Hearing Loss, Uveomeningitis, and Stroke in a
STEVEN YEH,1WAI L. LEE,2RICHARD B. ROSENBAUM,3AND JAMES T. ROSENBAUM1
A 55-year-old Cuban-born man presented to the emer-
gency room with hearing loss and bilateral visual loss.
History of the present illness
The patient had been in his usual state of good health until
4–6 weeks prior to presentation, when he began to de-
velop steadily decreasing vision in both eyes and severe,
bilateral hearing loss. He also experienced extreme photo-
phobia, eye redness, pain, and frontal headache. On pre-
sentation to the emergency room, he reported almost no
hearing in the right ear and very little hearing in the left
ear. Prior to the development of visual symptoms, he had
experienced sinus pressure and drainage, which he attrib-
uted to a sinus infection. He denied fevers, tinnitus, or
The patient’s medical history was significant for occa-
sional back pain.
Family and social histories
The patient reported a 6 pack-year history of smoking. He
also reported occasional cocaine, marijuana, and LSD use,
but denied use of intravenous drugs and alcohol. He de-
nied any family history of autoimmune disease or ophthal-
The patient was a well-nourished Cuban man who was
squinting in ambient lighting. His vital signs were stable
with a temperature of 37.1°C, blood pressure of 111/70 mm
Hg, pulse of 78 beats per minute, and a respiration rate of
18 breaths per minute. The cardiac, lung, abdomen, and
extremity examinations were unremarkable. Skin exami-
nation showed no rashes and no evidence of vasculitis.
There was no swelling, erythema, or synovitis in the
hands, wrists, elbows, shoulders, knees, or ankles. Geni-
tourinary examination revealed mild inguinal lymphade-
nopathy bilaterally, which was thought to be a benign
finding. The neurologic examination revealed normal sen-
sorimotor findings, negative Romberg’s sign, steady gait,
and normal 2? deep tendon reflexes bilaterally. The pa-
tient was unsteady with tandem gait. Heel-to-shin and
rapid alternating movements were unremarkable.
Ophthalmic examination revealed a visual acuity of 20/
400 in the right eye and 20/70 in the left eye. The pupils,
to the extent that they could be seen through edematous
corneas, appeared sluggishly reactive to light and showed
no relative afferent pupillary defect. The ocular motility
was normal in both eyes. Slit-lamp examination showed
mild diffuse perilimbal and bulbar conjunctival injection,
diffuse corneal edema predominantly involving the cor-
neal stroma, severe (3?) anterior chamber cellular inflam-
mation, normal irides, and mild cataracts in both eyes. The
fundus was poorly visualized due to the corneal edema.
No optic disc edema was observed in either eye. The
macula, vessels, and peripheral retina were grossly normal
in the right eye and unremarkable in the left eye. The
intraocular pressures were elevated in both eyes at 42 mm
Hg in the right eye and 27 mm Hg in the left eye (normal
Otologic examination showed clear tympanic mem-
branes. No evidence of erythema or fluid was visible be-
hind the tympanic membranes on both sides. The umbo
appeared normal in both ears. The external ear examina-
tion was unremarkable. The Weber and Rinne tests were
consistent with conductive hearing loss in both ears.
Results of routine laboratory examinations are summa-
rized in Table 1. A comprehensive metabolic panel, in-
Supported by an unrestricted grant from Research to Pre-
vent Blindness, New York, New York, the Stan and Madelle
Rosenfeld Family Trust, the William and Mary Bauman
Foundation, and the Fund for Arthritis and Infectious Dis-
ease Research. Dr. Yeh’s work was supported by the Ronald
G. Michels Fellowship Foundation.
1Steven Yeh, MD, James T. Rosenbaum, MD: Casey Eye
Institute, Oregon Health & Science University, Portland;
2Wai L. Lee, MD: Providence Arthritis Center, Portland,
Oregon;3Richard B. Rosenbaum, MD: The Oregon Clinic,
Dr. Richard B. Rosenbaum receives royalties for the book
Clinical Neurology of Rheumatic Disease.
Address correspondence to James T. Rosenbaum, MD,
Casey Eye Institute, Oregon Health & Science University,
3375 SW Terwilliger Boulevard, Portland, OR 97239. E-
Submitted for publication January 29, 2010; accepted in
revised form July 21, 2010.
Arthritis Care & Research
Vol. 63, No. 2, February 2011, pp 298–306
© 2011, American College of Rheumatology
Table 1. Results of laboratory evaluation early in the disease course*
Diagnostic testValue Normal value
Alkaline phosphatase, IU/liter
Total protein, gm/dl
WBC count, ? 109cells/liter
Platelets, ? 109cells/liter
Anti-ENA (Sm), units/ml
Anti-ENA (RNP/Sm), units/ml
Anti-SSA (Ro), units/ml
Anti-SSB (La), units/ml
HEp-2 cells, units/ml
ANCA (cANCA and pANCA)
Antibody to cyclic citrullinated peptide
Hepatitis B surface antigen
Hepatitis C antibody
Borrelia burgdorferi IgM, IgG (Lyme)
Serum toxoplasmosis IgM, IU/ml
Serum toxoplasmosis IgG, IU/ml
Serum Bartonella henselae IgM, IgG
Serum protein electrophoresis
Total protein, gm/dl
Gamma globulin, gm/dl
Nonspecific elevation of polyclonal
cluding liver enzyme testing, was normal. Complete blood
cell count with differentials showed mild anemia with a
hemoglobin level of 11.6 gm/dl and a hematocrit level of
35.1%. The white blood cell (WBC) count was normal at
6.2 ? 109cells/liter, and the platelet count was 443 ? 109
cells/liter. The differential cell count showed relatively
elevated monocytes at 23% (reference range 1–10%) and
decreased neutrophils at
40.0–81.0%). The erythrocyte sedimentation rate (ESR)
was elevated at 53 mm/hour. The QuantiFERON-TB Gold
test (Cellestis Limited) was negative and blood cultures
were negative. Serologic testing, including angiotensin-
converting enzyme level, rapid plasma reagin, fluorescent
treponemal antibody absorption test, and HLA–B27, were
normal or negative. Antineutrophil cytoplasmic antibody
(ANCA), C3, C4, antibody to cyclic citrullinated peptide,
rheumatoid factor, hepatitis B surface antigen, hepatitis C
antibody, Monospot test, and Lyme antibody tests were
negative. Antinuclear antibody was weakly positive, but
the anti–double-stranded DNA was negative. Serum toxo-
plasmosis IgM and Bartonella henselae IgG and IgM were
negative, while serum toxoplasmosis IgG was positive,
which is indicative of prior exposure. Serum protein elec-
trophoresis showed a nonspecific, polyclonal pattern.
Lumbar puncture showed a WBC count of 170 cells/?l,
95% lymphocytes, 2% neutrophils, and 3% monocytes.
The total protein level was elevated at 106 mg/dl (normal
range 15–45). Cerebrospinal fluid (CSF) gram stain and
cultures, acid-fast bacilli stain, and CSF VDRL were unre-
markable. Polymerase chain reaction for herpes simplex
virus (HSV), varicella-zoster virus (VZV), cytomegalovi-
rus, and Mycobacterium tuberculosis DNA was negative.
A chest radiograph showed no evidence of hilar adenop-
athy or any evidence of an acute infectious process. A
computed tomography (CT) scan of the orbits showed mild
ethmoid and frontal sinus mucosal thickening, but no
evidence of bony erosion to suggest Wegener’s granuloma-
tosis. A CT scan of the chest showed no evidence of hilar
adenopathy to suggest sarcoidosis. A magnetic resonance
imaging (MRI) scan of the brain was compatible with
chronic ischemic small-vessel disease.
Oral prednisone 80 mg/day (1 mg/kg) was initiated. The
hearing subjectively improved on the left side but re-
mained absent on the right side. Visual acuity improved to
20/40 in the right eye and 20/30 in the left eye 1 week after
starting topical and systemic corticosteroids. With a reduc-
tion in corneal edema, a clearer view could be obtained of
the posterior portion of the eye, and no evidence for retinal
detachment or elevation was found. The ESR was 7 mm/
hour 3 weeks after starting prednisone therapy.
After 3 weeks, the prednisone was tapered to 60 mg/day.
One week thereafter, the patient developed further central
nervous system (CNS) symptoms, including intermittent
confusion, drooling, memory changes, and episodes of
urinary and fecal incontinence. Repeat lumbar puncture
was significant for only a single leukocyte per microliter,
but an elevated protein level of 72 mg/dl. Gram stain,
acid-fast bacilli stain, and CSF cultures were negative. A
repeat MRI scan showed a right posterior capsular infarct
The rheumatology and uveitis/immunology services
were consulted for further management recommendations.
The patient is a 55-year-old Cuban-born man with a his-
tory of sinusitis with headaches, now with severe bilateral
hearing loss, bilateral keratouveitis, and aseptic meningi-
tis. All aspects of his disease seemed to respond to pred-
Table 1. (Cont’d)
Diagnostic test ValueNormal value
Red blood cells, cells/?l
Protein level, mg/dl
Cerebrospinal fluid cytology
Scattered lymphocytes, monocytes,
no malignant cells
3? WBCs, no organisms
Acid-fast bacilli stain
Bacterial and fungal cultures
Viral PCR: HSV, VZV, CMV
Mycobacterium tuberculosis PCR
* BUN ? blood urea nitrogen; AST ? aspartate aminotransferase; ALT ? alanine aminotransferase; WBC ? white blood cell; ESR ? erythrocyte
sedimentation rate; RPR ? rapid plasma reagin; FTA-ABS ? fluorescent treponemal antibody absorption; HIV ? human immunodeficiency virus;
ANA ? antineutrophil antibody; anti-dsDNA ? anti–double-stranded DNA; anti-ssDNA ? anti–single-stranded DNA; anti-ENA ? anti–extractable
nuclear antigen; ANCA ? antineutrophil cytoplasmic antibody; cANCA ? cytoplasmic ANCA; pANCA ? perinuclear ANCA; PCR ? polymerase chain
reaction; HSV ? herpes simplex virus; VZV ? varicella-zoster virus; CMV ? cytomegalovirus.
300Yeh et al
nisone until he developed focal neurologic symptoms and
confusion secondary to a presumed stroke.
The differential diagnosis for the patient’s constellation of
symptoms, which included hearing loss and uveomenin-
gitis, included infectious, inflammatory, and neoplastic
conditions. Among the infectious considerations for this
symptom complex were syphilis, tuberculosis, HSV-1,
HSV-2, VZV, Epstein-Barr virus, human immunodefi-
ciency virus, Lyme disease, and West Nile meningoen-
cephalitis. Autoimmune causes of uveitis and hearing loss
included sarcoidosis, primary angiitis of the CNS, Vogt-
Koyanagi-Harada (VKH) syndrome, systemic lupus ery-
thematosus (SLE), Wegener’s granulomatosis, Cogan’s syn-
drome, Susac’s syndrome, and Behc ¸et’s disease. CNS
lymphoma with intraocular involvement or lymphoma-
tous infiltration of the internal acoustic canal was also
Although this differential diagnosis is broad, many of
the conditions could be distinguished on the basis of the
anatomic location of the uveitic process. The anatomic
basis for the classification of uveitis recognized by the
Standardization of Uveitis Nomenclature guidelines sepa-
rates uveitis into the following anatomic subtypes: “ante-
rior,” “intermediate,” “posterior,” and “panuveitis,” de-
pending on the location of the inflammation visible on
ophthalmic examination (1). Specifically, the term “ante-
rior uveitis” refers to inflammation of the iris and ciliary
body, “intermediate uveitis” refers to inflammation in-
volving the vitreous humor and pars plana, and “posterior
uveitis” refers to retinal and/or choroidal involvement.
“Panuveitis” refers to a combination of anterior, interme-
diate, and posterior uveitis. “Keratouveitis” refers to cor-
neal and anterior segment inflammation (i.e., the iris and
ciliary body). Our patient’s inflammatory process ap-
peared to involve the cornea and the anterior uveal struc-
tures (i.e., the iris and ciliary body).
Whether the patient’s elevated intraocular pressure con-
tributed to the patient’s corneal edema was a consider-
ation, as an acute elevation in intraocular pressure may
cause a characteristic microcystic edema involving the
corneal epithelial layers. However, given the fact that the
patient’s edema was diffuse and bilateral and because the
pressure elevation in one of the eyes was slight, we attrib-
uted the patient’s clinical findings to a keratouveitic pro-
cess. We have described below the major inflammatory,
infectious, and neoplastic entities to be considered in this
context, and these are summarized in Table 2.
Sarcoidosis is a multisystem, granulomatous disease that
may result in ophthalmic manifestations in greater than
25% of affected patients (2). Sarcoidosis-associated uveitis
and related inflammatory disorders may affect multiple
tissue types depending on the location of the granulomas.
Patients most commonly present with bilateral, chronic
anterior uveitis. However, intermediate uveitis, posterior
uveitis, and panuveitis may also be observed (3). In pa-
tients with posterior uveitis and panuveitis, the appear-
ance of multiple, chorioretinal spots in the retinal periph-
ery may be suggestive of this diagnosis. The accumulation
of fluffy-appearing perivascular white blood cells, classi-
cally described as taches de bougie, or “candle-wax drip-
pings,” is also thought to be highly suggestive of sarcoid-
osis (3,4). Other less commonly seen ocular or orbital
inflammatory processes that may be attributable to sar-
coidosis include optic nerve granulomas, orbital inflam-
matory disease, dacryoadenitis, and stromal keratitis with
or without anterior uveitis. Because patients with neuro-
sarcoidosis may rarely present with keratouveitis and se-
vere hearing loss (5,6), sarcoidosis could fit with this pre-
sentation. Without proper treatment, severe visual loss or
complete deafness may ensue (7). However, a normal chest
Figure 1. A T2-weighted magnetic resonance image (MRI) shows abnormal increased
signal in the region of the right posterior capsule infarct (A). The diffusion-weighted MRI
also shows abnormal increased signal in this region (B).
CT scan is unlikely in patients with ocular and neurosar-
VKH syndrome is uveomeningitis syndrome, which is
diagnosed based on clinical features, including bilateral
panuveitis with multiple, exudative retinal detachments
(acute phase) or retinal pigment epithelial alterations or
depigmentation (chronic phase), neurootologic manifes-
tations (i.e., headache, meningismus, tinnitus, hearing
loss), and integumentary findings (i.e., vitiligo, poliosis,
alopecia), in the absence of trauma or other causes of
uveitis (9) (Figure 2). Diagnostic criteria and classifica-
tion of VKH syndrome based on clinical features have
been suggested (10). VKH syndrome is especially com-
mon among Southeast Asians, Native Americans, and
Spanish-speaking populations. The patient’s ethnic
background, severe uveitis, hearing loss, and sterile
meningitis fit well with a diagnosis of VKH syndrome,
except for the specifics of the uveitis.
The occurrence of significant corneal changes is rare in
VKH syndrome, although corneal decompensation may
result as a secondary complication of chronic anterior
uveitis, secondary glaucoma, or corneal endothelial de-
compensation from multiple intraocular surgeries, which
may be necessary in some patients. Because our patient
presented acutely with corneal findings (i.e., keratouveitis)
in the absence of posterior uveitis and normal funduscopic
appearance, VKH syndrome was less likely to be the cause
of our patient’s symptom complex.
Table 2. Differential diagnosis of uveomeningitis
DiseaseTypical anatomic location(s) of uveitis or inflammatory process
Sarcoidosis Anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis
Orbital pseudotumor, dacryoadenitis, optic neuropathy, choroidal granulomas,
Panuveitis with exudative retinal detachments
Panuveitis with retinal vasculitis
Choroidal vasculitis scleritis
Orbital inflammation, myositis, dacryoadenitis, scleritis, sclerokeratitis,
Optic neuritis, intermediate uveitis, anterior uveitis
Anterior uveitis, intermediate uveitis, chorioretinitis, retinal vasculitis
Behc ¸et’s disease
Systemic lupus erythematosus
Central nervous system angiitis
Sjo ¨gren’s syndrome
Antiphospholipid antibody syndrome†
Herpes simplex virus type 1
Herpes simplex virus type 2
Varicella zoster virus
West Nile meningoencephalitis
Human T cell lymphotrophic virus 1
Retinal arteriolar occlusions
Retinal artery or venous occlusions
Epithelial keratitis (dendritic), stromal keratitis
Epithelial keratitis, stromal keratitis, retinitis
Keratouveitis, anterior uveitis, retinitis
Anterior uveitis, retinitis
Intermediate uveitis, retinal vasculitis
Keratitis, scleritis, anterior uveitis, panuveitis, posterior uveitis (choroiditis),
Keratitis Mycobacterium leprae
Keratitis, intermediate uveitis, optic neuritis
Keratitis, scleritis, anterior uveitis, intermediate uveitis, posterior uveitis,
panuveitis, optic neuritis
Primary intraocular lymphoma Anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, subretinal
* A defined uveitis syndrome or specific anatomic location of uveitis in association with central nervous system angiitis has not been established.
† The precise etiopathogenesis of Susac’s syndrome and antiphospholipid antibody syndrome is unknown; however, inflammatory factors and retinal
vaso-occlusive etiologies have been postulated. The hypercoagulable state associated with antiphospholipid antibody syndrome is thought to be
involved with the retinal artery and venous occlusions observed in this context.
302Yeh et al
Primary angiitis of the CNS
A vasculitis that involves primarily vessels in the CNS is
rare but well recognized. We and others have reported
uveitis in association with this diagnosis, but the number
of cases is too small to conclude that the uveitis follows a
characteristic presentation (11). Primary angiitis of the
CNS could certainly account for a focal infarct in the brain,
although typically MRI findings are multifocal.
Susac et al described a group of patients with uveitis,
hearing loss, and sometimes extensive CNS disease. The
uveitis is characterized by an occlusive retinal vasculopa-
thy that was not present in this patient and therefore
excluded the diagnosis (12,13).
Although the classic ophthalmic manifestation of multiple
sclerosis (MS) is optic neuritis, uveitis is also an estab-
lished ophthalmic finding. The uveitis associated with MS
is variable in its presentation, but may manifest as pars
planitis with inflammation involving the vitreous cavity
(i.e., intermediate uveitis) with inflammatory cells accu-
mulating in the inferior peripheral retina and pars plana.
Uveitis associated with MS may also present as a bilateral,
granulomatous anterior uveitis, with the term “granuloma-
tous” referring to large aggregates of inflammatory cellular
precipitates that deposit on the inner, endothelial layer of
the cornea. Although MS was considered in the differen-
tial diagnosis, the degree of cell and protein abnormality in
the CSF was more than is typical of MS and the patient
never displayed multifocal CNS abnormalities on neuro-
SLE, Sjo ¨gren’s syndrome, and antiphospholipid
Uveitis is a rare but possible association with SLE,
Sjo ¨gren’s syndrome, or antiphospholipid antibody syn-
drome. In addition, retinal arterial and venous occlusions
have been observed in association with the antiphospho-
lipid syndrome and may be observed in the absence of
intraocular inflammation (14,15). Choroidal vasculitis and
retinal vasculitis have both been reported in SLE (16,17);
however, neither the systemic findings nor the serologic
results supported a diagnosis of lupus or a related disease
such as secondary Sjo ¨gren’s syndrome.
Behc ¸et’s disease
Behc ¸et’s disease is diagnosed primarily by the presence of
aphthous ulcers of the oral mucosa, genital ulcers, and
uveitis (i.e., recurrent anterior and posterior uveitis). Sev-
eral sets of clinical criteria have been proposed for the
diagnosis of Behc ¸et’s disease (18,19). Hearing loss may be
a prominent feature of Behc ¸et’s disease, particularly in
patients with CNS involvement (20,21). The uveitis in
Behc ¸et’s disease characteristically presents as a painful,
bilateral, or unilateral panuveitis with retinal vasculitis.
Patients may present with a hypopyon or WBC accumula-
tion in the anterior chamber. The panuveitis and retinal
vasculitis may lead to significant retinal hemorrhages, ret-
inal venous occlusive disease, and severe visual morbidity
in some patients (22). Keratouveitis is extremely unusual
in patients with Behc ¸et’s disease (23), and the presence of
corneal inflammation is more suggestive of other diagnos-
Herpes family of viruses
Several members of the herpesvirus family of viruses, i.e.,
HSV-1, HSV-2, VZV, and less commonly Epstein-Barr vi-
rus, may cause stromal keratitis. HSV-1– or HSV-2–asso-
ciated stromal keratitis most frequently occurs in a patient
with a history of dendritic epithelial keratitis. The stromal
keratitis may occur as disciform keratitis, in which a cir-
cular-shaped zone of corneal edema is observed. The cor-
neal endothelial cells, which are responsible for corneal
deturgescence, may also be affected. It is unclear whether
Figure 2. Fundus photograph (A) and optical coherence tomography scan (B) of the left eye
of a 39-year-old Hispanic woman with headaches, neck pain, tinnitus, alopecia, and bilateral
panuveitis with multiple exudative retinal detachments, resulting in visual loss to the
counting fingers level. She was diagnosed with Vogt-Koyanagi-Harada syndrome. The fun-
dus photograph shows hazy media due to moderate to severe vitritis, optic disc edema, and
yellow, exudative deposits in the subretinal space (A). Horizontal cross-sectional imaging
through the fovea (A; white arrow shows orientation of optical coherence tomography scan)
shows diffuse retinal edema and subretinal fluid (B; yellow arrows).
Clinicopathologic Conference 303
this underlying endotheliitis is immune mediated or due
to active viral replication. However, the treatment of this
condition includes both topical corticosteroids (i.e., pred-
nisolone phosphate or acetate 1%) and oral acyclovir to
prevent the occurrence of herpetic epithelial keratitis
(24,25). Bilateral stromal keratitis is infrequent, but has
been described. Unless the patient is immunocompro-
mised, HSV generally causes a unilateral corneal infection.
HSV can cause a severe, necrotizing panuveitis with
retinitis and a high incidence of retinal detachment. This
condition is known as acute retinal necrosis (ARN). Hear-
ing loss may rarely be associated with ARN and conse-
quently, patients with retinitis and hearing loss warrant
evaluation for HSV (26). Corneal findings are infrequently
associated with ARN; however, HSV-associated keratitis
has been described in the contralateral eye in patients with
unilateral ARN (27).
VZV-associated uveitis may present with stromal kera-
titis, anterior uveitis, retinitis, or a combination of these
conditions. VZV associated with stromal keratitis may ap-
pear similar to HSV-associated stromal keratitis, but dif-
fers in that it may be more commonly sectoral. Patients
with stromal keratitis may present with zoster in the V1
dermatome. In patients with isolated acute anterior uve-
itis, patients present with a unilateral, diffuse nongranu-
lomatous keratic precipitate on the corneal endothelium.
Iris hypochromia and transillumination defects may occa-
sionally be seen in patients with VZV-associated anterior
uveitis and are suggestive of VZV. Extremely elevated
intraocular pressures may be seen in patients with VZV-
associated anterior uveitis. Retinitis may occur secondary
to VZV, HSV-1, HSV-2, or cytomegalovirus. However, cor-
neal involvement in these contexts is rare. The retinal
involvement in acute retinal necrosis is characteristic and
the disease is rarely bilateral simultaneously.
Herpes zoster ophthalmicus with an ipsilateral focal
CNS angiitis, subsequent cerebral infarction, and con-
tralateral hemiplegia was a consideration given the CNS
signs observed in our patient; herpes zoster ophthalmicus
in association with hearing loss has been described
(26,28). While this spectrum of VZV-associated disease
was a consideration in our patient, the absence of a rash
typical for zoster made this symptom complex unlikely.
Human T cell lymphotrophic virus type 1
Human T cell lymphotrophic virus type 1 (HTLV-1) is the
cause of tropical spastic paraparesis and is associated with
adult T cell leukemia/lymphoma. HTLV-1 is endemic to
some parts of Asia, Africa, and the Caribbean. Intermediate
uveitis and retinal vasculitis, which may become chronic,
have been reported in association with HTLV-1. Keratopa-
thy featuring corneal haze and corneal opacities has been
reported in association with HTLV-1 (29,30), but frank
keratitis has not been reported.
M tuberculosis may affect a range of ocular structures.
Stromal keratitis, scleritis, anterior uveitis, intermediate
uveitis, posterior uveitis, and panuveitis may occur due to
M tuberculosis. M tuberculosis–associated stromal kerati-
tis is rare, but has been reported. In M tuberculosis–asso-
ciated posterior uveitis, patients may develop choroidal
granulomas with widespread overlying retinal pigment
epithelium alterations. Corneal involvement has not been
reported in patients with M tuberculosis–associated inter-
mediate uveitis, posterior uveitis, or panuveitis.
Patients with congenital syphilis may present with stromal
keratitis early or late in life with reactivation of latent
syphilis (31,32). Characteristic physical features include
saddle-nose deformity, saber shins, and rhagades. The
hearing loss may be mild or complete deafness. Patients
may present with anterior uveitis, intermediate uveitis,
posterior uveitis, or panuveitis. Syphilitic neuroretinitis
may also be observed (Figure 3). Serologic and CSF testing
are indicated in patients suspected of harboring syphilis in
association with ocular inflammation, and treatment with
intravenous or intramuscular penicillin is indicated for
patients diagnosed with neurosyphilis (33,34). In the pa-
tient described, all of the syphilis serologies were negative,
including CSF VDRL. Resolution and stabilization of his
keratitis following topical corticosteroids was suggestive
of a noninfectious etiology.
Whipple’s disease (WD), thought to be caused by the ba-
cillus Tropheryma whipplei, features a constellation of
symptoms, including malabsorption, diarrhea, and polyar-
thritis. CNS symptoms, including hearing loss, have ac-
companied WD and several types of uveitis, e.g., iridocy-
clitis, vitreitis, chorioretinitis, and retinal vasculitis, have
been reported in association with WD. Our patient’s ocular
inflammatory processes affected more anterior ocular
structures and were not consistent with a diagnosis of
Primary intraocular lymphoma
Primary intraocular lymphoma is considered a masquer-
ade syndrome because it may share disease features with
intermediate uveitis, posterior uveitis, or panuveitis. This
diagnosis should be considered in older patients (i.e., typ-
ically age ?50 years) who present with vitreous cells (i.e.,
intermediate uveitis) with or without chorioretinal in-
volvement. Besides vitritis, patients may present with sub-
retinal lesions or subretinal pigment epithelial deposits,
which are focal deposits of lymphoma cells (35). Hearing
loss is unusual, but may be seen if lymphomatous infiltra-
tion of the internal acoustic canals has occurred (36).
Prompt neuroimaging of the internal acoustic canals with
MRI is required in these circumstances. Patients with in-
traocular lymphoma do not typically present with corneal
involvement. The onset of the disease is typically insidi-
ous. Rarely, patients may present with anterior uveitis
(37), particularly in patients who have had cataract surgery
and lack their native crystalline lens. In these situations,
deposition of lymphoma cells on the corneal endothelium
has been observed; however, the stromal keratitis in our
patient was much more severe than the corneal involvement
that may rarely occur in primary intraocular lymphoma.
304 Yeh et al
Cogan’s syndrome: a diagnosis of exclusion
Cogan’s syndrome was classically described as a “syn-
drome of non-syphilitic interstitial keratitis and vestibulo-
auditory symptoms” (38–40). Reported systemic vasculi-
tis manifestations include CNS manifestations (e.g.,
headaches, Me ´nie `re’s disease–like attacks), aortitis, rash,
and arthritis/arthralgias (41,42). Originally, interstitial ker-
atitis was considered the ophthalmic hallmark of Cogan’s
syndrome, but the definition has widely been broadened to
include other forms of ocular inflammation such as uve-
itis, scleritis, episcleritis, and conjunctivitis. The term
“atypical Cogan’s syndrome” describes patients with au-
diovestibular dysfunction with ocular inflammatory signs
other than interstitial keratitis or patients who experience
a gap of more than 2 years before the onset of ophthalmic
and audiovestibular dysfunction. Patients with atypical
Cogan’s syndrome may develop other rheumatologic syn-
dromes that portend a less favorable prognosis than classic
Cogan’s syndrome (42). Cogan’s syndrome may also be
associated with polyarteritis nodosa and serologic positiv-
ity for perinuclear ANCA. Although the precise etiopatho-
genesis of Cogan’s syndrome is unknown, it is thought to
develop from small-vessel vasculitis involving multiple
organ systems. Therapies previously described for the
treatment of Cogan’s syndrome include systemic cortico-
steroids, local or systemic T cell calcineurin inhibitors,
and cyclophosphamide (42–44). Significant visual mor-
bidity, including visual loss, deafness, and even death,
may result from the ophthalmic, otologic, and CNS se-
quelae of Cogan’s syndrome. Fortunately, the development
of life-threatening complications of Cogan’s syndrome, in-
cluding aortitis, systemic vasculitis, and gastrointestinal
bleeding, is infrequent (41).
SUBSEQUENT CLINICAL COURSE
This patient’s presentation fit best with Cogan’s syndrome
because the thorough diagnostic evaluation did not sup-
port a diagnosis of infection, malignancy, or any alterna-
tive rheumatologic syndrome. VKH syndrome remained a
potential diagnosis, but the retinal findings did not sup-
port this. The development of a focal infarct after starting
oral prednisone and after the hearing loss, uveitis, and
sterile meningitis were improving raised additional con-
cerns such as a cerebral vasculitis. A transesophageal
echocardiogram, carotid ultrasound with Doppler, and
4-vessel cerebral angiography were obtained. Carotid ul-
trasound revealed severe bilateral stenosis and cerebral
angiography showed no evidence of cerebral vasculitis.
The stroke was deemed secondary to atherosclerotic dis-
ease and thought to be not directly related to the inflam-
matory process. Bilateral carotid stents were placed and
prednisone was continued.
The patient remains on a tapering dose of prednisone
and has had no recurrence of his ophthalmic disease at
3-month followup. His visual acuity improved to 20/25 in
both eyes at 3-month followup and his intraocular pres-
sures normalized to 18 mm Hg in the right eye and 17 mm
Hg in the left eye. In addition, his hearing loss has im-
proved slightly on both sides, but he remains more se-
verely affected on the right side.
Distinguishing Cogan’s syndrome from other causes of
uveomeningitis with hearing loss may be challenging.
However, key ophthalmic features, specifically the appear-
ance and location of uveal inflammation, are extremely
helpful in differentiating infectious, neoplastic, and auto-
immune causes of this unusual symptom complex. The
cerebral infarct further complicated the diagnostic evalu-
ation, but in the setting of improving inflammatory disease
and severe atherosclerotic disease, the infarct was almost
certainly unrelated to the initial process. Since the major-
ity of ophthalmologists are not comfortable with the man-
agement of a systemic inflammatory process and the pre-
ponderance of rheumatologists are not comfortable with
the differential diagnosis of uveitis, collaboration and
communication between subspecialists were crucial in
this patient’s care.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved the final version to be published. Dr. James T. Rosenbaum
had full access to all of the data in the study and takes responsi-
bility for the integrity of the data and the accuracy of the data
Study conception and design. Yeh, James T. Rosenbaum.
Acquisition of data. Yeh, Lee, Richard B. Rosenbaum, James T.
Analysis and interpretation of data. Yeh, Richard B. Rosenbaum,
James T. Rosenbaum.
1. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of
uveitis nomenclature for reporting clinical data: results of the
Figure 3. Optic nerve photograph of the left eye of a 28-year-old
human immunodeficiency virus–positive male patient with a his-
tory of a desquamating palmar rash due to secondary syphilis. He
presented with decreased vision, photophobia, and floaters. Fun-
duscopic examination showed hazy media due to mild vitritis,
optic disc edema, and peripapillary nerve fiber layer swelling
consistent with neuroretinitis, prompting intravenous penicillin
for tertiary syphilis.
Clinicopathologic Conference 305
First International Workshop. Am J Ophthalmol 2005;140: Download full-text
2. Bonfioli AA, Orefice F. Sarcoidosis. Semin Ophthalmol 2005;
3. Herbort CP, Rao NA, Mochizuki M. International criteria for
the diagnosis of ocular sarcoidosis: results of the first Interna-
tional Workshop On Ocular Sarcoidosis (IWOS). Ocul Immu-
nol Inflamm 2009;17:160–9.
4. Sivakumar M, Chee SP. A case series of ocular disease as the
primary manifestation in sarcoidosis. Ann Acad Med Singa-
5. Garcia Berrocal JR, Trinidad A, Vargas JA, Hijos M, Ramon y
Cajal S, Ramirez Camacho R. Sudden hearing loss and uveitis
as a form of presentation of neurosarcoidosis. Acta Otorrino-
laringol Esp 1998;49:488–90. In Spanish.
6. Colvin IB. Audiovestibular manifestations of sarcoidosis: a
review of the literature. Laryngoscope 2006;116:75–82.
7. John S, Yeh S, Lew JC, Nussenblatt RB. Protean manifesta-
tions of pediatric neurosarcoidosis. Can J Ophthalmol 2009;
8. Koczman JJ, Rouleau J, Gaunt M, Kardon RH, Wall M, Lee AG.
Neuro-ophthalmic sarcoidosis: the University of Iowa experi-
ence. Semin Ophthalmol 2008;23:157–68.
9. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syn-
drome. Surv Ophthalmol 1995;39:265–92.
10. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S,
Arellanes-Garcia L, et al. Revised diagnostic criteria for Vogt-
Koyanagi-Harada disease: a report of an international commit-
tee on nomenclature. Am J Ophthalmol 2001;131:647–52.
11. Rosenbaum JT, Roman-Goldstein S, Lindquist GR, Rosen-
baum RB. Uveitis and central nervous system vasculitis.
J Rheumatol 1998;25:593–7.
12. O’Halloran HS, Pearson PA, Lee WB, Susac JO, Berger JR.
Microangiopathy of the brain, retina, and cochlea (Susac
syndrome): a report of five cases and a review of the literature.
13. Susac JO, Egan RA, Rennebohm RM, Lubow M. Susac’s
syndrome: 1975-2005 microangiopathy/autoimmune endo-
theliopathy. J Neurol Sci 2007;257:270–2.
14. Miserocchi E, Baltatzis S, Foster CS. Ocular features associ-
ated with anticardiolipin antibodies: a descriptive study.
Am J Ophthalmol 2001;131:451–6.
15. Kalogeropoulos CD, Spyrou P, Stefaniotou MI, Tsironi EE,
Drosos AA, Psilas KG. Anticardiolipin antibodies and occlu-
sive vascular disease of the eye: prospective study. Doc Oph-
16. Graham EM, Spalton DJ, Barnard RO, Garner A, Russell RW.
Cerebral and retinal vascular changes in systemic lupus ery-
thematosus. Ophthalmology 1985;92:444–8.
17. Read RW, Chong LP, Rao NA. Occlusive retinal vasculitis
associated with systemic lupus erythematosus. Arch Ophthal-
18. Chang HK, Lee SS, Bai HJ, Lee YW, Yoon BY, Lee CH, et al.
Validation of the classification criteria commonly used in
Korea and a modified set of preliminary criteria for Behc ¸et’s
disease: a multi-center study. Clin Exp Rheumatol 2004;22:
19. International Study Group for Behc ¸et’s Disease. Criteria for
diagnosis of Behc ¸et’s disease. Lancet 1990;335:1078–80.
20. Agrup C. Immune-mediated audiovestibular disorders in the
paediatric population: a review. Int J Audiol 2008;47:560–5.
21. Bakhshaee M, Ghasemi MM, Hatef MR, Talebmehr M, Shakeri
MT. Hearing loss in Behc ¸et’s syndrome. Otolaryngol Head
Neck Surg 2007;137:439–42.
22. Nussenblatt RB. Uveitis in Behc ¸et’s disease. Int Rev Immunol
23. Dorot N, Coulon P, Poirier L, Brousse D, Mortemousque B,
Verin P. Corneal ulcer and Behc ¸et’s disease: apropos of a case.
J Fr Ophtalmol 1995;18:155–7. In French.
24. Barron BA, Gee L, Hauck WW, Kurinij N, Dawson CR, Jones
DB, et al, for the Herpetic Eye Disease Study. A controlled
trial of oral acyclovir for herpes simplex stromal keratitis.
25. Wilhelmus KR, Gee L, Hauck WW, Kurinij N, Dawson CR,
Jones DB, et al, for the Herpetic Eye Disease Study. A con-
trolled trial of topical corticosteroids for herpes simplex stro-
mal keratitis. Ophthalmology 1994;101:1883–95.
26. Verm AM, Scott IU, Davis JL. Necrotizing herpetic retinopa-
thy associated with Ramsay Hunt syndrome. Arch Ophthal-
27. Smith LK, Kurz PA, Wilson DJ, Flaxel CJ, Rosenbaum JT. Two
patients with the von Szily reaction: herpetic keratitis and
contralateral retinal necrosis. Am J Ophthalmol 2007;143:
28. Scott MJ Sr, Scott MJ Jr. Ipsilateral deafness and herpes zoster
ophthalmicus. Arch Dermatol 1983;119:235–6.
29. Buggage RR, Levy-Clarke GA, Smith JA. New corneal findings
in human T-cell lymphotrophic virus type 1 infection. Am J
30. Buggage RR. Ocular manifestations of human T-cell lympho-
tropic virus type 1 infection. Curr Opin Ophthalmol 2003;14:
31. Brooks AM, Weiner JM, Robertson IF. Interstitial keratitis in
untreated latent (late) syphilis. Aust N Z J Ophthalmol 1986;
32. Probst LE, Wilkinson J, Nichols BD. Diagnosis of congenital
syphilis in adults presenting with interstitial keratitis. Can J
33. Ormerod LD, Puklin JE, Sobel JD. Syphilitic posterior uveitis:
correlative findings and significance. Clin Infect Dis 2001;32:
34. Chao JR, Khurana RN, Fawzi AA, Reddy HS, Rao NA.
Syphilis: reemergence of an old adversary. Ophthalmology
35. Chan CC, Buggage RR, Nussenblatt RB. Intraocular lym-
phoma. Curr Opin Ophthalmol 2002;13:411–8.
36. Lenarz M, Durisin M, Becker H, Lenarz T, Nejadkazem M.
Primary central nervous system lymphoma presenting as bi-
lateral tumors of the internal auditory canal. Skull Base 2007;
37. Corriveau C, Easterbrook M, Payne D. Lymphoma simulating
uveitis (masquerade syndrome). Can J Ophthalmol 1986;21:
38. Cogan DG. Nonsyphilitic interstitial keratitis with vestibulo-
auditory symptoms; report of four additional cases. Arch
39. Cogan DG, Dickersin GR. Nonsyphilitic interstitial keratitis
with vestibuloauditory symptoms: a case with fatal aortitis.
Arch Ophthalmol 1964;71:172–5.
40. Norton EW, Cogan DG. Syndrome of nonsyphilitic interstitial
keratitis and vestibuloauditory symptoms; a long-term follow-
up. AMA Arch Ophthalmol 1959;61:695–7.
41. Gluth MB, Baratz KH, Matteson EL, Driscoll CL. Cogan
syndrome: a retrospective review of 60 patients throughout a
half century. Mayo Clin Proc 2006;81:483–8.
42. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan
syndrome: studies in thirteen patients, long-term follow-up,
and a review of the literature. Medicine (Baltimore) 1980;59:
43. Shimura M, Yasuda K, Fuse N, Nakazawa M, Tamai M. Effec-
tive treatment with topical cyclosporin A of a patient with
Cogan syndrome. Ophthalmologica 2000;214:429–32.
44. Orsoni JG, Zavota L, Pellistri I, Piazza F, Cimino L. Cogan
syndrome. Cornea 2002;21:356–9.
306Yeh et al