AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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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

The pathogenesis of VKH disease is uncertain. However, the wide spectrum of findings in this disorder suggests a central mechanism to account for the multisystem manifestations. Inflammation and loss of melanocytes has been described in a number of tissues, including the skin, inner ear, meninges, and uvea. These histopathologic changes suggest an infectious or autoimmune basis for the disease.

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

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Sympathetic ophthalmia
Intraocular lymphoma
Bilateral diffuse uveal melanocytic proliferation
Metastatic carcinoma
Idiopathic uveal effusion syndrome
Benign reactive lymphoid hyperplasia
Toxemia of pregnancy

WORKUP

Section 5 of 11  

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• Follow-up
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• Multimedia
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Lab Studies

• The diagnosis of VKH disease is based upon a constellation of clinical signs and symptoms with no confirmatory tests. However, several diagnostic procedures may be useful in establishing the diagnosis, including fluorescein angiography, ultrasonography, examination of the CSF, magnetic resonance imaging, and electrophysiologic testing.
• Examination of the CSF: This test is not necessary in typical cases of VKH disease but may be useful in cases with atypical manifestations. More than 80% of patients with VKH disease exhibit a transient CSF pleocytosis consisting primarily of lymphocytes during the first several weeks of the disease. The pleocytosis resolves within 8 weeks of onset in most patients.
• HLA typing: Although a number of HLA associations with VKH disease have been documented, HLA typing is not diagnostic of the syndrome and is not routinely recommended.

Imaging Studies

• Fluorescein angiography
• • Acute VKH disease: Multiple pinpoint areas of leakage at the level of the RPE overlying areas of choroiditis are visible during the arteriovenous phase. In the early and mid phases of the angiogram, radial folds of the choroid may be visible as alternating dark and light bands of fluorescence. During the later phases of the angiogram, the pinpoint areas gradually enlarge and stain the adjacent subretinal and sub-RPE fluid. Multiple serous retinal detachments with pooling of dye often are seen in the late phases of the study. Other less common findings include retinal vascular leakage and optic disc staining.
  • Recovery phase of VKH disease (after treatment with systemic corticosteroids): Most of the acute phase abnormalities, including exudative retinal detachment and disc edema, resolve during this period. Fluorescein angiography may show persistent pinpoint areas of leakage and disc staining. Some patients may exhibit window defects and areas of mottled background hyperfluorescence.
  • Chronic VKH disease: This is characterized clinically by depigmentation of the choroid. With angiography, signs of RPE atrophy are visible, such as a moth-eaten appearance, multiple window defects, and areas of alternating hyperfluorescence and hypofluorescence. Additional findings include choroidal neovascularization, retinochoroidal and arteriovenous anastomoses, and neovascularization of the disc. Macular edema is rare in this disorder but may be seen in the chronic phase.
• Optical coherence tomography (OCT): Serous retinal detachments with subretinal septa may be visible, especially early in the disease.  OCT may be useful to monitor serous detachments and response to therapy.
• Indocyanine green angiography
• • Acute VKH disease: Indocyanine green angiography findings include delay of choriocapillaris perfusion as well as fuzzy and indistinct choroidal vessels, multiple hypofluorescent dark spots during the intermediate and late phase, and disc hyperfluorescence during the late phase.
  • Recovery phase of VKH disease (after treatment with systemic corticosteroids): Most of the acute abnormalities resolve during this period. However, some of the hypofluorescent dark spots may persist for weeks.
  • Chronic VKH disease: Findings include hypofluorescent areas during the intermediate and late phases.
• Ultrasonography: The most characteristic finding is diffuse, low-to-medium reflective thickening of the posterior choroid. Additional findings include serous retinal detachments, mild thickening of the sclera and/or episclera adjacent to areas of choroidal thickening, and mild vitreous opacities. These ultrasonography features may be useful in monitoring the response to therapy.
• MRI: This imaging study may be useful in discriminating the sclera from the choroid and retina. With T1- and T2-weighted images, the sclera is hypointense and allows differentiation between VKH disease and posterior scleritis. During the active phase of the disease, the choroid is thickened visibly and enhances following administration of gadolinium.

Other Tests

• Electrophysiologic testing demonstrates nonspecific abnormalities in VKH disease; however, they may be useful in monitoring the progression of the disease.
• • Electroretinogram (ERG): During the early stages of the disease, the a and b wave amplitudes of the ERG may be depressed mildly. This may persist for extended periods but often recover to near normal levels during the chronic stages of the disease.
  • Electro-oculogram (EOG): During the early stages of the diseases, the light peak of the EOG may be depressed but returns toward normal with recovery and the chronic stages of the diseases.

Histologic Findings

In most cases, histopathology has shown nongranulomatous inflammation with a plasma cell infiltrate of the uvea. Lymphocytes, multinucleated giant cells, and epithelioid cells have been described in the uvea of patients with VKH disease.

Many of the giant cells and epithelioid cells contain melanin pigment. In many cases, the choriocapillaris is not involved in the inflammatory process; however, in eyes with chronic disease, inflammation may be seen in the choriocapillaris and retina. Also, in eyes with chronic VKH disease, there is loss of choroidal melanocytes.

TREATMENT

Section 6 of 11  

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Medical Care

The key to successful therapy for VKH disease is early and aggressive treatment with systemic corticosteroids. Those patients who are treated later in the course of the disorder have a more guarded prognosis for recovery of visual acuity and probably have a greater risk for chronic inflammation.

• Systemic therapy
• • For most patients with bilateral serous detachments and severe visual loss, begin therapy with systemic prednisone (1-2 mg/kg/d). In the most severe cases, some clinicians use intravenous methylprednisolone (up to 1 g/d) for several days before beginning oral prednisone (1 mg/kg/d).  However, the addition of intravenous therapy does not appear to alter the visual outcome or the development of significant ocular complications.
  • The length of treatment and subsequent taper must be individualized for each patient. Most patients require therapy for 6 months and occasionally up to 1 year before successful tapering of systemic corticosteroids. In general, systemic therapy should not be discontinued during the 3 months following the onset of the disease because of the risk for recurrence.
  • For those patients who fail to respond to high-dose systemic corticosteroids or develop intolerable adverse effects, immunodulatory therapy, such as cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, cyclophosphamide, or chlorambucil, should be instituted.
  • Increasing evidence supports the use of immunomodulatory therapy in virtually all patients with VKH.
• Topical therapy
• • Topical corticosteroids, such as prednisolone acetate, are used for the treatment of anterior uveitis. In severe cases, begin therapy with 1 drop up to every 1 hour and slowly taper based upon the therapeutic response. In patients with mild-to-moderate anterior uveitis, begin with 1 drop 4-6 times daily and taper slowly.
  • Topical cycloplegics are useful to relieve the discomfort of ciliary spasm and to prevent the formation of posterior synechiae. For VKH disease, agents, such as homatropine 5%, are used 2-4 times daily in adults. Discontinue as the inflammation wanes and symptoms resolve.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Cycloplegics

Instillation of a long-acting cycloplegic agent can relax any ciliary muscle spasm that can cause a deep aching pain and photophobia.

Drug Category: Immunosuppressive therapy

May be used when inflammation is not controlled adequately by systemic corticosteroids and/or in patients who develop intolerable adverse effects. Ophthalmologists should seek the assistance of a clinician experienced in the use of these drugs when treating patients with ocular inflammatory diseases.

Drug Category: Immunosuppressant agents

Agents in this category inhibit key factors involved in the immune response.

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• This chronic disorder requires monitoring for many years.

Complications

• Cataract
• Glaucoma
• • Closed-angle glaucoma - Pupillary block, forward rotation of the ciliary body
  • Open-angle glaucoma
• Subretinal fibrosis
• Choroidal neovascularization
• Neovascularization of the disc
• Pigmentary changes of the fundus
• Optic atrophy

Prognosis

• Visual loss in patients with VKH disease often is due to cataracts, glaucoma, and choroidal neovascularization. However, choroidal neovascularization is a major cause of late visual loss.
• The prognosis may be improved by the use of early high-dose corticosteroids during the acute phase of the disease and afterward a slow tapering reduction in dosage until therapy is discontinued. In most cases, therapy should not be discontinued during the 3 months after onset of the disease because of the high rate of recurrence during this period. Many patients require at least a 3- to 6-month tapering period (or longer) before the corticosteroids can be discontinued.

Patient Education

• Patients need to be educated so that they will have proper monitoring and care.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Misdiagnosis of infectious uveitis can lead to inappropriate treatment and potential toxicity, while losing valuable ground without the needed steroid therapy. On the other hand, infectious uveitis misdiagnosed as VKH disease and treated with systemic immunosuppression can lead to disastrous results. In particular, syphilis and tuberculosis may demonstrate significant deterioration when treated with steroids alone prior to aggressive appropriate antibiotic therapy.

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  Bilateral multifocal serous detachments in a patient with Vogt-Koyanagi-Harada disease. Disc hyperemia is evident in the right eye.
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Media type:  Photo

Media file 2:  Fluorescein angiography of the left eye from Media file 1. Mid phase is shown on the left with multiple areas of hyperfluorescence at the level of the retinal pigment epithelium. Late phase of the same angiogram (right) reveals multiple placoid areas of hyperfluorescence at the level of the retinal pigment epithelium and pooling of dye in the areas of serous detachment.
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Media type:  Photo

Media file 3:  Patient with progressive dysacusis and recent onset of visual loss. Fundus photo shows a large multifocal serous detachment of the right eye. B-scan ultrasonography reveals posterior choroidal thickening with an overlying retinal detachment.
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Media type:  Photo

Media file 4:  Same patient as in Media file 3 following 6 weeks of systemic corticosteroid therapy. Diffuse depigmentation of the choroid with retinal pigment epithelium migration is seen. Residual retinal striae are present in the peripapillary region. B-scan ultrasonography shows resolution of retinal detachment and choroidal thickening.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Jan 5, 2008