Assessing photoreceptor status in retinal dystrophies: from high resolution imaging to functional vision

Abstract Purpose Describe the value of integrating phenotype/genotype data, disease staging and evaluation of functional vision in patient-centered management of retinal dystrophies. Methods 1) Cross-sectional structure-function and retrospective longitudinal studies to assess the correlations between standard fundus autofluorescence (FAF), Optical Coherence Tomography (OCT), visual acuity (VA), perimetry (VF) exams to evaluate photoreceptor functional loss in a cohort of patients with rod-cone dystrophy (RCD); 2) flood-illumination adaptive optics (FIAO) imaging focusing on photoreceptor misalignment and orientation of outer segments; 3) Evaluation of the impact of visual impairment in daily life activities, based on functional (visual and mobility) vision assessment in a naturalistic environment in: i) visually impaired subjects with RCD and ii) subjects treated with Luxturna® for RPE65-related Leber Congenital Amaurosis before and therapy. Results The results of the cross-sectional transversal study showed that: i) VA and macular sensitivity (MS) were weakly correlated with the structural variables; ii) functional impairment (VF) was correlated with reduction of anatomical markers of photoreceptor structure and increased width of autofluorescent ring. The dimensions of the ring of increased FAF evolved faster. Other criteria which differed among groups were the lengths of the ellipsoid zone, the external limiting membrane, and the foveal thickness. FIAO revealed a variety of phenotypes: paradoxical visibility of foveal cones, heterogeneous brightness of cones, dim, inner-segment like, and RPE-like mosaic. Directional illumination by varying orientation of incident light (Stiles-Crawford effect) and the amount of side illumination (gaze-dependent imaging) affected photoreceptor visibility. Mobility assessment under different lighting conditions showed correlation with VF, VA, Contrast Sensitivity (CS) and Dark Adaptation (DA), with different predictive values depending on mobility study paradigms and illumination level. At high illumination level (235 lux), VF was a predictor for all mobility performance models. Under low illumination (1 and 2 lux), VF was the most significant predictor of mobility performance variables, while CS best explained the number of collisions and segments. In subjects treated with Luxturna®, a very favorable impact on travel speed and reduction in the number of collisions, especially at low luminance, was observable 6 months following injection, in both children and adults. Conclusions Our results suggest the benefit of development and implementation of quantitative and reproducible tools to evaluate the status of photoreceptors and the impact of both visual impairment and novel therapies in real life conditions.