Neuro-Ophthalmology 2nd Edition

i
Neuro-Ophthalmology
ii
What Do I Do Now?
S E R I E S C O -E D ITORS-I N-C HIE F
Lawrence C. Newman, MD
Director of the Headache Division
Professor of Neurology
New York University Langone
New York, New York
Morris Levin, MD
Director of the Headache Center
Professor of Neurology
University of California, San Francisco
San Francisco, California
OT H E R VO L U M E S IN T HE  SE RIE S
Headache and Facial Pain
Epilepsy
Pain
Emergency Neurology
Neuroinfections
Neurogenetics
Neurotology
Pediatric Neurology
Neurocritical Care
Stroke
Peripheral Nerve and Muscle Disease
Cerebrovascular Disease
Movement Disorders
Women’s Neurology
Neuroimmunology
iii
Neuro-Ophthalmology
SECOND EDITION
Matthew J. Thurtell, MBBS, FRACP

Associate Professor of Ophthalmology and Neurology
Director of Neuro-Ophthalmology Service
Department of Ophthalmology and Visual Sciences
University of Iowa
Iowa City, IA
Robert L. Tomsak, MD, PhD

Professor of Ophthalmology and Neurology
Kresge Eye Institute
Wayne State University
Detroit, MI
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1
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Published in the United States of America by Oxford University Press
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© Oxford University Press 2019
First Edition published in 2011
Second Edition published in 2019
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You must not circulate this work in any other form
and you must impose this same condition on any acquirer.
Library of Congress Cataloging-in-Publication Data
Names: Thurtell, Matthew J., author. | Tomsak, Robert L., author.
Title: Neuro-ophthalmology / by Matthew J. Thurtell, Robert L. Tomsak.
Description: Second edition. | New York, NY : Oxford University Press, [2019] |
Includes bibliographical references and index.
Identifiers: LCCN 2018054874 | ISBN 9780190603953 (pbk.)
Subjects: | MESH: Eye Diseases—diagnosis | Nervous System Diseases—complications |
Cranial Nerve Diseases | Eye Diseases—therapy | Diagnosis, Differential | Case Reports
Classification: LCC RE75 | NLM WW 460 | DDC 617.7075—dc23
LC record available at https://lccn.loc.gov/2018054874
This material is not intended to be, and should not be considered, a substitute for medical or other
professional advice. Treatment for the conditions described in this material is highly dependent on
the individual circumstances. And, while this material is designed to offer accurate information with
respect to the subject matter covered and to be current as of the time it was written, research and
knowledge about medical and health issues is constantly evolving and dose schedules for medications
are being revised continually, with new side effects recognized and accounted for regularly. Readers
must therefore always check the product information and clinical procedures with the most up-to-date
published product information and data sheets provided by the manufacturers and the most recent
codes of conduct and safety regulation. The publisher and the authors make no representations or
warranties to readers, express or implied, as to the accuracy or completeness of this material. Without
limiting the foregoing, the publisher and the authors make no representations or warranties as to the
accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do
not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed
or incurred as a consequence of the use and/or application of any of the contents of this material.
9 8 7 6 5 4 3 2 1
Printed by WebCom, Inc., Canada
v
Robert B. Daroff, MD—our mentor, colleague, and friend—in

recognition of his contributions to the field of neuro-ophthalmology.
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vi
Contents
Preface ix
Acknowledgments xi
SECTION I AFFERENT DISORDERS
1 Optic Neuritis 3
2 Arteritic Ischemic Optic Neuropathy 9
3 Nonarteritic Ischemic Optic Neuropathy 15
4 Compressive Optic Neuropathy 21
5 Leber Hereditary Optic Neuropathy 25
6 Autosomal Dominant Optic Atrophy 29
7 Neuroretinitis 35
8 Papilledema 41
9 Idiopathic Intracranial Hypertension 47
10 Pseudopapilledema 55
11 Chiasmal Syndromes 61
12 Homonymous Hemianopia 67
13 Disorders of Higher Visual Function 71
14 Visual Auras, Hallucinations, and Illusions 77
15 Transient Vision Loss 83
16 Unexplained Vision Loss 89
17 Nonorganic Vision Loss 93
SECTION II EFFERENT DISORDERS
18 Third Nerve Palsy 99
19 Fourth Nerve Palsy 105
20 Sixth Nerve Palsy 111
21 Intermittent Diplopia 115

vi
22 Ocular Myasthenia 121
23 Infranuclear Ophthalmoplegia 127
24 Internuclear Ophthalmoplegia 133
25 Supranuclear Ophthalmoplegia 137
26 Gaze-Evoked Nystagmus 141
27 Downbeat Nystagmus 145
28 Upbeat Nystagmus 151
29 Pendular Nystagmus 155
30 Infantile Nystagmus 161
31 Saccadic Intrusions and Dysmetria 167
SECTION III EYELID DISORDERS
32 Eyelid Ptosis 175
33 Benign Essential Blepharospasm 181
SECTION IV PUPIL DISORDERS
34 Anisocoria 187
35 Horner Syndrome 193

36 Tonic Pupil 199
SECTION V ORBITAL AND MISCELLANE O U S D I S O RD E R S
37 Thyroid Eye Disease 207
38 Syndromes of the Orbital Apex, Superior Orbital Fissure, and

Cavernous Sinus 213
39 Carotid-Cavernous Fistula 219
40 Dorsal Midbrain Syndrome 225
Index 231
viii Contents
ix
Preface
Patients with neuro-ophthalmic conditions are commonly encountered

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

of neuro-ophthalmology. We acknowledge those experts in the field who
agreed to discuss their personal approaches to such cases with us. In par-
ticular, we thank Drs. Randy H. Kardon, Michael Wall, Richard C. Allen,
and Wallace L. Alward for their helpful advice. We also thank the team at
Oxford University Press, Craig Panner and Tiffany Lu, for their help in
bringing this volume to completion.
xi
1
SECTION I
Afferent Disorders
2
3
1 Optic Neuritis
You are called to see a 22-year-old woman

who has had a subacute onset of vision
loss in her right eye over several days with
associated pain on eye movements. She
has no past medical history and denies
other neurologic symptoms. Examination
shows visual acuities of 20/100 in the
right eye and 20/15 in the left eye. She
can identify only the control Ishihara
color plate with the right eye, but she
correctly identifies all plates with the left
eye. Confrontation visual fields show a
central scotoma in the right eye. Her pupils
are equal and react to light, but there is a
right relative afferent pupillary defect. Her
funduscopic examination is normal.
What do you do now?
3
4
T he patient in this scenario has had a subacute onset of painful mo-

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

5
FIGURE 1.1. MRI of the orbits (top row) and brain (bottom row) in a patient with optic neuritis,
demonstrating left optic nerve enhancement and multiple ovoid periventricular white matter
lesions consistent with MS.
changes are nonspecific and cannot be considered diagnostic of idiopathic

optic neuritis. MRI of the brain should be obtained to assess for white
matter lesions, which are most obvious on the T2-weighted and FLAIR
(fluid-attenuated inversion recovery) sequences (see Figure 1.1), because
the presence of one or more lesions (especially when they have a periven-
tricular distribution) portends an increased risk of developing MS.
Laboratory investigations can be useful to screen for other causes of optic
neuritis, such as neuromyelitis optica (NMO), especially in patients with
atypical features to their presentation (Box 1.1). Patients with optic neuritis
in the setting of NMO with NMO-IgG (i.e., aquaporin-4) antibodies often
present with severe vision loss that can be bilateral and without associated
pain, and a poor recovery of vision despite aggressive treatment. Patients
1. Optic Neuritis 5

6
FIGURE 1.2. MRI of the orbits in a patient with bilateral optic neuritis in the setting of
neuromyelitis optica, demonstrating longitudinally extensive bilateral optic nerve enhancement.
with optic neuritis in the setting of NMO with myelin oligodendrocyte

glycoprotein (i.e., MOG-IgG) antibodies can also present with severe vision
loss that can be bilateral with associated optic disc edema, but usually have
a rapid and dramatic recovery of vision with treatment. With optic neuritis
in the setting of NMO, MRI of the orbits can show longitudinally exten-
sive optic nerve enhancement or bilateral optic nerve enhancement (Figure
1.2). Other laboratory investigations, such as antinuclear antibody, anti-
neutrophil cytoplasmic antibodies, angiotensin-converting enzyme level,
lysozyme level, syphilis serology, and Lyme serology, are often unrevealing
and, thus, unnecessary unless there are atypical features to the presentation
(see Box 1.1). Cerebrospinal fluid (CSF) analysis can be useful to evaluate
for other causes of optic neuritis in selected patients. However, CSF analysis
BOX 1.1 Atypical Features for Idiopathic Optic Neuritis
Lack of pain
Severe vision loss
Poor recovery of vision
Bilateral optic nerve involvement
Systemic symptoms or signs (e.g., fever or rash)
Intraocular inflammation, hemorrhages, or exudates
Immunocompromised patient (e.g., transplant recipient)
Longitudinally extensive optic nerve enhancement on MRI
Optic nerve sheath enhancement on MRI
Rapid improvement following initiation of steroids
Relapsing course following withdrawal of steroids

7
is not routinely required to evaluate for oligoclonal bands and other CSF
markers of MS, because an increased risk of MS is more reliably predicted
by the presence of white matter lesions on MRI.
The recommended treatment of idiopathic optic neuritis is based on the
findings of the Optic Neuritis Treatment Trial, which was a randomized
controlled trial comparing outcomes in patients who received intravenous
and then oral steroids, oral steroids alone, or placebo. The group receiving
intravenous and then oral steroids showed a more rapid recovery of vision
than the placebo group, although the final visual outcome was similar. This
group also showed a lower risk of developing clinically definite MS in the
first 2 years following treatment. The group receiving oral steroids alone did
not show a faster recovery compared with placebo but did show an increased
rate of recurrent optic neuritis attacks compared with the other two groups.
Thus, the recommended treatment protocol for idiopathic optic neuritis
is intravenous methylprednisone (1 g daily) for 3 days followed by oral
prednisone (1 mg/kg daily) for 11 days. The prognosis for visual recovery is
excellent, with vision recovering to near normal in most patients over weeks
to months, although there can be minor persisting visual deficits (e.g., in
contrast and color vision) and clinical signs of optic nerve dysfunction (e.g.,
a relative afferent pupillary defect and optic disc pallor).
In patients who have one or more white matter lesions on MRI, the risk
of developing MS is greater than 65% in the 15 years following an attack of
idiopathic optic neuritis, compared with 25% in patients who do not have
white matter lesions. Treatment with disease-modifying therapy for MS
(e.g., beta-interferon) can reduce the risk of developing MS in patients with
idiopathic optic neuritis who have white matter lesions on MRI. Although
not all optic neuritis patients with white matter lesions will develop clini-
cally definite MS, initiation of disease-modifying therapy should be care-
fully considered.
KEY POINT S TO REMEMBER
• The cardinal signs of an optic neuropathy are decreased visual

acuity, a central visual field defect, dyschromatopsia, and a
relative afferent pupillary defect.
1. Optic Neuritis 7

8
• Optic neuritis is characterized by a subacute onset of painful

monocular vision loss with a relative afferent pupillary defect;
optic disc edema may or may not be present, depending on the
portion of the nerve affected.
• Optic neuritis is often idiopathic but can be caused by
demyelinating disease, autoimmune disease, inflammatory
disease, infections, and vaccinations.
• MRI of the orbits and brain should be obtained acutely to
confirm the presence of optic nerve enhancement, evaluate for
white matter lesions in the brain, and exclude other causes of
optic neuropathy.
• The 15-year risk of developing MS is over 65% in optic neuritis
patients with one or more white matter lesions on MRI versus
about 25% in those with no white matter lesions.
• Treatment of optic neuritis with intravenous methylprednisone
(1 g daily) for 3 days and then oral prednisone (1 mg/kg daily)
for 11 days leads to a faster recovery of vision and decreased
risk of developing MS in the 2 years following treatment.
Further Reading
Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of
corticosteroids in the treatment of acute optic neuritis. N Engl J Med.
1992;326:581–588.
Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic
neuritis on the subsequent development of multiple sclerosis. N Engl J Med.
1993;329:1764–1769.
Chen JJ, Flanagan EP, Jitprapaikulsan J, et al. Myelin oligodendrocyte glycoprotein
antibody (MOG-IgG)-positive optic neuritis: clinical characteristics, radiologic
clues and outcome. Am J Ophthalmol. 2018;195:8–15.
Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic
neuritis treatment trial follow-up. Arch Neurol. 2008;65:727–732.
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017
revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173.

9
2 Arteritic Ischemic
Optic Neuropathy
A 75-year-old white woman presents to

your clinic after suddenly developing vision
loss in her right eye. She reports having
had several brief episodes of transient
vision loss in her right eye over the past
week, as well as a persistent dull right-
sided temporal headache. Examination
shows visual acuities of count fingers in
the right eye and 20/25 in the left eye. She
cannot identify the control Ishihara color
plate with the right eye, but she correctly
identifies all plates with the left eye. Her
pupils are equal and react to light, but there
is a right relative afferent pupillary defect.
Funduscopic examination shows pallid
optic disc edema in the right eye.
9
10
T he acute onset of severe monocular vision loss with associated pallid

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

1
FIGURE 2.1. Fundus photograph demonstrating pallid optic disc edema due to AAION, with
cilioretinal artery occlusion, in a patient with GCA (left). Fluorescein angiography shows patchy
choroidal nonperfusion and cilioretinal artery occlusion (right).
3). Since GCA causes inflammatory narrowing and occlusion of the poste-
rior ciliary arteries (which supply the choroid of the eye) and the cilioretinal
artery (which variably supplies the papillomacular portion of the retina),
concurrent choroidal or cilioretinal ischemia is highly suggestive of GCA
(see Figure 2.1). Prior to the onset of AAION, a significant proportion of
patients will have episodes of transient monocular or binocular vision loss,
which are typically precipitated by postural changes. Some patients expe-
rience transient diplopia, which is thought to be secondary to ischemia
of the extraocular muscles. Many report systemic symptoms, such as tem-
poral headache, jaw claudication, scalp tenderness, malaise, weight loss, and
fever, which should immediately suggest GCA. However, their absence does
not preclude GCA; over 20% of patients with biopsy-proven GCA do not
have systemic symptoms.
For the patient in this scenario, with a dull temporal headache and se-
vere monocular vision loss due to anterior ischemic optic neuropathy, the
clinical suspicion for GCA is high. Therefore, urgent investigations and
treatment are required. An erythrocyte sedimentation rate and C-reactive
protein level should be obtained immediately. Most patients with GCA
have elevation of both inflammatory markers, reflecting systemic inflam-
mation, but occasionally only one might be elevated. In patients who do
not have elevated inflammatory markers, further investigations should still
be obtained and empiric treatment initiated if the clinical suspicion for
2. Arteritic Ischemic Optic Neuropathy 11

12
GCA is high. Fluorescein angiography can be useful to demonstrate cho-

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

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

13
• AAION occurs because of inflammatory narrowing or occlusion

of the posterior ciliary arteries by vasculitis (e.g., GCA).
• GCA is a granulomatous vasculitis that most commonly occurs
in older white women.
• Systemic symptoms of GCA include temporal headache, jaw
claudication, scalp tenderness, malaise, weight loss, and fever.
• About 50% of patients with GCA present with vision loss, in
most cases due to AAION.
• High-dose corticosteroid treatment should be commenced
immediately whenever GCA is suspected and should not be
delayed while awaiting the results of laboratory studies or
temporal artery biopsy.
Further Reading
González-Gay MA, García-Porrúa C, Llorca J, et al. Visual manifestations of
giant cell arteritis: trends and clinical spectrum in 161 patients. Medicine.
2000;79:283–292.
Hayreh SS, Zimmerman B. Management of giant cell arteritis: our 27-year clinical
study: new light on old controversies. Ophthalmologica. 2003;217:239–259.
Kawasaki A, Purvin V. Giant cell arteritis: an updated review. Acta Ophthalmol.
2009;87:13–32.
Parikh M, Miller NR, Lee AG, et al. Prevalence of a normal C-reactive protein with an
elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis.
Ophthalmology. 2006;113:1842–1845.
Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N
Engl J Med. 2017;377:317–328.
2. Arteritic Ischemic Optic Neuropathy 13

14
15
3 Nonarteritic Ischemic
Optic Neuropathy
An overweight 58-year-old man presents

to the emergency department after waking
with vision loss in his right eye without
associated pain. He has a past history
of hypertension, diabetes, and erectile
dysfunction, and he is taking multiple
antihypertensive medications. Examination
shows visual acuities of 20/50 in the right
eye and 20/20 in the left eye. He correctly
identifies 10 of 14 Ishihara color plates with
the right eye and 14 of 14 plates with the
left eye. Confrontation visual fields show
an inferior altitudinal defect in the right
eye. His pupils are equal in size and react
to light, but there is a right relative afferent
pupillary defect. Funduscopic examination
shows superior segmental optic disc edema
in the right eye and a small, structurally
congested optic disc in the left eye.
15
16
T he acute onset of painless monocular vision loss with associated seg-

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

17
nerve head, the pathogenesis of NAION is not well understood. However,

it is not thought to occur as a result of emboli occluding the arteries
supplying the optic nerve head and, thus, a workup for an embolic source
is not required. Since many affected patients have vascular risk factors, such
as diabetes and hypertension, there may be atherosclerotic stenoses in the
vessels supplying the optic nerve head. Many patients awake with their vi-
sion loss and, thus, nocturnal hypotension and hypoxemia from obstructive
sleep apnea are thought to play an important role in the pathogenesis of
NAION. Consequently, it is important to ask patients about the timing of
their antihypertensive medication doses, since the use of antihypertensive
medications at night might exacerbate nocturnal hypotension. A number
of other factors (e.g., vasospasm and impaired vascular autoregulation)
might also play a role in the pathogenesis of NAION in some patients.
Consistently, however, affected patients have small, structurally congested
optic discs, with a small or absent physiologic cup (see Figure 3.1); this
normal variant is well established as a marker for increased risk of NAION
and has been called a “disc at risk.” The “disc at risk” is more common
in white patients, which might explain why there is a higher incidence of
NAION in whites than in other ethnic groups.
Several medications have been implicated as precipitants for NAION.
Amiodarone has been reported to cause bilateral simultaneous optic
neuropathies that are reminiscent of NAION. NAION may also occur
in association with use of phosphodiesterase type-5 inhibitors (sildenafil,
vardenafil, or tadalafil) for erectile dysfunction. The evidence suggesting a
relationship between NAION and phosphodiesterase type-5 inhibitor use
initially came from case reports or small case series, although one recent
study found an approximately twofold increased risk of NAION with phos-
phodiesterase type-5 inhibitor use. Consequently, it is important to ask and
counsel patients about the use of these medications, because their ongoing
use could increase the risk of NAION occurring in the fellow eye.
NAION is a clinical diagnosis that must be differentiated from AAION,
because patients with AAION can develop devastating vision loss in the
fellow eye if corticosteroid therapy is not started immediately. Although
AAION is also characterized by acute onset of severe monocular vision
loss with optic disc edema, the patient often has other symptoms that sug-
gest giant cell arteritis (GCA), such as headache, jaw claudication, or scalp
3. Nonarteritic Ischemic Optic Neuropathy 17

18
tenderness. The inflammatory markers should be checked in patients who

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

neuropathy in older adults.
• NAION causes a rapid onset of painless monocular vision loss
with a relative afferent pupillary defect and segmental optic
disc edema.
• NAION usually occurs in eyes with a small, structurally
congested optic disc (“disc at risk”).
• NAION can occur in association with obstructive sleep apnea
and nocturnal hypotension, which can be exacerbated by
evening dosing of antihypertensive medications.

19
• No treatment has been definitively shown to improve visual

recovery, prevent recurrence, or prevent fellow eye involvement
in NAION, although avoidance of precipitating factors,
treatment of vascular risk factors, and antiplatelet therapy
should be considered.
Further Reading
Campbell UB, Walker AM, Gaffney M, et al. Acute nonarteritic anterior ischemic optic
neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med.
2015;12:139–151.
Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role
of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol.
2008;246:1029–1046.
Hayreh SS, Zimmerman MB, Podhajsky PA, Alward WL. Nocturnal arterial
hypotension and its role in optic nerve head and ocular ischemic disorders. Am
J Ophthalmol. 1994;117:603–624.
Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve
decompression surgery for nonarteritic anterior ischemic optic neuropathy
(NAION) is not effective and may be harmful. JAMA. 1995;273:625–632.
Palombi K, Renard E, Levy P, et al. Non-arteritic anterior ischaemic optic neuropathy
is nearly systematically associated with obstructive sleep apnoea. Br J
Ophthalmol. 2006;90:879–882.
Purvin V, Kawasaki A, Borruat FX. Optic neuropathy in patients using amiodarone.
Arch Ophthalmol. 2006;124:696–701.
3. Nonarteritic Ischemic Optic Neuropathy 19

20
21
4 Compressive
Optic Neuropathy
A 40-year-old woman presents to your

clinic reporting a several-month history of
progressive painless vision loss in her right
eye. Examination shows visual acuities of
20/40 in the right eye and 20/20 in the left
eye. She correctly identifies 4 of 14 Ishihara
color plates with the right eye and 14 of 14
plates with the left eye. Confrontation visual
fields show a subtle central scotoma in the
right eye. Her pupils are equal in size and
react to light, but there is a right relative
afferent pupillary defect. Funduscopic
examination shows optic disc pallor in the
right eye. Magnetic resonance imaging
(MRI) of the orbits with contrast shows an
enhancing lesion surrounding the right
optic nerve.
21
2
T he progressive onset of painless monocular vision loss in this patient’s

right eye, with associated dyschromatopsia, a relative afferent pupil-
lary defect, and temporal optic disc pallor, suggests a compressive optic
neuropathy. Compressive optic neuropathies can be divided into anterior
and posterior forms: optic disc edema is often present when the compres-
sion is anterior (i.e., intraorbital), while it is usually absent when the com-
pression is posterior (i.e., intracranial). Both forms are characterized by
progressive, and usually painless, central vision loss. The patient often has
dyschromatopsia that is out of proportion to the degree of decrease in visual
acuity. Formal visual field testing should be obtained to determine the ex-
tent of visual field loss; it will often demonstrate a central visual field defect,
which may be subtle, and blind-spot enlargement in patients with optic
disc edema due to anterior compressive optic neuropathy. Optociliary col-
lateral vessels may be present in patients with chronic anterior compressive
optic neuropathy (Figure 4.1), and there may also be retinal folds. In con-
trast, patients with posterior compressive optic neuropathy have a normal
optic disc initially. However, with persistent compression, they gradually
develop optic disc pallor without collateral vessels or folds. Some patients
with chronic posterior compressive optic neuropathy develop optic disc
cupping, although they will usually have coexisting optic disc pallor and
FIGURE 4.1. Fundus photograph demonstrating mild right optic disc edema and pallor, with
optociliary collateral vessels (left). MRI of the orbit showing a large enhancing lesion in the right
orbit that has an appearance consistent with an optic nerve sheath meningioma (right).

23
a normal intraocular pressure to allow for differentiation from a glauco-

matous optic neuropathy. Patients with orbital pathology as the cause for
their compressive optic neuropathy often have orbital signs (i.e., proptosis,
chemosis, conjunctival injection, eyelid abnormalities, or limited ocular
ductions). However, the absence of orbital signs does not exclude an orbital
lesion as the cause for the optic neuropathy.
Common causes for compressive optic neuropathy include orbital
tumors (e.g., optic nerve sheath meningioma, optic glioma, capillary he-
mangioma, or lymphoma), intracranial tumors (e.g., pituitary adenoma,
meningioma, or craniopharyngioma; see Case 11), aneurysms (e.g., internal
carotid or ophthalmic artery), orbital infections (e.g., bacterial infection or
fungal infection; see Case 38), and orbital inflammation (e.g., idiopathic
orbital inflammation). Thyroid eye disease can also cause compressive optic
neuropathy, sometimes in the absence of obvious orbital signs (see Case
37). Most causes of compressive optic neuropathy can be diagnosed with
imaging. MRI of the orbits (with contrast and fat suppression) is the im-
aging modality of choice in most cases, although computed tomography
(CT) is preferable for demonstrating calcification or if details of the bony
anatomy are required (e.g., in patients with thyroid eye disease who might
require orbital decompression surgery; see Case 37). Depending on the im-
aging findings, biopsy of the lesion may be required for definitive diagnosis.
For the patient described in this scenario, MRI of the orbits has detected
an enhancing lesion surrounding the right optic nerve (see Figure 4.1),
which is likely to be an optic nerve sheath meningioma (ONSM). ONSMs
occur most commonly in middle-aged women and are usually unilateral.
MRI shows that the lesion is extrinsic to the optic nerve and thereby allows
differentiation from intrinsic tumors (e.g., optic glioma). The presence of
calcification produces a characteristic “tram-track” appearance on CT. Since
the imaging findings are usually diagnostic, biopsy is rarely required.
Treatment of ONSM varies depending on the severity and rate of vision
loss. Patients who have minimal or no vision loss can be observed, because
they may remain stable without intervention. Those with more signifi-
cant or progressive vision loss, such as the patient in this scenario, are best
managed with fractionated stereotactic radiotherapy, which can improve
or stabilize the vision with minimal morbidity. Surgical resection is not
appropriate unless there is already severe vision loss and another indication
4. Compressive Optic Neuropathy 23

24
for resection (e.g., severe proptosis, intractable pain), because it invariably

results in severe vision loss due to interruption of the blood supply to the
optic nerve.
• Compressive optic neuropathy is characterized by progressive

central vision loss, with dyschromatopsia and a relative afferent
pupillary defect; the optic disc appearance varies depending on
the location and chronicity of compression.
• Compressive optic neuropathy can be caused by orbital tumors,
intracranial tumors (e.g., pituitary adenomas, meningiomas,
and craniopharyngiomas), aneurysms, orbital infections, orbital
inflammation, and thyroid eye disease.
• MRI or CT of the orbits is usually sufficient to diagnose
the causative lesion, although biopsy and histopathologic
examination may be required in some cases.
• ONSM occurs most often in middle-aged women and is best
managed conservatively when there is minimal vision loss or
with stereotactic radiotherapy when there is more severe or
progressive vision loss.
Further Reading
Blandford AD, Zhang D, Chundury RV, Perry JD. Dysthyroid optic neuropathy: update
on pathogenesis, diagnosis, and management. Expert Rev Ophthalmol.
2017;12:111–121.
Hamilton SN, Nichol A, Truong P, et al. Visual outcomes and local control after
fractionated stereotactic radiotherapy for optic nerve sheath meningioma.
Ophthalmic Plast Reconstr Surg. 2018;34:217–221.
Moster ML. Detection and treatment of optic nerve sheath meningioma. Curr Neurol
Neurosci Rep. 2005;5:367–375.

25
5 Leber Hereditary
Optic Neuropathy
You are called to the emergency

department to see a 14-year-old boy who
has acutely developed painless vision loss
in his right eye. There is a history of vision
loss on the maternal side of his family.
Examination shows visual acuities of
20/200 in the right eye and 20/15 in the left
eye. He is unable to identify the control
Ishihara color plate with the right eye, but
he correctly identifies all plates with the
left eye. Confrontation visual fields show a
dense central scotoma in the right eye. His
pupils are equal in size and react to light,
but there is a right relative afferent pupillary
defect. Funduscopic examination shows
trace optic disc edema in the right eye and
a normal optic disc in the left eye.
25
26
W hen a young patient has an acute onset of monocular vision loss

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

27
FIGURE 5.1. Fundus photographs demonstrating coarsening of the peripapillary retinal nerve

fiber layer, as well as optic disc hyperemia and peripapillary telangiectatic vessels, in a patient
with sequential vision loss due to LHON.
is usually severe and permanent, although some patients with the 14484
mtDNA mutation have a spontaneous improvement in vision with time.
However, almost all patients will develop fellow eye involvement within
1 year, often within 6–8 weeks of their initial presentation.
LHON can be diagnosed by demonstrating the presence of a causative
mtDNA mutation. When testing for such mutations is unrevealing but
clinical suspicion for LHON is high, whole mtDNA genome sequencing
might demonstrate a rare or novel mutation. Once the diagnosis is con-
firmed, many patients ask if there is a way to prevent fellow eye involve-
ment. However, factors that influence the expression of the disease remain
uncertain. There is limited evidence that certain environmental factors, such
as tobacco and alcohol exposure, might play a role in triggering LHON.
Thus, the patient should be advised to avoid tobacco and excessive alcohol
consumption.
Treatment options for LHON remain limited. Many treatments have
been proposed, including coenzyme Q10, succinate, and various vitamins,
but there are only anecdotal reports of a beneficial effect. A prospective
randomized controlled study of idebenone (a coenzyme Q10 analog; 300
mg three times daily) showed a trend toward improvement in vision in
patients with LHON. Gene therapy might ultimately prove to be effective
for treating acute LHON and preventing fellow eye involvement; results
5. Leber Hereditary Optic Neuropathy 27

28
from clinical trials are promising. However, from a practical point of view,
genetic counseling and evaluation by a low-vision specialist are often most
helpful.
• LHON demonstrates maternal inheritance and most commonly

occurs in young men.
• LHON causes an acute onset of severe (and usually irreversible)
painless monocular vision loss, with subsequent fellow eye
involvement within 6–12 months.
• LHON can be definitively diagnosed if a pathogenic mtDNA
point mutation is detected; the most common mutations are at
positions 11778, 14484, and 3460 in the mtDNA.
• Treatment options for LHON are limited, although idebenone
treatment and gene therapies hold promise.
Further Reading
Carelli V, Carbonelli M, de Coo IF, et al. International consensus statement on the
clinical and therapeutic management of Leber hereditary optic neuropathy. J
Neuroophthalmol. 2017;37:371–381.
Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic
neuropathy: low-and medium-dose visual results. Ophthalmology.
2017;124:1621–1634.
Kirkman MA, Yu-Wai-Man P, Korsten A, et al. Gene-environment interactions in Leber
hereditary optic neuropathy. Brain. 2009;132:2317–2326.
Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial
of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677–2686.

29
6 Autosomal Dominant
Optic Atrophy
A 14-year-old boy presents to your clinic

for evaluation of longstanding vision loss
in both eyes. His vision loss was initially
detected on a vision screening examination
when he started school. He denies having
prior episodes of acute vision loss but
reports having more difficulty reading fine
print over the past several years. There is a
history of vision loss on the paternal side
of his family. Examination shows visual
acuities of 20/40 in both eyes. He correctly
identifies 4 of 14 Ishihara color plates with
both eyes. Confrontation visual fields show
a subtle central scotoma in both eyes. His
pupils are equal in size and react to light,
and there is no relative afferent pupillary
defect. Funduscopic examination shows
optic disc pallor in both eyes.
29
30
T he patient described in this scenario reports slowly worsening cen-

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

31
Most patients with ADOA come to medical attention in the first or

second decade of life after being found to have decreased visual acuities,
dyschromatopsia, or optic disc pallor in both eyes (e.g., on a vision
screening or routine eye examination). The vision loss is typically slowly
progressive over years. Visual acuity usually ranges from 20/20 to 20/200
and visual field testing shows central or ceco-central scotomas. Funduscopic
examination shows a characteristic optic disc appearance with pallor, optic
disc cupping, and atrophy of the papillomacular retinal nerve fiber layer
(Figure 6.1). The optic disc cupping is temporal, in contrast with glauco-
matous optic neuropathies, in which it is usually vertical. The severity of
optic disc pallor is often much greater than would be expected on the basis
of the patient’s visual function. Most patients with ADOA have no other
neurologic symptoms or signs. However, up to 20% develop other deficits,
which can include sensorineural hearing loss, ataxia, myopathy, peripheral
neuropathy, spastic paraparesis, and chronic progressive external ophthal-
moplegia (see Case 23).
ADOA can be diagnosed by demonstrating the presence of an OPA1
mutation. However, an OPA1 mutation is present in only two thirds of
pedigrees with ADOA and, thus, the absence of an OPA1 mutation does
not exclude the diagnosis. Consequently, it can be helpful to evaluate
FIGURE 6.1. Fundus photographs demonstrating optic disc pallor with temporal optic disc
cupping and atrophy of the papillomacular retinal nerve fiber layer in a patient with ADOA.
6. Autosomal Dominant Optic Atrophy 31

32
first-degree relatives (i.e., parents and siblings) for signs of ADOA, in-
cluding decreased visual acuity, dyschromatopsia, and optic atrophy. In
patients who do not have a known family history of ADOA or a first-
degree relative with signs consistent with ADOA, it is reasonable to ob-
tain investigations (i.e., magnetic resonance imaging of the orbits with
contrast and laboratory studies) to evaluate for other etiologies of bilateral
optic neuropathy.
There is no treatment that has been proven effective for ADOA. One
small clinical trial reported a modest improvement in vision with 12 months
of treatment with idebenone. Due to a lack of randomized controlled trials
with long-term follow-up, it remains unclear if long-term treatment with
idebenone is beneficial and, thus, it should not be routinely recommended.
From a practical point of view, genetic counseling and evaluation by a low-
vision specialist should be offered. However, most patients with ADOA
adapt to their vision loss and function well despite it.
• ADOA demonstrates dominant inheritance and has an equal sex

distribution.
• ADOA causes slowly progressive central vision loss with
associated dyschromatopsia.
• ADOA produces a characteristic optic disc appearance with
pallor, temporal optic disc cupping, and atrophy of the
papillomacular retinal nerve fiber layer.
• Since only two thirds of ADOA pedigrees have an OPA1
mutation, the absence of an OPA1 mutation does not exclude
the diagnosis.
• Treatment options for ADOA are limited, although idebenone
treatment may give a modest improvement in visual function.
Further Reading
Barboni P, Valentino ML, La Morgia C, et al. Idebenone treatment in patients with
OPA1-mutant dominant optic atrophy. Brain. 2013;136:e231.

3
Cohn AC, Toomes C, Potter C, et al. Autosomal dominant optic atrophy: penetrance

and expressivity in patients with OPA1 mutations. Am J Ophthalmol.
2007;143:656–662.
Yu-Wai-Man P, Griffiths PG, Burke A, et al. The prevalence and natural history
of dominant optic atrophy due to OPA1 mutations. Ophthalmology.
2010;117:1538–1546.
Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is
common in patients with OPA1 mutations. Brain. 2010;133:771–786.
6. Autosomal Dominant Optic Atrophy 33

34
35
7 Neuroretinitis

who has had a subacute onset of vision
loss in her right eye over several days.
She denies having associated pain on
eye movements. She has no past medical
history and denies other neurologic
symptoms. Examination shows visual
acuities of 20/50 in the right eye and
20/15 in the left eye. She correctly identifies
10 of 14 Ishihara color plates with the right
eye and 14 of 14 plates with the left eye.
Confrontation visual fields show a central
scotoma in the right eye. Her pupils are
equal and react to light, but there is a small
right relative afferent pupillary defect.
Funduscopic examination shows severe
optic disc edema with fluid extending from
the peripapillary region into the macula in
the right eye.
35
36
T he patient in this scenario has had a subacute onset of painless monoc-

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

37
FIGURE 7.2. Fundus photograph demonstrating optic disc edema and retinal exudates forming a
macular star in a patient with Bartonella neuroretinitis.
and polyarteritis nodosa. Neuroretinitis is usually a self-limited condition,

with gradual resolution over about 6–8 weeks. However, some patients with
idiopathic neuroretinitis have recurrent attacks that occur months or some-
times years apart.
Although neuroretinitis is a clinical diagnosis, diagnostic studies should be
obtained to evaluate for potential infectious etiologies and underlying inflam-
matory disease, depending on the history and clinical picture. In particular,
serology studies for the common infectious causes (i.e., cat-scratch disease,
syphilis, and Lyme disease) should be obtained, as this will influence the
choice of treatment. Diagnostic studies for inflammatory disease should also
be considered, including anti-neutrophil cytoplasmic antibodies, angiotensin-
converting enzyme level, lysozyme level, and chest x-ray or computed tomog-
raphy of the chest to evaluate for signs of pulmonary sarcoidosis. Magnetic
resonance imaging (MRI) of the orbits typically shows enhancement of the
optic nerve head acutely but is otherwise unrevealing and, thus, is usually not
necessary. Since there is no association between neuroretinitis and multiple
sclerosis, an MRI of the brain is not routinely indicated.
The prognosis for recovery of vision is variable. In most patients, there is
an excellent recovery of vision, although many have subtle persistent visual
7. Neuroretinitis 37
38
deficits from residual optic nerve dysfunction. Patients with severe vision
loss or a moderate to large relative afferent pupillary defect at presentation
have a poorer prognosis for recovery of vision. Likewise, patients with re-
current neuroretinitis have a poorer prognosis for recovery of vision.
Treatment of neuroretinitis should be tailored depending on the cause.
In patients with a history of a recent cat-scratch, empiric antibiotic therapy
(e.g., with azithromycin, ciprofloxacin, or doxycycline) is indicated, al-
though some studies have reported a benefit from corticosteroid therapy
in combination with antibiotics. In patients with an underlying inflam-
matory disease or idiopathic neuroretinitis, treatment with corticosteroids
(e.g., oral prednisone 1 mg/kg daily) should be considered. The prednisone
dose can be rapidly tapered once the optic disc edema has resolved (typically
about 4–6 weeks following initial presentation). In patients with recurrent
(noninfectious) neuroretinitis, treatment with oral prednisone (1 mg/kg
daily) should be offered acutely and long-term immunosuppressive therapy
(e.g., azathioprine or mycophenolate) should be considered to reduce the
frequency of further attacks.
• Neuroretinitis is an inflammatory condition characterized

by unilateral optic disc edema with fluid extending from
the peripapillary region into the macula and subsequent
development of retinal exudates forming a macular star.
• Neuroretinitis can be caused by a variety of infectious and
inflammatory diseases; the most commonly identified cause is
cat-scratch disease, due to infection with Bartonella henselae.
• There is a good prognosis for recovery of vision, although
patients with severe vision loss or a significant relative afferent
pupillary defect at presentation tend to have a poorer recovery.
• Patients with cat-scratch neuroretinitis should be treated
with antibiotics, whereas those with inflammatory
disease or idiopathic neuroretinitis should be treated with
corticosteroids.

39
• In patients with recurrent neuroretinitis, long-term

immunosuppressive therapy should be considered to reduce
the frequency of further attacks.
Further Reading
Chi SL, Stinnett S, Eggenberger E, et al. Clinical characteristics in 53 patients with cat
scratch optic neuropathy. Ophthalmology. 2012;119:183–187.
Habot-Wilner Z, Trivizki O, Goldstein M, et al. Cat-scratch disease: ocular
manifestations and treatment outcome. Acta Ophthalmol. 2018;96:e524–532.
Purvin V, Sundaram S, Kawasaki A. Neuroretinitis: review of the literature and new
observations. J Neuroophthalmol. 2011;31:58–68.
Sundaram SV, Purvin VA, Kawasaki A. Recurrent idiopathic neuroretinitis: natural
history and effect of treatment. Clin Exp Ophthalmol. 2010;38:591–596.
7. Neuroretinitis 39
40
41
8 Papilledema
A 32-year-old man presents to your clinic

with a several-month history of increasing
headaches. He also reports that his vision
is blurred. His wife reports some subtle
changes in his personality over the past few
years. Otherwise, he is healthy and does
not take any medications. Examination
shows visual acuities of 20/25 in both eyes.
With pinhole, his visual acuities improve to
20/20 in both eyes. He correctly identifies
all Ishihara color plates with both eyes.
Confrontation visual fields are full in both
eyes. His pupils are equal in size and react
to light, and there is no relative afferent
pupillary defect. Eye movements are
normal. Funduscopic examination shows
bilateral optic disc edema.
41
42
T he patient in this scenario presents with symptoms and signs of

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

43
FIGURE 8.1. Fundus photographs demonstrating bilateral papilledema in a patient with increased

ICP (top row). Automated perimetry shows enlarged blind spots in both eyes (bottom row).
BOX 8.1 Causes of Increased ICP
Mass lesions (e.g., benign and malignant tumors, intracerebral

hemorrhage)
Obstruction of ventricular system (e.g., aqueduct stenosis,
third-ventricular  tumor)
Obstruction of venous outflow (e.g., cerebral venous sinus
thrombosis)
Decreased CSF absorption (e.g., meningitis, subarachnoid
hemorrhage)
Increased CSF secretion (e.g., choroid plexus tumor)
Diffuse cerebral edema (e.g., post–head injury)
Medications (e.g., tetracyclines, retinoids, lithium)
Idiopathic intracranial hypertension
4
contrast. Although cerebral venous sinus thrombosis (CVST) is usually

evident on MRI of the brain with contrast, magnetic resonance venog-
raphy (MRV) of the head with contrast should be obtained if there is
a concern for CVST. If no cause for the increased ICP is identified on
MRI or MRV, the next step is to perform a lumbar puncture in the lat-
eral decubitus position in order to measure the cerebrospinal fluid (CSF)
opening pressure (normal in adults is <20 cm H2O) and evaluate the
CSF constituents for evidence of subarachnoid hemorrhage or a men-
ingitic process (e.g., viral meningitis, bacterial meningitis, or meningeal
carcinomatosis).
The patient described in this scenario has a history of subtle personality
changes, which could be due to frontal lobe dysfunction. Thus, a more de-
tailed history of his personality changes should be obtained and frontal re-
lease signs (e.g., snout, grasp, and palmomental reflexes) should be sought
on neurologic examination. The presence of decreased smell sensation might
suggest an anterior cranial fossa lesion involving the olfactory nerves. MRI
of the brain with contrast should then be obtained to evaluate for an intra-
cranial mass lesion, such as an olfactory groove meningioma (Figure 8.2).
The management of increased ICP depends on the underlying cause.
Patients who have an intracranial mass, subarachnoid hemorrhage, or
FIGURE 8.2. MRI of the brain demonstrating a large enhancing lesion in the anterior cranial
fossa, consistent with an olfactory groove meningioma. The patient had symptoms and signs of
increased ICP, personality changes, and decreased smell sensation at presentation.

45
hydrocephalus require urgent evaluation by a neurosurgeon. In patients

who have an intracranial mass with vasogenic edema, corticosteroids (e.g.,
dexamethasone) can decrease the edema and, thereby, help decrease ICP
prior to surgical debulking. Patients who have meningitis or CVST re-
quire urgent evaluation by a neurologist for initiation of antibiotics or
anticoagulation, respectively. Since recanalization of the venous sinuses
can take months in patients with CVST, concomitant treatment with
acetazolamide, which reduces CSF formation, is often required to
normalize ICP.
• Papilledema specifically refers to optic disc edema that is

secondary to increased ICP.
• Papilledema can produce transient visual obscurations and
progressive insidious visual field loss, with sparing of central
vision unless there is macular pathology (e.g., edema) or a
change in refractive error (e.g., hyperopic shift) due to posterior
globe flattening or folds.
• Increased ICP can be caused by intracranial mass lesions,
obstruction of the ventricular system, obstruction of cerebral
venous outflow, decreased CSF absorption, increased CSF
secretion, diffuse cerebral edema, medications, and idiopathic
intracranial hypertension.
• Patients with increased ICP require urgent MRI of the brain with
contrast and MRV of the head with contrast (when there is a
concern for CVST), followed by a lumbar puncture to measure
the CSF opening pressure and evaluate the CSF constituents.
Further Reading
Friedman DI. Papilledema and idiopathic intracranial hypertension. Continuum
(Minneap Minn). 2014;30:857–876.
Lee AG, Wall M. Papilledema: are we any nearer to a consensus on pathogenesis and
treatment? Curr Neurol Neurosci Rep. 2012;12:334–339.
Rigi M, Almarzouqi SJ, Morgan ML, Lee AG. Papilledema: epidemiology, etiology and
clinical management. Eye Brain. 2015;7:47–57.
8. Papilledema 45
46
47
9 Idiopathic
Intracranial Hypertension
A 22-year-old overweight woman presents

to your clinic with a several-month history
of increasing headaches. She also reports
having multiple brief episodes of complete
vision loss in both eyes, precipitated by
postural changes. She is otherwise healthy
and does not take any medications, but
has gained 60 pounds in weight over the
past 6 months. Examination shows visual
acuities of 20/20 in both eyes. She correctly
identifies all Ishihara color plates with both
eyes. Confrontation visual fields are full
in both eyes. Her pupils are equal in size
and react to light, and there is no relative
afferent pupillary defect. Eye movements
are normal. Funduscopic examination
shows bilateral optic disc edema. Magnetic
resonance imaging (MRI) of the brain with
contrast was reported to be unremarkable.
47
48
T he patient in this scenario is a young woman who has developed

symptoms and signs of increased intracranial pressure (ICP) in the
setting of weight gain. The patient’s presentation is highly suggestive for
idiopathic intracranial hypertension (IIH; Box 9.1). Formerly known as
pseudotumor cerebri, IIH is a syndrome of increased ICP of unclear eti-
ology that occurs most often in obese women of childbearing age, although
it can also occur in children, men, and older adults. There is often a history
of weight gain prior to symptom onset.
Common symptoms of IIH include headache, transient visual
obscurations, and pulse- synchronous tinnitus. Less common visual
symptoms include blurred vision (due to hyperopic shift secondary to pos-
terior globe flattening) and diplopia (due to unilateral or bilateral sixth
nerve palsy). Observant patients might notice enlargement of their phys-
iologic blind spot. However, most are not aware of visual field loss until
it is severe, since central vision is usually spared until late in the disease
course. Formal visual field testing (e.g., automated or Goldmann perim-
etry) must be obtained and, consequently, consultation with an ophthal-
mologist or neuro-ophthalmologist is essential. Of note, up to 25% of
patients are asymptomatic; these patients often come to medical attention
when papilledema (optic disc edema secondary to increased ICP) is discov-
ered on a routine eye examination. Papilledema is the most common sign
in IIH. There may be associated retinal hemorrhages (usually flame-shaped
retinal nerve fiber hemorrhages), retinal folds, cotton-wool spots, and
exudates, especially with increasing severity of papilledema (Figure 9.1).
Since the risk of vision loss is correlated with the severity of papilledema,
it is useful to grade the severity using the modified Frisén scale (Table 9.1;
BOX 9.1 Modified Dandy Diagnostic Criteria for IIH
1. Awake and alert patient

2. Symptoms and signs of increased ICP
3. No focal neurologic signs, except for sixth or seventh nerve palsy
4.
Normal diagnostic studies (i.e., neuroimaging and CSF evaluation),
except for evidence of increased ICP
5. No other cause for increased ICP identified

49
FIGURE 9.1. Fundus photographs demonstrating papilledema of increasing severity, graded using

the modified Frisén scale, from grade 0 (no papilledema) to grade V (severe papilledema). The
major features of each grade are listed in Table 9.1.
TABLE 9.1 Modified Frisén Scale for Grading Papilledema
Grade Major Feature
0 (none) No findings to suggest edema
I (minimal) C-shaped halo with sparing of temporal margin of

optic disc
II (mild) Circumferential halo with no obscuration of major

blood vessels
III (moderate) Obscuration of at least one segment of a major blood

vessel leaving the optic disc
IV (marked) Total obscuration of a segment of a major blood

vessel on the optic disc
V (severe) Total obscuration of all blood vessels on and leaving

the optic disc
9. Idiopathic Intracranial Hypertension 49

50
see Figure 9.1). Other signs can include unilateral or bilateral sixth nerve
palsy and, less commonly, facial nerve palsy.
IIH is diagnosed in accordance with the modified Dandy criteria (see
Box 9.1). It is a diagnosis of exclusion and, thus, other etiologies need to be
excluded with imaging and lumbar puncture (see Case 8). Even if no cause
for increased ICP is identified on MRI and magnetic resonance venography
(MRV), there are often findings on imaging that are suggestive of increased
ICP, such as an empty sella, posterior globe flattening, distension or tortu-
osity of the optic nerve sheaths, and transverse venous sinus stenoses (Figure
9.2). Certain medications (e.g., tetracyclines, retinoids, and lithium) can
cause a clinical syndrome that mimics IIH, although these might also pre-
cipitate or worsen preexisting IIH. Consequently, a thorough review of
FIGURE 9.2. MRI and MRV findings in IIH, including empty sella (asterisk, top left), posterior
globe flattening (arrows, top right), transverse venous sinus stenoses (arrows, bottom left), and
optic nerve sheath distention (top right and bottom right).

51
BOX 9.2 Features Suggesting CVST
Non-obese
Pregnant or postpartum
Acute or fulminant presentation
History of clotting or thrombophilia (e.g., pulmonary embolus)
History of connective tissue disease (e.g., Behçet disease)
History of recent ear, mastoid, or sinus infection
History of recent head or neck surgery or trauma
CSF abnormalities (e.g., increased protein, pleocytosis)
medication use is mandatory. Obstruction of cerebral venous outflow due

to cerebral venous sinus thrombosis (CVST) or extrinsic venous sinus com-
pression (e.g., by a meningioma) can also cause a clinical syndrome that
mimics IIH. Thus, MRV should be obtained if there is a concern for CVST
based on the patient’s presentation (Box 9.2).
The main goals of IIH treatment are to alleviate symptoms and preserve
vision; the approach depends on the severity of symptoms, papilledema,
and vision loss (Table 9.2 discusses the suggested approach based on se-
verity of vision loss). Treatment begins with the diagnostic lumbar puncture,
which may transiently improve symptoms and signs. The patient should be
counseled about the importance of modest weight loss (with a diet and
exercise program), which may be all that is required in patients who have
minimal symptoms and signs; a 6% to 10% loss of body weight is often
sufficient. Bariatric surgery can be considered for morbidly obese patients
TABLE 9.2 Approach to Management Based on Severity of Vision Loss
Severity of Vision Loss Treatment Approach
Minimal Weight loss ± medical therapy
Mild Weight loss + medical therapy
Moderate Weight loss + medical therapy ± surgical

therapy
Severe Weight loss + medical therapy + surgical

therapy

52
whose attempts at weight loss are unsuccessful. Potential contributing

factors (e.g., obstructive sleep apnea) should also be diagnosed and treated.
A number of medical and surgical treatments can be considered for
patients with IIH. Acetazolamide is a carbonic anhydrase inhibitor that
decreases the production of cerebrospinal fluid (CSF). A recent double-
masked, randomized controlled trial called the IIH Treatment Trial
(IIHTT) evaluated diet plus placebo versus diet plus maximally tolerated
acetazolamide for IIH patients who had mild vision loss at presentation.
In the IIHTT, acetazolamide treatment resulted in significant improve-
ment in visual field loss, papilledema grade, symptoms, and quality of
life. Acetazolamide treatment was also associated with greater amounts
of weight loss. Thus, when there is only mild visual field loss, treatment
with acetazolamide should be initiated. Doses of 1 to 2 g/day or more
are usually required for a clinical effect but can produce side effects (e.g.,
paresthesias, altered taste sensation, lethargy, and renal calculi). There is an
increased risk of failure of acetazolamide treatment in men and in patients
with moderate to severe papilledema (i.e., grade III or more), decreased
visual acuity, frequent transient visual obscurations, and peripapillary ret-
inal nerve fiber layer hemorrhages; these patients require closer monitoring
and may ultimately need more aggressive treatment. Topiramate is another
weak carbonic anhydrase inhibitor that has similar efficacy to acetazolamide
in treating patients with mild to moderate IIH and, therefore, can be
considered when acetazolamide is not tolerated or when headache is prom-
inent. Other diuretics (e.g., furosemide) can be administered alone or in
combination with acetazolamide or topiramate for a synergistic effect.
When visual field loss is severe or progressive despite maximally
tolerated medical treatment, surgical intervention should be considered.
The choice of surgical intervention will often vary depending on local
resources and practices. The three main options are CSF shunting, optic
nerve sheath fenestration (ONSF), and transverse venous sinus stenting.
CSF shunting often produces a rapid reduction in ICP but is associated
with a significant complication rate (e.g., shunt infection and obstruc-
tion) such that shunt revisions are often required. Stereotactic ventriculo-
peritoneal shunting is preferred over lumbo-peritoneal shunting, since
it has a lower complication rate. ONSF results in a rapid reduction in
the pressure on the optic nerve, leading to reduction in papilledema

53
and improvement in vision. Occasionally, unilateral ONSF improves

papilledema and vision on the contralateral side, but bilateral ONSF is
usually required. ONSF is not effective in treating other symptoms and
signs of increased ICP. Potential complications of ONSF include vision
loss (e.g., due to iatrogenic optic nerve trauma), tonic pupil (see Case 36),
and diplopia. Transverse venous sinus stenting is an option in patients
who have a transverse venous sinus stenosis with a pressure gradient across
the stenosis. Stenting is thought to reduce cerebral venous hypertension,
leading to an increase in CSF absorption and reduction in ICP. Potential
complications of transverse venous sinus stenting include in-stent throm-
bosis and subdural hemorrhage. Furthermore, a significant percentage of
patients develop recurrent venous sinus stenosis proximal to the stent.
The appropriate choice and timing of surgical intervention remains un-
clear due to a lack of clinical trials directly comparing the interventions.
However, since IIH is a chronic disease, patients require long- term
follow-up regardless of which treatment approach is used. The frequency
of follow-up will depend on the severity of symptoms and signs, response
to treatment, and subsequent clinical course.
• IIH is a syndrome of increased ICP of unclear etiology that most

often occurs in obese women of childbearing age.
• Common symptoms include headache, transient visual
obscurations, and pulse-synchronous tinnitus, with blurred
vision, visual field loss, and diplopia occurring less commonly.
• Most patients do not become aware of their visual field loss
until it is severe and, therefore, formal visual field testing must
be obtained to help guide treatment and follow-up decisions.
• The goals of treatment are to alleviate symptoms and preserve
vision; the treatment approach varies depending on the severity
of symptoms, papilledema, and vision loss.
• Treatment options include weight loss, medical therapy (i.e.,
acetazolamide and topiramate), and surgical interventions (i.e.,
CSF shunting, ONSF, and transverse venous sinus stenting).

54
Further Reading
Dinkin MJ, Patsalides A. Venous sinus stenting in idiopathic intracranial
hypertension: results of a prospective trial. J Neuroophthalmol. 2017;37:113–21.
Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial
pressure in women with idiopathic intracranial hypertension: prospective cohort
study. BMJ. 2010;341:c2701.
Wall M, Falardeau J, Fletcher WA, et al. Risk factors for poor visual outcome in
patients with idiopathic intracranial hypertension. Neurology. 2015;85:799–805.
Wall M, Kupersmith MJ, Kieburtz KD, et al. The idiopathic intracranial hypertension
treatment trial: clinical profile at baseline. JAMA Neurol. 2014;71:693–701.
Wall M, McDermott MP, Kieburtz KD, et al. Effect of acetazolamide on visual function
in patients with idiopathic intracranial hypertension and mild visual loss: the
idiopathic intracranial hypertension treatment trial. JAMA. 2014;311:1641–51.

5
10 Pseudopapilledema
A thin 14-year-old white girl presents to

your clinic with a several-month history of
headache. She has not noticed any changes
in her vision, but her neurologist noted
that her optic nerve heads were elevated.
20/20 in both eyes. She correctly identifies
all Ishihara color plates with both eyes.
Confrontation visual fields are full in both
eyes. Her pupils are equal in size and
reactive to light, and there is no relative
afferent pupillary defect. Eye movements
are normal. Funduscopic examination
shows elevated optic discs. She has already
undergone a thorough workup, including
magnetic resonance imaging (MRI) of the
brain with contrast, magnetic resonance
venography (MRV) of the head, and lumbar
puncture, but no cause for her optic nerve
head elevation has been identified.
55
56
W hen a patient with headaches is found to have elevated optic nerve

heads, the initial concern should be for papilledema (i.e., optic disc
edema due to increased intracranial pressure; see Case 8). However, optic
nerve head elevation can be due to optic disc edema from another cause
(e.g., nonarteritic anterior ischemic optic neuropathy or neuroretinitis; see
Cases 3 and 7). It can also be caused by optic nerve head infiltration (e.g., by
sarcoid granuloma or metastasis) or might simply reflect a benign anomaly
of the optic nerve head (Box 10.1). Since anomalous optic nerve head ele-
vation can mimic optic disc edema, it is often termed pseudopapilledema.
In many cases, pseudopapilledema can be distinguished from papilledema
on the basis of the clinical history and examination findings (Table 10.1).
Papilledema is characterized by retinal nerve fiber layer (RNFL) edema,
which gives the RNFL an opaque appearance that obscures the underlying
retinal vessels and produces a halo around the optic disc (Figure 10.1). In
pseudopapilledema, the optic disc margins are usually more clearly defined
and there is no obscuration of the vessels, because there is no RNFL edema
(see Figure 10.1). Several other clinical features can help to differentiate
pseudopapilledema from papilledema (see Table 10.1).
Many patients with optic nerve head elevation undergo extensive
investigations before the possibility of pseudopapilledema is considered.
The patient described in this scenario has had several investigations looking
for causes of increased intracranial pressure, but these have been unrevealing.
It is therefore possible that her optic nerve head elevation is an incidental
finding and unrelated to her headaches. The next step in her evaluation
BOX 10.1 Differential Diagnosis of Papilledema
Optic disc edema of another cause (e.g., anterior ischemic optic

neuropathy, neuroretinitis)
Optic nerve head infiltration (e.g., granuloma, optic nerve head
melanoma, metastasis)
Congenitally small, structurally congested optic disc (“little red disc”)
Congenitally tilted optic disc
Myelinated nerve fiber layer
Vitreopapillary traction
Optic nerve head drusen

57
TABLE 10.1 Clinical Features of Papilledema Compared with

Pseudopapilledema
Clinical Feature Papilledema Pseudopapilledema
Transient visual Yes Sometimes

obscurations
Visual field defects Yes Sometimes
Spontaneous venous No Yes

pulsations
Changing optic disc Yes No

appearance
Obscuration of vessels Yes No
Anomalous vascular No Sometimes

branching
Hemorrhages Yes (retinal nerve Rarely (subretinal)

fiber layer)
Preserved physiologic cup Yes (until late) No
Retinal folds Often No
Fluorescein leakage Yes (if moderate to No

severe)
Symptoms/signs of Often No
increased ICP
FIGURE 10.1. Fundus photographs demonstrating papilledema (left), with edematous retinal

nerve fiber layer causing vessel obscuration, compared with pseudopapilledema (right), in which
there is no vessel obscuration.
58
would be an examination of the optic discs, ideally by an ophthalmologist

or neuro-ophthalmologist, looking for features that might suggest a cause
for her optic nerve head elevation. The history of her headaches should also
be reevaluated, as there may be a treatable cause (e.g., migraine).
Optic nerve head elevation is often present in patients who have congen-
itally small, structurally congested optic discs (see Case 3 and Figure 3.1).
Since these optic discs are often red, they are sometimes called “little red
discs.” Optic nerve head elevation can also be evident in patients with con-
genitally tilted optic discs. Such patients can have bitemporal visual field
defects that do not respect the vertical meridian (see Case 11).
A common cause of optic nerve head elevation is optic nerve head
drusen (ONHD). ONHD are laminated acellular concretions that form
within the substance of the optic nerve head. Although their etiology re-
mains poorly understood, they usually occur in patients with small, struc-
turally congested optic nerve heads and can be inherited in an autosomal
dominant fashion. In younger patients, ONHD are often not visible on
funduscopic examination (“buried” ONHD). However, the optic disc is
usually elevated and can have a “lumpy bumpy” appearance (Figure 10.2).
As the patient ages, ONHD become visible as rounded, yellow, crystal-like
FIGURE 10.2. Fundus photographs (left), fundus autofluorescence (middle), and B-scan

ultrasonography (right) in patients with exposed (top row) and buried (bottom row) ONHD.

59
excrescences on the optic disc (“exposed” ONHD; see Figure 10.2). They
are usually most conspicuous at the nasal aspect of the disc. With time, they
can coalesce to form large “rock candy” conglomerates (see Figure 10.2).
Most patients with ONHD remain asymptomatic, but patients with a large
volume of ONHD can develop peripheral visual field defects secondary to
RNFL attrition, which can sometimes progress to severe visual field constric-
tion. Some patients experience transient visual obscurations. Occasionally,
ONHD can be complicated by sudden, painless monocular vision loss due
to nonarteritic anterior ischemic optic neuropathy (see Case 3) or central
retinal artery occlusion. Unfortunately, no intervention has been proven
to prevent the progressive visual field loss or vascular complications asso-
ciated with ONHD, although the findings of some studies suggest that
treatment with ocular hypotensive agents might slow the progression of
visual field loss.
While ONHD are easily diagnosed if they are visible on funduscopic
examination, optic nerve head elevation from buried ONHD can be dif-
ficult to distinguish from mild papilledema. Several forms of ophthalmic
imaging are often helpful for making the distinction. Since ONHD ex-
hibit autofluorescence, they may be detected with autofluorescence pho-
tography, even when they are not evident on funduscopic examination
(see Figure 10.2). When calcified, ONHD are usually obvious on B-scan
ultrasonography as foci of increased reflectivity within an elevated optic
nerve head, with a characteristic posterior reduplication artifact (see Figure
10.2). ONHD may also be evident as optic nerve head calcification on
computed tomography (CT). Therefore, the patient described in this sce-
nario should have further ophthalmic imaging to evaluate for ONHD if
another cause for pseudopapilledema is not evident on funduscopic exam-
ination. If there continues to be a concern for papilledema, several other
ophthalmic investigations could be considered. Optical coherence tomog-
raphy (OCT) of the optic nerves should show increased RNFL thickness in
papilledema and normal thickness in pseudopapilledema, although patients
with a large volume of ONHD can have RNFL thinning, sometimes in
the absence of visual field loss. ONHD can usually be detected using
enhanced depth imaging OCT. Alternatively, OCT may show another
cause for pseudopapilledema, such as vitreopapillary traction, in which
there is optic nerve head elevation secondary to vitreous traction. Lastly,
10. Pseudopapilledema 59
60
fluorescein angiography will show late leakage of dye beyond the optic disc
margin in moderate to severe papilledema, whereas there is no late leakage
in pseudopapilledema. If doubt remains, the patient should be followed
clinically; a stable optic nerve head appearance suggests pseudopapilledema,
whereas a changing appearance is concerning for papilledema. Regardless
of the outcome of any further evaluation for the patient in this scenario,
ongoing consultation with her neurologist is essential to optimize the treat-
ment of her headaches.
• Optic nerve head elevation can be due to true optic disc edema
(e.g., papilledema), optic nerve head infiltration, or a benign
optic nerve head anomaly.
• Pseudopapilledema occurs when benign optic nerve head
anomalies mimic papilledema (i.e., when there is optic nerve
head elevation).
• ONHD are a common cause for pseudopapilledema but are
difficult to diagnose clinically if the ONHD are not visible on
funduscopic examination.
• B-scan ultrasonography, autofluorescence photography,
OCT, and fluorescein angiography can help to distinguish
pseudopapilledema from papilledema.
Further Reading
Malmqvist L, Lindberg AW, Dahl VA, et al. Quantitatively measured anatomic location
and volume of optic disc drusen: an enhanced depth imaging optical coherence
tomography study. Invest Ophthalmol Vis Sci. 2017;58:2491–2497.
Pojda-Wilczek D, Wycislo-Gawron P. The effect of a decrease in intraocular pressure
on optic nerve function in patients with optic nerve drusen. Ophthalmic Res.
2017. doi: 10.1159/0 00481534.
Silverman AL, Tatham AJ, Medeiros FA, Weinreb RN. Assessment of optic nerve head
drusen using enhanced depth imaging and swept source optical coherence
tomography. J Neuroophthalmol. 2014;34:198–205.
Skaat A, Muylaert S, Mogil RS, et al. Relationship between optic nerve head drusen
volume and structural and functional optic nerve damage. J Glaucoma.
2017;26:1095–1100.

61
11 Chiasmal Syndromes
A 42-year-old man presents to the

emergency department following the
sudden onset of a severe global headache
with vomiting. He has a 10-month history
of galactorrhea. Examination shows visual
acuities of 20/20 in both eyes. He correctly
identifies all Ishihara color plates with both
eyes. Confrontation visual fields show a
dense bitemporal hemianopia. His pupils
are equal in size and react to light, and
there is no relative afferent pupillary defect.
Eye movements are normal. Funduscopic
examination is normal and his cranial nerve
examination is unrevealing.
61
62
B itemporal hemianopia is highly localizing to the optic chiasm, be-

cause this is the only location in the nervous system where the nerve
fibers subserving vision from both temporal fields are in close prox-
imity. Depending on the location of the lesion, several variations on the
bitemporal hemianopic field defect can be recognized (Figure 11.1). If the
optic chiasm is compressed from below, the visual field defects will initially
be superotemporal. If the optic chiasm is compressed from above, the visual
field defects will initially be inferotemporal. If the only posterior aspect of
FIGURE 11.1. Visual field defects occurring with chiasmal lesions.

63
the optic chiasm is compressed, the bitemporal visual field defects will be
paracentral. If the intracranial segment of one optic nerve is compressed,
there will typically be a central visual field defect in that eye (see Case 4);
the combination of a central visual field defect in one eye and a temporal
defect in the other is known as a junctional scotoma, because it is caused by
a lesion at the junction of the optic nerve and chiasm.
Bitemporal hemianopia most often results from optic chiasm dysfunc-
tion secondary to compression by pituitary adenomas, meningiomas,
craniopharyngiomas, Rathke cleft cysts, or aneurysms. Less common causes
of bitemporal hemianopia include optic chiasm dysfunction secondary to
inflammation (e.g., in multiple sclerosis or sarcoidosis), low-grade gliomas
(e.g., in neurofibromatosis type I), high-grade gliomas, lymphoma, vas-
cular malformations, trauma, and compression by arachnoid cysts, germ
cell tumors, epidermoid cysts, and dermoid cysts. When the compression
occurs gradually over months or years, the bitemporal hemianopia develops
insidiously and may go unnoticed by the patient. Thus, it is not uncommon
for a bitemporal hemianopia to be incidentally detected on a routine eye
examination or screening visual field testing. Bitemporal visual field defects
can occur in patients with tilted optic discs (see Case 10), but the defects
do not respect the vertical meridian, unlike those of a true bitemporal
hemianopia.
Although most causes of chiasmal dysfunction can be identified on im-
aging, the clinical presentation occasionally suggests a specific diagnosis.
The acute onset of severe headache in this patient with galactorrhea and
bitemporal hemianopia should suggest a macroprolactinoma with pi-
tuitary apoplexy. Pituitary apoplexy is a rare yet life-threatening clinical
syndrome that results from infarction of (or hemorrhage into) a pituitary
macroadenoma. In many cases, the macroadenoma is nonfunctioning.
When the infarction or hemorrhage occurs, there is a rapid increase in
the size of the tumor, leading to compression of adjacent structures in the
suprasellar cistern and cavernous sinuses. Subsequently, there is a dramatic
onset of symptoms and signs, which can include headache, meningism,
vomiting, vision loss, ophthalmoplegia (due to third, fourth, or sixth nerve
palsy), stupor, and vascular collapse. Factors implicated as precipitants for
pituitary apoplexy include major surgery (e.g., cardiac bypass surgery) and
anticoagulant use.
11. Chiasmal Syndromes 63

64
FIGURE 11.2. Coronal MRI of the brain showing a pituitary macroadenoma extending into the
suprasellar cistern to compress the optic chiasm (arrows). The patient had a dense bitemporal
hemianopia.
Magnetic resonance imaging (MRI) is the imaging modality of choice

for evaluating bitemporal hemianopia (Figure 11.2). In the setting of pi-
tuitary apoplexy, MRI clearly demonstrates both pituitary infarction and
hemorrhage as well as showing the degree of compression of neighboring
structures. The patient described in this scenario therefore requires an emer-
gent MRI brain with contrast, formal visual field testing (if possible), and
admission to the hospital for treatment. Intravenous corticosteroids (e.g.,
hydrocortisone) should be administered to treat acute hypoadrenalism. An
endocrinologist should be consulted because the patient may have or sub-
sequently develop panhypopituitarism. Although improvement in vision
sometimes occurs without surgical intervention, decompression is generally
advised unless there is a contraindication to general anesthesia. The optimal
timing of surgical decompression remains controversial, as there are reports
of a good visual outcome in patients with vision loss secondary to pituitary
apoplexy who did not have a decompression until several days after presen-
tation. However, visual recovery can be poor even when decompression is
performed emergently. In such cases, the poor visual recovery might be con-
sequent to longstanding optic chiasmal compression producing irreversible
damage, which would result in optic atrophy as well as retinal nerve fiber

65
layer and macular ganglion cell layer thinning on optical coherence tomog-
raphy (OCT). However, when the optic chiasm compression is acute, there
will be no optic atrophy. Furthermore, there will be no retinal nerve fiber
layer or macular ganglion cell layer thinning on OCT. Thus, urgent decom-
pression should be considered in all patients who have pituitary apoplexy to
maximize the chance of visual recovery.
• A bitemporal hemianopic visual field defect localizes the lesion

to the optic chiasm.
• Optic chiasmal dysfunction is most commonly secondary
to compression by pituitary adenomas, meningiomas,
craniopharyngiomas, Rathke cleft cysts, and aneurysms.
• Pituitary apoplexy is a rare, life-threatening clinical syndrome
that results from infarction of (or hemorrhage into) a pituitary
macroadenoma.
• Pituitary apoplexy requires immediate treatment with
intravenous steroids and, in many cases, emergent
decompression of the anterior visual pathways.
Further Reading
Agrawal D, Mahapatra AK. Visual outcome of blind eyes in pituitary apoplexy after
transsphenoidal surgery: a series of 14 eyes. Surg Neurol. 2005;63:42–46.
Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J
Neurol Neurosurg Psychiatry. 2001;71:542–545.
Piotin M, Tampieri D, Rufenacht DA, et al. The various MRI patterns of pituitary
apoplexy. Eur Radiol. 1999;9:918–923.
Semple PL, Webb MK, de Villiers JC, Laws ER Jr. Pituitary apoplexy. Neurosurgery.
2005;56:65–73.
11. Chiasmal Syndromes 65

6
67
12 Homonymous Hemianopia

who was brought to the emergency
department following a motor vehicle
accident. She was the driver of the vehicle
at fault and claims to have not seen the
other vehicle, but she denies vision loss.
Examination shows visual acuities of 20/25
in both eyes. She correctly identifies most
Ishihara color plates with both eyes but
occasionally misses the numbers on the
left side of the plates. Confrontation visual
fields show a dense left homonymous
hemianopia. Pupils, eye movements, and
funduscopic examination are all normal.
67
68
U nilateral lesions affecting the retrochiasmal visual pathways or primary

visual cortex produce homonymous visual field defects in the contra-
lateral hemifield of both eyes. The pattern of the visual field defect and
presence of other neurologic symptoms or signs can often help to localize
the causative lesion. For example, an incongruent homonymous visual field
defect (i.e., one that is dissimilar in the two eyes) with a relative afferent pu-
pillary defect in the eye with the temporal defect suggests a lesion affecting
the optic tract. It is also useful to know the tempo of onset of visual field
loss because this can also suggest the etiology (e.g., sudden onset of ho-
monymous visual field loss implies a stroke, whereas gradual onset implies
a tumor). The initial evaluation of a patient with homonymous visual field
loss should therefore include a careful history, to determine the temporal
profile of onset and to inquire about other neurologic symptoms, and a
neurologic examination looking for signs that aid in localizing the lesion.
Formal visual field testing should also be obtained, if possible, to determine
the pattern of the visual field defect.
When a complete homonymous visual field defect (homonymous
hemianopia) is present without other neurologic symptoms or signs, or
when the defect is small yet highly congruent, the lesion is likely to be in
the occipital lobe. In some such cases, the patient may not become aware
of the visual field defect until it is called to his or her attention (e.g., with
formal visual field testing or following a motor vehicle accident). Since the
most common causes of homonymous hemianopia are stroke, tumor, and
trauma, the causative lesion is usually evident on magnetic resonance im-
aging (MRI) of the brain (Figure 12.1). However, MRI of the brain can
be unrevealing or show only subtle abnormalities in patients who have ho-
monymous hemianopia secondary to migraine, seizures, encephalopathies
(e.g., nonketotic hyperglycemia), early visual variant of Alzheimer disease
(see Case 13), and the Heidenhain variant of Creutzfeldt-Jakob disease.
Subsequent evaluation and treatment depend on the nature of the under-
lying lesion. For instance, a patient with an acute occipital stroke requires
consideration for thrombolysis and a stroke workup, whereas a patient with
an occipital tumor might require a biopsy or workup for metastatic disease.
The prognosis for recovery of homonymous hemianopia varies depending
on the cause. Unfortunately, most patients are left with a permanent visual
field defect, although many patients report subjective improvement in their

69
FIGURE 12.1. MRI showing an old infarct in the right posterior cerebral artery territory (left) and
a posterior falcine meningioma extending into the right occipital lobe (right). Both patients had a
left homonymous hemianopia.
vision due to the development of adaptive strategies (e.g., increased eye and
head movements into the missing hemifield) to compensate for the visual
field loss. Numerous studies assessing on-road driving performance have re-
ported that some patients with homonymous hemianopia are able to drive
safely. However, such patients are not permitted to drive by law in many
jurisdictions. It is therefore crucial to obtain formal visual field testing and
consider referral to a low-vision specialist before allowing the patient to re-
sume driving.
Many therapies have been proposed for the rehabilitation of homon-
ymous hemianopia, but these remain controversial. Some commercially
available therapies claim to be able to reduce the size of the visual field
defect, but there is inadequate scientific evidence to support such claims.
Rather, these therapies are thought to bring about an apparent improve-
ment due to the development of adaptive strategies. The optimal means by
which to entrain such adaptive strategies remains under investigation. Other
approaches have been developed to functionally expand the visual field
in patients with homonymous hemianopia. One such approach involves
placing a temporary (Fresnel) prism onto the patient’s spectacle lenses above
12. Homonymous Hemianopia 69

70
or below the visual axis so that part of the missing hemifield is visible to the
patient when he or she is looking straight ahead through the central (prism-
free) area of the lens. Because these approaches can help some patients with
their navigation, referral to a low-vision specialist should be considered in
patients with functional impairment due to homonymous hemianopia.
• Homonymous visual field defects result from unilateral lesions

affecting the retrochiasmal visual pathways or primary visual
cortex.
• The pattern of the visual field defect and presence of other
neurologic symptoms or signs can help to localize the causative
lesion.
• Formal visual field testing must be obtained to determine the
extent of the hemianopia, because patients with homonymous
hemianopia are not permitted to drive in many jurisdictions.
• Many patients with persistent homonymous hemianopia report
improvement due to the development of adaptive strategies,
but rehabilitative interventions remain controversial.
Further Reading
Bowers AR. Driving with homonymous visual field loss. Clin Exp Optom.
2016;99:402–418.
Bowers AR, Keeney K, Peli E. Community-based trial of a peripheral prism visual field
expansion device for hemianopia. Arch Ophthalmol. 2008;126:657–664.
Reinhard J, Schreiber A, Schiefer U, et al. Does visual restitution training change
absolute homonymous visual field defects? A fundus controlled study. Br J
Ophthalmol. 2005;89:30–35.
Wood JM, McGwin G Jr, Elgin J, et al. Hemianopic and quadrantanopic field
loss, eye and head movements, and driving. Invest Ophthalmol Vis Sci.
2011;52:1220–1225.
Zhang X, Kedar S, Lynn MJ, Newman NJ, Biousse V. Homonymous
hemianopias: clinical–anatomic correlations in 904 cases. Neurology.
2006;66:906–910.

71
13 Disorders of Higher
Visual Function

reporting “difficulty seeing.” He has had
bilateral cataract extractions and wears
reading glasses but otherwise has no
significant ocular history. He has seen
multiple ophthalmologists, but eye
examinations have not identified a cause
for his complaints. Magnetic resonance
imaging (MRI) of the brain was reported
to be unremarkable. Examination shows
visual acuities of 20/25 in both eyes. He
is unable to identify the control Ishihara
color plate with either eye. Confrontation
visual fields are full. Pupil, eye movement,
and funduscopic examinations are normal.
However, when his wife enters the room at
the end of the examination, you notice that
he does not recognize her until she speaks.
71
72
W hen a patient reports having visual symptoms that are out of propor-
tion to the findings on ophthalmic examination, a disorder of higher
visual function should be considered. These disorders are caused by lesions
affecting visual association areas or their interconnections. They often go
undiagnosed for long periods because the routine ophthalmic examination
does not incorporate screening tests to allow for their detection. Affected
patients often have difficulty describing their visual problem, but its nature
will become apparent if a more detailed history is obtained. Furthermore,
there might be subtle examination findings that suggest a disorder of higher
visual function, such as difficulty reading despite normal or near-normal
visual acuity.
A variety of disorders of higher visual function have been described
(Table 13.1). Visual agnosia, a common disorder of higher visual function,
is characterized by an inability to recognize familiar objects despite intact
visual perception, attention, intellect, and language function. Observation
of the patient described in the case scenario has demonstrated that he may
have a subtype of visual agnosia called prosopagnosia, in which the ability
to recognize familiar faces is impaired. Prosopagnosia can often be detected
by asking the patient to identify relatives or famous public figures (e.g.,
politicians, actors, or sports stars) from photographs. Patients with pros-
opagnosia can have coexisting homonymous visual field defects (see Case
12), cerebral achromatopsia (inability to perceive colors), and impairment
of visual memory. Prosopagnosia usually arises because of bilateral lesions
involving the inferior temporo-occipital junction, most commonly due to
infarction in the posterior cerebral artery territory. However, it can also
occur with more diffuse pathologic processes (e.g., viral encephalitis) and
neurodegenerative diseases (e.g., Alzheimer disease). Simultanagnosia, an-
other common disorder of higher visual function, is characterized by dif-
ficulty interpreting an entire visual scene despite having retained ability to
interpret portions of the scene. It should be suspected when a patient cannot
identify the control Ishihara color plate despite having normal visual acuity.
Simultanagnosia can also be assessed by asking the patient to describe a
complex visual scene (e.g., the “cookie theft” picture). It most commonly
occurs in patients with neurodegenerative disease (e.g., Alzheimer disease).
It can occur as a component of Balint syndrome, in which there is also oc-
ular motor apraxia (inability to move the eyes toward a visual target despite

73
TABLE 13.1 Disorders of Higher Visual Function
Deficit Description Lesion Localization
Alexia Acquired inability to read Dominant medial

temporo-occipital
Cerebral Acquired inability to Ventral-medial

achromatopsia perceive colors occipital (V4)
Cerebral Acquired inability to Bilateral lateral

akinetopsia perceive motion temporo-occipital
Cortical blindness Bilateral homonymous Bilateral primary visual

visual loss cortex (V1)
Ocular motor Inability to move the eyes Bilateral

apraxia (can be toward a visual target parieto-occipital
a component of despite intact ductions Bilateral frontal
Balint syndrome)
Optic ataxia (can Inability to move a limb Bilateral

be a component (e.g., point a finger) toward parieto-occipital
of Balint a visual target despite
syndrome) intact motor function
Palinopsia Abnormally persistent Nondominant

visual after-images parieto-occipital
Prosopagnosia Inability to recognize Bilateral inferior

familiar faces temporo-occipital
Simultanagnosia Inability to interpret an Bilateral

(can be a entire visual scene despite parieto-occipital
component of retained ability to interpret
Balint syndrome) portions of the scene
Visual Visual perceptions Primary visual cortex

hallucinations in the absence of a (V1) for simple
corresponding external (unformed) visual
visual stimulus hallucinations
having intact ductions) and optic ataxia (inability to move a limb toward a
visual target despite having intact motor function). Balint syndrome results
from bilateral parieto-occipital lesions, most often secondary to stroke.
Patients with disorders of higher visual function due to focal lesions
(e.g., stroke or tumor) can have other neurologic symptoms or signs that
13. Disorders of Higher Visual Function 73

74
help to localize the lesion; MRI of the brain will usually demonstrate the
causative lesion. Patients with disorders of higher visual function due to
neurodegenerative disease will often have other cognitive deficits (e.g.,
deficits in short-term memory) that can be detected on screening tests to
evaluate higher cortical function (e.g., Mini-Mental State Examination).
However, in the visual variant of Alzheimer disease (VVAD), in which the
parieto-occipital lobes are preferentially affected, patients have only visual
complaints initially. Visual-spatial difficulties (e.g., getting lost in familiar
places) and reading difficulties are particularly characteristic of VVAD.
Since other cognitive domains are intact, patients with VVAD often present
to ophthalmologists rather than neurologists and pose a diagnostic chal-
lenge because the routine ophthalmic examination is unrevealing. Patients
with VVAD often have homonymous hemianopic visual field defects (see
Case 12) in addition to having other disorders of higher visual function
such as visual agnosias (e.g., alexia) and simultanagnosia. MRI of the brain
typically shows focal parieto-occipital atrophy (Figure 13.1), which might
not be appreciated unless specifically sought. Thus, the first steps in the
evaluation of the patient in this scenario are to obtain formal visual field
testing and to review his previous imaging. Positron emission tomography
FIGURE 13.1. MRI demonstrating parieto-occipital atrophy in a patient with the visual variant of
Alzheimer disease.

75
(PET) often shows parieto-occipital hypometabolism, which supports a di-

agnosis of VVAD. Nonetheless, other treatable causes of dementia should
be excluded with laboratory testing (e.g., vitamin B12 level, thyroid func-
tion tests, and syphilis serology).
Treatment for disorders of higher visual function should be directed to-
ward the underlying cause. Neurology evaluation should be arranged for
patients with VVAD because progression of the disease might be slowed
with standard treatments for Alzheimer disease (e.g., donepezil).
• A disorder of higher visual function should be considered in

patients with visual symptoms that are out of proportion to the
findings on ophthalmic examination.
• VVAD often presents with isolated visual symptoms because
other cognitive functions are intact.
• Patients with VVAD often have focal parieto-occipital atrophy on
MRI and parieto-occipital hypometabolism on PET.
• Progression of VVAD may be slowed with standard treatments
for Alzheimer disease.
Further Reading
Barton JJ. Disorders of face perception and recognition. Neurol Clin.
2003;21:521–548.
Brazis PW, Graff-Radford NR, Newman NJ, Lee AG. Ishihara color plates as a test for
simultanagnosia. Am J Ophthalmol. 1998;126:850–851.
Kaeser PF, Ghika J, Borruat FX. Visual signs and symptoms in patients with the visual
variant of Alzheimer disease. BMC Ophthalmol. 2015;15:65.
Lee AG, Martin CO. Neuro-ophthalmic findings in the visual variant of Alzheimer’s
disease. Ophthalmology. 2004;111:376–380.
13. Disorders of Higher Visual Function 75

76
7
14 Visual Auras, Hallucinations,

and Illusions
A 60-year-old woman presents to your clinic

following several recent episodes during
which she saw jagged silver lines in the left
half of her visual field. Each of the episodes
lasted for about 20 minutes. She denies
having any other symptoms before, during,
or after these episodes. There is no personal
or family history of migraine. Examination
shows visual acuities of 20/20 in both eyes.
She correctly identifies all Ishihara color
plates with both eyes. Her confrontation
visual fields are full. Pupil, eye movement,
and funduscopic examinations are normal.
77
78
T he patient in this scenario reports visual hallucinations that are sugges-

tive of migraine visual aura. Visual hallucinations are perceptions that
occur in the absence of a corresponding external visual stimulus. Visual
hallucinations range from simple or unformed visual phenomena (e.g.,
flashes of light) to complex or formed visual phenomena (e.g., animals and
people). Visual hallucinations can be caused by migraine, drugs (e.g., ly-
sergic acid diethylamide, phencyclidine, and psilocybin from mushrooms),
alcohol withdrawal, seizures, neurodegenerative diseases (e.g., Lewy body
disease), and focal central nervous system lesions (e.g., midbrain lesions).
Visual hallucinations can also occur as a release phenomenon in patients
with afferent vision loss (e.g., secondary to macular degeneration, retinitis
pigmentosa, or optic neuropathies). In contrast with hallucinations, visual
illusions are misinterpretations of a corresponding external visual stimulus.
Examples of visual illusions include misinterpretations of object shape (e.g.,
metamorphopsia from macular degeneration), size (e.g., micropsia from
central serous retinopathy), color (e.g., dyschromatopsia from optic neu-
ropathy), and orientation (e.g., illusory visual tilt with otolithic pathway
lesions).
Migraine visual aura is one of the most common causes of transient visual
hallucinations. The classic migraine visual aura is the fortification spectra,
in which a figure with an achromatic or sometimes colored scintillating
zigzag edge appears near the center of the visual field of both eyes and grad-
ually expands toward the periphery over minutes, leaving a bean-shaped
scotoma in its wake. The aura usually lasts for about 15–20 minutes but
rarely for more than an hour. In migraine with aura (i.e., classic migraine),
the aura is followed by a severe unilateral throbbing headache, often with
associated photophobia, phonophobia, nausea, or vomiting. The diag-
nosis of migraine with aura is clinical, in accordance with the International
Headache Society (IHS) diagnostic criteria, and further investigations are
usually not necessary.
Occasionally, a patient will report having a typical visual aura without
a subsequent migraine headache; this is known as acephalgic migraine.
Such patients typically have a history of migraine with visual aura, but the
headaches have either lost their migraine characteristics or have completely
remitted with time. A dilemma arises when an older patient without a his-
tory of migraine has a visual aura without an associated headache, as in

79
this case scenario. Even if the patient describes a typical visual aura and
has an unremarkable examination, including formal visual field testing,
investigations should be obtained to exclude an occipital lesion (e.g., tumor
or arteriovenous malformation; Figure 14.1) or vertebrobasilar ischemia.
Likewise, in cases where the visual aura is always lateralized to the same side,
as in this scenario, imaging must be obtained to exclude an occipital lesion,
even if there is no visual field defect evident on formal visual field testing.
Migraine visual aura can rarely persist in one part of the visual field
for weeks or even months. Prolonged migraine visual aura should be dis-
tinguished from persistent positive visual phenomena, which involve the
entire visual field of both eyes without associated vision loss or headache.
In visual snow, the most common form of persistent positive visual phe-
nomena, patients report seeing snow or “television static” superimposed on
their vision. Most patients with persistent positive visual phenomena have a
prior history of migraine. Although their visual phenomena can persist in-
definitely, these patients should be reassured; investigations, including im-
aging and electroencephalography, are almost always unrevealing.
FIGURE 14.1. T2-weighted magnetic resonance imaging (left) and magnetic resonance

angiography (right) demonstrating a left occipital arteriovenous malformation that caused episodic
right-sided positive visual phenomena reminiscent of migraine visual aura.
14. Visual Auras, Hallucinations, and Illusions 79

80
TABLE 14.1 Positive Visual Phenomena in Migraine Aura Versus Occipital

Seizures
Characteristic Migraine Visual Aura Occipital Seizure
Onset Sudden Sudden
Progression Slow over minutes Rapid over seconds
Duration <60 minutes, typically <1 minute, typically seconds

15–20 minutes
Shape Angular, zigzag Spots, circles, balls
Color Black and white or silver Bright (often primary) colors
Vision loss Bean-like scotoma Hemianopia during episode

following and (variably) after episode
scintillating edge
Associated Headache Eye–head deviation

symptoms Photophobia Eyelid fluttering
Phonophobia Altered level of
Nausea and vomiting consciousness
Postictal headache
Migraine visual aura should be distinguished from retinal migraine. The

IHS diagnostic criteria for retinal migraine require at least two attacks of
fully reversible monocular positive or negative visual phenomena associated
with a headache that meets diagnostic criteria for migraine without aura.
Migraine aura should also be distinguished from the positive visual phe-
nomena occurring with occipital seizures (Table 14.1). Occipital seizures
usually produce a sudden onset of binocular positive visual phenomena
that, in contrast with migraine, consist of multiple, brightly colored, small
circular spots or balls that are usually located in the contralateral visual
field. They can increase in size and multiply in number over the course of
the episode. They can also flash, move across the visual field, spin, or rotate.
Vision is obscured in the area occupied by the visual phenomena from the
onset. The positive visual phenomena usually last for less than a minute.
However, other ictal phenomena can develop with seizure propagation
(e.g., eye–head deviation, eyelid fluttering, or altered level of conscious-
ness). Occipital seizures can occur in a variety of conditions (Box 14.1).

81
BOX 14.1 Causes of Occipital Seizures
Posterior reversible encephalopathy syndrome (e.g., malignant

hypertension)
Metabolic encephalopathy (e.g., hypercalcemia)
Malformations of cortical development (e.g., cortical dysplasia)
Tumors (e.g., neuroepithelial tumors, astrocytoma)
Vascular lesions (e.g., arteriovenous malformations)
Prior head trauma (e.g., posttraumatic occipital gliosis)
Metabolic diseases (e.g., mitochondrial disorders)
Localized infections (e.g., bacterial abscesses)
Idiopathic
Adapted from Taylor I, Scheffer IE, Berkovic SF. Occipital epilepsies: identification of specific
and newly recognized syndromes. Brain. 2003;126:756.
The treatment for migraine with aura involves avoidance of precipitating

factors and the use of abortive treatments, such as triptan medications, at
the onset of attacks. Patients who have frequent or disabling migraines
should be offered prophylactic therapies, such as propranolol, amitripty-
line, or topiramate. However, if the patient is reporting occasional, short-
lived visual aura without subsequent headache, medical treatment might
not be required or requested by the patient.
• Visual hallucinations are perceptions that occur in the absence

of a corresponding external visual stimulus, whereas visual
illusions are misinterpretations of a visual stimulus.
• Migraine visual aura is a common visual hallucination
characterized as a scintillating zigzag figure that gradually
progresses across half of the visual field, leaving a bean-like
scotoma in its wake.
• Migraine visual aura is usually followed by a severe unilateral
throbbing headache, often with associated photophobia,
phonophobia, nausea, or vomiting.
• Patients should be investigated with formal visual field testing
and imaging if visual aura is always lateralized to the same side
14. Visual Auras, Hallucinations, and Illusions 81

82
or if there is no associated headache in an older patient without

a history of migraine.
• Migraine visual aura should be differentiated from persistent
positive visual phenomena (e.g., visual snow), retinal migraine,
and occipital seizures.
Further Reading
Panayiotopoulos CP. Elementary visual hallucinations, blindness, and headache in
idiopathic occipital epilepsy: differentiation from migraine. J Neurol Neurosurg
Psychiatry. 1999;66:536–540.
Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general
population. Brain. 1996;119:355–361.
Schankin CJ, Maniyar FH, Digre KB, Goadsby PJ. “Visual snow”—a disorder distinct
from persistent migraine aura. Brain. 2014;137:1419–1428.
Shams PN, Plant GT. Migraine-like visual aura due to focal cerebral lesions: case
series and review. Surv Ophthalmol. 2011;56:135–161.
Taylor I, Scheffer IE, Berkovic SF. Occipital epilepsies: identification of specific and
newly recognized syndromes. Brain. 2003;126:753–769.

83
15 Transient Vision Loss

following two episodes of vision loss
in his right eye. Both episodes began
suddenly, lasted for about 5 minutes, and
then resolved spontaneously. He had no
other symptoms during the episodes.
20/20 in both eyes. Color vision,
confrontation visual fields, pupils, and
eye movements are normal. Undilated
funduscopic examination is unremarkable.
83
84
T ransient vision loss (TVL) is an abrupt temporary monocular or bin-

ocular loss of vision that often results from reduced blood supply to
the afferent visual system. Common causes of TVL include primary ar-
terial occlusion or stenosis (e.g., atheroma), secondary arterial occlusion
due to embolism from a distant site (e.g., carotid artery, aortic arch, or
heart), vasospasm (e.g., migraine), or systemic hypoperfusion (e.g., cardiac
arrhythmia or hypotension) (Table 15.1). Many other less common causes
for TVL are recognized (see Table 15.1).
The first step in the evaluation of a patient with TVL is to obtain a careful
history. The history is often crucial, because physical examination and
investigations may be unrevealing. It is important to establish that there was
TVL rather than visual blurring, which is often due to a benign ophthalmic
problem (e.g., tear film dysfunction). It is also important to determine if the
TVL was monocular or binocular; monocular TVL arises from prechiasmal
pathology, whereas binocular TVL arises from chiasmal, retrochiasmal, or
bilateral prechiasmal pathology. Thus, it is essential to ask if the patient
checked for vision loss involving both eyes by covering each eye in turn
during the episode; homonymous visual field loss is often mistaken for mo-
nocular vision loss on the side with the temporal field defect. Although
TVL often occurs spontaneously, the presence of a precipitating factor can
help to determine the cause. For example, TVL can be precipitated by pos-
tural changes in systemic hypotension, papilledema, and giant cell arteritis
(GCA). A description of the pattern of vision loss might also suggest the
etiology; an altitudinal onset (“like a curtain descending over my vision”)
suggests embolic arterial occlusion, whereas a concentric onset may indicate
vasospasm or a neurologic cause. The duration of TVL sometimes suggests
a specific cause: TVL from papilledema and optic nerve head drusen usu-
ally lasts for seconds, TVL from retinal emboli or a transient ischemic at-
tack usually lasts for a few minutes (typically less than 15 minutes), and
TVL from migraine usually lasts for more than 15 minutes. Many causes
of TVL produce other symptoms during the attack, such as headache, pos-
itive visual phenomena, and focal neurologic symptoms (e.g., sensory or
speech disturbance), or the patient may have had other symptoms before
or after the attack that suggest a certain etiology. Patients should also be
asked about other symptoms that they may not volunteer or think relevant
(e.g., symptoms of GCA; see Case 2). A history of vascular risk factors,

85
TABLE 15.1 Causes of Transient Vision Loss
Monocular Vision Loss Binocular Vision Loss
Vascular Carotid artery stenosis, Transient

occlusion, or ischemic attack
dissection Bilateral carotid artery
Ophthalmic artery stenosis, stenosis or occlusion
occlusion, or dissection Systemic
Aortic arch atheroma hypoperfusion
Cardioembolic source
(arrhythmia,
structural defect)
Venous source (paradoxical
embolism)
Vasculitis (giant cell arteritis)
Arterial vasospasm
Impending central retinal vein
occlusion
Hypercoagulable state
Systemic hypoperfusion
Neurologic Retinal migraine Migraine visual aura

Occipital seizure
Posterior reversible
encephalopathy
syndrome
Exposure to
angiographic
contrast media
Head trauma
Ophthalmic Papilledema and optic Papilledema and optic

disc edema disc edema
Optic nerve head drusen Optic nerve
Optic neuritis (Uhthoff head drusen
phenomenon) Age-related macular
Orbital masses and degeneration
foreign bodies
Age-related macular
degeneration
Intermittent angle-closure
glaucoma
Corneal basement membrane
dystrophy
Tear film dysfunction and dry eye
Adapted from Thurtell MJ, Rucker JC. Transient visual loss. Int Ophthalmol Clin. 2009;49:148.
86
cardiovascular disease, and migraine should also be sought. A history of

ophthalmic disease, polymyalgia rheumatica, connective tissue disease, or
hematologic disease (e.g., hypercoagulable state) might be relevant in some
patients.
Physical examination is often unrevealing in patients with TVL.
Nevertheless, a thorough examination is required to assess the state of the
afferent visual system (e.g., the patient may have a persistent visual field
defect; Figure 15.1) and to detect signs that suggest a specific etiology
for the TVL. A thorough ophthalmic examination, including a dilated
funduscopic examination, is essential, because many ophthalmic conditions
can cause TVL (see Table 15.1) or there may be signs indicating the likely
etiology (e.g., retinal emboli; see Figure 15.1). The pulse and blood pressure
should be assessed, and the chest and neck should be auscultated for heart
murmurs and carotid bruits, respectively.
Investigations are often required when a vascular cause of TVL is
suspected. For the patient in this scenario, with several episodes of short-
lived painless monocular TVL, secondary arterial occlusion from embolism
must be excluded. Possible sources of embolism include the carotid arteries,
aortic arch, and heart. Because both episodes occurred in the right eye, ca-
rotid Doppler ultrasound, magnetic resonance angiography of the head and
FIGURE 15.1. Fundus photograph demonstrating a calcific embolus (left) causing a branch retinal
artery occlusion with a superior altitudinal visual field defect (right) in a patient who complained
of transient monocular vision loss.

87
neck vessels, or computed tomography angiography of the head and neck

vessels should be obtained to assess for a stenosis in the vascular supply of
the right eye. Echocardiography should be obtained to assess for structural
cardiac abnormalities and aortic arch atheroma, and electrocardiographic
monitoring should be obtained to screen for paroxysmal arrhythmias (e.g.,
atrial fibrillation). Magnetic resonance imaging (MRI) of the brain should
also be considered; approximately 20% of patients with monocular TVL sec-
ondary to retinal ischemia will also have an acute stroke on MRI of the brain.
The management of TVL depends on its etiology. In patients with a
cardiac source of embolism, anticoagulation with warfarin and treatment
of the underlying cardiac condition is indicated. In those with a vascular
stenosis, antiplatelet therapy with aspirin should be initiated. The manage-
ment of high-grade internal carotid artery stenosis (70–99%) in patients
with isolated TVL remains controversial, because the risk for stroke is
lower in patients with TVL than in those with hemispheric transient is-
chemic attacks. Findings from the North American Symptomatic Carotid
Endarterectomy Trial suggest that patients need to have three or more of the
following factors to benefit from carotid endarterectomy: male sex; age of
75 years or more; history of hemispheric transient ischemic attack or stroke;
history of intermittent leg claudication; stenosis of 80–94%; or absence of
collaterals on angiography. Carotid artery stenting is an alternative to end-
arterectomy but might result in a higher risk of periprocedural stroke.
• TVL is an abrupt temporary monocular or binocular loss of vision.

• TVL is often caused by primary arterial occlusion or stenosis,
secondary arterial occlusion due to embolism from a distant
site, vasospasm, or systemic hypoperfusion.
• The history of the event is often crucial for determining
the etiology of TVL, because physical examination and
investigations may be unrevealing.
• Patients with TVL that could be due to embolism require
urgent investigations and treatment that is directed toward the
underlying etiology.
15. Transient Vision  Loss 87

8
Further Reading
Benavente O, Eliasziw M, Streifler JY, et al. Prognosis after transient monocular
blindness associated with carotid-artery stenosis. N Engl J Med.
2001;345:1084–1090.
Biousse V, Nahab F, Newman NJ. Management of acute retinal ischemia.
Ophthalmology. 2018;125:1597–1607.
Donders RC. Clinical features of transient monocular blindness and the likelihood
of atherosclerotic lesions of the internal carotid artery. J Neurol Neurosurg
Psychiatry. 2001;71:247–249.
Helenius J, Arsava EM, Goldstein JN, et al. Concurrent acute brain infarcts in patients
with monocular visual loss. Ann Neurol. 2012;72:286–293.
Silver FL, Mackey A, Clark WM, et al. Safety of stenting and endarterectomy by
symptomatic status in the Carotid Revascularization Endarterectomy Versus
Stenting Trial (CREST). Stroke. 2011;42:675–680.
Thurtell MJ, Rucker JC. Transient visual loss. Int Ophthalmol Clin. 2009;49:147–166.

89
16 Unexplained Vision Loss

for evaluation of gradually progressive
vision loss in both eyes over the past
decade. He is sensitive to light. He has also
noticed that his vision seems clearer in dim
lighting conditions. He has seen multiple
ophthalmologists, but eye examinations
have not identified a cause for his
complaints. Examination shows visual
acuities of 20/50 in both eyes. There is no
improvement in visual acuity with pinhole.
He correctly identifies 4 of 14 Ishihara
color plates with both eyes. Confrontation
visual fields are full. His pupils are equal
in size and react to light, and there is no
relative afferent pupillary defect. Anterior
segment and funduscopic examinations are
unremarkable. Magnetic resonance imaging
(MRI) of the brain and orbits with contrast is
normal.
89
90
T he patient described in this scenario reports vision loss in both eyes

yet has a largely unremarkable ophthalmic examination. While the
lack of objective signs increases suspicion for a disorder of higher visual
function (see Case 13) or perhaps nonorganic vision loss (see Case 17),
ophthalmic causes must also be considered. Refractive error is a common
cause of decreased visual acuity. In most patients with uncorrected refractive
error, visual acuity improves to 20/20 when it is checked while the patient is
looking through a pinhole device. Visual acuity should be measured at both
distance and near; uncorrected presbyopia is a common cause of blurred vi-
sion at near and can be easily treated with over-the-counter reading glasses.
When refractive error is the likely cause of decreased visual acuity, con-
sultation with an optometrist or ophthalmologist is indicated for refrac-
tion. When there is irregular astigmatism, an abnormality of corneal shape
or structure (e.g., corneal basement membrane dystrophy or keratoconus)
should be considered. In such cases, special refractive techniques, such as
streak retinoscopy, and corneal topography may be needed for definitive di-
agnosis. As there was no improvement in visual acuity with pinhole for the
patient described in this scenario, other etiologies of vision loss must then
be considered.
The presence of dyschromatopsia raises the possibility of optic neurop-
athy as the cause for the patient’s vision loss, although the patient has no
other examination findings to suggest an optic neuropathy (i.e., no optic
disc edema or pallor). The optic disc can initially look normal in patients
with inflammatory and compressive optic neuropathies. However, MRI of
the brain and orbits shows no optic nerve enhancement or compression.
Since the optic discs can also look normal in patients with early toxic or
nutritional optic neuropathies, review of the patient’s medication list, diet,
medical history, and surgical history is indicated (see Case 6 for further dis-
cussion). Formal visual field testing should also be obtained to characterize
the pattern of the visual field loss; toxic and nutritional optic neuropathies
typically give central or ceco-central scotomas, which can be difficult to de-
tect on confrontation.
Dyschromatopsia and vision loss could also result from a retinal disease.
Funduscopic examination usually shows obvious abnormalities in patients
with retinal diseases causing vision loss. For example, in retinitis pigmentosa,
there is usually retinal arteriolar attenuation with a “bony spicule” pattern

91
of pigmentation that has a perivascular distribution. However, certain “oc-

cult” retinal diseases may not manifest with funduscopic abnormalities, yet
they can produce characteristic visual symptoms and visual field defects.
Diseases affecting the rod photoreceptors produce difficulty with vision
in dim lighting conditions (i.e., night blindness [nyctalopia]) and visual
field constriction, whereas diseases affecting the cone photoreceptors pro-
duce difficulty with vision in bright lighting conditions (i.e., day blindness
[hemeralopia]), dyschromatopsia, and central visual field defects (e.g., cen-
tral scotomas). Patients with certain diseases affecting the photoreceptors
(e.g., acute zonal occult outer retinopathy and cancer-associated retinop-
athy) also report seeing pinpoint flashes of light (photopsias).
When a patient reports symptoms that suggest photoreceptor disease,
further investigations to evaluate for photoreceptor dysfunction are indi-
cated. Spectral-domain optical coherence tomography may show structural
changes in the outer retina where the photoreceptors are located. However,
these changes are often very subtle or absent in patients with early or mild
disease. Consequently, electroretinography (ERG) should be obtained
to definitively evaluate for photoreceptor dysfunction. Full- field ERG
evaluates the rod and cone responses from the entire retina using varying
light stimuli in differing states of light adaptation. Multifocal ERG allows
for topographic evaluation of the macular photoreceptor responses and,
thus, is more sensitive for detecting macular photoreceptor dysfunction
than is full-field ERG. Dark adaptometry can be complementary to ERG
in evaluation of patients who have nyctalopia.
The patient described in this scenario reports progressive vision loss in
both eyes over a decade. His vision is clearer in dim lighting and he has
dyschromatopsia, suggesting cone disease. The slowly progressive course
over years with associated light sensitivity is highly suggestive of a cone dys-
trophy and, therefore, full-field and multifocal ERG should be obtained.
Cone dystrophy can be inherited but can also occur sporadically without an
apparent cause. Unfortunately, there is no cure for cone dystrophy, although
use of sunglasses can help to reduce light sensitivity. More sinister etiologies
of cone dysfunction, such as cancer-associated retinopathy (occurring as
a paraneoplastic phenomenon in patients who have undiagnosed lung,
breast, or gynecologic cancers) and other autoimmune retinopathies, must
be considered in the differential diagnosis. However, these usually cause
16. Unexplained Vision  Loss 91

92
photopsias and have a rapidly progressive course over weeks to months.

When clinical suspicion for a cancer-associated retinopathy is high, evalu-
ation for antiretinal (e.g., recoverin or enolase) antibodies in the patient’s
serum is indicated. If antiretinal antibodies are detected, further investiga-
tion for an occult neoplasm (e.g., with full-body positron emission tomog-
raphy and co-registered computed tomography) is required.
• Decreased visual acuity in a patient with an unremarkable

ophthalmic examination could be caused by uncorrected
refractive error, corneal pathology (e.g., keratoconus), early
optic neuropathy (e.g., compressive, toxic, or nutritional optic
neuropathy), or occult retinopathy.
• Diseases affecting the rod photoreceptors produce night
blindness (nyctalopia) and visual field constriction, whereas
diseases affecting the cone photoreceptors produce day
blindness (hemeralopia), dyschromatopsia, and central visual
field defects.
• ERG should be obtained in patients with symptoms that suggest
photoreceptor dysfunction.
• Cancer-associated retinopathy and other autoimmune
retinopathies should be considered in patients with photopsias
or a rapidly progressive onset of photoreceptor dysfunction.
Further Reading
Gokul A, Vellara HR, Patel DV. Advanced anterior segment imaging in keratoconus.
Clin Exp Ophthalmol. 2018;46:122–132.
Grewal DS, Fishman GA, Jampol LM. Autoimmune retinopathy and antiretinal
antibodies: a review. Retina. 2014;34:827–845.
Mrejen S, Khan S, Gallego-Pinazo R, Jampol LM, Yannuzzi LA. Acute zonal occult
outer retinopathy: a classification based on multimodal imaging. JAMA
Ophthalmol. 2014;132:1089–1098.
Wen Y, Klein M, Hood DC, Birch DG. Relationships among multifocal
electroretinogram amplitude, visual field sensitivity, and SD-OCT receptor layer
thicknesses in patients with retinitis pigmentosa. Invest Ophthalmol Vis Sci.
2012;53:833–840.

93
17 Nonorganic Vision Loss

complaining of decreased vision in his
left eye following a minor work injury
1 year ago. He is now seeking workers’
compensation. Examination shows visual
acuities of 20/20 in the right eye and
20/400 in the left eye. He correctly identifies
all Ishihara color plates with his right eye
but cannot see the control plate with his left
eye. Confrontation visual fields are full in
the right eye and constricted in the left eye.
His pupils are equal and briskly reactive to
light. There is no relative afferent pupillary
defect. Funduscopic examination is normal.
Magnetic resonance imaging of the orbits
with contrast is normal.
93
94
N onorganic vision loss is common but is often challenging to diag-

nose and treat. When confronted with a patient in whom nonor-
ganic vision loss is suspected, the main goal of the evaluation is to exclude
an organic disorder and to demonstrate that visual function is intact or
better than reported. The evaluation begins with a comprehensive his-
tory; there may be aspects of the history that suggest nonorganic disease
(e.g., highly positive review of systems, disability or workers’ compensation
claim, or impending litigation). A careful ophthalmic examination is the
next step, because patients with nonorganic vision loss can have coexisting
organic disease. In patients reporting monocular vision loss, there should
be a careful inspection of the cornea, ocular media, and retina on the af-
fected side, keeping in mind that the causative lesion may not be obvious
(e.g., in keratoconus). There should also be careful evaluation for signs
suggesting a unilateral optic neuropathy (e.g., relative afferent pupillary de-
fect or optic disc pallor). If any signs of organic disease are detected, further
investigations should be pursued as appropriate.
The maneuvers that can be used to demonstrate the presence of intact
visual function vary depending on the reported visual deficit and its se-
verity. When moderate monocular vision loss is reported, as in this patient,
the first step is to demonstrate that the visual acuity is better than reported.
One technique involves placing a vertical prism of 4 to 8 diopters over the
unaffected eye while both eyes are opened, to separate the images of the
two eyes. If the patient can see all of the optotypes on the two vertically
separated 20/20 lines, this proves normal visual acuity in the affected eye. In
another technique known as fogging, the patient undergoes a “refraction”
such that the unaffected eye is fogged with a high-plus spectacle lens while
the patient’s usual correction is placed in front of the affected eye. If the pa-
tient can see all of the optotypes on the 20/20 line with both eyes opened
and the unaffected eye fogged, this proves normal visual acuity in the af-
fected eye. Evaluation of the patient’s stereopsis (depth perception) can
also be helpful when monocular nonorganic vision loss is suspected, since
stereopsis correlates with the visual acuity of the two eyes. If the patient’s
stereopsis is 40 seconds of arc (i.e., the patient correctly identifies 9 of 9
circles on the Titmus test), this suggests a visual acuity of at least 20/40 in
the affected eye. When severe monocular vision loss is reported (e.g., no
light perception), the presence of optokinetic nystagmus while the patient

95
is viewing a rotating optokinetic drum with only the affected eye indicates
a visual acuity of at least 20/400 in that eye. In patients who do not show
optokinetic nystagmus, a large mirror can be oscillated in front of the eyes
instead; some degree of visual function can be assumed if smooth pursuit
movements are elicited when the patient is viewing the oscillating mirror
with only the affected eye.
Several maneuvers can be helpful in the assessment of suspected non-
organic visual field loss. In most patients with visual field constriction, the
cause is evident on examination (Box 17.1). When nonorganic visual field
constriction is suspected, a tangent screen can be used to assess for phys-
iologic expansion of the visual field with increasing distance between the
patient and the screen. Individuals with normal vision and patients with
organic visual field constriction will show expansion in the area of the visual
field when the distance between the patient and the screen is increased. In
contrast, patients with nonorganic visual field constriction will often not
show expansion of the visual field. Goldmann perimetry can also be helpful
in the evaluation of patients with suspected nonorganic visual field con-
striction and may show nonphysiologic crowding, crossing, or spiraling of
the isopters. A nonorganic monocular visual field defect (e.g., a monocular
hemianopia) will often persist when perimetry is performed with both eyes
opened.
The management of nonorganic vision loss can be challenging, especially
if there is a significant secondary gain for the patient (e.g., compensation
payout). Confronting the patient is rarely helpful. Rather, it is usually pref-
erable to reassure the patient that there is no evidence of permanent damage
to the visual system and that there is a good prognosis for spontaneous visual
BOX 17.1 Common Causes of Visual Field Constriction
Retinitis pigmentosa
Retinal dystrophies
End-stage glaucoma
Severe papilledema
Optic nerve head drusen
Increased response time
Nonorganic vision loss
17. Nonorganic Vision  Loss 95

96
recovery. One should state the objective examination findings if requested

to complete workers’ compensation or disability forms. Attempts to address
underlying motivating factors and reduce secondary gain are variably suc-
cessful, and are best handled by a psychiatrist or psychologist.
• Nonorganic vision loss is common and can sometimes coexist

with organic disease.
• The main goal of the evaluation is to exclude organic disease
and demonstrate that visual function is intact or better than
reported.
• Specific maneuvers can prove normal visual acuity and
demonstrate nonorganic visual field constriction.
• The patient with nonorganic vision loss should be reassured
that there is no evidence of permanent damage to the visual
system and that there is a good prognosis for spontaneous
visual recovery.
Further Reading
Bengtzen R, Woodward M, Lynn MJ, Newman NJ, Biousse V. The “sunglasses sign”
predicts nonorganic visual loss in neuro-ophthalmologic practice. Neurology.
2008;70:218–221.
Golnik KC, Lee AG, Eggenberger ER. The monocular vertical prism dissociation test.
Am J Ophthalmol. 2004;137:135–137.
Levy NS, Glick EB. Stereoscopic perception and Snellen visual acuity. Am J
Ophthalmol. 1974;78:722–724.Scott JA, Egan RA. Prevalence of organic
neuro-ophthalmologic disease in patients with functional visual loss. Am J
Ophthalmol. 2003;135:670–675.

97
SECTION II
Efferent Disorders
98
9
18 Third Nerve Palsy
You are called to see a 46-year-old man

who has presented to the emergency
department following the acute onset of
headache, left-sided ptosis, and binocular
diagonal diplopia. He has poorly controlled
type 2 diabetes. Examination shows normal
distance visual acuities, color vision, and
confrontation visual fields. There is a mid-
dilated unreactive left pupil and partial left-
sided ptosis. The left eye is “down and out.”
There is limited supraduction, infraduction,
and adduction of the left eye. Funduscopic
examination is normal. Computed
tomography (CT) of the brain is normal.
99
10
T he third cranial nerve innervates the iris sphincter, the levator palpebrae
superioris muscle, and all of the extraocular muscles apart from the lat-
eral rectus and superior oblique muscles. A complete third cranial nerve
palsy therefore produces a dilated and unreactive pupil, complete ptosis,
and an eye that is hypotropic and exotropic (“down and out”) with limited
supraduction, infraduction, and adduction. A third cranial nerve palsy can
be incomplete, where some muscles are spared (e.g., pupil-sparing third
nerve palsy), or partial, where all muscles are involved but are not totally
paretic. The palsy can be isolated, with or without associated pain, or it
can be associated with other neurologic symptoms and signs if there is in-
volvement of adjacent neural structures. A careful history and examination,
to determine if the third nerve palsy is isolated or associated with other
neurologic deficits, is the first step in the evaluation of this patient with a
suspected third nerve palsy. The presence of other neurologic symptoms
and signs helps to localize the causative lesion. For example, the presence
of contralateral hemiparesis, ataxia, or tremor suggests a midbrain lesion,
whereas the presence of other ipsilateral cranial nerve palsies suggests a le-
sion in the subarachnoid space, cavernous sinus, superior orbital fissure, or
orbital apex (see Case 38).
Common causes of isolated third nerve palsy include microvascular is-
chemia, trauma, compression by neoplasm, and compression by aneurysm
(Figure 18.1). The tempo of onset may suggest a particular etiology: acute
onset suggests microvascular ischemia; subacute onset suggests compres-
sion by a rapidly enlarging aneurysm; and slowly progressive onset suggests
FIGURE 18.1. Aneurysm of the left posterior communicating artery (arrows) on MRA source
images (left) and MRA reconstructions (coronal and sagittal; middle and right) in a patient with a
painful pupil-involving left third nerve palsy.
10 0 WHAT DO I DO NOW? Efferent Disorders

10
compression by a slowly enlarging neoplasm or aneurysm. Pain is common

in patients with third nerve palsy caused by aneurysmal compression or
microvascular ischemia. Signs of aberrant reinnervation (e.g., inappropriate
elevation of the upper eyelid with attempted adduction or infraduction of
the eye) should be specifically sought, because these suggest slowly pro-
gressive third nerve compression with misdirected regrowth of nerve fibers.
The pupil should also be carefully assessed. While the absence of pupil
involvement suggests that a third nerve palsy is not due to compression,
it is not a guarantee. Other conditions that can mimic third nerve palsy
(e.g., ocular myasthenia) should also be considered when the pupil is not
involved. In this case, there has been an acute onset of isolated, painful, par-
tial pupil-involving third nerve palsy in a patient with poorly controlled di-
abetes. While the cause could be microvascular ischemia, this presentation
is a medical emergency with a potentially catastrophic outcome, because a
rapidly enlarging aneurysm has not yet been excluded.
The investigation of acute pupil-involving third nerve palsy has evolved
in recent years. In the past, digital subtraction cerebral angiography (DSA)
was required for identifying and excluding aneurysm. Improvements in the
resolution of computed tomography angiography (CTA) and magnetic res-
onance angiography (MRA) have made noninvasive detection of aneurysms
possible with a sensitivity approaching that of DSA. CTA and MRA have
a similar sensitivity and specificity for detecting cerebral aneurysm, but
CTA is faster, more widely available, and cheaper than MRA. Thus, CTA
is the initial investigation of choice in patients with acute-onset isolated
nontraumatic third nerve palsy, except if radiation or iodine dye exposure
is contraindicated (e.g., in pregnant women, children, and patients with
renal failure). CT of the brain should be obtained at the same time, be-
cause it might show subarachnoid hemorrhage. If CTA does not show an
aneurysm or if the patient has other neurologic deficits, magnetic resonance
imaging (MRI) of the brain should be obtained looking for another cause
for the third nerve palsy. If the suspicion for aneurysm remains high, MRA
should be performed at the same time. MRA is the investigation of choice
in patients with isolated third nerve palsy who have a contraindication to
CTA (see Figure 18.1). DSA can be considered to definitively exclude an-
eurysm but is rarely necessary if there is no evidence of aneurysm on CTA
or MRA. Lastly, the inflammatory markers should be checked in patients
18. Third Nerve Palsy 101

102
with a presumed microvascular etiology who are more than 50 years old, es-
pecially if they have symptoms suggesting giant cell arteritis (e.g., temporal
headache, scalp tenderness, or jaw claudication), since giant cell arteritis
can also cause an acute pupil-involving or pupil-sparing third nerve palsy.
The management of this patient’s third nerve palsy depends on the
cause. If an aneurysm is detected, urgent referral to neurosurgery or inter-
ventional neuroradiology is required because there is a high risk of immi-
nent rupture. Definitive treatment of the aneurysm by clipping or coiling
is required as soon as possible, given the high mortality and morbidity of
subarachnoid hemorrhage. If there is no evidence of aneurysm or another
cause for the third nerve palsy on neuroimaging, microvascular ischemia is
the likely etiology, and conservative management is appropriate. Although
most patients with a microvascular third nerve palsy will completely recover
within 3–6 months, vascular risk factors should be addressed. Long-term
antiplatelet therapy should also be considered to reduce the risk of future
vascular events.
• Complete third nerve palsy produces a dilated and unreactive

pupil, complete ptosis, and a “down and out” eye with limited
supraduction, infraduction, and adduction.
• Third nerve palsy is often caused by microvascular ischemia,
trauma, compression by neoplasm, or compression by
aneurysm.
• Patients with acute-onset isolated nontraumatic third nerve
palsy should undergo urgent CTA or MRA to exclude aneurysm.
• Patients with acute-onset third nerve palsy due to compression
by aneurysm require urgent referral to neurosurgery or
interventional neuroradiology because there is a high risk of
imminent rupture.
• Microvascular third nerve palsy typically recovers completely
within 3–6 months.
102 WHAT DO I DO NOW? Efferent Disorders

103
Further Reading
Chen X, Liu Y, Tong H, et al. Meta-analysis of computed tomography angiography
versus magnetic resonance angiography for intracranial aneurysm. Medicine.
2018;97:e10771.
Jacobson DM. Pupil involvement in patients with diabetes-associated oculomotor
nerve palsy. Arch Ophthalmol. 1998;116:723–727.
Keane JR. Third nerve palsy: analysis of 1400 personally-examined inpatients. Can J
Neurol Sci. 2010;37:662–670.
Thurtell MJ, Longmuir RA. Third nerve palsy as the initial manifestation of giant cell
arteritis. J Neuroophthalmol. 2014;34:243–245.
Trobe JD. Searching for brain aneurysm in third cranial nerve palsy. J
18. Third Nerve Palsy 103

104
105
19 Fourth Nerve Palsy
A 48-year-old man presents to your

clinic with a several-month history of
progressively increasing binocular vertical
diplopia that is exacerbated by reading.
He is otherwise healthy. Examination
shows normal visual acuities, color vision,
eyelids. His ductions appear full, but there
is a right hypertropia that increases with
leftward gaze and rightward head tilt.
He has a spontaneous leftward head tilt.
Funduscopic examination shows extorsion
of the right fundus.
105
106
T he history and clinical findings in this case scenario suggest a fourth

nerve palsy. Fourth nerve palsy results in weakness of the superior
oblique muscle, which normally depresses and intorts the eye. Superior
oblique weakness produces binocular vertical diplopia that is often worse
with reading, although some patients also complain of binocular torsional
diplopia. A detailed history often helps to pinpoint the cause. In particular,
the tempo of onset can suggest a particular etiology. For example, sudden
onset with or without pain suggests a microvascular etiology, whereas
gradual onset suggests a compressive etiology or decompensation of a
longstanding fourth nerve palsy. It is important to ask about head trauma,
because this is a frequent cause of isolated fourth nerve palsy. Vascular risk
factors, such as hypertension and diabetes, might suggest a microvascular
etiology in acute onset of isolated fourth nerve palsy. It is also worthwhile
to ask about other neurologic symptoms, which can suggest a location for
the lesion, and about symptoms of giant cell arteritis in elderly patients.
It is often difficult to diagnose a fourth nerve palsy on physical exami-
nation because the clinical signs can be subtle. A head tilt to one side is a
valuable clue to the presence of a fourth nerve palsy on the other side. If
a head tilt is present, it is important to ask if it is longstanding and to in-
spect old photographs (e.g., on a driver’s license or Facebook profile). If a
fourth nerve palsy is diagnosed, a longstanding head tilt suggests that it is
either congenital or longstanding from another cause. Ocular motor ex-
amination will show vertical misalignment of the eyes, with one eye being
hypertropic (elevated) relative to the other. When a hypertropia is detected,
the Parks-Bielschowsky three-step test should be used to identify the paretic
muscle (Table 19.1). The first step of the test is to determine the side of the
hypertropia; the second step is to determine if the hypertropia increases with
adduction or abduction; and the final step is to determine if the hypertropia
increases with head tilt to the ipsilateral or contralateral side. In a patient
with right hypertropia due to a right fourth nerve palsy, the vertical misa-
lignment would be greatest with leftward gaze (adduction) and rightward
head tilt (see Table 19.1). When the deviation is small, it can be helpful
to quantify it at each stage of the test using prisms with a Maddox rod or
red glass. Prisms can also be used to determine the vertical fusional ampli-
tude; when it is increased by more than 6 prism diopters, a longstanding
fourth nerve palsy is likely (normal vertical fusional amplitude is 1–3 prism

107
TABLE 19.1 Results of the Parks-Bielschowsky Three-Step Test

for Individual Muscle Palsies Causing a Right Hypertropia (RHT)
Step 1 Step 2 Step 3 Affected Muscle
RHT RHT ↑ with RHT ↑ with right Right superior

adduction head tilt oblique
RHT RHT ↑ with RHT ↑ with right Left inferior

abduction head tilt oblique
RHT RHT ↑ with RHT ↑ with left Left superior

adduction head tilt rectus
RHT RHT ↑ with RHT ↑ with left Right inferior

abduction head tilt rectus
diopters). Extorsion of the affected eye may be seen on funduscopic ex-

amination, as in this patient, or demonstrated and quantified with double
Maddox rods.
Isolated fourth nerve palsies are often congenital, posttraumatic, or micro-
vascular in etiology. However, with improved magnetic resonance imaging
(MRI) resolution, fourth nerve schwannomas are becoming an increasingly
recognized cause for longstanding and progressive fourth nerve palsies.
These benign lesions can be identified on MRI as enhancing foci along the
course of the fourth nerve, typically in the ambient or perimesencephalic
cistern (Figure 19.1), and usually do not cause any other deficit. Rarely,
fourth nerve palsy can be caused by an intrinsic brainstem lesion, in which
case there may be an associated contralateral internuclear ophthalmoplegia,
Horner syndrome, or upbeat nystagmus due to involvement of adjacent
neural pathways. The presence of other cranial nerve palsies ipsilateral to
a fourth nerve palsy suggests a lesion in the subarachnoid space, cavernous
sinus, superior orbital fissure, or orbital apex (see Case 38).
Alternative causes of vertical misalignment should also be considered,
especially when the findings on the Parks-Bielschowsky three-step test are
not consistent with superior oblique weakness. The presence of areflexia
or ataxia suggests Miller Fisher syndrome. Fluctuating signs (e.g., ptosis)
suggest ocular myasthenia. Proptosis and lid retraction suggest thyroid eye
disease. Brainstem signs suggest a skew deviation from a lesion involving
19. Fourth Nerve Palsy 107

108
FIGURE 19.1. Axial (left) and coronal (right) MRI showing a left fourth nerve schwannoma
(arrows).
the central otolithic pathways. A skew deviation is usually comitant; the de-
gree of vertical misalignment is similar in different gaze directions. A skew
deviation can be incomitant and occasionally give findings on the three-
step test that are suggestive of superior oblique weakness, although there
will be intorsion rather than extorsion of the hypertropic eye with a skew
deviation.
The investigation of isolated fourth nerve palsy is controversial. Most
clinicians would not obtain neuroimaging in patients with suspected con-
genital fourth nerve palsy, isolated fourth nerve palsy due to head trauma,
or isolated acute-onset fourth nerve palsy in association with vascular risk
factors. However, some studies have reported that a significant percentage
of such patients have a sinister cause for their fourth nerve palsy that would
have been missed without neuroimaging. Thus, neuroimaging should prob-
ably be obtained in patients with a progressive-onset fourth nerve palsy,
including this patient, and in those with a presumed microvascular etiology
who do not recover within 3 months, although the imaging will rarely be
abnormal if there are no other neurologic signs. An extensive laboratory
workup is usually not fruitful, although inflammatory markers should be
checked in patients with a presumed microvascular fourth nerve palsy who
are more than 50 years old.
Treatment of fourth nerve palsy depends on the underlying cause. Most
patients with a presumed microvascular fourth nerve palsy will completely

109
recover within 3 months. However, vascular risk factors should be addressed,

and antiplatelet therapy should be considered to reduce their risk of future
vascular events. In this patient, who likely has a longstanding fourth nerve
palsy, treatment of his diplopia depends on the magnitude of the vertical
misalignment. Prisms can be prescribed to alleviate diplopia when the ver-
tical misalignment is small. However, if the vertical misalignment is large,
longstanding, and stable, strabismus surgery would be the most appropriate
treatment to alleviate the patient’s diplopia.
• Fourth nerve palsy causes a hypertropia that increases with

adduction and ipsilateral head tilt.
• Most isolated fourth nerve palsies are congenital, posttraumatic,
or microvascular.
• Neuroimaging should be performed in patients with
progressive-onset fourth nerve palsy or presumed
microvascular fourth nerve palsy that does not recover within
3 months.
• Treatment of fourth nerve palsy depends on the etiology and
degree of ocular misalignment.
Further Reading
Brodsky MC, Donahue SP, Vaphiades M, Brandt T. Skew deviation revisited. Surv
Ophthalmol. 2006;51:105–128.
Chou KL, Galetta SL, Liu GT, et al. Acute ocular motor
mononeuropathies: prospective study of the roles of neuroimaging and clinical
assessment. J Neurol Sci. 2004;219:35–39.
Elmalem VI, Younge BR, Biousse V, et al. Clinical course and prognosis of trochlear
nerve schwannomas. Ophthalmology. 2009;116:2011–2016.
Mollan SP, Edwards JH, Price A, Abbott J, Burdon MA. Aetiology and outcomes of
adult superior oblique palsies: a modern series. Eye (Lond). 2009;23:640–644.
Murchison AP, Gilbert ME, Savino PJ. Neuroimaging and acute ocular motor
mononeuropathies: a prospective study. Arch Ophthalmol. 2011;129:301–305.
Tamhankar MA, Kim JH, Ying GS, Volpe NJ. Adult hypertropia: a guide to diagnostic
evaluation based on review of 300 patients. Eye (Lond). 2011;25:91–96.
19. Fourth Nerve Palsy 109

10
1
20 Sixth Nerve Palsy
A 52-year-old woman presents to the

emergency department after waking
with binocular horizontal diplopia and
pain around her left eye. She has poorly
controlled diabetes and hypertension. She
denies recent head trauma. Examination
eyelids. Ocular motor examination shows
a large-angle esotropia and a severe left
abduction deficit. Funduscopic examination
shows nonproliferative diabetic retinopathy.
111
12
T he sixth cranial nerve innervates the lateral rectus muscle, which

abducts the eye. Lateral rectus weakness produces binocular horizontal
diplopia that is worse when looking into the distance and when looking to-
ward the affected side, with esotropia (inward deviation of the eye) and an
abduction deficit on the affected side. It is a mistake, however, to assume
that all patients with these symptoms and deficits have a sixth nerve palsy.
An abduction deficit can also be produced by orbital disease (e.g., thyroid
eye disease with medial rectus restriction or blowout fracture with medial
rectus entrapment), by neuromuscular disease (e.g., ocular myasthenia or
Miller Fisher syndrome), or by a brainstem lesion (e.g., fascicular lesion or
“pseudo-abducens” palsy). Therefore, clinical assessment for orbital, neu-
romuscular, and brainstem disease is the first step in the evaluation of the
patient described in this case scenario. If there are no symptoms or signs to
suggest any of these, a sixth nerve palsy is likely.
Common causes of unilateral sixth nerve palsy include microvascular
ischemia, trauma, multiple sclerosis, neoplasm, and stroke, although a
cause cannot be determined in as many as 25% of cases. The tempo of
onset varies depending on the etiology: sudden onset of sixth nerve palsy
suggests a microvascular etiology; subacute onset suggests demyelination;
and slowly progressive onset suggests compression (e.g., by a neoplasm).
The presence of associated symptoms also varies, with pain being present
in the majority of patients with microvascular sixth nerve palsy. There
may be other neurologic symptoms and signs if the sixth nerve palsy is
caused by a lesion that affects other neural structures. Sixth nerve palsies
can be caused by intrinsic brainstem lesions affecting the sixth nerve
fasciculus, in which case there may be associated ipsilateral facial weak-
ness, contralateral hemiparesis, or sensory symptoms due to involvement
of adjacent neural pathways. The presence of other cranial nerve palsies
ipsilateral to a sixth nerve palsy suggests a lesion in the subarachnoid
space, cavernous sinus, superior orbital fissure, or orbital apex (see Case
38). The presence of pulse-synchronous tinnitus or orbital signs in an
older patient with a sixth nerve palsy should suggest a carotid–cavernous
fistula (see Case 39). Common causes of bilateral sixth nerve palsy in-
clude increased intracranial pressure, decreased intracranial pressure (e.g.,
from cerebrospinal fluid leak), trauma, clival lesions (e.g., chordoma),
brainstem demyelination (e.g., multiple sclerosis), meningeal disease

13
(e.g., bacterial meningitis), and Wernicke encephalopathy (typically with

associated confusion, ataxia, and nystagmus; see Case 28). In the case
described, the sudden onset of a unilateral sixth nerve palsy with associ-
ated pain in a patient with poorly controlled vascular risk factors suggests
a microvascular etiology.
In the past, investigation of suspected microvascular sixth nerve palsy
with neuroimaging was not considered necessary. However, prospective
neuroimaging studies have demonstrated that a significant proportion of
patients with isolated unilateral sixth nerve palsy, including those with
presumed microvascular ischemia, have a causative intracranial lesion on
imaging. It has therefore been suggested that neuroimaging be performed
in all patients with isolated sixth nerve palsy, regardless of the presumed
etiology. However, the findings of other studies suggest that such an
approach is not cost-effective and increases the chance of discovering
“incidentalomas.” No large, prospective, multicenter study has been
performed to evaluate the role of neuroimaging in the investigation of
isolated sixth nerve palsy. Our approach is to image only those patients
whose symptoms, signs, or course is atypical for microvascular sixth nerve
palsy. The patient in this case scenario has had a typical presentation for
microvascular sixth nerve palsy and has several vascular risk factors. In
the absence of any other symptoms, signs, or atypical features, it would
be reasonable not to obtain neuroimaging in this patient. However, if the
subsequent course is not consistent with a microvascular etiology (e.g., if
there is ongoing progression or failure to recover within 3–6 months), neu-
roimaging should be obtained.
Treatment of sixth nerve palsy depends on the underlying cause.
Most patients with a microvascular sixth nerve palsy will completely re-
cover within 3–6 months. Management of vascular risk factors should be
optimized, and antiplatelet therapy could be considered to reduce the risk
of future vascular events. In the acute setting, monocular occlusion should
be advised to alleviate diplopia if the horizontal misalignment is large. If
the misalignment is small, a Fresnel prism could be prescribed. If there is
a failure to fully recover and neuroimaging excludes other etiologies, di-
plopia from small horizontal misalignments can be managed with prisms,
whereas large, stable horizontal misalignments can be managed with stra-
bismus surgery.
20. Sixth Nerve Palsy 113

14
• Esotropia with an abduction deficit suggests a sixth nerve palsy

but can also occur with orbital, neuromuscular, and brainstem
disease.
• Unilateral sixth nerve palsy is often caused by microvascular
ischemia, trauma, multiple sclerosis, neoplasm, or stroke,
although an etiology cannot be established in up to 25% of
patients.
• Bilateral sixth nerve palsy is often caused by increased or
decreased intracranial pressure, trauma, clival lesions, multiple
sclerosis, meningeal disease, or Wernicke encephalopathy.
• Neuroimaging should be performed in patients who do not
have a typical presentation for microvascular sixth nerve palsy
or who do not recover within 3–6 months.
• Microvascular sixth nerve palsy typically recovers completely
within 3–6 months.
Further Reading
Bendszus M, Beck A, Koltzenburg M, et al. MRI in isolated sixth nerve palsies.
Neuroradiology. 2001;43:742–745.
Chou KL, Galetta SL, Liu GT, et al. Acute ocular motor
mononeuropathies: prospective study of the roles of neuroimaging and clinical
assessment. J Neurol Sci. 2004;219:35–39.
Murchison AP, Gilbert ME, Savino PJ. Neuroimaging and acute ocular motor
mononeuropathies: a prospective study. Arch Ophthalmol. 2011;129:301–305.
Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations,
and evaluation of sixth nerve palsy using a population-based method.
Ophthalmology. 2004;111:369–375.
Wilker SC, Rucker JC, Newman NJ, Biousse V, Tomsak RL. Pain in ischaemic ocular
motor cranial nerve palsies. Br J Ophthalmol. 2009;93:1657–1659.

15
21 Intermittent Diplopia

clinic complaining of intermittent binocular
vertical-torsional diplopia that lasts for
seconds or less. Examination shows
normal visual acuities, color vision,
eyelids. Her ductions appear to be full.
There is no misalignment on cross-cover
testing. However, you see infrequent, small-
amplitude vertical-torsional movements
of her left fundus during the dilated
funduscopic examination.
115
16
I ntermittent diplopia is a common complaint that has a broad differential

diagnosis (Box 21.1). The neuro-ophthalmic examination may be unre-
vealing if the patient is asymptomatic when evaluated. Thus, the history is
often critical for determining the likely diagnosis. It is important to start
by asking if the diplopia is monocular (present when viewing with one eye
and resolving when that eye is covered) or binocular (present when viewing
with both eyes and resolving when either eye is covered). Patients with mo-
nocular diplopia will often report that the images overlap, with one looking
faded or like a “ghost” image relative to the other. Monocular diplopia is
usually caused by ocular diseases such as dry eye, astigmatism, or cataract,
whereas binocular diplopia is caused by misalignment of the eyes. Patients
BOX 21.1 Causes of Intermittent Diplopia
Eye:
Dry eye syndrome
Tear film dysfunction
Extraocular muscle:
Decompensated phoria
Thyroid eye disease
Ischemia from giant cell arteritis
Chronic progressive external ophthalmoplegia
Congenital myopathies
Brown syndrome
Orbital mass or foreign body
Neuromuscular junction:
Myasthenia gravis
Cranial nerve:
Superior oblique myokymia
Ocular neuromyotonia
Ischemia from giant cell arteritis
Brainstem/Cerebellum:
Vertebrobasilar transient ischemic attack
Internuclear ophthalmoplegia
Paroxysmal skew deviation
Alternating skew deviation
Other:
Spasm of the near triad
Convergence insufficiency
Divergence insufficiency

17
with monocular diplopia do not require a workup for underlying neurologic

disease, and should be referred to an ophthalmologist for further evaluation
and management. In patients with binocular diplopia, it can be helpful to
ask about diurnal variation in the diplopia; diplopia that is present imme-
diately after waking is characteristic of extraocular muscle congestion (e.g.,
due to thyroid eye disease; see Case 37), whereas diplopia that occurs when
fatigued later in the day is characteristic of ocular myasthenia (see Case
22) or decompensation of a longstanding ocular misalignment. It is also
helpful to ask about any precipitating factors for the diplopia and any asso-
ciated symptoms, such as proptosis, ptosis, eyelid retraction, or anisocoria,
which might suggest a particular etiology. Lastly, it is also important to ask
about a history of strabismus or amblyopia (lazy eye) during childhood,
as the patient’s diplopia might be secondary to a longstanding ocular mis-
alignment. The patient in this scenario reports brief attacks of binocular
vertical-torsional diplopia lasting for seconds or less. Funduscopic examina-
tion shows infrequent, small-amplitude vertical-torsional movements of her
left fundus that are highly suggestive of superior oblique myokymia.
Superior oblique myokymia causes brief recurrent attacks of binocular
vertical-torsional diplopia or monocular oscillopsia. The attacks can be
precipitated by adducting and infraducting the affected eye. Although very
annoying to the patient, the eye oscillations are often subtle and difficult to
detect on examination. With careful observation of the conjunctival vessels,
irregular, small-amplitude vertical-torsional movements of the affected eye
may be noted when the patient is symptomatic. These movements are often
more obvious on funduscopic examination, as in the patient described
in this scenario. When the diagnosis is suspected but no movements are
seen, they can sometimes be elicited by asking the patient to adduct and
infraduct the affected eye.
The pathogenesis of superior oblique myokymia remains uncertain.
Since the condition is benign and affected patients do not have other
neurologic deficits, the pathogenesis is thought to be analogous to that of
other paroxysmal cranial nerve disorders, such as trigeminal neuralgia. It
has been suggested, based on the findings of imaging studies, that supe-
rior oblique myokymia might arise because of vascular compression of the
fourth nerve causing focal demyelination. It would be reasonable to ob-
tain magnetic resonance imaging of the brain in this patient, looking for
21. Intermittent Diplopia 117

18
vascular compression of the fourth nerve. With the exception of eye move-
ment recordings, other investigations are unlikely to be informative and
therefore are not routinely required.
Although short-lived, the attacks of superior oblique myokymia are very
annoying to patients and, thus, treatment is often requested. Many patients
respond to medical therapy with carbamazepine, gabapentin, phenytoin,
or β-blockers (e.g., topical timolol or oral propranolol), but side effects can
limit dose escalation. Each of these medications could be tried in turn,
with the dose titrated according to beneficial response and side effects.
Occasional patients have a hyperphoria corresponding to the affected su-
perior oblique muscle; prismatic correction for the hyperphoria can some-
times have a salutary effect on the superior oblique myokymia. In those
who do not respond to medical treatment or prisms, strabismus surgery
on the superior oblique tendon can sometimes be effective. In those with
vascular compression of the fourth nerve who remain unresponsive to the
above treatments, a decompression surgery could be considered. However,
given the invasive nature of the procedure and the benign nature of this
condition, decompression should be considered as a last resort for patients
with severe intractable superior oblique myokymia.
• Monocular diplopia is usually caused by ocular diseases and

does not require a neurologic workup, whereas binocular
diplopia is caused by misalignment of the eyes.
• Superior oblique myokymia can cause brief, recurrent attacks of
binocular vertical-torsional diplopia or monocular oscillopsia.
• Superior oblique myokymia is often subtle but can sometimes
be detected with careful observation of the conjunctival vessels
or on funduscopic examination.
• Superior oblique myokymia might arise because of vascular
compression of the fourth nerve.
• Superior oblique myokymia often responds to medical
treatment with carbamazepine, gabapentin, phenytoin, or

19
β-blockers, but severe intractable cases may require strabismus

surgery or fourth nerve decompression surgery.
Further Reading
Kosmorsky GS, Ellis BD, Fogt N, Leigh RJ. The treatment of superior oblique
myokymia utilizing the Harada-Ito procedure. J Neuroophthalmol.
1995;15:142–146.
Leigh RJ, Tomsak RL, Seidman SH, Dell’Osso LF. Superior oblique
myokymia: quantitative characteristics of the eye movements in three patients.
Arch Ophthalmol. 1991;109:1710–1713.
Tomsak RL, Kosmorsky GS, Leigh RJ. Gabapentin attenuates superior oblique
myokymia. Am J Ophthalmol. 2002;133:721–723.
Williams PE, Purvin VA, Kawasaki A. Superior oblique myokymia: efficacy of medical
treatment. J AAPOS. 2007;11:254–257.
Yousry I, Dieterich M, Naidich TP, Schmid UD, Yousry TA. Superior oblique
myokymia: magnetic resonance imaging support for the neurovascular
compression hypothesis. Ann Neurol. 2002;51:361–368.
21. Intermittent Diplopia 119

120
12
22 Ocular Myasthenia

with a 6-month history of intermittent left-
sided ptosis and binocular diplopia. The
symptoms tend to occur toward the end
of the day. He has no other neurologic
symptoms. Examination shows normal
visual acuities, color vision, confrontation
visual fields, and pupils. There is partial
left-sided ptosis. His ductions and versions
are full, but he develops exotropia and
complete left-sided ptosis with prolonged
upward gaze. Funduscopic examination is
normal. The remainder of his neurologic
examination is normal. Acetylcholine-
receptor antibodies were not detected on a
blood sample sent by his referring doctor.
121
12
T he combination of intermittent binocular diplopia and fatigable ptosis is

highly suggestive of ocular myasthenia. Myasthenia gravis is an autoim-
mune disease in which there are antibodies to the acetylcholine receptor on
the postsynaptic membrane of the neuromuscular junction. Consequently,
there is abnormal neuromuscular transmission, which is manifest clinically
as fatigable muscle weakness. Many patients present with ocular symptoms,
such as binocular diplopia and ptosis. Approximately half of these patients
do not develop symptomatic systemic disease. Examination typically shows
fluctuating asymmetric ptosis that fatigues with prolonged upward gaze. If
there is unilateral ptosis, there can be contralateral eyelid retraction caused
by attempted neural compensation for the ptosis; the eyelid retraction often
decreases with manual elevation of the ptotic eyelid. There may be a brief
upper-eyelid overshoot during gaze shifts from down to straight ahead,
which is known as a Cogan’s lid twitch. The extraocular muscle weakness in
ocular myasthenia is typically variable and asymmetric, although complete
bilateral ophthalmoplegia can occasionally occur (see Case 23). Almost any
pattern of weakness can be seen. Ocular myasthenia often produces oc-
ular motor findings that mimic other central and peripheral ocular motor
disorders, such as internuclear ophthalmoplegia and third nerve palsy, al-
though the pupils will be normal. Orbicularis oculi weakness is common
and very suggestive of the diagnosis when seen in association with ptosis
or extraocular muscle weakness. When severe, weakness of the orbicularis
oculi can produce lower eyelid ectropion (eversion of the eyelid) or the
“peekaboo” sign, which is characterized by gradual eye opening during pro-
longed forceful eyelid closure.
While ocular myasthenia is easily suspected, it is often difficult to di-
agnose definitively; the sensitivities and specificities for various diagnostic
tests are listed in Table 22.1. Indeed, the situation described in this case
scenario is commonly encountered in clinical practice: the clinical presenta-
tion suggests ocular myasthenia, but acetylcholine-receptor antibodies were
not detected. The absence of acetylcholine-receptor antibodies does not ex-
clude the diagnosis, because only half of patients with ocular myasthenia
have these antibodies detected in serum. Performing an acetylcholine-
receptor antibody panel, looking for binding, blocking, and modulating
antibodies, increases the diagnostic yield only slightly. Although muscle-
specific kinase (MuSK) antibodies are sometimes present in patients with

123
TABLE 22.1 Accuracy of Diagnostic Tests for Ocular Myasthenia
Test Sensitivity Specificity
Ice test 80% 100%
Rest test 99% 91%
Edrophonium (Tensilon) test 88–97% 50–83%
Acetylcholine-receptor antibody 44–70% 100%
Repetitive nerve stimulation 15–50% 89–100%
Single-fiber electromyography 90–100% 67–100%
Adapted from Al-Haidar M, Benatar M, Kaminski HJ. Ocular myasthenia. Neurol Clin.
2018;36:241–251.
generalized myasthenia, there are few reported cases of ocular myasthenia

with MuSK antibodies. Routine testing for MuSK antibodies in patients
with presumed ocular myasthenia is therefore not recommended. Some
patients who are presumed to have seronegative ocular myasthenia (i.e.,
they are not found to have acetylcholine-receptor antibodies on commercial
assays) actually have low-affinity acetylcholine-receptor antibodies that can
only be detected on cell-based assays or lipoprotein receptor-related protein
4 (LRP4) antibodies.
Several bedside tests can be performed to evaluate for ocular myasthenia.
Intravenous administration of edrophonium (Tensilon), which inhibits ace-
tylcholinesterase and thereby prolongs the action of acetylcholine, can im-
prove the symptoms and signs of ocular myasthenia. Sequential doses of
edrophonium are administered over a several-minute period (e.g., in 2-mg
increments) until a total of 10 mg is given. The test is considered pos-
itive if there is unequivocal improvement in muscle weakness (e.g., im-
provement in ptosis or extraocular muscle weakness). The test can be safely
performed in an office setting in most patients, although many institutions
now require cardiac monitoring during the test, given the potential for
serious muscarinic side effects (e.g., bradycardia and syncope). Atropine
should always be available to reverse such side effects. Since edrophonium
is not always available, other clinical tests can be used to evaluate for oc-
ular myasthenia. The ice test is performed by placing a latex-free ice pack
over the eyes for several minutes, after which the clinician evaluates for an
22. Ocular Myasthenia 123

124
FIGURE 22.1. Ice test in ocular myasthenia demonstrating improvement in ptosis.
improvement in signs (Figure 22.1). The rest test (also known as the sleep
test) is performed by having patients rest with their eyes closed for about
30 minutes, after which the clinician evaluates for an improvement in their
signs. Both the ice and rest tests are considered positive if there is an une-
quivocal improvement in ptosis or ophthalmoplegia. The findings of these
tests need to be interpreted with caution, however, because their sensitivities
and specificities have not been evaluated in large studies. Furthermore, the
interobserver reliability of these tests remains unknown.
Electrophysiology testing can sometimes be useful in the evaluation of
patients with suspected ocular myasthenia. Repetitive nerve simulation
testing is specific but not sensitive for ocular myasthenia. Single-fiber elec-
tromyography (sfEMG), looking for increased “jitter,” is more sensitive for
ocular myasthenia, especially if the orbicularis oculi are studied. However,
sfEMG is only reliable when performed by examiners with specific expertise
in the technique and therefore may not be readily available.

125
In this patient with a suggestive presentation yet no acetylcholine-

receptor antibodies, a diagnosis of ocular myasthenia would be supported
by positive results on ice, rest, edrophonium, and electrophysiology testing.
Attention should then be turned to treatment to reduce symptoms and,
ideally, induce disease remission. Symptoms and signs often improve with
pyridostigmine, an acetylcholinesterase inhibitor that is longer acting than
edrophonium. Increases in dose and frequency may be required but must be
titrated to muscarinic side effects (e.g., cramps and diarrhea). Some patients
(e.g., those with persistent symptoms and signs despite maximally tolerated
pyridostigmine) require immunosuppressive therapy. Corticosteroids are the
mainstay of immunosuppressive therapy for ocular myasthenia, and their
use might decrease the risk of developing generalized myasthenia, but their
long-term use can result in numerous complications (e.g., steroid-induced
diabetes and osteoporosis). Steroid-sparing agents (e.g., azathioprine and
mycophenolate) can be effective in patients with complications or intol-
erable side effects from corticosteroids. Thymectomy is not routinely
recommended for patients with ocular myasthenia unless there is a thy-
moma, although thymectomy has been demonstrated to reduce cortico-
steroid requirements in generalized myasthenia gravis. Eyelid or strabismus
surgery could be considered in patients with stable, longstanding ptosis or
ocular misalignment.
• Ocular myasthenia usually presents with intermittent or

fluctuating ptosis and diplopia.
• About 50% of patients with ocular myasthenia do not have
acetylcholine-receptor antibodies.
• Positive findings on ice, rest, edrophonium (Tensilon), and
electrophysiology testing support a diagnosis of ocular
myasthenia.
• Symptoms and signs of ocular myasthenia improve with
pyridostigmine, but some patients require systemic treatment
with corticosteroids or other immunosuppressive agents to
control symptoms or achieve disease remission.
22. Ocular Myasthenia 125

126
Further Reading
Al-Haidar M, Benatar M, Kaminski HJ. Ocular myasthenia. Neurol Clin.
2018;36:241–251.
Benatar M, McDermott MP, Sanders DB, et al. Efficacy of prednisone for the
treatment of ocular myasthenia (EPITOME): a randomized, controlled trial.
Muscle Nerve. 2016;53:363–369.
Daroff RB. The office Tensilon test for ocular myasthenia gravis. Arch Neurol.
1986;43:843–844.
Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375:2570–2581.
Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for
management of myasthenia gravis. Neurology. 2016;87:419–425.
Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia
gravis. N Engl J Med. 2016;375:511–522.

127
23 Infranuclear
Ophthalmoplegia

with a several-year history of progressively
increasing bilateral ptosis and intermittent
binocular diplopia. She is otherwise healthy
and denies vision loss, bulbar weakness, or
other neurologic symptoms. Examination
confrontation visual fields, pupils, anterior
segments, and fundi. There is bilateral
nonfatigable ptosis. Her eye movements
are severely limited in all directions. You
are unable to overcome this limitation with
head movements.
127
128
W hen a patient with globally limited ductions is encountered, the

first step is to determine if the lesion is supranuclear or nuclear-
infranuclear. Supranuclear lesions affect the saccadic, pursuit, optokinetic,
or vergence inputs to the ocular motor nuclei. Nuclear-infranuclear lesions
affect the ocular motor nuclei, nerves, neuromuscular junction, or extra-
ocular muscles themselves. The distinction can easily be made at the bed-
side by checking if the limitation in ductions can be overcome using the
vestibulo-ocular reflex (VOR), as elicited with caloric stimulation or head
movements (the “doll’s eyes” maneuver). Provided that the peripheral ves-
tibular system is intact, the limitation can be overcome using the VOR
in patients with a supranuclear lesion but not in patients with a nuclear-
infranuclear lesion. The patient in this case scenario has a global limitation
of ductions that cannot be overcome using the VOR, suggesting a nuclear-
infranuclear lesion. In the absence of pupil involvement (so-called internal
ophthalmoplegia), the deficit is consistent with complete bilateral external
ophthalmoplegia.
The differential diagnosis of complete bilateral external ophthalmo-
plegia depends on whether the ophthalmoplegia has an acute onset or
chronic progressive course (Table 23.1). Miller Fisher syndrome is the most
TABLE 23.1 Causes of Complete Bilateral Ophthalmoplegia
Acute Onset Chronic Progressive Onset
Miller Fisher syndrome Mitochondrial diseases (e.g., Kearns-

Guillain-Barré syndrome Sayre syndrome, mitochondrial
encephalopathy with lactic acidosis
Brainstem stroke
and stroke-like episodes, myoclonic
Myasthenia gravis epilepsy with ragged red fibers)
Pituitary apoplexy Oculopharyngeal dystrophy
Botulism Myotonic dystrophy
Drug toxicity (e.g., phenytoin) Other congenital myopathies
Nasopharyngeal carcinoma Congenital cranial dysinnervation
Invasive fungal sinusitis syndromes
Wernicke encephalopathy Neurodegenerative diseases (e.g., end-
Trauma stage progressive supranuclear palsy)
Myasthenia gravis
Thyroid eye disease

129
common cause of acute complete bilateral ophthalmoplegia and produces

the triad of ophthalmoplegia, areflexia, and ataxia. It is a monophasic con-
dition that usually develops following an antecedent infectious illness, such
as Campylobacter jejuni gastroenteritis, in which there is a humoral immu-
nologic response to the infectious agent and similar host GQ1b gangliosides
on peripheral and cranial nerves. Miller Fisher syndrome can be diagnosed
by identifying GQ1b antibodies in serum. Most affected patients make a
complete spontaneous recovery over months. In Guillain-Barré syndrome,
there is an acute inflammatory demyelinating polyneuropathy that similarly
develops after an antecedent infectious illness or vaccination, producing
rapidly ascending paralysis with areflexia. Ophthalmoplegia is relatively un-
common in Guillain-Barré syndrome and does not usually occur until the
paralysis is severe (e.g., involving muscles of respiration). Treatment with in-
travenous immunoglobulin or plasma exchange hastens recovery, although
some patients are left with permanent neurologic deficits. Upper brainstem
(typically bilateral midbrain-thalamic) strokes can occasionally produce
acute complete bilateral ophthalmoplegia, although affected patients will
usually present with coma or decreased level of consciousness rather than
diplopia or ptosis. Since the pupils can be affected in Miller Fisher syn-
drome, Guillain-Barré syndrome, and midbrain-thalamic stroke, there may
be internal ophthalmoplegia as well as complete bilateral external ophthal-
moplegia in these patients. Myasthenia gravis can sometimes cause acute
complete bilateral external ophthalmoplegia without internal ophthalmo-
plegia, although affected patients will usually have other symptoms or signs
that suggest the diagnosis, such as fluctuating ptosis or bulbar weakness (see
Case 22). Other less common causes of acute complete bilateral ophthal-
moplegia are listed in Table 23.1.
Chronic progressive external ophthalmoplegia (CPEO) usually has a
slowly progressive course over many years. CPEO occurs with mitochon-
drial diseases; it is a characteristic feature of Kearns-Sayre syndrome, but
it can occur with the syndrome of mitochondrial encephalopathy with
lactic acidosis and stroke-like episodes (MELAS) and the syndrome of my-
oclonic epilepsy with ragged red fibers (MERRF). CPEO also occurs with
oculopharyngeal muscular dystrophy, which most commonly has an auto-
somal dominant inheritance pattern producing a phenotype with promi-
nent ptosis and bulbar weakness. CPEO can occur in myotonic dystrophy,
23. Infranuclear Ophthalmoplegia 129

130
which has an autosomal dominant inheritance pattern producing a vari-

able phenotype; common clinical features include myotonia (e.g., causing
difficulty releasing grip during a firm handshake), a distinctive “hatchet”
facial appearance due to temporalis and masseter muscle wasting, cortical
and subcapsular cataract with iridescent cortical opacities (“Christmas tree”
cataract), early frontal balding and testicular atrophy in men, and car-
diac conduction deficits. Other causes of CPEO include other congenital
myopathies, congenital cranial dysinnervation syndromes, neurodegener-
ative diseases (such as end-stage progressive supranuclear palsy; see Case
25), myasthenia gravis, and thyroid eye disease (see Table 23.1). Since the
patient in this scenario has had progressively worsening symptoms over sev-
eral years, it is likely that she has CPEO. Because the differential diagnosis
is broad, the next step in evaluation is to take a careful history, including
family history, and to then perform thorough neurologic and systemic
examinations looking for signs that might suggest a specific diagnosis.
Given the age of this patient, presence of bilateral nonfatigable ptosis,
lack of bulbar weakness, and lack of other neurologic symptoms, she likely
has CPEO due to a mitochondrial disease. There should be a careful in-
quiry about similar symptoms occurring in relatives on the maternal side
of the family, because these syndromes have a mitochondrial inheritance
pattern. Interestingly, despite a profound inability to move their eyes, many
patients do not report having constant diplopia or oscillopsia during head
movements, presumably because there are adaptive changes in the visual
system with the gradual onset of the ophthalmoplegia. However, patients
are often symptomatic from ptosis, especially when the pupil is occluded.
When encountering a patient with suspected mitochondrial disease, such as
this patient, it is important to ask about symptoms suggesting multisystem
involvement (e.g., hearing loss or cardiac arrhythmias). It is advisable to
look for other neuro-ophthalmic signs of mitochondrial disease, such as
pigmentary (“salt and pepper”) retinopathy and optic neuropathy. However,
the mitochondrial diseases are notorious for having variable manifestations,
even with the same mutation. Magnetic resonance imaging (MRI) shows
atrophic extraocular muscle bellies in patients with CPEO (Figure 23.1),
but this is a nonspecific finding that can also occur with chronic muscle de-
nervation. Thus, genetic testing or a muscle biopsy is required for definitive

13
FIGURE 23.1. Axial and coronal MRI showing severely atrophic extraocular muscle bellies in
a patient with chronic progressive external ophthalmoplegia in the setting of Kearns-Sayre
syndrome.
diagnosis. Muscle biopsy typically shows characteristic “ragged red” muscle

fibers and fibers with absent cytochrome C oxidase staining.
Several therapies have been proposed for mitochondrial diseases that
cause CPEO, including vitamins and coenzyme Q10, but their efficacy
remains uncertain. Symptomatic management, however, is often helpful.
Patients with constant diplopia often benefit from prism or strabismus
surgery, while patients with symptomatic ptosis often benefit from eyelid
surgery.
• Supranuclear ophthalmoplegia can be overcome using the

VOR (“doll’s eyes” maneuver), whereas nuclear-infranuclear
ophthalmoplegia cannot.
• Causes of acute complete bilateral ophthalmoplegia include
Miller Fisher syndrome, Guillain-Barré syndrome, brainstem
stroke, myasthenia gravis, and pituitary apoplexy.
• Causes of chronic progressive complete bilateral
ophthalmoplegia include mitochondrial diseases,
oculopharyngeal muscular dystrophy, myotonic
dystrophy, congenital cranial dysinnervation syndromes,
neurodegenerative diseases, myasthenia gravis, and thyroid eye
disease.
• Patients with CPEO do not usually complain of diplopia but can
have symptomatic ptosis.
23. Infranuclear Ophthalmoplegia 131

132
Further Reading
Keane JR. Acute bilateral ophthalmoplegia: 60 cases. Neurology. 1986;36:279–281.
Keane JR. Bilateral ocular paralysis: analysis of 31 inpatients. Arch Neurol.
2007;64:178–180.
Schoser BG, Pongratz D. Extraocular mitochondrial myopathies and their differential
diagnoses. Strabismus. 2006;14:107–113.
Thurtell MJ, Halmagyi GM. Complete ophthalmoplegia: an unusual sign of bilateral
paramedian midbrain-thalamic infarction. Stroke. 2008;39:1355–1357.

13
24 Internuclear
Ophthalmoplegia

with a 1-day history of blurred vision while
walking. She has had transient diplopia
previously but had not sought medical
attention for it. Examination shows normal
visual acuities in both eyes. However, her
visual acuity in both eyes decreases to
20/60 during vertical head movements. Her
color vision, confrontation visual fields,
and pupils are normal. She is unable to
adduct either eye past the midline. Her
eye movements are otherwise grossly
normal and there is no ptosis. Funduscopic
examination is normal, and the remainder
of her neurologic examination is
unrevealing.
133
134
T he combination of bilateral adduction deficits and decreased visual

acuity with vertical head movements is highly suggestive of bilateral
internuclear ophthalmoplegia (INO) due to a lesion affecting both medial
longitudinal fasciculi. The medial longitudinal fasciculus (MLF) conveys
the conjugate horizontal eye movement command from the sixth nerve nu-
cleus in the pons to the medial rectus subdivision of the contralateral third
nerve nucleus in the midbrain. A lesion affecting the MLF causes an ipsilat-
eral adduction deficit, since the internuclear neurons in the MLF decussate
after leaving the sixth nerve nucleus to ascend on the contralateral side of
the brainstem. The MLF also carries signals that have a role in vertical gaze
holding, vertical smooth pursuit, and the vertical vestibulo-ocular reflex
(VOR). Consequently, a lesion affecting the MLF can also impair these eye
movements. Indeed, the patient in this scenario reports blurred vision while
walking and her visual acuity decreases during vertical head movements,
suggesting that her vertical VOR is impaired.
The classic finding in patients with INO is an adduction deficit that can
be overcome with convergence, because the convergence input from the
midbrain to the medial rectus subdivision of the third nerve nucleus is usu-
ally not affected. Therefore, the first step in this patient is to confirm that
her bilateral adduction deficits can be overcome with convergence. Patients
with INO often have “dissociated” abducting nystagmus in the contralat-
eral eye, which is thought to represent an adaptive neural response to the
inability to adduct the ipsilateral eye during attempted versions. Patients
with INO often have a skew deviation, impaired vertical VOR, and (in
the acute setting) dissociated vertical-torsional nystagmus secondary to in-
volvement of the central otolithic and semicircular canal pathways traveling
in the MLF. When a unilateral lesion also involves the adjacent sixth nerve
nucleus, there will also be an ipsilateral conjugate gaze palsy; a unilateral
INO combined with an ipsilateral conjugate gaze palsy makes up the “one-
and-a-half ” syndrome.
Common causes of INO include demyelination in the setting of mul-
tiple sclerosis (MS), brainstem stroke, brainstem tumors, fourth ventricle
tumors, and hindbrain anomalies, such as Chiari malformation. Bilateral
INO is most commonly caused by MS, whereas unilateral INO is most
commonly caused by brainstem stroke. Thus, the investigation of choice in
this patient is magnetic resonance imaging (MRI) of the brain to evaluate

135
FIGURE 24.1. MRI showing a tiny plaque of demyelination in the brainstem tegmentum (arrows)
causing an isolated right internuclear ophthalmoplegia.
for a brainstem tegmentum lesion, although such a lesion may be subtle

and easily overlooked unless specifically sought (Figure 24.1). Although this
patient has no other symptoms or signs to suggest MS, apart from a prior
history of transient diplopia, MRI of the brain is also required to assess for
white matter lesions.
Other causes of adduction deficit should be kept in mind when
evaluating a patient with an apparent INO, especially if the MRI is normal.
Ocular myasthenia and chronic progressive external ophthalmoplegia can
give adduction deficits that can be difficult to distinguish from those seen
in INO (“pseudo-INO”); in contrast with INO, the adduction deficits in
pseudo-INO cannot be overcome with convergence. There will often be
accompanying ptosis or other signs that suggest the correct diagnosis. Eye
movement recordings can be used to distinguish INO from pseudo-INO
in difficult cases.
In many patients with INO due to MS or brainstem stroke, the def-
icit will spontaneously recover with time. A 3-day course of intravenous
methylprednisone could be considered in this patient with bilateral INO
if there is evidence of demyelination on MRI, because the treatment may
speed her recovery. Many patients with INO do not report diplopia. If
diplopia is present, it is best managed acutely with monocular occlusion
24. Internuclear Ophthalmoplegia 135

136
rather than prism. The long-term management of the patient depends on

the cause of the INO.
• INO is caused by a lesion affecting the ipsilateral MLF.

• The classic sign of INO is an adduction deficit that can be
overcome with convergence.
• Common causes of INO include brainstem demyelination in
the setting of MS, brainstem stroke, brainstem tumor, fourth
ventricle tumor, and hindbrain anomalies.
• Ocular myasthenia and chronic progressive external
ophthalmoplegia can produce adduction deficits that can be
difficult to distinguish from INO.
• INO from brainstem demyelination and stroke can recover
spontaneously.
Further Reading
Aw ST, Chen L, Todd MJ, Barnett MH, Halmagyi GM. Vestibulo-ocular reflex deficits
with medial longitudinal fasciculus lesions. J Neurol. 2017;264:2119–2129.
Kim JS. Internuclear ophthalmoplegia as an isolated or predominant symptom of
brainstem infarction. Neurology. 2004;62:1491–1496.
Schmidt F, Kastrup A, Nägele T, Krapf H, Küker W. Isolated ischemic internuclear
ophthalmoplegia: toward the resolution limits of DW-MRI. Eur J Neurol.
2004;11:67–68.
Serra A, Liao K, Matta M, Leigh RJ. Diagnosing disconjugate eye movements: phase-
plane analysis of horizontal saccades. Neurology. 2008;71:1167–1175.
Zee DS. Internuclear ophthalmoplegia: pathophysiology and diagnosis. Baillieres
Clin Neurol. 1992;1:455–470.

137
25 Supranuclear
Ophthalmoplegia

with a 6-month history of falls and difficulty
reading. Examination shows visual
acuities of 20/25 in both eyes. Color vision,
confrontation visual fields, pupils, and fundi
are normal. There is bilateral upper-eyelid
retraction. His vertical eye movements are
limited, with slowing of vertical saccades.
His horizontal eye movements are normal,
although he is unable to converge.
137
138
D ifficulty reading is a common complaint that can result from a number

of deficits, of which the most frequent is uncorrected presbyopia. While
correction of presbyopia is likely to help this patient, his inability to con-
verge and his limited vertical eye movements are likely to be playing a role.
For example, the patient’s inability to look down when attempting to read
would make it difficult for him to see through the reading portion of bifocal
or progressive-lens glasses. In addition, his inability to converge would result
in diplopia when he attempts to read at near (e.g., from a book or computer
screen) with both eyes open. There are several other concerning features in
this patient, including his falls, upper-eyelid retraction, and slowed vertical
saccades. Indeed, the combination of limited and slowed vertical saccades,
upper-eyelid retraction, and convergence insufficiency suggests midbrain
pathology (see Case 40). It should be determined if the limitation in ver-
tical eye movements is due to a supranuclear or nuclear-infranuclear lesion
by checking if it can be overcome using the vestibulo-ocular reflex (see Case
23). The presence of a vertical supranuclear ophthalmoplegia narrows the
differential diagnosis considerably; given the history of frequent falls, the
most likely diagnosis is progressive supranuclear palsy (PSP).
PSP is one of several neurodegenerative diseases, including corticobasal
degeneration and frontotemporal dementia, in which there is accumulation
of abnormally phosphorylated tau protein in the brain. PSP produces an
akinetic-rigid syndrome that is characterized by increased axial muscle tone,
abnormal posture, and difficulties with swallowing and speech. It can pro-
duce a number of characteristic neuro-ophthalmic signs, including slowing
and limitation of vertical (especially downward) saccades, convergence
insufficiency, square-wave jerks, and a variety of eyelid abnormalities, in-
cluding upper-eyelid retraction with reduced blink rate (which gives the pa-
tient a characteristic surprised or startled appearance and dry eye), apraxia
of eyelid opening, and blepharospasm. In the later stages of the disease, hor-
izontal saccades become impaired and the patient can eventually develop
complete ophthalmoplegia (see Case 23). The neurologic examination can
show dysarthria, retrocollis, axial rigidity, bradykinesis, and impaired pos-
tural reflexes, with a tendency to fall backward. Other extrapyramidal signs,
such as tremor and cogwheel rigidity, are usually absent. Impaired frontal
lobe function can result in decreased executive function, frontal release

139
signs, and the “applause” sign, which is an inability to clap only three times
despite being instructed to do so.
Although PSP is a clinical diagnosis, magnetic resonance imaging of the
brain can show characteristic midbrain atrophy (the “hummingbird” sign)
in the later stages of the disease. Eye movement recordings can show subtle
slowing of vertical saccades in the early stages of the disease. Several other rare
diseases can have a similar clinical appearance, including Creutzfeldt-Jakob
disease, Whipple disease (in which there can be pathognomonic verging-
diverging pendular eye oscillations with synchronous jaw movements; this
is called oculomasticatory myorhythmia), and anti-Ma2 brainstem enceph-
alitis. However, each of these diseases has a subacute onset and inexorably
progressive course over months, whereas PSP is usually slowly progressive
over years.
PSP is very difficult to manage medically. The extrapyramidal features
usually respond poorly to dopaminergic agents, although they can occa-
sionally provide some benefit. This patient’s complaint of difficulty reading
could be addressed by ensuring that he has appropriate correction for pres-
byopia. The patient should be given separate single-vision reading glasses so
that he does not have to look down through the reading portion of bifocal
or progressive-lens glasses to read. The patient may also benefit from base-
in prisms in his reading glasses to compensate for his convergence insuffi-
ciency. Regular application of artificial tears should be advised if he has dry
eye due to a decreased blink rate.
• PSP is an akinetic-rigid syndrome characterized by dysarthria,

axial rigidity, and postural instability, with a tendency to fall
backward.
• Neuro-ophthalmic findings in PSP include supranuclear vertical
gaze palsy, convergence insufficiency, square-wave jerks, and
eyelid abnormalities.
• PSP is a clinical diagnosis and often responds poorly to
treatment with dopaminergic agents.
25. Supranuclear Ophthalmoplegia 139

140
• Reading difficulties in PSP can be improved with correction

of presbyopia, separate reading glasses, prisms, and regular
application of artificial tears.
Further Reading
Chen AL, Riley DE, King SA, et al. The disturbance of gaze in progressive
supranuclear palsy: implications for pathogenesis. Front Neurol. 2010;
doi: 10.3389/fneur.2010.00147.
Dubois B, Slachevsky A, Pillon B, Beato R, Villalponda JM, Litvan I. “Applause sign”
helps to discriminate PSP from FTD and PD. Neurology. 2005;64:2132–2133.
Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural
history of progressive supranuclear palsy: a clinical cohort study. Neurology.
2003;60:910–916.
Stamelou M, Knake S, Oertel WH, Höglinger GU. Magnetic resonance imaging in
progressive supranuclear palsy. J Neurol. 2011;258:549–558.

14
26 Gaze-Evoked Nystagmus
A 52-year-old man presents for a routine

eye examination. He has a long history
of epilepsy but is otherwise healthy.
Examination shows normal visual acuities,
pupils, and fundi. His ductions and versions
are full. There is no nystagmus when he
is looking straight ahead. However, there
is left-beat nystagmus with leftward gaze,
right-beat nystagmus with rightward
gaze, and upbeat nystagmus with upward
gaze. The neurologic examination shows
an unsteady tandem gait but no other
abnormal signs. He does not have any
visual symptoms.
141
142
T he patient in this case scenario has gaze-evoked nystagmus, which is a

jerk-waveform nystagmus that is present only with attempted eccentric
fixation, such that leftward gaze evokes left-beat nystagmus, rightward gaze
evokes right-beat nystagmus, and upward gaze evokes upbeat nystagmus.
Gaze-evoked nystagmus is one of the most common types of nystagmus
encountered in clinical practice. It results from impaired function of the
ocular motor gaze-holding mechanism, better known as the “neural inte-
grator.” In health, the neural integrator generates a position signal to hold
the eyes in eccentric orbital positions by opposing elastic restoring forces
that are acting to bring the eyes back toward the center of the orbit. When
neural integrator function is impaired, the position signal is not adequate
to oppose those elastic restoring forces. As a result, the eyes drift toward the
center of the orbit and corrective saccades (quick phases) are required to
direct them back to the desired eccentric position. In contrast with other
forms of acquired nystagmus, patients do not usually have visual symptoms
from gaze-evoked nystagmus.
Before proceeding any further with this patient, it is important to be
convinced that he has gaze-evoked nystagmus rather than physiologic “end-
point” nystagmus. Physiologic end-point nystagmus looks similar to gaze-
evoked nystagmus but is low amplitude, low frequency, and occurs only
on adopting extremely eccentric gaze positions. It may be poorly sustained
and is not accompanied by abnormal ocular motor or cerebellar signs. In
contrast, gaze-evoked nystagmus usually appears with less extreme eccentric
gaze positions and is often accompanied by other abnormal ocular motor
signs, such as impaired (“saccadic”) smooth pursuit, or cerebellar signs.
Given that this patient has an unsteady tandem gait, the concern for gaze-
evoked nystagmus should be greater.
Gaze-evoked nystagmus has limited localizing value. It can rarely result
from focal lesions affecting components of the neural integrator in the me-
dial medulla, cerebellum, or midbrain reticular formation. More often, it
is caused by medications or neurologic conditions that affect neural inte-
grator function (Box 26.1). Anticonvulsant medications, such as pheny-
toin and carbamazepine, are a frequent cause of gaze-evoked nystagmus.
Indeed, gaze-evoked nystagmus and an unsteady tandem gait in patients
taking these medications were considered clinical signs of drug toxicity be-
fore monitoring of plasma drug levels came into routine practice. Of note,

143
BOX 26.1 Common Causes of Gaze-Evoked Nystagmus
Anticonvulsants (e.g., phenytoin, carbamazepine)

Other drugs (e.g., lithium, alcohol, marijuana)
Cerebellar degenerations
Multiple sclerosis
Episodic ataxias
acute intoxication with phenytoin can occasionally induce cerebellar at-

rophy and thereby cause persistent gaze-evoked nystagmus, even after the
drug is discontinued. Given that this patient has a history of epilepsy, it is
important to inquire about previous and current anticonvulsant use. If the
patient is indeed taking an anticonvulsant drug, the next step is to check its
plasma level (to confirm that it is elevated) and then liaise with the patient’s
neurologist to determine if a dose adjustment is needed. Transient with-
drawal of the anticonvulsant or a reduction in its dose is likely to be all that
is required for the gaze-evoked nystagmus and gait ataxia to resolve.
If the patient is not taking an anticonvulsant or is not intoxicated with
another implicated drug, such as alcohol or marijuana, a more thorough
history and workup is required. It will be important to inquire about
symptoms that might suggest the etiology of the gaze-evoked nystagmus
as well as about his past medical history and family history. A complete
neurologic examination might demonstrate other signs that suggest the eti-
ology. In terms of investigations, the next step, in most cases, would be to
obtain magnetic resonance imaging of the brain to look for a structural
abnormality (e.g., cerebellar atrophy). Genetic testing might be required if
the patient has a family history of progressive or episodic ataxia. Regardless
of the cause, gaze- evoked nystagmus does not usually produce visual
symptoms and therefore does not require specific treatment. However,
treatment should be directed toward the underlying condition.
• Gaze-evoked nystagmus is one of the most common types of

nystagmus encountered in clinical practice.
26. Gaze-Evoked Nystagmus 143

14
• Gaze-evoked nystagmus should be differentiated from

physiologic end-point nystagmus, which is of no concern.
• Common causes of gaze-evoked nystagmus include
anticonvulsant medications, other drugs, cerebellar
degenerations, multiple sclerosis, and episodic ataxias.
• Gaze-evoked nystagmus does not usually cause visual
symptoms and, therefore, treatment should be directed toward
the underlying cause.
Further Reading
Baier B, Dieterich M. Incidence and anatomy of gaze-evoked nystagmus in patients
with cerebellar lesions. Neurology. 2011;76:361–365.
Büttner U, Grundei T. Gaze-evoked nystagmus and smooth pursuit deficits: their
relationship studied in 52 patients. J Neurol. 1995;242:384–389.
Remler BF, Leigh RJ, Osorio I, Tomsak RL. The characteristics and mechanisms
of visual disturbance associated with anticonvulsant therapy. Neurology.
1990;40:791–796.
Shallo-Hoffmann J, Schwarze H, Simonsz HJ, Mühlendyck H. A reexamination of
end-point and rebound nystagmus in normals. Invest Ophthalmol Vis Sci.
1990;31:388–392.

145
27 Downbeat Nystagmus
A 72-year-old woman with a past history

of metastatic breast cancer presents to
your clinic with a 9-month history of
progressively increasing vertical oscillopsia.
Examination shows visual acuities of 20/30
in both eyes. Her color vision, confrontation
visual fields, pupils, and eyelids are
normal. Her ductions and versions are full.
However, you notice downbeat nystagmus
that is most prominent on down-lateral
gaze. Her funduscopic examination is
normal. The remainder of her neurologic
examination shows a wide-based, unsteady
gait without other abnormal signs.
145
146
D ownbeat nystagmus is a vertical jerk-waveform nystagmus with upward

slow phases and downward quick phases, which commonly causes an
illusory motion of the visual world termed oscillopsia. The nystagmus is
usually present when the patient is looking straight ahead, but it can be
difficult to detect without close inspection or magnification. It typically
increases with downward and lateral gaze. Convergence often exacerbates
it, but can convert it to upbeat nystagmus. The nystagmus often increases
when the patient is placed in a head-hanging or prone position. The nys-
tagmus is usually accompanied by other ocular motor abnormalities, such
as gaze-evoked nystagmus, impaired smooth pursuit, and impaired suppres-
sion of the vestibulo-ocular reflex.
Downbeat nystagmus results from lesions affecting the flocculonodular
lobe of the cerebellum (i.e., the vestibulo-cerebellum). Common causes are
listed in Box 27.1 and include inherited cerebellar degenerations (e.g., auto-
somal dominant spinocerebellar ataxia), acquired cerebellar degenerations
(e.g., paraneoplastic cerebellar degeneration), and congenital hindbrain
anomalies (e.g., Chiari malformation) (Figure 27.1). However, no cause
will be found in up to 40% of patients with downbeat nystagmus, despite
extensive investigations. For the patient in this scenario, the initial concern
should be for cerebellar metastases from breast cancer. These can be easily
diagnosed with magnetic resonance imaging (MRI). If they are present, sur-
gical debulking, radiation therapy, and chemotherapy could be considered
after consultation with the patient’s oncologist. If there are no metastases,
the MRI should be carefully scrutinized for signs of cerebellar atrophy (see
Figure 27.1) because the patient might have paraneoplastic cerebellar de-
generation. Paraneoplastic cerebellar degeneration has a subacute onset and
is most commonly associated with cancers of the lung, ovary, and breast.
Downbeat nystagmus is a frequent finding in affected patients. When there
BOX 27.1 Common Causes of Downbeat Nystagmus
Cerebellar degenerations (e.g., inherited, paraneoplastic)

Hindbrain anomalies (e.g., Chiari malformation)
Cerebellar stroke
Cerebellar mass lesions
Toxins (e.g., anticonvulsants, lithium, alcohol)

147
FIGURE 27.1. Atrophic cerebellum in a patient with downbeat nystagmus from paraneoplastic

cerebellar degeneration (left). Inferior cerebellar tonsillar descent below the level of the foramen
magnum in a patient with downbeat nystagmus from a Chiari I malformation (right).
is an underlying breast cancer, there may be anti-Yo or anti-Ri antibodies

in serum or cerebrospinal fluid. A significant percentage of patients with
suspected paraneoplastic cerebellar degeneration do not have antineuronal
antibodies or a history of cancer. Full-body positron emission tomography
with co-registered computed tomography (PET-CT) should be obtained in
these patients, looking for an occult neoplasm. Full-body PET-CT should
also be obtained in patients with suspected paraneoplastic cerebellar degen-
eration who have a history of cancer but no other evidence of relapse.
If this patient is ultimately diagnosed with paraneoplastic cerebellar de-
generation based on finding an antineuronal antibody or evidence of relapse,
treatment should be directed toward the neoplasm itself. Unfortunately,
the paraneoplastic syndrome rarely improves with such treatment, although
it may stabilize. There are, however, reports of paraneoplastic syndromes
improving in patients who are also treated with plasmapheresis, intrave-
nous immunoglobulin, or immunosuppressant medications, especially if
these treatments are commenced soon after the onset of the neurologic
symptoms.
Regardless of the cause, many patients with downbeat nystagmus re-
quest treatment to alleviate the associated oscillopsia. Clonazepam, a
GABAA-agonist, can improve downbeat nystagmus in some patients, but
27. Downbeat Nystagmus 147

148
its beneficial effect has not been proven in a controlled trial. Many other
drugs have been proposed as treatments for downbeat nystagmus (e.g.,
baclofen, gabapentin, and anticholinergic drugs), but beneficial effects
have not been verified in controlled trials. Several trials have demonstrated
that the potassium channel blocker 4- aminopyridine can effectively
suppress downbeat nystagmus. This agent tends to be more effective in
patients with downbeat nystagmus caused by cerebellar degenerations than
in those with focal or structural lesions. It is usually well tolerated and
sometimes improves gait ataxia, although it can lower the threshold for
epileptic seizures in predisposed patients or cause cardiac arrhythmias in
patients with a prolonged QT interval. Thus, if this patient’s nystagmus
and visual symptoms do not improve with treatment of the underlying
cause, a therapeutic trial with either 4-aminopyridine or clonazepam could
be considered.
• Downbeat nystagmus results from lesions of the

flocculonodular lobe of the cerebellum.
• Common causes of downbeat nystagmus include cerebellar
degenerations (e.g., inherited or paraneoplastic), hindbrain
anomalies (e.g., Chiari malformation), cerebellar stroke,
cerebellar mass lesions, and toxins.
• Downbeat nystagmus often produces disabling vertical
oscillopsia or blurred vision.
• Downbeat nystagmus can respond to 4-aminopyridine or
clonazepam.
Further Reading
Claassen J, Spiegel R, Kalla R, et al. A randomised double-blind, cross-over trial of
4-aminopyridine for downbeat nystagmus—effects on slowphase eye velocity,
postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry.
2013;84:1392–1399.
Currie JN, Matsuo V. The use of clonazepam in the treatment of nystagmus-induced
oscillopsia. Ophthalmology. 1986;93:924–932.

149
Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmologic manifestations of

paraneoplastic syndromes. J Neuroophthalmol. 2008;28:58–68.
Wagner JN, Glaser M, Brandt T, Strupp M. Downbeat nystagmus: aetiology and
comorbidity in 117 patients. J Neurol Neurosurg Psychiatry. 2008;79:672–677.
Yoshida S, Takahashi H. Cerebellar metastases in patients with cancer. Surg Neurol.
2009;71:184–187.
27. Downbeat Nystagmus 149

150
15
28 Upbeat Nystagmus
You are asked to see a 62-year-old man

who has presented to the emergency
department following the sudden onset
of vertical oscillopsia. He has had chronic
vomiting and has lost a large amount of
weight following gastric bypass surgery
6 months ago. Examination shows
visual acuities of 20/40 in both eyes.
He has bilateral abduction deficits and
upbeat nystagmus in all positions of
gaze. The upbeat nystagmus is partially
suppressed with convergence. Color vision,
confrontation visual fields, pupils, eyelids,
and fundi are normal.
151
152
U pbeat nystagmus is a vertical jerk-waveform nystagmus with down-

ward slow phases and upward quick phases. It is distinct from gaze-
evoked upbeat nystagmus, which is a type of gaze-evoked nystagmus that
is seen exclusively on upgaze and is not present when the patient is looking
straight ahead (see Case 26). Unlike downbeat nystagmus, upbeat nys-
tagmus is not increased on lateral gaze, but it typically increases on up-
ward gaze. Convergence can exacerbate the nystagmus in some patients,
can suppress it in others, and may even convert it to downbeat nystagmus.
Like downbeat nystagmus, upbeat nystagmus can be modulated by head
posture.
Upbeat nystagmus results from lesions affecting the central structures
that process compensatory upward eye movement signals, such as the
perihypoglossal nuclei in the medial medulla. It can also result from lesions
affecting the central pathways that convey these signals between the ves-
tibular nuclei in the medulla and the ocular motor nuclei in the midbrain,
including the crossing ventral tegmental tract, brachium conjunctivum
(superior cerebellar peduncle), and medial longitudinal fasciculus.
Consequently, upbeat nystagmus can result from lesions in a variety of
locations in the brainstem and cerebellum. While it might be tempting to
obtain imaging to look for a brainstem or cerebellar lesion, the first step
for the patient in this scenario is to complete the neurologic examination,
as there may be other signs that indicate the location of the lesion. For ex-
ample, the patient might have a bulbar palsy, suggesting a medial medul-
lary lesion. However, there may be signs that do not help with localization
of the lesion yet do suggest the correct diagnosis. The patient might have
confusion and gait ataxia in addition to upbeat nystagmus and bilateral ab-
duction deficits; with the history of chronic vomiting following gastric by-
pass surgery and this combination of neurologic signs, the primary concern
would be for Wernicke encephalopathy.
While upbeat nystagmus can have a variety of causes (Box 28.1), the
combination of upbeat nystagmus and abduction deficits is highly sugges-
tive of Wernicke encephalopathy. Suppression of upbeat nystagmus with
convergence can also occur in patients with Wernicke encephalopathy. The
decreased visual acuity in this patient is almost certainly a consequence of
upbeat nystagmus, but it could also be due to optic nerve involvement,
which can produce central visual field defects and, in some cases, mild

153
BOX 28.1 Common Causes of Upbeat Nystagmus
Brainstem and cerebellar stroke

Wernicke encephalopathy
Multiple sclerosis
Brainstem and cerebellar tumors
optic disc edema in patients with Wernicke encephalopathy. Given that

the patient has normal color vision, confrontation visual fields, and fundi,
optic nerve involvement is unlikely to be the cause for the decreased visual
acuities.
Although the diagnosis of Wernicke encephalopathy is clinical, mag-
netic resonance imaging (MRI) can show subtle yet highly characteristic
abnormalities, including signal change in the mammillary bodies, medial
thalami, periaqueductal gray, floor of the fourth ventricle, and cranial nerve
nuclei. Although MRI might be helpful, treatment of this patient with in-
travenous thiamine should not be delayed while awaiting imaging. Timely
treatment is not only important to prevent the development of Korsakoff
syndrome, which is characterized by irreversible amnesia and confabula-
tion, but will maximize recovery of his ocular motor deficits. Indeed, treat-
ment with intravenous thiamine will often result in a rapid and complete
resolution of the ocular motor deficits. Consequently, the upbeat nys-
tagmus does not usually require specific treatment in patients with acute
Wernicke encephalopathy. However, it can persist if there is a delay in thi-
amine treatment.
Patients with persistent upbeat nystagmus will usually request treat-
ment because of severe disabling oscillopsia. Unfortunately, there have
been few clinical trials of medical treatment for upbeat nystagmus. One
uncontrolled trial reported a beneficial effect with baclofen. A second trial
reported suppression of upbeat nystagmus with memantine, whereas an-
other study reported suppression with 4-aminopyridine. If this patient’s
nystagmus does not disappear with thiamine treatment, a therapeutic
trial with memantine, 4-aminopyridine, or baclofen could be considered.
Given that all of these medications have side effects, the choice of medi-
cation and dosage will depend on what other residual neurologic deficits
the patient has.
28. Upbeat Nystagmus 153

154
• Since upbeat nystagmus can result from lesions in a variety of

locations in the brainstem and cerebellum, other localizing signs
should be sought.
• Common causes of upbeat nystagmus include stroke, Wernicke
encephalopathy, multiple sclerosis, brainstem tumors, and
cerebellar tumors.
• The combination of upbeat nystagmus and abduction deficits is
highly suggestive of Wernicke encephalopathy.
• Wernicke encephalopathy should be immediately treated with
intravenous thiamine to maximize recovery of ocular motor and
neurologic deficits and to prevent the development of Korsakoff
syndrome.
• Persistent upbeat nystagmus might respond to memantine, 4-
aminopyridine, or baclofen.
Further Reading
Aasheim ET. Wernicke encephalopathy after bariatric surgery: a systematic review.
Ann Surg. 2008;248:714–720.
Dieterich M, Straube A, Brandt T, Paulus W, Büttner U. The effects of baclofen and
cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg
Psychiatry. 1991;54:627–632.
Fisher A, Gresty M, Chambers B, Rudge P. Primary position upbeating nystagmus: a
variety of central positional nystagmus. Brain. 1983;106:949–964.
Glasauer S, Kalla R, Büttner U, Strupp M, Brandt T. 4-Aminopyridine restores visual
ocular motor function in upbeat nystagmus. J Neurol Neurosurg Psychiatry.
2005;76:451–453.
Thurtell MJ, Joshi AC, Leone AC, et al. Crossover trial of gabapentin and memantine
as treatment for acquired nystagmus. Ann Neurol. 2010;67:676–680.
Zuccoli G, Pipitone N. Neuroimaging findings in acute Wernicke’s encephalopathy.
AJR Am J Roentgenol. 2009;192:501–508.

15
29 Pendular Nystagmus
A 44-year-old woman with a long history

of multiple sclerosis (MS) presents to
your clinic for evaluation of blurred and
“wobbly” vision. She has had multiple
attacks of optic neuritis in both eyes, but
she does not currently have any pain with
eye movement. Examination shows visual
acuities of 20/50 in both eyes. She has red
desaturation in both eyes, but confrontation
visual fields are full. Her pupils are equal in
size and sluggishly reactive to light. There
is a trace right relative afferent pupillary
defect. Her eye movements are full, but
there are low-amplitude and high-frequency
elliptical eye oscillations, without quick
phases, more prominent in the right eye.
Funduscopic examination shows optic
atrophy that is more prominent in the
right eye.
155
156
P atients with MS commonly have visual complaints, which can result

from involvement of the optic nerves, optic chiasm, retrochiasmal
visual pathways, or brainstem structures and pathways important for eye
movements. The patient in this scenario has had multiple attacks of optic
neuritis in both eyes (see Case 1) and has signs suggesting bilateral asym-
metric optic neuropathies, including red desaturation, a relative afferent pu-
pillary defect, and optic atrophy. Thus, optic neuropathy is almost certainly
contributing to her complaint of blurred vision. In addition, she has ellip-
tical eye oscillations consistent with acquired pendular nystagmus (APN).
APN is a form of nystagmus with a sinusoidal waveform such that there are
slow phases in both directions without corrective quick phases. The nys-
tagmus can have variable horizontal, vertical, and torsional components. In
patients with APN in the setting of MS, the oscillations are often low am-
plitude and may be difficult to see without careful observation of the eyes.
However, the oscillations usually have a high frequency, which is why they
often cause severe oscillopsia and blurring of vision. It is therefore likely that
this patient’s blurred vision is due to the unfortunate combination of optic
neuropathy and APN.
The pathogenesis of APN in MS patients is not well understood. One
possibility is that the APN arises because of delays in the conduction of
visual information, since it is often more prominent in the eye with greater
vision loss, as in this patient’s case. However, this does not fully explain why
APN occurs, since it remains unchanged in darkness and experimental delay
of visual feedback does not change its characteristics. A more likely expla-
nation is that APN arises due to an unstable “neural integrator.” The neural
integrator has an important role in ensuring steady gaze. Components of
the neural integrator are located in various parts of the brainstem. Whereas
impaired neural integrator function produces gaze-evoked nystagmus (see
Case 26), APN might result from loss of normal feedback to the neural in-
tegrator, thereby producing instability.
APN can also occur as a component of the syndrome of oculopalatal
tremor (OPT), which is characterized by irregular synchronous oscillations
of the eyes, palate, and other branchial muscles. The APN of OPT is usually
vertical-torsional and dysconjugate (i.e., the nystagmus differs in the two
eyes), with variable amplitude and frequency components. Unlike the APN
of MS, the APN of OPT results from disruption of connections between

157
FIGURE 29.1. Magnetic resonance imaging (MRI) showing a large pontine hemorrhage in a

patient who presented with acute coma and quadriparesis (left). Several months after discharge,
the patient developed OPT and repeat MRI showed hypertrophy of the left inferior olivary nucleus
(arrows, right).
the cerebellar dentate nucleus and the contralateral inferior olivary nucleus
(Guillain-Mollaret triangle) via the superior cerebellar peduncle, central
tegmental tract, and inferior cerebellar peduncle. OPT is most commonly a
delayed consequence of stroke in the brainstem tegmentum or cerebellum.
It results in degenerative hypertrophy of the inferior olivary nucleus in the
medulla, which can be visible on imaging (Figure 29.1). APN can also
occur in patients with vision loss from optic nerve or retinal disease (e.g.,
inherited retinal degenerations). Other common causes of APN are listed
in Box 29.1.
Given this patient’s history and clinical signs, her APN is likely to be
due to MS. The first step in her management is to optimize her vision
by ensuring that easily treated causes of blurred vision, such as refractive
BOX 29.1 Common Causes of Acquired Pendular Nystagmus
Vision loss
MS
OPT
Acute brainstem stroke
29. Pendular Nystagmus 157

158
error, are addressed. An ophthalmic consultation should be considered to

determine if her vision can be improved with a manifest refraction and to
screen for other easily treated causes of vision loss. Investigation and treat-
ment for acute optic neuritis is not indicated because she is not reporting
acute vision loss or pain with eye movements. The second step in the man-
agement of this patient is to decrease her oscillopsia by treating her APN.
Several clinical trials have demonstrated that gabapentin and memantine
can partially suppress APN in MS patients, thereby reducing oscillopsia and
increasing visual acuity. However, both can cause significant side effects; for
example, gabapentin can cause unsteadiness that can be problematic in MS
patients who also have ataxia, whereas memantine can cause a reversible
exacerbation of many MS symptoms. Consequently, gabapentin may be
the preferred first-line treatment for APN in MS patients, although its dose
will need to be carefully titrated according to both beneficial and adverse
effects. The final step in the management of this patient is to minimize her
risk of further vision problems due to MS exacerbations by ensuring that
she is being treated with appropriate disease-modifying therapy, such as
beta-interferon. Consultation with an MS neurologist may ultimately be
required to optimize her disease-modifying therapy.
• APN is characterized by a sinusoidal waveform with slow

phases in both directions and no corrective quick phases.
• APN can cause disabling oscillopsia and blurred vision.
• Common causes of APN include vision loss, MS, OPT, and acute
brainstem stroke.
• APN in MS often occurs in association with optic neuropathy
and is often more prominent in the eye with poorer vision.
• APN can be partially suppressed with gabapentin or memantine,
but the doses must be titrated according to benefit and side
effects.

159
Further Reading
Averbuch-Heller L, Tusa RJ, Fuhry L, et al. A double-blind controlled study of
gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol.
1997;41:818–825.
Averbuch-Heller L, Zivotofsky AZ, Das VE, DiScenna AO, Leigh RJ. Investigations of
the pathogenesis of acquired pendular nystagmus. Brain. 1995;118:369–378.
Thurtell MJ, Joshi AC, Leone AC, et al. Crossover trial of gabapentin and memantine
as treatment for acquired nystagmus. Ann Neurol. 2010;67:676–680.
Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J. Memantine induces
reversible neurologic impairment in patients with MS. Neurology.
2009;72:1630–1633.
29. Pendular Nystagmus 159

160
16
30 Infantile Nystagmus
A 16-year-old boy presents to your clinic

complaining of blurred vision in both
eyes. He has had an extensive workup for
nystagmus that has been present since
infancy, but no other ocular, neurologic,
or endocrine abnormality was found. He
now wants to apply for a driver’s license
but has been told that his visual acuity is
not adequate. Examination shows visual
confrontation visual fields, pupils, and fundi
are normal. His ocular ductions are full and
there is no ocular misalignment. However,
there is a large-amplitude horizontal jerk
nystagmus that is present in all positions
of gaze. The nystagmus becomes less
prominent when he converges. He asks
if there is anything that can be done to
improve his vision.
161
162
T he patient described in this scenario has infantile nystagmus. Formerly

known as congenital nystagmus, it can be sporadic or inherited (e.g.,
autosomal recessive in the setting of oculocutaneous albinism or X-linked
in the setting of FRMD7 gene mutations). Infantile nystagmus can occur
in isolation but can be associated with other visual, neurologic, and endo-
crine abnormalities (Box 30.1). Up to a third of patients have coexisting
strabismus.
Infantile nystagmus is usually first noted in infancy but is occasionally
not detected until adulthood. It can have a sinusoidal (pendular) or jerk
waveform with accelerating slow phases. In contrast with acquired nys-
tagmus, the nystagmus waveform is often complex and punctuated by
brief “foveation” periods, during which the eyes are transiently still. Since
patients are able to see clearly during foveation periods, their visual acuity is
often better than might be expected. Surprisingly, patients who have well-
developed foveation periods rarely complain of oscillopsia. Infantile nys-
tagmus is predominantly horizontal in most patients, but some have small
torsional and vertical components to their nystagmus. It is usually conju-
gate (i.e., the nystagmus is similar in the two eyes), more prominent when
attempting to fixate a distant target, and less prominent when converging
to fixate a near target. The nystagmus may be minimized and visual acuity
maximized when the eyes are in a certain position (or zone) known as the
“null” position (or zone). Patients may unconsciously adopt an anomalous
head position to keep their eyes in this position.
BOX 30.1 Conditions Associated With Infantile Nystagmus
Ocular and oculocutaneous albinism

Achromatopsia (“color blindness”)
Congenital cataract
Optic atrophy
Optic nerve hypoplasia
Septo-optic dysplasia
Achiasma (absent optic chiasm)
Retinopathy of prematurity
Cone-rod dystrophies
Leber congenital amaurosis
Congenital stationary night blindness

163
FIGURE 30.1. Diffuse iris transillumination defects in oculocutaneous albinism (left). Optical

coherence tomography of the macula showing loss of the normal macular contour with absence
of the foveal pit in foveal hypoplasia (right).
The first step in the evaluation of a patient with suspected infantile nys-
tagmus is a complete neuro-ophthalmic assessment, because the response to
treatment depends on the severity of any associated afferent visual system
abnormality. For example, examination of the anterior segments might
show iris transillumination deficits characteristic of oculocutaneous albi-
nism (Figure 30.1), whereas examination of the posterior segments might
show retinal or optic nerve abnormalities, such as optic nerve hypoplasia
(Figure 30.2). It can be helpful to record the patient’s eye movements when
the diagnosis is uncertain because identification of a characteristic infantile
nystagmus waveform (e.g., accelerating slow phases or foveation periods)
FIGURE 30.2. Fundus photograph demonstrating severe optic nerve hypoplasia in a patient with
septo-optic dysplasia (left). Mid-sagittal T1-weighted magnetic resonance imaging (MRI) showing
ectopic posterior pituitary (arrows) in septo-optic dysplasia (right).
30. Infantile Nystagmus 163

164
confirms the diagnosis. Further investigations should be considered to eval-

uate for other visual, neurologic, and endocrine abnormalities. Magnetic
resonance imaging (MRI) can be used to detect structural abnormalities of
the anterior visual pathways, brain, and pituitary gland (see Figure 30.2).
Electrophysiology (e.g., an electroretinogram) and optical coherence to-
mography may be required to detect retinal disease or abnormalities, such as
foveal hypoplasia in oculocutaneous albinism (see Figure 30.1). Endocrine
evaluation is required in patients with suspected pituitary hypofunction,
such as in septo-optic dysplasia.
The patient in this scenario has already had a thorough workup to eval-
uate for associated ocular, neurologic, and endocrine conditions. Thus, no
further investigations are required and you should focus on discussing treat-
ment options, which include optical, medical, and surgical treatments. In
this patient, an ophthalmic consultation should be obtained to screen for
easily treated causes of blurred vision, such as refractive error. If the patient
has uncorrected refractive error, prescription of contact lenses should be
considered, because they might partially suppress infantile nystagmus as
well as provide optical correction. Another optical treatment approach to
consider in this patient would be prescription of base-out prisms to induce
convergence and thereby suppress his nystagmus during distance viewing;
minus correction should be added to compensate for any induced accom-
modation. Correction of refractive error, use of contact lenses, or use of
base-out prisms may be all that is required to improve this patient’s visual
acuity so that he can get his driver’s license.
If optical therapies are inadequate to improve the patient’s visual acuity,
medical and surgical approaches could be considered. Medical therapy using
gabapentin and memantine has been shown to reduce nystagmus intensity,
prolong foveation periods, and improve visual acuity in patients with infan-
tile nystagmus, although patients with afferent visual system abnormalities
are less likely to respond. Medical therapy with acetazolamide could also be
considered, but this can cause unpleasant side effects (see Case 9). Several
surgical treatments might also be effective. Some patients benefit from a
tenotomy-and-reattachment procedure in which the horizontal extraocular
muscles are severed from the eye at their tendinous attachments and then
reattached at their original positions. Tenotomy-and-reattachment has been
shown to suppress nystagmus, prolong foveation periods, and increase the

165
range of the null zone. The mechanism by which the surgery works is uncer-
tain, although it has been proposed that it might modulate proprioceptive
feedback signals from the extraocular muscles. Tenotomy-and-reattachment
can be combined with conventional strabismus surgery if there is coexisting
strabismus, an eccentric null position, or an anomalous head position. It
could also be combined with a divergence procedure in this patient so that
viewing of distant targets will induce convergence and thereby further sup-
press his nystagmus. Because optical, medical, and surgical therapies act by
different mechanisms, therapies could be combined if the improvement in
visual acuity is insufficient with one therapy alone.
• Infantile nystagmus is usually sporadic, but it can be an

inherited (e.g., X-linked) trait.
• Infantile nystagmus can be associated with other visual,
neurologic, and endocrine abnormalities.
• Patients with infantile nystagmus sometimes report blurred
vision but rarely complain of oscillopsia.
• Eye movement recordings may be required to definitively
diagnose infantile nystagmus.
• Infantile nystagmus can be treated with optical, medical, and
surgical approaches.
Further Reading
Bagheri A, Abbasi H, Tavakoli M, Sheibanizadeh A, Kheiri B, Yazdani S. Effect of rigid
gas permeable contact lenses on nystagmus and visual function in hyperopic
patients with infantile nystagmus syndrome. Strabismus. 2017;25:17–22.
Bertsch M, Floyd M, Kehoe T, Pfeifer W, Drack AV. The clinical evaluation of infantile
nystagmus: what to do first and why. Ophthalmic Genet. 2017;38:22–33.
McLean R, Proudlock F, Thomas S, Degg C, Gottlob I. Congenital
nystagmus: randomized, controlled, double-masked trial of memantine/
gabapentin. Ann Neurol. 2007;61:130–138.
Serra A, Dell’Osso LF, Jacobs JB, Burnstine RA. Combined gaze-angle and vergence
variation in infantile nystagmus: two therapies that improve the high-
visual-acuity field and methods to measure it. Invest Ophthalmol Vis Sci.
2006;47:2451–2460.
30. Infantile Nystagmus 165

16
Thurtell MJ, Dell’Osso LF, Leigh RJ, Matta M, Jacobs JB, Tomsak RL. Effects of
acetazolamide on infantile nystagmus syndrome waveforms: comparisons to
contact lenses and convergence in a well-studied subject. Open Ophthalmol J.
2010;4:42–51.
Wang Z, Dell’Osso LF, Jacobs JB, Burnstine RA, Tomsak RL. Effects of tenotomy on
patients with infantile nystagmus syndrome: foveation improvement over a
broadened visual field. J AAPOS. 2006;10:552–560.

167
31 Saccadic Intrusions
and Dysmetria
A 42-year-old man presents to your

clinic complaining of difficulty reading.
Examination shows normal distance visual
acuities, color vision, confrontation visual
fields, pupils, and eyelids. His ductions
and versions are full, but he has ocular
dysmetria: he consistently overshoots the
visual target when he makes horizontal
saccades. The overshooting is so severe
that he makes a series of horizontal
saccades to either side of the new visual
target before he is finally able to fixate
on it. You note that he has difficulty
reading a short paragraph because of
these overshoots. You also note that he
has occasional inappropriate horizontal
saccades during attempted fixation. These
saccades are also evident on funduscopic
examination.
167
168
S accades are rapid eye movements that assist vision by redirecting the
line of sight from one target of interest to another, so that the image
of the new target falls onto the fovea of the retina. Saccadic disorders in-
clude abnormalities of saccadic initiation, speed, and amplitude. In saccadic
(ocular) dysmetria, the saccadic amplitude is inappropriately calibrated;
saccades that undershoot the target are hypometric, whereas those that over-
shoot are hypermetric. The patient in this scenario has saccadic hypermetria
because his horizontal saccades consistently overshoot the visual target.
Saccadic dysmetria does not usually cause visual symptoms unless it is se-
vere. This patient’s saccadic hypermetria is so severe that he makes several
overshooting saccades about a visual target before he is finally able to fixate
on it (Figure 31.1). Severe saccadic hypermetria makes reading very diffi-
cult because reading is a task that requires small saccades to be made ac-
curately and in quick succession. Whether symptomatic or not, saccadic
dysmetria, especially hypermetria, is highly suggestive of cerebellar disease
(Box 31.1 provides a list of causes).
The patient also has intermittent saccadic intrusions during attempted
fixation. Saccadic intrusions are inappropriate, involuntary, spontaneously
generated, and conjugate saccades that disrupt steady fixation; subtypes
include square-wave jerks, macrosaccadic oscillations, ocular flutter, and
opsoclonus. Square-wave jerks are small involuntary horizontal saccades
that take the eye away from a visual target and are followed, after about 250
milliseconds, by another saccade that brings the eye back onto the target.
They can occur in normal individuals but can be very prominent in patients
FIGURE 31.1. Profile of macrosaccadic oscillations (black line), with eye position plotted against
time, when attempting to fixate on a visual target (gray line).

169
BOX 31.1 Common Causes of Saccadic Dysmetria
Cerebellar degenerations (e.g., inherited, paraneoplastic)

Hindbrain anomalies (e.g., Chiari malformation)
Cerebellar and brainstem (e.g., lateral medullary) stroke
Cerebellar mass lesions
Multiple sclerosis
with certain neurodegenerative diseases, such as progressive supranuclear

palsy (see Case 25) and Friedreich ataxia. Square-wave jerks do not usually
cause any visual symptoms. In contrast, macrosaccadic oscillations often
cause patients to have difficulty reading. They are crescendo–decrescendo
runs of horizontal saccades, with an intersaccadic interval of about 200
milliseconds, which often occur following a gaze shift but can also occur
during attempted fixation. Macrosaccadic oscillations arise because of ex-
treme saccadic hypermetria; the oscillations consist of repeated hypermetric
saccades about a visual target, with eventual fixation of the target (see Figure
31.1). They usually occur in patients with cerebellar diseases involving the
fastigial nuclei (Figure 31.2) but can also occur in patients with pontine
lesions.
FIGURE 31.2. Magnetic resonance imaging (MRI) showing an anaplastic astrocytoma in the

vermis of the cerebellum. The patient had gait ataxia, saccadic hypermetria, and macrosaccadic
oscillations at presentation.
31. Saccadic Intrusions and Dysmetria 169

170
BOX 31.2 Drugs Causing Ocular Flutter and Opsoclonus
Lithium
Phenytoin
Amitriptyline and other tricyclic antidepressants
Diazepam and other benzodiazepines
Ocular flutter and opsoclonus consist of back- to-

back saccades
without an intersaccadic interval; the saccades are purely horizontal in
ocular flutter, whereas they are multidimensional in opsoclonus. When
frequent or continuous, these back-to-back saccades can cause distressing
and disabling oscillopsia. Ocular flutter and opsoclonus can occur in
many conditions, including brainstem encephalitis and paraneoplastic
syndromes, as well as with abnormal metabolic states and drug
intoxications (Box 31.2).
The patient in this case scenario has saccadic hypermetria and
macrosaccadic oscillations, which are highly suggestive of cerebellar disease
involving the fastigial nuclei. The first step is to obtain a detailed medical
history asking about other neurologic symptoms, medical conditions, and
family history. The next step is to complete the neurologic examination,
looking for other neurologic signs such as ataxia and cerebellar signs. Given
the complaint of difficulty reading, it is also important to check his near
visual acuity to exclude presbyopia. Investigations such as magnetic res-
onance imaging, laboratory studies, and genetic studies will likely be re-
quired to determine the cause of his cerebellar syndrome.
Although treatment should be directed toward the underlying cause, it
might not affect the saccadic abnormalities. There have been no clinical trials
evaluating medical treatment for saccadic hypermetria or macrosaccadic
oscillations. However, memantine has been reported to decrease the mag-
nitude and frequency of saccadic intrusions, and thereby improve reading,
in patients with certain cerebellar degenerations. Thus, in this patient with
difficulty reading due to macrosaccadic oscillations, a trial of memantine
treatment could be offered.

17
• Saccadic disorders include abnormalities in saccadic initiation,

speed, and amplitude.
• Saccadic disorders are often asymptomatic but can be a sign of
neurologic disease.
• When severe, saccadic intrusions can give rise to difficulty
reading or oscillopsia.
• Saccadic dysmetria and macrosaccadic oscillations are features
of cerebellar disease.
• The magnitude and frequency of saccadic intrusions can
sometimes be reduced with memantine.
Further Reading
Averbuch-Heller L, Kori AA, Rottach KG, Dell’Osso LF, Remler BF, Leigh
RJ. Dysfunction of pontine omnipause neurons causes impaired
fixation: macrosaccadic oscillations with a unilateral pontine lesion.
Neuroophthalmology. 1996;16:99–106.
Rosini F, Federighi P, Pretegiani E, et al. Ocular-motor profile and effects of
memantine in a familial form of adult cerebellar ataxia with slow saccades and
square wave saccadic intrusions. PLoS One. 2013;8:e69522.
Serra A, Liao K, Martinez-Conde S, Optican LM, Leigh RJ. Suppression of saccadic
intrusions in hereditary ataxia by memantine. Neurology. 2008;70:810–812.
Thurtell MJ, Tomsak RL, Leigh RJ. Disorders of saccades. Curr Neurol Neurosci Rep.
2007;7:407–416.
31. Saccadic Intrusions and Dysmetria 171

172
173
SECTION III
Eyelid Disorders
174
175
32 Eyelid Ptosis

clinic with a several-year history of bilateral
ptosis. She denies diplopia and has not
noticed a difference in the size of her pupils.
pupils, and eye movements. There is mild
nonfluctuating and nonfatigable ptosis
bilaterally, with high upper-eyelid skin
creases.
175
176
P tosis is a lowering of the upper- eyelid margin that is commonly

encountered in clinical practice. It has a broad differential diagnosis
because the causative lesion can involve any one of several anatomically
distinct structures: preseptal structures; levator palpebrae superioris muscle
(see Case 23); Müller muscle or oculosympathetic pathway (see Case 35);
neuromuscular junction (see Case 22); third nerve, third nerve fascicle,
or third nerve nucleus (see Case 18); or supranuclear inputs. Thus, the
first step in the evaluation of this patient is to obtain a thorough history.
There should be a careful inquiry about the tempo of onset, precipitating
factors (e.g., trauma or recent eye surgery), and associated symptoms (e.g.,
diplopia, unequal pupils, or neurologic symptoms) because these might
suggest the etiology (e.g., third nerve palsy, ocular myasthenia, or Horner
syndrome). While fluctuating ptosis suggests ocular myasthenia, it is not
specific; ptosis often gets worse later in the day or with fatigue, regardless of
its cause. It is worthwhile to ask if the ptosis is longstanding and to inspect
old photographs (e.g., driver’s license) if there is uncertainty about its du-
ration. The presence of systemic diseases or a family history might also be
relevant (e.g., in patients with ptosis caused by oculopharyngeal muscular
dystrophy, myotonic dystrophy, or chronic progressive external ophthalmo-
plegia; see Case 23).
The next step in the evaluation of this patient is to perform an eyelid
examination, as this may be all that is required to make the correct diag-
nosis. Ptosis should be distinguished from dermatochalasis, in which there
is excessive upper-eyelid tissue that can hang over the eyelid margin without
lowering the eyelid margin itself. Dermatochalasis is a common condition
that can cause visual impairment if the pupil is obscured, but it is not caused
by neurologic disease and therefore does not require neurologic workup.
Once it has been established that the upper eyelid does indeed have a lower
position, there should be a careful observation of the eyelid position, shape,
and movement. Several eyelid measurements should also be obtained. The
width of the palpebral fissure is measured with the patient looking straight
ahead (normal range is 8–10 mm). Upper-eyelid position is determined by
measuring the marginal-reflex distance, which is the distance between the
mid-pupil corneal light reflex and the upper-eyelid margin (normal range
is 2.5–4 mm). Levator function is determined by measuring the excursion
of the upper-eyelid margin from downward to upward gaze while the brow
176 WHAT DO I DO NOW? Eyelid Disorders

17
is firmly stabilized (normal range is 12–15 mm). Measurement of levator

function is especially important in the evaluation of patients with isolated
ptosis because the presence of normal levator function indicates that the
cause of ptosis is not weakness of the levator muscle or a lesion affecting
its innervation. The position of the upper-eyelid skin crease relative to the
upper-eyelid margin is also useful to measure (normal range is 6–8 mm in
men, 8–10 mm in women). Because the upper-eyelid skin crease is created
by the pull of the levator on the skin, levator weakness makes the crease less
prominent (Figure 32.1). When the upper-eyelid skin crease is prominent
and higher than normal (see Figure 32.1), the ptosis is likely to be due to
dehiscence of the levator aponeurosis rather than levator weakness. Other
signs that are important to look for include fatigability with prolonged up-
ward gaze and a Cogan lid twitch (see Case 22). It is also important to assess
orbicularis oculi strength, which is often decreased in neuromuscular junc-
tion disorders that cause ptosis. The pupils and eye movements should also
be assessed because either or both might be abnormal in patients with third
nerve palsy (see Case 18) or Horner syndrome (see Case 35).
The presence of a high upper-eyelid crease with normal pupils and eye
movements suggests that this patient does not have neurogenic or myo-
pathic ptosis. If her levator function is normal and there are no other signs
to suggest myopathy or neuromuscular disease, the diagnosis is levator de-
hiscence and no further investigations are required. Levator dehiscence is
the most common cause of acquired ptosis in adults and usually results
from involutional changes in the orbital connective tissues. When it occurs
in the setting of sagging eye syndrome, the patient will often have deep
superior sulci and strabismus. Levator dehiscence can also result from long-
term use of contact lenses; repeated stretching of the upper eyelid during
FIGURE 32.1. Absent upper-eyelid creases, backward head tilt, and frontalis activation in a patient
with bilateral myopathic ptosis (left). High upper-eyelid crease in a patient with left-sided levator
dehiscence (right).
32. Eyelid Ptosis 177
178
insertion of the contact lens, as well as constant rubbing of the contact

lens against the eyelid, results in thinning and eventual dehiscence of the
levator aponeurosis. Trauma to the eyelid (e.g., from chronic eye rubbing)
can cause levator dehiscence. The levator aponeurosis can easily be damaged
by anesthetic injections into the eyelid or by the use of eyelid retractors and,
thus, levator dehiscence can be iatrogenic.
When the pupil is encroached by the upper eyelid in a patient with
levator dehiscence, the effect on vision can be assessed by obtaining ki-
netic or static automated perimetry before and after the eyelid is taped up
into a normal position. If there is a significant superior visual field defect
that disappears after the eyelid is taped up, the most suitable treatment is
eyelid surgery, which is simple, safe, and effective. Patients who do not
have visual compromise do not require surgery, although any contributing
factors, such as contact lens use, should be addressed. Eyelid surgery can
also be considered in patients who are bothered by the cosmetic appearance
of the ptosis.
• Levator dehiscence is the most common cause of acquired

ptosis in adults.
• Signs of levator dehiscence include normal levator function and
a high upper-eyelid skin crease.
• Levator dehiscence is commonly caused by involutional
changes in the orbital connective tissues, long-term use of
contact lenses, or trauma (e.g., from use of eyelid retractors
during surgery) and does not require neurologic workup.
• Eyelid surgery is a simple, safe, and effective treatment for
levator dehiscence.
Further Reading
Ahmad SM, Della Rocca RC. Blepharoptosis: evaluation, techniques, and
complications. Facial Plast Surg. 2007;23:203–215.
Chaudhuri Z, Demer JL. Sagging eye syndrome: connective tissue involution as a
cause of horizontal and vertical strabismus in older patients. JAMA Ophthalmol.
2013;131:619–625.

179
Frueh BR. The mechanistic classification of ptosis. Ophthalmology. 1980;87:1019–1021.

Kersten RC, de Conciliis C, Kulwin DR. Acquired ptosis in the young and middle-aged
adult population. Ophthalmology. 1995;102:924–928.
Riemann CD, Hanson S, Foster JA. A comparison of manual kinetic and automated
static perimetry in obtaining ptosis fields. Arch Ophthalmol. 2000;118:65–69.
32. Eyelid Ptosis 179
180
18
33 Benign Essential
Blepharospasm
A 62-year-old woman complains of difficulty

keeping her eyes opened, especially when
she is exposed to bright lights. Examination
eye movements. There is no eyelid ptosis.
Upper-eyelid excursion is normal and
symmetric. Funduscopic examination is
normal but provokes bilateral orbicularis
oculi spasms that continue intermittently
throughout the rest of the consultation. The
remainder of her neurologic examination is
unremarkable.
181
182
B lepharospasm is an involuntary and inappropriate closure of the

eyes that results from spasm of the orbicularis oculi muscles. It can
occur in association with many ophthalmic and neurologic diseases, such
as progressive supranuclear palsy (PSP; see Case 25). When it occurs in
association with other involuntary lower facial, mandibular, and tongue
movements, it is called oromandibular dystonia or Meige syndrome. When
it occurs in isolation, it is called benign essential blepharospasm (BEB).
BEB most commonly occurs in women who are over 50 years of age. The
blepharospasm is bilateral and symmetric. It is often triggered by exposure
to bright lights or other relatively benign stimuli and can be disabling to
the point where affected patients are functionally blind. It does not occur
during sleep.
The etiology of BEB remains uncertain. It was previously thought to be
a manifestation of nonorganic disease, but it likely arises from abnormal
interactions between trigeminal blink circuits, basal ganglia, sensorimotor
cortex, and cerebellum. Despite this, investigations (e.g., neuroimaging) are
usually unrevealing and therefore are not routinely required in the evalua-
tion of BEB. Many patients with BEB have photophobia that is similar in
severity to that observed in migraine sufferers. Some patients have other
ocular complaints, such as dryness or irritation. While such complaints
warrant a careful ophthalmic examination, their treatment (e.g., with artifi-
cial tears) rarely results in a significant improvement in the blepharospasm.
Consequently, these conditions are not thought to play a direct role in the
pathogenesis of BEB.
BEB can sometimes be difficult to distinguish from other disorders,
such as apraxia of eyelid opening (AEO) and hemifacial spasm. AEO
is characterized by transient inability to open the eyes in the absence of
orbicularis oculi contraction. Patients with AEO often have frontalis acti-
vation during attempts to open the eyes without other neuro-ophthalmic
deficits to suggest a neurologic or neuromuscular cause for the inability to
open their eyes. AEO occurs in a variety of neurologic diseases, such as PSP
and Parkinson’s disease. The distinction between BEB and AEO is based
solely on clinical characteristics. AEO can sometimes occur in association
with BEB, although the pathogenesis of these disorders is thought to be
distinct. Hemifacial spasm is characterized by frequent involuntary contrac-
tions of the muscles innervated by the facial nerve. Unlike BEB, hemifacial

183
spasm is usually unilateral and, thus, the orbicularis oculi spasms are uni-
lateral rather than bilateral. Hemifacial spasm is usually caused by vascular
compression of the facial nerve. Consequently, patients with hemifacial
spasm often have associated ipsilateral facial weakness.
The patient in this scenario has a normal examination, with the excep-
tion of photophobia and blepharospasm. She should be carefully observed
for involuntary lower facial, mandibular, and tongue movements, which
would suggest a diagnosis of Meige syndrome. She should be examined
to look for ophthalmic causes of photophobia (e.g., dry eye or uveitis), as
treatment of these may help reduce her photophobia. Other investigations,
such as neuroimaging, are unlikely to be revealing.
Once satisfied that the patient’s blepharospasm does not have another
cause, the focus should turn to its management. The mainstay of treat-
ment for BEB is injection of botulinum toxin A into the orbicularis oculi
and surrounding muscles. For comfort, ice is applied over the patient’s eyes
prior to the injections. The injections are usually given in several places
around the eyes, and their effects are typically sustained for 2–4 months.
Higher doses than average may be required in some patients, depending
on response. Common complications from the injections include bleeding,
bruising, ptosis, and diplopia, but these are transient and usually mild.
Many patients report an improvement in their photophobia and bleph-
arospasm with the use of tinted lenses (e.g., FL-41) that filter out blue-
wavelength light. Medical treatments can be tried (e.g., trihexyphenidyl,
clonazepam, baclofen, or tetrabenazine) but are usually ineffective. Surgical
treatments can sometimes be helpful, especially in patients who have asso-
ciated dermatochalasis or are unresponsive to other treatments. Although
surgical treatments might reduce the severity of the blepharospasm in some
patients, they should not be considered the first line of therapy. Thus,
the most appropriate initial treatment for this patient is botulinum toxin
A injections into the orbicularis oculi and surrounding muscles every 2–
4 months, with escalating doses depending on response. If the patient
requires increasing doses of botulinum toxin A to control her BEB, use of
another formulation or type of botulinum toxin should be considered. The
patient should also be prescribed tinted (e.g., FL-41) lenses for her photo-
phobia. Surgical therapy should be considered only if the patient is unre-
sponsive to these interventions.
33. Benign Essential Blepharospasm 183

184
• Blepharospasm is a symmetric involuntary closure of the eyes

that is caused by spasm of the orbicularis oculi.
• BEB most often occurs in older women, in the absence of
neurologic or ophthalmic disease.
• Investigations are usually unrevealing and therefore not
routinely required in BEB.
• BEB is most effectively treated with botulinum toxin A injections
every 2–4 months.
• Associated photophobia can often be reduced by wearing tinted
(e.g., FL-41) lenses.
Further Reading
Adams WH, Digre KB, Patel BC, Anderson RL, Warner JE, Katz BJ. The evaluation
of light sensitivity in benign essential blepharospasm. Am J Ophthalmol.
2006;142:82–87.
Blackburn MK, Lamb RD, Digre KB, et al. FL-41 tint improves blink frequency,
light sensitivity, and functional limitations in patients with benign essential
blepharospasm. Ophthalmology. 2009;116:997–1001.Cillino S, Raimondi G,
Guépratte N, et al. Long-term efficacy of botulinum toxin A for treatment of
blepharospasm, hemifacial spasm, and spastic entropion: a multicenter study
using two drug-dose escalation indexes. Eye (Lond). 2010;24:600–607.
Defazio G, Hallet M, Jinnah HA, Conte A, Berardelli A. Blepharospasm 40 years later.
Mov Disord. 2017;32:498–509.
Peckham EL, Lopez G, Shamim EA, et al. Clinical features of patients with
blepharospasm: a report of 240 patients. Eur J Neurol. 2011;18:382–386.

185
SECTION IV
Pupil Disorders
186
187
34 Anisocoria
You are asked to see a 30-year-old

woman who was incidentally found to
have a difference in the size of her pupils
(anisocoria) by her optometrist. She has
not had diplopia, ptosis, or headaches.
color vision, confrontation visual fields, eye
movements, and eyelids. There is 1 mm of
anisocoria; the left pupil is larger than the
right. The degree of anisocoria is unchanged
in bright light and darkness. Both pupils
react briskly to light and near. There is no
relative afferent pupillary defect.
187
18
T he size of the pupil is determined by the net tone between the iris
sphincter and iris dilator muscles. The iris sphincter muscle is
innervated by the parasympathetic division of the autonomic nervous
system and produces pupil constriction (miosis) when it contracts. The iris
dilator muscle is innervated by the sympathetic division of the autonomic
nervous system and produces pupil dilation (mydriasis) when it contracts.
Unilateral or asymmetric disruption of the iris muscles or their innervation
by a structural or pharmacologic lesion can produce anisocoria, which is
defined as a difference of 0.4 mm or more in the size of the pupils.
The cause of the anisocoria (Table 34.1) can often be determined on
the basis of the clinical signs and findings on pharmacologic pupil testing
(Figure 34.1). However, the first step in the evaluation of a patient with
anisocoria is to obtain a history. When the anisocoria was noted inciden-
tally by a relative, friend, or health care professional, it is helpful to inspect
old photographs (e.g., driver’s license) to determine if it is longstanding.
The patient should be asked about symptoms that could be related to the
anisocoria, such as light sensitivity in one eye (e.g., with changes in lighting
level) or loss of accommodation (e.g., difficulty focusing with one eye at
near), because the ciliary muscle is also innervated by the parasympathetic
division of the autonomic nervous system. The presence of diplopia or
ptosis may suggest third nerve palsy (see Case 18) or Horner syndrome
(see Case 35) as the cause for the anisocoria. A history of trauma (e.g.,
eye trauma or chiropractic neck manipulation), certain medical problems
TABLE 34.1 Common Causes of Anisocoria
Anisocoria Greater in Darkness Anisocoria Greater in Bright Light
Horner syndrome Third nerve palsy
Iris adhesions (e.g., posterior Tonic pupil

synechiae)
Pharmacologic (e.g., pilocarpine) Iris trauma or ischemia
Physiologic anisocoriaa Pharmacologic (e.g., mydriatics)

a
The anisocoria is usually similar in bright light and darkness but can be slightly more prominent
in darkness.
188 WHAT DO I DO NOW? Pupil Disorders

189
FIGURE 34.1. Algorithm for the evaluation of anisocoria.
Adapted from Kawasaki A. Disorders of pupillary function, accommodation, and lacrimation. In: Miller NR, Newman NJ, Biousse
V, Kerrison JB, eds. Walsh & Hoyt’s clinical neuro-ophthalmology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2005:739–805.
190
(e.g., migraine), medication use (e.g., transdermal scopolamine), or envi-

ronmental exposure (e.g., jimsonweed) may also be relevant.
The next step in the evaluation of the patient is a careful examination.
Pupil size should be assessed in room light with the patient fixating on a
distant target, because near viewing will elicit the near triad (convergence,
accommodation, and pupillary miosis). If anisocoria is present, pupil size
should then be measured in bright light and darkness using a pupil gauge
(e.g., on a Rosenbaum near card). Pupil size should also be measured while
the patient is fixating on a near target. The relative speeds of pupil con-
striction and dilation should be assessed, and there should be a comparison
between the speed of pupil response to light and near. The presence or
absence of a relative afferent pupillary defect should be documented. The
anterior segments of the eyes should be assessed with the slit lamp to look
for relevant abnormalities (e.g., posterior synechiae, iris sphincter muscle
tear, transillumination defects, or segmental iris palsy). Abnormalities of oc-
ular alignment, ductions, and the eyelids should also be specifically sought.
The differential diagnosis and subsequent investigation of anisocoria
depends on the degree of anisocoria in bright light compared with that in
darkness (see Table 34.1 and Figure 34.1). The smaller pupil is abnormal
when anisocoria is greater in darkness, whereas the larger pupil is abnormal
when it is greater in bright light. In this patient, however, the anisocoria is
unchanged in bright light compared to darkness. She has no diplopia, ptosis,
or headaches, and her examination is otherwise normal. Her anisocoria is
therefore likely to be physiologic and of no concern. Thus, this patient does
not require further investigations and can be reassured.
Physiologic anisocoria (also known as benign, essential, or simple
anisocoria) is common in the general population, with up to 20% having
0.4–1 mm of anisocoria when their pupils are viewed in dim light. The
prevalence of physiologic anisocoria is not influenced by sex, age, or iris
color. The degree of anisocoria is usually the same in light and darkness,
although it can be slightly more prominent in darkness. The degree of
anisocoria often varies within an individual, but it does not usually reverse.
Physiologic anisocoria is important to recognize so as to avoid unnecessary
diagnostic testing.
A diagnostic dilemma can arise when physiologic anisocoria occurs in
combination with levator dehiscence (see Case 32) on the side of the smaller

19
pupil, mimicking Horner syndrome; this is known as pseudo-Horner syn-

drome. In such patients and in those with anisocoria that is more prom-
inent in darkness, pharmacologic pupil testing with 0.5% apraclonidine
can help to exclude a true Horner syndrome (see Figure 34.1 and Case 35).
• The differential diagnosis and investigation of anisocoria

depends on the degree of anisocoria in bright light compared
with darkness.
• The smaller pupil is abnormal when the anisocoria is greater
in darkness, whereas the larger pupil is abnormal when it is
greater in bright light.
• Physiologic anisocoria is characterized by 0.4–1 mm of
anisocoria that is similar in bright light and darkness with an
otherwise normal examination.
• Physiologic anisocoria does not require further investigation,
and the patient can be reassured.
Further Reading
Lam BL, Thompson HS, Corbett JJ. The prevalence of simple anisocoria. Am J
Ophthalmol. 1987;104:69–73.
Martin TJ. Horner’s syndrome, pseudo-Horner’s syndrome, and simple anisocoria.
Curr Neurol Neurosci Rep. 2007;7:397–406.
Thompson BM, Corbett JJ, Kline LB, Thompson HS. Pseudo-Horner’s syndrome. Arch
Neurol. 1982;39:108–111.
34. Anisocoria 191
192
193
35 Horner Syndrome
You are called to see a 24-year-old man who

was found to have anisocoria following
a motor vehicle accident. He is in the
emergency room and is complaining of
sharp left-sided neck pain. Examination
and confrontation visual fields. There is
1.5 mm of anisocoria. The left pupil is
smaller than the right. The anisocoria is
most prominent in darkness. Both pupils
show normal reactions to light and near,
and there is no relative afferent pupillary
defect. There is subtle left-sided ptosis.
Eye movements are normal, and the
remainder of his neurologic examination is
unremarkable.
193
194
T he combination of left-sided miosis and ptosis in this patient suggests

Horner syndrome. Horner syndrome results from a lesion affecting
the ipsilateral oculosympathetic pathway, which innervates the iris di-
lator muscle and the smooth muscle of the eyelids (Müller muscle). The
oculosympathetic pathway consists of three serial neurons: the first- ,
second-, and third-order neurons. The first-order neuron descends from
the hypothalamus through the lateral brainstem and cervical spinal cord
to synapse with the second-order neuron at the C8–T1 level. The second-
order neuron passes out of the spinal cord, across the lung apex, and up the
neck to synapse with the third-order neuron in the superior cervical gan-
glion, near the bifurcation of the common carotid artery. The third-order
neuron travels up along the internal carotid artery until it reaches the cav-
ernous sinus, where it briefly joins with the sixth nerve before joining the
ophthalmic division of the trigeminal nerve to enter the orbit.
The first step in the evaluation of this patient is to confirm that he does
indeed have Horner syndrome. The classic signs are miosis and ptosis on
the affected side. Denervation of the iris dilator muscle produces miosis
that is more prominent in darkness (Figure 35.1) because the action of the
iris dilator muscle is impaired. The anisocoria is less obvious in bright light
(see Figure 35.1) because the iris sphincter muscle is working normally in
both eyes. When the lights are turned out, a normal pupil dilates rapidly
(usually within 5 seconds) because of the simultaneous contraction of the
iris dilator (agonist) muscle and relaxation of the iris sphincter (antagonist)
FIGURE 35.1. Horner syndrome in a patient with right neck trauma. The anisocoria is less
prominent in bright light (top) than in darkness (bottom). Note that there is little, if any, ptosis.

195
muscle. When there is sympathetic denervation, however, the pupil dilates

slowly (over 15–20 seconds) because the iris dilator muscle is paretic. Thus,
a characteristic finding in Horner syndrome is a relative lag in the dila-
tion of the miotic pupil (“dilation lag”). The upper-eyelid ptosis in Horner
syndrome results from loss of the sympathetic innervation of the eyelid
smooth muscle (Müller muscle). The ptosis is often mild and can easily be
overlooked (see Figure 35.1). Loss of sympathetic innervation to the smooth
muscle in the lower eyelid often results in a slight elevation known as re-
verse or “upside-down” ptosis. The palpebral fissure narrowing that results
from combined upper-eyelid ptosis and lower-eyelid elevation can mimic
the appearance of enophthalmos. Facial anhidrosis can occur with lesions
involving the first-and second-order neurons as a result of sympathetic
denervation of the sweat glands in the face. When Horner syndrome is con-
genital, the ipsilateral iris is depigmented, giving rise to iris heterochromia.
Thus, this patient should be carefully examined, looking for dilation lag of
the left pupil, elevation of the left lower eyelid, facial anhidrosis, and iris
heterochromia. If these signs are not present, pharmacologic pupil testing
should be pursued to confirm the diagnosis (see Figure 34.1).
In the past, pharmacologic pupil testing with cocaine was the gold-
standard test for diagnosis of Horner syndrome. Cocaine blocks reuptake of
norepinephrine into sympathetic nerve terminals and therefore will cause a
normal pupil to dilate. When there is sympathetic denervation, norepineph-
rine is not being released from sympathetic nerve terminals and, thus, there
will be little or no dilation of the affected pupil following instillation of co-
caine. The cocaine test is performed by instilling two drops of 10% cocaine
into both eyes and then evaluating for anisocoria in darkness 45 minutes
later; anisocoria of 0.8 mm or more is diagnostic of Horner syndrome.
Pharmacologic pupil testing with apraclonidine has recently been
proposed as an alternative to the cocaine test because cocaine is a controlled
substance and is often not readily available. Apraclonidine is used for the
treatment of glaucoma and is an α-receptor agonist, with strong α2 action
and weak α1 action. It has minimal effect on a normal pupil but will dilate a
sympathetically denervated pupil because the α1 receptors on the iris dilator
muscle become supersensitive to apraclonidine in the absence of normal
sympathetic tone. The test is performed by instilling two drops of 0.5%
apraclonidine into each eye and then evaluating for anisocoria in darkness
35. Horner Syndrome 195

196
45 minutes later. The anisocoria reverses because the abnormal pupil dilates
more than the normal pupil dilates. Although the apraclonidine test is
reported to be close to 100% sensitive and specific for the diagnosis of
Horner syndrome, false-negative results can occur in the acute setting be-
cause α1 denervation supersensitivity has not yet developed. Given this
patient’s acute presentation, the possibility of a false-negative result should
be considered if an apraclonidine test is performed.
A lesion anywhere along the ipsilateral oculosympathetic pathway can cause
Horner syndrome (Table 35.1). The history and examination findings can help
TABLE 35.1 Causes of Horner Syndrome
First-Order Neuron Second-Order Neuron Third-Order Neuron
Hypothalamus/ Cervical cord: Superior cervical

brainstem: Trauma ganglion:
Stroke Tumor Trauma
Demyelination Syrinx Jugular ectasia
Cervical cord: Arteriovenous Iatrogenic
Trauma malformation Internal carotid artery:
Tumor Cervical spondylosis Dissection
Syrinx Brachial plexus: Trauma
Arteriovenous Trauma Thrombosis
malformation Pulmonary apex: Tumor
Iatrogenic Skull base:
Tumor (e.g., Pancoast) Trauma
Infection (e.g., apical Tumor
tuberculosis) Cavernous sinus:
Cervical rib Tumor
Vascular anomalies Inflammation
Neck: Aneurysm
Iatrogenic Carotid-cavernous fistula
Trauma Thrombosis
Tumor Other:
Cluster headache
Adapted from Kawasaki A, Kardon RH. Disorders of the pupil. Ophthalmol Clin North Am.
2001;14:149–168.

197
to localize the lesion. The presence of brainstem or cerebellar signs suggests a

first-order neuron lesion; the presence of arm pain, weakness, or sensory loss
suggests a second-order neuron lesion; and the presence of neck or facial pain
suggests a third-order neuron lesion. If localizing symptoms or signs are pre-
sent, targeted imaging studies can be performed. If a patient has no localizing
symptoms or signs, imaging of the entire oculosympathetic pathway will iden-
tify a causative lesion in about 20% of patients. When the location of the le-
sion is in doubt, pharmacologic pupil testing with hydroxyamphetamine can
be used to distinguish between a preganglionic (first-or second-order neuron)
and postganglionic (third-order neuron) lesion. However, the test cannot be
interpreted if it is performed within 24 hours of the cocaine or apraclonidine
test, so it is not practical in this patient. Given the history of recent trauma,
new-onset neck pain, and absence of other signs, this patient could have an
internal carotid artery (ICA) dissection. Thus, further investigations should be
obtained while he is still in the emergency room.
Acute isolated painful Horner’s syndrome is the most common finding
in patients with ICA dissection. Given the increased risk of stroke fol-
lowing ICA dissection, emergent imaging is required. The patient should
have magnetic resonance angiography (MRA) of the head and neck vessels
along with magnetic resonance imaging (MRI) of the head and neck with
fat suppression (Figure 35.2). If a dissection is identified, his vascular risk
FIGURE 35.2. Left ICA dissection (arrows) on MRA (left) and MRI of the neck with fat
suppression (right).
35. Horner Syndrome 197

198
factors should be addressed and antiplatelet therapy (e.g., aspirin) should be

started, because recent studies do not suggest a benefit from anticoagulation
with warfarin. Patients who go on to have a hemispheric stroke may re-
quire thrombolysis or definitive endovascular intervention for their ICA
dissection.
• Horner syndrome is caused by a lesion affecting the ipsilateral

oculosympathetic pathway.
• Horner syndrome is characterized by upper-eyelid ptosis and
lower-eyelid elevation with miosis and dilation lag.
• Horner syndrome can be diagnosed when there is reversal of
anisocoria on apraclonidine testing, but false-negative results
can occur acutely before denervation supersensitivity has
developed.
• Acute isolated painful Horner syndrome should be investigated
with MRI and MRA of the head and neck to evaluate for ICA
dissection.
Further Reading
Beebe JD, Kardon RH, Thurtell MJ. The yield of diagnostic imaging in patients with
isolated Horner syndrome. Neurol Clin. 2017;35:145–151.
Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine
test in the diagnosis of Horner’s syndrome. Arch Ophthalmol. 1990;108:384–387.
Kawasaki A, Kardon RH. Disorders of the pupil. Ophthalmol Clin North Am.
2001;14:149–168.
Kennedy F, Lanfranconi S, Hicks C, et al. Antiplatelets vs anticoagulation for
dissection: CADISS nonrandomized arm and meta-analysis. Neurology.
2012;79:686–689.
Koc F, Kavuncu S, Kansu T, Acaroglu G, Firat E. The sensitivity and specificity of 0.5%
apraclonidine in the diagnosis of oculosympathetic paresis. Br J Ophthalmol.
2005;89:1442–1444.

19
36 Tonic Pupil

clinic complaining of increased sensitivity
to light when looking through her left eye.
She has no other symptoms and has no
significant medical history. Examination
shows normal distance visual acuities,
eyelids, and eye movements. There is
3 mm of anisocoria. The left pupil is larger
than the right, especially in bright light.
The right pupil shows normal direct and
consensual reactions to light. The left pupil
shows sluggish direct and consensual
reactions to light. Both pupils constrict with
convergence, but the left pupil is slow to
redilate.
199
20
I ncreased sensitivity to light (photophobia) is a frequent complaint that

can result from ophthalmic disease (e.g., corneal ulcer, dry eye, or uveitis)
or neurologic disease (e.g., migraine or meningitis). When it is monocular,
as in the patient described in this scenario, it is likely to be due to unilat-
eral ophthalmic disease. A thorough ophthalmic examination is required,
with special attention to the anterior segments of the eyes. Occasionally,
increased sensitivity to light can directly result from a dilated pupil, be-
cause more light is being let into that eye. This patient has been found
to have anisocoria that is more prominent in bright light, suggesting that
the dilated left pupil is the abnormal pupil. Indeed, the left pupil shows
sluggish direct and consensual reactions to light, which likely explains her
increased sensitivity to light in that eye. The pupil also shows light–near
dissociation, responding better to the near stimulus. Together, these exam-
ination findings are highly suggestive of a tonic pupil. Since there was no
ptosis or ophthalmoplegia on the examination, a partial third nerve palsy is
very unlikely. Furthermore, the presence of light–near dissociation makes
pharmacologic mydriasis very unlikely.
A tonic pupil is caused by a lesion that involves the postganglionic
parasympathetic innervation of the pupil (i.e., ciliary ganglion or short
ciliary nerves in the retrobulbar space), resulting in palsies of the iris
sphincter muscle and ciliary muscle. The classic signs of tonic pupil
include poor pupillary reaction to light, segmental palsy of the iris
sphincter muscle, accommodation palsy, and tonic pupillary reaction to
near. Segmental palsy of the iris sphincter muscle is best appreciated
on slit-lamp examination and occurs because the causative lesion does
not affect all of the postganglionic fibers equally. Identification of seg-
mental palsy on slit-lamp examination is extremely important from a
diagnostic perspective because it does not occur with preganglionic par-
asympathetic lesions (e.g., third nerve palsy; see Case 18) or pharma-
cologic mydriasis (see Table 36.1 for a list of causes of pharmacologic
mydriasis). Segmental palsy can occasionally occur following iris trauma
or ischemia, in which case there will be iris atrophy and transillumina-
tion defects on anterior segment examination. The tonic response to near
is another characteristic sign of a tonic pupil that is thought to occur be-
cause there is aberrant reinnervation of the iris sphincter muscle by fibers
that previously innervated the ciliary muscle.
20 0 WHAT DO I DO NOW? Pupil Disorders

201
TABLE 36.1 Drugs That Commonly Cause

Pharmacologic Mydriasis
Parasympatholytics Sympathomimetics
(Anticholinergics) (Adrenergics)
Atropine Cocaine
Scopolamine Amphetamines
Homatropine Ephedrine
Tropicamide Pseudoephedrine
Cyclopentolate Phenylephrine
Ipratropium bromide Epinephrine
A tonic pupil can be caused by local factors, such as viral infections,

trauma, or orbital surgery, or by a neurologic lesion (Table 36.2). In a
young woman without any other medical problems or abnormal findings
on examination, it is likely to be an Adie pupil. Nevertheless, it is impor-
tant to obtain further history. She should be asked if the anisocoria has
been noticed previously, and old photographs (e.g., driver’s license) should
be inspected. She should be asked about a history of eye trauma or surgery.
She should have a slit-lamp examination looking for segmental palsy of
the iris sphincter muscle. If segmental palsy is identified, iris atrophy and
transillumination defects should be sought because their presence suggests
TABLE 36.2 Causes of Tonic Pupil
Local Neuropathic
Viral infections (e.g., zoster, syphilis) Syphilis
Orbital tumors Chronic alcoholism
Sarcoidosis Diabetes mellitus
Vasculitis (e.g., giant cell arteritis) Spinocerebellar ataxias
Trauma Guillain-Barré syndrome
Iatrogenic (e.g., orbital surgery) Miller Fisher syndrome
36. Tonic Pupil 201

20
prior iris trauma or ischemia as the cause for the mydriasis. The anterior
segments should be carefully assessed for findings that would suggest an
alternative cause for her monocular photosensitivity. Lastly, a neurologic
examination should be performed; the presence of hyporeflexia or areflexia
suggests Holmes-Adie syndrome or, if there is also ataxia or ophthalmo-
plegia, Miller Fisher syndrome.
Adie pupil, the likely cause of this patient’s tonic pupil, is sporadic and of
unknown etiology. It most often occurs in women between 20 and 50 years
of age. It is unilateral in the majority of cases, but bilateral Adie pupils can
develop sequentially, sometimes years apart. The tonic pupil persists indef-
initely but gets progressively smaller with time.
Pharmacologic pupil testing can assist in the diagnosis of tonic pupil
from any cause (see Figure 34.1) because the denervated iris sphincter
muscle becomes supersensitive to cholinergic agents. Instillation of di-
lute (0.1%) pilocarpine will result in intense constriction of a tonic pupil
but will have little if any effect on a normal or pharmacologically dilated
pupil. A potential caveat with the dilute pilocarpine test is that denerva-
tion supersensitivity can also develop with preganglionic parasympathetic
lesions (e.g., third nerve palsy; see Case 18). Consequently, there should be
a low threshold for close follow-up or for obtaining further investigations if
the presentation is atypical for tonic pupil.
An Adie pupil does not require specific treatment. The patient should be
reassured and advised to wear sunglasses when exposure to bright light is ex-
pected. Dilute pilocarpine eye drops can be prescribed for use in situations
where cosmetic appearance is important (e.g., job interviews or wedding
photographs) or when outdoors in sustained bright light. She should be
advised that there is a risk that she will eventually develop bilateral Adie
pupils.
• A tonic pupil shows poor reaction to light, with segmental iris

sphincter muscle palsy, and a tonic response to near, with a
slow subsequent redilation.

203
• A tonic pupil can be caused by local disease or a neurologic

lesion. When idiopathic, it is known as an Adie pupil.
• Instillation of dilute pilocarpine will produce intense constriction
of a tonic pupil, regardless of cause, but little if any constriction
of a normal or pharmacologically dilated pupil.
• Given that dilute pilocarpine can constrict a dilated pupil due to
third nerve palsy, the patient should be carefully examined for
ptosis and ophthalmoplegia.
• Tonic pupil does not require specific treatment, but use of
sunglasses or dilute pilocarpine drops can help to minimize
light sensitivity.
Further Reading
Bartleson JD, Trautmann JC, Sundt TM Jr. Minimal oculomotor nerve paresis
secondary to unruptured intracranial aneurysm. Arch Neurol. 1986;4:1015–1020.
Bourgon P, Pilley FJ, Thompson HS. Cholinergic supersensitivity of the iris sphincter
in Adie’s tonic pupil. Am J Ophthalmol. 1978;85:373–377.
Jacobson DM, Vierkant RA. Comparison of cholinergic supersensitivity in third nerve
palsy and Adie’s syndrome. J Neuroophthalmol. 1998;18:171–175.
Kardon RH, Corbett JJ, Thompson HS. Segmental denervation and reinnervation
of the iris sphincter as shown by infrared videographic transillumination.
Ophthalmology. 1998;105:313–321.
36. Tonic Pupil 203

204
205
SECTION V
Orbital and Miscellaneous

Disorders
206
207
37 Thyroid Eye Disease
A 52-year-old woman presents with a

several-month history of increasing
binocular diagonal diplopia. She has an
unremarkable medical history but is a
heavy smoker. Examination shows visual
confrontation visual fields, and pupils
are normal. Slit-lamp examination shows
conjunctival injection and punctate corneal
epithelial erosions in both eyes. She has
mild bilateral upper-eyelid retraction and
proptosis. There is an esotropia and right
hypotropia, and she has limited abduction
and elevation of her right eye. Funduscopic
examination is normal.
207
208
T he clinical presentation in this case scenario is highly suggestive of thy-

roid eye disease (TED), also known as thyroid-associated or Graves
ophthalmopathy. TED is the most common orbital disease encountered in
clinical practice and is most often associated with Graves disease. TED has
a course with two distinct phases: an active (inflammatory) phase lasting
12–24 months followed by an inactive (fibrotic) phase. It is typically bi-
lateral and painless, although it can be asymmetric and produce some eye
discomfort. The inferior and medial rectus muscles are the most commonly
affected extraocular muscles, resulting in restriction of eye elevation and ab-
duction. Consequently, patients with TED often present with binocular di-
plopia. The diplopia is typically worse in the morning because of dependent
engorgement of the extraocular muscles. Other signs of orbital disease are
usually present and include axial proptosis, periorbital edema, conjunctival
injection and chemosis, eyelid retraction, lagophthalmos (inability to close
the eye), lid lag (higher eyelid position than normal in downgaze), and the
von Graefe sign (slowed descent of the eyelid during movement from upgaze
to downgaze). The combination of eyelid retraction and lagophthalmos can
result in decreased visual acuity from exposure keratopathy, which often
gives rise to punctate corneal epithelial erosions. Vision loss can result from
compression of the optic nerve at the orbital apex by the enlarged extra-
ocular muscle bellies (Figure 37.1; see Case 4), sometimes in the absence
of significant proptosis. The vision loss is typically insidious and may not
be noticed by the patient until severe. Dyschromatopsia, often out of pro-
portion to the degree of visual acuity loss, is a common clinical finding in
patients with compressive optic neuropathy due to TED.
FIGURE 37.1. Coronal computed tomography showing asymmetric enlargement of the

extraocular muscle bellies in thyroid eye disease (left). There is marked crowding at the left orbital
apex with loss of the fat plane between the extraocular muscles and optic nerve (right).
208 WHAT DO I DO NOW? Orbital and Miscellaneous Disorders

209
TED is diagnosed and graded on the basis of clinical findings (Table

37.1). However, imaging of the orbits is the most useful investigation to
obtain when the diagnosis is suspected. Axial and coronal computed to-
mography (CT) or magnetic resonance imaging (MRI) of the orbit usually
shows characteristic enlargement of the extraocular muscle bellies with rel-
ative sparing of the tendons (see Figure 37.1). MRI is sometimes preferred
(e.g., when another cause of orbital inflammation is possible), but CT is
less expensive and also allows for visualization of the bony anatomy (which
is important when planning for orbital decompression surgery). While or-
bital echography can demonstrate enlargement of the extraocular muscle
bellies and changes in their reflectivity, it is inferior to CT and MRI in
evaluating for compression of the optic nerve at the orbital apex. Thyroid
function tests (i.e., thyroid-stimulating hormone and free-T4 levels) should
be obtained in all patients with TED because they can have undiagnosed
hyperthyroidism or hypothyroidism. Thyroid-stimulating antibodies are
often present in patients with TED and can be an important marker of
disease in euthyroid patients. Visual field testing should be obtained in
patients with vision loss. This patient’s visual acuities are decreased to
20/30 in both eyes. Given the findings on slit-lamp examination and ab-
sence of other signs to suggest optic neuropathy, the decrease in visual acuity
is likely secondary to exposure keratopathy. Nevertheless, visual field testing
should be obtained to assess for a visual field defect from compressive optic
TABLE 37.1 Grading of TED
Examination Finding Mild TED Moderate to Severe

TED
Eyelid retraction (mm) <2 ≥2
Proptosis (mm) <3 ≥3
Soft tissue involvement Mild Moderate to severe
Diplopia None or intermittent Intermittent or

constant
Corneal involvement Absent or mild Moderate
Adapted from Bartalena L, Tanda ML. Graves’ ophthalmopathy. N Engl J Med.

2009;360:994–1001.
37. Thyroid Eye Disease 209

210
neuropathy, especially if there is crowding at the orbital apex on imaging

(see Figure 37.1).
Most alternative diagnoses (e.g., idiopathic orbital inflammation, orbital
cellulitis, and carotid-cavernous fistula) can be excluded on the basis of clin-
ical and imaging findings (see Cases 38 and 39). When there are findings
consistent with TED with atypical features, such as an exotropia rather than
esotropia or ptosis rather than eyelid retraction, the possibility of coexisting
ocular myasthenia should be considered (see Case 22).
Many patients with TED have only mild disease and can be managed
conservatively. Supportive treatments, such as artificial tears for exposure
keratopathy and prisms for diplopia, can improve symptoms and quality of
life. In patients with mild TED, selenium supplementation (100 µg twice
daily) can also improve symptoms and quality of life while slowing progres-
sion of TED. In patients with moderate to severe TED, treatment options
include immunosuppression with systemic corticosteroids, orbital irradi-
ation, and orbital decompression surgery. Intravenous methylprednisone
(e.g., 500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks) is
more effective than oral prednisone with fewer side effects. If intrave-
nous methylprednisone fails to improve vision in patients with compres-
sive optic neuropathy, orbital decompression surgery should be offered.
Orbital irradiation (e.g., 20 Gy per orbit in 10 fractions) in combination
with corticosteroids could also be considered, although there is a paucity of
randomized clinical trials evaluating its efficacy for the treatment of com-
pressive optic neuropathy. Orbital irradiation should be avoided in patients
with severe hypertension or diabetes because it could cause retinopathy or
exacerbate existing retinopathy.
The choice of treatment in this patient depends on the severity of
the clinical signs (see Table 37.1) and whether or not there is compres-
sive optic neuropathy. She should be prescribed artificial tears for exposure
keratopathy, prisms for diplopia, and selenium supplementation. If she has
moderate to severe TED or vision loss from compressive optic neuropathy,
intravenous methylprednisone, orbital irradiation, or orbital decompression
surgery should be considered. If she continues to have significant ocular
misalignment and eyelid retraction, strabismus surgery followed by eyelid
surgery could be considered once the active phase of the disease has passed
and the deficits have stabilized. Thyroid dysfunction should be treated with

21
a goal of achieving and maintaining a euthyroid state. Radioactive iodine

therapy is sometimes given to patients with hyperthyroidism due to Graves
disease, but it should be avoided in this patient as it can worsen TED.
Lastly, smoking can also worsen TED and decrease the beneficial effects of
treatments for TED, so the patient should be encouraged to discontinue
smoking.
• TED is the most common orbital disease encountered in clinical

practice.
• Signs of TED include ocular misalignment, proptosis, periorbital
edema, conjunctival injection, chemosis, eyelid retraction,
lagophthalmos, lid lag, and the von Graefe sign.
• CT or MRI of the orbits typically shows enlargement of the
extraocular muscle bellies with relative sparing of the tendons.
• Mild TED can be treated with supportive therapies, including
artificial tears for exposure keratopathy, prisms for diplopia, and
selenium supplementation.
• Moderate to severe TED can be treated with corticosteroids,
orbital irradiation, or orbital decompression surgery.
• Ocular misalignment and eyelid retraction can be treated with
strabismus surgery followed by eyelid surgery, once the active
phase of the disease has passed and the deficits are stable.
Further Reading
Bartalena L, Tanda ML. Graves’ ophthalmopathy. N Engl J Med. 2009;360:994–1001.
Bhatti MT, Dutton JJ. Thyroid eye disease: therapy in the active phase. J
Gaddipati RV, Meyer DR. Eyelid retraction, lid lag, lagophthalmos, and von
Graefe’s sign: quantifying the eyelid features of Graves’ ophthalmopathy.
Ophthalmology. 2008;115:1083–1088.
Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’
orbitopathy. N Engl J Med. 2011;364:1920–1931.
Thornton J, Kelly SP, Harrison RA, Edwards R. Cigarette smoking and thyroid eye
disease: a systematic review. Eye (Lond). 2007;21:1135–1145.
37. Thyroid Eye Disease 211

21
213
38 Syndromes of the
Orbital Apex, Superior
Orbital Fissure, and
Cavernous Sinus
A 42-year-old woman with poorly controlled

type 1 diabetes presents to your clinic with
a 1-day history of painful vision loss in the
right eye. Examination shows visual acuities
of 20/400 in the right eye and 20/20
in the left eye. Confrontation visual fields
show a dense central scotoma in the right
eye. There is 2 mm of anisocoria; the right
pupil is larger than the left. The right pupil
reacts sluggishly to light and near, the left
pupil reacts normally to light and near, and
there is a right relative afferent pupillary
defect. There is partial ptosis and complete
ophthalmoplegia on the right. Funduscopic
examination is unremarkable. The
remainder of the cranial nerve examination
shows decreased sensation over the right
forehead with an absent right corneal reflex.
213
214
T he patient in this scenario has multiple cranial nerve palsies: a dense

central scotoma with a relative afferent pupillary defect indicates in-
volvement of the optic nerve; partial ptosis and complete external ophthal-
moplegia with a sluggish dilated pupil indicates involvement of the third,
fourth, and sixth nerves; and decreased forehead sensation with an absent
corneal reflex indicates involvement of the ophthalmic division of the fifth
nerve. Together, these findings localize the lesion to the orbital apex (Table
38.1). A variety of disease processes can cause an orbital apex syndrome
(Box 38.1). An acute presentation with associated pain suggests inflam-
mation or infection as the cause. Orbital inflammation is often idiopathic
but can also occur in the setting of systemic inflammatory disorders such
as sarcoidosis, granulomatosis with polyangiitis (formerly called Wegener
granulomatosis), and IgG4- related disease. Infections can be bacterial,
viral, or fungal (e.g., extending from the adjacent paranasal sinuses). The
rapid onset of symptoms and signs in this patient with poorly controlled
type 1 diabetes is particularly concerning for rhino-orbital mucormycosis.
Therefore, the patient requires immediate admission to the hospital for ur-
gent investigations and aggressive treatment.
Mucormycosis can be caused by a number of different fungi of the
order Mucorales, which are found in decaying organic matter. It occurs
most commonly in diabetic patients with ketoacidosis, but it can also occur
in patients who are neutropenic, immunocompromised for solid organ or
stem cell transplantation, or receiving deferoxamine chelation therapy (e.g.,
for hemochromatosis or thalassemia). It rarely occurs in immunocompetent
individuals. It arises from the paranasal sinuses, where the fungal hyphae
invade the sinus mucosa and spread to contiguous structures via blood
vessels or nerves. Angioinvasion can lead to thrombosis with infarction
of distal structures (Figure 38.1) or hematogenous dissemination. When
the disease is localized to the sinuses, the symptoms and signs are nonspe-
cific and include facial pain, nasal congestion, and bloody nasal discharge.
When the infection invades the orbit, there may be a partial or complete
orbital apex syndrome (see Table 38.1). Often, there are other signs of or-
bital involvement, such as periorbital edema (see Figure 38.1), proptosis,
and conjunctival chemosis. The infection can spread from the orbit into
the cavernous sinus to cause cavernous sinus thrombosis. The cavernous
segment of the internal carotid artery can also become affected as a result

215
TABLE 38.1 Structures Involved in Syndromes of the Orbital Apex, Superior

Orbital Fissure, and Cavernous Sinus
Structure Orbital Apex Superior Orbital Cavernous Sinus

Fissure
Cranial nerve II + – –a
Cranial nerve III + + +
Cranial nerve IV + + +
Cranial nerve V1 + + +
Cranial nerve V2 – – +
Cranial nerve VI + + +
Carotid artery – – +
Abbreviations: +, involved; –, not involved.
a
Can be indirectly involved (e.g., as a result of elevated intraocular pressure).
of the spread of hyphae within the blood vessel lumen, leading to occlusion
and cerebral infarction. Other intracranial complications include epidural
and subdural abscess, venous sinus thrombosis, and meningitis. Once the
process has spread beyond the sinuses and orbit, the prognosis for survival
is extremely poor.
BOX 38.1 Causes of Syndromes of the Orbital Apex, Superior Orbital

Fissure, and Cavernous Sinus
Inflammation (e.g., idiopathic inflammation, sarcoidosis, IgG4-related

disease)
Infection (e.g., mucormycosis, invasive aspergillosis, herpes zoster,
tuberculosis)
Neoplasm (e.g., lymphoma, nasopharyngeal carcinoma, meningioma,
metastases)
Vascular (e.g., cavernous sinus thrombosis, carotid aneurysm, carotid-
cavernous fistula)
Iatrogenic (e.g., endoscopic sinus surgery, orbital surgery, facial
surgery)
Trauma (e.g., penetrating injury, orbital fracture, retained
foreign body)
38. Apex, Fissure, and Cavernous Sinus 215

216
FIGURE 38.1. Clinical and radiologic features of mucormycosis in a patient with diabetic

ketoacidosis. Periorbital edema and facial infarction due to angioinvasion with thrombosis
(top, left). Opacification of maxillary and ethmoid sinuses with enlarged right extraocular
muscle bellies on computed tomography (top, right). Right-sided proptosis with orbital apex
enhancement and enlarged extraocular muscle bellies on magnetic resonance imaging (bottom,
left). Occlusion of left internal carotid artery on magnetic resonance angiography (bottom, right).
Accurate and timely diagnosis of mucormycosis requires a high index of

suspicion in predisposed patients. Computed tomography (CT) or magnetic
resonance imaging should be obtained urgently in this patient, looking for
signs of paranasal sinus or orbital involvement. Characteristic findings in-
clude sinus mucosal thickening, sinus opacification, bony erosion (only evi-
dent on CT), orbital apex enhancement, and enlargement of the extraocular
muscle bellies (see Figure 38.1). There may be cavernous sinus thrombosis,
occlusion of the internal carotid artery, cerebral infarction, or, once the di-
sease has spread into the intracranial cavity, signs of meningitis (see Figure
38.1). However, an important caveat is that the imaging findings can initially

217
be subtle or absent despite a dramatic clinical presentation. Nasal endoscopy

with biopsies of sinus mucosa should be obtained urgently in this patient be-
cause definitive diagnosis requires histopathologic documentation of fungal
invasion. Debridement of necrotic mucosa can be performed during the
same procedure. If the sinus biopsies are unrevealing and the clinical suspi-
cion remains high, orbital apex biopsy could be considered, although there
is a considerable risk of complications (e.g., vision loss) with this procedure.
Successful treatment of the patient will depend on rapid reversal of
predisposing factors, immediate initiation of empiric antifungal treat-
ment, and early surgical debridement of infected tissue. The most likely
predisposing factor for the patient in this scenario is diabetic ketoacidosis,
which can be quickly diagnosed on the basis of blood chemistry results.
Diabetic ketoacidosis should be aggressively treated with intravenous hy-
dration and insulin infusion, preferably in an intensive care setting. Empiric
antifungal treatment should be commenced without waiting for confirma-
tion of the diagnosis. Liposomal amphotericin B is the agent of choice,
although other antifungal therapies (e.g., posaconazole or isavuconazole)
may be effective in refractory disease. Unfortunately, the mortality rate with
antifungal treatment alone remains very high, even with early initiation of
treatment. Consequently, radical surgical debridement should be considered
early in patients with limited disease to prevent the spread of infection to
adjacent structures. The optimal extent and timing of surgical debridement
remain uncertain. Several adjunctive therapies could also be considered,
such as hyperbaric oxygen and granulocyte-macrophage colony-stimulating
factor, although the evidence for their efficacy remains circumstantial.
• Acute onset of an orbital apex syndrome with associated pain

suggests inflammation or infection as the cause.
• Mucormycosis can cause an acute-onset orbital apex syndrome
in immunocompromised patients (e.g., neutropenic or
transplant patients) or diabetic patients with ketoacidosis.
• Urgent investigations, including imaging, nasal endoscopy, and
mucosal biopsy, are required to make the diagnosis.
38. Apex, Fissure, and Cavernous Sinus 217

218
• Imaging changes can initially be subtle or absent despite a

dramatic clinical presentation.
• Successful treatment requires rapid reversal of predisposing
factors, immediate initiation of empiric antifungal therapy (e.g.,
amphotericin B), and early radical surgical debridement.
Further Reading
Abdel-Razek MA, Venna N, Stone JH. IgG4-related disease of the central and
peripheral nervous systems. Lancet Neurol. 2018;17:183–192.
Chang JR, Gruener AM, McCulley TJ. Orbital disease in neuro-ophthalmology. Neurol
Clin. 2017;35:125–144.
Keane JR. Cavernous sinus syndrome: analysis of 151 cases. Arch Neurol.
1996;53:967–971.
Thurtell MJ, Chiu AL, Goold LA, et al. Neuro-ophthalmology of invasive fungal
sinusitis: 14 consecutive patients and a review of the literature. Clin Exp
Ophthalmol. 2013;41:567–576.
Vaughan C, Bartolo A, Vallabh N, Leong SC. A meta-analysis of survival factors
in rhino-orbital-cerebral mucormycosis—has anything changed in the past
20 years? Clin Otolaryngol. 2018;43(6):1454–1464.
Yeh S, Foroozan R. Orbital apex syndrome. Curr Opin Ophthalmol. 2004;15:490–498.

219
39 Carotid-Cavernous Fistula

clinic with a several-month history of a red
right eye and binocular horizontal diplopia.
She denies recent eye or head trauma.
Her red eye has persisted despite use
of artificial tears, topical antibiotics, and
topical steroids. Examination shows visual
confrontation visual fields, and pupils are
normal. Slit-lamp examination shows mild
conjunctival chemosis with dilated and
tortuous conjunctival vessels in the right
eye. There is mild proptosis of her right eye.
There is also an esotropia and a mild right
abduction deficit. Funduscopic examination
is normal.
219
20
T he clinical presentation in this scenario suggests an indirect carotid-

cavernous fistula. Carotid-cavernous fistulas (CCFs) are abnormal vas-
cular communications allowing blood to flow from the carotid artery or its
branches into the cavernous sinus. Direct CCFs arise from the cavernous
segment of the internal carotid artery (ICA), whereas indirect CCFs arise
from branches of the ICA, external carotid artery (ECA), or both. Direct
CCFs are high-flow fistulas that are often caused by head trauma or rup-
ture of a cavernous ICA aneurysm, although they can result from iatrogenic
trauma (e.g., from transsphenoidal surgery or endovascular procedures).
Indirect CCFs are low-flow fistulas that develop spontaneously, although
systemic hypertension, atherosclerotic disease, and collagen vascular diseases
can predispose to their formation. Indirect CCFs occur most commonly in
postmenopausal women.
The clinical presentation varies depending on the type of fistula.
Direct CCFs typically have an abrupt onset with proptosis, conjunctival
chemosis, eyelid edema, and pain (Figure 39.1). Vision loss can rapidly
result from corneal exposure, elevated intraocular pressure, retinal is-
chemia, or optic nerve ischemia. Diplopia and ophthalmoplegia can re-
sult from cranial nerve compression, extraocular muscle engorgement, or
both. There is frequently an audible bruit. In contrast, indirect CCFs usu-
ally have a more insidious onset, with conjunctival injection being a fre-
quent presenting complaint. Patients are often initially misdiagnosed as
having another cause for conjunctival injection (e.g., conjunctivitis) and
FIGURE 39.1. Severe proptosis, hemorrhagic conjunctival chemosis, and eyelid edema in a

patient with a direct carotid-cavernous fistula following head trauma (left). Mild conjunctival
chemosis with dilated and tortuous conjunctival vessels in a patient with an indirect carotid-
cavernous fistula (right).

21
will often have seen several eye doctors with unsuccessful treatments using
artificial tears, topical antibiotics, and topical steroids. However, a close
inspection will show characteristically dilated and tortuous (“arterialized”
or “corkscrew”) conjunctival vessels (see Figure 39.1). There can be as-
sociated conjunctival chemosis, proptosis, and eyelid edema, but these
signs are often subtle or overlooked if not specifically sought. There can
be diplopia with an abduction deficit from sixth nerve compression, al-
though other motility deficits can also occur due to extraocular muscle
dysfunction from venous engorgement. The patient may report pulse-
synchronous tinnitus, and there is often an elevated intraocular pressure.
If the intraocular pressure is measured with applanation tonometry, ab-
normally increased pulsation of the tonometry mires may be evident.
Funduscopic examination is often unremarkable, although there can be
dilation and increased tortuosity of the retinal veins. Optic disc cupping
can be present in patients with glaucomatous optic neuropathy due to
untreated elevated intraocular pressure.
Based on the history and examination findings, the patient in this sce-
nario is likely to have an indirect CCF, and noninvasive vascular imaging
should be obtained. While definitive diagnosis of CCF requires digital
subtraction cerebral angiography (DSA), noninvasive approaches, such as
magnetic resonance imaging (MRI) and magnetic resonance angiography
(MRA), are helpful in the initial evaluation of suspected CCF. MRI often
shows expansion of the ipsilateral cavernous sinus, a dilated superior oph-
thalmic vein, engorged extraocular muscles, and proptosis (Figure 39.2).
MRA may show abnormal early filling of the ipsilateral cavernous sinus
FIGURE 39.2. Dilated right superior ophthalmic vein and engorged right extraocular muscle
bellies on coronal MRI (left). Abnormal early filling of the right cavernous sinus on axial MRA
source images (middle) and coronal MRA reconstructions (right).
39. Carotid-Cavernous Fistula 221

2
(see Figure 39.2). If noninvasive imaging is suggestive, DSA is required

to determine the exact location and type of fistula, which is important for
planning the treatment strategy. With its high resolution for small vessels,
DSA might show small feeding vessels that were not apparent on noninva-
sive imaging.
The overall goal of treatment is to occlude the CCF while preserving
normal blood flow through the ICA. Percutaneous embolization of the
CCF is the first-line treatment approach in most cases. Metallic coils or
liquid embolic agents can be placed using a transarterial or transvenous
approach; the approach used depends on the location and type of fis-
tula. In some cases, flow-diverting stents can be deployed within the
cavernous ICA over the site of the fistula. Most patients undergoing
endovascular treatment for CCF will be cured, although complete cure
can be difficult to achieve in patients who have multiple feeding vessels,
and some neuro-ophthalmic deficits (e.g., motility deficits) can persist,
depending on their severity and chronicity. Potential complications of
endovascular treatment include stroke, dissection, and vascular perfo-
ration with associated hemorrhage. Stereotactic radiosurgery could be
considered when symptoms and signs are mild or endovascular inter-
vention is considered risky based on comorbidities. A conservative ap-
proach could also be considered, since indirect CCFs can occasionally
occlude spontaneously.
For this patient, the first step in management is to measure the intraocular
pressure. If it is elevated, topical ocular hypotensive drops should be started
to minimize the risk of vision loss due to glaucomatous optic neuropathy.
The patient should then have noninvasive imaging with MRI and MRA
of the head. If the imaging findings are consistent with an indirect CCF,
cerebral DSA should be obtained to determine the location and type of
fistula, followed by tailored endovascular therapy. Following endovascular
therapy, the topical ocular hypotensive drops can be discontinued provided
that the intraocular pressure returns to normal and other signs of CCF have
improved or resolved. Any persisting neuro-ophthalmic deficits (e.g., an
esotropia from sixth nerve palsy) can be managed symptomatically (e.g.,
with prism).

23
• CCFs are abnormal vascular communications allowing

blood to flow from the carotid artery or its branches into the
cavernous sinus.
• Direct CCFs can be caused by head trauma, iatrogenic trauma,
or rupture of a cavernous ICA aneurysm and have an abrupt
onset with proptosis, conjunctival chemosis, and eyelid edema.
• Indirect CCFs develop spontaneously and have a more insidious
onset with characteristically dilated and tortuous (“arterialized”
or “corkscrew”) conjunctival vessels.
• Definitive diagnosis of CCF requires DSA, but noninvasive
approaches (MRI and MRA) are helpful in the initial evaluation
of suspected CCF.
• If the intraocular pressure is elevated, topical ocular
hypotensive drops should be prescribed to minimize the risk of
irreversible vision loss due to glaucomatous optic neuropathy.
• Percutaneous embolization is the first-line treatment
approach and is successful in most cases, although potential
complications include stroke, dissection, and vascular
perforation.
Further Reading
Barrow DL, Spector RH, Braun IF, Landman JA, Tindall SC, Tindall GT. Classification
and treatment of spontaneous carotid-cavernous sinus fistulas. J Neurosurg.
1985;62:248–256.
Ellis JA, Goldstein H, Connolly ES, Meyers PM. Carotid-cavernous fistulas.
Neurosurg Focus. 2012;32:E9.
Henderson AD, Miller NR. Carotid-cavernous fistula: current concepts in aetiology,
investigation, and management. Eye (Lond). 2018;32:164–172.
Tonetti DA, Gross BA, Jankowitz BT, et al. Stereotactic radiosurgery for dural
arteriovenous fistulas without cortical venous reflux. World Neurosurg.
2017;107:371–375.
Zanaty M, Chalouhi N, Tjoumakaris SI, Hasan D, Rosenwasser RH, Jabbour P.
Endovascular treatment of carotid-cavernous fistulas. Neurosurg Clin North Am.
2014;25:551–563.
39. Carotid-Cavernous Fistula 223

24
25
40 Dorsal Midbrain Syndrome
You are called to evaluate a 24-year-

old woman with a prior history of
ventriculoperitoneal shunting for congenital
aqueduct stenosis who has presented to
the emergency department with headaches.
She denies having vision loss, diplopia, or
ptosis. Examination shows normal visual
acuities, color vision, confrontation visual
fields, and fundi. Her pupils are equal
in size. They show sluggish direct and
consensual reactions to light but constrict
briskly when she converges. She has
bilateral upper-eyelid retraction. She has
severely limited upward gaze and develops
convergence–retraction nystagmus when
she attempts to make upward saccades.
225
26
D orsal midbrain lesions give rise to a characteristic combination of oc-

ular motor, eyelid, and pupil abnormalities (Figure 40.1). This com-
bination of abnormalities was previously called Parinaud syndrome but is
better termed the dorsal midbrain syndrome. The classic ocular motor signs
of the dorsal midbrain syndrome include supranuclear vertical gaze palsy,
skew deviation, convergence insufficiency, and convergence–retraction nys-
tagmus. The supranuclear vertical gaze palsy is due to involvement of the
posterior commissure and is worse for upward eye movements, although
downward eye movements can also be affected. There can sometimes be
a tonic downward deviation of the eyes (the “setting sun” sign; see Figure
40.1), especially in children with an acute dorsal midbrain syndrome.
Skew deviation results from involvement of the central otolithic pathways.
Convergence–retraction nystagmus is highly localizing to the dorsal mid-
brain, is characterized by rhythmic convergent–retraction eye movements
during attempted upward gaze, and can be elicited by asking the patient to
follow the downward-moving stripes of optokinetic tape or an optokinetic
drum. Eyelid abnormalities include upper-eyelid retraction (Collier sign;
see Figure 40.1) and, less often, upper-eyelid ptosis. The pupils are often
mid-dilated and show light–near dissociation, in which there is a slug-
gish pupillary response to light yet a brisk response to an accommodative
stimulus.
Common causes of the dorsal midbrain syndrome include hydroceph-
alus, stroke, intrinsic brainstem tumors, and compression by extrinsic
lesions (e.g., pineal teratomas, germinomas, and third-ventricular tumors;
FIGURE 40.1. Signs of the dorsal midbrain syndrome, including downward eye deviation, skew
deviation, and upper-eyelid retraction (Collier sign), following a dorsal midbrain hemorrhage. The
patient developed convergence–retraction nystagmus during attempted upward saccades.

27
FIGURE 40.2. Post-contrast T1-weighted magnetic resonance imaging showing a large pineal

germinoma compressing the dorsal midbrain. The patient had signs of the dorsal midbrain
syndrome at presentation.
Figure 40.2). Features of the dorsal midbrain syndrome can be present in

certain neurodegenerative diseases (e.g., progressive supranuclear palsy;
see Case 25), metabolic diseases (e.g., Niemann-Pick type C), and in-
fectious diseases (e.g., central nervous system Whipple disease). Unless
contraindicated, magnetic resonance imaging (MRI) of the brain should
be obtained as the initial investigation for a patient with dorsal midbrain
syndrome.
Malfunction of a ventriculoperitoneal shunt can produce a dorsal mid-
brain syndrome as well as other symptoms and signs of increased intra-
cranial pressure (ICP), such as headaches, vomiting, and papilledema (see
Case 8). For the patient in this case scenario, the first step is to obtain brain
imaging to determine if she has hydrocephalus from shunt malfunction;
computed tomography (CT) is usually obtained, although rapid-sequence
MRI should be considered to minimize exposure to radiation and sedation
in children. While the presence of hydrocephalus is a clear indicator of
shunt malfunction, its absence does not exclude it; a dorsal midbrain syn-
drome can sometimes occur without hydrocephalus in the setting of shunt
malfunction. Consequently, there should be a low threshold for obtaining
40. Dorsal Midbrain Syndrome 227

28
urgent shunt function studies and for requesting neurosurgical consultation

when the clinical suspicion for shunt malfunction is high, as in this patient.
Neurosurgical consultation and intervention are indicated when there
is concern for ventriculoperitoneal shunt malfunction because med-
ical treatments to reduce ICP are unlikely to be effective. In many cases,
shunt revision is required and will usually lead to a prompt resolution of
the dorsal midbrain syndrome as well as the other symptoms and signs of
increased ICP.
• Dorsal midbrain syndrome is characterized by supranuclear

vertical gaze palsy, skew deviation, convergence–retraction
nystagmus, eyelid retraction, and light–near dissociation of the
pupils.
• Common causes of dorsal midbrain syndrome include
hydrocephalus, stroke, intrinsic brainstem tumors, and
compression by extrinsic lesions (e.g., pineal tumors).
• Ventriculoperitoneal shunt malfunction can cause a dorsal
midbrain syndrome as well as other symptoms and signs of
increased ICP, sometimes without hydrocephalus.
• Shunt function studies and neurosurgical consultation
should be urgently obtained when there is evidence of shunt
malfunction or when clinical suspicion for shunt malfunction
is high.
Further Reading
Chou SY, Digre KB. Neuro-ophthalmic complications of raised intracranial
pressure, hydrocephalus, and shunt malfunction. Neurosurg Clin North Am.
1999;10:587–608.
Katz DM, Trobe JD, Muraszko KM, Dauser RC. Shunt failure without ventriculomegaly
proclaimed by ophthalmic findings. J Neurosurg. 1994;81:721–725.
Keane JR. The pretectal syndrome: 206 patients. Neurology. 1990;40:684–690.

29
O’Neill BR, Pruthi S, Bains H. Rapid sequence magnetic resonance imaging

in the assessment of children with hydrocephalus. World Neurosurg.
2013;80:e307–312.
Shields M, Sinkar S, Chan W, Crompton J. Parinaud syndrome: a 25-year (1991–2016)
review of 40 consecutive adult cases. Acta Ophthalmol. 2017;95:e792–793.
40. Dorsal Midbrain Syndrome 229

230
231
Index
Note: Page numbers followed by f, t, or b denote figures, tables, or boxes respectively.
AAION. See arteritic anterior ischemic compressive optic neuropathy caused

optic neuropathy by, 23
abducens nerve palsy, 111–14 third nerve palsy caused by, 100f, 100–2
abducting nystagmus, “dissociated,” 134 angioinvasion, 214–15
aberrant reinnervation, 100–1 anisocoria, 187–91, 188t, 189f
absent corneal reflex, 214 Horner syndrome and, 194f, 194–95
accommodation palsy, 200 tonic pupil and, 200
acephalgic migraine, 78–79 anomalous optic nerve head elevation, 56
acetazolamide, 44–45, 52, 164 anterior compressive optic
acetylcholine-receptor antibodies, neuropathy, 22–23
122–23, 123t anterior ischemic optic neuropathy, 10
acquired cerebellar degenerations, 146–47 anticonvulsant medications, 142–43
acquired pendular nystagmus antifungal treatment, 217
(APN), 156–58 anti-Ma2 brainstem encephalitis, 139
acute inflammatory demyelinating antiretinal antibodies, 91–92
polyneuropathy, 128–29 APN. See acquired pendular nystagmus
acute isolated painful Horner aponeurotic ptosis, 175–78
syndrome, 197–98 “applause” sign, 138–39
acute zonal occult outer retinopathy, 90–91 apraclonidine, 195–96
adduction deficits, 134, 135 apraxia, 138–39
Adie pupil, 201–2 apraxia of eyelid opening (AEO), 182–83
ADOA. See autosomal dominant optic areflexia, 107–8, 128–29, 201–2
atrophy “arterialized” conjunctival vessels, 220–21
AEO. See apraxia of eyelid opening arterial occlusion, 84
alcohol withdrawal, 78 arteritic anterior ischemic optic neuropathy
alexia, 73–74, 73t (AAION), 9–13, 11f, 17–18
Alzheimer disease astigmatism, irregular, 90
homonymous hemianopia and, 68 asymmetric papilledema, 42
prosopagnosia and, 72–73 ataxia
simultanagnosia and, 72–73 autosomal dominant
visual-variant, 73–75, 75f spinocerebellar, 146–47
amblyopia, 116–17 Friedreich, 168–69
amiodarone, 17 with gaze-evoked nystagmus, 142–43
amitriptyline, 81 Miller Fisher syndrome and, 107–8,
amphotericin B, 217 128–29, 201–2
anaplastic astrocytoma, 169f with saccadic intrusions, 170
aneurysms with third nerve palsy, 100
bitemporal hemianopia caused by, 63 with upbeat nystagmus, 152
23
atropine, 123–24 capillary hemangioma, 23

atypical optic neuritis, 26 carbamazepine, 118, 142–43
aura, visual, 77–82, 80t carotid-cavernous fistulas (CCFs), 112–13,
autoimmune retinopathies, 91–92 210, 219–23, 220f, 221f
autosomal dominant optic atrophy carotid Doppler ultrasound, 86–87
(ADOA), 26, 29–32, 31f carotid endarterectomy, 87
autosomal dominant spinocerebellar cat-scratch disease, 35–39, 37f
ataxia, 146–47 cavernous sinus syndrome, 213–18,
axial rigidity, 138–39 215b, 215t
cavernous sinus thrombosis, 214–15
baclofen, 147–48, 153, 183 CCFs. See carotid-cavernous fistulas
bacterial meningitis, 112–13 ceco-central scotoma, 26–27, 31
Balint syndrome, 72–73 central nervous system Whipple
bariatric surgery, 151, 152 disease, 226–27
Bartonella henselae infection, 36–37, 37f central scotoma, 26–27, 31, 214
bean-shaped scotoma, 78 central visual field defect, 22–23,
benign anisocoria, 190 62–63, 90–91
benign essential blepharospasm cerebellar degeneration, 142–43, 146–47
(BEB), 181–84 cerebellar disease, 168
bilateral adduction deficits, 134, 135 cerebellar metastases, 146–47
bilateral parieto-occipital lesions, 72–73 cerebellar syndrome, 170
binocular diplopia. See diplopia cerebral achromatopsia, 72–73, 73t
biopsy cerebral akinetopsia, 73t
orbital apex, 216–17 cerebral venous sinus thrombosis (CVST),
sinus, 216–17 42–45, 50–51, 51b
temporal artery, 11–12 cerebrospinal fluid (CSF), 5–7, 42–45
bitemporal hemianopia, 62–65, 64f chemosis, 22–23, 208, 214–15,
blepharospasm, 138–39, 181–84 220f, 220–21
blind-spot enlargement, 22–23 Chiari malformation, 134–35,
“bony spicule” pattern, 90–91 146–47, 147f
botulinum toxin A, 183 chiasmal syndromes, 61–65, 62f, 64f
bradykinesis, 138–39 chordoma, 112–13
brainstem encephalitis, 170 choroidal ischemia, 10–12
brainstem stroke, 134–36, 156–57 “Christmas tree” cataract, 129–30
brainstem tumors, 134–35, 226–27 chronic progressive external
breast cancer, cerebellar metastases ophthalmoplegia (CPEO), 129–30,
from, 146–47 131f, 135, 176
bruit, 220–21 cilioretinal ischemia, 10–12
B-scan ultrasonography, 58f, 59–60 clival lesions, 112–13
bulbar palsy, 152  clonazepam, 147–48
cocaine test, 195
Campylobacter jejuni gastroenteritis, 128–29 coenzyme Q10, 27
cancer-associated retinopathy, 90–92 Cogan’s lid twitch, 122, 176–77
232 Index
23
Collier sign, 226f, 226 CTA. See computed tomography

complete bilateral external ophthalmoplegia, angiography
128–29, 128t, 214 CVST. See cerebral venous sinus
compression. See also compressive optic thrombosis
neuropathy
optic chiasm, 63, 64f, 64–65 day blindness, 90–91
optic nerve, 208, 210 decompression
compressive optic neuropathy, 21–24, 22f for pituitary apoplexy, 64–65
TED and, 209–11 for superior oblique myokymia, 118
computed tomography (CT), 23, 208f, decreased forehead sensation, 214
209–10, 216–17 decreased intracranial pressure, 112–13
computed tomography angiography deferoxamine chelation therapy, 214–15
(CTA), 101–2 dementia, 71–75
cone dystrophy, 91–92 demyelinating diseases, 4
cone photoreceptor diseases, 90–92 dermatochalasis, 176–77
congenital cranial dysinnervation diabetic ketoacidosis, 214–15, 216f, 217
syndromes, 129–30 digital subtraction cerebral angiography
congenital hindbrain anomalies, 146–47 (DSA), 101–2, 221–22
congenital myopathies, 129–30 dilated and tortuous conjunctival vessels,
congenital nystagmus. See infantile 220f, 220–21
nystagmus “dilation lag,” 194–95
conjugate gaze palsy, 134 dilute pilocarpine test, 202
conjunctival chemosis, 214–15, diplopia, 48–50
220f, 220–21 anisocoria and, 188–90
conjunctival injection, 22–23, binocular
208, 220–21 diagonal, 107t
contact lenses, 177–78 horizontal, 112
convergence, 134, 138–39, 152, 226 vertical, 106, 108–9
convergence–retraction nystagmus, 226f, 226 CPEO and, 131
“corkscrew” conjunctival vessels, 220–21 with direct CCFs, 220–21
corneal basement membrane dystrophy, 90 INO and, 135–36
corneal exposure, 220–21 intermittent, 115–19, 116b
corneal topography, 90 ocular myasthenia, 121–25
cortical blindness, 73t supranuclear ophthalmoplegia and, 138
corticosteroids, 12, 17–18, 38, 125, 210 TED and, 208
cotton-wool spots, 48–50 transient, 10–11
CPEO. See chronic progressive external direct carotid-cavernous fistula, 220–21
ophthalmoplegia “disc at risk,” 16f, 16–17
craniopharyngioma, 23, 63 “dissociated” abducting nystagmus, 134
C-reactive protein, 11–12 “doll’s eyes” maneuver, 128
Creutzfeldt-Jakob disease, 68, 139 dopaminergic agents, 139
CSF. See cerebrospinal fluid dorsal midbrain syndrome, 225–28,
CT. See computed tomography 226f, 227f
. Index 233

234
downbeat nystagmus, 145–48, 146b, 147f extrinsic venous sinus

driving, homonymous hemianopia compression, 50–51
and, 67–70 exudates, 48–50
drugs eyelid
gaze-evoked nystagmus caused abnormalities, 22–23
by, 142–43 edema, 220f, 220–21
pharmacologic mydriasis, 200–2, 201t lower eyelid ectropion, 122
saccadic intrusions caused by, 170b ptosis, 175–78, 177f
visual hallucinations caused by, 78   retraction, 208
DSA. See digital subtraction cerebral surgery of, 178 
angiography
dysarthria, 138–39 facial anhidrosis, 194–95
dyschromatopsia, 22–23, 31, 78, facial infarction, 216f
90–91, 208 facial nerve palsy, 48–50
dysmetria, 167–71, 169b fascicular lesion, 112
fatigable muscle weakness, 122
ECA. See external carotid artery flocculonodular lobe, lesions of, 146–47
echocardiography, 86–87 flow-diverting stents, 222
edema. See optic disc edema fluorescein angiography, 11f, 11–12
edrophonium, 123–24, 123t fogging refraction, 94–95
electrophysiology, 124, 163–64 fortification spectra, 78
electroretinography (ERG), 91 Foster Kennedy syndrome, 42
elevated intraocular pressure, 220–21 4-aminopyridine, 147–48, 153
elliptical eye oscillations, 156   fourth nerve palsy, 105–9, 107t, 108f
embolism, with transient visual loss, fourth nerve schwannoma, 107, 108f
84–86, 86f fourth ventricle tumors, 134–35
empty sella, 50f, 50–51 foveation periods, 162
encephalopathies, 68 fractionated stereotactic
endovascular therapy, 222 radiotherapy, 23–24
end-point nystagmus, 142 Friedreich ataxia, 168–69
enophthalmos, 194–95 FRMD7 gene, 162
epidural abscess, 214–15 fungal infections, 23, 36–37, 213–18
epilepsy, 142–43 fungal sinusitis, 213–18
ERG. See electroretinography
erythrocyte sedimentation GABAA-agonist,  147–48
rate, 11–12 gabapentin, 157–58, 164
esotropia, 112 gait ataxia, 142–43, 152
essential anisocoria, 190 galactorrhea, 63
exposure keratopathy, 209–10 gastric bypass surgery, 151, 152
external carotid artery (ECA), 220 gaze-evoked nystagmus, 141–44, 143b, 146
extraocular muscle bellies, enlargement GCA. See giant cell arteritis
of, 208f, 208–10, 216f, gene therapy, 27
216–17, 221f germinomas, 226–27, 227f
234 Index
235
giant cell arteritis (GCA), 10–13, fourth nerve palsy and, 107

11f, 17–18 “hummingbird” sign, 139
third nerve palsy and, 101–2 hydrocephalus, 42–45, 226–28
TVL and, 84–86 hydroxyamphetamine, 196–97
glaucomatous optic neuropathy, 220–21 hyperopic shift, 42
glioma, 23, 63 hyperphoria, 118
Goldmann perimetry, 48–50, 95 hypertropia, 106–7, 107t
GQ1b antibodies, 128–29 hypoperfusion, systemic, 84
granulomatosis with polyangiitis, 214 hyporeflexia, 201–2
Graves ophthalmopathy, 207–11, hypotension, nocturnal, 16–17, 18
208f, 209t hypotension, systemic, 84–86
Guillain-Barré syndrome, 128–29 hypoxemia, 16–17
Guillain-Mollaret triangle, 156–57
ICA. See internal carotid artery
“hatchet” facial appearance, 129–30 ice test, 123–24, 123t, 124f, 125
headaches idebenone, 27, 32
chiasmal syndromes, 61–65 idiopathic intracranial hypertension (IIH),
IIH and, 48–50 47–53, 48b, 49f, 50f
migraine visual aura and, 77–82, 79f, 80t idiopathic optic neuritis, 4–5, 6b, 7, 26
neuroretinitis and, 36–37 idiopathic orbital inflammation, 210
papilledema and, 42 IgG4-related disease, 214
pseudopapilledema and, 56 IIH. See idiopathic intracranial
temporal, 10 hypertension
head tilt, 106–7 IIH Treatment Trial (IIHTT), 52
hemeralopia, 90–91 immunosuppressive therapy, 38, 210
hemifacial spasm, 182–83 increased intracranial pressure
hemiparesis, 100 causes of, 43b
hemorrhagic conjunctival chemosis, 220f IIH and, 48
hereditary optic neuropathy papilledema and, 42–45, 43f
ADOA, 29–32, 31f sixth nerve palsy and, 112–13
LHON, 25–28, 27f ventriculoperitoneal shunt malfunction
higher visual function, disorders of, and, 227–28
71–75, 73t indirect carotid-cavernous fistula,
high-grade gliomas, 63 219–23, 220f
hindbrain anomalies, 134–35 infantile nystagmus, 161–65, 162b, 163f
histoplasmosis, 36–37 infections
Holmes-Adie syndrome, 201–2 neuroretinitis caused by, 36–37
homonymous hemianopia, 67–70, orbital, 23
69f, 73–74 orbital apex syndrome and, 214
Horner syndrome, 193–98, 194f retrobulbar optic neuritis caused by, 4
anisocoria and, 188–90 inferior altitudinal visual field defect, 16
causes of, 196t inflammation, orbital, 23
eyelid ptosis and, 176–77 inflammatory diseases
. Index 235

236
inflammatory bowel disease, 36–37 jerk-waveform nystagmus

neuroretinitis caused by, 36–37, 38 downbeat nystagmus, 145–48,
retrobulbar optic neuritis caused by, 4 146b, 147f
infranuclear ophthalmoplegia, 127–31, gaze-evoked nystagmus, 141–44
128t, 131f upbeat nystagmus, 151–54, 153b
inherited cerebellar degenerations, 146–47 jimsonweed, 188–90
inherited retinal degenerations, 156–57 junctional scotoma, 62–63
injections
botulinum toxin A, 183 Kearns-Sayre syndrome, 129–30, 131f
INO. See internuclear ophthalmoplegia keratoconus, 90, 94
intermittent diplopia, 115–19, 116b Korsakoff syndrome, 153 
ocular myasthenia and, 121–25
internal carotid artery (ICA) lagophthalmos, 208
aneurysm, 23 lazy eye, 116–17
CCFs and, 220 Leber hereditary optic neuropathy
dissection, 196–98, 197f (LHON), 25–28, 27f
stenosis, 87 lesions
internal ophthalmoplegia, 128–29 bilateral parieto-occipital, 72–73
internuclear ophthalmoplegia (INO), 107, dorsal midbrain syndrome caused
122, 133–36, 135f by, 226–27
intracranial mass lesions, 42–45 downbeat nystagmus caused by, 146–47
intracranial tumors, 23 fourth nerve palsy caused by, 107
intraocular pressure, 220–21, 222 homonymous hemianopia caused by,
intravenous methylprednisone, 135–36, 67–70, 69f
210–11 infranuclear ophthalmoplegia, 128
intravenous thiamine, 153 intracranial mass, 42–45
iris atrophy, 201–2 nuclear-infranuclear,  138
iris dilator muscle, 188, 194–95 occipital, 78–79
iris sphincter muscle, 200 oculosympathetic pathway, 196–97
iris transillumination defects, optic chiasm, 62f
163f, 163–64 supranuclear, 138
irregular astigmatism, 90 third nerve palsy caused by, 100
isavuconazole, 217 tonic pupil caused by, 200
ischemia. See also microvascular ischemia upbeat nystagmus caused by, 152
choroidal, 10–12 levator dehiscence, 177f, 177–78, 190
cilioretinal, 10–12 levator function, 176–77
vertebrobasilar, 78–79 Lewy body disease, 78
ischemic optic neuropathy. See also LHON. See Leber hereditary optic
nonarteritic anterior ischemic optic neuropathy
neuropathy lid lag, 208
AAION, 10–13, 11f, 17–18 lid retraction, 107–8
anterior, 10 lipoprotein receptor-related protein 4
bilateral optic neuropathy due to, 30 (LRP4) antibodies, 122–23
posterior, 10  “little red discs,” 58
236 Index
237
lower eyelid ectropion, 122 medications

low-grade gliomas, 63 anisocoria and, 188–90 
lumbo-peritoneal shunting, 52–53 gaze-evoked nystagmus caused
Lyme disease, 36–37 by, 142–43
lymphadenopathy, 36–37 NAION caused by, 17
lymphoma, 23, 63  saccadic intrusions caused by, 170b
Meige syndrome, 182, 183
macroprolactinoma, 63 MELAS. See mitochondrial encephalopathy
macrosaccadic oscillations, 168f, 168–69, with lactic acidosis and stroke-like
169f, 170 episodes
macular star, 36, 37f memantine, 153, 157–58, 164, 170
magnetic resonance angiography (MRA), meningeal disease, 112–13
101–2, 197–98, 221f, 221–22 meningiomas, 23, 44f, 44, 50–51, 63
magnetic resonance imaging (MRI) meningitis, 214–15, 216–17
for CCFs, 221f, 221–22 MERRF. See myoclonic epilepsy with
for compressive optic neuropathy, 23 ragged red fibers
for CPEO, 130–31 metamorphopsia, 78
for downbeat nystagmus, 146–47 methylprednisone, 7, 12,
for fourth nerve palsy, 107, 108f 135–36, 210–11
for gaze-evoked nystagmus, 143 micropsia, 78
for homonymous hemianopia, 68, 69f microvascular ischemia
for Horner syndrome, 197–98 fourth nerve palsy and, 105–9
for IIH, 50f sixth nerve palsy and, 112–13
for increased intracranial pressure, third nerve palsy and, 100–1, 102
42–44, 44f midbrain-thalamic stroke, 128–29
for infantile nystagmus, 163f, 163–64 migraine
for INO, 134–35, 135f acephalgic, 78–79
for mucormycosis, 216–17 anisocoria and, 188–90
for neuroretinitis, 37 homonymous hemianopia and, 68
for optic chiasm compression, retinal, 80
64f, 64–65 TVL and, 84
for optic neuritis, 4–7, 5f, 6f visual aura, 77–82, 79f, 80t
for PSP, 139 Miller Fisher syndrome, 107–8, 112,
for TED, 209–10 128–29, 201–2
for third nerve palsy, 101–2 miosis, 188, 190, 194–95
for TVL, 86–87 mitochondrial disease, 129–31
for VVAD, 73–74, 75f mitochondrial DNA (mtDNA), 26–27
for Wernicke encephalopathy, 153 mitochondrial encephalopathy with lactic
magnetic resonance venography (MRV), acidosis and stroke-like episodes
42–44, 50f (MELAS), 129–30
malingering, 93–96 MLF. See medial longitudinal fasciculus
marginal-reflex distance, 176–77 modified Dandy criteria, 48b, 50–51
medial longitudinal fasciculus (MLF), 134 modified Frisén scale, 48–50, 49t
. Index 237

238
monocular diplopia, 116–17 NMO. See neuromyelitis optica

monocular hemianopia, 95 nocturnal hypotension, 16–17, 18
monocular oscillopsia, 117 nonarteritic anterior ischemic optic
MRA. See magnetic resonance angiography neuropathy (NAION), 10, 11–12,
MRI. See magnetic resonance imaging 15–19, 26
MRV. See magnetic resonance venography medications causing, 17
MS. See multiple sclerosis optic disc edema and, 10–11
mtDNA. See mitochondrial DNA pathogenesis of, 16–17
mucormycosis, 214–17, 216f nonorganic vision loss, 93–96, 95b
Müller muscle, 194–95 North American Symptomatic Carotid
multiple sclerosis (MS) Endarterectomy Trial, 87
APN caused by, 155–56 nuclear-infranuclear lesion, 128, 138
gaze-evoked nystagmus caused nutritional optic neuropathy, 30, 90
by, 142–44 nyctalopia, 90–91
INO caused by, 134–36 nystagmus
optic chiasm, 63 convergence–retraction, 226f, 226
optic neuritis caused by, 4–7, 5f downbeat, 145–48, 146b, 147f
sixth nerve palsy caused by, 112–13 end-point,  142
mumps, 36–37 gaze-evoked, 141–44, 143b
muscle-specific kinase (MuSK) infantile, 161–65, 162b, 163f
antibodies, 122–23 pendular, 155–58, 157b
myasthenia gravis, 122, 129–30 upbeat, 151–54, 153b
mydriasis, 188, 200–2, 201t
myoclonic epilepsy with ragged red fibers obstructive sleep apnea, 16–17, 18
(MERRF), 129–30 occipital seizures, 80, 80t, 81b
myotonia, 129–30 occipital stroke, 68
myotonic dystrophy, 129–30, 176  occult retinopathy, 90–91
OCT. See optical coherence tomography
NAION. See nonarteritic anterior ischemic ocular flutter, 168–70, 170b
optic neuropathy ocular motor apraxia, 72–73, 73t
neural integrator, 142, 156 ocular myasthenia, 100–1, 107–8, 112,
neurodegenerative diseases 121–25, 123f, 124f, 135, 210
CPEO and, 129–30 oculocutaneous albinism, 163f, 163–64
dorsal midbrain syndrome and, 226–27 oculomasticatory myorhythmia, 139
higher visual function disorders oculomotor nerve palsy, 99–102
and, 71–75 oculopalatal tremor (OPT), 156–57, 157f
PSP, 138–40 oculopharyngeal muscular dystrophy,
visual hallucinations caused by, 78 129–30, 176
neurofibromatosis type I, 63 oculosympathetic pathway, 194,
neuromyelitis optica (NMO), 4, 5–7, 6f 196–97, 196t
neuroretinitis, 4, 35–39, 36f, 37f olfactory groove meningioma, 44f, 44
Niemann-Pick type C, 226–27 “one-and-a-half ” syndrome,  134
night blindness, 90–91 ONHD. See optic nerve head drusen
238 Index
239
ONSF. See optic nerve sheath fenestration optic nerve hypoplasia, 163f, 163–64
ONSM. See optic nerve sheath optic nerve sheath fenestration
meningioma (ONSF), 52–53
OPA1 mutation, 31–32 optic nerve sheath meningioma (ONSM),
ophthalmic artery aneurysm, 23 22f, 23–24
ophthalmoplegia, 123–24 optic neuritis, 3–8, 5f, 6f
with direct CCFs, 220–21 bilateral optic neuropathy due to, 30
infranuclear, 127–31, 128t, 131f idiopathic, 4–5, 6b, 7, 26
internuclear, 133–36, 135f pendular nystagmus and, 156
Miller Fisher syndrome, 201–2 retrobulbar, 4
supranuclear, 137–40 Optic Neuritis Treatment Trial, 7
opsoclonus, 168–70, 170b optic neuropathy
OPT. See oculopalatal tremor AAION, 10–13, 11f, 17–18
optical coherence tomography (OCT), ADOA and, 30
59–60, 64–65, 163–64 compressive, 21–24, 22f
optic ataxia, 72–73, 73t infranuclear ophthalmoplegia
optic atrophy, 64–65 and, 129–31
autosomal dominant, 29–32, 31f ischemic, 10   
hereditary optic neuropathy LHON, 25–28, 27f
and, 26–27 neuroretinitis, 35–39, 36f, 37f
papilledema and, 42 nonorganic vision loss and, 94
pendular nystagmus and, 156 pendular nystagmus and, 156
optic chiasm, syndromes affecting, 61–65, unexplained vision loss and, 90
62f, 64f optociliary collateral vessels, 22–23
optic disc cupping, 31f, 31, 220–21 optokinetic nystagmus, 94–95
optic disc edema orbicularis oculi, 122, 176–77
compressive optic neuropathy orbital apex biopsy, 216–17
and, 22–23 orbital apex enhancement, 216–17
diffuse, 10–11 orbital apex syndrome, 213–18,
hereditary optic neuropathy and, 26–27 215b, 215t
hyperemic, 10–11 orbital cellulitis, 210
NAION and, 16f, 16–17 orbital decompression surgery, 23, 210–11
neuroretinitis and, 36f, 36 orbital echography, 209–10
pallid, 10–11, 11f orbital inflammation, 23, 214
papilledema and, 41–45, 43f, 44f orbital tumors, 23
pseudopapilledema and, 56 oromandibular dystonia, 182, 183
segmental, 16 oscillopsia, 146, 147–48, 153, 157–58,
Wernicke encephalopathy and, 152–53 162, 170 
optic glioma, 23
optic nerve compression, 18, 208 pain
optic nerve head drusen (ONHD), 58f, with monocular vision loss, 4
58–60, 84–86 with sixth nerve palsy, 112–13
optic nerve head elevation, 56–58, 59–60 with third nerve palsy, 100–1
. Index 239

240
painless monocular vision loss, 22–23 pituitary hypofunction, 163–64

palinopsia, 73t pituitary macroadenoma, 63, 64f
panhypopituitarism, 64–65 polyarteritis nodosa, 36–37
papilledema, 37f, 41–45, 43f, 44f posaconazole, 217
differential diagnosis of, 56b positron emission tomography (PET), 74
IIH and, 47–53, 49f positron emission tomography with co-
modified Frisén scale for grading, registered computed tomography
48–50, 49t (PET-CT),  146–47
ONHD compared to, 59–60 posterior compressive optic
pseudopapilledema compared with, 56, neuropathy, 22–23
57f, 57t posterior globe flattening, 50f, 50–51
TVL and, 84–86 posterior ischemic optic neuropathy, 10
paraneoplastic cerebellar degeneration, postganglionic parasympathetic innervation
146–47, 147f of pupil, 200
paraneoplastic syndromes, 170 postural reflexes, impaired, 138–39
parieto-occipital atrophy, 73–74, 75f prednisone, 7, 12, 18, 38
parieto-occipital hypometabolism, 74 presbyopia, 90, 138, 170
Parinaud syndrome, 225–28 prisms, 69–70, 164, 210
Parks-Bielschowsky test, 106–8, 107t progressive supranuclear palsy
paroxysmal cranial nerve disorders, 117–18 (PSP), 138–40
“peekaboo” sign, 122 blepharospasm and, 182
pendular nystagmus, 155–58, 157b dorsal midbrain syndrome and, 226–27
percutaneous embolization, 222 saccadic intrusions and, 168–69
periorbital edema, 208, 214–15, 216f propranolol, 81
peripapillary telangiectatic vessels, proptosis, 22–23, 107–8, 214–15,
26–27, 27f 220f, 220–22
PET. See positron emission tomography prosopagnosia, 72–73
PET-CT. See positron emission tomography protozoal infections, 36–37
with co-registered computed “pseudo-abducens” palsy, 112
tomography pseudo-Horner syndrome, 190
pharmacologic mydriasis, 200–2, 201t pseudo-INO,  135
pharmacologic pupil testing, 194–97, 202 pseudopapilledema, 55–60, 57f, 57t
phenytoin, 142–43 pseudotumor cerebri. See idiopathic
phosphodiesterase type-5 inhibitors, 17 intracranial hypertension
photophobia, 182, 183, 200 PSP. See progressive supranuclear palsy
photopsias, 90–91 ptosis, 100, 107–8, 214
photoreceptor disease, 90–92 anisocoria and, 188–90
physiologic anisocoria, 190 eyelid, 175–78, 177f
physiologic end-point nystagmus, 142 Horner syndrome and, 194f, 194–95
pigmentary retinopathy, 129–31 infranuclear ophthalmoplegia and,
pilocarpine, 202 128–29, 130–31
pineal teratomas, 226–27 ocular myasthenia and, 122,
pituitary adenoma, 23, 63 123–24, 125
pituitary apoplexy, 63–65 reverse, 194–95
240 Index
241
pulsatile tinnitus, 220–21 sagging eye syndrome, 177–78

pulse-synchronous tinnitus, 42, 48–50 “salt and pepper” retinopathy, 129–31
pupil-involving third nerve palsy, sarcoidosis, 4, 36–37, 63, 214
100f, 100–2 schwannoma, fourth nerve, 107, 108f
pupil size, measuring, 190 scotoma
pupil-sparing third nerve palsy, 100 bean-shaped,  78
pyridostigmine, 125  central, 26–27, 31, 214
junctional, 62–63
radioactive iodine therapy, 210–11 segmental palsy, 200–2
Rathke cleft cyst, 63 seizures, 68, 78
reading difficulties selenium, 210
with fourth nerve palsy, 106 septo-optic dysplasia, 163f, 163–64
with macrosaccadic seronegative ocular myasthenia, 122–23
oscillations, 168–69 “setting sun” sign, 226
with PSP, 138, 139 sfEMG. See single-fiber electromyography
with saccadic instrusions, 167–68 shunting, for cerebrospinal fluid, 52–53
refractive error, 90, 164 shunt malfunction, 227–28
relative afferent pupillary defect, 10–11, 16, simple anisocoria, 190
22–23, 68, 94, 156, 190, 214 simultanagnosia, 72–74, 73t
repetitive nerve simulation testing, single-fiber electromyography (sfEMG),
123t, 124 123t, 124
rest test, 123–24, 123t, 125 sinus mucosal thickening, 216–17
retinal emboli, 84–86 sinus opacification, 216–17
retinal folds, 22–23, 48–50 sixth nerve palsy, 48–50, 111–14
retinal hemorrhages, 48–50 skew deviation, 107–8, 134, 226f, 226
retinal migraine, 80 sleep test, 123–24, 123t, 125
retinal nerve fiber layer (RNFL), 10–11, smoking, 210–11
56, 64–65 smooth pursuit, impaired, 146
retinitis pigmentosa, 90–91 spectral-domain optical coherence
retrobulbar optic neuritis, 4 tomography, 91
retrocollis, 138–39 spirochete infections, 36–37
reverse ptosis, 194–95 square-wave jerks, 138–39, 168–69
rigidity, axial, 138–39 stereopsis, 94–95
RNFL. See retinal nerve fiber layer stereotactic radiosurgery, 222
rod photoreceptor diseases, 90–91 stereotactic ventriculo-peritoneal
shunting, 52–53
saccades, 168 strabismus surgery, 164, 210–11
horizontal, 138–39 streak retinoscopy, 90
vertical, 138–39 stroke
saccadic amplitude, 168   brainstem, 134–36
saccadic dysmetria, 167–71, 169b complete bilateral external
saccadic hypermetria, 168 ophthalmoplegia caused by, 128–29
saccadic intrusions, 167–71, 168f, dorsal midbrain syndrome caused
169f, 170b by, 226–27
. Index 241

24
stroke (cont.) thyroid eye disease (TED), 207–11, 208f

higher visual function disorders abduction deficit and, 112
and, 72–74 compressive optic neuropathy and, 23
homonymous hemianopia caused CPEO and, 129–30
by, 67–70 fourth nerve palsy and, 107–8
oculopalatal tremor and, 156–57 grading of, 209t
sixth nerve palsy caused by, 112–13 orbital irradiation for, 210–11
TVL and, 86–87 thyroid function tests, 209–10
subarachnoid hemorrhage, 44–45 tocilizumab, 12
subdural abscess, 214–15 tonic pupil, 199–203, 201t  
superior oblique myokymia, 116–18 topiramate, 52, 81
superior orbital fissure syndrome, 213–18, toxic optic neuropathy, 30, 90
215b, 215t toxoplasmosis, 36–37
supranuclear lesion, 128, 138 transient diplopia, 10–11, 115–19, 116b
supranuclear ophthalmoplegia, 137–40 transient ischemic attack, 84–86, 87
supranuclear vertical gaze palsy, 226 transient vision loss (TVL), 83–87,
surgery 85t, 86f
for blepharospasm, 183 transient visual hallucinations, 78
of eyelid, 178 transient visual obscurations, 42, 48–50
for IIH, 52–53 transillumination defects, 201–2
for infantile nystagmus, 164 transverse venous sinus stenoses, 50f, 50–51
orbital, 201–2 transverse venous sinus stenting, 52–53
orbital decompression, 23, 210–11 trauma, 63
strabismus, 164, 210–11 anisocoria caused by, 188–90
for superior oblique myokymia, 118 fourth nerve palsy caused by, 106
symmetric papilledema, 42 levator dehiscence caused by, 177–78
syphilis, 36–37 sixth nerve palsy caused by, 112–13
third nerve palsy caused by, 100–1
tear film dysfunction, 84–86 tonic pupil caused by, 201–2
TED. See thyroid eye disease traumatic optic neuropathy, 30
temporal artery biopsy, 11–12 tremor, 100
temporal headaches, 10 trigeminal neuralgia, 117–18
temporo-occipital junction, 72–73 triptan medications, 81
tenotomy-and-reattachment procedure,  164 trochlear nerve palsy, 105–9, 107t, 108f
Tensilon, 123–24, 123t tuberculosis, 36–37
thiamine, 153 tumors
third nerve palsy, 99–102, 100f, 176–77 dorsal midbrain syndrome caused
anisocoria and, 188–90 by, 226–27
ocular myasthenia and, 122 higher visual function disorders
third-ventricular tumors, 226–27 and, 72–74
thymectomy, 125 homonymous hemianopia caused
thymoma, 125 by, 67–70
thyroid-associated ophthalmopathy. See INO caused by, 134–35
thyroid eye disease intracranial, 23
242 Index
243
orbital, 23 with optic neuritis, 4, 5–7

TVL. See transient vision loss painless, 22–23, 36, 37–38
papilledema and, 42
unexplained vision loss, 89–92 with TED, 208
unilateral papilledema, 42 transient, 83–87, 85t, 86f
upbeat nystagmus, 107, 142, 151–54, 153b transient visual obscurations, 42
upper-eyelid ptosis, 226 unexplained, 89–92
upper-eyelid retraction, 138–39, visual agnosia, 72–74
226f, 226 visual field constriction, 95b, 95
upper-eyelid skin crease, 176–77 visual field defects
upside-down ptosis, 194–95 bitemporal, 62f, 62–63
central, 90–91
vaccinations, 4 homonymous, 68
vascular malformations, 63 inferior altitudinal, 16
vascular stenosis, 87 visual hallucinations, 73t, 77–82
vasospasm, 84 visual illusions, 77–82
venous sinus stenting, 52–53 visual memory impairment, 72–73
venous sinus thrombosis, 42–45, 50–51, visual snow, 79
51b, 214–15 visual-variant Alzheimer disease (VVAD),
ventriculo-peritoneal shunting, 73–75, 75f
52–53, 227–28 vomiting, with migraine, 78
vertebrobasilar ischemia, 78–79 von Graefe sign, 208
vertical gaze palsy, 226 VOR. See vestibulo-ocular reflex
vertical saccades, limited and VVAD. See visual-variant Alzheimer
slowed, 138–39 disease
vestibulo-cerebellum,  146–47
vestibulo-ocular reflex (VOR), 128, 134, warfarin, 87, 197–98
138, 146 Wegener granulomatosis, 214
viral encephalitis, 72–73 Wernicke encephalopathy, 112–13, 152–53
vision loss Whipple disease, 139
with direct CCFs, 220–21 white matter lesions, 4, 5f, 5–7
homonymous hemianopia, 67–70
management based on severity of, 51t X-linked infantile nystagmus syndrome,
nonorganic, 93–96 162
. Index 243

24

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i

S E R I E S C O -​E D ITORS-​I N-​C HIE F

Matthew J. Thurtell, MBBS, FRACP

Robert L. Tomsak, MD, PhD

Robert B. Daroff, MD—​our mentor, colleague, and friend—​in

SECTION I AFFERENT DISORDERS

2 Arteritic Ischemic Optic Neuropathy 9

3 Nonarteritic Ischemic Optic Neuropathy 15

4 Compressive Optic Neuropathy 21

5 Leber Hereditary Optic Neuropathy 25

6 Autosomal Dominant Optic Atrophy 29

9 Idiopathic Intracranial Hypertension 47

13 Disorders of Higher Visual Function 71

14 Visual Auras, Hallucinations, and Illusions 77

15 Transient Vision Loss 83

16 Unexplained Vision Loss 89

17 Nonorganic Vision Loss 93

SECTION II EFFERENT DISORDERS

18 Third Nerve Palsy 99

19 Fourth Nerve Palsy 105

20 Sixth Nerve Palsy 111

21 Intermittent Diplopia 115

22 Ocular Myasthenia 121

23 Infranuclear Ophthalmoplegia 127

24 Internuclear Ophthalmoplegia 133

25 Supranuclear Ophthalmoplegia 137

26 Gaze-​Evoked Nystagmus 141

27 Downbeat Nystagmus 145

28 Upbeat Nystagmus 151

29 Pendular Nystagmus 155

30 Infantile Nystagmus 161

31 Saccadic Intrusions and Dysmetria 167

SECTION III EYELID DISORDERS

32 Eyelid Ptosis 175

33 Benign Essential Blepharospasm 181

SECTION IV PUPIL DISORDERS

35 Horner Syndrome 193

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

37 Thyroid Eye Disease 207

38 Syndromes of the Orbital Apex, Superior Orbital Fissure, and

39 Carotid-​Cavernous Fistula 219

40 Dorsal Midbrain Syndrome 225

Patients with neuro-​ophthalmic conditions are commonly encountered

Many of the cases described in this book touch on controversial aspects

You are called to see a 22-​year-​old woman

What do you do now?

T he patient in this scenario has had a subacute onset of painful mo-

4 WHAT DO I DO NOW? Afferent Disorders

changes are nonspecific and cannot be considered diagnostic of idiopathic

1. Optic Neuritis 5

with optic neuritis in the setting of NMO with myelin oligodendrocyte

BOX 1.1 Atypical Features for Idiopathic Optic Neuritis

6 WHAT DO I DO NOW? Afferent Disorders

KEY POINT S TO REMEMBER

• The cardinal signs of an optic neuropathy are decreased visual

1. Optic Neuritis 7

• Optic neuritis is characterized by a subacute onset of painful

8 WHAT DO I DO NOW? Afferent Disorders

A 75-​year-​old white woman presents to

What do you do now?

T he acute onset of severe monocular vision loss with associated pallid

10 WHAT DO I DO NOW? Afferent Disorders

2. Arteritic Ischemic Optic Neuropathy 11

GCA is high. Fluorescein angiography can be useful to demonstrate cho-

S E R I E S C O -E D ITORS-I N-C HIE F

Matthew J. Thurtell, MBBS, FRACP

Robert L. Tomsak, MD, PhD

Robert B. Daroff, MD—our mentor, colleague, and friend—in

26 Gaze-Evoked Nystagmus 141

39 Carotid-Cavernous Fistula 219

Patients with neuro-ophthalmic conditions are commonly encountered

You are called to see a 22-year-old woman

What do you do now?

A 75-year-old white woman presents to

What do you do now?

An overweight 58-year-old man presents

What do you do now?

• NAION is the most common cause of acute-onset optic

A 40-year-old woman presents to your

What do you do now?

What do you do now?

A 14-year-old boy presents to your clinic

What do you do now?

You are called to see a 28-year-old woman

What do you do now?

and polyarteritis nodosa. Neuroretinitis is usually a self-limited condition,

• In patients with recurrent neuroretinitis, long-term

A 32-year-old man presents to your clinic

What do you do now?

A 22-year-old overweight woman presents

What do you do now?