Local Anatomic Precursors to New-Onset Geographic Atrophy in Age-Related Macular Degeneration as Defined on OCT

Abstract

Purpose: In macula-wide analyses, spectral-domain (SD) optical coherence tomography (OCT) features including drusen volume, hyperreflective foci, and OCT-reflective drusen substructures independently predict geographic atrophy (GA) onset secondary to age-related macular degeneration (AMD). We sought to identify SD OCT features in the location of new GA before its onset.

Design: Retrospective study.

Participants: Age-Related Eye Disease Study 2 Ancillary SD OCT Study participants.

Methods: We analyzed longitudinally captured SD OCT images and color photographs from 488 eyes of 488 participants with intermediate AMD at baseline. Sixty-two eyes with sufficient image quality demonstrated new-onset GA on color photographs during study years 2 through 7. The area of new-onset GA and one size-matched control region in the same eye were segmented separately, and corresponding spatial volumes on registered SD OCT images at the GA incident year and at 2, 3, and 4 years previously were defined. Differences in SD OCT features between paired precursor regions were evaluated through matched-pairs analyses.

Main outcome measures: Localized SD OCT features 2 years before GA onset.

Results: Compared with paired control regions, GA precursor regions at 2, 3, and 4 years before (n = 54, 33, and 25, respectively) showed greater drusen volume (P = 0.01, P = 0.003, and P = 0.003, respectively). At 2 and 3 years before GA onset, they were associated with the presence of hypertransmission (P < 0.001 and P = 0.03, respectively), hyperreflective foci (P < 0.001 and P = 0.045, respectively), OCT-reflective drusen substructures (P = 0.004 and P = 0.03, respectively), and loss or disruption of the photoreceptor zone, ellipsoid zone, and retinal pigment epithelium (RPE, P < 0.001 and P = 0.005-0.045, respectively). At 4 years before GA onset, precursor regions were associated with photoreceptor zone thinning (P = 0.007) and interdigitation zone loss (P = 0.045).

Conclusions: Evolution to GA is heralded by early local photoreceptor changes and drusen accumulation, detectable 4 years before GA onset. These precede other anatomic heralds such as RPE changes and drusen substructure emergence detectable 1 to 2 years before GA. This study thus identified earlier end points for GA as potential therapeutic targets in clinical trials.

Keywords: Age-Related Eye Disease Study 2; Age-related macular degeneration; Geographic atrophy; Localized precursors; Spectral-domain OCT.

Figure 1.

Flowchart on subset of participants from Age-Related Eye Disease Study 2 (AREDS2) enrolled in the present study. This study included 62 eyes of 62 participants with new onset geographic atrophy (GA).

Figure 2.

a-b. Graphical representation of mean and mean of differences between geographic atrophy and control regions (GA – Control) with respect to retinal pigment epithelium drusen complex (RPEDC) volume across all study years. c-d. Graphical representation of mean and mean of differences between geographic atrophy and control regions with respect to RPEDC abnormal thinning (RAT) volume across all study years. e-f. Graphical representation of mean and mean of differences between geographic atrophy and control regions with respect to RPEDC Abnormal Thickening volume across all study years. g-h. Graphical representation of mean and mean of differences between geographic atrophy and control regions with respect to neurosensory retinal (NSR) volume across all study years. Note: The 2 lines were not statistically compared because the individual values were paired.

Figure 3.

Color photographs (CP), spectral domain optical coherence tomography (SDOCT) B-scans at the site of the green line on CP, and SDOCT-derived retinal pigment epithelium drusen complex (RPEDC) thickness maps for the 5 mm diameter macular region, at year of new onset geographic atrophy (GA) (bottom row) and at one (first row from bottom), two (second row from bottom), three (third row from bottom) and four (fourth row from bottom) years prior to new onset of GA for a single study eye. On thickness maps, the dark gray areas designate RPEDC which is in the normal range of thickness in contrast to red and orange tones which designate areas of RPEDC Abnormal Thickening volume and blue tones which designate RPEDC Abnormal Thinning (RAT) volume. The region of interest (ROI) containing new onset GA is shown on the CP and SDOCT-derived thickness map at GA incident year (white circles, bottom row) and project to the white lines on the B-scan. The white circles in the rows above track the locations of this ROI at one, two, three, and four years prior to new onset GA. (The control ROI is shown as a gray circle on the CP in the bottom row and as a tracked location in the rows above; however these ROIs are not projected onto the B-scans or thickness maps). The ROI containing new onset GA correspond to atrophic changes on the CP (increased visibility of choroidal vessels, sharp edges, roughly circular shape, depigmentation), B-scan (loss of photoreceptor zone and RPE, hypertransmission), and thickness map (blue tone). The 3-year, 2-year and 1-year precursor regions correspond to drusen on CP; drusen, progressive thinning/loss of the external limiting membrane, photoreceptor zone, ellipsoid zone, interdigitation zone, and RPE, as well as hypertransmission on B-scan; thickened drusen on the thickness map. The 4-year precursor region is similar on the CP and thickness map; on B-scan, drusen, early thinning/loss of the photoreceptor zone, ellipsoid zone, interdigitation zone, and RPE is apparent. Note the OCT-reflective drusen substructure (conical debris subtype, indicated with a red arrow) on the 3-year precursor B-scan, which collapses into an atrophic region in the 2-year precursor B scan. Adjacent to this atrophic region on the 2-year precursor B scan, there is a new OCT-reflective drusen substructure (conical debris subtype, also indicated with a red arrow).