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.
Vogt-Koyanagi-Harada disease (VKH) is a T-cell-mediated autoimmune disease 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 uveitis, vitiligo and poliosis may also occur. 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. However, chronic disease may develop in over half of these patients, 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.
The initial visual acuity (VA) has been found to be an important predictive factor of the visual outcome. 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. 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. 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 nomenclature 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, best-corrected visual acuity (BCVA), the clinical course of 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 χ 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 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.
| Number of Eyes (%) | |
|---|---|
| Fluorescein angiography features a | |
| Early patchy choroidal filling | 17 (68.0) |
| Areas of delayed choroidal perfusion | 5 (41.7) |
| Early pinpoint hyperfluorescence | 21 (80.8) |
| Pinpoint peripapillary hyperfluorescence | 15 (53.6) |
| Disc hyperfluorescence | 28 (82.4) |
| Disc leakage | 18 (52.9) |
| Late pooling of fluorescein | 20 (58.8) |
| Late choroidal hyperfluorescence | 3 (8.8) |
| Choroidal striae | 20 (58.8) |
| Indocyanine green angiography features b | |
| Areas of delayed choroidal perfusion | 21 (100.0) |
| Early & intermediate large choroidal vessel hyperfluorescence | 21 (100.0) |
| Persistent small and large dark dots | 20 (95.2) |
| Disc hyperfluorescence | 8 (38.1) |
| Late choroidal hyperfluorescence | 14 (66.7) |
| Dark patches persisting to late phase | 18 (85.7) |
a Only right eye of patients with simultaneous onset is included.
On univariate analysis, the only FA feature that was significantly associated with disease outcome was the presence of pinpoint peripapillary hyperfluorescence ( P = .002, χ 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, χ 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).
| Risk Factor | Acute Resolved (13 Patients) | Chronic Disease (15 Patients) | P |
|---|---|---|---|
| Median age of onset in years (range) | 42.10 (23.70 to 77.20) | 35.50 (15.70 to 68.30) | .9 a |
| Median duration follow-up in years (range) | 4.20 (1.70 to 13.40) | 2.50 (0.90 to 7.30) | .007 a |
| Male sex, no. (%) | 5 (38.5) | 6 (40.0) | >.99 b |
| Chinese race, no. (%) | 10 (76.9) | 9 (60.0) | .30 b |
| Early high treatment, no. (%) | 13 (100.0) | 8 (53.3) | .003 b |
| Fluorescein angiography features c | 17 eyes | 17 eyes | |
| Early patchy choroidal filling, no. (%) | 8 (72.7) | 9 (64.3) | >.99 b |
| Areas of delayed choroidal perfusion, no. (%) | 1 (20.0) | 4 (57.1) | .30 b |
| Early pinpoint hyperfluorescence, no. (%) | 10 (76.9) | 11 (84.6) | >.99 b |
| Pinpoint peripapillary hyperfluorescence, no. (%) | 11 (84.6) | 4 (26.7) | .002 b |
| Disc hyperfluorescence, no. (%) | 15 (88.2) | 13 (76.5) | .70 b |
| Disc leakage, no. (%) | 9 (52.9) | 9 (52.9) | >.99 b |
| Late pooling of fluorescein, no. (%) | 11 (64.7) | 9 (52.9) | .50 b |
| Late choroidal hyperfluorescence, no. (%) | 3 (17.6) | 0 (0.0) | .20 b |
| Choroidal striae, no. (%) | 11 (64.7) | 9 (52.9) | .50 b |
| Indocyanine green angiography features d | 8 eyes | 13 eyes | |
| Areas of delayed choroidal perfusion, no. (%) | 8 (100.0) | 13 (100.0) | >.99 b |
| Early & intermediate large choroidal vessel hyperfluorescence, no. (%) | 8 (100.0) | 13 (100.0) | >.99 b |
| Persistent small and large dark dots, no. (%) | 8 (100.0) | 12 (92.3) | >.99 b |
| Disc hyperfluorescence, no. (%) | 4 (50.0) | 4 (30.8) | .70 b |
| Late choroidal hyperfluorescence, no. (%) | 7 (87.5) | 7 (53.8) | .20 b |
| Dark patches persisting to late phase, no. (%) | 8 (100.0) | 10 (76.9) | .30 b |
c Only right eye of patients with simultaneous onset is included.
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.
| Prognostic Factor | Standard Error | Odds Ratio | 95% Confidence Interval | P |
|---|---|---|---|---|
| Age at onset (years) | 0.059 | 1.04 | 0.93 to 1.17 | .49 |
| Male sex | 1.36 | 1.76 | 0.12 to 25.20 | .68 |
| Pinpoint peripapillary hyperfluorescence | 1.21 | 0.049 | 0.005 to 0.53 | .013 |
| Duration of follow-up (years) | 0.20 | 0.72 | 0.48 to 1.07 | .11 |
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.
