Vogt-Koyanagi-Harada disease (VKH) is a multisystem. Optic Disc Swelling in Vogt-Koyanagi-Harada Disease. Clinical and Epidemiologic Research

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1 Clinical and Epidemiologic Research Optic in Vogt-Koyanagi-Harada Disease Kumiko Nakao, Noriko Abematsu, Yuka Mizushima, and Taiji Sakamoto PURPOSE. This retrospective observational study was designed to evaluate the frequency of, and the factors associated with, optic disc swelling in Vogt-Koyanagi-Harada disease (VKH). METHODS. A retrospective observational study was conducted. We analyzed 116 eyes of 58 patients with VKH. Demographic and clinical differences between patients with and without disc swelling were analyzed. RESULTS. Thirty-two eyes (27.6%) of 16 VKH patients had disc swelling. The mean age of the patients with disc swelling was higher than that of those without disc swelling (58.9 vs. 41.4, P = ). The disc-macula distance to disc diameter (DM/DD) ratio of the eyes with disc swelling was higher than that of those without disc swelling (2.81 vs. 2.59, P = ). The cup to disc (C/D) ratio of the eyes with disc swelling was smaller than that of those without disc swelling (0.18 vs. 0.32, P = ). The intraocular pressure was lower (P = ), and the refractive error was larger (P = 0.019), in eyes with disc swelling than in those without. There was no significant association between the presence of disc swelling and the range of retinal detachment, cerebrospinal fluid cell count, recurrence rate of VKH, or the incidence of sunset glow fundus. Among the eyes with disc swelling, 13 eyes of 7 patients had visual field defects even after the inflammation subsided, and these patients were older, had a higher DM/DD ratio, and had a smaller C/D ratio than those without visual field defects. CONCLUSIONS. The occurrence of disc swelling in VKH was significantly correlated with age and disc morphology, rather than the severity of inflammation. Some VKH patients with disc swelling develop visual field defects from optic disc involvement. (Invest Ophthalmol Vis Sci. 2012;53: ) DOI: /iovs Vogt-Koyanagi-Harada disease (VKH) is a multisystem autoimmune disorder principally affecting the pigmented tissues in the ocular, auditory, integumentary, and central nervous systems. Patients with VKH usually have bilateral granulomatous panuveitis associated with poliosis, vitiligo, alopecia, dysacousia, and signs of meningeal irritation. 1 Optic disc swelling can often be seen in VKH, 1 7 and disc swelling with little or no exudative retinal detachment could be From the Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. Supported in part by a grant from the Research Committee on Chorioretinal Degeneration and Optic Atrophy, Ministry of Health, Labor,andWelfare,Tokyo,Japan. Submitted for publication November 1, 2011; revised January 25, 2012; accepted February 8, Disclosure: K. Nakao, None;N. Abematsu, None;Y. Mizushima, None;T. Sakamoto, None Corresponding author: Kumiko Nakao, Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences Sakuragaoka, Kagoshima, ; nakao@m2.kufm.kagoshima-u.ac.jp. mistaken for optic neuritis. 8 In uveitis owing to causes other than VKH, disc swelling is also a common finding, but the optic disc is rarely so swollen that it is mistaken for optic neuritis. Moreover, some VKH patients who had disc swelling have reportedly developed irreversible visual field defects (VFD) in the acute phase of VKH, and they were suggested to have anterior ischemic optic neuropathy (AION) associated with VKH Their fluorescein angiography showed both a filling delay and late leakage of the optic disc, and VFD remained after the exudative retinal detachments and disc swelling resolved. Subsequently, the optic disc developed pallor, and the retinal nerve fiber layer thickness decreased, usually in a topography corresponding to the pattern of field loss mapped out on automated perimetry. These findings suggest that AION developed nearly simultaneously with VKH. There have been few reports on disc swelling in subjects with VKH. We herein evaluated the frequency of, and the factors that are primarily and secondarily associated with, disc swelling and examined the correlation regarding the presence of disc swelling with various demographic and ophthalmic entities. MATERIALS AND METHODS A retrospective review was conducted of 58 consecutive new VKH patients who visited Kagoshima University Hospital from January 2003 to December The patients comprised 23 male and 35 female patients, with a mean age of 46.2 years (range, years). All patients were Japanese. They were diagnosed with complete or incomplete VKH according to the revised criteria of the International Committee on VKH disease, 12 and all were treated with high-dose corticosteroid therapy followed by a slow tapering of the drug over a 5- to 6-month period. The patients were followed up for at least 6 months, with a median follow-up period of 12 months (range, 6 84 months). Information about ophthalmologic, neurologic, and systemic findings was obtained from the records of each patient, and the data were compared between the subjects with and without disc swelling, and also between the subjects with and without VFD. This study was approved by the Institutional Review Board of Kagoshima University Graduate School of Medical and Dental Sciences and adhered to the tenets of the Declaration of Helsinki. The optic disc of each eye was evaluated to be either swollen or not swollen based on not only the ophthalmoscopic findings, but also the results of fluorescein angiography during the acute uveitic phase, since it can be unclear whether the optic disc is swollen when there is retinal detachment around the disc. On fluorescein angiography, the discs with hyperfluorescence and leakage were considered to have disc swelling. The discs with no hyperfluorescence or the discs with hyperfluorescence but no leakage were considered to have no disc swelling. The condition was judged only by the fundus ophthalmoscopy in the patients who were not able to undergo fluorescein angiography. The presence of VFD was judged based on visual field examinations using either a Humphrey Field Analyzer II (Carl Zeiss Meditec Inc., Dublin, CA) or Goldman perimeter after retinal detachment and disc swelling completely disappeared on the optical coherence tomography image at 1 to 2 months after the start of Investigative Ophthalmology & Visual Science, April 2012, Vol. 53, No Copyright 2012 The Association for Research in Vision and Ophthalmology, Inc.

2 1918 Nakao et al. IOVS, April 2012, Vol. 53, No. 4 treatment. If VFD were detected then, the visual fields were checked every several months thereafter. The refraction data were determined after the signs of inflammation subsided in order to avoid the ciliary body inflammation and submacular fluids affecting the refractive state, and the spherical equivalent value was used for the refractive evaluations. The visual acuities measured on decimal charts were converted to logmar for the statistical analysis; poor visual acuity of counting fingers was arbitrarily estimated to correspond to in decimal units. The proportion of the retinal detachment area seen on the 508 fundus photograph centered on the macula was measured. The extension of retinal detachment along the optic disc was also measured by the ratio of the circumferential length of the optic disc border adjacent to the retinal detachment to the optic disc circumference. Morphometric measurement of the vertical cup to disc (C/D) ratio and disc-macula distance to disc diameter (DM/DD) ratio were performed at least 6 months or more after starting the treatment when the disc swelling had completely resolved. The DM/ DD ratio was estimated using the formula described by Wakakura and Alvarez. 13 All measurements were performed twice by one observer on separate occasions using the ImageJ version 1.42q (NIH, Bethesda, MD), and the average of the two measurements was used for the statistical analysis. Normally distributed data were summarized by the means standard deviations, and non normally distributed data were summarized as the medians (interquartile range). The statistical analyses of continuous variables were performed with the use of Student s t-test or the Mann-Whitney U test, as appropriate. The categorical variables were compared by either the v 2 test, Fisher s exact test, or the Mann- Whitney U test, as appropriate. Statistical differences were considered to be significant at P < To verify the factors that significantly contribute to the development of disc swelling in VKH patients by excluding the possible cross-effects among the variables, a multivariate logistic regression analysis was performed with the items that showed a significant difference in the univariate analysis as independent variables. The analyses were performed using the IBM SPSS statistics Version 19 (SPSS Japan Inc., Tokyo, Japan). RESULTS Among the 116 eyes of 58 VKH patients, 84 eyes (72.4%) of 42 patients were judged as having no disc swelling: 26 eyes of 13 patients had no disc hyperfluorescence, 52 eyes of 26 patients had disc hyperfluorescence but no leakage, and 6 eyes of 3 patients without available fluorescein angiography. Thirty-two eyes (27.6%) of 16 patients had disc hyperfluorescence and leakage and were judged as having disc swelling. All eyes with no disc swelling had a complete recovery of the visual field after the retinal detachment subsided, while in the eyes with disc swelling, both eyes of 9 patients and one eye of one patient showed a complete visual field recovery, but 13 eyes of 7 patients (both eyes of 6 patients and one eye of one patient) demonstrated residual VFD. The VFD remained unchanged during the follow-up period (7 40 months), and the 13 eyes did not show any optic disc anomalies or any chorioretinal atrophy causing VFD. The detailed clinical findings of the 13 eyes with disc swelling and with VFD, suggesting the cooccurrence of AION, have been reported elsewhere. 10,11 Tables 1 and 2 summarize the demographic and clinical information of the no disc swelling and disc swelling groups, in which the disc swelling group is subdivided according to the presence or absence of VFD. There was no significant difference in the male to female ratio between patients with and without disc swelling. The mean age at the disease onset was significantly higher in the patients with disc swelling than in those with no disc swelling ( years vs years, P = ), and the TABLE 1. Demographic and Clinical Characteristics of Patients with Vogt-Koyanagi-Harada Disease with and without Optic * P Value vs. (n = 7 Patients ) (n = 9 Patients) P Value, No vs. (n = 16 Patients) No (n = 42 Patients) Sex, male/female 16/26 7/ /6 4/ Age, years Systemic disease, no. (%) 5 (11.9) 5 (31.3) (11.1) 4 (57.1) Diabetes mellitus, no. (%) 4 (9.5) 4 (25.0) (11.1) 3 (42.9) Hypertension, no. (%) 1 (2.4) 0 (0.0) (0.0) 0 (0.0) Hyperlipidemia, no. (%) 0 (0.0) 1 (6.3) (0.0) 1 (14.3) Headache, no. (%) 27 (64.3) 6 (37.5) (33.3) 3 (42.9) (6 101) (n = 12) 68 (20 127) (n = 11) (5 146) (n = 5) 116 (47 174) (n = 6) Cerebrospinal fluid cell count, per microliter, without visual field defects;, with visual field defects. * Data are presented as the means SD or medians (interquartile range) for continuous variables and as the number (%) for categorical variables.

3 IOVS, April 2012, Vol. 53, No. 4 Optic in VKH 1919 TABLE 2. The Ocular Findings of Patients with Vogt-Koyanagi-Harada Disease with and without Optic * P Value vs. (n = 13 Eyes) (n = 19 Eyes) P Value, No vs. (n = 32 Eyes) No (n = 84 Eyes) Initial IOP, mm Hg 15 (12 19) 12 (10 16) (10 13) 14 (10 18) Refractive error, diopters ( ) 0.0 ( ) ( ) ( ) Proportion of RD in the posterior pole, % 28.7 ( ) 32.5 ( ) ( ) 21.5 ( ) Extension of RD along the optic disc, ratio 0.36 (0 0.9) 0.56 ( ) ( ) 0.46 ( ) DM/DD ratio C/D ratio Initial visual acuity (logmar) 0.30 ( ) 0.52 ( ) ( ) 0.91 ( ) Final visual acuity (logmar) ( ) ( ) ( ) 0.13 ( ) Recurrence, no. (%) 20 (23.8) 10 (31.3) (26.3) 5 (38.5) Sunset glow fundus, no. (%) 30 (35.7) 14 (43.8) (42.1) 6 (46.2) PPA, no. (%) 18 (21.4) 10 (31.2) (21.2) 6 (46.2) RD, retinal detachment; PPA, peripapillary atrophy. * Data are presented as the means SD or medians (interquartile range) for continuous variables and as the number (%) for categorical variables. mean age in the patients with disc swelling with VFD ( years) was higher than in patients with disc swelling and without VFD ( years), although these differences were not significant. When patients were divided into two groups according to age (50 and >50 years old), the frequency of disc swelling was 15/26 (57.7%) in the over 50 years old group in contrast to 1/32 (3.1%) in the 50 years old and under group (P = ). With regard to systemic disease, diabetes mellitus coexisted with 25% of patients with disc swelling and 9.5% of patients with no disc swelling, and the coexistence of diabetes mellitus further increased in patients with disc swelling and with VFD (42.9%), but there was no statistical significance for this increase. Besides diabetes mellitus, other systemic diseases also coexisted, including hypertension in one patient with no disc swelling, and hyperlipidemia in one patient with disc swelling; and when both of these diseases were taken into consideration, the coexistence of a systemic disease giving rise to a vascular disorder increased significantly more in patients with disc swelling and with VFD than in patients with no disc swelling (57.1% vs. 11.9%, P = 0.016). There was no significant difference in the proportion of patients who had a headache, as a meningeal sign, between patients with and without disc swelling (37.5% vs. 64.3%). In the 23 patients from whom cerebrospinal fluid (CSF) was examined before the initiation of corticosteroid therapy, CSF pleocytosis (>5 leucocytes/ll) was seen in 9 (81.8%) of 11 patients with disc swelling and 9 (75.0%) of 12 with no disc swelling. The CSF cell count appeared to be higher in patients with disc swelling than in those with no disc swelling, but there was no significant difference. The intraocular pressure (IOP) at presentation was significantly lower in eyes with disc swelling than in eyes with no disc swelling (12 mm Hg [10 16 mm Hg] vs. 15 mm Hg [12 19 mm Hg], P = ). The refractive error was significantly larger in eyes with disc swelling than in eyes with no disc swelling (0.0 diopters [-1.3 to 0.6 diopters] vs diopters [-2.1 to 0.0 diopters], P = 0.019). There was no significant difference between eyes with and without disc swelling in the proportion of retinal detachment area seen on the 508 fundus photograph centered on the macula (32.5% [5.8% 60.6%] vs. 28.7% [10.1% 51.8%]) or the extent of retinal detachment along the optic disc, which was measured by the ratio of the circumferential length of the optic disc border adjacent to the retinal detachment to the optic disc circumference (0.56 [ ] vs [0 0.9]). The DM/DD ratio was significantly higher in eyes with disc swelling than in those with no disc swelling ( vs , P = ) and was also higher in eyes with disc swelling and with VFD ( ) than in those without VFD ( ). The incidence of small discs with a DM/DD ratio over 3 was significantly higher in eyes with disc swelling (P = ), and it was even higher in eyes with disc swelling and with VFD (Table 3). The C/D ratio was significantly smaller in eyes with disc swelling than in those with no disc swelling ( vs , P = ) and was even smaller in eyes with disc swelling and with VFD ( ) than in those without VFD ( ). The incidence of small cups with a C/D ratio below 0.2 was significantly higher in eyes with disc swelling (P = ), and it was even higher in eyes with disc swelling and with VFD (Table 4). There was no significant difference in the initial visual acuity between eyes with and without disc swelling, but it was significantly worse in eyes with disc swelling and with VFD than in eyes with no disc swelling and in eyes with disc swelling without VFD (0.91 logmar [ logmar] vs logmar [ logmar] and 0.30 logmar [ logmar], P = , P = , respectively). There was

4 1920 Nakao et al. IOVS, April 2012, Vol. 53, No. 4 TABLE 3. The DM/DD Ratio in Patients with Vogt-Koyanagi-Harada Disease with and without Optic DM/DD Ratio No (n = 84 Eyes) (n = 32 Eyes) (n = 19 Eyes) (n = 13 Eyes) < (32.1%) 2 (6.3%) 2 (10.5%) 0 (0.0%) 2.4 to <3 51 (60.7%) 22 (68.8%) 13 (68.4%) 9 (69.2%) (7.1%) 8 (25.0%) 5 (21.1%) 4 (30.8%) P = P = 0.02 P = P is the significance of differences compared with the no disc swelling group. also no significant difference in the final visual acuity between eyes with and without disc swelling, but it was significantly worse in eyes with disc swelling and with VFD than in eyes with no disc swelling and in eyes with disc swelling without VFD (0.13 logmar [-0.08 to 0.3 logmar] vs logmar [-0.18 to 0.07 logmar] and logmar [-0.18 to logmar], P = , P = , respectively). A recurrence was observed in 31.3% of eyes with disc swelling and 23.8% of eyes with no disc swelling, and the recurrence rate further increased in eyes with disc swelling and with VFD (38.5%), but the difference was not significant. At 6-month follow-up, the sunset glow fundus was observed in 43.8% of eyes with disc swelling and in 35.7% of eyes with no disc swelling, which was not significantly different. There was also no significant difference in the duration until appearance of sunset glow fundus between eyes with and without disc swelling ( months vs months). A small peripapillary atrophy was observed in 31.2% of eyes with disc swelling and in 21.4% of eyes with no disc swelling, which was not significantly different. A multivariate logistic regression analysis was performed using the presence of disc swelling as the dependent variable, and factors with P < 0.05 in a comparison between VKH patients with and without disc swelling as the independent variables, which included the patient s age, IOP, refractive error, DM/DD ratio, and C/D ratio. This analysis revealed that age and the C/D ratio were significant factors (odds ratio [OR] = 1.11, P = and OR = , P = 0.001, respectively), even after the exclusion of possible cross-effects among the independent variables (Table 5). In a multinomial logistic regression analysis, these factors were significantly and more strongly associated with eyes with disc swelling and with VFD than eyes with disc swelling without VFD. There were no significant differences for the IOP, refractive error, or DM/DD ratio after they were evaluated using the multivariate logistic regression analysis. DISCUSSION This was a hospital-based study with a relatively small sample size, and there may have been a selection bias, as patients who are admitted to our hospital may be different from patients admitted to other hospitals in Japan. However, most VKH patients in Kagoshima prefecture (southwest Japan) are referred to our hospital, and VKH patients in Kagoshima prefecture do not particularly differ from VKH patients in other parts of Japan, so we think that the selection bias in this study is probably negligible. In a consecutive series of 58 patients with VKH, 32 eyes (27.6%) of 16 patients had disc swelling. The incidence of disc swelling was not high in the present study, at 27.6%, while the incidence of disc swelling was as high as 87% in a previous Japanese report. 2 The reported incidences of disc swelling vary from 9% to 87%. 2 7 These disparities might be owing to the different criteria used for the definition of disc swelling. Most reports with a high incidence of disc swelling seem to include disc hyperemia in the disc swelling category. Among 32 eyes with disc swelling, 13 eyes (40.6%) developed irreversible VFD in the acute phase of VKH, while the eyes without disc swelling did not develop irreversible VFD in the acute phase of VKH. The possibility that VFD due to congenital disc or retinal disease was already present before the onset of VKH cannot be ruled out completely. However, the eyes with disc swelling and with VFD did not show any optic disc anomalies or congenital retinal disease. Although particularly superior segmental optic nerve hypoplasia (SSONH) may require differentiation, because SSONH patients usually have good visual acuity and asymptomatic inferior sector-like VFD, the eyes with VFD did not show the characteristic optic disc appearance of SSONH: a relative superior entrance of the central retinal artery, pallor of the superior optic disc, a superior peripapillary scleral halo, and thinning of the superior retinal nerve fiber layer. 14 There have been few reports about VFD in the eyes with disc swelling of VKH patients Although the initial and final visual acuities were significantly worse in eyes with disc swelling and with VFD than in eyes without disc swelling, if the VFD did not involve the central visual field, the visual acuity was still good even in eyes with disc swelling and with VFD. As reported elsewhere, the eyes with disc swelling and with VFD had various degrees of VFD, and the small and localized cases of VFD were asymptomatic. 11 For these reasons, we speculate that the VFD in eyes with disc swelling has more likely been overlooked. TABLE 4. The C/D Ratio in Patients with Vogt-Koyanagi-Harada Disease with and without Optic C/D Ratio No (n = 84 Eyes) (n = 32 Eyes) (n = 19 Eyes) (n = 13 Eyes) < (15.5%) 19 (59.4%) 10 (52.6%) 9 (69.2%) 0.2 to < (69.0%) 10 (31.3%) 6 (31.6%) 4 (30.8%) (15.5%) 3 (9.4%) 3 (15.8%) 0 (0.0%) P = P = P = P is the significance of differences compared to the no disc swelling group.

5 IOVS, April 2012, Vol. 53, No. 4 Optic in VKH 1921 TABLE 5. Multivariate Analysis for the Presence of Optic Multinomial (Ref: No ) No vs. without VFD with VFD OR 95% CI P Value OR 95% CI P Value OR 95% CI P Value Age Initial IOP Refractive error DM/DD ratio C/D ratio Ref, reference category; CI, confidence interval. The patients with disc swelling were significantly older in age at the onset than those without disc swelling, and they had a less myopic refractive error, lower IOP, a higher DM/DD ratio, and a smaller C/D ratio than those without disc swelling. Moreover, the patients with disc swelling and with VFD were significantly older and had a significantly higher DM/DD ratio and smaller C/D ratio; additionally, they had more systemic diseases such as diabetes mellitus than those without disc swelling. The results indicate that the frequency of disc swelling was significantly higher in the elderly group, which is similar to the results of a previous report demonstrating that the incidence of optic disc hyperemia in an elderly group is significantly higher than that in a non-elderly group. 6 The less myopic refractive error in eyes with disc swelling might be associated with the older age of patients with disc swelling, because the spherical equivalent was reported to be significantly correlated with age; the prevalence of myopia decreased and that of hyperopia increased in older patients. 15 Ocular hypotension associated with uveitis is thought to be one of the factors that produce edema of the disc, 16 and the IOP was lower in eyes with disc swelling than in those without disc swelling, but there was no significant difference in the frequencies of ocular hypotension (less than 10 mm Hg) between eyes with and without disc swelling. The DM/DD ratio for normal Japanese eyes was reported to be , 13 and the C/D ratio for normal Japanese eyes was reported to be Compared with these data, the DM/DD ratio of eyes with disc swelling was significantly higher and the C/D ratio of eyes with disc swelling was significantly smaller (P = 0.04, P = , respectively), although those of eyes without disc swelling did not show significant differences compared with the normal values. Since these variables (age, refractive error, IOP, DM/DD ratio, and C/D ratio) may be related to each other, we performed a multivariate logistic regression analysis to verify the significant contributing factors after the exclusion of possible crosseffects. This analysis yielded the patient age and the C/D ratio as the most significant factors contributing to the development of disc swelling in VKH patients. Old age, a small crowded optic disc with little or no cupping, and diabetes mellitus are known as risk factors for AION. 18,19 It is believed that crowding at the level of the lamina cribrosa predisposes to a compartment syndrome phenomenon, whereby axoplasmic stasis and edema following a microvascular ischemic event lead to further ischemia through the compression of the capillaries among nerve fiber bundles due to crowding of the optic nerve head. 19,20 The arterial supply of the optic disc is derived from the ciliary circulation. The prelaminar region of the optic disc is supplied by fine centripetal branches from the peripapillary choroid. The region of the lamina cribrosa is supplied from the branches of the short posterior ciliary artery either directly or by the socalled arterial circle of Zinn and Haller. 16 According to histopathological studies of sympathetic ophthalmia, which is thought to be pathologically identical to VKH, severe uveitis at the juxtapapillary choroid with obliteration of the choriocapillaris and inflammatory infiltration surrounding the emissarial vessels through the scleral canals are seen. 21 In VKH patients with crowded discs, circulatory disturbances of the branches of the short posterior ciliary artery and/or centripetal branches from the peripapillary choroid due to severe choroidal inflammation may cause axonal flow stasis and secondary axonal swelling of the optic nerve. In older patients with underlying systemic vascular disease, such as diabetes mellitus, this swelling is thought to be more likely to compromise the microvasculature of the optic nerve head, leading to more ischemia, and finally to AION. The extent and severity of VFD are thought to depend upon the extent of optic nerve damage caused by ischemia. On the other hand, various factors thought to be associated with the severity of inflammation, including the CSF cell count, range of retinal detachment, recurrence rate, and incidence of sunset glow fundus were examined, but there was no statistically significant association between these factors and disc swelling. The small number of patients in whom the CSF examination was performed might have influenced the results. The range of retinal detachment might not reliably reflect choroidal inflammation. If the severity of choroidal inflammation can be quantitated adequately, the association between the severity of inflammation and the development of disc swelling can be clarified. At present, it cannot be denied that the occurrence of disc swelling may be associated with the severity of choroidal inflammation, because the frequency of recurrence and sunset glow fundus tended to be higher in eyes with disc swelling. It is possible that with a larger sample size, the findings might have been different. In summary, disc swelling occurs frequently in older VKH patients with small discs and small cups. It should be noted that some VKH patients with disc swelling develop VFD from optic disc involvement, thus suggesting the coincidence of AION in the acute phase of VKH. References 1. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol. 1995;39: Ohno S, Minakawa R, Matsuda H. Clinical studies of Vogt- Koyanagi-Harada disease. Jpn J Ophthalmol. 1988;32: Beniz J, Forester DJ, Lean JS, Smith RE, Rao NA. Variations in clinical features of the Vogt-Koyanagi-Harada syndrome. Retina. 1991;11: Keino H, Goto H, Mori H, Iwasaki T, Usui M. Association between severity of inflammation in CNS and development of

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