Pseudodrusen Signals Late Age-Related Macular Degeneration Progression Risk

Scan of eyes showing macular degeneration
Scan of eyes showing macular degeneration
Researchers suggest that reticular pseudodrusen status be included in updated age-related macular degeneration classification systems, risk calculators, and clinical trials.

The presence of reticular pseudodrusen (RPD) upon fundus autofluorescence imaging indicates a significant risk factor for progression to late age-related macular degeneration (AMD), particularly geographic atrophy (GA), according to a study published in Ophthalmology.  

Researchers collected data from the Age-Related Eye Disease Study (AREDS) ( Identifier: NCT00000145) and AREDS2 ( Identifier NCT00345176). AREDS included 6959 eyes of 3780 patients (mean age 69.4 years), while AREDS2 included 3355 eyes of 2056 patients. The teams performed comprehensive eye exams and color fundus photography (CFP) on all participants in both investigations. Researchers graded CFP for soft drusen, pigmentary abnormalities, and late AMD. They identified RPD presence by grading fundus autofluorescence images (AREDS2) or through deep learning grading of CFP (AREDS). The team performed proportional hazards regression analyses while evaluating RPD presence through severity scales (AREDS) and a 9-step scale. 

The number of eyes with RPD at baseline (AREDS) was 368 (5.3%). The number of eyes that progressed to late AMD, during a mean follow-up period of  8.8 years, was 1183 (17.0%) eyes of 911 participants.

After analyzing AREDS data, the researchers identified an association between RPD and increased AMD progression (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, 95% CI, 1.60-6.51; HR, 3.81, 95% CI, 2.38-6.10; HR, 2.28, 95% CI, 1.59-3.27 and HR, 1.64, 95% CI, 1.20- 2.24, at levels 0-1/2/3/4, respectively). They confirmed this association with a 9-step scale (HR, 2.54, 95% CI, 2.07-3.13). The HRs were 5.11 (95% CI, 3.93-6.66) at levels 1-6 and 1.78 (95% CI, 1.43-2.22) at 7-8. 

After considering AREDS2 data by participant, the team determined that RPD presence was not associated with higher AMD progression risk (HR, 1.18, 95% CI, 0.90-1.56).  However, they did note an association between RPD and AMD progression risk when considering data by eye (HR, 1.57, 95% CI, 1.31-1.89). The team observed no significant differences in risk according to severity levels. 

In both cohorts, RPD presence carried a higher risk for GA than neovascularization (NV).  RPD represents a third macular risk factor for increased risk of progression to late AMD that may be at least partially independent of soft drusen and pigmentary abnormalities, according to the report. 

“RPD status must be considered in combination with the traditional features for an accurate understanding of progression risk and subtype predictions,” according to the investigators. “Ideally, RPD status should be included in updated AMD classification systems and risk calculators, as well as clinical trials.”

Study limitations include the absence of reading center grading of RPD presence due to a lack of fundus autofluorescence in AREDS and the failure to analyze associations according to RPD area or the number of lesions. 


Agrón E, Domalpally A, Cukras CA, Clemons TE, Chew EY, Keenan TDL. Reticular pseudodrusen: The third macular risk feature for progression to late age-related macular degeneration. Ophthalmology. Published online May 31, 2022. doi:https:10.1016/j.ophtha.2022.05.021