Update on uveomeningoencephalitides Shwu-Jiuan Sheu

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1 Update on uveomeningoencephalitides Shwu-Jiuan Sheu Purpose of review Uveomeningoencephalitides, commonly known as Vogt Koyanagi Harada (VKH) disease, are characterized by chronic bilateral granulomatous panuveitis involving the central nervous, auditory and integumentary systems. Visual prognosis is generally favourable, but outcomes in patients with VKH disease may vary. Also, the treatment of choice differs in different parts of the world. This review addresses the literature on the possible pathogenesis, diagnosis and treatment of this disorder. Recent findings Atypical presentations of VKH disease, as well as those associated with interferon-a therapy, have been reported. Most reports suggest an association with autoimmunity. The diagnostic criteria were revised by the International Workshop on VKH in 1999, allowing for the presence of different ocular findings in the early and late stages of the disease. New techniques have also been developed to aid in the rapid diagnosis of VKH disease and evaluation of treatment. Different routes of administration of corticosteroid and adjuvant therapy were tried, with positive results. Summary Although the pathogenesis of VKH disease is uncertain and antigen-specific treatment strategies have not yet been developed, reports increasingly suggest an autoimmune nature for uveomeningoencephalitides. Currently, systemic corticosteroid therapy remains the standard initial treatment. Different routes of administration are used to reduce the frequency of side effects of systemic corticosteroids, and there are various adjuvant therapies. With the aid of modern equipment, early diagnosis and prompt and appropriate treatment, resulting in better visual outcomes, can be anticipated. A large-scale, multinational, prospective study is warranted to determine the optimal initial therapy. Keywords diagnosis, treatment, uveomeningoencephalitides, visual prognosis, Vogt Koyanagi Harada disease Curr Opin Neurol 18: ß 2005 Lippincott Williams & Wilkins. Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung School of Medicine, National Yang-Ming University, Taipei, Taiwan Correspondence to Shwu-Jiuan Sheu, MD, Department of Ophthalmology, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, Kaohsiung, Taiwan 813 Tel: ; fax: ; sjsheu@isca.vghks.gov.tw, jiuansheu@yahoo.com.tw Current Opinion in Neurology 2005, 18: Abbreviations HLA human leucocyte antigen IVCM in-vivo confocal microscopy KP keratic precipitate OCT optical coherence tomography VKH Vogt Koyanagi Harada ß 2005 Lippincott Williams & Wilkins Introduction Uveomeningoencephalitides, commonly known as Vogt Koyanagi Harada (VKH) disease, are characterized by chronic bilateral granulomatous panuveitis involving the central nervous, auditory and integumentary systems. Case reports were first described by Vogt in 1906 and Koyanagi in 1929 in patients presenting with bilateral anterior uveitis, vitiligo, poliosis, alopecia and dysacousia. This became known as Vogt Koyanagi syndrome. In 1926 a similar condition was described by Harada, presenting with posterior uveitis, exudative retinal detachment and cerebrospinal fluid pleocytosis. This syndrome was termed Harada s disease. These syndromes are now considered variants of a single entity and are referred to as VKH disease or the uveomeningoencephalitides [1]. Neurological concomitants of uveitis are not uncommon. In their review of 1450 patients with uveitis, Smith and Rosenbaum [2 ] found that 115 (7.9%) had neurological disease that was considered to be causally related to the eye inflammation. The most frequent neurological associations were VKH disease, primary central nervous system lymphoma, multiple sclerosis and herpes virus infection. These investigators concluded that neurological disease is common among patients attending a uveitis service. The distinctive characteristics of the uveal inflammation may be useful in diagnosing the neurological disease. Epidemiology The typical age of onset for VHK disease is years, and women are affected more often than men. Because the disease occurs more frequently in pigmented groups [3,4], it is likely that certain ethnic groups have genetic backgrounds that predispose them to VKH disease. Specific human leucocyte antigen (HLA) types have been reported to be associated with the disease. Findings from different parts of the world [5,6] indicate that there is an association between class II, subtype DR4 HLA and 323

2 324 Inflammatory diseases and infection VKH disease, especially the HLA-DRB allele. A recent report on mestizo patients in southern California [7 ] identified a possible association between HLA- DRB and VKH disease. Aetiology and pathogenesis The precise cause of the disease is uncertain, but T- lymphocyte-mediated autoimmunity directed against melanocytes is likely to play an important role [8,9]. This is supported by the finding that lymphocytes taken from patients with VKH disease multiply when they are exposed to crude extracts of melanocyte [10]. Although the specific peptide target has not been identified, recent animal studies have shown that inoculation of rats with peptides derived from the family of tyrosinase proteins responsible for melanin formation can induce VKH disease-like syndromes [11]. The ultrastructural changes in rat eyes with experimental VKH disease are similar to those in eyes of humans with VKH disease [12 ]. Pras et al. [13 ] identified an underlying autoimmune disease in up to 40% of patients with intraocular inflammation. These included spondyloarthropathies, Behçet s disease, sarcoidosis, juvenile chronic arthritis, VKH disease, immune recovery syndrome and uveitis with tubulointerstitial disease. Further support for the hypothesis that VKH disease is an autoimmune syndrome comes from its association with other such diseases, including thyroid disease, rheumatoid arthritis, ulcerative colitis and keratoconjunctivitis sicca [14 17]. Although it may occur spontaneously, some evidence suggests that sensitization to melanocytic antigens by means of cutaneous injury or viral infection may precipitate the disease [18 20]. An exogenous factor such as viral infection has been suggested in the pathogenesis of VKH disease by a report of almost simultaneous onset of VKH disease in coworkers, friends and neighbours [21 ]. The presence of anti-ss-a/ro reactivity in sera from patients with VKH disease and similar histopathological findings in experimental rabbits also suggested a possible shared target autoantigen with ocular onchocerciasis [22 ]. However, the findings of an in-vivo confocal microscopy (IVCM) study of the keratic precipitate (KP) in patients with VKH disease [23 ] favoured a noninfectious origin for uveomeningoencephalitides. VKH disease was recently reported to occur during interferon-a therapy for chronic hepatitis C [24,25 ]. Interferon can induce a T-helper-1-type response and alter the expression of major histocompatibility complex class I and II antigens, possibly leading to the development of VKH disease. It is suggested that chronic hepatitis C patients undergoing interferon treatment, especially those with darkly pigmented skin, must be closely monitored for ophthalmological complications over a prolonged period through periodic check-ups of the fundi. This further supports the possibility that VKH disease has an autoimmune nature. Clinical manifestations and diagnosis The presenting complaint is usually loss of vision in one or both eyes, eye pain and hearing disturbance. Patients typically exhibit a prodromal aseptic meningitis-like syndrome that may include headache, vertigo, nuchal rigidity, vomiting and low-grade fever. Atypical presentations of VKH disease are not uncommon, with different manifestations such as unilateral posterior scleritis, bilateral conjunctival nodules, bilateral intermediate uveitis with macular edema, and even annular choroidal detachment [26,27,28,29]. There are no specific diagnostic tests for VKH disease. The diagnosis is therefore based on a combination of suggestive clinical and ancillary test findings when other uveitic conditions have been excluded. Early findings may also include optic disc swelling, exudative retinal detachment and cerebrospinal fluid pleiocytosis. Fluorescein angiography reveals multiple hyperfluorescent spots that coalesce over time. Later, extensive depigmentation of the fundus (sunset glow fundus) is seen, with variable involvement of additional melanocytecontaining tissue, such as the skin and hair, leading to alopecia, vitiligo and poliosis. The first attempt to establish diagnostic criteria for VKH took place in 1978 at the annual meeting of the American Uveitis Society [30]. Because the sequential development of these findings often makes prospective studies unfeasible, the diagnostic criteria were recently revised by the First International Workshop on VKH in 1999 [31,32]. The new criteria take into account the multisystemic nature of VKH disease, with allowance for the different ocular findings that are present in the early and late stages of the disease. A diagnosis of complete VKH disease depends upon the presence of the five criteria listed in Table 1. In recent years, several examinations have been reported to be helpful in the diagnosis and follow up of VKH disease, including indocyanine green angiography, ultrasound biomicroscopy, IVCM and optical coherence tomography (OCT). By allowing better visualization of the choroids, indocyanine green angiography has been reported to be a promising tool for diagnosing and monitoring treatment in VKH disease [33,34]. Ultrasound biomicroscopy is considered helpful in determining disease activity in the anterior segment and in monitoring the clinical course. It may improve evaluation of the efficacy of treatment, especially when the view of the fundus is blocked by synechiae and cataract [35,36].

3 Uveomeningoencephalitides Sheu 325 Table 1. Diagnostic criteria in Vogt Koyanagi Harada disease Diagnosis Complete VKH disease (criteria 1 5 must be present) Incomplete VKH disease (criteria 1 3 and either 4 or 5 must be present) Probable VKH disease (isolated ocular disease; criteria 1 3 must be present) Details (1) No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis (2) No clinical or laboratory evidence suggestive of other ocular disease entities (3) Bilateral ocular involvement (A or B must be satisfied, depending on the stage of disease when the patient is examined) (A) Early manifestations of disease (i) There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous anterior uveitis, vitreous inflammatory reaction, or optic disk hyperemia), which may manifest as one of the following: (a) Focal areas of subretinal fluid, or (b) Bullous serous retinal detachments (ii) With equivocal fundus findings, both of the following must be present as well: (a) Focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence, pooling within subretinal fluid, and optic nerve staining (listed in order of sequential appearance) by fluorescein angiography, and (b) Diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography (B) Late manifestations of disease (i) History suggestive of prior presence of findings from 3A, and either both (ii) and (iii) below, or multiple signs from (iii) (ii) Ocular depigmentation (either of the following manifestations is sufficient) (a) Sunset glow fundus (b) Sugiura sign (iii) Other ocular signs: (a) Nummular chorioretinal depigmented scars, or (b) Retinal pigment epithelium clumping and/or migration, or (c) Recurrent or chronic anterior uveitis (4) Neurological/auditory findings (may have resolved by time of examination): (A) Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors; however, headache alone is not sufficient to meet the definition of meningismus), or (B) Tinnitus, or (C) Cerebrospinal fluid pleocytosis (5) Integumentary findings (not preceding onset of CNS or ocular disease) (A) Alopecia, or (B) Poliosis, or (C) Vitiligo (1) No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis, and (2) No clinical or laboratory evidence suggestive of other ocular disease entities, and (3) Bilateral ocular involvement (4) Neurological/auditory findings (as defined for complete VKH disease, above), or (5) Integumentary findings (as defined for complete VKH disease, above) (1) No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis (2) No clinical or laboratory evidence suggestive of other ocular disease entities (3) Bilateral ocular involvement (as defined for complete VKH disease, above) CNS, central nervous system; VKH, Vogt Koyanagi Harada. Adapted with permission from Read et al. [32]. Recently, Wertheim et al. [23 ] reported the first time using in-vivo confocal microscopy (IVCM) to describe the architecture and heterogeneity keratic precipitates (KP) in uveitis. As documented by IVCM, their findings showed that KPs are markedly heterogeneous and variable. KPs in individual patients are consistent throughout the cornea; the morphological features of KPs change over time; and infectious and noninfectious causes of uveitis appear to be readily distinguishable by using IVCM. KPs may be consistent in specific disease states, and therefore they may have diagnostic importance.

4 326 Inflammatory diseases and infection Our understanding of the pathogenesis of and treatment planning for various vitreoretinal diseases has been revolutionized by the development of OCT. It permits noncontact, cross-sectional imaging of the retina at an axial resolution of mm, and enables direct, real-time imaging of the retinal pathology, which could not previously be visualized in vivo. It has been used to evaluate the rapid effects of pulse corticosteroid therapy on the serous retinal detachment found in the acute phase of VKH disease, and to elucidate the nature of serous retinal detachment in VKH disease [37,38 ]. OCT revealed two patterns of serous retinal detachment: true retinal detachment and intraretinal fluid accumulation in the outer retina. Intraretinal fluid accumulation appeared as an oval space in the outer retina. On fluorescein angiography, the eyes with intraretinal fluid accumulation exhibited more severe dye leakage from the retinal pigment epithelium (Fig. 1). These findings suggest disruption of the outer blood retinal barrier, which may allow fluid from the choroids to permeate the intraretinal potential space. This might reflect the severity of the disease. OCT has potential in grading the severity of uveomeningoencephalitides, as a guide to the efficacy of treatment, and as a monitoring tool. Complications Complications are the main causes of poor visual outcome. It is primarily during the chronic recurrent phases that patients develop these complications. The most frequently reported complications include cataract, glaucoma and choroidal neovascularization. The first two of these entities may also be caused by corticosteroid therapy. The occurrence of complications is known to be associated with the duration of disease, the number of recurrent episodes of inflammation and the extent of retinal detachment in the acute phase [39,40,41]. Although not listed among the complications, pigmentary changes and generalized atrophy of retina may contribute to impaired visual outcome in some patients [42,43]. Although uncommon, some patients will suffer recurrence in the form of chronic anterior uveitis. Increased expression of Fas and Fas ligand mrna in peripheral blood lymphocytes in VKH disease may be responsible for its perpetuation and recurrence [44 ]. Another possible vision-threatening complication, subretinal fibrosis, has attracted much attention during the past few years. Although the incidence of this complication varied greatly in different studies, it is generally agreed that presence of subretinal fibrosis is associated with a poor visual prognosis [45,46]. Treatments Although the visual prognosis in VKH disease is generally favourable, outcomes in terms of final visual acuity may vary. The treatment of choice also varies in different parts of the world. Usually, the aim of therapy for VKH disease is to suppress the initial intraocular inflammation with early and aggressive use of systemic corticosteroids. Typically, prednisolone 1 2 mg/kg per day (or equivalent) is used. Cytotoxic/immunosuppressive agents are needed in refractory cases [47]. Systemic corticosteroid therapy is generally accepted as the standard of care for initial therapy, but there is no consensus regarding the optimal route and dosage of administration. For refractory cases, repeated pulse corticosteroid therapy has been suggested. Alternatively, repeated pulse corticosteroid therapy with or without intravenous immunoglobulin therapy has been used [48,49 ]. Intravitreal triamcinolone (4 mg) was administered in one study [50 ], conferring short-term improvement in visual acuity and serous retinal detachment associated with VKH disease. This treatment may permit systemic corticosteroid use to be shortened or even eliminated in selected cases. Treatment not involving administering large doses of corticosteroids has been reported, with good visual Figure 1. Tomographic features of serous retinal detachment in Vogt Koyanagi Harada syndrome (a) Late-phase (10 min) fluorescein angiogram shows several lobes of diffuse hyperfluorescence. An intraretinal oval dye pooling at the fovea (arrowheads) overlaps anteriorly to subretinal dye pooling. Optical coherence tomography imaging was performed on the arrow including the fovea. (b) A cross-sectional image by optical coherence tomography shows both intraretinal fluid accumulation () and a true serous retinal detachment (arrow). A thin reflective layer is present on the retinal pigment epithelium (arrowheads). With permission from Maruyama and Kishi [38 ].

5 Uveomeningoencephalitides Sheu 327 outcome [51]. Considering the side effects of massive doses of corticosteroids, treatment that avoids the use of these agents is a sensible alternative in those cases that are likely to run a benign course. In order to determine which patients will have a benign course, as a treatment guideline, some factors should be recognized in the acute stage of VKH disease. A number of factors are reportedly related to poor visual outcome, including the presence of complications, age at onset, worse visual acuity at presentation, severity of anterior uveitis, extent of exudative retinal detachment, rapid tapering of steroids, interval between symptom and diagnosis, and greater number of recurrences [40,52,53]. The development of complications, recurrence and tapering of steroids are not good indicators in the early stage. The influence of age has been reported with controversial results [39,40,54 56]. As is usual, early diagnosis and prompt treatment are the key to success. Reports in the literature revealed that those patients who were treated early had better outcomes [52 56]. In our retrospective study of 31 patients with VKH disease who were diagnosed and treated within 1 month of the onset of ocular symptoms [40 ], we found that the extent of exudative retinal detachment was significantly correlated with the development of recurrence, complication and final visual outcome. In the acute stage, the extent of exudative retinal detachment might be an important prognostic factor for visual outcome, and might be a useful guide to treatment in the early stages of VKH disease [40 ]. Ethnicity was also postulated to be a significant prognostic factor, but as yet this is not confirmed [57 ]. In their retrospective study of 17 cases, Guenoun et al. [57 ] concluded that VKH disease, in a Caucasian and African population, has a presentation close to that in the Japanese population, but the cutaneous signs are much rarer. In addition to medical therapy, surgical intervention has been tried in severe cases of bullous retinal detachment, with good results [58 60]. The advantage of surgical drainage of the subretinal fluid can partly be attributed to the shortened duration of photoreceptor damage, which has been reported to require a significantly longer time than that of other macular functions in some patients with VKH disease [61 ]. Surgical intervention was also advised in cases with complications of VKH, such as cataract and uncontrolled glaucoma. Reports from different groups show that cataract extraction in patients with VKH disease can be safely and successfully performed if there is good preoperative and postoperative control of inflammation, careful surgical planning and meticulous surgical technique. The final visual outcome depends on the posterior segment complications of the syndrome [62,63 ]. Treatment of choroidal neovascularization in VKH presents a real challenge to the ophthalmologist. Considering its inflammatory nature, therapy works by decreasing the underlying inflammation, which may allow regression of the vascularization. As with choroidal neovascularization in other disease entities, surgical removal of the neovascular membrane may offer some hope, although recurrence is an important issue. Photodynamic therapy with verteporfin has been tried, resulting in regression of choroidal neovascularization, but unpredicted findings involving normal retina in the vicinity of the lesion suggest that further studies are required to assess its usefulness [64]. Conclusion Although the pathogenesis of VKH disease is uncertain and antigen-specific treatment strategies have not yet been developed, reports increasingly suggest an autoimmune nature for VKH disease. With international collaboration, more practical diagnostic criteria for VKH disease have been established. Modern equipment has been proposed to aid in rapid diagnosis and monitoring of the effect of treatment. Currently, corticosteroid therapy remains the standard initial treatment. Different routes of administration are used to reduce the frequency of side effects of systemic corticosteroids, and there are various adjuvant therapies. A large-scale, multinational, prospective study is warranted to determine the optimal initial therapy. Acknowledgements Work by the authors cited in the present review was supported in part by grant NSC B-075B-003 and VGHKS References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1 Babel J. Vogt Koyanagi syndrome (bilateral uveitis, poliosis, alopecia, vitiligo and dysacousia) [in German]. Schweiz Med Wochenschr Nr 1932; 44: Smith JR, Rosenbaum JT. Neurological concomitants of uveitis. Br J Ophthalmol 2004; 88: This retrospective review of 1450 patients with uveitis found that 115 (7.9%) had neurological disease that was considered to be causally related to eye inflammation. The most frequent neurological associations were VKH disease, primary central nervous system lymphoma, multiple sclerosis and herpes virus infection. 3 Snyder DA, Tessler HH. Vogt Koyanagi Harada syndrome. Am J Ophthalmol 1980; 90: Ohno S, Char DH, Kimura SJ, O Connor GR. Vogt Koyanagi Harada syndrome. Am J Ophthalmol 1977; 83: Numaga J, Matsuki K, Tokunaga K, et al. Analysis of human leukocyte antigen HLA-DR b amino acid sequence in Vogt Koyanagi Harada syndrome. Invest Ophthalmol Vis Sci 1991; 32: Shindo Y, Ohno S, Yamamoto T, et al. Complete association of the HLA- DRB1 04 and DQB1 04 alleles with Vogt Koyanagi Harada s disease. Hum Immunol 1994; 39: Levinson RD, See RF, Rajalingam R, et al. HLA-DRB1 and -DQB1 alleles in mestizo patients with Vogt-Koyanagi-Harada s disease in Southern California. Hum Immunol 2004; 65: This study was the first to identify a possible association between HLA-DRB and VKH disease, and to find DRB and DRB in mestizo patients.

6 328 Inflammatory diseases and infection 8 Rao NA. Mechanisms of inflammatory response in sympathetic ophthalmia and VKH syndrome. Eye 1997; 11: Gocho K, Kondo I, Yamaki K. Identification of autoreactive T cells in Vogt Koyanagi Harada disease. Invest Ophthalmol Vis Sci 2001; 42: Hammer H. Cellular hypersensitivity to uveal pigment confirmed by leukocyte migration test in sympathetic ophthalmitis and the Vogt Koyanagi Harada syndrome. Br J Ophthalmol 1974; 58: Yamaki K, Gocho K, Hayakawa K, et al. Tyrosinase family proteins are antigens specific to Vogt Koyanagi Harada disease. J Immunol 2000; 165: Hayakawa K, Ishikawa M, Yamaki K. Ultrastructural changes in rat eyes with experimental Vogt Koyanagi Harada disease. Jpn J Ophthalmol 2004; 48: Pigmented rats were immunized with tyrosinase family proteins, and the eyes were enucleated after various postinoculation times. Electron microscopy showed thickening of the choroid resulting from the invasion of many lymphocytes and epithelioid-like cells. The melanocytes were surrounded by lymphocytes and had lost their normal spindle shape. Neutrophils and eosinophils were also present in the choroid. These findings are very similar to the changes reported in eyes from patients with VKH disease or sympathetic ophthalmia. 13 Pras E, Neumann R, Zandman-Goddard G, et al. Intraocular inflammation in autoimmune diseases. Semin Arthritis Rheum 2004; 34: The authors reviewed the English medical literature using Medline ( ) employing the terms uveitis, intraocular inflammation and autoimmune diseases. An underlying autoimmune disease was identified in up to 40% of patients with intraocular inflammation, and included spondyloarthropathies, Behçets disease, sarcoidosis, juvenile chronic arthritis, VKH syndrome, immune recovery syndrome and uveitis with tubulointerstitial disease. 14 Wiesli P, Bernauer W, Furrer J. Headache and bilateral visual loss in a young hypothyroid Indian man. J Endocrinol Invest 1999; 22: Shinzato M, Yamamoto J, Hirata CE, et al. Eye disease in a patient with rheumatoid arthritis. Postgrad Med J 1999; 75: Federman DG, Kravetz JD, Ruser CB, et al. Vogt Koyanagi Harada syndrome and ulcerative colitis. South Med J 2004; 97: Pezzi PP, Paroli MP, Priori R, et al. Vogt Koyanagi Harada syndrome and keratoconjunctivitis sicca. Am J Ophthalmol 2004; 137: Rathinam SR, Namperumalsamy P, Nozik RA, Cunningham ET Jr. Vogt Koyanagi Harada syndrome after cutaneous injury. Ophthalmology 1999; 106: Bassili SS, Peyman GA, Gebhardt BM, et al. Detection of Epstein Barr virus DNA by polymerase chain reaction in the vitreous from a patient with Vogt Koyanagi Harada syndrome. Retina 1996; 16: Minoda H, Sakai J, Sugiura M, et al. High inducibility of Epstein Barr virus replication in B lymphocytes in Vogt Koyanagi Harada disease. Nippon Ganka Gakkai Zasshi 1999; 103: Hayasaka Y, Hayasaka S. Almost simultaneous onset of Vogt Koyanagi Harada syndrome in co-workers, friends, and neighbors. Graefes Arch Clin Exp Ophthalmol 2004; 242: This is an interesting report of almost simultaneous onset of VKH disease in coworkers, friends and neighbours. This finding suggests an exogenous factor such as viral infection in the pathogenesis of VKH disease. 22 Shinzato M, Yamamoto JH, Hirata CE, et al. Anti-SS-A/Ro reactivity in patients with Vogt Koyanagi Harada syndrome. Lupus 2004; 13: The authors report, for the first time, the presence of anti-ss-a/ro reactivity in patients with VKH syndrome. It has been demonstrated that its 60 kda protein has sequence homology with the carboxyl-terminal sequence of calreticulin. High reactivity against calreticulin is described in onchocerciasis eye disease. Similar histopathological findings in experimental studies of rabbits also suggested a possible shared target autoantigen with ocular onchocerciasis. 23 Wertheim MS, Mathers WD, Planck SJ, et al. In vivo confocal microscopy of keratic precipitates. Arch Ophthalmol 2004; 122: The authors evaluated the heterogeneity of KPs in varying subtypes of uveitis using IVCM. The results show that KPs are markedly heterogeneous and variable, as indicated by IVCM. KPs in individual patients are consistent throughout the cornea. The morphological features of KPs change across time. Infectious versus noninfectious causes of uveitis appear to be readily distinguishable by using IVCM, and KPs may be consistent in specific disease states and therefore may have diagnostic importance. 24 Sylvestre DL, Disston AR, Bui DP. Vogt Koyanagi Harada disease associated with interferon alpha-2b/ribavirin combination therapy. J Viral Hepatolo 2003; 10: Kasahara A, Hiraide A, Tomita N, et al. Vogt Koyanagi Harada disease occurring during interferon alpha therapy for chronic hepatitis C. J Gastroenterol 2004; 39: This is a case report of VKH disease occurring 4 months after the start of interferon-a treatment, probably induced by the immunomodulatory effects of interferon. The authors concluded that chronic hepatitis C patients, especially people with darkly pigmented skin, must be closely monitored for ophthalmological complications, by periodic check-ups of the optic fundi, for a prolonged period during interferon treatment. 26 Kouda N, Sasaki H, Harada S, et al. Early manifestation of Vogt Koyanagi Harada disease as unilateral posterior scleritis. Jpn J Ophthalmol 2002; 46: Yang MC, Huang AJ. Bilateral conjunctival nodules: an unusual manifestation of Vogt Koyanagi Harada syndrome. Arch Ophthalmol 2004; 122: This is a case report of bilateral conjunctival nodules, an unusual manifestation of VKH. The nodules disappeared after treatment. 28 Kodjikian L, Seve P, Le Hoang P, Garweg JG. Atypical Vogt Koyanagi Harada disease or new uveomeningitic syndrome? Graefes Arch Clin Exp Ophthalmol 2004;17: Epub ahead of print. 29 Yamamoto N, Naito K. Annular choroidal detachment in a patient with Vogt Koyanagi Harada disease. Graefes Arch Clin Exp Ophthalmol 2004; 242: Taylor S, Lightman S. Recurrent anterior uveitis in patients with Vogt Koyanagi Harada syndrome. Arch Ophthalmol 2004; 122: Read RW, Rao NA. Utility of existing Vogt Koyanagi Harada syndrome diagnostic criteria at initial evaluation of the individual patient: a retrospective analysis. Ocul Immunol Inflamm 2000; 8: Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt Koyanagi Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 131: Herbort CP, Borruat FX, de Court, Jaccard L. Indocyanine green angiography in posterior uveitis. Klin Monatsbl Augenheilkd 1996; 208: Stanga PE, Lim JI, Hamilton P. Indocyanine green angiography in choroidal diseases: indications and interpretation an evidence-based update. Ophthalmology 2003; 110: Nakamura H, Tsukamoto H, Shibahara R, et al. Ultrasound biomicroscopy in the management of Vogt Koyanagi Harada disease. Acta Ophthalmol Scand 2000; 78: Wada S, Kohno T, Yanagihara N, et al. Ultrasound biomicroscopic study of ciliary body changes in the post-treatment phase of Vogt Koyanagi Harada disease. Br J Ophthalmol 2002; 86: Yamanaka E, Ohguro N, Yamamoto S, et al. Evaluation of pulse corticosteroid therapy for Vogt Koyanagi Harada disease assessed by optical coherence tomography. Am J Ophthalmol 2002; 134: Maruyama Y, Kishi S. Tomographic features of serous retinal detachment in Vogt Koyanagi Harada syndrome. Ophthalmic Surg Lasers Imaging 2004; 35: Forty-two consecutive eyes from 21 patients with acute-phase VKH syndrome were examined using OCT. It revealed two patterns of serous retinal detachment: a true retinal detachment and intraretinal fluid accumulation in the outer retina. Intraretinal fluid accumulation appeared as an oval space in the outer retina. On fluorescein angiography, the eyes with intraretinal fluid accumulation exhibited more severe dye leakage from the retinal pigment epithelium. 39 Read RW, Rechodouni A, Butani N, et al. Complications and prognostic factors in Vogt Koyanagi Harada disease. Am J Ophthalmol 2001; 131: Sheu SJ, Kou HK, Chen JF. Significant prognostic factors for Vogt Koyanagi Harada disease in the early stage. Kaohsiung J Med Sci 2004; 20: In a retrospective study of 31 patients with VKH disease who were diagnosed and treated within 1 month of the onset of ocular symptoms, the authors found that the extent of exudative retinal detachment correlated significantly with the development of recurrence, complications and final visual outcome. In the acute stage, the extent of exudative retinal detachment might be an important prognostic factor for visual outcome and might be a useful treatment guide in the early stage of VKH disease. 41 Moorthy RS, Chong LP, Smith RE, Rao NA. Subretinal neovascular membranes in Vogt Koyanagi Harada syndrome. Am J Ophthalmol 1993; 116: Keino H, Goto H, Usui M. Sunset glow fundus in Vogt Koyanagi Harada disease with or without chronic ocular inflammation. Graefes Arch Clin Exp Ophthalmol 2002; 240: Sonoda S, Nakao K, Ohba N. Extensive chorioretinal atrophy in Vogt Koyanagi Harada disease. Jpn J Ophthalmol 1999; 43:

7 Uveomeningoencephalitides Sheu Chen L, Yang PZ, Zhou HY, et al. Increased expression of Fas and FasL mrna in peripheral blood lymphocytes in Vogt Koyanagi Harada syndrome. Zhonghua Yan Ke Za Zhi 2004; 40: A high level of Fas mrna and Fas ligand mrna expression in activated peripheral blood lymphocytes was observed in patients with VKH syndrome. These longlasting activated lymphocytes may be responsible for the perpetuation and recurrence of VKH syndrome. 45 Kuo IC, Rechdouni A, Rao NA, et al. Subretinal fibrosis in patients with Vogt Koyanagi Harada disease. Ophthalmology 2000; 107: Lertsumitkul S, Whitcup SM, Nussenblatt RB, et al. Subretinal fibrosis in Vogt Koyanagi Harada syndrome. Ophthalmology 2001; 108: Moorthy RS, Inomata H, Rao NA. Vogt Koyanagi Harada syndrome. Surv Ophthalmol 1995; 39: Denoyer A, Le Lez ML, Arsene S, Pisella PJ. Repeated pulse corticosteroid therapy in Vogt Koyanagi Harada disease. A case report [in French]. J Fr Ophtalmol 2004; 27: This is a case report of a patient with VKH disease who initially exhibited improvement in symptoms with three consecutive daily pulses of corticosteroid, but no improvement during the following oral therapy. A second phase of intravenous pulses of corticosteroid, 1 month after the first, induced great improvements in symptoms and retinal findings, whereas oral therapy seemed to be ineffective. This case provides an opportunity for a discussion on the advantages of multiple pulses of corticosteroid at the acute phase of this disease, because of the vascular effects associated with its anti-inflammatory action. 49 Gonzalez-DelgadoM,GonzalezC,BlazquezJI, etal.intravenousimmunoglobulin therapy invogt Koyanagi Harada syndrome. Neurologia2004; 19: Presented is a case report of a 25-year-old patient with VKH disease treated with intravenous steroid therapy and cycles of intravenous immunoglobulin, with good clinical response. The authors concluded that treatment of VKH disease should be early and aggressive, with high doses of systemic corticosteroids and intravenous immunoglobulin, assessing the maintenance of the latter by repeated cycles. 50 Andrade RE, Muccioli C, Farah ME, et al. Intravitreal triamcinolone in the treatment of serous retinal detachment in Vogt Koyanagi Harada syndrome. Am J Ophthalmol 2004; 137: Intravitreal injection of triamcinolone acetonide (4 mg) was used in three eyes from two patients in the acute phase of VKH disease with serous retinal detachment. The OCT images showed a marked decrease in retinal detachment during the first week after injection, with subsequent return to normal retinal thickness in all eyes. The authors conclude that intravitreal triamcinolone acetonide provides short-term improvement in visual acuity and serous retinal detachments associated with VKH disease. 51 Yamamoto T, Sasaki T, Saito H, et al. Visual prognosis in Harada s disease: a re-evaluation of massive systemic corticosteroid therapy. Jpn J Clin Ophthalmol 1986; 40: Mondkar SV, Biswas J, Ganesh SK. Analysis of 87 cases with Vogt Koyanagi Harada disease. Jpn J Ophthalmol 2000; 44: Rubsamen PE, Gass JDM. Vogt Koyanagi Harada syndrome: clinical course, therapy, and long-term visual outcome. Arch Ophthalmol 1991; 109: Ohno S, Minakawa R, Matsuda H. Clinical studies of Vogt Koyanagi Harada s disease. Jpn J Ophthalmol 1988; 32: Tabbara KF, Chavis PS, Freeman WR. Vogt Koyanagi Harada syndrome in children compared to adults. Acta Ophthalmol Scand 1998; 76: Rathinam SR, Vijayalakshmi P, Namperumalsamy P, et al. Vogt Koyanagi Harada syndrome in children. Ocular Immunol Inflamm 1998; 6: Guenoun JM, Parc C, Dhote R, Brezin AP. Vogt Koyanagi Harada Disease: clinical features, therapy and long-term visual outcome in a Caucasian and African population [in French]. J Fr Ophtalmol 2004; 27: The authors performed a retrospective review of 17 consecutive cases of VKH disease in a mixed white and African population. The results showed that VKH disease, in a Caucasian and African population, has a presentation close to that in the Japanese population. However, cutaneous signs are much rarer. Visual prognosis was generally favourable. 58 Gaun S, Kurimoto Y, Komurasaki Y, et al. Vitreous surgery for bilateral bullous retinal detachment in Vogt Koyanagi Harada syndrome. Ophthalmic Surg Lasers 2002; 33: Chen HC, Ho JD, Chen SN. Perfluorocarbon liquid-assisted external drainage in the management of central serous chorioretinopathy with bullous serous retinal detachment. Chang Gung Med J 2003; 26: Sonoda KH, Enaida H, Ueno A, et al. Pars plana vitrectomy assisted by triamcinolone acetonide for refractory uveitis: a case series study. Br J Ophthalmol 2003; 87: Okamoto Y, Miyake Y, Horio N, et al. Delayed regeneration of foveal cone photopigments in Vogt Koyanagi Harada disease at the convalescent stage. Invest Ophthalmol Vis Sci 2004; 45: Six eyes from three patients in the convalescent stage of VKH disease were studied. No regeneration of cone photopigments was detected within 7 min of testing foveal cone densitometry in all eyes at the first examination after the last episode. However, the other functional tests were normal, and the OCTdetermined macular morphology was normal. These findings suggest that a disorder of foveal cone photopigment regeneration, and its recovery, requires a significantly longer time to recover than do other macular functions in some patients with VKH disease. 62 Moorthy RS, Rajeev B, Smith RE, Rao NA. Incidence and management of cataracts in Vogt Koyanagi Harada syndrome. Am J Ophthalmol 1994; 118: Ganesh SK, Padmaja, Babu K, Biswas J. Cataract surgery in patients with Vogt Koyanagi Harada syndrome. J Cataract Refract Surg 2004; 30: This is a retrospective review of 59 eyes from 39 patients with VKH disease who underwent cataract surgery between May 1985 and June Visual acuity improved by 1 or more lines in 40 eyes (80.0%). The authors found subretinal gliosis and optic atrophy, sequelae of the syndrome, and restricted improvement in vision in the remaining eyes. The results show that cataract extraction in patients with VKH syndrome can be safely and successfully performed if there is good preoperative and postoperative control of inflammation, careful surgical planning and meticulous surgical technique. The final visual outcome depends on the posterior segment complications of the syndrome. 64 Farah ME, Costa RA, Muccioli C, et al. Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in Vogt Koyanagi Harada syndrome. Am J Ophthalmol 2002; 134: