Proliferative retinopathy as a feature of Vogt Koyanagi Harada Disease: a report of two cases

Vogt–Koyanagi–Harada (VKH) disease is a bilateral granulomatous panuveitis which leads to exudative retinal detachments (ERD) [1]. Extraocular manifestations of VKH include meningismus, tinnitus, dysacusia, vitiligo, alopecia and poliosis [2‐4]. Based on timely initiation of immunosuppressive treatments, it is classified to acute and chronic recurrent subtypes [5]. Chronic recurrent VKH is characterized by vitiligo, recurrent anterior uveitis, and sunset glow fundus [6]. Neovascularization of the optic disc (NVD) was reported in two cases of VKH in the pre-immunomodulation therapy era [7, 8]. Here we present two cases of chronic recurrent VKH presented with proliferative retinopathy. Both cases were diagnosed based on the revised diagnostic criteria for Vogt-Koyanagi-Harada disease [9].

Although retinal neovascularization is a known feature in uveitic entities like Behçet’s disease, juvenile idiopathic arthritis, sarcoidosis, pars planitis, Crohn’s disease and systemic lupus erythematosus [9], it is an uncommon feature of VKH. Only two VKH cases associated with NVDs were found in the literature. Table 1 summarizes all VKH patients who manifested proliferative retinopathy [7, 8]. Notably, all four patients were females, young or middle aged, and had granulomatous panuveitis with ERD. Duration between presentation and development of retinal neovascularization ranged between 6 months and 1 year. All patients were either on low dose or discontinued systemic steroids treatment. Systemic uveitis treatment resulted in regression of retinal neovascularization in three patients. The cause of proliferative retinopathy in VKH is not clear, but it seems to be related to long durations of either treatment discontinuation or suboptimal dosage. Although the second patient has type 1 diabetes, proliferative retinopathy was found in only one eye. No signs of diabetic retinopathy were found in the contralateral eye on fundus examination and FFA. Regression of retinal neovascularization upon initiation of systemic immunosuppression in association with a single dose of anti-vascular endothelial growth factor (Anti-VEGF) without the need for peripheral laser photocoagulation application further confirm the prominent role of persistent uveitis in the development of retinal neovascularization in this patient. Although Anti-VEGF injection was found to be effective in treating proliferative diabetic retinopathy in DRCR.net Protocol S, intravitreal injections were performed on monthly basis to control proliferative diabetic retinopathy [10]. Furthermore, only 19% of eyes achieved complete regression of neovascularizations after a single Anti-VEGF injection. Although the severity of proliferative diabetic retinopathy was not detailed for eyes which responded rapidly to Anti-VEGF, it is unlikely to achieve such rapid response in advanced clinical picture with pre-retinal and vitreous hemorrhages like our patient. Only few cases have been reported the association between VKH and type 1 diabetes mellitus in the literature, including two cases from Saudi Arabia [11‐15]. HLA types found in patients with this disease association included DR4, DQ4, DR9 and DQ3. In our second patient, HLA types found included DR3, DR4 and DQ2. These findings help to expand the knowledge about HLA types found in patients with VKH in association with type 1 diabetes mellitus. The finding of HLA-DR4 which is strongly associated with VKH is further suggestive of the diagnosis [16].

Extended period of uncontrolled inflammation is also thought to be associated with retinal neovascularization in other uveitis entities [17]. Although peripheral retinal capillary non perfusion could not be clearly appreciated in the second patient who had vitreous hemorrhage, the absence of capillary nonperfusion in the first patient decreases the likelihood of retinal ischemia as a sole factor for development of retinal neovascularization. Similar findings were observed in other uveitic entities as well, indicating an important role of prolonged inflammation in pathologic vasculogenesis [17]. Proinflammatory cytokines including IL-1b and TNF-a, can promote endothelial proliferation and pathologic angiogenesis [18]. Both IL-1b and TNF-a were found to be elevated in VKH disease [19]. Prolonged duration of inflammation prior to the development of retinal neovascularization, as well as regression of the new vessels upon proper uveitis control support the role of inflammation in proliferative retinopathy in uveitis patients. Anti-VEGF was used in the second patient as an adjunct treatment to inhibit further neovascularization prior to the complete response to systemic immunosuppression and prevent further progression of proliferative retinopathy [20]. Pars plana vitrectomy with membrane peeling can be used to address the fibrous tissue from regressed NVDs and epi-retinal membrane once proper control of inflammation is achieved.

In conclusion, Proliferative retinopathy is an uncommon feature of VKH, especially in patients with suboptimal control of their inflammation. Proper uveitis management is crucial to achieve regression of retinal neovascularization.