A Quantitative Approach to Predict Differential Effects of Anti-VEGF Treatment on Diffuse and Focal Leakage in Patients with Diabetic Macular Edema: A Pilot Study

Abstract

Purpose: We use semiautomated segmentation of fluorescein angiography (FA) to determine whether anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME) differentially affects microaneurysm (MA)-associated leakage, termed focal leakage, versus non-MA-associated leakage, termed diffuse leakage.

Methods: We performed a retrospective study of 29 subjects treated with at least three consecutive injections of anti-VEGF agents for DME (mean 4.6 injections; range, 3-10) who underwent Heidelberg FA before and after anti-VEGF therapy. Inclusion criteria were macula center involving DME and at least 3 consecutive anti-VEGF injections. Exclusion criteria were macular edema due to cause besides DME, anti-VEGF within 3 months of initial FA, concurrent treatment for DME besides anti-VEGF, and macular photocoagulation within 1 year. At each time point, total leakage was semiautomatically segmented using a modified version of our previously published software. Microaneurysms were identified by an expert grader and leakage within a 117 μm radius of each MA was classified as focal leakage. Remaining leakage was classified as diffuse leakage. The absolute and percent changes in total, diffuse, and focal leakage were calculated for each subject.

Results: Mean pretreatment total leakage was 8.2 mm² and decreased by a mean of 40.1% (P < 0.0001; 95% confidence interval [CI], [-28.6, -52.5]) following treatment. Diffuse leakage decreased by a mean of 45.5% (P < 0.0001; 95% CI, [-31.3, -59.6]) while focal leakage decreased by 17.9% (P = 0.02; 95% CI, [-1.0, -34.8]). The difference in treatment response between focal and diffuse leakage was statistically significant (P = 0.01).

Conclusions: Anti-VEGF treatment for DME results in decreased diffuse leakage but had relatively little effect on focal leakage as assessed by FA. This suggests that diffuse leakage may be a marker of VEGF-mediated pathobiology. Patients with predominantly focal leakage may be less responsive to anti-VEGF therapy.

Translational relevance: Fluorescein angiography can define focal and diffuse subtypes of diabetic macular edema and these may respond differently to anti-VEGF treatment.

Keywords: anti-VEGF; diabetic macular edema; fluorescein angiography; image segmentation.

Figure 1

Screen capture of the GUI used for image segmentation. The upper left shows the composite early frame and late images, and allow the user to zoom and scroll within each. Lower left shows the current segmentation result with leakage outlined in red. The right side of the GUI allows manual adjustment of leakage and segmentation of MAs. The user can toggle between early individual frames and the late image while maintaining registration of segmentation. The middle bottom portion allows input of scaling information allowing conversion of pixels to millimeters, altering region of interest, leakage radius attributed to individual MA, and selection/removal of individual MAs.

Figure 2

Fluorescein angiograms from three representative subjects are shown. For each subject, the top row shows pretreatment imaging and the bottom row shows post-treatment imaging. The left column is the composite early frame image, the middle column is the late image, and the right column shows the segmentation result. In the segmentation image, the region of interest is outlined by the yellow circle, leakage is outlined in red and shaded, and MAs are marked with green dots with the radius off attributable leakage appearing as a yellow circle around each MA.

Figure 3

Graphical representation of the percent change in focal and diffuse leakage following anti-VEGF treatment for each subject. Focal leakage is represented by blue bars and diffuse leakage is represented by red bars. In 22 of 29 subjects, diffuse leakage improved more than focal leakage.