Purpose Structural and compositional heterogeneity within drusen, composed of lipid, carbohydrates, and proteins, have been previously described. We sought to detect and define phenotypic patterns of drusen heterogeneity in the form of optical coherence tomography–reflective drusen substructures (ODS) and examine their associations with age-related macular degeneration (AMD)-related features and AMD progression. Design Retrospective analysis in a prospective study. Participants Patients with intermediate AMD (n = 349) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) ancillary spectral domain optical coherence tomography (SD OCT) study. Methods Baseline SD OCT scans of 1 eye per patient were analyzed for presence of ODS. Cross-sectional and longitudinal associations of ODS presence with AMD-related features visible on SD OCT and color photographs, including drusen volume, geographic atrophy (GA), and preatrophic features, were evaluated for the entire macular region. Similar associations were also made locally within a 0.5-mm diameter region around individual ODS and corresponding control region without ODS in the same eye. Main Outcome Measures Preatrophy SD OCT changes and GA, central GA, and choroidal neovascularization (CNV) from color photographs. Results Four phenotypic subtypes of ODS were defined: low reflective cores, high reflective cores, conical debris, and split drusen. Of the 349 participants, there were 307 eligible eyes and 74 (24%) had at least 1 ODS. The ODS at baseline were associated with (1) greater macular drusen volume at baseline (P < 0.001), (2) development of preatrophic changes at year 2 (P = 0.001–0.01), and (3) development of macular GA (P = 0.005) and preatrophic changes at year 3 (P = 0.002–0.008), but not development of CNV. The ODS at baseline in a local region were associated with (1) presence of preatrophy changes at baseline (P = 0.02-0.03) and (2) development of preatrophy changes at years 2 and 3 within the region (P = 0.008-0.05). Conclusions Optical coherence tomography–reflective drusen substructures are optical coherence tomography–based biomarkers of progression to GA, but not to CNV, in eyes with intermediate AMD. Optical coherence tomography–reflective drusen substructures may be a clinical entity helpful in monitoring AMD progression and informing mechanisms in GA pathogenesis.

Purpose The appearance of geographic atrophy (GA) on color photography (CP) is preceded by specific features on spectral domain optical coherence tomography (SDOCT). We aimed to build SDOCT-based risk assessment models for 5-year new onset of GA and central GA on CP. Design Prospective longitudinal study. Participants Age-related macular degeneration (AMD) patients with bilateral large drusen and/or non-central GA, and at least one eye without advanced disease (n=317) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) Ancillary SDOCT study. Methods For one eye per participant, qualitative and quantitative SDOCT variables were derived, respectively, from standardized grading and semi-automated segmentation at baseline. Up to 7 years later, annual outcomes were extracted and analyzed to fit multivariate logistic regression models and build a risk calculator. Main Outcome Measures New onset of CP-visible GA and central GA. Results Over a follow-up median of 4.0 years and among 292 AMD eyes (without advanced disease at baseline) with complete outcome data, 46 (15.8%) developed central GA. Among a subset of 265 eyes without any GA on baseline CP, 70 (26.4%) developed CP-visible GA. Final multivariate models were adjusted for age. In the model for GA, the independent predicting SDOCT factors (p <0.001 to 0.03) were (1) hyperreflective foci (HF) and (2) retinal pigment epithelium layer atrophy or absence (RPEA), followed by (3) choroidal thickness in absence of subretinal drusenoid deposits, (4) photoreceptor outer segment loss, (5) RPE drusen complex (RPEDC) volume and (6) RPEDC abnormal thinning (RAT) volume. For central GA, the independent predicting SDOCT factors (p<0.001) were (1) RAT volume, (2) intraretinal fluid or cystoid spaces, (3) HF, and (4) RPEA. The models yielded a calculator that computes the probabilities of CP-visible new-onset GA and central GA after 1 through 5 years. Conclusions For AMD eyes with large drusen and no advanced disease, we built a novel risk assessment model – based on age and SDOCT segmentation, drusen characteristics, and retinal pathology – for progression to CP-visible GA over up to 5 years. This calculator may simplify SDOCT grading and, with future validation, have a promising role as a clinical prognostic tool.

We have shown a high prevalence of OHT and glaucoma in eyes with VKH. Furthermore, in addition to secondary open angle from corticosteroid treatment and uveitis, secondary angle closure resulting from posterior synechiae, frequently associated with iris bombé configuration, is an important cause of glaucoma in VKH eyes.

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