Optical Coherence Tomography Reflective Drusen Substructures Predict Progression to Geographic Atrophy in Age-related Macular Degeneration

Abstract

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.

Multimodal Imaging Patterns for Development of Central Atrophy Secondary to Age-Related Macular Degeneration

“…29 A better classification that becomes widely established would be also helpful for interpretation of other potential precursor lesions that have been recently described by SD-OCT, such as thinning of retinal layers in the presence of drusen regression, evolution of HRF, and disintegrated RPE dots. 23,[26][27][28][47][48][49][50][51] Various limitations of this study need to be considered. The number of included subjects is relatively small, and a substantial high number of subjects dropped out of this natural history study (a total of 32.7% at year 6).…”

“…Furthermore, the Age-Related Eye Disease studies (AREDS 1 and AREDS 2) have reported the development of atrophy based on definitions by CFP in eyes with early and intermediate AMD (iAMD). 21,23 While CFP assessment has been established as the gold standard in clinical AMD trials, the ability to detect early stages of atrophy and precursor lesions is challenging due to low contrast and limited resolution. 24 Using high-resolution multimodal imaging, in particular spectral-domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy (cSLO) fundus autofluorescence (FAF), the evolution of atrophy has been scrutinized in more detail.…”

“…24 Using high-resolution multimodal imaging, in particular spectral-domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy (cSLO) fundus autofluorescence (FAF), the evolution of atrophy has been scrutinized in more detail. 23,[25][26][27][28] Among those observations, ''nascent GA'' as part of the chronological appearance of drusen-associated atrophy development has been analyzed by Wu et al 26 Recently, the Classification of Atrophy Meetings (CAM) group defined OCT-based criteria for complete RPE and outer retinal atrophy (cRORA) as atrophy in AMD. 29 The aim of the current study was to analyze the incidence and development of central atrophy in AMD eyes that were considered at high risk for development of late AMD stages.…”

Optical Coherence Tomography Predictors of Risk for Progression to Non-Neovascular Atrophic Age-Related Macular Degeneration

“…12 In the intermediate stage of AMD, various drusen-related patterns of reflectivity on SDOCT have been discovered, 8–14 and found to be early indicators of advancing disease. 14–21 It had been unknown if such SDOCT features implied a risk of progression to choroidal neovascularization or played a role in the sequence of degeneration in geographic atrophy (GA). Previous reports from the A2A SDOCT Study discovered features of intermediate AMD on SDOCT that can serve as biomarkers of disease progression, such as hyperreflective foci (HF).…”

“…Previous reports from the A2A SDOCT Study discovered features of intermediate AMD on SDOCT that can serve as biomarkers of disease progression, such as hyperreflective foci (HF). 14,18–21 Incidence of new-onset GA on CP followed after the qualitative SDOCT findings of atypical drusen (i.e. high or low internal reflectivity) 12 , OCT-reflective drusen substructures (ODS, i.e.…”