Abstract
PURPOSE: To characterise the natural history of poor-responder neovascular age-related macular degeneration (AMD) by tracking structural evolution and visual decline over time. METHODS: This retrospective longitudinal study analysed 70 eyes of 70 treatment-naive neovascular AMD patients who completed loading dose therapy, received ≥7 injections in the first year, and experienced ≥10 ETDRS letter visual acuity (BCVA) loss from post-loading baseline. Spectral-domain OCT imaging and BCVA were evaluated at three timepoints: baseline (post-loading), 10-letter loss, and worst visual outcome. Multivariate regression analysis identified independent predictors of visual acuity at each timepoint. Primary structural parameters assessed included macular atrophy, subretinal fibrosis, external limiting membrane (ELM) and ellipsoid zone (EZ) integrity, central retinal thickness (CRT), and fluid parameters. RESULTS: Mean follow-up was 38.5 ± 22.8 months. Macular atrophy progression was dramatic (7.1% → 41.4% → 81.4%, p < 0.001) and subretinal fibrosis increased substantially (11.4% → 25.7% → 57.1%, p < 0.001). CRT showed paradoxical biphasic evolution (262.6 → 278.6 → 252.0 μm). Multivariate analysis revealed three distinct phases: no independent predictors at baseline, comprehensive multi-pathway model at 10-letter loss with subretinal fibrosis (β = -0.536), hyperreflective material (β = -0.350), and intraretinal fluid (β = -0.223) as independent predictors (R² = 0.428), and fibrotic dominance at worst outcome where subretinal fibrosis emerged as the sole predictor (β = -0.469, R² = 0.220). CRT showed no predictive value across all timepoints. CONCLUSIONS: Poor-responder neovascular AMD follows a three-phase evolutionary journey with subretinal fibrosis as the dominant independent predictor of visual decline. These findings demand a paradigmatic shift toward qualitative structural assessment focusing on fibrotic changes rather than thickness-based monitoring.