Hyperreflective foci and specks are associated with delayed rod-mediated dark adaptation in non-neovascular age-related macular degeneration.

Abstract Purpose Hyperreflective foci (HRF) are optical coherence tomography (OCT) biomarkers for progression of non-neovascular age-related macular degeneration (AMD) attributed to anteriorly migrated retinal pigment epithelial (RPE) cells. We examined associations between rod- and cone-mediated vision and HRF plus smaller hyperreflective specks (HRS); we sought a histologic candidate for HRS. Design cross-sectional study; histologic survey Participants Patients with normal maculas (n=34), early AMD (N=26), and intermediate AMD (N=41) Methods AMD severity was determined via the 9-step Age-Related Eye Disease Study scale. In OCT scans HRF and HRS were manually counted. Vision tests probed cones (best corrected visual acuity (VA), contrast sensitivity), mixed cones and rods (low luminance VA, low luminance deficit, mesopic light sensitivity), or rods (scotopic light sensitivity, rod-mediated dark adaptation (RMDA)). An online AMD histopathology resource was reviewed. Main Outcome Measures Vision in eyes assessed for HRF and HRS; candidate histology for HRS. Results In 101 eyes of 101 patients, HRF and HRS were identified in 25 and 95 eyes, respectively, with good intra- and inter-rater reliability. HRF were present but sparse in normal eyes, infrequent in early AMD eyes, and frequent but highly variable among intermediate AMD eyes (number per eye, 0.1±0.2, 0.2±0.5, 1.9 ± 3.4; normal, early, intermediate, respectively). HRS outnumbered HRF in all groups (4.5 ± 3.2; 6.3±5.8; 19.4 ± 22.4). Delayed RMDA was strongly associated with more HRF and HRS (both p Conclusions HRF and HRS are markers of cellular activity associated with visual dysfunction, especially delayed RMDA, an AMD risk indicator assessing efficiency of retinoid re-supply. HRS may represent lipofuscin granules translocating inwardly within cone photoreceptors. Visible and quantifiable on SD-OCT, HRF and HRS may serve as structural endpoints in clinical trials targeting AMD stages earlier than atrophy expansion. These results should be confirmed in a larger sample.