Calcified Drusen Prevent the Detection of Underlying Choriocapillaris Using Swept-Source Optical Coherence Tomography Angiography.

Purpose: In age-related macular degeneration (AMD), choriocapillaris flow deficits (CCFDs) under soft drusen can be measured using established compensation strategies. This study investigated whether CCFDs can be quantified under calcified drusen (CaD). Methods: CCFDs were measured in normal eyes (n = 30) and AMD eyes with soft drusen (n = 30) or CaD (n = 30). CCFD density masks were generated to highlight regions with higher CCFDs. Masks were also generated for soft drusen and CaD based on both structural en face OCT images and corresponding B-scans. Dice similarity coefficients were calculated between the CCFD density masks and both the soft drusen and CaD masks. A phantom experiment was conducted to simulate the impact of light scattering that arises from CaD. Results: Area measurements of CCFDs were highly correlated with those of CaD but not soft drusen, suggesting an association between CaD and underlying CCFDs. However, unlike soft drusen, the detected optical coherence tomography (OCT) signals underlying CaD did not arise from the defined CC layer but were artifacts caused by the multiple scattering property of CaD. Phantom experiments showed that the presence of highly scattering material similar to the contents of CaD caused an artifactual scattering tail that falsely generated a signal in the CC structural layer but the underlying flow could not be detected. Similarly, CaD also caused an artifactual scattering tail and prevented the penetration of light into the choroid, resulting in en face hypotransmission defects and an inability to detect blood flow within the choriocapillaris. Upon resolution of the CaD, the CC perfusion became detectable. Conclusions: The high scattering property of CaD leads to a scattering tail under these drusen that gives the illusion of a quantifiable optical coherence tomography angiography signal, but this signal does not contain the angiographic information required to assess CCFDs. For this reason, CCFDs cannot be reliably measured under CaD, and CaD must be identified and excluded from macular CCFD measurements.

Machine Teaching Allows for Rapid Development of Automated Systems for Retinal Lesion Detection From Small Image Datasets.

Machine teaching, a machine learning subfield, may allow for rapid development of artificial intelligence systems able to automatically identify emerging ocular biomarkers from small imaging datasets. We sought to use machine teaching to automatically identify retinal ischemic perivascular lesions (RIPLs) and subretinal drusenoid deposits (SDDs), two emerging ocular biomarkers of cardiovascular disease. IRB approval was obtained. Four small datasets of SD-OCT B-scans were used to train and test two distinct automated systems, one identifying RIPLs and the other identifying SDDs. An open-source interactive machine-learning software program, RootPainter, was used to perform annotation and training simultaneously over a 6-hour period. For SDDs at the B-scan level, test-set accuracy = 92%, sensitivity = 100%, specificity = 88%, positive predictive value (PPV) = 82%, and negative predictive value (NPV) = 100%. For RIPLs at the B-scan level, test-set accuracy = 90%, sensitivity = 60%, specificity = 93%, PPV = 50%, and NPV = 95%. Machine teaching demonstrates promise within ophthalmic imaging to rapidly allow for automated identification of novel biomarkers from small image datasets. [Ophthalmic Surg Lasers Imaging Retina 2024;55:475-478.].

Drusen in the macula and parapapillary region.

PURPOSE: To examine histological characteristics and differences between drusen beneath the retinal pigment epithelium (small hard drusen) located in the macula and located in the parapapillary region. METHODS: We histomorphometrically examined human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. RESULTS: The study included 106 eyes (age, 62.6 ± 15.2 years) with macular drusen (n = 7 globes) or parapapillary drusen (n = 29 eyes) and 70 eyes without drusen. In all drusen, periodic-acid-Schiff-positive material was located between the RPE basal membrane and the inner collagenous layer of Bruch's membrane (BM). Macular drusen as compared with parapapillary drusen had lower height (15.2 ± 10.1 µm versus 34.3 ± 19.8 µm; P = 0.003), while both groups did not differ significantly in basal drusen width (74.0 ± 36.3 µm versus 108.7 ± 101.0 µm; P = 0.95). Eyes with macular drusen and eyes without drusen did not differ significantly in BM thickness (2.74 ± 0.44 µm versus 2.55 ± 0.88 µm; P = 0.57) or in RPE cell density (35.4 ± 10.4 cells/480 µm versus 32.8 ± 7.5 cells/480 µm; P = 0.53), neither in the drusen region nor in the drusen vicinity, while BM thickness (4.60 ± 1.490 µm; P < 0.001) and RPE cell density (56.9 ± 26.8 cells/480 µm; P = 0.005) were higher at the parapapillary drusen. Eyes with macular drusen, eyes with parapapillary drusen, and eyes without drusen did not differ significantly in choriocapillaris density (all P > 0.10) and thickness (all P > 0.35). Limitations of the study, among others, were a small number and size of drusen examined, diseases leading to enucleation, lack of serial sections, limited resolution of light microscopy, and enucleation-related and histological preparation-associated artefacts. CONCLUSIONS: The findings of this study, also taking into account its methodological limitations, suggest that macular drusen and parapapillary drusen shared the morphological feature of periodic-acid-Schiff-positive material between the RPE basal membrane and BM and that they did not vary significantly in choriocapillaris thickness and density. RPE cell density and BM thickness were higher in parapapillary drusen than in macular drusen.

Associations of drusen location with risk factors and incidence of late age-related macular degeneration in the Alienor study.

PURPOSE: To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD. METHODS: The Alienor study is a prospective population-based cohort study of residents of Bordeaux, France, followed from 2009 to 2017. On retinal photographs, we defined central drusen as at least one soft drusen (>63 µm) within 500 µm from fovea and pericentral drusen as at least one drusen 500-3000 µm from fovea, in the absence of any central drusen. Late AMD (atrophic and/or neovascular) was diagnosed using multimodal imaging. In total, 481 eyes were included in the analysis: 160 central and 321 pericentral. We investigated associations with systemic (age, sex, smoking, medical prescriptions, plasma concentrations of lipids and nutrients, UV exposure, blood pressure), ocular (retinal thickness, cataract extraction) and genetic risk scores (GRS). RESULTS: In multivariate logistic regression central drusen were associated with smoking (OR, 2.95 for smoking more than 20 pack-years, p = 0.02), HDL-cholesterol (OR, 1.57 for 1 standard deviation (SD) increase, p = 0.0048), pulse pressure (OR, 0.77 for 1 SD increase, p = 0.04), Age-Related Maculopathy Susceptibility 2 (ARMS2) GRS (OR, 1.42; 95% CI, 1.11-1.83) and complement GRS (OR, 1.55; 95% CI, 1.15-2.10). In Cox modelling, the central location of drusen (at baseline or during the follow-up) was associated with a 4.41-fold increased risk (95% CI,1.98-9.81) for an incident late AMD. CONCLUSION: Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.

Macular lesions associated with age-related macular degeneration in pachydrusen eyes.

BACKGROUND: To investigate the prevalence of macular lesions associated with age-related macular degeneration (AMD) in eyes with pachydrusen. METHODS: Clinical records and multimodal imaging data of patients over 50 years old with drusen or drusenoid deposits were retrospectively assessed, and eyes with pachydrusen were included in this study. The presence of AMD features, including drusen or drusenoid deposits, macular pigmentary abnormalities, geographic atrophy (GA), and macular neovascularization (MNV), were evaluated. RESULTS: Out of 967 eyes of 494 patients with drusen or drusenoid deposits, 330 eyes of 183 patients had pachydrusen (34.1%). The mean age was 66.1 ± 9.3 years, and the subfoveal choroidal thickness (SFCT) was 292.7 ± 100.1 µm. The mean number of pachydrusen per eye was 2.22 ± 1.73. The majority of eyes with pachydrusen had no other drusen or drusenoid deposits (95.2%). Only 16 eyes (4.8%) had other deposits, including soft drusen (10 eyes, 3.0%), cuticular drusen (3 eyes, 0.9%), and reticular pseudodrusen (RPD; 3 eyes, 0.9%). Macular pigmentary abnormalities accompanied pachydrusen in 68 eyes (27.4%). None of the eyes had GA, and 82 eyes (24.8%) had MNV. The majority of MNV was polypoidal choroidal vasculopathy (PCV; 65 eyes, 19.7%), followed by type 1 (10 eyes, 3.0%), type 2 (5 eyes, 1.5%), and type 3 MNV (2 eyes, 0.6%). CONCLUSIONS: Eyes with pachydrusen in Korean population have several characteristic AMD lesions in low frequencies. These findings indicate that pachydrusen might have diagnostic and prognostic values that are different from those of other drusen or drusenoid deposits.

Parapapillary drusen of the retinal pigment epithelium.

PURPOSE: To describe the occurrence, morphology and associations of parapapillary drusen of the retinal pigment epithelium (RPE-drusen). METHODS: Using light microscopy, we histomorphometrically examined enucleated human eyes. RESULTS: The study included 83 eyes (axial length: 25.9 ± 3.2 mm; range: 20.0-35.0 mm). Eyes with parapapillary RPE-drusen (n = 29 (35%) eyes) as compared to those without drusen had a significantly shorter axial length (24.0 ± 1.8 mm vs 27.0 ± 3.3 mm; p < 0.001), higher prevalence (27/29 vs 12/54; p < 0.001) and longer width (213 ± 125 µm vs 96 ± 282 µm; p < 0.0001) of parapapillary alpha zone, and thicker BM in parapapillary beta zone (8.4 ± 2.7 µm vs 3.9 ± 2.0 µm; p < 0.001) and alpha zone (6.6 ± 3.9 µm vs 4.4 ± 1.5 µm; p = 0.02). Prevalence of parapapillary RPE-drusen was 27 (69%) out of 39 eyes with alpha zone. Beneath the RPE-drusen and in total alpha zone, choriocapillaris was open, while it was closed in the central part of parapapillary beta zone. BM thickness was thicker (p = 0.001) in alpha zone than beta zone, where it was thicker (p < 0.001) than in the region outside of alpha/beta zone. BM thickness outside of alpha/beta zone was not correlated with prevalence of parapapillary RPE-drusen (p = 0.47) or axial length (p = 0.31). RPE cell density was higher in alpha zone than in the region adjacent to alpha zone (22.7 ± 7.3 cells/240 µm vs 18.3 ± 4.1 cells/240 µm; p < 0.001). In the parapapillary RPE-drusen, RPE cells were connected with a PAS-positive basal membrane. CONCLUSIONS: Parapapillary RPE-drusen as fibrous pseudo-metaplasia of the RPE were associated with shorter axial length, higher prevalence and larger size of alpha zone, and thicker BM in alpha zone and beta zone. The RPE-drusen may be helpful to differentiate glaucomatous parapapillary beta zone from myopic beta zone.

Drusen and Other Retinal Findings in People With IgA Glomerulonephritis.

PURPOSE: Retinal drusen have been described in people with IgA nephropathy. We examined the frequency of drusen in IgA nephropathy and compared their location and composition with those for drusen in age-related macular degeneration. DESIGN: Immunohistological case series of eyes of patients with IgA nephropathy, and a comparison eye with age-related macular degeneration. METHODS: Donor eyes from 4 individuals (3 male, 1 female, aged 40-80 years) with biopsy-proven IgA nephropathy and kidney failure were examined for the presence of drusen, and location and composition using antibodies for vitronectin, IgA, IgM, IgG, C3, and C1q. Results were compared with those for drusen in macular degeneration without IgA nephropathy. RESULTS: All 4 donors had sparse, subretinal pigment epithelium drusen of 55-65 mm diameter that stained for vitronectin but not for IgA or complement. All donors had retinal capillaries and choriocapillaris staining for IgA. The youngest donor (female, 40) had rare deposits in the outer nuclear layer that stained for IgA, but not for vitronectin. The oldest donor (male, 82) had large cystlike spaces in the inner nuclear and plexiform layers, and smaller cysts in the outer nuclear layer, with no staining for IgA or complement. CONCLUSIONS: Retinal drusen are uncommon in IgA nephropathy, even with kidney failure. Drusen in IgA nephropathy resemble drusen found in age-related macular degeneration. IgA-staining deposits in the outer nuclear layer were likely due to systemic deposition of IgA and complement activation. The nature of cystic spaces is unknown. Further analysis of the retinas of people with glomerulonephritis is recommended.

Inner Retinal Thickness and Vasculature in Patients with Reticular Pseudodrusen.

INTRODUCTION: The aim of this study was to investigate retinal layer thickness and vessel density differences between patients with reticular pseudodrusen (RPD) and intermediate dry age-related macular degeneration (iAMD). METHODS: Participants included in the study were patients diagnosed by retinal specialists with RPD, iAMD, and both RPD and iAMD at our academic referral center, seen from May 2021 until February 2022. The central 3 mm retinal thickness was measured using spectral-domain optical coherence tomography (Heidelberg Spectralis HRA+OCT System; Heidelberg Engineering, Heidelberg, Germany). Individual retinal thickness measurements were obtained from the innermost layer (nerve fiber layer) until the outermost layer (retinal pigment epithelium [RPE]). Each thickness measurement was subdivided into nine Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. For the vessel density, OCT angiography from the Heidelberg Spectralis System was measured using proprietary third-party software (AngioTool; National Institutes of Health, National Cancer Institute, Bethesda, MD). Clinical and demographic characteristics were compared across the three groups (iAMD, RPD, iAMD and RPD) and analyzed with necessary adjustments. Linear mixed-effects models with necessary corrections were employed to compare continuous eye-level measurements between our three groups as well as in pairwise fashion using the R statistical programming software (R version 4.2.1). RESULTS: A total of 25 eyes of 17 patients with RPD, 20 eyes of 15 patients with iAMD, and 14 eyes of 9 patients with both iAMD and RPD were analyzed. Retinal thickness analysis identified that the superior inner (p = 0.028) and superior outer (p = 0.027) maculas of eyes with both iAMD and RPD were significantly thinner than those with iAMD alone. In eyes with RPD, the superior inner and superior outer RPE (p = 0.011 and p = 0.05, respectively), outer plexiform layer (p = 0.003 and p = 0.013, respectively), and inner nuclear layer (p = 0.034 and p = 0, respectively) were noted to be thinner compared to eyes with iAMD alone. In addition, the macular deep capillary plexus vessel density was significantly reduced in eyes with RPD compared to eyes with iAMD (p = 0.017). CONCLUSION: Patients with RPD had inner retinal structural as well as vascular changes compared to iAMD patients. Inner retinal vascular attenuation should be investigated further to see if there is a causal association with retinal thinning.

Near-Complete Drusen Resolution With Brolucizumab: A Mechanism for Proinflammatory Mediated Drusen Clearance?

A 68-year-old woman with macular drusen was diagnosed with neovascular age-related macular degeneration (AMD) and treated with intravitreal brolucizumab. She had a good response to treatment with reduced height of the pigment epithelial detachment, and a good visual outcome. Remarkably, she had a near-complete resolution of macular drusen, yet this was accompanied by the development of anterior uveitis. We propose a proinflammatory-based mechanism for the brolucizumab-induced drusen resorption. Identifying the biochemical pathways responsible could hold the potential to discover novel forms of therapy for the treatment of AMD. [Ophthalmic Surg Lasers Imaging Retina 2023;54:371-374.].

CHORIOCAPILLARIS STRUCTURE IN THE FELLOW EYES OF PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: An OCT Angiography Image Averaging Study.

PURPOSE: Histological choriocapillaris abnormalities have been reported in age-related macular degeneration (AMD). Averaging multiple en face optical coherence tomography angiography improves the quality of imaging of the choriocapillaris. This study used multiple en face swept source optical coherence tomography angiography image averaging to examine the structural changes in the choriocapillaris in the fellow eyes of patients with neovascular AMD. METHODS: All patients underwent macular optical coherence tomography angiography imaging. One eye per subject was repeatedly imaged, and nine raster scan sets were obtained. Registered en face images were averaged, and area of flow voids and number of flow voids were measured using ImageJ software. RESULTS: Forty-eight patients with neovascular AMD were recruited for analysis. Twenty-seven patients had polypoidal choroidal vasculopathy, and 22 eyes had soft drusen. Twenty-six eyes of 26 healthy individuals were included as age-matched normal controls. The choriocapillaris had a meshwork appearance in all eyes. The mean flow void area of the choriocapillaris was larger in patients with AMD than normal controls (1.14 ± 0.16 mm2 vs. 1.01 ± 0.12 mm2, P = 0.002). The mean size of each flow void was greater in patients with AMD than normal controls (729 ± 210 µm2 vs. 583 ± 120 µm2, P = 0.003). The mean flow void area of the choriocapillaris was larger in eyes with soft drusen than without soft drusen (1.2 ± 0.2 mm2 vs. 1.1 ± 0.1 mm2, P = 0.024). CONCLUSION: Multiple en face image averaging revealed precise choriocapillaris structures in the fellow eyes of patients with neovascular AMD.

Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol.

AIMS: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD. METHODS: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models. CONCLUSIONS: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy: Longitudinal Evaluation in Age-Related Macular Degeneration.

PURPOSE: To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). DESIGN: Retrospective analysis of data from a longitudinal study. PARTICIPANTS: A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. METHODS: OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. MAIN OUTCOME MEASURES: Association with and variance explained in time to GA development. RESULTS: A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent or incident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P = 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P = 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R2 = 43%) was significantly lower than explained by nGA alone (R2 = 91%; P = 0.010). CONCLUSIONS: In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD.

BILATERAL MACULAR CHOROIDAL ABNORMALITIES WITH DRUSENOID DEPOSITS IN PATIENTS WITH UNILATERAL PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY.

PURPOSE: To investigate bilateral macular features on optical coherence tomography in patients with unilateral peripheral exudative hemorrhagic chorioretinopathy (PEHCR). METHODS: In this cross-sectional study, optical coherence tomography features of affected eyes (PEHCR group, n = 30) and unaffected contralateral eyes (contralateral group, n = 30) were investigated. Age-matched and sex-matched patients with polypoidal choroidal vasculopathy (PCV group, n = 51) and healthy controls (normal group, n = 50) were included to compare choroidal thickness, measured at six points apart from the fovea, with the PEHCR group. RESULTS: Subretinal drusenoid deposits were the most common feature in the PEHCR (20%) and contralateral (23%) groups, followed by soft drusen. Although the macular choroid was comparably thin in both the PEHCR and contralateral groups, pachyvessels were also observed. The choroids of the PEHCR group were significantly thinner than those of the normal group at the subfovea and 1-mm temporal to the fovea and considerably thinner than those of the polypoidal choroidal vasculopathy group from 3-mm nasal to 3-mm temporal to the fovea. CONCLUSION: In patients with unilateral PEHCR, bilateral choroidal thinning and drusenoid deposit accumulation were noted in the macula. The pathophysiology of PEHCR may be a rare peripheral complication of age-related macular degeneration with pathologic choroid.

Extramacular Drusen and Progression of Age-Related Macular Degeneration: Age Related Eye Disease Study 2 Report 30.

PURPOSE: To identify the prevalence of extramacular drusen and their role in the progression of age-related macular degeneration (AMD). DESIGN: Retrospective analysis of a prospective cohort study. PARTICIPANTS: The study was conducted in 4168 eyes (2998 participants) with intermediate AMD in one or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplements. METHODS: Baseline 3-field 30-degree color photographs were evaluated for drusen characteristics outside the macular grid, including size, area, and location. The characteristics of extramacular drusen were compared with those of drusen within the macula. MAIN OUTCOME MEASURES: Progression rates to late AMD. RESULTS: Although extramacular drusen were observed in 3624 (86.9%) eyes, they represented a small area (< 0.5 mm2) in 50.3% of eyes, with only 17.5% exhibiting an area of > 1 disc area. Eyes with extramacular drusen exhibited larger macular drusen size and area than eyes without extramacular drusen (P < 0.001). Extramacular drusen were not associated with progression to late AMD. The hazard ratio adjusted for baseline age, sex, smoking, AMD severity level, and reticular pseudodrusen for 4043 eyes at risk of developing late AMD over 5 years was 1.17 (95% confidence interval [CI], 0.88-1.54; P = 0.27) for geographic atrophy and 0.96 (95% CI, 0.76-1.2; P = 0.7) for neovascular AMD. CONCLUSIONS: Extramacular drusen are commonly observed in eyes with AMD and are more frequent with an increasing drusen burden within the macula. In eyes with intermediate AMD, extramacular drusen do not confer additional risk to previously identified risk factors in progression to late AMD.

Effects of Photobiomodulation in Patients Presenting with Reticular Pseudodrusen: A Retrospective Observational Case Series Study.

Background and Objectives: The purpose of this study is to describe the effects of photobiomodulation on drusen regression with patients presenting with reticular pseudodrusen (RPD). Materials and Methods: This study is a retrospective observational case series study including patients presenting with RPD who underwent treatment by photobiomodulation. All patients underwent a complete ophthalmic examination and multimodal imaging prior to treatment, including spectral-domain optical coherence tomography (SD-OCT). Eyes were treated two times per week for six consecutive weeks. Best corrected-visual acuity (BVCA) was measured prior and after treatment for all patients. The number of RPD on the SD-OCT scans centered on the macula and stages of RPD was noted at baseline and 6 months after the first treatment session. Results: Five eyes of five patients were included in the study. Mean BCVA did not change 6 months after treatment compared to baseline. Mean number of RPD per eye was 112.60 +/- 48.33 RPD at baseline and 111.6 +/- 49.29 in the same area 6 months after treatment. Changes in RPD distribution according to RPD classification were observed before and after treatment with photobiomodulation. Changes in distribution mostly concerned stages 1 and 3 RPD: Total number of stage 1 RPD was 289 and increased to 324 after treatment. Total number of stage 3 RPD was 97 at baseline and decreased to 67 6 months after treatment. Percentage of stage 1 RPD increased from 46% to 56% after treatment. Percentage of stage 3 RPD decreased from 20% to 13% after treatment. Conclusions: Changes in RPD distribution were observed before and after treatment with photobiomodulation. The number of stage 3 reticular pseudodrusen decreased while number of stage 1 reticular pseudodrusen increased after treatment.

Heritability and Risk Factors of Incident Small and Large Drusen in the Copenhagen Twin Cohort Eye Study: A 20-Year Follow-Up.

INTRODUCTION: The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursor lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. METHODS: Single-center, 20-year follow-up of 138 twins include biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) (1) <20 small hard drusen, (2) ≥20 small hard drusen, (3) drusen ≥63 µm, or (4) ≥20 small hard drusen combined with drusen ≥63 µm. Additive and dominant genetic effects as well as shared and nonshared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. RESULTS: Median participant age was 59 (range 41-66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥20 small hard drusen, and 18 had drusen ≥63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥20 small hard drusen (p = 0.04) and incident drusen ≥63 µm (p = 0.003). Having ≥20 small hard drusen at baseline was associated with incident drusen ≥63 µm at follow-up (p = 0.02). Development of drusen ≥63 µm was attributable to 49% genetic effects and 51% environmental effects. CONCLUSION: The risk of progressing from 0 to 19 small hard macular drusen per eye to having ≥20 small hard drusen or drusen ≥63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥20 small hard drusen in the absence of drusen ≥63 µm at baseline was associated with incident drusen ≥63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

A Screening Tool for Self-Evaluation of Risk for Age-Related Macular Degeneration: Validation in a Spanish Population.

Purpose: The objectives of this study were the creation and validation of a screening tool for age-related macular degeneration (AMD) for routine assessment by primary care physicians, ophthalmologists, other healthcare professionals, and the general population. Methods: A simple, self-administered questionnaire (Simplified Théa AMD Risk-Assessment Scale [STARS] version 4.0) which included well-established risk factors for AMD, such as family history, smoking, and dietary factors, was administered to patients during ophthalmology visits. A fundus examination was performed to determine presence of large soft drusen, pigmentary abnormalities, or late AMD. Based on data from the questionnaire and the clinical examination, predictive models were developed to estimate probability of the Age-Related Eye Disease Study (AREDS) score (categorized as low risk/high risk). The models were evaluated by area under the receiving operating characteristic curve analysis. Results: A total of 3854 subjects completed the questionnaire and underwent a fundus examination. Early/intermediate and late AMD were detected in 15.9% and 23.8% of the patients, respectively. A predictive model was developed with training, validation, and test datasets. The model in the test set had an area under the curve of 0.745 (95% confidence interval [CI] = 0.705-0.784), a positive predictive value of 0.500 (95% CI = 0.449-0.557), and a negative predictive value of 0.810 (95% CI = 0.770-0.844). Conclusions: The STARS questionnaire version 4.0 and the model identify patients at high risk of developing late AMD. Translational Relevance: The screening instrument described could be useful to evaluate the risk of late AMD in patients >55 years without having an eye examination, which could lead to more timely referrals and encourage lifestyle changes.

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

PURPOSE: 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. DESIGN: Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants). METHODS: 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. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), and neovascular AMD. RESULTS: 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. CONCLUSIONS: 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.

Dry age-related macular degeneration in the Japanese population.

PURPOSE: To elucidate the clinical characteristics of eyes with dry age-related macular degeneration (AMD) in Japan. STUDY DESIGN: Retrospective. METHODS: We performed a nationwide survey of dry AMD. A questionnaire on dry AMD was sent to 3,801 major hospitals and eye clinics nationwide. Whenever both eyes met the diagnostic criteria, only the eye with more advanced geographic atrophy was included. RESULTS: In the current survey, 81 patients (81 eyes) with dry AMD were included. Of the 81 patients, 56 (69.1%) were men, and the mean age of the patients was 76.6 ± 8.4 (range, 54-94) years. Twenty-four patients (29.6%) had a history of smoking. The decimal best corrected-visual acuity (BCVA) was equal to or better than 0.7 in 25 eyes (30.9%), but worse than 0.1 in 17 eyes (21.0%). The mean BCVA was 0.62 ± 0.59 in logarithm of the minimum angle of resolution. Lesion size (the greatest linear dimension of the largest geographic atrophy) was ≥ 2 disc diameter in 33 eyes (40.7%) and < 1 disc diameter in 21 eyes (25.9%). Soft drusen was observed in 27 eyes (33.3%), and reticular pseudodrusen was observed in 31 eyes (38.3%). Of the 81 patients, the other eye was diagnosed as dry AMD in 26 eyes (32.1%), neovascular AMD in 16 eyes (19.8%), and intermediate AMD in 18 eyes (22.2%). CONCLUSION: Dry AMD in the Japanese population has characteristics of male predominance, older age, high prevalence of reticular pseudodrusen, and high bilaterality.

Progression from intermediate to neovascular age-related macular degeneration according to drusen subtypes: Bundang AMD cohort study report 3.

PURPOSE: To investigate the ophthalmic risk factors related to neovascular change and the subtype-wise incidence of progression from intermediate to neovascular age-related macular degeneration (AMD). METHODS: In this retrospective cohort study, 632 eyes with intermediate AMD from 418 patients (older than 50 years) were enrolled. The systemic factors and ophthalmic factors were statistically analysed with respect to neovascular change. RESULTS: The 5-year cumulative incidence of progression to neovascular AMD (nAMD) from intermediate AMD was 17.8% and 17.0% in eyes with soft drusen and pachydrusen (p = 0.316). Older age (p = 0.025), preexisting nAMD in the fellow eye (p < 0.001), and reticular pseudodrusen (RPD; p = 0.007) were associated with the risk of progression to nAMD. In reference to soft drusen, pachydrusen was associated with progression to polypoidal choroidal vasculopathy (PCV; p < 0.001) and not to typical nAMD (p = 0.064). CONCLUSIONS: The ophthalmic risk factors related to the progression of nAMD from intermediate AMD were found to be preexisting nAMD in the fellow eye and RPD. Pachydrusen showed a similar incidence of neovascular change with soft drusen, and was associated with the progression to PCV but not to typical nAMD.