The Natural Course of Age-Related Scattered Hypofluorescent Spots on Late-Phase ICGA (ASHS-LIA): Structural Evolution and Neovascular Complications

Purpose: The purpose of this study was to characterize the longitudinal evolution and prognostic associations of age-related scattered hypofluorescent spots on late-phase indocyanine green angiography (ICGA; ASHS-LIA), a putative marker of early retinal pigment epithelium/Bruch's membrane (RPE/BM) dysfunction, in a Caucasian cohort. Methods: Retrospective longitudinal study of patients with ASHS-LIA who underwent optical coherence tomography (OCT) and ICGA. ASHS-LIA extent was graded from 1 (posterior pole) to 3 (beyond vascular arcades). Structural OCT features were categorized into three structural categories based on drusen status: S0 (no drusen), S1 (small drusen <63 µm), and S2 (large drusen ≥63 µm). Subretinal drusenoid deposits (SDDs) and choroidal neovascularization (CNV) were evaluated at each visit. Transitions between structural categories were analyzed using mixed-effects ordinal regression models adjusted for time, and the incidence of SDDs and CNV was evaluated using Cox regression. Results: A total of 278 eyes of 144 patients (mean age = 69.5 ± 9.3 years, 53% male patients) were followed for a mean of 6.2 years. At baseline, 56% of eyes were S0, 31% were S1, and 14% were S2, with age and ASHS-LIA extension increasing stepwise across structural categories (P < 0.001). CNV was observed across all categories. During follow-up, 16 incident CNV lesions were identified, showing heterogeneous presentations, including aneurysmal type 1 CNV in drusen-free eyes and mixed types 1 and 2 CNV in eyes with larger drusen. A change in structural categories occurred in 11% of eyes and was associated with older age (odds ratio [OR] = 1.73 per 10 years, P < 0.001) and greater ASHS-LIA extension (OR = 2.57 for grade 3 vs. 1, P = 0.03). Older age, extensive ASHS-LIA, and large drusen were also associated with increased risk of incident SDDs and CNV, whereas greater choroidal thickness was inversely associated with SDDs. The presence of a double-layer sign (DLS) was associated with CNV onset. Conclusions: ASHS-LIA is associated with long-term structural changes and neovascular complications in eyes exhibiting this phenotype. These findings support its role as a risk stratification feature within ASHS-LIA-positive eyes, although its relationship with AMD progression cannot be established from the present study.