Abstract
PURPOSE: The purpose of this study was to develop ground-truth histology about contributors to variable fundus autofluorescence (FAF) signal and thus inform patient selection for treating geographic atrophy (GA) in age-related macular degeneration (AMD). METHODS: One woman with bilateral multifocal GA, foveal sparing, and thick choroids underwent 535 to 580 nm excitation FAF in 6 clinic visits (11 to 6 years before death). The left eye was preserved 5 hours after death. Eye-tracked ex vivo imaging aligned sub-micrometer epoxy resin sections (n = 140, 60 µm apart) with clinic data. Light microscopic morphology corresponding to FAF features assessed included drusen-driven atrophy, persistent hyperautofluorescence (hyperFAF) islands and peninsulas within atrophy, and hyperFAF and hypoautofluorescence (hypoFAF) inner junctional zone (IJZ) and outer junctional zone (OJZ) relative to descent of external limiting membrane (ELM). Atrophy growth rate was calculated. RESULTS: HypoFAF atrophic spots appeared in association with drusen, and then expanded and coalesced. Over drusen (n = 45, all calcified), RPE was continuous and thin, photoreceptors were short or absent, and initially intact ELM descended where RPE was absent. In persistent hyperFAF within atrophy and in the OJZ, the RPE was continuous and dysmorphic, photoreceptors were present and short, and BLamD was thick. In the IJZ, mottled FAF corresponded to dissociated RPE atop persistent BLamD. Overall linear growth rate (0.198 mm/ year) typified multifocal GA. CONCLUSIONS: FAF in GA is locally multifactorial, with photoreceptor shortening potentially promoting hyperFAF by increasing incoming excitation light available to RPE fluorophores. RPE dysmorphia may lead to either longer or shorter pathlength for excitation light. At both atrophy initiation and expansion Müller glia are major participants.