Peripheral Retinal Vascular Biomarkers on Ultra-Widefield OCT Angiography for Severity Grading in Retinitis Pigmentosa.

Abstract

To identify peripheral retinal vascular phenotypes in retinitis pigmentosa (RP) using ultra-widefield OCT angiography (UWF-OCTA), validate a quantitative vascular biomarker, and develop a clinically applicable severity grading system. Development and validation of a severity grading system. We analyzed 544 eyes from 272 patients with primary RP from three tertiary centers. Peripheral vascular phenotypes were defined using UWF-OCTA. Structure-function correlations between the CNZ area and multimodal visual functions-including kinetic perimetry (KP), full-field stimulus threshold (FST), and static perimetry (SP)-were evaluated using linear mixed-effects models (LMMs) to account for inter-eye correlation. A four-stage severity grading system was developed using principal component analysis (PCA) to construct a composite functional score and regression tree analysis with cluster bootstrapping (1,000 resamples) to determine optimal CNZ cut-points; the system was then validated in internal and external datasets. Age-related severity distribution was evaluated through a Kaplan-Meier age-at-observation simulation. Two distinct peripheral vascular phenotypes were identified: Type 1 (Terminal Remodeling; 306 eyes, 56.2%) and Type 2 (Simple Atrophy; 238 eyes, 43.8%). Type 1 eyes showed greater disease severity than Type 2 eyes at comparable ages. The CNZ area demonstrated strong structure-function correlations, explaining substantial variance in KP (Marginal R² up to 0.77) and FST (Marginal R² up to 0.64). A CNZ-based 4-stage severity grading (Stage I, ≥ 260 mm²; Stage II, 200-260 mm²; Stage III, 150-200 mm²; Stage IV, < 150 mm²) effectively stratified disease severity, demonstrating high explanatory power for visual function (KP η² up to 0.75; FST η² up to 0.66) and maintaining discriminatory performance for best-corrected visual acuity (BCVA) in both internal (η² = 0.17) and external (η² = 0.28) validation cohorts. Peripheral retinal vascular alterations captured by UWF-OCTA define distinct RP phenotypes and identify the CNZ as a robust quantitative biomarker of disease severity. The CNZ-based severity grading system provides an objective framework for clinical severity assessment, disease monitoring, and patient stratification in future interventional trials.