Vogt-Koyanagi-Harada syndrome is an uncommon multisystem inflammatory disorder characterized by panuveitis with serous retinal detachments, and it is often associated with neurologic and cutaneous manifestations, including headache, hearing loss, vitiligo and poliosis.
Because of its varied clinical manifestations, the American Uveitis Society adopted in 1978 the following diagnostic criteria for VKH: No history of ocular trauma or surgery, and at least three of the following four signs, 1) bilateral chronic iridocyclitis, 2) posterior uveitis with any of the following:
- multifocal exudative retinal or retinal pigment epithelial detachments,
- disc hyperemia or edema, or
- “sunset glow” fundus, which is a yellow-orange appearance of the fundus due to depigmentation of the RPE and choroid, 3) neurologic signs, including tinnitus, neck stiffness, cranial nerve or central nervous system symptoms or cerebrospinal fluid (CSF) pleocytosis or 4) cutaneous findings, including alopecia, poliosis or vitiligo.
Stages of Disease
Four clinical stages have been described in VKH: prodromal stage, acute uveitic stage, convalescent stage and chronic recurrent stage. Experience shows that the stages of VKH are often indistinct. Moreover, it is not clinically relevant to distinguish the stages for a treat-ment strategy. The critical aspects of treatment are to make the correct diagnosis without delay, to institute appropriate systemic anti-inflammatory therapy, and to taper therapy appropriate to disease activity and side effects.
Stage 1: Prodromal. This stage, also called the meningeal stage, lasts for a few days to a few weeks and often mimics a viral infection. Patients present with fever and neurologic features, including meningeal involvement (headache, confusion, neck stiffness), encephalopathy (convulsions, paresis, aphasia), focal neurologic signs (cranial nerve palsies, hemiparesis, optic neuritis), auditory symptoms (tinnitus, vertigo, hearing loss) and CSF lymphocytosis. Some patients report a hypersensitivity of their scalp and skin to touch.
Stage 2: Acute uveitic. The second stage occurs within three to five days of the prodromal stage and lasts for several weeks. Patients often do not present to their ophthalmologist until this stage, when they experience acute ocular pain and red eyes associated with bilateral blurring of vision secondary to uveitis. Posterior segment involvement includes multifocal choroiditis with choroidal inflammation and thickening, Dalen-Fuchs nodules and disc hyperemia or edema. A hallmark finding is multifocal detachments of the neurosensory retina.
Eventually the inflammation extends into the anterior segment. Patients with VKH may have chronic bilateral granulomatous iridocyclitis with mutton- fat keratic precipitates, iris nodules and shallow anterior chambers due to ciliary edema and suprachoroidal fluid collection. As a result, secondary complications such as posterior synechiae, pupillary membrane, glaucoma and cataract are common.
Stage 3: Convalescent. The convalescent stage follows the acute uveitic stage gradually, usually a few months later, and may last months or years. Findings include vitiligo, alopecia and poliosis. These skin changes generally persist despite therapy. There is also uveal depigmentation, resulting in a “sunset glow” within two to six months.
Stage 4: Chronic recurrent. This stage may interrupt the convalescent stage. Studies report recurrence rates of 43 percent within the first three months and 52 percent within the first six months, often associated with rapid tapering of corticosteroids.¹ Recurrence mainly involves anterior uveitis. In this stage, complications of VKH such as glaucoma, cataract, subretinal neovascular membrane and subretinal fibrosis may develop.
The differential diagnosis of VKH includes the anatomical condition uveal effusion syndrome, infectious processes such as syphilis or herpes, malignancies such as leukemia or metastasis or inflammatory diseases. The main diagnoses to consider in cases with fluorescein angiographic findings are VKH, sympathetic ophthalmia, posterior scleritis and acute systemic arterial or pregnancy-related hypertension.
Sympathetic ophthalmia is histopathologically identical to VKH and can present in a similar fashion with rapid, bilateral visual loss associated with anterior segment inflammation, disc edema or hyperemia, choroidal thickening and serous retinal detachments. However, sympathetic ophthalmia is nearly always associated with a history of prior intraocular trauma or surgery.
Posterior scleritis initially may be difficult to distinguish from VKH until the “sunset glow” appears in the convalescent phase. Posterior scleritis can also present with ocular pain, redness and serous retinal detachments. However, it is usually unilateral and not associated with neurologic or dermatologic findings. Also, unique to posterior scleritis is the ultrasonographic “T sign,” or squaring of the interface between the optic nerve and the sclera, indicating the presence of fluid in the sub-Tenon’s space.
Systemic arterial hypertension and pregnancy-related hypertension may also result in serous retinal detachments. It is suspected that choroidal vascular changes predominate when acute elevation of blood pressure is present, whereas a more gradual onset of hypertension results in retinal vascular changes.
In the majority of VKH cases, the diagnosis is made clinically. However, fluorescein angiography, ultrasonography and optical coherence tomography (OCT) are often used to assist in the diagnosis.
In the acute uveitic stage, fluorescein angiography findings include multiple punctate hyperfluorescent dots at the level of the RPE (the characteristic “stars at night” appearance), which gradually enlarge and stain the subretinal fluid, delineating the serous retinal detachments. In 70 percent of cases, there is disc leakage. In the chronic recurrent stage, there are multiple hyperfluorescent RPE window defects and alternating hyper- and hypofluorescence from RPE alterations, sometimes referred to as “moth-eaten” scars. There may also be choroidal and disc neovascularization and anastomoses.
On ultrasonography, in the acute stages, VKH presents with diffuse choroidal thickening with low to medium reflectivity, serous retinal detachments, vitreous opacities without posterior vitreous detachment and scleral or episcleral thickening.
OCT is often used to diagnose and quantify subretinal fluid found in VKH. This modality also assists in following patients’ response to therapy.
Electrophysiologic tests, such as electroencephalogram, electroretinogram and electro-oculogram, are nondiagnostic. No specific serologic test exists to establish the diagnosis of VKH.
Early and aggressive treatment is critical. Systemic corticosteroids, particularly prednisone, are very effective in suppressing the intraocular inflammation of VKH and have a very well-characterized side effect profile. Patients typically respond immediately to corticosteroids with resolution of the exudative retinal detachment, which is a hallmark of VKH. Intravenous corticosteroids may be used if there is severe bilateral visual loss; however, hospital admission is generally not required. Patients in our retina clinic are kept on corticosteroids for up to one year with slow tapering, usually over six months. If the condition is refractory to corticosteroids or the patient is intolerant of the side effects, second-line immunosuppressive agents, particularly methotrexate (Rheumatrex, Trexall), may be considered to lower the dose of corticosteroid. Other second-line agents, including cyclosporine (Neoral, Gengraf), tacrolimus (Prograf), cyclophosphamide (Cytoxan, Neosar), chlorambucil (Leukeran), azathioprine (Azasan, Imuran) and intravenous immunoglobulin (Gamimune N, Venoglobulin-S), have also been used for treatment of VKH; however, the side effects of these agents are either more severe or less well-characterized than methotrexate.
With treatment, the visual outcome of VKH is generally good. Visual acuity is >20/40 in 50 to 90 percent of treated cases.² Visual acuity is influenced by secondary complications of VKH, including glaucoma, choroidal neovascularization, cataract, optic atrophy and phthisis bulbi.
Occurrence Rates of VKH
In the United States, the incidence of VKH is approximately 1.5 to 6 per 1 million patients. In Japan, it is seen in approximately 800 new patients each year. Women make up 55 to 78 percent of VKH patients in the United States and approximately 38 percent in Japan, showing a global variation in gender predilection. The disease usually occurs between ages 20 and 50. Certain groups of individuals appear to be at greater risk for the development of VKH, including Asians, Middle Easterners, Native Americans and Hispanics. It is less common for those of Caucasian and African heritage to develop VKH.
1 Rubsamen, P. E. and J. D. M. Gass. Arch Ophthalmol 1991;109:682–687.
2 Moorthy, R. S. et al. Surv Ophthalmol 1995;39:265–292.
Dr. Nguyen is a resident in ophthalmology and Dr. Duker is chairman of ophthalmology and a vitreoretinal specialist at Tufts-New England Medical Center.