrent optic
neuritis for AQP4-IgG and treat vision loss aggressively. Routine testing for AQP4-
IgG in patients with SLE with CNS manifestations that are nonsyndromic for
NMOSD, however, is unlikely to be informative.65,68 In some cases of SLE, optic
disc edema reflects an anterior ischemic optic neuropathy related to vasculitis or
antiphospholipid disorder, imparting a worse prognosis for visual recovery.
Paraneoplastic Optic Neuritis

Paraneoplastic optic neuritis is associated with an autoimmune response against
CRMP-5/CV-2.69 Small cell carcinoma is the most frequently associated tumor;
however, prostate cancer, renal cell carcinoma, lung adenocarcinoma, and
thymoma have been reported.69,70 Vision loss is typically subacute, progressive,
and bilateral within weeks to months. Pain is unusual. Fundus examination
shows optic disc edema typically with nerve fiber layer hemorrhages. Vitreitis is a
striking feature. Vascular leakage secondary to peripheral retinal inflammation is
also observed. CRMP-5 paraneoplastic optic neuritis rarely occurs in isolation;
however, isolated CRMP-5 perioptic neuritis suggestive of MOG-IgG–associated
1252 OCTOBER 2019

optic neuritis has been reported.71 Central and peripheral neurologic symptoms KEY POINTS
reported with CRMP-5 paraneoplastic optic neuritis include ataxia, nystagmus,
● Isolated optic neuritis
dementia, polyneuropathy, and myelitis. When concurrent myelitis is present, associated with systemic
CRMP-5 paraneoplastic disease may mimic NMOSD.70 For more information on lupus erythematosus or
the neuro-ophthalmic complications of paraneoplastic disease, refer to the article Sjögren syndrome is
“Paraneoplastic Syndromes in Neuro-ophthalmology” by Lynn Gordon, MD, rare. Patients diagnosed
with systemic lupus
PhD, and Marc Dinkin, MD,72 in this issue of Continuum.
erythematosus or Sjögren
syndrome and optic neuritis
OPTIC NEURITIS DUE TO GRANULOMATOUS DISEASE should be tested for
Ophthalmic complications are frequently observed in patients with AQP4-IgG.
granulomatous disease, and involvement of the optic nerve may result in
● Patients with systemic
substantial visual morbidity. The following sections review optic neuritis and lupus erythematosus or
ophthalmic manifestations of sarcoidosis and granulomatosis with polyangiitis. Sjögren syndrome with optic
neuritis who are seropositive
Sarcoidosis for AQP4-IgG are at higher
risk for poor visual recovery
Sarcoidosis frequently presents with ophthalmic complications and is than patients with systemic
proportionally more common in African and Caribbean ethnic groups.73 Anterior lupus erythematosus or
uveitis, vitreitis, periphlebitis, and keratoconjunctivitis are common findings. Sjögren syndrome without
Optic neuropathy and involvement of the CNS are relatively infrequent and AQP4-IgG.
occur in up to 10% of patients.29 Optic neuropathy from sarcoidosis commonly
● Paraneoplastic optic
presents as optic neuritis, although compressive and infiltrative injuries to the neuritis associated with
optic nerve have been described. In a large 2016 case series of sarcoid optic collapsin response mediator
neuropathy,29 82% of patients presented with subacute optic neuritis evolving protein-5 (CRMP-5)
autoantibodies may mimic
over days; roughly half were unilateral. Bilateral involvement was typically
idiopathic optic neuritis.
asynchronous. Similar to other case series,74 vision loss was significant, with Bilateral, asynchronous
median acuity ranging from 20/400 in unilateral disease to 20/150 in bilateral optic neuritis with
disease. Central field loss was the most common pattern of visual field loss; prominent vitreitis and
however, other hemianopic and altitudinal patterns were also observed. MRI retinal leakage in an older
adult should raise clinical
frequently showed swelling and enhancement of the affected optic nerve with concern.
rare cases of optic perineuritis (5%) or chiasmitis (2.5%).29 In cases of sarcoid
optic neuritis, additional inflammation in the orbital apex and CNS were ● CRMP-5 optic neuritis is
occasionally observed.29,74 frequently accompanied by
central or peripheral
Roughly one-third of patients with sarcoid optic neuritis demonstrate neurologic injury. The
concurrent intraocular inflammation at the time of presentation.60 Some presence of transverse
published series have found a myelitis may mimic NMOSD.
higher percentage of patients with
● Sarcoid optic neuropathy
ocular inflammation; however,
may be extremely difficult
the presentations were not limited to diagnose in the absence
to optic neuritis. Types of of ocular inflammation or
ocular inflammation include systemic disease.
granulomatous anterior uveitis,
panuveitis, vitreitis, nerve fiber
layer infarcts, macular exudates,
retinal vasculitis with its
characteristic perivascular
infiltrates known as “candle wax
droppings” (FIGURE 3-6), and
episcleritis.75 Serum ACE is FIGURE 3-6
elevated in roughly 50% of Perivascular infiltrates (candle wax droppings)
patients at the time of optic due to sarcoidosis.

OPTIC NEURITIS
neuropathy; however, some series have reported lower numbers of patients

who were positive.74 Abnormal CSF is uncommon (CASE 3-3). When
abnormal, CSF typically shows a lymphocytic pleocytosis with elevated CSF
protein. Oligoclonal bands are noted in approximately 15% of patients. In cases
of neurosarcoidosis, ACE levels in the CSF may be tested. The reported
sensitivity and specificity of CSF ACE are 66.7% and 67.3%, respectively,
when using a cutoff value of 2.76 The diagnosis of sarcoid optic neuritis should
be confirmed with pathology showing noncaseating granulomas; chest CT,
gallium scan, and fludeoxyglucose positron emission tomography (FDG-PET)
often prove useful to identify inflamed tissue for sampling.73
Since sarcoidosis typically demonstrates multiorgan involvement, treatment
of sarcoid optic neuritis will often require long-term immunosuppression. Oral
CASE 3-3 A 41-year-old man presented with 3 months of subacute, painless vision
loss in the left eye. The vision loss was maximal by 2 weeks and had not
recovered. He denied any additional neurologic or eye symptoms.
On examination, his visual acuity was 20/15 right eye and 20/50 left
eye, and color vision was diminished in the left eye. He had
superotemporal field loss in the left eye and a left afferent pupillary
defect. The left optic disc was pale (FIGURE 3-7A), and the retina was
normal. MRI of the orbits showed diffuse enhancement of the left optic
nerve from the globe to the chiasm (FIGURE 3-7B).
IV steroids had no effect on his vision. CSF analysis showed no
pleocytosis, normal protein, normal CSF angiotensin-converting enzyme
level, and no oligoclonal bands. Serologic testing for antinuclear
antibody, angiotensin-converting enzyme level, aquaporin-4 IgG, and
myelin oligodendrocyte glycoprotein (MOG) IgG was negative.
Repeat MRI 3 months later demonstrated no change, and his vision
worsened. CT of the chest showed hilar adenopathy. Mediastinal lymph
node biopsy showed non-necrotizing granulomas diagnostic of
sarcoidosis (FIGURES 3-7C and 3-7D). Chronic oral prednisone improved
his vision to 20/30.
COMMENT Subacute painless vision loss is an unusual presentation for optic neuritis
associated with longitudinally extensive optic nerve lesions (ie,
neuromyelitis optica (NMO) spectrum disorder or MOG-IgG optic neuritis).
Progressive decline in this patient and persistent enhancement of the
optic nerve months after presentation prompted additional investigation
for alternative inflammatory disorders. Because of the common pulmonary
involvement in sarcoidosis, a chest CT was performed and hilar
adenopathy was identified. Hilar lymph node biopsy was diagnostic of
sarcoidosis, and the patient improved with chronic steroid therapy.
1254 OCTOBER 2019

corticosteroids (0.5 mg/kg/d to 1.0 mg/kg/d) are the most common approach to
initial therapy, although an initial administration of 3 to 5 days of IV
methylprednisolone (1 g/d) may be warranted based on the acuity and severity
of vision loss.29,73,74 Prolonged immunosuppression with steroid-sparing agents
such as azathioprine, methotrexate, tumor necrosis factor-a inhibitors, and
mycophenolate mofetil may be necessary to address breakthrough disease or
steroid dependence. Final visual acuity varies significantly, and improvement
does not correlate with initial MRI findings.29
Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (previously known as Wegener granulomatosis)
is a multisystem small vessel granulomatous vasculitis that commonly
FIGURE 3-7
Findings of the patient in CASE 3-3. A, Fundus photography of the left eye revealing optic disc
pallor. B, Axial fat-suppressed postcontrast T1-weighted MRI showing longitudinally extensive
enhancement of left optic nerve. C, Low-magnification image of hilar lymph node biopsy
stained with hematoxylin and eosin (H&E) showing replacement of the normal lymph node
architecture by multiple small, well-defined, non-necrotizing granulomas of relatively uniform
sizes and shapes that coalesce with variable degrees of fibrosis. D, High-magnification image
of granuloma showing cytologic features of the epithelioid histiocytes.
Panels C and D courtesy of Jeffrey Schowinsky, MD.

OPTIC NEURITIS
presents with sinonasal, respiratory, and renal disease.77 Approximately 30%

of patients with granulomatosis with polyangiitis are reported to have ocular
involvement,78 and, in rare cases, the disease may be limited to the eye.79
Granulomatosis with polyangiitis may occur across all age groups, with a peak
incidence between 64 and 75 years of age. Granulomatosis with polyangiitis
has no sex predilection, and the disease can be seen in all racial and ethnic
groups. The upper respiratory tract is most frequently involved; however,
lower respiratory involvement with cough, dyspnea, and hemoptysis is
common. Renal involvement may not be evident at disease onset, but
glomerulonephritis usually develops within the first 2 years of disease.
CNS involvement occurs in one-third of patients, and signs include peripheral
neuropathy, cranial neuropathy, seizure, stroke, and ophthalmoplegia.80
The optic nerve is infrequently involved in granulomatosis with polyangiitis,
and both retrobulbar optic neuritis and optic perineuritis have been reported.81,82
Loss of visual acuity is generally severe; however, improvement in vision has
been reported with corticosteroids and immunosuppression in a limited number
of cases. Compressive and ischemic optic neuropathies have also been
described.78 Additional ophthalmic and neuro-ophthalmic features of
granulomatosis with polyangiitis include ulcerative conjunctivitis, dacryoadenitis,
orbital cellulitis, uveitis, vitreitis, vasculitis, chorioretinal ischemia, central retinal
vein occlusion, and diplopia. Ocular manifestations, such as necrotizing scleritis,
are indicators of both increased morbidity and mortality.78 The diagnosis of
granulomatosis with polyangiitis may be made with objective evidence of two or
more features of disease in the kidneys, lungs, and nasal sinuses.77 With systemic
disease, 80% to 90% of patients will have positive c-ANCA. The vast majority of
c-ANCA autoantibodies are directed against proteinase-3, and the remainder are
against myeloperoxidase. Because of high mortality risk, treatment regimens
typically combine high-dose corticosteroids with immunosuppressants such as
cyclophosphamide, methotrexate, rituximab, and tumor necrosis factor-a
inhibitors.77,78
INFECTIOUS OPTIC NEURITIS

Direct infection of the optic nerve is a rare cause of optic nerve inflammation.
Infectious optic neuritis, however, is important to identify as rapid initiation of
appropriate antimicrobial, antiviral, antifungal, or antiprotozoal agents may
be important for preventing further vision loss, facilitating visual recovery, or
treating concurrent systemic or CNS disease. Optic neuritis occurring in
conjunction with fever, meningitis, cranial nerve palsies, and encephalitis
should always raise concern for an infectious cause. A detailed history
regarding infectious risk factors and travel history may help to focus on
probable agents. On examination, concurrent papillitis may result in severe
optic disc edema with a macular star, and concurrent ocular inflammation
may generate signs of uveitis, retinitis, and chorioretinitis. A complete review
of infectious optic neuritides is beyond the scope of the current review;
however, the following sections focus on some common presentations and
infectious agents.
Neuroretinitis
Infectious optic neuritis frequently results in neuroretinitis, a term that describes
optic disc edema in combination with a starlike pattern of lipid exudate in the
1256 OCTOBER 2019

macula and fovea (FIGURE 3-8). Multiple bacterial, spirochetal, viral, fungal, and KEY POINTS
protozoal infections of the optic nerve may result in neuroretinitis, including
● Angiotensin-converting
Bartonella, Rickettsia, spirochetes, Coxsackievirus B, HIV, histoplasmosis, and enzyme levels in the serum
toxoplasmosis.83 Although infectious agents are common causes of neuroretinitis, and CSF are notoriously
many cases are idiopathic since any cause of significant leakage from the optic insensitive for
disc may result in outer retinal exudates. Neuroretinitis has been reported with neurosarcoidosis. When
suspicious, CT chest, gallium
sarcoidosis, Behçet disease, and severe ischemic optic neuropathy and following
scan, or fludeoxyglucose
severe papilledema. Neuroretinitis is commonly preceded by a febrile illness, and positron emission
additional symptoms such as arthralgia, headache, rash, and lymphadenopathy tomography are
further support an infectious etiology in many cases. Vision loss is usually recommended for
identifying involved tissue
painless, and central or centrocecal field loss is most common.83,84 The macular
amenable to biopsy.
exudates (macular star) may not be evident for 2 to 6 weeks after initial
presentation and may take several months to resolve. OCT may demonstrate ● While multiple infectious
subretinal fluid, retinal thickening, or exudates in the outer plexiform layer agents have been associated
before they are evident on fundus examination.85 In most cases, vision loss with neuroretinitis, many
cases are idiopathic.
spontaneously resolves; however, visual recovery in recurrent disease is Exposure to common
less common.84 infectious causes should be
The most common cause of neuroretinitis is catscratch disease resulting from evaluated. When the
B. henselae infection. The majority of cases are transmitted by cat scratch or bite; infectious workup is
negative, alternative
however, transmission by dog has been documented. Vision loss may be mild noninflammatory causes of
or severe, and MRI of the optic nerves may show enhancement of the optic disc optic disc edema with a
and proximal nerve.86 Serum antibodies to Bartonella confirm exposure. The macular star should be
benefit of antibiotic therapy for Bartonella neuroretinitis is unclear.41 Antibiotic considered.
treatment may not be prudent except for cases with systemic infection, severe
vision loss, or immunocompromise.
Lyme Disease
Infection with the spirochete Borrelia burgdorferi may result in CNS infection
and either primary or secondary optic nerve injury. Primary infection of the
optic nerve may result in optic neuritis, neuroretinitis, papillitis, or ischemic
optic neuropathy.87,88 Secondary injury may result from papilledema due to
elevated intracranial pressure from Lyme meningitis. In Lyme optic neuritis,
vision loss is typically preceded
by signs of systemic infection:
headache, myalgia, and arthralgia.
Vision loss is typically painless,
varies from mild to severe (20/30
to count fingers vision), and is
often bilateral or consecutive. Disc
edema is common. Lyme optic
neuritis may show optic nerve
enhancement on orbital MRI and
nonspecific white matter lesions
on brain MRI.87 CSF will
demonstrate a lymphocytic
pleocytosis with intrathecal
synthesis of Borrelia-specific FIGURE 3-8
antibodies in the vast majority of Optic disc edema with partial macular star (macular
patients.89 Borrelia-specific IgM fan) due to neuroretinitis. Note the dilated venules
and IgG antibodies are usually due to venous compression from disc edema.

OPTIC NEURITIS
CASE 3-4 A 42-year-old man presented with 2 weeks of splotchy vision in the right
eye. He had noticed transient loss of vision in the right eye with postural
changes. He denied any eye pain but reported fever and body rash
5 weeks prior.
On examination, vision was 20/15 in both eyes with superotemporal
field loss in the right eye and a right afferent pupillary defect. Fundus
examination showed significant right optic nerve edema with associated
nerve fiber layer hemorrhages (FIGURE 3-9). He had increased lower
extremity tone, hyperreflexia, and bilateral extensor plantar responses.
MRI of the orbits showed mild T2-hyperintense signal in the right optic
nerve without gadolinium enhancement. Slit-lamp examination
showed iritis.
FIGURE 3-9
Funduscopy of the patient in CASE 3-4. Fundus photos demonstrate severe disc edema
with nerve fiber layer hemorrhages in the right eye. The left optic nerve is normal. The
diagnosis was optic neuritis due to syphilis.
COMMENT Visual field loss, transient visual obscurations, and significant disc edema
with hemorrhages and ocular inflammation are atypical for idiopathic optic
neuritis. While myelin oligodendrocyte glycoprotein (MOG) IgG commonly
causes significant disc edema, ocular inflammation is not observed with
MOG-IgG optic neuritis and MRI typically shows significant nerve
enhancement. This patient’s prior fever and rash, ocular inflammation, and
disc edema with hemorrhage suggest an infectious cause. The patient
acknowledged high-risk behavior for HIV and tested positive for HIV and
syphilis. He was treated with a 14-day course of IV penicillin G, and the disc
edema and visual field loss resolved over the next 3 months.
1258 OCTOBER 2019

detected in the blood; however, equivocal and negative tests during early disease KEY POINTS
should prompt retesting during the convalescent phase. Treatment is typically
● Optic neuritis with disc
with doxycycline for CNS involvement; however, parenteral ceftriaxone is often edema and cranial
recommended for late-stage disease.90 neuropathies should be
investigated for Lyme
Syphilis disease in endemic areas.
Infection with the spirochete Treponema pallidum may progress to involve the
● Syphilitic optic neuritis is
CNS in secondary and tertiary stages of disease. Syphilitic optic neuritis is clinical often associated with ocular
evidence of neurosyphilis independent of any additional neurologic findings. inflammation. Optic disc
Vision loss may be unilateral or bilateral; pain is uncommon. Papillitis and disc edema, when present, is
swelling are frequently observed, and the fundus examination may eventually usually prominent. A
detailed social history
demonstrate a macular star.91 Associated ocular inflammation is common.92 MRI identifying high-risk
of the orbits often shows perineuritis,93 in which enhancement is seen within behavior for HIV should be
the optic nerve sheath, but inflammation of the nerve may also be observed performed in suspicious
(CASE 3-4).94 Additional brain MRI abnormalities display a spectrum of cases.
meningovascular, inflammatory, and degenerative pathology.95 CSF typically
shows a lymphocytic pleocytosis with elevated protein and intrathecal IgG
synthesis. Testing for antitreponemal antibodies (eg, fluorescent treponemal
antibody absorption) should be performed in the blood and CSF. Lipid antigen
testing (Venereal Disease Research Laboratory [VDRL]) may be a better
reflection of disease activity but has low diagnostic sensitivity in the CSF. HIV
testing should be performed in patients suspected of having neurosyphilis, and
clinicians should be mindful that false-negative tests for antitreponemal
antibodies are common with concomitant HIV infection.91 Vision loss is usually
responsive to IV antibiotics. Treatment is generally with benzathine penicillin G;
however, long-term IV aqueous penicillin G is generally recommended for
syphilitic optic neuritis because of its outstanding CNS penetration.91
Viral Infections
Acute viral infection is an uncommon cause of isolated optic neuritis. Herpes
simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV),
Epstein-Barr virus (EBV), HIV, West Nile virus, dengue fever, mumps, measles,
and rubella infections have been implicated in cases of acute optic neuritis, many
with concurrent retinal, brain, or ocular inflammation.96 HSV optic neuritis may
occur concurrently with or following HSV encephalitis or acute retinal necrosis.
HSV optic neuritis is usually responsive to acyclovir; however, any additional
benefit to the use of concurrent methylprednisolone is uncertain. VZV papillitis
has been reported during primary VZV infection (chickenpox) and secondary
reactivation (zoster). Vision loss is usually bilateral with primary infection and
unilateral following zoster ophthalmicus. Onset after zoster may be delayed by
weeks. The role of corticosteroids and antivirals again remains uncertain.
Visual recovery is generally good but is limited in cases associated with posterior
outer retinal necrosis.
CMV- and EBV-associated optic neuritides are rare. CMV papillitis is typically
associated with CMV retinitis in patients who are immunocompromised. EBV
optic neuritis is generally bilateral and retrobulbar, but papillitis, chiasmitis, and
neuroretinitis cases have been reported. Most cases of EBV-associated optic
neuritis respond to corticosteroids. Primary HIV infection of the optic nerve is
rare but, in some cases, may be the initial manifestation of disease. Presentations
include retrobulbar optic neuritis, papillitis, and neuroretinitis. Mosquito-borne

OPTIC NEURITIS
KEY POINTS arboviruses and flaviviruses (West Nile virus, dengue fever, chikungunya virus,
Rift Valley fever) may cause acute optic neuritis often in association with
● Optic neuritis due to
direct viral infection is rare.
chorioretinitis and other signs of ocular inflammation. Signs of systemic infection
Clinical and examination are common, and visual prognosis is generally good except for dengue fever. Rare
clues include recent zoster cases of optic neuritis have been reported with acute mumps, rubella, and
ophthalmicus, encephalitis, measles virus infections; vision generally recovers with corticosteroid treatment.
immunosuppression, risk for
mosquito-borne illness, or
associated retinitis or Tuberculosis
chorioretinitis. CNS infection with Mycobacterium tuberculosis is an infrequent cause of
inflammatory optic neuropathy. Affected individuals typically reside in or have
● Optic neuritis from traveled to an endemic area. The most common presentation of optic neuritis
tuberculosis is often
associated with uveitis associated with tuberculosis is papillitis.97 Neuroretinitis and retrobulbar optic
and orbital apex syndrome. neuritis are less common. Optic nerve involvement is frequently accompanied
MRI brain findings by posterior uveitis or panuveitis; the orbital apex syndrome is also frequently
include leptomeningeal observed. The onset of vision loss may be acute or insidious, with roughly half of
enhancement, ependymitis,
abscess, infarct,
the patients displaying a chronic course. Loss of visual acuity at presentation may
encephalitis, and tubercles. vary from mild (20/30) to severe (<20/200), and the most common pattern of
visual field loss is an enlarged blind spot. Vision loss from CNS tuberculosis
may also arise from tubercular meningitis resulting in hydrocephalus, optic
chiasmatic arachnoiditis, and compression of either the optic nerve or chiasm
due to tuberculomas.96 Tuberculous optic perineuritis may be evident on
orbital imaging.98
MRI of the brain may show a constellation of pathology ranging from
leptomeningeal enhancement to abscesses and tuberculomas.99 CSF will typically
show a chronic mixed pleocytosis with elevated protein and low glucose.100 CSF
polymerase chain reaction (PCR) for M. tuberculosis is a rapid and sensitive
method for diagnostic confirmation.100 Antituberculosis medications are often
effective in improving vision, with roughly 75% of patients reaching 20/40 vision
or better. Davis and colleagues97 did not report any benefit to visual recovery
with the additional use of corticosteroids.
CONCLUSION
Optic neuritis may result from a diverse number of inflammatory and infectious
conditions. Subacute, painful vision loss accompanied by an afferent pupillary
defect should routinely raise concern for optic neuritis. Nevertheless, vision loss
may sometimes be chronic and painless, especially with granulomatous
inflammation or certain infections. Idiopathic optic neuritis associated with MS is
often self-limited and has a strong chance of recovery. Inflammatory optic
neuropathies associated with MOG-IgG disease and NMOSD, however, are
typically more severe and often recur without prophylactic therapy. Importantly,
NMOSD optic neuritis has a lower probability of visual recovery, and early
intervention with plasma exchange may enhance visual recovery.
Moving forward, optimal visual recovery from acute optic neuritis may
require treatment decisions before a definitive serologic, molecular, or
histopathologic diagnosis. Therefore, clinicians must be aware of pertinent
fundus, neuroimaging, and laboratory data that favor various inflammatory or
infectious etiologies. Aggressive anti-inflammatory therapy coupled with
targeted immunosuppression and/or antibiotics is likely to become the standard
for minimizing short- and long-term vision loss from optic neuritis.
1260 OCTOBER 2019

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1264 OCTOBER 2019

Toxic-Metabolic REVIEW ARTICLE

and Hereditary Optic C O N T I N U UM A U D I O
ONLINE
Neuropathies
By Cristiano Oliveira, MD
ABSTRACT
PURPOSE OF REVIEW: The diagnosis of visual loss from toxic-metabolic and
hereditary optic neuropathies may be delayed in some cases because of a
failure to elicit important information in the clinical history or to recognize
typical examination findings. An understanding of the features specific to
each type of toxic-metabolic and hereditary optic neuropathy, and of the
underlying mechanism of insult to the optic nerve, could lead to earlier
recognition, diagnosis, and treatment (when available).
RECENT FINDINGS:Understanding of the role of mitochondria in toxic-

metabolic and hereditary optic neuropathies is growing, particularly
regarding the mechanism of insult of certain agents (medications and
toxins) and of vitamin B12 deficiency. New developments in the quest for
treatment for hereditary optic neuropathy, specifically Leber hereditary
optic neuropathy, are being seen.
SUMMARY: Toxic-metabolic and hereditary optic neuropathies present in a

similar fashion, with painless, progressive, bilateral visual loss with
dyschromatopsia and cecocentral visual field defects. The associated
CITE AS:
retinal ganglion cell and axonal loss is typically due to mitochondrial
dysfunction caused by an exogenous agent (toxic), by insufficient or 25(5, NEURO-OPHTHALMOLOGY):
deficient substrate (metabolic or nutritional), or by abnormal proteins or 1265–1288.
mitochondrial structure determined by a genetic mutation (hereditary).

Address correspondence to
Dr Cristiano Oliveira, 1305 York
Ave, 11th Floor, New York, NY,
10021, cro9004@med.cornell.
INTRODUCTION edu.
R
egardless of the underlying etiology, the visual dysfunction in
optic neuropathies is characterized by loss of visual acuity, RELATIONSHIP DISCLOSURE:
Dr Oliveira reports no disclosure.
dyschromatopsia (color vision dysfunction), and visual field
loss/defect. Toxic-metabolic and hereditary optic neuropathies, with UNLABELED USE OF
few exceptions, present with these findings bilaterally and fairly
USE DISCLOSURE:
symmetrically. In addition to bilateral involvement, a pattern of visual field Dr Oliveira discusses the
defect with central or cecocentral (defect extending from center to the unlabeled/investigational use of
gene therapy and idebenone
physiologic blind spot) scotomas should raise a concern for toxic-metabolic and for Leber hereditary optic
hereditary optic neuropathies. neuropathy.
The underlying mechanism of axonal and retinal ganglion cell injury in
toxic-metabolic and hereditary optic neuropathies is, primarily, the result of © 2019 American Academy
some degree of mitochondrial dysfunction. This can be due to an exogenous of Neurology.

TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES
FIGURE 4-1
Oxidative phosphorylation in the mitochondrial respiratory chain located within the inner
membrane, with subunit polypeptide complexes (I through V). The exchange of electrons in
oxidation and reduction reactions in complexes I through IV generate an electrochemical
gradient across the inner mitochondrial membrane allowing the conversion of adenosine
diphosphate (ADP) to adenosine triphosphate (ATP) by complex V (ATP synthase). Also
demonstrated here are the locations in which different causes of toxic-metabolic and
hereditary optic neuropathy cause mitochondrial dysfunction.
DOA = autosomal dominant optic atrophy; e = electron; H = hydrogen proton; LHON = Leber
hereditary optic neuropathy; mtDNA = mitochondrial DNA; NAD = nicotinamide adenine
dinucleotide, reduced form; NADH = nicotinamide adenine dinucleotide, oxidized form.
agent (toxic), insufficient or deficient substrate (metabolic or nutritional), or

abnormal proteins or structure of the mitochondria determined by a genetic
mutation (hereditary). As proposed by Sadun and Wang,1,2 mitochondrial optic
neuropathy seems to be an appropriate umbrella under which to include these
groups of optic neuropathies, divided into genetic mitochondrial optic neuropathies
(Leber hereditary optic neuropathy and autosomal dominant optic atrophy) and
acquired mitochondrial optic neuropathies (nutritional, toxic, and mixed).
THE ROLE OF MITOCHONDRIA

Mitochondria are double membrane–bound organelles found in most eukaryotic
cells, with the essential role of providing most of the cell’s energy requirements in
the form of adenosine triphosphate (ATP). According to the endosymbiotic
theory, mitochondria were once aerobic prokaryotic cells that were gradually
assimilated by glycolytic bacteria in a symbiotic relationship.3
Oxidative phosphorylation, the process of ATP production, takes place in
the mitochondrial respiratory chain, which is constituted by four subunit
1266 OCTOBER 2019

polypeptide complexes (I through IV) and located within the inner membrane of KEY POINTS
the organelle. The exchange of electrons in oxidation and reduction reactions
● Optic neuropathies
along the complexes of the respiratory chain releases energy that is used to present with visual acuity
generate an electrochemical gradient across the inner mitochondrial membrane, loss, dyschromatopsia
which allows the conversion of adenosine diphosphate to ATP by complex V (color vision dysfunction),
(ATP synthase) (FIGURE 4-1).4 Free radicals are highly reactive molecular and visual field defect.
Toxic-metabolic and
fragments that can cause oxidative cellular damage, some of which are derived
hereditary neuropathies
from oxygen and therefore known as reactive oxygen species. Superoxide, should be considered when
which is the primary reactive oxygen species, is formed during oxidative vision loss is bilateral,
phosphorylation when leaked electrons bind to ubiquitous oxygen. The particularly when central or
cecocentral (central defect
mitochondria end up being a major generator of reactive oxygen species and,
extending to the physiologic
consequently, the main target of oxidative damage.4 blind spot) visual field loss
Mitochondria have their own genome (a circular, double-stranded is present.
molecule). The mitochondrial DNA accumulates mutations at a faster rate
than the nuclear genome because of the absence of protective histones and ● The underlying
mechanism of retinal
effective repair mechanisms, its high replication rate, and the close exposure ganglion cell and axonal loss
to respiratory chain complexes with high levels of reactive oxygen species. in toxic-metabolic and
Despite having their own genome, the majority of the structural and functional hereditary neuropathies is
subunits of the mitochondria are encoded by the nuclear DNA. Each mitochondrial dysfunction
caused by an exogenous
one of the respiratory chain complexes has subunits encoded by both agent (toxic), insufficient
mitochondrial DNA and nuclear DNA. Thus, mitochondrial-related disorders or deficient substrate
can be the product of both primary mitochondrial DNA mutations and (metabolic or nutritional),
nuclear DNA mutations, both compromising the production of mitochondrial or abnormal proteins or
structure of the
proteins.3,4
mitochondria determined
Retinal ganglion cell and axon loss seems to be the result of a double-hit by a genetic mutation
mechanism related to mitochondrial dysfunction. Specifically, a decline in ATP (hereditary).
production, an increase in free radicals, and consequent oxidative stress lead
to injury of these highly metabolic neurons. The ATP generated by the ● The mitochondria are
responsible for adenosine
mitochondria is mainly used for axon organelle transport that is driven by the triphosphate production via
motor proteins kinesin and dynein, and for ion pumps dependent on oxidative phosphorylation
sodium-potassium-adenosine triphosphatase (ATPase)–mediated membrane that occurs in the
repolarization. Therefore, mitochondrial dysfunction causing ATP deficit respiratory chain
polypeptide complexes.
compromises the above functions.1,2,4 Superoxide causes oxidative damage when They are also the major site
combined with molecules such as nitric oxide, reacting directly with proteins and of production of free
nucleic acid. Superoxide is scavenged by three isoforms of superoxide dismutase radicals, which are highly
(SOD): intracellular SOD-1, mitochondrial SOD-2, and extracellular SOD-3. In reactive molecular
fragments that can cause
addition to oxidative damage, superoxide also signals the death of the retinal oxidative cellular damage.
ganglion cell body when the axon is injured.5
VULNERABILITY OF THE PAPILLOMACULAR BUNDLE

The human optic nerve is composed of 1.2 million retinal ganglion cell axons.
Within the eye, up to the level of the lamina cribrosa, these axons are
unmyelinated, providing a transparent media. A cecocentral visual field defect
(central field loss that extends to the physiologic blind spot) is the result of
injury to the retinal ganglion cells and their axons that form the papillomacular
bundle, which is located between the perineural macula and the optic disc
(FIGURE 4-2).
Most of the ATP used for axon conduction is consumed by the sodium-
potassium-ATPase, which renormalizes the sodium and potassium concentrations
following an action potential. Unlike the myelinated retrolaminar portion of

each retinal ganglion cell axon

that uses saltatory conduction,
the unmyelinated prelaminar
segment depolarizes through the
length of its segment and,
therefore, demands greater ATP
for reestablishment of the
polarized state.
The small diameter of the
papillomacular bundle axons is
thought to be the basis of their
greater vulnerability. As
discussed by Sadun and Wang,1,2
FIGURE 4-2 ATP is essential for organelle
Dilated fundus photo of the right eye with graphic transport from the soma down
representation of the papillomacular bundle (red), the axon, and, therefore, the
the retinal ganglion cell axons between the fovea
(F), and the optic disc. The fibers represented in
presence of mitochondria at the
blue are not part of the papillomacular bundle and unmyelinated segments of the
originate from retinal ganglion cells temporal to axons is critical. As a result,
the fovea. mitochondrial dysfunction and
the associated ATP deficiency
impair axonal transport. This
creates a vicious cycle in which decreased mitochondrial transport leads to
further ATP deficit, eventually causing a total shutdown of axonal transport.
Small-diameter and frequently firing fibers, such as the papillomacular axons,
are more prone to enter this vicious cycle, resulting in cellular dysfunction
and death.
Since superoxide is a by-product of ATP production, its formation is
proportional to the ATP demand of the axon based on the activity of the
sodium-potassium-ATPase pump. The enzymatic clearance of superoxide by
SOD, on the other hand, is proportional to the axon volume. Therefore, the
papillomacular axons suffer from an imbalance between superoxide production
and their ability to clear it compared to large-diameter fibers. This mismatch
alone does not seem to be enough to explain the greater vulnerability of those
axons, and some additional anatomic/mechanical factors, such as the fiber
density and the area where they enter the disc, are likely contributory.2,5
TOXIC AND METABOLIC OPTIC NEUROPATHIES

Toxic and metabolic (nutritional) optic neuropathies are discussed together,
since they both present with slowly progressive, painless visual loss in both eyes.
In addition to the pattern of visual loss, a careful history is essential to elicit
information regarding ongoing or previous toxic exposure (medications or other
substances), prior surgery (bariatric or gastrointestinal resections and bypass),
and dietary habits/restrictions.
Toxic Optic Neuropathies

Exogenous substances, such as antibiotics, antiarrhythmics, and anti-
inflammatory medications, can cause mitochondrial dysfunction by interfering
with one or more complex subunits in the electron transport chain. More
substances than those discussed below have the potential to disrupt
1268 OCTOBER 2019

mitochondrial oxidative phosphorylation and cause toxic optic neuropathy KEY POINTS
(FIGURE 4-1). Here, the agents with better established associations with this type
● Mitochondrial
of optic neuropathy are emphasized. dysfunction leads to
damage of retinal ganglion
ETHAMBUTOL. With 1 million new cases of tuberculosis reported worldwide cells and their axons through
each year and approximately 55% of those patients taking ethambutol, the a double-hit mechanism.
The first hit results from
estimated annual incidence of ethambutol-associated toxic optic neuropathy is
impaired axon organelle
100,000.6 As a metal chelator, ethambutol destroys bacteria by inhibiting transportation and impulse
arabinosyl transferase, which is important in mycobacterial wall synthesis. In conduction due to
mammalian mitochondria, ethambutol disrupts oxidative phosphorylation and adenosine triphosphate
deficit, and the second hit
mitochondrial function by interfering with iron-containing complex I and
results from superoxide-
copper-containing complex IV and with the function of cytochrome c oxidase, induced oxidative
which has copper as a cofactor.7 Ethambutol also promotes oxidative damage, damage and signaling
thereby raising levels of superoxide in retinal ganglion cells, as demonstrated in of apoptosis.
vitro and in animal models.5
● The papillomacular
Ocular toxicity is dose related and more likely to occur in patients receiving bundle is formed by the
daily doses of 25 mg/kg/d or greater. It has been reported in 50% of patients retinal ganglion cell axons
treated with 60 mg/kg/d to 100 mg/kg/d, in 5% to 6% taking 25 mg/kg/d, located between the
and in 1% taking the recommended therapeutic dose (15 mg/kg/d to 25 mg/kg/d). perineural macula and the
optic disc, and its injury
Although toxicity is also related to the duration of treatment, typically occurring results in cecocentral visual
2 to 8 months after starting therapy, an idiosyncratic reaction within 3 days of field loss. The small
therapy with the standard dose has been described.8 Because of renal excretion, diameter of the
dose adjustment is necessary in patients with renal dysfunction.9,10 papillomacular bundle
axons is thought to be the
In addition to the expected cecocentral field loss from papillomacular bundle
basis of their greater
involvement, some patients may exhibit a pattern of bitemporal field defects. vulnerability when facing
Some authors have found no MRI evidence of optic chiasm pathology,11 whereas adenosine triphosphate
others described the findings of T2-hyperintense signal in the chiasm, which deficit and increased
superoxide production in
resolved after the medication was discontinued.12 The latter suggests that
the setting of mitochondrial
ethambutol toxicity may affect multiple regions in the visual pathway. Multifocal dysfunction.
electroretinography has revealed low-amplitude responses in nasal regions
corresponding with temporal visual field loss, suggesting a component of retinal ● Obtaining information
toxicity in some patients.13 regarding ongoing or
previous toxic exposure
Early diagnosis and withdrawal are key and may result in visual recovery. (medications or other
Visual decline is often seen even after therapy interruption, followed by substances), prior surgery
stabilization and, eventually, progressive improvement over months. Sustained (bariatric or gastrointestinal
and prolonged ethambutol treatment, typically over 6 months, may lead to resections and bypass), and
dietary habits/restrictions is
irreversible damage. Bouffard and colleagues14 reported the case of a patient with an essential step in the
ocular toxicity who recovered after cessation of therapy but had to resume investigation of patients
treatment later because of recurrence of multiresistant infection. Fortunately, presenting with bilateral
vision loss was avoided on resumption of therapy because of a dose adjustment to progressive visual loss.
3 times a week plus copper supplementation.14
Before or immediately after starting treatment, a baseline ophthalmologic
examination should be obtained, including visual acuity, color vision (using
formal color plates), and visual field testing, preferably with programs that
examine the central 10 degrees. The examination should be repeated at any
time if the patient develops visual symptoms. Otherwise, patients who are
asymptomatic and taking the recommended doses may be reexamined every 1 to
3 months. Closer monitoring with monthly examinations may be required for
patients with risk factors for toxicity, such as chronic renal failure, renal
manifestation of tuberculosis, malnutrition, and diabetes mellitus.9,10,15,16

LINEZOLID. A member of the group of oxazolidinone antibiotics, linezolid was

introduced in 2000 for the treatment of methicillin-resistant staphylococcus and
vancomycin-resistant enterococci. It inhibits protein synthesis by binding to the
50S ribosomal subunit. Since mitochondrial ribosomes are similar to those of
bacteria, they also are affected by the drug. Linezolid is usually well tolerated
within the period of 28 days; toxicity occurs with long-term use. The visual
outcome in cases of toxicity is usually favorable, with full recovery typically
occurring after discontinuation of the medication. Long-term use of the
medication may also cause peripheral neuropathy, which, unfortunately, tends
to be irreversible.2,17,18
CHLORAMPHENICOL. This older-generation antibiotic, which had a marked

decline in use after the 1980s because of high toxicity, is an option in
difficult-to-treat infections with antibiotic resistance to more widely used drugs.
As with other antimicrobials, toxicity occurs after a prolonged course and high
cumulative doses of the medication, particularly beyond 6 weeks and with
cumulative doses greater than 100 g. Like linezolid, it inhibits mitochondrial
protein synthesis by binding to the 50S ribosomal subunit. In addition to the
expected acute to subacute bilateral visual loss with cecocentral scotomas, the
optic nerves may be hyperemic with subtle edema of the retinal nerve fiber layer.
Immediate discontinuation may lead to full recovery. Supplementation with B
complex vitamins has been recommended as both a prophylactic and
therapeutic measure.2,17,18
OTHER ANTIBIOTICS. Fluoroquinolones have wide use in the treatment of

respiratory tract and urinary tract infections. No clear evidence of a direct effect
on mitochondrial function has been established, but fluoroquinolones have been
shown to increase reactive oxygen species production in mammalian cells at
clinically relevant doses. Two reports exist in the literature of toxic optic
neuropathy associated with ciprofloxacin, with visual recovery after discontinuation
of the medication. Interestingly, both patients also had a history of alcohol abuse
with some degree of liver dysfunction.
Aminoglycosides are used in complicated intraabdominal and urinary tract
infections, hospital-acquired pneumonia, and multidrug-resistant tuberculosis.
Again, like linezolid and chloramphenicol, aminoglycosides affect protein
synthesis, in this case by impairing translation proofreading, thus generating
altered proteins. They are more commonly known for nephrotoxicity,
ototoxicity, and neuromuscular blockade, but cases of optic neuropathy have
been reported.2,17
AMIODARONE. Amiodarone is an important and widely prescribed

antiarrhythmic with well-recognized ocular side effects, including the common
and benign verticillate keratopathy (corneal deposits forming a faint
golden-brown whorl pattern). An optic neuropathy with optic disc swelling and
visual acuity and field loss, similar to a nonarteritic anterior ischemic optic
neuropathy, may also occur. Unlike cases of nonarteritic anterior ischemic optic
neuropathy, which are typically monocular (although the fellow eye may be
affected subsequently), amiodarone-associated optic neuropathy presents
bilaterally in two-thirds of patients. It is still unclear if this is, in fact, an optic
neuropathy distinct from nonarteritic anterior ischemic optic neuropathy, which
occurs in the same population (typically elderly patients with vascular risk
1270 OCTOBER 2019

factors). In addition to more frequent bilateral involvement, amiodarone- KEY POINTS
induced optic neuropathy tends to have an insidious onset versus the acute loss in
● Ethambutol affects
nonarteritic anterior ischemic optic neuropathy, a protracted resolution of the mitochondrial function by
disc edema (months versus weeks in nonarteritic anterior ischemic optic interfering with complexes I
neuropathy), and no requirement for a small cup to disc ratio (disc at risk). The and IV and cytochrome c
optic neuropathy typically occurs within 1 year of treatment (mean treatment oxidase. The ocular toxicity
is dose related and more
duration of 9 months). No screening guidelines have been established, but,
likely to occur in patients
ideally, patients should undergo a baseline examination before starting treated with 25 mg/kg/d or
treatment, with frequent follow-ups in the first year of treatment and at least higher (dose must be
yearly ophthalmology visits thereafter. Direct communication with the adjusted for renal
insufficiency). In addition to
cardiologist for prompt substitution is important in the event the diagnosis of
the bilateral cecocentral
amiodarone-induced optic neuropathy is established. The majority of patients field defect, patients may
experience some improvement following discontinuation of the agent (58%), present with bitemporal
whereas 21% are unchanged and 21% have further visual decline.18–20 field defects, some with
evidence of chiasmal
ANTI–TUMOR NECROSIS FACTOR-α AGENTS. Anti–tumor necrosis factor-α abnormal signal. Early
diagnosis and drug cessation
(TNF-α) agents have been used to treated inflammatory diseases such as rheumatoid
are essential and may result
arthritis, inflammatory bowel disease, and refractory uveitis. Numerous reports in visual recovery.
describe an association between TNF-α inhibitors and demyelinating disorders,
including optic neuritis, which is typically unilateral. Controversy remains as to ● Antibiotics such as
whether such demyelination is a manifestation of the underlying autoimmune disease linezolid, chloramphenicol,
and ciprofloxacin have been
itself, a coexisting process unmasked by the medication, or a completely independent implicated in toxic optic
entity. Alexandre and colleagues21 described 12 cases of inflammatory optic neuropathies through
neuropathy seen in patients with inflammatory bowel disease, 80% of whom were inhibition of mitochondrial
taking anti–TNF-α. Most patients had unilateral and retrobulbar optic nerve protein synthesis.
involvement, with response to steroid treatment and a partial to complete ● Amiodarone has been
visual recovery.21 associated with an optic
neuropathy with optic disc
TACROLIMUS. The optic neuropathy associated with tacrolimus is usually swelling and visual acuity
bilateral and sometimes sequential. The level of visual dysfunction may vary and field loss, similar to
from mild subnormal visual acuity to no light perception, and the optic nerves nonarteritic anterior
ischemic optic neuropathy.
may look normal or be edematous or pale. When present, the optic disc edema
However, it is more often
may resemble nonarteritic anterior ischemic optic neuropathy. The bilateral, with an insidious
pathophysiology is still unknown. Because it is typically used to prevent rejection course and protracted
of transplanted organs, the decision to withdraw the medication may be resolution of the disc
edema.
challenging. Thorough investigation to exclude infectious and neoplastic
etiologies is particularly important in these patients given their ● Toxic optic neuropathies
immunosuppressed state.22 It is important to keep in mind that patients being due to tumor necrosis
treated with tacrolimus may develop visual symptoms secondary to posterior factor-α inhibitors and
reversible encephalopathy syndrome (PRES), including blurry vision, tacrolimus can be unilateral,
bilateral, or sequential.
homonymous visual field loss, and cortical blindness. However, the systemic As patients receiving
hypertension, other symptoms of PRES (such as altered mental status, seizures, these agents may be
and headaches), and MRI brain findings (typical vasogenic edema of the immunosuppressed, a
parietooccipital lobes) help differentiate the two entities.23,24 thorough investigation to
exclude infectious and
VIGABATRIN. Vigabatrin is an antiepileptic agent that is typically used for neoplastic etiologies is
particularly important.
treatment of infantile spasms. A pattern of bilateral visual field defects with
progressive concentric constriction, sparing central vision, has been observed in
15% to 31% of infants, 15% of children, and 25% to 30% of adults taking the
medication. Although visual loss in vigabatrin toxicity is primarily the result
of retinal accumulation of the medication or elevated levels of retinal

γ-aminobutyric acid (GABA), or both, it is important to mention the peculiar pattern

of binasal optic nerve pallor (with temporal sparing), which is presumably secondary
to the pattern of retinal atrophy sparing the papillomacular fibers that enter the disc
at its temporal side.18,25 Typically, patients taking vigabatrin should have baseline
ophthalmic examination, followed by reassessments every 3 months during continued
vigabatrin treatment and at 3 to 6 months after discontinuation.26
METHANOL. Methanol is converted to formate (formic acid), which directly

interferes with oxidative phosphorylation by inhibiting cytochrome c oxidase. In
addition to visual loss, methanol causes metabolic acidosis and potentially lethal
intoxication. Eye symptoms may be present within 6 hours of consumption.
Treatment focuses on correction of the metabolic acidosis and clearance of
TABLE 4-1 Common Agents Associated With Toxic Optic Neuropathies
Optic Nerve
Appearance at
Agent Tempo Laterality Presentation Additional Features Mechanism
Antimicrobials
Ethambutol Subacute Bilateral May be normal, Chiasmal involvement Disrupts oxidative

hyperemic with and bitemporal field phosphorylation
retinal nerve defect (complexes I and IV
fiber layer and cytochrome c
edema, or pale oxidase)
Linezolid Subacute Bilateral May be normal, Peripheral neuropathy Inhibits/affects

hyperemic with mitochondrial protein
retinal nerve synthesis
fiber layer
edema, or pale
Chloramphenicol Subacute Bilateral Hyperemic with Aplastic anemia Inhibits/affects

retinal nerve mitochondrial protein
fiber layer synthesis
edema
Aminoglycosides Subacute Bilateral May be normal, Nephrotoxicity and Inhibits/affects

hyperemic with ototoxicity mitochondrial protein
retinal nerve synthesis
fiber layer
edema, or pale
Fluoroquinolones Subacute Bilateral May be normal, In the setting of alcohol Inhibits mitochondrial
hyperemic with abuse and liver DNA synthesis
retinal nerve dysfunction
fiber layer
edema, or pale
1272 OCTOBER 2019

methanol and its metabolites using hemodialysis and competitive inhibition of
alcohol dehydrogenase.1,18 A prospective study of 16 patients with visual loss
from methanol toxicity treated with IV erythropoietin demonstrated that the
cytokine, known to have neuroprotective effects, may have a beneficial effect in
cases of toxic optic neuropathy due to methanol.27
TABLE 4-1 summarizes important aspects of the presentation of the toxic optic
neuropathy for each of the agents discussed.
Nutritional Optic Neuropathies

Although nutritional optic neuropathies are less prevalent in the United States
and Western Europe than in developing regions of the world, it is essential to
recognize individuals who are at greater risk of developing them even in these
Optic Nerve
Appearance at
Agent Tempo Laterality Presentation Additional Features Mechanism
Anti-inflammatories/
immunosuppressants
Anti–tumor necrosis Acute Unilateral Normal disc (pale Other MRI findings Demyelination
factor-α agents later on) consistent with
demyelination
Tacrolimus Acute to Unilateral, but May be normal, Posterior reversible Neurotoxic causing
subacute often with with disc edema, encephalopathy axonal edema, but
bilateral or pale syndrome (PRES) also ischemia
involvement
later on
Antiepileptics
Vigabatrin Subacute Bilateral Normal, followed Retinopathy with Retinal accumulation

by nasal pallor secondary optic disc of the medication
atrophy; initially sparing
the papillomacular
bundle and central
vision
Antiarrhythmics
Amiodarone Acute to May be Optic disc Similar to nonarteritic Uncertain, possibly

subacute unilateral; edema (with anterior ischemic optic ischemic
bilateral in two- subsequent neuropathy, but more
thirds of cases pallor) often bilateral, slow
resolution of the edema
Other
Methanol Acute Bilateral Hyperemic disc Metabolic acidosis Inhibits oxidative

with retinal nerve phosphorylation
fiber layer (cytochrome c oxidase)
edema
DNA = deoxyribonucleic acid; MRI = magnetic resonance imaging.

regions. These individuals include (but are not limited to) patients who have
undergone gastrointestinal bypass surgery, those with stringent dietary
restrictions, and those with a history of substance abuse, who may also be
malnourished. The clinical presentation is indistinct from most cases of toxic
optic neuropathy, with painless, bilateral, symmetric progressive loss of central
visual acuity, dyschromatopsia (color vision dysfunction), and cecocentral scotoma.
VITAMIN B 12 (COBALAMIN) DEFICIENCY. Cobalamin is an essential micronutrient

acquired through the consumption of animal products, such as liver, beef, fish,
and dairy, as well as fortified cereals. Digestion by stomach enzymes releases
cobalamin, which then binds to intrinsic factor, allowing it to be absorbed by the
distal ileum. Once separated from intrinsic factor, cobalamin is secreted to the
blood and stored in the liver.
Vitamin B12 deficiency can cause an array of hematologic and neurologic
symptoms. A macrocytic anemia may result and, rarely, a thrombocytopenia. A
myriad of neurologic manifestations may ensue, including subacute combined
degeneration of the spinal cord, which affects both the dorsal columns, leading to
vibration and position sense loss (and a sensory ataxia), and the lateral
corticospinal tracts, causing a spastic paresis. Other neurologic manifestations
include cognitive decline (through cortical dysfunction), a peripheral
neuropathy, and bilateral vision loss from optic neuropathy.
In 1980, Chester and colleagues28 described segmental temporal
demyelination of the retrobulbar optic nerves in monkeys with experimental
cobalamin deficiency, which they postulated as the site of injury in the optic
neuropathy due to vitamin B12 deficiency. They theorized that alterations in fatty
acid metabolism due to cobalamin deficiency disrupted myelin formation, with
secondary retinal ganglion cell loss by retrograde degeneration.28 A more recent
hypothesis for the underlying mechanism takes into account the evidence that
cobalamin, in addition to being an important cofactor for various enzymes, acts
as an intracellular superoxide scavenger, which is particularly important for
unmyelinated axons in the papillomacular bundle. As demonstrated by Chan
and colleagues,29 cobalamin is an endogenous SOD mimetic. As previously
discussed, since superoxide signals retinal ganglion cell apoptosis, superoxide
accumulation due to cobalamin deficiency leads to retinal ganglion cell and
axonal loss.5,29
It is very important to recognize patients and populations at risk for cobalamin
and other deficiencies. For example, children with autism spectrum disorders
may have stereotyped diets (refusing certain colors or texture) and may
present with progressive decline in behavior due to visual loss. Pineles and
colleagues30 described three patients with autism spectrum disorders found
to have cobalamin deficiency and elevated methylmalonic acid levels who
showed improvement of their visual behavior following parenteral
supplementation.
In addition to complete blood cell count and serum vitamin B12 level, serum
methylmalonic acid and homocysteine should be used to confirm deficiency in
patients with low-normal levels of vitamin B12. Replacement can be oral or via IM
injections, the latter being faster and indicated in severe deficiency. In case of
optic neuropathy and other neurologic deficits, 1000 mcg IM daily or every other
day is given for 1 to 2 weeks, followed by weekly injections until improvement is
observed and then 500 mcg to 1000 mcg IM monthly.31
1274 OCTOBER 2019

FOLATE DEFICIENCY. Although malnutrition often causes combined folic acid KEY POINTS
(folate in its ionic form) and vitamin B deficiencies, cases of optic neuropathy
● Vigabatrin causes retinal
caused by isolated folate deficiency with normal vitamin B12 levels have been toxicity and a peculiar
reported.32,33 Folic acid is required for the formation of tetrahydrofolate, which pattern of secondary optic
helps oxidize and eliminate formic acid. The accumulation of formic acid impairs nerve atrophy with nasal
ATP production via mitochondrial oxidative phosphorylation due to blocking of disc pallor sparing the
temporal region (spared
cytochrome oxidase.1
papillomacular bundle).
Patients present with
COPPER DEFICIENCY. Copper is involved in cell oxidation and signaling systems.
progressive concentric
It is absorbed in the stomach and duodenum, and its deficiency typically manifests constriction sparing
with hematologic (anemia and neutropenia) and neurologic (myelopathy and central vision.
peripheral neuropathy) disorders. Typical causes of copper deficiency include
inflammatory bowel disease, celiac disease, prolonged total parenteral nutrition, ● Nutritional optic
neuropathies have a clinical
and gastric bypass surgery. Additionally, chronic zinc ingestion can cause presentation indistinct from
copper deficiency due to interfering with copper absorption in the gut. With a most cases of toxic optic
presentation that is indistinct from other nutritional and toxic optic neuropathies, neuropathy and should be
it is important to include a serum copper level in the investigation of patients considered in patients who
have had gastrointestinal
with bilateral visual loss, dyschromatopsia, cecocentral scotoma, and optic disc bypass surgery, have
temporal pallor. Again, mitochondrial dysfunction and oxidative stress are stringent dietary
thought to be the underlying mechanism of retinal ganglion cell axon and soma restrictions, or have a
injury. No guidelines have been defined for replacement.34–36 history of substance
abuse and secondary
Combined Insult (Toxic Plus Metabolic) malnourishment.
Certain individuals may be subject to both toxic exposure and substrate ● Vitamin B12 (cobalamin) is
deficiency, with a negative synergistic effect on mitochondrial oxidative an intracellular superoxide
phosphorylation resulting in optic neuropathy. scavenger, which is
particularly important for
CUBAN EPIDEMIC OPTIC NEUROPATHY. In the early 1990s, an outbreak of optic unmyelinated axons in the
papillomacular bundle.
neuropathy in Cuba reached epidemic proportions, affecting close to 50,000 Cobalamin deficiency may
individuals. A quite uniform clinical presentation was observed, with visual cause superoxide
acuity loss, dyschromatopsia, cecocentral visual field defect, and loss of the accumulation, which is a
papillomacular bundle in both eyes, in association with swelling of the adjacent signal for retinal ganglion
cell apoptosis, therefore
arcuate nerve fiber layers. Patients reported subacute onset of bilateral visual loss causing retinal ganglion cell
and changes in color perception. Most patients were malnourished, with very and axon loss.
little or no consumption of animal protein or green leafy vegetables. Most
patients also smoked and drank heavily, including consumption of a homemade
rum that was found to have 1% methanol content. The epidemic was attributed
to both nutritional (vitamin B12 and folic acid deficiency) and toxic (methanol
and cyanide exposure) causes. Nutritional supplementation resulted in a reversal
and improvement in visual function of many patients, although many were left
with residual visual dysfunction.1,18,37
TOBACCO-ALCOHOL AMBLYOPIA. The term tobacco-alcohol amblyopia is

misleading as it is not a true amblyopia. Historically, an isolated presentation of
bilateral optic neuropathy attributed to the synergistic effects of tobacco and
alcohol was reported, but little evidence supports such an entity resulting from the
toxic effects of tobacco and alcohol alone. Many patients diagnosed as such were,
in fact, Leber hereditary optic neuropathy mutation carriers or had developed an
inflammatory optic neuropathy. Individuals who are heavy drinkers and smokers
tend to be malnourished as well, confounding the picture further. If this entity
truly exists, it is definitely a diagnosis of exclusion after a thorough workup.18

GENETIC PREDISPOSITION TO TOXICITY. Carriers of genetic mutations

determining mitochondrial dysfunction may be more vulnerable to both toxic
and metabolic optic neuropathies. Certain therapeutic agents that are not
typically associated with toxic optic neuropathy may cause visual dysfunction, to
a variable degree, in those individuals. A particular class of antiretroviral
medications, the nucleoside analogue reverse transcriptase inhibitors, which are
part of the combined therapy strategy for HIV infection known as highly active
antiretroviral therapy, has been reported to trigger visual loss in Leber hereditary
optic neuropathy carriers. The mitochondrial toxicity occurs by inhibition of
mitochondrial DNA replication and through mitochondrial DNA depletion.
Similarly, ethambutol has been implicated in the development of bilateral visual
loss in an individual harboring the 11778 mutation2 and in a patient with the OPA1
gene mutation.3
This highlights the importance of avoiding such medications in patients
known to have Leber hereditary optic neuropathy or OPA mutations but also
shows how challenging the interactions of nutrition, toxins (including
medications), and genetic factors may be, especially since, in most cases, the
carrier status is unknown at the time the individual presents with vision loss.
HEREDITARY OPTIC NEUROPATHIES

Proteins with key roles in mitochondrial oxidative phosphorylation and reactive
oxygen species scavenging are encoded by mitochondrial and nuclear DNA;
therefore, genetic mutations can result not only in optic neuropathy but also
account for other neurologic deficits, myopathies, and cardiac conduction
abnormalities.
Leber Hereditary Optic Neuropathy

One hundred and thirty years after von Graefe reported the first case of Leber
hereditary optic neuropathy, the first Leber hereditary optic neuropathy–
associated mitochondrial DNA mutation was discovered by Wallace and
colleagues38 in 1988. More than 90% of all Leber hereditary optic neuropathy
cases have been associated with one of the three primary mutations in different
NADH dehydrogenase genes located within the mitochondrial DNA, coding
for protein subunits of complex I electron transport chain. They are ND4
(m.11778G>A), ND1 (m.3460G>A), and ND6 (m.14484T>C), in the order they
were described. For simplification, they will be referred to by their locus
numbers, 11778, 3460, and 14484, respectively. Locus 11778 is the most prevalent
mutation, followed by 14484 and 3460. NADH dehydrogenase catalyzes the
oxidation of NADH. The electrons donated to complex I move down the electron
transport chain to complex II. At the same time, protons are pumped across the
mitochondrial inner membrane (from the matrix to the intermembrane space)
by complexes I, III, and IV, using the energy released by the oxidative reaction.
Those protons generate an electron gradient that is used by complex V (ATP
synthase) to convert adenosine diphosphate (ADP) to ATP (FIGURE 4-1).3,39,40
The typical clinical presentation of Leber hereditary optic neuropathy is sudden
unilateral painless central visual loss, although it is bilateral at presentation in 25%
of cases, with fellow eye involvement within weeks to months (CASE 4-1). More
than 90% of the carriers become symptomatic before 50 years of age, with peak
age of onset in the second and third decades of life. For reasons yet unknown,
more male carriers (50%) become symptomatic than female carriers (10%) with
1276 OCTOBER 2019

the same mutation (gender-biased penetrance). Although the presence of a KEY POINTS
primary mutation is the prerequisite for developing the disease, secondary factors
● Toxins and malnutrition
(genetic and environmental) are thought to be the basis for the variability in can have a synergistic
penetrance among the mutations and also within the same pedigree.3,39–41 effect, causing optic
The visual loss in Leber hereditary optic neuropathy may worsen over weeks neuropathy and visual loss.
to months, reaching levels of 20/200 or worse, and is accompanied by a central Carriers of genetic
mutations determining
scotoma, dyschromatopsia, and a relative afferent pupillary defect (if unilateral
mitochondrial dysfunction
or asymmetric). The dilated funduscopic examination may be completely normal may be more vulnerable to
or may show a hyperemic optic nerve with swelling of the retinal nerve fiber both toxic and metabolic
layer and tortuosity of the central retinal vessels, the latter being the only finding optic neuropathies.
observed in the fundus examination of the patient in CASE 4-1.42 Optic disc
● More than 90% of all
pallor, initially temporal, ensues within 6 weeks of the onset of visual loss. Leber hereditary optic
Pathologic cupping may be observed, particularly later in the course of the neuropathy cases have been
disease, as a result of more extensive retinal ganglion cell loss. It is not associated with one of the
uncommon to encounter patients with Leber hereditary optic neuropathy at this three primary mitochondrial
DNA mutations of genes
point in their disease (the chronic phase), when the optic nerve appearance is coding for protein subunits
similar to that of other chronic optic neuropathies of inflammatory, ischemic, or of complex I (m.11778G>A,
compressive etiology. Therefore, thorough investigation, including m.14484T>C, m.3460G>A),
neuroimaging, should be obtained even when a strong suspicion for Leber with the first being the most
prevalent mutation.
hereditary optic neuropathy is present.
Optical coherence tomography (OCT) analysis has provided valuable ● Leber hereditary optic
information regarding the pattern of axonal and retinal ganglion cell soma loss neuropathy presents with
via retinal nerve fiber layer thickness and ganglion cell–inner plexiform layer sudden unilateral painless
central visual loss with
thickness assessment. Increased retinal nerve fiber layer thickness is present in
fellow eye involvement
the asymptomatic state preceding visual loss in a pattern that first involves the within weeks to months
inferior temporal quadrant, corresponding to the papillomacular bundle, and (sequential optic
then progresses to involve the superior and nasal quadrants of the disc. Three neuropathy). More than 90%
months after the onset of visual loss, progressive thinning of the retinal nerve of the carriers become
symptomatic before
fiber layer ensues, beginning in the inferior temporal quadrant and later 50 years of age, with peak
spreading to superior and nasal quadrants.43 As reported by Balducci and onset in the second and
colleagues,44 ganglion cell–inner plexiform layer thickness changes begin as early third decades of life.
as 6 weeks before the onset of visual loss, first noted in the inner ring of the nasal
● In Leber hereditary optic
sectors, which corresponds to the soma of the papillomacular bundle axons neuropathy, dilated
(FIGURE 4-5). This is followed by a progressive thinning that occurs up to funduscopy may be
6 months after the onset of visual loss (FIGURE 4-6).44 completely normal or may
The visual prognosis is poor, given the level of visual impairment in most show a hyperemic optic
nerve with swelling of the
cases. Visual recovery is minimal and rare, with patients noticing small islands of
retinal nerve fiber layer and
vision within their central scotoma, which allow some scanning of visual targets. tortuosity of the central
The 14484 mutation is associated with the greatest likelihood for recovery (37% retinal vessels. Optic disc
to 50%), followed by the 3460 mutation (22%).39,45 temporal pallor is typically
seen within 6 weeks of onset
Additional clinical manifestations may include cardiac arrhythmias,
of visual loss, and cupping
peripheral neuropathy, dystonia, and ataxia, in which case the term Leber may also be observed.
hereditary optic neuropathy plus is used, and additional mitochondrial DNA
mutations are typically present.
Leber hereditary optic neuropathy mutation carriers, especially females, have
been found to have a greater risk of developing demyelinating disease (multiple
sclerosis–like).3 Although most patients with Leber hereditary optic neuropathy
have an unremarkable brain MRI, various abnormalities have been described.
T2-hyperintense white matter lesions are the most common, occurring in up to
one-fourth of patients with Leber hereditary optic neuropathy.46 In rare cases,

enlargement and enhancement of the optic tracts, chiasm, and optic radiations
have been described.47 Gray matter lesions, on the other hand, are extremely
rare, primarily seen in patients with Leber hereditary optic neuropathy plus
dystonia, implicating G11696A, G14459A, and T14596A mutations.48–50
Data from the prospective observation of a large pedigree of patients with the
11778 mutation in Brazil have disclosed preconversion subclinical changes in
CASE 4-1 A 24-year-old man was referred to the neuro-ophthalmology service

because of sudden painless visual loss in the left eye 5 days earlier. He
had no associated symptoms and no changes in the right eye. He was
otherwise healthy and was not taking any medications. His social history
was significant for cigarette smoking (5 to 10 cigarettes per day),
marijuana smoking a few times a week, and alcohol consumption on
weekends (binge drinking). He also had a family history of a maternal
uncle and his older brother becoming legally blind in their twenties.
His examination revealed normal visual acuity in the right eye (20/20)
and abnormal in the left (20/100), with left eye dyschromatopsia and a
relative afferent pupillary defect. The anterior segment and intraocular
pressure were normal in both eyes. Humphrey visual field testing was
normal in the right eye and showed a cecocentral scotoma in the left
(FIGURE 4-3). Dilated funduscopy disclosed normal optic nerves in both
eyes with retinal vessel tortuosity (FIGURE 4-4).
His family history of early blindness in his older brother and maternal
uncle and his social history were highly suspicious for Leber hereditary
optic neuropathy. Therefore, genetic testing was performed. Contrast-
enhanced MRI of his brain and orbits was also obtained and was
unremarkable. He was found to have the m.11778G>A mutation on the
NADH dehydrogenase gene located within the mitochondrial DNA. His
uncle and older brother later were tested and confirmed to have the
same mutation.
COMMENT This case demonstrates a typical presentation of acute unilateral painless

loss of central vision in a young adult patient. Leber hereditary optic
neuropathy typically manifests in young men in the second and third
decades of life, and exposure to alcohol, tobacco, and other substances
such as antibiotic and antiretroviral medications, may be the trigger to
phenotypic expression in individuals carrying the genetic mutation. The
pattern of sequential visual loss from optic neuropathy with cecocentral
scotoma should raise concern for Leber hereditary optic neuropathy.
Careful review of the family history is essential, searching for similar cases,
history of blindness, and bilateral visual impairment, particularly in younger
individuals.
1278 OCTOBER 2019

visual acuity and Humphrey visual field mean deviation, along with an increase
in circumpapillary retinal nerve fiber layer thickness (pseudoedema), which is
thought to be the result of a compensatory aggregation of mitochondria in the
nerve fibers in response to dysfunction. After symptomatic conversion, the visual
function and associated structural parameters continue to decline for about 8 to
10 months, longer than previously described.41
FIGURE 4-3
Humphrey visual field testing 24-2 of the patient in CASE 4-1 demonstrating normal testing in
the right eye and cecocentral scotoma in the left eye (right eye on the right and left eye
on the left). The designation 24-2 means testing up to 24 degrees from the center
temporally, superiorly, and inferiorly and 30 degrees from the center nasally.
FIGURE 4-4
Dilated fundus color photos of the right eye (on the left) and left eye (on the right) of the
patient in CASE 4-1, depicting normal-appearing optic nerves and retina but with retinal vessel
tortuosity, left eye greater than right.

KEY POINTS Although decreased ATP

production due to the primary
● Because of the level of
visual loss at presentation
Leber hereditary optic
and the infrequent visual neuropathy mutations has been
recovery, the visual demonstrated in vitro, it cannot
prognosis in Leber fully account for the pathogenesis
hereditary optic neuropathy
of the disease. It certainly cannot
is typically poor. Patients
with the 14484 mutation are explain why only the retinal
the most likely to recover, ganglion cells and their axons are
followed by those with the targeted. As previously
3460 mutation.
discussed, increased superoxide
FIGURE 4-5 production occurs as a result of
● No treatment has been Macular optical coherence tomography with
proven effective for ganglion cell layer (retinal cell bodies of the axons
the disruption of the electron
Leber hereditary optic forming the optic nerve) thickness map divided transport chain by the
neuropathy. The early use of into sectors in a patient with Leber hereditary dysfunctional complex I.
idebenone, an antioxidant optic neuropathy scanned 6 weeks before onset
that can transport electrons
Superoxide as a free radical can
of visual loss. Note that the thickness map detects
directly to complex III a localized defect in the inner ring of the
cause oxidative damage, but for
bypassing a dysfunctional inferonasal sector, represented in red, which is retinal ganglion cells it has
complex I, may be indicative of ganglion cell loss taking place before another more important
beneficial. Gene therapy vision loss.
trials are currently
deleterious role: signaling
IN = inferonasal; Inf = inferior; IT = inferotemporal; SN =
under way. superonasal; Sup = superior; ST = superotemporal.
apoptosis after axonal injury.
Reprinted with permission from Balducci N, et al, Br J The increased superoxide
● Most patients with and Ophthalmol.44 © 2016 BMJ Publishing Group Limited. production signals to the retinal
carriers of autosomal
ganglion cell soma that its axon
dominant optic atrophy
harbor mutations in the OPA1 was damaged when, in fact, it was not, therefore initiating a process of
gene, a nuclear gene on apoptosis.5
chromosome 3 that codes Although no treatment has been proven effective for Leber hereditary optic
for an inner mitochondrial neuropathy, hope has come from multiple research trials over the past few years.
membrane protein essential
for maintenance of the The sequential presentation of this disease provides a unique opportunity for
mitochondrial cristae investigation and therapeutic trials even before the second eye has been affected.
network. The mutation Furthermore, the target cells for potential treatments, the retinal ganglion
results in a decrease in cells, are fairly accessible, since drugs and gene therapy can be delivered via
adenosine triphosphate
production and increased
intravitreal injection. Finally, close monitoring of visual function (visual acuity,
formation of reactive color, and Humphrey visual field testing) can be accompanied by quantitative
oxygen species. assessment of structural changes using OCT.51,52
Idebenone is a benzoquinone related to coenzyme Q10, which works as an
● Typical patients with
antioxidant but can also transport electrons directly to complex III, bypassing
autosomal dominant optic
atrophy present with a a dysfunctional complex I. A randomized placebo-controlled double-blind study
history of insidious, of idebenone treatment for patients with Leber hereditary optic neuropathy
bilateral, painless loss of failed to meet its primary outcome. However, subgroup analysis suggested
visual acuity and color vision
that patients with discordant visual dysfunction at the beginning of the trial
beginning in the first or
second decades of life, with (perhaps indicative of an earlier stage of the disease) had better visual acuity at
cecocentral field loss and the end of the study compared to patients with more symmetric visual loss.53
the finding of optic disc Further analysis of the study population revealed that patients in the treatment
temporal pallor. Of patients arm experienced an improvement in tritan color vision (blue-yellow spectrum,
with autosomal dominant
optic atrophy, 50% to 75% which indicates the dysfunction is less likely to be of congenital nature) than
will experience further protan color vision (red-green spectrum) by week 12, but this effect did not
visual decline later in life, reach statistical significance by week 24. The additional analysis suggests that
and no spontaneous early use of idebenone may be beneficial to patients with Leber hereditary
recovery has been reported.
optic neuropathy.54 An ongoing single-arm open-label multicenter trial is
1280 OCTOBER 2019

FIGURE 4-6
Macular optical coherence tomography of two patients with Leber hereditary optic
neuropathy followed since before onset of visual loss. The progressive loss of reginal
ganglion cells is demonstrated by the progressive thinning both superimposed to the
macular scan and also on the map with the sectorial thickness in microns (superior,
superotemporal, inferotemporal, inferior, inferonasal and superonasal, clockwise
from the top of the circle).
CF = count fingers; m = months after onset of visual loss; w = weeks before onset of visual loss.
Reprinted with permission from Balducci N, et al, Br J Ophthalmol.44 © 2016 BMJ Publishing Group Limited.
assessing the efficacy and safety of idebenone (LEROS [Study to Assess the
Efficacy and Safety of Raxone in LHON Patients]).55
Gene therapy may be the most promising treatment modality for Leber
hereditary optic neuropathy. Viral vectors injected intravitreally are used to
insert exogenous DNA into the affected retinal ganglion cells. The dual
membrane of the mitochondria represents a challenge for exogenous DNA
insertion into its genome. This is bypassed by insertion and incorporation of
DNA into the nuclear genome; this is then transcribed into mRNA, which is then
released into the cytoplasm, where it is translated into a protein with an
incorporated target signal for translocation into the mitochondria (allotopic
expression). Once there, the protein is incorporated into complex I, replacing
the defective subunit and therefore improving mitochondrial function
(FIGURE 4-7).52
The preliminary results of an ongoing prospective open-label trial with
unilateral single-dose injection of viral vector with allotropic ND4 gene therapy
(low and medium dose) were encouraging. The results demonstrated that the
therapy is safe, with relatively mild adverse effects and spontaneous resolution.
Most notably, OCT showed stable retinal nerve fiber layer in the study eye,
whereas the fellow untreated eye showed progression of retinal nerve fiber layer
loss over the 1-year follow-up period; therefore, it was shown that the therapy
caused no direct harm and potentially provided a protective effect. More
patients need to be enrolled and followed to confirm these observations, and the
authors plan to include high-dose injection cohorts as well to determine dose
response.55–57

FIGURE 4-7
Gene therapy by allotopic expression. A viral vector is prepared carrying DNA with the
sequence for the production of a normal complex I protein subunit with a mitochondrial
target segment. The vector is injected into the cell and the DNA sequence is transcribed into
mRNA, which is later translated into the protein. The protein enters the mitochondria and is
incorporated into the respiratory chain (complex I), improving ATP production and decreasing
the formation of free radicals.
ATP = adenosine triphosphate; mRNA = messenger ribonucleic acid; mtDNA = mitochondrial
deoxyribonucleic acid; nDNA = nuclear deoxyribonucleic acid; P = phosphate; rAAV2/2-ND4 = recombinant
adeno-associated virus vector containing wildtype of gene Nd4; rRNA = ribosomal ribonucleic acid.
Figure courtesy of Marc Dinkin, MD.
As in other inherited diseases, genetic counseling should be part of the

management of patients with Leber hereditary optic neuropathy and should
include a discussion of the risk of transmission to subsequent generations and the
risk of relatives of developing the disease. While children of females who have
the mutation are expected to harbor the mutation as well, the offspring of males
with the mutation are spared, since mitochondria are maternally transmitted.
Because of its incomplete penetrance, the lifetime risk of visual loss in male
carriers with Leber hereditary optic neuropathy is 50% and in female carriers is
10%.3,52 Given their level of visual impairment and the impact of that impairment
in their quality of life,58 a referral for low-vision evaluation and services is
another important step in the care of these patients. Finally, both patients
with Leber hereditary optic neuropathy and their relatives who are potential
carriers should be counseled about refraining from tobacco use and heavy
alcohol consumption.3,45,58
1282 OCTOBER 2019

Autosomal Dominant Optic Atrophy KEY POINTS
Autosomal dominant optic atrophy, also known as Kjer optic atrophy after
● The assessment of
Dr Poul Kjer, who first described the entity,59 is another common inherited optic patients with a history of
neuropathy, with prevalence ranging from 1 per 12,000 (in the Danish progressive bilateral visual
population) to 1 per 30,000.60 The most common mutation responsible is in the loss and bilateral optic disc
OPA1 gene, a nuclear gene found on chromosome 3 (3q28-q29) that codes for a pallor should include a
thorough medical history
dynamin-related guanosine triphosphatase (GTPase). This inner mitochondrial
and examination, followed
membrane protein is essential for maintenance of the mitochondrial cristae by laboratory testing for
network. More than 200 OPA1 mutations have been reported in which their vitamins B12, B1, and B6;
dysfunctional protein products cause impairment of oxidative phosphorylation, folate; methylmalonic acid;
copper; and zinc and
a decrease in ATP production, and increased formation of reactive oxygen
contrast-enhanced MRI of
species, all leading to retinal ganglion cell apoptosis.61 A mutation in the OPA3 the brain and orbits. Genetic
gene (on chromosome 19) causes optic neuropathy, premature cataracts,62 and, testing is typically done as a
in cases of homozygous mutations (in a recessive pattern), an optic neuropathy subsequent step in the
plus Costeff syndrome (spasticity, extrapyramidal dysfunction, and cognitive workup.
deficit).63 The typical incomplete penetrance of autosomal dominant optic ● No proven treatment is
atrophy, along with highly variable clinical expression (intrafamilial and available for autosomal
interfamilial variation among families carrying the same mutation), results in a dominant optic atrophy.
spectrum of visual acuity ranging from 20/200 (or worse) to 20/20. Unlike in Routine follow-up
examinations to assess
Leber hereditary optic neuropathy, autosomal dominant optic atrophy has no visual acuity and color vision
gender bias.3,60,64 as well as Humphrey visual
The clinical presentation of autosomal dominant optic atrophy is field testing and optical
characterized by an insidious, bilateral, painless loss of visual acuity and color coherence tomography to
assess structural changes
vision beginning in the first or second decade of life, with cecocentral field loss
help ensure that patients are
and optic disc temporal pallor.3,60,64 Although it has a milder phenotype than following the natural history
Leber hereditary optic neuropathy, with overall better visual prognosis, 50% to of the disease and can
75% patients will experience further visual decline later in life.60 No spontaneous identify concurrent
pathology when deviation
recovery has been reported in autosomal dominant optic atrophy.
from the expected clinical
As with Leber hereditary optic neuropathy, OCT is useful in the diagnosis and evolution is seen.
follow-up of patients with autosomal dominant optic atrophy. Not surprisingly,
the average retinal nerve fiber layer and ganglion cell–inner plexiform thickness ● Although a 50% risk of
is smaller compared to controls, with a segmental decrease in retinal nerve fiber transmission to offspring
exists in autosomal
layer thickness in the temporal sectors and in ganglion cell–inner plexiform layer dominant optic atrophy,
thickness in the nasal sectors corresponding to the papillomacular bundle axons because of variable
and their cell bodies, respectively. Milder cases, with better visual acuity at penetrance, the risk of
presentation, may show ganglion cell–inner plexiform layer loss with fairly developing visual loss is 60%
to 88%. Even among those
preserved retinal nerve fiber layer thickness (CASE 4-2).65 who develop the disease,
The syndromic manifestation of OPA1 mutation, also known as the autosomal great variability may exist
dominant optic atrophy plus phenotype, is rare, with a prevalence estimated as 1 in the level of visual
per 250,000. In those cases, the penetrance of optic neuropathy is greater than dysfunction.
90%, and bilateral sensorineural hearing loss is the most common extraocular
manifestation.66 TABLE 4-2 summarizes the most common clinical features in
patients with syndromic autosomal dominant optic atrophy and their frequency.
With no proven treatment available, the management of patients with
autosomal dominant optic atrophy focuses on proper diagnosis, thoroughly
excluding potentially treatable etiologies of bilateral optic neuropathy, including
toxic-metabolic, inflammatory, and compressive entities. Routine follow-up
examinations to assess visual acuity and color vision as well as Humphrey visual
field testing and OCT allow the practitioner to further investigate and detect
alternative pathologic entities when a deviation from the expected natural

history of autosomal dominant optic atrophy is seen. Genetic counseling provides

the patient with the knowledge that the risk of transmitting the gene to offspring
is 50% and that those who inherit the mutation have a 60% to 88% risk of
manifesting the disease because of variable penetrance. The variability in
phenotypic expression of the disease (ie, the spectrum of visual dysfunction)
should also be conveyed.67 Patients should be referred for low-vision evaluation,
with some benefiting from visual aids. Finally, patients should be counseled
about the dangers of tobacco and alcohol consumption, the importance of a
balanced diet, and the risks associated with certain medications known to cause
mitochondrial dysfunction.
As discussed with Leber hereditary optic neuropathy, gene therapy is a novel
and promising therapeutic option. As the evidence for safety and efficacy of such
CASE 4-2 A 40-year-old man presented to the neuro-ophthalmology service with

slowly progressive, painless vision loss since his teenage years. A
detailed history failed to elicit exposure to toxic substances or
medications, risk factors, known nutritional deficiencies, or family history
of blindness or visual loss (particularly in younger relatives).
On examination, his visual acuity was 20/60 in the right eye and 20/80
in the left, with symmetric dyschromatopsia, no relative afferent
pupillary defect, and a normal intraocular pressure and anterior segment
in both eyes. Humphrey visual field testing disclosed cecocentral field
loss in both eyes (FIGURE 4-8), and dilated funduscopic examination
showed optic disc temporal pallor with cupping and loss of the temporal
neural rim (FIGURE 4-9). Optical coherence tomography revealed normal
average and segmental retinal nerve fiber layer analysis with diffuse
ganglion cell–inner plexiform layer loss in both eyes.
The extensive workup included serum testing for vitamins B12, B1, and
B6; folate; methylmalonic acid; copper; and zinc, which were within
normal limits, and a contrast-enhanced MRI of the brain and orbits was
unrevealing. Genetic testing for the autosomal dominant optic atrophy
mutation was submitted after the results of the above workup and was
positive for the OPA1 mutation.
COMMENT This case illustrates the typical history of progressive visual loss beginning
in the first or second decade of life in patients with autosomal dominant
optic atrophy. It is not uncommon for patients with autosomal dominant
optic atrophy to be diagnosed as adults, in the fourth or fifth decades of
life, after being evaluated by many providers. Some are initially diagnosed
with normal tension glaucoma because of the cupping and loss of temporal
rim, as observed in this case. In addition to adjusting to the visual loss,
patients may experience anxiety and frustration related to the uncertainty
about the diagnosis and prognosis. The differential diagnosis in this patient
also included toxic-metabolic and compressive etiologies of bilateral optic
neuropathy, which were investigated for during his workup.
1284 OCTOBER 2019

therapy in Leber hereditary optic neuropathy accumulates, one can expect that it
will be just a matter of time until similar progress is made in autosomal dominant
optic atrophy.
CONCLUSION
The hallmark feature of toxic-metabolic and hereditary optic neuropathies is
bilateral visual loss with central or cecocentral scotoma. A better understanding
of the potential causes and underlying mechanisms of insult should prepare
clinicians to elicit important information in the clinical history and recognize
typical examination findings. Early diagnosis is especially important in cases of
toxic-metabolic optic neuropathies, so that the inciting toxin or metabolic
FIGURE 4-8
Humphrey visual field testing of the patient in CASE 4-2 demonstrating bilateral cecocentral
scotomas (defect extending from the center to the blind spot that is temporal) (right eye
on the right and left eye on the left).
FIGURE 4-9
Optic disc photos of the right eye (OD) and left eye (OS) of the patient in CASE 4-2
demonstrating bilateral optic disc temporal pallor with cupping and loss of the temporal
neural rim.

TABLE 4-2 Major Clinical Features Observed in Patients With Autosomal Dominant
Optic Atrophy Plusa
95% Confidence Interval

b
Clinical Features n= % Lower Upper
Optic atrophy 89/104 85.6 77.5 91.2
Deafness 65/104 62.5 52.9 71.2
Ataxia 31/104 29.8 21.8 39.2
Neuropathy 31/104 29.8 21.8 39.2
Myopathy 37/104 35.6 27.0 45.2
Progressive external ophthalmoplegia 48/104 46.2 36.9 55.7
a
Reprinted with permission from Yu-Wai-Man P, et al, Brain.66 © 2010 The Authors
b
Meta-analysis of 104 OPA1 mutation carriers from 45 autosomal dominant optic atrophy plus families, which includes previously published data on
44 individuals from 18 autosomal dominant optic atrophy plus families.
derangement can be removed to prevent further decline in visual function and to

maximize the chance of recovery. Early diagnosis is now also essential in cases of
hereditary optic neuropathy, given the current advances in gene therapy.
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1288 OCTOBER 2019

Idiopathic Intracranial REVIEW ARTICLE

Hypertension C O N T I N U UM A U D I O
ONLINE
By Matthew J. Thurtell, MBBS, MSc, FRACP
ABSTRACT
PURPOSE OF REVIEW: Idiopathic intracranial hypertension is a syndrome of
increased intracranial pressure of unclear etiology that most often occurs
in obese women of childbearing age but can also occur in men, children,
and older adults. This article reviews the diagnostic criteria, clinical
features, neuroimaging findings, differential diagnosis, and management
options for this condition.
RECENT FINDINGS: Recent population studies have found that the annual
incidence of idiopathic intracranial hypertension is increasing in association
with obesity rates, whereas recent scientific studies indicate a possible
role for androgen sex hormones and adipose tissue in the pathogenesis of
the disease. Prospective clinical trials have demonstrated a role for weight
loss, acetazolamide, and topiramate in the management of mild disease. A
CITE AS:
recently begun randomized multicenter trial of surgical interventions will
provide insight into the indications for surgical intervention, optimal timing 25(5, NEURO-OPHTHALMOLOGY):
and choice of intervention, and long-term outcomes. 1289–1309.
SUMMARY: Idiopathic intracranial hypertension is a disorder producing Dr Matthew J. Thurtell,
symptoms and signs of increased intracranial pressure in the absence of an University of Iowa Hospitals &
alternative cause. The main goals of treatment are to preserve visual Clinics, 200 Hawkins Dr,
Pomerantz Family Pavilion,
function and alleviate symptoms, which can usually be achieved with a Iowa City, IA 52242,
combination of weight loss, medical therapies, and surgical interventions matthew-thurtell@uiowa.edu.
depending on the severity of symptoms and vision loss, response to
treatment, and subsequent clinical course. Dr Thurtell serves on the
editorial board of the Journal of
Neuro-Ophthalmology, receives
research/grant support from
the National Eye Institute
INTRODUCTION (U10-EY025990), and receives
I
diopathic intracranial hypertension (IIH; formerly known as pseudotumor book royalties from Oxford
cerebri or benign intracranial hypertension) is a syndrome of increased University Press.
intracranial pressure of unclear etiology that most often occurs in obese UNLABELED USE OF
women of childbearing age. Since IIH is a diagnosis of exclusion, other PRODUCTS/INVESTIGATIONAL
etiologies of increased intracranial pressure (TABLE 5-11) must be ruled out. A USE DISCLOSURE:
Dr Thurtell discusses the
number of diagnostic criteria for IIH have been proposed, but a diagnosis can unlabeled/investigational use
usually be confidently made in accordance with the modified Dandy criteria: of acetazolamide, furosemide,
methazolamide, and topiramate
(1) awake and alert patient; (2) symptoms and signs of increased intracranial for the treatment of idiopathic
pressure; (3) absence of focal signs on neurologic examination (although intracranial hypertension.
sixth and seventh nerve palsies are permitted); (4) normal diagnostic studies
(ie, neuroimaging and CSF evaluation), except for evidence of increased © 2019 American Academy
intracranial pressure (ie, a CSF opening pressure greater than 20 cm H2O with of Neurology.

IDIOPATHIC INTRACRANIAL HYPERTENSION
signs of increased intracranial pressure on neuroimaging); and (5) no other etiology

for increased intracranial pressure identified.2
The pathogenesis of IIH remains poorly understood and controversial.3 A
variety of mechanisms have been proposed, including blockage of CSF absorption
at the level of the arachnoid villi, perhaps as a consequence of or exacerbated by
cerebral venous hypertension secondary to transverse venous sinus stenosis.3
Given the increased incidence in women and strong association with obesity, sex
hormones (eg, androgens) and adipose tissue may play a role in the pathogenesis
of IIH.4
EPIDEMIOLOGY
IIH most commonly occurs in obese women of childbearing age. The incidence
of IIH is variable, being higher in geographic areas that have a higher prevalence
of obesity. A study published in 1988 reported an annual incidence of IIH of
about 1 per 100,000 in the general populations of Iowa and Louisiana.5 However,
a study published in 2017 reported that the incidence of IIH had more than
doubled from 1.0 per 100,000 (in 1990–2001) to 2.4 per 100,000 (in 2002–2014)
in Minnesota.6 The incidence increased to 22 per 100,000 in obese women aged
15 to 44 years.6 Of note, this study reported a strong correlation between IIH
incidence and obesity rates (R2 = 0.7).6 A high body mass index (BMI) was found
to be associated with increased risk of IIH in a multicenter case-control study
that compared women with newly diagnosed IIH to women with other neuro-
ophthalmic disorders.7 This study found that greater levels of weight gain were
associated with an increased risk of IIH, although an increased risk of IIH also
existed in women who were not obese (BMI <30) in the setting of moderate
weight gain.7
IIH can also occur, albeit much less commonly, in men, children, and older
adults. A 2017 study reported that the annual incidence of IIH in Minnesota
was 0.3 per 100,000 in men compared to 3.3 per 100,000 in women.6 However,
in the Idiopathic Intracranial Hypertension Treatment Trial, only four of the
165 participants (2.4%) were men; of note, patients who had diagnosed
untreated obstructive sleep apnea were excluded, which may partly account
for the low percentage of men recruited.8 The BMI of men with IIH is similar
to that of women with IIH, although men tend to be older at the time of initial
TABLE 5-1 Differential Diagnosis of Increased Intracranial Pressurea
◆ Intracranial mass: eg, tumor, hemorrhage

◆ Blockage of ventricular system (obstructive hydrocephalus): eg, tumor
◆ Blockage of CSF absorption (communicating hydrocephalus): eg, subarachnoid hemorrhage
◆ Obstruction of venous outflow: eg, cerebral venous sinus thrombosis
◆ Diffuse cerebral edema: eg, following head injury
◆ Increased CSF secretion: eg, choroid plexus tumor
◆ Idiopathic: eg, idiopathic intracranial hypertension
CSF = cerebrospinal fluid.

a
Modified with permission from Thurtell MJ, Tomsak RL.1 © 2019 Oxford University Press.
1290 OCTOBER 2019

presentation.9 IIH also occurs in children but is not common. In a 2017 British KEY POINTS
study, the annual incidence of IIH in children and adolescents (aged 1 to 16 years)
● Idiopathic intracranial
was 0.71 per 100,000.10 The incidence increased to 4.18 per 100,000 in obese hypertension is a syndrome
males aged 12 to 15 years and 10.7 per 100,000 in obese females aged 12 to of increased intracranial
15 years.10 Another large retrospective multicenter study confirmed a similar pressure that usually occurs
trend in children and adolescents, suggesting the presence of three distinct in obese women of
childbearing age.
groups of patients in this population: a young group that is not overweight, an
early adolescent group that is overweight or obese, and a late adolescent group ● Idiopathic intracranial
that is mostly obese.11 Only a small percentage of patients present at an older hypertension is a diagnosis
age (ie, >50 years of age).12 Although older patients with IIH are usually obese, of exclusion. Therefore,
they tend to have a more benign clinical course compared to their younger other etiologies of increased
intracranial pressure must
counterparts.12 be ruled out based on
clinical history,
CLINICAL FEATURES neuroimaging, and CSF
Patients with IIH usually present with symptoms and signs of increased examination.
intracranial pressure. Common symptoms include headache, transient visual ● The incidence of
obscurations, and pulse-synchronous (pulsatile) tinnitus, whereas common idiopathic intracranial
signs include papilledema with or without associated retinal hemorrhages, hypertension appears to be
folds, cotton wool spots, and exudates. increasing and is strongly
correlated with obesity
rates.
Symptoms
Headache is the most common symptom of IIH. In the Idiopathic Intracranial ● Greater levels of weight
Hypertension Treatment Trial, 84% of participants had headache at presentation, gain are associated with
although neck and back pain were often reported too.8 The headache of increased increased risk of idiopathic
intracranial hypertension,
intracranial pressure is typically a global headache that is most severe in the although the condition can
morning and is often aggravated by maneuvers that increase the intracranial also develop in the setting of
pressure (eg, Valsalva-like maneuvers), with associated nausea and vomiting. moderate weight gain in
However, many patients with IIH have headaches with features of other headache patients who are not obese.
disorders, such as migraine and tension headache.13,14 Some have a significant ● Headache is the most
rebound component to their headache due to excessive use of simple analgesic common symptom of
medications.13,14 Although headache is often disabling and associated with poor idiopathic intracranial
quality of life, headache disability (based on the Headache Impact Test-6 score) is hypertension. However,
many patients have
not correlated with CSF opening pressure.14 Furthermore, the headache may or
headaches that have
may not improve with lowering of intracranial pressure.14 features of other primary
Transient visual obscurations (TVOs) occur in about 68% of patients with headache disorders, such as
IIH.8,15 TVOs are characterized by a partial or complete loss of vision that lasts for migraine and tension
headache.
several seconds, followed by a rapid recovery of vision back to baseline. TVOs
can occur many times per day and are often precipitated by postural changes or ● Headache in idiopathic
Valsalva-like maneuvers. TVOs are thought to result from transient ischemia of intracranial hypertension is
the edematous optic nerve head. They are associated with higher grades of often disabling and
papilledema and were found to be a predictor of treatment failure in the associated with poorer
quality of life but is not
Idiopathic Intracranial Hypertension Treatment Trial.16 correlated with intracranial
Patients with IIH are less likely to report persisting visual symptoms than pressure and, thus, may not
TVOs at initial presentation.8,17 Some have blurred vision due to hyperopic improve with lowering of
shift (from shortening of the globe due to increased intracranial pressure) or intracranial pressure.
metamorphopsia (distortion of vision) due to retinal folds.18 While an observant
patient might notice an enlarged blind spot, many do not notice visual field loss.
Consequently, the visual field loss from papilledema can go unnoticed until it is
severe and irreversible, underscoring the importance of perimetry (visual field
testing) in the evaluation and monitoring of patients with IIH.17,19 Central vision

KEY POINTS (including visual acuity and color vision) is usually spared until late in the
disease course, although a small percentage of patients have a central visual
● Transient visual
obscurations are the second
field defect at presentation, usually due to retinal pathology, such as retinal
most common symptom of fluid or folds.20
idiopathic intracranial Pulse-synchronous (pulsatile) tinnitus occurs in about 52% to 60% of patients.8,17
hypertension. They are It may not be spontaneously reported; therefore, patients must be specifically asked
thought to result from
about its presence. Pulse-synchronous tinnitus can be unilateral or bilateral.21 While
transient ischemia of the
optic nerve head and are it is frequently intermittent, it can also be continuous.21 Since it can often be
associated with higher decreased with ipsilateral jugular compression and often resolves following
grades of papilledema. stenting of transverse venous sinus stenoses, it likely arises because of turbulent
blood flow across stenoses in the transverse venous sinuses.22,23
● Progressive visual field
loss may not be appreciated Other, less common, symptoms in IIH include diplopia due to unilateral or
by patients, underscoring bilateral sixth nerve palsy, usually with moderate to severe disease. Occasional
the importance of formal patients have facial weakness at presentation, although this is not common and
perimetry (visual field should prompt a thorough workup for alternative diagnoses.24 Of note, up to 25%
testing) in the evaluation and
monitoring of idiopathic
of patients are asymptomatic, with their papilledema being discovered during a
intracranial hypertension. routine eye examination.25
● Pulse-synchronous Signs
(pulsatile) tinnitus occurs in
Papilledema (optic disc edema secondary to increased intracranial pressure) is
about half of patients with
idiopathic intracranial the most common and important sign in IIH. It is usually bilateral and
hypertension and is thought symmetric, although occasional patients have highly asymmetric papilledema.26,27
to arise because of turbulent Papilledema is a result of axoplasmic flow stasis secondary to increased intracranial
blood flow across
pressure, producing edema of the retinal nerve fibers emanating from the optic
transverse venous sinus
stenoses. disc. The threat of vision loss is correlated with the severity of papilledema.16,26
Thus, it is important to determine the severity of papilledema to help guide
● Papilledema is the most management. The severity of papilledema can be graded based on the appearance
common and important sign of the optic disc using the modified Frisén scale (FIGURE 5-1): grade I (minimal
in idiopathic intracranial
hypertension. It is usually
papilledema) is characterized by a C-shaped halo with sparing of the temporal
bilateral and symmetric. The margin of the optic disc; grade II (mild papilledema) is characterized by a
threat of vision loss is circumferential halo; grade III (moderate papilledema) is characterized by
correlated with its severity. obscuration of at least one segment of a major blood vessel leaving the optic disc;
grade IV (marked papilledema) is characterized by total obscuration of a segment
● If untreated, papilledema
can result in progressive and of a major blood vessel on the optic disc; and grade V (severe papilledema) is
irreversible vision loss with characterized by total obscuration of all blood vessels on and leaving the
optic atrophy. optic disc.28,29
Hemorrhages in the peripapillary retinal nerve fiber layer commonly occur
● Visual field loss is difficult
to exclude with in association with papilledema (FIGURE 5-2A) and are correlated with the
confrontation visual field severity of papilledema.30 Subretinal hemorrhages can occur in association
testing. Consequently, with papilledema (FIGURE 5-2B). Since they can also occur with pseudopapilledema,
formal perimetry is they do not help to distinguish papilledema from pseudopapilledema
mandatory in the evaluation
and monitoring of idiopathic
(TABLE 5-2).30,31 In rare cases, subretinal hemorrhage can result from peripapillary
intracranial hypertension. choroidal neovascularization (FIGURE 5-2C).32 Retinal folds can often be detected
with careful observation; the folds may be circumferential around the optic disc
(Paton lines or peripapillary wrinkles [FIGURE 5-3A]) or radial with extension into
the macula (FIGURE 5-3B).33 Cotton wool spots (ie, retinal nerve fiber layer
infarcts) and retinal exudates can also be present, especially in patients with
more severe grades of papilledema (FIGURE 5-4A).30 Pseudodrusen are small
white refractile deposits overlying the optic disc that can develop in patients
with long-standing papilledema (FIGURE 5-4B).30,34 Pseudodrusen must be
1292 OCTOBER 2019

FIGURE 5-1
Appearance of papilledema of increasing severity, graded using the modified Frisén scale,
from grade 0 (no papilledema) through to grade V (severe papilledema). The major features
of each grade are described in the text.
distinguished from optic disc drusen, which are larger yellow refractile bodies
arising from the substance of the optic disc.
If untreated, papilledema can result in progressive and irreversible vision
loss with optic atrophy.17,19 Since the vision loss is typically slow and insidious,
it may not be appreciated by the patient. However, it can be rapidly progressive
in patients with a fulminant presentation, resulting in early and sometimes
irreversible central vision loss.35
Visual field defects are often difficult to exclude with confrontation visual
field testing. Consequently, formal perimetry (visual field testing) is mandatory
in the evaluation and monitoring of patients with IIH.17,19 Automated perimetry
(eg, Humphrey visual field testing using the 24-2 or 30-2 SITA [Swedish
Interactive Threshold Algorithm]-standard protocols) is usually adequate for
patients who have minimal to moderate visual field loss. Automated perimetry
is quantitative and compares the patient’s responses to those of age-matched
controls. The sensitivities at each test location are expressed in decibels. The
total deviation plot shows the difference (in decibels) between the patient’s
sensitivities and those of age-matched controls at each test location, whereas the
pattern deviation plot shows the patient’s sensitivities adjusted for generalized
depression of the entire visual field (eg, due to refractive error or media
opacities, such as cataract). The mean deviation is a measure (in decibels) of the

average deviation of all test

locations compared to
age-matched controls. Patients
with a normal visual field will
usually have a mean deviation
greater than –2 dB. Patients
with mild papilledema (less
than grade II) might have
no visual field defects on
automated perimetry
(FIGURE 5-5A). An enlarged
physiologic blind spot is the
first visual field defect to
develop, producing a slight
decrease in mean deviation
(FIGURE 5-5B). The enlarged
blind spot is a refractive
scotoma resulting from
peripapillary hyperopia.36 With
increasing severity and
duration of papilledema, FIGURE 5-2
arcuate visual field defects can Peripapillary hemorrhages occurring in association
with papilledema include flame-shaped
develop, initially in the retinal nerve fiber layer hemorrhages (A) and
inferonasal portion of the subretinal hemorrhages (B). Occasionally,
visual field (FIGURE 5-5C).37 extensive subretinal hemorrhage may be seen
With more severe or secondary to peripapillary choroidal
neovascularization (C).
TABLE 5-2 Differentiation of Papilledema From Pseudopapilledemaa
Clinical Feature Papilledema Pseudopapilledema
Transient visual obscurations Yes Sometimes
Visual field defects Yes Sometimes
Spontaneous venous pulsations No Yes
Changing optic disc appearance Yes No
Obscuration of vessels Yes No
Anomalous vascular branching No Sometimes
Hemorrhages Yes (usually retinal nerve fiber layer, Occasionally (subretinal)

but occasionally subretinal)
Preserved physiologic cup Yes (until late) No
Retinal folds Often No
Leakage on fluorescein angiogram Yes (if moderate-severe) No
Symptoms of increased intracranial pressure Often No
a
Modified with permission from Thurtell MJ, & Tomsak RL.1 © 2019 Oxford University Press.
1294 OCTOBER 2019

FIGURE 5-3
Peripapillary retinal folds occurring in association with papilledema include circumferential
folds around the optic disc (A, arrowheads) and radial folds extending into the macula
(B, arrows).
long-standing papilledema, the visual field becomes progressively constricted,

with sparing of the central visual field until late.37 Nonphysiologic visual field
constriction can occur in patients with coexisting organic visual field loss;
such constriction can also result from a poor performance in a patient having
difficulty concentrating or staying awake during the test, giving a
characteristic cloverleaf appearance on automated perimetry (FIGURE 5-5D).38
Manual perimetry, such as kinetic perimetry using the Goldmann perimeter,
may give more reliable results in patients who have severe visual field
constriction or difficulties with performance on automated perimetry.
FIGURE 5-4
Cotton wool spots (retinal nerve fiber layer infarcts) and retinal exudates can develop with
more severe degrees of papilledema (A). Small white refractile deposits overlying the optic
disc, known as pseudodrusen, can occasionally develop with chronic severe papilledema (B).

FIGURE 5-5
Formal perimetry, obtained using the Humphrey 24-2 SITA-standard protocol in these
examples, is mandatory in the evaluation and monitoring of patients with idiopathic
intracranial hypertension. Patients with mild papilledema can have a normal visual field (A).
However, with increasing severity and duration of papilledema, patients will develop an
enlarged physiologic blind spot (B), arcuate visual field defects (C), and ultimately
generalized constriction with sparing of central vision. Patients who struggle with perimetry
testing (eg, difficulty concentrating or staying awake during the test) often have a cloverleaf
pattern of constriction on automated perimetry (D).
1296 OCTOBER 2019

Other examination findings in IIH include unilateral or bilateral sixth nerve KEY POINTS
palsy causing an esotropia with limitation of abduction, although other ocular
● An enlarged physiologic
motility deficits (eg, third nerve palsy, fourth nerve palsy, and skew deviation) blind spot is the first visual
can rarely occur.39,40 Occasional patients have a facial nerve palsy at field defect to develop in
presentation.24 idiopathic intracranial
Rare patients may have normal optic discs (ie, no papilledema) but have hypertension, followed by
arcuate visual field defects
symptoms and imaging findings suggesting increased intracranial pressure as
(initially in the inferonasal
well as an increased CSF opening pressure; this controversial entity is known as visual field) and,
IIH without papilledema.41,42 It has been proposed that papilledema might not subsequently, progressive
develop in such cases because of anatomic compartmentalization of the constriction with sparing of
central vision until late.
subarachnoid space around the optic nerve stopping the CSF pressure gradient
from reaching the retrolaminar portion of the optic nerve.43 Another possibility is ● Sixth and seventh nerve
that papilledema might not develop or could resolve because of the presence of a palsies can occur as false
CSF leak (eg, causing CSF rhinorrhea or otorrhea) helping to decrease the localizing signs in patients
intracranial pressure in a patient with IIH. When papilledema is absent and no with idiopathic intracranial
hypertension.
damage to the optic nerve from resolved papilledema is evident (ie, no optic
atrophy or evidence of structural damage to the optic nerve on the basis of optical ● Ophthalmic investigations
coherence tomography [OCT]), visual function should be normal; the presence are necessary to determine
of visual field defects should raise concern for nonorganic vision loss.42 the severity of vision loss
and papilledema. In
patients with equivocal
INVESTIGATIONS papilledema or possible
When evaluating a patient with presumed IIH, further investigations are obtained pseudopapilledema,
for two broad purposes. First, neuroimaging and CSF evaluation are required to consultation with an
ophthalmologist or, ideally,
exclude other etiologies of increased intracranial pressure (TABLE 5-1). Second,
a neuro-ophthalmologist is
ophthalmic investigations should be obtained to determine the severity of vision suggested.
loss and papilledema to help guide management. However, before further
investigations are obtained, other etiologies of optic disc edema and conditions ● In patients with an
that mimic optic disc edema (eg, optic disc drusen) should be considered. atypical or fulminant
presentation of idiopathic
Differentiation of papilledema from pseudopapilledema can be challenging; a intracranial hypertension,
distinction can usually be made based on clinical and investigation findings magnetic resonance
(TABLE 5-2). However, it is important to keep in mind that occasional patients venography of the head with
have papilledema that is superimposed on pseudopapilledema. Consultation with contrast should be obtained
to exclude cerebral venous
an ophthalmologist or neuro-ophthalmologist is suggested for patients with sinus thrombosis.
equivocal papilledema or pseudopapilledema, or when another etiology for optic
disc edema is suspected. Specialized ophthalmic investigations (eg, fundus
autofluorescence, ultrasonography, and OCT) are often needed for definitive
diagnosis of optic disc drusen (FIGURE 5-6).
Neuroimaging
Neuroimaging is the first step in the evaluation of a patient with increased
intracranial pressure. Most structural causes of increased intracranial pressure
can be identified on MRI of the brain with contrast. However, magnetic resonance
venography (MRV) of the head with contrast should also be obtained to ensure
that cerebral venous sinus thrombosis is excluded, especially in patients with an
atypical or fulminant presentation for IIH (CASE 5-1).44
Several somewhat subtle findings on neuroimaging can suggest increased
intracranial pressure. An empty sella turcica is a common finding (FIGURE 5-7A)
but can also be present in the absence of increased intracranial pressure.45
Dilation and increased tortuosity of the optic nerve sheaths may be seen as
well as posterior globe flattening (FIGURE 5-7B).45 Occasionally, the swollen

KEY POINTS
● Common imaging findings

in idiopathic intracranial
hypertension include an
empty sella turcica,
increased optic nerve
sheath dilation and
tortuosity, posterior globe
flattening, optic disc
elevation and enhancement,
inferior cerebellar tonsillar
descent, and transverse
venous sinus stenosis.
● In adults, a CSF opening

pressure of greater than
25 cm H2O is high, while an
opening pressure of 20 cm
H2O to 25 cm H2O is
probably abnormal if
symptoms, signs, and
imaging findings are
consistent with increased
intracranial pressure. In
children, recent studies
suggest that a CSF opening
pressure of greater than
28 cm H2O is high.
FIGURE 5-6
Optic disc drusen can be mistaken for papilledema. With buried optic disc drusen (A), the
optic disc drusen are located beneath the surface of the disc and are not visible on funduscopic
examination; the optic disc is often elevated and can have an appearance that can be
difficult to distinguish from mild papilledema. When optic disc drusen become exposed,
they are yellow in color and refractile, with a “rock candy” appearance (B). Since exposed
optic disc drusen display autofluorescence, they are often prominent on fundus
autofluorescence (C). Buried optic disc drusen may not be visible on fundus autofluorescence
but can usually be detected on ultrasonography (D) as a focus of increased reflectivity
within the elevated optic nerve head (arrowheads) with a characteristic posterior reduplication
artifact (arrows).
optic discs may be visible and enhancing (FIGURE 5-7C).45 In some patients,
acquired cerebellar tonsillar descent below the level of the foramen magnum
is seen; this can be mistaken for a (congenital) Chiari malformation
(FIGURE 5-7A).46
MRV of the head often shows smoothly tapered stenoses in the transverse
venous sinuses (FIGURE 5-8).47 These are thought to result from mechanical
compression of the venous sinus in the setting of increased intracranial pressure.48
Less commonly, stenoses can result from intrinsic factors, such as arachnoid
granulations, septations, and organized thrombus. Catheter venography with
manometry often shows a pressure gradient across these stenoses, with increased
venous pressures in the superior sagittal sinus and transverse venous sinuses
proximal to the stenoses.49 The stenoses might play a role in the pathogenesis of
1298 OCTOBER 2019

IIH or exacerbate it. Thus, transverse venous sinus stenting has been proposed as
a potential surgical treatment for the disease.22,50
CSF Evaluation
The lumbar puncture has a dual role in the diagnosis of IIH. First, it is obtained
to confirm the presence of an increased CSF opening pressure. Second,
evaluation of the CSF constituents is required to exclude other etiologies of
increased intracranial pressure (eg, infectious, inflammatory, or neoplastic
meningitis).
Ideally, the lumbar puncture should be obtained with the patient positioned in
the left lateral recumbent position. The CSF opening pressure should be
measured with the legs extended, head in a neutral position, and the patient
breathing normally. The normal CSF opening pressure in adults is 10 cm H2O to
20 cm H2O. A CSF opening pressure of greater than 25 cm H2O is considered
high, whereas a pressure of 20 cm H2O to 25 cm H2O is considered borderline,
although probably abnormal in a patient who has symptoms, signs, and
neuroimaging findings suggesting increased intracranial pressure. Recent
studies have found that the normal range for CSF opening pressure in children
A 23-year-old woman with a normal body mass index had a motor vehicle CASE 5-1
accident resulting in a head injury without loss of consciousness. She
subsequently developed severe headaches, transient visual obscurations,
and pulse-synchronous tinnitus. Her eye care provider noted bilateral
papilledema. MRI of her brain with contrast was reported to be
unremarkable. Subsequent lumbar puncture showed a CSF opening
pressure of 32 cm H2O with normal CSF constituents. Thus, she was
diagnosed with idiopathic intracranial hypertension and started on
acetazolamide 1000 mg 2 times a day.
She presented for a second opinion because of worsening of her
papilledema on treatment. On examination, her visual acuity was 20/15 in
both eyes. Her pupils were equal and briskly reactive without a relative
afferent pupillary defect. Ocular motility was normal. Funduscopic
examination showed grade IV optic disc edema in the right eye and grade
III optic disc edema in the left eye. Visual fields showed an enlarged blind
spot in both eyes. Review of her previous MRI was unrevealing. However,
a repeat MRI of her brain with contrast and magnetic resonance
venography (MRV) of her head with contrast showed superior sagittal
venous sinus thrombosis with left parietal venous infarction.
She was admitted for anticoagulation, and her acetazolamide dose
was increased to 1500 mg 2 times a day. Her symptoms and signs
eventually resolved, and the acetazolamide dose was gradually
decreased over months.
This case highlights the importance of considering cerebral venous sinus COMMENT
thrombosis in a patient with increased intracranial pressure but an atypical
presentation for idiopathic intracranial hypertension.

FIGURE 5-7
MRI findings suggesting increased intracranial pressure. A, Sagittal T1-weighted MRI showing
an empty sella turcica with mild inferior cerebellar tonsillar descent. B, Axial T2-weighted
MRI showing dilated and tortuous optic nerve sheaths with posterior globe flattening.
C, Axial T1-weighted postcontrast MRI showing enhancing optic discs (arrowheads).
is higher than in adults; less than 28 cm H2O is considered normal in children.51

The CSF opening pressure can be influenced by a number of factors, such as
incorrect positioning of the patient or manometer during the opening pressure
measurement and use of sedation during the procedure; in children who
receive minimal or no sedation, less than 25 cm H2O is considered normal.51
The CSF constituents should be normal (ie, normal white cell count with
normal protein and glucose concentrations) in patients with IIH. The presence of
an increased white cell count or protein concentration should raise concern for
another etiology of increased intracranial pressure.
Ophthalmic Investigations
Formal perimetry is mandatory for evaluation and monitoring of patients with
IIH (as discussed earlier). Other investigations, such as fundus autofluorescence
and ultrasonography, can be helpful in the evaluation of suspected
pseudopapilledema. OCT may have a role in quantifying the severity of
papilledema (FIGURE 5-9); the retinal nerve fiber layer thickness correlates well
with papilledema severity based on the modified Frisén scale, especially for lower
grades of papilledema.29 However, OCT measures of retinal nerve fiber layer
thickness must be interpreted with caution, since combined retinal nerve fiber
layer edema and atrophy might give a retinal nerve fiber layer thickness that
appears to be close to normal despite significant visual field loss from optic nerve
damage. In such cases, OCT might show thinning of the retinal ganglion cell and
inner plexiform layer complex (containing the cell bodies for retinal nerve
fibers), which correlates well with the severity of vision loss secondary to optic
nerve damage.20 Finally, high-resolution raster scans obtained through the optic
1300 OCTOBER 2019

KEY POINTS
● Retinal nerve fiber layer

thickness from optical
coherence tomography
correlates with papilledema
severity. However, retinal
nerve fiber layer thickness
measurements must be
interpreted with caution in
patients who could have
combined optic disc edema
and atrophy.
● Raster scans obtained

through the optic nerve
head with optical coherence
tomography may show
biomechanical changes that
correlate with increased
intracranial pressure and
FIGURE 5-8
might be useful for
Lateral (A) and frontal (B) reconstructions of magnetic resonance venography (MRV) of the
monitoring response to
head with contrast demonstrating bilateral transverse venous sinus stenoses (arrowheads).
treatment.
● Several medications (eg,

tetracycline antibiotics,
nerve head using OCT can demonstrate biomechanical changes that correlate retinoids, and lithium) and
well with increased intracranial pressure; an inward deflection of the cerebral venous outflow
peripapillary retinal pigment epithelium and Bruch membrane complex toward obstruction (eg, due to
cerebral venous sinus
the vitreous of the eye (FIGURE 5-10) appears to reverse with a decrease in thrombosis) can cause a
intracranial pressure.52,53 clinical syndrome that
mimics idiopathic
DIFFERENTIAL DIAGNOSIS
Several etiologies of increased intracranial pressure can mimic IIH and,
therefore, must be specifically considered. Several medications are associated
with a clinical syndrome that mimics IIH, although they might also precipitate
or worsen preexisting IIH. These medications include the tetracycline
antibiotics (eg, minocycline), retinoids (eg, vitamin A derivatives and
all-trans retinoic acid), and lithium. Corticosteroid withdrawal has also
been reported to cause rebound intracranial hypertension. Thus, a thorough
review of medication use is mandatory in the evaluation of a patient with
suspected IIH (CASE 5-2).
Cerebral venous hypertension due to cerebral venous sinus thrombosis,
extrinsic venous sinus compression (eg, by a meningioma), or arterialization of
the sinus by a dural arteriovenous fistula can cause a clinical syndrome that
mimics IIH.44,54,55 Features suggesting cerebral venous sinus thrombosis are
listed in TABLE 5-3. When cerebral venous sinus thrombosis is suspected, MRV of
the head with contrast should be obtained (CASE 5-1).
MANAGEMENT
The two main goals of treatment are to preserve visual function and alleviate
symptoms. Many treatment approaches have been proposed for IIH, including
lifestyle interventions (weight loss), medical therapies, and surgical
interventions.

KEY POINT Weight Loss

Studies suggest that weight loss
● Weight loss of 6% to 10%
of initial body weight can be
of about 6% to 10% of initial
effective in inducing a body weight is adequate to
remission of idiopathic induce remission in most
intracranial hypertension. patients with IIH. In a 2010
Bariatric surgery can be
prospective cohort study, a
effective in patients who are
morbidly obese and struggle low-calorie diet resulted in a
to lose weight. significant reduction in CSF
opening pressure, papilledema,
and headache disability based on
the Headache Impact Test-6
score; participants lost an
average of about 15.5 kg (34 lb).56
While effective in the long term,
weight loss is not a practical or
effective treatment in the short
term; other treatments must be
initiated in parallel for most
patients with IIH. Of note,
bariatric surgery is an option for
patients who are morbidly obese
whose weight loss attempts have
been unsuccessful, although
visual outcomes from bariatric
surgery have not been studied
in detail.57
Medical Therapy
Carbonic anhydrase inhibitors,
FIGURE 5-9
such as acetazolamide and
Optical coherence tomography showing diffuse
retinal nerve fiber layer (RNFL) edema in a patient methazolamide, are the mainstay
with grade II papilledema (A). The peripapillary of medical therapy for IIH. These
RNFL thickness in micrometers (μm) is determined drugs are thought to decrease
after segmentation of the retinal layers (B, purple CSF production, although they
circle). The peripapillary RNFL thickness of the
right eye (OD, solid line) and left eye (OS, dashed do have a mild diuretic effect.
line) can be plotted and compared to an The 2014 Idiopathic Intracranial
age-matched normal dataset (C, shaded green Hypertension Treatment Trial
area indicates the 95% confidence limits of RNFL was a double-masked
thickness for the age-matched normal dataset).
The RNFL quadrant analysis indicates the average
randomized controlled trial of
RNFL thickness for the superior (S), nasal (N), diet plus placebo versus diet
inferior (I), and temporal (T) quadrants (D). The plus maximally tolerated
average RNFL thickness for this patient was 218 μm acetazolamide in patients with
for the right eye and 177 μm for the left eye (normal
range is about 80 to 100 μm).
newly diagnosed IIH and mild
INF = inferior; NAS = nasal; SUP = superior; TEMP = vision loss (mean deviation of
temporal. –2 dB to –7 dB).58 The
acetazolamide dose was titrated
up, as tolerated, to a maximum
of 2000 mg 2 times a day. The
primary outcome measure was
1302 OCTOBER 2019

FIGURE 5-10
High-resolution raster scans obtained using optical coherence tomography through the
optic nerve head (A, blue line) can show inward deflection of the retinal pigment epithelium
and Bruch membrane complex toward the vitreous cavity (B, arrowheads) when increased
intracranial pressure is present.
A 15-year-old girl presented with headaches and transient visual CASE 5-2
obscurations in both eyes. She reported weight gain of 11.3 kg (25 lb) over
12 months. Her local eye care provider noted bilateral papilledema and
referred her to a pediatric neurologist for further evaluation. MRI of her
brain with contrast and magnetic resonance venography (MRV) of her
head with contrast showed signs suggesting increased intracranial
pressure but no cause for it. Subsequent lumbar puncture showed a CSF
opening pressure of 27 cm H2O with normal CSF constituents. Based on
these findings, she was felt to have idiopathic intracranial hypertension
and was started on acetazolamide 500 mg 2 times a day.
The patient’s parents requested a second opinion regarding the
diagnosis. At the time of evaluation, the patient’s visual acuity was 20/20
in both eyes. Her pupils were equal and briskly reactive without a relative
afferent pupillary defect. Ocular motility was normal. Funduscopic
examination showed grade II optic disc edema in both eyes. Visual fields
showed an enlarged blind spot in both eyes.
Further history revealed that the patient had been started on
doxycycline for acne 1 month before the onset of her symptoms. The
doxycycline was discontinued. Acetazolamide was continued until her
symptoms and signs had fully resolved. The patient had no recurrence of
symptoms or signs after the acetazolamide was discontinued.
This case highlights the importance of a thorough review of medication use COMMENT
in the evaluation of a patient with suspected idiopathic intracranial
hypertension.

change in mean deviation (from Humphrey 24-2 SITA-standard perimetry).

Secondary outcome measures included changes in papilledema grade,
symptoms, quality of life, and weight. Treatment with acetazolamide was
associated with statistically significant improvements in mean deviation,
papilledema grade, symptoms, and quality of life.58 Of note, participants in the
acetazolamide group lost more weight than those in the placebo group.58
Acetazolamide was well tolerated by most participants, although common side
effects included paresthesia, dysgeusia, nausea, vomiting, and diarrhea.59 The
risk factors for treatment failure included male sex, higher papilledema grade
(ie, grades III–V), decreased visual acuity at presentation, greater than 30
transient visual obscurations per month, and peripapillary retinal nerve fiber
layer hemorrhages at presentation, suggesting that such patients require closer
monitoring and may need more aggressive treatment.16,30 While the
acetazolamide dose was increased to a maximum of 2000 mg 2 times a day,
most patients with IIH and mild vision loss seem to respond well to doses of
500 mg to 1000 mg 2 times a day. The optimum acetazolamide dose for
patients with moderate to severe vision loss at presentation remains unclear,
although many clinicians rapidly titrate up to high doses (eg, 1500 mg to
2000 mg 2 times a day), as tolerated, before considering surgical interventions.
Topiramate is often used for treatment of primary headache disorders, such
as migraine. It is also a weak carbonic anhydrase inhibitor that seems to have
similar efficacy to acetazolamide in treating patients with mild to moderate
IIH.60 Since topiramate often causes some weight loss, it can be considered when
acetazolamide cannot be tolerated or when headache is prominent. The dose of
topiramate required for a therapeutic response has not been specifically studied.
However, many patients appear to respond to low doses of 25 mg/d to 50 mg/d,
although the dose can be titrated up to 100 mg 2 times a day for improved
symptom control. Topiramate seems to be better tolerated than acetazolamide,
although common side effects include mental slowing, lethargy, paresthesia, and
decreased appetite. Other important, but less common, side effects include renal
stones and acute angle-closure glaucoma.
Other diuretics, such as furosemide, can be administered alone or in combination
with other medications for a synergistic effect.61 However, monitoring of
TABLE 5-3 Clinical Features Suggesting Cerebral Venous Sinus Thrombosisa
◆ Nonobese
◆ Pregnant or postpartum
◆ Acute or fulminant presentation
◆ History of clotting or thrombophilia (eg, deep venous thrombosis, pulmonary embolus)
◆ History of connective tissue disease (eg, systemic lupus erythematosus, Behçet disease)
◆ History of recent ear, mastoid, or sinus infection
◆ History of recent head or neck surgery or trauma
◆ CSF abnormalities (eg, raised protein, pleocytosis)
a
Modified with permission from Thurtell MJ, Tomsak RL.1 © 2019 Oxford University Press.
1304 OCTOBER 2019

electrolytes and potassium supplementation is required when furosemide is KEY POINTS
used. Corticosteroids were used for treatment in the past but produce
● Treatment of idiopathic
undesirable long-term complications, such as weight gain. Furthermore, intracranial hypertension
corticosteroid withdrawal can result in a rebound increase in intracranial with acetazolamide
pressure. High-dose IV corticosteroids are sometimes used for the short-term produces improvement in
treatment of patients who have a fulminant presentation while awaiting visual field loss,
papilledema, symptoms,
definitive surgical intervention (eg, CSF shunting).35,62
and quality of life. Common
side effects of
Surgical Therapies acetazolamide therapy
Surgical intervention is often required for patients with a fulminant presentation include paresthesia,
dysgeusia, nausea, vomiting,
of IIH but may also be needed in those who fail to improve or worsen despite
and diarrhea.
maximally tolerated medical therapy. The three most commonly used
interventions are CSF shunting, optic nerve sheath fenestration, and transverse ● Topiramate is effective in
venous sinus stenting.63 treatment of mild to
CSF shunting is very effective for rapidly reducing intracranial pressure moderate idiopathic
intracranial hypertension
and papilledema. Stereotactic ventriculoperitoneal shunting is preferred over and can be considered in
lumboperitoneal shunting because of its lower complication rate.64 Incorporation patients who are unable to
of an adjustable valve into the shunt apparatus allows the CSF flow rate to be tolerate acetazolamide or
adjusted according to symptoms and signs. Unfortunately, shunting has a when headache is
prominent. Common side
significant complication rate, including infection, obstruction, and migration of effects of topiramate
shunt tubing.63 Consequently, shunt revisions are often needed. Given the therapy include mental
potential for complications and need for revision, CSF shunting should not be slowing, lethargy,
considered for the management of isolated intractable headache unless the paresthesia, and loss of
appetite.
headache is known to respond to decreases in intracranial pressure (eg, following
a lumbar puncture) and noninvasive management options have been ineffective. ● Surgical therapies are
One large retrospective study found that headache initially improved in most usually reserved for patients
patients with IIH following CSF shunting, but almost 50% had recurrent with idiopathic intracranial
headaches at 36 months following CSF shunting.65 hypertension who have a
fulminant presentation and
Optic nerve sheath fenestration is an effective intervention to consider for patients who fail to
when vision is threatened. A superior or medial orbital approach is used to improve or worsen despite
create slits or a window in the retrolaminar optic nerve sheath, thereby creating maximally tolerated medical
a fistula between the subarachnoid space and orbital cavity. The resultant therapy.
decrease in pressure on the optic nerve results in reduced papilledema with ● CSF shunting is effective
improved visual function.63 In some patients, unilateral optic nerve sheath for rapidly reducing
fenestration improves the papilledema and visual function on the contralateral intracranial pressure.
side, but many patients will require bilateral sequential optic nerve sheath Complications can include
infection, obstruction,
fenestrations. Complications of optic nerve sheath fenestration include transient
and migration of shunt
or persistent vision loss (eg, from optic nerve trauma), tonic pupil (eg, from tubing; shunt revision is
damage to the ciliary ganglion or postganglionic parasympathetic fibers), often needed.
and diplopia.63
Transverse venous sinus stenting is a surgical intervention to consider in ● Optic nerve sheath
fenestration is effective in
patients who have transverse venous sinus stenoses with pressure gradients relieving pressure on the
(>8 mm Hg) across the stenoses and increased venous pressures in the optic nerve, thereby
superior sagittal sinus and venous sinuses proximal to the stenoses.22,50 It reducing papilledema and
has been proposed that stenting will reduce cerebral venous hypertension, improving visual function.
Complications can include
resulting in increased CSF absorption, reduced intracranial hypertension, and, vision loss, tonic pupil,
thus, improved symptoms and signs. Accordingly, several retrospective and diplopia.
and prospective studies have reported improvement in symptoms, signs,
visual function, and intracranial pressure.22,50,66 Potential complications of
transverse venous sinus stenting include in-stent thrombosis and subdural

KEY POINTS
hemorrhage as well as development of recurrent stenoses immediately
● Transverse venous sinus proximal to the stent.22,50,63
stenting has been reported The choice of surgical intervention remains controversial and often varies
to improve symptoms, signs, depending on local resources or practices. However, the patient’s symptoms
visual function, and and signs should be considered in the decision-making process. For example, a
intracranial pressure.
Complications can include
patient who has papilledema and vision loss without other symptoms and signs
in-stent thrombosis, of increased intracranial pressure might be best treated with an optic nerve
subdural hemorrhage, and sheath fenestration, whereas a patient with severe symptoms (eg, headache),
development of new papilledema with vision loss, and other signs (eg, sixth nerve palsy) might be
stenoses proximal to
the stent.
best treated with CSF shunting. Given the controversy with regard to choice
and timing of surgical intervention for IIH, the National Eye Institute of the
● The indications for National Institutes of Health (NIH) has sponsored a multicenter, randomized,
surgical intervention in single-masked clinical trial comparing maximal medical therapy versus maximal
idiopathic intracranial
medical therapy plus optic nerve sheath fenestration versus maximal medical
hypertension, the timing and
choice of surgical therapy plus CSF shunting for management of patients with IIH and moderate to
intervention, and long-term severe vision loss at initial presentation.67 This trial, called the SIGHT (Surgical
outcomes remain unclear. Idiopathic Intracranial Hypertension Treatment) trial, will evaluate short- and
long-term outcomes of these therapies, with the primary outcome being change
● The main goals of
treatment of idiopathic
in mean deviation on automated perimetry. Other outcomes will include time to
intracranial hypertension are treatment failure and change in CSF opening pressure, papilledema grade,
to preserve vision and quality of life, and headache disability.67
alleviate symptoms. Thus,
the management is tailored
depending on the severity of Summary of Management Approach
vision loss, papilledema, The management approach for individual patients with IIH depends on the
and symptoms as well as the severity of their vision loss based on formal perimetry, severity of papilledema
patient’s response to based on Frisén grade, severity of symptoms, response to medical therapy, and
medical therapy and ability
to tolerate medical therapy.
ability to tolerate medical therapy. Patients with minimal vision loss (mean
deviation better than –3 dB) can often be managed with weight loss alone
● Patients with idiopathic (low-calorie and low-sodium diet plus exercise), although medical therapy can
intracranial hypertension be added depending on the severity of symptoms and response to weight-loss
with minimal to mild vision
attempts. Patients with mild vision loss (mean deviation of –3 dB to –7 dB)
loss can usually be managed
with weight loss and medical can usually be managed with weight loss plus medical therapy. Patients with
therapy, whereas patients moderate vision loss (mean deviation of –7 dB to –15 dB) can often be managed
with moderate to severe with weight loss plus more aggressive medical therapy, although surgical
vision loss often need a
intervention could be considered depending on the response to weight loss and
combination of weight loss,
aggressive medical therapy, medical therapy. Patients with severe vision loss (mean deviation worse than
and, occasionally, surgical –15 dB) often require a combination of weight loss plus aggressive medical
intervention. therapy plus surgical intervention, although the timing and choice of surgical
intervention remains controversial.
● Patients with idiopathic
intracranial hypertension
Patients with IIH require long-term monitoring, since this is a chronic disease
should be managed in prone to relapses in association with weight gain. The severity of vision loss,
coordination with an papilledema, and symptoms influence treatment decisions. Comanagement with
ophthalmologist or an ophthalmologist or neuro-ophthalmologist is crucial, with the timing of
neuro-ophthalmologist,
since formal perimetry and
follow-up tailored according to the severity of symptoms and signs at
monitoring of papilledema presentation, response to treatment, and subsequent clinical course.
severity is needed to guide
management.
CONCLUSION
IIH is a syndrome of increased intracranial pressure of unclear etiology that
most often occurs in obese women of childbearing age. Recent studies have
1306 OCTOBER 2019

found that the annual incidence of IIH is increasing in parallel with obesity
rates. Common symptoms of IIH include headache, transient visual obscurations,
and pulse-synchronous (pulsatile) tinnitus. Papilledema is the most common and
important clinical sign. If untreated, it can result in progressive and irreversible
vision loss with optic atrophy, underscoring the importance of funduscopic
examination and formal visual field testing (perimetry) for the monitoring of IIH.
Management options include weight loss, medical therapy (eg, acetazolamide or
topiramate), and surgical interventions (eg, CSF shunting, optic nerve sheath
fenestration, or transverse venous sinus stenting). The management approach
should be tailored for each patient according to the severity of vision loss,
severity of papilledema, severity of symptoms, response to medical therapy,
and ability to tolerate medical therapy.
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2015.08.497.

REVIEW ARTICLE

Chiasmal and
C O N T I N UU M A UD I O
ONLINE
Postchiasmal
Disease
By Heather E. Moss, MD, PhD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article reviews the anatomy, symptoms, examination
findings, and causes of diseases affecting the optic chiasm, optic tracts,
optic radiations, and occipital lobes.
RECENT FINDINGS: Modern ophthalmic imaging can be used to monitor the

CITE AS:
effects of diseases of the optic chiasm and tract on the retinal ganglion
25(5, NEURO-OPHTHALMOLOGY): cells. It can also be used to visualize transsynaptic degeneration of the
1310–1328. anterior visual pathway in the setting of acquired retrogeniculate lesions.
Visual prostheses that directly stimulate the occipital lobe are a potential
Dr Heather E. Moss, Spencer strategy for rehabilitation that is in active clinical trials.
Center for Vision Research;
2370 Watson Ct, Ste 200,
SUMMARY: Detecting and characterizing visual deficits due to optic chiasm
Palo Alto, CA 94303,
hemoss@stanford.edu. and retrochiasmal disease are important for the diagnosis, localization,
and monitoring of neurologic disease; identifying patient disability; and
Dr Moss serves on the board of
guiding rehabilitation.
directors of the North American
Neuro-Ophthalmology Society
and as a review editor for Current
Eye Research, an associate INTRODUCTION
A
editor for Frontiers in Neurology, number of ways to organize a discussion of the afferent visual
a section editor for the Journal
pathway are reasonable. A division point at the lateral geniculate
of Neuro-ophthalmology, and a
special section editor for nucleus separates disorders affecting retinal ganglion cells
Neuro-ophthalmology. Dr Moss (pregeniculate) from those affecting cells after the first synapse in
receives research/grant support
from the Myelin Repair Foundation,
the neurologic visual pathway (postgeniculate). A division point
the National Institutes of behind the chiasm separates disorders characterized by heteronomous field loss
Health/National Eye Institute (impacting different fields in each eye, seen in prechiasmal and chiasmal lesions)
(K23 EY024345, P30 EY 026877),
and Research to Prevent from those causing unilateral homonymous visual field loss (postchiasmal). A
Blindness and publishing division point in front of the chiasm separates optic nerve disorders, in which
royalties from Elsevier. Dr Moss a single lesion affects monocular vision, from chiasmal and retrochiasmal
has served as a legal consultant
providing record review and disorders, in which a single lesion affects vision in both eyes. This issue of
deposition on neuro-ophthalmic Continuum divides discussion at the chiasm. Accordingly, this article discusses
diseases.
the anatomy, symptoms, and common causes of vision loss related to visual
UNLABELED USE OF pathway lesions affecting anywhere from the chiasm to the primary visual cortex
PRODUCTS/INVESTIGATIONAL USE in the occipital lobe, including the optic tracts and optic radiations (FIGURE 6-11).
DISCLOSURE:
Dr Moss reports no disclosure.
EXAMINATION
Testing of central and peripheral vision in each eye separately is an essential step
of Neurology. in localizing vision loss due to retrobulbar (behind the eye) pathologies.
1310 OCTOBER 2019

Central Vision KEY POINTS
Visual acuity represents spatial
● Central vision can be
resolution of vision at the point affected in chiasmal lesions
of visual fixation (eg, the but is spared in unilateral
smallest size of a character such retrochiasmal lesions.
as a letter, number, or shape a
● If a homonymous field
person can distinguish) and is
defect is complete,
typically measured by using localization beyond a
black letters on a white retrochiasmal location is not
background. For monitoring and possible based on
localizing neuro-ophthalmic peripheral vision testing
alone.
diseases, visual acuity should be
measured by using appropriate ● Confrontation visual field
glasses or a pinhole to exclude deficits are specific but not
impairment due to refraction or sensitive for peripheral
vision loss.
mild cataract. Visual acuity can
be affected in eyes that have both ● Optic nerve head pallor in
nasal and temporal field loss both eyes is diagnostic of
from chiasmal disorders but is chronic injury to the retinal
ganglion cells in both optic
FIGURE 6-1 not affected by unilateral
nerves, the chiasm, or one
Major afferent visual pathway structures retrochiasmal lesions. optic tract.
highlighted on prosected gross specimen (ventral
view). Optic chiasm (yellow arrow), optic tracts
(white arrows), lateral geniculate nuclei (red
Peripheral Vision
arrows), optic radiations (blue arrows), and Tests of peripheral vision guide
primary visual cortex (green arrows). localization of vision loss, with
Modified with permission from Sherbondy et al, J Vision.1 chiasmal disturbances classically
© 2008 Association for Research in Vision and
Ophthalmology. causing bitemporal vision loss in
both eyes and retrochiasmal
disturbances causing unilateral
homonymous visual field defects (ie, same side affected in both eyes). If a
homonymous field defect is complete, further localization is not possible based
on peripheral vision testing alone. In cases of incomplete homonymous visual
field loss, some visual field features have localizing value (FIGURE 6-2). These are
highlighted in the relevant anatomic sections below.
Peripheral vision is assessed at the bedside by various confrontation visual
field techniques that are specific for visual field loss but not sensitive when
compared with gold standard visual field testing such as Humphrey visual fields.2
It is particularly difficult to detect visual field loss that spares the far peripheral
fields (ie, central to midperipheral vision loss) or that only involves the far
peripheral fields (ie, spares central and midperipheral fields) on confrontation
testing. Visual field testing, like most sensory aspects of the neurologic
examination, requires active patient participation and is subject to conscious and
unconscious manipulation on this basis.3
Fundus Examination
Pallor of the optic nerve heads suggests chronic injury to the retinal ganglion
cells anywhere along their pathway from the retina to the lateral geniculate
nucleus. Optical coherence tomography (OCT), a near infrared laser–based
technique that is widely used in ophthalmologic clinical settings to obtain
micron-level–resolution images of the retina, can be used to measure the

CHIASMAL AND POSTCHIASMAL DISEASE
FIGURE 6-2
Visual field loss patterns due to neurologic disease.
thickness of the ganglion cell layer in the retina, thereby quantifying injury.4 It is
important to note that, although ganglion cell changes in the retina support a
diagnosis of retinal ganglion cell injury, absence of atrophy on OCT (and, in fact,
absence of pallor on funduscopy) does not exclude retrobulbar ganglion cell
injury because lesions that do not result in cell death will not manifest retinal
changes, and retinal changes for lesions that do result in cell death can take
2 weeks to be detected in the retina and 20 weeks to stabilize.5
Pupil Examination
Anisocoria is not caused by lesions involving the afferent visual pathway.
However, any lesion that affects the retinal ganglion cells coming from each eye
in an unequal manner can cause a relative afferent pupillary defect. Relevant
to this article are optic chiasm lesions that affect the eyes asymmetrically and
optic tract lesions that affect more fibers from the contralateral eye than
ipsilateral eye to cause a contralateral relative afferent pupillary defect.6
DISEASES OF THE CHIASM

The optic chiasm’s clinical importance is out of proportion to its size because of
the presence of all afferent fibers from both eyes within its small confines and its
common involvement by sellar and suprasellar tumors.
Anatomy
Visual input coming from the optic nerves of both eyes redistributes by field
at the optic chiasm. Axons supplying the temporal visual fields of each eye
decussate to join axons supplying the nasal visual fields of the contralateral eyes
1312 OCTOBER 2019

such that the right visual field of both eyes feeds into the left optic tract and the KEY POINTS
left visual field of both eyes feeds into the right optic tract. The central temporal
● Lack of optic nerve head
fibers from both eyes decussate in the posterior chiasm. pallor does not exclude
injury to the ganglion cells in
Symptoms the optic nerves, chiasm, or
Visual symptoms of chiasmal disease are broad and depend on the anatomic optic tracts.
manner in which the chiasm is affected. Compressive lesions affecting the
● Relative afferent pupillary
chiasm affect the crossing fibers to cause vision loss in the temporal visual fields defects can occur in
in both eyes. Because of the anatomy of the crossing ganglion cell axons, lesions asymmetric chiasm and
affecting the posterior chiasm cause central temporal field loss in both eyes unilateral optic tract lesions.
and spare the periphery, whereas anterior chiasmal compression affects the
● Lesions affecting the
peripheral fields. Anterior lesions can concurrently affect the optic nerves, anterior chiasm affect the
causing superimposed nasal or central visual field defects and potentially visual peripheral temporal fields,
acuity loss in the affected eye(s). When an optic nerve visual field defect is whereas those affecting the
accompanied by a temporal defect in the other eye from concomitant chiasmal posterior chiasm affect the
central temporal fields with
involvement, it is termed a junctional scotoma. Posterior lesions can concurrently sparing of the periphery.
affect the optic tracts, causing superimposed contralateral homonymous visual
field loss. A complete chiasmal lesion causes complete vision loss in both eyes.
Lateral chiasmal compression can cause a nasal field deficit in the ipsilateral eye,
but this is rarely seen in practice.
In the case of complete bitemporal hemianopic visual field loss, the spared
visual fields in each eye are complementary, meaning that the missing field in
each eye is seen by the other eye, so that as long as both eyes are open, the whole
visual world is seen. However, the lack of overlapping vision between the
eyes can cause difficulties with depth perception. Rarer symptoms include
postfixation blindness, in which a blind spot exists behind the object of focus
where the seeing fields diverge,7 and hemifield slide, in which difficulty fusing
the remaining fields from separate eyes results in a vertical or horizontal offset,
the latter manifesting as split or central overlap of images from the two eyes
(CASE 6-1).8 Photophobia has been reported in cases of acute chiasmopathy.9
Ocular motility abnormalities associated with chiasmal pathology include
spasmus nutans in young children10 and seesaw nystagmus, which is a vertical,
pendular dissociated nystagmus during which one eye moves up and intorts
while the other moves down and extorts; this is thought to reflect dysfunction of
the visuovestibular control system, perhaps related to injury to the interstitial
nucleus of Cajal.11 Because of the proximity of the chiasm to the hypothalamus,
pituitary, and cavernous sinuses, lesions in this area can be associated with
endocrine disturbances, ocular motor nerve palsies, and facial numbness.
Examination and Evaluation

Vision loss in chiasmal diseases occurs because of retinal ganglion cell
dysfunction. Accordingly, examination findings can include optic nerve head
pallor in the case of chronic injury, and relative afferent pupillary defect in the
case of asymmetric vision loss. Because the crossing fibers are affected in patients
with a bitemporal hemianopia, the typical optic disc appearance is bowtie
atrophy (in one or both eyes), in which the temporal and nasal sides of the disc
are paler than the superior and inferior poles. OCT can be helpful in detecting
subtle retinal ganglion cell injury that may not affect visual function and in
quantifying chronic visual pathway injury.12 This may have relevance for
prognosis after surgical intervention to remove lesions compressing the chiasm.13

CASE 6-1 A 34-year-old woman presented to her optometrist because of gradual

blurring of vision in the right eye more than the left eye. Based on concern
for optic neuropathy, she was referred for urgent neuro-ophthalmic
consultation.
Visual acuity with correction was 20/100 in the right eye and 20/25 in
the left eye. Color vision was decreased in the right eye. There was a
relative afferent pupillary defect in the right eye. Confrontation visual
fields showed an inability to count fingers in the lower temporal fields of
both eyes. Funduscopic examination showed mild temporal pallor of
both optic nerve heads. Cranial nerves III to XII and the rest of the
neurologic examination were unremarkable.
Optical coherence tomography showed retinal ganglion cell injury in
both eyes, limited to the nasal retina in the left eye and diffuse in the right
(FIGURE 6-3A). MRI of the sella showed a prominent suprasellar lesion
displacing the chiasm upward (FIGURES 6-3B). Endocrine evaluation was
unremarkable.
The patient underwent transsphenoidal resection of the lesion with
decompression of the chiasm (FIGURES 6-3C). Pathology showed a pituitary
adenoma. The postoperative course was complicated by hyponatremia.
One month postoperatively, the patient reported that vision in her
right eye had improved and that she could read with it. She felt that
reading with the left eye was harder than it had been before surgery,
although it remained easier than with the right eye. When she read with
both eyes, she had trouble focusing and noted shifting distance between
the letters. She was coping by covering the right eye, although this made
her notice the visual field loss on the left. Visual acuity was 20/50 with
the right eye and 20/20 with the left eye. There was a relative afferent
pupillary defect in the right eye. She could not count fingers in the
upper or lower temporal field of the right eye or in the lower temporal
field of the left eye. Alternate cover testing revealed an esotropia
with distance or near fixation. Visual field testing showed bitemporal
hemianopia with involvement of the central nasal field of the right
eye (FIGURE 6-4A).
By 8 months after resection, the patient’s vision had improved in both
eyes and the variable letter-spacing symptoms had resolved. She had
stopped closing one eye to control this symptom. She was driving
without difficulty and had returned to work. Visual acuity was 20/40 in
the right eye and 20/20 in the left eye. There was a relative afferent
pupillary defect in the right eye. She had deficits to finger counting in the
upper and lower temporal fields of both eyes and temporal pallor of both
optic nerve heads. Visual field testing showed persistent bitemporal
hemianopia with improvement in the central field of the right eye and
superior fields of both eyes (FIGURE 6-4B).
1314 OCTOBER 2019

FIGURE 6-3
Findings of the patient in CASE 6-1. Macular optical coherence tomography (A). Purple circle
indicates the fovea, which is the retinal region where central vision is sensed. Red shading
indicates regions of retinal ganglion cell thinning. Yellow shading indicates regions of
borderline retinal ganglion cell thinning. Images are oriented as viewed by the examiner.
Coronal T2-weighted MRIs show preoperative chiasmal compression (B) and reduced
compression postoperatively (C) (arrows indicate left side of chiasm).
CONTINUED ON
PAGE 1316

CONTINUED FROM
PAGE 1315
FIGURE 6-4
Visual fields of the patient in CASE 6-1. A, Visual fields 1 month postoperatively show
bitemporal hemianopia with involvement of the central nasal field of the right eye. B,
Visual fields 8 months postoperatively show persistent bitemporal hemianopia with
improvement in the central field of the right eye and superior fields of both eyes. Images
are oriented as seen by the patient.
COMMENT This patient had a typical presentation of pituitary adenoma with vague
symptoms of vision loss. The patient did not notice the visual field deficits,
which were complementary (ie, temporal loss in each eye was made up for
by nasal field sparing in the other eye) and, therefore, did not affect
binocular vision. Central vision was decreased in both eyes, and optical
coherence tomography results indicated injury of the retinal ganglion cells
at the time of diagnosis, with nasal ganglion cell injury in the left eye
suggesting chiasmal pathology. After chiasmal decompression, she
experienced a recovery of central vision in the left eye and incomplete
recovery in the right eye. She had persistent bitemporal visual field loss.
After struggling with hemifield slide symptoms in which her esotropia
resulted in a gap between the seeing visual fields of both eyes, her ocular
motility normalized and she was able to function well with both eyes open.
1316 OCTOBER 2019

The classic pattern of ganglion cell layer thinning on OCT of the macula is KEY POINTS
binasal, such that identification of this finding in patients with cryptic optic
● The optic chiasm is best
atrophy should prompt imaging of the chiasm. viewed on coronal or sagittal
The chiasm is best visualized on coronal and sagittal neuroimaging obtained MRI or CT sequences
by using narrow spacing between slices. Coronal T2-weighted MRI sequences are obtained with narrow slice
particularly useful because the white CSF outlines the chiasm where it passes spacing.
through the suprasellar area. Pathology is more difficult to detect on axial slices
● Homonymous peripheral
because of the anatomic angle of the chiasm. Thus, specialized sequences beyond vision loss affects
a standard head CT are necessary to exclude chiasmal pathology. navigation, and
homonymous visual field
Common Pathologies loss that reaches central
vision affects reading.
In adults, the most common pathology affecting the chiasm is compression
due to pituitary adenoma,14 craniopharyngioma,15 and meningioma.16 Internal
carotid aneurysms can also compress the chiasm.17 Pituitary apoplexy, caused
by hemorrhage into a pituitary adenoma, is a cause of chiasmal vision loss that
necessitates emergent management. The chiasm can be affected by optic nerve
diseases, such as optic neuritis and optic pathway gliomas, as well as other
inflammation, other tumors, vascular malformations, and infections both
intrinsic and extrinsic to the chiasm. It is worth noting that optic neuritis due to
neuromyelitis optica (NMO) is more likely to affect the optic chiasm than optic
neuritis due to multiple sclerosis or idiopathic optic neuritis.18
COMMON FEATURES OF DISEASES OF THE VISUAL PATHWAY BEHIND

THE CHIASM
Although the regions behind the chiasm contain multiple anatomically distinct
structures, they produce similar visual symptoms and signs since they are part of
the same conduit for visual information from the contralateral hemifield.
Symptoms
Visual symptoms of afferent visual pathway disease behind the chiasm are
related to loss of vision in the same field of both eyes. If the vision loss extends to
the far periphery, patients often have difficulty with awareness of objects that
approach them from the affected side and with navigation. If the vision loss
extends to fixation (ie, central vision), patients often have difficulty reading.
This is because vision used for reading extends to the right and left of fixation to
allow whole-word reading. Patients with a right homonymous hemianopia that
extends to fixation who read from left to right are unable to see entire words
at once and often adapt a letter-by-letter strategy of reading. They are also unable
to locate the end of a line of text. Patients with a left homonymous hemianopia
that extends to fixation who read from left to right usually are less impaired,
although they have difficulty locating the start of lines of text.
Although Charles Bonnet syndrome is classically described in association with
central vision loss from retinal disease, a similar phenomenon of release
hallucinations, which are spontaneous visual perceptions in a blind field, can
occur in unilateral homonymous visual field loss.19 They are typically formed and
nonthreatening, although this is not always the case. Patients may not volunteer
these symptoms for fear that they represent psychiatric disease.
Patients will often attribute homonymous visual field loss to a problem with
the eye ipsilateral to the field loss. Thus, particularly in cases of transient visual
loss, in which the examination will not confirm or refute this impression, it is

important to maintain an open mind regarding reported unilateral vision loss

being due to either one eye or the contralateral brain.
Common Pathologies
In adults, stroke, trauma, and tumors are the most common cause of isolated
unilateral homonymous hemianopias.20 Because these deficits occur on an
anatomic basis, any disease affecting the optic tracts or brain parenchyma is
capable of causing them.
DISEASES OF THE OPTIC TRACT

The optic tract is the first segment in the conduit carrying visual information
from the contralateral hemifield defined by redistribution of the retinal ganglion
cell axons in the chiasm.
Symptoms
Lesions cause contralateral homonymous hemianopias that can be complete or
incomplete. Because of incongruity, this may affect the two eyes asymmetrically.
Optic tract lesions spare central visual acuity, although they can cause substantial
reading impairment if they reach fixation for the reasons discussed above.

Incomplete homonymous hemianopias from optic tract lesions can be highly
incongruous, meaning the area of visual field loss is different in each eye. Optic
tract diseases affect retinal ganglion cells. Therefore, examination may detect
optic nerve head pallor in chronic lesions. Because of the pattern of ganglion cells
at the optic nerve head, this is characteristically seen as temporal pallor in the
ipsilateral eye and “bowtie” pallor affecting the temporal and nasal sectors but
sparing the inferior and superior sectors in the contralateral eye. The optic tract
contains more fibers from the contralateral eye than the ipsilateral eye, and this
can result in a contralateral relative afferent pupillary defect (CASE 6-2).
Neuroimaging of the optic tract is challenging, with clinical input often
necessary to identify subtle imaging findings.21 Typical OCT findings in chronic
tractopathies include ganglion cell loss in both eyes that is homonymous (ie, on
the same side of both eyes) and ipsilateral to the optic tract lesion.
Causes
Lesions of the optic tract are relatively rare. Many of the diseases that affect the
chiasm can affect the optic tract. This includes compressive lesions in the
suprasellar region and optic nerve diseases, such as optic neuritis and optic
pathway gliomas. The optic tract can become involved in temporal lobe tumors
and their treatment.
DISEASES OF THE LATERAL GENICULATE NUCLEUS

The lateral geniculate nucleus is the first relay in the conduit carrying
contralateral visual field information.
Anatomy
The unique vascular supply to this region results in two unique and highly
localizing visual field patterns. Damage to the region supplied by the lateral
choroidal artery causes a wedge-shaped visual field deficit straddling the
1318 OCTOBER 2019

horizontal midline. The region supplied by the anterior choroidal artery is KEY POINTS
complementary to this, consisting of two wedge-shaped visual field regions
● Homonymous visual
immediately adjacent to the upper and lower vertical midlines.22 These patterns field loss with an afferent
of visual field loss are known as sectoranopia. pupillary defect on the same
side of the visual field
Symptoms loss suggests a contralateral
optic tract lesion.
Lesions of the lateral geniculate nucleus cause contralateral homonymous
hemianopias that can be complete or incomplete. Because of incongruity ● Visual symptoms due to
(differences in area of field loss between the eyes), symptoms may be perceived optic radiation disease are
predominantly in one eye compared with the other. usually accompanied by
other neurologic symptoms
localizing to the affected
Examination and Evaluation territory.
Like optic tract lesions, lateral geniculate nucleus lesions produce incongruous
homonymous hemianopias. Lateral geniculate nucleus damage can affect ● Congruous homonymous
presynaptic retinal ganglion cells and lead to optic nerve head pallor in a similar visual field loss is a hallmark
of occipital lobe disease.
pattern to optic tract lesions. However, afferent pupillary defects are not seen
because the retinal ganglion cells subserving this reflex do not reach the lateral
geniculate nucleus.
Causes
Lesions of the lateral geniculate nucleus are rare and can occur from any pathology
affecting the thalamus. Of particular note is localizing sectoral visual field deficits
(described above) caused by anterior and posterior circulation ischemic strokes
via disruption of the anterior and lateral choroidal arteries, respectively.
DISEASES OF THE OPTIC RADIATIONS

The optic radiations are the second leg of the contralateral visual field pathway
connecting the lateral geniculate nucleus to the primary visual cortex.
Symptoms
The optic radiations extend diffusely through the white matter of the temporal
and parietal lobes; temporal lobe lesions cause contralateral superior homonymous
visual field loss, and parietal lobe lesions cause contralateral inferior homonymous
visual field loss. The inferior bundle, also known as the Meyer loop, detours into
the anterior temporal lobe before coursing posteriorly to the inferior striate cortex.
Because of the diffuse spread of the optic radiations, the visual symptoms due
to field loss are often incongruous, with one eye affected more than the other,
and are usually accompanied by other neurologic symptoms localizing to the
affected territory. Relevant to this topic are higher-order visual symptoms
related to deficits in visual processing in the temporal (ventral stream) and
parietal (dorsal stream) pathways. For more information on higher-order visual
disturbances, refer to the article “Higher Cortical Visual Disorders” by Sashank
Prasad, MD, and Marc Dinkin, MD, in this issue of Continuum.23

Visual field testing is typically incongruous (ie, different in both eyes) and does
not necessarily respect the horizontal meridian because this is not an anatomic
boundary. The retinal ganglion cells are not directly affected, and, therefore,
pupillary changes and optic nerve head pallor are not observed unless the patient
has postpapilledema atrophy related to high intracranial pressure caused by the

CASE 6-2 A 35-year-old woman was referred for evaluation of optic nerve head
pallor that had been noted by her optometrist on routine examination for
an updated glasses prescription. She had no visual symptoms.
Visual acuity with correction was 20/20 in each eye. She could not
count fingers in the left upper or lower fields with either eye. Right visual
fields were intact to confrontation in both eyes. She had a left afferent
pupillary defect. There was temporal pallor of the right optic nerve head
and bowtie pallor of the left optic nerve head.
Formal visual field testing showed an incongruous left homonymous
hemianopia (FIGURE 6-5A). Optical coherence tomography showed
temporal retinal thinning in the right eye and nasal retinal thinning in
the left eye (FIGURE 6-5B). MRI showed bilateral polymicrogyria and
schizencephaly in the right temporal lobe with right optic tract atrophy
(FIGURES 6-5C through 6-5E). These findings were felt to be developmental
in origin. On further questioning, the patient reported having seizures as
a child.
COMMENT This case illustrates the features of an optic tract lesion, including
contralateral hemianopia, optic nerve head pallor in both eyes, and
contralateral afferent pupillary defect. The patient likely had minimal
symptoms related to her visual field loss because she had had it her whole
life and had developed adaptive strategies.
1320 OCTOBER 2019

FIGURE 6-5
Findings of the patient in CASE 6-2. Visual field testing shows an incongruous left
homonymous hemianopia (A). Images are oriented as seen by the patient. Optical coherence
tomography of the macula (central retina) (B). Purple circle indicates the retinal region
where central vision is sensed (fovea). Red shading indicates regions of retinal ganglion
cell thinning. Yellow shading indicates regions of borderline retinal ganglion cell thinning.
Images are oriented as viewed by the examiner. Axial (C) and coronal (D, E) postcontrast
T1-weighted MRIs show a schizencephalic cleft in the right temporal lobe (C, D, large arrows)
and atrophic right optic tract corresponding to the ganglion cell layer atrophy seen on the
right side of both maculae (E, small arrow).

lesion affecting the optic radiations. Interestingly, OCT testing has highlighted
the potential for retinal ganglion cell thinning from retrogeniculate lesions due to
transsynaptic degeneration.24,25 However, this is not typically severe enough to
manifest as optic nerve head pallor.
Causes
The causes of visual field loss from optic radiation injury are broad, with middle
cerebral artery ischemic stroke, parietal or temporal lobe hemorrhage, and
tumors as common causes. Because of the anterior course of the Meyer loop,
anterior temporal lobectomies performed for epilepsy treatment may be
complicated by a superior quadrantanopia.
DISEASES OF THE OCCIPITAL LOBE

The primary visual cortex in the occipital lobe is the second relay in the conduit
carrying information from the contralateral visual hemifield connecting
elementary visual input to the circuits that process it.
Anatomy
The visual field in the primary visual cortex is arranged with the contralateral
central visual field at the occipital pole and contralateral far peripheral visual
field anteriorly (FIGURE 6-626). Because the temporal visual field in each eye is
larger than the nasal field, the deep occipital cortex represents far temporal
peripheral vision in the contralateral eye without corresponding representation
in the nasal field of the ipsilateral eye. This monocular region of vision is known
as the temporal crescent. Because of secondary contribution to the occipital pole
by branches of the middle cerebral artery, posterior cerebral artery infarcts often
spare the pole with associated sparing of the contralateral central vision (macula).
FIGURE 6-6
Primary visual cortex organization around the calcarine sulcus in the contralateral occipital
lobe. Visual field as seen by a patient (A), represented in the primary visual cortex (B), and
location on MRI (C). The contralateral visual field is distorted, folded on the horizontal
meridian, and inserted into the calcarine sulcus, with resulting representation of central
vision at the occipital pole and peripheral vision anteriorly.
Panels A and B reprinted with permission from Wurtz RH, Kandel ER.26 © 2000 McGraw-Hill Education.
1322 OCTOBER 2019

The deep occipital cortex may also be spared by posterior cerebral artery infarcts,
leading to preservation of the temporal crescent. The contralateral visual field is
folded around the calcarine sulcus with the horizontal meridian in the trough and
the vertical meridians along the adjacent superior and inferior gyri.
Symptoms
Congruous (same in both eyes) homonymous hemianopic or quadrantanopic
visual field loss is the norm, and symptoms are often isolated to the visual system.
Interestingly, some patients have no symptoms and are diagnosed on screening
examination. This is more commonly seen in superior quadrant visual loss that
spares the central visual field because vision in that region is used less frequently
in common activities. Some patients with hemianopic loss also fail to notice
their deficit, which may be due to macular and temporal crescent sparing that
mitigates reading and navigation difficulties that might otherwise be caused by
complete homonymous hemianopic deficits. Patients may report a sensation of
movement in the blind field (the Riddoch phenomenon).
If occipital disease is limited to an anterior lesion, patients may only have loss
of the temporal crescent in the contralateral eye without a deficit in the
ipsilateral eye.
Bilateral visual field constriction, sometimes referred to as a keyhole deficit,
can occur in lesions affecting both occipital lobes and sparing the occipital poles.
Loss of the entire lower or upper visual field in both sides of both eyes can occur
with midline lesions that affect both upper or lower banks of the occipital cortex.
In cases of complete vision loss due to disease affecting both occipital lobes,
patients are often agnostic to their visual deficit and confabulate (Anton
syndrome). In these cases, vision loss only becomes apparent based on
observation of function or direct questioning about visual stimuli.
Superior quadrant visual field deficits may be associated with color vision loss in
the ipsilateral inferior field due to involvement of the central color processing
pathways in the inferior occipital lobe or temporal lobe. Alexia without agraphia
can accompany visual field loss due to occipital disease in the dominant
hemisphere that extends to the splenium of the corpus collosum. This results from
an inability to transfer visual information from the seeing field, perceived in the
nondominant hemisphere, to the language centers in the dominant hemisphere.
Positive visual phenomena occur in homonymous visual fields in the case of
occipital lobe seizures, migraine, and release hallucinations. Occipital lobe
seizures typically cause simple hallucinations in the contralateral field but have
also been reported to cause transient hemianopia.27 When associated with a
lesion, there may be interictal visual field loss, but this is not found in
cryptogenic cases.

Visual field testing shows highly congruous homonymous visual field defects.
Because of the anatomic layout of the visual field in primary visual cortex,
characteristic visual field patterns are seen from lesions in this area, including
quadrantic visual field loss that sharply respects the horizontal meridian, macular
sparing, peripheral temporal field sparing, and its converse, monocular peripheral
temporal field loss. Pupil examination is not affected. Although retinal changes
can occur due to transsynaptic degeneration, this is typically not apparent on the
funduscopic examination and requires OCT for visualization (CASE 6-3).

CASE 6-3 A 57-year-old woman presented for evaluation of visual deficits

associated with a lung adenocarcinoma metastasis to the right occipital
lobe. She reported some fuzziness in the left field but no difficulties with
navigation or reading. Her cancer had been diagnosed 2 years previously
on workup for back pain. Multiple brain metastases were identified on
initial staging workup, including one in the right inferior occipital pole.
She had received stereotactic radiation therapy to the brain lesions as
well as systemic chemotherapy. The right occipital lesion was smaller
than at initial presentation (FIGURE 6-7).
Visual acuity was 20/20 with each eye, and the patient correctly
counted fingers in all peripheral fields with each eye. Funduscopic
evaluation was normal. Formal visual field testing showed a left superior
quadrantanopia, respecting the horizontal and nasal meridians in both
eyes (FIGURE 6-8A). Optical coherence tomography showed inferior
temporal ganglion cell thinning in the right eye and inferior nasal ganglion
cell thinning in the left eye (FIGURE 6-8B).
FIGURE 6-7
Imaging of the patient in CASE 6-3. Coronal
postcontrast T1-weighted MRI 2 years after initial
diagnosis and treatment with stereotactic
radiation and chemotherapy shows an enhancing
right occipital pole lesion inferior to the calcarine
sulcus (arrow).
1324 OCTOBER 2019

FIGURE 6-8
Findings of the patient in CASE 6-3. A, Visual field testing 2 years after diagnosis of a right
occipital pole lesion. Images are oriented as seen by the patient. B, Optical coherence
tomography of the macula 2 years after diagnosis of a right occipital pole lesion. Purple circle
indicates retinal region where central vision is sensed (fovea). Red shading indicates regions
of retinal ganglion cell thinning. Yellow shading indicates regions of borderline retinal
ganglion cell thinning. Images are oriented as viewed by the examiner.
This case illustrates the functional-structural correlation of primary visual COMMENT

cortex lesions. The right occipital pole lesion caused homonymous visual
field loss affecting the horizontal and vertical meridians. Although this was
evident on formal visual field testing, the patient was able to count fingers
in all peripheral fields and had minimal disability from her vision loss
because of sparing of the deeper occipital cortex and corresponding
peripheral visual fields. This reinforces the limited sensitivity of
confrontation visual field testing, particularly when far peripheral vision is
not affected. The optical coherence tomography result is an example of
transsynaptic degeneration of retinal ganglion cells from an acquired
occipital lesion with inferior temporal retinal thinning in the right eye
corresponding to superior nasal visual field loss and inferior nasal retinal
thinning in the left eye corresponding to superior temporal visual field loss.

Causes
Posterior cerebral artery ischemic stroke is a common cause of occipital lobe
visual field loss in the adult population with vascular risk factors. As such, acute
presentations with visual field loss are a medical emergency. As discussed earlier
in this article, these often spare the occipital pole and anterior occipital lobe to
spare central vision and the temporal crescent contralateral to the infarct. These
features limit disability in reading and navigation. Any pathology that involves
the occipital lobes, including hemorrhage, tumors, demyelinating disease, and
posterior reversible encephalopathy syndrome (PRES), can also cause visual field
loss. All of these have characteristic neuroimaging findings that will guide the
differential diagnosis.
Rare causes of occipital cortex damage include posterior cortical atrophy,28,29 a
progressive neurodegenerative disease with multiple different pathologic bases,
and Creutzfeldt-Jakob disease,30 both of which may be accompanied by more
subtle neuroimaging findings (parietooccipital atrophy in the case of posterior
cortical atrophy and cortical ribboning on diffusion-weighted imaging in the case
of Creutzfeldt-Jakob disease).
REHABILITATION
Although the focus on visual field loss is often on diagnosis, characterization of
deficits and inquiring of symptoms in patients with lesions involving the visual
pathway are critically important to assess disability and guide rehabilitation.
Prominent nonvisual symptoms may lead to a delay in diagnosis of vision-
related disability.20
Therapies for visual field loss purport to restitute damaged tissue, teach
compensation, or substitute the intact visual field. Although a 2011 Cochrane
Review found that evidence for efficacy was limited and insufficient for many
interventions,31 given the low cost and minimal potential harm of many of these,
consideration remains important. Low-vision specialists, institutes for the blind,
and state departments of rehabilitation often have extensive resources that are
available to patients with visual disability due to neurologic disease. The reader is
referred to the excellent review by Agarwal and Kedar32 for treatment options,
some of which are briefly discussed below.
Orientation Support
Many states have a visual field restriction for legal driving.33 For patients who do
meet visual criteria for driving in their state, assessment by a driver rehabilitation
specialist or specialized occupational therapist is helpful for assessing safety and
providing training.
Wayfinding training offered by low-vision optometrists can guide
compensatory strategies with regard to navigation. Peli prism lenses, consisting
of small prisms placed on glasses in the seeing field, are an optical method to
redirect a portion of the blind field into the seeing field. This is a substitution
technique that should be considered for the motivated patient.34 Compensatory
saccadic training may also be helpful.35
Reading Support
For reading difficulties, using a bright marker to indicate the margin on the side
of the visual field loss and using a straight edge to help follow lines are relatively
simple strategies that can be helpful. Saccadic training, in which the patient
1326 OCTOBER 2019

learns to make predictive saccades in the direction of the text, can mitigate KEY POINTS
letter-by-letter reading in patients with hemianopic dyslexia.36 Scrolling text,
● Posterior cerebral artery
which moves text into the seeing field, may also be helpful. Alternative strategies infarcts often spare central
for gaining visual information (eg, books on tape, text recognition) should be vision and far peripheral
explored. vision in the affected field,
which can limit disability
from vision loss.
Cortical Visual Prostheses
For visual field loss due to injury anterior to the occipital lobe, electrical ● Posterior cortical atrophy
stimulation of the occipital lobe based on the visual scene in front of the and Creutzfeldt-Jakob
patient is a potential solution to restore vision in the blind field.37 Active clinical disease can cause
trials of implanted cortical visual prostheses are ongoing in the United States homonymous visual field
loss with only subtle
and abroad. neuroimaging findings.
CONCLUSION
Visual field testing guides localization of diseases affecting the chiasmal and
retrochiasmal visual pathways. Beyond their diagnostic role, visual symptoms are
important as a cause of disability in affected individuals. Various strategies may
help to rehabilitate navigational and reading impairments due to homonymous
visual field loss.
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1328 OCTOBER 2019

Higher Cortical Visual REVIEW ARTICLE

Disorders C O N T I N U UM A U D I O
ONLINE
By Sashank Prasad, MD; Marc Dinkin, MD

VIDEO CONTENT
A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: This article reviews the disorders that result from
disruption of extrastriate regions of the cerebral cortex responsible for
higher visual processing. For each disorder, a historical perspective is CITE AS:
offered and relevant neuroscientific studies are reviewed. 25(5, NEURO-OPHTHALMOLOGY):
1329–1361.
RECENT FINDINGS: Careful analysis of the consequences of lesions that disrupt

visual functions such as facial recognition and written language processing Dr Sashank Prasad, Department
has improved understanding of the role of key regions in these networks. of Neurology, Brigham and
In addition, modern imaging techniques have built upon prior lesion studies Women’s Hospital, 60 Fenwood
Ave, Boston, MA 02115,
to further elucidate the functions of these cortical areas. For example, sprasad2@bwh.harvard.edu.
functional MRI (fMRI) has identified and characterized the response
properties of ventral regions that contribute to object recognition and RELATIONSHIP DISCLOSURE:
Dr Prasad serves as an associate
dorsal regions that subserve motion perception and visuospatial attention. editor for the Journal of Neuro-
Newer network-based functional imaging studies have shed light on the Ophthalmology, receives
publishing royalties from
mechanisms behind various causes of spontaneous visual hallucinations.
McGraw-Hill, and has provided
expert medicolegal opinion on
SUMMARY: Understanding the regions and neural networks responsible for legal cases involving idiopathic
intracranial hypertension,
higher-order visual function helps the practicing neurologist to diagnose ischemic optic neuropathy, and
and manage associated disorders of visual processing and to identify and traumatic brain injury. Dr Dinkin
treat responsible underlying disease. serves as an associate editor
for the Journal of Neuro-
Ophthalmology and as an editor
for Practical Neurology and has
received compensation for
INTRODUCTION travel for speaking
T
he diagnosis of disorders of higher visual processing often poses a engagements from The
American Austrian Foundation
considerable clinical challenge.1,2 While lesions affecting the eye, optic and research/grant support
nerve, chiasm, radiations, or primary visual cortex present with easily from the Helen and Robert Apel
Foundation. Dr Dinkin has
recognized patterns of monocular, bitemporal, or homonymous provided depositions and
visual field loss, lesions in higher-order visual areas affect vision in expert testimony on
nuanced ways specific to the particular functions of those areas. Patients with medicolegal cases involving
idiopathic intracranial
disorders of higher visual processing may have difficulty describing their hypertension, ischemic optic
symptoms, and routine evaluations of visual function may not readily identify neuropathy, and head trauma.
the problem. A refined examination of higher visual functions is often necessary
UNLABELED USE OF
to correctly localize and identify these syndromes. PRODUCTS/INVESTIGATIONAL
The original detailed descriptions of each disorder of higher visual processing, USE DISCLOSURE:
Drs Prasad and Dinkin report
often from European literature from the 19th century and early 20th century,
no disclosures.
demonstrate how careful clinical observation coupled with postmortem anatomic
investigation yielded tremendous insights that contributed to the foundations
of modern neurology. More recently, scientific investigations using functional © 2019 American Academy
neuroimaging and other techniques have offered further insights into the complex of Neurology.

HIGHER CORTICAL VISUAL DISORDERS
FIGURE 7-1
Simplified representation of striate and extrastriate cortical regions involved in visual processing.
Visual data feed anteriorly through successive specialized regions of the extrastriate cortex
(V1–V6). These regions of the extrastriate cortex are considered part of either the ventral
or dorsal stream. V1, the striate cortex, lies posteriorly and receives raw visual information
from the optic radiations. The basic position and orientation of borders of visual stimuli are
encoded at this level. The ventral stream, which processes features of visual object identity
(the “what” pathway) begins with V2v (ventral V2), which begins to analyze color and the
foreground/background (level of depth) of visual stimuli. Further processing occurs in V3v
and continues in V4, which plays an important role in color discrimination and contains
neurons whose response frequency is tuned to different wavelengths of light. Basic geometric
shapes are encoded at this level as well. Information is fed anteriorly to the inferotemporal
cortex, where the fusiform face area (FFA) resides, encoding facial features to enable
efficient facial recognition. The visual word form area (VWFA) also resides within the fusiform
gyrus and, when disrupted, may cause pure alexia, without associated hemianopia. Visual
spatial processing proceeds along the dorsal stream or “where” pathway in V2d and V3d
and feeds anteriorly to the mesial temporal visual area (MT/V5), which plays an important
role in the perception of motion. The dorsomedial cortex (V6/DM) responds to visual stimuli
associated with self-motion and helps guide reaching and other visually guided motor
actions. Further visuospatial processing occurs in the posterior parietal cortex (PPC).
L = left; R = right.
1330 OCTOBER 2019

structure-function relationships of the human visual system. Disorders of higher KEY POINT
visual processing not only have significant clinical importance but also shed light
● After initial processing in
on important neuroscientific questions regarding normal visual processing in the primary visual cortex,
the brain. Visual disorders resulting from discrete lesions in the brain’s visual numerous adjacent cortical
processing areas often highlight the ways in which higher visual functions may areas continue the work of
be separable, leaving certain aspects of visual processing preserved while others analyzing specific aspects of
visual information. These
are impaired.
areas, which are situated in
the occipital, temporal, and
PRIMARY VISUAL CORTEX AND HIGHER VISUAL AREAS parietal lobes, are given
Visual inputs to the brain are conveyed from the anterior visual pathway through names such as V2, V3, V4,
V5, lateral occipital area, or
the lateral geniculate nucleus of the thalamus and then the optic radiations to
fusiform face area.
arrive in the primary visual cortex, also called area V1, on the mesial surface of
the occipital lobe. No other area of the brain receives such concentrated afferent
sensory input. The abundant myelinated axons of the optic radiations synapse in
cortical layer 4, where they are visible even on gross inspection of the brain,
forming what is termed the stripe of Gennari.3 (This distinctive feature gives the
primary visual cortex its other names, which are striate [striped] or calcarine
[chalky] cortex.) An important feature of the primary visual cortex is that the
arrangement of its inputs is strictly retinotopic, precisely corresponding to
spatial locations in the contralateral homonymous visual field. Neurons in the
primary visual cortex are selective for specific orientations of luminance
contrast; thus, the response properties of these neurons endow them with the
ability to identify the edges of a visual object.4 In addition, initial processing of
color composition, brightness, and direction of motion occurs in the primary
visual cortex.5
After the initial processing in the primary visual cortex, numerous adjacent
cortical areas continue the work of analyzing specific aspects of visual
information. These areas, which are situated in the occipital, temporal, and
parietal lobes, are given names such as V2, V3, V4, V5, lateral occipital area, and
fusiform face area (FIGURE 7-1). A key property of the organization of the cortical
visual system is that the size and complexity of a neuron’s receptive field
progressively increases from lower-order to higher-order processing areas.
Unlike the retinotopic organization in the primary visual cortex, where responses
greatly depend upon circumstantial variables such as the position, orientation,
and lighting of an object within the visual field, in higher-order visual areas,
responses show considerable constancy despite changes in viewing conditions.6,7
Neuronal representations in these higher areas do not possess the strict
point-to-point retinotopic arrangement that is seen in lower areas.8 In higher
cortical areas, integrated information processing endows neurons with receptive
fields responsive to content and context rather than the simpler aspects of
image composition.
THE DORSAL AND VENTRAL STREAMS

The visual processing areas that follow area V1 are spatially arranged by the type
of processing that they perform. The overarching concept of a dorsal (“where”)
pathway and ventral (“what”) pathway was put forth by Ungerleider and
Mishkin9 in 1982. They proposed that occipitotemporal areas in the ventral
stream selectively process the identity of visual objects, with regions that are
specialized for identifying faces, specific objects, or visual scenes. Meanwhile,
occipitoparietal areas in the dorsal stream are selective for spatial features of

visual processing, such as the direction and speed of motion; previously,

subcortical areas such as the superior colliculus were thought to be the major
contributors to the spatial aspects of visual processing.
Ungerleider and Mishkin supported the dorsal/ventral stream model with
several converging lines of evidence, relying heavily on experiments previously
published by Pohl10 in which selective lesions were placed in the frontal, parietal,
or temporal lobes of macaque monkeys. Monkeys with parietal lesions had
significant difficulty judging spatial relationships between objects. Conversely,
monkeys with temporal lobe lesions showed impaired performance on an object
identification task.
Ungerleider and Mishkin’s influential “what/where” concept of visual
processing provides a useful framework with which to localize the clinical
syndromes that occur in humans when a discrete lesion causes a specific disorder
of higher visual processing. One criticism of this classification of the visual
systems, however, is that the distinction is not absolute and categorical; to some
CASE 7-1 A 48-year-old man presented with

complete loss of vision following
bilateral occipital cardioembolic
strokes. He denied blindness and
said he felt “super” (VIDEO 7-1 [online]).
He confabulated that he could see
objects in front of him but when
asked to describe them in detail,
said “I don’t know how to tell.”
He had no difficulty identifying
objects when he held them in his hand.
Even following demonstrations that
he was not seeing properly, he
insisted “my vision is OK.” Despite
the severe visual loss, the remainder
FIGURE 7-2
of his mental status examination
Imaging of the patient in CASE 7-1 with
was normal, and the fundus Anton syndrome. Axial diffusion-
examination and pupillary responses weighted MRI shows acute bilateral
were normal. Diffusion-weighted MRI occipital infarcts with complete loss of
showed acute bilateral occipital vision following bilateral occipital
cardioembolic strokes.
infarcts (FIGURE 7-2). Several months
later, the patient had mild improvement
of vision, and he became fully aware of
the extent of visual loss that remained.
COMMENT The case illustrates that when severe visual loss localizes to the bilateral
occipital cortex, as opposed to the anterior visual pathway, the visual loss
can be accompanied by the fascinating feature of anosognosia constituting
Anton syndrome.
1332 OCTOBER 2019

degree, significant overlap exists in the specialization of discrete visual areas and KEY POINT
their functions are not fully separable. Nevertheless, the conceptual framework
● Anton syndrome refers
retains important value, an idea nicely encapsulated by the cognitive to cortical blindness with
psychologist Martha Farah: “It would be quite surprising if the visual system lack of awareness (ie,
happened to conform to the precise meanings of English-language words like anosognosia) of the deficit.
‘what,’ ‘where,’ or for that matter, ‘how.’ The search for the perfect everyday
word to label these neural systems, or the worry that not all features of these
words’ meanings are appropriate to describing these systems’ functions, may
distract us from the important points: the insight that there is extensive, if not
total, division of labor between these two systems.”11
ANTON SYNDROME
Anton syndrome refers to blindness due to bilateral occipital lesions with lack of
awareness (ie, anosognosia) of the deficit.
Clinical Presentation
Patients with Anton syndrome have a dramatic presentation characterized by
lack of awareness or denial of complete visual loss owing to bilateral occipital
lesions (CASE 7-1). Even after direct demonstration of their severe visual loss,
they remain certain that their vision has no significant impairment. They often
confabulate responses when asked to describe the visual features of an object
presented to them. The anosognosia accompanying cortical blindness generally
wanes over weeks to months, as patients begin to demonstrate recognition of
the loss of vision that has occurred. As with all cases of postgeniculate vision
loss, the pupillary responses and optic nerve appearance on funduscopy
remain normal.
Historical Background
In 1899, the Austrian neuropsychiatrist Gabriel Anton12 described a 56-year-old
woman who was unware of her severe acute visual loss. At autopsy, he
found infarction of both occipital lobes. Based on these findings, he advanced
the powerful concept of network connections in the brain, accounting for
the fact that bilateral occipital lesions would produce profound visual loss while
functional disturbances in distributed networks would give rise to anosognosia.
Neuroscientific Investigations
The precise neuroanatomic substrate for the loss of awareness of the profound
vision loss in patients with Anton syndrome is not known, but a good deal of
work has been done to try to elucidate the mechanisms that govern conscious
awareness of vision in general. One model proposes that activity in regions of the
visual cortex immediately downstream of area V1 form the neural correlate of
visual awareness. For example, using functional MRI (fMRI) to assess responses
to visual masking illusions (in which the same simple stimulus is either perceived
or not perceived depending on the timing of presentation of a specific
surrounding context), Tse and colleagues13 found that activity in area V3 and
other downstream regions of the extrastriate cortex correlated with visual
awareness. In contrast, activation in areas V1 and V2 did not reflect conscious
visual perception.
Along these lines, some investigators emphasize that the intensity of activation
in visual areas is a critical component of awareness. Moutoussis and colleagues14

CASE 7-2 A 23-year-old woman presented with severe visual impairments after
hypoxic arrest from a narcotic overdose. She described her vision as
distorted or blurred. She could tell an object was in front of her but could
not tell what it was. Faces were “completely distorted” (VIDEO 7-2
[online]). She could not identify any visually presented objects, could not
read letters, and could not copy simple line drawings correctly. Visual
acuity, tested with the preferential looking test (in which the patient
directs the eyes toward a set of black-and-white stripes, with the
thickness of the stripes in some examples approximating 20/20 vision)
was normal, and she had no other cognitive deficits. Despite the profound
difficulty with visual processing, she avoided obstacles when walking,
reached for targets, and grasped objects accurately. Fluid-attenuated
inversion recovery (FLAIR) MRI showed sulcal hyperintensity from hypoxic
injury in occipital areas (FIGURE 7-3).
FIGURE 7-3
Imaging of the patient in CASE 7-2 with apperceptive visual agnosia. Axial fluid-attenuated
inversion recovery (FLAIR) MRIs show bilateral occipital cortical hyperintensities (arrows).
COMMENT This case exemplifies the profound visual processing defect that occurs
with apperceptive visual agnosia, obliterating visual object recognition
although elementary visual acuity remains essentially normal, with relative
sparing of reaching, grasping, and navigating under visual guidance.
1334 OCTOBER 2019

used a dichoptic color fusion experimental paradigm (in which simple two-colored KEY POINT
line drawings of houses or faces were shown to each eye with either the same
● Visual agnosia refers to a
color contrast, so the composite image was visible to the subject, or the opposite specific impairment of the
color contrast, so the composite image was invisible). fMRI data collected ability to recognize or
during this experiment revealed that the same face-responsive areas and interpret visually presented
house-responsive areas were activated in both conditions but activated more information although
elementary aspects of vision
strongly in the condition in which the objects were perceived consciously. These
remain intact.
data suggest that it is not just the presence but also the strength of activation in
key visually responsive areas that may determine visual awareness.
Another model proposes that visual awareness involves more distributed
regions of the brain, including frontoparietal areas. Lumer and colleagues15,16
used a binocular rivalry experiment (presenting a face to one eye and moving
stripes to the other eye) while fMRI images were acquired to elucidate which
regions reflected the conscious perception of a particular image. The authors
found that activation in the extrastriate visual cortex, inferior parietal areas, and
prefrontal areas together correlated with conscious visual perception. These
findings emphasize that conscious visual perception may be determined by
interactions in widely distributed networks rather than modular activation in
specific visual areas.
Godwin and colleagues17 built on this idea by showing that visual awareness
relates to decreased modularity of functional networks of the brain. They used
graph theory analytical methods to evaluate functional connectivity fMRI data
acquired during a visual masking experiment (in which presentation of a visual
target stimulus may or may not have been consciously perceived depending on
the masking effect of a second brief stimulus that was shown almost immediately
before or after the target). Their results showed that conscious perception
correlated with distributed cortical areas activating in concert rather than as
separate modules.
It remains unclear which explanations will prove to best define the neural
correlates of visual awareness, and the proposed models may not be mutually
exclusive. It is clear, however, that the clinical phenomenon of Anton syndrome
demonstrates how acute injury to the primary visual cortex can disrupt
functioning of the neural mechanisms that normally allow recognition of a lack
of vision.
APPERCEPTIVE AND ASSOCIATIVE VISUAL AGNOSIA

Visual agnosia refers to a specific impairment of the ability to recognize or
interpret visually presented information although elementary aspects of vision
remain intact.
Patients with visual agnosia cannot identify objects presented visually, but other
cognitive functions are normal and patients have no difficulty identifying objects
perceived through touch or sound (CASE 7-2). These patients cannot read
because they incoherently process visual forms, so a standard eye chart cannot be
used to measure the preserved visual spatial acuity. Despite the profound
abnormality of visual processing, the spatial acuity remains essentially normal in
these patients, which can be demonstrated with tests that do not require
conscious visual processing. One example is the preferential looking test, in
which a patient does not need to recognize or name any visual stimulus but

simply looks at black-and-white gratings if they are perceived. The different

gratings comprise a range of spatial frequencies, including some that approximate
20/20 vision.
In apperceptive visual agnosia, although spatial acuity is preserved, the
remaining steps of visual processing are disrupted at a very early stage, rendering
patients unable to perceive even the most basic geometric relationships that
create the contours of a visual object. For example, they cannot judge the position
or orientation of a line; perceive the way in which a group of contours come
together to create a coherent, unified perceptual whole; or judge how one visual
object might overlap and partially obscure another. Essentially, their visual
system does not perform the basic automatic geometric analyses that are the
building blocks of visual perception.
Most cases of apperceptive visual agnosia result from anoxic injury, such as
respiratory arrest or carbon monoxide poisoning.18–20 Some patients with
apperceptive visual agnosia will try to trace the visual stimulus overtly with a finger,
or sometimes covertly with head movements, because the kinesthetic sense may
allow them to perceive the composition of a shape based on its local contours.19
Heinrich Lissauer21 described visual agnosia in an extensive case report published
in 1889. He described an 80-year-old man with severe difficulty visually
recognizing even the most common objects, but testing his vision in a manner
akin to the preferential looking test showed that his visual acuity was essentially
normal. After autopsy analysis of the case, Lissauer concluded that visual agnosia
is caused by moderately extensive damage to the occipital cortex. Lissauer
proposed the existence of two types of visual agnosia: apperceptive, in which the
patient does not coherently perceive the geometric relationship of contours
defining visual objects, and associative, in which the patient can perceive and
even copy the shape of an object but is unable to recognize it.
Defining the edges of a visual object is a necessary step in the efficient handling of
large volumes of visual information. Without the ability to segment an image
into regions corresponding to objects, we would have no way of understanding
complex visual stimuli and would fruitlessly try to recognize nonobjects composed
of overlapping or juxtaposed items.
Area V2 makes significant contributions to image segmentation by manipulating
the inputs it receives from area V1. The image segmentation that occurs at this stage
is critically influenced not just by objective bottom-up inputs but also by internal
top-down mechanisms representing the current perceptual interpretation of the
visual stimulus. The Kanizsa triangle is a dramatic illustration of this phenomenon;
when three “Pac-Man” figures are positioned in a specific orientation relative to one
another, the image is perceived as being composed of a triangle lying atop three
circles (FIGURE 7-4).22 The edges of the perceived triangle are illusory and are not, in
fact, part of the physical visual stimulus. In a remarkable illustration of the neural
mechanisms underlying image segmentation and perceptual grouping, Von der
Heydt and colleagues23 showed that unlike neurons in area V1 that respond to
true contours alone, neurons in cortical area V2 respond to illusory contours as
well. This finding is supported by similar studies24 also showing that neuronal
processing in area V2 blurs the distinction between truth and perception.
1336 OCTOBER 2019

Further insights about the KEY POINTS
nature of apperceptive visual
● In apperceptive visual
agnosia emerged from agnosia, although spatial
landmark studies of a acuity is preserved, the
35-year-old woman who remaining steps of visual
experienced severe carbon processing are disrupted at
a very early stage, rendering
monoxide poisoning in 1988.20
patients unable to perceive
Like other patients with even the most basic
apperceptive visual agnosia, she geometric relationships that
demonstrated severe deficits in create the contours of a
visual object.
shape recognition and orientation,
despite preserved acuity, color ● Associative visual agnosia
vision, and tactile discrimination. describes a disorder in
When she was shown a mail slot which basic visual
FIGURE 7-4 perception is preserved,
Efficient image segmentation in the visual system. at varying angles, she could not
including grouping of visual
The Kanizsa triangle is a vivid demonstration of the describe or match its orientation forms, but visual percepts
role of illusory contours in visual processing, in space; however, when she cannot be associated with
allowing efficient image segmentation and reached her arm forward to put a relevant stored semantic
perceptual grouping of objects. knowledge.
card into the slot, her accuracy
was perfect. Similarly, when she
was shown objects of various sizes, she could not describe the dimensions;
however, when she reached for the object, her grip aperture scaled perfectly
relative to its size. Based upon these detailed psychophysical investigations,
Goodale and Milner25 refined the traditional concept of the Ungerleider-Mishkin
what/where framework. They suggested that, in addition to its characterization
as a “where” pathway, the dorsal stream should be recognized as a “how”
pathway, emphasizing its role in using visual information to guide limb
movements that allow a person to interact with and manipulate the environment.
fMRI studies in this patient have supported their theory, revealing severe
disruption of regions in the ventral stream but preserved activity in regions of
the dorsal stream during visually guided motor actions.26,27
In patients with associative visual agnosia, as opposed to apperceptive
visual agnosia, basic aspects of visual perception are generally preserved, but
the visual percept is no longer associated with relevant stored semantic
knowledge. In the words of Teuber,28 the visual percept for a patient with
associative visual agnosia becomes “stripped of its meaning.” Patients with
associative visual agnosia can see an object well enough to describe its
appearance, make an accurate drawing of it, and correctly distinguish it as the
same or different from other examples, although they cannot state its name or
describe its purpose. In one well-documented case, a physician developed
associative visual agnosia after hypoxic brain injury and described a
stethoscope as a “long cord with a round thing at the end” and could not
recognize what it was used for.29 The failure of object recognition is limited to
visual perception alone; patients are able to answer factual questions about
objects and can recognize them when queried through other sensory
modalities, such as touch or hearing.
CENTRAL HEMIACHROMATOPSIA
Abnormalities of color vision are a common consequence of disorders of the
optic nerve or retinal photoreceptors, including congenital color blindness due

KEY POINT to inherited differences in the responses of cone photoreceptors. In these cases,
the impairment of color vision affects one or both eyes. Lesions of the central
● Central
hemiachromatopsia
nervous system can also lead to altered color perception in which the deficit
describes loss of color is limited to one homonymous visual field. Such a deficit, called central
recognition in the hemifield hemiachromatopsia, arises when a lesion disrupts area V4 in the inferior
contralateral to a lesion of occipital cortex, which is specialized for color vision processing in the
V4, a region in which
contralateral hemifield.
neurons are selectively
responsive to specific
wavelengths of light. In Clinical Presentation
clinical practice, lesions Although rare, a circumscribed lesion isolated to area V4 in one hemisphere
often encompass this area
would produce hemiachromatopsia affecting only the contralateral hemifield;
as well as the adjacent
inferior striate cortex (V1), other visual functions, including color vision in the ipsilateral visual field, would
causing an overlapping be spared. In clinical practice, it is more common to encounter a lesion that
superior quadrantanopia, so affects V4 in the inferior occipital cortex but also includes the inferior bank of the
that the achromatopsia is primary visual cortex. In this case, a contralateral superior field defect also
only evident in the seeing
inferior visual field. occurs, and the color vision impairment in the contralateral hemifield will be
detected only in the inferior quadrant (FIGURE 7-5, CASE 7-3).
In 1888, the Swiss ophthalmologist Louis Verrey30 first reported loss of color
vision isolated to a homonymous visual field. Carefully examining a 60-year-old
woman, he found that color perception was abolished in one binocular hemifield
and the colored object had to be brought into the other hemifield for its color
to be recognized. At autopsy, he found that the patient had a hemorrhagic stroke
FIGURE 7-5
Consequences of lesions involving area V4. A, A lesion circumscribed to area V4 in the inferior
occipital cortex (red oval) would cause loss of color vision perception in the contralateral
homonymous visual field. B, In clinical practice, it is more common to see a lesion that
involves area V4 but also involves the inferior bank of area V1, producing a loss of color vision
perception in the contralateral homonymous visual field coupled with a contralateral
superior quadrant field deficit.
1338 OCTOBER 2019

in the inferior occipital cortex and concluded that this region was specialized
for color vision in the contralateral hemifield. For many years, Verrey’s notion of
a cortical center for color was rejected, including by prominent neurologists
such as Holmes,31 because it was not yet appreciated that different aspects of
visual processing were subserved by discrete cortical areas.
Verrey was finally vindicated in 1973, when Zeki32 used single-cell recordings to
identify a region of neurons in a macaque whose responses were, in fact, purely
selective for color, with each neuron responding to a certain band of wavelengths.
He named this cortical region area V4. Shortly afterward, the homologous
cortical area specialized for color processing was identified in humans using
functional neuroimaging.33,34
Color-specific cortical responses in human V4 have also been studied in patients
undergoing intracranial EEG monitoring; direct electric stimulation of area V4 in
A 57-year-old woman CASE 7-3

presented with a left
superior quadrant
homonymous field deficit
due to a right inferior
occipital stroke. Examination
showed that she was unable
to discriminate colors in the
left inferior homonymous
field, saying that cards of
various colors shown in
that area were gray or white
(VIDEO 7-3 [online]).
Diffusion-weighted MRI
showed acute right inferior
occipital infarction involving
the inferior bank of area V1 FIGURE 7-6
and area V4 (FIGURE 7-6). Findings of the patient in CASE 7-3 with central
hemiachromatopsia. A, Automated perimetry
shows left superior quadrant homonymous field
deficit. B, Axial diffusion-weighted MRI shows
acute right inferior temporooccipital infarction
involving the inferior bank of V1 and area V4.
If the left superior quadrant homonymous field deficit were due to a COMMENT
lesion disrupting the inferior optic radiations (the Meyer loop), then
color vision in the spared inferior quadrant would be expected to be
normal. Instead, this case demonstrates loss of color vision in the spared
inferior quadrant of the contralateral homonymous visual field,
implicating a lesion in the inferior occipital cortex affecting both the
inferior bank of area V1 and area V4.

these patients produces alterations in color perception.35 In addition to its critical

role in color processing, area V4 plays an important role in processing form, such
as the aspect ratio and spatial frequencies of a visual stimulus.36 It is the major
source of input to downstream areas in the temporal lobes that process different
types of visual objects.
Since Verrey’s time, much has been learned about how color vision is analyzed
at each level of the visual system before the specialized processing that occurs in
area V4 within occipital cortex. Color vision inputs are processed and relayed
from retinal cone photoreceptors to P-type retinal ganglion cells, to parvocellular
cell layers in the lateral geniculate nucleus, to blob and interblob regions in layers
2 and 3 of primary visual cortex, to the thin stripes of area V2, and finally to area
V4. Unlike all the color-responsive areas before it, however, area V4 is unique in
that it encodes a key aspect of color perception called color constancy (FIGURE 7-7).
The normal perception of the color of an object not only accounts for the
wavelengths of light that are reflected by the object but also the spectral
composition of the lighting conditions. For example, a red bike will reflect very
different wavelengths of light in daylight or dusk or under a fluorescent light
bulb, but it will generally be perceived as being red in all these conditions. Before
area V4, color-responsive neurons convey information about the precise
wavelengths of light that are reflected from the object and are significantly
influenced by changes in overall illumination. Remarkably, this is not the case in
area V4; processing in V4 adjusts for the spectral balance of incident light so that
the redness of the bike is perceived as being fairly constant despite considerable
differences in lighting environments. As Land37 showed in 1977, V4 neurons are
not influenced by changes in illumination, and their responses match the color
that is consciously perceived. V4 neurons accomplish color constancy because
their receptive fields have large inhibitory surrounds,38 allowing correction for
wavelengths comprising the background illumination.
In addition to hemiachromatopsia that results from a lesion in area V4,
other cortical disorders relating to color processing also exist. Color anomia is a
categorical language disorder in which patients have a specific impairment in
producing the names of colors but can name other types of objects.39 Color
FIGURE 7-7
Color constancy. A red bike is perceived as red despite considerable changes in lighting
conditions. Lower-level areas processing color signals, beginning with cone photoreceptors
in the retina, are sensitive to the exact wavelengths of light being reflected in these settings.
In contrast, area V4 accounts for the ambient spectra of light to achieve the psychophysical
property of color constancy.
1340 OCTOBER 2019

perception is intact in this disorder; although colors cannot be named correctly, KEY POINTS
performance remains normal on a color-matching task. Another entity referred
● Processing in V4 adjusts
to as color agnosia lacks a clear definition and has been interpreted in various for the spectral balance of
ways.40–42 The most common interpretation is that it refers to impaired semantic incident light so that the
knowledge about colors despite intact color perception (eg, not knowing that a apparent color of an object
strawberry is red or a school bus is yellow). is perceived as being
fairly constant despite
considerable differences in
ALEXIA WITHOUT AGRAPHIA lighting environments. This
Alexia without agraphia, also referred to as pure alexia or pure word blindness, phenomenon is known as
describes the loss of the ability to read, although the ability to write remains color constancy.
intact (CASE 7-4).
● Alexia without agraphia,
also referred to as pure
Clinical Presentation alexia or pure word
The deficiency in alexia without agraphia is limited to the perception of blindness, describes the
written language; production and comprehension of spoken language is fully loss of the ability to read,
although the ability to write
preserved, indicating that the patient does not have a broader aphasia and that remains spared. It is often
language areas remain intact. Patients with alexia without agraphia read the result of a lesion
extremely slowly and make numerous errors. They may try to compensate by affecting both the left
using letter-by-letter reading but frequently confuse similar looking letters. occipital cortex and the
splenium of the corpus
They have extreme difficulty with irregular phonemic words (such as yacht or callosum. A right
colonel.) Degraded writing, such as handwriting rather than typed script, homonymous hemianopia
often poses even greater challenges. Remarkably, patients will not be able to ensues, while visual
read a sentence that they have written themselves. information in the right
occipital cortex cannot
In most cases, alexia without agraphia results from a lesion in the left occipital
reach the left-sided
cortex that also involves the splenium of the corpus callosum. Alexia occurs because language areas to allow
vision cannot be transmitted to intact language areas; there is no vision processing in linguistic analysis of the
the left occipital cortex, and the splenium lesion disconnects visual areas in the right visualized symbols.
occipital cortex from the left hemisphere (FIGURE 7-9). As such, alexia without
● Alexia without agraphia
agraphia is a type of disconnection syndrome in which primary regions responsible may also result from a single
for neurologic function are intact (in this case, vision within the left field and lesion in the visual word
language centers), but pathways allowing cross talk between them are not. form area within the
In rare cases, a version of alexia without agraphia can occur without a right fusiform gyrus.
homonymous hemianopia. These cases result from a discrete lesion situated in
the visual word form area in the fusiform gyrus (FIGURE 7-10).43
The syndrome of alexia without agraphia was first described by Joseph Jules
Dejerine44 in 1892 in a 68-year-old man who was walking in Paris when he
suddenly noticed that he could no longer read. Dejerine found that the patient
had normal spoken language, with no trace of aphasia. The patient’s writing was
normal, with no mistakes or spelling errors. However, it was impossible for the
patient to read. The patient was frustrated, writing words and then saying, “I still
know how to write letters; here they are; why am I unable to read them?”44
Dejerine called the deficit pure word blindness. The patient had a right
homonymous visual field deficit, as occurs in most (but not all) patients with
alexia without agraphia. At autopsy, the patient was found to have an ischemic
stroke affecting the left occipital lobe, extending anteriorly to involve the
splenium of the corpus callosum.
Dejerine knew that normal reading requires that vision be linked to
language areas in the dominant hemisphere, and he reasoned that the syndrome

CASE 7-4 A 41-year-old man with an infiltrating glioma involving the left occipital
lobe and splenium of the corpus callosum (FIGURES 7-8A and 7-8B) had a
profound inability to read words with both regular or irregular phonemic
spelling, although writing and spoken language remained normal. He was
unable to read a sentence he had written himself, saying “I don’t know,
it’s almost like I didn’t write it” (VIDEO 7-4 [online]). Examination
demonstrated a right superior greater than inferior homonymous
hemianopia (FIGURE 7-8C).
FIGURE 7-8
Findings of the patient in CASE 7-4. A, Axial fluid-attenuated inversion recovery (FLAIR)
MRI demonstrates edema within the left occipital and temporal cortices and across the
splenium of the corpus callosum. B, Axial contrast-enhanced T1-weighted MRI
demonstrates enhancing tumor extending into the left occipital cortex. C, Humphrey
automated perimetry demonstrates a right superior greater than inferior hemianopia.
COMMENT This case demonstrates pure alexia. The ability to write remains normal,
and the patient has no disturbance of spoken language. Language areas in
the left hemisphere remain intact, but the connections from visual areas are
disrupted, rendering the patient unable to read the language in which he was
once fluent. As in most cases of alexia without agraphia, the responsible
lesion involves the left occipital cortex and crossing fibers in the
splenium of the corpus callosum. As such, a right homonymous field
defect is also present.
1342 OCTOBER 2019

of alexia without agraphia
occurred when visual
information could no longer be
relayed to intact language areas.
The large left occipital lesion in
this patient disrupted any visual
information being processed in
the left occipital lobe, and the
posterior corpus callosum
involvement meant that visual
information in the right occipital
lobe was disconnected from
intact language areas on the left
FIGURE 7-9 (FIGURE 7-8C).
Anatomy of alexia without agraphia showing
disconnection of intact vision in the right Neuroscientific Investigations
hemisphere from language areas in the left
Geschwind45 popularized the
hemisphere.
idea that alexia without agraphia
was one of the classic neurologic
disconnection syndromes. The Damasios46 subsequently analyzed a series of
cases and confirmed the localization of lesions to the left occipital lobe,
compromising both interhemispheric and intrahemispheric visuo-language
pathways. Since that time, functional imaging studies have shown that a
FIGURE 7-10
Pure alexia and the visual word form area. A 59-year-old woman developed difficulty reading
due to a glioblastoma involving the visual word form area in the left occipitotemporal lobe.
Writing and spoken language were normal. Visual field testing was also normal, without a
homonymous field deficit. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI of this
patient showing postsurgical changes following biopsy of a left lateral occipitotemporal
glioblastoma. B, Functional MRI (fMRI) showing the location of the visual word form area
(yellow areas) in healthy individuals demonstrated by experiments identifying responses
selective for written words more than nonword stimuli otherwise matched for the amount of
visual information.
Panel B reprinted with permission from Dehaene S, Cohen L, Trends Cogn Sci.43 © 2011 Elsevier Ltd.

particular region in the left inferior occipital lobe known as the visual word form
area is specialized for words compared to other arbitrary symbols.47,48 A 2005
investigation using MRI diffusion tensor tractography in a patient with alexia
without agraphia demonstrated a reduction of interoccipital fibers and left
occipitotemporal fibers.49 Some have suggested that alexia without agraphia is a
circumscribed type of simultanagnosia, impairing the ability to process multiple
letters at a time and thus forcing the patient to read letter by letter.50
Conversely, agraphia without alexia, in which reading is intact but motor
output of written graphemes is impaired, may occur in the setting of a left
CASE 7-5 A 37-year-old woman presented with difficulty distinguishing faces due
to a metastatic lesion involving the right occipitotemporal cortex in the
fusiform face area. She said that faces look “smoother and less defined.”
She called it the “Instagram filter in my brain” (VIDEO 7-5 [online]). The
remainder of her examination was normal, including visual acuity and
visual field testing. Brain MRI showed a large postoperative surgical
resection cavity in the right inferior temporal cortex (FIGURE 7-11).
FIGURE 7-11
Imaging of the patient in CASE 7-5 with prosopagnosia. A, Axial postcontrast T1-weighted
MRI shows a large metastatic lesion in the right temporal lobe (arrow). B, Postoperative
fluid attenuated inversion recovery (FLAIR) MRI shows the surgical resection cavity in the
right temporal lobe (arrow). The lesion disrupts the fusiform face area, which contributes
to the normal visual processing of faces as a special category of objects.
COMMENT This case illustrates the specific isolated deficit in visual processing of
faces that can result from a lesion that affects face-selective processing
areas in the inferotemporal cortex.
1344 OCTOBER 2019

angular gyrus lesion.51 When agraphia is accompanied by acalculia, left-right KEY POINT
confusion, and finger agnosia (the inability to name the different fingers), it is
● Prosopagnosia is a
known as Gerstmann syndrome.52 specific form of visual
agnosia in which face
PROSOPAGNOSIA perception is impaired while
Prosopagnosia is a specific form of visual agnosia in which face perception is elementary aspects of
vision, such as acuity and
impaired while elementary aspects of vision, such as acuity and visual field,
visual field, remain intact.
remain intact (CASE 7-5).
Patients with prosopagnosia lack the ability to perceive the unique features that
distinguish an individual face from others. They have significant difficulty
recognizing the identity of a face or distinguishing whether it is familiar to them.
When looking in a mirror, even their own face is not recognized as being their own.
Typically, patients with this debilitating disorder rely on identifying individuals
by using other clues, such as gait, physical mannerisms, clothing, or voice.
The term prosopagnosia was first used by Bodamer53 in 1947. He described three
patients who lost the ability to identify faces after sustaining injury to the
occipitotemporal lobes. One of these cases was a 24-year-old man who had
suffered a bullet wound to the left occipitotemporal lobe and then described faces
as looking “blurred, pressed flat, without particular expressions.” He described
an inability to see what was special or unique about an individual face. Bodamer
performed an experiment in which the man was unable to distinguish his wife
when she stood beside several nurses who were of a similar height and weight
and dressed the same. He concluded that normal visual perception includes
specialization for face processing and defined prosopagnosia as the selective
disruption of this capacity.
Human beings are expert at extracting information from a face to accurately and
effortlessly identify it. In many ways, most people are face experts, possessing
a critical ability to discern subtle identifying features between one face and
the next. Unlike the generality with which we identify many other objects, in
most cases, the specific identity of a face must be determined. Adding to this
complexity is the fact that the exact visual information contained in the contours
of a face can be highly variable depending on the viewing angle and illumination.
Human expertise for face perception stems from a specialized group of
neurons in the ventral processing stream known as the fusiform face area.
Kanwisher and colleagues54 first identified this area of inferior occipitotemporal
cortex in their 1997 fMRI experiments detecting areas that were selectively
more responsive to faces than other types of objects or scrambled images
(FIGURE 7-12). The concept that face identification has a privileged status in the
visual system was not unique, however. For example, the 17th century Italian
artist Giuseppe Arcimboldo created a popular series of paintings depicting a bowl
of fruit or vegetables, but when the paintings were inverted, it became very easy
to see a face “hiding” in the picture (FIGURE 7-1355,56). Over 400 years before
Kanwisher’s fMRI experiments identified the fusiform face area, Arcimboldo
was well aware of the human visual system’s innate tendency to see faces

FIGURE 7-12
The fusiform face area. Functional MRI (fMRI) studies in healthy individuals identified cortical
areas showing specialization for face processing. This image is from Kanwisher’s landmark
study showing the selective neural responses to faces (F) compared to objects (O). The
fusiform face area exists in the bilateral occipitotemporal cortex in most individuals, with
preferential lateralization to the right more than left hemisphere.
Modified with permission from Kanwisher N, et al, J Neurosci.54 © 1997 Society for Neuroscience.
wherever it could. In fact, his paintings presaged the finding that facial
recognition in the visual system is particularly sensitive to the orientation of an
image, much more so than other types of object processing.57 This phenomenon
is the basis of the “Thatcher illusion” created by the psychologist Peter Thompson,
which dramatically shows how changes in facial features (in this case, inverting
the eyes and mouth in an image of Margaret Thatcher) are easily detected in a
right-side up representation when the fusiform face area processes the image but
not in an upside-down representation when object recognition areas process the
image instead (FIGURE 7-13).
A key question arises when considering how the visual system processes
faces: Is face perception simply a component of a general object recognition
system or does it represent a distinct specialized neural mechanism? Although
some patients with prosopagnosia also have difficulty recognizing other types
of objects, in most cases, face perception is affected almost in isolation.58 In
contrast, other patients with a general visual agnosia will frequently have the
opposite pattern—a severe deficit for object recognition but relative sparing of
face perception.59,60 For example, one report describes an episode in which a
patient with visual object agnosia, who had normal face perception, struggled to
drink his coffee because he could not identify which object in front of him was
the coffee mug.60 When this patient viewed paintings by Arcimboldo, he would
see the face but not the fruits or vegetables comprising the picture. Thus, the dual
dissociation between disorders of face perception and object perception suggests
that the neural processes mediating face perception are, to some degree,
independent of the processes involved generally in object perception.
Although evidence suggests the existence of right-hemispheric specialization
for face processing, in most individuals a significant contribution is made by
the fusiform face area in both hemispheres. For this reason, cases of acquired
prosopagnosia that are severe typically require bilateral lesions involving
inferotemporal cortex. Damasio and colleagues61 described three original cases
of prosopagnosia and 10 previously reported cases with autopsy confirmation
of the lesion localization, finding bilateral lesions in every case. On the other
1346 OCTOBER 2019

hand, although quite infrequent, KEY POINTS
occasional cases may occur in
● Facial recognition in the
which a single right- or left-sided visual system is particularly
lesion in this location is sufficient sensitive to the orientation
to cause clinically significant of an image, much more so
prosopagnosia.62 than other types of object
processing.
In contrast to cases of acquired
prosopagnosia (from lesions in ● Riddoch syndrome
the inferior occipitotemporal describes the preserved
cortex), some individuals ability to detect motion in an
demonstrate developmental otherwise blind visual field.
prosopagnosia from childhood

not due to any apparent cortical
injury. fMRI studies in some of
these individuals have shown
diminished face-specific
activation in the region normally
identified as the fusiform face
area.63 Similarly, measurement
of evoked potentials in these
FIGURE 7-13 individuals also demonstrates
Specialization for face perception in the human loss of expected face-selective
visual system. The 17th century Italian artist waveforms in the region
Giuseppe Arcimboldo created a series of pictures
containing the fusiform face
that took advantage of the proclivity of the human
visual system to extract the features of a face. area.64
This example shows a bowl of vegetables (A), but
when the picture is inverted (B), face-selective RIDDOCH SYNDROME
regions activate and a face is inevitably perceived. Riddoch syndrome describes the
Similarly, in the striking example of face-specific
processing known as the Thatcher illusion, one preserved ability to detect motion
can barely notice something wrong with this in an otherwise blind visual
manipulated image of Margaret Thatcher’s face field.65 This phenomenon is
when it is upside down (C), but when the face is referred to as statokinetic
viewed right side up (D), the features that do not
conform to a normal face are easily recognized.
dissociation, in which the
Panels A and B reprinted from giuseppe-arcimboldo.org.55 presence of an object is perceived
Panels C and D reprinted from Thompson P, Perception.56 only if it is moving (FIGURE 7-14,
VIDEO 7-6 [online]).
© 1980 SAGE Publications.
Patients with Riddoch syndrome have a visual field deficit in which the form
and color of an object cannot be appreciated. The patient is unaware of an object
if it is stationary. However, if the object moves, it can be reliably but coarsely
perceived, albeit without accurate sense of form or color. The preserved motion
discrimination can include the ability to distinguish features such as direction
and speed of motion. A similar, related phenomenon is termed blindsight, in
which patients lack conscious awareness of vision, yet their actions indicate
awareness of some aspects of visual information, such as motion alone.
Riddoch66 described the phenomenon of statokinetic dissociation in 1917. He
described 10 patients, all soldiers in World War I who had been injured with

shrapnel from bullets. British

soldiers at that time wore what
was known as a Brodie helmet,
which had the shape of a soup
bowl; it offered protection from
projectiles bursting above but did
not protect the base of the head,
leaving soldiers vulnerable to
penetrating trauma affecting the
occipital lobe. Performing
confrontation visual field testing
on these patients, Riddoch
found that fingers were not
perceived in the blind hemifield
when they were kept stationary
but were accurately identified
when they were moving. By
FIGURE 7-14
Riddoch syndrome. A 15-year-old developed a examining the location of the
dense right homonymous visual field deficit after entry wound and x-ray films, he
a left PCA stroke following a traumatic head injury reasoned that a circumscribed
with expansion of an epidural hematoma. As she portion of the primary visual
recovered, she found that she could detect
motion in the otherwise blind field. A, Axial fluid- cortex was affected and that
attenuated inversion recovery (FLAIR) MRI shows nearby motion processing
a left posterior cerebral artery stroke (arrow) in areas were spared.
the acute phase. B, Axial T1-weighted MRI 2 years
later shows atrophy of the left occipital cortex
(arrow) with dilatation ex vacuo of the left lateral
The cortical area specialized for
ventricle. C, Static Humphrey automated perimetry
demonstrates a right homonymous field defect. processing motion is called V5
and is situated dorsal to the
primary visual cortex in the
occipital lobe. Some controversy
persists regarding how visual inputs arrive at this area to give rise to the
statokinetic dissociation seen in Riddoch syndrome. Some researchers have
assessed fMRI responses in a patient with this disorder and, failing to find
responses in V1, have suggested the existence of additional direct subcortical
projections to area V5.67,68 Furthermore, MRI diffusion-weighted
tractography has suggested the presence of an intact structural connection
between the lateral geniculate nucleus and V5 in patients with blindsight,
which is not preserved in patients without blindsight.69 Kinoshita and
colleagues70 studied the phenomenon of hemifield blindsight induced in
monkeys following inactivation of neurons in the ventrolateral pulvinar that
receive superior colliculus input. They argue that this ventrolateral
pulvinar–superior colliculus pathway plays an important role in preservation
of motion detection in blindsight through direct communication with
extrastriate areas, including V5.
On the other hand, the clinical phenomenology of Riddoch syndrome does not
necessarily need to rely on spared direct inputs to area V5. Other investigators
have found small islands of activation within the lesioned portion of the primary
visual cortex; these spared areas may be too sparse to support aspects of vision
processing such as shape, color, or form, yet they may adequately relay
1348 OCTOBER 2019

information to V5 that is sufficient for KEY POINTS
motion processing.71 Along these lines, it is
● Balint syndrome
known that severely impoverished inputs describes a profound
at any level of the visual system will disruption of visuospatial
compromise most aspects of visual attention mechanisms
processing while leaving coarse motion resulting from bilateral
parietal lesions. Its
perception preserved (FIGURE 7-15).
key features are
simultanagnosia, optic
BALINT SYNDROME ataxia, and ocular apraxia.
Balint syndrome describes a profound
disruption of visuospatial attentional ● Simultanagnosia refers to
an ability to perceive the
mechanisms resulting from bilateral local elements of a scene
parietal lesions. Despite preservation of but not the global elements
elementary aspects of vision (such as in their totality.
acuity) and ventral stream functions
● Optic ataxia refers to
(such as object recognition), patients are impaired reaching under
profoundly affected by an inability to visual guidance, in
disengage and shift their attention to which reaching under
various parts of a visual scene (CASE 7-6). proprioceptive guidance (ie,
FIGURE 7-15 back to one’s own nose) is
Theoretical explanations for Riddoch preserved. Ocular apraxia
Clinical Presentation syndrome. While some data suggest the refers to inaccurate
One deficit in patients with Balint existence of direct projections to area saccades stemming from a
syndrome is simultanagnosia, which refers V5, many cases result from incomplete disorder of visuospatial
lesions that disrupt visual inputs in early attention.
to an ability to perceive the local elements areas such as V1, allowing only motion
of a scene but not the global elements in perception to persist without other
their totality. In colloquial terms, this visual abilities. The image shows
perceptual problem might be described as functional MRI (fMRI) data from a
16-year-old with Riddoch syndrome,
“missing the forest for the trees.” This may revealing islands of spared activation in
be tested using a Navon figure, which is a the lesioned cortex (depicted in dark
large letter (eg, S) composed of many blue) spanning area V1.
smaller letters (eg, E) (FIGURE 7-17); the Reprinted with permission from Radoeva,
et al, J Cogn Neurosci.71 © 2008
patient with simultanagnosia will see the Massachusetts Institute of Technology.
small letters but be unable to see the
larger one.72 In clinical practice,
simultanagnosia may also be detected by
asking the patient to describe a visual scene, such as the National Institutes of
Health Stroke Scale cookie theft picture. The patient may recognize individual
items, such as water, a child, cookies, and dishes, but fail to recognize the overall
story being depicted in the scene. Another component of Balint syndrome is optic
ataxia, referring to impaired reaching under visual guidance. Unlike cerebellar
ataxia, the movement back to touch one’s nose remains accurate with optic
ataxia, since proprioception, not visuospatial attention, is required for this
action. A third component is termed ocular apraxia, which describes the
inaccurate saccades that are made when a patient tries to shift gaze from one
object to another target in the environment.
Virtually all cases of Balint syndrome result from bilateral parietooccipital
damage. When the presentation is subacute, a common cause is posterior
cortical atrophy,73 a neurodegenerative disease predominately affecting the
posterior cortex, which is often, but not always, caused by underlying
Alzheimer pathology. Other causes of Balint syndrome include metastatic

CASE 7-6 A 70-year-old woman reported difficulty reaching for things such as forks
and cups. She could read single words but had difficulty moving from one
word to the next and often lost her place in the text. She felt confused
when she entered a place with complex visual stimuli, such as a
supermarket. Neurologic examination revealed intact visual acuity and
fields. Reaching for targets was inaccurate, although she could
accurately bring her finger to her own nose (optic ataxia) (VIDEO 7-7
[online]). Saccadic searching eye movements were also inaccurate
(ocular apraxia). When asked what letter she saw in a picture of an H
made of little As, she answered “A,” even when directed to look at the
whole picture (simultanagnosia). Balint syndrome was diagnosed, and an
MRI showed severe cortical atrophy, especially in the posterior
parietal and occipital regions, leading to a diagnosis of posterior
cortical atrophy (FIGURE 7-16).
FIGURE 7-16
Imaging of the patient in CASE 7-6 with Balint syndrome. Axial MRIs show severe cortical
atrophy, especially in the posterior parietal and occipital regions. (A, B, arrows).
COMMENT This case illustrates the severity of visual symptoms that can occur with
significant disruption of the mechanisms that control normal visuospatial
attention. Although visual acuity and object recognition were normal in this
patient, she had a severe deficit of disengaging and shifting attention in a
coordinated fashion to relevant elements of the visual environment.
1350 OCTOBER 2019

lesions, hypotensive insult affecting the
bilateral watershed zones between the
middle and posterior cerebral arteries,74
the Heidenhain variant of Creutzfeldt-
Jakob disease, posterior reversible
encephalopathy syndrome (PRES),75
and progressive multifocal
leukoencephalopathy.76
In 1909, the Hungarian physician Rudolph
Balint77 described an engineer who could
no longer assemble models because of a
profound inability to shift spatial attention,
although visual acuity, strength, and
dexterity were normal. He tried to light a
cigar in the middle rather than the end and
directed his knife outside the plate when
trying to cut a steak. At autopsy, he was
found to have bilateral parietal infarcts.
In 1918, Holmes78 expanded on Balint’s
concept of “psychic paralysis of gaze,”
using the term ocular apraxia to describe
FIGURE 7-17 five patients who could direct their eyes
Navon figure to assess for
accurately to the location of a sound or to a
simultanagnosia. While a person with
normal perception will identify a large region verbally described by the practitioner
S composed of many small Es, a but not to a target that was presented
person with Balint syndrome will visually.78
report only seeing small Es.
Of note, simultanagnosia was not
actually described as a component of
Balint syndrome until Wolpert’s79 case
description in 1924. When observing his patient try to describe the events in a
scene (which showed a boy being scolded after breaking a window during a
snowball fight), he found that the patient saw “only details that he could not
sum up” and was unable to recognize the action represented in the figure.
While optic ataxia and ocular apraxia frequently co-occur, they localize to
unique regions of the posterior parietal cortex. Functional imaging studies
suggest that optic ataxia stems from damage to the pathways connecting the
parietal reach region and medial interparietal area to the dorsal premotor
cortex, while ocular apraxia results from disrupted connections from the lateral
interparietal area to the superior colliculus and frontal eye fields.80 Dorsal area
5 appears to be involved in online control of reaching, meaning that it helps
correct for mistakes in reaching movements during an action based on
proprioceptive and visual feedback.81 Difficulty with grasping for objects,
which also may occur in patients with Balint syndrome, appears to localize to
damage to the anterior interparietal area and its connections to the ventral
premotor cortex (FIGURE 7-18).

FIGURE 7-18
Anatomy of optic ataxia and ocular apraxia. The parietal reach region (PRR), which includes area
V6A and the medial interparietal area (MIP), connects with the dorsal premotor cortex and
governs visually guided reach. The MIP may play a role in the finer aspects of reach. Dorsal area
5 (5d) is important for online control, correcting mistakes in reach, based on visual feedback.
Disruption of the PRR/MIP/5d network leads to optic ataxia. The lateral interparietal area
makes connections with the frontal eye fields and superior colliculus, subserving visually
mediated saccades; lesions in this area produce ocular apraxia. The anterior interparietal area
(AIP) projects to the ventral premotor cortex, and disruption of these pathways causes deficits
in grasping for objects. Note there is input to the system from inferotemporal cortical regions;
ie, the “what” pathway feeds information into the “where” pathway.
HEMISPATIAL NEGLECT
Unilateral parietal lobe lesions, especially of the right parietal cortex, often cause
the syndrome of hemispatial neglect to the contralateral side.
Hemispatial neglect not only affects visual perception of extrapersonal space but
also often involves perception of personal space (one’s body) as well. Patients
may be able to consciously perceive the contralateral field when sparse stimuli
are presented, but when multiple stimuli are presented simultaneously and
compete for visual attention, the patient demonstrates a rightward attentional
bias and the stimulus on the left becomes “extinguished.” When asked to show
the midpoint of a horizontal line, patients with left hemispatial neglect will mark
a line to the right of center. On a target cancellation test in which multiple lines
on a page must be crossed out, patients will start toward the right side and miss
several targets on the left side.82,83 When asked to circle all the As on a page with
both As and Bs, the patient with neglect will miss the letters on the neglected
side, while a patient with a simple hemianopia will still search into the blind area
and is therefore less likely to miss letters on that side.
The coordinates by which left hemispatial neglect is defined can differ
between patients. It might occur in egocentric coordinates that are centered
primarily to the patient’s body, head, or eyes. In other patients, the left neglect
may be defined by coordinates of a given object, regardless whether it is to the
patient’s right or left side.
1352 OCTOBER 2019

Historical Background KEY POINT
Hemispatial neglect was described as a “hemianopic weakness of attention” by
● Unilateral parietal lobe
Poppelreuter84 in 1917. In 1945, Paterson and Zangwill85 described a right parietal lesions, especially of the
syndrome in a 34-year-old man who had an irregular mortar fragment shot right parietal cortex, often
through his right parietal lobe. The patient demonstrated a marked neglect of the cause hemispatial neglect to
left side of his environment and his left upper extremity as well as significant the contralateral side.
difficulty copying figures, drawing, or arranging puzzles. The doctors drove the
patient through Edinburgh and found that while he could name streets, he could
not successfully figure out how to navigate to other parts of the city. Attempts to
draw his neighborhood demonstrated major errors, and a freehand drawing of
Scotland omitted the entire left side.
A major question to consider when studying hemispatial neglect is why left
hemispatial neglect following a right hemispheric lesion is so much more
common than right hemispatial neglect following a left hemispheric lesion.
One explanation is that the left hemisphere is capable of shifting visuospatial
attention only toward the right, but the right hemisphere is capable of shifting
attention to either side. Patients do not commonly have significant hemispatial
neglect following a lesion in the left hemisphere because the right hemisphere
remains capable of directing attention to either side. Following a right
hemispheric lesion, however, the left hemisphere directs attention to the right,
and the mechanisms that should direct attention to the left are no longer intact.
In essence, the syndrome of left hemispatial neglect represents an unchecked
rightward bias of attention, without the ability to effectively shift attentional
mechanisms leftward.
Evidence supporting this theory comes from the classic experiment of
Posner and colleagues,86 who measured response time and accuracy of
individuals to detect a target presented either in the right or left visual field
after attention was briefly cued with an indication of where the target would
appear. On a “valid” trial, the target appeared in the location where attention
was cued. On an “invalid” trial, attention would be cued to one side, but the
target would appear on the opposite side. Individuals without neurologic
lesions and those with left hemispheric lesions did reasonably well on both
types of trials. In contrast, patients with right hemispheric lesions had
significant difficulty on invalid trials if their attention was cued to the right but
the target appeared to the left. However, their performance was essentially
normal on valid trials and on invalid trials in the opposite direction, where
attention was cued to the left but the target then appeared to the right. This
experiment illustrates the rightward bias in attention that commonly occurs
following a right hemispheric lesion.
Left hemispatial neglect not only affects the way an individual perceives
and interacts with the external surrounding environment but also affects
internal representations and mental imagery. In one famous experiment
conducted by Bisiach and Luzzatti,87 two Italian patients with left hemispatial
neglect were asked to imagine themselves standing in the Piazza del Duomo in
Milan, facing the cathedral in the center of the square, and name the buildings
they could recall. The patients named buildings on the right side of the square
but failed to name buildings on the left. Later, the investigators asked the same
patients to imagine themselves standing in the square but on the steps of the

cathedral facing the opposite direction as before. This time, with the right and
left side of the square flipped in their mental representation, the patients only
named the buildings on the side opposite of the buildings they had named
previously.
CHARLES BONNET SYNDROME

Charles Bonnet syndrome refers to “release” hallucinations that occur in the
context of visual loss (VIDEO 7-8 [online]).
Release hallucinations are typically nonthreatening; patients often describe
seeing small people, animals, or flowers. Auditory hallucinations are not typical.
It is important to recognize this syndrome based on these characteristics and
correctly differentiate it from other causes of hallucinations, including
psychotic disorders.
CASE 7-7 A 66-year-old man presented with the sudden onset of vivid visual
hallucinations during wakefulness following bariatric surgery. Apart from
describing the hallucinations, he was alert, attentive, and fully oriented
without any confusion. Examination showed normal visual acuity and
visual fields. Nevertheless,
he described seeing
synchronized swimmers
dressed in red, white, and
blue in his hospital room
(VIDEO 7-9 [online]). He also
saw snakes crawling up to
the bed, numbers melting
off the clock, and plumes
of smoke at the nursing
station. Diffusion-weighted
imaging (DWI) and apparent
FIGURE 7-19
diffusion coefficient Imaging of the patient in CASE 7-7 with Lhermitte
MRI demonstrated a peduncular hallucinosis. Diffusion-weighted imaging
mesencephalic stroke (DWI) (A) and apparent diffusion coefficient MRI
consistent with a diagnosis (B) demonstrated a mesencephalic stroke
(arrows), consistent with a diagnosis of
of peduncular hallucinosis peduncular hallucinosis.
(FIGURE 7-19).
COMMENT This case illustrates the acute, vivid, formed visual hallucinations that can
occur with a rostral brainstem or thalamic stroke. The patient had no visual
deficits to suggest a diagnosis of release hallucinations. His cognition was
normal, not suggestive of a delirious state, and he was not intoxicated.
Although he had no objective neurologic deficits to localize the lesion
clinically, MRI demonstrated the responsible lesion.
1354 OCTOBER 2019

Historical Background KEY POINTS
The syndrome is given its eponym because it was described by Charles Bonnet,88
● Charles Bonnet syndrome
a Swiss naturalist and lawyer, in 1760. He described a man with normal cognitive refers to “release”
function who experienced formed hallucinations of men, women, birds, cars, hallucinations that occur in
and buildings. The man that Bonnet described was his own 87-year-old the context of visual loss,
grandfather, who was nearly blind from cataracts. often due to anterior lesions
such as cataracts or macular
degeneration.
Functional imaging studies have shown spontaneous increases in activity in ● Lhermitte peduncular
visual association areas in the ventral extrastriate cortex that temporally correlate hallucinosis describes vivid,
with the reported hallucinations.89 These findings lend credence to the idea that dreamlike hallucinations
that occur during normal
in the absence of receiving external sensory information, the visual system can wakefulness and may result
generate internally formed hallucinations instead. from lesions to areas of the
midbrain and thalamus that
LHERMITTE PEDUNCULAR HALLUCINOSIS regulate the sleep-wake
state and normally prevent
Lhermitte peduncular hallucinosis describes vivid, dreamlike hallucinations that dreams from encroaching on
occur during normal wakefulness (CASE 7-7) and that typically result from wakefulness.
lesions of the brainstem or thalamus.
The hallucinations in this fascinating disorder generally begin abruptly and are
attributed to a lesion in the upper brainstem or thalamus. Some patients have
objective deficits referable to the location of the lesion in the brainstem, but other
patients have isolated hallucinations without coexisting abnormalities on
examination.90 After the acute onset of the hallucinations, patients tend to show
some gradual improvement over time. Other cognitive faculties remain normal
in these patients.
This condition was described in 1922 by Lhermitte91 in a 72-year-old
woman who reported bizarre, formed hallucinations including “radiant”
animals, people dressed in tinsel, and strange-appearing children.
Lhermitte inferred that the acute hallucinations were caused by a lesion
in the upper brainstem (called the peduncle in French), localizing the
lesion on the basis of the patient’s coexisting eye movement abnormalities
although a confirmatory autopsy was not available. Lhermitte offered the
provocative explanation that the vivid hallucinations were essentially a
dream state intruding upon wakefulness. Five years later, Van Bogaert92
described a similar patient with the sudden onset of vivid hallucinations and
showed at autopsy that the patient indeed had infarction of regions of
the midbrain.
Analysis of the lesions reported to cause the syndrome of peduncular hallucinosis
shows that no single site is uniformly involved, but the responsible lesions
most often tend to be in the midbrain or thalamus.93 In these regions, the
reticular activating system and thalamic intralaminar nuclei regulate the state
of wakefulness of the brain, permitting vivid dreams to arise during rapid eye
movement (REM) sleep. In keeping with Lhermitte’s hypothesis about the
pathogenesis of hallucinations in this disorder, analysis of network connectivity

FIGURE 7-20
The lesion-based network mapping method demonstrates the disinhibited networks involved
in peduncular hallucinosis. Individual discrete lesions in reported cases of peduncular
hallucinosis do not uniformly overlap but tend to occur in the thalamus or midbrain (columns 1
and 2, showing 3 of the 23 cases analyzed in this study). A database of resting state functional
MRI (fMRI) from healthy individuals can be used to define the distributed network of correlated
and anticorrelated neural activity associated with the lesion location in each case (column 3).
Overlap of these individual network maps reveals the areas of commonality, including visual
association areas that are functionally anticorrelated with the location of the lesion in all cases
(areas in blue on the overlap image on the right). These findings suggest that the lesions
implicated in peduncular hallucinosis engender disinhibited activity in visual association areas
that correlates with perceived visual hallucinations.
L = left; R = right.
Reprinted with permission from Boes AD, et al, Brain.93 © 2015 Oxford University Press.
shows that lesions producing peduncular hallucinosis are functionally

anticorrelated with visual association areas (FIGURE 7-20).93 This evidence
supports the notion that a discrete thalamic or mesencephalic lesion may give
rise to internally generated imagery by causing disinhibition of higher visual
areas, akin to the dream state intruding upon normal wakefulness suggested
by Lhermitte.
CONCLUSION
Timely diagnosis and optimal management of patients with disorders of visual
processing are important challenges faced by the practicing neurologist. In
these cases, elementary aspects of vision may appear normal on examination
and will not account for the patient’s particular visual symptoms. Detailed
testing of higher visual functions will define specific cortical visual syndromes
and have localizing value (FIGURE 7-21). The study of these disorders provides
an important framework to consider important neuroscientific concepts
regarding the functional organization of the brain.
1356 OCTOBER 2019

FIGURE 7-21
Higher-order cortical disorders of vision organized by localization. Succeeding regions
of extrastriate cortex are labeled as being part of either the ventral or dorsal stream.
Anton syndrome, apperceptive visual agnosia, and Riddoch syndrome result from
damage to the primary visual cortex (V1). The anosognosia of Anton syndrome presumably
relates to dysfunction in broader networks that serve to judge the presence or absence of
vision. Connections between the lateral geniculate nucleus (LGN) and mesial-temporal
region/V5 (MT/V5), as well as between superior colliculus (SC)–responsive neurons in the
ventrolateral pulvinar (vlP) and MT/V5, may play a role in preserved visual function found
in blindsight and Riddoch phenomenon. Central hemiachromatopsia localizes to V4 and
prosopagnosia localizes to the fusiform face area (FFA) within the fusiform gyrus, which is
located more medially than represented here. While alexia without agraphia commonly
results from lesions affecting both the left occipital cortex and splenium, it may also result
from a more discrete lesion affecting the left-sided visual word form area (VWFA) in the
fusiform gyrus. Balint syndrome results from bilateral damage to the occipitoparietal
areas that control visuospatial attention. Charles Bonnet syndrome refers to release
hallucinations that result from vision loss anywhere along the early visual pathways, but it
most commonly results from ocular disease such as cataracts or macular degeneration.
L = left; PPC = posterior parietal cortex; R = right; V6/DM = dorsomedial cortex.

VIDEO LEGENDS
VIDEO 7-1 VIDEO 7-6
Anton syndrome. Video shows a 48-year-old man Riddoch syndrome. Video shows a 15-year-old girl
with complete loss of vision following bilateral who developed a dense right homonymous visual
occipital cardioembolic strokes. He denied field deficit after left posterior cerebral artery
blindness and said he felt “super.” He confabulated stroke following a traumatic head injury with
that he could see objects in front of him but when expansion of an epidural hematoma. As she
asked to describe them in detail, said “I don’t know recovered, she found that she could detect motion
how to tell.” He had no difficulty identifying objects in the otherwise blind field. Static Humphrey
when he held them in his hand. Even following automated perimetry testing demonstrated the
demonstrations that he was not seeing properly, he right homonymous field defect.
insisted “my vision is OK.”
© 2019 American Academy of Neurology.
VIDEO 7-7
VIDEO 7-2 Balint syndrome. Video shows a 70-year-old
Apperceptive visual agnosia. Video shows a woman who reported difficulty reaching for
23-year-old woman who developed severe visual things such as forks and cups. She could read but
impairments after hypoxic arrest from a narcotic had difficulty moving from one word to the next.
overdose. She described her vision as distorted or She stated she could see everywhere but felt
blurred. She could tell an object was in front of her visually confused when she entered a place with
but could not tell what it was. Faces were “completely complex visual stimuli, such as a supermarket.
distorted.” She could not identify any visually Neurologic examination revealed intact visual
presented objects, could not read letters, and could acuity and fields. Reaching for targets was
not copy simple line drawings correctly. Visual acuity, inaccurate, although she could accurately bring
tested with the preferential looking test (in which the her finger to her own nose (optic ataxia). Saccadic
patient directs the eyes toward a set of black-and- searching eye movements were also inaccurate
white stripes, with the thickness of the stripes in (ocular apraxia). When asked what letter she saw
some examples approximating 20/20 vision) was in a picture of an H made of little As, she
normal, and she had no other cognitive deficits. answered “A,” even when directed to look at the
whole picture (simultanagnosia). Balint syndrome
© 2019 American Academy of Neurology. was diagnosed, and an MRI showed severe
cortical atrophy, especially in the posterior
VIDEO 7-3 parietal and occipital regions, leading to a
Central hemiachromatopsia. Video shows a diagnosis of posterior cortical atrophy.
57-year-old woman who presented with a left
superior quadrant homonymous field deficit due to © 2019 American Academy of Neurology.
a right inferior occipital stroke. Examination showed
that she was unable to discriminate colors in the left VIDEO 7-8
inferior homonymous field, saying that cards of Charles Bonnet syndrome. Video shows a 93-year-
various colors shown in that area were gray or white. old woman with severe visual loss from macular
Diffusion-weighted MRI showed acute right inferior degeneration and glaucoma who had frequent
occipital infarction, involving the inferior bank of complex visual hallucinations. She described seeing
area V1 and area V4. “a little blond dressed very nice…in a wool plaid
suit, skirt, and jacket, and curly, curly hair and big,
© 2019 American Academy of Neurology. round eyes.” The hallucinations were nonthreatening,
and she had no auditory hallucinations.
VIDEO 7-4
Alexia without agraphia. Video shows a 41-year-old © 2019 American Academy of Neurology.
man with an infiltrating glioma involving the left
occipital lobe and splenium of the corpus callosum VIDEO 7-9
with a profound inability to read words with both Lhermitte peduncular hallucinosis. Video shows a
regular or irregular phonemic spelling, although writing 66-year-old man with the sudden onset of vivid
and spoken language remained normal. He was unable visual hallucinations during wakefulness following
to read a sentence he had written himself, saying bariatric surgery. Apart from describing the
“I don’t know; it’s almost like I didn’t write it.” The hallucinations, he was alert, attentive, and fully
examination also demonstrated a right superior oriented without any confusion. He described
greater than inferior homonymous hemianopia. seeing in his hospital room synchronized swimmers,
snakes crawling up to the bed, numbers melting off
© 2019 American Academy of Neurology. the clock, and plumes of smoke at the nursing
station. Diffusion-weighted imaging (DWI) and
VIDEO 7-5 apparent diffusion coefficient MRI demonstrated a
Prosopagnosia. Video shows a 37-year-old woman mesencephalic stroke, consistent with a diagnosis
with difficulty distinguishing faces due to breast of peduncular hallucinosis.
cancer metastasis involving the right occipitotemporal
cortex in the fusiform face area. She said that faces © 2019 American Academy of Neurology.
look “smoother and less defined.” She called it the
“Instagram filter” in her brain.
1358 OCTOBER 2019

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REVIEW ARTICLE

Approach to Diplopia
C O N T I N UU M A UD I O By Christopher C. Glisson, DO, MS, FAAN
ONLINE

VIDEO CONTENT ABSTRACT
A VA I L A B L E O N L I N E PURPOSE OF REVIEW: “Double vision” is a commonly encountered concern in
neurologic practice; the experience of diplopia is always sudden and is
frequently a cause of great apprehension and potential disability for patients.
Moreover, while some causes of diplopia are benign, others require
immediate recognition, a focused diagnostic evaluation, and appropriate
treatment to prevent vision- and life-threatening outcomes. A logical,
easy-to-follow approach to the clinical evaluation of patients with diplopia
is helpful in ensuring accurate localization, a comprehensive differential
diagnosis, and optimal patient care. This article provides a foundation for
formulating an approach to the patient with diplopia and includes practical
examples of developing the differential diagnosis, effectively using
confirmatory examination techniques, determining an appropriate
diagnostic strategy, and (where applicable) providing effective treatment.
RECENT FINDINGS:Recent population-based analyses have determined that

diplopia is a common presentation in both ambulatory and emergency
department settings, with 850,000 such visits occurring annually. For
patients presenting to an outpatient facility, diagnoses are rarely serious.
However, potentially life-threatening causes (predominantly stroke or
transient ischemic attack) can be encountered. In patients presenting with
diplopia related to isolated cranial nerve palsy, immediate neuroimaging
can often be avoided if an appropriate history and examination are used to
exclude worrisome etiologies.
SUMMARY: Binocular diplopia is most often due to a neurologic cause.

The onset of true “double vision” is debilitating for most patients and
CITE AS:
commonly prompts immediate access to health care services as a
25(5, NEURO-OPHTHALMOLOGY): consequence of functional impairment and concern for worrisome
1362–1375. underlying causes. Although patients may seek initial evaluation through
the emergency department or from their primary care/ophthalmic
Dr Christopher C. Glisson, provider, elimination of an ocular cause will not infrequently result in the
Mercy Health Hauenstein patient being referred for neurologic consultation. A logical, localization-
Neurosciences, 204 Cherry driven, and evidence-based approach is the most effective way to arrive at
St SE, Ste 204, Grand Rapids,
MI 49503. the correct diagnosis and provide the best outcome for the patient.
Dr Glisson reports no disclosure.
INTRODUCTION
A
UNLABELED USE OF s with many forms of visual disturbance, the report of “double vision”
USE DISCLOSURE:
is entirely subjective and compels the clinician to consider many
Dr Glisson reports no disclosure. possible etiologies. Fortunately, a focused history (provided that the
reporter is reliable) can often provide a framework for accurately
of Neurology. localizing the cause of the diplopia, limiting the differential diagnosis,
1362 OCTOBER 2019

and directing the examination toward the underlying pathology. The majority of KEY POINTS
this article is dedicated to neurologic causes of diplopia with an emphasis on
● A detailed history and
understanding the relevant neuroanatomy subserving ocular motility and providing systematic examination can
a framework for interpreting ocular misalignment seen at examination. Armed with often accurately localize the
this information, the localization of diplopia (to relevant structures of the central cause of diplopia.
nervous system, cranial nerves, neuromuscular junction, extraocular muscles, or
● Monocular diplopia is
orbit) is relatively straightforward and can allow the clinician to develop a viable
rarely due to neurologic
differential diagnosis, a prudent diagnostic evaluation, and, in some cases, an pathology.
effective therapeutic strategy to mitigate symptoms.
● Eliciting the orientation of
MONOCULAR DIPLOPIA the double image
Monocular diplopia is defined as the perception of double (or multiple) (horizontal, vertical, or
oblique), whether diplopia is
images when viewing with only one eye. Except in very rare circumstances of present at distance or near,
bilateral monocular diplopia (eg, cerebral diplopia, polyopia, and palinopsia as and whether the diplopia
manifestations of disease involving the primary or secondary visual cortices1,2), worsens in any direction of
the perception of a “shadow,” “ghost,” “haze,” or even an overt “double image” that gaze are fundamental to
accurate localization.
persists with the nonviewing eye closed is strongly supportive of an ocular cause.
Common causes for this include refractive error (uncorrected or outdated
correction), corneal defects (including dry eye), cataract, or macular disease.
This can be easily confirmed by placing a pinhole occluder (or similar
apparatus) over the viewing eye and asking the patient if this improves or
resolves the double vision.3 If so, the patient should be reassured that he or she
does not harbor neurologic pathology and should be referred to an optometrist
or ophthalmologist for further evaluation.
While not strictly monocular, it is also helpful for the clinician to be aware of
physiologic diplopia, which is a normal perception that can be precipitated by
misalignment of the ocular axes when viewing a specific object. For example,
focusing on a hand held close to the face will cause objects in the background to
appear “double.” Likewise, focusing on a distant target and holding an object up
close within the field of view will cause a similar phenomenon (ie, “floating
finger” or “frankfurter illusion”).4 Concerned patients presenting for evaluation
after discovering this phenomenon can be reassured that it is completely natural,
and no further investigations are required.
APPROACH TO BINOCULAR DIPLOPIA

Binocular diplopia occurs as a result of misalignment of the eyes/visual axes and,
as such, must be regarded as neurologic in etiology. Proper clinical evaluation
of binocular diplopia begins with a detailed history with an emphasis on any prior
episodes of diplopia, a history of strabismus or “lazy eye” during childhood, and
whether the patient has had recent or remote head trauma (CASE 8-1). Perhaps
most important is eliciting a detailed description of the patient’s perception of
the diplopia, including whether the diplopia is constant or intermittent (and
any relevant patterns thereof ), what the orientation of the diplopia is (that is,
whether the relationship between two images is horizontal, vertical, or
oblique/diagonal), whether the diplopia is more noticeable at distance or near,
and whether the diplopia becomes more (or less) prominent in different
directions of gaze. In many cases, accurate localization of the diplopia can be
identified by a careful history alone. One recent study found that an effective
history and thorough examination accurately identified the cause for the diplopia
in the majority (70.5%) of cases, and only a relatively small number (4.7%)

APPROACH TO DIPLOPIA
harbored underlying pathology that required urgent management.5 Likewise,

another study found that for patients presenting to an outpatient facility
(representing 95% of the population analyzed), diagnoses were rarely serious, but
potentially life-threatening causes (predominantly stroke or transient ischemic
attack) were present in 16% of diplopia-related emergency department visits.6 Such
studies highlight the value of an effective strategy for obtaining a relevant history
and examination and the utility of using these to guide management.
Intermittent Versus Constant Diplopia

Diplopia that is intermittent tends to either be situation dependent (ie, only
noticeable with certain tasks or in specific environments) or worsen with fatigue.
The former may suggest a tendency toward ocular misalignment or exacerbating
CASE 8-1 A 64-year-old man presented for evaluation of “double vision” that he
had been experiencing for 1 month. He initially noted the double vision
while reading his morning newspaper, but over time he became aware of
a similar visual disturbance when attempting to descend stairs in his local
shopping center.
A detailed history revealed that he did not notice diplopia with other
activities. The double image was obliquely oriented and binocular. He stated,
“I close one eye when I want to read, and it goes away.” The patient did not
have eye pain, ptosis, dysphagia, dyspnea, or other neurologic symptoms.
During the interview, the patient relayed that he had been involved in a
motor vehicle accident in his thirties, in which he had been “knocked out for a
few minutes” but had no other immediate sequelae.
The ocular motility examination revealed a left hypertropia that became
more pronounced in right gaze. The patient endorsed diplopia when looking
down; when asked to view the junction between the wall and the floor, he
reported “seeing two lines, one straight and one diagonal,” which, if
extended, would intersect to the left. The patient had a head tilt to the right,
and review of requested family photographs confirmed that this had been
present for many years.
The description of the patient’s symptoms, in association with the ocular
motility examination and the presence of a long-standing head tilt, was
consistent with a posttraumatic left cranial nerve IV palsy with
age-related decompensation.
COMMENT This case exemplifies the utility of eliciting certain characteristics of the
diplopia (eg, orientation, presence/absence in specific directions of gaze
and with specific activities) in determining a potential localization. It can
also be helpful to ascertain whether remote head trauma has occurred and
to be attentive to correlating features of a long-standing etiology (such as a
head tilt that can be confirmed by photographs). In many cases, patients
are able to compensate for ocular misalignment to the extent that they do
not notice diplopia for several years until such time as their unrecognized
adaptive strategies become decompensated.
1364 OCTOBER 2019

elements that are amenable to modification and therefore may eliminate the KEY POINTS
symptoms. Diplopia that worsens with fatigue immediately raises suspicion
● Diplopia that occurs with
for myasthenia gravis (MG) (refer to the section on MG), but it is important to fatigue does not necessarily
recognize that many other forms of diplopia, such as decompensation of a imply myasthenia gravis;
long-standing strabismus, may also follow this pattern. long-standing and
decompensated ocular
misalignment can also
Orientation of Images
become symptomatic when
Binocular diplopia that is horizontal in orientation suggests involvement of the patients are tired or under
medial or lateral rectus muscle. Diplopia that is vertical and torsional (with the stress or in the setting of
lower image tilted) suggests involvement of the superior oblique muscle concomitant illness.
(particularly if associated with a compensatory head tilt to the side opposite the
● Diplopia/ocular
weak muscle), while pure vertical diplopia is more likely to reflect brainstem or misalignment that does not
cerebellar pathology (manifesting as an acquired vertical misalignment of the change with the direction of
eyes, referred to as skew deviation). Diplopia that is oblique/diagonal, reflecting gaze is classified as
dysfunction of both vertical and horizontal muscles, suggests dysfunction of comitant; diplopia that
varies depending on the
the oculomotor nerve (involving some combination of the inferior rectus, direction of gaze is termed
superior rectus, and inferior oblique muscles). Further localizing information can be incomitant and most often
obtained by asking the patient whether the diplopia is worse in a specific direction of indicates extraocular
gaze (eg, diplopia that is most pronounced at distance and on gaze to the left is muscle dysfunction.
supportive of dysfunction of the left lateral rectus muscle/cranial nerve VI).
Additional localizing information can be ascertained by determining if the
diplopia is more pronounced at distance or at near. Difficulty with reading or
other near tasks suggests dysfunction of convergence, reflecting possible
involvement of cranial nerve III or medial rectus muscle or convergence
insufficiency. Conversely, if the patient notices diplopia when viewing at
distance, dysfunction of divergence should be suspected, prompting further
investigation for involvement of the lateral rectus muscle or cranial nerve VI.
Associated Features
Diplopia is always sudden in onset (the perception of double vision is a present or
absent phenomenon), although very mild diplopia may be perceived as “blurriness”
to some patients; patients and medical personnel often ascribe undue importance to
the onset of diplopia as it relates to the potential for a severe underlying cause, and it
is appropriate to provide reassurance in this regard. However, consideration of the
duration of diplopia (in association with the other historical elements discussed
above) can be useful in the elucidation of a differential diagnosis. Additionally, it
should be determined whether the patient’s diplopia is associated with headache,
pain with (attempted) eye movement, ptosis, dysphagia, dyspnea, weakness, or,
in patients older than 55 years of age, scalp tenderness, jaw/tongue claudication,
fever, chills, unexplained weight loss, or body pain to suggest giant cell arteritis.
Diplopia/ocular misalignment that does not change with direction of gaze is
classified as comitant and suggests a congenital strabismus (or skew deviation if
vertical); diplopia that varies depending on the direction of gaze is termed
incomitant (and most often indicates extraocular muscle dysfunction).
Ascertainment of the above historical information is of vital importance.
Following this, a schema to discover whether the causative ocular misalignment
is due to pathology affecting candidate structures including the brainstem nuclei,
cranial nerves, neuromuscular junction, extraocular muscles, or orbital tissues
can be employed (FIGURE 8-17) based on supportive findings at the
neurologic examination.

Examination
Detailed examination of the
ocular motor system is
straightforward and time
efficient and does not require
sophisticated diagnostic
instrumentation. Additionally,
evaluation of eye movements is
not perceived as threatening
(even to the most apprehensive
patient), and aspects of clinically
relevant dysfunction can be
ascertained even in patients who
are unable to fully participate.
Key components of the ocular
motility examination include
FIGURE 8-1 fixation/gaze holding, monocular
Innervation of the muscles of the eye. Origin and
distribution of the cranial nerves and their eye movements (ductions), and
respective innervation of the extraocular muscles. assessment of binocular eye
CN = cranial nerve. movements (versions, pursuits,
Reprinted from what-when-how.com/neuroscience.7
and saccades).
Initially, fixation should be
evaluated by asking the patient
to view a target of visual interest (the large letter on an eye chart at distance or
the “95” at the top of a near card) in primary viewing position. Careful attention
should be paid to any instability of fixation, which may include square-wave
jerks (spontaneous, small-amplitude horizontal saccades away from fixation
followed promptly by a corrective saccade in the opposite direction [note that
square-wave jerks occurring fewer than 9 times per minute can be normal in
most individuals]) or nystagmus, which may suggest pathology affecting ocular
coordination (VIDEO 8-1 [online]).
Next, evaluation of ductions is completed by occluding one eye and asking
the patient to follow a visual target through all cardinal gaze positions (VIDEO 8-2
[online]). Assessment should be made of any apparent limitation or restriction
of eye movements; additionally, the pursuit movements (ie, tracking) should
be smooth and uninterrupted. Examination of fixation is commonly overlooked
during the ocular motility examination but is essential in identifying potential
pathologic features that may be associated with diplopia. Subtle asymmetry in
ocular alignment is sometimes easer to discern with testing of versions, in which
the same process is repeated but with both eyes viewing (thereby allowing for
comparison of symmetry between the two eyes simultaneously) (VIDEO 8-3
[online]).
Finally, testing of saccades involves asking the patient to rapidly and
alternately fixate on two different targets (eg, a finger held eccentrically and
the examiner’s nose in primary gaze). This should be performed in both the
horizontal and vertical planes (VIDEO 8-4 [online]). In addition to noting any
apparent ocular misalignment, consideration should be given to any delay in
initiation, the velocity of the saccades, and any inaccuracy (ocular dysmetria) as
a potential indicator of brainstem or cerebellar dysfunction that may accompany
the diplopia.
1366 OCTOBER 2019

Diagnostic Evaluation KEY POINTS
In the setting of trauma, and particularly with any indication of restricted
● Assessment of fixation is
ocular motility, CT of the skull bones may be indicated. In all nontraumatic cases, commonly overlooked
MRI (with dedicated skull base and orbital imaging) is preferable to CT. When during the ocular motility
cranial nerve dysfunction is suspected, care should be taken to directly review examination but is essential
the images and “follow the course” of the involved cranial nerve from its origin to in identifying potential
pathologic features that may
identify structural pathology. If other signs or symptoms of increased
be associated with diplopia.
intracranial pressure are present, it is also important to visualize the brain
parenchyma to exclude space-occupying lesions. In general, neuroimaging has a ● Neuroimaging has a low
low diagnostic yield in isolated fourth, pupil-sparing third, and sixth nerve diagnostic yield in isolated
palsies in older patients with vascular risk factors. However, in one study, 10% of fourth, pupil-sparing third,
and sixth nerve palsies in
patients older than 50 years of age with one vascular risk factor were found to older patients with vascular
have other causes, including neoplasm, infarction, and giant cell arteritis.8 Other risk factors. However, a
disease-specific considerations related to the diagnostic evaluation are included small number of patients
below. older than 50 years of age
may have other causes
including neoplasm,
CAUSES OF BINOCULAR DIPLOPIA infarction, and giant cell
A thorough evaluation of ocular motility allows the examiner to consider the arteritis.
various potential causes of ocular misalignment, which can be broadly localized
● While the localization of
to supranuclear, internuclear, infranuclear, neuromuscular junction, extraocular
isolated diplopia can be
muscle, or orbital dysfunction. A systematic and stepwise approach to relatively straightforward,
considering the relative likelihood of each of these neuroanatomic locations is the complex nature of
helpful in the clinical setting. ocular motility and
coordination makes them
susceptible to disruption by
Dysfunction of Supranuclear and Internuclear Ocular Motor Control more diffuse cerebral
It is important to remember that the intracranial apparatus responsible for dysfunction.
directing and coordinating ocular motility (and thereby ensuring single vision) is
complex. Therefore, while more distal pathologies that cause diplopia (eg,
isolated cranial nerve palsies, disorders of the neuromuscular junction, and
orbital restrictive processes) can be straightforward, more proximal lesions may
be difficult for the practicing neurologist to precisely localize in the setting of a
single examination. Lesions affecting the cortical connections to the nuclei of II,
IV, and VI are termed supranuclear; lesions affecting the connections between
nuclei are internuclear; and those affecting the nerves, neuromuscular junction,
or muscles are infranuclear.
Broadly considered, dysfunction of the cerebral hemispheres (precipitated by
metabolic disorders or medications); neurodegenerative diseases that compromise
the basal ganglia (such as the parkinsonian syndromes and Huntington
disease); or structural injury to the pons, midbrain, or cerebellum are all
potential causes of (or contributors to) diplopia. Each of these, however, will be
accompanied by other neurologic signs and symptoms, often more prominent
than the diplopia itself, that will provide helpful diagnostic information.
However, important considerations within this category that may present
with isolated diplopia include skew deviation and internuclear ophthalmoplegia
(INO). Skew deviation results in vertical ocular misalignment/diplopia that
typically results from injury to the utricular-vestibular-ocular pathway
(brainstem or cerebellum) governing vertical and torsional eye position in
response to body tilt. It is similar in presentation to cranial nerve IV palsy but can
be differentiated by its propensity for the vertical misalignment to decrease by
50% or more when the patient is measured in the supine position as compared to

CASE 8-2 A 34-year-old man presented for evaluation of visual distortion, which he
had noticed in the past week when watching his daughter’s youth tennis
tournament. He reported that when watching her serve the ball from the
right side of the court to the left, he would see “two tennis balls for a
second, and then things went back to normal.” He did not report any
other occasions of double vision, nor did he endorse eye pain, ptosis, or
other neurologic symptoms.
Testing of saccades confirmed a right internuclear ophthalmoplegia
with otherwise normal ocular motility and alignment. Given the patient’s
age and otherwise unremarkable examination, brain MRI was required to
evaluate for a demyelinating lesion involving the medial longitudinal
fasciculus (MLF). Given the patient’s report that the symptom manifested
later in the day, ocular myasthenia gravis (MG) was also considered.
(Patients with MG may develop dyscoordinated eye movements that
can mimic a lesion of the MLF, known as pseudointernuclear
ophthalmoplegia.)
MRI of the brain disclosed an enhancing lesion involving the right MLF,
in addition to other characteristic lesions of multiple sclerosis within
the brain parenchyma. He was treated with a 3-day course of IV steroids,
and the ocular motility disturbance resolved within 6 weeks.
COMMENT This case highlights a common description of patients with internuclear

ophthalmoplegia, a transient perception of two images that “have to catch
up with each other.” Although this cause of diplopia may be associated
with failure of adduction on smooth pursuit testing, in certain cases pursuit
appears normal, and saccadic testing is needed to make the diagnosis
(showing a delay in adduction). Given that the predominant feature of
myasthenia gravis is worsening with fatigue, patients who are symptomatic
later in the day or when tired should be evaluated for neuromuscular
junction disease.
TABLE 8-1 Innervations and Actions of the Ocular Motor System
Cranial Nerve Muscle Action
III (Superior branch) Superior rectus Elevation, intorsion, adduction
III (Inferior branch) Medial rectus Abduction
Inferior rectus Depression, extorsion, adduction
Inferior oblique Extorsion, elevation, abduction
IV Superior oblique Intorsion, depression, abduction
VI Lateral rectus Adduction
1368 OCTOBER 2019

the upright position.9 INO presents with horizontal diplopia that may be KEY POINT
characterized by brief, specific exacerbations; patients often describe a sense of
● Internuclear
“one eye catching up to the other” with horizontal saccades. Key examination ophthalmoplegia is best
findings are slowed adduction in one eye with corresponding abducting identified by testing
nystagmus in the other eye (these findings are most often best ascertained by saccades.
testing saccades, as discussed above). INO can sometimes be mistaken for third
nerve palsy, but the ocular motility examination can exclude this based on absent
involvement of other muscles innervated by the third nerve (superior rectus,
inferior rectus, and levator among them). Therefore, a key examination feature
that helps distinguish INO from medial rectus muscle weakness or a partial third
nerve palsy is that adduction with convergence is preserved. INO results from
the dysfunction of the medial longitudinal fasciculus, which connects the
ipsilateral sixth nerve nucleus in the pons to the contralateral third nerve nucleus
(medial rectus subnucleus) in the midbrain. Although several possible causes
exist, the most frequently encountered are demyelination (in patients younger
than 50 years of age) and brainstem stroke (in patients older than 50 years of
age). Because of the potential causes of both skew deviation and INO,
neuroimaging (preferably brain MRI) is indicated for patients presenting with
these findings. It is also important to remember that INO may be bilateral; these
lesions often occur in the midbrain and affect the convergence nucleus, resulting
in a large-angle exotropia (meaning the eyes are deviated outward) and
convergence insufficiency (the so-called wall-eyed bilateral INO) (CASE 8-2).
Dysfunction of Nuclear and Infranuclear Ocular Motor Control

The oculomotor (third), trochlear (fourth), and abducens (sixth) cranial nerves
are the final mediators of the complex mechanism of ocular motility that
originates in the brainstem, with modulation from the frontal eye fields,
cerebellum, and other structures within the brain. Failure of these nerves to
orient the globes in a coordinated fashion, even to a mild degree, will result in the
perception of double vision (or, if subtler, ”blurred vision” that resolves when
the patient occludes either eye). Principal actions of these cranial nerves are
reviewed in TABLE 8-1, but as a practical matter, it is helpful to remember that
cranial nerve VI (innervating the lateral rectus muscle) abducts the eye, cranial
nerve IV (innervating the superior oblique muscle) depresses and intorts the eye
for actions such as reading and negotiating curbs/going down stairs or
escalators/addressing golf balls, and cranial nerve III does “everything else.”
A thorough understanding of the patterns and causes of diplopia related to
cranial nerve dysfunction is of vital importance to the clinician when it comes to
evaluating diplopia. As evidence of this, a study by O’Colmain and colleagues5
found that of 149 patients presenting with diplopia of fewer than 4-weeks
duration, more than 50% had an isolated third, fourth, or sixth cranial nerve
palsy; the remainder of the patients were determined to have a mechanical cause
(10.7%), a dysfunction of higher cortical control (10.1%), decompensation of a
preexisting ocular misalignment (8.1%), an idiopathic cause (6.7%), or a
monocular cause (5.4%).
Adding to the localizing information that can be gleaned from dysfunction of
the third nerve is the possibility of levator involvement (resulting in ptosis) or
involvement of the pupil (resulting in anisocoria due to mydriasis of the involved
eye) caused by disruption of the central caudal nucleus (a midline, unpaired
structure, one of the third nerve nuclei responsible for innervation of the bilateral

levator palpebrae muscles) or Edinger-Westphal nucleus (or their axons),

respectively. When the palsy results from injury to the third nerve nucleus on
one side, the patient may present with ptosis and supraduction weakness in the
eye contralateral to the more complete third nerve palsy because of bilateral
innervation by the central caudal nucleus and decussation of fibers from the
superior rectus nucleus. If, instead, the fascicles of the third nerve are affected as
they course through the midbrain, patients may present with diplopia that is
accompanied by ataxia, tremor, or hemiparesis. The discovery of a new
pupil-involving third nerve palsy should prompt a search for a compressive
CASE 8-3 A 64-year-old man presented for evaluation of binocular horizontal

diplopia that began 2 weeks earlier and was most bothersome when
viewing at a distance and when driving. He noted that the diplopia was
more prominent when he directed his gaze to the left but otherwise it was
present “all the time.” He had a history of hypertension, diabetes
mellitus, and dyslipidemia.
On examination, the patient’s left eye did not fully abduct, but all other
movements were intact. Alternate cover testing identified an esodeviation
(or “in-turning” of the eyes) that was minimal in right gaze but increased in
left gaze. The fundus examination was normal, without optic disc edema.
Given the patient’s history of hypertension, diabetes mellitus, and
dyslipidemia, his presentation was consistent with microvascular cranial
nerve VI palsy. No other cranial nerve palsies were evident, and the
remainder of the neuro-ophthalmic examination was normal (with specific
regard to papilledema or other features to suggest elevated intracranial
pressure). A restrictive process within the orbit (causing restriction of the
medial rectus muscle) was also a possibility, but the absence of abnormal
eyelid findings, pain with eye movements, or proptosis made this less likely.
Although the patient was older than 55 years of age, giant cell arteritis was
not supported due to the paucity of systemic symptoms. Appropriate
modification of cerebrovascular risk factors was recommended.
The patient returned for follow-up 8 weeks later, at which time he
volunteered that the “double vision is gone, except when I look all the way
to the left.” Ocular motility had improved, and the reduced abduction of the
left eye was virtually resolved. Neuro-ophthalmic follow-up continued for
another month, at which time the ocular motility examination was normal
and diplopia had fully resolved.
COMMENT This case highlights the importance of determining the pattern of the
ocular misalignment. Binocular horizontal diplopia that is worse at distance
and in left gaze is consistent with impairment of divergence and suggests
involvement of the left lateral rectus muscle/cranial nerve VI. Given the
potential for increased intracranial pressure to present with a sixth nerve
palsy as a false localizing sign, a fundus examination should be performed
to evaluate for papilledema, and consideration should be given to
neuroimaging to exclude a space-occupying lesion.
1370 OCTOBER 2019

lesion, specifically an aneurysm of the posterior communicating artery. In KEY POINTS
patients older than 50 years of age, third nerve palsies that spare the pupil but are
● Patients presenting with
otherwise complete are frequently the result of ischemia, and patients tend to cranial nerve VI palsy should
recover in approximately 3 months. be evaluated for signs and
Isolated fourth nerve palsies are frequently the result of trauma but also may symptoms of increased
reflect decompensation of a congenital dysgenesis of the nerve or superior intracranial pressure,
which includes fundus
oblique muscle.
examination.
Isolated sixth cranial nerve palsies (CASE 8-3) may be falsely localizing given
that the protracted course of the nerve from the pontomedullary junction, along ● Myasthenia gravis can
the clivus, then piercing the dura at the Dorello canal, over the petrous ridge, and mimic any pupil-sparing
finally into the cavernous sinus, makes it especially susceptible to disruption via ocular motility deficit.
stretching of the nerve caused by increased intracranial pressure. Therefore,

patients presenting with diplopia due to cranial nerve VI palsy should be
carefully evaluated for papilledema or other features suggestive of intracranial
structural pathology.
Dysfunction of the Neuromuscular Junction

MG is an autoimmune disease in which circulating antibodies block the effective
communication between the neurotransmitter acetylcholine and its receptors on
the postsynaptic membrane. While generalized forms of the disease exist and
patients with ocular MG may progress to generalized MG,10 intermittent diplopia
and ptosis remain the predominant presenting symptoms.
A long-regarded clinical rule of thumb is that ocular MG can mimic any
pupil-sparing cause of diplopia, and thus this should be considered within the
differential for most patients presenting with isolated diplopia. The primary historical
feature that should prompt consideration of MG, however, is the intermittency of
the double vision and its tendency to occur with fatigue and resolve with rest. This
can be easily demonstrated during the examination by noting any abnormalities in
ocular motility and by careful measurement of ocular misalignment, then repeating
the same portions of the examination after asking the patient to rest (or sleep) with
his or her eyes closed for 30 minutes or following the application of ice to the closed
eyes for 2 minutes (the ice pack test).11,12 Improvement in the examination under
these conditions is highly suggestive of MG; recrudescence of the findings over a short
period of time thereafter is also supportive.
Additionally, patients and their family members should be queried about
potential associated symptoms such as ptosis (which is also commonly variable
and more prominent with fatigue), dysphagia, dyspnea, or other symptoms of
generalized neuromuscular junction dysfunction. In addition to the symptoms
improving with rest and worsening with fatigue, which can be demonstrated
during the examination, additional ocular findings can assist with clinical
confirmation. These findings include eyelid curtaining (lifting of one eyelid by
the practitioner causes the fellow eyelid to droop), the Cogan eyelid twitch sign
(in which the upper eyelid jerks up once or twice upon return to primary gaze
from downgaze, especially if following a prolonged period of upgaze),13 and
weakness of the orbicularis muscles with forced or prolonged eye closure.
Serum testing for acetylcholine receptor (AChR) antibodies can be helpful in
confirming autoimmune MG but is positive in only 50% to 70% of patients with
purely ocular disease.14 Approximately half of patients with clinical features of
MG but who are negative for the AChR antibody may harbor antibodies to
muscle-specific tyrosine kinase (MuSK).15 These patients are likely to have a

distinct constellation of features including prominent bulbar weakness and may

worsen when treated with acetylcholinesterase inhibitors.16 Anti–lipoprotein
receptor–related protein 4 (LRP4) antibody has been reported in approximately
10% of patients who are negative for both anti-AChR and anti-MuSK
antibodies,17 but the presence of LRP4 antibodies is widely variable based on a
number of factors.18 Nerve conduction testing looking for a decrement on
repetitive nerve stimulation or assessing for jitter on single-fiber EMG19 can be
used in equivocal cases but is often relegated to patients with symptoms of
systemic disease. In patients with pure ocular MG, single-fiber EMG of the
orbicularis oculi is more sensitive than repetitive nerve stimulation.20 Treatment
for ocular MG is varied and principally relies on inhibition of the metabolism of
acetylcholine (pyridostigmine) or modulation of the immune system (steroids
or other immunomodulatory therapies).
Orbital Disease
Various pathologic processes within the orbit can impair the normal contraction
of the extraocular musculature or mechanically restrict the movement of the
globe. Thyroid ophthalmopathy (also referred to as thyroid eye disease or Graves
ophthalmopathy) is an autoimmune disease that causes progressive edematous
changes of the orbital musculature resulting in restriction of eye movements. The
inferior rectus muscles are most commonly involved, followed by medial and
superior rectus muscles21; diplopia is most commonly vertical as the lateral rectus
muscles are less likely to be involved. Because of progressive enlargement of the
extraocular muscles, proptosis and periorbital edema, which tends to be more
pronounced on awakening and improves during the course of the day, are
associated features. Most important, progressive muscle enlargement may cause
compression of the optic nerve at the orbital apex; for this reason, formal visual
field studies are required to monitor for insidious visual field constriction.
Diagnosis can be confirmed by imaging (CT or MRI) of the orbits documenting
characteristic edema and hypertrophy of the extraocular muscles; laboratory
studies for thyroid dysfunction may or may not be abnormal, but measurement
of thyroid-stimulating hormone (TSH) receptor antibodies can correlate with
disease severity and help monitor for response to treatment.22 In the absence
of severe symptoms or impending visual decline, most patients can be managed
conservatively with a focus on treating underlying thyroid dysfunction (if
present), mitigating corneal exposure related to proptosis, and discontinuation of
smoking. Moderate disease can be treated with immunomodulation (typically
oral prednisone); severe disease may require surgery for orbital decompression.
More recently, an insulin-like growth factor I receptor (IGF-IR) inhibitor
(teprotumumab) has been shown to improve proptosis and produce rapid
symptomatic improvement as compared to placebo.23
Idiopathic orbital myositis, also known as idiopathic orbital inflammation, is a
rare inflammatory disorder resulting in painful, isolated extraocular muscle
dysfunction most commonly in the distribution of the third cranial nerve. It is
more likely to occur in women and in the third decade of life.24 Horizontal diplopia
with the presence of pain is central to the diagnosis; proptosis, periocular edema,
and conjunctival hyperemia may also be present. The diagnosis is confirmed by
MRI of the orbits documenting unilateral thickening and enhancement of the
involved muscle and its myotendinous insertion.25 Similar orbital inflammation
can be seen in IgG4-related disease, an immune-mediated fibro-inflammatory
1372 OCTOBER 2019

condition with potential effects on multiple structures (including the orbits); KEY POINTS
screening for elevation of serum IgG4 should be considered. Orbital lymphoma
● Antibody and
may appear similar to idiopathic orbital inflammation and should be considered in electrophysiologic testing
progressive or recurrent cases, especially in older patients. For patients with for myasthenia gravis may
idiopathic orbital myositis–associated diplopia, systemic corticosteroids with a be supportive, but this
protracted taper is the principal form of treatment; a more thoughtful algorithm remains a primarily clinical
diagnosis.
for management of this disorder has been proposed.26
● Patients with known or
TREATMENT APPROACH suspected thyroid
Ideally, resolution of the underlying cause of the diplopia is achieved. However, ophthalmopathy should
depending on the etiology, this may require time for the therapeutic intervention have periodic monitoring
with formal visual fields
to take effect. In other circumstances, such as with patients harboring a because of the possibility
decompensated strabismus or stroke, the diplopia may remain. of peripheral vision
Generally speaking, long-standing or residual diplopia can always be resolved. constriction by compression
Careful consideration should be given to which therapeutic strategy is most of the optic nerves as a
consequence of enlarging
satisfactory, will provide the greatest return to the desired functional status, extraocular muscles.
and is consistent with the patient’s concomitant conditions and long-term
goals. ● For patients with new-
onset (eg, microvascular)
or transient (eg, myasthenia
Monocular Occlusion
gravis–related) diplopia,
For patients with binocular diplopia, the most straightforward approach is monocular occlusion for
covering one eye. Many patients will recognize this independently and may mitigation of symptoms is
unconsciously close one eye to improve their visual experience. On a longer-term immediately effective and
can be employed as needed
basis, this can be achieved through the use of an eye patch, although some
when symptoms are
patients may eschew this given the cosmetic implications. Moreover, it is crucial present.
to instruct patients using an eye patch to ensure that the eyelid under the patch
is fully closed to minimize the potential for corneal injury. For similar reasons,
this method should be avoided for any patient with impaired corneal sensation
(eg, because of concomitant cranial neuropathy or other causes). A more
acceptable approach is to place translucent tape over one lens of the patient’s
spectacles; some patients prefer to fashion a fabric cover that they place over the
frame of one lens. Patients should be assured that occlusion of either eye will
mitigate the diplopia, but care should be taken to ensure that the better-seeing
eye is not covered. They should also be informed that this method will disrupt
binocular vision as it relates to depth perception, so care should be taken when
driving or when engaging in other potentially hazardous tasks.
Prism Lenses
For patients who wear spectacles, a prism lens can be applied to one or both
lenses to “bend” the disparate images into single vision. This is most effective for
patients with comitant and relatively small-angle ocular misalignment; for other
patients this may still be beneficial, but the expectation should be for single
vision in primary position (as the prism will not mitigate the incomitant ocular
misalignment in all directions of gaze simultaneously). Ideally, a Fresnel
(temporary) prism is applied, and the patient is asked to determine over a
period of days to weeks whether the prism is effective. This allows for easy
adjustment of the prism strength based on the patient’s experience or in the
event that the degree of ocular misalignment changes, such as with an improving
microvascular cranial nerve VI palsy. Once the appropriate prism strength is
confirmed, this can be “ground in” to a pair of spectacles for full-time wear.

KEY POINT Eye Alignment Surgery

For patients with large-angle, incomitant ocular misalignment that is not
● Prism correction is useful
for patients with stable
amenable to (or has failed) prism correction, surgery to reposition the
or comitant ocular extraocular muscles with the goal of “realigning the eyes” may be beneficial. Of
misalignment; eye alignment note, surgical intervention for diplopia related to MG is rarely recommended as a
surgery is useful for patients consequence of the intermittent and variable nature of the ocular misalignment
with incomitant diplopia.
and the potential for complete recovery with medical therapy.
CONCLUSION
Diplopia of any pattern or degree is disconcerting to patients and often provokes
consternation for the evaluating clinician. However, a systematic approach
that relies on a careful history to elucidate candidate sites of localization
(brainstem/nuclear, cranial nerve, neuromuscular junction, muscle), followed
by precise examination techniques to support the most likely etiology, allows for
accurate bedside diagnosis in most cases. It is on this basis that the potential for
worrisome underlying etiologies can be evaluated and confirmatory diagnostic
studies can be judiciously directed.
Finally, it is often very comforting for patients to know that diplopia (in most
instances) is not associated with pathology that will cause overt vision loss.
Furthermore, although the elimination of the underlying cause (if possible) is
ideal, the symptom of double vision can always be mitigated. Interventions range
from simple monocular occlusion to eye alignment surgery, but the patient need
not expect that long-term resolution is in question.
VIDEO LEGENDS
VIDEO 8-1 VIDEO 8-3
Examination of fixation. The patient is asked to Examination of versions. The patient is asked to
maintain focus on a visual target (the “big 95” at the follow a target through the cardinal positions of
top of a Rosenbaum Vision Screen is preferred). The gaze while viewing it with both eyes. The examiner
examiner should note the patient’s ability to should note whether ocular pursuit movements are
maintain stability of gaze, paying particular attention smooth and controlled; this also allows for any
to square-wave jerks, other saccadic intrusions, or asymmetry between the degree of movement of
nystagmus. each globe compared to the other to be noted.
© 2019 American Academy of Neurology. © 2019 American Academy of Neurology.
VIDEO 8-2 VIDEO 8-4

Examination of ductions. One of the patient’s eyes Examination of saccades. The patient is asked to
is covered, and with the other eye, he is asked to maintain fixation on a central target, then to rapidly
follow a visual target slowly through the cardinal direct his gaze to an eccentric target, then back to
positions of gaze. central fixation. This should be performed in both
the horizontal and vertical planes.
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1 Norton JW, Corbett JJ. Visual perceptual 3 Smith JL. Monocular diplopia. J Clin
abnormalities: hallucinations and illusions. Semin Neuroophthalmol 1986;6(3):184–185.
Neurol 2000;20(1):111–121. doi:10.1055/s-2000-6837.
4 Sharp WL. The floating-finger illusion. Psychol
2 Jones MR, Waggoner R, Hoyt WF. Cerebral Rev 1928;35(2):171–173. doi:10.1037/h0070164.
polyopia with extrastriate quadrantanopia:
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REVIEW ARTICLE

Nystagmus and Saccadic
C O N T I N UU M AUDIO
ONLINE
Intrusions
By Janet C. Rucker, MD

VIDEO CONTENT
A VA I L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of nystagmus and
saccadic intrusions with the goal of facilitating recognition and
differentiation of abnormal eye movements to assist with accurate
diagnosis of neurologic disease and evidence-based specific treatment of
oscillopsia. Myriad advances have been made in the understanding of
several types of nystagmus and saccadic intrusions, even in the past 5 to
10 years, especially regarding underlying pathophysiology, leading to
pharmacologic advances rooted in physiologic principles.
RECENT FINDINGS:Specific recent advances in the study of nystagmus and

saccadic intrusions include (1) improved understanding of the underlying
etiologies and mechanisms of nystagmus enhanced or unmasked by
provocative maneuvers such as supine position or head shaking; (2)
recognition of the differences in behavior and treatment responsivity of
acquired pendular nystagmus in demyelinating disease versus oculopalatal
myoclonus; (3) recognition that oculopalatal myoclonus results from a dual
CITE AS:
mechanism of abnormal inferior olivary gap junction connection formation
25(5, NEURO-OPHTHALMOLOGY): and maladaptive cerebellar learning; and (4) well-controlled clinical trials
1376–1400. to evaluate the efficacy of pharmacologic interventions, such as
memantine for acquired pendular nystagmus and 4-aminopyridine for
Dr Janet C. Rucker, Bernard A. downbeat nystagmus.
and Charlotte Marden Professor
of Neurology and SUMMARY: Accurate recognition of nystagmus and saccadic intrusions,
Ophthalmology, New York
University School of Medicine, including familiarity with the subtleties of examination techniques that
222 E 41st St, 14th Floor, allow such eye movements to be unmasked, is critical to proper diagnosis
New York, NY 10016,
janet.rucker@nyulangone.org.
and ultimate alleviation of the visual impairment these patients
experience.
Dr Rucker reports no disclosure.
UNLABELED USE OF
INTRODUCTION
F
USE DISCLOSURE: ixation and image clarity of a visual target require placement and
Dr Rucker discusses the maintenance of the fovea, the retinal region with the highest cone
unlabeled/investigational
use of medications for the photoreceptor density and best visual acuity, on the target. Maintaining
management of abnormal eye a visual target on the fovea is largely achieved by three mechanisms: (1)
movements, none of which are
approved by the US Food and
stabilization of fixation, including via visual feedback mechanisms by
Drug Administration. which the visual system suppresses unwanted saccades and detects retinal drifts
followed by programming of corrective eye movements; (2) vestibuloocular
reflexes by which eye position is maintained despite small head and body
of Neurology. movements; and (3) neuronal pathways called neural integrators that largely
1376 OCTOBER 2019

serve to maintain the eyes in a desired eccentric gaze position by counteracting KEY POINTS
the elastic pull of orbital tissues that draws the eyes back toward the center.1
● Nystagmus can be
These three mechanisms provide a physiologic framework upon which to congenital or acquired; it
consider nystagmus and saccadic intrusions and the symptoms they may tends to be rhythmic and
produce. regular and, if present in
central gaze, continuous and
sustained. Saccadic
OVERVIEW OF NYSTAGMUS AND SACCADIC INTRUSIONS
intrusions are more often
Nystagmus and saccadic intrusions include abnormal and physiologically normal nonrhythmic, intermittent,
spontaneous involuntary eye movements, most typically in the form of repetitive and unsustained.
oscillations of the eyes. These spontaneous eye movements remove the eyes from
a desired position and, when they occur during central gaze fixation, remove the ● The initial abnormal eye
movement with nystagmus is
fovea from the visual target, thereby creating motion on the retina; thus, they always a slow drift of the
may cause oscillopsia2 (a subjective sense of visual motion) and/or reduction in eyes that is also called a
visual acuity and clarity. slow phase; in contrast,
Nystagmus can be congenital or acquired; it tends to be rhythmic and regular saccadic intrusions are
initiated by a fast saccadic
and, if present in central gaze, continuous and sustained. Saccadic intrusions eye movement.
are more often nonrhythmic, intermittent, and unsustained. Nystagmus and
saccadic intrusions are differentiated and defined by the type of eye movement ● The two main types, or
that initiates the shift in eye position from a desired location. The initial abnormal waveforms, of nystagmus
are jerk and pendular,
eye movement with nystagmus is always a slow drift of the eyes that is also called
both of which may have
a slow phase; in contrast, saccadic intrusions are initiated by a fast saccadic eye horizontal, vertical, and/or
movement. The two main types, or waveforms, of nystagmus are jerk and torsional trajectories, which
pendular, both of which may have horizontal, vertical, and/or torsional may be different in the
two eyes, especially for
trajectories (FIGURE 9-13), which may be different in the two eyes, especially for
pendular nystagmus.
pendular nystagmus. Jerk nystagmus (VIDEO 9-1 [online]) and pendular
nystagmus (VIDEO 9-2 [online]) are defined by the type of eye movement that
follows the initial slow drift of the eyes away from desired position. With jerk
nystagmus, the initial slow drift is followed by a fast corrective movement, after
which the nystagmus is named. Slow drifting of the eyes upward with fast
corrective downward movements is named downbeat nystagmus; slow drifting of
the eyes right with fast corrective leftward movements is named left-beat
nystagmus (VIDEO 9-1 [online]). With pendular nystagmus, the initial slow
drift is followed by further to-and-fro slow movements (VIDEO 9-2 [online]).
Slow phases of jerk nystagmus may have linear, decreasing, or increasing
velocity (FIGURE 9-1), and correct identification of this may assist with
diagnosis. For example, acquired forms of nystagmus tend to have linear or
decreasing slow-phase velocities (FIGURES 9-1A and 9-1B), whereas congenital
nystagmus slow phases in the infantile nystagmus syndrome are typically of
increasing velocity (FIGURE 9-1C), although these are not pathognomonic.4
The term saccadic intrusions includes a range of saccade types that intrude
upon fixation, from single saccades to sustained saccadic oscillations
(FIGURE 9-25).
The underlying localization and etiology of nystagmus is often clear following
a careful history and examination. Important historical features include the
duration of nystagmus, the presence or absence of resultant vision impairment
and/or oscillopsia and accompanying neurologic symptoms.
Examination of a patient with nystagmus or saccadic intrusions should include
assessment of visual acuity, documentation of any aberrant head positioning,
notation of the nystagmus behavior in all gaze positions (with distance and near
fixation and with each eye separately), assessment of all eye movement types (ie,

NYSTAGMUS AND SACCADIC INTRUSIONS
saccades, smooth pursuit,

vestibuloocular reflexes,
optokinetic nystagmus, and
convergence), and a full
neurologic examination.
Subtle forms of nystagmus in
central gaze position may be
picked up only during
ophthalmoscopic examination.
The effects of provocative
maneuvers, such as elimination
of visual fixation (which can
be achieved during
ophthalmoscopic examination
with coverage of the contralateral
eye or with specialized
equipment such as Frenzel
goggles, consisting of lenses that
blur the patient’s vision and
magnify the examiner’s view of
the eyes), supine positioning,
FIGURE 9-1
Waveforms of nystagmus. Each solid black line horizontal or vertical head
represents eye position and each dotted line shaking, hyperventilation, and
represents intended gaze position. By convention, mastoid vibration on nystagmus
an upward movement in the eye position
behavior should ideally also be
represents an eye movement either rightward if it is
a horizontal position trace or upward if it is a noted and are most helpful for
vertical position trace. A, Jerk nystagmus with identifying peripheral vestibular
linear-velocity slow phases, which typically occurs forms of nystagmus.6 Even if no
with peripheral or central vestibular dysfunction. nystagmus is seen on standard
B, Jerk nystagmus with decreasing-velocity slow
phases, which typically occurs with impaired examination with the patient in
neural integration, such as in gaze-evoked the upright position, provocative
nystagmus. C, Jerk nystagmus with increasing- maneuvers often unmask
velocity slow phases, which is characteristic, but nystagmus and assist with
not pathognomonic, of jerk forms of congenital
nystagmus. D, Pendular nystagmus with to-and-fro
diagnosis. Thus, they should
slow ocular oscillations in a sinusoidal pattern be incorporated into the
with no fast phases, such as is typically seen in examination of any patient with
multiple sclerosis or oculopalatal tremor. E, symptoms of oscillopsia,
Pendular nystagmus of the type seen with pendular
forms of congenital nystagmus. The arrowheads
imbalance, or vertigo. Quantified
correspond to brief moments called foveation recordings of abnormal
periods during which the oscillations stop spontaneous eye movements,
and clear vision occurs. such as with infrared
Reprinted with permission from Thurtell MJ, Leigh RJ.3
© 2011 Elsevier BV.
video-oculography of the type
often used for video-
nystagmography, may further
assist with accurate identification of nystagmus type and assessment of
treatment responses.
Specific treatments for various types of nystagmus and saccadic intrusions
are discussed in their respective sections; however, some general principles
apply. Appropriate treatment of nystagmus and saccadic intrusions requires
accurate identification of the specific type of the abnormal eye movement.
1378 OCTOBER 2019

FIGURE 9-2 KEY POINT
Saccadic dysmetria and various types
of saccadic intrusions. By convention, ● Even if no nystagmus is
an upward movement in the eye seen on standard
position represents an eye movement examination with the patient
either rightward if it is a horizontal in the upright position,
position trace or upward if it is a provocative maneuvers
vertical position trace. A, Saccadic often unmask nystagmus
dysmetria from cerebellar disease. At and assist with diagnosis.
the beginning of the solid black line, Thus, they should be
the eye is stationary. The rapid upward incorporated into the
deflection of the solid black line examination of any patient
corresponds to a saccade to a visual with symptoms of
target, which is represented by the oscillopsia, imbalance,
hatched black line. Note that the eye or vertigo.
overshoots the target, then makes a
corrective saccade in the opposite
direction but again overshoots the
target. A final upward deflection
corresponds to a second corrective
saccade that brings the eye to the
target. This movement occurs as part
of an intended saccade and is not
classified as a saccadic intrusion. It
should be contrasted with the saccadic
intrusion in B. B, Macrosaccadic
oscillations from cerebellar disease.
In this illustration, the eye initially
fixates on a central target but then
spontaneously makes saccades back
and forth across the midline position in
a crescendo-decrescendo pattern.
Note that each saccade is separated
by an intersaccadic interval during
which the eye is transiently stationary
before making another saccade. C,
Square-wave jerks. The eye initially
fixates on a central target but then
makes small pairs of saccades away
from and back to that target, with each
pair of saccades separated by an
intersaccadic interval. D, Macro–
square-wave jerks. Similar to the
square-wave jerks in C but larger in
amplitude. E, Back-to-back saccades
that oscillate about the midline
fixation target with no intervening
intersaccadic interval between
saccades. When this type of movement
occurs in the horizontal plane, it is
called ocular flutter. When it occurs in
horizontal, vertical, and torsional
planes, it is called opsoclonus.
Reprinted with permission from Leigh RJ and
Rucker JC.5 © 2005 Lippincott Williams &
Wilkins.

TABLE 9-1 Common Evidence-Based Treatments for Abnormal Spontaneous

Eye Movementsa
Drug Condition Used For Standard Dosageb Main Side Effects Notes
Memantine Acquired pendular 5 mg/d oral dose; increase Fatigue, body or Main drug interactions:
nystagmus, saccadic by 5 mg/wk to maximum back pain, amantadine, ketamine,
intrusion oscillations daily dose of 20 mg (10 mg dizziness, dextromethorphan
(especially square- 2 times a day)c headache,
Dosage listed is for
wave oscillations and confusion
normal renal function;
macrosaccadic
dosage must be adjusted
oscillations)
for impaired renal
function
Gabapentin Acquired pendular 100 mg oral dose 1 to Dizziness, Dosage listed for normal
nystagmus, downbeat 3 times a day as tolerated; somnolence, renal function; dosage
nystagmus increase as tolerated every fatigue must be adjusted for
3 weeks up to maximum impaired renal function
dose 1200 mg 3 times a day
4-Aminopyridine Downbeat nystagmus Sustained-release Rare seizures, Contraindications:

formulation: 10 mg oral perioral and seizure disorder, history
dose 2 times a day digital of seizure
paresthesia
Immediate release Also contraindicated in
formulation (typically must moderate to severe renal
be obtained through dysfunction, defined in
compounding pharmacy): the United States as a
5–10 mg oral dose 4 to glomerular filtration rate
5 times a day with of 50 mL/min and lower;
maximum total daily this is different than in
dose of 30 mg/d Canada, where the definition
for contraindication is a
glomerular filtration rate
of 80 mL/min or lower
(mild, moderate, and severe
renal impairment)
Chlorzoxazone Downbeat nystagmus 500 mg oral dose 3 to Drowsiness,

4 times a day lightheadedness,
dizziness,
gastrointestinal
bleeding
Clonazepam Downbeat nystagmus, 1.5 mg/d oral dose in three Drowsiness, Contraindications:
acquired pendular divided doses; increase by ataxia, behavior significant liver disease,
nystagmus 0.5–1.0 mg every 3 days to problems narrow-angle glaucoma
maximum total daily dose
of 20 mg/d
Baclofen Periodic alternating 5 mg oral dose 3 times a Drowsiness,

nystagmus, downbeat day; increase by 5 mg/wk weakness,
nystagmus to maximum total daily fatigue,
dose of 80 mg/d headache,
insomnia, nausea
a
None of the drugs listed in this table are approved by the US Food and Drug Administration (FDA) for nystagmus.
b
The dose titrations listed represent the fastest recommended titration. Slower titration may be needed as per patient tolerance.
c
Drug trials for acquired pendular nystagmus in Europe have used a dose as high as 20 mg 2 times a day.
1380 OCTOBER 2019

Further, not all types require treatment. Intervention is indicated when the KEY POINTS
oscillation is present in central gaze and/or visual symptoms of oscillopsia or
● Saccadic intrusions are
reduced visual acuity or clarity are present. Treatment options include divided into two broad
medications, surgery, and optical interventions such as prisms for nystagmus categories: those with an
that damps at near or in upgaze. intersaccadic interval
In general, medications represent the mainstay of therapy for acquired between subsequent
saccades and those lacking
nystagmus (TABLE 9-1) and surgery represents the mainstay of therapy for
such an interval.
congenital nystagmus; however, multimodal approaches may be effective when
monotherapy fails. As in the treatment of many neurologic conditions (such as ● Saccadic intrusions with
migraine prophylaxis), the general approach is selection of an agent based on an intersaccadic interval
evidence where available and initiation of a low dose followed by gradual include square-wave jerks,
macro–square-wave jerks,
titration every 3 to 4 weeks to one of three end points: (1) effective treatment, and macrosaccadic
(2) limitation by side effects, or (3) maximal dose of medication reached without oscillations. Saccadic
effective relief. Given advances in understanding of the neural networks intrusions without an
involved in eye movement control over recent decades, many pharmacologic intersaccadic interval
include ocular flutter and
treatment options are now rooted in pathophysiologic mechanisms and a opsoclonus.
bidirectional flow of information exists, by which the identification of nystagmus
mechanisms may assist with targeted therapy and recognition of medication
efficacy may lead to elucidation of nystagmus mechanisms.
IMPAIRED VISUAL FIXATION STABILITY

In this structural framework, findings due to impaired visual function stability
include saccadic intrusions and acquired pendular nystagmus.
Saccadic Intrusions
Saccadic intrusions represent a group of spontaneous eye movements that
intrude upon fixation and are initiated by fast saccadic movements that drive
the eye away from central fixation. As a group, they are often provoked by
shifts of gaze (ie, having the patient look eccentrically and then back to center
will often induce a saccadic intrusion in these patients). They should be
differentiated from saccadic dysmetria, in which the eyes overshoot or
undershoot a target following an intended saccade (FIGURE 9-2A). Saccadic
intrusions are divided into two broad categories: those with an intersaccadic
interval between subsequent saccades and those lacking such an interval.
Saccadic intrusions with an intersaccadic interval include square-wave jerks,
macro–square-wave jerks, and macrosaccadic oscillations (FIGURES 9-2B
through 9-2D). Saccadic intrusions without an intersaccadic interval include
ocular flutter and opsoclonus (FIGURE 9-2E). So-called voluntary nystagmus also
falls into the category of a saccadic intrusion, as it comprises only fast saccadic
eye movements without any initial slow drift of the eyes and is, therefore, not
truly nystagmus.
All forms of saccadic intrusions discussed here, with exception of square-wave
jerks, frequently result in oscillopsia. With experience, the examiner can often
identify the various types of saccadic intrusions on clinical examination;
however, these eye movements have been defined by quantified eye movement
recordings with detailed specification of typical amplitude ranges, movement
directions, whether the abnormal saccades remove and return the eyes to the
central fixation point or oscillate about it, the presence or absence of an
intersaccadic interval, and the duration of the intersaccadic intervals (when
present). At times, certainty as to the type of saccadic intrusion is challenging on

clinical examination; in these settings, it is ideal to obtain quantified recordings,

as these eye movement disorders vary widely in terms of underlying diagnosis
and prognosis.
SQUARE-WAVE JERKS. Square-wave jerks (FIGURE 9-2C) are pairs of small

saccades (0.5 degrees to 5 degrees in amplitude), typically in the horizontal plane,
that remove the eyes from and then return them to the midline without crossing
it and have an intersaccadic interval (200 milliseconds on average).1 These eye
movements can occur in healthy normal individuals, especially with advancing
age, in which case the frequency is fewer than around 20 per minute. In younger
persons, fewer than 10 square-wave jerks per minute can be normal,7,8 but
careful evaluation to ensure the absence of neurologic disease is important.
Square-wave jerks occur excessively, sometimes nearly continuously, in patients
with Friedreich ataxia,9,10 multisystem atrophy,11 and progressive supranuclear
palsy (FIGURE 9-3) (VIDEO 9-3 [online]),12 although they may also occur in
idiopathic Parkinson disease at any stage of the illness.13–15 Macro–square-wave
jerk (FIGURE 9-2D) is a term used to describe a square-wave jerk of larger
amplitude (larger than 5 degrees), and, similar to excessive square-wave jerks,
macro–square-wave jerks nearly always represent underlying pathology such
as cerebellar involvement from multiple sclerosis (MS), structural lesions, or
multiple system atrophy. Square-wave jerks are typically attributed to lesions
affecting the frontal eye fields and the rostral pole of the superior colliculus or
its inputs from the substantia nigra pars reticularis and mesencephalic
reticular formation; pharmacologic inactivation studies in primates in these
structures result in square-wave jerks16–19; however, nearly continuous
square-wave jerks and macro–square-wave jerks may also occur with
cerebellar pathology.
Even when very frequent, square-wave jerks do not tend to cause visual
dysfunction or oscillopsia and generally do not require treatment. An exception is
when runs of back-to-back square-wave jerks occur, in which case the eye
movements are termed square-wave oscillations (FIGURE 9-4). On clinical
examination, these eye movements often occur in bursts precipitated by gaze
FIGURE 9-3
Eye movement recordings from a patient with progressive supranuclear palsy. Horizontal saccade
tracings demonstrate fairly normal horizontal saccades (the black eye position trace follows
the pink hatched target trace well when it jumps to the right or to the left and back to center);
however, very frequent (several per second) pathologic square-wave jerks occur. The patient
had slow vertical saccades characteristic of progressive supranuclear palsy (not shown).
1382 OCTOBER 2019

shifts and may be mistaken for ocular flutter (VIDEO 9-4 [online]); quantitative KEY POINTS
eye movement recordings are required to reliably differentiate these square-
● Square-wave jerks are
wave oscillations from ocular flutter. Although the prognosis and underlying pairs of small saccades,
etiologies of square-wave oscillations are still being determined, they have been typically in the horizontal
reported with cerebellar disease associated with glutamic acid decarboxylase plane, that remove the eyes
(GAD) antibodies20 and recessive cerebellar degeneration,21 as well as from from and then return them
to the midline without
doping-related injury (ie, administration of performance-enhancing drugs in
crossing it and have an
sports).22 The oscillopsia and visual dysfunction in this setting may be improved intersaccadic interval.
with memantine (TABLE 9-1).21
● Square-wave jerks occur
MACROSACCADIC OSCILLATIONS. Macrosaccadic oscillations are runs of excessively, sometimes
horizontal saccades that are larger than square-wave jerks, have an intersaccadic nearly continuously, in
patients with Friedreich
interval (200 milliseconds), cross the midline, and build and decay around ataxia, multisystem atrophy,
the central fixation point in a crescendo-decrescendo pattern (FIGURE 9-2B).23 or progressive supranuclear
This eye movement disorder is typically suggestive of cerebellar dysfunction, palsy, although they may
specifically of the caudal fastigial nucleus, and may also be seen with also occur in idiopathic
Parkinson disease at any
pontine lesions (VIDEO 9-5 [online]).24 Macrosaccadic oscillations can be stage of the illness.
thought of as an extreme and spontaneous form of cerebellar saccadic
hypermetria (FIGURE 9-2A). ● Macrosaccadic
oscillations are runs of
horizontal saccades that are
larger than square-wave
jerks, have an intersaccadic
interval, cross the midline,
and build and decay around
the central fixation point in a
crescendo-decrescendo
pattern.
FIGURE 9-4
Eye movement recordings from a patient with square-wave oscillations. Horizontal saccade
tracings demonstrate continuous runs of back-to-back square-wave jerks. The patient had
a history of malignancy; however, neuroimaging, malignancy screening, and paraneoplastic
evaluation were unrevealing. The etiology of these eye movements remains undetermined.
Refer to VIDEO 9-4 for the clinical appearance of these eye movements.

OCULAR FLUTTER/OPSOCLONUS. Ocular flutter and opsoclonus consist

of erratic bursts of very-high-frequency (10 to 25 cycles per second),
high-velocity, back-to-back saccades that oscillate about the midline and have
no intersaccadic interval between subsequent saccades (FIGURE 9-2E). This
is termed ocular flutter when the saccades occur only in the horizontal plane
(VIDEO 9-6 [online]). Opsoclonus, in contrast, contains saccades in all
trajectories: horizontal, vertical, and torsional (VIDEO 9-6 [online]). As with
all saccadic intrusions, these movements are usually not continuously present.
They occur sporadically and are often provoked by shifting gaze. These eye
movements are most often large enough (1 degree to 5 degrees) to see easily
on clinical examination; however, they can occur with very tiny amplitudes,
making them invisible to the naked eye. Any patient with new-onset
oscillopsia that is unexplained on examination should have a careful
assessment for small oscillations on ophthalmoscopy and quantified eye
movement recordings. Microflutter and micro-opsoclonus can occur and
may carry the same ominous prognosis as flutter and opsoclonus, although
cases with no ominous underlying etiology are reported.25–27
Flutter and opsoclonus are well reported with pathology affecting either the
pons,28 where burst neurons that control horizontal saccades are located, or
the cerebellum.29 A model simulation of these oscillations supports increased
γ-aminobutyric acid A (GABAA) receptor sensitivity in a circuit involving the
cerebellum, inferior olives, and brainstem saccadic premotor burst neurons.30
Inherent properties of the saccadic burst neurons themselves predispose them
to oscillating, and ion channel dysfunction of burst neurons is also proposed
as a contributory mechanism.31 These neurons are inherently prone to
oscillations due to synaptic feedback loops and their postinhibitory
rebound properties.
Flutter and opsoclonus occur in two main clinical settings: paraneoplastic
conditions and parainfectious brainstem encephalitis.32 The latter is
typically accompanied by truncal myoclonus, ataxia, and emotional lability.
Reported infectious causes include Enterovirus, West Nile virus, Lyme
disease, mumps, HIV, malaria, dengue, and Zika virus,33–36 although often
a specific infection is not identified. Antibodies reported with paraneoplastic/
autoimmune disease include Hu, Yo, Ma, amphiphysin, P/Q-type calcium
channel, N-methyl-D-aspartate (NMDA) receptor, GAD, and GQ1b.37,38
Ocular flutter has also been reported as a consequence of severe traumatic
brain injury39,40 and, recently, ocular flutter and opsoclonus have been reported
following mild traumatic brain injury.41,42 Not infrequently, in adults, the
etiology remains obscure. Neuroblastoma should be sought in children with
opsoclonus.43
Voluntary nystagmus may mimic ocular flutter and may be more appropriately
termed voluntary flutter.44 This eye movement can be voluntarily created by
some individuals, usually via convergence of the eyes, which is then also
accompanied by other features of the near vision response, including pupillary
constriction. This voluntary flutter typically cannot be sustained for a long period
of time. Occasionally, this is seen in individuals embellishing true underlying
neurologic conditions or in the setting of nonphysiologic conditions; thus, it is
important for the examiner to have familiarity with the features that allow
for diagnosis of this voluntary movement. It can, at times, be difficult to
differentiate pathologic ocular flutter and even opsoclonus from voluntary eye
1384 OCTOBER 2019

movements, as some individuals are capable of generating large-amplitude KEY POINTS
movements in the horizontal plane and even of producing voluntary
● Ocular flutter and
multidirectional opsoclonus.44 opsoclonus consist of
erratic bursts of
Acquired Pendular Nystagmus very-high-frequency,
Acquired pendular nystagmus occurs most often in the setting of high-velocity, back-to-back
saccades that oscillate
demyelinating disease (VIDEO 9-7 [online]) or within the context of
about the midline and have
oculopalatal myoclonus following a brainstem ischemic or hemorrhagic stroke no intersaccadic interval
(VIDEO 9-8 [online]).45 In diseases involving myelin, it is most common in MS between subsequent
but also characteristic of the childhood condition Pelizaeus-Merzbacher saccades. This is termed
ocular flutter when the
disease and of toluene abuse from glue sniffing. In diseases involving myelin,
saccades occur only in the
it frequently has a horizontal or elliptical trajectory. Oculopalatal tremor horizontal plane.
occurs weeks to months after a brainstem stroke and tends to have a Opsoclonus, in contrast,
vertical-torsional trajectory. Very rarely, pendular nystagmus in a seesaw contains saccades in all
pattern (with elevation and intorsion of one eye and depression and extorsion trajectories: horizontal,
vertical, and torsional.
of the other eye in one half cycle and the reverse pattern in the other half
cycle) has been reported with chiasmal pathology with an accompanying ● Flutter and opsoclonus
bitemporal hemianopia or with cerebellar lesions.46–48 This seesaw nystagmus occur in two main clinical
is related to a mismatch between visual and vestibular systems.47,49 Even settings: paraneoplastic
conditions and
rarer, a convergent-divergent form of pendular nystagmus may occur in the parainfectious brainstem
setting of oculomasticatory myorhythmia, which is pathognomonic for encephalitis.
Whipple disease due to Tropheryma whipplei infection and also features
concurrent masticatory muscle contractions. ● Acquired pendular
nystagmus occurs most
In the setting of MS, acquired pendular nystagmus usually consists of
often in the setting of
regular oscillations with a frequency of 3 Hz to 5 Hz50 and is often accompanied demyelinating disease or
by coexistent optic neuropathy, leading to the Heimann-Bielschowsky within the context of
phenomenon of disconjugate nystagmus with larger-amplitude movement in oculopalatal myoclonus
the eye with more severe vision loss and occasionally nystagmus in only one following a brainstem
ischemic or hemorrhagic
eye (VIDEO 9-7 [online]).51,52 However, experiments in healthy people with a stroke.
technique that delays visual feedback and can induce nystagmus argue against
demyelinating vision loss as a primary cause of the high-frequency type of
acquired pendular nystagmus seen in MS.53 It is likely that these oscillations in
MS occur primarily because of dysfunction of brainstem and cerebellar
connections and instability of the neural integrator.54 Brainstem lesion burden
tends to be high (FIGURE 9-5), and the majority of patients with MS with
acquired pendular nystagmus have additional signs of cerebellar disease
(VIDEO 9-7 [online]).51 Dysconjugacy of the nystagmus regarding amplitude
or trajectory is also common in individuals with no optic nerve involvement or
vision loss.51
Acquired pendular nystagmus in oculopalatal myoclonus, also sometimes called
oculopalatal tremor, has a typical frequency of 1 Hz to 3 Hz, is irregular, and is
of larger amplitude and faster velocity than the acquired pendular nystagmus in
MS.55,56 The trajectory is typically either pure vertical (VIDEO 9-8 [online]) or
vertical-torsional (VIDEO 9-9 [online]), and the movement may be asymmetric
between the two eyes (VIDEO 9-9 [online]). It is accompanied by abnormal
spontaneous palatal movement and hypertrophy with T2 hyperintensity of the
inferior olive on MRI (FIGURE 9-6), although a substantial time delay may
exist between development of all three features. The presence of dissociated
nystagmus is predictive of unilateral inferior olivary changes on MRI ipsilateral
to the eye oscillating with larger amplitude, whereas bilaterally symmetric

FIGURE 9-5
Axial T2-weighted MRI through the cortex/lateral ventricles (A) and posterior fossa (B) in a patient
with multiple sclerosis and acquired pendular nystagmus reveals extensive demyelinating
lesions, including extensive involvement of the brainstem and cerebellar peduncles.
pendular nystagmus may be associated with either unilateral or bilateral inferior

olivary changes.57
Historically, this condition was attributed to disruption of Guillain-Mollaret
triangle, the three sides of which connect the medullary inferior olivary nucleus
and deep cerebellar nuclei (through the inferior cerebellar peduncle), the deep
cerebellar nuclei and the midbrain red nucleus (through the superior cerebellar
peduncle), and the red nucleus and the inferior olivary nucleus (through the
central tegmental tract). More contemporary descriptions of the mechanism
do not implicate involvement of the red nucleus. In this modern explanation,
it is reported that inferior olivary neurons typically, in a healthy state, fire
FIGURE 9-6
Axial (A) and sagittal (B) fluid-attenuated inversion recovery (FLAIR) MRIs of a patient with
oculopalatal myoclonus demonstrates increased T2 signal in the inferior olivary nuclei.
1386 OCTOBER 2019

dyssynchronously via dendrite-to-dendrite connections.55 Following a brainstem KEY POINTS
lesion affecting the central tegmental tract, such as from hemorrhage of a
● Acquired pendular
cavernous malformation or stroke, inferior olivary soma hypertrophy occurs and nystagmus is typically very
new soma-to-soma electronic coupling via gap junctions (connexins) leads to visually disabling because
synchronous firing of inferior olivary neurons, which negatively impacts the of the constant slow
cerebellum and leads to maladaptive learning.55,58–60 to-and-fro foveal drifting
it creates.
Acquired pendular nystagmus is typically very visually disabling because
of the constant slow to-and-fro foveal drifting it creates (CASE 9-1). ● Nystagmus induced by
Variability in treatability exists in that acquired pendular nystagmus in the vestibular system, via
demyelinating disease often responds to moderately high medication doses, peripheral or central
but in oculopalatal tremor, it tends to be treatment resistant. This is very disruption, is jerk nystagmus
with linear-velocity slow
unfortunate, as patients with acquired pendular nystagmus from oculopalatal phases that tends to follow
tremor report higher visual disability.56 Best evidence-based treatment for the Alexander law, with
acquired pendular nystagmus is with gabapentin or memantine (TABLE 9-1).62–66 worsening of the amplitude
In a double-blind, placebo-controlled, crossover design study comparing and frequency of fast
phases in the direction of
gabapentin and baclofen in 15 patients with acquired pendular nystagmus, gaze of the nystagmus
gabapentin was effective in reducing oscillopsia and oscillation frequency as fast phases (ie, right-beat
measured with quantified recordings.63 A trial comparing gabapentin with jerk nystagmus worsens in
vigabatrin confirmed the beneficial effects of gabapentin; however, similar right gaze).
efficacy was not seen with vigabatrin, an inhibitor of GABA aminotransferase,
the enzyme responsible for the catabolism of GABA.64 It is possible that the
mechanism of gabapentin in acquired pendular nystagmus relates to
voltage-gated calcium channel blockade or NMDA receptor glutamate
inhibition, or both, which reduces inhibition on cerebellar Purkinje cells and
depolarizes cells of the nucleus prepositus hypoglossi, an element of the neural
integrator.58 The notion that NMDA receptor glutamate inhibition underlies
gabapentin’s use in acquired pendular nystagmus is supported by efficacy of the
NMDA receptor antagonist memantine for acquired pendular nystagmus, which
was shown to reduce oscillations in a nine-patient study.65 Clonazepam,
valproate, and scopolamine are also effective in some patients. Although the
mainstay of therapy is pharmacologic for acquired pendular nystagmus,
beneficial outcomes have been reported in some cases with combined medical
and surgical intervention, with surgical procedures more classically used in
congenital nystagmus.67–69
IMPAIRED VESTIBULAR RESPONSES

Nystagmus may occur as a consequence of vestibular impairment, whether
peripheral or central.
Peripheral Vestibular Nystagmus

Nystagmus induced by the vestibular system, via peripheral or central
disruption, is jerk nystagmus with linear-velocity slow phases (VIDEO 9-1
[online]) that tends to follow the Alexander law, with worsening of the
amplitude and frequency of fast phases in the direction of gaze of the nystagmus
fast phases (ie, right-beat jerk nystagmus worsens in right gaze). Patients
with peripheral vestibular dysfunction, including benign paroxysmal positional
vertigo (BPPV) and vestibular neuritis, often seek medical attention because
of vertigo rather than oscillopsia. Nystagmus in specific patterns induced by
specific provocative maneuvers is often the key to establishing the proper
diagnosis.

CASE 9-1 A 42-year-old woman with a more than 15-year history of multiple
sclerosis (MS) presented with oscillopsia, binocular horizontal double
vision, and poor vision in general. She had been wheelchair dependent
for 10 years because of gait imbalance and lower extremity weakness and
had an episode of acute right optic neuritis 20 years earlier with poor
subsequent visual recovery. Over the previous 10 years, she had noted a
slow decline in vision in both eyes. She had prisms in her glasses to
correct her double vision.
Examination revealed visual acuity of counting fingers in each eye with
markedly reduced color vision in each eye, right red desaturation, and
bilateral optic nerve pallor. Bilateral internuclear ophthalmoplegia was
present, with impaired adduction of the right eye and bilateral slowing of
adducting saccades. She had a large exodeviation of the eyes. In central
gaze, she had large-amplitude nystagmus that appeared predominantly
pendular. Acquired pendular nystagmus was confirmed by quantitative
eye movement recording traces (VIDEO 9-7 [online]).
MRI of the brain revealed extensive demyelination, with extensive
involvement of the brainstem and cerebellar peduncles (FIGURE 9-5).
Gabapentin was initiated at a dose of 100 mg 3 times a day, with a plan
to gradually titrate over time.
COMMENT This patient with long-standing MS leading to substantial visual and gait
disability had multiple ophthalmic and ocular motor findings, as is common
in progressive MS associated with substantial disability. She had three
different visual symptoms, each corresponding to an examination finding:
(1) oscillopsia corresponding to her acquired pendular nystagmus, (2)
horizontal double vision corresponding to her wall-eyed bilateral
internuclear ophthalmoplegia (WEBINO), and (3) vision loss in each eye
owing to her history of acute optic neuritis and chronic, likely progressive,
optic nerve demyelination. All three contributed to her overall sense of
visual disability. As is common with acquired pendular nystagmus in MS,
both optic nerve disease and a high lesion burden in the posterior fossa
were present. The objective was to improve this patient’s visual quality to
any extent possible. Her optic nerve disease was not amenable to
intervention, as she had no acute vision loss or acute optic neuritis to treat
with steroids at this time. Her prism lenses were already alleviating her
diplopia. Thus, the focus was on attempting to pharmacologically dampen
her nystagmus. The best evidence-based treatments are gabapentin and
memantine. As cases of pseudoexacerbation have been reported with
memantine in MS,61 the first choice is gabapentin.
1388 OCTOBER 2019

In peripheral vestibular nerve dysfunction, such as with vestibular neuritis KEY POINTS
or compressive lesions of the vestibular nerve, a mixed horizontal-torsional or
● Posterior canal benign
predominantly horizontal jerk nystagmus beating away from the affected side paroxysmal positional
is typically present. It is critical to remember that unidirectional horizontal vertigo represents over 80%
nystagmus may also occur rarely with central vestibular nucleus lesions of benign paroxysmal
(VIDEO 9-1 [online]). A hallmark of this peripheral type of nystagmus is that positional vertigo cases and
is confirmed by the presence
it may not be present while the patient is fixating on a visual target and may only
of a vertical-torsional
be unmasked with elimination of visual fixation. This may be achieved either nystagmus induced by the
with Frenzel goggles (VIDEO 9-10 [online]) or more simply at the bedside with Dix-Hallpike maneuver.
occlusive ophthalmoscopy. To perform this technique, the ocular fundus of one
eye is examined with ophthalmoscopy while the other eye is occluded. Visual ● Observation of the
patient over several minutes
examination of the retinal vasculature will allow the examiner to determine if is required when pure
any abnormal oscillations develop with elimination of visual fixation. Posterior horizontal jerk nystagmus is
canal BPPV represents over 80% of BPPV cases and is confirmed by the presence present, as this type of
of a vertical-torsional nystagmus induced by the Dix-Hallpike maneuver. nystagmus may also occur
with periodic alternating
Following this maneuver, in which the head is turned 45 degrees in the direction nystagmus. However, with
of the overactive canal, an upbeat-torsional nystagmus occurs, in which the periodic alternating
top poles of the eyes beat in the direction of the ear that is down, with delayed nystagmus, the nystagmus
onset and fatigability (VIDEO 9-10 [online]). will reverse horizontal
direction approximately
every 90 to 120 seconds,
Periodic Alternating Nystagmus of Central Origin
often with a few beats of
It is important to note that observation of the patient over several minutes is vertical nystagmus during
required when pure horizontal jerk nystagmus is present, as this type of the transition zone.
nystagmus may also occur with periodic alternating nystagmus. However,
with periodic alternating nystagmus, the nystagmus will reverse horizontal ● In nearly all cases,
vertical and torsional
direction approximately every 90 to 120 seconds, often with a few beats of nystagmus should be
vertical nystagmus during the transition zone (VIDEO 9-11 [online]). Periodic present in central gaze
alternating nystagmus is one of the only nystagmus types for which the fixation with the patient
mechanism has been established in a primate model.70 Ablation of the upright, although the
oscillations may be of very
cerebellar nodulus and uvula leads to periodic alternating nystagmus in the tiny amplitude in this patient
animal model, as it leads to impaired inhibitory control of velocity storage, position and only visible
which is the time course of rotationally induced nystagmus, by cerebellar with magnified views of
Purkinje cells. Acute-onset periodic alternating nystagmus has been reported the eye, such as with
high-resolution infrared
with infarction of the cerebellar nodulus71 and is typically associated with
video or during
cerebellar or pontomedullary disease, although a similar phenotype has been ophthalmoscopy.
rarely reported as transiently present with peripheral vestibular disease.72 Ocular
motion is typically exquisitely ablated with the GABAB agonist baclofen ● Upbeat nystagmus is most
(TABLE 9-1), although the congenital form is less responsive.73–75 One report commonly seen with
Wernicke encephalopathy
showed benefit from amantadine.76 secondary to thiamine
deficiency (in combination
Central Vestibular Nystagmus with horizontal gaze
Vertical (including upbeat and downbeat) and torsional nystagmus are often deficits and often with
described as central vestibular forms of nystagmus, although several different accompanying gaze-evoked
nystagmus), demyelinating
mechanisms by which they arise may exist. In nearly all cases, these forms of
disease, or stroke of the
nystagmus should be present in central gaze fixation with the patient upright, medulla or midbrain.
although they may be of very tiny amplitude in this patient position and only
visible with magnified views of the eye, such as with high-resolution infrared
video or during ophthalmoscopy.
UPBEAT NYSTAGMUS. Upbeat nystagmus is jerk nystagmus induced by slow
downward drifts of the eyes followed by resetting upward fast phases. In keeping

with the Alexander law, nystagmus amplitude and frequency often increase with
upward gaze. Upbeat nystagmus is most commonly seen with medullary lesions
and less often with midbrain lesions. It commonly occurs due to Wernicke
encephalopathy secondary to thiamine deficiency (in combination with
horizontal gaze deficits and often with accompanying gaze-evoked nystagmus)
(FIGURE 9-777) (VIDEO 9-1278 [online]), demyelinating disease, or stroke.
Evidence is emerging that nystagmus in Wernicke encephalopathy may manifest
as upbeat nystagmus that converts to downbeat nystagmus either during
convergence in initial presentation or temporally, with conversion of upbeat to
chronic persistent downbeat nystagmus at some unknown time point in the
disease course.79 Medullary lesions cause upbeat nystagmus via involvement of a
group of brainstem neurons in the perihypoglossal nuclei.80
DOWNBEAT NYSTAGMUS. Downbeat nystagmus, one of the most common forms

of acquired central nystagmus seen clinically, is jerk nystagmus induced by slow
upward drifts of the eyes followed by resetting downward fast phases. It may
or may not follow the Alexander law by increasing in downward gaze (and
often does not), but it nearly always increases in amplitude and frequency in
downward lateral gaze. For this reason, it is sometimes called side-pocket
nystagmus. In fact, it may only be visible to the examiner’s naked eye in this gaze
position. When it is seen in downward and lateral gaze but is not visible in central
gaze, ophthalmoscopy or high-resolution infrared video will often reveal it to be
present in central gaze as well (VIDEO 9-13 [online]). If not present in central
gaze fixation, even with ophthalmoscopy, it may be inducible in the central
position after horizontal or vertical headshaking or in a supine or supine
head-hanging position. Downbeat nystagmus induced after horizontal
headshaking is variably called cross-coupled nystagmus or perverted nystagmus and
is a sign of central cerebellar dysfunction from a wide range of pathologies,81–85
although it also has been reported in peripheral vestibular disease.86 Diagnostic
caution is advised when downbeat nystagmus is seen solely with the supine or
supine head-hanging position, as this may be a sign of either cerebellar dysfunction
or anterior canal BPPV.87–90
Downbeat nystagmus, in most
cases, represents cerebellar
dysfunction, typically with lesions
involving the vestibulocerebellum
(flocculus, paraflocculus,
nodulus, and uvula), although
cases are reported due to
primary brainstem lesions,
usually involving a group of
brainstem neurons called the
paramedian tracts.91 Downbeat
nystagmus is a characteristic
FIGURE 9-7
Axial fluid-attenuated inversion recovery (FLAIR) finding with craniocervical
MRIs in a patient with Wernicke encephalopathy abnormalities, such as Chiari I
demonstrate increased T2 signal in the medial malformations (FIGURE 9-8,
thalamus (A) and dorsal midbrain (B). CASE 9-2), and is seen in a wide
Reprinted with permission from Li M, Rucker JC,
77
J Neuroophthalmal. © North American variety of cerebellar diseases,
Neuro-Ophthalmology Society. including degenerative,
1390 OCTOBER 2019

paraneoplastic, metabolic-toxic, KEY POINTS
and ischemic etiologies. A large
● Downbeat nystagmus,
percentage of cases are one of the most common
idiopathic. forms of acquired central
The mechanism of downbeat nystagmus seen clinically, is
nystagmus is most often jerk nystagmus induced by
slow upward drifts of the
considered to be a tone imbalance
eyes followed by resetting
in central connections of the downward fast phases. It
semicircular or otolithic vestibular may or may not follow the
pathways that control vertical Alexander law by increasing
in downward gaze (and
eye movements and contain
often does not), but it nearly
asymmetries in upward versus always increases in
downward connections, although amplitude and frequency in
other mechanisms, such as downward lateral gaze.
asymmetry in smooth pursuit FIGURE 9-8 ● Downbeat nystagmus, in
pathways, may also be Sagittal noncontrast T1-weighted MRI showing a most cases, represents
causative.92,93 For example, Chiari I malformation, a common cause of cerebellar dysfunction,
efferent cerebellar Purkinje cells of downbeat nystagmus. typically with lesions
the flocculus inhibit upward, but involving the
vestibulocerebellum
not downward, eye movements (flocculus, paraflocculus,
via vestibular nuclei connections92; thus, reduced inhibition from a cerebellar nodulus, and uvula),
lesion will result in slow upward drifts of the eyes and downbeat nystagmus. although cases are also
Potassium channel blockade to restore normal cerebellar inhibition and reported due to primary
brainstem lesions, usually
neural integrator function is the mechanism behind treatment of downbeat
involving a group of
nystagmus with 4-aminopyridine (TABLE 9-1).94–97 A randomized crossover study brainstem neurons called
of 4-aminopyridine in downbeat nystagmus demonstrated improvement in the paramedian tracts.
visual acuity and 50% reduction in the slow-phase velocities of the nystagmus
with the medication, although the patients did not report subjective ● One of the prevalent
forms of physiologic
improvement.98 This has been interpreted in a positive light to suggest that the nystagmus commonly seen
medication is effective with regard to its mechanism, and future trials should on clinical examination is
assess the long-acting forms of the medication or different doses/longer gaze-evoked nystagmus,
durations of treatment to improve subjective patient experience.99 which is also variably called
end-gaze nystagmus or
Chlorzoxazone, gabapentin, memantine, and baclofen are helpful in some direction-changing
patients.63,100,101 nystagmus.
IMPAIRED ECCENTRIC GAZE-HOLDING

Not all forms of nystagmus are pathologic. One of the prevalent forms of
physiologic nystagmus commonly seen on clinical examination is gaze-evoked
nystagmus, which is also variably called end-gaze nystagmus or direction-changing
nystagmus. By definition, gaze-evoked nystagmus is present only in eccentric
gaze, in which fast phases of the nystagmus beat in the direction of gaze (ie, right
beating in right gaze, left beating in left gaze, upbeating in upgaze). Downbeat
nystagmus in downgaze is often not a component of gaze-evoked nystagmus
and, if seen on examination, should prompt a search for downbeat nystagmus in
central position or with provocative maneuvers. Reassuring features that suggest
that gaze-evoked nystagmus is physiologic include (1) it is present only in
extreme lateral right and left gaze, where its size and amplitude are symmetric;
(2) it is poorly sustained and fatigues over time—often just a few small beats of
nystagmus are seen in each direction; (3) it has a small amplitude; and (4) it is
present only in right and left gaze and absent in upgaze. If the gaze-evoked

nystagmus is present in less than extreme gaze, asymmetric, sustained, of large

amplitude, and/or present in upgaze, underlying causative cerebellar or
brainstem dysfunction is likely (VIDEO 9-14 [online]). Pathologic gaze-evoked
nystagmus has many underlying etiologies and may occur from structural
brainstem or cerebellar pathology (CASE 9-2). It is also common with drug
toxicities (eg, anticonvulsants, alcohol, sedatives).
Special mention of rebound nystagmus is warranted. With rebound
nystagmus, gaze-evoked nystagmus is present, but upon return to central gaze
position, nystagmus transiently ensues in the direction opposite to the
preceding gaze direction (eg, right-beat nystagmus in right gaze is followed
by left-beat nystagmus upon return to central gaze) (VIDEO 9-14 [online]).
Rebound nystagmus is most typically suggestive of an underlying structural
cerebellar lesion.
CONGENITAL FORMS OF NYSTAGMUS

Broad coverage of congenital nystagmus is beyond the scope of this article;
however, the two main forms are described in brief to facilitate differentiation
from acquired nystagmus. The two main forms of congenital nystagmus are
referred to as congenital nystagmus and latent nystagmus. The National Eye
CASE 9-2 A 32-year-old woman with a history of strabismus surgery for congenital
esotropia years earlier presented with imbalance and oscillopsia that
developed and progressively worsened over the previous 3 years. Her
pediatric ophthalmologist had suggested to her that nystagmus seen on
examination was likely congenital nystagmus. She had never had brain
imaging.
Examination revealed impaired tandem gait and gaze-evoked
nystagmus in right gaze and left gaze, with a few beats of right-beat
rebound nystagmus upon return to central gaze position following left
gaze (VIDEO 9-14 [online]). Downbeat nystagmus was also visible to the
naked eye in downgaze and present upon ophthalmoscopic examination
in central gaze.
MRI of the brain revealed a Chiari I malformation (FIGURE 9-8), for which
she underwent decompressive surgery with subsequent improvement of
the downbeat nystagmus and gradual improvement in balance.
COMMENT Although this patient had a history of congenital esotropia, she was not
previously documented to have nystagmus. The development of
oscillopsia, with or without other neurologic symptoms, as an adult strongly
suggests development of an acquired type of nystagmus. Some forms of
congenital nystagmus can mimic cerebellar nystagmus, but this patient had
three distinct forms of classic cerebellar nystagmus directly suggesting an
underlying cerebellar impairment and warranting neuroimaging. These
included pathologic-appearing large-amplitude gaze-evoked nystagmus,
rebound nystagmus, and downbeat nystagmus. Impaired tandem gait
further suggested cerebellar dysfunction.
1392 OCTOBER 2019

Institute Sponsored Classification of Eye Movements and Strabismus Working
Group has recoined congenital nystagmus as infantile nystagmus syndrome and
latent nystagmus as fusional maldevelopment nystagmus syndrome102; for ease of
discussion, the former terms are used here.
Congenital nystagmus may occur in isolation or may be accompanied by
afferent visual dysfunction. Individuals with congenital nystagmus tend not to
have oscillopsia,103 despite fairly constant predominantly pendular ocular
motion, typically in the horizontal plane (VIDEO 9-15 [online]). Diagnostic
hallmarks of congenital nystagmus include maintenance of its horizontal
trajectory even in upward and downward gaze, an increase in amplitude
and frequency induced by visual fixation and anxiety, a reduction in
amplitude and frequency with convergence, the presence of a “null region”
or specific gaze position in which nystagmus is minimized (which often
also results in an aberrant resting head position to station the null region in
central fixation), and increasing velocity slow phases. This latter finding,
however, is not pathognomonic, as increasing velocity slow phases have also
been reported in cases of acquired nystagmus.4,93 In addition to allowing
analysis of the slow-phase velocity, quantitative ocular motor recordings in
congenital nystagmus also reveal the diagnostic feature of foveation periods
(FIGURE 9-1E), which are brief epochs in which the nystagmus stops or dampens.
Foveation periods are typically not found with acquired nystagmus.
Latent nystagmus is a congenital form of nystagmus that is present only with
occlusion of either eye. With both eyes open, no nystagmus is present. Occlusion
of an eye unmasks a horizontal jerk nystagmus with fast phases beating away
from the closed eye. For example, closure or occlusion of the right eye will
unmask left-beat nystagmus. This type of nystagmus results from failure of
development of binocular vision, often due to the presence of congenital
strabismus. True latent nystagmus is rare. Manifest latent nystagmus, in which
a low-amplitude horizontal jerk nystagmus is present with both eyes open, is
more common. The direction of the nystagmus changes depending on which
eye is fixating. For example, fixation with the left eye is accompanied by left-
beat nystagmus and suppression of the vision from the right eye, which is
often esotropic.
OSCILLOPSIA NOT DUE TO NYSTAGMUS OR SACCADIC

INTRUSIONS
Proper diagnosis of the underlying etiology of oscillopsia requires familiarity
with forms that are not due to nystagmus or saccadic intrusions: bilateral
vestibular failure and superior oblique myokymia. Bilateral vestibular failure
results in generalized dysfunction of vestibuloocular reflexes. As a result, the
patient is unable to make compensatory eye movements for head and body
movements and, thus, is unable to maintain a visual target on the fovea. Such
individuals will report oscillopsia while in motion that resolves when they are
perfectly still.104,105 The most common causes of bilateral vestibular failure
include aminoglycoside toxicity, Ménière disease, meningitis, and
neurodegenerative disorders.
Superior oblique myokymia should be considered when the patient
reports episodes of monocular torsional or vertical oscillopsia. These episodes
result from cyclovertical oscillations that occur because of ipsilateral
superior oblique contraction. The classically described underlying etiology

is neurovascular compression of the trochlear nerve. This condition may

respond to treatment with timolol eye drops, carbamazepine, or gabapentin.
CONCLUSION
Common forms of nystagmus and saccadic intrusions have very different
underlying etiologies and pathophysiologic mechanisms. Accurate identification,
enhanced by familiarity of the subtle techniques to unmask abnormal
movements, of each type of nystagmus and saccadic intrusion will assist with
establishing the proper diagnosis and ensuring the highest likelihood of an
effective treatment plan.
VIDEO LEGENDS
VIDEO 9-1 VIDEO 9-5
Jerk nystagmus. Video shows unidirectional Macrosaccadic oscillations. Video shows
left-beat jerk nystagmus in a patient with multiple macrosaccadic oscillations in a patient who had a
sclerosis with a demyelinating lesion of the right pontine infarction and subsequently reported
vestibular nuclei. The pathologic component of the oscillopsia.
nystagmus is repetitive slow drifting of the eyes
toward the right followed by corrective resetting Reproduced with permission from Leigh RJ, Zee DS.1
fast phases toward the left, for which the © 2015 Oxford University Press.
nystagmus is named.
VIDEO 9-6
© 2019 American Academy of Neurology. Ocular flutter and opsoclonus. The first video
segment shows ocular flutter, and the second video
VIDEO 9-2 segment shows opsoclonus in a patient with a
Acquired pendular nystagmus. Video shows parainfectious brainstem encephalitis, with
acquired pendular nystagmus in a patient with subacute-onset oscillopsia, ataxia, and truncal
multiple sclerosis with chronic optic nerve myoclonus. No specific infectious organism was
demyelination and diffuse cortical and posterior identified. Neoplastic and paraneoplastic
fossa demyelinating lesions. In the upper black- evaluation was unremarkable. Recovery occurred
and-white eye movement videos, note the over 3 months. In the video, flutter transitions to
predominantly horizontal sinusoidal back-to-back opsoclonus at 33 seconds.
slow oscillations without any fast phases. The
bottom portions of the video show the eye position © 2019 American Academy of Neurology.
(red line is horizontal eye position, blue line is
vertical eye position) and velocity (purple and green VIDEO 9-7
Acquired pendular nystagmus in multiple
lines) traces of the nystagmus. The sinusoidal
oscillation in the red line corresponds to the sclerosis. Video shows acquired pendular
horizontal oscillations of the eyes. A slight vertical nystagmus in a patient with multiple sclerosis. The
oscillation is also seen. Note the similarity of the red first video segment shows minimal to no movement
line to the graphic representation of pendular in the right eye and small horizontal pendular
nystagmus in FIGURE 9-1D. oscillations in the left eye. The second segment
shows a magnified view of the right eye, with
© 2019 American Academy of Neurology. minimal to no visible movement in the right eye. The
third segment shows a magnified view of the left
VIDEO 9-3 eye, with small horizontal pendular oscillations. The
Square-wave jerks. The first video segment fourth video segment shows marked saccadic
shows nearly continuous square-wave jerks in a hypermetria (overshooting of the target with
patient with progressive supranuclear palsy. The saccades), evidence that this patient also had
second video segment shows impaired upgaze cerebellar dysfunction, as is typical of most
range with slow upward saccades. patients with acquired pendular nystagmus from
multiple sclerosis.
VIDEO 9-4
Square-wave oscillations. Video shows high- VIDEO 9-8
resolution infrared video recordings of a patient Acquired pendular nystagmus in oculopalatal
with back-to-back runs of square-wave jerks, myoclonus. The first video segment shows
termed square-wave oscillations. Refer to oculopalatal myoclonus with large vertical pendular
FIGURE 9-4 for the eye position tracings of these nystagmus, and the second video segment shows
movements and clinical information about palatal myoclonus in a patient who developed
this patient. severe oscillopsia several months after a brainstem
stroke. In the first segment, note the lack of
© 2019 American Academy of Neurology. horizontal eye movement from the original pontine
infarction. Vertical range of eye motion is full.
1394 OCTOBER 2019

VIDEO 9-9 VIDEO 9-13
Acquired pendular nystagmus in oculopalatal Downbeat nystagmus. Video shows downbeat
myoclonus. Video shows a patient with nystagmus, which, by definition, should be
oculopalatal tremor with asymmetric pendular present in central gaze, in a patient with a Chiari I
nystagmus. The movement is vertical-torsional in malformation. The first video segment shows
the right eye and predominantly torsional in the left downbeat nystagmus visible in downgaze. The
eye with smaller-amplitude movement. second video segment shows a magnified view
of the right eye with a trace amount of downbeat
© 2019 American Academy of Neurology. nystagmus seen in right downward gaze (best
visualized by looking at tiny scleral blood vessels
VIDEO 9-10 for vertical motion). The downbeat nystagmus is
Posterior canal benign paroxysmal positional more obvious in left downward gaze. This
vertigo. Video demonstrates the nystagmus seen nystagmus was not seen in central gaze position
following a positive Dix-Hallpike maneuver in a patient (central gaze not shown). The third video segment
with right posterior canal benign paroxysmal positional shows high-resolution infrared video demonstrating
vertigo. When the patient is rapidly positioned supine downbeat nystagmus in down and lateral gaze.
with the right ear down, torsional upbeat nystagmus At the end of the video, the downbeat nystagmus is
begins after a short delay, with the torsional finally also visualized in the central position.
component manifested as the top poles of the eyes
beating toward the right ear. Note the fatigable
intensity of the nystagmus over time. Frenzel goggles
eliminate the patient’s ability to fixate and enhance the VIDEO 9-14
view of the examiner, although this type of nystagmus Gaze-evoked nystagmus. Video shows
will typically be visible without Frenzel goggles. pathologic gaze-evoked nystagmus in a patient
with a Chiari I malformation. The first segment
Reproduced with permission from Leigh RJ, Zee DS.1 shows right-beat nystagmus in right gaze, the
© 2015 Oxford University Press. second segment shows left-beat nystagmus in left
gaze followed by rebound right-beat nystagmus
VIDEO 9-11 upon return to central position and rebound
Periodic alternating nystagmus. The first video nystagmus, and the third segment shows
segment shows the left-beat component of downbeat nystagmus.
periodic alternating nystagmus in a patient with
multiple sclerosis who had oscillopsia; the second
video segment shows the right-beat component.
Transitioning between right-beat and left-beat VIDEO 9-15
nystagmus occurred every 90 seconds. Treatment Congenital nystagmus. Video shows congenital
with baclofen stopped the nystagmus completely. nystagmus (infantile nystagmus syndrome) in a
patient with lifelong nystagmus, albinism, and no
© 2019 American Academy of Neurology. oscillopsia. Note the horizontal, predominantly
pendular trajectory of the nystagmus that is
VIDEO 9-12 consistent in all gaze positions, even vertical gaze.
Upbeat nystagmus. Video shows a patient with
Wernicke encephalopathy with upbeat nystagmus in © 2019 American Academy of Neurology.
the central position that, in keeping with the Alexander
law, increases in upgaze. Bilateral horizontal ocular
motor range limitations are also present, with
incomplete right eye abduction and incomplete left
eye abduction and adduction.
Reproduced with permission from Koontz DW, et al,
Neurology.78 © 2004 American Academy
of Neurology.
USEFUL WEBSITE
NEURO-OPHTHALMOLOGY VIRTUAL EDUCATION LIBRARY
The Neuro-Ophthalmology Virtual Education
Library is a rich resource of neuro-ophthalmologic
cases for learning purposes and includes many
video examples of eye movement disorders.
library.med.utah.edu/NOVEL/
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1400 OCTOBER 2019

Paraneoplastic REVIEW ARTICLE

Syndromes in C O N T I N U UM A U D I O
ONLINE
Neuro-ophthalmology 
VIDEO CONTENT
By Lynn Gordon, MD, PhD; Marc Dinkin, MD A V AI L A B L E O N L I N E
CITE AS:
ABSTRACT 25(5, NEURO-OPHTHALMOLOGY):
PURPOSE OF REVIEW: This article discusses the varied types of paraneoplastic 1401–1421.
syndromes that commonly have neuro-ophthalmologic manifestations.

Diagnostic considerations and therapeutic options for individual diseases Dr Lynn Gordon, Jules Stein Eye
are also discussed. Institute, David Geffen School
of Medicine, University of
California Los Angeles, 885
RECENT FINDINGS: Paraneoplastic syndromes can affect the afferent and Tiverton Dr, Los Angeles, CA
efferent visual systems. Paraneoplastic syndromes may result in reduced 90095, lgordon@mednet.ucla.edu.
visual acuity from retinal degeneration, alterations in melanocyte
proliferation and uveal thickening, or acquired nystagmus. Ocular motor RELATIONSHIP DISCLOSURE:
Dr Gordon serves on the board
abnormalities related to paraneoplastic syndromes may present with of trustees of the American
symptoms from opsoclonus or from neuromuscular junction disease. Academy of Ophthalmology
Diagnosis remains challenging, but serologic identification of some specific Continued on page 1421
antibodies may be helpful or confirmatory. Treatment, in addition to

directed therapies against the underlying cancer, often requires systemic UNLABELED USE OF
corticosteroids, plasma exchange, or immunosuppression, but some USE DISCLOSURE:
specific syndromes improve with use of targeted pharmacologic therapy. Drs Gordon and Dinkin discuss
the unlabeled/investigational
use of azathioprine for cancer-
SUMMARY: Diagnosis and therapy of paraneoplastic syndromes presenting associated retinopathy;
with neuro-ophthalmic symptoms remain a challenge, but strategies are corticosteroids for bilateral
diffuse uveal melanocytic
evolving and new approaches are on the horizon. proliferation, cancer-associated
retinopathy, melanoma-
associated retinopathy,
opsoclonus-myoclonus
INTRODUCTION syndrome, and paraneoplastic
P
araneoplastic syndromes affecting the nervous system arise from optic neuropathy; IV
immunoglobulin (IVIg) for
remote tumor effects largely through autoimmune responses against cancer-associated retinopathy,
normal tissue that result from or are triggered by tumor expression of melanoma-associated
neuronal proteins that elicit immune responses.1–5 Neuro-ophthalmic retinopathy, and opsoclonus-
myoclonus syndrome;
consequences of paraneoplastic syndromes may be seen in patients lenalidomide for POEMS
presenting to the neurologist or ophthalmologist with symptoms as varied as a (polyneuropathy,
organomegaly, endocrinopathy,
red eye, photopsia, decreased vision, oscillopsia, or double vision. The variety of
monoclonal plasma cell
clinical presentations creates diagnostic challenges as the clinician must first disorder, and skin changes);
recognize that the signs and symptoms may possibly be a consequence of a mycophenolate mofetil for
cancer-associated retinopathy
neoplasm, either through direct or indirect effects, and then perform the critical and paraneoplastic optic
testing to attempt to identify the etiology. Finally, the clinician must select the neuropathy; and rituximab for
best course of treatment to alleviate the symptoms and care for the patient. cancer-associated retinopathy.
Differentiating direct neoplastic infiltration of a specific region of the nervous © 2019 American Academy
system from a remote paraneoplastic effect can also be a challenge. of Neurology.

PARANEOPLASTIC SYNDROMES IN NEURO-OPHTHALMOLOGY
In some paraneoplastic syndromes, specific antibodies known to be associated

with paraneoplastic syndromes can be identified in the serum or CSF6; however,
these are not always present. Commercial laboratories now provide testing for
various “paraneoplastic panels”; yet, in some cases, the panel may be reported
as negative when, in fact, the results are positive if tested using a different
method by a different laboratory.7 Alternatively, sometimes the report is
negative because the antigenic stimulus for the immune response is not yet
known. In such cases, the testing is accurate and reproducible among different
laboratories but misses a novel antigenic target not yet included in the panel.1,8–12
Compounding these potential testing-related problems is that sometimes
multiple names for the same antigenic target are present in the literature. In
addition, antibodies against the same protein may result in multiple different
clinical findings.
Either the afferent or efferent visual pathway may be involved by
paraneoplastic processes, and while a history of cancer may help the clinician to
consider a paraneoplastic syndrome, the presentation may precede a cancer
diagnosis by months or, in rare cases, years. Afferent pathway presentations of
paraneoplastic syndromes involve the retina or optic nerve. Paraneoplastic
syndromes may also produce symptoms and signs resulting from efferent
pathway dysfunction, in which case additional neurologic manifestations outside
of the visual system are typically present. The range of eye movement
abnormalities includes neuromuscular junction diseases, cranial nerve palsies,
and involuntary eye movements. In all these types of presentation, astute clinical
observation is critical in recognizing a possible paraneoplastic disease and
initiating testing to define the underlying etiology. TABLE 10-1 reviews the most
significant neuro-ophthalmologic paraneoplastic conditions and the cancers that
lead to them.
AFFERENT VISUAL SYSTEM

The afferent visual system involves the perception of light and transmission
of those neurologic signals to the brain. This first begins with the
stimulation of photoreceptors, which are the rods and cones that transmit
and collate the initial signals through the intricate retinal wiring to bipolar
cells that then pass on the signal to the retinal ganglion cells whose axons
form the optic nerve. The characteristic afferent visual paraneoplastic
syndromes involve the retina in conditions such as cancer-associated
retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal
melanocytic proliferation, but a paraneoplastic optic neuropathy also rarely
occurs.5,13–16
Symptoms of afferent visual involvement in a paraneoplastic process may
include painless and progressive loss of vision, photopsia (brief flashes of light in
one or both eyes), night blindness, and visual field constriction.13 The differential
diagnosis for these symptoms is large; however, a careful ophthalmologic history
and comprehensive examination, including evaluation of the pupils for a relative
afferent pupillary defect, formal color vision testing, slit-lamp and dilated
funduscopic examinations, formal visual field testing, and optical coherence
tomography (OCT) with evaluation of the retinal nerve fiber layer and ganglion
cell layer of the macula, can help determine the correct diagnosis. Many patients
will require additional testing, including electroretinogram, to help confirm loss
of retinal function.17
1402 OCTOBER 2019

Cancer-Associated Retinopathy KEY POINTS
Cancer-associated retinopathy, first described in 1976, is one of the most common
● Neuro-ophthalmologic
paraneoplastic retinopathies.18 It is now understood that many types of cancers paraneoplastic syndromes
involving numerous organs may result in cancer-associated retinopathy, the most arise from remote tumor
common of which are small cell lung, breast, ovarian, endometrial, and cervical effects largely through
cancers. Other cancers that may result in cancer-associated retinopathy include autoimmune responses
against normal tissue that
cancer of the prostate, bladder, thyroid, thymus, pancreas, and colon, in addition to
arise or are triggered by
hematologic malignancies.19 The symptoms of cancer-associated retinopathy reflect tumor expression of
its target cell: the photoreceptor. Loss of acuity, color vision, and central visual field neuronal proteins that elicit
as well as sensitivity to light and glare, photopsia, and flickering lights all result immune responses.
from cone dysfunction, while paracentral (ring) scotomas, impaired dark
● Detection of specific
adaptation, and nyctalopia (difficulty seeing at night) result from damage to the antibodies against neuronal
rods.17,20,21 Symptoms are typically progressive over months with an insidious onset. antigenic targets can be
The patient may have an essentially normal slit-lamp examination and visual helpful in identifying
retinal inspection but, in some cases, intraocular inflammation (uveitis) of the paraneoplastic disease.
However, the practitioner
anterior or posterior segment, cystoid macular edema (thickening of the central should be aware of
retina [the macula] because of fluid leakage), vasculitis of the retinal vasculature, false-negative and
narrowing of the retinal blood vessels, or alterations in the retinal pigment false-positive errors, the
epithelium may be observed. OCT testing may identify atrophy and thinning possibility of novel
antibodies not yet described
of the retinal photoreceptor layer and decrease in the segment junction of the or available for testing, and
inner and outer segments, while autofluorescence photos of the fundus may the spectrum of varied
demonstrate a hyperfluorescent region surrounding the central macula, in clinical presentations for
particular around the foveal area.22 The electroretinogram in patients with any one antibody.
cancer-associated retinopathy typically exhibits global retinal dysfunction.
● Paraneoplastic
Additional diagnostic evidence is provided by the presence of antiretinal syndromes may precede a
antibodies.9 The challenge in testing for antiretinal antibodies is the lack of cancer diagnosis by months
standardization across testing sites, the scarcity of commercial testing sites in or even years.
the United States, and the limited sensitivity and specificity for the presence
● The characteristic
of antiretinal antibodies. Multiple techniques have been used to identify afferent visual
antiretinal antibodies, including Western blot against retinal protein extracted paraneoplastic syndromes
from cells or from tissue, enzyme-linked immunosorbent assay (ELISA) involve the retina in
testing against purified proteins, and immunofluorescent identification of conditions such as
cancer-associated
antibody binding to cultured cells or tissues. retinopathy, melanoma-
The presence of antibodies against self is a common finding in healthy patients associated retinopathy, and
and in patients with many diseases. In one study that aimed to characterize the bilateral diffuse uveal
presence of antiretinal antibodies in normal sera that was used as laboratory melanocytic proliferation,
but a paraneoplastic optic
controls, the majority of sera reacted with at least one retinal protein antigen.23
neuropathy may also occur,
Another study, using a novel system of 188 antigens in an antigen suspension although rarely.
bead array, confirmed that serum antiretinal antibodies can be found in other
types of retinal diseases or even in patients with cataracts.8 Furthermore, testing ● Workup for possible
across different laboratories may produce discordant results.24 Despite these paraneoplastic syndromes
affecting the afferent visual
potential pitfalls, great value can be found in identifying the presence of system should include visual
antiretinal antibodies and confirming the suspicion for cancer-associated acuity, color vision, pupillary
retinopathy or other autoimmune retinopathies. However, this testing should testing, formal visual field
not be used as a screening tool without clinical evidence in support of the disease. testing, funduscopy, optical
coherence tomography of
Only about 60% of individuals affected with cancer-associated retinopathy the retina, and
demonstrate antibodies against retinal proteins.8,9,17,25 The most validated antigenic electroretinogram.
target in cancer-associated retinopathy is the retinal protein recoverin, a 23-kDa
calcium-binding molecule that helps regulate phosphorylation of rhodopsin and
therefore plays an important role in phototransduction. Although antibodies against

recoverin were the first to be described in cancer-associated retinopathy, they have

only been identified in about 10% of patients with cancer-associated retinopathy.9
Another relatively common protein target is α-enolase, a 46-kDa molecule,
which is found in about one-third of those who are tested. Targets of antienolase
antibodies include ganglion cells and Müller cells, in addition to photoreceptors.
Clinically, antienolase cancer-associated retinopathy is more likely to manifest as
pure cone dysfunction as compared with antirecoverin cancer-associated
retinopathy and is much more likely to develop months or years after the
diagnosis of cancer.17 Other putative targets include transducin and carbonic
anhydrase II, among others. Some of the identified antibodies initiate the retinal
degeneration by entering retinal photoreceptors and inducing cell death, while
TABLE 10-1 Summary of Paraneoplastic Syndromes in Neuro-ophthalmology
Other Retinal Cell

Types That May
Primary Disease- Suspected Disease- Be Immunologic
Syndrome Associated Antigen(s) Target Cell Type Associated Antigen(s) Targets Neoplasm/Malignancy
Cancer-associated Recoverin Photoreceptors: Major antigens: Müller cells, Small cell lung,
retinopathy rods and cones α-enolase, carbonic bipolar cells, breast, colon,
anhydrase II, retinal ganglion prostate, ovarian,
transducin, and cells endometrial, cervical,
phosphodiesterase and hematologic
cancers and
Other antigens
melanoma are the
include arrestin,
most common; other
tubby-related protein
cancers include
1 (TULP1),
prostate, bladder,
neurofilament, heat
thyroid, thymus, and
shock protein 27 and
pancreatic
heat shock cognate
protein 70 (HSC 70),
and transient
receptor potential
cation channel
subfamily M member 1
(TRPM1)
Melanoma- TRPM1 Bipolar cells S-arrestin, recoverin, Photoreceptors, Melanoma

associated heat shock protein 60, Müller cells
retinopathy carbonic anhydrase II,
α-enolase, transducin,
rhodopsin, aldolase A,
aldolase E, mitofilin,
titin
Bilateral diffuse Unknown Melanocytes NA NA Primary endocrine

uveal melanocytic tumors; ovarian, lung,
proliferation and urogenital
cancers; rarely other
cancers
1404 OCTOBER 2019

others appear to be induced by release of immunologic proteins from the dying
photoreceptors and may either further propagate retinal cell death or, in some
cases, serve only as markers of the disease.26
To make the diagnosis of cancer-associated retinopathy, all evidence must be
evaluated so that other potential etiologies of retinal damage can be excluded.
Retinal damage may also result from cancer-associated malnutrition and from
the treatments used to treat cancer, including checkpoint inhibitors27 and
mitogen-activated protein kinase (MEK) inhibitors.28 In the setting of
autoimmune retinopathy in the absence of a neoplasm, a published consensus
statement exists about the diagnosis and management of the disease as well as the
need for additional prospective investigation.29
Other Retinal Cell

Types That May
Primary Disease- Suspected Disease- Be Immunologic
Syndrome Associated Antigen(s) Target Cell Type Associated Antigen(s) Targets Neoplasm/Malignancy
POEMS Unknown, but Unknown NA NA Monoclonal plasma
(polyneuropathy, pathophysiology cell disorder
organomegaly, involves
endocrinopathy, overproduction of
monoclonal cytokines driven by
plasma cell vascular endothelial
disorder, and skin growth factor
changes (VEGF)
Paraneoplastic Collapsin response Neurons Aquaporin-4 Unknown Lung and thymus

optic neuropathy mediator protein-5 (neuromyelitis optica cancer; rarely other
(CRMP-5) [NMO]–like), Hu, cancers
glutamic acid
decarboxylase 65
(GAD65), P/Q voltage-
gated calcium
channel, other
antigens
Opsoclonus- ANNA 1 (Hu), Possibly Purkinje Ma, other antigens NA Children:

myoclonus ANNA-2 (Ri) cells and neuroblastoma
pontine neurons
Adults: small cell
lung, ovarian, breast,
thymus, and other
cancers
Lambert-Eaton P/Q voltage-gated Presynaptic nerve NA NA Small cell lung

myasthenic calcium channel terminals at the cancer, other cancers
syndrome neuromuscular
junction
Myasthenia gravis Acetylcholine Postsynaptic NA NA Thymoma/thymus

junctions at the cancer, melanoma
neuromuscular
junction
ANNA-1 = antineuronal nuclear antibody type 1; ANNA-2 = antineuronal nuclear antibody type 2; NA = not applicable.

Although treatment for the underlying malignancy must be performed in any

patient with cancer-associated retinopathy, direct tumor treatment alone will
generally not result in improvements in visual function in patients with
cancer-associated retinopathy. Therapies that may be accompanied by some
visual improvement include systemic corticosteroids, plasma exchange, IV
immunoglobulin (IVIg), and immunosuppressive agents such as azathioprine or
mycophenolate mofetil.13,30 In addition, several articles have documented the
benefit of rituximab, a monoclonal antibody against the CD20 antigen on the B
cell,31,32 and some experimental evidence in animal models supports the use of a
calcium channel blocker, although this has not yet been tested in humans with
cancer-associated retinopathy.13 Some evidence even exists for reversal of some
of the retinal findings in cancer-associated retinopathy33,34; a case report
documented that treatment of the cancer and use of topical steroid treatment
resulted in resolution of cystoid macular edema and some recovery of the
structure of the outer retina by OCT.12
Retinal degeneration may also result from autoimmune attack by
antibodies including antirecoverin antibody in the absence of an underlying
cancer. Such cases, which are more likely in younger patients, are referred
to as nonparaneoplastic autoimmune retinopathy, but treatment with
immunosuppressive therapy may be less effective than in paraneoplastic
retinopathies.35
Melanoma-Associated Retinopathy
A specific paraneoplastic retinopathy in the setting of melanoma is referred to as
melanoma-associated retinopathy. In contrast to cancer-associated retinopathy,
the symptoms of melanoma-associated retinopathy, which include nyctalopia
(difficulty seeing in dim light), photopsia (described as sparkles or shimmering
vision), moderately decreased central visual acuity, and generalized scotomas
(area of decreased or absent visual field affecting all or part of the field), develop
rapidly (CASE 10-1). The syndrome typically occurs in patients with a prior
diagnosis of cutaneous melanoma, although it has been seen in patients with
choroidal melanoma as well.37 In a review of more than 50 patients with
melanoma-associated retinopathy, the time period between diagnosis of melanoma
and melanoma-associated retinopathy ranged widely, from months to almost
20 years.38 For reasons that are not yet well understood, patients with melanoma-
associated retinopathy typically present in midlife, and males develop
melanoma-associated retinopathy much more frequently than females, significantly
exceeding the male to female ratio of patients with cutaneous melanoma. Rarely,
melanoma-associated retinopathy can precede the diagnosis of melanoma.13
The retina, as evaluated by fundus evaluation, may appear normal, but optic
atrophy, retinal pigment epithelium atrophy or loss, and attenuation of the
retinal vasculature may also be present. Vitreous cells are also rarely seen.
Electroretinogram may reveal a classic pattern consistent with dysfunction of the
retinal ON-bipolar cells (the bipolar cells that are depolarized/excited in the
presence of light) as the primary cause of the disease, with a relative sparing of
photoreceptors. This pattern is also seen in patients with certain genetic diseases
of the retina that also effect bipolar cell dysfunction.13 Evaluation of the patient’s
serum for antiretinal activity by immunohistochemistry may reveal staining of
the retinal inner nuclear cell layer, where the bipolar cells reside, concordant with
the prediction based on electroretinogram.37 Multiple proteins have been
1406 OCTOBER 2019

identified using Western blot detection of antibodies against retinal proteins.13,17,39–41 KEY POINTS
As with cancer-associated retinopathy, identification of a diagnostic antibody
● The symptoms of
test has been elusive, but the presence of antiretinal antibodies in the correct cancer-associated
setting of enhanced clinical suspicion may help to confirm the diagnosis. retinopathy reflect its target
Management of melanoma-associated retinopathy typically consists of cell: the photoreceptor.
primary treatment of the melanoma, if disease persistence or recurrence is Loss of acuity, color vision,
and central visual field as
present, and use of steroids or IVIg.42 In cases in which no prior diagnosis of
well as sensitivity to light
melanoma was made, tumor should be searched for in locations in which the and glare, photopsia, and
tumor burden is not obviously visible, such as the mucosal membranes. flickering lights all result
Treatment of melanoma was revolutionized by use of immune checkpoint from cone dysfunction,
while paracentral (ring)
inhibitors, which are now used to treat advanced cases of melanoma. However,
scotomas, impaired dark
these agents that boost antitumor immunity also have the potential to increase adaptation, and nyctalopia
the autoimmune response against the retina, and melanoma-associated (difficulty seeing at night)
retinopathy has been observed in a patient who was treated with cytotoxic result from damage to
T-lymphocyte–associated antigen 4 (CTLA-4), a checkpoint inhibitor known to the rods.
be associated with a high percentage of autoimmune conditions.43 The ● Testing for

checkpoint inhibitors that block the programmed cell death receptor 1 (PD1)/ paraneoplastic antibodies
programmed death receptor ligand 1 are known for increasing the tumor should not be used as a
immune response and have produced dramatic improvements in terms of tumor screening tool for
paraneoplastic disease in
reduction/remission in some patients and, in contrast to CTLA-4, carry less the absence of a suspicious
observed risk for immune-related adverse events. They are now being used to clinical presentation.
treat a variety of cancers, and a recent report documented the development
of autoimmune retinopathy after use of an anti–PD1 antibody, nivolumab, for ● Antibodies against
recoverin, a photoreceptor
small cell lung cancer.44 The extent to which the checkpoint inhibitors will be
protein involved in
associated with development of a melanoma-associated retinopathy or cancer- phototransduction, were
associated retinopathy syndrome will be of great interest and importance. the first to be described in
Patients who have received any of the immune checkpoint inhibitor blockade cancer-associated
agents should be promptly evaluated by an ophthalmologist if they develop any retinopathy. Cancer-
associated retinopathy
concerning visual symptoms. associated with antibodies
against α-enolase is more
Bilateral Diffuse Uveal Melanocytic Proliferation likely to involve pure cone
Bilateral diffuse uveal melanocytic proliferation is an unusual paraneoplastic dysfunction and to present
months or years after the
disorder with a highly typified presentation that includes symptoms of cancer diagnosis.
progressive, bilateral painless loss of vision, which can precede the diagnosis of
cancer in about half of reported cases. Bilateral diffuse uveal melanocytic ● Some of the identified
proliferation typically presents in the seventh decade of life but has been observed antibodies in cancer-
associated retinopathy
in patients ranging in age from 34 to 89 years with a female predominance of
initiate retinal degeneration
61%.45–47 Associated cancers include primary endocrine tumors, ovarian cancer, by entering retinal
lung cancer, and other cancers of the urogenital system, among others.19,45,46,48 photoreceptors and
Signs on slit-lamp examination include progressive cataracts, diffuse thickening of inducing cell death, while
others appear to be induced
the uveal tract, exudative retinal detachment, uveal melanocytic tumors that can
by release of immunologic
be pigmented or nonpigmented, and multiple retinal pigment epithelium patches proteins from the dying
that appear red and hyperfluorescent on fluorescein angiography. OCT also may photoreceptors and may
identify characteristic findings of retinal pigment epithelium atrophy, subretinal either further propagate
fluid, and pigment deposition. Conjunctival hyperpigmentation and nonocular retinal cell death or, in some
cases, serve only as markers
hyperpigmentation of the skin and mucosa surfaces have been observed in some of the disease.
patients.19,49 Histopathology confirms proliferation of melanocytes that may
appear benign or may indicate a more aggressive type of lesion.19 Historically, the
diagnosis of bilateral diffuse uveal melanocytic proliferation was associated with
poor overall prognosis, but the numbers of reported cases in the literature are low

CASE 10-1 A 63-year-old woman presented for evaluation of positive visual

phenomena. She had initially been diagnosed with melanoma of the
cervix when she presented for a pap smear 11 months before her visual
symptoms. She underwent radiation and chemotherapy with the immune
checkpoint inhibitor ipilimumab, which targets the cytotoxic
T-lymphocyte–associated
antigen 4 (CTLA-4) receptor,
followed by a resection.
Three months later, a CT
showed pericardial metastasis,
and she was treated with the
programmed cell death
receptor 1 (PD1) blocker
pembrolizumab. Two months
later, she started seeing
blinking lights, swirly shapes,
and smokiness, all of which
blocked her vision. She felt
as if her right eye was “dying”
with progressive dimming.
Her vision was worse at night,
and red lights seemed yellow
in the darkness. Light to dark
transitions were particularly
difficult.
Neuro-ophthalmic
examination revealed an
acuity of 20/60 in her right
eye, 20/20 in her left eye,
with dyschromatopsia
(7.5/10 Ishihara color plates),
and a trace relative afferent
pupillary defect in her right
eye. She had severe visual
field loss on formal perimetry,
with only some nasal sparing
in the left eye (FIGURE 10-1A).
Slit-lamp examination revealed FIGURE 10-1
Findings of the patient in CASE 10-1 with
cells in the anterior chambers melanoma-associated retinopathy. A, Severe
and vitreous humor of both visual field loss on formal perimetry with only
eyes. Peripapillary thickening some nasal sparing in the left eye. B, Fundus photo
was present around both showing peripapillary thickening around both
optic nerves. C, Optical coherence tomography
optic nerves (FIGURE 10-1B) and revealing significant thickening of the retinal
a peripapillary hemorrhage nerve fiber layer around both optic nerves.
was present in the left eye. D, Fluorescein angiogram revealing a periphlebitis
Optical coherence tomography with leakage from venules in both eyes.
N = nasal; NI = nasal inferior; NS = nasal superior; OD = right
(OCT) revealed significant eye; OS = left eye. T = temporal; TI = temporal inferior;
thickening of the retinal nerve TS = temporal superior.
1408 OCTOBER 2019

fiber layer around both optic nerves (FIGURE 10-1C). She was referred to a retina
specialist, who performed OCT of the macula that revealed thinning of the
outer retinal layers in the region between the fovea and nerve, especially in
the left eye. Fluorescein angiogram revealed a periphlebitis with leakage
from venules in both eyes (FIGURE 10-1D). Pembrolizumab was stopped, and she
was treated with intravitreal steroids and IV immunoglobulin (IVIg) infusions.
Her vision improved to 20/20, and her fundus examination normalized as
well. An electroretinogram performed after recovery showed normal
amplitudes. A paraneoplastic panel was not covered by her insurance so was
not performed.
Melanoma-associated retinopathy presents with the rapid onset of COMMENT

nyctalopia, photopsia typically described as “sparkles” or “shimmering
vision,” and moderately decreased central visual fields and acuity, all of
which were present in this case. Fundus findings are typically mild, but
patients may experience vessel attenuation, retinal pigment epithelium
changes, and, in a substantial minority, a vitreitis, as in this case. In rare
cases, such as this one, the patient may have retinal periphlebitis as well.36
With neither the antibody testing nor a pretreatment electroretinogram,
confirmation of melanoma-associated retinopathy was difficult in this
case. Although the patient was on a checkpoint inhibitor, which could
cause a posterior uveitis, the presence of photopsia and nyctalopia in this
case strongly suggested melanoma-associated retinopathy. It was
concluded that checkpoint inhibition had likely predisposed this patient to
melanoma-associated retinopathy, as has previously been reported.

and cancer treatment has dramatically changed since the first reported cases. An
IgG antibody that induces melanocytic proliferation has been identified in the
serum of some patients, offering insight into the underlying pathophysiology of
the disease.50 Treatment of bilateral diffuse uveal melanocytic proliferation has
included use of local or systemic steroids with some evidence of benefit; however,
plasma exchange has been shown to be the most successful therapy, likely as a
result of the pathophysiology of disease.45,46
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Plasma Cell

Disorder, and Skin Changes Syndrome (POEMS)
POEMS is a paraneoplastic syndrome resulting from a monoclonal plasma cell
disorder associated with a polyneuropathy that may initially involve the sensory
system but ultimately includes both sensory and motor function.13,51 Ophthalmic
consequences of POEMS typically include optic disc edema that may be
asymptomatic.52–55 Patients with papilledema due to POEMS have a worse
prognosis.56 Other consequences include blurred or double vision that may be
secondary to retina changes, including cystoid macular edema, serous retinal
detachment, central retinal artery occlusion, neovascularization of the
choroid or the optic disc, or uveitis. The pathophysiology of POEMS is not well
understood but is believed to result from an overproduction of cytokines,
including interleukin-1β, tumor necrosis factor-α, and interleukin-6, driven in
great part by vascular endothelial growth factor (VEGF).57 Evaluation of the CSF
demonstrates increased protein and a variable elevation in opening pressure, and
bone marrow examination reveals plasma cells. Therapy typically includes
radiation therapy when solitary myelomatous lesions are present. Chemotherapy
with the thalidomide analogue lenalidomide and autologous stem cell
transplantation are used for widespread or advanced disease.52 With treatment,
the 5-year survival of patients with POEMS may be as high as 84%.53
Paraneoplastic Optic Neuropathy

The classic example of the relatively rare paraneoplastic optic neuropathy/
neuritis is a patient who presents in middle or older age with a subacute, painless,
bilaterally simultaneous or sequential loss of vision.13,16,58–60 Patients may present
with central vision loss, moderately decreased to no light perception, and
“sparkles” or “flashes” in their vision, similar to the symptoms seen in cancer-
associated retinopathy or melanoma-associated retinopathy, and with observed
defects on formal visual field testing. Optic disc edema is seen in 50% to 90% of
reported patients, and vitreous cells, retinal hemorrhages, and retinitis were
commonly seen in these patients.16,60,61 Anterior uveitis has been described as an
unusual finding in these patients. Evaluation by fluorescein angiography may
reveal swelling or atrophy of the optic disc, subretinal fluid, and peripheral
retinal vascular leakage. Electroretinogram may reveal abnormalities in scotopic
or photopic responses as well.
Histopathology was reported in two cases in which a lymphocytic infiltration
was seen in the optic nerve.2,60,62 Many patients with paraneoplastic optic
neuropathy present with a variety of neurologic deficits, including a progressive
myelopathy that may resemble a neuromyelitis optica(NMO)–like syndrome,
gaze palsy, internuclear ophthalmoplegia, or opsoclonus.60,63 In fact, several case
reports now exist of a paraneoplastic NMO spectrum–like disorder in which the
classic anti–aquaporin-4 antibody was present.64,65
1410 OCTOBER 2019

Paraneoplastic optic neuropathy may be difficult to differentiate from direct KEY POINTS
leptomeningeal infiltration of the optic nerves by the cancer, radiation-induced
● Some evidence exists for
optic neuropathy, and in cases with bilateral disc edema from papilledema reversal of some of the
related to elevated intracranial pressure from brain metastases or leptomeningeal retinal findings in cancer-
disease. A workup with MRI of the brain and orbits and a lumbar puncture associated retinopathy
searching for tumor cells may be helpful in delineating one from the other, with treatment.
although perineural enhancement may be seen in some cases of paraneoplastic
● Rarely, melanoma-
optic neuropathy66 just as with leptomeningeal disease and radiation-induced associated retinopathy can
optic neuropathy. precede the diagnosis of
The neuronal cytoplasmic protein collapsin response mediator protein-5 melanoma.
(CRMP-5) (also known as CV2), which helps regulate neurite outgrowth in
● Melanoma-associated
development and regeneration, was originally identified as the target of retinopathy is typically
autoantibodies found in 0.017% of serum samples tested for paraneoplastic associated with a response
screening at the Mayo Clinic over a 17-year time period.58 The underlying cancer on the electroretinogram
involved the lung in about 75% of cases, thymus in about 6% of cases, and a that reflects bipolar cell
dysfunction.
variety of other neoplasms. Neurologic associations were many and included,
most commonly, peripheral neuropathy, cerebellar ataxia, and subacute ● Management of
dementia, with an optic neuropathy occurring 7% of the time. CSF evaluation melanoma-associated
was abnormal in 86% of patients in the initial cohort and included a lymphocytic retinopathy includes
immunosuppression and
pleocytosis, elevated protein, or elevated IgG index or IgG synthesis rate.58
treatment of the underlying
Management of paraneoplastic optic neuropathy includes treatment of the cancer. However,
underlying cancer with or without the use of adjunctive therapy, including checkpoint inhibitors used
systemic corticosteroids, mycophenolate mofetil, or plasma exchange.67 to treat melanoma have
The majority of patients with paraneoplastic optic neuropathy express multiple been associated with the
occurrence or exacerbation
additional paraneoplastic autoantibodies, including anti-Hu, anti–glutamic acid of melanoma-associated
decarboxylase 65 (GAD65), and anti–voltage-gated calcium channel, among retinopathy in rare cases.
others.60 In addition, some patients with the combination of optic neuropathy and
retinal degeneration are positive for both CRMP-5 and recoverin or negative for ● POEMS is a
paraneoplastic syndrome
known paraneoplastic-associated antibodies.21,68 Therefore, substantial overlap whose name describes
exists in the paraneoplastic neuro-ophthalmic diseases both in terms of the protean clinical
presentation and presence of autoreactive antibodies and in the involvement of the manifestations of cytokine
afferent only, efferent only, or combined afferent and efferent visual pathways. production, driven in part by
vascular endothelial growth
factor, all resulting from a
EFFERENT VISUAL SYSTEM monoclonal plasma cell
Abnormalities of eye movement are seen in cases of paraneoplastic conditions disorder. Papilledema may
and include opsoclonus-myoclonus, ocular flutter, nystagmus, and abnormalities accompany the disorder, in
which case CSF evaluation
of the mechanisms of pursuit and saccades.69–71
may reflect an increase in
protein and intracranial
Opsoclonus-Myoclonus Syndrome pressure.
Short, sudden, involuntary jerking movements are characteristic of myoclonus
and may involve lower or upper extremities, trunk, or face; they may be
precipitated or exacerbated by stress or postural change. Opsoclonus is a form of
saccadic intrusion characterized by multidirectional, chaotic, high-frequency
saccadic movements that may be of large amplitude and lack an intersaccadic
interval (VIDEO 10-1 [online]).70,72–76 The opsoclonus-myoclonus syndrome has
sometimes been called “dancing eyes, dancing feet” and is debilitating in terms of
loss of function. Both opsoclonus-myoclonus and the pure opsoclonus syndrome
are commonly associated with cerebellar signs. Ocular flutter (VIDEO 10-2
[online]) is characterized by involuntary horizontal, high-frequency but low-
amplitude eye movements without an intersaccadic interval and may arise

secondary to a paraneoplastic syndrome, most often cancer of the lung or breast.77

Although ocular flutter and opsoclonus are identified through clinical evaluation,
the absence of the intersaccadic interval is difficult to see on inspection and may
require eye movement recording.
Many underlying etiologies may be responsible for opsoclonus, including
paraneoplastic syndromes, which are responsible for about 50% of the pediatric
cases of opsoclonus, and infectious or parainfectious cerebellitis.73,78,79 The associated
tumor is most likely to be neuroblastoma in children and small cell lung cancer,
ovarian cancer, or breast cancer in adults, although case reports show an association
with other cancers, including thymic carcinoma.70,71,78,80–83 A 2012 review found
that of more than 130 adult patients who either presented with opsoclonus-
myoclonus or were previously reported in the literature, 28% of patients had visual
difficulties, and a cancer diagnosis was also identified in about 50% of the patients.75
Evaluation of the patient with opsoclonus or ocular flutter must include
serologic evaluation for paraneoplastic-associated antibodies, including
antineuronal nuclear antibody type 1 (ANNA 1) (anti-Hu) and antineuronal
nuclear antibody type 2 (ANNA-2) (anti-Ri).84–87 Such testing is helpful if
positive but does not eliminate a paraneoplastic syndrome when negative.88,89
The pathologic mechanism by which these antibodies lead to opsoclonus is not
fully elucidated, but pathologic postmortem examinations have revealed
perivascular infiltrates and loss of cerebellar Purkinje cells and pontine neurons,
particularly in the parapontine reticular formation.90
In addition to the complete neurologic and physical examination, other studies
may include neuroimaging; CT of the chest, abdomen, and pelvis; mammography;
and whole-body fludeoxyglucose positron emission tomography (FDG-PET).
Evaluation of the CSF for antibodies may be helpful, and urine catecholamine
levels to detect homovanillic and vanillylmandelic acids may help identify
neuroblastoma.54 Therapies include primary tumor treatment as well as IV pulse
steroids, IVIg, or plasma exchange for the acute symptoms and longer-term
immunosuppressive therapy for chronic management.91
Lambert-Eaton Myasthenic Syndrome

LEMS occurs due to an antibody-mediated attack on the P/Q voltage-gated
calcium channel located on the presynaptic nerve terminals resulting in their loss
of function.92–94 It is believed that the responsible antibody, which can result
either from a paraneoplastic syndrome or a primary autoimmune condition, acts
directly at the neuromuscular junction causing a decrease in the voltage-gated
calcium channel expression at the cell membrane and subsequent decrease in
calcium internalization, ultimately resulting in decreased release of acetylcholine
at the neuromuscular junction.95,96
Typical findings in LEMS include hyporeflexia or areflexia, autonomic
dysfunction, proximal muscle weakness, and ocular symptoms of diplopia,
although associated ptosis may be a mild and late feature of the disease71,81,93,94
and, in contrast to patients with myasthenia gravis, patients with LEMS may
experience decreased ptosis with prolonged upgaze. In one study, diplopia was
present in approximately 20% and ptosis in 23% of patients with LEMS.92
Additional neuro-ophthalmic manifestations include pupillary abnormalities and
involuntary lid closure.
Within 3 months of disease onset, autonomic symptoms are experienced by up
to 90% of affected patients. In contrast to myasthenia gravis, improvement in
1412 OCTOBER 2019

strength or tendon reflexes may occur after muscle use or exercise. In addition, KEY POINTS
EMG features of LEMS are distinct and show a low-amplitude compound muscle
● Management of
action potential (CMAP) and an increase, by 100%, in the CMAP amplitude paraneoplastic optic
with high-frequency repetitive nerve stimulation or after maximal voluntary neuropathy includes
muscle contraction. treatment of the underlying
Since the most common associated tumor is small cell lung cancer, patients cancer with or without the
use of adjunctive therapy,
with suspected LEMS should undergo chest CT imaging, and if that is negative,
including systemic
patients should be evaluated with FDG-PET. corticosteroids,
At least 8% of patients with LEMS may be negative for the antibody, and no mycophenolate mofetil, or
correlation exists between the antibody level and disease severity.95 In addition, plasma exchange.
similar to antibody testing for cancer-associated retinopathy, the prevalence of some
● Opsoclonus is a form of
antibodies against the voltage-gated calcium channel can be detected in the absence saccadic intrusion
of LEMS, and therefore a positive result must be interpreted carefully and only in characterized by
the context of the clinical presentation.97 In fact, in a test of serum from 100 patients, omnidirectional, chaotic,
58% of those positive for anti–voltage-gated calcium channel antibodies did not high-frequency saccadic
movements that may be of
have an autoimmune or paraneoplastic process, six patients (6%) had LEMS, large amplitude and lack an
and two (2%) of the patients had small cell lung cancer without LEMS.97 intersaccadic interval.
Discussion of management of LEMS is outside the scope of this article; for
more information on LEMS, refer to the article “Myasthenia Gravis and ● Reflective of brainstem or
cerebellar damage,
Lambert-Eaton Myasthenic Syndrome” by Michael W. Nicolle, MD,98 in the
opsoclonus may result from
December 2016 issue of Continuum. paraneoplastic disease, with
or without myoclonus,
Myasthenia Gravis typically from
neuroblastoma in children
Myasthenia gravis is an autoimmune disease in which antibody-mediated
and small cell lung
attacks on the acetylcholine receptors on the postsynaptic membrane of the carcinoma or ovarian cancer
neuromuscular junction result in fatigable generalized weakness. Diplopia and in adults. Responsible
ptosis are common presenting symptoms and are the sole manifestations in purely antibodies include
ocular myasthenia gravis. Some patients will develop bilateral medial rectus muscle antineuronal nuclear
antibodies type 1 (anti-Hu)
weakness that can mimic a bilateral internuclear ophthalmoplegia and can be seen and type 2 (anti-Ri).
in, but is not pathognomonic for, myasthenia gravis. In addition, the Cogan lid
twitch sign is actually an overshoot of the eyelid followed by a drooping in the eyelid ● Lambert-Eaton
position. This occurs when the patient looks upward after a prolonged rest in myasthenic syndrome is a
disease in which antibodies
downgaze and can be seen in, but is not pathognomonic for, myasthenia gravis. against the P/Q voltage-
Although most cases are not associated with a tumor, a thymoma may be gated calcium channel
found in a minority of patients, suggesting a paraneoplastic etiology in at least located on the presynaptic
some of these cases. In one series of 132 patients, eight (6%) had a thymoma and terminal of the
neuromuscular junction
25 (19%) had thymic hyperplasia.99 Of 197 patients with thymoma in one series,
result in their dysfunction
111 (56%) had an invasive tumor, but only four (2%) had thymic carcinomas, and and secondary weakness
11 patients (5.58%) died because of their thymoma.100 Myasthenia gravis may that improves with exercise.
also occur as a consequence of the immune-promoting effects of checkpoint Neuro-ophthalmic
manifestations may include
inhibitors used to treat melanoma and other cancers.101
diplopia and ptosis, the
Discussion of management of myasthenia gravis is outside the scope of latter of which may
this article; for more information on myasthenia gravis, refer to the article improve with upgaze. The
“Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome” by Michael W. underlying cause may be
Nicolle, MD,98 in the December 2016 issue of Continuum. paraneoplastic or primary
immune.
Other Associated Paraneoplastic Neuro-ophthalmic Disorders

Multiple other antibodies associated with paraneoplastic disease may also present
with associated efferent neuro-ophthalmic symptoms or signs. The best known of
these include anti-Yo, anti-Hu, anti-Ma, anti-Ri, and anti-CV2/CRMP5,

although other antibodies have also been implicated in sporadic case

reports.102 In addition to opsoclonus-myoclonus, which was discussed earlier
in this article, other ocular motor abnormalities have been described,
including nystagmus, ocular dysmetria, apraxia of eyelid opening, upgaze
palsy, horizontal gaze palsy (CASE 10-2), saccadic abnormality, pursuit
impairment, skew deviation, eyelid retraction, unilateral fourth or sixth nerve
palsies, and bilateral sixth nerve palsies.71,103–105 Typically, these are seen in
CASE 10-2 A 66-year-old woman presented to the emergency department with

double vision. Her symptoms began as blurriness several days prior and
progressed to a frank horizontal diplopia, accompanied by imbalance,
dizziness, and multiple falls.
She was diagnosed with breast cancer 3 years earlier, which was
treated with lumpectomy and radiation, and was maintained on
hormonal therapy. She was also diagnosed with small cell lung
carcinoma of the right upper lobe 3 years prior with spread to
mediastinal lymph nodes, and she had received chemotherapy with
cisplatin and etoposide, followed by prophylactic whole-brain cranial
irradiation, resulting in no evidence of disease. She also had a history of
Graves disease and coronary artery disease.
Neuro-ophthalmologic examination revealed normal afferent
function with a right gaze preference, left gaze palsy (FIGURE 10-2A–C),
and a concomitant right hypertropia suggestive of a skew deviation. On
neurologic examination, her gait was ataxic, but mental status, motor
function, and sensation were all normal.
Contrast-enhanced brain MRI was negative for any ischemic,
infiltrative, or compressive lesion. Lumbar puncture showed a mild
pleocytosis with 11 white blood cells/mm3 and normal protein and
glucose but was negative for leptomeningeal disease. A paraneoplastic
panel revealed a positive antibody against antineuronal nuclear antibody
type 1 (ANNA-1) (anti-Hu). Chest CT showed a new right upper lobe mass
(FIGURE 10-2D) with associated mediastinal adenopathy. With the history of
two prior cancers, a biopsy was performed and revealed recurrent small
cell carcinoma. Her clinical examination and symptoms were unchanged
despite starting treatment with etoposide and carboplatin and 5 days of
IV immunoglobulin (IVIg) therapy.
1414 OCTOBER 2019

association with brainstem and cerebellar symptoms, and that combination
of neurologic and neuro-ophthalmic findings should prompt an evaluation for
a paraneoplastic process. In some cases, a lag of many years may occur
between the onset of neurologic disease and cancer diagnosis. The types of
cancers associated with these disorders include small cell lung cancer; thymoma;
Hodgkin lymphoma; breast cancer; melanoma; and cancers of the endometrium,
ovary, and fallopian tubes.
FIGURE 10-2
Anti-Hu gaze palsy demonstrated in the patient in CASE 10-2. Photographs show: A, right gaze;
B, primary gaze demonstrating a right gaze preference; and C, left gaze demonstrating a left
gaze paresis. D, Chest CT showing a right upper lobe mass (asterisk) with associated
mediastinal adenopathy.
Most patients with anti-Hu–associated paraneoplastic disease present with COMMENT

either a sensory neuropathy or limbic encephalopathy with confusion and
memory loss. However, up to 6% of patients may present with isolated
brainstem pathology, as in this case, with 10% of these patients demonstrating
a gaze palsy. The lack of MRI findings in most cases helps rule out metastases
as the cause of the gaze palsy but also makes confirmation of the localization
challenging. In this case, the presence of a gaze palsy in the absence of a
pontine metastasis led to an early diagnosis of paraneoplastic brainstem
encephalitis since only a parenchymal lesion could affect the nuclei
responsible for gaze (parapontine reticular formation and abducens nucleus),
while leptomeningeal disease could only affect cranial nerves involved in
ocular motility, none of which would cause a gaze palsy.

KEY POINTS
CONCLUSION
● Myasthenia gravis is an Neuro-ophthalmologic paraneoplastic syndromes that affect the nervous
autoimmune disease in system are believed to result from an immunologic response that is an
which an antibody- indirect consequence of the tumor. The paraneoplastic syndromes may
mediated attack on the
acetylcholine receptors on occur before or after the diagnosis of cancer; therefore, patients with a
the postsynaptic junction of suspected paraneoplastic syndrome must be carefully evaluated for
the neuromuscular junction neoplastic disease.
result in fatigable Specific targets for antibodies that may cause paraneoplastic disease
generalized weakness, often
accompanied by ptosis and
have been identified in a number of diseases (eg, the retinal syndromes
ophthalmoparesis. A cancer-associated retinopathy [enolase] and melanoma-associated
minority of cases are retinopathy [TRPM1]), yet many other antigenic targets for each of these
associated with thymoma, syndromes also have been identified. It is highly likely that antibody activity
which, despite its typically
indolent nature, can be
against multiple antigens will lead to the same disease phenotype. However,
invasive and, rarely, challenges remain in using antibody detection in diagnosis, including
malignant. the lack of standardization of detection of certain antibodies between the
various laboratories, and the consideration that healthy individuals as well
● Involvement of bilateral
as those with nonparaneoplastic disease may have circulating antibodies
medial rectus muscles in
myasthenia gravis may against a variety of retinal proteins. Therefore, it is critical to perform
mimic a bilateral strategic testing for antibodies as confirmation for patients with clinically
internuclear suspected paraneoplastic syndromes. Future directions require improvements
ophthalmoplegia. in the identification of pathologic antibodies and in the clinical detection
● The Cogan lid twitch is an
of immune responses that are pathogenic through enhanced cytokine
overshoot of the eyelid responses, as suspected in POEMS, or in cellular responses against
when the patient looks tissue antigens.
upward following a period Clinical suspicion is critical in making the diagnosis of a paraneoplastic
of fixation on a target in
downgaze. Although not
antibody-associated disease, and it is best to order a neurologic panel for
pathognomonic for paraneoplastic disease. MRI findings may be abnormal but are often
myasthenia gravis, it may nonspecific. CSF evaluation is also nonspecific but may show a mild
provide supporting clinical lymphocytosis, oligoclonal bands, and elevated protein. In the case of patients
evidence for the disease.
without a known tumor, the use of FDG-PET with CT may be helpful in
diagnosis.
Treatment of the paraneoplastic syndromes, with the exception
perhaps of LEMS, lack precision and specificity and use strategies that
range from general immunosuppressive medications such as corticosteroids
to specific monoclonal antibodies such as rituximab (anti-CD20). However,
we now understand that effective antitumor responses, notably in
melanoma, among others, may require an activated immune response.
Therefore, judicious treatment selection for paraneoplastic syndromes must
be directed in part by the patient’s need to maintain the ability to drive
immune responses both to help control the tumor and to prevent infection.
In addition, use of the newer checkpoint blockade antibodies in cancer
therapy, such as the PD1 and programmed death receptor ligand 1 antibodies,
may enhance autoimmune disease, resulting in an increase in autoimmune
neuro-ophthalmic diseases. Dissecting the specific disease mechanisms
as well as individual patient characteristics are required to develop enhanced
personalized medicine approaches to address the diagnostic and therapeutic
challenges of the paraneoplastic neuro-ophthalmic diseases.
1416 OCTOBER 2019

VIDEO LEGENDS
VIDEO 10-1 VIDEO 10-2
Ocular flutter. Video shows a patient with runs of Opsoclonus. Video shows a patient with runs of
back-to-back horizontal saccades, consistent with back-to-back saccades in all directions, consistent
ocular flutter. Note that in this patient, they were with opsoclonus. Opsoclonus consists of high-
elicited by voluntary lateral saccades. Ocular flutter frequency saccadic movements that may be of
typically occurs in the setting of cerebellar disease, large amplitude and lack an intersaccadic interval.
either from an infectious or parainfectious It localizes to brainstem or cerebellar damage, often
cerebellitis or paraneoplastic disease. resulting from paraneoplastic disease, with or
without myoclonus, typically from neuroblastoma
© 2019 American Academy of Neurology. in children and small cell lung carcinoma or ovarian
cancer in adults.
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DISCLOSURE
Continued from page 1400

and on the editorial boards of Ophthalmology Neurology and has received compensation for
Retina, Ocular Immunology and Inflammation, and travel for speaking engagements from The
the Journal of Neuro-Ophthalmology. Dr Gordon has American Austrian Foundation and research/grant
received research/grant support from the National support from the Helen and Robert Apel
Institutes of Health and licensing fees from the Foundation. Dr Dinkin has provided depositions and
University of California Los Angeles for epithelial expert testimony on medicolegal cases involving
membrane protein 2. Dr Dinkin serves as an idiopathic intracranial hypertension, ischemic optic
associate editor for the Journal of Neuro- neuropathy, and head trauma.
Ophthalmology and as an editor for Practical

REVIEW ARTICLE
Infectious Optic
Neuropathies

ONLINE
By Eric R. Eggenberger, DO, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article reviews common infectious optic neuropathies,
focusing on the more common and globally important entities.
RECENT FINDINGS: Novel infections continue to emerge and drift geographically

over time; not infrequently, these have important neurologic or ocular
features. Malarial retinal findings comprise a relatively specific set of
findings and serve as an invaluable aid in the diagnosis of cerebral malaria.
Therapy continues to evolve and is best formulated in concert with an
infectious disease expert.
SUMMARY: Infectious optic neuropathies are less common than inflammatory

or ischemic optic neuropathies; may present with varied, overlapping, and
nonspecific clinical appearances; and comprise an important differential
consideration demanding specific therapy.
INTRODUCTION
T
he optic nerve is vulnerable to a variety of insults, and infection
comprises a relatively common treatment-altering diagnosis.
Infectious optic neuropathies may selectively affect the optic disc or
CITE AS:
CONTINUUM (MINNEAP MINN) 2019; retrobulbar optic nerve but more commonly concomitantly involve
25(5, NEURO-OPHTHALMOLOGY): the retina (eg, neuroretinitis) and vitreous, or adjacent sinuses,
1422–1437.
meninges, or brain. They may occur with, following, or in the absence of
systemic features. Optic nerve dysfunction in the setting of infection may reflect
Dr Eric R. Eggenberger, Mayo direct infection, while resultant ischemia, edema, or inflammation may coexist.
Clinic Florida Departments of The epidemiology of these conditions is challenging as the findings are often
Ophthalmology, Neurology,
Neurosurgery, 4500 San Pablo,
nonspecific, raising the possibility of inflammatory or other noninfectious
Jacksonville, FL 32224 diagnoses. Our understanding of these disorders is incomplete and continues to
eggenberger.eric@mayo.edu. evolve, and the most commonly encountered pathogens depend heavily on the
RELATIONSHIP DISCLOSURE: region of practice. The clinician must maintain a high index of suspicion,
Dr Eggenberger reports no especially among susceptible populations, and partner with colleagues providing
disclosure.
pulmonary, otolaryngology, and infectious disease expertise to facilitate timely
UNLABELED USE OF diagnosis. This article focuses on the more common and globally important
PRODUCTS/INVESTIGATIONAL bacterial, viral, parasitic, and fungal agents with a predilection to involve the
USE DISCLOSURE:
Dr Eggenberger reports no
optic nerve.
disclosure.
CLINICAL AND EPIDEMIOLOGIC FEATURES
© 2019 American Academy Infectious optic neuropathies present with typical features common to most
of Neurology. optic nerve disorders, including combinations of decreased acuity, field defects,
1422 OCTOBER 2019

and dyschromatopsia (decrease in color vision); a relative afferent pupillary KEY POINT
defect is encountered in unilateral or asymmetric optic neuropathies, and the
● Infectious optic
disc may be edematous or normal. Additional features may also be present neuropathy often presents
depending upon the agent and presentation, including retinal changes; orbital or with a nonspecific clinical
other symptoms related to affected adjacent or distant tissues; and systemic picture including adjacent
features such as fever, headache, myalgia, weight loss, leukocytosis, and elevated structures, most commonly
the retina and vitreous.
inflammatory laboratory markers.1,2 Often, the ocular features show very little
Travel and increasingly
specificity indicative of the exact infectious agent; accordingly, a high index of global exposures influence
suspicion and partnership with infectious disease consultants is frequently the the differential diagnosis.
most successful approach. While we often preach that it is wise to consider New pathogens continue to
emerge and frequently
horses when hearing hoofbeats, the commonality of infectious optic
involve ocular structures.
neuropathies depends largely on the population in question. Certain infectious
agents have traditionally been rare in the developed world while common in
underdeveloped areas; however, increasing globalization, travel, and comorbid
immunosuppressive states have blurred these lines. Within US populations,
inflammatory and ischemic optic neuropathies outnumber infectious cases;
however, infection remains an important consideration in the differential
diagnosis as treatment differs dramatically from other entities. The “horses”
among the relatively commonly encountered or considered infectious optic
nerve disorders (tuberculosis, catscratch disease, Lyme disease, syphilis,
cytomegalovirus, and malaria) are important global infectious diseases. In
addition, abundant case reports of infectious optic neuropathy related to
innumerable organisms exist (the “zebras and unicorns”), with nonspecific
presentations that foster some degree of doubt regarding causal infectious origin.
BACTERIA
Bacterial agents are among the most common and important infectious optic
neuropathies. Appropriate therapy is dependent upon accurate and timely
diagnosis.
Tuberculosis
Mycobacterium tuberculosis complex species cause human tuberculous disease,
and this bacterial group is responsible for more human deaths over the past
2 centuries than any other infection. Despite the global commonality of this
infection (an estimated 25% of the world population harbors latent infection,
with 10 million new cases per year), diagnostic and therapeutic tools remain
somewhat antiquated, drug resistance is common, and HIV and other
comorbidities have combined to drive epidemics and highlight unmet clinical
needs. Although the mycobacterial group has over 170 distinct species and
Mycobacterium avium and Mycobacterium bovis are important pathogens, the two
most important species of neuro-ophthalmic interest are M. tuberculosis sensu
stricto and Mycobacterium africanum. One key feature of mycobacteria is the
semi-impermeable cell wall, containing an outer membrane with a lipid bilayer;
components of this cell wall are the targets of some antimicrobials, including
isoniazid and ethambutol.3
Human disease is acquired by inhaling as few as five bacilli in aerosolized
droplets that may only be 5 microns in diameter, allowing the agent to remain
suspended in air for hours. Once in the host alveoli, the pathogen is phagocytized
by macrophages. If the bacilli survive macrophage innate immune mechanisms,
they can replicate and disperse through lymphatic or hematologic spread to other

INFECTIOUS OPTIC NEUROPATHIES
organs. Once adaptive immune mechanisms activate, the components for

granuloma formation assemble, with a fibrotic calcified encapsulation of latent
viable bacilli. The organism has a complex life cycle in which latent infection
plays a key role. In the latent phase of infection, the bacteria are controlled by
host immune mechanisms; however, if the immune system weakens with age,
comorbidities (eg, cancer), concurrent medication (eg, corticosteroids,
chemotherapy, tumor necrosis factor-α inhibitors, other immunosuppressants),
or coinfection (eg, HIV), the bacilli reemerge with active and transmissible
infection. It has been estimated that 90% of infected people never develop
clinical disease, while 5% develop disease in the first 2 years and the remaining
5% develop disease as a function of latent disease reactivation.4
Diagnosis of ocular tuberculosis (TB) relies on clinical acumen in addition to
laboratory testing. The latter has traditionally taken the form of the tuberculous
purified protein derivative (PPD) skin test (also known as the Mantoux skin
test). The usefulness of the TB skin test is confounded by host immune status
and prior bacille Calmette-Guerin vaccine; this vaccine is rarely used in the
United States but is often administered to children in countries with endemic
TB. Following vaccine, the PPD is usually positive. Newer laboratory tests
include interferon gamma release assays (such as QuantiFERON-TB Gold),
which function via detection of interferon production by a patient’s lymphocytes
in response to exposure with specific TB antigens (but not bacille Calmette-Guerin
vaccine or PPD antigens). Despite this advance, neither of these tests is
capable of distinguishing latent disease from active infection.
The US Centers for Disease Control and Prevention (CDC) reported over
9000 new TB cases in 2017, for an incidence rate of 2.8 per 100,000 population;
state-specific rates range from 0.3 per 100,000 in Montana to 8 per 100,000 in
Hawaii. These figures represent a continued but slight decline in TB cases over
the past several years. High-incidence groups include persons born outside the
United States, with Asians representing the ethnic group with the highest
incidence. The top countries of origin for non–US-born persons with TB were
Mexico, Philippines, India, Vietnam, and China. Among people born in the
United States, blacks were the ethnic group with the highest rate of TB,
followed by non-Hispanic whites. Homelessness, long-term care residence,
correctional facility exposure, and coinfection with HIV appear to confer
additional risk.5
Although TB is primarily a pulmonary infection, extrapulmonary involvement
is not uncommon, and rates approximate 50% in patients coinfected with HIV
(correlated with CD4 counts).6 Common sites for extrapulmonary involvement
beyond the pleura include the lymph nodes, bone, abdomen, genitourinary
system, skin, central nervous system (CNS), and ocular structures; miliary forms
involve widespread dissemination to multiple organs.
The true incidence of ocular involvement with TB is difficult to estimate
because of varied definitions, and diagnostic methods weaken case ascertainment;
rates in the literature range from approximately 2% to almost 20%, with wide
variations across sampled populations or regions.7,8
Ocular involvement with TB can take several forms, accounting for its
reputation as a mimic of other inflammatory, infectious, or neoplastic eye
diseases. Complex interactions between host factors, including comorbidities
and medications in addition to specific bacterial virulence, explain part of this
wide clinical variation. Among a cohort of patients with a clinical diagnosis of
1424 OCTOBER 2019

presumed intraocular TB evaluated at a clinic in India, posterior uveitis was KEY POINTS
the most common presentation (42%), followed by anterior uveitis (36%),
● Tuberculosis is a common
panuveitis (11%), and intermediate uveitis (11%).9 TB-related uveitis has a worldwide infection and
strong tendency toward bilaterality, often with keratic precipitates (including a shares a synergistic
“mutton fat” appearance), posterior synechiae, and Koeppe nodules (iris margin interconnection with HIV.
collections of epithelioid giant cells and lymphocytes). Choroidal granulomas Diagnosis can be
challenging; however,
related to TB appear as bright mass lesions in the posterior pole, although they
interferon-based laboratory
also may result from ocular sarcoidosis.10 tests represent a useful
Tuberculous involvement of the optic nerve usually results from and involves advance.
contiguous tissues, including the choroid and retina. The optic nerve can be
involved anywhere along its course, producing varied forms, including ● Tuberculosis can affect
any part of the visual system
neuroretinitis, papillitis (anterior optic neuropathy with optic disc edema), optic from the globe, optic nerve,
nerve tubercles, and retrobulbar forms related to optic nerve or chiasmal chiasm, and tracts to the
arachnoiditis; anterior forms, including neuroretinitis, appear to be most occipital lobe. Optic nerve
common. In addition to direct infection of the optic nerve, papilledema due to and ocular involvement are
accompanied by uveitis in
increased intracranial pressure may result from tuberculous meningitis. Among a the vast majority of cases.
cohort of 49 patients with tuberculous optic neuropathy from several clinics,
approximately 50% presented with papillitis, while 15% presented with
neuroretinitis; optic nerve tubercles, compressive optic neuropathy, and
retrobulbar optic neuritis were less commonly encountered. Associated uveitis
was present in approximately 90% of these cases, with the majority of these
involving the posterior segment. Residence in or travel to endemic areas was
noted in 70% of patients. Approximately half the patients in this optic
neuropathy cohort reported sudden visual loss. While 63% presented with acuity
of 20/50 or worse, 77% of patients achieved acuity of 20/40 or better at 1 year.11
Visual field defects were present in approximately half of this cohort and
included, in descending order, blind spot enlargement, central scotoma, and
altitudinal or mixed defects; approximately one-third of patients experienced
resolution of the field defect, one-third improved, and in one-third field
defects remained.11
The diagnosis of ocular TB is suggested by the clinical examination in the
context of a thorough history, taking into account risk factors including
exposure, travel, comorbidities, and medications. Gupta and colleagues9
proposed diagnostic guidelines for definite ocular TB that include appropriate
clinical signs with demonstration of TB in ocular fluid by smear, culture, or
polymerase chain reaction (PCR). They also proposed criteria for presumed
ocular TB, including appropriate clinical signs with either positive ancillary
testing (positive PPD, tubercular lesions on chest imaging, or confirmed
extrapulmonary tuberculosis) or response to a treatment trial (isoniazid,
ethambutol, rifampicin, and pyrazinamide therapy for 4 to 6 weeks), with
exclusion of other causes of the clinical picture.
Antimicrobial treatment of TB is complex and prolonged, usually employing
at least two agents for 6 months. Newer antibiotics are emerging and have a place
in drug-resistant TB; however, most patients still receive some combination of
older medications, including isoniazid, rifampin, ethambutol, and pyrazinamide.
Ethambutol in particular has a well-described association with optic neuropathy,
with an overall dose-related incidence of approximately 1%.12
Treatment with single agents should be avoided because of increased
incidence of drug resistance, and therapy is best undertaken in concert with an
infectious disease expert.

Catscratch Disease
Bartonella is a gram-negative bacterial family linked to three distinct
human diseases:
u Catscratch disease (Bartonella henselae) with fever, lymphadenopathy, a pustule at the

site of inoculation, and less common ocular or CNS features
u Trench fever (Bartonella quintana), characterized by single or recurrent fevers, headache,
rash, and bone pain
u Carrión disease (Bartonella bacilliformis), which manifests early with fever, headache,
and myalgia with a later nodular subcutaneous phase
Catscratch disease, caused by the B. henselae species, has the potential to

produce an important late ocular complication of neuroretinitis, in which optic
disc edema is accompanied by macular edema with retinal exudates in the shape
of a star centered around the fovea (CASE 11-1). B. henselae bacteria are often
normal flora in feline saliva or nail bed but are also found in other animals,
CASE 11-1 A 35-year-old woman presented with decreased vision in her left eye
with mild soreness around the eye. The initial examination noted acuity of
20/60 with a swollen left optic disc (FIGURE 11-1A); 1 week later, examination
documented improved disc edema in her left eye with the emergence of
a macular star due to lipid exudate (FIGURE 11-1B). This appearance is
consistent with neuroretinitis, a syndrome that may result from several
conditions, but perhaps most commonly from Bartonella henselae
infection. The patient’s B. henselae titer returned elevated; with
antibiotics and time, acuity in her left eye returned to 20/20.
FIGURE 11-1
Neuroretinitis in the patient in CASE 11-1. Optic disc edema at presentation, with minimal
macular changes (A), and 1 week later, showing resolving disc edema and new emergence
of a macular star figure (B).
Figure courtesy of James Bolling, MD.
COMMENT This case illustrates the typical presentation and evolution over time of
B. henselae neuroretinitis.
1426 OCTOBER 2019

including fleas and ticks; accordingly, cat contact is not a necessary antecedent to KEY POINT
disease. Catscratch disease, with fever and lymphadenopathy, leads to ocular
● Neuroretinitis is a
involvement in only 5% to 10% of cases. The neuroretinitis is typically unilateral nonspecific clinical
and occurs approximately 4 weeks after the initial infection. Optic disc edema, at syndrome that may be
times with peripapillary hemorrhage, precedes the development of the macular related to any of several
star by approximately 1 week. Optical coherence tomography may demonstrate different infectious agents
in addition to inflammatory
macular thickening before an obvious star appears. Neuroretinitis is not specific
or neoplastic
or unique to Bartonella (it may result from numerous infectious, inflammatory, pathophysiologies.
or neoplastic conditions), but it is certainly characteristic; Bartonella accounts for
the majority of neuroretinitis presentations in most North American practices.
Most, but not all, patients recover visual function over weeks even without
therapy; however, many experts tend to treat with antibiotics because therapy is
typically well tolerated, some patients are left with significant optic nerve
dysfunction, and some evidence exists for treatment efficacy in generalized
catscratch disease. A typical course of antibiotics for B. henselae may include
doxycycline or azithromycin. Concomitant corticosteroids have been employed
for Bartonella neuroretinitis treatment, but this is somewhat controversial.13,14
Spirochetes
Spirochetes are gram-negative spiral-shaped mobile bacteria. The most relevant
spirochetes for neuro-ophthalmic consideration are Borrelia burgdorferi (Lyme
disease) and Treponema pallidum (syphilis).
LYME DISEASE. Lyme disease results from infection with Borrelia species and has
protean manifestations with potential dermatologic, cardiac, musculoskeletal,
and neurologic consequences. Within North America, B. burgdorferi is the
pathogenic species, while in Europe and Asia, Borrelia afzelii and Borrelia garinii
are endemic. The bacterium is vector-spread via ticks from the Ixodes genus
(species vary by geographic region). Tick attachment typically requires at least
24 hours to facilitate spirochete transmission and causes disease occurring in
three distinct stages:
u Stage 1: Erythema migrans (red maculopapular rash with or without central clear zone)
u Stage 2: Disseminated disease, including malaise and cardiac, musculoskeletal, and
neurologic manifestations
u Stage 3: Persistent infection with intermittent arthritis and subacute encephalopathy
Neurologic involvement with Lyme disease occurs in approximately 15% of

infections; the classic triad is lymphocytic meningitis, painful radiculitis, and
cranial neuropathy, while facial nerve paresis is the most common feature.15 The
laboratory diagnosis of Lyme disease can be challenging; the CDC currently
recommends a two-stage approach using enzyme immunoassay as the first
screening step and an immunoblot (Western blot) for confirmation in equivocal or
positive immunoassay results. Ocular involvement occurs rarely with Lyme disease,
with reported instances of follicular conjunctivitis, keratitis, uveitis, retinal
vasculitis, and choroiditis; optic neuropathy may occur in the early or disseminated
stages in the form of papillitis, neuroretinitis, or papilledema with meningitis. A
causal link between optic neuropathy and positive serology is especially difficult to
establish in endemic areas; isolated Lyme disease optic neuropathy appears to
be extremely rare, as many reported cases are likely the result of concomitant

CASE 11-2 A 65-year-old man presented with a 2-month history of visual decline
in both eyes. Examination demonstrated acuity of 20/50, vitreitis,
cecocentral scotomas (FIGURE 11-2), and optic disc edema in both eyes
(FIGURE 11-3). Optical coherence tomography showed the retinal nerve
fiber layer was elevated.
Brain MRI was unremarkable, while rapid plasma reagin (RPR) and
treponemal antibody were positive and CSF white blood cell count was
321 cells/mm3, with glucose 57 mg/dL and protein 130 g/dL, all
consistent with syphilitic meningitis. He was treated with penicillin,
and a follow-up examination documented optic atrophy with acuity of
20/100 in both eyes.
FIGURE 11-2
Humphrey field testing of the patient in CASE 11-2
showing bilateral cecocentral scotomas.
FIGURE 11-3
Optic funduscopy of the patient in CASE 11-2 showing bilateral optic disc edema.
COMMENT This is a typical case of syphilitic optic neuropathy, a treatable condition

with the potential to progress dramatically if unrecognized.
1428 OCTOBER 2019

comorbidities. While the literature is rich with reports of “Lyme optic KEY POINTS
neuritis,” strong evidence for a causal link between Lyme disease infection
● Although Borrelia is an
and a retrobulbar optic neuritis (without associated papillitis) is lacking.16 important neuropathogen,
retrobulbar optic
SYPHILIS. T. pallidum is a chronic multiorgan spirochete infection spread most neuropathy related to Lyme
commonly through sexual contact involving direct contact via a skin chancre. disease is extremely rare.
While in 2001, the United States evidenced the lowest syphilis incidence rate
● Syphilis rates are
since 1941 (2.1 per 100,000), subsequent years have witnessed continued steady increasing, and diagnostic
rate increases (in 2016, 8.7 syphilis cases per 100,000 population nationally). testing can be challenging;
During this period, most of the increased rates were in men who have sex with diverse clinical
men.17 Like several other organisms, HIV and syphilis interact in a synergistic presentations and a
well-earned reputation as
manner to enhance transmission and disease virulence. “the great mimic” make
Syphilis is traditionally divided into primary, secondary, latent, and tertiary syphilis an important
stages. The primary stage is manifest by the appearance of one or more painless treatment-altering
skin chancres, marking the location of the spirochete’s entrance to the host, point in the differential
of many clinical
which spontaneously heals in 3 to 6 weeks. Untreated, the secondary stage neuro-ophthalmologic
develops as or after the chancre heals, marked by a nonpruritic reddish skin rash presentations.
(often on the palms and soles), accompanied by fever, pharyngitis, patchy
alopecia, headache, myalgia, and weight loss. Although symptoms spontaneously
resolve, untreated disease gives rise to a latent asymptomatic stage. In a small
subset of patients with latent-stage syphilis, the tertiary stage will emerge after
up to 30 years, potentially affecting the CNS, eye, heart, vasculature (ascending
aortitis), liver, and osseous structures; however, syphilis may involve the brain or
eye at any stage. Uveitis is the most common ocular manifestation of acquired
syphilis and can present as granulomatous or nongranulomatous disease,
involving the anterior or posterior ocular segments. Although posterior or
panuveitis is the most common ocular manifestation, several other ocular
presentations may occur, including interstitial keratitis, chorioretinitis, and
retinal vasculitis; it is its varied clinical symptomatology that accounts for
syphilis’s reputation as the great mimic. Neurosyphilis with diffuse cerebral
involvement may produce cranial neuropathy, supranuclear ocular motor
dysfunction, nystagmus, visual field defects, and chiasmal dysfunction,
depending upon the site of infection. Optic nerve dysfunction can take the form
of anterior or retrobulbar optic neuropathy (CASE 11-2) or neuroretinitis in the
secondary or tertiary phases of the disease, while tertiary syphilis–related
obliterative endarteritis may produce an ischemic optic neuropathy.18,19
T. pallidum cannot be cultured, and the laboratory diagnosis of syphilis may
be challenging. Both nontreponemal tests (detecting antibody against lipoidal
antigen released from the host cell or treponemes) and treponemal antibody
directed against T. pallidum are available, each with advantages and
disadvantages. Nontreponemal tests may be falsely negative early or late in the
disease course and usually become nonreactive after treatment of early syphilis.
Treponemal antibodies typically appear earlier in the disease and remain despite
successful antibiotic treatment. The CDC continues to recommend screening
with nontreponemal laboratory tests (Venereal Disease Research Laboratory
[VDRL] or rapid plasma reagin [RPR]) followed by a confirmatory treponemal
test to identify patients with potentially untreated disease and minimize
false-positive results. The availability of automated treponemal tests has
prompted others to pursue a reverse screening procedure starting with the
treponemal antibodies (usually enzyme or chemiluminescence assays). Using the

reverse screening procedure, a positive treponemal test with negative RPR or

VDRL defines a difficult subset and may indicate early disease, previous
treponemal disease (potentially treated), or a false-positive treponemal antibody
test. These cases are best adjudicated by expert guidance considering the pretest
probability of disease and the treponemal pallidum particle agglutination test as
the most suitable confirmatory assay.
The drug of choice for syphilis therapy remains penicillin G for all stages,
although the preparation (aqueous crystalline or procaine penicillin) and
exact regimen varies with stage. Ocular involvement should be managed as
neurosyphilis and mandates CSF examination. The CDC-recommended treatment
for ocular or neurosyphilis is aqueous crystalline penicillin G 3 million to 4 million
units IV every 4 hours; if compliance can be assured, then procaine penicillin G
2.4 million units IM daily and probenecid 500 mg 4 times a day for 10 to 14 days
could be considered. Consulting with an infectious disease expert is always
advantageous, especially in special circumstances such as pregnancy or drug allergy.
Nontreponemal test titers decline with therapy and may revert to negative
with time (titers from either RPR or VDRL should be consistently used as the two
assays are not interchangeable and RPR titers are often higher than VDRL).
Treponemal tests usually remain positive despite treatment and should not be
used to monitor therapeutic response.
VIRUSES
Viruses are an important cause of infectious optic neuropathies.
Herpes
Herpes is a DNA virus family containing several common human pathogens,
including herpes simplex virus type 1 and type 2, varicella-zoster virus (human
herpesvirus 3, also called shingles), Epstein-Barr virus (human herpesvirus 4),
and CMV (human herpesvirus 5). Herpesviridae appears to have several
mechanisms to evade the human
immune system and has the
ability to establish a latent
infectious stage with later
reemergence.
Optic neuropathy in herpes
simplex virus type 1 or type 2
may occur in association with
acute retinal necrosis or, less
commonly, with herpes
encephalitis. Acute retinal
necrosis produces rapidly
progressive visual loss (typically
in individuals who are
immunocompetent), with FIGURE 11-4
typical retinal features including Acute retinal necrosis. The retinal details are hazy
retinal necrosis, occlusive retinal due to vitreitis. The optic disc is edematous with
vasculitis, and vitreitis/ lost details of the vessels crossing over the
optic disc edge (blue arrow). Areas of retinal
uveitis (FIGURE 11-4). Optic whitening (edema) are present, most notably in the
nerve involvement is usually superotemporal arcade (yellow arrow). In addition,
coincident or follows retinal widespread retinal hemorrhages are seen.
1430 OCTOBER 2019

involvement, with an overall incidence that approximates 50% across most cases, KEY POINTS
often presenting with papillitis or neuroretinitis. Acute retinal necrosis may also
● Syphilis may involve the
rarely result from varicella-zoster virus. Antivirals administered systemically or brain and ocular structures
intravitreally are the mainstays of therapy. Steroids (topically or systemically), at any stage. When syphilis
aspirin, and cycloplegics may also play a therapeutic role. affects the eye, uveitis is the
Varicella-zoster virus produces varicella (chickenpox), usually presenting as a most common form;
however, the disease is
primary infection of childhood, and herpes zoster (shingles), in which painful
notoriously variable and may
vesicles emerge along a specific dermatome due to recurrent disease in older, affect the bulbar or
often immunocompromised, populations. Varicella-associated papillitis and retrobulbar segment of the
herpes zoster ophthalmicus–complicated optic neuritis are rare occurrences; optic nerve with
granulomatous,
therapy with corticosteroids in the former is controversial, while antivirals and
nongranulomatous, or
corticosteroids are generally employed to treat the latter.20 ischemic pathophysiologies.
CMV affects approximately 50% of adults by age 40 and may remain latent
for life. A variety of ocular presentations are associated with CMV infection, ● Acute retinal necrosis is
most characteristically a retinitis in patients who are immunocompromised an important ocular
condition producing rapidly
(eg, patients with HIV/AIDS) (CASE 11-3). CMV retinitis is associated with progressive retinal vasculitis
papillitis in a minority of cases. The visual prognosis in such cases is with retinal necrosis, often
generally poor. with coincident or
subsequent papillitis.
Zika Virus
● Zika virus is the latest in
The Zika virus is named after the Ugandan Zika forest in which the virus was novel infectious epidemics,
first isolated in monkeys. The virus remained relatively isolated to Africa until a with a relatively distinct
2007 outbreak in Micronesia, which produced typical self-limited symptoms of congenital syndrome of
microcephaly and retinal/
rash, fever, headache, arthralgia, and conjunctivitis; however, subsequent
optic nerve changes.
infectious outbreaks in French Polynesia, followed by Brazil in 2014, were
associated with a high rate of Guillain-Barré syndrome in addition to microcephaly
in children born to mothers infected with the virus.21 With increasing case
numbers and spread through Central America, the World Health Organization
(WHO) declared the Zika outbreak a public health emergency in 2016. The virus
generally shares many features with other flaviviruses, including mosquito spread
and nonspecific viremic symptoms in most cases; however, the emergence of the
congenital Zika syndrome in infants was unique. This relatively distinct syndrome
is characterized by birth defects, including microcephaly, cerebral atrophy with
calcifications, congenital musculoskeletal contractures, and hypertonia, in
addition to retinal changes. The retinal changes include pigmentary mottling and
chorioretinal atrophy, while the optic nerve components include optic nerve
cupping, hypoplasia, and atrophy. In a study of 43 children with Zika syndrome
from Venezuela and Columbia, eye examinations disclosed bilateral abnormalities
in all patients (88% had macular or optic nerve abnormalities, while 12% had
anterior segment anomalies). Ocular findings involved the macula (pigment
mottling 63%, lacunar maculopathy 7%), retina (chorioretinal scar 7%), or optic
nerve (hypoplasia, atrophy, and increased cup to disc ratio 12%; congenital
glaucoma 12%).22,23
Human Immunodeficiency Virus

HIV-related optic neuropathy is rare; although the virus has been demonstrated
in select cases, most instances of optic neuropathy in AIDS are related to other
opportunistic infections, rendering HIV optic neuropathy a diagnosis of exclusion.
Optic neuropathies also may result from the antimitochondrial effects of HIV
medications, adding further challenges to diagnosis.

Chikungunya
Chikungunya virus is an emerging pathogen transmitted by the Aedes mosquito.
Headache, myalgia, rash, arthralgia, and fatigue often characterize the presentation,
while ocular involvement commonly takes the form of uveitis, retinitis with
occlusive vasculitis, vitreitis, and optic neuropathy. The latter feature may occur
concomitantly or following viral infection and may appear as unilateral or bilateral
papillitis, neuroretinitis, or even retrobulbar optic neuropathy. The visual
prognosis appears favorable and may be improved with corticosteroid use.24
West Nile Virus

This single-strand RNA arthropod-borne flavivirus made its appearance in North
America in 1999. Humans are unintended hosts, as the natural transmission cycle is
between mosquito and bird hosts. While most infections are subclinical, a minority
CASE 11-3 A 42-year-old man presented with a 2-week history of visual loss that
started in his left eye and then spread to his right eye. Associated
symptoms included unexplained weight loss.
On examination, his visual acuity was 20/400 and count fingers at
4 feet bilaterally; he had disc edema with subretinal fluid in both eyes
(FIGURES 11-5A through 11-5C). HIV, cytomegalovirus (CMV), and
Bartonella IgG antibodies were positive. He was treated with highly
active antiretroviral therapy, ciprofloxacin, and valganciclovir, with
improvement in vision and fundus appearance.
COMMENT This case exemplifies the typical combined optic nerve and retinal
involvement from many infections involving the eye, such as CMV and
Bartonella. While the visual prognosis of Bartonella neuritis is generally
favorable, the visual outcome of CMV ocular infections depends upon the
patient’s underlying immunocompetence.
1432 OCTOBER 2019

follow a neuroinvasive course, causing meningoencephalitis and poliomyelitis
(poliolike syndrome). The ocular manifestations most commonly appear as a
multifocal chorioretinopathy with whitish-yellow fundus lesions, usually with
vitreitis; isolated optic neuropathy appears to be very rare. At present, no specific
therapy has been identified for West Nile virus or its associated complications; the
visual prognosis for West Nile–related optic neuropathy appears generally favorable.25
PARASITES
Parasitic infections are a common worldwide source of visual loss.
Malaria
Malaria is a parasitic infection caused by one of the Plasmodium species (most
severe disease is related to Plasmodium falciparum), whose life cycle involves
FIGURE 11-5
Findings of the patient in CASE 11-3. Cytomegalovirus infection of the optic disc and retina, with
right (A) and left (B) optic disc edema. Optical coherence tomography documents macular
and retinal edema (C, arrows). Optical coherence tomography is an invaluable aid to optic
disc and retinal evaluation.
Figure courtesy of Dr Michael Stewart, MD.

humans and the Anopheles mosquito (which acts only as a vector without evidence
of parasite-related disease). Within the human host, the parasite multiplies in
the liver before entering red blood cells. The blood phase is responsible for the
classic malarial symptoms, with lysed red blood cells releasing the merozoites.
Fever, chills, headache, and myalgia (similar to many viremias) occur in this
stage, while cerebral malaria is defined by the WHO as coma with the
presence of Plasmodium species within peripheral blood smears. In practice,
these criteria are very nonspecific because of the commonality of this blood
finding in endemic regions; however, the recognition of retinal features has
added much-needed specificity to this definition. Although retinal changes
with cerebral malaria have been known for decades, researchers have
characterized the specifics and related these changes to cerebral pathology.26-29
Malarial retinopathy has four key components: retinal whitening, retinal
vascular change, retinal hemorrhage, and papilledema. The retinal whitening
may involve the macula/perifoveal region or periphery and is frequently
noted extending temporally along the horizontal raphe from the macula; this
appears to result from retinal hypoperfusion. Retinal vascular change refers to
a shift to orange or white coloration; this appears to be related to sequestration
of parasitized red blood cells. The retinal whitening and retinal vascular
changes appear to be specific for malarial infection. Retinal hemorrhages
usually take the form of white-centered (fibrinoid-containing) hemorrhages
akin to Roth spots and may be quite numerous in advanced cases; blot- and
flame-shaped hemorrhages also may occur. The amount of retinal hemorrhage
corresponds to the amount of cerebral hemorrhage. Papilledema is a nonspecific
sign indicative of elevated intracranial pressure from cerebral malaria. Among
a cohort of 278 children with cerebral malaria, retinopathy was present in
61%, hemorrhage in 46%, macular whitening in 46%, peripheral whitening in
44%, retinal vascular changes in 32%, and papilledema in 15%.30 The severity of
retinal findings is directly related to disease severity, the risk of death, and the
duration of coma in survivors, with increased retinal abnormalities in more
severe disease.31
Toxoplasmosis
Toxoplasma gondii is a ubiquitous obligate intracellular protozoan parasite
capable of infecting most mammals; while rodents or birds serve as intermediate
hosts, the only known definitive hosts are from the Felidae family (eg, domestic
cats). Humans may acquire toxoplasmosis through consumption of undercooked
meat containing tissue cysts, ingestion of material contaminated by oocyte-
containing cat feces, transplacental transmission, or blood transfusion. Ingested
oocytes become tachyzoites in an infected human, which form cysts in neural
tissue (most commonly brain or eye) and muscle tissue. Approximately one-
third of humans worldwide are estimated to be infected by Toxoplasma, with
wide geographic variations.31,32 While cerebral infection most commonly
presents with seizures, ocular infection typically takes the form of chorioretinitis,
which can be progressive or recurring in approximately two-thirds of patients
(FIGURE 11-6).
Toxoplasmosis may also involve the optic nerve. In a retrospective cross-
sectional study from a Brazilian uveitis clinic, 926 cases of ocular toxoplasmosis
were reviewed, in which 5% (49 patients) had involvement of the optic nerve.
Only three patients had isolated papillitis, while the majority also demonstrated
1434 OCTOBER 2019

juxtapapillary (35%), distant KEY POINTS
(43%), or both juxtapapillary and
● Cerebral malaria is often
distant (16%) chorioretinal associated with relatively
toxoplasmosis lesions. No cases distinct retinal changes,
of isolated neuroretinitis were including retina whitening,
observed.33 The appearance and retinal vascular changes,
retinal hemorrhage, and
course in immunocompromised
occasional papilledema.
hosts may appear atypical and
progress aggressively. ● Toxoplasmosis is
The diagnosis of Toxoplasma widespread geographically
optic neuropathy is challenging and the most common
infectious cause of uveitis in
on laboratory testing, and high many clinics. Treatment is
FIGURE 11-6 rates of IgG antibody are common effective at preventing
Toxoplasmosis. A 30-year-old man presented in many populations; elevated visual loss in most patients.
with decreased visual function in his left eye. IgM titers or PCR for Toxoplasma
Fundus photo documents inferotemporal ● Fungal infections are
DNA from ocular fluid may assist rapidly progressive in the
retinitis.
Figure courtesy of Michael Stewart, MD. in the diagnosis. Although the immunocompromised host,
infection is usually self-limiting, with frequent lethal
therapy is indicated to arrest outcomes in the absence
of early diagnosis and
active parasitic multiplication with attendant retinal and optic nerve damage.
aggressive therapy.
Indications for treatment vary but often include lesions threatening the optic
nerve or fovea, persistent or multiple active lesions, severe vitreitis, and
occurrence in the immunocompromised host. Treatment often consists of
pyrimethamine and sulfadiazine, in combination with corticosteroids and folinic
acid. Treatment-associated visual outcomes are generally favorable.
FUNGI
Fungi remain important human pathogens, especially in the immunocompromised
host.
Mucormycosis
Mucormycosis is important to consider among the infectious optic neuropathies.
The Mucorales family of organisms includes Mucor, Rhizopus, Absidia, and
Cunninghamella. Most Mucor infections involving the optic nerve are related to
rhino-orbital-cerebral involvement, with contiguous spread through the sinuses.
The organism generally affects immunocompromised hosts, with a particular
linkage to diabetic ketoacidosis and a relationship to iron availability. Acidosis tends
to dissociate iron from transferrin, making iron available for fungal use in
replication and invasion. Optic nerve involvement may be related to infarction or
direct fungal invasion. The organism has a strong affinity for blood vessel invasion
and is typically rapidly lethal without early aggressive therapy, which often consists
of surgical debridement and antifungal medications, including amphotericin B.
Cryptococcus
Cryptococcus neoformans is a common cause of optic neuropathy in the setting
of cryptococcal meningitis; this may be related to a combination of direct
infection, inflammation, and increased intracranial pressure–related
papilledema. Cryptococcal infections almost always occur in patients who are
immunocompromised; they are treated with amphotericin B intravenously and,
in rare cases, intravitreally.

CONCLUSION
Many infectious agents have been causally implicated in the development of
optic neuropathy. Although these agents are less common than inflammatory,
ischemic, and other optic neuropathies, their specific therapeutic approaches
mandate their importance in differential diagnosis. Tuberculosis, Lyme disease,
syphilis, CMV, and malaria commonly involve the optic nerve as well as adjacent
retina and ocular structures, and they remain among the more important causal
agents. Because of the relatively nonspecific clinical appearance of many of these
conditions, infectious sources are important to consider in the evaluation of optic
neuropathies, especially if high-risk comorbidities, such as immunosuppression
and suspicious exposures, exist.
USEFUL WEBSITE
US CENTERS FOR DISEASE CONTROL AND PREVENTION
This website provides updated information on
infectious diseases of note within the United States.
cdc.gov/oid/index.html
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7 Donahue HC. Ophthalmologic experience in a 15 Halperin JJ. Central nervous system Lyme
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19 Bhatti MT. Optic neuropathy from viruses and
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20 Witmer MT, Pavan PR, Fouraker BD, Levy-Clarke
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of the spectrum of clinical ocular fundus findings
21 Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al.
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Possible association between Zika virus infection
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22 Yepez JB, Murati FA, Pettito M, et al. Ophthalmic
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manifestations of congenital Zika syndrome in
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32 Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma
24 Mittal A, Mittal S, Bharati MJ, et al. Optic neuritis
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33 Eckert GU, Melamed J, Menegaz B. Optic nerve
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Ophthalmol 2013;24(6):574–580. doi:10.1097/
ICU.0b013e3283654e09.

REVIEW ARTICLE
Imaging in
Neuro-ophthalmology

ONLINE
By Fiona Costello, MD, FRCPC; James N. Scott, MD, MSc
ABSTRACT
PURPOSE OF REVIEW: This article discusses an approach to imaging in patients
with neuro-ophthalmologic disorders, with emphasis on the clinical-
anatomic localization of lesions affecting afferent and efferent visual
function.
Advances in MRI, CT, ultrasound, and optical coherence

RECENT FINDINGS:
tomography have changed how neuro-ophthalmic disorders are diagnosed
and followed in the modern clinical era.
SUMMARY: The advantages, disadvantages, and indications for various imaging

techniques for neuro-ophthalmologic disorders are discussed, with a view
to optimizing how these tools can be used to enhance patient care.
INTRODUCTION
N
CITE AS: euro-ophthalmology is a field of medicine that examines the
relationship between disorders of the central and peripheral
1438–1490. nervous systems and visual function.1 From a clinical perspective,
neuro-ophthalmic patients report a variety of symptoms, including
Address correspondence to vision loss, diplopia, oscillopsia, and pupillary dysfunction. The
Dr Fiona Costello, Foothills
Medical Centre, Clinical
bedrock of clinical localization remains first and foremost a focused history,
Neurosciences, 12th Floor 1403, coupled with a thorough examination. Ancillary investigations, such as MRI, CT,
29 St NW, Calgary, Alberta T2N and optical coherence tomography (OCT) serve to complement the diagnostic
2T9, Canada, Fiona.Costello@
ahs.ca. process. But these imaging technologies are limited in their use if the pathologic
mechanisms underpinning visual dysfunction are poorly understood.
Overreliance on imaging in the absence of clinical localization can lead a
Dr Costello has served on
advisory boards for Frequency physician down the proverbial rabbit hole of diagnostic confusion, a plight that is
Therapeutics and Alexion exacerbated by using the wrong test to image the right place or, alternatively,
Pharma Canada and receives
research/grant support from
using the right test to image the wrong anatomic region. Misadventure may also
the Hotchkiss Brain Institute and arise from focusing on spurious imaging findings, which ultimately distract
the MS Research Program. from, rather than inform, our clinical understanding.
Dr Scott reports no disclosure.
To optimize the value of imaging in neuro-ophthalmology, it is helpful to
UNLABELED USE OF consider the following:
USE DISCLOSURE:
Drs Costello and Scott report no
u What are the potential mechanisms that could explain the patient’s problem?
disclosures.
u Which urgent mechanisms must be initially ruled out?
© 2019 American Academy u What additional imaging options should be considered once the immediate
of Neurology. vision-threatening or life-threatening problems have been excluded?
1438 OCTOBER 2019

u When in doubt about what test to order, talk to a radiology colleague
u When in doubt about an imaging interpretation, talk to a radiology colleague
Indeed, it is sometimes necessary to sacrifice image resolution in the interest

of time, with a view to performing a more refined study at a later date. One case
scenario in which this is especially true, for example, is ordering a CT scan of the
head in lieu of an MRI study to exclude intracranial hemorrhage for a patient
presenting with a thunderclap headache. Other emergent circumstances in which
urgent CT is indicated include acute trauma and suspected hydrocephalus. It is
also very helpful to discuss cases with radiology colleagues, as this dialogue will
provide clarity regarding the urgency of the clinical problem, expedite necessary
testing, and help tailor the imaging study to optimize diagnostic yield. These
conversations can be initiated in post hoc fashion if concern exists that an imaging
finding may have been missed or misinterpreted. After all, to err is human, and
radiologists are often placed in the unfortunate position of having to base their
interpretations on clinical histories provided to them that could be described as
sometimes penurious and, at other times, misleading.
This article describes the principles, advantages, limitations, and clinical
indications for imaging techniques used for patients with neuro-ophthalmologic
disorders. The overarching goal is to discuss how imaging modalities currently
available to the neurologist in the clinical arena can aid the diagnostic process and
provide prognostic information that impacts patient care.
HOW TO CHOOSE THE RIGHT IMAGING TECHNIQUE

A key step to optimizing the role of imaging in neuro-ophthalmology is
determining what test is best to use in a given clinical scenario while remaining
mindful of the advantages and disadvantages of the different modalities available
(TABLE 12-1). MRI has been the mainstay for evaluating structural substrates
that govern afferent and efferent visual pathway function, yet the small caliber
and divergent oblique orientations of the optic nerves create challenges in
interpreting conventional MRI studies.2 Fortunately, recent developments in
ocular imaging, specifically with respect to OCT, have enabled indirect visualization
of axonal and neuronal structures in the retina affected by optic nerve injuries.1
Moreover, emerging MRI techniques are on the horizon that may enhance our ability
to monitor structurally relevant changes in the anterior visual pathway.
Magnetic Resonance Imaging

MRI is the preferred imaging modality to evaluate most afferent and efferent
visual pathway disorders, with the exception of acute hemorrhage and bony
abnormalities, which are both better assessed with CT.2–12 MRI offers several
distinct advantages over CT (TABLE 12-1): first, it provides superior contrast
between pathologic lesions and normal tissue; second, it allows for direct,
multiplanar imaging without patient repositioning; and, third, unhindered by the
effects of beam-hardening artifacts, MRI provides better visualization of
posterior fossa structures.3–6
While a detailed discussion regarding the principles of physics that govern
MRI function are beyond the scope of this article, it bears mentioning that MRI
signals are derived from the interaction of hydrogen protons within a magnetic
field.3–5 Thus, MRI does not pose a radiation risk to patients. The use of magnetic
forces, however, does introduce contraindications for patients with embedded

IMAGING IN NEURO-OPHTHALMOLOGY
TABLE 12-1 Imaging Modalities Used in Neuro-ophthalmology
Imaging
Modality Advantages Disadvantages Indications
MRI Provides optimal sensitivity in High cost, long scan times, patient- The preferred imaging modality
differentiating normal tissue related factors (eg, claustrophobia, for most brain and orbital lesions
from pathology in the brain high body mass index) may prohibit use
and orbit
MRI is contraindicated in patients
Allows multiplanar imaging with implanted materials vulnerable
without patient repositioning to magnetic fields, including metallic
substances, cardiac pacemakers, and
Enables good resolution of
cochlear implants
posterior fossa structures
Gadolinium is contraindicated in patients
Poses no risks of radiation
with hemolytic or sickle cell anemia
exposure
Nephrogenic systemic fibrosis can
occur in patients with renal disease
CT Scans are widely available, Exposes patients to ionizing radiation CT is superior to MRI in visualizing
easy to obtain, relatively bony structures, calcified lesions,
Beam-hardening artifacts from bone,
inexpensive, and rapidly and acute hemorrhage
metallic clips, and dental fillings can
accessible
degrade image quality CT is the modality of choice in
trauma, emergency cases (acute
Iodinated contrast may cause
stroke, brain abscess, pituitary
nephrotoxicity and allergic reactions
apoplexy, intracranial shunt
malfunction) and in patients with
contraindications to MRI
Optical Noninvasive, inexpensive, and Media opacity and optic nerve Used to track acute and chronic
coherence easily accessible edema can result in loss of signal and effects of lesions affecting the
tomography introduce artifacts in retinal layer retina, optic nerves, chiasm, and
segmentation and interpretation optic tracks
Above average axial eye length
associated with high myopia is
associated with thinner retinal nerve
fiber layer values
Fixation errors can prohibit reliable
optical coherence tomography
measurements
Ultrasound Widely available, noninvasive, Operator dependent Can be used to examine the ocular
and involves no ionizing globe even in the presence of
Contraindicated in the setting of
radiation cataracts, vitreous hemorrhages,
suspected open-globe injury
and media opacities
Provides real-time information
regarding vascular anatomy Useful in pediatric patients since it
and blood flow does not require sedation
Digital Provides high-resolution Invasive and carries the risk of Considered the gold standard for
subtraction imaging of vascular structures radiation exposure evaluating aneurysms, vascular
angiography stenoses, vessel occlusions, and
Adverse reactions to the contrast
dissections
agent may occur, and injection sites
can be painful
Rare complications include shock,
seizures, renal failure, and stroke
CT = computed tomography; MRI = magnetic resonance imaging.
1440 OCTOBER 2019

ferromagnetic devices or hardware (TABLE 12-1). The magnetic field created by
the scanner is expressed in the unit tesla (T), and MRI machines commonly used
in clinical practice range in strength from 1.5 T to 3.0 T.3–5 By controlling the
radiofrequency pulse and gradient waveforms, computer programs produce
specific sequences that determine how various tissues are depicted.3–5 These
protocols can be tailored, in turn, to provide optimal visualization of anatomic
structures and identify pathologic findings. In conventional MRI scans, fatty tissues
appear bright (hyperintense) on T1-weighted sequences and relatively dark
(hypointense) on T2-weighted images, whereas water-based fluids appear
relatively dark on T1-weighted images compared to T2-weighted images.3 As such,
gray matter appears dark on T1-weighted and bright on T2-weighted images,
while white matter is bright on T1-weighted and dark on T2-weighted images. In
practical terms, T1-weighted MRI sequences are used to characterize normal soft
tissue anatomy, whereas T2-weighted studies demonstrate fluid shifts arising from
pathology (tumors, inflammation, and demyelination).3–6 Since CSF is bright on
T2-weighted images, it may be difficult to distinguish periventricular lesions from
CSF signal on T2-weighted MRIs. Therefore, the fluid-attenuated inversion
recovery (FLAIR) sequence was created, which is a T2-weighted image in which
the CSF signal has been suppressed to allow better visualization of adjacent
pathologic signal. MRI is enhanced with the use of gadolinium, a paramagnetic
contrast material, which, when used in concert with T1-weighted sequences,
provides better visualization of pathologic lesions affecting the brain, orbit, and
spinal cord, by indicating areas of blood-brain barrier breakdown.3–6
MRI of the orbits and various orbit-related conditions similarly includes
different sequences that each have specific uses as well as advantages and
disadvantages compared to the others. A routine orbit MRI protocol typically
includes T1-weighted sequences before IV injection of contrast medium for
anatomic overview, T2-weighted sequences or FLAIR sequences to highlight
inflammatory changes, short tau inversion recovery (STIR) sequences to
highlight inflammatory changes, and contrast-enhanced T1-weighted sequences
to evaluate abnormal enhancement in the characterization of inflammatory/
infectious changes and tumors. Because the orbits contain a relatively large
amount of fat, it is important for T2-weighted and contrast-enhanced
T1-weighted sequences to have fat saturation to increase the conspicuity of
pathology. Concurrent imaging of the brain may include other sequences, such as
diffusion-weighted imaging (DWI) to identify acute ischemic stroke and active
demyelination; gradient recalled echo (GRE) or susceptibility-weighted imaging
(SWI), which are helpful to identify microhemorrhages in vascular lesions;
magnetic resonance venography (MRV) to detect venous sinus thrombosis or
venous stenoses; and magnetic resonance angiography (MRA) to examine
normal vascular anatomy and vascular lesions, including aneurysms, arterial
stenoses, and vascular malformations. The introduction of MRA has reduced
reliance on invasive catheter angiography as a means of investigating vascular
structures (TABLE 12-1).
Newer sequences, such as diffusion tensor imaging (DTI) and magnetic
resonance spectroscopy,10 may be included on a case-by-case basis but are not
routinely performed in most orbital MRI examinations used for clinical purposes.
DTI is sensitive to white matter structure and organization, making this
technique a useful surrogate marker for axon and myelin integrity. Magnetic
resonance spectroscopy can detect several specific brain metabolites and, as a

problem-solving tool, may help distinguish between neoplasms, demyelinating

lesions, radiation necrosis, inflammatory lesions, and mitochondrial disorders
that can affect the visual pathways.10
Computed Tomography
CT scans are derived from x-ray attenuation caused by tissues of various
densities.3–5 Since denser tissues block x-rays, these anatomic regions appear
brighter (hyperdense) with CT.4,5 Used together, CT and MRI can provide
complementary information about disorders involving the craniofacial bony
structures or sinuses, including orbital fractures, hyperostosis (associated with
meningiomas), fibrous dysplasia, sphenoid wing agenesis (associated with
neurofibromatosis type 1), craniosynostosis syndromes, sinus tumors and
inflammatory processes, and pathologic lesions of the skull base.5 CT can also be
used to characterize lesions such as optic nerve head drusen, craniopharyngiomas,
meningiomas, and retinoblastomas that calcify over time.5 CT is the modality of
choice in the setting of orbital trauma, because images can be rapidly acquired and
may be performed as part of a more extensive body imaging protocol when
multiorgan injury is suspected.4,5,11 As is the case for MRI, advances in CT
angiography (CTA) have allowed for highly precise, rapidly available noninvasive
angiographic methods to study the head and neck vasculature. Finally, positron
emission tomography (PET)/CT imaging is used to understand functional
correlates of diseases such as cancers and systemic sources of inflammation.10
Optical Coherence Tomography

Ophthalmoscopy has been traditionally used to provide direct and indirect views
of the fundus, thus identifying a variety of pathologic findings germane to
neuro-ophthalmic practice, including optic disc edema, optic atrophy, and
vascular occlusions affecting the arterial and venous circulation of the retina.
Arguably, a skillful fundus examination can be a challenge for many physicians,
particularly if this is not a routine part of their patient assessments. Nonmydriatic
fundus photography may represent an alternative means of examining the optic
nerve and retinal vasculature, although this technology may currently be too
costly to gain mainstream use in many clinical environments. In ophthalmologic
practice, fluorescein angiography is used to assess the vascular status of the retina
in real time and may also be helpful in distinguishing cases of true optic disc
edema from pseudopapilledema. This technique is invasive in nature, however,
and may cause allergic reactions in some individuals. As a practical option, OCT
is a readily accessible, noninvasive means of examining the optic nerve and
retinal structure. OCT uses principles of low-coherence interferometry to acquire
high-resolution (3 μm to 6 μm), noninvasive imaging of retinal structures in
vivo.1,13–15 Recent developments in retinal segmentation have allowed the
thickness of individual layers of the retina to be quantified with spectral domain
OCT (FIGURE 12-116). This feature facilitates indirect quantification of axonal loss
(measured as retinal nerve fiber layer thinning) and neuronal damage (measured
as macular ganglion cell–inner plexiform layer thinning) (FIGURE 12-1) referable
to lesions involving the optic nerves, chiasm, and optic tracts.1,13–15 OCT-
measured retinal nerve fiber layer and ganglion cell–inner plexiform layer
thinning correlates strongly with functional outcomes across a spectrum of optic
neuropathies, including glaucoma, optic neuritis, ischemic optic neuropathy,
hereditary disorders, toxic optic nerve insults, gliomas, and papilledema.1,13
1442 OCTOBER 2019

FIGURE 12-1
Macular optical coherence tomography (OCT) with intraretinal layers.
BM = Bruch membrane; ELM = external limiting membrane; GCIP = ganglion cell–inner plexiform;
GCL = ganglion cell layer; ILM = internal limiting membrane; INL = inner nuclear layer; IPL = inner plexiform
layer; ISOS = inner segment–outer segment (junction); ONL = outer nuclear layer; OPL = outer plexiform
layer; OPT = outer photoreceptor tip; RNFL = retinal nerve fiber layer; RPE = retinal pigment epithelium.
Reprinted from Brandt A, Translational Neuroimaging.16 © 2019 Translational Neuroimaging.
Moreover, the improved penetrance of OCT techniques such as enhanced depth

imaging has changed the way clinicians detect buried optic disc drusen.15,17 In
addition to refining the diagnosis and management of optic neuropathies, OCT
has proven instrumental in distinguishing subtle retinal conditions from diseases
of the optic nerve, especially in the clinical context of a nondiagnostic fundus
examination.1,13 OCT angiography enables visualization of the retinal capillary
network. Recent OCT angiography studies have identified patterns of decreased
optic disc perfusion and loss of peripapillary capillary density in optic nerve
disorders.1 Finally, high-definition imaging of the macula may help rule out
retinal disease in cases of visual loss that present to the neurologist or
neuro-ophthalmologist.
Ultrasonography
Ultrasound uses the reflection of sound waves at acoustic interfaces to provide
real-time display of tissues.3,18 In ophthalmology, B-mode ultrasound is used
to evaluate the posterior segment of the eye and is especially useful in the
presence of media opacities that obscure reliable ophthalmoscopy.18 This type
of ultrasonography can be used to detect optic nerve head drusen, retinal
detachments, and ocular tumors.3,18 Doppler ultrasound can identify alterations
in flow dynamics and characterize vascular lesions of the orbit, including orbital
varices and carotid-cavernous sinus fistulas. Ultrasound is especially useful in
the evaluation of pediatric patients with ocular tumors, since it does not require
sedation and can be performed longitudinally to monitor treatment response.18
More recently, ultrasound-detected vessel wall edema has been used to
identify active vasculitis in conditions such as giant cell arteritis (GCA).19 In
suspected cases of GCA, ultrasound-detected vessel wall edema generates a
hypoechoic signal around the vessel lumen, referred to as the halo sign.19 This
finding may prove useful in rendering the diagnosis, particularly in temporal
artery biopsy–negative cases, since the halo sign can be detected in extracranial
(subclavian and axillary) arteries.19

FIGURE 12-2
Optic neuritis and multiple sclerosis. A 19-year-old man presented with left retrobulbar
optic neuritis. Axial postcontrast MRI (A) and coronal T1-weighted MRI with fat saturation
(B) showed enhancement of the retrobulbar intraorbital segment of the left optic nerve
(A, B, arrows) and multiple intracranial enhancing lesions. Axial fluid-attenuated inversion
recovery (FLAIR) sequence (C) showed hyperintense lesions in the cerebral white matter,
with active lesions demonstrating surrounding edema. Axial postcontrast T1-weighted MRI
(D) showed active enhancing lesions with an incomplete, or open-ring, pattern. The imaging
findings demonstrated in this patient are highly characteristic for multiple sclerosis, with
FLAIR being more sensitive than T2-weighted images in detecting juxtacortical and
periventricular lesions. However, T2-weighted imaging is more sensitive than FLAIR in
detecting infratentorial lesions in the brainstem and cerebellum.
USING THE BEST TEST TO IMAGE ANATOMIC REGIONS OF INTEREST

The diagnostic pursuit of “what” the problem is in neuro-ophthalmology is often
spearheaded by knowledge of “where” the problem is because of the elegant
topographical organization of the afferent and efferent visual systems. Patterns
of visual field damage can localize lesions anywhere along the afferent visual
pathway from the retina to the visual cortices. Similarly, patterns of ocular
misalignment can implicate specific regions of brainstem involvement. Once
clinical-anatomic localization has been established, the best imaging modality
can be selected to evaluate the region of interest.
Optic Neuropathies
Optic neuropathies may be caused by ischemic, inflammatory, infiltrative,
infectious, toxic-metabolic, traumatic, and compressive mechanisms. Vision loss
may be abrupt, subacute, or slowly progressive. Pain is a variable symptom. At
clinical presentation, patients typically manifest vision loss, dyschromatopsia
(altered color perception), and a relative afferent pupil defect in the affected eye.
The optic nerve may appear edematous, normal, or pale, depending upon the
cause and chronicity of the optic nerve injury. Perimetry techniques can help
localize the site of injury to one or both optic nerves. When evaluating the
anterior region of the afferent visual pathway, structural neuroimaging
techniques (MRI and CT), OCT, and functional outcome measures can provide
valuable diagnostic and prognostic information.
DEMYELINATING SYNDROMES AND AUTOIMMUNE ASTROCYTOPATHIES. Once it

exits the eye behind the lamina cribrosa, the optic nerve acquires myelin and
thus becomes vulnerable to demyelinating injury in its retrobulbar course.3
1444 OCTOBER 2019

Central nervous system (CNS) demyelinating disorders and autoimmune KEY POINTS
astrocytopathies such as multiple sclerosis (MS), neuromyelitis optica spectrum
● The diagnostic pursuit of
disorder (NMOSD), anti–myelin oligodendrocyte glycoprotein (MOG)–IgG “what” the problem is in
disease, acute disseminated encephalomyelitis (ADEM), and glial fibrillary neuro-ophthalmology is
acidic protein (GFAP)–IgG astrocytopathy presenting with variants of optic often spearheaded by
neuritis can be identified by their salient MRI and OCT characteristics. From a knowledge of “where” the
problem is because of the
practical perspective, differentiating these conditions is important, because they
elegant topographic
require different treatment strategies. In the case of NMOSD, for example, early organization of the afferent
initiation of effective immunosuppressive therapy can prevent attack-related and efferent visual systems.
disability.20 Moreover, some drugs used effectively in the treatment of MS may
exacerbate the disease course for patients with NMOSD.20 ● The diagnosis of optic
neuritis associated with
MS-associated optic neuritis typically demonstrates T2-weighted MRI neuromyelitis optica
hyperintense signal changes and gadolinium enhancement on postcontrast spectrum disorder can be
T1-weighted sequences of the affected nerve (FIGURE 12-2).20,21 According to the aided by adding orbital MRI
2017 revision of the McDonald criteria for the diagnosis of MS, MRI evidence of sequences to cranial
imaging; orbital views
disease dissemination in space is evident by the presence of one or more typically reveal longitudinal
characteristic T2-hyperintense lesions in two (or more) of four CNS regions, lesion(s) that extend back to
including periventricular, cortical or juxtacortical, and infratentorial brain the optic chiasm.
locations and the spinal cord.21 Dissemination in time is supported by the
● MRI of the brain, orbits,
simultaneous presence of gadolinium-enhancing and nonenhancing lesions at
and spinal cord can help
any time or by a new T2-hyperintense or gadolinium-enhancing lesion on identify patterns of central
follow-up, with reference to a baseline scan.21 Hence, MRI plays an instrumental nervous system
diagnostic role for the high proportion of patients with MS (20%) who present inflammation that are
pathognomonic for
with optic nerve involvement as a clinically isolated syndrome.14,21
neuromyelitis optica
The MRI features of NMOSD-associated optic neuritis differ from those spectrum disorder.
associated with MS, because often more posterior involvement of the optic nerve(s)
is seen, extending back to the optic chiasm in the former (FIGURE 12-3).20,22,23 ● Anti–myelin
Certain MRI lesions have a location or appearance that can be specifically oligodendrocyte
glycoprotein IgG–
characteristic for NMOSD, including diencephalic lesions surrounding the third associated optic neuritis
ventricles and cerebral aqueduct, dorsal brainstem lesions adjacent to the commonly presents with
fourth ventricle (which may manifest as intractable hiccups or vomiting), optic disc edema and MRI
periependymal lesions surrounding the lateral ventricles, and longitudinal evidence of perineural
enhancement of the optic
lesions of the optic nerves and chiasm.20,22,23 Arguably, the most distinctive MRI nerve extending into
finding associated with NMOSD is longitudinally extensive transverse myelitis, surrounding tissues in
a spinal cord lesion that spans over three (or more) contiguous vertebral the orbit.
segments and predominantly involves central gray matter (FIGURE 12-3).
Brainstem lesions that are contiguous with upper cervical cord lesions may also
be noted in patients with NMOSD presenting with nystagmus, dysarthria,
dysphagia, ataxia, or ophthalmoplegia.20,22,23
Patients with anti–MOG-IgG antibodies are prone to recurrent optic neuritis
events.24,25 In a 2018 observational case series (n = 87 patients), Chen and
colleagues24 reported MRI evidence of perineural enhancement in 50% of
seropositive MOG cases. Furthermore, the enhancement observed tended to be
extensive and involve the orbital portion of the optic nerve.24 Optic disc edema
was present in 86% of patients, which confirmed this finding as a common
feature of MOG-IgG–positive optic neuritis that can help distinguish these
patients from patients with other demyelinating optic neuropathies.24 In a larger
French cohort (n = 197 patients), a preponderance of thalamic and pontine
lesions was seen in the seropositive MOG group presenting with optic neuritis,
myelitis, and brainstem or encephalopathy syndromes compared to the patients

FIGURE 12-3
Optic neuritis associated with neuromyelitis optica spectrum disorder (NMOSD). A 21-year-old
woman presented with a 1-week history of hiccups, a burning sensation in her neck/ trunk/
legs, decreased rectal tone, and lower limb weakness. A, Sagittal T2-weighted MRI showed
poorly delineated hyperintense signal changes within an enlarged spinal cord extending over
eight to nine spinal segments (longitudinally extensive transverse myelitis). A hyperintense dorsal
medulla/area postrema lesion was also seen (arrow). B, Sagittal postcontrast T1-weighted
MRI demonstrated patchy enhancement of the spinal cord lesion. As a second example, a
37-year-old man presented with left monocular vision loss and progressive upper extremity
weakness. C, Axial fluid-attenuated inversion recovery (FLAIR) MRI showed hyperintense
signal change in the left optic retrobulbar nerve (arrow). D, Sagittal T2-weighted MRI showed
hyperintense signal changes in the cervical cord extending over five to six spinal segments.
The lesion occupied over two-thirds of the cross-sectional diameter of the cord and did not
enhance (not shown).
with NMOSD, who demonstrated preferential involvement of the medulla

oblongata and area postrema on MRI.25
Autoimmune GFAP-IgG astrocytopathy is a steroid-responsive meningo-
encephalomyelitis.26 Patients who are seropositive typically present with
symptoms and signs of encephalopathy, myelopathy, and papillitis (the
appearance of optic nerve head edema secondary to inflammation).26 Cranial
MRI reveals a highly characteristic radial pattern of periventricular gadolinium
enhancement (FIGURE 12-4), which can facilitate diagnosis.26 Other reported
MRI findings associated with this astrocytopathy include diffuse T2-weighted
abnormalities located in the periventricular white matter, leptomeningeal
enhancement, and longitudinal T2-weighted hyperintense lesions in the spinal cord.26
Most optic neuropathies are associated with OCT-measured retinal nerve fiber
layer and ganglion cell–inner plexiform layer thinning, reflecting neuroaxonal
injury in the postacute phase.14 Yet the extent of OCT-measured damage is
helpful in differentiating whether the patient harbors a diagnosis of MS or
NMOSD. In a 2017 meta-analysis, Petzold and colleagues27 compared OCT
findings in 1667 eyes of MS patients with optic neuritis and 4109 eyes of MS
patients without optic neuritis to 1697 eyes from healthy control subjects.
Peripapillary retinal nerve fiber layer values were thinner in the eyes of MS
patients with optic neuritis (mean difference −20 μm, 95% CI, −23 μm to −17 μm;
P<.0001) and in the eyes of MS patients without optic neuritis (−7 μm, −9 μm to
−6 μm; P<.0001), compared to healthy control eyes.27 OCT-measured ganglion
1446 OCTOBER 2019

FIGURE 12-4
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. A 30-year-old man
presented with new-onset headaches, slurred speech, and bilateral papillitis. Axial fluid-
attenuated inversion recovery (FLAIR) MRIs (A, B) showed bilateral patchy hyperintense
lesions involving the brainstem, cerebellum, and supratentorial white matter. Axial
postcontrast T1-weighted MRI (C) showed a dotted/punctate pattern of enhancement
representing linear perivascular enhancement, seen better on a reformatted sagittal image
(D) extending outward from the ventricles (arrow).
cell–inner plexiform layer thinning was also prominent in both the eyes of MS
patients with optic neuritis (−16 μm, −19 μm to −14 μm; P<.0001) and the eyes of
MS patients without optic neuritis (−6 μm, −8 μm to −5 μm; P<.0001) compared
to control eyes.27 Lower retinal nerve fiber layer and ganglion cell–inner
plexiform layer values predict worse visual outcomes and correlate with other
surrogate end points used to monitor MS disease activity, including MRI-
measured brain atrophy, MRI-measured T2-weighted and gadolinium-
enhancing lesions, neurologic disability scores, and clinical relapses.1,13,14 In
contrast to MS, NMOSD-associated optic neuritis causes more extensive
retinal nerve fiber layer and ganglion cell–inner plexiform layer thinning,
commensurate with the severity of the neuroaxonal injury in these patients.1,28
Moreover, 20% to 26% of patients with NMOSD have OCT evidence of
microcystic edema in the macula compared to 5% of patients with MS, which is
believed to reflect more active inflammatory injury in the former.28 It is
noteworthy that while retinal nerve fiber layer thinning occurs in the absence of
clinically overt optic neuritis events in MS, subclinical axonal attrition is rare in
NMOSD.28 Recent studies have shown that neuroaxonal damage affecting the
afferent visual pathway in patients who are anti–MOG-IgG seropositive may be
driven predominantly by the frequency of optic neuritis attacks, whereas
damage in patients with NMOSD reflects the severity of optic neuritis events.1
Future studies will be needed to better define the OCT phenotypes that
distinguish patients with NMOSD, MS, and MOG-IgG disease.
In the acute setting, retinal nerve fiber layer values are often slightly elevated
in eyes with optic neuritis, often in the absence of clinically apparent optic disc
swelling (papillitis).14 This retinal nerve fiber layer thickening reflects
axoplasmic flow stasis that is part and parcel of the inflammatory process
affecting the optic nerves. Initial thickening of the retinal nerve fiber layer masks
the effects of evolving optic atrophy, making it difficult to detect axonal injury
for weeks to months.14 In contrast, ganglion cell–inner plexiform layer thinning
is detectable within 2 to 4 weeks of symptom onset, which makes it an earlier
marker of neuronal damage arising from the retrobulbar site of optic nerve

inflammation.1,14 Over a series of months, retinal nerve fiber layer and ganglion
cell–inner plexiform layer values continue to thin and plateau thereafter.14
INFLAMMATORY, INFECTIOUS, INFILTRATIVE, AND COMPRESSIVE OPTIC

NEUROPATHIES. Inflammatory (including sarcoidosis, lupus, and granulomatosis
with polyangiitis), infectious (including tuberculosis, syphilis, and Lyme
disease), and infiltrative (including lymphoma, leukemia, and optic nerve
glioma) causes of optic nerve injury are often heralded by specific aspects of the
history and examination that prompt diagnostic suspicion. Orbital MRI
discloses T2-weighted and FLAIR hyperintense signal changes in the optic nerve,
with variable degrees of optic nerve thickening and enhancement. Sarcoidosis,
tuberculosis, syphilis, IgG4 disease, and Lyme disease are among a heterogeneous
group of disorders that may also cause hypertrophic pachymeningitis
(TABLE 12-2).29 Patients with tuberculosis may demonstrate additional MRI
features of hydrocephalus, cerebral edema, and tuberculomas,3,30 which can
sometimes affect the optic chiasm. In the context of syphilis, strokelike lesions
TABLE 12-2 Causes of Hypertrophic Pachymeningitisa
Connective Tissue Diseases

◆ IgG4-related pachymeningitis
◆ Granulomatosis with polyangiitis
◆ Rheumatoid arthritis
◆ Sarcoidosis
◆ Giant cell arteritis
◆ Behçet disease
◆ Sjögren syndrome
Infections
◆ Mycobacterium tuberculosis
◆ Syphilis
◆ Lyme disease
◆ Cysticercosis
◆ Fungal
Neoplasms
◆ Lymphoma
◆ Dural carcinomatosis
◆ En plaque meningioma
◆ Erdheim-Chester disease
Other
◆ Mucopolysaccharidoses
◆ Intracranial hypotension
IgG4 = immunoglobulin G4.

a
Reprinted with permission from AbdelRazek MA, et al, Lancet.29 © 2018 Elsevier Ltd.
1448 OCTOBER 2019

from vasculitic involvement of the brain can occur.3,30 Syphilitic gummas have KEY POINTS
increased signal on T2-weighted MRI and may or may not enhance.3 Patients
● Autoimmune glial
with Lyme disease may demonstrate enhancement of multiple cranial nerves.3,30 fibrillary acidic protein–IgG
Optic nerve gliomas are well characterized with MRI and show a tubular or astrocytopathy presents
fusiform enlargement of the nerve (FIGURE 12-5).3 These lesions appear with a highly characteristic
isointense to hypointense compared to adjacent tissues on T1-weighted MRI and radial pattern of
periventricular enhancement
may enhance after gadolinium injection. Optic nerve gliomas may demonstrate a
best seen with cranial MRI.
“pseudo CSF” sign, which refers to the increase in T2-weighted signal around
the optic nerve caused by perineural arachnoid gliomatosis.3 By way of ● Optic perineuritis with
comparison, optic nerve sheath meningiomas cause a uniformly enlarged MRI evidence of a
appearance to the optic nerve and appear isointense with respect to surrounding tram-track sign is a
nonspecific radiologic
tissues on T1-weighted studies (FIGURE 12-6).3 Orbital MRI is especially useful in finding and may be seen in a
distinguishing optic nerve gliomas from meningiomas by showing that the latter variety of inflammatory and
are separate from the optic nerve on coronal views, forming a concentric ring neoplastic disorders
around the substance of the nerve.3 Moreover, MRI reveals lower apparent affecting the optic nerve.
Complementary CT images
diffusion coefficient values in optic nerve gliomas compared to meningiomas. can reveal calcification in
As a complementary imaging technique, CT shows perineural calcification or suspected cases of optic
“tram-tracking” in cases of optic nerve sheath meningiomas in addition to nerve sheath meningioma,
hyperostosis of neighboring bone.3 Since intracanalicular optic nerve sheath but in other cases a systemic
evaluation of the patient
meningiomas can be challenging to detect, it may, at times, be necessary to may be needed to render
perform serial imaging with thin cuts in the region of the optic canal. the diagnosis.
Optic perineuritis refers to inflammation of the optic nerve sheath with relative
sparing of the nerve itself.31 Optic nerve sheath inflammation can be optimally
visualized using gadolinium-enhanced fat-saturated T1-weighted MRI. The typical
appearance is that of circumferential optic nerve sheath enhancement, which on
axial views creates the aforementioned tram-track sign.31 Hence, this sign is not
specific but may be seen in a variety of inflammatory or neoplastic disorders
affecting the optic nerve sheath, including meningiomas, orbital pseudotumor,
sarcoidosis, leukemia, lymphoma, metastases, perioptic hemorrhage, GCA,32 and
Erdheim-Chester disease.31 Coexisting intracranial leptomeningeal enhancement
visualized on cranial MRI may indicate infection or neoplasm as a potential etiology
of the clinical presentation.31
The OCT findings in cases of inflammatory, infectious, infiltrative, and
compressive optic nerve lesions are variable and must be interpreted in the
context of the underlying disorder. Optic pathway gliomas associated with
neurofibromatosis type 1 demonstrating increased lesional volume as measured
with MRI high-resolution T1-weighted sequences (FIGURE 12-5) are associated
with worse retinal nerve fiber layer loss as a marker of axonal degeneration.33 As
a general rule, irrespective of cause, chronic optic nerve injury will lead to retinal
nerve fiber layer and ganglion cell–inner plexiform layer thinning over time.1
Tracking the early effects of neuroaxonal injury in anteriorly located optic nerve
lesions such as optic nerve sheath meningiomas can be challenging, because
concomitant mild axoplasmic flow stasis may be present.1 Consequently, initial
OCT testing may reveal subclinical retinal nerve fiber layer thickening in the face
of ganglion cell–inner plexiform layer thinning, akin to the pattern commonly
seen in cases of acute optic neuritis.
OPTIC DISC DRUSEN. Optic disc drusen are acellular hyaline deposits located in
the optic nerve that tend to calcify over time.1,15,17 When drusen are superficial in
location, the fundus examination is often diagnostic because the optic nerve

appears elevated with a nodular border.1,15,17 Buried drusen, however, can be

mistaken for other causes of an elevated optic nerve appearance, including
papilledema.1,15,17 Traditionally, B-mode ultrasonography has been viewed as the
gold standard test for the detection of buried optic disc drusen.15,17 With this
imaging modality, drusen appear as hyperechoic, highly reflective round
structures, distinguished by their posterior acoustic shadowing.15,17 Because
FIGURE 12-5
Optic nerve glioma in a 3-year-old girl with neurofibromatosis type 1. A, B, Coronal postcontrast
T1-weighted MRI sequences with fat saturation show enlargement of both intraorbital and
prechiasmatic optic nerves (A, arrows) with patchy enhancement. C, Coronal T2-weighted image
shows the optic nerve glioma as isointense/hyperintense compared to brain parenchyma, typical
of most optic nerve gliomas. D, Axial T2-weighted MRI shows focal areas of hyperintensity
involving the dentate nucleus of the cerebellum (arrow). Other similar focal hyperintensities
were present in the hippocampus and corpus callosum of this patient (not shown), representing
dynamic reactive white matter lesions typical of this disorder.
FIGURE 12-6
Optic nerve sheath meningioma. A 35-year-old woman presented with progressive vision loss
in her right eye. Postcontrast fat-suppressed T1-weighted MRI showed an enhancing lesion
tracking along the right optic nerve sheath, forming the tram-track sign on axial image (A) and
the donut sign on coronal image (B). The tumor extended across the optic canal with trace
en plaque meningioma adjacent to the anterior clinoid process (not shown). In a second case
example, a 54-year-old woman presented with progressive monocular vision loss in the left
eye and mild exophthalmos. Coronal T2-weighted MRI (C) showed loss of the normal
hyperintense CSF signal surrounding the left optic nerve and compression of the nerve. Axial
T1-weighted postcontrast fat-suppressed MRI (D) showed a bulky enhancing tumor along the
left optic nerve.
1450 OCTOBER 2019

drusen calcify over time, they are also evident on orbital CT imaging as a KEY POINT
hyperdense signal within the optic nerve head (FIGURE 12-7).15,17
● Enhanced-depth optical
Autofluorescence photography demonstrates surface drusen as avidly coherence tomography can
autofluorescent but does not show buried drusen.15 Enhanced-depth OCT allows be used to detect buried
visualization of deeply lying structures within the optic nerve. With this imaging optic disc drusen, which
modality, drusen typically appear as a signal-poor core surrounded by a appear as signal-poor
structures surrounded by a
hyperreflective margin.1,15,17 In the current OCT era, it is feasible to quantify
hyperreflective rim.
drusen size and delineate their borders and to assess the integrity of adjacent
retinal structures.1,15,17 Going forward, OCT may be used to follow longitudinal
changes in drusen structure and associated neuroaxonal changes in the retina. As
a result, OCT may help identify risk factors and potentially provide prognostic
guidance regarding vision loss in patients with optic disc drusen.
PAPILLEDEMA IN IDIOPATHIC INTRACRANIAL HYPERTENSION. Idiopathic

intracranial hypertension (IIH) is a cryptogenic condition associated with
increased intracranial pressure and characterized by headaches, papilledema,
and visual loss.1,17,34 Since IIH is a diagnosis of exclusion, neuroimaging with
either CT or MRI is needed to exclude mass lesions as a basis of papilledema.
Furthermore, CT venography or MRV is useful in excluding cerebral venous
sinus thrombosis as a potential diagnostic mimic. Various radiologic “soft signs”
of raised intracranial pressure have been identified in patients with IIH. In a 2016
review on this topic, Markey and colleagues34 highlighted key radiologic clues
that may facilitate the diagnostic process. T1-weighted sagittal views of the brain
may show an empty sella turcica in approximately 70% of patients with IIH
(FIGURE 12-8).34 Axial T2-weighted MRI views of the orbit reveal distension and
tortuosity of the optic nerve sheaths in 45% of patients with IIH.34 Orbital MRI
views identify flattening of the posterior globes in 80% of patients with IIH,34
and, in some cases of IIH, MRI evidence of optic disc edema may be visible. Farb
and colleagues35 have shown that gadolinium-enhanced MRV identifies a high
prevalence of venous sinus
stenosis (FIGURE 12-8), which
allows patients with IIH to be
reliably distinguished from
healthy control subjects
(sensitivity and specificity of
93%). In related work, Morris
and colleagues36 performed a
retrospective study to define
the sensitivity with which
neuroradiologists may detect signs
of transverse sinus stenosis with
non-MRV imaging by focusing
on coronal postgadolinium
T1-weighted images. These
investigators observed bilateral
transverse sinus stenosis in MRV
studies in 94% of patients with
IIH compared to 3% in control FIGURE 12-7
subjects.36 These findings may Orbital CT images showing hyperdense optic
help refine the diagnostic process nerve head drusen (arrows).

for patients with symptoms and signs suggestive of raised intracranial pressure
and help determine whether venous sinus stenting is a potential option for
patients with IIH at risk of vision loss.
OCT can also play a role in diagnosing and monitoring patients with IIH.1,17 Not
surprisingly, patients with papilledema manifest elevated retinal nerve fiber layer
values at acute presentation.1,17 A reduction in OCT-measured peripapillary retinal
nerve fiber layer thickness in patients with IIH may arise from improved pressure
control or, alternatively, evolving optic nerve atrophy.1,17 In this clinical setting,
combining the macular ganglion cell–inner plexiform layer thickness with the
peripapillary retinal nerve fiber layer thickness may distinguish improving
papilledema from evolving optic atrophy.1,17 Successful treatment of IIH, with
reduced optic disc swelling and protection of neuroaxonal structure, results in
reduced peripapillary retinal nerve fiber layer thickness with preserved macular
ganglion cell–inner plexiform layer thickness.1,17 In contrast, decreased retinal nerve
fiber layer values occurring with and corresponding to loss of macular ganglion
cell–inner plexiform layer thickness could be an indication of treatment failure in
IIH.1 Patients with raised intracranial pressure may also manifest a deflection of the
Bruch membrane toward the vitreous, which can be demonstrated by OCT as a
means of differentiating papilledema from pseudopapilledema (FIGURE 12-9).1,17
Furthermore, Sibony and colleagues37 have shown that OCT is more sensitive than
FIGURE 12-8
Radiologic manifestations of idiopathic intracranial hypertension (IIH). A, Axial T2-weighted
orbital MRI showing expanded perineural optic nerve sheaths (arrow) and anterior bowing
of the posterior sclera (asterisk) in both eyes. B, Axial T1-weighted postcontrast orbital MRI
showing anterior bowing of the posterior sclera and enhancement of the optic discs (arrow),
right greater than left. C, Magnetic resonance venogram (MRV) showing severe stenosis
(arrows) at the junction of the transverse and sigmoid sinuses bilaterally. D, Axial T2-weighted
MRI shows expansion of Meckel caves bilaterally (arrows). E, Sagittal T1-weighted MRI shows
an empty sella (arrow). F, Sagittal T1-weighted MRI shows inferior tonsillar herniation through
the foramen magnum. A second patient (G, H) presented with headache and clear rhinorrhea
months after a significant amount of weight gain. G, Coronal noncontrast CT shows a large
right ethmoidal encephalocele (asterisk). Bilateral venous sinus stenosis was also found (not
shown) and supported IIH as the underlying cause of the encephalocele. H, Sagittal
postcontrast CT of the same patient again showed the encephalocele (asterisk) and an
empty sella (arrow), lending further support to IIH.
1452 OCTOBER 2019

fundus photography alone in detecting choroidal wrinkles and folds in patients with KEY POINT
IIH (FIGURE 12-9).
● Tortuosity of the optic
TOXIC-METABOLIC AND NUTRITIONAL OPTIC NERVE INJURIES . Toxic optic nerve nerve sheaths, flattening of
the posterior globes, an
injuries may be caused by a variety of substances that impair papillomacular empty sella turcica, and
function, causing painless, progressive central vision loss.7,38 Nutritional transverse venous sinus
deficiencies (eg, vitamin B12), toxic injuries, and metabolic causes of stenosis are radiologic signs
dysregulation (eg, Leber hereditary optic neuropathy, dominant optic atrophy) of raised intracranial
pressure in patients with
can manifest in similar fashion.38 Consideration for these conditions is often idiopathic intracranial
prompted by the patient’s history, which may indicate potential sources of hypertension.
medication ingestion (eg, ethambutol, linezolid, amiodarone, cyclosporine,
isoniazid, dapsone, tacrolimus, paclitaxel, disulfiram), toxic exposure (eg,
glycol, carbon monoxide [FIGURE 12-10], levamisole [FIGURE 12-11], methanol
[FIGURE 12-12]), or a genetic predisposition ( eg, Leber hereditary optic
FIGURE 12-9
A 32-year-old woman with idiopathic intracranial hypertension. A, Fundus photo showing
Frisén grade II to III papilledema with inferotemporal peripapillary wrinkles (Paton folds)
(arrow). B, Optical coherence tomography demonstrating the wrinkles (arrow). C, Transverse
axial optical coherence tomography image (stretched 3×) showing wrinkles on the temporal
side of the optic nerve head (white arrow). Note the anterior displacement of the
peripapillary retinal pigment epithelium-Bruch membrane layer (nasal more than temporal)
typically seen in many idiopathic intracranial hypotension patients (black arrows).
Figure courtesy of Patrick Sibony, MD.

neuropathy, dominant optic

atrophy) that may account for the
patient’s clinical presentation.38
Neuroimaging is performed with
a view to excluding alternate
causes of vision loss, particularly
mass lesions compressing afferent
visual pathway structures. In some
cases, however, characteristic
imaging features may provide
FIGURE 12-10
Carbon monoxide poisoning in a 37-year-old man. clues to the underlying diagnosis.
A, Axial brain CT shows hypodense lesions Carbon monoxide poisoning, for
involving the globus pallidus nuclei. B, Axial example, is suggested by
fluid-attenuated inversion recovery (FLAIR) MRI hypodense signal changes in the
shows symmetric hyperintense lesions (arrow).
Notably, cocaine toxicity and chronic 3,4-
globus pallidus on CT
methylenedioxy-methamphetamine (MDMA) use (FIGURE 12-10). On MRI scans,
can present with similar imaging features. these areas show increased signal
on T2-weighted, FLAIR, and DWI
sequences (FIGURE 12-10).
Furthermore, gadolinium-enhanced T1-weighted images may demonstrate patchy
enhancement of the necrotic globus pallidus in cases of acute carbon monoxide
poisoning.39 MRI may reveal loss of CSF space surrounding both optic nerves
without contrast enhancement or restricted diffusion in some toxic optic nerve
injuries.40 Evidence of T2-weighted hyperintense signal changes may also be
seen within the optic chiasm without evidence of restricted diffusion.40 Leber
hereditary optic neuropathy can be associated with T2-weighted MRI
hyperintensities in the posterior portion of both optic nerves and in the optic
chiasm (without gadolinium enhancement), with occasional enlargement of the
optic chiasm.41 Patients with Leber hereditary optic neuropathy may also manifest
FIGURE 12-11
Levamisole-contaminated cocaine toxicity. A 48-year-old man presented with a left facial
droop and right Horner syndrome. A, Axial head CT showed ill-defined hypodense lesions
involving the cerebral white matter of both hemispheres. B, Axial fluid-attenuated inversion
recovery (FLAIR) MRI showed numerous asymmetric hyperintense lesions involving the
periventricular, subcortical, and juxtacortical white matter. C, Axial postcontrast T1-weighted
MRI showed patchy, incomplete, marginal enhancement of the largest of the lesions. The
patient reported binge cocaine use during the 3 weeks before presentation. Toxicology was
positive for cocaine and levamisole. The latter can cause a multifocal inflammatory
leukoencephalopathy, with imaging features similar to multiple sclerosis.
1454 OCTOBER 2019

CNS evidence of T2-weighted
hyperintense subcortical/
periventricular signal changes
that resemble MS, particularly in
female mutation carriers.42
OCT-detected ganglion
cell–inner plexiform layer
thinning is typical in the setting
of toxic nerve injuries, with
variable degrees of retinal nerve
fiber layer thickening, depending FIGURE 12-12
on the extent of concomitant Acute methanol toxicity. A 33-year-old man
presented with a decreased level of consciousness
axoplasmic flow stasis. In cases and seizures. Head CT at hospital admission was
of Leber hereditary optic normal (not shown). A, Axial fluid-attenuated
neuropathy, ganglion cell–inner inversion recovery (FLAIR) brain MRI 7 days after
presentation showed symmetric cystlike lesions in
plexiform layer loss manifests the putamen bilaterally. B, Axial postcontrast
with retinal nerve fiber layer T1-weighted MRI showed lesional enhancement
thickening in the acute phase of consistent with early putaminal necrosis. A history
of intentional methanol ingestion was confirmed at
optic nerve injury. Over time, the time of admission to hospital.
retinal nerve fiber layer swelling
tends to abate and thinning
ensues thereafter, so that retinal nerve fiber layer and ganglion cell–inner
plexiform layer values are both reduced in the chronic phase.43 It is noteworthy
that loss of ganglion cell–inner plexiform layer thickness may precede vision loss
in some patients with Leber hereditary optic neuropathy.43 Therefore, the OCT
finding of ganglion cell–inner plexiform layer thinning simultaneous with retinal
nerve fiber layer thickening in an asymptomatic eye may aid in the diagnosis of
this condition and offer a window of opportunity for early intervention.43
TRAUMATIC OPTIC NEUROPATHIES. The optic nerve is fixed in its intracanalicular

segment, where it exits the orbit through the optic foramen (the anterior opening
of the optic canal in the orbital apex).3 In this location, it is particularly vulnerable
to indirect injury from the effects of percussive forces transmitted from frontal
skull trauma.3 CT imaging is especially useful in assessing cases of traumatic optic
neuropathy by capturing evidence of optic canal fracture, edema (or blood) within
the optic canal (or optic nerve sheath), intraconal hematoma, or foreign
body/fracture fragments causing impingement on the optic nerve itself.12 In
suspected cases of traumatic optic nerve injury, DTI may demonstrate reduced
diffusivity within the affected optic nerve.12 OCT has shown that retinal nerve
fiber layer loss and ganglion cell–inner plexiform layer thinning manifest as early
as 2 weeks after a traumatic optic nerve injury; over time (by 20 weeks), these
OCT measures of neuroaxonal injury plateau and remain stable thereafter.44
RADIATION OPTIC NEUROPATHY. Radiation-induced optic neuropathy is a late

complication of radiation therapy that causes acute, profound, irreversible visual
loss.45 This syndrome is generally a consequence of radiation necrosis, most
likely caused by cumulative doses of radiation that exceed 50 Gy or single doses
to the anterior visual pathway greater than 10 Gy.45 When manifesting as a
retrobulbar process, the optic disc appears normal in the acute phase.45
Alternatively, if the ischemic damage affects the optic nerve head, disc edema

will be evident.45 In cases of radiation-induced optic neuropathy, CT imaging

is typically normal, as are unenhanced T1-weighted and T2-weighted MRI
sequences. Gadolinium-enhanced T1-weighted MRI sequences may reveal
marked enhancement of the optic nerve(s) and chiasm, which resolves over
months.45 OCT angiography has been used to establish a putative grading system
for radiation optic neuropathy that ranges from no detectable radial peripapillary
capillary plexus abnormality to the presence of complete radial peripapillary
capillary plexus dropout.46 Notably, more severe grades of peripapillary capillary
injury correlate with worse visual acuity in affected eyes.46
ARTERITIC ISCHEMIC OPTIC NEUROPATHY. For more information on the diagnosis

and management of arteritic ischemic optic neuropathy and GCA, refer to the
article “Ischemic Optic Neuropathy” by Mark J. Morrow, MD, FAAN,47 in this
issue of Continuum. From an imaging perspective, ultrasonography has gained
increasing interest for the diagnostic evaluation of patients with GCA, since
vessel wall edema generates a hypoechoic signal around the vessel lumen,
referred to as the halo sign.19 This finding may prove useful in rendering the
diagnosis, particularly in temporal artery biopsy–negative cases, since the halo
sign can be detected in extracranial (subclavian and axillary) arteries.19 Previous
studies have shown a sensitivity of 69% and specificity of 82% for the so-called
halo sign compared to biopsy.48 MRI may also play a role in the diagnosis of GCA.
High-resolution imaging of the temporal artery reveals increased vessel wall
thickness and edema and increased mural enhancement on postcontrast
T1-weighted images (FIGURE 12-13).48 Moreover, MRA may demonstrate
corresponding luminal stenosis.48 Bley and colleagues49 reported that MRI of the
temporal artery had a sensitivity of 81% and a specificity of 97% for GCA
diagnosis. Furthermore, in patients treated for this condition, MRI patterns of
enhancement have been shown to decrease in a manner that correlates with
clinical and serologic remission.50,51 Finally, as an alternative imaging modality,
fludeoxyglucose (FDG)–PET can be used to detect large vessel vasculitis,
including GCA.51 Blockmans and colleagues52 studied 35 patients with biopsy-
proven GCA and observed FDG uptake in at least one vascular territory among
83% of cases. In this study, subclavian involvement was most common (74%),
followed by uptake in the aortic (50%) and iliac/femoral (37%) vascular
regions.51,52 With treatment, by 3 months, the intensity of FDG uptake
subsequently decreased.51,52 CT combined with FDG-PET addresses some of the
limitations of PET scanning alone, including failure to localize the uptake
anatomically and accurately; furthermore, CT PET may also help differentiate
calcified atherosclerotic plaques from vasculitic changes in patients with GCA.51
Lesions of the Orbit

Orbital lesions may present with vision loss, pain, proptosis (or, alternatively,
enophthalmos), and ophthalmoplegia. It is important to remember that diplopia
may arise from a restrictive mechanism (due to mass effect, trauma, vascular
congestion, or inflammation) in the orbit or ocular motor nerve dysfunction,
particularly if the lesional pathology involves the orbital apex or the cavernous
sinuses. One clinical clue to the location of an orbital process is that the ocular
appearance is often abnormal on inspection, albeit the signs may be subtle. The
orbits can become involved in pathologic processes due to contiguous spread of
inflammation or infection from sinuses (FIGURE 12-14), metastases, or vascular
1456 OCTOBER 2019

FIGURE 12-13
An 87-year-old woman presented with headache and indurated temporal arteries. Her
erythrocyte sedimentation rate was 73 mm/h, and C-reactive protein was 19.5 mg/L; platelets
were elevated at 545,000/mm3. MRI was performed as part of her workup. A, Axial
postcontrast T1-weighted MRI showed enhancement of the vessel walls around both temporal
arteries (arrows). B, Close-up of right temporal artery showing enhancement of vessel walls
(arrows). C, Coronal postcontrast T1-weighted MRI of the orbits showed enhancement within
the right orbit, including within optic nerve sheath (arrow). D, Axial postcontrast T1-weighted
MRI of the orbits showed perineural enhancement. E, F, Diffusion-weighted imaging (DWI)
revealed small occult bilateral infarctions (arrows). G, Fluorescein angiogram revealed patchy
choroidal filling in the left eye (between dotted lines). Temporal artery biopsy revealed
temporal arteritis. Imaging may be completely negative in temporal arteritis. However, fine
cuts through the temporal arteries may reveal vessel wall enhancement. Rarely, orbital
inflammation may be observed and DWI may reveal infarcts. Fluorescein angiogram can help
in the diagnosis as it may reveal patchy or delayed choroidal filling.
FIGURE 12-14
Onodi (sphenoethmoidal) cell opacification and vision loss. A 65-year-old man presented
with a 4-day history of progressive vision loss in the right eye. He was being treated for
sinusitis. CT of the orbits demonstrated a variant midline sphenoethmoidal air cell (Onodi cell)
that extended posteriorly to lie superior to the sphenoid sinus. This opacified soft tissue may
have represented recently active inflammatory sinus disease. Dehiscent bone separating
the air cell from right and left optic canals was shown in coronal (A) and axial (B) bone
window images (arrows). Axial CT soft tissue window imaging (C) showed the proximity
of the dehiscent bone to the left internal carotid artery.

congestion (FIGURE 12-15) or as a primary site of inflammation/infiltration

(FIGURE 12-16).3,12 A list of orbital lesions and associated imaging findings is
located in TABLE 12-3.3,53–57
CT can complement MRI in the evaluation of orbital pathology and is the
imaging study of choice in cases of orbital trauma or foreign body detection,
particularly when the object of interest may be ferromagnetic.3–5,12 When
vascular lesions of the orbit are suspected, including carotid-cavernous sinus
fistulas (FIGURE 12-15) and vascular tumors/malformation, ultrasound can be
invaluable. MRI can help define the extent of soft tissue (extraocular muscles
[FIGURE 12-17] and lacrimal glands) and cavernous sinus involvement. As
stated, with this imaging technique, fat-suppression techniques are essential
to optimize contrast between normal anatomic structures and lesional
pathology. Otherwise, hyperintense fat signals can obscure the view of
gadolinium-enhancing lesions. Moreover, fat-suppression techniques can also
confirm the content of fat-containing masses, such as orbital dermoid cysts
and lipomas.3,5 It bears mentioning that incomplete fat suppression can be
caused by metallic artifacts (eg, orthodontic braces or metallic eyelash mascara)
and at the air-bone interface of adjacent paranasal sinuses (eg, high-signal area at
the inferior rectus muscle adjacent to very-low-signal air in the maxillary sinus).5
Consequently, hyperintense artifacts may sometimes be misinterpreted as
abnormal, and careful clinical correlation is therefore required.
Orbital imaging can also reveal clues to congenital, acquired, and mechanical
causes of diplopia. For example, careful examination of extraocular muscles on
coronal MRI or CT may reveal superior oblique muscle atrophy, confirming a
long-term trochlear nerve palsy in cases in which the cause of vertical strabismus
is unclear. Patients with chronic progressive external ophthalmoplegia may
demonstrate more global atrophy of the extraocular muscles on axial and coronal
FIGURE 12-15
Direct carotid-cavernous sinus fistula. A 19-year-old man was involved in a traumatic boating
accident. A, Axial CT showed highly attenuating acute subarachnoid hemorrhage in the
right sylvian fissure and small-volume intraventricular hemorrhage within the left occipital
ventricular horn. B, Axial head CT with bone windows demonstrated severe craniofacial
injuries with basisphenoid, bilateral temporal bones, and right zygomatic fractures. C, Axial
CT angiography source images demonstrated an abnormal right cavernous internal carotid
artery segment surrounded by soft tissue clot distending the cavernous sinus (arrow).
D, Digital subtraction catheter angiography with right internal carotid artery injection in lateral
projection depicted the direct carotid-cavernous sinus fistula with abnormal retrograde
arterial phase filling of the superior ophthalmic vein (arrow) and severe segmental narrowing
of the distal internal carotid artery from nonocclusive vessel dissection and vasospasm.
1458 OCTOBER 2019

FIGURE 12-16
Cholesterol granuloma of the orbit. A 35-year-old man presented with slowly progressive
proptosis of the right eye. Coronal CT showed a large extraconal cystic mass in the superior-
temporal quadrant of the right orbit (A), with irregular bony erosion of the orbital roof (B).
The expansile mass caused inferior displacement of the globe. C, Axial T2-weighted MRI
showed high signal with a peripheral dark hemosiderin rim. D, Coronal T1-weighted MRI showed
the lesion to be hyperintense precontrast. E, Coronal postcontrast fat-suppressed T1-weighted
images showed only peripheral enhancement. F, Histology revealed multinucleated giant cells
associated with cholesterol clefts. More common sites for cholesterol granulomas include the
petrous apex, middle ear, and mastoid antrum.
MRI.58 Individuals affected by sagging eye syndrome often present with

blepharoptosis and superior sulcus defects.59 Chaudhuri and Demer59 have
shown that divergence insufficiency in these cases is due to bilaterally symmetric
downward displacement (termed sag) of the lateral rectus pulleys and elongated
resting lengths of the extraocular muscles. In some cases of sagging eye
syndrome, the bilaterally asymmetric lateral rectus pulley causes hypotropia and
excyclotropia (an ocular deviation causing torsion of the eye such that the upper
pole of the cornea is deviated temporally) of the more affected eye, resulting in
symptomatic cyclovertical diplopia.59 MRI can be used to demonstrate bilateral
rupture of the lateral rectus–superior rectus band ligament that supports the
lateral rectus muscle, along with lengthening and alteration in the paths of the
rectus extraocular muscles.59 These imaging characteristics may be helpful in
identifying the mechanism of diplopia as being non-neurologic in origin and
instead due to the gradual effects of aging on orbital connective tissues.59 In the
heavy eye syndrome associated with axial high myopia, esotropia, and
hypotropia,59 inferior displacement of the lateral rectus muscle causes impaired
abduction and supraduction, resulting in diplopia.60 In these cases, orbital MRI
shows degeneration of the lateral rectus-superior rectus band, so that the lateral
rectus muscle slips inferiorly to produce esotropia and hypotropia.60

TABLE 12-3 Imaging Features of Orbital Lesions
Orbital Lesion Imaging Characteristics
Benign masses and infiltrative lesions
Dermoid cyst3 Ultrasound of superficial lesions shows medium to high internal reflectivity,
and deep lesions show low internal reflectivity
CT shows a well-defined lesion with rim enhancement and calcification, which

may be associated with a bony defect
Most dermoid tumors have MRI signal intensity characteristics similar to fat
and are hyperintense on T1-weighted images and hypointense on T2-weighted
images; fat-suppressed MRI sequences may confirm the presence of fat
Neurofibroma Lesions are commonly extraconal in the superior orbit, similar to schwannomas,
causing downward globe displacement; in the absence of a capsule, however,
solitary neurofibromas are less well defined than schwannomas53
CT and plain radiography may detect a classic defect in the greater wing of the
sphenoid called the Harlequin eye appearance54
Both CT and MRI can show the characteristic orbital and periorbital infiltrative
soft tissue masses and sphenoid wing dysplasia
MRI reveals T2-weighted hyperintense and heterointense T1-weighted signal

changes
Neurofibromas cross tissue planes and involve large portions of the face53
Schwannoma55 Lesions appear as smooth, ovoid, orbital retrobulbar masses, found in the
intraconal or extraconal space, with the long axis in the anterior-posterior direction.
CT shows isodensity or hypodensity compared to gray matter
MRI shows isointense T1-weighted signal and hyperintense T2-weighted signal;

most lesions enhance with contrast administration
The MRI and CT appearance of schwannomas overlap with optic nerve sheath
meningiomas; extension into the superior orbital fissure is more common in
schwannomas, while extension into the optic canal favors meningioma
Fibrous dysplasia53 CT shows expanded bone with lytic, sclerotic, and cystic regions; a “ground-
glass” pattern is characteristic
MRI depicts fibrous areas as T1-weighted isointense regions and T2-weighted

hyperintense regions, while areas of mineralized matrix are T1-weighted
hypointense and T2-weighted hypointense
The fibrous component is highly vascularized, and intense enhancement is

present on contrast-enhanced CT and MRI
Lacrimal gland pleomorphic adenoma3 Ultrasound shows well-defined surface spikes with medium to high reflectivity
CT shows a well-circumscribed lesion with remodeling of bone, which may

appear cystic and show calcification
MRI shows relatively homogeneous lesions with low signal intensities on T1-
weighted images and high signal intensities on T2-weighted images; large
tumors with hemorrhage or necrosis exhibit heterogeneous signal intensities
on T1-weighted and T2-weighted images
Optic nerve sheath meningioma See Optic Neuropathies section in text
1460 OCTOBER 2019

Malignant lesions
Orbital lymphoid tumors3,54,55 Ultrasound shows low internal reflectivity
CT typically shows a hyperdense mass involving the lacrimal gland, with

significant contrast enhancement and molding to surrounding tissues; bony
erosion or infiltration is not seen, except with high-grade lesions
MRI shows a well-defined intraconal mass that is hypointense on T1-weighted

images and hyperintense on T2-weighted images; perineural spread also
suggests an aggressive histology
Diffusion-weighted MRI can distinguish lymphoma from inflammatory disease;

the densely packed cells in lymphoma inhibit the nonrandom motion of water,
causing lymphoma to appear bright on diffusion-weighted images, with
associated reduction in apparent diffusion coefficient
Malignant tumors of epithelial origin CT shows a poorly circumscribed mass involving the lacrimal gland with
(adenoid cystic carcinoma, associated bony destruction
mucoepidermoid carcinoma,
adenocarcinoma, squamous cell Lesions may appear hypointense or isointense on T1-weighted MRI sequences
carcinoma, and undifferentiated and hypointense or hyperintense on T2-weighted images and demonstrate
carcinoma types, such as the prominent gadolinium enhancement; fat-saturated gadolinium-enhanced MRI
mammary analog secretory is ideal for local tumor staging and for evaluating perineural spread
carcinoma of salivary origin)54
Fibrous histiocytoma3 CT and MRI show a well-circumscribed lesion in benign cases, whereas
malignant lesions show local infiltration
Rhabdomyosarcoma3 Lesion typically arises in the extraconal compartment, but intraconal extension
can occur
CT shows the lesion isodense to muscle, with no significant enhancement, and

bony destruction
MRI shows an irregular mass that enhances with gadolinium and is isointense
with muscle on T1-weighted images and hyperintense on T2-weighted images
Metastatic lesions3,53,54,a Metastases commonly involve the orbital bones and extraconal compartment;
they may also involve the choroid
CT and MRI may show an enhancing infiltrative lesion and associated bony
destruction; choroidal metastases from melanoma may appear hyperdense on
plain CT and hyperintense on T1-weighted MRI sequences and show
enhancement; gadolinium-enhanced MRI also helps to detect associated
intracranial metastases; orbital metastases can mimic lymphomas on
conventional CT and MRI
An orbital metastatic deposit may be incidentally diagnosed for the first time
on a positron emission tomography (PET) CT; PET CT can also help to detect
the primary tumor site and metastatic deposits to other organs


55,b
Primary orbital melanoma MRI is superior to CT in the evaluation of melanomas as melanin has intrinsic
T1-weighted and T2-weighted shortening effects, thereby manifesting with
increased T1-weighted signal intensity and decreased T2-weighted signal; the
degree of melanomatous pigmentation correlates with quantitative T1-
weighted signal, with strong pigmentation conferring a less favorable
prognosis
MRI characterizes tumor size, extraocular extension, and ciliary body

involvement (which also portend a poorer prognosis) and is superior to CT for
identifying retinal detachment and extrascleral spread of choroidal lesions
Hemangiopericytoma53 Lesions are typically extraconal lobulated, well-circumscribed masses

adjacent to the paranasal sinuses; aggressive lesions show possible bone
erosion; calcification is rare
Unlike cavernous malformations, hemangiopericytomas demonstrate marked

arterial enhancement and early venous phase enhancement with rapid
washout on multiphase CT
The lesions tend to be isointense compared to gray matter on T1-weighted and

T2-weighted MRI sequences, another feature that helps in differentiating
them from cavernous malformations
Malignant tumors of the eyelid Tumors are often highly aggressive and show contiguous invasion of orbital
(squamous cell carcinoma, basal cell structures; perineural spread along the branches of the trigeminal nerve is also
carcinoma, melanoma, sebaceous common
cell carcinoma, and lymphoma)54
Cross-sectional imaging helps in the local staging of the disease
PET CT detects local nodal and distant metastases from eyelid carcinomas
Optic nerve glioma See Optic Neuropathies section in text
Inflammatory lesions
Systemic vasculitic conditions Granulomatosis with polyangiitis: MRI may show an enhancing optic nerve
(granulomatosis with polyangiitis, lesion, and both MRI and CT may demonstrate infiltration and inflammation of
polyarteritis nodosa, giant cell the orbits, frequently involving the mastoid regions; orbital masses with
arteritis, IgG4 disease) and drug- infiltration and obliteration of the orbital fat planes are seen, and midline
induced inflammation involvement can include bone erosion; MRI shows a marked decrease in the
(bisphosphonates)3 T2-weighted signal, which is a characteristic feature of granulomatosis with
polyangiitis; the unenhanced, non–fat-suppressed T1-weighted sequence is
the preferred method for lesion detection and for definition of the pattern of
anatomic involvement; adjacent paranasal sinuses and nasal cavity may show
extensive mucosal inflammation with destruction of the nasal septum and
sinus walls
Polyarteritis nodosa: CT can reveal orbital, sinus, parasellar, and intracranial

involvement; brain and orbital MRI with axial and coronal views may show an
enhancing lesion within the optic nerve
Enhancement of the orbit and intracranial vasculitis may also be seen with MRI
in giant cell arteritis
1462 OCTOBER 2019

IgG4 disease: the characteristic lymphocytic infiltration is seen as inflammation

of the lacrimal glands and extraocular muscles; the most frequently affected
muscle is the inferior rectus; postcontrast T1-weighted axial and coronal MRI
with fat suppression reveals hypertrophy of the extraocular muscles with
involvement of the myotendinous junctions; enhancement of the optic nerve
and retroorbital fat may be seen; enlargement of the infraorbital nerve
suggests the possibility of IgG4-related orbital disease but is generally an
asymptomatic radiographic finding; IgG4 lesions enhance homogeneously on
postcontrast imaging and are typically isointense or hypointense on T2-
weighted MRI sequences, which serves to distinguish IgG4-related disease
from other diseases that infiltrate the orbit; destruction of adjacent bone is not
a classic feature of IgG4-related orbital disease but has been described in
some cases of IgG4-related sinus disease29,56
Graves orbitopathy3 CT and MRI reveal enlarged extraocular muscles, with sparing of the tendinous
insertions; the inferior and medial recti are often involved
Isolated lateral rectus muscle enlargement without other evidence of muscle

enlargement is uncommon and suggests another disease process, such as
orbital myositis
Apical crowding of the optic nerve is well visualized on MRI, which is more
sensitive for showing optic nerve compression
CT may be used to delineate the bony architecture of the orbit before

decompression
CT and MRI may show straightening of the optic nerve, increased orbital fat,
lacrimal gland enlargement, and eyelid edema
Granulomatous inflammation Sarcoidosis: CT and MRI may show enlargement of the lacrimal gland,
(sarcoidosis, Erdheim-Chester occasionally beyond the orbital rim; orbital involvement is seen as diffuse
disease, adult orbital enhancement within the orbital fat, optic nerve, and extraocular muscles
xanthogranuloma, necrobiotic
xanthogranuloma, Sjögren Erdheim-Chester disease: CT and MRI views of the orbits, parasellar
syndrome)3 structures, and pituitary can be used to define the extent of involvement
Necrobiotic xanthogranuloma: CT and MRI can show opacification and

enlargement of the eyelids and anterior orbital structures
Sjögren syndrome: CT and fat-suppressed MRIs of the orbit can show

nonspecific enlargement of the lacrimal glands; however, significant
enlargement or bony erosion should prompt consideration of other diagnoses
Orbital myositis3 CT and MRI show diffuse enlargement of affected extraocular muscles
including the tendinous insertion, which differentiates myositis from thyroid
orbitopathy
Orbital tissue adjacent to the muscle may be locally infiltrated, showing a

ragged enhancement on contrast CT adjacent to the muscle substance
MRI features include focal enlarged muscular lesions showing increased T2-
weighted signal and decreased T1-weighted signal with contrast enhancement
Optic perineuritis See Optic Neuropathies section in text

Nonspecific inflammatory CT shows oblong enlargement of the lacrimal gland, which molds to the
dacryoadenitis3,57 curvature of the globe as it extends posteriorly; primary epithelial tumors of
the lacrimal gland show a more rounded appearance; if erosion of the bony
orbit is seen, a neoplasm should be suspected
Ultrasound can be used to differentiate lacrimal gland lesions; the lacrimal

gland shows enlargement with internal reflectivity; echolucency is apparent
anteriorly near the sclera if lateral rectus involvement occurs
MRI may show isointense signal changes on T1-weighted images, a hypointense

signal on T2-weighted images, and moderate contrast enhancement;
additional features that suggest an inflammatory process are a compressed,
almond-shaped appearance of the gland as well as a tapered posterior margin
of the gland; in contrast, epithelial neoplasms appear well circumscribed and
rounder to more oval in shape
Idiopathic orbital inflammatory Gadolinium-enhanced MRI demonstrates nonspecific, ill-defined inflammatory

syndrome (orbital pseudotumor)3,57 stranding and enhancement that may affect a number of sites, including
extraocular muscles, lacrimal glands, retrobulbar fat, ocular walls, orbital apex, or
optic nerve sheath (eg, optic perineuritis) or a combination of these structures
Differential diagnostic considerations of orbital inflammation include orbital

cellulitis, granulomatosis with polyangiitis, sarcoidosis, and lymphoma;
apparent diffusion coefficient values may be helpful in differentiating
idiopathic orbital inflammatory syndrome from lymphoma and orbital cellulitis
Idiopathic sclerosing inflammation With CT or MRI, lesion appears as a homogeneous, diffuse, ill-defined mass
of the orbit3,57 most frequently in the anterior orbit and midorbit
CT allows visualization of bone and paranasal sinuses
Fat-suppressed orbit and brain MRI views can show involvement of the cavernous
sinuses and soft tissues within the orbits; orbital studies show homogeneously
enhanced areas of opacification with ragged margins; opacification of the
extraocular muscles and the lacrimal gland may also be present
In severe cases, there may be wall-to-wall opacification of all the orbital

structures except the globe
MRI shows low signal intensities on T1-weighted and T2-weighted images
Infections
Orbital cellulitis3,12,57 CT or MRI can be used to differentiate preseptal cellulitis from orbital cellulitis;
CT in axial and coronal planes determines whether the sinuses are involved and
whether bone and intracranial extension exists
Orbital cellulitis will demonstrate inflammatory stranding and enhancement

posterior to the orbital septum; a subperiosteal abscess appears as a rim-
enhancing fluid collection along the orbital wall with adjacent paranasal sinus
infection (most commonly seen along the medial orbital wall with associated
acute ethmoid sinusitis)
On MRI, subperiosteal or intraorbital abscesses will demonstrate rim

enhancement with internal T2-weighted hyperintensity and restricted
diffusion; orbital cellulitis appears hypointense on T1-weighted images and
hyperintense on T2-weighted images;
1464 OCTOBER 2019

Mass may displace orbital structures and may be associated with enhancing
orbital fat; increased radiodensity with intervening lucencies may indicate
gas-forming organisms; opacification of the paranasal sinuses may be seen
Fungal infections (Zygomycetes, On contrast-enhanced CT, intraorbital involvement is seen as variably

Ascomycetes, histoplasmosis, enhancing soft tissue within the orbit and adjacent opacification of the
blastomycosis, sporotrichosis)3,12 paranasal sinus with or without osseous destruction
MRI shows T2-weighted hyperintensity and postcontrast enhancement of the

involved intraorbital soft tissues
CT and fat-suppressed MRI views show opacification of the sinuses with

adjacent orbital mass, with or without bone erosion; orbital soft tissues,
including the optic nerve, may be enlarged; a pattern of enhancement may not
be seen with fungal infections because fungal invasion of vessels erodes the
vascular pathways required for contrast enhancement to be visualized
MRI findings in orbital fungal infections include hypointense to isointense

signals on T1-weighted images, hypointense changes on T2-weighted images,
and enhancement on postcontrast T1-weighted images
Parasitic infections (Echinococcus, CT and MRI (fat-suppressed, gadolinium-enhanced axial and coronal images)
Cysticercus, Trichinella, show intraorbital cysts with centers of water density; tissue enhancement
Onchocerca, Ascaris, Schistosoma, consistent with inflammation may be seen; calcification can be seen with
Entamoeba)3 trichinosis, and cysts may be seen in the extraocular muscles with trichinosis
and cysticercosis
Ultrasound can also be used to identify intraorbital cysts;
Orbital neurocysticercosis lesions appear hypointense on T2-weighted MRI

sequences
Vascular lesions
Carotid-cavernous sinus fistula3,12 Ultrasound, CT, and MRI show a dilated superior ophthalmic vein and
enlargement of the extraocular muscles
Ultrasound can show arterialized blood flow through the superior

ophthalmic vein
CT angiography is more sensitive than magnetic resonance angiography (MRA)

in the detection of carotid cavernous fistulas
Digital subtraction angiography is required for definitive diagnosis and possible

endovascular treatment. Digital subtraction angiography will demonstrate
retrograde flow within the superior ophthalmic vein and corresponding
cavernous sinus in the arterial phase of injection and allow for identification of
the site of fistula, whether directly from the internal carotid artery or internal
carotid artery/external carotid artery feeding vessels in the case of indirect
fistula; direct carotid-cavernous fistulas may be treated endovascularly with
transarterial detachable balloon occlusion, transvenous coil embolization,
covered stent across the fistula, or carotid sacrifice


3,12,54,55
Cavernous hemangioma Ultrasound shows high internal reflectivity with prominent anterior and
posterior spikes
MRI may show lesions that are isointense to hypointense on T1-weighted

images and hyperintense on T2-weighted images
Orbital varices12,c Contrast-enhanced CT performed with and without provocative maneuvers

(eg, Valsalva maneuver or internal jugular vein compression) will demonstrate
increased size of the enhancing intraorbital mass during the increase in
venous pressure
CT may also demonstrate internal phleboliths within the varix, retrobulbar

hemorrhage (if present), or hyperattenuating clot without enhancement in the
setting of thrombosis
MRI will show variable T1-weighted and T2-weighted signal intensity within the
varix, diffuse enhancement, and enlargement of the varix with provocative
maneuvers
Orbital venous lymphatic These benign congenital low-flow vascular malformations typically
malformations (also known as demonstrate an infiltrative transspatial growth pattern in which they violate
orbital lymphangiomas)12,55 natural tissue planes that restrict other pathologies; therefore, they may
involve both intraconal and extraconal compartments or preseptal and
postseptal compartments
MRI demonstrates multiloculated, transspatial T2-weighted hyperintensities

with thin walls; in the setting of internal hemorrhage, multiple fluid levels with
variable T1/T2-weighted signal corresponding to hemorrhage products of
varying ages are present
The venous components of these lesions will demonstrate enhancement; the

thin walls and septations of the lymphatic components show thickening and
enhancement in the setting of upper respiratory tract infection
CT = computed tomography; MRI = magnetic resonance imaging.

a
Metastatic lesions represent the most common orbital malignancy in adults and include breast, lung, and prostate cancer; leukemia; lymphoma;
and melanoma. In children, neuroblastomas can metastasize.
b
Primary orbital melanoma is the most common primary intraocular malignancy in adults. The majority of lesions (90%) derive from the choroid.
c
Orbital venous varices are congenital low-flow venous malformations with connection to the systemic venous system that dilate in the setting of
increased venous pressure (eg, Valsalva maneuver) and are the most common cause of spontaneous retrobulbar hemorrhage.
1466 OCTOBER 2019

Lesions of the Cavernous Sinuses
The oculomotor, trochlear, abducens,
trigeminal (V1 and V2 branches), and
sympathetic nerves all course through the
cavernous sinuses. Therefore, multiple
cranial neuropathies involving the ocular
motor nerves with or without Horner
syndrome implicate a lesion in this region,
which may be inflammatory, vascular, or
neoplastic in origin. Cavernous sinus
lesions include meningiomas, invasive
pituitary adenomas, metastases,
tuberculomas, aneurysms (FIGURE 12-18),
thrombosis (FIGURE 12-19),
schwannomas, sarcoidosis, chordomas,
nasopharyngeal carcinomas, cavernous
sinusitis (Tolosa-Hunt syndrome)
(FIGURE 12-20), and dural arteriovenous
fistulas (FIGURE 12-21).3 Cavernous sinus
lesions are best detected with
gadolinium-enhanced MRI, but the
practitioner should specifically request
thin cuts through the region to get the
highest resolution and detection rate;
MRA techniques can help characterize
the relationship between cavernous sinus
structures and the intracavernous
segment of the internal carotid artery.
FIGURE 12-17
Notably, CT can be used to delineate
Thyroid orbitopathy. A 67-year-old
woman with known Graves disease the relationship between cavernous sinus
presented with progressive left structures and bony landmarks
monocular vision loss. A, Axial CT of the (including the sella and clivus).3 This
orbits showed bilateral fusiform
imaging modality is useful in detecting
enlargement of the extraocular
muscles with sparing of the tendon aneurysms that invade bone.3 Catheter
sheaths. B, Coronal CT showed angiography helps to better characterize
bilateral enlargement of the inferior, vascular lesions and offers the option of
medial, and superior recti with relative treatment of cavernous sinus fistulas and
sparing of the lateral recti. The muscle
enlargement resulted in soft tissue other vascular lesions.
crowding at the orbital apex and optic
nerve compression. Lesions of the Optic Chiasm
The optic chiasm lies in proximity to the
pituitary gland (inferiorly), infundibulum
(posteriorly), third ventricle and hypothalamus (superiorly), frontal lobe
(anteriorly), and supraclinoid internal carotid arteries (laterally).61 These
neighboring structures all represent potential sources of compression. Mass
lesions of the pituitary gland typically compress the central portion of the
chiasm, resulting in classic bitemporal hemianopia or variants of this visual
defect, depending upon whether prechiasmatic segments of the optic nerves are
involved and the extent of posterior chiasm/tract injury. The most common causes
of chiasmal compression include pituitary tumors, craniopharyngiomas, and

meningiomas, which are best detected with gadolinium-enhanced T1-weighted

and T2-weighted MRI of the sella.3–5,61 With MRI, macroadenomas appear
isointense compared to surrounding brain on T1-weighted studies and
hyperintense on FLAIR imaging; these lesions will manifest “bloom” if
hemorrhage is present on GRE studies.3 By way of comparison, on CT, pituitary
macroadenomas are isodense with surrounding gray matter and show
FIGURE 12-18
Cavernous internal carotid artery aneurysm. A 53-year-old woman presented with headache
and a left third nerve palsy. A, Axial CT showed a large heterogeneous soft tissue parasellar
mass (arrow) with adjacent areas of chronic bone remodeling. B, Axial CT angiography source
imaging showed the mass represented a giant cavernous internal carotid artery aneurysm
(arrow). The central contrast-filling defect represented partial thrombosis within the
enhancing patent lumen. C, Catheter angiography with left internal carotid artery injection
depicted the lesion. Following a successful carotid balloon test procedure, the patient later
underwent left internal carotid artery occlusion for successful treatment of the aneurysm.
FIGURE 12-19
Septic cavernous sinus thrombosis. A 20-year-old man presented with fever, a painful right
eye, and dehydration. A, Axial contrast CT of the orbits showed acute right-sided ethmoid
and sphenoid sinusitis, inflammatory fatty soft tissue stranding at the orbital apex, and
cavernous sinus thrombosis with gas blebs (arrow). B, Axial fluid-attenuated inversion
recovery (FLAIR) MRI demonstrated meningitis with proteinaceous hyperintense signal
changes diffusely within the cortical sulci (arrows).
1468 OCTOBER 2019

heterogeneous enhancement with contrast administration.3 In cases of suspected
pituitary apoplexy, CT is the first imaging modality of choice and shows a sellar
mass with patchy or confluent hyperdense signal and minimal to no
enhancement with contrast (FIGURE 12-22). If acute, pituitary apoplexy appears
isointense to hypointense compared to brain on T1-weighted MRI, whereas
FLAIR imaging shows hyperintense signal change.3–5,61 With the administration
of gadolinium, rim enhancement is also seen on postcontrast T1-weighted
images. Craniopharyngiomas often demonstrate partial calcification, solid
constituents, and high signal intensity on precontrast T1-weighted MRI
sequences.3–5,61 Parasellar aneurysms tend to appear smooth and lobular in shape.
These vascular lesions have variable internal density and show heterogeneous
enhancement after contrast administration.3 Parasellar meningiomas appear
isodense on CT and isointense on MRI and enhance with contrast administration.3
FIGURE 12-20
Tolosa-Hunt syndrome. A 72-year-old man presented with severe pain around the right
eye and horizontal diplopia. Neuro-ophthalmologic examination revealed a right abducens
palsy and partial right third nerve palsy. A, Coronal postcontrast T1-weighted MRI
revealed an enhancing soft tissue mass within the right cavernous sinus (arrow). B, Axial
postcontrast T1-weighted MRI showed enlargement of the right cavernous sinus (arrow).
C, Axial postcontrast T1-weighted MRI showed enhancement of the right anterior clinoid
process (arrow). D, Some enhancement around the right optic nerve was also seen (arrow).
An extensive workup for primary causes of cavernous sinus inflammation was negative,
as was a search for malignancy including positron emission tomography (PET)/CT of the
chest, abdomen, and pelvis (not shown). Presumed Tolosa-Hunt syndrome with a component
of idiopathic orbital inflammation was diagnosed. The clinical examination and MRI
findings improved after several months of corticosteroid treatment and have not recurred
for 3 years.

FIGURE 12-21
Dural arteriovenous fistula. A 37-year-old man presented years after experiencing severe
visual field loss from papilledema related to a venous sinus thrombosis. A noncontrast CT
acquired at the time of his initial presentation showed hyperdensity within the right transverse
sinus (A) and vein of Galen (B) consistent with acute thrombus. Neuro-ophthalmic examination
revealed bilateral optic atrophy (C). Since a hypercoagulable workup was negative, and
since there was chronic dural enhancement (which can sometimes accompany a dural
arteriovenous fistula), a conventional catheter arteriogram was performed to rule out this
rare cause of venous sinus thrombosis and elevated intracranial pressure. The arteriogram
(D) revealed a dural arteriovenous fistula connecting the right superficial temporal and middle
meningeal arteries with the superior sagittal sinus. Venous sinus thrombosis may result from
or lead to dural arteriovenous fistula. Both conditions can produce elevated intracranial
pressure and associated papilledema.
Chiasmal-hypothalamic gliomas are best evaluated with MRI using coronal

sequences. These tumors are typically hyperintense on T2-weighted images and
isointense to hypointense on T1-weighted images, with variable enhancement.3,7
Extension into the optic nerve and tracts may be seen, which is better visualized
with MRI than with CT. Optochiasmatic arachnoiditis may arise from trauma,
infection (FIGURE 12-2363), drugs, tumors, and subarachnoid hemorrhage.7
Imaging studies demonstrate enhancing exudates surrounding the optic chiasm
with extension along the postchiasmal tract.7
While MRI is useful in rendering the diagnosis of pituitary macroadenomas
and other lesions in the parasellar space, this imaging modality does not reliably
predict the extent of associated vision loss from chiasmal compression.62 In this
respect, OCT can provide better prognostic information. Compression of the
prechiasmatic optic nerves or chiasm leads to optic atrophy over time, which can
be easily visualized on OCT.1 The macular ganglion cell–inner plexiform layer
analysis shows a pattern of binasal hemiretinal thinning, which allows chiasmal
damage from compression to be appreciated before the manifestation of visual
field defect or fundus changes (FIGURE 12-24). Thus, with OCT, the diagnosis of a
1470 OCTOBER 2019

FIGURE 12-22
Pituitary apoplexy. A 49-year-old man underwent surgical debulking of a pituitary
macroadenoma. A, Sagittal T1-weighted MRI showed the early postoperative changes with
residual intrasellar tumor. Four weeks after surgery, the patient presented with severe
headache and vision loss. He underwent urgent repeat MRI. B, Sagittal T1-weighted MRI
showed enlargement of the mass with some T1-weighted hyperintense signal changes
consistent with tumor hemorrhage. C, Coronal T2-weighted MRI showed suprasellar mass
effect on the optic chiasm, accounting for the new (bitemporal) vision loss.
chiasmal lesion can be localized before visual field testing and ultimately prompt
consideration for neuroimaging.1 From a prognostic perspective, preoperative
decrements in ganglion cell–inner plexiform layer and retinal nerve fiber layer
thickness are associated with worse visual outcomes, whereas patients with
relatively well-preserved preoperative measures of neuroaxonal integrity
correlate with better visual recovery after surgical or medical decompression.1,64
Lesions of the Retrochiasmal Visual Pathways

Beyond the chiasm, the afferent visual pathway is composed of the optic tracts,
lateral geniculate bodies, optic radiations, and visual cortices. Lesions affecting
these posterior regions of the afferent visual pathway produce homonymous
visual field defects. Owing to the substantial brain regions involved, it is
not surprising that a wide array of pathologic processes can cause visual
disturbances, including hypoxic/ischemic injury, tumors, infections, vascular
malformations, demyelination, trauma, hemorrhage, osmotic myelinolysis, and
neurodegenerative diseases (eg, posterior cortical atrophy, Alzheimer disease,
Creutzfeldt-Jakob disease).3,65
In cases of acute ischemic stroke, CT reveals a hypodense tissue appearance in
a vascular territory, with loss of gray-white matter differentiation. These imaging
findings may be accompanied by a hyperdense vessel as a manifestation of
acute vascular occlusion.3 Furthermore, CTA techniques may be used to detect
vessel occlusions/stenoses and characterize the status of collateral flow.3
Diffusion-weighted MRI shows hyperintense restriction from cytotoxic edema
(FIGURE 12-25).3
Posterior reversible encephalopathy syndrome (PRES), a disorder of
cerebrovascular autoregulation causing headaches, seizures, and vision loss, is
associated with vasogenic edema best seen with MRI (FIGURE 12-26).66
Reversible cerebral vasoconstriction syndrome often presents with severe,
sudden-onset headache; at times focal neurologic deficits, including vision loss,
can occur.67 Conventional angiography showing segmental arterial narrowing

FIGURE 12-23
Tuberculosis-associated optochiasmatic arachnoiditis. A 24-year-old woman presented to
the emergency department with fever, headaches, and vomiting, which progressed after
several days to severe mental deterioration. CT was initially negative, but lumbar puncture
revealed a pleocytosis of 190 white blood cells/mm3, 92% of which were lymphocytes, and an
elevated protein of 120 g/L. She was treated with multiple antibiotics. QuantiFERON Gold test
was positive, and she was started on rifampin, isoniazid, and pyrazinamide to cover
tuberculous meningoencephalitis. Hydrocephalus was observed, and a right frontal
ventriculoperitoneal shunt was placed. As her mental status improved, she reported severe
vision loss in both eyes, and she had persistent injection of the right eye. Neuro-
ophthalmologic examination showed no light perception in both eyes and bilateral optic
atrophy (A). Coronal postcontrast T1-weighted MRI (B, C) revealed leptomeningeal
enhancement, especially at the base of the skull, and enhancement and enlargement of the
optic chiasm (C, thin arrow) and multiple tuberculomas (C, thick arrow). Note the shunt tract
through the right frontal lobe (C, asterisk). One month after admission, CSF from the initial
lumbar puncture grew acid-fast bacilli.
Panels A and B courtesy of Marc Dinkin, MD. Panel C reprinted with permission from Chee R, Dinkin MJ,
Neurology.63 © 2016 American Academy of Neurology.
has been considered the gold standard for this diagnosis, but transcranial
Doppler ultrasonography, CTA, and MRA are being used to diagnose this
condition with increasing frequency.67 Specifically, CT may show subarachnoid
and intraparenchymal hemorrhage. Moreover, CTA can identify segmental
vasoconstriction, and CT venography shows cortical vein or dural sinus
thrombosis.67 MRI (including T2-weighted and FLAIR sequences) reveals subtle
radiologic features, including watershed infarcts (seen best with DWI), PRES,
subarachnoid blood, and cerebral edema.67 Hyperintense vessels visualized along
cerebral sulci with T2-weighted and FLAIR MRI sequences are associated with
more severe grades of vasoconstriction and may predict complications, including
ischemic strokes and PRES.67 Cranial MRI is also the most effective means of
differentiating reversible cerebral vasoconstriction syndrome from alternative
conditions, including primary angiitis of the CNS and dural venous sinus
thrombosis.67
1472 OCTOBER 2019

KEY POINTS
● Optical coherence
tomography–derived
ganglion cell–inner
plexiform layer analysis can
detect the presence of a
compressive lesion in the
region of the optic chiasm,
sometimes in advance of
visual field loss. Moreover,
the extent of optical
coherence tomography–
measured retinal nerve fiber
layer thinning and ganglion
cell–inner plexiform layer
FIGURE 12-24 loss in the preoperative
Binasal hemiretinal ganglion cell–inner plexiform layer thinning with chiasmal compression. phase can help predict the
Ganglion cell–inner plexiform layer optical coherence tomography analysis (A) demonstrates extent of postoperative
binasal thinning in a patient with a pituitary macroadenoma causing chiasmal compression visual recovery after surgical
shown on coronal postcontrast T1-weighted image (B, arrow). or medical decompression
Reprinted with permission from Chen JJ, Costello F, Ann Eye Sci.1 © 2018 Annals of Eye Science.
of compressive lesions.
● In cases of tumefactive
multiple sclerosis, lesions
Demyelinating lesions of the retrochiasmal visual pathways are best detected can appear masslike and
with T2-weighted and FLAIR MRI sequences. Gadolinium-enhanced MRI can may be confused with
reveal lesional enhancement as a sign of active disease. In cases of tumefactive neoplasms. In this setting,
MS, lesions can appear masslike and may be confused with neoplasms the so-called open pattern
of ring enhancement is a
(FIGURE 12-27). In this setting, the useful radiologic sign to help
so-called open pattern of ring distinguish demyelinating
enhancement is a useful radiologic sign lesions.
to help distinguish demyelinating
● Recently, a punctate
lesions.68 Progressive multifocal pattern depicted with MRI
leukoencephalopathy (PML) is a rare (referring to T2-weighted
and often fatal disease of the CNS that hyperintense or enhancing
primarily affects immunosuppressed punctate lesions) has been
shown to be a highly
individuals.69 The JC virus causes lysis of
specific feature of
infected oligodendrocytes and subsequent progressive multifocal
demyelination of axons.69 Patients with leukoencephalopathy and
MS using certain immunosuppressant may be the first detectable
imaging feature.
agents are vulnerable to developing
PML69; therefore, distinguishing the
radiologic findings of MS from PML has
obvious clinical relevance. In PML cases,
CT reveals hypodense lesions of the FIGURE 12-25
affected white matter that exhibit no mass Acute posterior cerebral artery
69 territory infarction. A 55-year-old man
effect and infrequently enhance. MRI
presented with acute-onset right
shows hyperintense T2-weighted and
homonymous hemianopia. Axial
FLAIR lesions in affected regions of the diffusion-weighted MRI showed
CNS, whereas T1-weighted images depict restricted diffusion (hyperintense
lesions as hypointense (FIGURE 12-28).69 signal) in the left occipital lobe. The
infarct was secondary to thrombotic
The established MRI findings for
occlusion of a left posterior cerebral
presymptomatic natalizumab-associated artery-P2 branch artery demonstrated
PML include subcortical lesion location on CT angiography (not shown).

FIGURE 12-26
Posterior reversible encephalopathy syndrome (PRES). A 35-year-old woman with
pregnancy-induced hypertension presented with blurred vision, headaches, and seizures. A,
Axial CT showed low-attenuation/hypodense signal changes in the occipital lobes. B, Axial
fluid-attenuated inversion recovery (FLAIR) MRI demonstrated hyperintense signal changes
in the occipital and posterior temporal lobe white matter and gray matter and, to a lesser
extent, the central capsuloganglionic structures. The MRI findings represented vasogenic
edema, which subsequently reversed with aggressive management of her hypertension.
(involving U fibers); a sharp lesional border toward the gray matter compared to
an ill-defined border toward the white matter; and increased signal intensity on
T2-weighted and DWI sequences.69 Recently, a punctate pattern depicted with
MRI (referring to T2-weighted hyperintense or enhancing punctate lesions) has
been shown to be a highly specific feature of PML and may be the first detectable
imaging feature.70 Thus, MRI may facilitate early recognition of PML cases and
hasten therapeutic intervention for affected individuals.
Neurodegenerative disorders involving the retrochiasmal visual pathways are
sometimes associated with characteristic radiologic signs (TABLE 12-4).68 Cases
of posterior cortical atrophy, Alzheimer disease, and Creutzfeldt-Jakob disease
may demonstrate atrophy, best seen with T1-weighted MRI sequences, in
anatomic regions of the brain showing patterns of hypometabolism and altered
blood flow. These regions of altered cortical activity are best visualized with
functional imaging techniques including FDG-PET and single-photon emission
CT (SPECT).71 The parietooccipital lobes are affected in posterior cortical
atrophy.71 Creutzfeldt-Jakob disease cases may also reveal restricted diffusion
and T2-weighted hyperintense signal changes without enhancement or mass
effect along the cortical ribbon and basal ganglia (affecting the pulvinar and
dorsomedial thalamic nuclei) (TABLE 12-4).72
Neoplasms affecting the retrochiasmal visual pathways are typically of
neuroepithelial origin (pilocytic astrocytomas, low-grade gliomas, glioblastomas)
or secondary metastases.65 Low-grade gliomas appear hyperintense on T2-
weighted and FLAIR MRI sequences and hypointense on T1-weighted images. In
these cases, magnetic resonance spectroscopy may reveal an increase in choline
and a drop in N-acetylaspartate (NAA), without a lipid or lactate peak.65 For
higher-grade lesions, including anaplastic gliomas and glioblastomas, the MRI
1474 OCTOBER 2019

FIGURE 12-27
Tumefactive demyelination. A 55-year-old man presented with acute right-sided weakness
and expressive aphasia. A, Axial postcontrast CT showed two ill-defined hypodense lesions
in the left frontal lobe. B, Axial fluid-attenuated inversion recovery (FLAIR) MRI showed
hyperintense lesions centered in the white matter and involving the subcortical U fibers.
Minimal surrounding edema was seen. C, Axial postcontrast T1-weighted MRI demonstrated
an open-ring pattern of mild enhancement along the inner leading margin of both lesions. D,
Axial diffusion-weighted imaging (DWI) revealed associated peripheral restricted diffusion.
Stereotactic biopsy confirmed the pathology to be demyelination. Notably, the imaging
features of tumefactive demyelination and its associated metabolic profile using magnetic
resonance spectroscopy can often mimic neoplasm.
FIGURE 12-28
Progressive multifocal leukoencephalopathy. A 55-year-old man presented with subacute
right hemiparesis and unsteadiness. His past medical history included Waldenström
macroglobulinemia and a stem cell transplant. A, Axial T2-weighted MRI revealed an ill-defined
hyperintense lesion involving the left capsuloganglionic structures that was nonexpansile and
appeared more infiltrative (respecting underlying anatomic structures) than destructive. B,
Axial postcontrast T1-weighted MRI showed no lesional enhancement. C, Axial diffusion-weighted
imaging (DWI) revealed some peripheral restricted diffusion (arrow) at its leading edge. D,
Magnetic resonance spectroscopy of the lesion demonstrated a marked reduction of the
N-acetylaspartate (NAA) (peak at 2.0 ppm) to indicate neuronal injury or loss. The lack of an
elevated choline peak (3.2 ppm) relative to creatine (3.0 ppm) was unusual for a neoplasm,
prompting concern regarding an atypical infection. The patient continued to deteriorate
from a clinical point of view. The lesion enlarged on a follow-up MRI performed 1 week later
(not shown), and a biopsy was performed. The diagnosis of progressive multifocal
leukoencephalopathy was confirmed.

signals may be heterogeneous, reflecting hemorrhagic or necrotic components,

with surrounding edema (FIGURE 12-29).65 Proton spectroscopy in higher-grade
lesions may reveal a choline peak of high amplitude, a drop in NAA peak, and the
presence of lipids or lactate indicating malignancy.65 At times, prolonged seizure
activity secondary to neoplasms can cause transient radiologic changes that may
obscure the detection of underlying lesions or create confusion about whether a
known tumor has progressed.65,73 Associated MRI findings may affect regions of
epileptic focus or distal sites, presumably reflecting seizure transmission along
neuronal networks.73 Patients may demonstrate hyperintense changes on
T2-weighted MRI sequences, with some degree of mass effect.73 Additionally,
evidence of leptomeningeal enhancement and restricted diffusion patterns in
cortical and subcortical structures may be seen.73
OCT can show a distinctive pattern of macular ganglion cell–inner plexiform
layer thinning that correlates to lesions involving posterior visual pathways.1,14
These OCT changes arise due to retrograde axonal degeneration from
pregeniculate lesions that cause a “dying back” phenomenon, which affects
measures of neuroaxonal integrity in the retina.14 This OCT pattern of
TABLE 12-4 Radiographic Signs Associated With Neurodegenerative Conditionsa
Radiologic Clue Neurodegenerative Condition(s) Imaging Findings
Absent swallow Parkinson disease Absence of the normal-appearing nigrosome-1 in the

tail sign dorsolateral substantia nigra is seen on high-resolution axial
T2-weighted/susceptibility-weighted imaging (SWI) MRI
sequences
Dawson fingers Multiple sclerosis The “fingers” represent inflammatory hyperintense signal
changes extending from the corpus callosum, oriented
perpendicularly to the lateral ventricles and extending
radially outward along medullary veins (representing
perivenular inflammation) best seen on sagittal fluid-
attenuated inversion recovery (FLAIR) MRI sequences
Elephant sign Alzheimer disease Selective atrophy of the medial aspect of the temporal
lobes and hippocampi is seen on T1-weighted MRI
sequences
Eye of the tiger sign Pantothenate kinase–associated Hyperintense signal surrounded by a hypointense area at
neurodegeneration the medial aspects of the globus pallidus is seen on coronal
T2-weighted MRI sequences; the hypointense signal
change is due to abnormal accumulation of iron, and the
hyperintense signal results from gliosis and spongiosis
Hockey stick sign Creutzfeldt-Jakob disease Axial T2-weighted and FLAIR MRI shows symmetric signal
hyperintensity in the region of the pulvinar and dorsomedial
nuclei of the thalamus
Hot cross bun sign Multiple system atrophy, spinocerebellar A cross-shaped hyperintensity in the pons is seen on axial
ataxia, Creutzfeldt-Jakob disease T2-weighted MRI sequences, reflecting degeneration of the
pontocerebellar tracts
1476 OCTOBER 2019

homonymous hemiretinal thinning corresponds to the homonymous visual field
defect and can persist even when the corresponding visual field defect has
resolved (FIGURE 12-30).1,14 A persistent macular ganglion cell–inner plexiform
layer defect in the setting of transient visual field loss can provide clues to the
diagnosis and may help distinguish cases of stroke from CNS demyelination.
Strokes are more likely to lead to persistent visual field defects, whereas visual
field defects from demyelinating lesions may be more likely to resolve. In both
cases, corresponding OCT ganglion cell–inner plexiform layer patterns of
homonymous thinning persist. In cases of transsynaptic degeneration, lesions in
the optic radiations and occipital cortex can cause similar ganglion cell–inner
plexiform layer patterns of homonymous hemiretinal thinning, which are
detectable by OCT and correlate to homonymous visual field defects.1 In contrast
to optic tract lesions, which cause OCT-measured ganglion cell–inner plexiform
layer thinning within weeks of injury, transsynaptic retrograde degeneration
takes months or years to develop.1
The eye has been described as a window to the brain, because OCT can reveal
manifestations of neuroaxonal loss across a spectrum of neurodegenerative
Radiologic Clue Neurodegenerative Condition(s) Imaging Findings
Hummingbird sign Progressive supranuclear palsy Midbrain atrophy with a relatively normal structural
appearance to the pons is seen on midsagittal MRI
sequences; the floor of the third ventricle forms the beak,
while the atrophic midbrain forms the head of the
hummingbird, with the body represented by the normal pons
Mickey Mouse sign Progressive supranuclear palsy Axial MRI shows selective atrophy of the midbrain
tegmentum, with relative sparing of the midbrain tectum
Panda sign Wilson disease The appearance of the face of the giant panda in the
midbrain on T2-weighted MRI sequences
Pulvinar sign Creutzfeldt-Jakob disease, Wernicke These bilateral hyperintense signal changes in the posterior
encephalopathy, Fabry disease thalami are evident on axial T2-weighted FLAIR MRI
sequences
Putaminal slit sign Multiple system atrophy Axial T2-weighted MRI hyperintense signal changes seen
in the putamen are considered to be due to gliosis,
demyelination, and increased extracellular fluid, caused by
severe atrophy of the putamen and enlargement of the
space between the putamen and external capsule
Tigroid pattern sign Metachromatic leukodystrophy, Symmetrically spared perivascular hypointense white
Pelizaeus-Merzbacher disease, matter signal findings are seen within the brightly
Krabbe disease demyelinated periventricular white matter features on
axial and coronal T2-weighted MRI sequences, giving an
appearance of numerous linear structures with hypointense
signal intensity in a radiating pattern within the
periventricular white matter (tigroid pattern or stripe sign)
or numerous dots (leopard skin sign), depending on the
plane of cross-section
MRI = magnetic resonance imaging.

a
Data from Krupa K, et al.68

FIGURE 12-29
Glioblastoma (IDH1-wildtype, ATRX FIGURE 12-30
retained, MGMT unmethylated). A A 30-year-old woman with relapsing-remitting
73-year-old man presented with a new multiple sclerosis presented with difficulty seeing
left homonymous hemianopia. A, Axial the beginning of words. She had a left relative
postcontrast T1-weighted MRI afferent pupillary defect. The ganglion cell–inner
demonstrated a ring-enhancing mass plexiform layer analysis showed a pattern of right
with central necrosis in the right hemiretinal loss (A, arrows) correlating to a right
occipital lobe. B, Axial fluid-attenuated optic tract lesion. B, Automated perimetry
inversion recovery (FLAIR) MRI showed showed an incongruous left quadrantanopia.
heterogeneous signal changes within the Reprinted with permission from Chen JJ, Costello F, Ann
mass, with surrounding hyperintensity Eye Sci.1 © 2018 Annals of Eye Science.
representing infiltrative tumor and
vasogenic edema.
disorders.1,14 Multiple studies have shown that retinal nerve fiber layer and
ganglion cell–inner plexiform layer thinning occurs more often in patients with
Alzheimer disease compared to age-matched controls. Furthermore, OCT-
measured retinal nerve fiber layer thinning correlates with severity of cognitive
impairment in Alzheimer disease.74,75 Similar OCT abnormalities have been
noted in patients with Parkinson disease and frontotemporal dementia.75 These
observations suggest that degeneration of retinal ganglion cells should be
considered among the constellation of neuropathologic changes found in patients
1478 OCTOBER 2019

with neurodegenerative KEY POINT
conditions and that
● Specific MRI patterns of
OCT-measured retinal nerve brainstem involvement are
fiber layer thickness may help highly suggestive of
distinguish the effect of neuromyelitis optica
neurodegenerative disorders spectrum disorder,
including lesions of the
from normal aging.75 Emerging
dorsal medulla and area
studies with OCT-angiography postrema structures.
indicate that patients with
FIGURE 12-31 Alzheimer disease have vascular
Acute midbrain infarction. A 25-year-old man with abnormalities that may be
known Fabry disease presented with acute-onset involved in the pathogenesis of
oculomotor nerve palsy. A, Axial fluid-attenuated
this condition.1
inversion recovery (FLAIR) MRI showed a small
oval hyperintense lesion involving the right
superior midbrain tegmentum near the midline Lesions of the Posterior Fossa
(arrow). B, Axial diffusion-weighted imaging (DWI)The posterior fossa houses the
demonstrated restricted diffusion, compatible brainstem and cerebellum,
with an acute perforator territory infarct. The
patient did not have contralateral hemiparesis to which together play important
suggest Weber syndrome. roles in governing efferent visual
function. Lesions affecting these
anatomic regions can cause
ptosis, pupillary abnormalities, ocular misalignment, and nystagmus.3
Beam-hardening effects challenge the sensitivity of CT imaging, and MRI is a
superior imaging modality for posterior fossa structures.3 DWI MRI is very
sensitive to acute ischemic changes in the brainstem (FIGURE 12-31), which
escape detection in two-thirds of cases with conventional CT scans.76 Yet, small
lesion size and susceptibility artifacts have been identified as confounding factors
that contribute to false-negative MRIs.77 For this reason, it is helpful
to recognize these vascular syndromes by their cardinal clinical features to
ensure optimal imaging techniques are employed and treatments initiated
(TABLE 12-578).
Brainstem hemorrhages may arise from underlying vascular lesions, such as
ruptured arteriovenous malformations and spontaneous bleeding into cavernous
angiomas. With CT imaging, these hemorrhages appear hyperdense with
indistinct margins, whereas MRI demonstrates well-circumscribed, lobulated
lesions with a core of heterogeneous T1-weighted and T2-weighted
hyperintensity and a peripheral ring of T2 hypointensity corresponding to
hemosiderin deposition. Chronically, brainstem hemorrhages and other lesions
of the Guillain-Mollaret triangle may be associated with palatal myoclonus and
ocular myoclonus due to damage to the central tegmental tract. As a result,
hypertrophic olivary degeneration (FIGURE 12-32) may evolve as a form of
transsynaptic degeneration, secondary to altered neuronal connections in the
dentatorubral-olivary pathway.79
Demyelinating lesions of the brainstem are seen as T2-weighted and FLAIR
hyperintense signal changes, with postgadolinium enhancement evident on
T1-weighted images. As mentioned, specific MRI patterns of demyelination
involving the brainstem are suggestive of NMOSD, including area postrema
clinical syndromes causing intractable hiccups, nausea, and vomiting and
involving dorsal medulla/area postrema structures.20,22,23 Inflammatory
conditions such as chronic lymphocytic inflammation with pontine perivascular

enhancement responsive to steroids (CLIPPERS) have distinctive radiologic

characteristics, which include multiple punctate or curvilinear gadolinium
enhancement (FIGURE 12-33).80 Since the original description of this clinical
entity, these MRI features have also been described in other inflammatory
disorders, such as primary angiitis of the CNS, lymphoma, and MS.80
Central pontine myelinolysis, also known as osmotic demyelination syndrome, is
known to affect alcoholics and patients who experience rapid correction of
hyponatremia.81 Affected individuals may develop dysphagia, dysarthria,
pupillary abnormalities, and paresis.81 MRI findings include symmetric signal
intensity abnormality in the central pons visualized on T2-weighted and FLAIR
TABLE 12-5 Vascular Syndromes of the Brainstem Presenting with Neuro-Ophthalmic

Signsa
Syndrome Clinical Findings Anatomic Correlations
Midbrain
Top of the Paralysis of vertical gaze, loss of convergence, Occlusion of basilar artery (usually embolic) with
basilar artery pseudoabducens palsy, convergence retraction infarction of the midbrain, thalamus, and portions
nystagmus, lid retraction, skew deviation, pupil of the temporal and occipital lobes
abnormalities, hemianopia, cortical blindness,
Balint syndrome, loss of consciousness
Parinaud Lid retraction, light-near dissociation of the pupils, Seen with pineal tumors and other pathologies but
upgaze palsy, convergence retraction nystagmus also with occlusion of the artery of Percheron
causing damage to the mesencephalic tectum
(superior colliculus, oculomotor, and Edinger-
Westphal nuclei)
Weber Ipsilateral third nerve palsy, contralateral Damage to cerebral peduncle (corticospinal and
hemiparesis corticobulbar tracts) due to vascular compromise
of the paramedian branches of the basilar artery or
posterior cerebral artery (PCA)
Claude Ipsilateral third nerve palsy, contralateral Infarction of third nerve and red nucleus due to
hemiataxia PCA occlusion
Benedikt Ipsilateral third nerve palsy, contralateral Damage to third nerve, red nucleus, and brachium
involuntary movements conjunctivum cerebelli due to occlusion of
branches of the PCA
Pons
Raymond-Cestan Ipsilateral paralysis of conjugate gaze, ataxia, Damage to the upper dorsal pons involving the
contralateral weakness and sensory loss middle and superior cerebellar peduncle,
corticospinal tracts, medial lemniscus,
spinothalamic tracts, and paramedian pontine
reticular formation caused by thromboembolic
disease of the basilar artery involving the long
circumferential arteries
Raymond Ipsilateral sixth nerve palsy, contralateral Damage to the ventral pons (including ipsilateral
weakness sixth nerve palsy and corticospinal tracts) caused
by basilar artery thromboembolic disease, and
paramedian branches
1480 OCTOBER 2019

imaging.81 These lesions may progress to manifest the classic hyperintense
trident-shaped or “Mexican hat–shaped” central pontine abnormality, with
relative sparing of the ventrolateral pons and corticospinal tracts.81 MRI evidence
of T1-weighted hypointensity without enhancement or mass effect is seen.
Recent reports suggest that diffusion-weighted MRI may be the most sensitive
means of detecting early features of this condition.81
MRI features of Wernicke encephalopathy include bilateral, symmetric
T2-weighted and FLAIR hyperintense signal changes affecting the tectal plate,
periaqueductal gray matter, mammillary bodies, and thalami (FIGURE 12-34).82
It is noteworthy that in these anatomic regions, the maintenance of cellular
Syndrome Clinical Findings Anatomic Correlations
Millard-Gubler Ipsilateral sixth and seventh nerve palsies, Damage to the ventrocaudal pons involving the
contralateral weakness basis pontis and the fascicles of the sixth and
seventh nerves caused by basilar artery occlusion,
with involvement of the short circumferential
arteries/paramedian arteries
Foville Contralateral hemiplegia, loss of conjugate gaze, Damage to the corticospinal tracts, abducens nerve,
ipsilateral lower motor neuron facial weakness paramedian pontine reticular formation, and medial
lemniscus due to occlusion of paramedian or short
circumferential branches of the basilar artery
Medulla
Babinski-Nageotte Ipsilateral ataxia; loss of pain and temperature Damage to the dorsolateral medulla due to
sensation in the face; weakness of soft palate, vertebral artery occlusion with posterior inferior
larynx, and pharynx; ipsilateral Horner syndrome; cerebellar artery involvement (anatomic structures
contralateral weakness; loss of pain and implicated in Wallenberg syndrome plus
temperature sensation in the body corticospinal tract involvement)
Cestan-Chenais Ipsilateral loss of pain and temperature sensation Similar to Babinski-Nageotte syndrome, with sparing
in the face; weakness of soft palate, larynx, and of the ipsilateral cerebellar ataxia because of
pharynx; ipsilateral Horner syndrome; sparing of the posterior spinocerebellar tract
contralateral weakness and loss of pain and
temperature sensation in the body
Reinhold Ipsilateral ataxia; loss of pain and temperature Lateral medullary infarct (with features of
sensation in the face; weakness of soft palate, Wallenberg syndrome) and medial medullary infarct
larynx, pharynx, and tongue; ipsilateral Horner (hemimedullary syndrome); due to occlusion of the
syndrome; contralateral weakness and loss of ipsilateral vertebral artery proximal to the posterior
touch, pain, and temperature sensation in the inferior cerebellar artery and its anterior spinal
body artery branches
Wallenberg Crossed hemisensory loss, ipsilateral Horner Infarction within the lateral medulla involving
syndrome, ipsilateral cerebellar dysfunction spinothalamic tract, sympathetic chain, vagus
nerve, and olivary nucleus due to occlusion/
dissection of the vertebral artery or posterior
inferior cerebellar artery
a
Data from Nix JL, et al.76 and Hurley, et al, J Neuropsychiatry Clin Neurosci.78

FIGURE 12-32
Inferior olivary hypertrophy as a delayed consequence of a pontine cavernous angioma with
associated oculopalatal tremor. A 56-year-old woman presented with headaches and vertical
oscillopsia. A neuro-ophthalmic examination revealed vertical acquired pendular nystagmus
synchronous with palatal tremor, together consistent with oculopalatal tremor. Axial T2-
weighted MRI showed a round lesion with regions of hyperintensity and hypointensity consistent
with a cavernous angioma in the dorsal right pons (A, arrow). Coronal T1-weighted MRI (B)
showed regions of hyperintensity and hypointensity consistent with blood of different ages,
reflecting multiple prior microhemorrhages within the lesion. Two months later, hypertrophy
of both inferior olives was seen on axial fluid-attenuated inversion recovery (FLAIR) (C, arrow)
and T2-weighted (D, arrow) images. Olivary hypertrophy occurs as a result of damage to the
triangle of Mollaret (E), a pathway linking the red nucleus, inferior olive, cerebellar cortex,
and dentate nucleus of the cerebellum. Interruption of the inhibitory signal through the central
tegmental tract allows neurons of the inferior olive to form a syncytium with synchronized
firing that results in oculopalatal tremor.
osmotic gradients correlates tightly with thiamine levels.82 Gadolinium-

enhanced T1-weighted MRI detects areas with blood-brain barrier disruption,
such that enhancement in these affected CNS regions can be seen in about
50% of cases.82
Neoplastic lesions in the posterior cranial fossa may be intraaxial
(intraparenchymal) or extraaxial (outside of brain substance; meningeal, dural,
epidural, or intraventricular). This distinction is important as diagnostic
considerations differ significantly depending on the lesional location. In general
terms, the origin and extent of these lesions are best characterized with MRI.3
Intrinsic brainstem gliomas present with diffuse infiltration of the pons, which
often increases the size of the brainstem. These tumors are associated with
1482 OCTOBER 2019

increased signal intensity on KEY POINT
T2-weighted images and reduced
● In addition to vascular
signal intensity on T1-weighted insults, the brainstem is
images.3 Brainstem gliomas also vulnerable to
usually do not show contrast demyelinating, neoplastic,
enhancement.3 Lesions of the neurodegenerative,
inflammatory, infectious,
pineal gland cause compression
and metabolic disorders.
of the dorsal midbrain,
manifesting with lid retraction,
FIGURE 12-33 supranuclear gaze palsy, tonic
Chronic lymphocytic inflammation with pontine pupils, and convergence
perivascular enhancement responsive to steroids
(CLIPPERS). A 57-year-old man developed
retraction nystagmus. These
symptoms of brainstem and cerebellar lesions are best detected with
dysfunction, with prominent gait instability. A, B, sagittal T1-weighted MRI with
Axial postcontrast T1-weighted MRI showed and without contrast. The
symmetric foci of pontine enhancement with a
brainstem is also a site for
curvilinear pattern highly suggestive of a
perivascular distribution. This pattern of congenital or acquired structural
enhancement is suggestive of CLIPPERS. The brainstem malformations.
patient had partial clinical improvement with Abnormalities of the
corticosteroid therapy.
craniocervical junction, such
as Chiari malformations,
can present with downbeat
nystagmus and are seen best
with sagittal MRI. Newer
techniques allow for
simultaneous measurements of
arterial, venous, and CSF flow
in a single MRI acquisition.
Patients with acquired
intracranial hypotension may
present with headaches and
FIGURE 12-34
bilateral sixth nerve palsies. In
Wernicke encephalopathy. A 17-year-old girl
developed intractable vomiting and nausea for 2 these cases, cranial MRI will
to 3 weeks during early pregnancy and then demonstrate pachymeningeal
developed nystagmus and diplopia. Cranial CT thickening and enhancement,
was normal (not shown). A, Axial T2-weighted
dural venous engorgement,
imaging showed subtle hyperintense signal
changes involving the medial thalami. B, Axial tonsillar herniation, and
diffusion-weighted imaging (DWI) demonstrated subdural effusions.83
symmetric diffusion restriction within the thalami
(arrow), with concordant decreased apparent SPECIAL CONSIDERATIONS
diffusion coefficient signal (not shown). The
patient was diagnosed with acute thiamine AND FUTURE DIRECTIONS
deficiency secondary to hyperemesis gravidarum. Localizing the cause of visual
Following vitamin supplementation, the MRI disturbances in neuro-
abnormalities resolved, although the patient had ophthalmology sometimes
incomplete clinical recovery.
requires looking beyond the
obvious. Specifically, this may
mean exploring regions of the
neural axis that are distal from the clinical finding of interest or interrogating
functional dynamics within the CNS when the preliminary structural imaging
studies fail to explain the patient’s deficits.

Horner Syndrome—A High Stakes, Low Yield Situation?

Horner syndrome presents with a classic clinical triad of miosis, ptosis, and
anhidrosis and implicates a lesion of the oculosympathetic pathway.84–86 The
most cost-effective approach to imaging Horner syndrome is to harness clues
from the history and examination to determine the most likely anatomic site
of the culprit lesion and to guide imaging accordingly.84 Acute-onset Horner
syndrome associated with head or face pain should prompt urgent head and neck
vascular imaging with CTA or MRA to exclude carotid artery dissection. Horner
syndrome accompanied by other neurologic findings in the brain or spinal cord
requires cranial MRI or spinal sequences, or both. Notably, MRI protocols can be
adapted to evaluate second-order lesions in the lung apex and at the skull base.
Alternatively, lung apex lesions can also be evaluated with routine CT of the
thorax. A single neuroimaging study of the entire oculosympathetic pathway
extending from the hypothalamus to the T2 level in the chest with a contrast-
enhanced MRI (with or without MRA) has been proposed as a cost-effective
method to investigate Horner syndrome.85 Urgent imaging is not required in
cases of chronic isolated Horner syndrome, in which no localizing signs, acute
pain, or history of recent trauma is elicited, largely because the vast majority of
these cases (approximately 70%) will be deemed idiopathic.86 Yet, a significant
proportion (15%) of patients with Horner syndrome who lack recognition of
their clinical signs (anisocoria or ptosis) will show serious pathology, defined as a
brain mass, neck mass, or carotid artery dissection, on imaging.86 Because both
benign and life-threatening lesions are associated with Horner syndrome, a
thorough clinical evaluation is recommended, regardless of duration of
symptoms and patient presentation. For cases of proven postganglionic Horner
syndrome, MRI of the head should be adequate, whereas for preganglionic
locations, imaging of the entire oculosympathetic pathway is a recommended
investigative strategy.86
Spinal Imaging—Extending the View of the Neural Axis

As previously discussed, spinal imaging plays an important role in diagnosing
NMOSD.20,22,23 A role also exists for spinal imaging in cases of suspected MS,
since asymptomatic spinal cord lesions are found in 30% to 50% of patients with a
clinically isolated syndrome.21,87 Hence, expanding the view of the CNS to
include the spinal cord may improve the diagnostic yield for patients who have
not yet shown a significant burden of inflammatory brain lesions. In suspected
cases of acute inflammatory demyelinating polyradiculoneuropathy (AIDP),
which can sometimes present with pupillary abnormalities and ophthalmoplegia,
gadolinium-enhanced MRI can detect reveal thickening and enhancement of the
cauda equina roots in 95% of cases.88 Preganglionic Horner syndrome can also
result from spinal cord lesions above the level of T1. Finally, spinal cord lesions,
particularly tumors in the lumbosacral region, cause papilledema in some
individuals (FIGURE 12-35).89,90 For this reason, spinal imaging should be
considered for patients with suspected IIH presenting with atypical demographic
features or abnormal CSF findings.
Skull Base Imaging and Perineural Disease Spread

Perineural spread refers to a direct form of cancer extension, defined as the
presence of gross tumor spread along a nerve that is distinct from the main
tumor mass.91–93 Patients with perineural spread may present with vision
1484 OCTOBER 2019

FIGURE 12-35
Spinal ependymoma. A 36-year-old man presented with headaches and papilledema (A, B). His
brain MRI with venography was normal (not shown). C, Sagittal postcontrast T1-weighted spinal
imaging revealed an intradural, extramedullary tumor located inferior to the conus medullaris.
The tumor showed avid enhancement, with small amounts of intratumoral hemorrhage. Soft
tissue material was seen within the lower thecal sac in the sacral level that could have
represented dependent subarachnoid hemorrhage/debris from the tumor, although spillage of
tumor cells or subarachnoid blood relating to a recent lumbar puncture were also considered
but felt to be less likely. Resection of the lesion resulted in rapid improvement (D, E) and,
ultimately, complete resolution of the signs and symptoms of raised intracranial pressure. Note
an unrelated choroidal nevus inferior to the disc in the left eye (B, E).
loss and diplopia from cranial nerve involvement. The mechanism for these
visual disturbances may be overlooked if a high index of clinical suspicion is
not present.91 MRI has a sensitivity of 95% to 100% for detection of
perineural tumoral spread, and its accuracy in predicting the entire extent of
disease is as high as 83%.91–93 Improved utilization of high-field-strength
techniques with 3T MRI and careful attention to these regions can now
delineate perineural involvement along structures, including small facial
nerve branches within the parotid gland, which may be overlooked with
conventional 1.5T MRI.91–93
Diaschisis Syndromes
The term diaschisis describes a state of neural depression in the brain caused
by loss of connections to injured neural structures that are remote from the
affected area.94 Crossed cerebellar diaschisis arises from interruption of
corticopontocerebellar white matter tracts, which causes deafferentation and
hypometabolism of the contralateral cerebellar hemisphere (FIGURE 12-36).94,95
This phenomenon may be caused by supratentorial tumors, hemorrhages,
encephalitis, Dyke-Davidoff-Masson syndrome (an imaging finding
characterized by hemicerebral atrophy secondary to brain injury acquired
early in life), neurodegenerative disorders, and radiation necrosis.94,95 Other

FIGURE 12-36
Crossed cerebellar diaschisis. A 60-year-old woman presented with evidence of right
hemiataxia, visuospatial difficulties, and right-sided neglect. Axial diffusion-weighted MRI
showed restricted diffusion consistent with an acute right-sided cerebellar infarct (A, arrow),
but this finding did not explain the full extent of the patient’s neurologic presentation.
Follow-up coronal single-photon emission CT (SPECT) images showed diffuse hypoperfusion
of the left central temporal lobe (B, arrow) and hemisphere and right cerebellum (C, arrow).
The left cerebral hemisphere abnormalities confirming the diaschisis syndrome were not
evident on the MRI (D, E).
Figure courtesy of Gordon Jewett, MD.
diaschisis syndromes include ipsilateral thalamic diaschisis (occurring after an

ipsilateral middle cerebral artery territory infarction), crossed transhemispheric
diaschisis (occurring after a contralateral infarct), and ipsilateral
thalamocortical diaschisis (occurring after an ipsilateral thalamic infarct).94,95
PET is the gold standard for detection of diaschisis syndromes, although
dynamic susceptibility contrast perfusion MRI may be sensitive in detecting the
hemodynamic alterations of this condition.94,95
CONCLUSION
The role of imaging in neuro-ophthalmology continues to evolve. Advances
in ultrasound, CT, MRI, and OCT have changed the way neuro-ophthalmic
disorders are diagnosed and followed. In particular, the advent of OCT has
helped characterize structure-functional relationships that predict the long-term
visual recovery for many afferent visual pathway disorders. The expanding role
of neuroimaging, however, does not diminish the role of clinical-anatomic
localization. On the contrary, these imaging techniques should be considered an
extension of a process that begins with a focused history and thorough physical
examination. Strong clinical acumen is needed to ensure that imaging tools are
used in the most effective way possible to enhance patient care.
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70 Hodel J, Darchis C, Outteryck O, et al. Punctate
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71 Rondina JM, Ferreira LK, de Souza Duran FL, et al.
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1490 OCTOBER 2019

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POSTREADING TEST
ARTICLE 1: THE PUPIL
1 A 51-year-old woman who is in the medical intensive care unit for

a severe exacerbation of chronic obstructive pulmonary disease is
noted to have a dilated left pupil during a routine nursing evaluation at
2:00 PM. Neurologic examination is normal except for a large,
nonreactive left pupil. She is intubated, but briskly follows all
commands and expresses herself clearly in writing. Instillation of
2% pilocarpine causes the right pupil to constrict strongly but has no
effect on the left pupil. Which of the following is the most likely cause
of this patient’s anisocoria?
A aneurysmal compression of the left third nerve

B damage to the left ciliary ganglion (tonic pupil)
C hypoxic damage to the left third nerve nucleus
D pharmacologic dilation of the left pupil
E transtentorial herniation compressing the left third nerve
2 In a patient with miosis and mild ptosis on the left, the presence of left
facial anhidrosis indicates damage to which of the following portions
of the sympathetic pathway?
A anywhere distal to the carotid bifurcation

B anywhere distal to the cavernous sinus
C anywhere in the entire pathway
D anywhere proximal to the carotid bifurcation
E anywhere proximal to the cavernous sinus
3 If a patient has had Horner syndrome on the left side for a week or
longer, instillation of two drops of 0.5% apraclonidine into each eye
will result in which of the following pupillary responses?
A constriction of left pupil only, increasing the magnitude of the

anisocoria
B constriction of right pupil only, reversing the anisocoria (ie, the
right pupil will be smaller than the left)
C dilation of left pupil only, reversing the anisocoria (ie, the right
pupil will be smaller than the left)
D dilation of right pupil only, increasing the magnitude of the
anisocoria
E equal constriction of both pupils, leaving magnitude of the
anisocoria unchanged
1494 OCTOBER 2019

4 A 27-year-old woman with no previous medical problems noticed that
her right pupil was dilated about 2 weeks ago, and it has not changed
since then. She has no pain, ptosis, or vision disturbance. Neurologic
examination reveals a large, irregularly shaped right pupil that
constricts very slowly to bright light, with more normal constriction to
approaching visual stimuli. After constriction, the right eye redilates
very slowly. Instillation of one drop of dilute (0.125%) pilocarpine into
each eye results in miosis on the right and no change in the left pupil,
thereby reversing the anisocoria. The remainder of the neurologic
examination, including visual acuity, visual fields, and extraocular
muscle function, is normal. Which of the following conditions is
most likely?
A damage to the right ciliary ganglion (tonic pupil)

B diabetic third nerve palsy
C hypoxic damage to the left third nerve nucleus
D pharmacologic dilation of the left pupil
E transtentorial herniation compressing the left third nerve
ARTICLE 2: ISCHEMIC OPTIC NEUROPATHY
5 A 62-year-old man presents to the emergency department after

awakening with left eye vision loss. He reports no eye pain and no
headache and has no other associated symptoms. On examination, a
left relative afferent pupillary defect and loss of the inferior visual field
of the left eye is found. Visual acuity is 20/100 on the left and 20/25 on
the right (best corrected). He has marked hyperemic swelling of the
left optic disc. The right disc appears normal with a cup to disc ratio of
approximately 0.2. The erythrocyte sedimentation rate, C-reactive
protein, and complete blood cell count were normal. Which of the
following conditions is most likely in this patient?
A arteritic anterior ischemic optic neuropathy

B branch retinal artery occlusion
C central retinal artery occlusion
D nonarteritic anterior ischemic optic neuropathy
E posterior ischemic optic neuropathy
6 Which of the following medications predisposes to development of

nonarteritic anterior ischemic optic neuropathy?
A aspirin
B levodopa
C phenytoin
D sildenafil
E vigabatrin

POSTREADING TEST
7 A 77-year-old woman presents to the emergency department with

sudden painless vision loss in her left eye. She reports increased fatigue
over the past month and pain in her jaw muscles while chewing. On
examination, she has temporal tenderness on the left. Her visual acuity
is 20/30 in the right eye and 20/400 in the left eye, with a prominent left
relative afferent pupillary defect. Her left optic disc appears pallid and
edematous, while her right disc is normal. She has inferior visual field
loss in the left eye. Her erythrocyte sedimentation rate is 80 mm/hr.
Which of the following is the most important next step in this patient’s
management?
A administer aspirin
B initiate treatment with IV steroids
C initiate treatment with tocilizumab
D obtain an MRI of the orbit
E schedule an urgent temporal artery biopsy
8 A 55-year-old man awakens from prolonged spinal surgery with

painless bilateral vision loss. On examination, visual acuity is 20/400 in
both eyes, ocular fundi appear normal, and the pupils react slowly to
light, with no relative afferent pupillary defect. Which of the following
conditions is the most likely cause of his vision loss?
A anterior optic neuritis

B arteritic anterior ischemic optic neuropathy
C central retinal artery occlusion
D nonarteritic ischemic optic neuropathy
E posterior ischemic optic neuropathy
ARTICLE 3: OPTIC NEURITIS
9 A 38-year-old woman has a 1-day history of progressively worsening

pain and loss of vision in her right eye. The pain is worse when she
moves the eye. Which of the following features would make
neuromyelitis optica (NMO) spectrum disorder more likely than
multiple sclerosis?
A normal funduscopic examination bilaterally

B oligoclonal bands in CSF
C right afferent pupillary defect
D right optic nerve lesion extending into optic chiasm on MRI
E visual acuity better than 20/200 in the right eye
1496 OCTOBER 2019

10 Which of the following treatments has been shown to improve visual
outcomes in patients with optic neuritis who fail to respond to
high-dose corticosteroid treatment?
A acyclovir
B azathioprine
C bone marrow transplant
D IV immunoglobulin (IVIg)
E plasma exchange
11 A 61-year-old woman with a 5-day history of progressive pain with eye

movement and loss of vision in both eyes has visual acuity of 20/200
and optic disc edema in both eyes, and MRI reveals longitudinally
extensive inflammation with perineural enhancement of both optic
nerves. Which of the following conditions is most likely?
A chronic relapsing inflammatory optic neuropathy

B idiopathic optic neuritis
C myelin oligodendrocyte glycoprotein–IgG-seropositive optic
neuritis
D optic neuritis associated with multiple sclerosis
E optic neuritis associated with neuromyelitis optica (NMO)
spectrum disorder
ARTICLE 4: TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES
12 A 70-year-old woman presents with subacute bilateral visual loss

increasing insidiously over the course of 2 weeks. Her eye examination
reveals optic disc edema with a normal cup to disc ratio. Her visual loss
is characterized by decreased visual acuity, dyschromatopsia, and
altitudinal visual field defect in both eyes. An MRI of her brain is
normal. Which of the following medications is most likely responsible
for her optic neuropathy?
A amiodarone
B ethambutol
C linezolid
D tacrolimus
E vigabatrin

POSTREADING TEST
13 A 27-year-old man presents to the emergency department with acute

bilateral vision loss, incoordination, and confusion. Examination
reveals a hyperemic optic disc with large bilateral central scotomas. A
noncontrast head CT is normal, as is his complete blood cell count. His
electrolyte panel reveals a metabolic acidosis. Which of the following
agents is most likely responsible for the patient’s presentation?
A amiodarone
B choramphenicol
C ciprofloxacin
D gentamycin
E methanol
14 A 20-year-old man without history of visual problems presents with

sudden painless visual loss from his right eye. On dilated funduscopy,
the optic disc and retina appear normal in both eyes. He has a right
afferent pupillary defect, a right monocular central scotoma, and red
color desaturation on the right. His neurologic examination is
otherwise unremarkable. An MRI of the brain with and without
contrast is unremarkable. Which of the following investigations is
most likely to reveal the cause of this patient’s vision loss?
A NADH dehydrogenase gene sequencing

B OPA1 gene sequencing
C retinal fluorescein angiography
D serum copper level
E vitamin B12 level
ARTICLE 5: IDIOPATHIC INTRACRANIAL HYPERTENSION
15 Which of the following visual field abnormalities typically occurs

earliest in the course of idiopathic intracranial hypertension?
A arcuate defect in the inferior nasal portion of the visual field

B arcuate defect in the superior temporal portion of the visual field
C central scotoma
D constriction of the peripheral visual field
E enlarged physiologic blind spot
1498 OCTOBER 2019

16 A 25-year-old woman with a 2-month history of headaches and
occasional transient visual obscurations has optic disc edema in both
eyes. She is a vegan, and to avoid nutritional deficiencies, she takes
large doses of various vitamins and other supplements. Which of the
following is most likely to be responsible for her headaches and visual
symptoms?
A coenzyme Q10
B melatonin
C omega-3 fatty acids
D vitamin A
E vitamin D
17 A 32-year-old woman who is 2 weeks postpartum presents to the

emergency department because of a severe headache over the past
week that is different in character from her previous migraines. She
has had no fevers, neck stiffness, or sensitivity to light or noise. Her
examination is normal except for optic disc edema in both eyes. In
addition to MRI, which of the following diagnostic tests should be
performed?
A carotid artery ultrasound

B magnetic resonance angiogram (MRA)
C magnetic resonance venogram (MRV)
D slit-lamp examination
E transthoracic echocardiogram
ARTICLE 6: CHIASMAL AND POSTCHIASMAL DISEASE
18 A 67-year-old man has been bumping into people and objects on his
right side for the past week. On examination, he has normal visual
acuity in both eyes, normal-appearing discs, and normal pupillary
light response bilaterally without a relative afferent pupillary defect.
He is able to count fingers accurately in all four quadrants of both eyes.
However, on formal visual field testing, he is found to have a right
homonymous visual field loss that spares central vision. Ischemia in
which of the following vascular distributions would be most likely to
cause this constellation of findings?
A anterior cerebral
B anterior choroidal
C lateral choroidal
D middle cerebral
E posterior cerebral

POSTREADING TEST
19 A 57-year-old man awakened with abnormal vision and came to the

emergency department for evaluation. His visual acuity is 20/20 in
both eyes, but he is unable to count fingers in the upper and lower left
visual fields with either eye. His funduscopic examination is normal, as
is his pupillary light reflex. On formal visual field testing, he has
homonymous loss of vision in the left upper and lower visual fields
with sparing of a wedge along the horizontal meridian (pointing
toward the center of the visual world). Which of the following anatomic
localizations is most likely responsible for this visual field defect?
A lateral geniculate nucleus

B occipital lobe
C optic chiasm
D optic radiations
E optic tract
20 A 12-year-old girl with neuromyelitis optica (NMO) has a dense central

scotoma in her right eye as well as a superior temporal visual field
defect in her left eye. A lesion at which of the following chiasmal
locations would produce these findings?
A left anterior
B left lateral
C left posterior
D right anterior
E right posterior
21 Which of the following therapeutic strategies is currently used in

visual rehabilitation for hemianopias?
A cortical visual prostheses

B full-lens prism glasses
C hyperbaric oxygen treatment
D inverting lenses
E Peli prism lenses
ARTICLE 7: HIGHER CORTICAL VISUAL DISORDERS
22 Which of the following deficits is most likely to be present in a 79-year-old

man who recently developed bilateral inferior temporal cortical lesions?
A agraphia
B alexia
C inability to detect motion
D prosopagnosia
E simultanagnosia
1500 OCTOBER 2019

23 A 68-year-old woman began having trouble with her vision 2 years ago,
and it has been getting progressively worse. She has normal visual
acuity and can recognize and name the local elements of a picture, but
she has difficulty grasping the totality of the scene or redirecting her
gaze from one part of the picture to another. She also has difficulty
reaching toward visual stimuli, but when her arms are extended, she
can accurately touch the tip of her own nose with the index finger of
either hand. Which of the following diagnoses is most likely?
A cyanocobalamin (vitamin B12) deficiency

B frontotemporal dementia
C macular degeneration
D optic chiasm glioma
E posterior cortical atrophy
24 Which of the following visual symptoms is most likely to occur after a

midbrain stroke?
A achromatopsia
B hallucinosis
C metamorphopsia
D neglect
E prosopagnosia
ARTICLE 8: APPROACH TO DIPLOPIA
25 Binocular horizontal diplopia that is more pronounced with near tasks

such as reading most strongly suggests dysfunction of which of the
following extraocular muscles?
A inferior oblique
B lateral rectus
C medial rectus
D superior oblique
E superior rectus

POSTREADING TEST
26 A 20-year-old woman presents for evaluation of transient double

vision that she has experienced for the past week. She experiences the
symptoms when looking to the left but has no problem when looking
straight ahead. Closing either eye stops the diplopia, but she feels as if
“her eyes aren’t moving right.” On examination, she has normal
ocular alignment in primary gaze. When she looks to the left there is
slowed adduction of the right eye and left-beat (or abducting)
nystagmus of the left eye. Her examination is otherwise unremarkable.
Which of the following processes is most likely responsible for this
patient’s symptoms?
A brainstem demyelination
B brainstem stroke
C idiopathic orbital myositis
D neuromuscular junction dysfunction
E posterior communicating artery aneurysm
27 A 25-year-old woman reports right eye pain and double vision when
looking to the left over the past 2 weeks. On examination, her right
eye has limited adduction, and attempting to look to the left worsens
her eye pain. Her right eye is mildly proptotic with conjunctival
injection. The remainder of her vision examination is normal as is her
neurologic examination. Which of the following diagnostic tests
would be most likely to confirm the cause of her symptoms?
A lumbar puncture with opening pressure

B MRI of the brain with contrast
C MRI of the orbits with contrast
D serum anti–acetylcholine receptor antibody titer
E serum anti–thyroid-stimulating hormone (TSH) receptor antibody titer
28 A 35-year-old man presents for evaluation of intermittent double vision

that he has been experiencing for the past 3 weeks. This symptom is not
present in the morning but becomes worse over the course of the day,
particularly on weekdays when he works as an editor. His examination
reveals incomplete elevation of both eyes in upward gaze affecting the
right eye more than the left eye. When one eyelid is elevated, the other
droops. The patient is instructed to sit in the waiting room with his eyes
closed for 30 minutes and, upon reexamination, his eye elevation is
almost normal. Which of the following processes is most likely
responsible for this patient’s symptoms?
A brainstem demyelination
B brainstem stroke
C idiopathic orbital myositis
D neuromuscular junction dysfunction
E posterior communicating artery aneurysm
1502 OCTOBER 2019

ARTICLE 9: NYSTAGMUS AND SACCADIC INTRUSIONS
29 Which of the following is the most accurate description of left-beat

jerk nystagmus?
A rapid leftward eye movement away from the desired position

followed by slow drift of the eyes back toward the desired position
B rapid rightward eye movement away from the desired position
followed by slow drift of the eyes back toward the desired position
C slow leftward eye movement away from the desired position
followed by further to-and-fro slow movements
D slow leftward eye movement away from the desired position followed
by rapid movement of the eyes back toward the desired position
E slow rightward eye movement away from the desired position followed
by rapid movement of the eyes back toward the desired position
30 A 71-year-old man has erratic bursts of spontaneous saccades that

oscillate about the midline without any intersaccadic interval. The
saccades have trajectories with simultaneous vertical, horizontal, and
torsional components. These bursts are sporadic, and they are often
provoked by shifting gaze. Which of the following underlying
conditions is most likely?
A corticobasal syndrome
B diabetes mellitus
C hereditary hemorrhagic telangiectasia
D small cell lung cancer
E thyrotoxicosis
ARTICLE 10: PARANEOPLASTIC SYNDROMES IN NEURO-OPHTHALMOLOGY
31 A 45-year-old man presents for evaluation of slowly progressive visual

problems at night. The symptoms were first noted approximately
6 months ago, and he can no longer safely drive after dark. His best
corrected visual acuity in normal lighting is 20/25 in each eye. Slit-lamp
examination and funduscopy are normal, but optical coherence
tomography reveals mild thinning of the photoreceptor layer. Neurologic
examination is otherwise unrevealing. Which of the following
conditions is most likely responsible for this patient’s night blindness?
A bilateral diffuse uveal melanocytic proliferation

B cancer-associated retinopathy
C melanoma-associated retinopathy
D paraneoplastic optic neuropathy
E POEMS (polyneuropathy, organomegaly, endocrinopathy,
monoclonal plasma cell disorder, and skin changes) syndrome

POSTREADING TEST
32 A 50-year-old man reports “sparkles” in his vision and more difficulty

seeing at night. These symptoms began 3 weeks ago and have been
rapidly worsening. His visual acuity is 20/80 in his left eye and 20/60
in his right eye. Funduscopic examination is normal, but his
electroretinogram suggests bipolar cell dysfunction. Which of the
following tumors is most likely underlying this patient’s
paraneoplastic visual syndrome?
A colon
B melanoma
C prostate
D small cell lung
E thyroid
33 A 65-year-old woman presents with progressive painless vision loss

that she has experienced over the past several months. On slit-lamp
examination, she has cataracts and thickening of the uveal tract. Her
examination is also notable for conjunctival hyperpigmentation.
Optical coherence tomography demonstrates retinal pigment
epithelium atrophy, subretinal fluid, and pigment deposition. Which
of the following conditions would be most likely in this patient?
A bilateral diffuse uveal melanocytic proliferation

B cancer-associated retinopathy
C melanoma-associated retinopathy
D paraneoplastic optic neuropathy
E POEMS (polyneuropathy, organomegaly, endocrinopathy,
monoclonal plasma cell disorder, and skin changes) syndrome
ARTICLE 11: INFECTIOUS OPTIC NEUROPATHIES
34 Interferon gamma release assays for tuberculosis, such as

QuantiFERON-TB Gold, have which of the following advantages over
purified protein derivative skin testing?
A they are less expensive

B they are more reliable in patients who need annual testing
C they are unaffected by prior immunization with bacille
Calmette-Guerin (BCG) vaccine
D they can be used to monitor response to antituberculous
treatment
E they can distinguish between active and latent infection
1504 OCTOBER 2019

35 Which of the following medications for tuberculosis is most likely to
cause optic neuropathy?
A ethambutol
B isoniazid
C pyrazinamide
D rifampin
E rifapentine
36 A 22-year-old man develops a vesicular rash on his right forearm just

above the wrist, and, over the next week, it evolves through
erythematous and papular phases. Ten days after he first noticed the
rash, he develops a low-grade fever and a tender, enlarged right
epitrochlear lymph node. One month after he first noticed the rash, he
develops neuroretinitis of the left eye, with macular edema and
retinal exudates in the shape of a star centered around the fovea.
Which of the following is the most likely causative organism?
A Bartonella henselae
B Borrelia burgdorferi
C Cryptococcus neoformans
D Mycobacterium tuberculosis
E Treponema pallidum
37 Which of the following infectious agents is associated with retinopathy

characterized by retinal whitening, retinal vascular change with a shift
to orange or white coloration, retinal hemorrhages, and papilledema?
A Cryptococcus neoformans
B Herpes simplex type 1
C Plasmodium falciparum
D Toxoplasma gondii
E Treponema pallidum
ARTICLE 12: IMAGING IN NEURO-OPHTHALMOLOGY
38 In which of the following conditions is fludeoxyglucose positron

emission tomography (FDG-PET) most likely to be useful?
A arteritic ischemic optic neuropathy

B idiopathic intracranial hypertension
C neuromyelitis optica (NMO) spectrum disorder
D toxic optic neuropathy
E traumatic optic neuropathy

POSTREADING TEST
39 A patient is being evaluated for eye movement abnormalities. With

the eyes looking straight ahead, the sclera is visible above the cornea.
There is minimal pupillary constriction with light but normal
constriction when looking at near as compared to distant targets. The
patient is able to look down but not up, and upon attempted upgaze,
the eyes converge and the globes retract. Lateral eye movements
are normal. Funduscopic examination is normal. A lesion in which of
the following anatomic locations would best explain this patient’s
clinical findings?
A cerebral peduncle
B lateral medulla
C mesencephalic tectum
D upper dorsal pons
E ventrocaudal pons
40 A patient with optic disc edema and increased retinal nerve fiber layer
thickness has an MRI that shows extensive perineural enhancement
extending into the orbital portion of the optic nerve. There is also
abnormal signal in the thalamus and pons, but the spinal cord is
normal. Which of the following conditions is most likely in this
patient?
A Leber hereditary optic neuropathy

B myelin oligodendrocyte glycoprotein–IgG (MOG-IgG)-
seropositive optic neuritis
C multiple sclerosis
D neuromyelitis optica (NMO) spectrum disorder
E optic pathway glioma
1506 OCTOBER 2019

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
By Douglas J. Gelb, MD, PhD, FAAN; James W. M. Owens Jr, MD, PhD
NEURO-OPHTHALMOLOGY
Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon completion of the Postreading Self-Assessment and

CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This

program is an Accredited Self-Assessment
Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the Office of Continuing Medical Education and Professional
Development, University of Calgary, on April 1, 2017. Refer to the CME
tab on ContinuumJournal.com for dates of accreditation. Canadian
participants should visit MAINPORT (mainport.org) to record learning and
outcomes. Canadian participants can claim a maximum of 20 hours (credits
are automatically calculated).
ARTICLE 1: THE PUPIL
1 The preferred response is D (pharmacologic dilation of the left pupil).

Instillation of 2% pilocarpine should reverse mydriasis from all causes except
pharmacologic dilation. Even without the information about the response to
pilocarpine, transtentorial herniation is unlikely in a patient with normal mental
status. For more information, refer to page 1201 of the Continuum article
“The Pupil.”

POSTREADING TEST—PREFERRED RESPONSES
2 The preferred response is D (anywhere proximal to the carotid bifurcation).

The third-order sympathetic neuron fibers that innervate the sweat glands of
the face diverge from those that innervate the pupillary dilator and the Müller
tarsal muscles at the level of the carotid bifurcation. Therefore, the presence
of ipsilateral anhidrosis in a patient with Horner syndrome implies that the
damage to the sympathetic pathway must be proximal to the carotid
bifurcation. For more information, refer to page 1201 of the Continuum article
“The Pupil.”
3 The preferred response is C (dilation of left pupil only, reversing the

anisocoria [ie, the right pupil will be smaller than the left]). In patients with
Horner syndrome, whether the lesion is at the level of first-order, second-order,
or third-order neurons, increased expression of catecholamine receptors on the
pupillary dilator muscle results in hypersensitivity, so that the pupil dilates in
response to a weak α-2 agonist, such as 0.5% apraclonidine, which has no effect
on the normal pupil. This hypersensitivity usually develops within a few days of
the onset of symptoms but occasionally takes a week. For more information,
refer to page 1203 of the Continuum article “The Pupil.”
4 The preferred response is A (damage to the right ciliary ganglion [tonic pupil]).
The large irregular pupil, light-near dissociation, slow redilation after
constriction, and cholinergic hypersensitivity are all typical of the tonic pupil
that results from damage to the ciliary ganglion or its axons. On rare occasions,
cholinergic hypersensitivity also occurs in patients with a third nerve palsy, but
a diabetic third nerve palsy is very unlikely in a 27-year-old with no previous
medical problems, and both transtentorial herniation and damage to the third
nerve nucleus would cause additional abnormalities on neurologic examination.
Pharmacologic dilation would not be reversed with pilocarpine. For more
information, refer to pages 1200–1201 of the Continuum article “The Pupil.”
ARTICLE 2: ISCHEMIC OPTIC NEUROPATHY
5 The preferred response is D (nonarteritic anterior ischemic optic neuropathy).

This patient most likely has nonarteritic anterior ischemic optic neuropathy.
The combination of hyperemic swelling of the affected optic disc together
with a small cup to disc ratio in the unaffected eye strongly suggests this
possibility. With normal erythrocyte sedimentation rate, C-reactive protein, and
complete blood cell count and no systemic symptoms, arteritic anterior
ischemic optic neuropathy is unlikely. Posterior ischemic optic neuropathy
would not be associated with any visible changes in the optic disc. Retinal
artery occlusion would be associated with retinal edema rather than optic disc
edema. For more information, refer to page 1218 of the Continuum article,
“Ischemic Optic Neuropathy.”
1508 OCTOBER 2019

6 The preferred response is D (sildenafil). Sildenafil and other PDE5 inhibitors
have been associated with an increased risk of nonarteritic ischemic optic
neuropathy. Aspirin, levodopa, and phenytoin have all been considered as
potential treatments for nonarteritic anterior ischemic optic neuropathy. For
more information, refer to page 1218 of the Continuum article, “Ischemic
Optic Neuropathy.”
7 The preferred response is B (initiate treatment with IV steroids). This patient’s

constellation of symptoms, signs, and laboratory results is highly suggestive of
arteritic ischemic optic neuropathy due to giant cell arteritis. Given this, it is
very important that steroid therapy be initiated immediately. Temporal artery
biopsy should be undertaken in all patients suspected of having giant cell
arteritis, given the long-term risk of steroid treatment in the population at risk.
However, scheduling of the biopsy is less important than immediate initiation
of high-dose steroids, especially in patients in whom vision loss has already
occurred. Tocilizumab is an adjunct to and not a substitute for immediate
steroid treatment. For more information, refer to pages 1228–1229 of the
Continuum article, “Ischemic Optic Neuropathy.”
8 The preferred response is E (posterior ischemic optic neuropathy). Normal

fundi rule out any form of anterior ischemic optic neuropathy, retinal artery
occlusion, or anterior optic neuritis (papillitis). Slow pupillary light responses,
together with normal fundi, imply bilateral retrobulbar optic neuropathy.
Posterior ischemic optic neuropathy is often seen after prolonged operations,
particularly spinal procedures. For more information, refer to page 1231 of
the Continuum article, “Ischemic Optic Neuropathy.”
ARTICLE 3: OPTIC NEURITIS
9 The preferred response is D (right optic nerve lesion extending into optic
chiasm on MRI). The optic nerve lesions in patients with optic neuritis due to
neuromyelitis optica spectrum disorder (NMOSD) tend to be more
longitudinally extensive and posterior than the optic nerve lesions in patients
with optic neuritis due to multiple sclerosis (MS) and more likely to involve the
optic chiasm and optic tract. Visual acuity is typically 20/400 or worse in
patients with optic neuritis due to NMOSD, whereas it is typically 20/200 or
better in patients with optic neuritis due to MS. Oligoclonal bands are present
more commonly in patients with MS than in patients with NMOSD. A right
afferent pupillary defect and normal funduscopic examination would be typical
of patients with right optic neuritis due to either NMOSD or MS. For more
information, refer to pages 1237–1241 of the Continuum article “Optic Neuritis.”

10 The preferred response is E (plasma exchange). Studies have shown

improved visual outcomes in patients who received plasma exchange for
corticosteroid-refractory optic neuritis. Studies of IV immunoglobulin (IVIg) for
corticosteroid-refractory optic neuritis have not shown any improvement in
visual outcomes, although this might have been because of too long a delay
before initiating the treatment. Acyclovir, azathioprine, and bone marrow
transplant have not been studied in patients with corticosteroid-refractory
optic neuritis. For more information, refer to page 1244 of the Continuum
article “Optic Neuritis.”
11 The preferred response is C (myelin oligodendrocyte glycoprotein–IgG-

seropositive optic neuritis). Optic disc edema is uncommon in patients who
have chronic relapsing inflammatory optic neuropathy, idiopathic optic
neuritis, optic neuritis associated with multiple sclerosis, or optic neuritis
associated with neuromyelitis optica (NMO) spectrum disorders, but it is
common in patients who have optic neuritis associated with myelin
oligodendrocyte glycoprotein immunoglobulin. Perineural optic nerve
enhancement is also common in patients who have optic neuritis associated
with myelin oligodendrocyte glycoprotein immunoglobulin. For more
information, refer to pages 1246–1247 of the Continuum article “Optic Neuritis.”
ARTICLE 4: TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES
12 The preferred response is A (amiodarone). Amiodarone optic neuropathy

presents much like nonarteritic anterior ischemic neuropathy, with decreased
visual acuity and altitudinal visual field loss, although it is often bilateral and
tends to be subacute in onset rather than acute. Disc edema is prominent and
may take months to resolve. Ethambutol and linezolid tend to produce
subacute bilateral vision loss with cecocentral field defects. Tacrolimus optic
neuropathy may present similarly to amiodarone optic neuropathy, but the
associated disc edema tends to be less profound and the MRI often reveals
posterior reversible encephalopathy syndrome (PRES). Vigabatrin produces a
loss of peripheral vision with central sparing. For more information, refer to
pages 1270–1271 of the Continuum article “Toxic-Metabolic and Hereditary
Optic Neuropathies.”
13 The preferred response is E (methanol). Methanol intoxication produces acute

bilateral vision loss with a hyperemic optic disc and a metabolic acidosis, a
finding not expected with any of the other options. Chloramphenicol,
aminoglycosides, and fluoroquinolones can all produce disc hyperemia but
tend to produce more subacute vision loss without metabolic acidosis.
Amiodarone produces vision loss with disc edema. For more information, refer
to pages 1272–1273 of the Continuum article “Toxic-Metabolic and Hereditary
1510 OCTOBER 2019

14 The preferred response is A (NADH dehydrogenase gene sequencing). NADH
dehydrogenase gene sequencing is most likely to reveal the cause of this
patient’s vision loss. This patient’s presentation would be typical of Leber
hereditary optic neuropathy, with acute unilateral painless central vision loss in
a male in the second to third decades of life. The OPA1 gene is a cause of
autosomal dominant optic atrophy, which usually causes insidious bilateral
painless vision loss. Copper deficiency and vitamin B12 deficiency would both
cause subacute vision loss. For more information, refer to pages 1276–1277 of
the Continuum article “Toxic-Metabolic and Hereditary Optic Neuropathies.”
ARTICLE 5: IDIOPATHIC INTRACRANIAL HYPERTENSION
15 The preferred response is E (enlarged physiologic blind spot). The typical

progression of visual field defects in idiopathic intracranial hypertension is initial
enlargement of the physiologic blind spot, followed by arcuate field defects,
initially in the inferonasal portion of the visual field, then progressive
constriction of the field with relative sparing of central vision until late in the
course. For more information, refer to pages 1294–1295 of the Continuum
article “Idiopathic Intracranial Hypertension.”
16 The preferred response is D (vitamin A). Vitamin A and retinoids (which are
derived from vitamin A) can cause intracranial hypertension. For more
information, refer to page 1301 of the Continuum article “Idiopathic Intracranial
Hypertension.”
17 The preferred response is C (magnetic resonance venogram [MRV]). During

pregnancy and the postpartum period, patients have an increased risk of
developing cerebral venous sinus thrombosis, which can cause a clinical
syndrome that mimics idiopathic intracranial hypertension. For more
information, refer to page 1301 and Table 5-4 of the Continuum article
“Idiopathic Intracranial Hypertension.”

ARTICLE 6: CHIASMAL AND POSTCHIASMAL DISEASE
18 The preferred response is E (posterior cerebral). The presence of macular (ie

central) sparing in this case of homonymous hemianopia points to a vascular injury
to the contralateral occipital cortex due to posterior cerebral artery occlusion.
Macular sparing occurs in these cases because the occipital tip (which processes
the central visual field) receives backup perfusion from a branch of the
unaffected middle cerebral artery. Occlusions of the anterior or lateral choroidal
arteries would cause a lateral geniculate nucleus infarct and associated
homonymous sectoral loss (top and bottom thirds of the affected visual field
from anterior choroidal artery and middle third from lateral choroidal artery). A
middle cerebral artery would cause ischemia to the optic radiations, causing a
homonymous hemianopia without macular sparing. For more information, refer to
page 1326 of the Continuum article “Chiasmal and Postchiasmal Disease.”
19 The preferred response is A (lateral geniculate nucleus). This patient has a

homonymous sectoranopia consistent with a lesion in the lateral geniculate
nucleus due to lateral choroidal artery infarct contralateral to the defect. For
more information, refer to page 1319 of the Continuum article “Chiasmal and
Postchiasmal Disease.”
20 The preferred response is D (right anterior). This patient has a junctional

scotoma consistent with a lesion in the right anterior aspect of the chiasm
involving the right optic nerve (producing the right central scotoma)
and the left inferior crossing fibers, which travel near the junction of the
chiasm and right optic nerve (producing the left superior temporal defect). For
more information, refer to page 1313 of the Continuum article “Chiasmal
and Postchiasmal Disease.”
21 The preferred response is E (Peli prism lenses). Peli prism lenses direct a
portion of the blind field into the seeing field of one eye. Cortical visual
prostheses, while currently in clinical trials, are not a presently employed
rehabilitation strategy. For more information, refer to pages 1326–1327 of the
Continuum article “Chiasmal and Postchiasmal Disease.”
ARTICLE 7: HIGHER CORTICAL VISUAL DISORDERS
22 The preferred response is D (prosopagnosia). Neurons in the inferior

occipitotemporal cortex are selectively responsive to faces more than
other visual stimuli, and most patients with acquired prosopagnosia have
bilateral inferotemporal cortex lesions. For more information, refer to
pages 1345–1347 of the Continuum article “Higher Cortical Visual Disorders.”
1512 OCTOBER 2019

23 The preferred response is E (posterior cortical atrophy). This patient
has simultanagnosia, ocular apraxia, and optic ataxia, all of which are
characteristic of Balint syndrome. Patients with this syndrome have bilateral
parietooccipital damage. When the syndrome develops over the course of
months or years, a common cause is posterior cortical atrophy, which is
often associated with the histopathologic features of Alzheimer disease.
For more information, refer to pages 1349, 1351 of the Continuum article
“Higher Cortical Visual Disorders.”
24 The preferred response is B (hallucinosis). Lesions in the midbrain or thalamus

affecting the reticular activating system or thalamic intralaminar nuclei may
cause a syndrome called peduncular hallucinosis that is thought to represent
internally generated imagery resulting from disinhibition of higher visual areas.
For more information, refer to pages 1355–1356 of the Continuum article
“Higher Cortical Visual Disorders.”
ARTICLE 8: APPROACH TO DIPLOPIA
25 The preferred response is C (medial rectus). Vision for near tasks such as
reading requires convergence, which would be mediated by the medial rectus
muscle. Binocular horizontal diplopia that worsens with distance vision
suggests a problem with the lateral rectus muscle (or cranial nerve VI) as
divergence is needed for far tasks. For more information, refer to page 1365 of
the Continuum article “Approach to Diplopia.”
26 The preferred response is A (brainstem demyelination). This patient has

intranuclear ophthalmoplegia, which, in an otherwise healthy 20-year-old,
would most likely be caused by brainstem demyelination affecting the medial
longitudinal fasciculus. In a patient older than 50 years of age, a brainstem
stroke would be more likely. For more information, refer to page 1369 of the
Continuum article “Approach to Diplopia.”
27 The preferred response is C (MRI of the orbits with contrast). The clinical
presentation is most consistent with idiopathic orbital myositis: a woman in
her third decade with unilateral eye pain, conjunctival injection and proptosis,
and diplopia due to a muscle innervated by the third cranial nerve (the medial
rectus in this case). An MRI of the orbit with contrast would be most likely to
demonstrate diagnostic findings (thickening and enhancement of the
myotendinous insertion of the affected muscle). For more information, refer
to pages 1372–1373 of the Continuum article “Approach to Diplopia.”

28 The preferred response is D (neuromuscular junction dysfunction). This

patient’s constellation of symptoms and signs is most consistent with
myasthenia gravis caused by dysfunction of the neuromuscular junction.
Particularly key are that his symptoms are worse over the course of the day
but still intermittent and that his symptoms improve with rest. For
more information, refer to page 1371 of the Continuum article “Approach
to Diplopia.”
ARTICLE 9: NYSTAGMUS AND SACCADIC INTRUSIONS
29 The preferred response is E (slow rightward eye movement away from the
desired position followed by rapid movement of the eyes back toward the
desired position). Jerk nystagmus is characterized by slow drift of the eyes
away from the desired position followed by a rapid corrective movement in
the opposite direction. The nystagmus is named for the rapid corrective
movement. For example, left-beat jerk nystagmus is characterized by slow
rightward drift of the eyes away from the desired position followed by a rapid
leftward corrective movement. Pendular nystagmus is characterized by
slow drift of the eyes away from the desired position followed by further
to-and-fro slow movements. For more information, refer to page 1377 of the
Continuum article “Nystagmus and Saccadic Intrusions.”
30 The preferred response is D (small cell lung cancer). This patient’s eye
movements are characteristic of opsoclonus, which most often occurs as
a paraneoplastic condition or in the setting of parainfectious brainstem
encephalitis. Small cell lung cancer and breast cancer are the tumors most
often associated with opsoclonus in adults. For more information, refer to
page 1384 of the Continuum article “Nystagmus and Saccadic Intrusions.”
ARTICLE 10: PARANEOPLASTIC SYNDROMES IN NEURO-OPHTHALMOLOGY
31 The preferred response is B (cancer-associated retinopathy). The slowly

progressive retinal photoreceptor dysfunction together with a normal
slit-lamp and funduscopic examinations would be most suggestive of
cancer-associated retinopathy. Melanoma-associated retinopathy would
present much more rapidly, while bilateral diffuse uveal melanocytic
proliferation would be characterized by loss of vision and cataracts in an
older patient. Patients with POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes) often
have disc edema as well as sensory and motor symptoms. Patients with
paraneoplastic optic neuropathy would also have decreased central vision as
well as disc edema. For more information, refer to page 1403 of the Continuum
article “Paraneoplastic Syndromes in Neuro-ophthalmology.”
1514 OCTOBER 2019

32 The preferred response is B (melanoma). This patient’s clinical presentation
is typical for melanoma-associated retinopathy. The other tumors listed are
all associated with cancer-associated retinopathy, which tends to present
more slowly. For more information, refer to page 1406 of the Continuum article
“Paraneoplastic Syndromes in Neuro-ophthalmology.”
33 The preferred response is A (bilateral diffuse uveal melanocytic

proliferation). This patient’s demographics (a woman in her sixties) and
clinical presentation (slowly progressive painless vision loss) together with
cataracts and thickening of the uveal tract all point to bilateral diffuse uveal
melanocytic proliferation. This diagnosis also supported by her optical
coherence tomography findings. For more information, refer to page 1407 of
the Continuum article “Paraneoplastic Syndromes in Neuro-ophthalmology.”
ARTICLE 11: INFECTIOUS OPTIC NEUROPATHIES
34 The preferred response is C (they are unaffected by prior immunization with

bacille Calmette-Guerin (BCG) vaccine). Interferon gamma release assays
for tuberculosis, such as QuantiFERON-TB Gold, detect interferon production
in response to exposure with specific tuberculosis antigens but not bacilli
Calmette-Guerin (BCG) vaccine. They cannot distinguish between active and
latent infection, and they cannot be used to monitor response to treatment.
They are not recommended for annual screening. For more information, refer
to page 1424 of the Continuum article “Infectious Optic Neuropathies.”
35 The preferred response is A (ethambutol). Optic neuropathy occurs in about

1% of patients taking ethambutol. It is dependent on dose, occurring in 18% of
patients taking more than 35 mg/kg/d for more than 2 months, 5% to 6% of
patients taking 25 mg/kg/d for more than 2 months, and less than 1% of
patients taking 15 mg/kg/d for more than 2 months. For more information,
refer to page 1425 of the Continuum article “Infectious Optic Neuropathies.”
36 The preferred response is A (Bartonella henselae). The clinical history of a

localized cutaneous lesion at the site of inoculation with development
of a tender, enlarged lymph node proximal to the inoculation site about
2 weeks after the initial inoculation is typical of catscratch disease, caused by
B. henselae. About 5% to 10% of patients develop ocular involvement, most
often unilateral neuroretinitis, usually about 4 weeks after the initial infection.
A star-shaped macular exudate is characteristic but not specific. For more
information, refer to pages 1426–1427 of the Continuum article “Infectious

37 The preferred response is C (Plasmodium falciparum). The four key

components of malarial retinopathy are retinal whitening, retinal vascular
change, retinal hemorrhage, and papilledema. For more information, refer to
pages 1433–1434 of the Continuum article “Infectious Optic Neuropathies.”
ARTICLE 12: IMAGING IN NEURO-OPHTHALMOLOGY
38 The preferred response is A (arteritic ischemic optic neuropathy). In arteritic

ischemic optic neuropathy due to giant cell arteritis, fludeoxyglucose positron
emission tomography (FDG-PET) can detect uptake in at least one affected
vascular territory. For more information, refer to page 1456 of the Continuum
article “Imaging in Neuro-ophthalmology.”
39 The preferred response is C (mesencephalic tectum). This patient has

Parinaud syndrome, which is caused by damage to the mesencephalic
tectum. Damage to the cerebral peduncle would cause ipsilateral third nerve
palsy and contralateral hemiparesis. A lesion of the upper dorsal pons could
cause ipsilateral paralysis of conjugate gaze, ataxia, and contralateral
weakness and sensory loss. Injury to the ventrocaudal pons could cause
ipsilateral sixth and seventh nerve palsies with contralateral weakness. Lateral
medullary injury can cause contralateral hemisensory loss from the body,
ipsilateral sensory loss from the face, ipsilateral ataxia, dysarthria, and
dysphagia as well as other symptoms. For more information, refer to
pages 1480–1481 of the Continuum article “Imaging in Neuro-ophthalmology.”
40 The preferred response is B (myelin oligodendrocyte glycoprotein–

IgG-seropositive optic neuritis [MOG-IgG]). This constellation of ocular and
imaging findings would be most consistent with MOG-IgG–positive optic
neuritis. In particular, the extensive perineural enhancement and optic disc
edema together with thalamic lesions would not fit any of the other options
well. For more information, refer to pages 1445–1446 of the Continuum article
“Imaging in Neuro-ophthalmology.”
1516 OCTOBER 2019

LIST OF ABBREVIATIONS
Neuro-ophthalmology GTPase Guanosine triphosphatase

HIV Human immunodeficiency virus
HSV Herpes simplex virus
ACE Angiotensin-converting enzyme IgG Immunoglobulin G
AChR Acetylcholine receptor IgM Immunoglobulin M
ACTH Adrenocorticotropic hormone IIH Idiopathic intracranial hypertension
ADEM Acute disseminated encephalomyelitis IM Intramuscular
ADP Adenosine diphosphate INO Internuclear ophthalmoplegia
AIDP Acute inflammatory demyelinating polyradiculoneuropathy IV Intravenous
AIDS Acquired immunodeficiency syndrome IVIg Intravenous immunoglobulin
ANA Antinuclear autoantibodies LEMS Lambert-Eaton myasthenic syndrome
ANNA-1 Antineuronal nuclear antibody type 1 LRP4 Lipoprotein receptor–related protein 4
ANNA-2 Antineuronal nuclear antibody type 2 MG Myasthenia gravis
APD Afferent pupillary defect MOG Myelin oligodendrocyte glycoprotein
AQP4-IgG Aquaporin-4 autoantibodies MRA Magnetic resonance angiogram;
ATP Adenosine triphosphate magnetic resonance angiography
ATPase Adenosine triphosphatase MRD1 Margin-to-reflex distance 1
BMI Body mass index MRD2 Margin-to-reflex distance 2
BPPV Benign paroxysmal positional vertigo MRI Magnetic resonance imaging
c-ANCA Cytoplasmic antineutrophil cytoplasmic antibodies mRNA Messenger ribonucleic acid
CBC Complete blood cell count MRV Magnetic resonance venography
CDC Centers for Disease Control and Prevention MS Multiple sclerosis
CLIPPERS Chronic lymphocytic inflammation with pontine MuSK Muscle-specific tyrosine kinase
perivascular enhancement responsive to steroids NAA -acetylaspartate
N-acetylaspartate
CMAP Compound muscle action potential NMDA -methyl-D-aspartate
N-methyl-
CMV Cytomegalovirus
NMO Neuromyelitis optica
CNS Central nervous system
NMOSD Neuromyelitis optica spectrum disorder
CRMP-5 Collapsin response mediator protein-5
OCT Optical coherence tomography
CRP C-reactive protein
PCR Polymerase chain reaction
CSF Cerebrospinal fluid
PDE 5 Phosphodiesterase 5
CT Computed tomography
PET Positron emission tomography
CTA Computed tomography angiography
PML Progressive multifocal leukoencephalopathy
CTLA-4 Cytotoxic T-lymphocyte–associated antigen 4
POEMS Polyneuropathy, organomegaly, endocrinopathy,
DNA Deoxyribonucleic acid
monoclonal plasma cell disorder, and skin changes
DTI Diffusion tensor imaging
PPD Purified protein derivative
DWI Diffusion-weighted imaging
PRES Posterior reversible encephalopathy syndrome
EBV Epstein-Barr virus
REM Rapid eye movement
EEG Electroencephalography
RNA Ribonucleic acid
ELISA Enzyme-linked immunosorbent assay
RPR Rapid plasma reagin
EMG Electromyography
SLE Systemic lupus erythematosus
ESR Erythrocyte sedimentation rate
SOD Superoxide dismutase
FDA US Food and Drug Administration
SPECT Single-photon emission computed tomography
FDG Fludeoxyglucose
FDG-PET Fludeoxyglucose positron emission tomography STIR Short tau inversion recovery
FLAIR Fluid-attenuated inversion recovery SWI Susceptibility-weighted imaging
fMRI Functional magnetic resonance imaging TB Tuberculosis
GABA γ-Aminobutyric
-Aminobutyric acid TNF-α
TNF- Tumor necrosis factor1-
factor1-α
GABAA γ-Aminobutyric
-Aminobutyric acid A TSH Thyroid-stimulating hormone
GABAB γ-Aminobutyric
-Aminobutyric acid B TVO Transient visual obscuration
GAD Glutamic acid decarboxylase VDRL Venereal Disease Research Laboratory
GAD65 Glutamic acid decarboxylase 65 VEGF Vascular endothelial growth factor
GCA Giant cell arteritis VZV Varicella-zoster virus
GFAP Glial fibrillary acidic protein WEBINO Wall-eyed bilateral internuclear ophthalmoplegia
GRE Gradient recalled echo WHO World Health Organization

Neuro-Ophthalmology
Article 1: The Pupil
Marc A. Bouffard, MD. Continuum (Minneap Minn). October 2019;
25 (5 Neuro-Ophthalmology):1194–1214.
ABSTRACT
PURPOSE OF REVIEW:
The goal of this article is to review the anatomy and physiology of pupillary function and then
employ that information to develop a comprehensive framework for understanding and
diagnosing pupillary disorders.
RECENT FINDINGS:
The contribution of rods and cones to the pupillary light reflex has long been known. A third
photosensitive cell type, the intrinsically photosensitive retinal ganglion cell, has recently been
discovered. This cell type employs melanopsin to mediate a portion of the pupillary light reflex
independent of rods and cones (the postillumination pupillary response) and photic regulation of
circadian rhythm.
SUMMARY:
The autonomic nervous systemregulates pupil size in response to stimuli. The parasympathetic
nervous system causes miosis in response to light and near visual stimuli. These stimuli activate
supranuclear pathways that project to the Edinger-Westphal nuclei. The sympathetic nervous
system causes mydriasis in response to a variety of arousing factors, both physiologic
(wakefulness) and pathologic (pain). Abnormalities of physiologic function cause disturbances of
pupil size, shape, and response to stimuli. The clinical approach to pupillary abnormalities
should focus on the clinical and pharmacologic assessment of the pupil’s expected response to
diverse stimuli.
KEY POINTS
• The pupillary sphincter muscle is located concentrically near the inner margin of the iris and mediates
pupillary constriction via cholinergic stimulation from parasympathetic neurons.
• The pupillary dilator is composed of muscles radially arranged around the pupil that are stimulated by the
sympathetic nervous syndrome via adrenergic input.
• The pupil constricts to both light and viewing of a near target. These two reflexes share the same anatomic
efferent limb, the first-order neuron of which is located in the parasympathetic Edinger-Westphal nucleus
and the second-order neuron of which is located in the ciliary ganglion. However, the parasympathetic
neurons that mediate the near reflex outnumber those involved in the pupillary light reflex by a ratio of 30:1.
• Rods, cones, and intrinsically photosensitive retinal ganglion cells all contribute to the pupillary light reflex.

• Retinal ganglion cells stimulate the ipsilateral olivary pretectal nucleus in response to light. Each olivary
pretectal nucleus innervates the bilateral Edinger-Westphal nucleus, although the contralateral
Edinger-Westphal nucleus is more highly innervated.
• The near triad encompasses pupillary miosis, convergence, and accommodation. Accommodation refers to
relaxation of the ciliary body and a resulting increase in the concavity of the lens to allow for focus on an
object at near; accommodation does not refer to the miosis that accompanies it as part of the near triad.
• Axons originating from the third-order sympathetic neurons in the superior cervical ganglion that innervate
the superior and inferior Müller tarsal muscles and the pupillary dilator form a plexus around the internal
carotid artery. Axons originating from third-order sympathetic neurons in the superior cervical ganglion that
innervate the sweat glands of the face adhere to the external carotid artery on route to their target.
• Every examination of patients with anisocoria should include a detailed assessment of eye movements
including cover-uncover testing) and of lid position and function.
• Anisocoria resulting from parasympathetic denervation is maximized in the light (when both pupils should
constrict maximally).
• Chronic mydriasis in complete isolation is extraordinarily unlikely to result from a third nerve palsy.
• Tonic pupils are irregular, display sectoral hypokinesis (which may require the aid of a slit lamp to visualize),
are slow to redilate after constriction (thus their name), and demonstrate light-near dissociation (reacting
better to near stimuli than light). They may be idiopathic, occur frequently in young women, and are only
rarely associated with other pathologic processes. Ninety percent of cases are monocular.
• Constriction of a mydriatic pupil by dilute pilocarpine (0.125%) was traditionally thought to be specific to
tonic pupils. However, this is incorrect; preganglionic third nerve palsies resulting from compression and
trauma may result in a mydriatic pupil responsive to 0.125% pilocarpine.
• Pilocarpine 2% will cause constriction of any mydriatic pupil other than one that is pharmacologically dilated.
• Anisocoria resulting from sympathetic denervation of the pupil is maximized in the dark (when both pupils
should dilate maximally).
• The ptosis that results from sympathetic denervation is often subtle (1 mm to 2 mm), and frequently both the
upper and lower lids are affected (as both the superior and inferior tarsus receive sympathetic innervation),
which sometimes results in the optical illusion of enophthalmos (pseudoenophthalmos).
• Apraclonidine, a weak α-2 agonist, has largely supplanted cocaine and hydroxyamphetamine in confirmation
of sympathetic denervation of the pupil. Denervation supersensitivity may take up to 1 week to occur;
apraclonidine testing will not detect acute sympathetic denervation of the pupil. Apraclonidine cannot be
used in young children because of the possibility of respiratory depression.
• Tonic pupils, which are mydriatic at the outset, may eventually become miotic and irregular.
• Bilaterally small pupils may result from bilateral sympathetic denervation of the pupillary dilator, from
factors causing predominance of parasympathetic tone over sympathetic tone, or from chronic reinnervation
as seen with bilateral tonic pupils.
• Bilaterally small irregular pupils should prompt consideration of chronic tonic pupils and Argyll Robertson
pupils. Treponemal syphilis serologies should be ordered.
• When in doubt as to the etiology of an irregularly shaped pupil, enlist the aid of an ophthalmologist who can
employ a slit lamp to look for important anatomic details and signs of inflammation that are difficult to
observe with the naked eye.
• The most common congenital causes of irregular pupils include coloboma, aniridia, and pupillary
decentration, referred to as corectopia.
• When evaluating irregular pupils, consider trauma, inflammation with synechiae formation, tonic pupils, and
Argyll Robertson pupils.
• Light-near dissociation typically localizes to the ciliary ganglion, dorsal midbrain, or bilateral optic nerves.

Article 2: Ischemic Optic Neuropathy
Mark J. Morrow, MD, FAAN. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
Vision is often threatened or lost by acute ischemic damage to the optic nerves. Such pathology
most often affects the anterior portion of the nerve and is visible on funduscopic examination.
Ischemic optic neuropathy is associated with typical vascular risk factors and with one systemic
disease in particular: giant cell arteritis (GCA). This article provides an overview of the three
major classes of ischemic optic neuropathy, including information on risk factors, differential
diagnosis, evaluation, and management.
RECENT FINDINGS:
Optical coherence tomography provides precise anatomic imaging in ischemic optic neuropathy,
showing neural loss weeks before it is visible on examination. Refinements of optical coherence
tomography reveal optic nerve microvasculature and may assist in understanding pathogenesis
and verifying diagnosis. New diagnostic algorithms and cranial vascular imaging techniques help
define the likelihood of GCA in patients with ischemic optic neuropathy. Finally, intraocular drug
and biological agent delivery holds promise for nonarteritic ischemic optic neuropathy, whereas
newer immunologic agents may provide effective steroid-sparing treatment for GCA.
SUMMARY:
It is essential to recognize ischemic optic neuropathy upon presentation, especially to determine
the likelihood of GCA and the need for immediate steroid therapy. A broad differential diagnosis
should be considered so as not to miss alternative treatable pathology, especially in cases with
retrobulbar optic nerve involvement.
KEY POINTS
• Anterior ischemic optic neuropathy presents as acute, painless monocular visual loss that may progress over
several days.
• Anterior ischemic optic neuropathy must be distinguished from optic neuritis, compressive masses, and
retinal artery and vein occlusions. This distinction is usually clear-cut after a thorough history and
examination, but imaging is occasionally needed in equivocal cases. Blood work for giant cell arteritis and
vascular risk factors is indicated in most cases.
• Nonarteritic anterior ischemic optic neuropathy is the most common cause of acute optic neuropathy in
people older than age 50, peaking in incidence around age 60 and somewhat more common in men than
women. It is most strongly linked to congenitally crowded optic discs. Other putative risk factors include
hypertension, diabetes mellitus, and obstructive sleep apnea.
• Examination in arteritic and nonarteritic anterior ischemic optic neuropathy shows visual field impairment,
variable loss of acuity, a swollen optic disc, and a relative afferent pupillary defect in the affected eye.
Visual loss and optic disc swelling tend to be worse in the arteritic form (arteritic anterior ischemic
optic neuropathy).
• The optic disc in the unaffected eye almost always shows a small cup in nonarteritic anterior ischemic optic
neuropathy. Over 1 to 3 months, optic disc swelling resolves to a flat, atrophic disc in all cases of anterior
ischemic optic neuropathy. Optical coherence tomography shows evidence of retinal ganglion cell body loss
after only a few weeks.

• Because no treatment has been established for nonarteritic cases, it is especially important to exclude giant
cell arteritis as a cause of anterior ischemic optic neuropathy.
• Although most patients with nonarteritic anterior ischemic optic neuropathy will show some spontaneous
improvement, many are left with significant deficits. No therapy has been proven to improve outcomes,
although several clinical trials are ongoing.
• Nonarteritic anterior ischemic optic neuropathy strikes the second eye in 15% to 20% of patients over 5 years.
Limited evidence has shown that aspirin may reduce risk over the first few years, but no clear long-term
benefit of aspirin or any other preventive treatment has been proven. Vascular risk factors such as
hypertension and diabetes mellitus should be addressed as a matter of general health maintenance.
• Arteritic anterior ischemic optic neuropathy, like giant cell arteritis itself, is more common with advancing
age (mean 70 to 75 years) and in women by at least 2:1 over men. Although most patients presenting with
arteritic anterior ischemic optic neuropathy have signs and symptoms of giant cell arteritis, about 20%
present with visual problems alone and have no systemic features; this has been described as occult giant
cell arteritis. Thus, a high level of suspicion is essential.
• Erythrocyte sedimentation rate and C-reactive protein are the most sensitive tests for giant cell arteritis,
each being elevated in about 85% of cases. These test results are nonspecific, however, and both are
negative in about 10% of patients. Thrombocytosis and anemia are also common in giant cell arteritis and
should increase diagnostic suspicion if present.
• Temporal artery biopsy remains the gold standard for the diagnosis of giant cell arteritis and should be
arranged within the first few days of a suspected presentation. Although pathologic findings are eventually
altered by therapy, these changes take weeks and are not a consideration with regard to the immediate
initiation of corticosteroid treatment.
• For patients at moderate to high risk of giant cell arteritis who present with anterior ischemic optic
neuropathy or transient visual loss, most experts recommend immediate initiation of high-dose IV steroids
(eg, 1000 mg/d methylprednisolone) followed by oral therapy, typically prednisone 1 mg/kg or 80 mg/d.
Many advocate initial hospital admission to monitor for steroid side effects, arrange temporal artery biopsy,
and provide patient education.
• Corticosteroids are the mainstay of acute and chronic therapy in giant cell arteritis. They have many side
effects, especially in the elderly population at highest risk for the condition.
• In most patients, systemic manifestations of giant cell arteritis respond quickly to treatment. Despite this,
steroids must be tapered very slowly over 1 year or more to avoid relapse, while monitoring symptoms,
erythrocyte sedimentation rate, and C-reactive protein. Various immune suppressant drugs have been used
to augment steroids and reduce their long-term risks.
• Tocilizumab recently became the first US Food and Drug Administration–approved option for giant cell
arteritis.
• The diagnosis of posterior ischemic optic neuropathy requires contrast imaging of the brain and orbits to
exclude inflammatory and compressive conditions. Outside of the postoperative setting, giant cell arteritis
should be suspected and thoroughly excluded.
• Posterior ischemic optic neuropathy is a diagnosis of exclusion because no confirmatory funduscopic
findings are seen and many other processes may affect the retrobulbar optic nerve. It is reasonable to
anticipate an ischemic cause of acute, fundus-negative optic neuropathy after major surgery and in giant cell
arteritis.
• No specific treatment for posterior ischemic optic neuropathy has been established, other than in those
cases presumed to be of arteritic origin.

Article 3: Optic Neuritis
Jeffrey L. Bennett, MD, PhD, FAAN. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
This article discusses the clinical presentation, evaluation, and management of the patient with
optic neuritis. Initial emphasis is placed on clinical history, examination, diagnostic testing, and
medical decision making, while subsequent focus is placed on examining specific inflammatory
optic neuropathies. Clinical clues, examination findings, neuroimaging, and laboratory testing
that differentiate autoimmune, granulomatous, demyelinating, infectious, and paraneoplastic
causes of optic neuritis are assessed, and current treatments are evaluated.
RECENT FINDINGS:
Advances in technology and immunology have enhanced our understanding of the pathologies
driving inflammatory optic nerve injury. Clinicians are now able to interrogate optic nerve
structure and function during inflammatory injury, rapidly identify disease-relevant autoimmune
targets, and deliver timely therapeutics to improve visual outcomes.
SUMMARY:
Optic neuritis is a common clinical manifestation of central nervous system inflammation.
Depending on the etiology, visual prognosis and the risk for recurrent injury may vary. Rapid and
accurate diagnosis of optic neuritis may be critical for limiting vision loss, future neurologic
disability, and organ damage. This article will aid neurologists in formulating a systematic
approach to patients with optic neuritis.
KEY POINTS
• The classic presentation of optic neuritis associated with multiple sclerosis is unilateral, moderate,
painful vision loss with an afferent pupillary defect and normal fundus examination. Bilateral vision
loss, lack of pain, and severe loss of vision should raise concern for an alternative inflammatory
optic neuropathy.
• Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)–IgG
optic neuritis cause severe vision loss and are more frequently bilateral. MOG–IgG optic neuritis frequently
causes significant optic disc edema.
• Ophthalmic testing is not generally helpful in differentiating acute optic neuropathies. Visual evoked
potentials may help to detect subtle optic nerve injury when clinical examination findings are uncertain.
• Optical coherence tomography may be useful in detecting subtle retinal pathology or documenting the
extent of prior injury in cases of recurrent optic neuritis.
• MRI of the orbits is the most sensitive diagnostic test (90%) for optic neuritis; however, a normal orbital MRI
scan does not exclude optic neuritis.
• The pattern of inflammation of the optic nerve on MRI may provide diagnostic information. NMOSD optic
neuritis more often affects the optic chiasm, intracranial optic nerve, and optic tracts; MOG-IgG optic
neuritis frequently inflames the intraorbital optic nerve and optic nerve sheath. Both disorders may be
bilateral with longitudinally extensive lesions.
• Antinuclear autoantibodies are observed in many patients with optic neuritis; however, they are much less
frequent in multiple sclerosis–associated optic neuritis.
• CSF pleocytosis may be highest in MOG-IgG optic neuritis, whereas CSF eosinophils are suggestive of NMOSD.
• Oligoclonal bands should suggest multiple sclerosis–associated optic neuritis, especially if they persist.

• Aquaporin-4 IgG is rarely, if ever, isolated to the CSF.
• High-dose IV methylprednisolone (1000 mg/d IV for 3 days) is effective at improving the speed of recovery of
optic neuritis. Small studies have demonstrated that the type of steroid and mode of delivery (oral versus IV)
are likely inconsequential. Lower dosages of oral prednisone (1 mg/kg) are contraindicated for acute optic
neuritis treatment because of a higher risk of relapse.
• Plasma exchange may be useful in treating steroid-resistant optic neuritis, severe optic neuritis due to
NMOSD, and recurrent optic neuritis at risk for poor recovery. Time to administration of plasma exchange
may be critical to treatment success.
• Optic neuritis is the initial presentation of multiple sclerosis in 25% of individuals. The presence of enhancing
and nonenhancing brain MRI lesions meeting dissemination in space criteria by the 2017 McDonald criteria is
diagnostic of multiple sclerosis. If no enhancing lesions are present, oligoclonal bands may provide
dissemination in time criteria according to the 2017 McDonald criteria.
• It is important to differentiate optic neuritis due to NMOSD from that due to multiple sclerosis. The prognosis
for visual recovery is poorer for NMOSD optic neuritis, and the risk for recurrence is high.
• NMOSD optic neuritis should prompt consideration for early plasma exchange.
• Treatments for multiple sclerosis, such as interferon beta, fingolimod, and natalizumab, have been
documented to exacerbate NMOSD disease activity.
• MOG-IgG disease frequently causes recurrent optic neuritis. Bilateral optic neuritis, longitudinal optic nerve
lesions, optic nerve sheath enhancement, and steroid responsiveness are important clinical and radiologic
clues.
• GFAP-IgG encephalomyelitis is commonly associated with optic nerve papillitis. As a result, disc edema is
prominent, but vision loss is rare.
• Perivascular radial enhancement on MRI is highly suggestive of GFAP-IgG disease. GFAP-IgG may be isolated
to the CSF in a large fraction of patients.
• Autoimmune optic neuropathy, relapsing isolated optic neuritis, and chronic relapsing inflammatory optic
neuropathy are idiopathic seronegative optic neuropathies characterized by their responsiveness to or
dependency on steroid immunosuppression. They are currently a diagnosis of exclusion for patients with
recurrent optic neuritis seronegative for AQP4-IgG and MOG-IgG.
• Isolated optic neuritis associated with systemic lupus erythematosus or Sjögren syndrome is rare. Patients
diagnosed with systemic lupus erythematosus or Sjögren syndrome and optic neuritis should be tested for
AQP4-IgG.
• Patients with systemic lupus erythematosus or Sjögren syndrome with optic neuritis who are seropositive for
AQP4-IgG are at higher risk for poor visual recovery than patients with systemic lupus erythematosus or
Sjögren syndrome without AQP4-IgG.
• Paraneoplastic optic neuritis associated with collapsin response mediator protein-5 (CRMP-5)
autoantibodies may mimic idiopathic optic neuritis. Bilateral, asynchronous optic neuritis with prominent
vitreitis and retinal leakage in an older adult should raise clinical concern.
• CRMP-5 optic neuritis is frequently accompanied by central or peripheral neurologic injury. The presence of
transverse myelitis may mimic NMOSD.
• Sarcoid optic neuropathy may be extremely difficult to diagnose in the absence of ocular inflammation or
systemic disease.
• Angiotensin-converting enzyme levels in the serum and CSF are notoriously insensitive for neurosarcoidosis.
When suspicious, CT chest, gallium scan, or fludeoxyglucose positron emission tomography are
recommended for identifying involved tissue amenable to biopsy.
• While multiple infectious agents have been associated with neuroretinitis, many cases are idiopathic.
Exposure to common infectious causes should be evaluated. When the infectious workup is negative,
alternative noninflammatory causes of optic disc edema with a macular star should be considered.
• Optic neuritis with disc edema and cranial neuropathies should be investigated for Lyme disease in endemic
areas.

• Syphilitic optic neuritis is often associated with ocular inflammation. Optic disc edema, when present, is
usually prominent. A detailed social history identifying high-risk behavior for HIV should be performed in
suspicious cases.
• Optic neuritis due to direct viral infection is rare. Clinical and examination clues include recent zoster ophthalmicus,
encephalitis, immunosuppression, risk for mosquito-borne illness, or associated retinitis or chorioretinitis.
• Optic neuritis from tuberculosis is often associated with uveitis and orbital apex syndrome. MRI brain
findings include leptomeningeal enhancement, ependymitis, abscess, infarct, encephalitis, and tubercles.
Article 4: Toxic-Metabolic and

Hereditary Optic Neuropathies
Cristiano Oliveira, MD. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
The diagnosis of visual loss from toxic-metabolic and hereditary optic neuropathies may be
delayed in some cases because of a failure to elicit important information in the clinical history or
to recognize typical examination findings. An understanding of the features specific to each type
of toxic-metabolic and hereditary optic neuropathy, and of the underlying mechanism of insult
to the optic nerve, could lead to earlier recognition, diagnosis, and treatment (when available).
RECENT FINDINGS:
Understanding of the role of mitochondria in toxic-metabolic and hereditary optic neuropathies
is growing, particularly regarding the mechanism of insult of certain agents (medications and
toxins) and of vitamin B12 deficiency. New developments in the quest for treatment for
hereditary optic neuropathy, specifically Leber hereditary optic neuropathy, are being seen.
SUMMARY:
Toxic-metabolic and hereditary optic neuropathies present in a similar fashion, with painless,
progressive, bilateral visual loss with dyschromatopsia and cecocentral visual field defects. The
associated retinal ganglion cell and axonal loss is typically due to mitochondrial dysfunction
caused by an exogenous agent (toxic), by insufficient or deficient substrate (metabolic or
nutritional), or by abnormal proteins or mitochondrial structure determined by a genetic
mutation (hereditary).
KEY POINTS
• Optic neuropathies present with visual acuity loss, dyschromatopsia (color vision dysfunction), and visual
field defect. Toxic-metabolic and hereditary neuropathies should be considered when vision loss is bilateral,
particularly when central or cecocentral (central defect extending to the physiologic blind spot) visual field
loss is present.
• The underlying mechanism of retinal ganglion cell and axonal loss in toxic-metabolic and hereditary
neuropathies is mitochondrial dysfunction caused by an exogenous agent (toxic), insufficient or deficient
substrate (metabolic or nutritional), or abnormal proteins or structure of the mitochondria determined by a
genetic mutation (hereditary).
• The mitochondria are responsible for adenosine triphosphate production via oxidative phosphorylation that
occurs in the respiratory chain polypeptide complexes. They are also the major site of production of free
radicals, which are highly reactive molecular fragments that can cause oxidative cellular damage.

• Mitochondrial dysfunction leads to damage of retinal ganglion cells and their axons through a double-hit
mechanism. The first hit results from impaired axon organelle transportation and impulse conduction due to
adenosine triphosphate deficit, and the second hit results from superoxide-induced oxidative damage and
signaling of apoptosis.
• The papillomacular bundle is formed by the retinal ganglion cell axons located between the perineural
macula and the optic disc, and its injury results in cecocentral visual field loss. The small diameter of the
papillomacular bundle axons is thought to be the basis of their greater vulnerability when facing adenosine
triphosphate deficit and increased superoxide production in the setting of mitochondrial dysfunction.
• Obtaining information regarding ongoing or previous toxic exposure (medications or other substances), prior
surgery (bariatric or gastrointestinal resections and bypass), and dietary habits/restrictions is an essential
step in the investigation of patients presenting with bilateral progressive visual loss.
• Ethambutol affects mitochondrial function by interfering with complexes I and IV and cytochrome coxidase.
The ocular toxicity is dose related and more likely to occur in patients treated with 25 mg/kg/d or higher
(dose must be adjusted for renal insufficiency). In addition to the bilateral cecocentral field defect, patients
may present with bitemporal field defects, some with evidence of chiasmal abnormal signal. Early diagnosis
and drug cessation are essential and may result in visual recovery.
• Antibiotics such as linezolid, chloramphenicol, and ciprofloxacin have been implicated in toxic optic
neuropathies through inhibition of mitochondrial protein synthesis.
• Amiodarone has been associated with an optic neuropathy with optic disc swelling and visual acuity and field
loss, similar to nonarteritic anterior ischemic optic neuropathy. However, it is more often bilateral, with an
insidious course and protracted resolution of the disc edema.
• Toxic optic neuropathies due to tumor necrosis factor-α inhibitors and tacrolimus can be unilateral, bilateral,
or sequential. As patients receiving these agents may be immunosuppressed, a thorough investigation to
exclude infectious and neoplastic etiologies is particularly important.
• Vigabatrin causes retinal toxicity and a peculiar pattern of secondary optic nerve atrophy with nasal disc
pallor sparing the temporal region (spared papillomacular bundle). Patients present with progressive
concentric constriction sparing central vision.
• Nutritional optic neuropathies have a clinical presentation indistinct from most cases of toxic optic
neuropathy and should be considered in patients who have had gastrointestinal bypass surgery, have
stringent dietary restrictions, or have a history of substance abuse and secondary malnourishment.
• Vitamin B12 (cobalamin) is an intracellular superoxide scavenger, which is particularly important for
unmyelinated axons in the papillomacular bundle. Cobalamin deficiency may cause superoxide
accumulation, which is a signal for retinal ganglion cell apoptosis, therefore causing retinal ganglion cell and
axon loss.
• Toxins and malnutrition can have a synergistic effect, causing optic neuropathy and visual loss. Carriers of
genetic mutations determining mitochondrial dysfunction may be more vulnerable to both toxic and
metabolic optic neuropathies.
• More than 90% of all Leber hereditary optic neuropathy cases have been associated with one of the three
primary mitochondrial DNA mutations of genes coding for protein subunits of complex I (m.11778G>A,
m.14484T>C, m.3460G>A), with the first being the most prevalent mutation.
• Leber hereditary optic neuropathy presents with sudden unilateral painless central visual loss with fellow
eye involvement within weeks to months (sequential optic neuropathy). More than 90% of the carriers
become symptomatic before 50 years of age, with peak onset in the second and third decades of life.
• In Leber hereditary optic neuropathy, dilated funduscopy may be completely normal or may show a
hyperemic optic nerve with swelling of the retinal nerve fiber layer and tortuosity of the central retinal
vessels. Optic disc temporal pallor is typically seen within 6 weeks of onset of visual loss, and cupping may
also be observed.
• Because of the level of visual loss at presentation and the infrequent visual recovery, the visual prognosis in
Leber hereditary optic neuropathy is typically poor. Patients with the 14484 mutation are the most likely to
recover, followed by those with the 3460 mutation.

• No treatment has been proven effective for Leber hereditary optic neuropathy. The early use of idebenone,
an antioxidant that can transport electrons directly to complex III bypassing a dysfunctional complex I, may
be beneficial. Gene therapy trials are currently under way.
• Most patients with and carriers of autosomal dominant optic atrophy harbor mutations in the OPA1 gene, a
nuclear gene on chromosome 3 that codes for an inner mitochondrial membrane protein essential for
maintenance of the mitochondrial cristae network. The mutation results in a decrease in adenosine
triphosphate production and increased formation of reactive oxygen species.
• Typical patients with autosomal dominant optic atrophy present with a history of insidious, bilateral, painless
loss of visual acuity and color vision beginning in the first or second decades of life, with cecocentral field
loss and the finding of optic disc temporal pallor. Of patients with autosomal dominant optic atrophy, 50% to
75% will experience further visual decline later in life, and no spontaneous recovery has been reported.
• The assessment of patients with a history of progressive bilateral visual loss and bilateral optic disc pallor
should include a thorough medical history and examination, followed by laboratory testing for vitamins B12,
B1, and B6; folate; methylmalonic acid; copper; and zinc and contrast-enhanced MRI of the brain and orbits.
Genetic testing is typically done as a subsequent step in the workup.
• No proven treatment is available for autosomal dominant optic atrophy. Routine follow-up examinations to
assess visual acuity and color vision as well as Humphrey visual field testing and optical coherence
tomography to assess structural changes help ensure that patients are following the natural history of the
disease and can identify concurrent pathology when deviation from the expected clinical evolution is seen.
• Although a 50% risk of transmission to offspring exists in autosomal dominant optic atrophy, because of
variable penetrance, the risk of developing visual loss is 60% to 88%. Even among those who develop the
disease, great variability may exist in the level of visual dysfunction.
Article 5: Idiopathic Intracranial

Hypertension
Matthew J. Thurtell, MBBS, MSc, FRACP. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
Idiopathic intracranial hypertension is a syndrome of increased intracranial pressure of unclear
etiology that most often occurs in obese women of childbearing age but can also occur in men,
children, and older adults. This article reviews the diagnostic criteria, clinical features,
neuroimaging findings, differential diagnosis, and management options for this condition.
RECENT FINDINGS:
Recent population studies have found that the annual incidence of idiopathic intracranial
hypertension is increasing in association with obesity rates, whereas recent scientific studies
indicate a possible role for androgen sex hormones and adipose tissue in the pathogenesis of the
disease. Prospective clinical trials have demonstrated a role for weight loss, acetazolamide, and
topiramate in the management of mild disease. A recently begun randomized multicenter trial of
surgical interventions will provide insight into the indications for surgical intervention, optimal
timing and choice of intervention, and long-term outcomes.
SUMMARY:
Idiopathic intracranial hypertension is a disorder producing symptoms and signs of increased
intracranial pressure in the absence of an alternative cause. The main goals of treatment are to

preserve visual function and alleviate symptoms, which can usually be achieved with a
combination of weight loss, medical therapies, and surgical interventions depending on the
severity of symptoms and vision loss, response to treatment, and subsequent clinical course.
KEY POINTS
• Idiopathic intracranial hypertension is a syndrome of increased intracranial pressure that usually occurs in
obese women of childbearing age.
• Idiopathic intracranial hypertension is a diagnosis of exclusion. Therefore, other etiologies of increased
intracranial pressure must be ruled out based on clinical history, neuroimaging, and CSF examination.
• The incidence of idiopathic intracranial hypertension appears to be increasing and is strongly correlated with
obesity rates.
• Greater levels of weight gain are associated with increased risk of idiopathic intracranial hypertension,
although the condition can also develop in the setting of moderate weight gain in patients who are not obese.
• Headache is the most common symptom of idiopathic intracranial hypertension. However, many patients
have headaches that have features of other primary headache disorders, such as migraine and tension
headache.
• Headache in idiopathic intracranial hypertension is often disabling and associated with poorer quality of life but is
not correlated with intracranial pressure and, thus, may not improve with lowering of intracranial pressure.
• Transient visual obscurations are the second most common symptom of idiopathic intracranial hypertension.
They are thought to result from transient ischemia of the optic nerve head and are associated with higher
grades of papilledema.
• Progressive visual field loss may not be appreciated by patients, underscoring the importance of formal
perimetry (visual field testing) in the evaluation and monitoring of idiopathic intracranial hypertension.
• Pulse-synchronous (pulsatile) tinnitus occurs in about half of patients with idiopathic intracranial hypertension
and is thought to arise because of turbulent blood flow across transverse venous sinus stenoses.
• Papilledema is the most common and important sign in idiopathic intracranial hypertension. It is usually
bilateral and symmetric. The threat of vision loss is correlated with its severity.
• If untreated, papilledema can result in progressive and irreversible vision loss with optic atrophy.
• Visual field loss is difficult to exclude with confrontation visual field testing. Consequently, formal perimetry
is mandatory in the evaluation and monitoring of idiopathic intracranial hypertension.
• An enlarged physiologic blind spot is the first visual field defect to develop in idiopathic intracranial
hypertension, followed by arcuate visual field defects (initially in the inferonasal visual field) and,
subsequently, progressive constriction with sparing of central vision until late.
• Sixth and seventh nerve palsies can occur as false localizing signs in patients with idiopathic intracranial
hypertension.
• Ophthalmic investigations are necessary to determine the severity of vision loss and papilledema. In patients
with equivocal papilledema or possible pseudopapilledema, consultation with an ophthalmologist or,
ideally, a neuro-ophthalmologist is suggested.
• In patients with an atypical or fulminant presentation of idiopathic intracranial hypertension, magnetic resonance
venography of the head with contrast should be obtained to exclude cerebral venous sinus thrombosis.
• Common imaging findings in idiopathic intracranial hypertension include an empty sella turcica, increased
optic nerve sheath dilation and tortuosity, posterior globe flattening, optic disc elevation and enhancement,
inferior cerebellar tonsillar descent, and transverse venous sinus stenosis.
• In adults, a CSF opening pressure of greater than 25 cm H2O is high, while an opening pressure of 20 cm H2O
to 25 cm H2O is probably abnormal if symptoms, signs, and imaging findings are consistent with increased
intracranial pressure. In children, recent studies suggest that a CSF opening pressure of greater than 28 cm
H2O is high.
• Retinal nerve fiber layer thickness from optical coherence tomography correlates with papilledema severity.
However, retinal nerve fiber layer thickness measurements must be interpreted with caution in patients who
could have combined optic disc edema and atrophy.

• Raster scans obtained through the optic nerve head with optical coherence tomography may show
biomechanical changes that correlate with increased intracranial pressure and might be useful for monitoring
response to treatment.
• Several medications (eg, tetracycline antibiotics, retinoids, and lithium) and cerebral venous outflow
obstruction (eg, due to cerebral venous sinus thrombosis) can cause a clinical syndrome that mimics
idiopathic intracranial hypertension.
• Weight loss of 6% to 10% of initial body weight can be effective in inducing a remission of idiopathic
intracranial hypertension. Bariatric surgery can be effective in patients who are morbidly obese and
struggle to lose weight.
• Treatment of idiopathic intracranial hypertension with acetazolamide produces improvement in visual field
loss, papilledema, symptoms, and quality of life. Common side effects of acetazolamide therapy include
paresthesia, dysgeusia, nausea, vomiting, and diarrhea.
• Topiramate is effective in treatment of mild to moderate idiopathic intracranial hypertension and can be
considered in patients who are unable to tolerate acetazolamide or when headache is prominent. Common
side effects of topiramate therapy include mental slowing, lethargy, paresthesia, and loss of appetite.
• Surgical therapies are usually reserved for patients with idiopathic intracranial hypertension who have
a fulminant presentation and for patients who fail to improve or worsen despite maximally tolerated
medical therapy.
• CSF shunting is effective for rapidly reducing intracranial pressure. Complications can include infection,
obstruction, and migration of shunt tubing; shunt revision is often needed.
• Optic nerve sheath fenestration is effective in relieving pressure on the optic nerve, thereby reducing
papilledema and improving visual function. Complications can include vision loss, tonic pupil, and diplopia.
• Transverse venous sinus stenting has been reported to improve symptoms, signs, visual function, and
intracranial pressure. Complications can include in-stent thrombosis, subdural hemorrhage, and
development of new stenoses proximal to the stent.
• The indications for surgical intervention in idiopathic intracranial hypertension, the timing and choice of
surgical intervention, and long-term outcomes remain unclear.
• The main goals of treatment of idiopathic intracranial hypertension are to preserve vision and alleviate
symptoms. Thus, the management is tailored depending on the severity of vision loss, papilledema, and
symptoms as well as the patient’s response to medical therapy and ability to tolerate medical therapy.
• Patients with idiopathic intracranial hypertension with minimal to mild vision loss can usually be managed
with weight loss and medical therapy, whereas patients with moderate to severe vision loss often need a
combination of weight loss, aggressive medical therapy, and, occasionally, surgical intervention.
• Patients with idiopathic intracranial hypertension should be managed in coordination with an
ophthalmologist or neuro-ophthalmologist, since formal perimetry and monitoring of papilledema severity is
needed to guide management.
Article 6: Chiasmal and Postchiasmal

Disease
Heather E. Moss, MD, PhD, FAAN. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the anatomy, symptoms, examination findings, and causes of diseases
affecting the optic chiasm, optic tracts, optic radiations, and occipital lobes.

RECENT FINDINGS:
Modern ophthalmic imaging can be used to monitor the effects of diseases of the optic chiasm
and tract on the retinal ganglion cells. It can also be used to visualize transsynaptic degeneration
of the anterior visual pathway in the setting of acquired retrogeniculate lesions. Visual
prostheses that directly stimulate the occipital lobe are a potential strategy for rehabilitation
that is in active clinical trials.
SUMMARY:
Detecting and characterizing visual deficits due to optic chiasm and retrochiasmal disease are
important for the diagnosis, localization, and monitoring of neurologic disease; identifying
patient disability; and guiding rehabilitation.
KEY POINTS
• Central vision can be affected in chiasmal lesions but is spared in unilateral retrochiasmal lesions.
• If a homonymous field defect is complete, localization beyond a retrochiasmal location is not possible based
on peripheral vision testing alone.
• Confrontation visual field deficits are specific but not sensitive for peripheral vision loss.
• Optic nerve head pallor in both eyes is diagnostic of chronic injury to the retinal ganglion cells in both optic
nerves, the chiasm, or one optic tract.
• Lack of optic nerve head pallor does not exclude injury to the ganglion cells in the optic nerves, chiasm, or
optic tracts.
• Relative afferent pupillary defects can occur in asymmetric chiasm and unilateral optic tract lesions.
• Lesions affecting the anterior chiasm affect the peripheral temporal fields, whereas those affecting the
posterior chiasm affect the central temporal fields with sparing of the periphery.
• The optic chiasm is best viewed on coronal or sagittal MRI or CT sequences obtained with narrow slice
spacing.
• Homonymous peripheral vision loss affects navigation, and homonymous visual field loss that reaches central
vision affects reading.
• Homonymous visual field loss with an afferent pupillary defect on the same side of the visual field loss
suggests a contralateral optic tract lesion.
• Visual symptoms due to optic radiation disease are usually accompanied by other neurologic symptoms
localizing to the affected territory.
• Congruous homonymous visual field loss is a hallmark of occipital lobe disease.
• Posterior cerebral artery infarcts often spare central vision and far peripheral vision in the affected field,
which can limit disability from vision loss.
• Posterior cortical atrophy and Creutzfeldt-Jakob disease can cause homonymous visual field loss with only
subtle neuroimaging findings.
Article 7: Higher Cortical Visual Disorders

Sashank Prasad, MD; Marc Dinkin, MD. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the disorders that result from disruption of extrastriate regions of the
cerebral cortex responsible for higher visual processing. For each disorder, a historical
perspective is offered and relevant neuroscientific studies are reviewed.

RECENT FINDINGS:
Careful analysis of the consequences of lesions that disrupt visual functions such as facial
recognition and written language processing has improved understanding of the role of key
regions in these networks. In addition, modern imaging techniques have built upon prior lesion
studies to further elucidate the functions of these cortical areas. For example, functional MRI
(fMRI) has identified and characterized the response properties of ventral regions that
contribute to object recognition and dorsal regions that subserve motion perception and
visuospatial attention. Newer network-based functional imaging studies have shed light on the
mechanisms behind various causes of spontaneous visual hallucinations.
SUMMARY:
Understanding the regions and neural networks responsible for higher-order visual function
helps the practicing neurologist to diagnose and manage associated disorders of visual
processing and to identify and treat responsible underlying disease.
KEY POINTS
• After initial processing in the primary visual cortex, numerous adjacent cortical areas continue the work of
analyzing specific aspects of visual information. These areas, which are situated in the occipital, temporal,
and parietal lobes, are given names such as V2, V3, V4, V5, lateral occipital area, or fusiform face area.
• Anton syndrome refers to cortical blindness with lack of awareness (ie, anosognosia) of the deficit.
• Visual agnosia refers to a specific impairment of the ability to recognize or interpret visually presented
information although elementary aspects of vision remain intact.
• In apperceptive visual agnosia, although spatial acuity is preserved, the remaining steps of visual processing
are disrupted at a very early stage, rendering patients unable to perceive even the most basic geometric
relationships that create the contours of a visual object.
• Associative visual agnosia describes a disorder in which basic visual perception is preserved, including
grouping of visual forms, but visual percepts cannot be associated with relevant stored semantic knowledge.
• Central hemiachromatopsia describes loss of color recognition in the hemifield contralateral to a lesion of
V4, a region in which neurons are selectively responsive to specific wavelengths of light. In clinical practice,
lesions often encompass this area as well as the adjacent inferior striate cortex (V1), causing an overlapping
superior quadrantanopia, so that the achromatopsia is only evident in the seeing inferior visual field.
• Processing in V4 adjusts for the spectral balance of incident light so that the apparent color of an object is
perceived as being fairly constant despite considerable differences in lighting environments. This
phenomenon is known as color constancy.
• Alexia without agraphia, also referred to as pure alexia or pure word blindness, describes the loss of the
ability to read, although the ability to write remains spared. It is often the result of a lesion affecting both the
left occipital cortex and the splenium of the corpus callosum. A right homonymous hemianopia ensues, while
visual information in the right occipital cortex cannot reach the left-sided language areas to allow linguistic
analysis of the visualized symbols.
• Alexia without agraphia may also result from a single lesion in the visual word form area within the
fusiform gyrus.
• Prosopagnosia is a specific form of visual agnosia in which face perception is impaired while elementary
aspects of vision, such as acuity and visual field, remain intact.
• Facial recognition in the visual system is particularly sensitive to the orientation of an image, much more so
than other types of object processing.
• Riddoch syndrome describes the preserved ability to detect motion in an otherwise blind visual field.
• Balint syndrome describes a profound disruption of visuospatial attention mechanisms resulting from
bilateral parietal lesions. Its key features are simultanagnosia, optic ataxia, and ocular apraxia.
• Simultanagnosia refers to an ability to perceive the local elements of a scene but not the global elements in
their totality.

• Optic ataxia refers to impaired reaching under visual guidance, in which reaching under proprioceptive
guidance (ie, back to one’s own nose) is preserved. Ocular apraxia refers to inaccurate saccades stemming
from a disorder of visuospatial attention.
• Unilateral parietal lobe lesions, especially of the right parietal cortex, often cause hemispatial neglect to
the contralateral side.
• Charles Bonnet syndrome refers to “release” hallucinations that occur in the context of visual loss, often
due to anterior lesions such as cataracts or macular degeneration.
• Lhermitte peduncular hallucinosis describes vivid, dreamlike hallucinations that occur during normal
wakefulness and may result from lesions to areas of the midbrain and thalamus that regulate the sleep-wake
state and normally prevent dreams from encroaching on wakefulness.
Article 8: Approach to Diplopia

Christopher C. Glisson, DO, MS, FAAN. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
“Double vision” is a commonly encountered concern in neurologic practice; the experience
of diplopia is always sudden and is frequently a cause of great apprehension and potential
disability for patients. Moreover, while some causes of diplopia are benign, others require
immediate recognition, a focused diagnostic evaluation, and appropriate treatment to prevent
vision- and life-threatening outcomes. A logical, easy-to-followapproach to the clinical
evaluation of patients with diplopia is helpful in ensuring accurate localization, a comprehensive
differential diagnosis, and optimal patient care. This article provides a foundation for
formulating an approach to the patient with diplopia and includes practical examples of
developing the differential diagnosis, effectively using confirmatory examination techniques,
determining an appropriate diagnostic strategy, and (where applicable) providing effective
treatment.
RECENT FINDINGS:
Recent population-based analyses have determined that diplopia is a common presentation in
both ambulatory and emergency department settings, with 850,000 such visits occurring
annually. For patients presenting to an outpatient facility, diagnoses are rarely serious. However,
potentially life-threatening causes (predominantly stroke or transient ischemic attack) can be
encountered. In patients presenting with diplopia related to isolated cranial nerve palsy,
immediate neuroimaging can often be avoided if an appropriate history and examination are used
to exclude worrisome etiologies.
SUMMARY:
Binocular diplopia is most often due to a neurologic cause. The onset of true “double vision”
is debilitating for most patients and commonly prompts immediate access to health care
services as a consequence of functional impairment and concern for worrisome underlying
causes. Although patients may seek initial evaluation through the emergency department or
from their primary care/ophthalmic provider, elimination of an ocular cause will not infrequently
result in the patient being referred for neurologic consultation. A logical, localization-driven,
and evidence-based approach is the most effective way to arrive at the correct diagnosis
and provide the best outcome for the patient.

KEY POINTS
• A detailed history and systematic examination can often accurately localize the cause of diplopia.
• Monocular diplopia is rarely due to neurologic pathology.
• Eliciting the orientation of the double image (horizontal, vertical, or oblique),whether diplopia is present at distance
or near, and whether the diplopia worsens in any direction of gaze are fundamental to accurate localization.
• Diplopia that occurs with fatigue does not necessarily imply myasthenia gravis; long-standing and
decompensated ocular misalignment can also become symptomatic when patients are tired or under stress
or in the setting of concomitant illness.
• Diplopia/ocular misalignment that does not change with the direction of gaze is classified as comitant;
diplopia that varies depending on the direction of gaze is termed incomitant and most often indicates
extraocular muscle dysfunction.
• Assessment of fixation is commonly overlooked during the ocular motility examination but is essential in
identifying potential pathologic features that may be associated with diplopia.
• Neuroimaging has a low diagnostic yield in isolated fourth, pupil-sparing third, and sixth nerve palsies in older
patients with vascular risk factors. However, a small number of patients older than 50 years of age may have
other causes including neoplasm, infarction, and giant cell arteritis.
• While the localization of isolated diplopia can be relatively straightforward, the complex nature of ocular
motility and coordination makes them susceptible to disruption by more diffuse cerebral dysfunction.
• Internuclear ophthalmoplegia is best identified by testing saccades.
• Patients presenting with cranial nerve VI palsy should be evaluated for signs and symptoms of increased
intracranial pressure, which includes fundus examination.
• Myasthenia gravis can mimic any pupil-sparing ocular motility deficit.
• Antibody and electrophysiologic testing for myasthenia gravis may be supportive, but this remains a primarily
clinical diagnosis.
• Patients with known or suspected thyroid ophthalmopathy should have periodic monitoring with formal
visual fields because of the possibility of peripheral vision constriction by compression of the optic nerves as
a consequence of enlarging extraocular muscles.
• For patients with new-onset (eg, microvascular) or transient (eg, myasthenia gravis–related) diplopia,
monocular occlusion for mitigation of symptoms is immediately effective and can be employed as needed
when symptoms are present.
• Prism correction is useful for patients with stable or comitant ocular misalignment; eye alignment surgery is
useful for patients with incomitant diplopia.
Article 9: Nystagmus and Saccadic

Intrusions
Janet C. Rucker, MD. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of nystagmus and saccadic intrusions with the goal of
facilitating recognition and differentiation of abnormal eye movements to assist with accurate
diagnosis of neurologic disease and evidence-based specific treatment of oscillopsia. Myriad
advances have been made in the understanding of several types of nystagmus and saccadic
intrusions, even in the past 5 to 10 years, especially regarding underlying pathophysiology,
leading to pharmacologic advances rooted in physiologic principles.

RECENT FINDINGS:
Specific recent advances in the study of nystagmus and saccadic intrusions include (1) improved
understanding of the underlying etiologies and mechanisms of nystagmus enhanced or
unmasked by provocative maneuvers such as supine position or head shaking; (2) recognition of
the differences in behavior and treatment responsivity of acquired pendular nystagmus in
demyelinating disease versus oculopalatal myoclonus; (3) recognition that oculopalatal
myoclonus results froma dual mechanism of abnormal inferior olivary gap junction connection
formation and maladaptive cerebellar learning; and (4) well-controlled clinical trials to evaluate
the efficacy of pharmacologic interventions, such as memantine for acquired pendular
nystagmus and 4-aminopyridine for downbeat nystagmus.
SUMMARY:
Accurate recognition of nystagmus and saccadic intrusions, including familiarity with the
subtleties of examination techniques that allow such eye movements to be unmasked, is critical
to proper diagnosis and ultimate alleviation of the visual impairment these patients experience.
KEY POINTS
• Nystagmus can be congenital or acquired; it tends to be rhythmic and regular and, if present in central gaze,
continuous and sustained. Saccadic intrusions are more often nonrhythmic, intermittent, and unsustained.
• The initial abnormal eye movement with nystagmus is always a slow drift of the eyes that is also called a slow
phase; in contrast, saccadic intrusions are initiated by a fast saccadic eye movement.
• The two main types, or waveforms, of nystagmus are jerk and pendular, both of which may have
horizontal, vertical, and/or torsional trajectories, which may be different in the two eyes, especially
for pendular nystagmus.
• Even if no nystagmus is seen on standard examination with the patient in the upright position, provocative
maneuvers often unmask nystagmus and assist with diagnosis. Thus, they should be incorporated into the
examination of any patient with symptoms of oscillopsia, imbalance, or vertigo.
• Saccadic intrusions are divided into two broad categories: those with an intersaccadic interval between
subsequent saccades and those lacking such an interval.
• Saccadic intrusions with an intersaccadic interval include square-wave jerks, macro–square-wave jerks, and
macrosaccadic oscillations. Saccadic intrusions without an intersaccadic interval include ocular flutter and
opsoclonus.
• Square-wave jerks are pairs of small saccades, typically in the horizontal plane, that remove the eyes from
and then return them to the midline without crossing it and have an intersaccadic interval.
• Square-wave jerks occur excessively, sometimes nearly continuously, in patients with Friedreich ataxia,
multisystem atrophy, or progressive supranuclear palsy, although they may also occur in idiopathic Parkinson
disease at any stage of the illness.
• Macrosaccadic oscillations are runs of horizontal saccades that are larger than square-wave jerks, have an
intersaccadic interval, cross the midline, and build and decay around the central fixation point in a
crescendo-decrescendo pattern.
• Ocular flutter and opsoclonus consist of erratic bursts of very-high-frequency, high-velocity, back-to-back
saccades that oscillate about the midline and have no intersaccadic interval between subsequent saccades.
This is termed ocular flutter when the saccades occur only in the horizontal plane. Opsoclonus, in contrast,
contains saccades in all trajectories: horizontal, vertical, and torsional.
• Flutter and opsoclonus occur in two main clinical settings: paraneoplastic conditions and parainfectious
brainstem encephalitis.
• Acquired pendular nystagmus occurs most often in the setting of demyelinating disease or within the context
of oculopalatal myoclonus following a brainstem ischemic or hemorrhagic stroke.
• Acquired pendular nystagmus is typically very visually disabling because of the constant slow to-and-fro
foveal drifting it creates.

• Nystagmus induced by the vestibular system, via peripheral or central disruption, is jerk nystagmus with
linear-velocity slow phases that tends to follow the Alexander law, with worsening of the amplitude and
frequency of fast phases in the direction of gaze of the nystagmus fast phases (ie, right-beat jerk nystagmus
worsens in right gaze).
• Posterior canal benign paroxysmal positional vertigo represents over 80% of benign paroxysmal positional vertigo
cases and is confirmed by the presence of a vertical-torsional nystagmus induced by the Dix-Hallpike maneuver.
• Observation of the patient over several minutes is required when pure horizontal jerk nystagmus is present,
as this type of nystagmus may also occur with periodic alternating nystagmus. However, with periodic
alternating nystagmus, the nystagmus will reverse horizontal direction approximately every 90 to
120 seconds, often with a few beats of vertical nystagmus during the transition zone.
• In nearly all cases, vertical and torsional nystagmus should be present in central gaze fixation with the patient
upright, although the oscillations may be of very tiny amplitude in this patient position and only visible with
magnified views of the eye, such aswith high-resolution infrared video or during ophthalmoscopy.
• Upbeat nystagmus is most commonly seen with Wernicke encephalopathy secondary to thiamine deficiency
(in combination with horizontal gaze deficits and often with accompanying gaze-evoked nystagmus),
demyelinating disease, or stroke of the medulla or midbrain.
• Downbeat nystagmus, one of the most common forms of acquired central nystagmus seen clinically, is
jerk nystagmus induced by slow upward drifts of the eyes followed by resetting downward fast phases.
It may or may not follow the Alexander law by increasing in downward gaze (and often does not), but it nearly
always increases in amplitude and frequency in downward lateral gaze.
• Downbeat nystagmus, in most cases, represents cerebellar dysfunction, typically with lesions involving the
vestibulocerebellum (flocculus, paraflocculus, nodulus, and uvula), although cases are also reported due
to primary brainstem lesions, usually involving a group of brainstem neurons called the paramedian tracts.
• One of the prevalent forms of physiologic nystagmus commonly seen on clinical examination is gaze-evoked
nystagmus, which is also variably called end-gaze nystagmus or direction-changing nystagmus.
Article 10: Paraneoplastic Syndromes in

Neuro-ophthalmology
Lynn Gordon, MD, PhD; Marc Dinkin, MD. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
This article discusses the varied types of paraneoplastic syndromes that commonly have
neuro-ophthalmologic manifestations. Diagnostic considerations and therapeutic options for
individual diseases are also discussed.
RECENT FINDINGS:
Paraneoplastic syndromes can affect the afferent and efferent visual systems.
Paraneoplastic syndromes may result in reduced visual acuity from retinal degeneration,
alterations in melanocyte proliferation and uveal thickening, or acquired nystagmus. Ocular
motor abnormalities related to paraneoplastic syndromes may present with symptoms from
opsoclonus or from neuromuscular junction disease. Diagnosis remains challenging, but
serologic identification of some specific antibodies may be helpful or confirmatory. Treatment,
in addition to directed therapies against the underlying cancer, often requires systemic
corticosteroids, plasma exchange, or immunosuppression, but some specific syndromes
improve with use of targeted pharmacologic therapy.

SUMMARY:
Diagnosis and therapy of paraneoplastic syndromes presenting with neuro-ophthalmic symptoms
remain a challenge, but strategies are evolving and new approaches are on the horizon.
KEY POINTS
• Neuro-ophthalmologic paraneoplastic syndromes arise from remote tumor effects largely through
autoimmune responses against normal tissue that arise or are triggered by tumor expression of neuronal
proteins that elicit immune responses.
• Detection of specific antibodies against neuronal antigenic targets can be helpful in identifying
paraneoplastic disease. However, the practitioner should be aware of false-negative and false-positive
errors, the possibility of novel antibodies not yet described or available for testing, and the spectrum of
varied clinical presentations for any one antibody.
• Paraneoplastic syndromes may precede a cancer diagnosis by months or even years.
• The characteristic afferent visual paraneoplastic syndromes involve the retina in conditions such as
cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic
proliferation, but a paraneoplastic optic neuropathy may also occur, although rarely.
• Workup for possible paraneoplastic syndromes affecting the afferent visual system should include visual
acuity, color vision, pupillary testing, formal visual field testing, funduscopy, optical coherence tomography
of the retina, and electroretinogram.
• The symptoms of cancer-associated retinopathy reflect its target cell: the photoreceptor. Loss of acuity,
color vision, and central visual field as well as sensitivity to light and glare, photopsia, and flickering lights all
result from cone dysfunction, while paracentral (ring) scotomas, impaired dark adaptation, and nyctalopia
(difficulty seeing at night) result from damage to the rods.
• Testing for paraneoplastic antibodies should not be used as a screening tool for paraneoplastic disease in the
absence of a suspicious clinical presentation.
• Antibodies against recoverin, a photoreceptor protein involved in phototransduction, were the first to be
described in cancer-associated retinopathy. Cancer-associated retinopathy associated with antibodies
against α-enolase is more likely to involve pure cone dysfunction and to present months or years after the
cancer diagnosis.
• Some of the identified antibodies in cancer-associated retinopathy initiate retinal degeneration by
entering retinal photoreceptors and inducing cell death, while others appear to be induced by release of
immunologic proteins from the dying photoreceptors and may either further propagate retinal cell death or,
in some cases, serve only as markers of the disease.
• Some evidence exists for reversal of some of the retinal findings in cancer-associated retinopathy with treatment.
• Rarely, melanoma-associated retinopathy can precede the diagnosis of melanoma.
• Melanoma-associated retinopathy is typically associated with a response on the electroretinogram that
reflects bipolar cell dysfunction.
• Management of melanoma-associated retinopathy includes immunosuppression and treatment of the
underlying cancer. However, checkpoint inhibitors used to treat melanoma have been associated with the
occurrence or exacerbation of melanoma-associated retinopathy in rare cases.
• POEMS is a paraneoplastic syndrome whose name describes the protean clinical manifestations of cytokine
production, driven in part by vascular endothelial growth factor, all resulting from a monoclonal plasma cell
disorder. Papilledema may accompany the disorder, in which case CSF evaluation may reflect an increase in
protein and intracranial pressure.
• Management of paraneoplastic optic neuropathy includes treatment of the underlying cancer with or
without the use of adjunctive therapy, including systemic corticosteroids, mycophenolate mofetil, or
plasma exchange.
• Opsoclonus is a form of saccadic intrusion characterized by omnidirectional, chaotic, high-frequency
saccadic movements that may be of large amplitude and lack an intersaccadic interval.

• Reflective of brainstem or cerebellar damage, opsoclonus may result from paraneoplastic disease, with or
without myoclonus, typically from neuroblastoma in children and small cell lung carcinoma or ovarian cancer
in adults. Responsible antibodies include antineuronal nuclear antibodies type 1 (anti-Hu) and type 2 (anti-Ri).
• Lambert-Eaton myasthenic syndrome is a disease in which antibodies against the P/Q voltage-gated calcium
channel located on the presynaptic terminal of the neuromuscular junction result in their dysfunction and
secondary weakness that improves with exercise. Neuro-ophthalmic manifestations may include diplopia
and ptosis, the latter of which may improve with upgaze. The underlying cause may be paraneoplastic or
primary immune.
• Myasthenia gravis is an autoimmune disease in which an antibody-mediated attack on the acetylcholine
receptors on the postsynaptic junction of the neuromuscular junction result in fatigable generalized
weakness, often accompanied by ptosis and ophthalmoparesis. A minority of cases are associated with
thymoma, which, despite its typically indolent nature, can be invasive and, rarely, malignant.
• Involvement of bilateral medial rectus muscles in myasthenia gravis may mimic a bilateral internuclear
ophthalmoplegia.
• The Cogan lid twitch is an overshoot of the eyelid when the patient looks upward following a period of
fixation on a target in downgaze. Although not pathognomonic for myasthenia gravis, it may provide
supporting clinical evidence for the disease.
Article 11: Infectious Optic Neuropathies

Eric R. Eggenberger, DO, FAAN. Continuum (Minneap Minn). October 2019;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews common infectious optic neuropathies, focusing on the more common and
globally important entities.
RECENT FINDINGS:
Novel infections continue to emerge and drift geographically over time; not infrequently, these
have important neurologic or ocular features. Malarial retinal findings comprise a relatively
specific set of findings and serve as an invaluable aid in the diagnosis of cerebral malaria.
Therapy continues to evolve and is best formulated in concert with an infectious disease expert.
SUMMARY:
Infectious optic neuropathies are less common than inflammatory or ischemic optic
neuropathies; may present with varied, overlapping, and nonspecific clinical appearances; and
comprise an important differential consideration demanding specific therapy.
KEY POINTS
• Infectious optic neuropathy often presents with a nonspecific clinical picture including adjacent structures,
most commonly the retina and vitreous. Travel and increasingly global exposures influence the differential
diagnosis. New pathogens continue to emerge and frequently involve ocular structures.
• Tuberculosis is a common worldwide infection and shares a synergistic interconnection with HIV. Diagnosis
can be challenging; however, interferon-based laboratory tests represent a useful advance.
• Tuberculosis can affect any part of the visual system from the globe, optic nerve, chiasm, and tracts to the
occipital lobe. Optic nerve and ocular involvement are accompanied by uveitis in the vast majority of cases.
• Neuroretinitis is a nonspecific clinical syndrome that may be related to any of several different infectious
agents in addition to inflammatory or neoplastic pathophysiologies.

• Although Borrelia is an important neuropathogen, retrobulbar optic neuropathy related to Lyme disease is
extremely rare.
• Syphilis rates are increasing, and diagnostic testing can be challenging; diverse clinical presentations and a
well-earned reputation as “the great mimic” make syphilis an important treatment-altering point in the
differential of many clinical neuro-ophthalmologic presentations.
• Syphilis may involve the brain and ocular structures at any stage. When syphilis affects the eye, uveitis is the
most common form; however, the disease is notoriously variable and may affect the bulbar or retrobulbar
segment of the optic nerve with granulomatous, nongranulomatous, or ischemic pathophysiologies.
• Acute retinal necrosis is an important ocular condition producing rapidly progressive retinal vasculitis with
retinal necrosis, often with coincident or subsequent papillitis.
• Zika virus is the latest in novel infectious epidemics, with a relatively distinct congenital syndrome of
microcephaly and retinal/optic nerve changes.
• Cerebral malaria is often associated with relatively distinct retinal changes, including retina whitening, retinal
vascular changes, retinal hemorrhage, and occasional papilledema.
• Toxoplasmosis is widespread geographically and the most common infectious cause of uveitis in many
clinics. Treatment is effective at preventing visual loss in most patients.
• Fungal infections are rapidly progressive in the immunocompromised host, with frequent lethal outcomes in
the absence of early diagnosis and aggressive therapy.
Article 12: Imaging in

Neuro-ophthalmology
Fiona Costello, MD, FRCPC; James N. Scott, MD, MSc. Continuum (Minneap Minn).
October 2019; 25 (5 Neuro-Ophthalmology):1438–1490.
ABSTRACT
PURPOSE OF REVIEW:
This article discusses an approach to imaging in patients with neuro-ophthalmologic disorders,
with emphasis on the clinical-anatomic localization of lesions affecting afferent and efferent
visual function.
RECENT FINDINGS:
Advances in MRI, CT, ultrasound, and optical coherence tomography have changed how
neuro-ophthalmic disorders are diagnosed and followed in the modern clinical era.
SUMMARY:
The advantages, disadvantages, and indications for various imaging techniques for
neuro-ophthalmologic disorders are discussed, with a view to optimizing how these tools can be
used to enhance patient care.
KEY POINTS
• The diagnostic pursuit of “what” the problem is in neuro-ophthalmology is often spearheaded by knowledge
of “where” the problem is because of the elegant topographic organization of the afferent and efferent
visual systems.
• The diagnosis of optic neuritis associated with neuromyelitis optica spectrum disorder can be aided by
adding orbital MRI sequences to cranial imaging; orbital views typically reveal longitudinal lesion(s) that
extend back to the optic chiasm.

• MRI of the brain, orbits, and spinal cord can help identify patterns of central nervous system inflammation
that are pathognomonic for neuromyelitis optica spectrum disorder.
• Anti–myelin oligodendrocyte glycoprotein IgG–associated optic neuritis commonly presents with optic
disc edema and MRI evidence of perineural enhancement of the optic nerve extending into surrounding
tissues in the orbit.
• Autoimmune glial fibrillary acidic protein–IgG astrocytopathy presents with a highly characteristic radial
pattern of periventricular enhancement best seen with cranial MRI.
• Optic perineuritis with MRI evidence of a tram-track sign is a nonspecific radiologic finding and may be
seen in a variety of inflammatory and neoplastic disorders affecting the optic nerve. Complementary CT
images can reveal calcification in suspected cases of optic nerve sheath meningioma, but in other cases a
systemic evaluation of the patient may be needed to render the diagnosis.
• Enhanced-depth optical coherence tomography can be used to detect buried optic disc drusen, which
appear as signal-poor structures surrounded by a hyperreflective rim.
• Tortuosity of the optic nerve sheaths, flattening of the posterior globes, an empty sella turcica, and
transverse venous sinus stenosis are radiologic signs of raised intracranial pressure in patients with idiopathic
• Optical coherence tomography–derived ganglion cell–inner plexiform layer analysis can detect the presence
of a compressive lesion in the region of the optic chiasm, sometimes in advance of visual field loss.
Moreover, the extent of optical coherence tomography– measured retinal nerve fiber layer thinning and
ganglion cell–inner plexiform layer loss in the preoperative phase can help predict the extent of
postoperative visual recovery after surgical or medical decompression of compressive lesions.
• In cases of tumefactive multiple sclerosis, lesions can appear masslike and may be confused with neoplasms.
In this setting, the so-called open pattern of ring enhancement is a useful radiologic sign to help
distinguish demyelinating lesions.
• Recently, a punctate pattern depicted with MRI (referring to T2-weighted hyperintense or enhancing
punctate lesions) has been shown to be a highly specific feature of progressive multifocal
leukoencephalopathy and may be the first detectable imaging feature.
• Specific MRI patterns of brainstem involvement are highly suggestive of neuromyelitis optica spectrum
disorder, including lesions of the dorsal medulla and area postrema structures.
• In addition to vascular insults, the brainstem is also vulnerable to demyelinating, neoplastic,
neurodegenerative, inflammatory, infectious, and metabolic disorders.

Issue Overview
Neuro-ophthalmology, Volume 25, Number 5, August 2019
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Neuro-ophthalmology
issue, participants will be able to:
 Define the anatomy and physiology of the pupil and its innervation, leveraging that
knowledge of proper function to comprehensively approach abnormal pupillary function
 Describe the diagnosis, treatment, and prognosis of anterior and posterior ischemic optic
neuropathy and identify giant cell arteritis as a cause of these conditions
 Differentiate, diagnose, and treat inflammatory optic nerve injuries
 Discuss the features and underlying mechanism of toxic-metabolic and hereditary optic
neuropathies
 Discuss the diagnostic criteria, clinical features, imaging findings, differential diagnosis, and
management approach for idiopathic intracranial hypertension
 Describe the symptomatic, examination, and evaluation implications of neurologic diseases
affecting the optic chiasm, optic tracts, optic radiations, and occipital lobes
 Describe the anatomic regions responsible for higher visual processing and discuss the
spectrum of symptoms that may accompany disorders of these regions
 Systematically use elements of the history and examination to localize and develop a
differential diagnosis to guide further confirmatory testing in patients with diplopia

 List the most common types of nystagmus and saccadic intrusions, discuss the most common
etiologies and mechanisms for abnormal spontaneous eye movements, and initiate the
pharmacologic management of oscillopsia
 Recognize the wide range of neuro-ophthalmic clinical manifestations of paraneoplastic
disease and discuss the diagnostic and therapeutic approaches to patients with these diseases
 Describe the clinical features and management of infectious optic neuropathies
 Discuss how various imaging modalities can be used to refine the diagnosis and management
of neuro-ophthalmic disorders
Core Competencies
This Continuum: Lifelong Learning in Neurology Neuro-ophthalmology issue covers the
following core competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Marc Dinkin, MD, Guest Editor

Associate Professor, Departments of Neurology, Ophthalmology, and Neurosurgery; Director of
Neuro-ophthalmology, Weill Cornell Medical College, New York, New York
Relationship Disclosure: Dr Dinkin serves as an associate editor for the Journal of Neuro-Ophthalmology and as an
editor for Practical Neurology and has received compensation for travel for speaking engagements from The
American Austrian Foundation and research/grant support from the Helen and Robert Apel Foundation. Dr Dinkin
has provided depositions and expert testimony on medicolegal cases involving idiopathic intracranial hypertension,
ischemic optic neuropathy, and head trauma.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Dinkin discusses the unlabeled/investigational use of
azathioprine for cancer-associated retinopathy; corticosteroids for bilateral diffuse uveal melanocytic proliferation,
cancer-associated retinopathy, melanoma-associated retinopathy, opsoclonus-myoclonus syndrome, and
paraneoplastic optic neuropathy; IV immunoglobulin (IVIg) for cancer-associated retinopathy, melanoma-associated
retinopathy, and opsoclonus-myoclonus syndrome; lenalidomide for POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes); mycophenolate mofetil for cancer-associated
retinopathy and paraneoplastic optic neuropathy; and rituximab for cancer-associated retinopathy.
Jeffrey L. Bennett, MD, PhD, FAAN

Gertrude Gilden Professor for Neurodegenerative Disease Research, Professor of Neurology,
Ophthalmology, and Immunology Program in Neuroscience, University of Colorado School of
Medicine, Aurora, Colorado
Relationship Disclosure: Dr Bennett serves on the editorial boards of the Journal of Neuro-Ophthalmology, Multiple
Sclerosis and Neurology: Neuroimmunology & Neuroinflammation and as a consultant for AbbVie Inc; Alexion;
Chugai Pharmaceutical Co, Ltd; Clene Nanomedicine; EMD Serono, Inc; Equillium, Inc; Frequency Therapeutics;
Genentech, Inc; MedImmune; and SanofiGenzyme. Dr Bennett has received research/grant support from EMD
Serono, Inc; the Guthy-Jackson Charitable Foundation; Mallinckrodt Pharmaceuticals; the National Eye Institute
(R01EY022936);the National Institute of Allergy and Infectious Diseases (UM1AI110498); and Novartis AG. Dr
Bennett receives publishing royalties from UpToDate, Inc, and has received personal compensation for serving as a
medicolegal consultant on medical cases involving neuroinflammatory and neuro-ophthalmologic disorders.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bennett discusses the unlabeled/investigational use of
plasma exchange and apheresis for the treatment of optic neuritis.
Instructor in Neurology, Harvard Medical School; Codirector of Neuro-Ophthalmology, Beth
Israel Deaconess Medical Center, Boston, Massachusetts
Relationship Disclosure: Dr Bouffard serves as a consultant for the US Department of Justice Vaccine Injury
Compensation Program.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bouffard reports no disclosure.
Fiona Costello, MD, FRCPC

Associate Professor, Departments of Clinical Neurosciences and Surgery, Cumming School of
Medicine, University of Calgary, Calgary, Alberta, Canada
Relationship Disclosure: Dr Costello has served on advisory boards for Frequency Therapeutics and Alexion Canada
and receives research/grant support from the Hotchkiss Brain Institute and the MS Research Program.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Costello reports no disclosure.
Eric R. Eggenberger, DO, FAAN

Professor of Ophthalmology, Neurology, and Neurosurgery, Mayo Clinic College of Medicine
and Science, Jacksonville, Florida

Relationship Disclosure: Dr Eggenberger reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Eggenberger reports no disclosure.
Christopher C. Glisson, DO, MS, FAAN

Medical Director, Neuro-Ophthalmology, Mercy Health Hauenstein Neurosciences, Grand
Rapids, Michigan; Assistant Professor, Department of Neurology and Ophthalmology, Michigan
State University, East Lansing, Michigan
Relationship Disclosure: Dr Glisson reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Glisson reports no disclosure.
Lynn Gordon, MD, PhD

Professor of Ophthalmology, Stein Eye Institute; Senior Associate Dean, David Geffen School of
Medicine at University of California Los Angeles, Los Angeles, California
Relationship Disclosure: Dr Gordon serves on the board of trustees of the American Academy of Ophthalmology
and on the editorial boards of Ophthalmology Retina, Ocular Immunology and Inflammation, and the Journal of
Neuro-Ophthalmology. Dr Gordon receives licensing fees from the University of California Los Angeles for
epithelial membrane protein 2.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gordon discusses the unlabeled/investigational use of
azathioprine for cancer-associated retinopathy; corticosteroids for bilateral diffuse uveal melanocytic proliferation,
cancer-associated retinopathy, melanoma-associated retinopathy, opsoclonus-myoclonus syndrome, and
paraneoplastic optic neuropathy; IV immunoglobulin (IVIg) for cancer-associated retinopathy, melanoma-associated
retinopathy, and opsoclonus-myoclonus syndrome; lenalidomide for POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes); mycophenolate mofetil for cancer-associated
retinopathy and paraneoplastic optic neuropathy; and rituximab for cancer-associated retinopathy.
Mark J. Morrow, MD, FAAN

Chair, Department of Neurology, Harbor-University of California Los Angeles Medical Center;
Clinical Professor of Neurology, David Geffen School of Medicine at University of California
Los Angeles, Los Angeles, California
Relationship Disclosure: Dr Morrow reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Morrow discusses the unlabeled/investigational use
of medications for the treatment of ischemic optic neuropathy, none of which are approved by the US Food and
Heather E. Moss, MD, PhD, FAAN

Assistant Professor of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto,
California; Assistant Professor of Neurology and Neurological Sciences, Stanford University,
Stanford, California
Relationship Disclosure: Relationship Disclosure: Dr Moss serves on the board of directors of the North American
Neuro-Ophthalmology Society and as a review editor for Current Eye Research, an associate editor for Frontiers in
Neurology, a section editor for the Journal of Neuro-Ophthalmology, and a special section editor for Neuro-
Ophthalmology. Dr Moss receives research/grant support from the Myelin Repair Foundation, the National Institutes
of Health/National Eye Institute (K23 EY024345, P30 EY 026877), and Research to Prevent Blindness and
publishing royalties from Elsevier. Dr Moss has served as a legal consultant providing record review and deposition
on neuro-ophthalmic diseases.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Moss reports no disclosure.
Cristiano Oliveira, MD
Assistant Professor of Ophthalmology, Weill Cornell Medicine, New York, New York

Relationship Disclosure: Dr Oliveira reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Oliveira discusses the unlabeled/investigational use
of gene therapy and idebenone for Leber hereditary optic neuropathy.
Sashank Prasad, MD
Associate Professor of Neurology, Harvard Medical School; Director, Harvard Brigham and
Women’s Hospital–Massachusetts General Hospital Neurology Residency; Chief, Division of
Neuro-ophthalmology, Brigham and Women’s Hospital, Boston, Massachusetts
Relationship Disclosure: Dr Prasad serves as an associate editor for the Journal of Neuro-Ophthalmology, receives
publishing royalties from McGraw-Hill, and has provided expert medicolegal opinion on legal cases involving
idiopathic intracranial hypertension, ischemic optic neuropathy, and traumatic brain injury.
Unlabeled/Investigational Use Disclosure: Dr Prasad reports no disclosure.
Janet C. Rucker, MD
Bernard A. and Charlotte Marden Professor of Neurology; Professor of Ophthalmology, New
York University School of Medicine, New York, New York
Relationship Disclosure: Dr Rucker reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rucker discusses the unlabeled/investigational use of
medications for the management of abnormal eye movements, none of which are approved by the US Food and
James N. Scott, MD, MSc

Clinical Associate Professor, Departments of Diagnostic Imaging and Clinical Neurosciences,
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Relationship Disclosure: Dr Scott reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Scott reports no disclosure.
Matthew J. Thurtell, MBBS, MSc, FRACP

Associate Professor of Ophthalmology and Neurology; Director of Neuro-ophthalmology,
University of Iowa, Iowa City, Iowa
Relationship Disclosure: Dr Thurtell serves on the editorial board of the Journal of Neuro-Ophthalmology, receives
research/grant support from the National Eye Institute (U10-EY025990), and receives book royalties from Oxford
University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Thurtell discusses the unlabeled/investigational use of
acetazolamide, furosemide, methazolamide, and topiramate for the treatment of idiopathic intracranial hypertension
Self-Assessment and CME Test Writers

Douglas J. Gelb, MD, PhD, FAAN
Professor of Neurology, University of Michigan, Ann Arbor, Michigan
Relationship Disclosure: Dr Gelb receives royalties from MedLink, Oxford University Press, and UpToDate, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gelb reports no disclosure.
James W. M. Owens Jr, MD, PhD

Associate Professor of Neurology, Adjunct Associate Professor of Pediatrics, University of
Washington School of Medicine, Seattle, Washington

Relationship Disclosure: Dr Owens serves as CME co-editor for Neurology and receives publishing royalties from
UpToDate, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Owens reports no disclosure.
Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

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What are the main topics covered in this issue of Continuum?

What are the main topics covered in this issue of Continuum?

What are some of the goals of the Continuum publication?

What are some of the goals of the Continuum publication?

OCTOBER 2019

VOL. 25 NO. 5 Neuro-ophthalmology

1192 Editor’s Preface

1194 The Pupil

1215 Ischemic Optic Neuropathy

1236 Optic Neuritis

1265 Toxic-Metabolic and Hereditary Optic Neuropathies

1289 Idiopathic Intracranial Hypertension

1310 Chiasmal and Postchiasmal Disease

1329 Higher Cortical Visual Disorders

1362 Approach to Diplopia

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1422 Infectious Optic Neuropathies

1438 Imaging in Neuro-ophthalmology

SELF-ASSESSMENT AND CME

1186 Learning Objectives and Core Competencies

1491 Instructions for Completing Postreading Self-Assessment and CME

1493 Postreading Self-Assessment and CME Test

1507 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Learning Objectives ◆ List the most common types of nystagmus and

◆ Discuss the features and underlying mechanism

◆ Describe the symptomatic, examination, and ◆ Medical Knowledge

◆ Systematically use elements of the history and

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Marc Dinkin, MD Jeffrey L. Bennett, MD, PhD,

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Christopher C. Glisson, DO, MS,

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Mark J. Morrow, MD, FAAN Cristiano Oliveira, MD

Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Self-Assessment and CME Test Writers

Douglas J. Gelb, MD, PhD, James W. M. Owens Jr, MD, PhD

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1192 OCTOBER 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

SUMMARY: The autonomic nervous system regulates pupil size in response to

1194 OCTOBER 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

ANATOMY OF THE PUPIL

PHYSIOLOGIC FUNCTION OF THE PUPIL

Pupil Examination TABLE 1-1

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Pupillary Constriction (Miosis)

THE FINAL COMMON PATHWAY (EDINGER-WESTPHAL NUCLEUS/CILIARY

1196 OCTOBER 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

ACTIVATION OF THE FINAL COMMON PUPILLOMOTOR PATHWAY VIA THE NEAR

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

The near triad consists of miosis, convergence, and accommodation. During

Pupillary Dilation (Mydriasis)