Long-Term Natural History of Ellipsoid Zone Length in USH2A-Related Retinitis Pigmentosa

Abstract

Purpose : Residual ellipsoid zone (EZ) length is an important parameter correlating with visual function in patients with USH2A-related retinitis pigmentosa (RP), but the long-term natural history of the residual EZ length remains poorly characterized due to limited patients’ follow-ups. We applied Bayesian Entry Time Realignment (BETR), a recently developed hierarchical Bayesian modeling framework, to determine the long-term disease progression model of EZ length using data from patients followed over short durations.

Methods : We obtained EZ length measurements for 330 visits from 110 eyes (55 patients) with molecularly-confirmed biallelic USH2A variants followed over 2.85±0.87 years from Moorfields Eye Hospital, London, UK. We used BETR to compare 3 models of decline: linear, quadratic, and exponential based on deviance information criterion (DIC), a common Bayesian model comparison tool.

Results : The exponential decay model (Fig.B) had the lowest DIC value (-1367) compared to the linear (-730) and quadratic (-597) models, suggesting it provides the best balance of fit to the data and model complexity. BETR estimated that the age at which EZ length had declined to 6000 µm (age₆₀₀₀) was 22.21±10.72 years. The decline rate of the log-transformed EZ length was 0.066±0.030 years^-1. After stratifying by the presence of syndromic (64 eyes) or non-syndromic (46 eyes) disease, we found no significant difference in the log-transformed EZ length decline rate (0.065 vs 0.068 years^-1, p=0.65) nor the mean age at initial visit (37.66 vs 39.96 years, p=0.29), but the age₆₀₀₀ was lower in syndromic than in non-syndromic disease (20.45 vs 24.67 years, p=0.045).

Conclusions : Our results suggest EZ length follows an exponential decay pattern over approximately 50 years. Patients with syndromic USH2A-related RP have an earlier age₆₀₀₀ compared to non-syndromic patients although the rate of decline was similar thereafter. Future applications of BETR can assist clinical trial planning and better characterize the long-term natural history of other inherited retinal degenerations.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Fig.(A) Raw EZ length of individual eyes during limited follow ups. Initial EZ length varies extensively among individual eyes, suggesting that different eyes had different durations of diseases at baseline and progression rates.

 

Fig.(B) Same data shown in (A) after application of BETR shows disease progression over 50 years.