Ocular Immunology and Inammation, 15:351357, 2007 Copyright c Informa Healthcare USA, Inc.

ISSN: 0927-3948 print; 1744-5078 online DOI: 10.1080/09273940701459453

CASE REPORT

Vogt-Koyanagi-Harada Syndrome in Children: Report of a Case and Review of the Literature

Nilufer Berker, MD, Yasemin Ozdamar, MD, Emel Soykan, MD, Pinar Ozdal, MD, and Seyhan Sonar Ozkan, MD Department of Retinal and Uveal Diseases, Ulucanlar Eye Research Hospital, Ankara, Turkey

ABSTRACT This article reviews the therapeutic approaches in children with Vogt-Koyanagi-Harada (VKH) syndrome, and reports on a 9-year-old girl with progressive visual loss due to VKH syndrome in spite of treatment. In previous reports, corticosteroids were found to be the most effective agents in the treatment of VKH syndrome, while combination therapies with cyclosporine, methotrexate, or azathioprine were used with favorable results in refractory cases. In the current case, none of the treatments sufciently stabilized the vision, but triple combination of corticosteroids, cyclosporine, and methotrexate suppressed the relapses of intraocular inammation. Treatment of children with VKH syndrome is challenging. Various treatment modalities have been reported with various responses, but there is still no denite treatment regimen, and the treatment is usually individualized in pediatric VKH cases.
KEYWORDS Corticosteroid, immunosupressives, pediatric uveitis, treatment, VogtKoyanagi-Harada (VKH) syndrome

INTRODUCTION
Vogt-Koyanagi-Harada (VKH) syndrome is a rare systemic autoimmune disease characterized by numerous ocular, cutaneous. and neurologic abnormalities. The most common clinical features include chronic, bilateral granulomatous panuveitis in association with vitiligo, poliosis, alopecia, signs of meningeal irritation, and auditory disturbances. The disease usually affects heavily pigmented Asian people in their third to fourth decades of life, with a slight predominance for women (Andreoli & Foster, 2006; Damico et al., 2005). The aim of the treatment for VKH syndrome is to suppress the intraocular inammation with prompt and prolonged usage of high-dose systemic corticosteroids. In general, adequate treatment with corticosteroids leads to favorable visual prognosis in most of the patients. However, a number of factors may inuence the response to treatment and visual outcome, including age of onset, the presence of complications, low visual acuity at onset, severity of intraocular inammation, late diagnosis, frequent recurrences, and early tapering of steroids (Read et al., 2001; Sheu, 2005). In refractory
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Accepted 15 May 2007. Correspondence and reprint requests to: Nilufer Berker, MD, Huseyinonat Sokak, Sahinbey Apt., 10/6, Asagi Ayranci, 06540, Ankara, Turkey; e-mail: niluferberker@hotmail.com, niluferberker@gmail.com

cases, combination therapies with immunosuppressive agents, including cyclosporine, azathioprine, and cyclophosphamide, have been reported to be benecial (Agarwal et al., 2006). Vogt-Koyanagi-Harada syndrome rarely occurs in childhood. (Rathinam et al., 1998; Tabbara et al., 1998; Ikeda et al., 1999; Gruich et al., 1995; Al Hemidan et al., 2006; Soheilian et al., 2006) As with other types of uveitis, treatment of VKH syndrome is more challenging in the pediatric age group compared to adults. Prolonged usage of corticosteroids is a great problem concerning the risk of growth retardation and other systemic side effects. Corticosteroids are usually combined with immunomodulatory agents such as cyclosporine and methotrexate, which have been found to be more benecial in suppressing the ocular inammation (Rao, 2006; Paredes, et al., 2006; Tabbara et al., 1998). In this report, we review the latest therapeutic approaches for the treatment of VKH syndrome in children, and describe a 9-year-old girl with severe and impressive course of VKH syndrome with progressive visual deterioration, in spite of combined treatments with high-dose corticosteroids and immunosuppressive agents.

CASE REPORT
A 9-year-old girl was referred to our clinic for bilateral visual loss and redness. Her family history was unremarkable. She had no history of ocular trauma or other ocular disease. Neurologic examination revealed normal ndings, but moderate headache and tinnitus. Her cutaneous evaluation was remarkable, with vitiligo on her back, shoulder, and upper leg (Figure 1). Poliosis

FIGURE 1 The appearance of vitiligo on the back of the patient.

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was detected on her scalp, eyebrows, and eyelashes, and she had focal eyelash loss. Her ocular examination revealed best-corrected visual acuities of 20/60 OD, and 20/40 OS. Intraocular pressures (IOP) were bilaterally high (24 mmHg OD, 28 mmHg OS). Biomicroscopic anterior segment examination revealed corneal mutton-fat keratic precipitates, posterior synechiae, cataract formation, and moderate anterior chamber cells in both eyes. Ultrasonic biomicroscopy detected iris nodules on the iris surface. Gonioscopic examination revealed partial angle closure due to anterior synechiae, in the absence of neovascularization. Her fundus examination revealed severe vitritis, multifocal choroiditis, and optic disc edema. Ocular Bmode ultrasound evaluation revealed no ocular masses. The laboratory testings included blood chemistry, total blood count, and serologic titers for infective and parasitic diseases and were all unremarkable. Sedimentation rate was moderately high. Antinuclear antibody and rheumatoid factor were negative. Pleocytosis was present in cerebrospinal uid. Based on the VKH Committees revised diagnostic criteria (Read et al., 2001) she was diagnosed with complete VKH syndrome, which had already progressed to ocular complications at presentation. Treatment was initiated and consisted of oral prednisolone (1 mg/kg/day), hourly instillations of topical corticosteroid, 3 times per day instillation of mydriatic drops (tropicamide 0.5%), and antiglaucoma medications (dorzolamide HCl 2% twice daily, carteolol HCl 1% twice daily). The response to medical treatment was closely followed up. Her panuveitis regressed in 2 months time, but at her second month examination, her visual acuity was found to be 20/200 OU due to increased lens opacities and total posterior synechiae. IOP decrease was also insufcient in spite of antiglaucoma medication. Bilateral YAG laser iridotomies were performed, and the IOP was dropped to 11 mmHg OU, but the antiglaucoma medications were continued. At the third month examination, the ocular inammation was inactive, and oral corticosteroid was gradually tapered to 0.5 mg/kg/day. The IOP was within normal limits under antiglaucoma medications. At the sixth month examination, the inammation was still inactive. As cataract, posterior synechiae, and vitreous condensation were obscuring the fundus details, lensectomy and pars plana vitrectomy were performed under the coverage of 1 mg/kg/day oral corticosteroid therapy, which was continued with the same dosage
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for 2 months, and then very slowly decreased to 0.5 mg/kg/day over several weeks. The eyes were left aphakic and spectacles were prescribed. After a quiet period of 4 months following the operation, she presented with bilateral exudative retinal detachment. Her visual acuity had dropped to counting ngers. The dosage of corticosteroid was increased to 1 mg/kg/day and combined with oral cyclosporine (5 mg/kg/day). This combination was found benecial in the suppression of panuveitis at rst. However, when the corticosteroid was gradually decreased to 0.5 mg/kg/day, her panuveitis was exacerbated, leading to further visual deterioration. At the second year of her rst presentation, she again developed a severe recurrence of panuveitis with retinal hemorrhages, optic disc edema, choroiditis, and dense vitritis. Also the sequelae of previous recurrences, including subretinal brosis, macular scar formation, and Dalen-Fuchs-like nummu-

FIGURE 3 Fundoscopy of the right eye at the patients last examination. Note that intraocular inammation was inactive, and sunset glow appearance of the fundus was apparent.

(a)

lar depigmented lesions, were visible in the fundus. (Figure 2). Her visual acuity decreased to hand motions, and oral methotrexate (7.5 mg/week) and folic acid (1 mg/day) were added to her combination therapy of prednisolone (1 mg/kg/day) and cyclosporine (5 mg/kg/day). After this combination therapy, the inammation was suppressed to some extent. At present, which means at the third year of her rst presentation, her visual acuities are counting ngers OU, IOP remains within normal limits in both eyes with topical antiglaucoma therapy, and the recurrences of inammation are less severe under the combined treatment of 0.5 mg/kg/day oral corticosteroid, which cannot be tapered anymore, 5 mg/kg/day cyclosporine, and 7.5 mg/kg/week methotrexate. Fundus examination shows the ndings of sunset glow appearance, subretinal brosis, macular scar, and nummular depigmented lesions (Figure 3). Liver and renal functions, which are in normal ranges, are being checked by laboratory tests every 6 weeks. However, the risk of growth retardation and other side effects of systemic corticosteroids are still a great concern.

DISCUSSION
Vogt-Koyanagi Harada syndrome is a multisystemic disease, which has been suggested to be T-lymphocytemediated autoimmune process directed against one or more antigenic components of melanocytes (Rao, 1997). The exact mechanisms that trigger the autoimmune process are unknown, but some evidence suggests that sensitization to melanocytic antigens by means
Vogt-Koyanagi-Harada Syndrome in Children

(b)
FIGURE 2 Fundoscopy of the (a) right, and (b) left eyes showing macular scars, subretinal brosis, and peripheral DalenFuchs-like lesions. The fundus details are blurred due to the dense vitritis.

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of cutaneus injury or viral infection may precipitate the disease (Rathinam et al., 1999; Bassili et al., 1996). It is also associated with other autoimmune diseases (Pras et al., 2004; Al Hemidan et al., 2006). Immunogenetic factors have also been found to play role in the pathogenesis of VKH disease. A strong association with the human leukocyte antigen (HLA) class II, especially HLA-DRB1*0405 has been shown (Shindo et al., 1994). The syndrome is characterized by bilateral granulomatous panuveitis associated with cutaneous ndings of vitiligo, alopecia, and poliosis, and neurologic/auditory ndings of tinnitus, dysacusis, vertigo, headache, meningismus, and cerebrospinal uid pleocytosis. The diagnostic criteria of VKH syndrome is based on those clinical ndings and ancillary testings. The most recent diagnostic criteria revised by the First International Workshop on VKH in 1999 categorize the disease as complete, incomplete, and probable VKH disease based on the number of positive criteria (Read et al., 2001). Briey, complete VKH disease involves 5 criteria, including ocular, neurologic/auditory and integumentary ndings in the absence of ocular trauma, surgery, and other ocular disease entities, whereas the incomplete form includes all ocular, but either neurological/auditory or integumentary ndings, and the probable form includes only the ocular ndings. Vogt-Koyanagi-Harada syndrome consists of four phases, with variable ocular features (Andreoli & Foster, 2006; Yamaki et al., 2005). The disease usually starts with a prodromal phase characterized by neurologic and auditory manifestations. In acute phase the common ndings include bilateral granulomatous anterior uveitis with mutton-fat keratic precipitates, iris nodules, choroiditis, exudative retinal detachment, optic nerve edema, vitritis, and multifocal leakages from the choroid in uorescein angiogram. Those ndings regress in the chronic phase of the disease, leaving sunset glow fundus due to the loss of retinal pigment epithelial cells, and Dalen-fuchs-like nummular depigmented scars caused by the healing of multifocal choroiditis. In most patients, VKH syndrome persists in that phase for years. However, in some patients, particularly in children, the disease progresses to chronic recurrent phase, and the prolonged inammation triggers potentially blinding complications, including choroidal neovascularization, subretinal brosis, posterior synechiae, cataract, and glaucoma (Andreoli & Foster, 2006; Damico et al., 2005; Tabbara et al., 1998; Read et al., 2001). The clinical course of the disease was quite atypical in
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our patient. Exudative retinal detachment was absent at presentation, and developed during the chronic phase of the disease, which was an uncommon nding for VKH syndrome. Moreover, the recurrences of inammation generally involved the posterior segment of the eye, causing retinal hemorrhages, dense vitritis, subretinal brosis, and macular scar formation. Anterior granulomatous uveitis and associated complications developed early in the disease, while anterior uveitis was mild or absent during the chronic recurrent phase. Vogt-Koyanagi-Harada syndrome has been rarely reported in children (Gruich et al., 1995; Rathinam et al., 1998; Tabbara et al., 1998; Ikeda et al., 1999; Soheilian et al., 2006; Al Hemidan et al., 2006). In a recent multicenter study describing the clinical features of VKH disease in Turkish patients, 15% of patients were aged 16 years or younger at presentation (Tugal-Tutkun et al., 2006). Among the uveitic patients followed up in our clinic, the one reported on here was our youngest patient, who was diagnosed as VKH syndrome at the age of 9 years. To the best of our knowledge the youngest patients in the literature with VKH syndrome have been reported as a 4-year-old child (Gruich et al., 1995; TugalTutkun et al., 2006) and a 3-year-old child with coexisting type-1 diabetes mellitus and celiac disease (Al Hemidan et al., 2006). VKH syndrome generally follows an aggressive and chronic recurrent course leading to rapid visual deterioration in children. Ohno et al. (1988) reported that visual acuity was worse in patients with younger age at disease onset than the older ones. Tabbara et al. found that ocular complications occur more frequently in children than in adults (Tabbara et al., 1998; Rao, 2006). Soheilian et al. (2006) proposed that, as with other pediatric uveitic diseases, the diagnosis of pediatric VKHassociated uveitis was often delayed, and consequently the complications were usually present at presentation. In their series, many patients were asymptomatic and were referred with diminished vision secondary to the presence of destructive sequelae of the disease. Our patient also demonstrated multiple complications at presentation. The clinical course of the disease in our patient was quite impressive. Read et al., on the other hand, reported contradictory data, with better visual prognosis in patients with younger age at disease onset than the older ones. Ranitham et al. (1998) also reported favorable visual prognosis with 20/40 or better nal visual acuity in 75% of their pediatric cases with VKH disease.
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Ocular complications leading to visual loss in children with VKH syndrome include glaucoma, cataract, retinal pigment epithelial (RPE) alterations, subretinal brosis, and subretinal neovascularization. RPE alterations, including RPE proliferation, pigment clumping, or pigment loss, are frequent ndings in VKH syndrome, and have been reported as the major causes of visual loss in this disease. Tugal-Tutkun et al. (1996) reported pigment clumping in 73% of their patients. Rao (2006) also proposed that RPE proliferation was a common complication of VKH, and usually resulted in signicant loss of vision due to subretinal neovascularization and subretinal brosis. Soheilian et al. (2006) reported that 10% of their patients with VKH syndrome lost their vision due to RPE alterations and inammatory damage to Bruchs membrane, leading to subretinal neovascular membrane. We found that RPE proliferation, as well as other alterations of RPE, are sequelae of the effects of chronic inammation on Bruchs membrane and choriocapillaris. Those may consequently lead to subretinal brosis and choroidal neovascularization, resulting in visual loss. Glaucoma, which has been suggested to be secondary to the immune-mediated damage to the melanocytes in the trabecular meshwork has been reported to be present in up to 46% of children (Tabbara et al., 1998). Cataract is also a common complication of VKH syndrome, which is known to be a result of both chronic intraocular inammation and

steroid therapy. Tabbara et al. (1998) reported the incidence of cataract development in pediatric age group as 61%. In cases with signicant lens opacity and extensive posterior synechiae, cataract surgery without intraocular lens implantation is suggested. Cataract surgery should be accompanied by temporarily increased dosage of corticosteroids to prevent postoperative relapses of inammation (Soheilian et al., 2006). The initial step in the treatment of VKH syndrome consists of high-dose systemic corticosteroid therapy, either oral or intravenous pulse administration, followed by oral steroid therapy over a period of 6 months. The route of administration of corticosteroids does not matter in terms of visual prognosis (Read et al., 2006), while the duration of the therapy does. Systemic steroids are suggested to be used for at least 6 months and tapered slowly to prevent inammatory relapses (Rao, 2006; Read et al., 2001). Topical steroids are also used in eyes with anterior chamber inammation. Transseptal steroid usage has also been reported (Soheilian et al., 2006). Prolonged steroid therapy effectively suppresses intraocular inammation and avoids recurrences and consequent complications in most adult patients. In patients who are intolerant or resistant to prolonged corticosteroid therapy, corticosteroid-sparing therapy with cytotoxic agents is suggested, but those agents are generally reserved for the chronic recurrent phases (Rao, 2006; Damico et al., 2005; Read et al., 2001).

TABLE 1 Summary of different therapeutic approaches with various outcomes in children with VKH syndrome
Reference Soheilian et al., 2006 No. of cases 10 Mean age (years) 11.1 2.9 Treatment Steroid (topical, regional, oral) & methotrexate in 7 steroid resistant cases Steroid (oral, IV pulse) Steroid (topical, oral) Combined IV pulse steroid & cyclosporine Combined cyclosporine & azathioprine (in one of them) IV pulse steroid followed by oral steroid Triple-agent combination of steroid, cyclosporine, methotrexate Visual outcome Favorable (VA was preserved or improved in all cases) Unfavorable (VA 20/200 in 61%) Favorable (VA 20/40 in 75%) Favorable Favorable

Tabbara et al., 1998 Rathinam et al., 1998 Al Hemidan et al., 2006 Tugal-Tutkun et al., 1996

13 3 1 2

10 6,8,12 3 9,15

Gruich et al., 1995 Current case

1 1

4 12 (treated since 9)

Favorable Unfavorable with steroid alone or steroid-cyclosporine; favorable with triple combination

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The management of VKH syndrome is challenging and debatable in children as a consequence of the chronic recurrent course of pediatric disease, delayed diagnosis, and the limited tolerance to prolonged systemic corticosteroid therapy (Rao, 2006; Tabbara et al., 1998; Rathinam et al., 1998). The side effects of systemic corticosteroids, especially growth retardation, are a major concern in children. Various treatment modalities have been suggested by different authors (Table 1). Rathinam et al. described 3 children, as well as reviewed the literature for previously reported children with VKH syndrome, and noted that the children with VKH syndrome responded well to systemic corticosteroid therapy (Rathinam et al., 1998). On the contrary, Tabbara et al. reported that systemic corticosteroids did not adequately control the inammatory reactions in their series of 13 children with VKH syndrome who were compared to 84 adult patients. Despite high-dose corticosteroid therapy, the nal visual outcome was poor, and the complication rate was high in their children group. So they concluded by suggesting the alternative therapy of low-dose prednisone (0.25 mg/kg) and cyclosporine (5 mg/kg) (Tabbara et al., 1998). Al Hemidan et al. treated their 3-year-old child with intravenous methylprednisolone pulse therapy and cyclosporine 5 mg/kg orally per day, and obtained a favorable result within 3 weeks time (Al Hemidan et al., 2006). Our patient also was not sufciently responsive to systemic corticosteroids. The recurrences of inammation seemed to be controlled with high-dose corticosteroids, but inammation exacerbated in any effort of tapering the corticosteroid dose. Moreover, cyclosporine addition was noted to be ineffective in our patient. However, the unfavorable prognosis and poor response to steroids and other agents, was probably a consequence of late presentation and delayed therapy in our patient. Although VKH syndrome in children tends to have a more aggressive course than in adults, the main reason for that might be the late diagnosis and late initiation of treatment rather than being refractory to treatment in children. Similar severe course is also seen in adults with late diagnosis and poor management of VKH syndrome. Soheilian et al. (2006) described 10 children with VKH syndrome who were successfully treated by oral prednisolone and/or methotrexate in refractory cases, and all improved or preserved their visual acuities. So they suggested that methotrexate might be effective in inducing remission in pediatric VKH-associated panuveitis with minimal side effects. We are in agreement
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with their study to some extent. Methotrexate addition signicantly reduced the severity of the recurrences, and appeared to stabilize the vision in our patient. However, it did not help us to stop, or even taper, the corticosteroid dose to a relatively safe level for growth retardation. Paredes et al. (2006) compared the usage of immunomodulatory agents for VKH patients as rst-line therapy with corticosteroid therapy, and reported that immunomodulatory agents as rst-line therapy was associated with a superior visual outcome when compared to rst-line corticosteroid therapy, or corticosteroid monotherapy. However, before making denite conclusions, their results need to be veried with prospective studies (Rao, 2006). We experienced two major problems during the follow-up of our case. Firstly, her visual acuity decreased due to the rapidly developing ocular complications despite high doses of corticosteroid and immunosuppressive agent combinations. This might have been prevented to some extent by earlier addition of methotrexate to the treatment regimen. Also, earlier presentation and prompt initiation of therapy might have altered her responses to treatment. Secondly, we could not stop or even taper the systemic corticosteroid dosage to the safe levels described for children in spite of the concurrent usage of cyclosporine and methotrexate. This case supports the idea that the treatment of children with VKH syndrome is challenging. However, the main reason for that challenging course in children might be the delayed therapy due to late presentation, which is a common problem in most of the cases with childhood uveitis. We believe that it might be better to individualize the treatment in children, since the course of the disease largely differs from case to case. It appears to be hard to suggest immunosppressive agents as rst-line therapy in each case, but it might have been benecial in our case. Although rare in children, the signicance and poor prognosis of the disease necessitates prospective randomized controlled studies to denitely determine the best path of treatment in children with VKH syndrome.

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