Vogt-Koyanagi-Harada (VKH) Disease


Background

Vogt-Koyanagi-Harada (VKH) disease is a multisystem autoimmune inflammatory disorder with ocular, auditory, skin and neurologic involvement. VKH disease occurs more commonly in patients with a genetic predisposition to the disease, including those from 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. (See Etiology and Epidemiology.) [12345]

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 (see the image below). (See Presentation and Workup.) [678910]

Bilateral, multifocal serous detachments in a patiBilateral, multifocal serous detachments in a patient with Vogt-Koyanagi-Harada disease. Disc hyperemia is evident in the right eye.

With such a wide spectrum of manifestations, typical cases of VKH disease are uncommon. To help clarify the diagnostic features of VKH disease, the International Committee on Nomenclature established revised criteria for the diagnosis of VKH disease, published in 2001. The revised criteria defined the following 3 categories of disease: [1112]

  • Complete VKH disease

  • Incomplete VKH disease

  • Probable VKH disease

Common to all forms of VKH disease are the following requirements, with additional criteria provided below for each form of the disease (see Presentation and Workup):

  • Patients have no prior history of ocular trauma or surgery

  • Patients have no evidence of another ocular disease based on clinical or laboratory evidence

  • Patients have bilateral ocular involvement.

Complete VKH disease

Early manifestations of complete VKH disease include diffuse choroiditis, which may include serous retinal detachment or focal areas of subretinal fluid. Patients without these findings must have diffuse choroidal thickening—as seen using 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.

While involvement of all three systems is necessary for classification as complete disease, the neurologic and auditory manifestations often resolve before an ophthalmic examination.

Patients with complete VKH disease must also have evidence of neurologic and auditory manifestations, as well as integumentary signs. However, the neurologic and auditory manifestations may resolve before an ophthalmic examination.

The neurologic and auditory signs include the following:

  • Meningismus - Malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors; headache alone is not sufficient to meet the definition of meningismus

  • Tinnitus

  • Cerebrospinal fluid pleocytosis

Integumentary signs include the following:

  • Alopecia

  • Poliosis

  • Vitiligo

However, the 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 have either neurologic and auditory manifestations or integumentary signs, but not both.

Probable VKH disease

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

In a 2007 study of patients diagnosed with acute VKH disease, approximately half (54%) had only probable disease, with only ocular manifestations. In the same study, 40.9% of patients with chronic disease had isolated ocular disease. [13It is speculated that early and aggressive systemic treatment may prevent progression to complete VKH disease. [14]

Etiology

VKH disease is currently considered to be a T-cell–mediated autoimmune response directed against melanocytes, although the exact antigens involved are incompletely understood. However, the pathogenesis of VKH disease is uncertain, although the wide spectrum of findings in this disorder suggests a central mechanism to account for the multisystemic manifestations. Inflammation and loss of melanocytes have 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.

The possibility that VKH disease has an autoimmune pathogenesis is supported by the statistically significant frequency of HLA-DR4, an antigen commonly associated with other autoimmune diseases.

An autoimmune reaction seems to be directed against an antigenic component shared by uveal, dermal, and meningeal melanocytes. The exact target antigen has not been identified, but possible candidates include tyrosinase- or tyrosinase-related proteins, [151617an unidentified 75-kd protein obtained from cultured human melanoma cells (G-361), [15and S-100 protein. [18Evidence suggests that Th1 and Th17 subsets of T cells together with the cytokines interleukin (IL)-7, IL-17 and IL-23 are likely involved in the initiation and maintenance of the inflammatory process. [192021]

VKH disease can be associated with other autoimmune disorders, such as autoimmune polyglandular syndrome, [22hypothyroidismHashimoto thyroiditisdiabetes mellitus, [2324Guillain-Barré syndrome, [25and immunoglobulin A (IgA) nephropathy. [26This syndrome has also been reported to be linked to malignant lymphoma. [27]

Immunologic analysis of cerebrospinal fluid (CSF) lymphocytes in VKH disease and studies of human uveal melanocytes show that uveal pigment can stimulate lymphocyte cultures from patients with VKH syndrome. Lymphocytes of peripheral blood and CSF from these patients may reveal in vitro cytotoxicity against allogenic melanoma cells.

Circulating antibodies against a retinal photoreceptor region have been detected in patients with this disorder.

The clinical course of VKH disease with an influenzalike illness (ILI) suggests a viral or postinfectious origin. Some studies invoke a possible role of Epstein-Barr virus reactivation [28or cytomegalovirus infection in this disease. [29Although a viral cause has been proposed, however, no virus has been isolated or cultured from patients with VKH disease. Nonetheless, Schlaegel and Morris found viruslike inclusion bodies in the subretinal fluid of a patient with the disorder. [30]

Single reports of patients developing VKH disease after cutaneous injury have been noted, [3132as well as 2 cases of this condition occurring after bacillus Calmette Guérin (BCG) therapy for melanoma [33and 1 case following surgery for metastatic malignant melanoma. [34Case reports indicate that even an indirect trauma in melanocyte-containing tissue may induce an inflammatory response in the eye, with VKH disease following a closed head trauma. [35]

A study revealed that a decreased vitamin D-3 level has been associated with active intraocular inflammation in patients with VKH disease. [36]

Genetics

Although almost all instances of VKH syndrome are sporadic, and familial cases are rare, some authors suggest that the condition may be inherited, probably as an autosomal recessive trait.

The strong association between VKH disease and certain racial and ethnic groups suggests that the disorder may have an immunogenetic predisposition. [37HLA typing can be useful to identify these common genetic factors, with several HLA haplotypes apparently being more common in certain populations with VKH disease.

Among Japanese patients, HLA-DR4, HLA-DR53, and HLA-DQ4 are associated strongly with the disease. [38In Chinese patients, HLA associations are seen with HLA-DR4, HLA-DR53, and HLA-DQ7. [39In a mixed group of American patients, Davis and colleagues found an association with HLA-DR4 and HLA-DR53, while HLA-DR1 and HLA-DR4 were reported in Hispanic patients living in southern California. [40]

An association with HLA-DR4, HLA-DRw53, and HLA-DQw3 has been found in subjects of Native American ancestry, and HLA-DR4 also was found to be significantly related to VKH syndrome in white Europeans, specifically in Italian patients. [41]

Data indicate that patients with VKH disease are sensitized to melanocyte epitopes and display a peptide-specific Th1 cytokine response. Patients bearing HLA-DRB1*0405 recognize a broader melanocyte-derived peptide repertoire, so the presence of this allele increases susceptibility to the development of VKH disease. [42In a group of French VKH disease DRB1*04-positive patients, the HLA-DRB1*0405 subtype was found in 71% of them. [43]

Epidemiology

VKH disease is uncommon, but it may be seen in Asian (primarily from eastern and southeastern Asia), Middle Eastern, Hispanic, and Native American populations. The disorder is less common in whites and blacks from sub-Saharan Africa. [4445]

In Japan, VKH disease represents 7-8% of all patients with uveitis. [46This disorder rarely is seen in Northern European individuals. (The manifestations of VKH disease in whites resemble those in the Japanese population, but cutaneous signs are much rarer.)

Race-related demographics

In a report from the National Eye Institute, Nussenblatt et al noted that among patients with VKH disease in the study, 50% were white, 35% were African American, and 13% were Hispanic; however, most patients had remote Native American ancestry. [47]

VKH disease is one of the most common forms of uveitis among darkly pigmented races. Individuals with the disorder 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. Moreover, VKH disease is distinctly uncommon in Africans, reaffirming that skin pigmentation alone is not a predisposing factor in the pathogenesis of the disease.

Sex- and age-related demographics

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

The age of onset of VKH disease has been reported to range from 3-89 years, with the maximum frequency in persons in their fourth decade of life. While VKH disease is seen more frequently in the adult population, it has been reported in children as young as age 3 years. [4849]

Prognosis

Long-term complications of VKH disease include reversible and irreversible vision loss. In patients with this disorder, vision loss is often is due to cataracts, glaucoma, and choroidal neovascularization (with this last being a major cause of late vision loss). Patients with optic disc swelling may develop visual field defects that persist following resolution of the inflammation. [50Final visual outcome depends on the rapidity and appropriateness of treatment. [51]

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 a tapering period of at least 3-6 months before the corticosteroids can be discontinued.

Ocular complications of VKH disease are more severe in children than in adults, leading to rapid deterioration in vision.

Complications

VKH disease is not associated with mortality. Complications of the disorder include the following:

  • Cataract

  • Closed-angle glaucoma - Pupillary block, forward rotation of the ciliary body

  • Subretinal fibrosis

  • Choroidal neovascularization

  • Neovascularization of the disc

  • Pigmentary changes of the fundus

  • Optic atrophy

  • 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; cutaneous changes may be permanent

  • Auditory manifestations - Inner ear manifestations typically respond to corticosteroid therapy within weeks to months; hearing is restored completely in most patients with VKH disease


History

Patients with Vogt-Koyanagi-Harada (VKH) disease usually initially present to an ophthalmologist for ocular problems, including sudden loss of vision, ocular pain, and photophobia. Hearing disturbances and dizziness may be present. After weeks or months, most patients notice cutaneous signs (eg, hair loss, poliosis, vitiligo).

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 7-10 days and is characterized by flu-like symptoms, such as the following:

  • Fever
  • Headache
  • Meningismus
  • Nausea
  • Vertigo
  • Orbital pain
  • 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/acute stage

The acute uveitic stage follows the prodromal stage by several days in most patients and typically lasts for several weeks. 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; in most of the remaining patients, the fellow eye is involved within several days.

Clinically, this stage manifests as bilateral posterior uveitis with retinal edema, exudative retinal detachments, optic disc hyperemia or edema, posterior choroid thickening, and, eventually, serous retinal detachments. Often, an accompanying anterior uveitis characterized by mutton-fat keratic precipitates and iris nodules are present. At this stage, an accompanying anterior uveitis can occur. The intraocular pressure may be elevated because of forward rotation of the lens-iris diaphragm.

Chronic stage

This convalescent stage typically occurs several weeks after the acute stage and can continue for months afterward. [2During 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, resulting in the sunset glow fundus. 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. Other signs of depigmentation include the Sugiura sign (perilimbal depigmentation), more common in patients of Japanese descent. [52The vitiligo tends to be distributed symmetrically over the head, eyelids, and trunk.

Recurrent stage

During the recurrent stage, patients may develop recurrent or chronic anterior uveitis. In some patients, low-grade choroidal inflammation may accompany the anterior uveitis, which may require indocyanine green angiography for visualization. [53Recurrent posterior uveitis with serous retinal detachment is rare. Patients treated inadequately with corticosteroids and/or immunomodulator therapy for 6 months or less may be at higher risk for recurrent serous retinal detachment. [54At this stage, the anterior uveitis is typically of granulomatous nature, with the presence of mutton fat keratic precipitates and Koeppe/Busacca nodules. [55]

Ocular complications are relatively common during this stage and include cataracts, glaucoma, choroidal neovascularization, and subretinal fibrosis.

Physical Examination

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

Cutaneous manifestations

Sensitivity to touch of the hair and skin may be noted during the prodromal stage, while 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; they include meningismus, headache, and occasional confusion. CSF pleocytosis is relatively common during the prodrome.

Focal neurologic signs include the following:

  • Cranial nerve palsies

  • Hemiparesis

  • Transverse myelitis

  • 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

Anterior-segment manifestations include the following:

  • Perilimbal vitiligo (Sugiura sign) - One of the earliest manifestations of depigmentation; uncommon, except in Japanese patients

  • 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, with forward rotation of the lens-iris diaphragm and possible angle-closure glaucoma. Glaucoma may occur secondary not only to angle closure but also to pupillary block, or it may arise in association with chronic uveitis.

Cataracts may develop as a result of chronic inflammation and/or chronic corticosteroid therapy.

Posterior segment

Anterior vitreous cells may be noted, especially in patients with severe anterior uveitis. Optic disc hyperemia or edema may be present.

A study by Nakao et al indicated that a patient’s age and optic disc morphology, not the severity of inflammation, are associated with optic disc swelling in VKH disease. The retrospective, observational study included 58 patients (116 eyes), with 16 patients (32 eyes) demonstrating disc edema. Patients with disc swelling had a mean age of 58.9 years, compared with 41.4 years for those without swelling. Other factors, such as intraocular pressure, refractive error, and the cup-to-disc ratio, as well as the ratio of the disc-macula distance to the disc diameter, also differed between patients with swelling and those without it. [50]

One of the earliest retinal manifestations of VKH disease 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. (See the image below.)

Bilateral, multifocal serous detachments in a patiBilateral, multifocal serous detachments in a patient with Vogt-Koyanagi-Harada disease. Disc hyperemia is evident in the right eye.

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.


Diagnostic Considerations

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 Vogt-Koyanagi-Harada (VKH) disease and treated with systemic immunosuppression can lead to disastrous results. In particular, patients with syphilis or tuberculosis may demonstrate significant deterioration when treated with steroids alone prior to aggressive appropriate antibiotic therapy. [56]

Conditions to consider in the differential diagnosis of Vogt-Koyanagi-Harada disease include the following:

  • Sympathetic ophthalmia

  • Intraocular lymphoma

  • Bilateral diffuse uveal melanocytic proliferation

  • Metastatic carcinoma

  • Idiopathic uveal effusion syndrome

  • Benign reactive lymphoid hyperplasia

  • Toxemia of pregnancy

  • Sarcoidosis

  • Vitiligo with poliosis

  • Scleritis

  • Peripheral anterior synechia

  • Tuberculosis

  • Anterior granulomatous uveitis

  • Intermediate uveitis

  • White dot syndromes

  • Alezzandrini syndrome

  • Alopecia areata

  • Piebaldism

  • Vitiligo

  • Ocular manifestations of syphilis

Differential Diagnoses


Approach Considerations

For quick diagnosis and early treatment, Vogt-Koyanagi-Harada (VKH) disease requires a multidisciplinary management strategy involving dermatologists and ophthalmologists.

The diagnosis of VKH disease is based on 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 (MRI), and electrophysiologic testing.

Examination of the CSF

This test is not necessary in typical cases of VKH disease but may be useful in patients with atypical manifestations. More than 80% of patients with VKH disease exhibit a transient CSF pleocytosis, which consists primarily of lymphocytes during the first several weeks of the disease. The pleocytosis resolves within 8 weeks of onset in most patients. [57]

Other changes in the CSF include the presence of melanin-laden macrophages (specific for VKH disease and helpful in confirming the diagnosis), increased protein levels, and increased pressure.

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.

Audiologic testing

Many patients experience some degree of sensorineural hearing loss. If possible, all patients with auditory symptoms should undergo audiologic testing. [58]

Imaging Studies

Fluorescein Angiography

Acute VKH disease

Multiple pinpoint areas of leakage at the level of the retinal pigment epithelium (RPE) overlying areas of choroiditis are visible during the arteriovenous phase. [5960Peripapillary pinpoint hyperfluorescence may be seen if angiography is performed early in the disease course. [61. In the angiogram’s early phase and midphase, 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. (See the image below.)

Fluorescein angiography of the left eye in a patieFluorescein angiography of the left eye in a patient with Vogt-Koyanagi-Harada disease. Midphase is shown on the left, with multiple areas of hyperfluorescence at the level of the retinal pigment epithelium (RPE). Late phase on the same angiogram (right) reveals multiple placoid areas of hyperfluorescence at the level of the RPE and pooling of dye in the areas of serous detachment.

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. [5960]

Indocyanine green angiography

Indocyanine green angiography probably has limited prognostic value regarding outcomes. A report suggests, however, that this modality may be useful for monitoring choroidal inflammation and response to therapy. [6263]

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 ultrasonographic 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 ultrasonographic features may be useful in monitoring the patient’s response to therapy. (See the images below.)

Patient with progressive dysacusis and recent onsePatient 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.
Patient with progressive dysacusis and recent onsePatient with progressive dysacusis and recent onset of visual loss is shown here 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.

OCT scanning

Serous retinal detachments with subretinal septa may be visible, especially early in the disease. Optical coherence tomography (OCT) scanning may be useful for monitoring serous detachments and response to therapy. Enhanced depth imaging OCT scanning has revealed a markedly thickened choroid in patients with active VKH. [64]

In recent years, enhanced depth imaging OCT (EDI-OCT) has been introduced to evaluate the thickness of the choroid and retina in VKH disease. [65These studies have shown that choroidal thickness is significantly increased in the acute phase and decreases after treatment.

MRI

This imaging study may be useful in discriminating the sclera from the choroid and retina. In 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. [6667]

Electrophysiology

Electrophysiologic testing demonstrates nonspecific abnormalities in VKH disease. Such tests, however, may be useful in monitoring the progression of the disease.

Electroretinogram

During the early stages of the disease, the a- and b-wave amplitudes of the electroretinogram (ERG) may be mildly depressed. This may persist for extended periods, but the amplitudes often recover to near normal levels during the chronic stages of the disease.

Electro-oculogram

During the early stage of the disease, the light peak of the electro-oculogram (EOG) may be depressed; it rises toward normal with recovery and the chronic stage of the disease.

Histologic Findings

Typically, VKH disease is primarily considered as a non-necrotizing diffuse granulomatous inflammation of the uveal tract. 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, with disease progression, the choriocapillaris becomes involved. In addition, in eyes with chronic VKH disease, there is loss of choroidal melanocytes. Typical histologic features include Dalen-Fuchs nodules. They present as deposits between the RPE and Bruch membrane, consisting of macrophages, epithelioid cells, lymphocytes, and proliferated RPE cells. [68]

A skin biopsy specimen taken a month after the onset of ocular symptoms of VKH disease will likely reveal a mononuclear infiltrate concentrated in the area of hair follicles and sweat glands, consisting mostly of T lymphocytes with a small number of B cells. In depigmented skin, the absence of melanin, as anticipated in vitiligo, can be noted. Vasodilatation in the dermis, pigment-laden macrophages, and a lymphocytic infiltrate have also been described.


Approach Considerations

The key to successful therapy for Vogt-Koyanagi-Harada (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.

For pigmentary changes in VKH disease, treatment options mirror those for vitiligo. Chronic VKH disease requires monitoring for many years.

Surgical care

Surgical therapy for glaucoma is necessary in some patients. Surgical intervention includes laser iridotomy, surgical iridectomy, and trabeculectomy.

Consultations

Ophthalmologic and neurologic consultations are necessary in the treatment of VKH disease.

Systemic Therapy

For most patients with bilateral serous detachments and severe visual loss, begin therapy with systemic prednisone (1-2 mg/kg/day). In the most severe cases, some clinicians use intravenous methylprednisolone (up to 1 g/day) for several days before beginning oral prednisone (1 mg/kg/day). 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 patients who fail to respond to high-dose systemic corticosteroids or who develop intolerable adverse effects, immunomodulatory therapy, such as treatment with 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. [16970717273The role of early immunosuppressive use is an area of novel interest. Case series have shown that patients who received prompt immunosuppressive agents had a better visual outcome than those who received prolonged treatment with corticosteroids. [74]

Case reports suggest that intravenous immunoglobulins (IVIGs) [7576and infliximab [7778may be of interest in the treatment for VKH syndrome. Further trials are needed to assess the efficacy of these agents.

If systemic medications are not effective, [79subtenon injections may be considered before intraocular treatment modalities are used. [80]

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 hour and slowly taper based on the therapeutic response. In patients with mild to moderate anterior uveitis, begin with 1 drop 4-6 times daily and taper slowly.

Cycloplegic-mydriatic eye drops are used symptomatically. Topical cycloplegics are useful for the relief of the discomfort of ciliary spasm and for the prevention of 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 Summary

As previously mentioned, early, aggressive treatment with systemic corticosteroids—including prednisone and possibly, in the most severe cases, intravenous methylprednisolone—is key to the effective treatment of VKH disease (although intravenous therapy has not been found to improve visual outcomes).

Immunomodulatory treatment can be used in patients who are not responsive to high-dose systemic corticosteroids or who suffer from intolerable adverse effects. Immunomodulatory agents include cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, cyclophosphamide, and chlorambucil. [16970717273]

Infliximab is a chimeric immunoglobulin monoclonal antibody to tumor necrosis factor alpha. Infliximab has previously been shown to be effective in the treatment of uveitis. Several case reports have shown a promising role of infliximab in the treatment of VKH. [81]

Adalimumab, another biologic agent targeting TNF, was also reported to be effective in the treatment of VKH disease. [82]

Rituximab, a human-murine chimeric monoclonal antibody against CD20, has been reported to be effective in patients with VKH disease who did not respond to anti-TNF agents. [83]

Corticosteroids

Class Summary

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

Prednisone

Prednisone is a synthetic adrenocortical steroid with predominantly glucocorticoid properties. An immunosuppressant, it is used for the treatment of autoimmune disorders. Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Prednisolone acetate (Millipred, Orapred, Pred Forte)

This agent is useful for the treatment of associated anterior uveitis. It decreases inflammation by suppressing the migration of PMN leukocytes and reversing increased capillary permeability.

Cycloplegics

Class Summary

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

Homatropine (Isopto Homatropine), Cyclopentolate (Cyclogyl)

Homatropine and cyclopentolate block responses of the sphincter muscle of the iris and the muscle of the ciliary body to cholinergic stimulation, producing pupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia). These agents induce mydriasis in 10-30 minutes and cycloplegia in 30-90 minutes. These effects last up to 48 hours. Individuals with heavily pigmented irides may require larger doses.

Immunosuppressants

Class Summary

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

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclosporine is a cyclic polypeptide that suppresses humoral immunity and, to a greater extent, cell-mediated immunity.

Mycophenolic Acid (Myfortic), Mycophenolate Mofetil (CellCept)

Myfortic is an enteric-coated formulation that delivers the active moiety mycophenolic acid (MPA). MPA is the same active moiety delivered by the prodrug mycophenolate mofetil (CellCept), which is combined to the mofetil moiety to improve the agent's oral bio­availability.

MPA inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It inhibits antibody production.

Azathioprine (Imuran)

Azathioprine may be used alone or as a steroid-sparing agent. It antagonizes purine metabolism and inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Azathioprine may decrease the proliferation of immune cells, in this way lowering autoimmune activity.

Tacrolimus (Prograf)

Tacrolimus is a macrolide immunosuppressive agent that inhibits the activation of T cells.

Cyclophosphamide (Procytox, Endoxan)

Cyclophosphamide may be used as monotherapy or as a steroid-sparing agent. It is a cyclic polypeptide that is chemically related to nitrogen mustards and that suppresses some humoral activity. It is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Cyclophosphamide is biotransformed by the cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. The interaction of phosphoramide mustard with DNA is considered to be cytotoxic.

When used in autoimmune diseases, cyclophosphamide's mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, the drug affects B cells by inhibiting clonal expansion and by suppressing the production of immunoglobulins. With long-term, low-dose therapy, cyclophosphamide affects T-cell functions.

Chlorambucil (Leukeran)

Chlorambucil is a bifunctional, slow-acting, aromatic nitrogen mustard derivative that interferes with DNA replication, transcription, and nucleic acid function by alkylation. Known chemically as 4-[bis(2chlorethyl)amino]benzene butanoic acid, the drug alkylates and cross-links strands of DNA.

Alkylation takes place through formation of the highly reactive ethylenimonium radical. Chlorambucil's probable mode of action involves cross-linkage of the ethylenimonium derivative between 2 strands of helical DNA and subsequent interference with replication.

Dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as an abrupt fall in the white blood cell count occurs.

Methotrexate (Trexall, Rheumatrex)

Methotrexate ameliorates the symptoms of inflammation (eg, pain, swelling, stiffness). Its mechanism of action in the treatment of inflammatory reactions is unknown, but immune function may be affected. Gradually adjust the dose to achieve a satisfactory response.

Infliximab

Infliximab is a chimeric immunoglobulin monoclonal antibody to tumor necrosis factor alpha. Infliximab has previously been shown to be effective in the treatment of uveitis. Several case reports have shown a promising role of infliximab in the treatment of VKH.

Adalimumab

Adalimumab, another biologic agent targeting TNF, was also reported to be effective in the treatment of VKH disease.

Rituximab

Rituximab, a human-murine chimeric monoclonal antibody against CD20, has been reported to be effective in patients with VKH disease who did not respond to anti-TNF agents.