Imaging Features of Radiation Retinopathy
Globe-sparing treatment of choroidal melanoma through various forms of radiation results in excellent tumor control, but not without consequences [63–65]. Gunduz et al. [66] studied 1,300 eyes with uveal melanoma treated with plaque radiotherapy and found 42% developed radiation retinopathy at 5 years leading to loss of vision. The mechanism of radiation retinopathy likely involves increased inflammatory cytokines, notably VEGF, since prophylactic intravitreal injections of the anti-VEGF agent bevacizumab results in a reduction of radiation complications [67]. Clinically, radiation retinopathy can manifest in non-proliferative and proliferative forms, similar to diabetic retinopathy [64–72]. Non-proliferative radiation retinopathy appears as nerve fiber layer infarcts (cotton wool spots), microaneurysms, intraretinal hemorrhages, hard exudates, and CME [65–69]. Proliferative radiation retinopathy, on the other hand, is characterized by either preretinal neovascularization resulting in preretinal or vitreous hemorrhage or iris neovascularization resulting in neovascular glaucoma [64–66, 70–72].
Among imaging modalities relevant to the evaluation and management of radiation retinopathy, IVFA and OCT are arguably the most important. IVFA allows evaluation of FAZ, documentation of non-perfusion or points of leakage in the macula for laser treatment planning, and even grading of radiation retinopathy with ultra-wide-field angiography [18, 71]. On the other hand, OCT is useful in grading the severity of macular edema and is critical in the early detection of radiation maculopathy. Horgan et. al. [27] studied 135 eyes that had plaque radiotherapy for uveal melanoma and found that the mean time to onset of OCT-evident macular edema was 12 months, with some occurring as early as 4 months post-radiation. Furthermore, OCT resulted in the identification of more cases of macular edema (61 vs. 38%) at a much earlier time point after radiation (12 vs. 17 months) compared to clinical evaluation [27]. Similar to the management of diabetic retinopathy, OCT has also become the de facto imaging device used to guide therapy in radiation-related macular edema given its reproducibility and efficiency [73, 74].
OCTA Features of Radiation Retinopathy
Perhaps the greatest value of OCTA would be in the management of radiation retinopathy. Veverka et. al. [75] first described OCTA features of radiation retinopathy and found capillary dropout, microaneurysms at the superficial and deep plexus, FAZ enlargement, and discontinuity of retinal vasculature in 7 eyes. They also recognized that changes on OCTA occur earlier than OCT, IVFA, or clinical findings, and created a new grading scheme that combined OCTA features with clinical, IVFA, and OCT-based grading systems previously proposed by Horgan et al. [27] and Finger and Kurli [75, 76]. Later on, Shields et al. [34] reported a more extensive study of OCTA findings in 65 eyes treated with plaque radiotherapy for unilateral choroidal melanoma. They reported parafoveal non-perfusion (29 and 31%) and telangiectasia (5 and 3%) at the superficial and deep plexus, respectively, as well as loss of choriocapillaries within tumor margins (11/65, 17%) [34]. Quantitatively, the authors demonstrated that irradiated eyes compared to fellow eyes had significant FAZ enlargement (0.647 vs. 0.280 mm2, p < 0.001; 0.765 vs. 0.641 mm2, p < 0.001) and CVD reduction (21 vs. 35%, p < 0.001; 17 vs. 41%, p < 0.001) at the superficial and deep plexus levels, respectively [34]. Furthermore, the authors described that even in the absence of ophthalmoscopic evidence of radiation maculopathy, FAZ enlargement and CVD reduction still persists [34]. In order to ensure image quality were not affecting results, the same group reported parafoveal microvascular changes on OCTA in eyes without clinical or OCT-evident radiation retinopathy in 10 eyes, and found a significant decrease in CVD at the superficial (28 vs. 40%, p < 0.001) and deep (31 vs. 47%, p < 0.001) plexuses, without significant changes in CMT (272 vs. 273 μm, p = 0.932), superficial FAZ (0.319 vs. 0.256 mm2, p = 0.1595), and deep FAZ (0.510 vs. 0.391 mm2, p = 0.153) [35]. The isolated reduction in CVD was also associated with mild but statistically significant reduction in visual acuity (20/32 vs. 20/20, p = 0.025) [35]. In essence, the authors presented early evidence that reduction in CVD likely precedes clinically evident radiation retinopathy, OCT-evident radiation retinopathy, and even FAZ enlargement [34, 35]. The relationship of CVD and radiation retinopathy is similar to diabetic retinopathy, as CVD was observed to be inversely correlated with diabetic retinopathy severity, as well as visual acuity, and is seen even in eyes without clinically evident disease [53–57]. Sellam et al. [77] described similar changes in 37 eyes with small choroidal melanoma treated with proton beam radiation. In contrast to other studies, the authors only included those that received the full radiation dose (60 Gy) to the macula and found OCTA abnormalities (FAZ disruption, non-perfusion, vascular dilation, microaneurysms, intraretinal flow voids, or cysts) in all eyes [77]. In contrast, only 47% had OCT-evident radiation retinopathy and 77% had clinically evident radiation retinopathy [77]. The authors also described “signal voids” at the level of the choriocapillaries in 88% of eyes, as well as a significant reduction in retinal global CVD (combined superficial and deep plexus CVD, 23 vs. 26%, p < 0.001) and choriocapillaries CVD (79 vs. 99%, p < 0.001) compared to matched healthy controls [77]. Matet et al. [40] also described OCTA features in 35 eyes with uveal melanoma treated with proton beam radiation with at least 12 months post-radiation follow-up using paired fellow eyes as controls. They found similar enlargement of FAZ and CVD at both superficial and deep plexuses, along with reduction in FD (1.83 vs. 1.91, p < 0.001 and 1.82 vs. 1.90, p < 0.001) at the level of the superficial and deep plexus in irradiated eyes relative to fellow control eyes [40]. Retinal FD is a measurement of vessel
