Directional Analysis of Residual RPE Area Loss in the Natural History of Choroideremia

Purpose: To longitudinally evaluate whether residual RPE area loss in choroideremia (CHM) demonstrates directional asymmetry over 12 months. Methods: This study analyzed 106 participants (163 eyes) from the Natural History of the Progression of Choroideremia Study cohort with eligible paired baseline and month 12 fundus autofluorescence imaging. Rigid image registration was performed to align baseline and follow-up images. Residual RPE area reduction was quantified using a progression heatmap and segmented into 12 clock-hour sectors. Directional differences were assessed using generalized estimating equations accounting for within-eye clustering and baseline area. A supplementary analysis evaluated within-eye variance with bootstrap-derived confidence intervals. Results: Across all sectors, the mean RPE area reduction ranged from -0.0236 to -0.0404 mm² equivalents (estimated marginal means). Although minor numerical differences were observed, no statistically significant directional effect was detected after accounting for intraeye correlation. Within-eye variance was low (mean 0.0051; 95% confidence interval, 0.0031-0.0076), indicating limited spatial heterogeneity in progression over 12 months. Conclusions: In this longitudinal analysis of CHM, residual RPE area loss did not demonstrate a consistent directional predilection over 12 months. These findings suggest that short-term structural progression in CHM may occur relatively symmetrically rather than preferentially along specific meridians. A comprehensive assessment of the entire lesion boundary may therefore be more appropriate than direction-specific monitoring in natural history studies and therapeutic trials.