Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration

Written by: Andrew Tye, MD

January 2020

Domalpally AD, Agron E, Pak JW, et al. Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration (Age-Related Eye Disease Study 2 Report 21). Ophthalmology 2019; 126: 1659-66.

In recent years, reticular pseudodrusen (RPD) have become their own distinct category from drusen; histopathology has confirmed that RPD are located in the subretinal space vs. below the retinal pigmented epithelium (drusen). RPD are best recognized with multimodal imaging techniques such as optical coherent tomography (OCT), infrared imaging, and autofluorescence. RPD have been recognized as a risk marker for progression to geographic atrophy and neovascular AMD, particularly retinal angiomatous proliferation, in advanced age-related macular degeneration (AMD). To date, this observation has been characterized in cross-sectional studies showing RPD association with late stages of AMD, and prospective studies of high-risk eyes where RPD confers additional risk of progression.

This study evaluated RPD in the 5021 eyes (2516 participants) of the AREDS2 cohort. The authors’ purpose was to determine the prevalence of RPD in eyes with intermediate AMD, assess the role of RPD as an independent risk factor for progression to late AMD, and evaluate genetic associations of RPD. The authors used digital color fundus photos and autofluorescence images to identify eyes with RPD.

RPD were seen in 1186 eyes (24% of eyes, 29% of participants), were more frequent in female participants (65% RPD vs. 53% no RPD), older age, and baseline AREDS severity: 6% in early AMD, 26% in intermediate AMD, 36% in geographic atrophy, and 19% in neovascular AMD. An odds ratio (adjusted for baseline age, gender, race, education, smoking, and AMD severity) was calculated for 1710 eyes at risk of developing late AMD at the next annual visit. The authors found that in the AREDS2 cohort, participants with RPD have an increased risk of progression to geographic atrophy (p<0.001) but not neovascular AMD (p=0.26). This amplified risk of progression was seen at every level of the AREDS scale, although was found to be higher (nearly 10-fold) in eyes with RPD at earlier stages of AMD (level 1-5). The presence of RPD was also significantly associated with higher GRS and ARMS2 risk alleles (p<0.0001), and nominally associated with C3 and CFH risk alleles (p≥0.04).

This study is the first large longitudinal multicenter study evaluating RPD in early AMD to assess its role in progression to late AMD over 5 years. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis.

One of the major limitations to prognostication with RPD is the proper recognition of RPD due to the subtle nature of their appearance. Studies have shown that infrared imaging and OCT are the best detection modalities, which were not available for use in this study. The authors argue that they circumvented these issues by using 2 independent readers who had an agreement of 94% in identifying RPD presence. However, it is possible that some eyes that had RPD were not recognized due to study method limitations. Additionally, while the AREDS2 cohort is a large study population, additional characteristics of RPD such as progression, regression, area, and patterns, were not included in this risk profile analysis.

The pathogenesis and pathologic role of RPD remains to be fully understood. With improved understanding and better recognition of this phenotype in AMD eyes, future studies will help improve patient prognostication, stratify higher risk eyes, and possibly guide treatment planning in the future of caring for AMD patients.