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)

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

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

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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.
Marc A. Bouffard, MD
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

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 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.
Unlabeled Use of Products/Investigational
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.

Unlabeled Use of Products/Investigational

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

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

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 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.
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, 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.

C O N T I N U U M J O U R N A L .C O M 1191

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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

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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.

[Link] 1193

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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@[Link]. 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

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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.

[Link] 1195

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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

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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.

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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

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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

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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

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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.

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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.

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 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

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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.

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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).

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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

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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,

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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

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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.

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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

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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.

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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

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 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.

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10 Saper CB. Central autonomic system. In: 17 Anzai T, Uematsu D, Takahashi K, et al. Guillain-
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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
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cge.13148.

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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;
25(5, NEURO-OPHTHALMOLOGY):
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@[Link].

RELATIONSHIP DISCLOSURE:
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.

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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

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 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

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ISCHEMIC OPTIC NEUROPATHY

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
ISCHEMIC OPTIC NEUROPATHY
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

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 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

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ISCHEMIC OPTIC NEUROPATHY

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

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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.

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ISCHEMIC OPTIC NEUROPATHY

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

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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.

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ISCHEMIC OPTIC NEUROPATHY

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

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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

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ISCHEMIC OPTIC NEUROPATHY

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

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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

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ISCHEMIC OPTIC NEUROPATHY

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

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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

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ISCHEMIC OPTIC NEUROPATHY

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

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 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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ISCHEMIC OPTIC NEUROPATHY

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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
25(5, NEURO-OPHTHALMOLOGY):
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
[Link]@[Link]. treatments are evaluated.
RELATIONSHIP DISCLOSURE:
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
PRODUCTS/INVESTIGATIONAL
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
© 2019 American Academy
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

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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

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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

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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.

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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

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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

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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.

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 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

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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

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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.

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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

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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

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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.

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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.

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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.

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 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

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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

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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.

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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.

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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.

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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

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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.

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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.

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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

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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.

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Toxic-Metabolic REVIEW ARTICLE


and Hereditary Optic 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

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
CONTINUUM (MINNEAP MINN) 2019;
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@[Link].
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
PRODUCTS/INVESTIGATIONAL
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.

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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

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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

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

CONTINUED ON PAGE 1273

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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

CONTINUED FROM PAGE 1272

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.

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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,

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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.

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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.

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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

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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.

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TOXIC-METABOLIC AND HEREDITARY OPTIC NEUROPATHIES

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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“inverse” optic atrophy identifies vigabatrin
40 Kirches E. LHON: mitochondrial mutations
toxicity in children. Ophthalmology 2004;111(10):
and more. Curr Genomics 2011;12(1):44–54.
1935–1942. doi:10.1016/[Link].2004.03.036.
doi:10.2174/138920211794520150.
26 Sergott RC. Recommendations for visual
41 Hwang TJ, Karanjia R, Moraes-Filho MN, et al.
evaluations of patients treated with vigabatrin.
Natural history of conversion of Leber’s hereditary
Curr Opin Ophthalmol 2010;21(6):442–446.
optic neuropathy: a prospective case series.
doi:10.1097/ICU.0b013e32833f0085.
Ophthalmology 2017;124(6):843–850. doi:10.1016/
[Link].2017.01.002.

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42 Fraser JA, Biousse V, Newman NJ. The 55 [Link]. Leber hereditary optic
neuro-ophthalmology of mitochondrial disease. neuropathy. [Link]/ct2/results?cond=
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[Link].2009.10.002. &cntry=&state=&city=&dist=. Accessed
July 30, 2019.
43 Barboni P, Carbonelli M, Savini G, et al. Natural
history of Leber’s hereditary optic neuropathy: 56 Guy J, Feuer WJ, Davis JL, et al. Gene therapy for
longitudinal analysis of the retinal nerve fiber Leber hereditary optic neuropathy: low- and
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[Link].2009.07.026. 2017.05.016.
44 Balducci N, Savini G, Cascavilla ML, et al. Macular 57 Feuer WJ, Schiffman JC, Davis JL, et al. Gene
nerve fibre and ganglion cell layer changes in therapy for Leber hereditary optic neuropathy
acute Leber’s hereditary optic neuropathy. Br J initial results. Ophthalmology 2016;123(3):
Ophthalmol 2016;100(9):1232–1237. doi:10.1136/ 558–570. doi:10.1016/[Link].2015.10.025.
bjophthalmol-2015-307326.
58 Kirkman MA, Korsten A, Leonhardt M, et al.
45 Carelli V, Carbonelli M, de Coo IF, et al. Quality of life in patients with Leber hereditary
International consensus statement on the clinical optic neuropathy. Invest Ophthalmol Vis Sci
and therapeutic management of Leber hereditary 2009;50(7):3112–3115. doi:10.1167/iovs.08-3166.
optic neuropathy. J Neuroophthalmology 2017;
59 Kjer P. Infantile optic atrophy with dominant
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mode of inheritance: a clinical and genetic study
46 Matthews L, Enzinger C, Fazekas F, et al. MRI in of 19 Danish families. Acta Ophthalmol Suppl
Leber’s hereditary optic neuropathy: the 1959;164(suppl 54):1–147.
relationship to multiple sclerosis. J Neurol
60 Yu-Wai-Man P, Griffiths PG, Burke A, et al. The
Neurosurg Psychiatry 2015;86(5):537–542.
prevalence and natural history of dominant optic
doi:10.1136/jnnp-2014-308186.
atrophy due to OPA1 mutations. Ophthalmology
47 Phillips PH, Vaphiades M, Glasier CM, et al. 2010;117(8):1538–1546. doi:10.1016/[Link].
Chiasmal enlargement and optic nerve 2009.12.038.
enhancement on magnetic resonance imaging
61 Olichon A, Baricault L, Gas N, et al. Loss of OPA1
in Leber hereditary optic neuropathy. Arch
perturbates the mitochondrial inner membrane
Ophthalmol 2003;121(4):577–579. doi:10.1001/
structure and integrity, leading to cytochrome c
archopht.121.4.577.
release and apoptosis. J Biol Chem 2003;278(10):
48 Mercuri MA, White H, Oliveira C. Vision loss 7743–7746. doi:10.1074/jbc.C200677200.
and symmetric basal ganglia lesions in Leber
62 Reynier P, Amati-Bonneau P, Verny C, et al. OPA3
hereditary optic neuropathy. J Neuroophthalmol
gene mutations responsible for autosomal
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dominant optic atrophy and cataract. J Med
0000000000000524.
Genet 2004;41(9):e110. doi:10.1136/jmg.2003.
49 Gropman A, Chen TJ, Perng CL, et al. Variable 016576.
clinical manifestation of homoplasmic G14459A
63 Grau T, Burbulla LF, Engl G, et al. A novel
mitochondrial DNA mutation. Am J Med Genet A
heterozygous OPA3 mutation located in the
2004;124A(4):377–382. doi:10.1002/ajmg.a.20456.
mitochondrial target sequence results in altered
50 Tarnopolsky MA, Baker SK, Myint T, et al. Clinical steady-state levels and fragmented mitochondrial
variability in maternally inherited leber hereditary network. J Med Genet 2013;50(12):848–858.
optic neuropathy with the G14459A mutation. doi:10.1136/jmedgenet-2013-101774.
Am J Med Genet A 2004;124A(4):372–376.
64 Chun BY, Rizzo JF 3rd. Dominant optic atrophy
doi:10.1002/ajmg.a.20449.
and Leber’s hereditary optic neuropathy: update
51 Newman NJ. Treatment of hereditary optic on clinical features and current therapeutic
neuropathies. Nat Rev Neurol 2012;8(10):545–556. approaches. Semin Pediatr Neurol 2017;24(2):
doi:10.1038/nrneurol.2012.167. 129–134. doi:10.1016/[Link].2017.06.001.
52 Peragallo JH, Newman NJ. Is there treatment for 65 Barboni P, Savini G, Cascavilla ML, et al. Early
Leber hereditary optic neuropathy? Curr Opin macular retinal ganglion cell loss in dominant
Ophthalmol 2015;26(6):450–457. doi:10.1097/ optic atrophy: genotype-phenotype correlation.
ICU.0000000000000212. Am J Ophthalmol 2014;158(3):628–636.e3.
doi:10.1016/[Link].2014.05.034.
53 Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al.
A randomized placebo-controlled trial of 66 Yu-Wai-Man P, Griffiths PG, Gorman GS, et al.
idebenone in Leber’s hereditary optic Multi-system neurological disease is common in
neuropathy. Brain 2011;134(pt 9):2677–2686. patients with OPA1 mutations. Brain 2010;133(3):
doi:10.1093/brain/awr170. 771–786. doi:10.1093/brain/awq007.
54 Rudolph G, Dimitriadis K, Büchner B, et al. 67 Cohn AC, Toomes C, Potter C, et al. Autosomal
Effects of idebenone on color vision in patients dominant optic atrophy: penetrance and
with leber hereditary optic neuropathy. expressivity in patients with OPA1 mutations.
J Neuroophthalmol 2013;33(1):30–36. doi:10.1097/ Am J Ophthalmol 2007;143(4):656–662.e1.
WNO.0b013e318272c643. doi:10.1016/[Link].2006.12.038.

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Idiopathic Intracranial REVIEW ARTICLE


Hypertension 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 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
CONTINUUM (MINNEAP MINN) 2019;
provide insight into the indications for surgical intervention, optimal timing 25(5, NEURO-OPHTHALMOLOGY):
and choice of intervention, and long-term outcomes. 1289–1309.

Address correspondence to
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@[Link].
depending on the severity of symptoms and vision loss, response to
RELATIONSHIP DISCLOSURE:
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.

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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.

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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

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IDIOPATHIC INTRACRANIAL HYPERTENSION

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

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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

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IDIOPATHIC INTRACRANIAL HYPERTENSION

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

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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).

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IDIOPATHIC INTRACRANIAL HYPERTENSION

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).

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 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

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IDIOPATHIC INTRACRANIAL HYPERTENSION

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

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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.

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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

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 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
intracranial hypertension.
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.

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IDIOPATHIC INTRACRANIAL HYPERTENSION

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

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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.

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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