Incidence and Progression of Reticular Drusen in Age-related Macular Degeneration: Findings from an Older Australian Cohort

doi:10.1016/j.ophtha.2013.10.043

Ophthalmology

Volume 121, Issue 4, April 2014, Pages 917-925

Presented at: Association for Research in Vision and Ophthalmology Annual Meeting, May 2013, Seattle, Washington.

https://doi.org/10.1016/j.ophtha.2013.10.043 Get rights and content

Purpose

To assess the 15-year incidence and progression of reticular drusen and associations of this lesion with age-related macular degeneration (AMD) risk factors.

Design

Population-based cohort.

Participants

Blue Mountains Eye Study participants (n = 3654) 49 years of age and older attended baseline examinations; of these, 75.8%, 76.7%, and 56.1% of survivors attended 5-year, 10-year, and 15-year follow-up examinations, respectively.

Methods

Color retinal photographs were obtained and comprehensive questionnaires were administered at each visit, and DNA samples were genotyped. Fundus autofluorescence images were not available. Reticular drusen identified from photographs were confirmed with side-by-side grading using the Wisconsin AMD grading protocol. Incidence was assessed using Kaplan-Meier product limit survival methods, controlling for competing risk of death. Associations between smoking, fish consumption, serum lipids, systemic and dietary factors, the CFH single nucleotide polymorphism (SNP) rs1061170 and ARMS2 SNP rs10490924, and the 15-year incidence of reticular drusen were analyzed in discrete logistic regression models. Generalized estimating equation models were used to analyze eye-specific relationships between these risk factors and 5-year progression from reticular drusen to late AMD.

Main Outcome Measures

Incidence and progression of reticular drusen.

Results

The 15-year cumulative incidence of reticular drusen was 4.0% (n = 95). Increasing age (per decade increase; odds ratio [OR], 3.4; 95% confidence interval [CI], 2.6–4.4), female sex (OR, 2.0; 95% CI, 1.3–3.2), and presence of risk alleles of CFH-rs1061170 (OR, 1.8; 95% CI, 1.3–2.4) or ARMS2-rs10490924 (OR, 3.0; 95% CI, 2.1–4.4) were associated with higher reticular drusen incidence. Current smoking at baseline predicted higher reticular drusen incidence (OR 2.1, 95% CI 1.0–4.5) after adjusting for age, sex, CFH-rs1061170 and ARMS2-rs10490924 polymorphisms. Of 118 eyes with reticular drusen, 40 (33.9%) developed late AMD over 5 years. A higher proportion of eyes with reticular drusen located outside versus within the macular area progressed to late AMD (50.0% vs. 37.8%). Dietary lutein–zeaxanthin intake was associated with decreased likelihood of progression from reticular drusen to late AMD (adjusted OR, 0.5; 95% CI, 0.3–1.0).

Conclusions

Known AMD risk factors were associated with greater long-term risk of reticular drusen. Neither total area nor central location of reticular drusen predicted 5-year progression to late AMD. Increased consumption of lutein–zeaxanthin predicted a lower risk of progression.

Section snippets

Population

Details of the BMES have been reported previously.12, 13 Briefly, 3654 permanent residents (82.4% of those eligible) living in 2 postcodes of the Blue Mountains region, west of Sydney, Australia, participated in the study from 1992 through 1994 (baseline examination [BMES I]). Of these, 2334 participants (75.8% of survivors) were examined from 1997 through 1999 (BMES II); 1952 participants (76.7% of survivors) were re-examined from 2002 through 2004 (BMES III); and 1149 participants (56.1% of

Prevalence and Incidence of Reticular Drusen

Reticular drusen were present in 1.95% of the baseline BMES population sample. Of the 65 participants with reticular drusen, in 38 (58.5%), this sign was present in both eyes (bilateral). The copresence of reticular drusen with late AMD occurred in 7 of the total 103 eyes (6.8%) with prevalent reticular drusen.

Incident reticular drusen were identified in 95 (152 eyes) of 2738 participants at risk, with an overall 15-year incidence of 4.0% (95% CI, 3.2–4.8) after controlling for the competing

Discussion

We found an overall 15-year incidence of reticular drusen of 4.0% in this older Australian cohort, with more than 50% of incident cases developing bilaterally. The incidence of reticular drusen rose with increasing age and was significantly higher in women than in men. Current smoking and presence of the rs1061170 in CFH and rs10490924 in ARMS2 risk alleles also were associated independently with higher 15-year incidence of reticular drusen. A substantially higher proportion (34%) of eyes with

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Cited by (91)

Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration
2022, American Journal of Ophthalmology
Citation Excerpt :
Furthermore, both of these previous population-based studies did not account for important conventional risk factors for late AMD development, such as the extent of drusen present (or even the presence of large [>125-µm] drusen alone1) and the presence of pigmentary abnormalities in a multivariable model when evaluating if RPD is an independent risk factor for progression.22,23 For instance, the finding by Joachim and associates23 that RPD is associated with a 14-fold increased risk of developing GA over a 15-year period is made in comparison to those with no or small (hard) drusen only. Their study also reported that the presence of soft indistinct drusen was associated with a 29-fold increased risk of progression compared to the presence of no or small (hard) drusen.
To examine the association between reticular pseudodrusen (RPD) and progression to late age-related macular degeneration (AMD) in individuals with intermediate AMD.
Prospective cohort study.
Two hundred eighty eyes from 140 participants with bilateral large drusen underwent multimodal imaging (MMI), including optical coherence tomography (OCT), near-infrared reflectance (NIR), fundus autofluorescence, and color fundus photography (CFP), at 6-monthly intervals up over a 36-month follow-up period. The presence of RPD per eye was determined based on either a combined MMI criterion, or each individual imaging modality, and their extent measured on combined OCT and NIR imaging. The association between the presence of RPD on different imaging modalities, and their extent, with the development of late AMD (including OCT-defined atrophy) was evaluated.
The presence of RPD on MMI, or any of its individual modalities, at baseline was not significantly associated with an increased rate of developing late AMD, with or without adjusting for risk factors for AMD progression (age, drusen volume on OCT, and pigmentary abnormalities on CFP; all P ≥ 0.205). The extent of RPD present was also not significantly associated with an increased rate of developing late AMD, with or without adjustment for risk factors for AMD progression (both P ≥ 0.522).
In this cohort with bilateral large drusen, the presence of RPD was not significantly associated with an increased risk of developing late AMD. Additional longitudinal studies in all stages of AMD are needed to understand the implications of RPD on vision loss in this condition.
Reticular pseudodrusen: A critical phenotype in age-related macular degeneration
2022, Progress in Retinal and Eye Research
Citation Excerpt :
The Beaver Dam Eye Study observed that 33 eyes with CFP-defined RPD showed a significantly higher 15-year likelihood of developing late AMD compared 1174 eyes with either soft distinct or indistinct drusen (Klein et al., 2008). Similarly, the Blue Mountains Eye Study reported that 40 (34%) out of 118 eyes with prevalent or incident CFP-defined RPD developed late AMD over a 5-year period, compared to 62 (8%) out of 722 eyes with other early AMD lesions (Joachim et al., 2014). However, no adjustments for the maximum drusen size, drusen extent, presence of pigmentary abnormalities, or AMD severity at the individual level, were performed in these two population-based studies.
Reticular pseudodrusen (RPD), or subretinal drusenoid deposits (SDD), refer to distinct lesions that occur in the subretinal space. Over the past three decades, their presence in association with age-related macular degeneration (AMD) has become increasingly recognized, especially as RPD have become more easily distinguished with newer clinical imaging modalities. There is also an increasing appreciation that RPD appear to be a critical AMD phenotype, where understanding their pathogenesis will provide further insights into the processes driving vision loss in AMD. However, key barriers to understanding the current evidence related to the independent impact of RPD include the heterogeneity in defining their presence, and failure to account for the confounding impact of the concurrent presence and severity of AMD pathology. This review thus critically discusses the current evidence on the prevalence and clinical significance of RPD and proposes a clinical imaging definition of RPD that will help move the field forward in gathering further key knowledge about this critical phenotype. It also proposes a putative mechanism for RPD formation and how they may drive progression to vision loss in AMD, through examining current evidence and presenting novel findings from preclinical and clinical studies.
Genetics of reticular pseudodrusen in age-related macular degeneration
2022, Trends in Genetics
Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.
Population-Based Prevalence and 5-Year Change of Soft Drusen, Pseudodrusen, and Pachydrusen in a Japanese Population
2021, Ophthalmology Science
To elucidate the prevalence of soft drusen, pseudodrusen, and pachydrusen and their 5-year changes in a Japanese population.
Longitudinal population-based cohort study conducted from 2013 through 2017.
Residents 40 years of age or older.
Nonmydriatic color fundus photographs were used to grade drusen subtypes and retinal pigment epithelium (RPE) abnormalities according to the Three Continent Age-Related Macular Degeneration Consortium. The 5-year changes of each drusen were investigated.
The prevalence of each drusen subtype and the 5-year changes of each drusen.
Among 1731 participants, 1660 participants had gradable photographs that were assessed. The age-adjusted prevalence of soft drusen, pachydrusen, and pseudodrusen was 4.3% (95% confidence interval [CI], 3.2%–5.8%), 7.7% (95% CI, 6.2%–9.7%), and 2.8% (95% CI, 1.7%–4.2%), respectively. Pachydrusen accounted for 82.0% (n = 50) of the extramacular drusen (n = 61). Pigment abnormalities were seen in 28.3% and 8.3% of eyes with soft drusen and pachydrusen, respectively (P < 0.0001). Longitudinal changes were investigated in 1444 participants with follow-up examinations, which showed an increase in size in 8.3% and 3.7% and regression in 1.7% and 5.5% for eyes with soft drusen and pachydrusen, respectively. No participants demonstrated RPE atrophy after pachydrusen regression.
The prevalence of pachydrusen was higher than that of soft drusen and pseudodrusen combined. Pachydrusen may regress over time and typically is not associated with RPE atrophy as detected using color fundus photographs.
Reticular Pseudodrusen in Late-Onset Retinal Degeneration
2021, Ophthalmology Retina
To characterize the association of reticular pseudodrusen (RPD) with late-onset retinal degeneration (L-ORD) using multimodal imaging.
Prospective, 2-center, longitudinal case series.
Twenty-nine patients with L-ORD.
All patients were evaluated within a 3-year interval with near-infrared reflectance, fundus autofluorescence, and spectral-domain OCT. In addition, a subset of patients also underwent indocyanine green angiography, fundus fluorescein angiography, mesopic microperimetry, and multifocal electroretinography.
Prevalence, topographic distribution, and temporal phenotypic changes of RPD in L-ORD.
A total of 29 patients with molecularly confirmed L-ORD were included in this prospective study. Reticular pseudodrusen was detected in 18 patients (62%) at baseline, 10 of whom were men. The prevalence of RPD varied with age. The mean age of RPD patients was 57.3 ± 7.2 years. Reticular pseudodrusen was not seen in patients younger than the fifth decade of life (n = 3 patients) or in the eighth decade of life (n = 5 patients). Reticular pseudodrusen were found commonly in the macula with relative sparing of the fovea and also were identified in the peripheral retina. The morphologic features of RPD changed with follow-up. Two patients (3 eyes) demonstrated RPD regression.
Reticular pseudodrusen is found frequently in patients with L-ORD and at a younger age than in individuals with age-related macular degeneration (AMD). Reticular pseudodrusen exhibits quick formation and collapse, change in type and morphologic features with time, and relative foveal sparing and also has a peripheral retinal location in L-ORD.
Reticular Pseudodrusen Characteristics and Associations in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2), an Ancillary Study of the Women's Health Initiative
2021, Ophthalmology Retina
To determine the prevalence and morphologic features of reticular pseudodrusen (RPD) and their association with participant demographics and age-related macular degeneration (AMD) status in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2) sample, an ancillary study of the Women’s Health Initiative Observational Study.
Cross-sectional, multicenter, natural history study.
Nine hundred and twenty-seven eyes from 466 postmenopausal women 69 to 101 years of age.
Multimodal imaging, including spectral-domain (SD) OCT and infrared reflectance (IR), were used to identify RPD characteristics, including location (within or outside the 6-mm diameter circle centered at the macula), presence of peripapillary RPD, pattern of RPD, and RPD area. Age-related macular degeneration features from SD OCT, IR, and color photographs also were assessed and AMD severity was categorized.
Reticular pseudodrusen prevalence using SD OCT and IR imaging and AMD status.
Reticular pseudodrusen were present in 130 eyes (14% of eyes, 16% of participants), with increasing prevalence with age: 7% in those younger than 78 years, 14% in those 78 to 83 years of age, and 30% in those older than 83 years. Using clinical classification of AMD with color photography, RPD were seen in 2.4% of eyes with no AMD or aging changes, 11.5% in early AMD, 25.1% in intermediate AMD, and 51.1% in late AMD. Mean RPD area was 17.4 mm² (standard deviation, 14.7 mm²). Ribbon morphologic RPD (53%) was more common than dot morphologic RPD (36%). Reticular pseudodrusen mostly were located both within and outside the 6-mm circle with primarily superior retinal distribution. Reticular pseudodrusen were visualized with corresponding color fundus photography in only 38 eyes (4% of total eyes). Participants with and without RPD had a visual acuity±standard error of 77.9 ± 1.4 letters and 81.3 ± 0.4 letters, respectively (P = 0.02).
The prevalence of RPD in CAREDS2 increased with age and was associated with AMD severity. Reticular pseudodrusen were detected in eyes without other features of AMD and could represent an earlier disease state. Multimodal imaging with SD OCT and IR has significantly greater sensitivity for visualizing RPD than color fundus photography.

View all citing articles on Scopus

: Financial Disclosure(s): The author(s) have made the following disclosure(s): Paul Mitchell - Consultant - Novartis, Inc., Bayer, Inc.

: Supported by the National Health and Medical Research Council, Canberra, Australia (grant nos.: 974159, 211069, and 457349). The sponsor had no role in the design or conduct of this research.

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Original articleIncidence and Progression of Reticular Drusen in Age-related Macular Degeneration: Findings from an Older Australian Cohort

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Population

Prevalence and Incidence of Reticular Drusen

Discussion

Ophthalmology

Am J Ophthalmol

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

J Am Diet Assoc

Atherosclerosis

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Prog Retin Eye Res

Ophthalmology

Evolution of reticular pseudodrusen

Br J Ophthalmol

The epidemiology of retinal reticular drusen

Am J Ophthalmol

Reticular pseudodrusen. A risk factor in age-related maculopathy

Retina

Original article
Incidence and Progression of Reticular Drusen in Age-related Macular Degeneration: Findings from an Older Australian Cohort