Date of Award

January 2024

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Lucian V. Del Priore

Abstract

The purpose of this study is to characterize the long-term progression of ellipsoid zone (EZ) width and hyperautofluorescent (hyperAF) ring area in a cohort of patients with USH2A-retinopathy.

We obtained longitudinal measurements of the EZ width and hyperAF ring area on optical coherence tomography and fundus autofluorescence, respectively, from 110 eyes in a cohort of 55 participants with molecularly confirmed biallelic USH2A mutations enrolled from Moorfields Eye Hospital. We used Bayesian Entry Time Realignment (BETR) to compare linear, quadratic, and exponential models describing the long-term decline of EZ width and of hyperAF ring area. We estimated the duration of macular EZ width loss, and the duration since constriction of the hyperAF ring to the near peripheral retina, using BETR by horizontally translating data along the time axis to account for the different entry times of each eye.

The progression of EZ width and hyperAF ring area were both best described by exponential decay. The log-transformed EZ width of individual eyes declined at a median rate of 0.063 [IQR: 0.040 – 0.086] log(m)/year (equal to 6.1 [IQR: 3.96 – 8.28] %/year), while the log-transformed hyperAF ring area declined at a rate of 0.095 [IQR: 0.053 – 0.157] log(mm2)/year (equal to 9.07 [IQR: 5.13 – 14.5] %/year). The log EZ width decline rate was uncoupled from baseline EZ width (Spearman  = -0.18, P = 0.06) and age ( = -0.10, P = 0.31); log hyperAF ring area decline rate was uncoupled from age ( = -0.17, P = 0.08) and borderline uncoupled from baseline ring area ( = 0.19, P = 0.047). Eyes with Usher syndrome exhibited earlier median onset ages of macular EZ width loss (18.8 [IQR: 13.1 – 24.7] vs 28.1 [IQR: 18.5 – 35.8] years, P < 0.001) and earlier onset of constriction of the hyperAF ring to within the near peripheral retina (16.1 [IQR: 9.9 – 19.8] vs 24.9 [IQR: 11.9 – 29.7] years, P = 0.007) compared to nonsyndromic eyes, but with no difference in the log EZ width and log hyperAF ring area decline rates.

EZ width and hyperAF ring area decline exponentially over 50 years of synthesized disease progression. Log transformation of EZ width and hyperAF ring area decline rates reduced the dependence of these rates on baseline size and age. Patients with Usher syndrome exhibited earlier onset of disease in the macula and near periphery, but progressed at comparable rates to those with nonsyndromic disease.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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