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The Prognostic Value of Angiography in Vogt-Koyanagi-Harada Disease
The Prognostic Value of Angiography in Vogt-Koyanagi-Harada Disease SOON-PHAIK CHEE, ALIZA JAP, AND CHUI MING GEMMY CHEUNG ● PURPOSE:
To determine the prognostic value of fluorescein angiography (FA) and indocyanine green angiography (ICGA) in Vogt-Koyanagi-Harada disease (VKH). ● DESIGN: Retrospective noninterventional study. ● METHODS: Chart, FA, and ICGA review of VKH patients of Singapore National Eye Centre for age at onset, gender, race, timing of treatment, and angiographic features during the different phases of FA and ICGA. Outcome measure was disease outcome (acute resolved or chronic recurrent). ● RESULTS: Twenty-one of the 28 patients with pretreatment FA also had ICGA. Median follow-up duration was 3.6 years (range 0.94 –13.42 years). Median age was 42.2 years (range 15.7–77.2 years). The majority (18, 64.3%) were Chinese. The most frequently observed FA features included early pinpoint hyperfluorescence in the posterior pole and disc hyperfluorescence. Large choroidal vessel hyperfluorescence (early and intermediate phase), areas of delayed choroidal perfusion (early phase), and persistent dark dots were the 3 most common ICGA features. Pinpoint peripapillary hyperfluorescence was found to be a significant prognostic FA factor on both univariate and multivariate analysis. None of the ICGA features were found to be significant prognostic factors. ● CONCLUSION: Early pinpoint peripapillary hyperfluorescence on pretreatment FA is a useful prognostic sign in VKH patients, whereas pretreatment ICGA has limited prognostic value. (Am J Ophthalmol 2010;150: 888 – 893. © 2010 by Elsevier Inc. All rights reserved.)
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OGT-KOYANAGI-HARADA DISEASE (VKH) IS A T-CELL-
mediated autoimmune disease1–3 directed against antigens found on or associated with melanocytes. It presents acutely, and during the prodromal phase, auditory and central nervous system manifestations may precede the acute uveitic phase. During the acute phase, bilateral panuveitis with choroiditis and exudative detachments are seen. In patients who develop chronic recurrent
Accepted for publication Jun 23, 2010. From Singapore National Eye Centre, Singapore (S.P.C., A.J., C.M.G.C.); the Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (S.P.C.); Singapore Eye Research Institute, Singapore (S.P.C., C.M.G.C.); and the Division of Ophthalmology, Changi General Hospital, Singapore (A.J.). Inquiries to Soon-Phaik Chee, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; e-mail: chee.soon.phaik@ snec.com.sg
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uveitis, vitiligo and poliosis may also occur.4 Patients who receive adequate doses of corticosteroids soon after the onset of disease often have rapid resolution of the ocular and systemic manifestations, with good visual outcomes.4 –11 However, chronic disease may develop in over half of these patients,12 with consequent complications such as cataract, glaucoma, subretinal fibrosis, choroidal neovascular membranes, and chorioretinal atrophy, resulting in visual loss over the years. The introduction of immunomodulatory therapy in severe disease, however, holds promise of arresting the chronic inflammation and preserving vision in patients with relentless disease.13 The initial visual acuity (VA) has been found to be an important predictive factor of the visual outcome.14 –16 We investigated the early prognostic factors and found that good VA at 1 month, younger age at onset, and early treatment with high-dose corticosteroids were associated with better outcomes.11 In this paper, we studied the value of fluorescein angiography (FA) and indocyanine green angiography (ICGA), performed during the acute uveitic phase, to try to identify potential prognostic features for the disease outcome that could be used to guide the ophthalmologist in the strategy of immunotherapy.
METHODS WE RETROSPECTIVELY REVIEWED THE CASE RECORDS OF
all VKH patients seen in the Singapore National Eye Centre uveitis clinic. The diagnosis was made based on the VKH International Committee criteria published in 2001.17 We only included patients who had received at least 1 mg/kg prednisolone tapered over a minimum of 6 months (high-dose steroid) and who had angiograms done before initiating treatment. The treatment group was defined as early high (EH) if the patient received the therapy 2 weeks or less following onset of ocular symptoms, and late high (LH) if treatment was started after 2 weeks up to 1 month after ocular symptoms. The outcome of treatment was defined according to standard nomenclature18 as acute resolved or chronic/chronic persistent or recurrent disease according to the status of inflammation at 3 months post onset of disease. Eyes with less than 18 months of follow-up were excluded unless they had developed features of chronic disease earlier. Data were collected on patient demographics, bestcorrected visual acuity (BCVA), the clinical course of
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disease (acute resolved or chronic recurrent), timing, and mode of therapy. A masked investigator (C.M.G.C.) read all the FAs and ICGAs of these eyes, which had been done during acute phase before initiation of treatment. In view of the fact that both eyes of cases with bilateral simultaneous onset tend to have similar features, in patients where there was less than 48 hours difference in onset of symptoms between the 2 eyes, the FA of only 1 eye was analyzed so as to minimize the risk of correlation between eyes. The right eye was selected as this is the eye that was imaged first by convention in patients with simultaneous onset. Similarly, only the ICGA of the eye that was imaged first was analyzed. The FA and ICGA were performed using the Topcon 50 IA camera (Tokyo, Japan) coupled to an Imagenet (Topcon) image digitalizing system. A standard protocol was used. After injection of 2 mL of fluorescein 20%, early frames concentrating on the posterior pole were acquired up to 40 seconds. Mid-phase frames of the posterior pole and 4 quadrants were captured between 1 and 3 minutes, and late-phase images at 10 minutes after fluorescein injection. This was followed by a bolus injection of 50 mg of indocyanine green in 4 mL of normal saline. ICGA frames were captured at close intervals for the first 2 to 3 minutes (early phase). The intermediate phase was captured 10 to 15 minutes after dye injection and the late phase at 30 to 40 minutes. ● FLUORESCEIN ANGIOGRAM: The features studied included patchy choroidal filling persisting for more than 2 to 3 seconds in the early frames, areas of delayed choroidal nonperfusion in early frames, early pinpoint hyperfluorescence, pinpoint peripapillary hyperfluorescence, disc hyperfluorescence, disc leakage, late pooling of fluorescein, late choroidal hyperfluorescence, and choroidal striae. ● INDOCYANINE GREEN ANGIOGRAM: The features studied included areas of delayed choroidal perfusion, early and intermediate large choroidal vessel hyperfluorescence, persistent small and large dark dots, disc hyperfluorescence, late choroidal hyperfluorescent patches, and dark patches persisting to late phase. Statistical analysis was performed using SPSS (Version 13.0; Chicago, Illinois, USA). Univariate analysis was performed using 2 test or Mann-Whitney test as appropriate. Age, gender, and other significant univariate risk factors were included in the multivariate logistic regression model for outcome of VKH disease; statistical significance was defined as P ⬍ .05.
RESULTS ONE HUNDRED THREE PATIENTS DIAGNOSED WITH VKH
were seen in the uveitis clinic from February 1, 1994 to February 29, 2008. This group includes patients who had been followed up since the 1970s when FAs were not VOL. 150, NO. 6
TABLE 1. Frequencies of Pretreatment Fluorescein and Indocyanine Green Angiographic Features in Eyes With Vogt-Koyanagi-Harada Disease Number of Eyes (%) a
Fluorescein angiography features Early patchy choroidal filling Areas of delayed choroidal perfusion Early pinpoint hyperfluorescence Pinpoint peripapillary hyperfluorescence Disc hyperfluorescence Disc leakage Late pooling of fluorescein Late choroidal hyperfluorescence Choroidal striae Indocyanine green angiography featuresb Areas of delayed choroidal perfusion Early & intermediate large choroidal vessel hyperfluorescence Persistent small and large dark dots Disc hyperfluorescence Late choroidal hyperfluorescence Dark patches persisting to late phase
17 (68.0) 5 (41.7) 21 (80.8) 15 (53.6) 28 (82.4) 18 (52.9) 20 (58.8) 3 (8.8) 20 (58.8) 21 (100.0) 21 (100.0) 20 (95.2) 8 (38.1) 14 (66.7) 18 (85.7)
a
Only right eye of patients with simultaneous onset is included. b Only 1 eye per patient is analyzed.
routinely done. Being a tertiary referral clinic, some of the patients had been referred from other eye specialists and the majority of the referred patients did not receive high-dose steroids, nor did they have FAs done within the first 1 month of onset of symptoms. Hence there were only 28 eligible patients, and 21 of these 28 patients (42 eyes) also had pretreatment ICGA. There were 13 male and 15 female patients whose median age was 42.2 years (range 15.7-77.2 years). Eighteen were Chinese, 6 were Malay, 2 were Indian, and 2 were classified as “other,” similar to the racial distribution of our population. The median duration of follow-up was 3.6 years (range 0.94-13.42 years). The disease outcome was categorized as acute resolved in 26 eyes and chronic in 30 eyes. Twenty-two patients had less than 48 hours difference from onset of symptoms to FA between the 2 eyes. Of the remaining 6 patients, the median interval between the 2 eyes was 3.5 days, with a range of 3 to 9 days. On FA the most commonly seen features (Table 1) were early pinpoint hyperfluorescence in the posterior pole and disc hyperfluorescence. On ICGA, large choroidal vessel hyperfluorescence and fuzziness in the early and intermediate phase, and areas of delayed choroidal perfusion in the early phase, were seen in all the eyes. Other common findings included persistent small and large dark dots and dark patches persisting to the late phase.
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TABLE 2. Demographic and Angiographic Prognostic Factors for Developing Chronic Vogt-Koyanagi-Harada Disease Risk Factor
Acute Resolved (13 Patients)
Chronic Disease (15 Patients)
P
Median age of onset in years (range) Median duration follow-up in years (range) Male sex, no. (%) Chinese race, no. (%) Early high treatment, no. (%) Fluorescein angiography featuresc Early patchy choroidal filling, no. (%) Areas of delayed choroidal perfusion, no. (%) Early pinpoint hyperfluorescence, no. (%) Pinpoint peripapillary hyperfluorescence, no. (%) Disc hyperfluorescence, no. (%) Disc leakage, no. (%) Late pooling of fluorescein, no. (%) Late choroidal hyperfluorescence, no. (%) Choroidal striae, no. (%) Indocyanine green angiography featuresd Areas of delayed choroidal perfusion, no. (%) Early & intermediate large choroidal vessel hyperfluorescence, no. (%) Persistent small and large dark dots, no. (%) Disc hyperfluorescence, no. (%) Late choroidal hyperfluorescence, no. (%) Dark patches persisting to late phase, no. (%)
42.10 (23.70 to 77.20) 4.20 (1.70 to 13.40) 5 (38.5) 10 (76.9) 13 (100.0) 17 eyes 8 (72.7) 1 (20.0) 10 (76.9) 11 (84.6) 15 (88.2) 9 (52.9) 11 (64.7) 3 (17.6) 11 (64.7) 8 eyes 8 (100.0)
35.50 (15.70 to 68.30) 2.50 (0.90 to 7.30) 6 (40.0) 9 (60.0) 8 (53.3) 17 eyes 9 (64.3) 4 (57.1) 11 (84.6) 4 (26.7) 13 (76.5) 9 (52.9) 9 (52.9) 0 (0.0) 9 (52.9) 13 eyes 13 (100.0)
.9a .007a ⬎.99b .30b .003b
8 (100.0) 8 (100.0) 4 (50.0) 7 (87.5) 8 (100.0)
13 (100.0) 12 (92.3) 4 (30.8) 7 (53.8) 10 (76.9)
⬎.99b .30b ⬎.99b .002b .70b ⬎.99b .50b .20b .50b ⬎.99b ⬎.99b ⬎.99b .70b .20b .30b
a
Mann-Whitney test. test. c Only right eye of patients with simultaneous onset is included. d Only 1 eye per patient is analyzed. b 2
Pinpoint peripapillary hyperfluorescence was found to be a significant risk factor on multivariate analysis controlling for age at onset, gender, and duration of follow-up (odds ratio 0.049, 95% confidence interval 0.005 to 0.53) (Table 3). The variance inflation factor for treatment group and peripapillary hyperfluorescence was 1.26. As none of the observed subjects in the LH treatment group had complete resolution of their disease, we were unable to perform a logistic model that included and estimated treatment group effect. Comparison of the features of the angiograms acquired within 14 days of onset of symptoms and those acquired after 14 days showed that pinpoint peripapillary hyperfluorescence and late pooling of fluorescein were more likely to be seen when the FAs were acquired earlier (Figure, Table 4). Persistent dark patches were more commonly encountered in the ICGAs done within 2 weeks than those done after 2 weeks of onset of the disease.
TABLE 3. Adjusted Multivariate Model of Prognostic Factors for Developing Chronic Vogt-Koyanagi-Harada Disease
Prognostic Factor
Age at onset (years) Male sex Pinpoint peripapillary hyperfluorescence Duration of follow-up (years)
Standard Error
Odds Ratio
95% Confidence Interval
P
0.93 to 1.17 0.12 to 25.20
.49 .68
0.059 1.36
1.04 1.76
1.21
0.049
0.005 to 0.53
.013
0.20
0.72
0.48 to 1.07
.11
On univariate analysis, the only FA feature that was significantly associated with disease outcome was the presence of pinpoint peripapillary hyperfluorescence (P ⫽ .002, 2 test) (Table 2). None of the ICGA features were found to be significant prognostic factors. Patients who received EH doses of corticosteroids were more likely to have complete resolution of their disease (65.4%) as compared to those who received LH steroids (0.0%, P ⫽ .003, 2 test). Patients with acute resolved disease were more likely to have a longer follow-up period than those with chronic disease (P ⫽ .007, Mann-Whitney test). 890
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DISCUSSION ANGIOGRAPHY IS WIDELY USED IN THE MANAGEMENT OF
VKH. FA findings are in fact 1 of the diagnostic criteria for VKH and ICGA is especially useful during follow-up to detect subclinical recurrence and persistence of disOF
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FIGURE. Fluorescein Angiography (FA) features by time of onset in Vogt-Koyanagi-Harada disease. FA done 16 days after onset of symptoms shows (Top left) disc hyperfluorescence and (Top right) inferior exudative retinal detachment with no pinpoint hyperfluorescence. FA done 4 days after onset of symptoms shows (Bottom left) disc hyperfluorescence and leakage with multiple pinpoint hyperfluorescence in the peripapillary region and around the fovea at 38 seconds. (Bottom right) FA of the same eye shows pooling within neurosensory retinal detachments at 10 minutes 41 seconds.
ease.19,20 Therefore, we explored the potential prognostic value of both angiographic modalities and we were expecting that ICGA would be the more valuable tool, as VKH is a choroidal disease. However, none of the ICGA signs were found to be significant prognostic factors, perhaps because nearly all cases had similar ICGA findings when active, whether or not they were destined to develop chronic disease. Pretreatment FA, on the other hand, was found to be a useful prognostic tool. During the initial phases of inflammation in VKH, the choroidal vessels become dilated and leak fluid, especially around the posterior pole, as shown on ICGA.19 The inflammation subsequently spreads to involve the retinal pigment epithelium around the peripapillary region and macula, which manifests as early pinpoint peripapillary hyperfluorescence on FA. Clinically, the juxtapapillary choroid is 1 of the sites of the most severe inflammation, which is supported by histopathologic studies21 and also by the fact that peripapillary atrophy is a common feature observed in eyes with chronic disease.22 Hence, although pinpoint hyperfluorescence at the peripapillary region has not hitherto been studied as a separate entity apart from pinpoint hyperfluorescence elsewhere, we propose that this is a useful sign that deserves special attention. In fact, pinpoint peripapillary hyperfluorescence VOL. 150, NO. 6
was more frequently seen in the eyes that resolved (85% [11/13]) than in eyes that developed chronic disease (27% [4/15]) (P ⫽ .002, 2 test). Pinpoint peripapillary hyperfluorescence was also more likely to be seen in the eyes that were imaged early in the course of the disease (67% [14/20]) as compared to the eyes that were imaged later in the course of the disease (14% [1/7]) (P ⫽ .03, 2 test). Given that this is a referral population, it is unclear whether the eyes that were imaged later in the course of the disease could previously have resembled the eyes that were imaged early in the course of the disease, or whether many of these eyes never had the feature and were following a different inflammatory course from onset. Nevertheless, our results suggest that eyes that demonstrate this feature and are treated with high-dose corticosteroids often experience disease remission. In contrast, early pinpoint hyperfluorescence at any location was a nonspecific sign. As the inflammation progresses, contiguous retinal pigment epithelial inflammation allows the dye to leak and accumulate in the subretinal space over the posterior pole. This is subsequently imaged as late pooling of fluorescein, which is seen in only 25% (2/8) of eyes after 2 weeks but was present in 69% (18/26) of eyes presenting earlier (P ⫽ .04, 2 test). This indicates that after 2 weeks, the hyperpermeable exudative phase of the choroidal inflammation can resolve both clinically and on FA, even without treatment, as has been observed. However, as shown by the ICGA, choroidal inflammation is still ongoing at this phase of the disease, which accounts for the progression of chorioretinal changes, even in some of the apparently adequately treated eyes.23,24 Our FA findings are supported by similar findings in a study of 410 VKH patients by Yang and associates, who found that patients presenting within 2 weeks of symptoms revealed early punctuate staining and late subretinal pooling in all eyes, but those presenting between 2 weeks and 2 months had subretinal pooling in only 47.7% of eyes and disc hyperfluorescence in 63.9%. In eyes whose presentation exceeded 2 months, window defects were the most common feature, seen in 96.9% of patients.25 There is no well-defined critical value for a large variance inflation factor; however, a value of 5 of more is generally taken to indicate multicollinearity.26 Thus the value of 1.26 for treatment group and peripapillary hyperfluorescence suggests that there is no multicollinearity in our regression model. Of even greater importance, the marked difference in the likelihood of pinpoint peripapillary hyperfluorescence being present in early cases versus later cases may help explain why clinical studies have found a better outcome in eyes that were treated early.8,22,27 Hence, eyes that do not show significant early pinpoint peripapillary leaks and late pooling of dye should perhaps be maintained at a higher dose of immunosuppressants and for a longer period than currently recommended. The ophthalmologist may hence wish to introduce steroid-sparing agents early
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TABLE 4. Comparison of Fluorescein and Indocyanine Green Angiographic Features Seen Within 14 Days Versus More Than 14 Days of Onset, in Eyes With Vogt-Koyanagi-Harada Disease Imaging ⱕ14 Days
Risk Factor b
Fluorescein angiography features Early patchy choroidal filling, no. (%) Areas of choroidal nonperfusion, no. (%) Early pinpoint hyperfluorescence, no. (%) Pinpoint peripapillary hyperfluorescence, no. (%) Disc hyperfluorescence, no. (%) Disc leakage, no. (%) Late pooling of fluorescein, no. (%) Late choroidal hyperfluorescence, no. (%) Choroidal striae, no. (%) Indocyanine green angiography featuresc Areas of delayed choroidal perfusion, no. (%) Early & intermediate large choroidal vessel hyperfluorescence, no. (%). Persistent small and large dark dots, no. (%) Disc hyperfluorescence, no. (%) Late choroidal hyperfluorescence, no. (%) Dark patches persisting to late phase, no. (%)
Imaging ⬎14 Days
Pa
26 eyes 13 (72.2) 5 (45.5) 17 (85.0) 14 (66.7)
8 eyes 4 (57.1) 0 (0.0) 4 (66.7) 1 (14.3)
21 (80.8) 12 (46.2) 18 (69.2) 3 (11.5) 17 (65.4) 13 eyes 13 (100.0)
7 (87.5) 6 (75.0) 2 (25.0) 0 (0.0) 3 (37.5) 8 eyes 8 (100.0)
⬎.99
13 (100.0) 13 (100.0) 5 (38.5) 11 (84.6) 13 (100.0)
8 (100.0) 7 (87.5) 3 (37.5) 3 (37.5) 5 (62.5)
⬎.99 .40 ⬎.99 .06 .04
.60 ⬎.99 .60 .03 ⬎.99 .20 .04 ⬎.99 .20
test. Only right eye of patients with simultaneous onset is included. c Only 1 eye per patient is analyzed. a 2 b
in the course of treatment,13 so as to avoid the sequelae of long-term high-dose corticosteroid therapy. The duration of therapy may be further guided by ICGA monitoring.19,20,23 The difference in duration of follow-up between patients with acute resolved disease and chronic disease is partly attributable to the required minimum period of 18 months for a patient to be defined to have acute resolved disease. Despite the limitations of a small sample size and the retrospective nature, we feel that our study results are significant and contribute substantially to our understanding of VKH and have important clinical and management
implications. In conclusion, the absence of early pinpoint peripapillary hyperfluorescence on FA is a poor prognostic factor as it suggests that the disease is no longer in the hyperacute phase, and hence it may possibly need to be treated more aggressively and with a more prolonged course of immunosuppressive therapy. FA is thus not only useful for the diagnosis of VKH, but it also has value as a prognostic tool. Although ICGA is useful for monitoring for residual or recurrent inflammation following treatment,19,20,23 pretreatment ICGA is of limited prognostic value.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN OF THE STUDY (S.P.C.); conduct of the study (S.P.C.); collection (A.J., C.M.G.C., S.P.C.), management (S.P.C.), analysis (A.J., C.M.G.C., S.P.C.), and interpretation of the data (A.J., C.M.G.C., S.P.C.); and preparation (A.J., C.M.G.C., S.P.C.) and review or approval of the manuscript (A.J., C.M.G.C., S.P.C.). The study was approved by the Institutional Review Board of the Singapore Eye Research Institute and conducted in compliance with its requirements.
Harada disease recognize human melanocyte antigens. Invest Ophthalmol Vis Sci 2006;47(6):2547– 2554. 4. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada Syndrome. Surv Ophthalmol 1995;39(4):265–292. 5. Beniz J, Forster DJ, Lean JS, Smith RE, Rao NA. Variations in the clinical features of the Vogt-Koyanagi-Harada syndrome. Retina 1991;11(3):275–280. 6. Goto H, Rao NA. Sympathetic ophthalmia and VogtKoyanagi-Harada syndrome. Int Ophthalmol Clin 1990; 30(4):279 –285.
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7. Rubsamen PE, Gass JDM. Vogt-Koyanagi-Harada syndrome: clinical course, therapy, and long-term visual outcome. Arch Ophthalmol 1991;109(5):682– 687. 8. Sheu S-J, Kou H-K, Chen J-F. Prognostic factors for VogtKoyanagi-Harada Disease. J Chin Med Assoc 2003;66(3): 148 –154. 9. Sasamoto Y, Ohno S, Matsuda H. Studies on corticosteroid therapy in Vogt-Koyanagi-Harada Disease. Ophthalmologica 1990;201(3):162–167. 10. Keino H, Goto H, Usui M. Sunset glow fundus in VogtKoyanagi-Harada disease with or without chronic ocular inflammation. Graefes Arch Clin Exp Ophthalmol 2002; 240(10):878 – 882. 11. Chee SP, Jap A, Bacsal K. Prognostic factors of VogtKoyanagi-Harada disease in Singapore. Am J Ophthalmol 2009;147(1):154 –161. 12. Chee SP, Jap A, Bacsal K. Spectrum of Vogt-KoyanagiHarada disease in Singapore. Int Ophthalmol 2007;27(2–3): 137–142. 13. Bykhovskaya I, Thorne JE, Kempen JH, Dunn JP, Jabs DA. Vogt-Koyanagi-Harada disease: clinical outcomes. Am J Ophthalmol 2005;140(4):674 – 678. 14. Ohno S, Minakawa, Matsuda H. Clinical studies of VogtKoyanagi-Harada’s disease. Jpn J Ophthalmol 1988;32(3): 334 –343. 15. Read RW, Rechodouni A, Butani N, et al. Complications and prognostic factors in Vogt-Koyanagi-Harada Disease. Am J Ophthalmol 2001;131(5):599 – 606. 16. Al-Kharashi AS, Aldibhi H, Al-Fraykh H, Kangave D, Abu El-Asrar AM. Prognostic factors in Vogt-Koyanagi-Harada disease. Int Ophthalmol 2007;27(2–3):201–210. 17. 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(5):647– 652.
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18. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140(3):509 –516. 19. Bouchenaki N, Herbort CP. The contribution of indocyanine green angiography to the appraisal and management of Vogt-Koyanagi-Harada disease. Ophthalmology 2001;108(1): 54 – 64. 20. Herbort CPH, Mantovani A, Bouchenaki N. Indocyanine green angiography in Vogt-Koyanagi-Harada disease: angiographic signs and utility in patient follow-up. Int Ophthalmol 2007;27(2–3):173–182. 21. Rao NA. Pathology of Vogt-Koyanagi Harada disease. Int Ophthalmol 2007;27(2–3):81– 85. 22. Jap A, Luu CD, Yeo I, Chee SP. Correlation between peripapillary atrophy and corticosteroid therapy in patient with Vogt-Koyanagi-Harada disease. Eye 2008;22(2):240 – 245. 23. Kawaguchi T, Horie S, Bouchenaki N, Ohno-Matsui K, Mochizuki M, Herbort CP. Suboptimal therapy controls clinically apparent disease but not subclinical progression of Vogt-Koyanagi-Harada disease. Int Ophthalmol 2010;30(1): 41–50. 24. Suzuki S. Quantitative evaluation of “Sunset Glow” fundus in Vogt-Koyanagi-Harada Disease. Jpn J Ophthalmol 1999; 43(4):327–333. 25. Yang P, Ren Y, Li B, Fang W, Meng Q, Kijlstra A. Clinical characteristics of Vogt-Koyanagi-Harada syndrome in Chinese patients. Ophthalmology 2007;114(3):606 – 614. 26. O’Brien RM. A caution regarding rules of thumb for variance inflation factors. Qual Quant 2007;41(5):673– 690. 27. Fujioka T, Fukuda M, Okinami S. A statistic study of Vogt-Koyanagi-Harada syndrome. Nippon Ganka Gakkai Zasshi 1980;84(11):1979 –1982.
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Biosketch Soon-Phaik Chee graduated from the National University of Singapore and became a Fellow of the Royal College of Ophthalmologists in 1990. She did her ocular inflammation fellowship in Moorfields Eye Hospital, UK. She is currently the Senior Consultant and Head of the Ocular Inflammation and Immnology Service at the Singapore National Eye Centre, and the Associate Professor, Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore.
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To determine the prognostic value of fluorescein angiography (FA) and indocyanine green angiography (ICGA) in Vogt-Koyanagi-Harada disease (VKH). ● DESIGN: Retrospective noninterventional study. ● METHODS: Chart, FA, and ICGA review of VKH patients of Singapore National Eye Centre for age at onset, gender, race, timing of treatment, and angiographic features during the different phases of FA and ICGA. Outcome measure was disease outcome (acute resolved or chronic recurrent). ● RESULTS: Twenty-one of the 28 patients with pretreatment FA also had ICGA. Median follow-up duration was 3.6 years (range 0.94 –13.42 years). Median age was 42.2 years (range 15.7–77.2 years). The majority (18, 64.3%) were Chinese. The most frequently observed FA features included early pinpoint hyperfluorescence in the posterior pole and disc hyperfluorescence. Large choroidal vessel hyperfluorescence (early and intermediate phase), areas of delayed choroidal perfusion (early phase), and persistent dark dots were the 3 most common ICGA features. Pinpoint peripapillary hyperfluorescence was found to be a significant prognostic FA factor on both univariate and multivariate analysis. None of the ICGA features were found to be significant prognostic factors. ● CONCLUSION: Early pinpoint peripapillary hyperfluorescence on pretreatment FA is a useful prognostic sign in VKH patients, whereas pretreatment ICGA has limited prognostic value. (Am J Ophthalmol 2010;150: 888 – 893. © 2010 by Elsevier Inc. All rights reserved.)
V
OGT-KOYANAGI-HARADA DISEASE (VKH) IS A T-CELL-
mediated autoimmune disease1–3 directed against antigens found on or associated with melanocytes. It presents acutely, and during the prodromal phase, auditory and central nervous system manifestations may precede the acute uveitic phase. During the acute phase, bilateral panuveitis with choroiditis and exudative detachments are seen. In patients who develop chronic recurrent
Accepted for publication Jun 23, 2010. From Singapore National Eye Centre, Singapore (S.P.C., A.J., C.M.G.C.); the Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (S.P.C.); Singapore Eye Research Institute, Singapore (S.P.C., C.M.G.C.); and the Division of Ophthalmology, Changi General Hospital, Singapore (A.J.). Inquiries to Soon-Phaik Chee, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; e-mail: chee.soon.phaik@ snec.com.sg
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uveitis, vitiligo and poliosis may also occur.4 Patients who receive adequate doses of corticosteroids soon after the onset of disease often have rapid resolution of the ocular and systemic manifestations, with good visual outcomes.4 –11 However, chronic disease may develop in over half of these patients,12 with consequent complications such as cataract, glaucoma, subretinal fibrosis, choroidal neovascular membranes, and chorioretinal atrophy, resulting in visual loss over the years. The introduction of immunomodulatory therapy in severe disease, however, holds promise of arresting the chronic inflammation and preserving vision in patients with relentless disease.13 The initial visual acuity (VA) has been found to be an important predictive factor of the visual outcome.14 –16 We investigated the early prognostic factors and found that good VA at 1 month, younger age at onset, and early treatment with high-dose corticosteroids were associated with better outcomes.11 In this paper, we studied the value of fluorescein angiography (FA) and indocyanine green angiography (ICGA), performed during the acute uveitic phase, to try to identify potential prognostic features for the disease outcome that could be used to guide the ophthalmologist in the strategy of immunotherapy.
METHODS WE RETROSPECTIVELY REVIEWED THE CASE RECORDS OF
all VKH patients seen in the Singapore National Eye Centre uveitis clinic. The diagnosis was made based on the VKH International Committee criteria published in 2001.17 We only included patients who had received at least 1 mg/kg prednisolone tapered over a minimum of 6 months (high-dose steroid) and who had angiograms done before initiating treatment. The treatment group was defined as early high (EH) if the patient received the therapy 2 weeks or less following onset of ocular symptoms, and late high (LH) if treatment was started after 2 weeks up to 1 month after ocular symptoms. The outcome of treatment was defined according to standard nomenclature18 as acute resolved or chronic/chronic persistent or recurrent disease according to the status of inflammation at 3 months post onset of disease. Eyes with less than 18 months of follow-up were excluded unless they had developed features of chronic disease earlier. Data were collected on patient demographics, bestcorrected visual acuity (BCVA), the clinical course of
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disease (acute resolved or chronic recurrent), timing, and mode of therapy. A masked investigator (C.M.G.C.) read all the FAs and ICGAs of these eyes, which had been done during acute phase before initiation of treatment. In view of the fact that both eyes of cases with bilateral simultaneous onset tend to have similar features, in patients where there was less than 48 hours difference in onset of symptoms between the 2 eyes, the FA of only 1 eye was analyzed so as to minimize the risk of correlation between eyes. The right eye was selected as this is the eye that was imaged first by convention in patients with simultaneous onset. Similarly, only the ICGA of the eye that was imaged first was analyzed. The FA and ICGA were performed using the Topcon 50 IA camera (Tokyo, Japan) coupled to an Imagenet (Topcon) image digitalizing system. A standard protocol was used. After injection of 2 mL of fluorescein 20%, early frames concentrating on the posterior pole were acquired up to 40 seconds. Mid-phase frames of the posterior pole and 4 quadrants were captured between 1 and 3 minutes, and late-phase images at 10 minutes after fluorescein injection. This was followed by a bolus injection of 50 mg of indocyanine green in 4 mL of normal saline. ICGA frames were captured at close intervals for the first 2 to 3 minutes (early phase). The intermediate phase was captured 10 to 15 minutes after dye injection and the late phase at 30 to 40 minutes. ● FLUORESCEIN ANGIOGRAM: The features studied included patchy choroidal filling persisting for more than 2 to 3 seconds in the early frames, areas of delayed choroidal nonperfusion in early frames, early pinpoint hyperfluorescence, pinpoint peripapillary hyperfluorescence, disc hyperfluorescence, disc leakage, late pooling of fluorescein, late choroidal hyperfluorescence, and choroidal striae. ● INDOCYANINE GREEN ANGIOGRAM: The features studied included areas of delayed choroidal perfusion, early and intermediate large choroidal vessel hyperfluorescence, persistent small and large dark dots, disc hyperfluorescence, late choroidal hyperfluorescent patches, and dark patches persisting to late phase. Statistical analysis was performed using SPSS (Version 13.0; Chicago, Illinois, USA). Univariate analysis was performed using 2 test or Mann-Whitney test as appropriate. Age, gender, and other significant univariate risk factors were included in the multivariate logistic regression model for outcome of VKH disease; statistical significance was defined as P ⬍ .05.
RESULTS ONE HUNDRED THREE PATIENTS DIAGNOSED WITH VKH
were seen in the uveitis clinic from February 1, 1994 to February 29, 2008. This group includes patients who had been followed up since the 1970s when FAs were not VOL. 150, NO. 6
TABLE 1. Frequencies of Pretreatment Fluorescein and Indocyanine Green Angiographic Features in Eyes With Vogt-Koyanagi-Harada Disease Number of Eyes (%) a
Fluorescein angiography features Early patchy choroidal filling Areas of delayed choroidal perfusion Early pinpoint hyperfluorescence Pinpoint peripapillary hyperfluorescence Disc hyperfluorescence Disc leakage Late pooling of fluorescein Late choroidal hyperfluorescence Choroidal striae Indocyanine green angiography featuresb Areas of delayed choroidal perfusion Early & intermediate large choroidal vessel hyperfluorescence Persistent small and large dark dots Disc hyperfluorescence Late choroidal hyperfluorescence Dark patches persisting to late phase
17 (68.0) 5 (41.7) 21 (80.8) 15 (53.6) 28 (82.4) 18 (52.9) 20 (58.8) 3 (8.8) 20 (58.8) 21 (100.0) 21 (100.0) 20 (95.2) 8 (38.1) 14 (66.7) 18 (85.7)
a
Only right eye of patients with simultaneous onset is included. b Only 1 eye per patient is analyzed.
routinely done. Being a tertiary referral clinic, some of the patients had been referred from other eye specialists and the majority of the referred patients did not receive high-dose steroids, nor did they have FAs done within the first 1 month of onset of symptoms. Hence there were only 28 eligible patients, and 21 of these 28 patients (42 eyes) also had pretreatment ICGA. There were 13 male and 15 female patients whose median age was 42.2 years (range 15.7-77.2 years). Eighteen were Chinese, 6 were Malay, 2 were Indian, and 2 were classified as “other,” similar to the racial distribution of our population. The median duration of follow-up was 3.6 years (range 0.94-13.42 years). The disease outcome was categorized as acute resolved in 26 eyes and chronic in 30 eyes. Twenty-two patients had less than 48 hours difference from onset of symptoms to FA between the 2 eyes. Of the remaining 6 patients, the median interval between the 2 eyes was 3.5 days, with a range of 3 to 9 days. On FA the most commonly seen features (Table 1) were early pinpoint hyperfluorescence in the posterior pole and disc hyperfluorescence. On ICGA, large choroidal vessel hyperfluorescence and fuzziness in the early and intermediate phase, and areas of delayed choroidal perfusion in the early phase, were seen in all the eyes. Other common findings included persistent small and large dark dots and dark patches persisting to the late phase.
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TABLE 2. Demographic and Angiographic Prognostic Factors for Developing Chronic Vogt-Koyanagi-Harada Disease Risk Factor
Acute Resolved (13 Patients)
Chronic Disease (15 Patients)
P
Median age of onset in years (range) Median duration follow-up in years (range) Male sex, no. (%) Chinese race, no. (%) Early high treatment, no. (%) Fluorescein angiography featuresc Early patchy choroidal filling, no. (%) Areas of delayed choroidal perfusion, no. (%) Early pinpoint hyperfluorescence, no. (%) Pinpoint peripapillary hyperfluorescence, no. (%) Disc hyperfluorescence, no. (%) Disc leakage, no. (%) Late pooling of fluorescein, no. (%) Late choroidal hyperfluorescence, no. (%) Choroidal striae, no. (%) Indocyanine green angiography featuresd Areas of delayed choroidal perfusion, no. (%) Early & intermediate large choroidal vessel hyperfluorescence, no. (%) Persistent small and large dark dots, no. (%) Disc hyperfluorescence, no. (%) Late choroidal hyperfluorescence, no. (%) Dark patches persisting to late phase, no. (%)
42.10 (23.70 to 77.20) 4.20 (1.70 to 13.40) 5 (38.5) 10 (76.9) 13 (100.0) 17 eyes 8 (72.7) 1 (20.0) 10 (76.9) 11 (84.6) 15 (88.2) 9 (52.9) 11 (64.7) 3 (17.6) 11 (64.7) 8 eyes 8 (100.0)
35.50 (15.70 to 68.30) 2.50 (0.90 to 7.30) 6 (40.0) 9 (60.0) 8 (53.3) 17 eyes 9 (64.3) 4 (57.1) 11 (84.6) 4 (26.7) 13 (76.5) 9 (52.9) 9 (52.9) 0 (0.0) 9 (52.9) 13 eyes 13 (100.0)
.9a .007a ⬎.99b .30b .003b
8 (100.0) 8 (100.0) 4 (50.0) 7 (87.5) 8 (100.0)
13 (100.0) 12 (92.3) 4 (30.8) 7 (53.8) 10 (76.9)
⬎.99b .30b ⬎.99b .002b .70b ⬎.99b .50b .20b .50b ⬎.99b ⬎.99b ⬎.99b .70b .20b .30b
a
Mann-Whitney test. test. c Only right eye of patients with simultaneous onset is included. d Only 1 eye per patient is analyzed. b 2
Pinpoint peripapillary hyperfluorescence was found to be a significant risk factor on multivariate analysis controlling for age at onset, gender, and duration of follow-up (odds ratio 0.049, 95% confidence interval 0.005 to 0.53) (Table 3). The variance inflation factor for treatment group and peripapillary hyperfluorescence was 1.26. As none of the observed subjects in the LH treatment group had complete resolution of their disease, we were unable to perform a logistic model that included and estimated treatment group effect. Comparison of the features of the angiograms acquired within 14 days of onset of symptoms and those acquired after 14 days showed that pinpoint peripapillary hyperfluorescence and late pooling of fluorescein were more likely to be seen when the FAs were acquired earlier (Figure, Table 4). Persistent dark patches were more commonly encountered in the ICGAs done within 2 weeks than those done after 2 weeks of onset of the disease.
TABLE 3. Adjusted Multivariate Model of Prognostic Factors for Developing Chronic Vogt-Koyanagi-Harada Disease
Prognostic Factor
Age at onset (years) Male sex Pinpoint peripapillary hyperfluorescence Duration of follow-up (years)
Standard Error
Odds Ratio
95% Confidence Interval
P
0.93 to 1.17 0.12 to 25.20
.49 .68
0.059 1.36
1.04 1.76
1.21
0.049
0.005 to 0.53
.013
0.20
0.72
0.48 to 1.07
.11
On univariate analysis, the only FA feature that was significantly associated with disease outcome was the presence of pinpoint peripapillary hyperfluorescence (P ⫽ .002, 2 test) (Table 2). None of the ICGA features were found to be significant prognostic factors. Patients who received EH doses of corticosteroids were more likely to have complete resolution of their disease (65.4%) as compared to those who received LH steroids (0.0%, P ⫽ .003, 2 test). Patients with acute resolved disease were more likely to have a longer follow-up period than those with chronic disease (P ⫽ .007, Mann-Whitney test). 890
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DISCUSSION ANGIOGRAPHY IS WIDELY USED IN THE MANAGEMENT OF
VKH. FA findings are in fact 1 of the diagnostic criteria for VKH and ICGA is especially useful during follow-up to detect subclinical recurrence and persistence of disOF
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FIGURE. Fluorescein Angiography (FA) features by time of onset in Vogt-Koyanagi-Harada disease. FA done 16 days after onset of symptoms shows (Top left) disc hyperfluorescence and (Top right) inferior exudative retinal detachment with no pinpoint hyperfluorescence. FA done 4 days after onset of symptoms shows (Bottom left) disc hyperfluorescence and leakage with multiple pinpoint hyperfluorescence in the peripapillary region and around the fovea at 38 seconds. (Bottom right) FA of the same eye shows pooling within neurosensory retinal detachments at 10 minutes 41 seconds.
ease.19,20 Therefore, we explored the potential prognostic value of both angiographic modalities and we were expecting that ICGA would be the more valuable tool, as VKH is a choroidal disease. However, none of the ICGA signs were found to be significant prognostic factors, perhaps because nearly all cases had similar ICGA findings when active, whether or not they were destined to develop chronic disease. Pretreatment FA, on the other hand, was found to be a useful prognostic tool. During the initial phases of inflammation in VKH, the choroidal vessels become dilated and leak fluid, especially around the posterior pole, as shown on ICGA.19 The inflammation subsequently spreads to involve the retinal pigment epithelium around the peripapillary region and macula, which manifests as early pinpoint peripapillary hyperfluorescence on FA. Clinically, the juxtapapillary choroid is 1 of the sites of the most severe inflammation, which is supported by histopathologic studies21 and also by the fact that peripapillary atrophy is a common feature observed in eyes with chronic disease.22 Hence, although pinpoint hyperfluorescence at the peripapillary region has not hitherto been studied as a separate entity apart from pinpoint hyperfluorescence elsewhere, we propose that this is a useful sign that deserves special attention. In fact, pinpoint peripapillary hyperfluorescence VOL. 150, NO. 6
was more frequently seen in the eyes that resolved (85% [11/13]) than in eyes that developed chronic disease (27% [4/15]) (P ⫽ .002, 2 test). Pinpoint peripapillary hyperfluorescence was also more likely to be seen in the eyes that were imaged early in the course of the disease (67% [14/20]) as compared to the eyes that were imaged later in the course of the disease (14% [1/7]) (P ⫽ .03, 2 test). Given that this is a referral population, it is unclear whether the eyes that were imaged later in the course of the disease could previously have resembled the eyes that were imaged early in the course of the disease, or whether many of these eyes never had the feature and were following a different inflammatory course from onset. Nevertheless, our results suggest that eyes that demonstrate this feature and are treated with high-dose corticosteroids often experience disease remission. In contrast, early pinpoint hyperfluorescence at any location was a nonspecific sign. As the inflammation progresses, contiguous retinal pigment epithelial inflammation allows the dye to leak and accumulate in the subretinal space over the posterior pole. This is subsequently imaged as late pooling of fluorescein, which is seen in only 25% (2/8) of eyes after 2 weeks but was present in 69% (18/26) of eyes presenting earlier (P ⫽ .04, 2 test). This indicates that after 2 weeks, the hyperpermeable exudative phase of the choroidal inflammation can resolve both clinically and on FA, even without treatment, as has been observed. However, as shown by the ICGA, choroidal inflammation is still ongoing at this phase of the disease, which accounts for the progression of chorioretinal changes, even in some of the apparently adequately treated eyes.23,24 Our FA findings are supported by similar findings in a study of 410 VKH patients by Yang and associates, who found that patients presenting within 2 weeks of symptoms revealed early punctuate staining and late subretinal pooling in all eyes, but those presenting between 2 weeks and 2 months had subretinal pooling in only 47.7% of eyes and disc hyperfluorescence in 63.9%. In eyes whose presentation exceeded 2 months, window defects were the most common feature, seen in 96.9% of patients.25 There is no well-defined critical value for a large variance inflation factor; however, a value of 5 of more is generally taken to indicate multicollinearity.26 Thus the value of 1.26 for treatment group and peripapillary hyperfluorescence suggests that there is no multicollinearity in our regression model. Of even greater importance, the marked difference in the likelihood of pinpoint peripapillary hyperfluorescence being present in early cases versus later cases may help explain why clinical studies have found a better outcome in eyes that were treated early.8,22,27 Hence, eyes that do not show significant early pinpoint peripapillary leaks and late pooling of dye should perhaps be maintained at a higher dose of immunosuppressants and for a longer period than currently recommended. The ophthalmologist may hence wish to introduce steroid-sparing agents early
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TABLE 4. Comparison of Fluorescein and Indocyanine Green Angiographic Features Seen Within 14 Days Versus More Than 14 Days of Onset, in Eyes With Vogt-Koyanagi-Harada Disease Imaging ⱕ14 Days
Risk Factor b
Fluorescein angiography features Early patchy choroidal filling, no. (%) Areas of choroidal nonperfusion, no. (%) Early pinpoint hyperfluorescence, no. (%) Pinpoint peripapillary hyperfluorescence, no. (%) Disc hyperfluorescence, no. (%) Disc leakage, no. (%) Late pooling of fluorescein, no. (%) Late choroidal hyperfluorescence, no. (%) Choroidal striae, no. (%) Indocyanine green angiography featuresc Areas of delayed choroidal perfusion, no. (%) Early & intermediate large choroidal vessel hyperfluorescence, no. (%). Persistent small and large dark dots, no. (%) Disc hyperfluorescence, no. (%) Late choroidal hyperfluorescence, no. (%) Dark patches persisting to late phase, no. (%)
Imaging ⬎14 Days
Pa
26 eyes 13 (72.2) 5 (45.5) 17 (85.0) 14 (66.7)
8 eyes 4 (57.1) 0 (0.0) 4 (66.7) 1 (14.3)
21 (80.8) 12 (46.2) 18 (69.2) 3 (11.5) 17 (65.4) 13 eyes 13 (100.0)
7 (87.5) 6 (75.0) 2 (25.0) 0 (0.0) 3 (37.5) 8 eyes 8 (100.0)
⬎.99
13 (100.0) 13 (100.0) 5 (38.5) 11 (84.6) 13 (100.0)
8 (100.0) 7 (87.5) 3 (37.5) 3 (37.5) 5 (62.5)
⬎.99 .40 ⬎.99 .06 .04
.60 ⬎.99 .60 .03 ⬎.99 .20 .04 ⬎.99 .20
test. Only right eye of patients with simultaneous onset is included. c Only 1 eye per patient is analyzed. a 2 b
in the course of treatment,13 so as to avoid the sequelae of long-term high-dose corticosteroid therapy. The duration of therapy may be further guided by ICGA monitoring.19,20,23 The difference in duration of follow-up between patients with acute resolved disease and chronic disease is partly attributable to the required minimum period of 18 months for a patient to be defined to have acute resolved disease. Despite the limitations of a small sample size and the retrospective nature, we feel that our study results are significant and contribute substantially to our understanding of VKH and have important clinical and management
implications. In conclusion, the absence of early pinpoint peripapillary hyperfluorescence on FA is a poor prognostic factor as it suggests that the disease is no longer in the hyperacute phase, and hence it may possibly need to be treated more aggressively and with a more prolonged course of immunosuppressive therapy. FA is thus not only useful for the diagnosis of VKH, but it also has value as a prognostic tool. Although ICGA is useful for monitoring for residual or recurrent inflammation following treatment,19,20,23 pretreatment ICGA is of limited prognostic value.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN OF THE STUDY (S.P.C.); conduct of the study (S.P.C.); collection (A.J., C.M.G.C., S.P.C.), management (S.P.C.), analysis (A.J., C.M.G.C., S.P.C.), and interpretation of the data (A.J., C.M.G.C., S.P.C.); and preparation (A.J., C.M.G.C., S.P.C.) and review or approval of the manuscript (A.J., C.M.G.C., S.P.C.). The study was approved by the Institutional Review Board of the Singapore Eye Research Institute and conducted in compliance with its requirements.
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Biosketch Soon-Phaik Chee graduated from the National University of Singapore and became a Fellow of the Royal College of Ophthalmologists in 1990. She did her ocular inflammation fellowship in Moorfields Eye Hospital, UK. She is currently the Senior Consultant and Head of the Ocular Inflammation and Immnology Service at the Singapore National Eye Centre, and the Associate Professor, Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore.
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