eMedicine Specialties > Ophthalmology > Unclassified Disorders

Vogt-Koyanagi-Harada Disease

Author: R Christopher Walton, MD, Professor, Director of Uveitis and Ocular Inflammatory Diseases Service, Assistant Department of Ophthalmology, Assistant Dean for Graduate Medical Education and Continuing Education, University of Tennessee College of Medicine; Consulting Staff, Regional Medical Center, Memphis Veterans Affairs Medical Center, St Jude Children's Research Hospital
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Updated: Jan 5, 2008

Introduction

Background

Vogt-Koyanagi-Harada (VKH) disease is a multisystem disorder characterized by granulomatous panuveitis with exudative retinal detachments that is often associated with neurologic and cutaneous manifestations. VKH disease occurs more commonly in patients with a genetic predisposition to the disease, including Asian, Middle Eastern, Hispanic, and Native American populations. Several human leukocyte antigen (HLA) associations have been found in patients with VKH disease, including HLA-DR4, HLA-DR53, and HLA-DQ4.

Independently, Vogt, Koyanagi, and Harada described several patients during a 20-year period with bilateral uveitis, exudative retinal detachments, neurologic abnormalities, and disorders of the integument. Despite differences in their patients, the manifestations appeared to represent a spectrum of disease and several authors suggested that the disorder should be termed Vogt-Koyanagi-Harada syndrome.

With such a wide spectrum of the disease, typical cases of VKH disease are uncommon. To help clarify the diagnostic features of VKH disease, an International Committee on Nomenclature established revised criteria for the diagnosis of VKH disease. The revised criteria defined 3 categories of disease: complete VKH, incomplete VKH, and probable VKH. Common to all forms of VKH disease are the requirements that: (1) patients have no prior history of ocular trauma or surgery, (2) patients have no evidence of another ocular disease based upon clinical or laboratory evidence, and (3) patients have bilateral ocular involvement. Additional criteria for each form of the disease are outlined below.

Complete VKH disease

Early manifestations of complete VKH disease include diffuse choroiditis that may include serous retinal detachment or focal areas of subretinal fluid. Patients without these findings must have diffuse choroidal thickening by ultrasonography with fluorescein angiographic abnormalities, including focal areas of delayed choroidal perfusion, multifocal pinpoint leakage, areas of placoid hyperfluorescence, pooling of subretinal fluid, and optic nerve staining.

Late manifestations of complete VKH disease include evidence of previous early manifestations of the disease, as outlined above, with ocular depigmentation and nummular chorioretinal scars, retinal pigment epithelium (RPE) clumping and migration, or anterior uveitis.

Patients with complete VKH disease must also have evidence of neurologic and auditory findings as well as integumentary signs. However, the neurologic and auditory manifestations may have resolved before an ophthalmic examination. The neurologic and auditory manifestations include meningismus (but not headache alone), tinnitus, and cerebrospinal fluid pleocytosis. Integumentary signs include alopecia, poliosis, and vitiligo. However, these integumentary signs should not occur prior to the onset of ocular signs and central nervous system signs.

Incomplete VKH disease

Patients with incomplete VKH disease are similar to those with complete VKH disease, but patients with incomplete VKH disease do not have both the neurologic and auditory manifestations and the integumentary signs. To be diagnosed with incomplete VKH disease, patients must have either the neurologic and auditory manifestations or the integumentary signs.

Probable VKH disease

Patients with probable VKH disease include those with isolated ocular disease.

Pathophysiology

VKH disease currently is considered to be a cell-mediated autoimmune disease directed against melanocytes. Yamaki and coworkers have shown that the tyrosinase-related proteins, TRP1 and TRP2, can induce disease in Lewis rats that is similar to VKH disease in humans.¹ These findings suggest that the tyrosinase family proteins induce VKH disease.

Genetics

The strong association between VKH disease and certain racial and ethnic groups suggests that the disorder may have an immunogenetic predisposition. HLA typing can be useful to identify these common genetic factors. As a result, several HLA haplotypes appear to be more common in certain populations with VKH disease. Among Japanese patients, HLA-DR4, HLA-DR53, and HLA-DQ4 are associated strongly with the disease. In Chinese patients, HLA associations are seen with HLA-DR4, HLA-DR53, and HLA-DQ7. In a mixed group of American patients, Davis and coworkers found an association with HLA-DR4 and HLA-DR53, while HLA-DR1 and HLA-DR4 were reported in Hispanic patients living in southern California.²

Frequency

United States

VKH disease is uncommon, but it may be seen in Asian, Middle Eastern, Hispanic, and Native American populations. VKH disease is extremely uncommon in whites. In a report from the National Eye Institute, Nussenblatt and coworkers noted that 50% of their patients were Caucasian, 35% were African American, and 13% were Hispanic; however, most patients had remote Native American ancestry.³

International

VKH disease commonly is seen in Asian (primarily from eastern and southeastern Asia), Middle Eastern, and Hispanic populations.

Mortality/Morbidity

• Neurologic manifestations: Many of the neurologic manifestations may persist for weeks. Most signs and symptoms resolve with corticosteroid therapy, although severe meningoencephalitic impairment has been reported.
• Cutaneous manifestations: Most of the integumentary changes, including alopecia, poliosis, and vitiligo, persist despite therapy.
• Auditory manifestations: Inner ear manifestations typically respond to corticosteroid therapy within weeks to months.

Race

Historically, VKH disease is reported to be more common in darkly pigmented races. However, individuals with VKH disease most likely have an immunogenetic predisposition that is probably more common in certain ethnic groups with increased skin pigmentation, such as Asian, Middle Eastern, Hispanic, and Native American populations. Also, VKH disease is distinctly uncommon in Africans, reaffirming that skin pigmentation alone is not a predisposing factor in the pathogenesis of the disease.

• In Japan, VKH disease represents 7-8% of all patients with uveitis.
• This disorder rarely is seen in Northern European individuals.

Sex

Females are more commonly affected than males. The female-to-male ratio in most large series is 2:1.

Age

VKH disease affects individuals aged 20-50 years, most frequently during the third decade. Yet, children as young as 4 years have been reported with VKH disease.

Clinical

History

Four clinical stages have been described in VKH disease, consisting of the prodromal stage, uveitic stage, chronic stage, and recurrent stage.

• Prodromal stage
  • The prodrome typically lasts for a few days and is characterized by fever, headache, meningismus, nausea, vertigo, orbital pain, and tinnitus. CSF pleocytosis occurs in more than 80% of patients during this stage. Photophobia and tearing may develop, and patients also may note that their skin and hair is sensitive to touch during this stage.
  • Uncommon manifestations during the prodrome include cranial nerve palsies and optic neuritis.
  • Some patients may not develop or report the symptoms characteristic of the prodrome.
• Uveitic stage
  • The acute uveitis stage follows the prodromal stage by several days in most patients. During this stage, the most common symptom is acute bilateral blurring of vision. As many as 70% of patients present with bilateral blurring of vision, and, in the remaining patients, the fellow eye is involved within several days in most cases.
  • Clinically, this is manifest as bilateral posterior uveitis with retinal edema, optic disc hyperemia or edema, and eventually serous retinal detachments. Often, an accompanying anterior uveitis characterized by mutton-fat keratic precipitates and iris nodules are present. The intraocular pressure may be elevated because of forward rotation of the lens-iris diaphragm.
  • This stage typically lasts for several weeks.
• Chronic stage
  • During the chronic stage, ocular and dermatologic manifestations are common. Depigmentation of the choroid begins within the first 3 months after the onset of the disease. Areas of hyperpigmentation also may develop in the fundus. Dalen-Fuchs nodules may be seen in the peripheral and midperipheral retina. These nodules are small yellow lesions that typically are located in the midperiphery of the retina. Eventually, the lesions fade and become atrophic.
  • Dermatologic changes include vitiligo and poliosis of the lashes, eyebrows, and hair. The vitiligo tends to be distributed symmetrically over the head, eyelids, and trunk.
  • The duration of the chronic stage is typically several months but may last for many years.
• Recurrent stage
  • During the recurrent stage, patients may develop chronic panuveitis with recurrent granulomatous anterior uveitis; however, recurrent posterior uveitis with serous retinal detachment is rare.
  • Ocular complications are relatively common during this stage and include cataracts, glaucoma, choroidal neovascularization, and subretinal fibrosis.

Physical

Patients suspected of having VKH disease should undergo a thorough physical examination to search for cutaneous, neurologic, and ophthalmic manifestations of the disorder.

• Cutaneous manifestations
  • Sensitivity to touch of the hair and skin may be noted during the prodromal stage.
  • Vitiligo, poliosis, and alopecia typically develop during the chronic stage. Vitiligo often is distributed symmetrically over the head, face, and trunk. The sacral region is a common site for the development of vitiligo.
  • Poliosis may involve the scalp hair, eyebrows, and eyelashes.
• Neurologic manifestations
  • Meningeal signs develop during the prodromal stage and include meningismus, headache, and occasional confusion. CSF pleocytosis is relatively common during the prodrome.
  • Focal neurologic signs include cranial nerve palsies, hemiparesis, transverse myelitis, and ciliary ganglionitis.
  • Inner ear disorders, including dysacusis, tinnitus, and vertigo, occur in as many as 75% of patients. Cochlear hearing loss occurs mainly in high-frequency ranges. Inner ear dysfunction improves several months after onset in most patients.
• Ophthalmic manifestations
  • Visual acuity may be decreased markedly in both eyes at the onset of the uveitic stage. Patients may present with unilateral loss of vision, but most develop bilateral disease within the first 10 days following onset.
  • Ocular adnexa involvement includes poliosis of the scalp, eyebrows, or eyelashes, which may develop during the convalescent stage of VKH disease. Vitiligo also may occur on the eyelids and face during this stage.
  • Anterior segment
    • Perilimbal vitiligo (Sugiura sign) is one of the earliest manifestations of depigmentation but is uncommon, except in Japanese patients.
    • A granulomatous or nongranulomatous anterior uveitis may occur. Busacca nodules, Koeppe nodules, and mutton-fat keratic precipitates are characteristic of granulomatous anterior uveitis.
    • Posterior synechiae may be noted, especially in chronic cases. Pupillary membrane formation is relatively common.
    • Some patients may present with a shallow anterior chamber due to edema and infiltration of the ciliary body, resulting in forward rotation of the lens-iris diaphragm and possible angle-closure glaucoma.
    • Cataracts may develop as a result of chronic inflammation and/or chronic corticosteroid therapy.
    • Glaucoma may occur secondary to pupillary block or angle closure or in association with chronic uveitis.
  • Posterior segment
    • Anterior vitreous cells may be noted, especially in patients with severe anterior uveitis.
    • Optic disc hyperemia or edema may be present.
    • One of the earliest retinal manifestations is retinal edema, which is often located within the posterior pole. This typically is followed by the development of bilateral multifocal serous retinal detachments. The detachments occur most commonly in the inferior retina.
    • During the chronic stage of the disease, the serous detachments resolve and retinal pigment epithelium (RPE) alterations are common, including depigmentation, demarcation lines, and areas of hyperpigmentation. The fundus of Asian and Hispanic patients may develop the characteristic red-orange appearance of the sunset-glow fundus, although this is relatively uncommon in other groups of patients. Areas of hyperpigmentation are also common and reflect changes occurring at the level of the RPE. Subretinal fibrosis, RPE migration, and disciform scars also may occur.
    • Neovascularization of the disc and retina may develop and can result in vitreous hemorrhage.
    • Choroidal neovascularization of the macula may occur in the chronic stage and can result in profound loss of visual acuity.

Causes

The pathogenesis of VKH disease is uncertain. See Pathophysiology.

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