Vogt–Koyanagi–Harada Disease

M. de Lourdes Arellanes-García, M.D. ( ) L.E. Concha-del-Río, M.D.

M. del Carmen Preciado-Delgadillo, M.D., Ph.D. Inflammatory Eye Disease Clinic,

Hospital “Dr. Luis Sánchez Bulnes”, Asociación para Evitar la Ceguera en México. I.A.P. Vicente García Torres 46, San Lucas Coyoacán, 04030, México, D.F., México e-mail: Lourdes.arellanes@apec.com.mx; luzelena.conchadelrio@gmail.com; w987366@prodigy. net.mx

C. Recillas-Gipsert, M.D.

Departamento de Oftalmología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Vasco de Quiroga 15, Seccion XVAI, Tlalpan, Mexico, Distrito Federal 14000, Mexico

e-mail: crecillas@yahoo.com

Vogt–Koyanagi–Harada syndrome (VKH) is an inflammatory disease that affects different organs including eye, inner ear, skin, and meninges. Typical ocular manifestations are severe bilateral iridocyclitis, serous retinal detachment, diffuse choroidal edema, and optic disk hyperemia.

Central nervous system involvement manifests as headache, meningismus, and occasionally focal neurologic signs. Dermatologic alterations include alopecia, skin and scalp hypersensibility, poliosis, and vitiligo. Auditory manifestations are tinnitus, hearing loss, and vertigo. In most cases, diagnosis is made clinically, although some ancillary testing may be useful to confirm it.

Vogt–Koyanagi–Harada syndrome is more common in certain ethnic groups such as Japanese, Chinese, Indian-Americans, and Mexican-Mestizo, among others. Prognosis depends on age at onset, initial visual acuity (VA), ethnicity, duration of disease, initial treatment, number of recurrences, and associated complications.

History

An Arab physician Ali-Ibn-Isa (940–1010 C.E.) was the first to describe a patient with poliosis and ocular inflammation. In the nineteenth century, Jacobi et al. described patients with poliosis, neuralgia, and hearing disorders [1]. This clinical description was also reported by Schenkl in 1873, by Hutchison in 1882 [2], and by Vogt in 1906 [3]. In 1926, Harada [4] reported a patient with serous retinal detachment associated with cerebrospinal fluid pleocytosis. In 1929, Koyanagi described six patients with bilateral chronic iridocyclitis associated with vitiligo, alopecia, poliosis, deafness, and tinnitus [5].

Babel in 1939 [6] and, 10 years later, Bruno and McPherson [7] proposed that these manifestations corresponded to a spectrum of the same disease. Since then, this group of signs and symptoms receives the name of VKH syndrome [1].

Epidemiology

VKH disease has been reported around the world; however, some ethnic and racial groups are more frequently affected. It is common in people with dark skin pigmentation such as Asians [8, 9], Native Americans [10], Hispanics [11], AsianIndians [12], and Middle East population. It is uncommon in Caucasians [12].

Most of the studies report that women are more commonly affected than men. In North America, female patients represent 55–78% of the cases, and in Mexico 69.5% [13]. In Japan, it has been reported that only 38% of their VKH patients are women [10].

Age of presentation has a wide range, from 3 to 63 years. The highest frequency is reported between the third and fourth decades of life. Small children may be affected; however, VKH is a rare cause of pediatric uveitis [14–17].

Recently we reviewed the clinical files of 156 VKH patients, seen in a 15-year period at a referral Inflammatory Eye Disease Clinic; only nine of them were 16 years old or younger at admittance (unpublished data).

Prevalence of VKH syndrome depends on the studied population. In Japan it represents 10% of referral uveitis patients [18, 19]. It is also one of the most common uveitis in China [9, 19], Brazil [20], and Saudi Arabia. In the Middle East, 13.4% of uveitis diagnosis corresponds to VKH, 14.4% in Argentina, and 6.4% in a referral center of Mexico City [21]. In the United States, prevalence is lower, between 1% and 4% of all uveitis diagnosis [22].

Immunopathogenesis

The exact immunopathogenic mechanisms of VKH syndrome are still unknown, but there are clinical and experimental evidences that indicate an autoimmune process involving melanocytes.

In VKH patients, it has been demonstrated that melanin-laden cells of the epidermis are partially lost, and the presence of infiltrates composed mainly by T cells suggests that a cell-mediated immune response plays a central role in the pathogenesis of dermal lesions [23]. Vitiligo lesions show an increase in helper/inducer CD4+ lymphocytes and an altered ratio of CD4+/CD8+ (3:1) cells.

In 1991, Sakamoto demonstrated that eyes affected with VKH had an increased CD4+/CD8+ ratio and that activated lymphocytes expressed costimulatory molecules such as CD2 and CD26 in the choroidal inflammatory foci. In active VKH patients, choroidal infiltrates show predominantly activated CD4+ T cells that express CD25, a transmembrane protein; this molecule is an interleukin-2 (IL-2) alpha-chain receptor for lymphocytes, and it is involved in the proliferation

process of T cells. In the choroidal inflammatory foci, T cells also express CD26, which is considered a T cell activation antigen; CD26 costimulation potentiates T cell receptor-mediated response leading to an effector function. CD26 is considered a marker of lymphocytic late activation [11, 24–26]. Other authors have shown an increased expression of CD1a+ in lymphocytes of peripheral blood in patients with active VKH, suggesting an activation of the immune system that is increased by the T cells lymphokines released as product of activated signaling cascades [27].

Choroidal melanocytes and endothelial cells from choriocapillaris do not express molecules of the major histocompatibility complex (MHC) class II (HLA-DR and HLA-DQ) in physiological conditions. These molecules require for antigen presentation CD4+ cells; these are expressed abnormally in choroid tissue of VKH patients. Innomata and Sakamoto demonstrated the absence of choroidal melanocytes in chronic VKH patients. These findings suggest a retarded hypersensibility against melanocytes with aberrant expression of class II molecules that can play a role in the inflammatory process in patients with VKH [28].

Norose et al. have demonstrated cytotoxic activity of leukocytes against a human melanoma cellular lineage in patients with VKH [29]. Specific cytotoxic T cells against an antigen expressed on melanocytes and the retina were demonstrated using CD8+ T cell clones from intraocular fluid from HLA-A2-positive VKH patients. These cell lyses the eye melanocytes, suggesting a cellular basis of the HLA-restricted autoimmune process [30]. Tyrosinase or tyrosi- nase-related proteins have been implicated as target antigens on the melanocytes [31]. Several studies have shown that tyrosinase family protein in a rat model can induce an autoimmune disease strongly resembling human VKH and that lymphocytes of VKH patients are reactive to tyrosinase family proteins [32]. Chan detected serum antibodies against the external segments of the photoreceptors and Müller cells, as well as antibodies against anti-ganglioside in 71% of their VKH patients [33]; however, it is not known if

these changes are secondary to retinal damage produced during inflammatory response. Chan also observed that lymphocytes of patients with active disease, without treatment, proliferated when they were exposed to a union of interphotoreceptor protein and retinal antigen.

Damico and coworkers [34] demonstrated that in patients with VKH, T cells recognize peptides derived from melanocytes with greater affinity and proliferative response when compared to controls. They also found that peripheral blood mononuclear cells (PBMC) produce a cytokine response with a specific Th1 profile. Other authors suggest that an external factor may bind to Toll-like receptors (TLRs), a receptor family that recognizes molecular patterns usually found in pathogens, and produce an intracellular signaling cascade; the stimulation of TLR [35] induces changes in chemokine and cytokine secretion and costimulatory molecule expression. Chan et al. proposed [36] that meningeal and auditory system involvement was a response against melanocytes that express altered antigens on their surface. It is not known if these changes are due to a spontaneous alteration or if they are secondary to exogenous factors such as Epstein-Barr virus (EBV). Bassili and coworkers believe that EBV could be related to the stimulus that starts a specific immune response against melanocytes [37]. Sugita et al. [31] studied the cross-reaction between tyrosinase peptides and cytomegalovirus (CMV) antigen by T cells in VKH patients. Cytomegalovirus (CMV) infection could stimulate production of T cells that cross-react with tyrosinase by a mechanism of molecular mimicry and could be responsible of the onset of VKH. Also VKH-like disease has been reported in patients treated with interferon (IFN)-a2a for chronic viral hepatitis [38–40].

MHC class I molecules can interact with other immune cells and can play a role in the pathogenesis of VKH. Killer cell immunoglobulin-like receptors (KIR) are members of a group of regulatory molecules found on subsets of lymphoid cells, which either activate or inhibit natural killer (NK) cells and certain subsets of T lymphocytes [41, 42]. Levinson et al. reported that VKH

patients had a higher frequency of KIR geneassociated B haplogroup. Signals transduced by the activated KIRs upon their binding to putative class I ligands may overcome HLA class-I- dependent inhibition and trigger natural killer (NK) reactivity, leading to the autoimmune condition in VKH [43].

Recently, an increased expression of IL-23 (interleukin-23) and elevated production of IL-17 (interleukin-17) have been reported in PBMC of VKH patients [44]. This finding led to the hypothesis that IL-23 stimulated production of IL-17 by CD4+T cells and these may be involved in the development of VKH syndrome [45].

Histopathology

VKH has been described as a bilateral granulomatous uveitis, similar to sympathetic ophthalmia. The main feature of VKH is a diffuse thickening of the uveal tract caused by a nonnecrotizing granulomatous inflammation that predominates in the juxtapapillary choroid, with less involvement at equatorial and peripheral areas [46].

In 1977, Perry and Font reported nine eyes with chronic VKH, with a granulomatous response in only four of them. In these cases, a diffuse inflammation of the uvea consisting of epithelioid cells, lymphocytes, some plasma cells, and multinucleated giant cells was observed; epithelioid cells and multinucleated giant cells contained melanin pigment. There was a relative sparing of the choriocapillaris from inflammation; in long-standing cases, inflammation may extend into the choriocapillaris and retina, resulting in chorioretinal adhesions.

In the uveitic stage, the neurosensory retina is detached by an eosinophilic exudate with proteinaceous material. In immunohistochemical studies, the presence of T suppressor/cytotoxic cells and macrophages [46, 47] and T lymphocytes close to uveal melanocytes, which express class II MHC, has been reported [29, 48]. These inflammatory cells do not reach the choriocapillaris or retina, but do involve the ciliary body and iris.

In the chronic stage, the melanocytes tend to disappear from the choroid; focal collections of lymphocytes, pigment-laden macrophages, epithelioid cells, and proliferative retinal pigment epithelium (RPE) cells with altered histologic appearance are noted. They are virtually identical to Dalen-Fuchs nodules, described in sympathetic ophthalmia, and become more evident in the convalescent stage [49].

In the convalescent stage, a mild to moderate nongranulomatous inflammatory cell infiltration occurs, mainly with lymphocytes and macrophages. Choroid is depigmented, exhibiting spindle cells without melanin granules; these changes are observed clinically as the “sunset glow” fundus image [50]. Histopathologic analysis shows focal RPE loss with chorioretinal adhesions [46].

RPE proliferation has the clinical appearance of hyperpigmented changes on ophthalmoscopic examination. Subretinal neovascular channels and mound-likepigmentedlesionsmayalsobeobserved. In other cases, hyperplasic RPE can be reorganized as subretinal fibrosis [50]. There is also a combination of photoreceptor degeneration and gliosis of the overlying neural retina. The choriocapillaris has a degenerative process, and chorioretinal adhesions are apparent at these sites [50]. In this phase, Dalen- Fuchs-like nodules may be observed. They are constituted by proliferated RPE with few inflammatory cells and sometimes are calcified.

Friedman and Deutsch-Sokol made a clinicpathologic correlation of Sugiura sign; absence of pigment in the basal epithelial layer at the limbus was found. Extraocular changes have also been studied. Vitiligo shows aggregates of lymphocytes, mostly around sweat glands, hair follicles, and small blood vessels of the dermis; melanin-laden cells are disrupted [51]. Dermal inflammatory infiltrate with melanin-containing macrophages is observed. Alopecia areas have a mononuclear cell infiltration with discharge of melanin pigment from the matrix into the dermal papillae and surrounding perifollicular sheaths of hair follicles [46].

These previous reports confirmed what Rao and coworkers proposed: “… at tissue level, there is a role of autoimmunity in the pathogenesis of