Natural History of Drusenoid Pigment Epithelial Detachment Associated with Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report No. 17

Abstract

Purpose: To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD).

Design: Retrospective analysis of a prospective cohort study.

Participants: Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED.

Methods: Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan-Meier analyses and multivariable proportional hazard regressions were performed.

Main outcome measures: Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype.

Results: Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98-2.82; P < 0.001); 67% of eyes progressed to late AMD 5 years after DPED detection. Drusenoid pigment epithelial detachment was associated with increased risk of ≥3 lines of VA loss (HR, 3.08; CI, 2.41-3.93; P < 0.001) with 46% of eyes experiencing vision loss at 5 years (with or without progression to late AMD). ARMS2 risk alleles (1 vs. 0: HR, 2.72, CI, 1.58-4.70; 2 vs. 0: HR, 3.16, CI, 1.60-6.21, P < 0.001) and increasing GRS group (4 vs. 1) (HR, 12.17, CI, 3.66-40.45, P < 0.001) were significantly associated with DPED development in AREDS. There were no significant genetic results in AREDS2.

Conclusions: This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Figure 1:

Kaplan-Meier curves for progression to late age-related macular degeneration by year after drusenoid pigment epithelial detachment (DPED) detection

Figure 2:

Prevalence of fundus features in eyes with drusenoid pigment epithelial detachment (DPED) that did not progress to late age-related macular degeneration by year

Figure 3:

Average visual acuity score plotted over time for eyes with central DPED Footnotes: DPED = drusenoid pigment epithelial detachment; CGA = central geographic atrophy; NV-AMD = neovascular age-related macular degeneration; AMD = age-related macular degeneration. Eighty letters of visual acuity translates to Snellen visual acuity of 20/25. Analyses exclude the 18 eyes with DPED located greater than 500 μ m away from the fovea.

Figure 4:

Kaplan-Meier curves for percentage of eyes losing ≥ 15 letters from time of DPED detection for eyes with central DPED Footnotes: DPED = drusenoid pigment epithelial detachment; CGA = central geographic atrophy; NV-AMD = neovascular age-related macular degeneration; AMD = age-related macular degeneration. Analyses exclude the 18 eyes with DPED located greater than 500 μ m away from the fovea.

Figure 5:

These fundus photographs demonstrate the natural course of bilateral drusenoid pigment epithelial detachments of an AREDS2 participant who was a 61 year old white female. Baseline fundus photographs of both eyes (Figures 5A [right eye] and B [left eye]) showed presence of bilateral, confluent large drusen. Visual acuities were 20/16 and 20/25, right and left eyes respectively. At one year follow-up, bilateral DPEDs were detected and the fundus photographs demonstrated elevated mounds of confluent drusen (Figures 5C and D) and retinal pigment epithelial hyperpigmentary changes (Figure 5C). The visual acuities were 20/25 and 20/30, right and left eyes respectively. Both DPEDs began to regress one year later (Figures 5E and F), giving way to geographic atrophy in the right eye (Figure 5E) and the development of retinal pigmentary changes in the left eye (Figure 5F). Further changes of geographic atrophy are seen in both eyes through the next 2 years of follow-up (Figures 5G, H, I and J). Visual acuities remained 20/25 and 20/30, right and left eyes, respectively throughout the entire follow-up as the fovea was preserved in both eyes.

Figure 6:

This 65 year old man developed drusenoid pigment epithelial detachment in his left eye in year 2 of his follow up with visual acuity of 20/40. The DPED resulted in central geographic atrophy 1 years later, with visual acuity ot 20/250.

Figure 7:

This 81 year white female had baseline large drusen (Figure 7A) which increased in area (Figure 7B) over the next year. Drusenoid pigment epithelial detachment (DPED) was detected in year 4 of the study (Figure 7C) and the regression of the DPED was accompanied by the progression to neovascular AMD 2 years later (Figure 7D). Anti-vascular endothelial growth factor therapy was administered. Visual acuity remained, on the average, around 20/30 throughout the course of the study.