Secondary glaucoma is one of the most feared complications of VKH disease. The prevalence of secondary glaucoma in VKH disease ranges from 2.6% to 45% [10, 14-16]. The chronic recurrent form of VKH disease [15, 17], significant anterior chamber reaction (> 2+) [16, 17], three or more VKH recurrences, and the presence of posterior synechiae, extraocular manifestations, and a worse VA at disease onset , are deemed as significant risk factors for secondary glaucoma development. As expected, patients who develop OHT or glaucoma have the worst visual prognosis [10, 11].
The present study findings suggest that the chronic recurrent stage, recurrent episodes of inflammation, ACD, and peripapillary atrophy are all significant risk factors for the development of glaucoma in eyes with VKH. In this cohort of 50 patients, we found a 20% prevalence of glaucoma, which is consistent with previous reports [6, 10].
Numerous mechanisms have been implicated in the development of glaucoma in VKH eyes. Traditionally, open-angle mechanisms associated with corticosteroid-induced OHT and inflammatory trabecular meshwork dysfunction have been considered the leading causes of glaucoma in VKH . However, the role of angle-closure mechanisms has gained considerable interest in uveitic glaucoma . Clinical signs of ACD are the development of peripheral anterior synechiae, complete pupillary block associated with posterior synechiae (secclusio pupillae), iris bombé configuration, and ciliary body detachment with anterior rotation of ciliary processes . In our VKH population, angle-closure was an important pathogenic mechanism in most eyes that developed glaucoma (71.4%). Chronic recurrent episodes of anterior segment inflammation are certainly a significant factor in the high prevalence of ACD. A retrospective case series of 48 VKH patients in Thailand reported glaucoma in 29% of the eyes. The authors, however, reported no association between the development of ocular complications, including glaucoma, and the stage of VKH disease at presentation and treatment modalities .
In their study, only 6/45 patients (13%) had VKH disease recurrences, all of them associated with early corticosteroid therapy withdrawal. Thus, the authors suggest that the lack of associated risk factors (i.e., chronic recurrent VKH disease) and glaucoma development might be related to long-term use of corticosteroids and/or IMT . These findings are supported by Al-Kharashi et al., who reported that rapid corticosteroid tapering, defined as 1 mg/kg of oral prednisone for less than 2 months or tapering to 10 mg in less than two months, was associated with > 3 recurrences. Moreover, the authors reported that multiple recurrences were significantly associated with a higher incidence of glaucoma development .
The optimal management of acute VKH with a combination of a corticosteroid and a nonsteroidal immunosuppressive agent is critical for avoiding disease progression to the chronic recurrent phase, which may occur in up to two-thirds of patients . Impending disease progression can only be possible if prompt and adequate treatment is started within three weeks of symptoms onset . In the present study, the time interval between symptoms onset and the first consultation was longer (23 months) in the glaucoma group than in eyes without glaucoma (one month). This finding demonstrates that glaucoma development is related to chronic disease progression, which is more refractory to treatment and requires prolonged anti-inflammatory treatment. The high prevalence of vitiligo in the glaucoma group could be related to the chronic recurrent phase at presentation. VKH Hispanic patients usually present without extraocular changes, developing once they evolve into a chronic disease . The survival analysis shows a clear difference between VKH phases, where none of the eyes developed glaucoma in the first and second year of follow up probably related to adequate anti-inflammatory treatment. The survival analysis highlights the importance of the VKH phase at presentation. In eyes presented in the uveitic stage, only 22.1% developed glaucoma in a 5-year follow-up. In contrast, in the eyes in the chronic recurrent stage, the same incidence of glaucoma was found in the first year of follow-up.
Regarding anterior segment inflammation, our findings are consistent with previous reports of severity of anterior chamber reaction (≥ +2 cells) and more than two recurrences of inflammation as risk factors for glaucoma development in VKH [10, 11]. Chronic inflammation requires prolonged and repeated corticosteroid administration. In the present study, patients with VKH who received oral prednisone for more than 24 months and/or topical corticosteroids for more than 12 months had a nine-fold and four-fold increased risk of developing glaucoma during the follow-up time. The correlation of peripapillary atrophy (PPA) as a risk factor for glaucoma in VKH can be related to corticosteroid use. There is evidence that the development of PPA is dependent on exposure to high doses of systemic corticosteroids . Moreover, the development of PPA is significantly associated with an increased risk of either cataract, glaucoma, or subretinal neovascular membrane formation . In our study, PPA has been deemed a significant risk factor for glaucoma development (RR 3.56 95% CI 1.43 – 8.85, p<0.001), and as stated above, glaucoma development was associated with prolonged topical and systemic corticosteroid exposure. Thus, recognizing that oral prednisone exposure might represent a modifiable risk factor for the development of glaucoma emphasizes the critical role of early IMT. Urzua et al. reported that the chronic-recurrent form of VKH disease, a VA < 20/200, tinnitus, and the presence of SGF at presentation were risk factors for poor glucocorticoid response, which the authors defined as (1) persistent retinal detachment and (2) absence of visual and (3) inflammatory improvement . The authors reported no significant differences in VA improvement or reduced risk of ocular complications (i.e., glaucoma, OHT, cataract) in patients with or without early IMT (<6 weeks). However, they found a significant improvement in VA in eyes unresponsive to oral corticosteroids receiving early IMT (p=0.04) . Moreover, authors describe that delaying IMT in patients with initial SGF (4.4 vs. 12.3 months, p=0.02) or chronic-recurrent disease (6.5 vs. 14.5 months, p=0.01) was associated with a reduced improvement in VA . Similar findings were described by El-Asrar et al., who reported that the use of IMT was significantly associated with a reduced risk of SGF and that SGF was associated with the development of ocular complications, including glaucoma, cataract, and subretinal neovascular membrane formation . However, when analyzing glaucoma alone, the authors found no significant differences in the occurrence of secondary glaucoma in acute (p=0.227) and/or chronic-recurrent (p=0.241) VKH patients receiving IMT .
Choroidal depigmentation, the so-called “sunset glow fundus”, is the loss of choroidal melanocytes after inflammatory T-cell infiltration that develops during the convalescent stage of VKH disease, typically 2 to 6 months after onset [5, 7, 24]. SGF was previously considered part of the “natural course” of VKH disease; however, it is currently a marker of ongoing choroidal inflammation . As with glaucoma development, the presence of SGF is highly associated with the chronic-recurrent form of VKH disease . In our study, we found a significantly higher prevalence of SGF in eyes with glaucoma at the initial (p=0.002) and final (p=0.031) visits. However, the presence of SGF failed to reach statistical significance as a risk factor for secondary glaucoma development (RR 2.53 95% CI 0.99 – 6.49, p=0.08). Concerning the development of glaucoma, we also failed to demonstrate a reduced risk of occurrence in patients receiving early IMT (RR 0.40, 95% CI 0.12-1.30, p=0.183). In the present study, three hypotheses could explain why early IMT did not confer a reduced risk of secondary glaucoma development. First, the duration of immunosuppression might have been inadequate. El-Asrar et al. reported a prevalence of glaucoma and SGF of 2.6% and 0%, respectively, in 76 eyes (38 patients) with initial-onset acute VKH disease who were initially managed with aggressive immunosuppression, including mycophenolate mofetil (MMF, 2g daily) and high-dose systemic corticosteroids (1 mg/kg/day). Steroids were maintained for three weeks and subsequently tapered 10 mg every two weeks until a 40 mg daily dose was reached. Next, prednisone was tapered 5 mg until 5-10 mg was reached. The median duration of oral prednisone and MMF was 17.5 (range: 10 – 34) and 20.2 (9 – 34) months, respectively . In our study, the median duration of oral prednisone was 14 months (range: 8 – 45) and, at 12-months follow-up, only 32 patients (80%, 64 eyes) were still under IMT. Moreover, the median dose of oral prednisone at baseline was 50 mg (range: 5 – 120), at one month 30 mg (range: 5 – 100), and at 3 months 10 mg (range: 0 – 60). Although all patients received IMT at the first visit, dosing of systemic steroids might have been insufficient. Aggressive and sustained immunosuppression at the acute phase of VKH disease might result in a reduced progression to chronic-recurrent VKH, thus, a lower risk of developing ocular complications, including SGF and glaucoma .
Second, a significant number of eyes within our cohort were at the chronic-recurrent stage of VKH disease. In our study, all eyes were initially managed with IMT. Despite the latter, and after excluding 4 eyes with a previous diagnosis of glaucoma, 16 eyes developed glaucoma during follow-up. Of those, 43% vs. 17% non-glaucoma eyes were at the chronic-recurrent phase of the disease (RR 2.88 95% CI 1.11 – 12.63, p=0.037). Our results are consistent with other studies reporting an increased risk of secondary glaucoma in patients with chronic-recurrent VKH disease [15, 17].
Finally, the retrospective nature of the study design, the number of patients included, along the fact that not all clinical and therapeutic risk factors for glaucoma were considered for analysis precluded us from drawing definitive conclusions about our findings. Also, the selection bias of Hispanic patients with a usually larger proportion of severe and advanced disease referred to tertiary referral centers may not represent the general population of VKH disease in Mexico. Nevertheless, our findings are valuable, showing related to ethnic and environmental factors that can further influence the response to anti-inflammatory treatment and the development of glaucoma.
The main risk factors for glaucoma development in the present study were the chronic recurrent stage of the disease at presentation, more than two recurrences of inflammation during the follow-up time, ACD, and prolonged exposure to oral and topical corticosteroids. These findings have important implications for the clinical management of VKH patients. Prompt and combined systemic corticosteroid and IMT for active disease, detecting early manifestations of angle-closure, and limiting topical and oral corticosteroid exposure are crucial to reducing ocular complications and secondary glaucoma development in patients with VKH disease. The recognition of glaucoma as a prominent complication of chronic progressive disease could eventually encourage adequate inflammatory control to prevent a poor visual outcome.