Jeong W. Pak, David Lopez, Emily Y. Chew, Barbara A. Blodi,  Amitha Domalpally

Abstract

Purpose: Reticular pseudodrusen (RPD) is associated with increased risk of progression to late age-related macular degeneration (AMD), particularly geographic atrophy (GA). While most studies focused on eyes with intermediate AMD, risk of RPD at earlier stages of disease has been less studied. We aimed to investigate the significance of RPD association with early AMD stages and its role in 2 year progression.

Methods: This is a post hoc analysis from multiple AMD cohorts with multimodal imaging evaluated at the Wisconsin Reading Center. AREDS AMD 12-step severity scale was assessed using color fundus photograph. Eyes with AMD levels 1–4 at baseline and at least 2 annual visits were included (209 eyes, 136 participants). At these levels, pathology is minimal, with maximum drusen area <0.2 disc area (0.5 mm²) and no depigmentation or <0.5 disc area (1.27 mm²). RPD presence was determined by multimodal assessment using autofluorescence and infrared (IR) OCT. Detailed RPD characterization included location within the ETDRS grid, distribution, peripapillary involvement, and pattern. The RPD area was measured using planimetry on IR images.

Results: Baseline included 48 eyes (33 participants) with RPD (23.0%). Among RPD eyes, AMD severity levels were 10% (level 1), 23% (level 2), 12% (level 3), and 54% (level 4), compared to 21%, 31%, 18%, and 30% in no RPD eyes. The proportion of level 4 eyes was significantly higher among eyes with RPD compared with those without RPD (p=0.013), while levels 1–3 did not differ between groups.

None of the eyes progressed to late AMD (GA or neovascular AMD) in 2-year follow-up regardless of RPD status. Two steps or greater progression occurred in 6.3% (3/48) with RPD and 11.2% (18/161) (p=0.42) without RPD. Nine eyes with RPD showed no AMD at baseline and remained as no AMD in 2-year follow-up.

The mean RPD area (SD) was 24.3 (16.1) mm². The majority of RPD was located both within and outside the ETDRS grid (69%), predominantly distributed in 2 or more quadrants (50%), ribbon pattern (50%), and stage 3 and 4 RPD (59%). Peripapillary RPD was seen in 23%.

Conclusions: In early AMD (AREDS levels 1–4), the presence of RPD did not correspond to higher AMD severity nor increased risk of 2-step progression or late AMD over 2 years. These findings contrast with intermediate AMD, where RPD is a well-established risk factor, suggesting that RPD in very early stage of the disease may not confer the same prognostic significance.