Reticular Pseudodrusen: the Third Macular Risk Feature for Progression to Late Age-related Macular Degeneration

Ophthalmology. 2022 May 31;S0161-6420(22)00410-9. doi: 10.1016/j.ophtha.2022.05.021. Online ahead of print.


Purpose: To analyze reticular pseudodrusen (RPD) as an independent risk factor for progression to late age-related macular degeneration (AMD), alongside traditional macular risk factors (soft drusen and pigmentary abnormalities) considered simultaneously.

Design: Post hoc analysis of two clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2.

Participants: Eyes with no late AMD at baseline in AREDS (n=6959 eyes, 3780 participants; mean age 69.4y) and AREDS2 (n=3355 eyes, 2056 participants; mean age 72.3y).

Methods: Color fundus photographs (CFP) from annual study visits were graded for soft drusen, pigmentary abnormalities, and late AMD. RPD presence was determined by grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFP (AREDS). Proportional hazards regression analyses were performed, considering AREDS AMD severity scales (modified simplified severity scale (person) and 9-step scale (eye)) and RPD presence simultaneously.

Main outcome measures: Progression to late AMD, geographic atrophy (GA), and neovascular AMD (NV).

Results: In AREDS, for late AMD analyses by person, in a model considering the modified simplified severity scale simultaneously, RPD presence was associated with higher risk of progression: hazard ratio (HR) 2.15 (95% CI 1.75-2.64). However, the risk associated with RPD presence differed significantly at different simplified severity scale levels: HR 3.23 (1.60-6.51), 3.81 (2.38-6.10), 2.28 (1.59-3.27), and 1.64 (1.20-2.24), at levels 0-1/2/3/4, respectively. Considering the 9-step scale (by eye), RPD presence was also associated with higher risk: HR 2.54 (2.07-3.13). The HRs were 5.11 (3.93-6.66) at levels 1-6 and 1.78 (1.43-2.22) at 7-8. In AREDS2, by person, RPD presence was not associated with higher risk: HR 1.18 (0.90-1.56); by eye, it was: HR 1.57 (1.31-1.89). No significant differences in risk were observed at different severity levels, for the limited spectrum in AREDS2. In both cohorts, RPD presence carried higher risk for GA than NV.

Conclusions: RPD represent an important anatomical risk factor for progression to late AMD, particularly GA. However, the added risk associated with RPD varies markedly by severity level. It carries highly increased risk at lower/moderate levels and less increased risk at higher levels. RPD status should be included in updated AMD classification systems, risk calculators, and clinical trials.