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A 55-year-old Cuban-born man presented to the emergency 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 develop steadily decreasing vision in both eyes and severe, bilateral hearing loss. He also experienced extreme photophobia, eye redness, pain, and frontal headache. On presentation 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 attributed to a sinus infection. He denied fevers, tinnitus, or neck pain.
The patient's medical history was significant for occasional 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 denied any family history of autoimmune disease or ophthalmic conditions.
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 examination showed no rashes and no evidence of vasculitis. There was no swelling, erythema, or synovitis in the hands, wrists, elbows, shoulders, knees, or ankles. Genitourinary examination revealed mild inguinal lymphadenopathy bilaterally, which was thought to be a benign finding. The neurologic examination revealed normal sensorimotor findings, negative Romberg's sign, steady gait, and normal 2+ deep tendon reflexes bilaterally. The patient 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 corneal stroma, severe (3+) anterior chamber cellular inflammation, 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 range 9–22).
Otologic examination showed clear tympanic membranes. No evidence of erythema or fluid was visible behind the tympanic membranes on both sides. The umbo appeared normal in both ears. The external ear examination was unremarkable. The Weber and Rinne tests were consistent with conductive hearing loss in both ears.
Results of routine laboratory examinations are summarized in Table 1. A comprehensive metabolic panel, including 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 × 109 cells/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 29% (reference range 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 toxoplasmosis IgM and Bartonella henselae IgG and IgM were negative, while serum toxoplasmosis IgG was positive, which is indicative of prior exposure. Serum protein electrophoresis showed a nonspecific, polyclonal pattern.
Table 1. Results of laboratory evaluation early in the disease course*
Nonspecific elevation of polyclonal immunoglobulin
Red blood cells, cells/μl
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
Lumbar puncture showed a WBC count of 170 cells/μl, 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 unremarkable. Polymerase chain reaction for herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus, and Mycobacterium tuberculosis DNA was negative.
A chest radiograph showed no evidence of hilar adenopathy 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 granulomatosis. 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 remained 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 reduction 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 (Figure 1).
The rheumatology and uveitis/immunology services were consulted for further management recommendations.
The patient is a 55-year-old Cuban-born man with a history of sinusitis with headaches, now with severe bilateral hearing loss, bilateral keratouveitis, and aseptic meningitis. All aspects of his disease seemed to respond to prednisone 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 uveomeningitis, 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 immunodeficiency virus, Lyme disease, and West Nile meningoencephalitis. Autoimmune causes of uveitis and hearing loss included sarcoidosis, primary angiitis of the CNS, Vogt-Koyanagi-Harada (VKH) syndrome, systemic lupus erythematosus (SLE), Wegener's granulomatosis, Cogan's syndrome, Susac's syndrome, and Behçet's disease. CNS lymphoma with intraocular involvement or lymphomatous infiltration of the internal acoustic canal was also considered.
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 separates uveitis into the following anatomic subtypes: “anterior,” “intermediate,” “posterior,” and “panuveitis,” depending on the location of the inflammation visible on ophthalmic examination (1). Specifically, the term “anterior uveitis” refers to inflammation of the iris and ciliary body, “intermediate uveitis” refers to inflammation involving the vitreous humor and pars plana, and “posterior uveitis” refers to retinal and/or choroidal involvement. “Panuveitis” refers to a combination of anterior, intermediate, and posterior uveitis. “Keratouveitis” refers to corneal and anterior segment inflammation (i.e., the iris and ciliary body). Our patient's inflammatory process appeared to involve the cornea and the anterior uveal structures (i.e., the iris and ciliary body).
Whether the patient's elevated intraocular pressure contributed to the patient's corneal edema was a consideration, 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 attributed the patient's clinical findings to a keratouveitic process. We have described below the major inflammatory, infectious, and neoplastic entities to be considered in this context, and these are summarized in Table 2.
Table 2. Differential diagnosis of uveomeningitis
Typical anatomic location(s) of uveitis or inflammatory process
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.
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 patients with posterior uveitis and panuveitis, the appearance of multiple, chorioretinal spots in the retinal periphery may be suggestive of this diagnosis. The accumulation of fluffy-appearing perivascular white blood cells, classically described as taches de bougie, or “candle-wax drippings,” is also thought to be highly suggestive of sarcoidosis (3, 4). Other less commonly seen ocular or orbital inflammatory processes that may be attributable to sarcoidosis include optic nerve granulomas, orbital inflammatory disease, dacryoadenitis, and stromal keratitis with or without anterior uveitis. Because patients with neurosarcoidosis may rarely present with keratouveitis and severe hearing loss (5, 6), sarcoidosis could fit with this presentation. Without proper treatment, severe visual loss or complete deafness may ensue (7). However, a normal chest CT scan is unlikely in patients with ocular and neurosarcoidosis (8).
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 manifestations (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 classification of VKH syndrome based on clinical features have been suggested (10). VKH syndrome is especially common 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 decompensation 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.
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 vasculopathy 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 established 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 accumulating in the inferior peripheral retina and pars plana. Uveitis associated with MS may also present as a bilateral, granulomatous anterior uveitis, with the term “granulomatous” referring to large aggregates of inflammatory cellular precipitates that deposit on the inner, endothelial layer of the cornea. Although MS was considered in the differential 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 neuroimaging.
SLE, Sjögren's syndrome, and antiphospholipid antibody syndrome
Uveitis is a rare but possible association with SLE, Sjögren's syndrome, or antiphospholipid antibody syndrome. In addition, retinal arterial and venous occlusions have been observed in association with the antiphospholipid 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 Sjögren's syndrome.
Behçet'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). Several sets of clinical criteria have been proposed for the diagnosis of Behçet's disease (18, 19). Hearing loss may be a prominent feature of Behçet's disease, particularly in patients with CNS involvement (20, 21). The uveitis in Behçet's disease characteristically presents as a painful, bilateral, or unilateral panuveitis with retinal vasculitis. Patients may present with a hypopyon or WBC accumulation in the anterior chamber. The panuveitis and retinal vasculitis may lead to significant retinal hemorrhages, retinal venous occlusive disease, and severe visual morbidity in some patients (22). Keratouveitis is extremely unusual in patients with Behçet's disease (23), and the presence of corneal inflammation is more suggestive of other diagnostic entities.
Herpes family of viruses
Several members of the herpesvirus family of viruses, i.e., HSV-1, HSV-2, VZV, and less commonly Epstein-Barr virus, may cause stromal keratitis. HSV-1– or HSV-2–associated 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 circular-shaped zone of corneal edema is observed. The corneal endothelial cells, which are responsible for corneal deturgescence, may also be affected. It is unclear whether this underlying endotheliitis is immune mediated or due to active viral replication. However, the treatment of this condition includes both topical corticosteroids (i.e., prednisolone 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 immunocompromised, 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). Hearing loss may rarely be associated with ARN and consequently, 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 keratitis, anterior uveitis, retinitis, or a combination of these conditions. VZV associated with stromal keratitis may appear similar to HSV-associated stromal keratitis, but differs 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 uveitis, patients present with a unilateral, diffuse nongranulomatous keratic precipitate on the corneal endothelium. Iris hypochromia and transillumination defects may occasionally 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, corneal 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 contralateral 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. Keratopathy 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 keratitis is rare, but has been reported. In M tuberculosis–associated 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 intermediate 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 patient 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 bacillus Tropheryma whipplei, features a constellation of symptoms, including malabsorption, diarrhea, and polyarthritis. CNS symptoms, including hearing loss, have accompanied WD and several types of uveitis, e.g., iridocyclitis, 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 ocular WD.
Primary intraocular lymphoma
Primary intraocular lymphoma is considered a masquerade syndrome because it may share disease features with intermediate uveitis, posterior uveitis, or panuveitis. This diagnosis should be considered in older patients (i.e., typically age >50 years) who present with vitreous cells (i.e., intermediate uveitis) with or without chorioretinal involvement. Besides vitritis, patients may present with subretinal lesions or subretinal pigment epithelial deposits, which are focal deposits of lymphoma cells (35). Hearing loss is unusual, but may be seen if lymphomatous infiltration of the internal acoustic canals has occurred (36). Prompt neuroimaging of the internal acoustic canals with MRI is required in these circumstances. Patients with intraocular lymphoma do not typically present with corneal involvement. The onset of the disease is typically insidious. 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.
Cogan's syndrome: a diagnosis of exclusion
Cogan's syndrome was classically described as a “syndrome of non-syphilitic interstitial keratitis and vestibuloauditory symptoms” (38–40). Reported systemic vasculitis manifestations include CNS manifestations (e.g., headaches, Ménière's disease–like attacks), aortitis, rash, and arthritis/arthralgias (41, 42). Originally, interstitial keratitis 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 uveitis, scleritis, episcleritis, and conjunctivitis. The term “atypical Cogan's syndrome” describes patients with audiovestibular 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 syndromes that portend a less favorable prognosis than classic Cogan's syndrome (42). Cogan's syndrome may also be associated with polyarteritis nodosa and serologic positivity for perinuclear ANCA. Although the precise etiopathogenesis 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 corticosteroids, local or systemic T cell calcineurin inhibitors, and cyclophosphamide (42–44). Significant visual morbidity, including visual loss, deafness, and even death, may result from the ophthalmic, otologic, and CNS sequelae of Cogan's syndrome. Fortunately, the development of life-threatening complications of Cogan's syndrome, including 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 support a diagnosis of infection, malignancy, or any alternative rheumatologic syndrome. VKH syndrome remained a potential diagnosis, but the retinal findings did not support this. The development of a focal infarct after starting oral prednisone and after the hearing loss, uveitis, and sterile meningitis were improving raised additional concerns such as a cerebral vasculitis. A transesophageal echocardiogram, carotid ultrasound with Doppler, and 4-vessel cerebral angiography were obtained. Carotid ultrasound revealed severe bilateral stenosis and cerebral angiography showed no evidence of cerebral vasculitis. The stroke was deemed secondary to atherosclerotic disease and thought to be not directly related to the inflammatory 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 pressures normalized to 18 mm Hg in the right eye and 17 mm Hg in the left eye. In addition, his hearing loss has improved slightly on both sides, but he remains more severely 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 appearance and location of uveal inflammation, are extremely helpful in differentiating infectious, neoplastic, and autoimmune causes of this unusual symptom complex. The cerebral infarct further complicated the diagnostic evaluation, but in the setting of improving inflammatory disease and severe atherosclerotic disease, the infarct was almost certainly unrelated to the initial process. Since the majority of ophthalmologists are not comfortable with the management of a systemic inflammatory process and the preponderance 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 approved the final version to be published. Dr. James T. Rosenbaum had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Yeh, James T. Rosenbaum.
Acquisition of data. Yeh, Lee, Richard B. Rosenbaum, James T. Rosenbaum.
Analysis and interpretation of data. Yeh, Richard B. Rosenbaum, James T. Rosenbaum.