Chapter 177 – Vogt-Koyanagi-Harada Disease
• An idiopathic bilateral uveitis featuring exudative retinal detachment associated with extraocular involvement, including neurological symptoms.
• Bilateral granulomatous panuveitis.
• Exudative retinal detachment.
• Pigmentary changes in the eye in the chronic and recurrent phases (sunset glow fundus).
• Iris atrophy.
• Retinochoroidal atrophy.
• Meningitic manifestations: fever, headache, nausea, vomiting, and pleocytosis in cerebrospinal fluid.
• Auditory signs: tinnitus, vertigo, and neurosensory hearing loss.
• Dermal signs: vitiligo, alopecia, and poliosis.
Vogt-Koyanagi-Harada (VKH) disease is a bilateral uveitis of unknown cause. The disease is often associated with extraocular involvement, including pleocytosis in cerebrospinal fluid, dysacousia, alopecia, poliosis, and vitiligo. Histopathology of eyes with VKH disease shows bilateral granulomatous inflammation throughout the uveal tissues. Originally, VKH disease was classified as two separate entities:
Vogt-Koyanagi syndrome, characterized by chronic anterior uveitis associated with alopecia, vitiligo, and dysacousia. 
Harada’s disease, characterized by bilateral exudative uveitis, primarily in the posterior segment of the eye, accompanied by pleocytosis of cerebrospinal fluid.
These two entities are known to overlap in many aspects, clinically and histopathologically, so are now combined as Vogt-Koyanagi-Harada disease.   
EPIDEMIOLOGY AND PATHOGENESIS
The occurrence of VKH disease is more frequent in the pigmented races: Asians, Hispanics, Native Americans, and Asian Indians. It is rare in Caucasians. Women seem to be affected more frequently than men. In the author’s Eye Clinic at Kyushu University, Japan, 148 new patients (all Japanese) with VKH disease were registered in the 22 years from 1974 to 1995, an incidence of 7 cases per year. Of the 148 patients, 81 (55%) were women and 67 (45%) men. Ages ranged from 15 to 85 years, but the disease occurs mainly in the fourth and fifth decades of life (80 of the 148 cases [54%] were in this age group). In a study from Southern California, of the 65 patients with VKH disease, 78% were Hispanic, 10% were Asian, 6% were African-American, and 3% were white; one patient was an Asian Indian, and one was a Native American. In this study, 74% of the patients were women, and most patients were in the second to fifth decades of life at the onset of the illness. The age range was 7–71 years, with a mean of 32 years.
There is a genetic link in the development of VKH disease. Evidence of increased risk among those with certain HLA genotypes indicates a genetically determined susceptibility for VKH disease. 
The cause of the disease remains unknown. Viral infection has been suggested, but no direct evidence exists to support this. From histopathological and immunological studies, an autoimmune reaction to melanocytes has been suggested to play an important role in the pathogenesis. It was recently reported that tyrosinase related proteins experimentally induced inflammatory changes similar to those seen in patients with VKH disease. However, the trigger that initiates the immune reaction to the melanocytes is yet to be discovered.
The diagnostic criteria for VKH disease were suggested by the International Committee on Nomenclature of the disease. Clinically, the disease is categorized into prodromal, uveitic, chronic, and recurrent phases.
Patients who have VKH disease may visit internists first because of influenza-like symptoms with fever, headache, and sometimes nausea. Within 1–2 days of the prodromal phase, the patient complains of blurring of vision, photophobia, injection of bulbar conjunctiva, ocular pain, and metamorphopsia. Sensitivity of the hair and skin to touch is another sign during the prodromal phase.
In the early stage of the uveitic phase, cells are present in both anterior chambers, and in typical cases, bilateral exudative retinal detachments are present. Cells in the anterior chamber become more prominent in the later stage. The anterior chamber often is slightly shallow. The blurring of vision is caused mainly by exudative retinal detachment due to inflammation in the choroid ( Fig. 177-1 ). The pattern of the retinal detachment in VKH disease is characteristic. It shows discrete and shallow elevation of the neural retina, with small folds that radiate from the macula. A cloverleaf pattern of detachment often is seen in the posterior fundus. In severe cases, the detachment becomes bullous. The optic disc becomes hyperemic and edematous.
After treatment with systemic corticosteroids, elevation of the neural retina gradually disappears with absorption of the subretinal fluid. Cells in the anterior chamber decrease or disappear and the depth of the anterior chamber becomes normal. As inflammation
Figure 177-1 Fundus in the uveitic phase of Vogt-Koyanagi-Harada disease. Note the exudative detachment of the neural retina due to inflammation in the choroid. The retinal detachment appears to be discrete; it can be of various sizes, depending on the amount of accumulated subretinal fluid.
in the uveal tissue subsides, depigmentation occurs in the fundus to give it the appearance of a sunset glow. Small, discrete, and scattered depigmented lesions are seen within the sunset-glow fundus ( Fig. 177-2 ). Most of these lesions represent degenerated or disappeared retinal pigment epithelium (RPE). Only a few of them may represent resolved Dalen-Fuchs nodules. Depigmentation in the corneal limbus sometimes is noticed about 1 month after the onset and is known as Sugiura’s sign.
The uveitis in VKH disease often recurs or becomes chronic. In recurrent cases, anterior uveitis is more predominant than posterior uveitis. Though the neural retina is free from the primary inflammation, retinal vasculitis and arteriovenous anastomosis occur as secondary reactions to the severe or long-standing inflammation in the choroid. Subretinal neovascularization is seen in the peripapillary region and in the macula; it often causes retinal hemorrhage.
The eyes show signs of chronic iridocyclitis. Mutton-fat keratic precipitates, Koeppe iris nodules, and posterior synechiae are signs of the chronic and recurrent phase. The iris becomes atrophic, with less pigmentation. Gonioscopy reveals depigmentation of the ciliary body band. Neovascularization in the chamber angle may occur in recurrent and long-standing cases.
DIAGNOSIS AND ANCILLARY TESTING
Fluorescein Fundus Angiography
In the early, active stage of the disease, subretinal exudation from the choroid can be demonstrated by fluorescein fundus angiography, which shows numerous hyperfluorescent dots located at the level of the RPE that have a tendency to gradually enlarge. The dye leaks through the pigment epithelial layer and accumulates in the subretinal space ( Fig. 177-3 ). When the exudative retinal detachment disappears after treatment, the hyperfluorescent dots and diffuse dye accumulation in the subretinal space no longer can be observed. In the chronic phase, fundus angiography shows diffusely scattered dots of hyperfluorescence due to window defects at the level of the RPE.
Indocyanine Green Fundus Angiography
Indocyanine green fundus angiography is a useful technique to evaluate the choroidal circulation in VKH disease. Circulatory
Figure 177-2 Sunset-glow fundus in the chronic phase of Vogt-Koyanagi-Harada disease. The fundus has a slightly reddish appearance, mainly due to the disappearance of melanocytes in the choroid. Note the numerous small, depigmented dots, most of which are lesions of degenerated or disappeared retinal pigment epithelium (RPE). Only a few of them may represent resolved Dalen-Fuchs nodules.
Figure 177-3 Fluorescein fundus angiography in the uveitic phase of Vogt-Koyanagi-Harada disease. Note the dot-like lesions with dye leakage from the damaged retinal pigment epithelium and fluid accumulation in the subretinal space.
disturbance occurs in the choroid in the early, active stage, with the choroid showing a decrease in the number of large choroidal vessels filled with fluorescein dye. The number of large fluorescent choroidal vessels increases after the exudative retinal detachment subsides. Indocyanine green fundus angiography also may reveal choroidal neovascularization, if present.
Ultrasound biomicroscopy of the anterior segment of the eye reveals a narrow anterior chamber angle due to accumulation of exudate between the ciliary body and sclera ( Fig. 177-4 ).  After treatment with systemic corticosteroids, the supraciliary exudate disappears. Standardized echography is another helpful technique with which to diagnose VKH disease, particularly in patients who have opaque media. The echographic manifestations include diffuse thickening of the posterior choroid, serous detachment of the retina, vitreous opacities, and posterior thickening of the sclera or episclera. Resolution of these findings occurs with systemic corticosteroid therapy.
Figure 177-4 Ultrasound biomicroscopy of the uveitic phase in a patient with Vogt-Koyanagi-Harada disease. A, Cross section of the anterior angle. B, Posterior section of the anterior segment. The anterior chamber is narrow, and a layer of fluid has accumulated external to the ciliary body and choroid.
Cerebrospinal Fluid Analysis
Pleocytosis is seen in the cerebrospinal fluid in approximately 80% of patients within 1 week and in 97% of patients within 3 weeks of the onset of the disease. Most of the cells in cerebrospinal fluid are small lymphocytes. Protein levels in the cerebrospinal fluid are elevated in about half the patients.
Sympathetic uveitis should be differentiated from VKH disease. Clinical manifestations and histopathology of eyes with sympathetic uveitis include bilateral granulomatous uveitis, which resembles that seen in VKH disease. In both diseases, uveal melanocytes are the target of the ocular inflammation. The sunset-glow appearance of the fundus due to depigmentation throughout the choroid is one of the most characteristic features of the chronic phases of both diseases. The only difference between sympathetic uveitis and VKH disease is a history of penetrating ocular injury or intraocular surgery in sympathetic uveitis and the absence of such a history in patients who have VKH disease.
Central serous chorioretinopathy must be differentiated from the uveitic phase of VKH disease. Shallow retinal detachment occurs in the macular area in central serous chorioretinopathy. The retinal detachment in VKH disease, however, is very specific in ophthalmological appearance, with a discrete and sometimes cloverleaf pattern. No inflammatory signs occur in central serous chorioretinopathy.
Posterior scleritis often shows exudative retinal detachment. Computed tomography scans and ultrasonography help make the correct diagnosis, as they reveal thickening of the posterior sclera.
Acute posterior multifocal placoid pigment epitheliopathy may be confused with VKH disease because multiple white-yellow flat to placoid lesions at the level of the RPE are seen. However, acute posterior multifocal placoid pigment epitheliopathy usually shows no cells in the anterior chamber or in the vitreous.
Figure 177-5 Vitiligo seen during the chronic phase in a patient with Vogt-Koyanagi-Harada disease. The skin on the lower back is one of the preferred sites for vitiligo in this disease.
Bilateral chronic uveitis, as occurs in Behçet’s syndrome, needs to be differentiated from VKH disease in the chronic and recurrent phases, but the characteristic sunset-glow fundus does not occur in Behçet’s syndrome. Extraocular manifestations of these diseases are the key to differentiating them.
Auditory disturbance in VKH disease consists of a sensory neural hearing loss due to inner ear dysfunction. Some patients complain of tinnitus and vertigo at the onset. An audiogram demonstrates hearing loss in the high-frequency ranges; hearing usually returns to normal within several weeks.
Meningitic manifestations at the onset of the disease may include fever, headache, nausea, and vomiting, but in many cases, none of these signs occurs. Examination of the cerebrospinal fluid demonstrates pleocytosis and an increase in protein content. The cells in the cerebrospinal fluid are lymphocytes and disappear after the systemic administration of corticosteroids. However, many cases of VKH disease occur without pleocytosis. Central nervous system involvement in VKH disease has been emphasized, but encephalitic signs occur rarely, if at all.
About 2–3 months after onset, vitiligo occurs on the face (around the eyelashes), hands, shoulders, breasts, and back. One site of predilection for vitiligo is the lower back region ( Fig. 177-5 ), where mongolian spots are seen in Asian children. Erythema of the skin sometimes precedes the vitiligo.
Poliosis (whitened hair or canities) and alopecia (loss of hair) often occur.
The pathology of VKH disease is basically the same as that for sympathetic uveitis, with granulomatous inflammation throughout the uveal tissues. The uveal tissues are thickened by diffuse infiltration of lymphocytes, macrophages, and epithelioid cells, and the neural retina is detached from the RPE due to fluid accumulation in the subretinal space ( Fig. 177-6 ). The infiltrating lymphocytes and macrophages are related closely to uveal
Figure 177-6 The uveitic phase of Vogt-Koyanagi-Harada disease. The choroid is thickened with inflammatory cell infiltration. Note fluid accumulation in the sub-neural retinal space secondary to choroidal inflammation.
melanocytes. The peripapillary choroid is the predominant area of lymphocytic infiltration. Inflammation of the ciliary body and iris is essentially the same as that in the choroid.
Granulomatous inflammation also is seen in the perivascular and perineural loose connective tissues in the sclera, because melanocytes are present in these areas. The epithelioid and giant cells contain pigment granules. It appears that the pigment granules of damaged melanocytes are engulfed by activated macrophages, and these histiocytes subsequently transform into epithelioid cells and multinucleated giant cells.
Immunohistochemical techniques reveal that the choroidal infiltrate in VKH disease is composed predominantly of T lymphocytes of the suppressor-cytotoxic subset. Class II major histocompatibility complex antigens are expressed on choroidal melanocytes and on the endothelium of the choriocapillaris. In severe cases, lymphocytic infiltration extends into the chorio-capillaris and Bruch’s membrane, and even underneath the RPE. Exudative fluid from the choroid accumulates in the subretinal space, which results in exudative retinal detachment. Dalen-Fuchs nodules represent granulomas between the RPE and Bruch’s membrane.
Chronic and Recurrent Phases
The melanocytes decrease in number and disappear from the choroid, which results in the sunset-glow appearance of the fundus. The inflammation in the choroid tends to subside with the disappearance of the choroidal melanocytes, but lymphocytic infiltration remains in the ciliary body and iris. In long-standing cases, however, degenerative changes occur in the RPE and neural retina, in association with subretinal neovascularization. Small, depigmented atrophic lesions, which are seen predominantly in the peripheral fundi of the chronic phase, show degeneration or disappearance of the RPE cells.
Uveitis due to VKH disease is treated effectively by the systemic administration of corticosteroids, and in most cases, a favorable prognosis exists for visual recovery. Inadequate treatment, however, results in recurrent long-standing uveitis, which finally becomes intractable.
In the early, active stage, high doses of corticosteroids should be given intravenously (100–200?mg/day prednisolone) for a week. Thereafter, corticosteroids are given orally for 2–3 months, with a gradual tapering dose once an angiogram reveals the disappearance of dye leakage through the RPE. Topical corticosteroids in the form of 0.1% dexamethasone and cyclo-plegics are administered, the former 2–6 times/day and the latter 2–4 times/day. The eyedrops should be continued for about 3 months, unless the cells in the anterior chamber disappear.
When the intraocular inflammation cannot be controlled with systemic corticosteroids, or when a patient cannot tolerate the side effects of corticosteroids, cytotoxic and/or immunosuppressive agents may be utilized; the latter includes azathioprine, cyclophosphamide, and cyclosporine. 
COURSE AND OUTCOME
Uveitis due to VKH disease is treated effectively with the systemic administration of corticosteroids. However, as a complication of prolonged uveitis and a side effect of corticosteroids, posterior subcapsular cataract may develop. Other complications include secondary angle-closure glaucoma and subretinal neovascularization in the area of the optic papilla or at the macula and ora serrata.
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