Jurnal Embriologi

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
case records of the massachusetts general hospital

Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor
Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor
Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor
Christine C. Peters, Assistant Editor
Case 24-2011: A 36-Year-Old Man

with Headache, Memory Loss, and Confusion
Don C. Bienfang, M.D., Michael J. McKenna, M.D., George N. Papaliodis, M.D.,
R. Gilberto Gonzalez, M.D., Ph.D., and Anat Stemmer-Rachamimov, M.D.
Pr e sen tat ion of C a se

Dr. M. Brandon Westover (Neurology): A 36-year-old right-handed man was seen in the
neurology clinic of this hospital because of headaches, confusion, and memory loss.
The patient had been well until 1 month earlier, when nausea, fevers, chills, diarrhea, malaise, and myalgias developed and lasted 2 days. During the next 3 days, he
had a constant headache centered between his eyes, with a sensation of squeezing.
The headache resolved, but 5 days later his wife noted that he seemed apathetic and
confused on awakening, with loss of short-term memory. He was admitted to another hospital. On examination, the patient, who appeared to be unconcerned, had
decreased concentration and was unable to remember three items when questioned
3minutes later; the examination was otherwise normal.
Results of routine laboratory tests were normal; a test for Lyme disease was
negative. Magnetic resonance imaging (MRI) reportedly showed lesions with restricted diffusion in the periventricular and subcortical white matter and the corpus
callosum. A scan of the head and neck obtained with magnetic resonance angiography was reportedly normal. A lumbar puncture was performed; the results of cerebrospinal fluid analysis are shown in Table 1. Treatment with acyclovir was begun.
Electroencephalography (EEG) reportedly revealed episodes of generalized irregular
high-voltage delta activity throughout, but more prominent anteriorly and enhancing
on hyperventilation. There were also intermittent, brief episodes of sharp theta activity and transient sharp waves with phase reversals over the left midtemporal region.
Treatment with levetiracetam was begun. A repeat EEG revealed occasional left
frontotemporal sharp waves with phase reversals at T3, with intermittent generalized slowing, slightly more severe on the left and a diffusely slow background, with
no spike or polyspike activity. MRI performed after the administration of gadolinium
reportedly showed new hyperintense, nonenhancing lesions in the corpus callosum
and left cerebellum.
The patient was discharged on the sixth day in improved condition, with prescriptions for levetiracetam and butalbitalacetaminophencaffeine and instructions to
follow up with a neurologist. He returned to work but was unable to concentrate.
Two weeks later, he was seen in the neurology clinic of this hospital.
From the Division of Neuro-Ophthalmology, Brigham and Womens Hospital

(D.C.B.); the Otology and Neurotology
Service (M.J.M.) and the Department of
Ophthalmology (G.N.P.), Massachusetts
Eye and Ear Infirmary; the Departments
of Radiology (R.G.G.) and Pathology
(A.S.-R.), Massachusetts General Hospital; and the Departments of Ophthalmology (D.C.B., G.N.P.), Otology and Laryngology (M.J.M.), Radiology (R.G.G.), and
Pathology (A.S.-R.), Harvard Medical
School all in Boston.
N Engl J Med 2011;365:549-59.
Copyright 2011 Massachusetts Medical Society.
n engl j med 365;6 nejm.org august 11, 2011
The New England Journal of Medicine

Downloaded from nejm.org on September 13, 2011. For personal use only. No other uses without permission.
Copyright 2011 Massachusetts Medical Society. All rights reserved.
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Table 1. Cerebrospinal Fluid Analysis.*

Reference Range,
Adults
Variable
Other Hospital
On Admission, 20 Days
before Presentation to
Neurology Clinic
Opening pressure (cm of water)
This Hospital
1st Admission, 4.25 Mo
after Presentation
2nd Admission, 5 Mo
after Presentation
26
24
Appearance
Tube 1
Colorless, clear
Colorless, clear
Light pink, slightly turbid
Tube 4
Colorless, clear
Colorless, clear
Light yellow, clear
None
Yes
Xanthochromia
Red cells (per mm
3)
Tube 1
83
12
2070
Tube 4
Tube 1
05
Tube 4
05
Lymphocytes
98
94
95
Monocytes
White cells (per mm3)
Differential count, tube 4 (%)
Protein (mg/dl)
555
266
211
257
Glucose (mg/dl)
5075
65
63
89
No cells or organisms
Few mononuclear cells,

no organisms
Moderate mononuclear
cells, no organisms
Grams stain
Fungal wet preparation
Culture
No organisms
No organisms
No growth
No growth
Enterovirus RNA, PCR
Negative
Negative
Herpes simplex virus DNA, PCR
Negative
Negative
Cytomegalovirus DNA, PCR
Negative
Varicellazoster virus, PCR

EpsteinBarr virus DNA, PCR
No growth
No growth
Negative, types 1 and 2

Negative
Negative
Negative
None detected
None detected
Venereal Disease Research Laboratory

test
Nonreactive
Cryptococcal antigen
Negative
Angiotensin-converting enzyme (U/liter)

IgG (mg/dl)
<10
<2
08.0
Albumin (mg/dl)
Oligoclonal bands on agarose-gel
electrophoresis
Ratio of CSF IgG:albumin to serum
IgG:albumin
23.6
11.050.9
159.0
None seen in 80
concentrate
Two seen in 63
concentrate
<0.66
0.67
* CSF denotes cerebrospinal fluid, and PCR polymerase chain reaction. To convert the values for glucose to millimoles per liter, multiply by
0.05551.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They
may therefore not be appropriate for all patients.
This ratio is calculated by dividing the ratio of CSF levels of IgG to albumin by the ratio of serum levels of IgG to albumin.
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case records of the massachusetts gener al hospital
The patient had a history of allergic rhinitis

and reported having had one episode of sinusitis.
He was born and lived in New England with his
wife and child, worked in a professional occupation, and owned a dog. He drank alcohol in moderation; he did not smoke or use illicit drugs. His
father had coronary artery disease and a myocardial infarction at 40 years of age; his mother had
a history of poorly defined cognitive symptoms
that started when she was 60 years of age, congestive heart failure, and alcohol abuse; and his
maternal grandmother had dementia in late adulthood. His brother was well.
On examination, the patient appeared well,
with normal social behavior and articulate speech,
and he was fully oriented to person, place, and
time. He recalled 2 items out of 5 viewed 5 minutes earlier, and after cues recalled 4 items out of
5 viewed 10 minutes earlier. He named 14 animals in 1 minute; the result of the forward digitspan test was 7, and that of the reverse digit-span
test was 5. The tone in his limbs was slightly
above normal, more on the right than on the left;
all reflexes were brisk, and the plantar responses
were flexor; the remainder of the neurologic examination was normal. Levetiracetam was discontinued.
During the next 3 months, intermittent tremulousness of his left hand developed; his fatigue
and mental endurance gradually improved, and
he returned to work part-time. Four weeks after
evaluation, an EEG showed no epileptiform activity. MRI of the brain showed multiple hyperintense lesions in the periventricular, infratentorial,
and subcortical white matter and the corpus callosum on T2-weighted images. Repeat MRI of the
brain 2 months later showed a decrease in the
size and number of the white-matter lesions; MRI
of the spine was normal.
Approximately 3 months after the patients initial presentation, insomnia and increasing fatigue
developed. One month later, frontal headache,
somnolence, and memory loss recurred, and he
came to the emergency department. On examination, the blood pressure was 148/76 mm Hg; other
vital signs were normal. On neurologic examination, he was fully oriented, recalled one out of
three items presented 5 minutes earlier, was unable to spell world backward, and exhibited perseveration. The remainder of the examination was
normal. A complete blood count and differential
count, electrolyte levels, glucose levels, and tests

of renal function were normal. A computed tomographic (CT) scan of the brain was normal.
T2-weighted, fluid-attenuated inversion recovery
(FLAIR) images obtained with MRI showed new
bilateral, hyperintense lesions in the right frontal
subcortical and deep white matter, with enhancing lesions in the right cingulate and superior
frontal gyri, the left caudate body, and cerebellum. The images also revealed persistent lesions
in the corpus callosum and in areas of mildly
restricted diffusion in the right cingulate gyrus
and left parietal lobe. The patient was admitted
to the hospital.
Evaluations for hypercoagulability, rheumatologic and autoimmune diseases, and infectious
agents were negative. Cytologic examination of
the cerebrospinal fluid showed no evidence of
cancer; flow cytometry showed no abnormal
cells; the results of other analyses are shown in
Table 1. CT angiography of the head and cerebrum was normal. Transthoracic echocardiography was normal, and a skin test for tuberculosis
was negative. A biopsy of the right frontal lobe
and meninges was performed; pathological examination of tissue specimens revealed small
vessels with changes suggestive of a microangiopathy. Methylprednisolone (a daily intravenous
dose of 1000 mg for 3 days) and cefazolin were
administered. The patient was discharged on the
seventh day with a prescription for 80 mg of oral
prednisone to be taken daily for 4 weeks and
then tapered.
Two weeks later, increased confusion developed, and the patient awoke with a black spot
in the superior visual field of the left eye, which
resolved spontaneously after 12 hours. He came
to the emergency room, where he reported lightheadedness, a mild headache, and fluctuating
hearing loss. An MRI scan revealed a new punctate focus of restricted diffusion in the left splenium of the corpus callosum and unchanged foci
of hyperintensity on T2-weighted FLAIR images
in the white matter of both hemispheres. He was
readmitted.
Findings on examination were unchanged.
The results of CT angiography were normal. Although the patient reported no diplopia or visual
loss, ophthalmologic examination revealed nonspecific visual-field constriction in both eyes,
vascular narrowing in both retinas, with sheath-

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ing, and vascular beading in the left eye, with no affects the brain, the eyes, and the auditory syspapillitis. Results of cerebrospinal fluid analysis tem, and we must consider disorders that can afare shown in Table 1.
fect these systems.
A diagnostic procedure was performed.
Cogans Syndrome
Differ en t i a l Di agnosis
Dr. Don C. Bienfang: May we review the imaging
studies?
Dr. R. Gilberto Gonzalez: MRI was performed at
this hospital 1 month after the patients initial
evaluation in the clinic. Axial FLAIR-weighted
images obtained with MRI at the level of and
superior to the lateral ventricles reveal multiple,
small T2-weighted and FLAIR hyperintense signal
abnormalities in the white matter within the corpus callosum and in the periventricular white
matter. A few similar signal abnormalities were
identified in the deep gray matter, including that
in the right caudate nucleus. The sagittal FLAIR
sequence (Fig. 1A) shows that a few of the lesions involved the entire thickness of the corpus
callosum. Several of the signal abnormalities displayed hyperintensity on diffusion-weighted imaging, but none showed reduced diffusion. An
MRI study repeating that performed at the time
of his first admission to this hospital revealed
new signal abnormalities with similar characteristics (Fig. 1B), but several of the lesions showed
areas of enhancement after the administration of
contrast material, and several of the abnormalities showing hyperintensity on diffusion-weighted
imaging now showed reduced diffusion (Fig. 1C).
Before the diagnostic procedure, another MRI revealed additional new lesions with characteristics
similar to those of the lesions previously identified (not shown).
Dr. Bienfang: This young man presented with a
waxing and waning illness, the major manifestations of which were changes in mental status
and evidence of inflammation, suggested by the
symptom of headache and confirmed by cytologic
and chemical analysis of cerebrospinal fluid. Extensive testing for infectious and rheumatologic
conditions was negative. The MRI of the brain
disclosed multiple lesions in the gray and white
matter, the most striking of which were punchedout holes in the corpus callosum. Finally, the patient reported symptoms of retinal vascular occlusion in both eyes and hearing loss, both of
which were confirmed on examination. The patient thus has an inflammatory condition that
552
In 1945, David Cogan1 described a syndrome of

interstitial corneal keratitis associated with sudden onset of deafness and vestibular symptoms,
occurring most commonly in persons in their 20s.
A characteristic of the deafness in most cases is its
sudden onset, whereas the visual symptoms (reduced vision and light sensitivity) fluctuate. Slitlamp examination reveals interstitial keratitis that
may mimic that which occurs in syphilis, and
there may be episcleritis or retinal vascular occlusion. The latter may be associated with systemic
vasculitis or inflammatory bowel disease.2,3 This
patient was not reported to have corneal abnormalities, did not have the vestibular symptoms
characteristic of Cogans syndrome, and had
rather subtle hearing loss.
Acute Posterior Multifocal Placoid Pigment
Epitheliopathy
The inflammatory disorder acute posterior multifocal placoid pigment epitheliopathy affects the
retina and choroid of otherwise young healthy
adults4 and has some features in common with
the presentation of this patient in that the retina
is involved with visual changes and in some cases
the central nervous system can be affected,5 with
headache, changes in mentation, and even strokelike episodes. However, this disorder creates creamycolored plaques in the retina, which have not been
found in this patient, and it is self-limited and typically lasts only a few weeks. Hearing changes are
not present.
Eales Disease
The retinal venous and arterial vasculopathy known

as Eales disease can sometimes affect the vestibularauditory system, and thus it has some similarity to the findings in this patient.6 However,
the findings within the retina are not subtle, as
they are in this case,7 but are usually characterized
by dramatic hemorrhages.
Whipples Disease
Infection with Tropheryma whipplei is manifested in

numerous locations, including the central nervous
system.8,9 However, gastrointestinal involvement
with malabsorption, a cardinal feature of the ill-

Figure 1. MRI Studies.

A sagittal fluid-attenuated inversion recovery image obtained 1 month after the patients first evaluation at this hospital shows multiple hyperintense signal abnormalities involving the corpus callosum (Panel A, arrows). Several of
the abnormalities involved the entire thickness of the corpus callosum. A diffusion-weighted image (Panel B) and an
apparent-diffusion-coefficient image (Panel C) from an MRI scan obtained at the first admission to this hospital
show a signal abnormality with reduced diffusion in the left splenium of the corpus callosum (arrows).
ness, is not present in this patient, and joint symptoms are common. Finally, the findings in the eye
in Whipples disease are predominantly visible
cellular infiltrates in the vitreous or aqueous humor, in contrast to the findings in this case.10
it is associated with cellular infiltration of the peripheral vitreous.

ChurgStrauss Syndrome
Although the ChurgStrauss syndrome may be

manifested in the eye as a uveitis,14 asthma is the
Lyme Disease
primary feature of this disease.15 The pathology is
Late in the evolution of Lyme disease, which is that of a necrotizing vasculitis.16
similar to another spirochetal infection, syphilis,
the central nervous system can be affected. How- Crohns Disease
ever, the major manifestation of Lyme disease is Patients with Crohns disease always have bowel
meningitis.11,12 The nerve most commonly affect- symptoms, and when the disease involves the eye,
ed is the facial nerve (cranial nerve VII).13 Retinal the features mimic those of anterior or posterior
vasculitis and hearing loss would be unusual, and uveitis, not retinal vasculitis.
testing for antibodies to Borrelia burgdorferi should
Susacs Syndrome
be positive.
Dr. Bienfang: I believe this patient must have Susacs
Central Nervous System Lymphoma
syndrome,17-20 a vasculopathic condition that afLymphoma of the central nervous system may fects the brain, vision (owing to retinal artery ochave variable neurologic manifestations and may clusion), and hearing. All three features may not
affect the eye by means of cellular infiltration of be present, or they may emerge slowly, thus obthe vitreous. However, the results of the brain bi- scuring the diagnosis. However, this patient has
opsy in this patient did not show evidence of this all three of the crucial features, which confirm
diagnosis.
this diagnosis clinically.
The clinician might wonder what points to this
Multiple Sclerosis
diagnosis without confirmatory tests. The features
The pattern of white patches seen on MRI could that should be emphasized as strongly suggestive
be that of multiple sclerosis, but involvement of of Susacs syndrome are the age of the patient,
the auditory system with hearing loss is rare in the waxing and waning changes in mental status,
multiple sclerosis. In addition, the vasculitis of the blotchy visual changes suggesting a dysfuncmultiple sclerosis is peripheral in the retina, and tion of the retinal arterioles, and the hearing loss.
n engl j med 365;6
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553
The
This is a disease of adults and is not seen in children or very elderly patients. Its expression in the
brain is well demonstrated in this patient. Changes
in mental status dominate, and the mental status
fluctuates. Often, the first abnormality noticed by
persons who know the patient is the behavioral
change.
In the eye, the vasculopathy is well expressed.
It was helpful for diagnostic purposes that the
retinal arteries affected were those of the posterior pole, which meant that the patient was symptomatic and that the vessels could be carefully
examined. It appears his mental status did not
allow detailed visual-field testing, which would
probably have revealed scotomas in a pattern defined by the blood vessels. The changes in the
retinal arterioles may be subtle and escape detection with routine funduscopy. Fluorescein angiography may be necessary to expose them. In more
dramatic expression of the vascular changes of
the retina, plaques that have the appearance of a
string of pearls along the vessels may be seen.
The hearing loss is sensorineural. I believe the
cochlea is affected by the vascular insufficiency.
The changes seen on MRI predominate in the
white matter but also occur in the gray matter. A
characteristic feature is said to be the presence of
a row of holes in the center of the corpus callosum,
probably reflective of the distribution of blood vessels to this structure. The reported changes in the
cerebrospinal fluid reflect meningeal expression,
and the findings on biopsy of the patients brain
are typical of Susacs syndrome in that the vessel
walls are thickened but show little inflammation.
The syndrome is thus considered to be a vasculopathy rather than a vasculitis.
The disease tends to be self-limited by time. The
severity and expression fluctuate, as they did in this
patient, over the course of weeks and months before becoming inactive. The encephalopathic phase
of the illness lasts as long as 2 years, and headache
is common. Sadly, in many cases, permanent damage to mental status, vision, and hearing may
limit the patients return to normal functioning.
The usual therapeutic approach involves the
use of antiinflammatory medications of various
types. The rarity of this condition combined with
its fluctuating course make assessment of the effectiveness of any therapy problematic.
Dr. Eric S. Rosenberg (Pathology): Dr. Cho, could
you tell us what you were thinking when you saw
this patient?
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Dr. Tracey A. Cho (Neurology): The initial workup was begun by Dr. Daniel Costello, who has
returned to Ireland. I assumed the patients care.
Dr. Brandon Westover maintained continuity of
care. My initial impression, formed on the basis
of the preceding viral illness, the prominent encephalopathy, and the headache, was one of primary central nervous system vasculitis, particularly
because of the initial response to the administration of high-dose intravenous glucocorticoids.
It was only later, with the development of visual
and auditory symptoms, that we began to expand
our differential diagnosis. Dr. Westover was one
of the first to point out the possibility of Susacs
syndrome.
Cl inic a l Di agnosis
Susacs syndrome.
Dr . D on C . Bienfa ngs Di agnosis

Susacs syndrome.
Pathol o gic a l Discussion

Dr. George N. Papaliodis: The first diagnostic test was
fluorescein angiography, which showed occlusion
of the superior branch of the retinal artery in the
right eye along with regions of retinal vascular
staining and leakage in both eyes, all of which
were consistent with retinal vasculitis. Ten days
after the initial examination, when the patient
reported worsening vision, funduscopic examination (Fig. 2A and 2B) and fluorescein angiography
revealed multiple branch retinal arterial occlusions in both eyes, with regions of edematous
retina (Fig. 2C and 2D).
Dr. Michael J. McKenna: When I first saw this
patient, although he reported bilateral hearing
loss, his neurootologic examination was normal,
with the exception of diminished acuity of conversational speech on the left side. The audiogram (Fig. 3A) showed a low-frequency sensorineural hearing loss on the left side; the right
side was essentially normal. This pattern of lowfrequency sensorineural hearing loss on the left is
not unusual for patients with Mnires disease;
they can present with fluctuating hearing loss in
the low frequencies. However, in Mnires disease, which is a peripheral otologic problem,
word recognition rarely drops below 50% at ini-

Figure 2. Funduscopic Examination and Fluorescein Angiography.

Multiple bilateral branch retinal arterial occlusions, with regions of edematous retina, can be seen on funduscopic
examination (Panels A and B, arrows) 10 days after the initial examination, when the patient reported worsening vision in both eyes. Fluorescein angiograms show multiple occlusions in the branches of the retinal arteries bilaterally
(Panels C and D, arrows) and impressive vascular staining and leakage involving most of the major arterial arcades
(arrowheads), features that are consistent with worsening retinal vasculitis. After treatment with methylprednisolone
and cyclophosphamide, the funduscopic examination (Panel E) and fluorescein angiogram (Panel F) show resolution of the retinal edema and occlusions, with normal flow.
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555
The
Air conduction,
right ear
Bone conduction,
unmasked, right ear
Air conduction,
left ear
Bone conduction,
masked, left ear
No response, left ear
10
0
10
Hearing Level (dB)
20
30
40
50
60
70
90
100
Word recognition
Right: 94%
Left: 0%
110
120
62.5 125
250
500
1000
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Figure 3. Audiograms.
An audiogram performed during the patients second
admission to this hospital (Panel A) shows normal
hearing in the right ear (red symbols), with an isolated moderate loss at 8000 Hz only. There is normal
word recognition in the right ear. The left ear (blue
symbols) has a moderate, predominantly sensorineural hearing loss at low frequencies. The up-sloping
pattern indicates that the hearing loss is mild at high
frequencies. However, the word-recognition score
for the left ear is 0%, which means that a hearing aid
would not have been helpful at that time. A repeat
audiogram 2 months later (Panel B) again shows
essentially normal hearing in the right ear. The left ear
shows stable sensorineural hearing loss at low frequencies but shows better (lower) thresholds of hearing at frequencies of 2000 Hz and above. The wordrecognition score for the left ear has improved notably,
to 42%, indicating a significant improvement in the
patients ability to understand speech. Air conduction
refers to stimuli delivered through headphones. Bone
conduction refers to stimuli delivered with the use of a
bone oscillator applied to the skull; during the testing
of one ear, the contralateral ear may receive masking
noise to ensure that the responses are actually from
the ear being tested.
80
of
2000 4000 8000 16,000
Frequency (Hz)
B
10
0
10
Hearing Level (dB)
20
30
40
50
60
70
80
90
100
Word recognition
Right: 92%
Left: 42%
110
120
62.5 125
250
500
1000
2000 4000 8000 16,000
Frequency (Hz)
tial presentation. In this case, the word-recognition score on the left side was 0%, a feature that
is not consistent with Mnires disease.
Dr. Anat Stemmer-Rachamimov: The brain-biopsy
specimen obtained during the patients first admission contained fragments of cortex and white
matter. The leptomeninges were unremarkable.
The medium-sized leptomeningeal arteries showed
no evidence of granulomatous inflammation, and
Verhoeffs elastic staining showed intact elastic
556
n engl j med 365;6
lamina. Some of the small vessels in the cortex

and white matter showed a spectrum of changes:
swollen endothelial cells (Fig. 4A), scant mononuclear-cell perivascular inflammation (Fig. 4B),
and intraluminal hyaline thrombi (Fig. 4C). These
changes are suggestive of a microangiopathy. No
infarcts were seen in this small specimen. There
was no evidence of granulomatous angiitis, demyelination, lymphoma, or a specific infectious
process. Although in the context of the clinical
and imaging findings these features were not specific, they are consistent with Susacs syndrome,
or retinocochleocerebral vasculopathy. The first
case of Susacs syndrome was reported in 1979,19
and more than 100 cases have now been reported
in the literature.21 There is no specific diagnostic
test for this syndrome; rather, the diagnosis is
based on the combination of clinical features and
the absence of another specific diagnosis on pathological examination.
The greatest amount of information on the
underlying process in Susacs syndrome comes
from pathological analysis of the brain, the only
site from which biopsy material is available in
this case. The most common finding in brain
biopsies is the presence of microinfarcts. These
can be acute or subacute and involve both the
cortex and white matter. Also reported are chang-
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august 11, 2011

es in the microvasculature similar to those seen

in this patient, including scant perivascular inflammation, swelling of endothelial cells, and the
presence of intraluminal hyaline thrombi. Less
frequently, scarring of arteriolar walls may be
present.19,22-26
In the retina, information is derived indirectly,
from ophthalmologic examination and fluorescein angiography. As in the brain, and as seen in
this patient, there are infarcts and changes in the
microvasculature, including narrowing and occlusion of arterioles and leaking of dye. It is likely
that the underlying pathologic process in the
retina is similar to that observed directly in the
brain.
Information about the changes leading to hearing loss is the least accessible, but combined findings from clinical observation and imaging studies localize the process to the cochlea. Because of
the more pronounced loss of the ability to hear
sounds at low frequencies, it has been suggested
that the underlying process is microinfarction of
the cochlear apex,24 which is supplied by small end
arteries.
What is the cause of the microinfarcts? Proposed explanations include a hypercoagulable state,
vasospasm, and vasculitis, none of which are supported by laboratory results or findings on brain
biopsies.26 The unique distribution of arteriolar
disease affecting the brain, the retina, and the
cochlea suggests selective vulnerability of these
three structures. The brain, retina, and cochlea
all have a bloodtissue barrier, and the endothelium in these sites shares a common embryologic
origin and unique structural and antigenic characteristics.24,27 It has therefore been proposed that
Susacs syndrome is an autoimmune disease in
which the endothelium is the primary target, and
damage to the endothelium triggers arteriolar occlusion and microinfarcts.24,27 However, the pathogenesis remains unknown.
Dr. Rosenberg: Dr. Cho, would you tell us how
you managed the care of this patient and how he
is doing?
Dr. Cho: Despite the administration of pulsed
intravenous glucocorticoids and first 80 and then
120 mg of prednisone daily, he continued to have
headaches and mild encephalopathy, followed by
the development of visual changes and hearing
loss. After the diagnostic testing, we began treatment with a 4-day course of cyclophosphamide,
to which he had a good response, and he was
n engl j med 365;6
Figure 4. Brain-Biopsy Specimen (Hematoxylin

and Eosin).
Sections of cortex and white matter show a small vessel
with prominent activated endothelial cells (Panel A), a
small vessel with scant perivascular chronic inflammation (Panel B), and a small vessel with intraluminal hyaline thrombus (Panel C, arrow). These changes are
suggestive of a microangiopathy.
maintained on monthly pulsed cyclophosphamide and daily prednisone, starting at 120 mg and
then tapering to 80 mg. A cushingoid appearance
developed, as did an early, or mild, cataract; the
patient also gained weight. He was followed by a
multidisciplinary team, including physicians from
neurotology and neuroophthalmology. Approxi-
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557
The
mately 1 year after the onset of symptoms, prednisone was tapered and discontinued, and monthly intravenous methylprednisolone was added to
the monthly cyclophosphamide pulses. The patient
is now working full time and is neurologically
normal, approximately 2 years after the onset of
symptoms.
Dr. Rosenberg: Drs. Papaliodis and McKenna,
can you tell us what happened in terms of the
eye findings and audiogram?
Dr. Papaliodis: After initiation of therapy with
intravenous cyclophosphamide, the findings in the
fundus stabilized, with no new regions of involvement. Fluorescein angiography showed the
previously noted branch retinal arterial occlusions
but no new regions of involvement. Later frames
of the fluorescein angiogram revealed decreased
vascular staining and leakage in both eyes (although one focal area of active disease remained
in the left eye). During the next 18 months there
was fluctuating evidence of retinal inflammation
and vasculopathy, but at the most recent examination (Fig. 2E and 2F) the retinal vasculature was
normal in appearance, and no evidence of retinal
vasculopathy was detected on fluorescein angiography. The patient has a normal fundus and 20/20
visual acuity. I have recommended discontinuation
of cyclophosphamide and glucocorticoids and initiation of mycophenolate mofetil.
Dr. McKenna: A second audiogram obtained
after the initiation of treatment (Fig. 3B) showed
that the right ear remained normal. There had
been slight improvement in hearing at midfrequencies in the left ear, but with persistent lowfrequency sensorineural hearing loss; word recognition had improved from 0 to 42%. Examination
1 year later showed essentially no change.
A Physician: Would someone comment on the
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m e dic i n e
natural history of this disease? It is my understanding that this patient had an exceptionally
good response to treatment or was this the
expected outcome?
Dr. Cho: Dr. Susac, in a review of his experience, described three different courses of disease28: monocyclic, characterized by fluctuations
but eventual resolution over the course of 1 to
2 years, without recurrence; polycyclic, characterized by remissions between episodes for more than
2 years; and chronic smoldering, in which there is
active disease without remission for more than
2 years. Early encephalopathy, as seen in this patient, tends to occur more frequently in the monophasic form of the disease than in the other forms,
and our hope is that the course of disease for this
patient will fit that category. Our goal in management of care is to prevent permanent organ
damage, since recovery after neurologic injury
is often incomplete. Although the treatment of
Susacs syndrome has not been studied in controlled trials, most patients have a good response
to treatment with glucocorticoids, with the addition of intravenous immune globulin or cyclophosphamide for cases in which the disease is
refractory to glucocorticoids. We decided to use
cyclophosphamide because we wanted to preserve
brain function, vision, and hearing to the extent
possible. The patients response to cyclophosphamide was in keeping with glucocorticoid-refractory cases described by Susac and others.
A nat omic a l Di agnosis

Susacs syndrome (retinocochleocerebral vasculopathy).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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The

case records of the massachusetts general hospital

Case 24-2011: A 36-Year-Old Man

Pr e sen tat ion of C a se

From the Division of Neuro-Ophthalmology, Brigham and Womens Hospital

n engl j med 365;6 nejm.org august 11, 2011

The New England Journal of Medicine

Table 1. Cerebrospinal Fluid Analysis.*

Opening pressure (cm of water)

Light pink, slightly turbid

Light yellow, clear

White cells (per mm3)

Differential count, tube 4 (%)

Few mononuclear cells,

Enterovirus RNA, PCR

Herpes simplex virus DNA, PCR

Cytomegalovirus DNA, PCR

Varicellazoster virus, PCR

Negative, types 1 and 2

Venereal Disease Research Laboratory

Angiotensin-converting enzyme (U/liter)

n engl j med 365;6 nejm.org august 11, 2011

The New England Journal of Medicine

case records of the massachusetts gener al hospital

The patient had a history of allergic rhinitis

count, electrolyte levels, glucose levels, and tests

n engl j med 365;6 nejm.org august 11, 2011

The New England Journal of Medicine

In 1945, David Cogan1 described a syndrome of

The retinal venous and arterial vasculopathy known

Infection with Tropheryma whipplei is manifested in

n engl j med 365;6 nejm.org august 11, 2011

The New England Journal of Medicine

case records of the massachusetts gener al hospital

Figure 1. MRI Studies.

it is associated with cellular infiltration of the peripheral vitreous.

Although the ChurgStrauss syndrome may be

n engl j med 365;6

august 11, 2011

The New England Journal of Medicine

Dr . D on C . Bienfa ngs Di agnosis

Pathol o gic a l Discussion

n engl j med 365;6 nejm.org august 11, 2011

The New England Journal of Medicine

case records of the massachusetts gener al hospital

Figure 2. Funduscopic Examination and Fluorescein Angiography.

n engl j med 365;6

august 11, 2011

The New England Journal of Medicine

No response, left ear

Hearing Level (dB)

2000 4000 8000 16,000

Hearing Level (dB)

2000 4000 8000 16,000

n engl j med 365;6

lamina. Some of the small vessels in the cortex

august 11, 2011

The New England Journal of Medicine

case records of the massachusetts gener al hospital