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Original Investigation
August 13, 2020

Progression of Photoreceptor Degeneration in Geographic Atrophy Secondary to Age-related Macular Degeneration

Author Affiliations
  • 1Department of Biomedical Data Science, Stanford University, Stanford, California
  • 2Department of Ophthalmology, University of Bonn, Bonn, Germany
  • 3Research and Development, Carl Zeiss Meditec Inc, Dublin, California
  • 4Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago
  • 5Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California
  • 6John A. Moran Eye Center, University of Utah, Salt Lake City
JAMA Ophthalmol. 2020;138(10):1026-1034. doi:10.1001/jamaophthalmol.2020.2914
Key Points

Question  Is progressive photoreceptor degeneration outside of geographic atrophy (GA) in eyes with nonexudative age-related macular degeneration evident and quantifiable?

Findings  In this cohort study, fully automated segmentation facilitated an accurate quantification of photoreceptor degeneration. Progressive degeneration of the outer nuclear layer and photoreceptor inner segments was evident, even accounting for age or distance to the GA boundary.

Meaning  Progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. These findings support macula-wide photoreceptor degeneration as a candidate end point to monitor treatment effects beyond GA progression.


Importance  Sensitive outcome measures for disease progression are needed for treatment trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Objective  To quantify photoreceptor degeneration outside regions of GA in eyes with nonexudative AMD, to evaluate its association with future GA progression, and to characterize its spatio-temporal progression.

Design, Setting, and Participants  Monocenter cohort study (Directional Spread in Geographic Atrophy [NCT02051998]) and analysis of data from a normative data study at a tertiary referral center. One hundred fifty-eight eyes of 89 patients with a mean (SD) age of 77.7 (7.1) years, median area of GA of 8.87 mm2 (IQR, 4.09-15.60), and median follow-up of 1.1 years (IQR, 0.52-1.7 years), as well as 93 normal eyes from 93 participants.

Exposures  Longitudinal spectral-domain optical coherence tomography (SD-OCT) volume scans (121 B-scans across 30° × 25°) were segmented with a deep-learning pipeline and standardized in a pointwise manner with age-adjusted normal data (z scores). Outer nuclear layer (ONL), photoreceptor inner segment (IS), and outer segment (OS) thickness were quantified along evenly spaced contour lines surrounding GA lesions. Linear mixed models were applied to assess the association between photoreceptor-related imaging features and GA progression rates and characterize the pattern of photoreceptor degeneration over time.

Main Outcomes and Measures  Association of ONL thinning with follow-up time (after adjusting for age, retinal topography [z score], and distance to the GA boundary).

Results  The study included 158 eyes of 89 patients (51 women and 38 men) with a mean (SD) age of 77.7 (7.1) years. The fully automated B-scan segmentation was accurate (dice coefficient, 0.82; 95% CI, 0.80-0.85; compared with manual markings) and revealed a marked interpatient variability in photoreceptor degeneration. The ellipsoid zone (EZ) loss-to-GA boundary distance and OS thickness were prognostic for future progression rates. Outer nuclear layer and IS thinning over time was significant even when adjusting for age and proximity to the GA boundary (estimates of −0.16 μm/y; 95% CI, −0.30 to −0.02; and −0.17 μm/y; 95% CI, −0.26 to −0.09).

Conclusions and Relevance  Distinct and progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. The degree of photoreceptor degeneration outside of regions of retinal pigment epithelium atrophy varied markedly between eyes and was associated with future GA progression. Macula-wide photoreceptor laminae thinning represents a potential candidate end point to monitor treatment effects beyond mere GA lesion size progression.

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