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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pfau reported funding from German Research Foundation PF950/1-1 and the Association of Rhine-Westphalian Ophthalmologists to during the conduct of the study and nonfinancial support from Heidelberg Engineering, Heidelberg, Germany outside the submitted work. Dr de Sisternes reported other support from Carl Zeiss Meditec Inc outside the submitted work. Dr Leng reported grants from Kodiak, Topcon, and Targeted Therapy Technologies; grants and personal fees from Genentech; and personal fees from Zeiss outside the submitted work. Dr Schmitz-Valckenberg reported grants from Acucela/Kubota Vision and Katairo; grants and personal fees from Alcon/Novartis, Allergan, Bayer, Roche/Genentech, and Bioeq/Formycon; grants, personal fees, and nonfinancial support from Carl Zeiss MediTec AG; grants and nonfinancial support from Centervue; personal fees from Galimedix and Oxurion; grants and nonfinancial support from Heidelberg Engineering; and nonfinancial support from Optos outside the submitted work. Dr Holz reported grants and personal fees from Heidelberg Engineering and Zeiss and grants from Centervue and Optos during the conduct of the study; grants and personal fees from Novartis, Bayer, Roche/Genentech, Geuder, Acucela, Apellis, Allergan, and Kanghong outside the submitted work; and personal fees from Pixium Vision and Lin Bioscience outside the submitted work. Dr Fleckenstein reported grants from German Research Foundation and personal fees and nonfinancial support from Heidelberg Engineering during the conduct of the study; nonfinancial support from Carl Zeiss Meditec and CenterVue; and grants and personal fees from Alcon/Novartis, Bayer, and Genentech/Roche outside the submitted work; in addition, Dr Fleckenstein had a patent to US20140303013A1 pending. Dr Rubin reported a patent to US Patent issued. The Department of Ophthalmology, University of Bonn, received technical support from Heidelberg Engineering, Heidelberg, Germany, Carl Zeiss Meditec, Jena, Germany, and Centervue, Padova, Italy. No other disclosures were reported.

Figures

Figure 1.. Image Segmentation Pipeline

A, Resulting segmentation generated by the first convolutional neural network (CNN, Deeplabv3 model with a ResNet-50 backbone) providing a 6-layer segmentation: inner retina, outer nuclear layer (ONL), photoreceptor inner and outer segments, retinal pigment epithelium drusen complex (RPEDC, including reticular pseudodrusen, retinal pigment epithelium (RPE), drusen, and basal laminar deposit, and choroid. The insert on the upper right side provides a magnified view (B). En face projections and thickness maps generated based on these segmentations as well as the confocal laser scanning laser ophthalmoscopy (cSLO) infrared reflection (IR) image were passed on as 6-layered input stack to the second CNN (Deeplabv3 model with a ResNet-50 backbone). As shown in D, the second CNN provided an en face segmentation of geographic atrophy (yellow outline), peripapillary atrophy (red outline), and the optic nerve head (green outline). proj. indicates projection, SD-OCT, spectral-domain optical coherence tomography.

Figure 2.. Spatial Registration and Data Standardization

As a first step (A), all eyes were registered to a left-eye reference coordinate system followed by exclusion of (1) the optic nerve head or peripapillary atrophy, (2) vignetting artifacts, or (3) regions with lack of normative data (peripapillary retina). Next (B), each pointwise thickness value was standardized (z score, accounting for retinal location and age). For clarity, nonsignificant alterations in thickness (−2 to 2 normative SDs) were plotted with the same color.

Figure 3.. Exemplary Patients

A, Standardized (z scores, accounting for retinal location and age) outer nuclear layer thickness maps of 2 patients. The area of retinal pigment epithelium atrophy is indicated by the black outline in the thickness maps. B, En face spectral-domain optical coherence tomography mean volume projections of the same patients 1 year later. The yellow and cyan outline demarcate the baseline and year 1 geographic atrophy (GA) boundaries, respectively. Notably, the first patient exhibits a milder degree of outer retinal degeneration at baseline and slower GA progression compared with the second patient. eFigure 4 in the Supplement provides a more comprehensive overview of these patients including the other outer retinal layer thicknesses.

Figure 4.. Photoreceptor Degeneration at the Boundary of Geographic Atrophy (GA)

The 3 panels show the outer nuclear layer (ONL; A), photoreceptor inner segments (IS; B), and outer segments (OS; C) thicknesses in dependence of the distance to the GA boundary. The y-axis denotes the z scores (accounting for retinal location and age). Each visit of each eye is plotted by a semitransparent line. The red dashed lines indicate the z score range of −2 to 2 normative SDs. eFigure 6 in the Supplement shows these data in terms of the absolute thickness deviations.