Clinical Characteristics of Reticular Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration

doi:10.1016/j.ophtha.2014.03.015

Ophthalmology

Volume 121, Issue 9, September 2014, Pages 1748-1755

https://doi.org/10.1016/j.ophtha.2014.03.015 Get rights and content

Purpose

To describe associations between reticular pseudodrusen, individual characteristics, and retinal function.

Design

Cohort study.

Participants

We recruited 105 patients (age range, 52–93 years) who had advanced neovascular age-related macular degeneration (AMD) in only 1 eye from 3 clinical centers in Europe.

Methods

Minimum follow-up was 12 months. The eye selected for study was the fellow eye without advanced disease. Clinical measures of vision were distance visual acuity, near visual acuity, and results of the Smith-Kettlewell low-luminance acuity test (SKILL). Fundus imaging included color photography, red-free imaging, blue autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and optical coherence tomography using standardized protocols. These were used to detect progression to neovascular AMD in the study eye during follow-up. All imaging outputs were graded for the presence or absence of reticular pseudodrusen (RPD) using a multimodal approach. Choroidal thickness was measured at the foveal center and at 2 other equidistant locations from the fovea (1500 μm) nasally and temporally. Metrics on retinal thickness and volume were obtained from the manufacturer-supplied automated segmentation readouts.

Main Outcome Measures

Presence of RPD, distance visual acuity, near visual acuity, SKILL score, choroidal thickness, retinal thickness, and retinal volume.

Results

Reticular pseudodrusen was found in 43 participants (41%) on 1 or more imaging method. The SKILL score was significantly worse in those with reticular drusen (mean score ± standard deviation [SD, 38±12) versus those without (mean score ± SD, 33±9) (P = 0.034). Parafoveal retinal thickness, parafoveal retinal volume, and all of the choroidal thickness parameters measured were significantly lower in those with reticular drusen than in those without. The presence of RPD was associated with development of neovascular AMD when corrected for age and sex (odds ratio, 5.5; 95% confidence interval, 1.1–28.8; P = 0.042). All participants in whom geographic atrophy developed during follow-up had visible RPD at baseline.

Conclusions

Significant differences in retinal and choroidal anatomic features, visual function, and risk factor profile exist in unilateral neovascular AMD patients with RPD compared with those without; therefore, such patients should be monitored carefully because of the risk of developing bilateral disease.

Section snippets

Methods

The study adhered to the tenets of the Declaration of Helsinki on research using human volunteers and was approved by the institutional review board or ethics committees of each of the participating institutions. The protocol was explained in full to all subjects and written informed consent was obtained.

Results

Participants (n = 105) were between 52 and 93 years of age (mean, 75.6 years; standard deviation [SD], 7.5 years; Table 1). Reticular pseudodrusen was found in 43 participants (41%) on 1 or more imaging method. On color fundus grading, most eyes exhibited at least 1 of the following features: small drusen larger than 63 μm in 81 eyes (76%), hypopigmentation in 60 eyes (57%), and hyperpigmentation in 41 eyes (39%). Between-grader repeatability (κ statistics) for each imaging method was as

Discussion

Motivated by the current interest in the significance of RPD in the context of AMD, this prospective study incorporating multimethod imaging and clinical measures of visual function identified novel associations and confirmed findings from previous studies. The prevalence of RPD (41%) in the present study is in accordance with previous studies indicating an association between this drusen phenotype and the development of late AMD manifestations. Our findings indicate a slightly higher

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Cited by (93)

Reticular Pseudodrusen: Interreader Agreement of Evaluation on OCT Imaging in Age-Related Macular Degeneration
2023, Ophthalmology Science
To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence.
Interreader agreement study.
Twelve readers from 6 reading centers.
All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image.
Interreader agreement, as assessed by Gwet’s first-order agreement coefficient (AC₁).
When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC₁ = 0.60–0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC₁ = 0.58–0.65) and increasing levels of agreement with increasing RPD stage (AC₁ = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC₁ = 0.68), but only fair agreement for this evaluation on selected B-scans (AC₁ = 0.30).
There was generally substantial or near-substantial—but not near-perfect—agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading.
Proprietary or commercial disclosure may be found after the references.
Investigation of the choroidal structure in non-neovascular age-related macular degeneration patients with reticular pseudodrusen
2023, Photodiagnosis and Photodynamic Therapy
This study aimed to compare choroidal thickness, total choroidal area (TCA), luminal area (LA), stromal area (SA) and choroidal vascularity index (CVI) in patients with reticular pseudodrusen (RPD) and drusen.
A total of 100 eyes of 100 patients with non-neovascular age related macular degeneration (AMD) with five or more medium drusen (63–125 µm) and RPD in two or more quadrants were recruited to the study. 48 eyes of 48 patients with RPD were assigned as Group 1 and 52 eyes of 52 patients with drusen were assigned as Group 2. 40 right eyes of 40 healthy subjects were included as controls. Patients with neovascular AMD or advanced non-neovascular AMD were excluded from the study. After a detailed ophthalmic examination, infrared reflectance images and OCT with enhanced depth imaging mode was obtained from all patients. TCA, SA, LA and CVI were calculated using the Image J program. The data were analyzed for statistics using SPSS software.
The female/male ratio was 56/44 in the patient groups and 20/20 in the control group. The mean age was 73.63±6.14 (61–91) years for Group 1 and 69.43± 6.97 (59–87) years for Group 2 (p=0.005). The mean age of Group 3 patients was 71.14±8.17 (60–79) years and was statistically similar to Groups 1 and 2 (p=0.09 and p=0.12, respectively). Choroidal thickness, TCA, SA and LA were significantly lower in Group 1 (p<0.001). CVI and foveal thicknesses were not significantly different between Group 1 and 2 (p=0.214 and p=0.384 respectively). CVI was significantly lower in Group 3 (p<0.01). RPD was most commonly seen in the superior quadrant followed by temporal, nasal, and inferior quadrants.
TCA, SA and LA, which reflect choroidal vasculature, were decreased in patients with RPD. These parameters can help evaluate the pathophysiology of the disease.
Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration
2022, American Journal of Ophthalmology
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 :
Given the high spatial colocalization of these lesions on NIR with subretinal accumulations on OCT imaging (Querques et al., 2011; Schmitz-Valckenberg et al., 2010; Spaide, 2014), we and others have previously defined RPD as being present when corroborating evidence is detected on these two imaging modalities simultaneously (Boddu et al., 2014; Cleland et al., 2020; Finger et al., 2014b; Puche et al., 2013; Wu et al., 2015, 2016a). RPD defined on OCT imaging based on the presence of discrete lesions with sharp peaks – likely corresponding to “dot SDDs” only – were detected by NIR imaging in 88% eyes in one previous study, although at a specificity of 83% (Hogg et al., 2014). A more recent study of eyes with AMD also observed that 83% of eyes with “dot SDDs” on OCT imaging were detected with NIR imaging with a specificity of 91%, whilst only 10% of eyes with “ribbon SDDs” were detected with NIR imaging with a specificity of 100% (Cozzi et al., 2020).
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.
Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30
2022, Ophthalmology
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.
Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2.
Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants).
Color fundus photographs (CFPs) from annual visits were graded for soft drusen, pigmentary abnormalities, and late AMD. Presence of RPD was from grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFPs (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.
Progression to late AMD, geographic atrophy (GA), and neovascular AMD.
In AREDS, for late AMD analyses by person, in a model considering the simplified severity scale simultaneously, RPD presence was associated with a higher risk of progression: hazard ratio (HR), 2.15 (95% confidence interval [CI], 1.75–2.64). However, the risk associated with RPD presence differed at different 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, and 4, respectively. Considering the 9-step scale (by eye), RPD presence was associated with higher risk: 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 levels 7 and 8. In AREDS2, by person, RPD presence was not associated with higher risk: HR, 1.18 (95% CI, 0.90–1.56); by eye, it was HR, 1.57 (95% CI, 1.31–1.89). In both cohorts, RPD presence carried a higher risk for GA than neovascular AMD.
Reticular pseudodrusen represent an important risk factor for progression to late AMD, particularly GA. However, the added risk varies markedly by severity level, with highly increased risk at lower/moderate levels and less increased risk at higher levels. Reticular pseudodrusen status should be included in updated AMD classification systems, risk calculators, and clinical trials.
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.

View all citing articles on Scopus

: Supplemental material is available at www.aaojournal.org.

Financial Disclosure(s): The author(s) have made the following disclosure(s):

Usha Chakravarthy - Financial support - Pfizer, Inc.

G. Staurenghi: Consultant—Heidelberg Engineering, Zeiss Meditec; Lecturer—Novartis, Allergan, Zeiss, Alcon; Financial support—Novartis.

: Supported by an educational grant from Pfizer, Inc., New York, New York (grant no.: A9011051 [U.C., R.S., G.S.]).

: R. Silva: Grant support—Pfizer (during the conduct of the study); Novartis, Bayer; Personal fees—Bayer, Allergan, Alcon, and THEA (outside the submitted work); Lecturer—Bayer; Member of Advisory Board: Novartis, Bayer, Allergan, Alcon, THEA.

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Original articleClinical Characteristics of Reticular Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Methods

Results

Discussion

Prog Retin Eye Res

Ophthalmology

Surv Ophthalmol

Ophthalmology

The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS report no. 17

Arch Ophthalmol

The risk and natural course of age-related maculopathy: follow-up at 6 1/2 years in the Rotterdam study

Arch Ophthalmol

Reticular pseudodrusen are subretinal drusenoid deposits

Ophthalmology

The epidemiology of retinal reticular drusen

Am J Ophthalmol

Reticular macular disease

Am J Ophthalmol

Drusen characterization with multimodal imaging

Retina

Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation

Br J Ophthalmol

Prevalence and genomic association of reticular pseudodrusen in age-related macular degeneration

Am J Ophthalmol

Complement factor H 402H variant and reticular macular disease

Arch Ophthalmol

Original article
Clinical Characteristics of Reticular Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration