Photoreceptor Degeneration beyond Ellipsoid Zone Loss in ABCA4-associated Retinopathy

Abstract

Purpose : To quantify photoreceptor degeneration outside ellipsoid zone (EZ) loss in ABCA4-associated retinopathy, and investigate the association of this photoreceptor degeneration with EZ loss progression.

Methods : As part of a prospective, natural-history study (NCT01736293), patients with a Stargardt disease (STGD1) phenotype and at least one pathogenic ABCA4-mutation underwent spectral-domain optical coherence tomography (SD-OCT) annually. SD-OCT data (37 B-scans, 30°×15°) were segmented using custom deep-learning-based software and standardized (Z-scores) to account for retinal topography and age. Standardized thickness data of the outer nuclear layer (ONL), photoreceptor inner segments (IS) and outer segments (OS) were extracted along evenly spaced contour lines surrounding the EZ loss boundary (spacing of 0.43°). Peri-papillary A-scans (2.5° from disc margin) were excluded. Linear mixed models were used for all analyses considering the hierarchical data structure (visits in eyes in patients). Last, random forest regression was applied to predict EZ loss progression rates.

Results : A total of 95 eyes from 48 patients with a median [IQR] follow-up of 4.19 years [2.88, 5.95] were included. Patients exhibited an average (sqrt transformed) EZ loss progression rate of (estimate [95% CI]) 0.10 mm/y [0.09 – 0.11]. ONL thinning extended well beyond the area of EZ loss; ONL thinning occurred along a steep gradient and the average distance from the EZ loss boundary to normalization of ONL thickness (i.e. within ±2 Z-score units) was 4.36° [4.11 – 4.62]. IS and OS thinning was less pronounced in gradient and extent of change; the average distance from the EZ loss boundary to layer thickness normalization was 0.86° [0.61 – 1.11] for OS and 2.43° [2.17 – 2.68] for IS. ONL, OS and IS thickness outside of EZ loss explained (patient-wise leave-one-out cross-validated R²) 23.6% of the variability in future sqrt EZ loss progression rates.

Conclusions : Patients with ABCA4-associated retinopathy exhibit significant alterations of photoreceptor laminae outside of EZ loss. This degeneration is prognostic for future EZ loss progression. Deep-learning-based analysis of photoreceptor laminae may help to monitor disease progression beyond mere enlargement of EZ loss.

This is a 2021 ARVO Annual Meeting abstract.

 

Figure 1. Photoreceptor degeneration outside ellipsoid zone loss (delineated by the red contour) in an exemplary eye.