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Home , Sympathetic ophthalmia, Uveitis

Ophthalmol Clin N Am 15 (2002) 333–341

Vogt-Koyanagi-Harada disease

Russell W. Read, MD

Department of , University of Alabama School of Medicine, University of Alabama at Birmingham, 700 18th Street South, EFH DB110-0009, Birmingham, AL 35233, USA

Vogt-Koyanagi-Harada (VKH) disease has been Historical background known, but not necessarily recognized in its complete form, for over a millennium. Despite this, information The association of with inflammatory regarding the exact cause and best treatment regimen disease was recognized as early as the 10th century for this potentially blinding condition are not estab- AD, when Ali-ibn-Isa described what is now termed lished. Manifesting ophthalmologically as a bilateral, chronic VKH disease [2,3]. The current tripartite granulomatous panuveitis, VKH disease seems to be a eponym stems from descriptions of the chronic dis- T-cell mediated systemic autoimmune process, which ease phase by Vogt [4] in 1906 and Koyanagi [5] in evidence increasingly suggests is directed at one or 1929, and of the acute disease phase by Harada [6] in more antigens associated with melanocytes. As such, 1926. Babel [7] in 1932 and Bruno and McPherson [8] any organ system that contains melanocytes is a in 1949 realized that these descriptions were points on potential target of attack, including the eye, skin and a disease spectrum and coalesced these entities under hair, inner ear, and meninges. VKH disease occurs the rubric of VKH disease. Although the acute pre- more frequently in certain ethnic groups. The disease sentation is still occasionally referred to as Harada’s has distinct phases, with acute disease involving disease, recently published revised diagnostic criteria primarily the ocular posterior segment, central nervous favor always using the full name, given the know- system, and inner ear. By contrast, chronic-recurrent ledge that this is one disease process [1]. disease involves the ocular anterior segment and integumentary system. Aggressive anti-inflammatory therapy is typically required, but no quality clinical Epidemiology trial data exist to guide the agent of choice, dosage, or duration of therapy. Complications are not uncommon Vogt-Koyanagi-Harada disease occurs most com- and are typically the reason for decreased vision. monly in certain ethnic groups. Although not estab- Many questions remain to be answered regarding lished definitively, it is possible that the link between VKH disease. Work toward these answers continues, these groups arises from a common ancestry in the as evidenced by the occurrence of an ongoing series original peoples of Asia. Dispersion then occurred of international workshops directed specifically at through migration across the Asian continent, over this disease. Out of the two workshops held to date, the Bering Strait land bridge, and into the Americas revised diagnostic criteria [1] have been issued and a [9]. This susceptible group of individuals includes disease severity grading scheme is in formation, both modern-day East and Southeast Asians, Asian Indians, for use in planned prospective clinical trials. Middle Easterners, Native Americans, and Hispanics. The disease occurs, but is uncommon, in whites and Africans [10]. An American Indian ancestry has been Supported in part by unrestricted grants from Research reported as important in patients from the United to Prevent Blindness, Inc., New York, NY and the EyeSight States [11,12]. Rarity in Africans suggests that amount Foundation of Alabama, Inc., Birmingham, AL. of pigmentation alone is not the main factor in the E-mail address: [email protected] (R.W. Read). etiology of VKH disease. Rather, something within

0896-1549/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S0896-1549(02)00025-1 334 R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 the immune repertoire of susceptible individuals likely similarities with [23]. Immu- predisposes them to sensitization to antigens of mela- nohistochemical investigations have shown the pre- nocytic origin. Details of the relationship between dominant infiltrating cell in the is the genetics and VKH disease are discussed further in T lymphocyte, with a larger proportion of helper the next section. (CD4+) cells than cytotoxic (CD8+) cells [24]. Present Vogt-Koyanagi-Harada disease has been reported also are epithelioid and multinucleated giant cells to be responsible for up to 9.2% of cases of containing melanin [25]. Choroidal melanocytes have clinics in Japan [2], is the main cause of autoimmune been shown to express major histocompatibility com- noninfectious uveitis in Brazilians [13], and is the plex class II molecules on their surface in from second most common uveitic diagnosis made in Saudi patients with VKH disease [24]. These molecules are Arabia [14]. In contrast, earlier publications from the required to participate in antigen presentation to CD4+ United States reported a prevalence in uveitis clinics T cells. In the cerebrospinal fluid of VKH disease of 1% [15] to 4% [16]. Read et al [17] recently ex- patients, activated CD4+ T cells predominate [26,27] amined uveitic disease prevalence in a uveitis tertiary and melanin-containing macrophages have been found referral center in Southern California for the 3-year [28,29]. Similar findings have been reported from period 1996 to 1998. They found the frequency of studies of sites of in VKH disease [30,31]. VKH disease to be 7%. This more frequent occurrence Animal studies have shown that a VKH-like compared with previous reports was believed to be disease is inducible in rats by immunization with secondary to the large Hispanic and Asian populations peptides derived from proteins of the tyrosinase in Southern California and referral bias to this par- family, which are found in melanocytes [32]. In this ticular clinic. It is highly likely that as the demo- disease, the rats develop uveitis 12 to 21 days after graphics of the remainder of the United States immunization, followed by fundus depigmentation at continue to diversify, VKH disease will become a 2 to 3 months. Histopathologically, the disease re- more frequently encountered entity in practices across vealed granulomatous in the choroid the country. and , similar to that observed in patients with Most series have reported an approximate female VKH disease [2]. to male disease ratio of 2:1 [2,10,18]. Most patients With the exception of patient history, marked have the onset of disease while in their third to fifth similarities exist between the clinical and pathologic decade of life, but cases have been reported in children manifestations of VKH disease and sympathetic oph- as young as 4 years of age [19,20]. It has been thalmia. Because the latter condition is almost cer- suggested that VKH disease in children may be more tainly caused by immune sensitization to uveal tissue aggressive than in adults. In one series, Tabbara et al following trauma, this provides further circumstantial [21] found that 61% of children with VKH disease evidence that VKH disease shares a similar immune had final visual acuities of 20/200 or worse despite pathophysiology, although dissimilar avenues of medical and surgical therapy. In a review of world sensitization. literature on pediatric VKH disease, however, Rathi- As in other autoimmune conditions, associations nam et al [22] found that 85.7% of children had a final with certain HLA subtypes are not unexpected because visual acuity of 20/30 or better in the best eye. The these cell surface molecules are involved in antigen prognosis in this subpopulation seems to be quite presentation and recognition. HLA typing and asso- variable, and final visual outcome may be related to ciation studies have been performed in a number of as yet unknown differences between the various different ethnic groups with high frequencies of VKH ethnic groups, time to treatment, type of treatment, disease, including the Japanese [33], Koreans [34], and duration of treatment. Chinese [35], Vietnamese [36], Hispanics [37], Brazil- ians [13], Mexican Mestizos [38], and Italians [39]. In these studies, the strongest associations have been with Etiology and pathogenesis the HLA-DR4 allele, and when further subtyping was performed, the greatest association has been found The exact cause of VKH disease is unknown. with HLA-DRB1 * 0405 or HLA-DRB1 * 0410. Ana- Most research on its pathophysiology has been direc- lyses of the amino acid sequence of the HLA- ted at identifying the precise target of autoimmune DRB1 * 0405 allele indicates that a serine at position attack and associations of the disease with specific 57 or glutamine at position 70 may play a crucial role immune profiles. in determining disease susceptibility, because these Ophthalmic histopathology has shown VKH dis- locations are within the antigen-binding grove of the ease to be a granulomatous panuveitis that has many molecule [33,40]. Recent studies have shown that R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 335 lymphocytes from patients with VKH disease who inclusive of the entire potential disease process. Never- possess the HLA-DRB1 * 0405 allele recognize pep- theless, this term does emphasize two of the most tides derived from melanocytes and pro- prominent areas of acute disease involvement, teins [41]. Among these peptides are those derived although not in chronologic order. Melanocytes con- from tyrosinase [42] and other tyrosinase family pro- tained within the meninges [48] are apparently the first teins, such as tyrosinase-related proteins 1 and 2 [43]. site of autoimmune attack, along with the inner ear, Moreover, T-cell clones established from patients with although lack of knowledge of the initiating events in VKH disease and stimulated with tyrosinase family this disease prohibits definitive conclusions about the peptides have demonstrated a predominately proin- initial site of involvement. As mentioned previously, flammatory, Th1-type T-cell response [44]. the occurrence of VKH disease following cutaneous Existing evidence points to a T-lymphocyte– trauma [47] raises the possibility that perhaps similar mediated autoimmune process directed against a subclinical sensitizing events are present in all VKH melanocyte-associated antigen or antigens, occurring disease patients. Regardless, patients typically report in a permissive immune environment, more com- severe headaches, nuchal rigidity, possibly fever and monly found in certain groups. As in other auto- nausea, and auditory symptoms (mainly tinnitus and immune diseases, however, it seems likely that dysacousia) as initial disease manifestations. Occa- because there are a greater number of individuals sionally, cutaneous symptoms, such as skin erythema with the susceptible genetic background than there [49] and scalp tenderness [50], may occur early in the are who actually develop the disease, some triggering disease course, presumably as a consequence of event may be required. Multiple theories exist regard- inflammatory cell infiltration into the skin. The prod- ing a possible trigger. Epstein-Barr virus DNA has romal stage of VKH disease may last from only a few been isolated from the vitreous of patients with VKH days to several weeks [51]. Patients have been admit- disease [45] and the Epstein-Barr virus is able to ted to the hospital with a diagnosis of aseptic men- activate B lymphocytes from patients with VKH ingitis before the onset of ocular disease led to the full disease more easily than B lymphocytes from patients diagnosis [52]. Cerebrospinal fluid analysis at this with other uveitic entities [46]. VKH disease has also point usually reveals a pleocytosis, possibly with been reported to occur following cutaneous injury, melanin-laden macrophages, suggesting VKH disease presumably by direction of an autoimmune attack [52]. The pleocytosis resolves despite persistence of against cutaneous melanocytic antigens liberated at disease manifestations elsewhere, so if performed, the site of injury [47]. lumbar puncture must be carried out early in the disease course. If sufficient neurologic symptoms exist followed by the expected ocular signs, then lumbar Clinical features puncture is not required for diagnosis by the VKH Workshop Revised Criteria [1]. Vogt-Koyanagi-Harada disease typically consists Hearing loss, if present, usually involves the of four phases: (1) prodromal, characterized by neuro- higher frequencies and may persist for years. Audio- logic and auditory manifestations; (2) acute uveitic, metric abnormalities, as measured by pure tone characterized by a diffuse choroiditis, which may stimuli, middle ear analysis, and auditory brainstem result in exudative retinal detachments and papillitis, responses, were shown in 20 of 26 patients from the and possibly an intraocular cellular reaction; (3) [51]. chronic, characterized by depigmentation of various structures, including ocular (fundus and limbus) and Acute uveitic phase integumentary (poliosis and vitiligo, also possibly with alopecia); and (4) chronic-recurrent, with an The ocular hallmark of acute VKH disease is a iridocyclitis that may be recurrent, chronic, or both diffuse inflammatory cell infiltrate into the choroid, [2]. Based on these features and their distinctive timing producing thickening detectable on ultrasonography within the overall disease course, diagnostic criteria [53]. This is commonly accompanied by hyperemia of were recently revised and published (Table 1) [1]. the head. Leakage of fluid from the choroid through the retinal pigment epithelium occurs, with the Prodromal phase resultant formation of focal areas of subretinal fluid accumulation, development of larger bullous detach- Vogt-Koyanagi-Harada disease has been termed a ments, or both. Fluorescein angiography performed uveomeningitis, which although accurate and useful in at this stage typically reveals focal areas of delay in directing the clinician’s differential diagnosis, is not choroidal perfusion, multifocal areas of pinpoint leak- 336 R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341

Table 1 (continued) Incomplete Vogt-Koyanagi-Harada disease (1–3 must be present and either 4 or 5) Table 1 1. No history of penetrating ocular trauma or surgery Vogt-Koyanagi-Harada disease workshop revised diagnos- preceding the initial onset of uveitis tic criteria 2. No clinical or laboratory evidence suggestive of other entities Complete Vogt-Koyanagi-Harada disease (1–5 must 3. Bilateral ocular involvement be present) and either 1. No history of penetrating ocular trauma or surgery 4. Neurologic-auditory findings preceding the initial onset of uveitis or 2. No clinical or laboratory evidence suggestive of other 5. Integumentary findings entities 3. Bilateral ocular involvement Probable Vogt-Koyanagi-Harada disease (isolated ocular A. Early manifestations of disease disease) (1–3 must be present) There must be evidence of a diffuse choroiditis (with 1. No history of penetrating ocular trauma or surgery or without anterior uveitis, vitritis, or optic nerve preceding the initial onset of uveitis hyperemia) which may manifest as: 2. No clinical or laboratory evidence suggestive of other 1. Focal areas of subretinal fluid entities or 3. Bilateral ocular involvement 2. Bullous serous retinal detachments or both of the following in the face of equivocal fundus From Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, findings: Arellanes-Garcia L, et al. Revised diagnostic criteria for 3. Ultrasonography: diffuse choroidal thickening, Vogt-Koyanagi-Harada disease: report of an International without evidence of posterior Committee on Nomenclature. Am J Ophthalmol 2001;131: 4. Fluorescein angiography: focal areas of delay in 647–52; with permission. choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence, pooling within subretinal fluid, optic nerve staining (listed in chronologic order of occurrence) age, large placoid areas of hyperfluorescence, pooling B. Late manifestations of disease (with history within subretinal fluid, and optic nerve staining suggestive of prior presence of findings from 3A) and (Figs. 1–3) [1]. Cells may be present in the vitreous 1. Ocular depigmentation or aqueous humors but are not necessary to the a. Sunset glow fundus diagnosis. VKH disease is a bilateral ocular condition. or The suspicion of unilateral ocular involvement should b. Sugiura sign prompt a diligent investigation for either subtle AND involvement of the fellow eye or a different diagnosis 2. One of the following other signs (or 2 of the following in the absence of above depigmentation [1]. Patients with VKH disease may present with findings) shallowed anterior chambers, because of ciliochoroi- A. Chorioretinal nummular scars (previously dal detachment [54–56], or edema [57], referred to as Dalen-Fuchs nodules) resulting in anterior rotation of the -iris diaphragm. B. RPE clumping or migration Elevated is not uncommon in C. Recurrent or chronic anterior uveitis these presentations, but the angle shallowing and 4. Neurologic-auditory findings (manifesting in initial stage closure typically resolve with therapy. of disease or reliable documentation of such) A. Meningismus (headache alone is not sufficient to meet Chronic definition of meningismus) or B. Tinnitus The chronic phase of VKH disease is character- or ized by depigmentation of various structures. On the C. Cerebrospinal fluid pleocytosis external ocular surface, pigmentation seen at the 5. Integumentary (not preceding onset of central nervous limbus in more heavily pigmented races may dis- system or ocular disease) appear, termed Sugiura’s sign [58]. Within the eye, A. Alopecia loss of choroidal melanocytes results in an orange or coloration to the fundus, termed the sunset-glow B. Poliosis fundus, more commonly seen in Asians and His- or panics than whites [59]. Migration of retinal pigment C. Vitiligo epithelial cells may result in pigment clumping in R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 337

Fig. 1. Red-free photograph of right eye of patient with Fig. 3. Fluorescein angiogram of same eye as Figs. 1 and 2 acute Vogt-Koyanagi-Harada disease. Note the presence of during late phase. Note extensive pooling of dye in subretinal subretinal fluid in the posterior pole, with whitish subreti- space, better outlining the extent of exudative detachment. nal material. rent bouts of intraocular inflammation occur. When various areas of the fundus. Rounded hypopigmented recurrent inflammation does occur, it is usually an lesions appear, primarily inferiorly. These lesions anterior uveitis, in stark contrast to the primarily have most commonly been referred to as resolved posterior involvement in acute disease. When recur- Dalen-Fuchs nodules [2], but a recent report shows rent posterior segment disease occurs, it is usually that although these areas represent a loss of retinal within 6 months of the initial onset, and is a con- pigment epithelial cells, there is no direct evidence sequence of a too rapid taper of medication [61]. that they are or were Dalen-Fuchs nodules [60]. Why Multiple recurrences of exudative retinal detachments these lesions appear primarily inferiorly is unknown. have been reported, occurring as long as 35 months after disease onset [62], although this is considered an Chronic-recurrent uncommon disease course. It is during the chronic-recurrent phase of the The chronic-recurrent phase does not affect all disease that many of the vision-reducing complica- patients, but by definition only those in whom recur- tions associated with VKH disease are most likely to occur, including , , choroidal neovascular membrane development, and subretinal fibrosis. Read et al [10] recently reviewed the records of 101 patients with VKH disease, reporting on the frequencies of complications and predictive factors for final visual acuity. Out of the 202 eyes included, 103 eyes (51%) developed at least one complication, including cataract in 84 eyes (42%), glaucoma in 54 eyes (27%), choroidal neovascular membranes in 22 eyes (11%), and subretinal fibrosis in 13 eyes (6%).

Management

Medical

Fig. 2. Fluorescein angiogram of same eye as Fig. 1 during The mainstay of management of VKH disease re- mid-phase. Note presence of multiple areas of pinpoint mains , and because of the potential for leakage of dye into subretinal space. visual morbidity, treatment should be both prompt and 338 R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 aggressive [63]. In the United States, most clinicians improvement in visual acuity following cataract begin with high-dose oral corticosteroids, typically in extraction with lens implantation. the range of 1 to 2 mg/kg/day of oral [2]. Glaucoma may occur in up to 45% of patients Supplemental regional corticosteroid injections may with VKH disease [61]. Forster et al [70] reported be used. If the retinal detachments fail to resolve, that in 31% of patients with VKH disease and intravenous therapy may be tried, usually with meth- glaucoma, medical therapy alone was sufficient, ylprednisolone, 1 g/day over 3 consecutive days. If whereas 69% required surgical therapy. This study corticosteroid therapy is effective, retrospective data was published in 1993, when many of the currently suggest that tapering the therapy over a minimum of available medications for intraocular pressure control 6 months is required to minimize complications and were not yet approved in the United States. recurrences [2,61]. Outside the United States, clini- Choroidal neovascular membranes may occur in cians may frequently admit patients to the hospital for up to 11% of eyes [10]. Typically ill-defined in nature, intravenous therapy as a first-line treatment, based on these neovascular membranes may be treated inad- anecdotal evidence that this early, aggressive treatment equately with photocoagulation therapy [71]. In- reduces recurrences and the development of compli- creased anti-inflammatory therapy may result in cations. Whether this is in fact the case remains to be resolution, as reported for other posterior and panu- proved in a prospective clinical trial. veitis entities [72–74]. One small series showed an Patients with resistant or recurrent disease may improvement of vision in two of three eyes following require noncorticosteroid immunosuppressive therapy surgical removal of subretinal neovascularization [75]. [2]. Multiple therapeutic classes and agents have been used, including the antimetabolite azathioprine, and the alkylating agents cyclophosphamide and chlor- Prognosis ambucil [64]. Based on the etiologic discussion presented previously, such agents as cyclosporine In their review of complications and visual out- and , which target T-lymphocyte function, comes in VKH disease, Read et al [10] found that a seem ideal. In fact, these agents have been used with longer median duration of disease and a greater success in cases of corticosteroid intolerance or number of recurrent episodes of inflammation were resistance [65–68]. All of these agents have signifi- significantly associated with the development of com- cant potential side effects, and their use should be plications. A poor final visual acuity was predicted by under the direction of an experienced clinician. greater numbers of complications developing, older Topical corticosteroids are mainly an adjunctive age at disease onset, a longer median duration of dis- therapy in VKH disease. In acute disease, they are ease, and greater number of recurrent episodes of wholly inadequate in treating the posterior segment inflammation. The better the visual acuity at presenta- manifestations. In chronic disease, where the inflam- tion, the more likely that eye was to have a better mation is primarily anterior, topical therapy is still visual acuity at final follow-up. In their study, 49% of frequently insufficient, because recurrent disease is eyes obtained a final visual acuity of 20/40 or better, notoriously resistant to treatment. Cycloplegics 22% of eyes obtained 20/50 to 20/100, and 29% of should be used to prevent posterior synechiae and eyes obtained a final visual acuity of 20/200 or worse improve comfort. Nonsteroidal anti-inflammatory [10]. African-Americans did worse overall, with 70% drugs have essentially no role. of eyes having final visual acuities of 20/200 or worse. Many questions remain to be answered regarding Surgical VKH disease. Identification of the exact target anti- gen may allow development of more specific ther- Surgical therapy in VKH disease is limited pri- apies. Until that point, prospective clinical trials are marily to addressing the complications induced by the needed to identify the most efficacious therapeutic disease. Rarely, surgical drainage of subretinal fluid protocols to control acute disease and prevent future that was resistant to medical therapy may be indicated. vision-limiting complications. , which may develop in up to 42% of eyes [10], seem to be safe to remove if the disease has been controlled for at least 3 months [69]. The decision of References whether or not to implant a lens should be based on the patient’s past disease course, including whether there [1] Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, is a demonstrated tendency to develop posterior syn- Arellanes-Garcia L, et al. Revised diagnostic criteria echiae [2]. Moorthy et al [69] reported a significant for Vogt-Koyanagi-Harada disease: report of an Inter- R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 339

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