Relationship of Topographic Distribution of Geographic Atrophy to Visual Acuity in Nonexudative Age-Related Macular Degeneration

Abstract

Purpose: To investigate the topographic distribution of geographic atrophy (GA) and to identify an anatomic endpoint that correlates with visual acuity (VA) in eyes with GA.

Design: Retrospective analysis of a multicenter, prospective, randomized controlled trial.

Participants: The Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration.

Methods: We manually delineated GA on 1654 fundus photographs of 365 eyes. We measured GA areas in 9 subfields on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r² between GA area in the central zone and VA was achieved. We estimated the VA decline rate over 8 years using a linear mixed model.

Main outcome measures: Geographic atrophy area in macular subfields and VA.

Results: The percentage of area affected by GA declined as a function of retinal eccentricity. GA area was higher in the temporal than the nasal region (1.30 ± 1.75 mm² vs. 1.10 ± 1.62 mm²; P = 0.005) and in the superior than the inferior region (1.26 ± 1.73 mm² vs. 1.03 ± 1.53 mm²; P < 0.001). Total GA area correlated poorly with VA (r² = 0.07). Among GA areas in 9 subfields, only GA area in the central zone was associated independently with VA (P < 0.001). We determined 1 mm as the optimal diameter for the central zone in which GA area correlated best with VA (r² = 0.45). On average, full GA coverage of the central 1-mm diameter zone corresponded to 34.8 letters' decline in VA. The VA decline rate was comparable between eyes with initial noncentral and central GA before GA covered the entire central 1-mm diameter zone (2.7 letters/year vs. 2.8 letters/year; P = 0.94).

Conclusions: The prevalence of GA varies significantly across different macular regions. Although total GA area was associated poorly with VA, GA area in the central 1-mm diameter zone was correlated significantly with VA and may serve as a surrogate endpoint in clinical trials.

Keywords: Color fundus photography; Geographic atrophy; Nonexudative age-related macular degeneration; Topography; Visual acuity.

Figure 2.

Demonstration of the grading and registration of color fundus photographs (CFPs) of an eye with geographic atrophy (GA). A, CFP of the eye at year 10 after enrollment into the AREDS. The white lines represent manually delineated GA borders. The 3 blue dots represent manually placed registration points at the vessel bifurcations, which allowed registration of images from the same eye at different visits. B, CFP of the same eye at year 12 after enrollment into AREDS. C, Registered CFP images from year 10 (green image) and year 12 (purple image) based on the 3 registration points. D, Delineation data of the GA, foveal center, and optic disc shown in a coordinate system for our quantitative analysis. The coordinate system was defined by using the foveal center as the origin and the optic nerve-fovea axis as the horizontal axis.

Figure 4.

Intergrader reproducibility of geographic atrophy (GA) area (N = 240 visits). A, Bland-Altman plot comparing the grading of GA area between 2 teams; GA area had a mean difference of −0.01 mm² (the solid line) and 95% limits of agreement of −0.84 to +0.82 mm² (dashed lines), indicating no systematic difference in the measurement of GA area between the 2 teams. B, The GA area measured by team A was highly correlated with measurement by team B. The intraclass correlation coefficient (ICC) was 0.997.

Figure 5.

Topographic distribution of geographic atrophy (GA) in (A, B) all eyes (N = 365 eyes), (C, D) eyes with central GA (N = 171 eyes), and (E, F) eyes with noncentral GA (N = 194 eyes) at the baseline visit. The grid represents ETDRS grid, comprising of 3 concentric circles (i.e., central, inner, and outer zones) with diameters of 1, 3, and 6 mm. The grey circle represents the optic disc. The left panel shows the frequency of GA in each topographic location (decimal scale), and the right panel depicts the mean percentage of area of each topographic region affected by GA. In all 3 groups, GA lesions most frequentlyappeared in the central and inner zones (i.e., within central 3 mm). C = central zone; iINF = inner inferior; iNAS = inner nasal; iSUP = inner superior; iTEM = inner temporal; oINF = outer inferior; oNAS = outer nasal; oSUP = outer superior; oTEM = outer temporal.

Figure 6.

Topographic distribution of geographic atrophy (GA) by (A) retinal eccentricity and (B) macular quadrants in the ETDRS grid among all 365 eyes at the baseline visit. The error bar represents 95% confidence interval for the mean. A, We divided the macula into 15 regions using concentric circles with a 0.2 mm increment in radius. The percentage of area affected by GA in each region was calculated as GA area divided by total retinal area in the region. The percentage of area affected by GA peaked between 0 and 0.5 mm from the foveal center and then declined as the distance from the foveal center increased. On average, GA affected approximately 50% of the retina within 0.5 mm from the foveal center; by comparison, GA affected approximately 15% or less of the retina beyond 2 mm away from the foveal center. B, GA area in the temporal quadrant (1.30 ± 1.75 mm²) and superior quadrant (1.26 ± 1.73 mm²) was significantly higher than the GA area in the nasal quadrant (1.10 ± 1.62 mm²) and inferior quadrant (1.03 ± 1.53 mm²) of the macula. The P values were calculated from Wilcoxon signed rank test using data from all 365 eyes.

Figure 7.

Correlation between visual acuity (VA) and area of geographic atrophy (GA) at the baseline visit. A, VA correlated poorly with the total area of GA (r² = 0.07). B, Correlation coefficient (r² from the linear regression) between VA and GA area in the central zone is plotted against the diameter of the central zone. After we varied the diameter of the central zone from 0 to 10 mm, we found that the GA area in the central 1-mm-diameter zone resulted in the highest correlation with visual acuity (dotted red line; r² = 0.45). This suggests 1 mm as the optimal diameter of the central zone in our analysis, since either a smaller or larger diameter of the central zone reduced the predictive power. C, We calculated the central residual area as 0.785 mm² – GA area in the central zone. The grey circles represent data of individual eyes, and the black circles represent the binned data for every 0.1 mm² intervals. The error bar represents 95% confidence interval (CI) for the mean. Interestingly, the decline of VA as a function of central residual area followed a segmented regression with a transition at 0.136 mm² (r² = 0.47). As the central residual area decreased from 0.785 to 0.136 mm² (blue line), VA declined 19.0 letters with a decline rate of 2.9 letters (95% CI, 2.1–3.8) per 0.1 mm² decrease of central residual area. In comparison, as the central residual area dropped from 0.136 to 0 mm² (red line), VA dropped 15.8 letters with a higher decline rate at 11.6 letters (95% CI, 5.0–18.3) per 0.1 mm² decrease of central residual area (P < 0.001).

Figure 8.

Longitudinal changes in visual acuity and central residual area for eyes with initial central GA (red) and noncentral GA (blue). The error bar represents 95% confidence interval (CI) for the mean. A, At year 0, VA in eyes with noncentral GA (74.5 letters; 95% CI, 72.6–76.4) was significantly higher than VA in eyes with central GA (52.8 letters; 95% CI, 49.9–55.6) (P < 0.001). Over 8 years of follow-up, VA in eyes with central GA declined continuously over the first 4 years and then plateaued at approximately 45 letters, while VA in eyes with noncentral GA decreased at a relatively constant rate over time. During the first 4 years of follow-up, the decline rate of VA was comparable between eyes with noncentral GA (2.7 letters/year; 95%CI, 2.3 to 3.2) and eyes with central GA (2.8 letters/year; 95%CI, 2.2–3.3) (P = 0.94). However, after year 4, the decline rate of VA was significantly higher in eyes with noncentral GA (3.8 letters/year; 95% CI, 3.0–4.6) than in eyes with central GA (1.4 letters/year; 95% CI, 0.8–2.0) (P < 0.001). B, The central residual area was calculated as 0.785 mm² – GA area in the central 1-mm-diameter zone. The reduction of the central residual area appeared to be parallel with the decline of VA in both central and noncentral GA groups (compare A and B). Of note, the mean central residual area in eyes with central GA was only 0.02 mm² at year 4, consistent with the observation that VA plateaued around year 4. C, Using the longitudinal data of central residual area and VA from all visits of all eyes, we calculated the mean and 95% CI of the central residual area for every 15 letters interval of VA. GA = geographic atrophy.