LOW-DOSE SUPPLEMENTATION WITH RETINOL IMPROVES RETINAL FUNCTION IN EYES WITH AGE-RELATED MACULAR DEGENERATION BUT WITHOUT RETICULAR PSEUDODRUSEN.

PURPOSE: The aim of this study was to determine the functional impact of oral vitamin A supplementation in patients with intermediate age-related macular degeneration with and without reticular pseudodrusen (RPD) demonstrating dysfunction in dark adaptation. METHODS: Five patients with intermediate age-related macular degeneration and without RPD (AMD group; mean ± SD age 78.0 ± 4.7 years) and seven with RPD (RPD group; age 74.1 ± 11.2 years) were supplemented with 16,000 IU of vitamin A palmitate for 8 weeks. Assessment at baseline, 4, 8, and 12 weeks included scotopic thresholds, dark adaptation, best-corrected and low luminance visual acuities, and the low-luminance quality of life questionnaire. RESULTS: In the linear mixed model, rod intercept time improved significantly in the AMD group (mean [95% CI] change -1.1 minutes [-1.8; -0.5] after 4 weeks ( P < 0.001) and -2.2 min [-2.9 to -1.6] after 8 weeks of vitamin A supplementation ( P < 0.001). The dark adaptation cone plateau also significantly improved (i.e., more sensitive cone threshold) at 4 and 8 weeks ( P = 0.026 and P = 0.001). No other parameters improved in the AMD group, and there was no significant improvement in any parameter in the RPD group despite significantly elevated serum vitamin A levels measurable in both groups after supplementation ( P = 0.024 and P = 0.013). CONCLUSION: Supplementation with 16,000 IU vitamin A, a lower dose than used in previous studies, partially overcomes the pathophysiologic functional changes in AMD eyes. The lack of improvement in the RPD group may indicate structural impediments to increasing vitamin A availability in these patients and/or may reflect the higher variability observed in the functional parameters for this group.

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.].

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.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Association of Single-Nucleotide Polymorphisms in Age-Related Macular Degeneration With Pseudodrusen: Secondary Analysis of Data From the Comparison of AMD Treatments Trials.

Importance: Previous studies investigating the association of single-nucleotide polymorphisms (SNPs) that confer increased risk of age-related macular degeneration (AMD) with pseudodrusen have yielded conflicting results and have not evaluated other AMD SNPs or pseudodrusen subtypes. Objective: To determine the association of SNPs in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), HtrA serine peptidase 1 (HTRA1), complement C2 (C2), complement C3 (C3), lipase C (LIPC), and complement factor B (CFB) genes with the presence of pseudodrusen and pseudodrusen subtypes (ie, dot, reticular, and confluent). Design, Setting, and Participants: In this post hoc analysis of cross-sectional data from US participants in the Comparison of AMD Treatments Trials, genotyping was performed in 835 participants with TaqMan assays for the SNPs rs1061170 (Y402H variant in CFH), rs800292 (I62V variant in CFH), rs10490924 (A69S variant in ARMS2), rs11200638 (HTRA1), rs547154 (C2), rs2230199 (R102G variant in C3), rs10468017 (LIPC), and rs4151667 (L9H variant in CFB). Main Outcomes and Measures: Presence and subtype of baseline pseudodrusen in either eye determined using color fundus photography, red-free images, and fluorescein angiograms. Results: Among 835 participants enrolled for genotyping, 755 (90.4%) were evaluated for pseudodrusen. Of these, 471 (62.4%) were female and 750 (99.3%) were white, and the mean (SD) age was 78.3 (7.5) years. A total of 213 of 755 participants (28.2%) had pseudodrusen (107 [14.2%] had dot pseudodrusen, 180 [23.8%] had reticular pseudodrusen, and 102 [13.5%] had confluent pseudodrusen). After adjusting for age, sex, and smoking status, the ARMS2 risk allele T was associated with higher risk of pseudodrusen (odds ratio [OR], 1.93; 95% CI, 1.19-3.12) for TT vs GG (P = .04). A similar association was found for HTRA1 (OR, 2.04; 95% CI, 1.26-3.31) for AA vs GG (P = .03). The CFH Y402H risk allele C was associated with lower risk of pseudodrusen (OR, 0.61; 95% CI, 0.38-0.97) for CC vs TT but was not statistically significant after correcting for multiple comparison (P = .20). CFH Y402H, ARMS2, HTRA1, and C3 were significantly associated with reticular pseudodrusen. Conclusions and Relevance: Among patients with neovascular AMD, the AMD risk alleles ARMS2 and HTRA1 were associated with an increased risk of pseudodrusen and the risk allele CFH Y402H was associated with lower risk of pseudodrusen, supporting findings from previous studies. Understanding the role of these SNPs in the development of pseudodrusen might improve our understanding of the pathogenesis of AMD and help develop future therapies.

A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.

PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.

Choroidal Neovascularization and Geographic Atrophy are Potential Complications of Early Onset Large Colloid Drusen.

The authors report a case of large colloid drusen (LCD) complicated by choroidal neovascularization (CNV) and geographic atrophy (GA). A 54-year-old man was referred to the authors' department with diagnosis of early onset retinal drusen. Multimodal imaging led to a diagnosis of LCD complicated by GA in the right eye and CNV in the left eye. The patient received a single injection of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) in the left eye. Six months later, best-corrected visual acuity improved to 20/25, and spectral-domain optical coherence tomography still showed absence of subretinal and intraretinal fluid. GA and CNV are possible complications of LCD, and contrary to previous beliefs, it should therefore not be considered as a benign condition. Intravitreal aflibercept could be considered as a useful treatment in cases complicated by CNV. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:586-590.].

Optical Coherence Tomography Features Preceding the Onset of Advanced Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is a progressive disease with multifactorial etiology. There is a need to identify clinical features that are harbingers of advanced disease. We evaluated morphologic features of the retina and choroid on optical coherence tomography (OCT) to determine if they predict progression to advanced disease. Methods: Progressors transitioned from early or intermediate AMD to advanced disease (n = 40 eyes), and were matched on baseline AMD grade and follow-up interval to nonprogressors who did not develop advanced AMD (n = 40 eyes). Features of the neurosensory retina, photoreceptors, retinal pigment epithelium (RPE), and choroid were evaluated. Logistic regression was used to evaluate univariate associations between features and progression to overall advanced AMD, geographic atrophy (GA), and neovascular disease (NV). Multivariate associations based on stepwise regression models were also assessed. Results: Ellipsoid zone disruption was associated with progression to overall advanced AMD and NV (odds ratios [ORs]: 17.9 and 30.6; P < 0.001), with a similar trend observed for GA. Drusenoid RPE detachment, RPE thickening, and retinal pigmentary hyperreflective material were significantly associated with higher risk of progression to advanced AMD (ORs: 5.0-8.5) and NV (ORs: 10.8-17.2). Pigmentary hyperreflective material was associated with progression to GA (OR: 7.5, P = 0.009). Total retinal thickness, pigmentary hyperreflective material, nascent GA features, and choroidal vessel abnormalities were independently associated with progression to advanced AMD in a multivariate stepwise model. Conclusions: Abnormalities in the photoreceptors, retinal thickness, RPE, and choroid were associated with higher risk of developing advanced AMD. These findings provide insights into disease progression, and may be helpful to identify earlier endpoints for clinical studies.

Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group.

PURPOSE: To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen). DESIGN: Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study. PARTICIPANTS: Participants from prospective studies. METHODS: The 200° pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions. MAIN OUTCOME MEASURES: Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities. RESULTS: A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls. CONCLUSIONS: Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas pigment changes and features of advanced AMD are less frequent. Age-related macular degeneration may be more than a "macular" condition but one that involves the entire retina. Future longitudinal studies of peripheral changes in AMD and their impact on visual function may contribute to understanding AMD pathogenesis.

Polypoidal Choroidal Vasculopathy Occurring in the Context of Large Colloid Drusen.

The authors report, for the first time, an association between large colloid drusen (LCD) and choroidal neovascularization in a 58-year-old man. Multimodal imaging confirmed the diagnosis of LCD in both eyes and polypoidal choroidal vasculopathy in the left eye. The patient was treated with monthly intravitreal injections of aflibercept (Eylea; Regeneron, Tarrytown, NY). The authors hypothesize that these deposits are probably associated with retinal pigment epithelium dysfunction and could thus lead to delayed neovascularization and atrophy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1154-1156.].

Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment.

IMPORTANCE: Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. OBJECTIVE: We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. DESIGN: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). RESULTS: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. CONCLUSIONS: High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

Drusen Volume as a Predictor of Disease Progression in Patients With Late Age-Related Macular Degeneration in the Fellow Eye.

PURPOSE: Increasing drusen volume was proposed to be a predictor of disease progression in age-related macular degeneration (AMD). In patients with late AMD in one eye, the fellow eyes without neovascularization are known to be at higher risk of developing exudative AMD. We evaluated the relationship between drusen volume in these fellow eyes and their progression to late AMD. METHODS: A retrospective analysis included fellow eyes with drusen associated with nonexudative AMD. All eyes with neovascular AMD were treated with intravitreal ranibizumab, aflibercept, and/or bevacizumab and followed for 2 years. All eyes were scanned with the Cirrus HD-OCT using a 512 × 128 scan pattern. Optical coherence tomography (OCT) data at baseline, month 12, and month 24 were collected using the advanced RPE analysis tool to quantify drusen volume within 3- and 5-mm-diameter circles centered on the fovea. Optical coherence tomography scans were also evaluated for the development of geographic atrophy (GA) or macular neovascularization (MNV). RESULTS: Eighty-nine patients who had neovascular AMD in only one eye were studied. Optical coherence tomography drusen volume in the absence of MNV could be measured in 61 participants (68.5%). After 12 months, 4 eyes (4.5%) developed MNV and 15 eyes (16.9%) developed GA. By 24 months of follow-up, an additional 5 eyes (7.1%) developed MNV and an additional 10 eyes (14.3%) developed GA. At month 24, the eyes that developed GA or MNV had baseline drusen volumes that were significantly larger than in eyes that did not develop late AMD. Patients with a drusen volume over 0.03 mm3 had a greater than 4-fold increased risk for developing late AMD compared with those with lower drusen volumes. CONCLUSIONS: Baseline drusen volume appears to be an important predictor for the development of late AMD within 2 years in eyes that have fellow eyes being actively treated for MNV. This suggests that OCT-derived drusen volume measurements may be a useful biomarker to identify eyes at the highest risk for progression to late AMD.

Drusen maculopathy: a risk factor for visual deterioration.

Age-related macular degeneration (AMD), the most common cause of visual loss after the age of 65, displays a degeneration of the retinal pigment epithelial (RPE) cells and photoreceptors in the retinal centre (macula). The central macula (fovea) that contains mostly cone photoreceptors mediates the high visual acuity. Drusen maculopathy may lead to visual deterioration. Drusen are extracellular deposits of debris that accumulate on Bruch's membrane. Drusen attract inflammatory, immunological and vasoactive stimuli. RPE and photoreceptor cells overlying drusen exhibit biochemical and morphological signs of degeneration. Strong and intermittent light exposure (photons) induces the formation of free radicals in the very high oxygen tension milieu of the retina. The negative effects of irradiation stimulate accumulation of lipofuscin in RPE and photoreceptor cells leading to mitochondrial dysfunction and apoptotic cell death. A hydrophobic barrier is built up in Bruch's membrane reducing diffusion to the choroid. Hereditary and inflammatory factors modify the risk for AMD. There is a genetic dysregulation of the complement system leading to inappropriate complement activation. The genetic polymorphism of complement factor H (CFH) and age-related maculopathy susceptibilty 2 (ARMS2) increase the risk of progression to advanced AMD. The photoelectric effect creates free radicals, resulting in a continuous increase of lipofuscin formation and impairing mitochondrial activity. In addition, inflammation and complement dysregulation contribute to the formation of drusen and vasoproliferative reactions with neovascularization. Antioxidants neutralize reactive oxygen species and reduce lipofuscin accumulation in RPE and photoreceptor cells. For prophylactic treatment of drusen maculopathy, high doses of antioxidants such as vitamins C and E, lutein, zeaxanthine and zinc are used according to the Age-Related Eye Disease Study 2 (AREDS 2). The risk of developing advanced AMD was reduced by 27% at 10 years follow-up. No adverse events were noted.

TYPE 2 (SUBRETINAL) NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION ASSOCIATED WITH PURE RETICULAR PSEUDODRUSEN PHENOTYPE.

PURPOSE: To report the association of pure type 2 neovascularization (NV) in age-related macular degeneration occurring almost exclusively in patients with reticular pseudodrusen. METHODS: An observational retrospective cohort study of all eyes receiving antivascular endothelial growth factor therapy for newly diagnosed neovascular age-related macular degeneration by a single practitioner over a 6-year period. Only patients with treatment-naive, pure type 2 NV who also had either pre-neovascular imaging of the study eye or imaging of a nonneovascular fellow eye available to determine baseline characteristics including drusen type and choroidal thickness were incuded. RESULTS: Of 694 patients treated for neovascular age-related macular degeneration, only 8 met the inclusion criteria with pure type 2 NV. Of these, 7 (88%) had exclusively reticular pseudodrusen (5 in the nonneovascular fellow eye, 2 in the study eye before developing NV). Six (75%) patients in the affected neovascular eye and 6 (75%) in the fellow nonneovascular eye had choroidal thickness <120 µm. Mean follow-up was 46 months (range, 3.0-63.3). Best-corrected vision improved from 20/89 (range, 20/30-20/796) at baseline to 20/60 (range, 20/20-20/399) at last follow-up. CONCLUSION: Pure type 2 NV is rare in age-related macular degeneration, occurring almost exclusively in patients with reticular pseudodrusen and thin choroids.

Choroidal neovascularization associated with extensive macular atrophy and pseudodrusen.

PURPOSE: To describe a case of extensive macular atrophy and pseudodrusen complicated by bilateral choroidal neovascularization (CNV). METHODS: A 53-year-old woman showed extensive macular atrophy at the posterior pole associated with disciform scar in the right eye and fibrotic juxtafoveal CNV in the left eye. RESULTS: The patient underwent a complete ophthalmological examination including fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography, showing a disciform scar at the posterior pole of the right eye and an extensive macular atrophy associated with a fibrotic juxtafoveal CNV. The patient was previously treated with four and seven intravitreal bevacizumab injections, respectively, in the right eye and in the left eye. Molecular analyses of the ABCA4 gene revealed the variant c.1268A

Regression of drusen after combined treatment using photodynamic therapy with verteporfin and ranibizumab.

Drusen are the clinical hallmark of age-related macular degeneration. The regression of these deposits in patients treated with argon, krypton, or diode laser photocoagulation has been reported previously. However, previous protocols with conventional laser for drusen may result in retinal pigment epithelium (RPE) damage and unwanted scotomas. The authors report a case of complete regression of soft drusen in a 65-year-old man with central visual loss and metamorphopsia due to a drusenoid RPE detachment and soft drusen who underwent reduced-fluence photodynamic therapy (PDT) and three monthly intravitreal injections of ranibizumab. Reduced-fluence PDT combined with anti-VEGF therapy may reduce drusen without inducing RPE cell damage.

Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3.

IMPORTANCE: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURE: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176.

Change in drusen volume as a novel clinical trial endpoint for the study of complement inhibition in age-related macular degeneration.

BACKGROUND AND OBJECTIVE: To evaluate the change in drusen volume following treatment with eculizumab, a systemic inhibitor of complement component 5. PATIENTS AND METHODS: Single-center, prospective, randomized, double-masked clinical trial. Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 26 weeks. MAIN OUTCOME MEASURE: decrease in drusen volume of at least 50% at 26-week follow-up. RESULTS: Mean drusen cube root volumes were 0.49 mm and 0.47 mm (P = .64) at baseline and 0.51 mm and 0.42 mm (P = .17) at 26 weeks in the eculizumab and placebo groups, respectively. In the placebo group, one eye had a decrease in drusen volume of at least 50% and two eyes developed neovascularization through 26 weeks. CONCLUSION: Systemic complement inhibition with eculizumab did not significantly reduce drusen volume. Drusen growth was dependent on the number of complement at-risk alleles. Future trials should consider the use of a composite clinical trial endpoint in which efficacy is defined by the treatment's ability to prevent drusen growth, neovascularization, and the formation of geographic atrophy over 1 year.