Presence Of Reticular Pseudodrusen Research Articles

Rediscovering Age-Related Macular Degeneration with Swept-Source OCT Imaging: The 2022 Charles L. Schepens, MD, Lecture

Swept-source OCT angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and dye-based fundus angiographic imaging for the diagnosis and staging of AMD. Through the use of different algorithms with the SS-OCTA scans, both structural and angiographic information can be viewed and assessed using both cross sectional and en face imaging strategies. Presented at the 2022 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on September 30,2022. Patients with AMD. Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD. Swept-source OCT angiography imaging of AMD at different stages of disease progression. Volumetric SS-OCTA dense raster scans were used to diagnose and stage both exudative and nonexudative AMD. In eyes with nonexudative AMD, a single SS-OCTA scan was used to detect and measure structural features in the macula such as the area and volume of both typical soft drusen and calcified drusen, the presence and location of hyperreflective foci, the presence of reticular pseudodrusen, also known as subretinal drusenoid deposits, the thickness of the outer retinal layer, the presence and thickness of basal laminar deposits, the presence and area of persistent choroidal hypertransmission defects, and the presence of treatment-naïve nonexudative macular neovascularization. In eyes with exudative AMD, the same SS-OCTA scan pattern was used to detect and measure the presence of macular fluid, the presence and type of macular neovascularization, and the response of exudation to treatment with vascular endothelial growth factor inhibitors. In addition, the same scan pattern was used to quantitate choriocapillaris (CC) perfusion, CC thickness, choroidal thickness, and the vascularity of the choroid. Compared with using several different instruments to perform multimodal imaging, a single SS-OCTA scan provides a convenient, comfortable, and comprehensive approach for obtaining qualitative and quantitative anatomic and angiographic information to monitor the onset, progression, and response to therapies in both nonexudative and exudative AMD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical Characteristics and Progression of Geographic Atrophy in a Japanese Population

To elucidate the clinical characteristics and progression rate of geographic atrophy (GA) associated with age-related macular degeneration (AMD) in a Japanese population. Retrospective, multicenter, observational study. A total of 173 eyes from 173 patients from six university hospitals in Japan were included. Of 173 study eyes, 101 eyes from 101 patients were included in the follow-up group. All patients were Japanese, aged ≥ 50 years, and had definite GA associated with AMD in at least one eye. The GA area was measured semi-automatically using fundus autofluorescence (FAF) images. In the follow-up group followed for more than six months with FAF images, the GA progression rate was calculated by two methods: mm2/year and mm/year using the square-root transformation (SQRT) strategy. Simple and multiple linear regression analyses were used to identify the baseline factors associated with the GA progression rate. Clinical characteristics of GA and the GA progression rate. The mean age was 76.8 ± 8.8 years and 109 (63.0%) were males. Sixty-two (35.8%) patients had bilateral GA. The mean GA area was 3.06 ± 4.00 mm2 (1.44 ± 1.00 mm [SQRT]). Thirty-eight eyes (22.0%) were classified as having pachychoroid GA. Drusen and reticular pseudodrusen were detected in 115 (66.5%) and 73 eyes (42.2%), respectively. The mean subfoveal choroidal thickness was 194.7 ± 105.5 μm. In the follow-up group (follow-up period: 46.2 ± 28.9 months), the mean GA progression rate was 1.01 ± 1.09 mm2/year (0.23 ± 0.18 mm/year [SQRT]). In the multivariable analysis, baseline GA area [SQRT] (P=0.002) and the presence of reticular pseudodrusen (P<0.001) were significantly associated with a greater GA progression rate [SQRT]. Certain clinical characteristics of GA in Asian populations may differ from those in Caucasians. Asian patients with GA showed male-dominance and relatively thicker choroid than Caucasian patients. There was a group with GA without drusen but with features of pachychoroid. The GA progression rate in this Asian population was relatively lower than that in Caucasians. Large GA and reticular pseudodrusen were associated with a greater GA progression rate.

Nascent Geographic Atrophy as a Predictor of Type 3 Macular Neovascularization Development

To investigate the association of nascent geographic atrophy (GA) preceding the development of exudative type 3 macular neovascularization (MNV) in patients with age-related macular degeneration (AMD). Retrospective longitudinal study. AMD patients diagnosed with treatment-naïve exudative type 3 MNV in one or both eyes were evaluated. Inclusion criteria included serial tracked structural optical coherence tomography (OCT) examinations for ≥ 2 years prior to the detection of exudative type 3 MNV. Clinical characteristics and retinal imaging including structural OCT at baseline and at each follow-up examination were analyzed. Eyes showing the presence of nascent GA during the follow-up were selected for analysis of prevalence, and clinical characteristics at the site of subsequent type 3 MNV development. Description of prevalence and clinical characteristics of nascent GA at the site of subsequent type 3 MNV development. Ninety-seven eyes affected by type 3 MNV meeting inclusion criteria were analyzed. Of 97 eyes (71 patients), 22 eyes of 21 patients (mean age 82±9 years) showed nascent GA preceding exudative type 3 MNV. The observed prevalence of nascent GA preceding exudative type 3 MNV was 22.7% (95% CI: 14.4-31.0%). Exudative Type 3 MNV developed a mean of 9±6 months following detection of nascent GA. The presence of reticular pseudodrusen in the study eye did not significantly influence the timing of exudative type 3 MNV development after the observation of nascent GA (p>0.1 in all analyses). Reduced BCVA was recorded at the exudative type 3 stage in comparison to the nascent GA stage (p=0.003). As nascent GA may precede the development of exudative type 3 MNV, the detection of nascent GA in eyes with AMD may warrant closer surveillance in order to identify early exudative type 3 MNV warranting treatment.

SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY DETECTION OF BRUCH MEMBRANE AND CHORIOCAPILLARIS ABNORMALITIES IN SORSBY MACULAR DYSTROPHY.

Swept-source optical coherence tomography angiography (SS-OCTA) was used to analyze Bruch membrane (BM) and choriocapillaris (CC) abnormalities in undiagnosed family members with Sorsby macular dystrophy (SMD). In a family with SMD ( TIMP3 Tyr191Cys), SS-OCTA imaging was performed using the 6 × 6 mm scan patter and previously validated algorithms to detect abnormalities in BM and the CC, as well as the presence of reticular pseudodrusen and macular neovascularization. Genetic analyses were performed for TIMP3 mutations. Of eight family members, two were previously diagnosed with SMD and six were asymptomatic. SS-OCTA imaging of the 33-year-old proband revealed type 1 macular neovascularization in the left eye and bilateral reticular pseudodrusen, thickening of BM, CC thinning, and increases in CC flow deficits. A TIMP3 mutation was confirmed. His niece, despite having no clinical evidence of SMD, showed BM thickening and CC thinning on SS-OCTA. A TIMP3 mutation was confirmed. The proband's younger nephew and niece also carried the TIMP3 mutation without clinical evidence of SMD. Two additional members had normal examinations, unremarkable SS-OCTA findings, and no TIMP3 mutation. Swept-source optical coherence tomography angiography imaging can detect BM and CC abnormalities in vivo in subjects unaware of their TIMP3 status in a family with SMD.

Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30

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.

Prevalence and determinants of reticular pseudodrusen in the Russian Ural Eye and Medical Study.

To assess the prevalence of reticular pseudodrusen (RPD) and their determinants. The Population-based Ural Eye and Medical Study conducted in Bashkortostan/Russia included 5899 participants aged 40+ years. Presence of RPDs was assessed on conventional colour fundus photographs, red-free fundus images and optical coherence tomographic images. The study included 4914 (83.3%) individuals (mean age: 58.5 ± 10.5 years; range: 40-94 years). Using two age limits (>55 years and 40+ years) for the definitions of RPD and AMD (age-related macular degeneration), RPD prevalence was 186/4914 (3.8%; 95% confidence interval (CI): 3.3, 4.3) and 246/4914 (5.0%, 95% CI: 4.4, 5.6), respectively, and the prevalence of any AMD without RPD was 182/4914 (3.7%: 95% CI: 3.2, 4.2) and 224/4914 (4.6%; 95% CI: 4.0, 5.1) respectively. Within the subgroup of early AMD, intermediate AMD and late AMD, RPD prevalence (age limit: 40+ years) was 55.1% (95% CI: 49.5, 60.8), 42.9% (95% CI: 33.8, 51.9) and 33.3% (95% CI: 16.4, 50.3) respectively. In multivariable analysis, higher RPD prevalence (age limit 40+ years) was associated with higher age (odds ratio (OR): 1.08; 95% CI: 1.07, 1.10; p < 0.001), rural region of habitation (OR: 3.81; 95% CI: 2.76, 5.24; p < 0.001) and lower percentage of lymphocytes on leukocyte counts (OR: 0.95; 95% CI: 0.93, 0.97; p < 0.001). Higher prevalence of any AMD without RPD was associated with urban region (OR: 1.58; 95% CI: 1.18, 2.11; p = 0.002), lower diabetes prevalence (OR: 0.55; 95% CI: 0.33, 0.90; p = 0.02) and shorter axial length (OR: 0.85; 95% CI: 0.74, 0.98; p = 0.03), after adjusting for age. Reticular pseudodrusen (mean prevalence: 3.8% (age limit >55 years); 5.0% (age limit 40+ years)) differs from AMD without RPD in its association with urban region (AMD without RPD: rural region), lower lymphocyte percentage (AMD without RPD: no association) and a lack of associations with axial length (AMD without RPD: shorter axial length) and with diabetes prevalence (AMD without RPD: lower diabetes prevalence).

Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration

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.

Morphologic and Microvascular Differences Between Macular Neovascularization With and Without Subretinal Fibrosis.

PurposeTo evaluate morphologic and microvascular differences between eyes with and without subretinal fibrosis (SF) caused by neovascular age-related macular degeneration (nAMD).MethodsPatients with nAMD with a minimum history of 12 months of anti-VEGF treatment were prospectively included in this cross-sectional study. Patients were imaged using standard imaging, swept-source optical coherence tomography angiography for quantitative microvascular analysis and polarization-sensitive OCT as an ancillary method for automated SF segmentation. The presence of reticular pseudodrusen, hyperreflective foci (HRF), and outer retinal tubulation (ORT) were also evaluated.ResultsSixty eyes of 60 participants (37 female) with nAMD and a mean 3.1 (±2.7)-year history of anti-VEGF treatment were included, 20 (33%) of which were diagnosed with SF. Eyes with SF had a higher prevalence of ORT (P < 0.001) and a lower prevalence of HRF (P = 0.004) than eyes without SF. Fifty eyes were analyzed quantitatively for microvascular biomarkers. Eyes with SF had a larger greatest vascular caliber (P = 0.001) and greatest linear diameter (P = 0.042), a larger microvascular neovascularization (MNV) area (P = 0.026), larger vessel area (P = 0.037), higher number of vessel junctions (P = 0.025), longer total vessel length (P = 0.027), higher number of vessel endpoints (P = 0.007), and higher endpoint density (P = 0.047).ConclusionsThis multimodal imaging approach demonstrated in vivo microvascular and morphological differences in eyes with and without SF. Eyes with SF tend to have larger MNV lesions with thicker vessels and are often associated with the presence of ORT.Translational RelevanceThis study points out imaging biomarkers in patients with SF, which may help identifying high-risk patients.

Plasma C-C Chemokine Concentrations in Intermediate Age-Related Macular Degeneration.

Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration.Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups.Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls.Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.

Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration.

PurposeC-reactive protein (CRP) and decreased choroidal thickness (CT) are risk factors for progression to advanced age-related macular degeneration (AMD). We examined the association between systemic levels of CRP and CT in patients with intermediate AMD (iAMD).MethodsPatients with iAMD in the Colorado AMD Registry were included. Baseline serum samples and multimodal imaging including spectral domain–optical coherence tomography (SD-OCT), fundus photography, and autofluorescence were obtained. Medical and social histories were surveyed. CT was obtained by manual segmentation of OCT images. High-sensitivity CRP levels were quantified in serum samples. Univariate and multivariable linear regression models accounting for the intrasubject correlation of two eyes were fit using log-transformed CT as the outcome.ResultsThe study included 213 eyes from 107 patients with a mean age of 76.8 years (SD, 6.8). Median CT was 200.5 µm (range, 86.5–447.0). Median CRP was 1.43 mg/L (range, 0.13–17.10). Higher CRP was associated with decreased CT in the univariate model (P = 0.01). Older age and presence of reticular pseudodrusen (RPD) were associated with decreased CT (P < 0.01), whereas gender, body mass index, and smoking were not associated with CT. Higher CRP remained significantly associated with decreased CT after adjustment for age and RPD (P = 0.01).ConclusionsIncreased CRP may damage the choroid, leading to choroidal thinning and increased risk of progression to advanced AMD. Alternatively, CRP may be a marker for inflammatory events that mediate ocular disease. The results of this study further strengthen the association between inflammation and AMD.Translational RelevanceIncreased CRP is associated with choroidal thinning, a clinical risk factor for AMD.

Unaffected fellow eye neovascularization in patients with type 3 neovascularization: Incidence and risk factors.

To evaluate the incidence and risk factors of neovascularization in unaffected fellow eyes of patients diagnosed with type 3 neovascularization in Korea. This retrospective study included 93 unaffected fellow eyes of 93 patients diagnosed with type 3 neovascularization. For initial type 3 neovascularization diagnosis, optical coherence tomography and angiography were conducted. These baseline data were compared between patients with and without neovascularization in their fellow eyes during the follow-up period. The mean follow-up period was 66.1±31.1 months. Neovascularization developed in 49 (52.8%) fellow eyes after a mean period of 29.5±19.6 months. In the fellow eye neovascularization group, the incidence of soft drusen and reticular pseudodrusen was significantly higher than that in the non-neovascularization group (83.7% vs. 36.5%, p<0.001; 67.3% vs. 40.9%, p = 0.017, respectively), but the choroidal vascularity index (CVI) showed a significantly lower value (60.7±2.0% vs. 61.7±2.5%; p = 0.047). The presence of reticular pseudodrusen was related with the duration from baseline to development of fellow eye neovascularization (p = 0.038). Neovascularization developed in 52.8% of unaffected fellow eyes. The presence of soft drusen, reticular pseudodrusen, and lower CVI values can be considered risk factors of neovascularization in unaffected fellow eyes of patients with type 3 neovascularization. The lower CVI values suggest that choroidal ischemic change may affect the development of choroidal neovascularization in these patients.

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy.

Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age‐related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease‐causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross‐sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype‐phenotype study was performed. Four hundred and sixty‐eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

Impact of ocular and systemic risk factors on progression of geographic atrophy in age-related macular degeneration.

Geographic atrophy (GA) corresponds to an end-stage form of age-related macular degeneration and the leading cause of irreversible vision loss. The aim of this study was to investigate the role of fundus autofluorescence (FAF) patterns surrounding GA, baseline GA size, the presence of reticular pseudodrusen (RPD), the condition of the fellow eye and the presence of systemic vascular diseases (diabetes, atherosclerosis, systemic hypertension) on the progression of GA due to age-related macular degeneration. Seventy-five eyes of 52 patients with GA were included into this retrospective study. Digital FAF images were achieved using scanning laser ophthalmoscopy. Areas of GA were measured with the Region Finder software program on an Heidelberg Retinal Angiograph 2. FAF patterns around GA were classified and the presence of RPD and systemic diseases were noted. The median follow-up of the patients was 2.6 years (interquartile range, 1-9.2). The median progression rate of the banded pattern (median 0.97 mm2/year) was significantly higher than the other patterns (median 0.85 mm2/year) (p = 0.03). Eyes with RPD had a significantly higher progression rate (median 1.21 mm2/year) than those without RPD (median 0.79 mm2/year) (p = 0.007). The presence of systemic diseases was not related with lesion progression rates. The results demonstrate that the banded pattern and the presence of RPD accelerate the progression of GA and function as predictive factors.

Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration

To identify baseline risk factors for macular atrophy (MA) development in HARBOR via a longitudinal assessment of monthly spectral-domain (SD)-OCT scans. Previous analyses of MA in HARBOR examined data from color fundus photography (CFP) and fluorescein angiography (FA). Retrospective, post hoc analysis of SD-OCT images from HARBOR (ClinicalTrials.gov identifier, NCT00891735), a phase 3, multicenter, prospective, randomized, double-blind, active treatment-controlled clinical trial. Patients (N= 1097) with subfoveal choroidal neovascularization secondary to neovascular age-related macular degeneration (nAMD) treated with intravitreal ranibizumab 0.5 mg monthly (n= 275), 0.5 mg pro re nata (PRN) after 3 loading doses (n= 275), 2.0 mg monthly (n= 274), or 2.0 mg PRN (n= 273). Evaluable SD-OCT macular cube scans from patients with 24 months of follow-up (N= 941) were examined monthly from baseline to month 24 by masked reading center-trained graders. Atrophy diagnosis criteria were consistent with those proposed by the Classification of Atrophy Meetings (CAM) group: hypertransmission of light into the choroid, loss of retinal pigment epithelium, and loss of outer retinal layers. Multivariable proportional hazards regression was performed for time to atrophy development. Risk factors for MA as determined by time to MA development over 24 months of treatment. Baseline risk factors for MA were confirmed from prior analyses that used CFP and FA data: absence of subretinal fluid, presence of intraretinal cysts, presence of Type 3 neovascularization, and presence of atrophy in the fellow eye. This analysis of SD-OCT data identified new baseline risk factors for MA: higher central drusen volume, lower choroidal thickness, presence of nascent atrophy, presence of reticular pseudodrusen, and increased central foveal thickness. Ranibizumab treatment regimen and dose level were not found to be risk factors for MA development. In this analysis of a major nAMD trial using CAM atrophy criteria, new baseline risk factors for MA development were identified using an SD-OCT dataset. Risk factors for MA development identified by prior analyses were confirmed. Monthly treatment with ranibizumab 0.5 mg was not found to be a risk factor for MA development over 24 months.

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging

ObjectiveSystemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been...

Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 Report 21

To determine the prevalence of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD), assess the role of RPD as an independent risk factor for late AMD development, and evaluate genetic association with RPD. Prospective cohort study. Participants with intermediate AMD in 1 or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplement. Fundus autofluorescence (FAF) images from a subset of AREDS2 participants were evaluated at annual visits for presence of RPD. Six single nucleotide polymorphisms-rs10490924 (ARMS2), rs1061170 (CFH), rs2230199 (C3), rs116503776 and rs114254831 (C2/CFB), and rs943080 (VEGF-A)-and the genetic risk score (GRS) were assessed for association with RPD. Development of late AMD, defined as geographic atrophy (GA) or neovascular AMD (NVAMD), was identified. Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD. The FAF images were evaluated for 5021 eyes (2516 participants). Reticular pseudodrusen were seen in 1186 eyes (24% of eyes, 29% of participants). Prevalence of RPD varied with baseline AREDS AMD severity level: 6% in early AMD (n= 458), 26% in intermediate AMD (n= 2606), 36% in GA (n= 682), and 19% in NVAMD (n= 1246). Mean age of participants with RPD was 79 years (standard deviation [SD], 7) and 75 years (SD, 8) in those without RPD (P < 0.0001). Reticular pseudodrusen were more frequent in female participants (65% RPD vs. 53% no RPD). Odds ratio adjusted for baseline age, gender, race, educational status, smoking, and AMD severity level for 1710 eyes at risk of developing late AMD at the next annual visit was 2.42 (95% confidence interval [CI], 1.80-3.24; P < 0.001) for GA and 1.21 (95% CI, 0.87-1.7; P= 0.26) for NVAMD. Presence of RPD was significantly associated with higher GRS (P < 0.0001) and ARMS2 risk alleles (P < 0.0001) and, at a nominal level, with C3 risk alleles (P= 0.04) and CFH risk alleles (P= 0.048 for homozygotes). Participants with RPD have an increased risk of progression to GA but not NVAMD. ARMS2 risk alleles and higher GRS were associated with the presence of RPD. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis.

Precursors and Development of Geographic Atrophy with Autofluorescence Imaging: Age-Related Eye Disease Study 2 Report Number 18

To describe the sequence of events leading to development of geographic atrophy (GA) in age-related macular degeneration with fundus autofluorescence (FAF) imaging. Post hoc analysis of FAF images from the Age-Related Eye Disease Study2. Fundus autofluorescence images of 120 eyes (109 patients) with incident GA and at least 2 years of preceding FAF images. Images of incident GA were stacked and aligned over FAF images of preceding annual visits. The regions of retina where incident GA developed were assessed on prior years' FAF images. These regions, defined as precursor lesions, were classified into minimal change autofluorescence, predominant hypoautofluorescence (decreased autofluorescence), predominant hyperautofluorescence (increased autofluorescence), and mixed autofluorescence. The natural progression in precursor lesions leading to GA formation and their associations with incident GA size and GA enlargement rate were evaluated. Incident GA area and enlargement rate and precursor pattern frequency. Incident GA had a mean area of 1.00 mm2 (range, 0.15-8.22 mm2) and an enlargement rate of 0.97 mm2/year (standard deviation, 1.66 mm2/year). Predominant hypoautofluorescence was the most common precursor lesion, increasing from 42% to 81% over 3 years before onset of GA. Almost 30% of eyes showed minimal change autofluorescence 3 years before GA. Among the other precursors, 70% progressed to predominant hypoautofluorescence before GA developed. The type of precursor lesions was not associated with incident GA area. Geographic atrophy evolving from minimal change autofluorescence precursor lesions was associated with faster GA enlargement rates compared with other precursor lesion classes. Using image registration, we identified changes in autofluorescence images before the onset of GA. Decreased autofluorescence was the most common change, although minimal changes also were seen in one third of the images. Incident GA that arises from predominantly normal autofluorescence is associated with faster enlargement rates compared with GA arising from abnormal autofluorescence. Faster GA enlargement rates also were associated with incident GA size, area of surround abnormal autofluorescence, and presence of reticular pseudodrusen.

Relationship between reticular pseudodrusen and choroidal thickness in intermediate age-related macular degeneration.

Reticular pseudodrusen (RPD) is strongly associated with late age-related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD. To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT. Retrospective cohort study. Participants were recruited from Centre for Eye Research Australia. Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 μm nasal, temporal, superior and inferior from centre of fovea. ChT between RPD and non-RPD group. A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 ± 5.4 years and 68.7 ± 6.9 years, respectively; P < 0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P ≤ 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P ≥ 0.132 for all locations) but age (P < 0.001) and refractive error (P = 0.002) remained significantly associated with ChT. Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered.

Outer Retina and Choroidal Thickness in Intermediate Age-Related Macular Degeneration: Reticular Pseudodrusen Findings

Purpose: To evaluate outer retina and choroidal thickness in subjects with intermediate age-related macular degeneration (iAMD) and to describe associations with the presence of reticular pseudodrusen (RPD). Methods: This was a retrospective, cross-sectional analysis of 157 consecutive eyes (specifically: 62 eyes classified as having RPD and 95 eyes with drusen ≥125 µm). Only cases with digital color fundus photographs, red-free, and infrared, obtained and graded according to the Age-Related Eye Disease Study to define iAMD, were used for this study. Outer retina and choroidal thickness were manually segmented and quantified at 12 locations in the horizontal meridian. Results: RPD appeared to be associated with thinning of the outer layers even after adjustment for gender and age. The presence of RPD in iAMD decreased with increase of choroidal thickness (total odds ratio [OR] 0.991, 95% confidence interval [CI] 0.985-0.996; nasal OR 0.992, 95% CI 0.986-0.997), with increased thickness of the myoid zone of the photoreceptors (total OR 0.812, 95% CI 0.688-0.958; nasal OR 0.863, 95% CI 0.755-0.987) and with increased thickness of the outer segment of the photoreceptors (total OR 0.850, 95% CI 0.731-0.989; nasal OR 0.857, 95% CI 0.736-0.989). Conclusions: The greatest differences between eyes with and without RPD are found at the level of the choroidal thickness and at the level of the photoreceptors.

Retinal pigment epithelial features indicative of neovascular progression in age-related macular degeneration

Background/aimsTo identify characteristic retinal pigment epithelium (RPE) changes in fellow eyes of patients with neovascular age-related macular degeneration (nAMD) using polarisation-sensitive optical coherence tomography (PS-OCT).MethodsThirty-one fellow eyes of 31 patients...