**4. Best vitelliform macular dystrophy**

Best vitelliform macular dystrophy (BVMD) is a rare IRD caused by dominant variants in the *BEST1* gene, encoding for the bestrophin-1 protein, a RPE chloride channel [56]. The typical clinical presentation is a central yellowish vitelliform or egg-yolk-like lesion, made by lipofuscin and photoreceptors' outer segment remnants [56]. The classic BVMD classification includes different stages. Stage I (subclinical) is characterized by the absence of biomicroscopic fundus abnormalities. Stage II (vitelliform) shows the typical egg yolk subretinal macular lesion. Stage III (pseudohypopyon) is characterized by partial fluid reabsorption in the upper part of the lesion and persistence of the yellowish subretinal deposition in the lower part. Stage IV (vitelliruptive) shows the reabsorption and breakdown of the material, giving a "scrambled egg" appearance. Stage V (atrophic/fibrotic) is complicated by the development of chorioretinal atrophy or macular neovascularization [57]. A complete noninvasive multimodal retinal imaging BVMD Stage IV case is shown in **Figure 3**.

FAF showed no alterations in the subclinical stage. Conversely, the vitelliform stage is characterized by a well-defined hyperautofluorescent alteration. The FAF signal progressively decreased passing through the pseudohypopyon stage, up to the vitelliruptive stage. Stage five is characterized by decreased FAF signal due to RPE atrophy [58]. However, BVMD-FAF appearance may be characterized by quite heterogeneous presentations, including classic, hyperautofluorescent, hypoautofluorescent, patchy, multifocal, and spoke-like patterns [59]. NIR-AF remarkably contributed to provide the pathognomonic sign of the subclinical BVMD stage, namely the presence of a central well-defined area of NIR-AF decrease [60]. The relationship between FAF assessment and retinal functionality is very close, making FAF a mandatory diagnostic tool for BVMD [61].

Regarding OCT findings, the subclinical stage may show only thickening of the interdigitation zone of cones and RPE in about 40% of cases [60]. The vitelliform stage is characterized by a dome-shaped subretinal hyperreflective lesion, which leaves space for the progressively increasing subretinal fluid hyporeflective signal occurring as pseudohypopyon and vitelliruptive stages proceed. The advanced stage shows either outer retinal atrophy or hyperreflective neovascular scar [62]. The presence of subretinal fluid is associated with worse visual acuity and retinal sensitivity values, compared with the persistence of vitelliform material [63–65]. Moreover, OCT was able to describe a clinically relevant outer retinal finding, namely the optically preserved islet in the context of the vitelliform accumulation, corresponding with EZ integrity and good macular function; its disappearance causes a remarkable decrease of visual acuity and retinal sensitivity [66, 67]. A high number of hyperreflective foci correlated with disease severity and progression rate also in BVMD [68]. Focal choroidal excavation is a frequent finding in BVMD, occurring in correspondence with a significant choroidal thinning [69, 70].

OCTA contributed by detecting a progressively increasing vascular impairment as the BVMD stages progress [71]. In the subclinical stage, OCTA was allowed to describe an early sign of choriocapillaris impairment, represented by central

#### **Figure 3.**

*Multimodal retinal imaging in BVMD. Confocal multicolor image (A) shows a scrumble egg appearance, which is suggestive of Stage IV vitelliruptive BVMD stage. FAF image (B) shows central alterations of the autofluorescent signal, either with hyper- or hypoautofluorescent changes. Structural OCT (C) shows the subretinal fluid corresponding with the vitelliform material in progressive reabsorption. OCTA shows almost preserved SCP (D), altered DCP with some alterations secondary to possible segmentation artifacts (E), and central CC alterations, probably related to the masking effect of the above localized subretinal fluid (F).*

increased choriocapillaris flow voids [60]. In clinical stages, DCP first, followed by SCP, resulted altered in BVMD. However, the biggest OCTA contribution is regarding the radical change of macular neovascularization prevalence in BVMD. Indeed, before OCTA the prevalence of macular neovascularization was estimated at around 2–9% of cases [72]. After OCTA, the prevalence increases up to 65% of eyes [73, 74]. BVMD is characterized by two different macular neovascularization subtypes on OCTA: exudative and non-exudative. Exudative macular neovascularization is rare, more typical of Stages II and III, whereas non-exudative macular neovascularization develops very commonly in the advanced IV and V Stages [73]. Unfortunately, OCTA is less useful in evaluating the status of the choriocapillaris, since affected by the masking effect of the vitelliform material. Conversely, as expected, choriocapillaris is markedly impaired in advanced stages. Although the increased choriocapillaris flow voids detected in the subclinical stage may suggest that CC is effectively impaired in BVMD, further technological improvements are warranted to assess the choriocapillaris involvement in early BVMD stages.
