The Total Macular Burden of Hyperreflective Foci and the Onset of Persistent Choroidal Hypertransmission Defects in Intermediate AMD

Purpose: The association between the total macular burden of hyperreflective foci (HRF) in eyes with intermediate AMD (iAMD) and the onset of persistent choroidal hypertransmission defects (hyperTDs) was studied using swept-source optical coherence tomography (SS-OCT). Design: Post hoc subgroup analysis of a prospective study. Methods: A retrospective review of iAMD eyes from subjects enrolled in a prospective SS-OCT study was performed. All eyes underwent 6×6 mm SS-OCT angiography (SS-OCTA) imaging at baseline and follow-up visits. En face sub-retinal pigment epithelium (subRPE) slabs with segmentation boundaries positioned 64 to 400 µm beneath Bruch's membrane (BM) were used to identify persistent choroidal hyperTDs. None of the eyes had persistent hyperTDs at baseline. The same subRPE slab was used to identify choroidal hypotransmission defects (hypoTDs) attributable to HRF located either intraretinally (iHRF) or along the RPE (rpeHRF) based on corresponding B-scans. A semiautomated algorithm was used by 2 independent graders to validate and refine the HRF outlines. The HRF area and the drusen volume within a 5 mm fovea-centered circle were measured at each visit. Results: The median follow-up time for the 171 eyes from 121 patients included in this study was 59.1 months (95% CI: 52.0-67.8 months). Of these, 149 eyes (87%) had HRF, and 82 (48%) developed at least one persistent hyperTD during the follow-up. Although univariable Cox regression analyses showed that both drusen volume and total HRF area were associated with the onset of the first persistent hyperTD, multivariable analysis showed that the area of total HRF was the sole significant predictor for the onset of hyperTDs (P < .001). ROC analysis identified an HRF area ≥ 0.07 mm² to predict the onset of persistent hyperTDs within 1 year with an area under the curve (AUC) of 0.661 (0.570-0.753), corresponding to a sensitivity of 55% and a specificity of 74% (P < .001). Conclusions: The total macular burden of HRF, which includes both the HRF along the RPE and within the retina, is an important predictor of disease progression from iAMD to the onset of persistent hyperTDs and should serve as a key OCT biomarker to select iAMD patients at high risk for disease progression in future clinical trials.