A 47-Year-Old Man With Sudden Onset of Blindness, Pleocytosis, and Temporary Hearing Loss

Twelve years before his death, a 47-year-old white man presented with sudden onset of blindness, pleocytosis, increased intracranial pressure, papilledema, uveitis, and temporary hearing loss. He had no history of eye trauma or surgery. No serologic abnormality was encountered. His symptoms were controlled by a high dose of hydrocortisone, which was tapered 6 months after the beginning of therapy. Through his multiple visits to our clinic, his ophthalmic examination revealed progressive bilateral enlarged blind spot and loss of the inferior lateral margins of his left eye. Fundoscopy showed bilateral blurred discs. He also complained of type II diabetes mellitus, lifelong obesity, and daytime hypersomnolence. Four months before his death, he presented with onset of dyspnea with exertion, which had increased gradually during the previous year. Lastly, he presented to the emergency department with multiple seizures and died shortly after that.

A complete postmortem examination was performed. External examination revealed poliosis of the scalp hair with no vitiligo. High-resolution HLA typing showed HLA-DRB1*0405, HLA-DRB*07, and HLA-DR4*01. Histologic examination of the eyes showed heavy lymphocytic infiltration involving the choroid, subjacent to the retinal pigment epithelium (Figure 1, arrowheads), and advanced degeneration of neuronal retina with complete disappearance of the outer nuclear layer (photoreceptors). The vitreous body was seen inside the neuronal retina (Figure 1). Chorioretinal dense adhesions were evident. The choroid was separated from the sclera by processing artifact (Figure 2). Loss of choroidal melanocytes was evident; retinal pigment epithelium was identified (Figure 3, arrowheads). A moderate lymphocytic infiltration also involved the iris and was more pronounced around the sphincter muscle than around the blood vessels (Figure 4). No giant cells, epithelioid cells, Dalen-Fuchs nodules (collections of epithelial cells lying between Bruch membrane and the retinal pigment epithelium), or rupture of Bruch membrane was seen. Examination of the leptomeninges revealed mild fibrosis around the optic nerves and optic chiasm. No gross or microscopic changes in the brain cortex or white matter were evident. There was no microscopic abnormality in the skin.

What is your diagnosis?

Vogt-Koyanagi-Harada syndrome (VKH) is generally a rare multisystemic autoimmune disease affecting eyes, meninges, ears, and skin. It is characterized by severe bilateral panuveitis associated with serous retinal detachments and signs of meningeal irritation with or without auditory disturbances and integumentary changes. Other ocular manifestations include iridocyclitis, diffuse choroidal thickening, and hyperemia of the optic disc. The meningeal or neurologic manifestations generally occur in the initial stage of the disorder and consist of headache, meningismus, and occasionally focal neurologic signs. The auditory disturbances include tinnitus, hearing loss, and vertigo. Integumentary signs primarily include patchy alopecia, poliosis of lashes and scalp hair, and patchy vitiligo. The disease can be categorized into the prodromal, uveitis, convalescent, and recurrent phases.1 Although the disease predominantly involves nonvvhite patients,2 whites, as in our case, can be affected by this syndrome.

Because of the variability in clinical presentation of this disease, the first international workshop on VKH syndrome in 1999 proposed diagnostic criteria. The VKH syndrome was divided into 3 categories: complete, incomplete, and probable. For all types, there must be no penetrating ocular trauma or surgery at the initial onset of uveitis and no laboratory evidence for other ocular disease. There must be ocular involvement in all types. Complete VKH must include neurologic, auditory, and integumentary findings; incomplete VKH must have at least one of these findings; and probable VKH has none.3 Our patient fulfilled the criteria for complete VKH syndrome. He did not have a history of penetrating ocular trauma or surgery at the initial onset of uveitis; he had no clinical or laboratory evidence suggestive of other ocular disease; there was bilateral ocular involvement by diffuse choroiditis; neurologic manifestations included cerebrospinal fluid pleocytosis; and integumentary findings included poliosis.

The etiology and pathogenesis of this disease is unknown. Earlier studies reported that the melanocytes of all organs are affected in VKH disease. The lymphocytes of patients with VKH disease attach to and attack the melanocytes.4 These lymphocytes also proliferated when challenged by antigens from melanocytes, and were cytotoxic to the melanocytes in vitro.5 Results of numerous studies in various ethnic groups demonstrated a strong association between class II, subtype DR4 HLA, and VKH disease. Among the many polymorphic variations in the ß-chain of the DR4 haplotype, the HLA-DRB1*0405 allele has been considered the most significant.2 Results of recent studies showed that lymphocytes from patients with VKH disease who possessed the HLA-DRB1*0405 allele recognized peptides derived from melanocytes and melanoma proteins.6 Among these peptides were those derived from tyrosinase7 and other tyrosinase family proteins, such as tyrosinase-related proteins 1 and 2.8 Among all patients with VKH syndrome, the prevalence of the HLA-DRB1*0405 gene was significantly higher among patients in the chronic phase of the illness.9

The largest series of histologic studies of the eyes of patients with chronic VKH syndrome was reported by Perry and Font,10 who studied the eyes of 9 patients with this disease. There were 5 cases of nongranulomatous infiltration mixed with plasma cells in the uvea. The other 4 cases demonstrated diffuse granulomatous inflammation of the uvea. The authors also noted the presence of Dalen-Fuchs nodules, altered retinal pigment epithelium, and disappearance of melanocytes from the choroid. In longstanding cases, inflammation may extend into the choriocapillaries and retina, forming chorioretinal adhesions. Inomata et al11 noticed choroidal neovascularization in eyes with long-standing VKH disease. Our findings are consistent with the group of patients with nongranulomatous and long-standing chorioretinal, dense adhesions.

Although there is no specific treatment for VKH disease, symptoms usually can he controlled by corticosteroids, cytotoxic agents, and/or immunosuppressants.1 Few studies have addressed prognostic factors for final visual acuity. Increased interval between onset of ocular symptoms and treatment, number of complications, greater age, and worse acuity at presentation are associated with worse final visual acuity.12,13

This work was supported in part by a Challenge grant from Research to Prevent Blindness, New York, NY to the Department of Ophthamology (Dr Gonzalez-Fernandez).

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