Age-Related Macular Degeneration: A Review.

Importance: Age-related macular degeneration (AMD) affects approximately 20 million people in the US and 196 million people worldwide. AMD is a leading cause of severe vision impairment in older people and is expected to affect approximately 288 million people worldwide by 2040. Observations: Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD. AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older. The estimated heritability of late-stage AMD is approximately 71% (95% CI, 18%-88%). Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked. AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil. Exudative neovascular AMD is best identified using angiography and by optical coherence tomography. Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo. In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment. Conclusions and Relevance: The prevalence of AMD is anticipated to increase worldwide to 288 million individuals by 2040. Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD.

The management of neovascular age-related macular degeneration: A systematic literature review of patient-reported outcomes, patient mental health and caregiver burden.

PURPOSE: The aim of this systematic literature review was to describe patient-reported outcomes, mental health and caregiver burden in patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents in routine clinical practice. METHODS: Electronic searches were conducted in Embase and MEDLINE according to pre-defined criteria. RESULTS: Of 856 records identified, 63 met inclusion criteria. Depression or depressive symptoms were reported in up to 42% of patients with nAMD. Of 25/63 (40%) studies evaluating quality of life (QoL) and using various tools, eight studies reported composite National Eye Institute Visual Functioning Questionnaire scores following anti-VEGF treatment. Of these, seven reported a statistically significant improvement at the earliest time point measured (Month 3-12) and approximately 50% reported sustained QoL benefits at 12 months. In studies comparing the attributed or different regimens, the most important factor from the patient's perspective was the likelihood that a particular regimen would maintain vision. There was a preference towards treat and extend, which was associated with a perceived reduction in patient and caregiver burden, compared to fixed dosing. CONCLUSIONS: A coordinated holistic approach to patient care is key to optimizing patient well-being as well as visual outcomes. Further research regarding the patient-reported impact of nAMD management outside the trial setting (particularly international longitudinal studies) is warranted. Standardization of QoL studies would assist in establishing whether sustained QoL improvement, rather than prevention of QoL decline, should be a realistic expectation of treatment of nAMD in the longer term.

Ocular and Systemic Complement Activation during Anti-Vascular Endothelial Growth Factor Treatment and Age-Related Eye Disease Study 2 Dietary Supplementation in Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to investigate the influence of dietary supplementation using Age-Related Eye Disease Study 2 (AREDS2) on complement activation in patients with neovascular age-related macular degeneration (nAMD) under ongoing treatment. METHODS: In this prospective, single-center, controlled, open-label investigator-initiated trial, eligible nAMD patients were randomized at a ratio of 1:1 in 2 groups: those with and without dietary AREDS2 supplementation for 4 weeks. Zinc, plasma, and aqueous humor (AH) complement levels were quantified via enzyme-linked immunosorbent assays. RESULTS: Fifty of 62 enrolled patients completed the trial (AREDS2 n = 27, controls n = 23). Systemic zinc and complement levels were not different at baseline between the 2 groups (p > 0.1). At the final visit, systemic zinc levels were significantly higher in the AREDS2 group (10.16 ± 2.08 µmol/L; 8.66 ± 1.17 µmol/L; p = 0.007), whereas systemic and AH complement levels were not different (p > 0.1). In both groups, no significant change was observed in systemic levels of C3, C3a, FH, FI, and sC5b-9 (p > 0.1). Only systemic complement component Ba showed an increase from baseline to the end visit (p = 0.01). This increase was higher in the control group (p = 0.02) than in the AREDS2 group (p = 0.23). CONCLUSIONS: Short-term dietary AREDS2 supplementation leads to a significant increase in systemic zinc levels without any influence on complement activation levels.

Dietary Nutrient Intake and Progression to Late Age-Related Macular Degeneration in the Age-Related Eye Disease Studies 1 and 2.

PURPOSE: To analyze associations between the dietary intake of multiple nutrients and risk of progression to late age-related macular degeneration (AMD), its subtypes, and large drusen. DESIGN: Post hoc analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline among AREDS participants (n = 4504) and AREDS2 participants (n = 3738) totaled 14 135 eyes. Mean age was 71.0 years (standard deviation, 6.7 years), and 56.5% of patients were women. METHODS: Fundus photographs were collected at annual study visits and graded centrally for late AMD. Dietary intake of multiple nutrients was calculated from food frequency questionnaires. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), neovascular AMD, and (separate analyses) large drusen. RESULTS: Over median follow-up of 10.2 years, of the 14 135 eyes, 32.7% progressed to late AMD. For 9 nutrients, intake quintiles 4 or 5 (vs. 1) were associated significantly (P ≤ 0.0005) with decreased risk of late AMD: vitamin A, vitamin B6, vitamin C, folate, ß-carotene, lutein and zeaxanthin, magnesium, copper, and alcohol. For 3 nutrients, quintiles 4 or 5 were associated significantly with increased risk: saturated fatty acid, monounsaturated fatty acid, and oleic acid. Similar results were observed for GA. Regarding neovascular AMD, 9 nutrients were associated nominally with decreased risk-vitamin A, vitamin B6, ß-carotene, lutein and zeaxanthin, magnesium, copper, docosahexaenoic acid, omega-3 fatty acid, and alcohol-and 3 nutrients were associated with increased risk-saturated fatty acid, monounsaturated fatty acid, and oleic acid. In separate analyses (n = 5399 eyes of 3164 AREDS participants), 12 nutrients were associated nominally with decreased risk of large drusen. CONCLUSIONS: Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD. These associations are stronger for GA than for neovascular AMD. The same nutrients also tend to show protective associations against large drusen development. Strong genetic interactions exist for some nutrient-genotype combinations, particularly omega-3 fatty acids and CFH. These data may justify further research into underlying mechanisms and randomized trials of supplementation.

Screening Medications for Association with Progression to Wet Age-Related Macular Degeneration.

PURPOSE: There is an urgent need for treatments that prevent or delay development to advanced age-related macular degeneration (AMD). Drugs already on the market for other conditions could affect progression to neovascular AMD (nAMD). If identified, these drugs could provide insights for drug development targets. The objective of this study was to use a novel data mining method that can simultaneously evaluate thousands of correlated hypotheses, while adjusting for multiple testing, to screen for associations between drugs and delayed progression to nAMD. DESIGN: We applied a nested case-control study to administrative insurance claims data to identify cases with nAMD and risk-set sampled controls that were 1:4 variable ratio matched on age, gender, and recent healthcare use. PARTICIPANTS: The study population included cases with nAMD and risk set matched controls. METHODS: We used a tree-based scanning method to evaluate associations between hierarchical classifications of drugs that patients were exposed to within 6 months, 7 to 24 months, or ever before their index date. The index date was the date of first nAMD diagnosis in cases. Risk-set sampled controls were assigned the same index date as the case to which they were matched. The study was implemented using Medicare data from New Jersey and Pennsylvania, and national data from IBM MarketScan Research Database. We set an a priori threshold for statistical alerting at P ≤ 0.01 and focused on associations with large magnitude (relative risks ≥ 2.0). MAIN OUTCOME MEASURES: Progression to nAMD. RESULTS: Of approximately 4000 generic drugs and drug classes evaluated, the method detected 19 distinct drug exposures with statistically significant, large relative risks indicating that cases were less frequently exposed than controls. These included (1) drugs with prior evidence for a causal relationship (e.g., megestrol); (2) drugs without prior evidence for a causal relationship, but potentially worth further exploration (e.g., donepezil, epoetin alfa); (3) drugs with alternative biologic explanations for the association (e.g., sevelamer); and (4) drugs that may have resulted in statistical alerts due to their correlation with drugs that alerted for other reasons. CONCLUSIONS: This exploratory drug-screening study identified several potential targets for follow-up studies to further evaluate and determine if they may prevent or delay progression to advanced AMD.

Incidence of Macular Atrophy after Untreated Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study Report 40.

PURPOSE: To report the natural history of untreated neovascular age-related macular degeneration (nAMD) regarding subsequent macular atrophy. DESIGN: Prospective cohort within a randomized, controlled trial of oral micronutrient supplements. PARTICIPANTS: Age-Related Eye Disease Study (AREDS) participants (55-80 years) who demonstrated nAMD during follow-up (1992-2005), prior to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Color fundus photographs were collected at annual study visits and graded centrally for late age-related macular degeneration (AMD). Incident macular atrophy after nAMD was examined by Kaplan-Meier analysis and proportional hazards regression. MAIN OUTCOME MEASURES: Incident macular atrophy after nAMD. RESULTS: Of the 4757 AREDS participants, 708 eyes (627 participants) demonstrated nAMD during follow-up and were eligible. The cumulative risks of incident macular atrophy after untreated nAMD were 9.6% (standard error, 1.2%), 31.4% (standard error, 2.2%), 43.1% (standard error, 2.6%), and 61.5% (standard error, 4.3%) at 2, 5, 7, and 10 years, respectively. This corresponded to a linear risk of 6.5% per year. The cumulative risk of central involvement was 30.4% (standard error, 3.2%), 43.4% (standard error, 3.8%), and 57.0% (standard error, 4.8%) at first appearance of atrophy, 2 years, and 5 years, respectively. Geographic atrophy (GA) in the fellow eye was associated with increased risk of macular atrophy (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.17-2.49; P = 0.006). However, higher 52-single nucleotide polymorphism AMD genetic risk score was not associated with increased risk of macular atrophy (HR, 1.03; 95% CI, 0.90-1.17; P = 0.67). Similarly, no significant differences were observed according to SNPs at CFH, ARMS2, or C3. CONCLUSIONS: The rate of incident macular atrophy after untreated nAMD is relatively high, increasing linearly over time and affecting half of eyes by 8 years. Hence, factors other than anti-VEGF therapy are involved in atrophy development, including natural progression to GA. Comparison with studies of treated nAMD suggests it may not be necessary to invoke a large effect of anti-VEGF therapy on inciting macular atrophy, although a contribution remains possible. Central involvement is present in one third of eyes at the outset (similar to pure GA) and increases linearly to half at 3 years.

The association between clinically diagnosed insomnia and age-related macular degeneration: a population-based cohort study.

PURPOSE: The decreased level of melatonin, the substance involved in the control of the sleep-wake cycle, has been reported among the patients with age-related macular degeneration (AMD). However, knowledge about the relationship between sleep disturbance and AMD is still limited. This longitudinal case-control study aims to investigate the risk of incident AMD among the patients with clinically diagnosed insomnia using the Taiwan National Health Insurance Research Database. METHODS: The insomnia cohort (n = 15 465) consisted of newly diagnosed insomnia cases aged ≥55 years between 2000 and 2009. Subjects without insomnia, matched for age, gender and enrolment time, were randomly sampled as the control cohort (n = 92 790). Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of incident AMD for the two cohorts after adjusting for potential confounders. RESULTS: Of the 108 255 sampled subjects, 2094 (1.9%) were diagnosed with AMD, including 214 (0.2%) with neovascular AMD, during a mean follow-up period of 5.1 ± 2.8 years. Insomnia patients were more likely to have subsequent AMD than those without insomnia (2.5% versus 1.8%, p < 0.001). Further, the incidence of exudative AMD was also higher in the insomnia cohort than the control cohort (0.3% versus 0.2%, p = 0.002). The adjusted HR was 1.33 (95% confidence interval [CI], 1.18-1.48, p < 0.001) for AMD and 1.67 (95% CI, 1.20-2.33, p = 0.002) for exudative AMD. CONCLUSIONS: Clinically diagnosed insomnia is an independent indicator for the increased risk of subsequent AMD development.

Telemedicine in the Management of Exudative Age-Related Macular Degeneration within an Integrated health care System.

PURPOSE: To investigate the outcomes of patients with exudative age-related macular degeneration (AMD) treated with intravitreal antivascular endothelial growth factors (VEGF) using a telemedicine system. DESIGN: Interventional case series. METHODS: This study examined all patients with exudative AMD who were receiving intravitreal anti-VEGF injections from September 1, 2015, through August 31, 2017, using electronic consultations at a single academic center and health system. Patients were managed initially by a retinal specialist and then allowed to receive further care with their local ophthalmologist. There were 200 electronic consultations placed during this time period for 83 eyes of 59 patients. Data collected included the retina specialist's recommendations: intravitreal agent, interval between injections, number of injections, and when the patient was to follow-up. All occurrences of recommendations that were not completed were reported. RESULTS: The mean age of the patients at the time of electronic consultations was 82.3 ± 7.3 years with a mean follow-up time of 2.4 ± 0.81 years. The mean distance from the home of the patient to the retina specialist was 70 ± 44 miles. There were 14 consultations (7.1%) that did not comply with the recommendations of the retina specialist. Most of these were due to other medical comorbidities leading to missed appointments or scheduling errors. CONCLUSIONS: In an integrated health care setting, 59 patients with exudative AMD were identified who were able to be effectively managed using a telemedicine system. In the appropriate setting, telemedicine may be able to assist in the management of patients with wet AMD.

ASSOCIATION BETWEEN ORAL IRON SUPPLEMENTATION AND RETINAL OR SUBRETINAL HEMORRHAGE IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENT TRIALS.

PURPOSE: Because patients often take iron supplements without medical indication, and iron can accumulate in vascular endothelial cells, the authors evaluated the association of oral iron supplementation with retinal/subretinal hemorrhage in patients with neovascular age-related macular degeneration. METHODS: A post hoc secondary data analysis of comparison of age-related macular degeneration treatments trials was performed. Participants were interviewed for use of oral iron supplements. Trained readers evaluated retinal/subretinal hemorrhage in baseline fundus photographs. Adjusted odds ratios from multivariate logistic regression models assessed the association between iron use and baseline hemorrhage adjusted by age, sex, smoking, hypertension, anemia, and use of antiplatelet/anticoagulant drugs. RESULTS: Among 1,165 participants, baseline retinal/subretinal hemorrhage was present in the study eye in 71% of 181 iron users and in 61% of 984 participants without iron use (adjusted odds ratio = 1.47, P = 0.04), and the association was dose dependent (adjusted linear trend P = 0.048). Iron use was associated with hemorrhage in participants with hypertension (adjusted odds ratio = 1.87, P = 0.006) but not without hypertension. The association of iron use with hemorrhage remained significant among hypertensive participants without anemia (adjusted odds ratio = 1.85, P = 0.02). CONCLUSION: Among participants of comparison of age-related macular degeneration treatments trials, the use of oral iron supplements was associated with retinal/subretinal hemorrhage in a dose-response manner. Unindicated iron supplementation may be detrimental in patients with wet age-related macular degeneration.

Repeated intravitreal injections of antivascular endothelial growth factor in patients with neovascular age-related macular degeneration may increase the risk of ischemic optic neuropathy.

BACKGROUND: Previous case reports have demonstrated the occurrence of ischemic optic neuropathy (ION) following intravitreal injections of antivascular endothelial growth factor (anti-VEGF). However, no previous studies have investigated the impact of injection numbers on the risk of ION. The aim of our study was to investigate whether repeated intravitreal injections of anti-VEGF would increase the risk of subsequent ION in patients with neovascular age-related macular degeneration (AMD). METHODS: A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from 2007 to 2013. Neovascular AMD patients receiving intravitreal injections of anti-VEGF during the study period were enrolled in the study cohort. Enrollees were divided into three groups according to the categorized levels of injection number (first level: < 10 times, second level: 10-15 times, and third level: > 15 times). Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent ION among the three groups. Cox regression analyses were used to estimate crude and adjusted hazard ratios (HRs) for ION development with respect to the different levels of injection numbers. The confounders included for adjustment were age, sex, and comorbidities (diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). RESULTS: In total, the study cohort included 77,210 patients. Of these, 26,520, 38,010, and 12,680 were in the first-, second-, and third-level groups, respectively. The Kaplan-Meier method revealed that the cumulative hazards of ION were significantly higher in those who had a higher injection number. After adjusting for confounders, the adjusted HRs for ION in the second- and third-level groups were 1.91 (95% confidence interval [CI], 1.32-2.76) and 2.20 (95% CI, 1.42-3.43), respectively, compared with those in the first-level group. CONCLUSIONS: Among patients with neovascular AMD, those who receive a higher number of anti-VEGF injections have a significantly higher risk of developing ION compared with individuals who receive a lower number of injections.

Incidence of exudative age-related macular degeneration and treatment load under the Korean national health insurance system in 2010-2015.

BACKGROUND/AIM: The aim of this study was to estimate the nationwide incidence of clinically diagnosed exudative age-related macular degeneration (AMD) and associated use of ranibizumab and aflibercept in South Korea. METHODS: In this retrospective, population-based cohort study, claims data for 2010-2015 were analysed in a randomly selected sample of 519 661 adults aged ≥40 years. The incidence per 10 000 person-years was estimated, along with the 95% CI. Incident exudative AMD was defined based on the registration code for rare intractable diseases. Use of ranibizumab and aflibercept and the incidence of exudative AMD were recorded. RESULTS: Nine hundred and twelve patients were newly diagnosed with exudative AMD in 2010-2015. The 6-year incidence in the general population aged ≥40 years was 2.9 (95% CI 2.8 to 3.0) per 10 000 person-years. The incidence was highest in individuals aged 75-79 years (12.0, 95% CI 10.3 to 13.8). The incidence was higher in men than in women in all age groups. Six hundred and twenty-five (69%) of the 912 newly diagnosed patients started ranibizumab or aflibercept as a first-line treatment. The average number of injections administered was 6.1 (SD 3.9; minimum of 1 injection and maximum government-supported limit of 14) during 2010-2015; the number increased with increasing government funding support (from 5 to 10 and from 10 to 14 in 2013 and 2014, respectively). CONCLUSIONS: This study describes the incidence of exudative AMD in South Korea and its treatment under the national health insurance system in this country. Its findings could be used for reference purposes and be useful when planning treatment for exudative AMD.

Neovascular age-related macular degeneration is associated with cataract surgery.

PURPOSE: This retrospective cohort study examines the association between cataract surgery and neovascular age-related macular degeneration (AMD) during 5-year follow-up using population-based claims data. METHODS: We analysed data sourced from the Taiwan Longitudinal Health Insurance Database 2005. The study included 3465 patients who had undergone cataract operations and did not have a diagnosis of AMD before or on the surgery date (study group), and 10 395 age- and sex-matched comparison patients selected randomly from the remaining patients without an AMD diagnosis before the index date. We tracked the claims of each patient for a 5-year period to identify patients with a subsequent diagnosis of neovascular AMD. RESULTS: The incidence rate of neovascular AMD was 0.88 (95% confidence interval (CI): 0.66-1.14) per 1000 person-years among all sampled patients, 1.60 (95% CI: 1.04-2.36) among the cataract surgery patients and 0.64 (95% CI: 0.43-0.91) among comparison patients (p < 0.001). Stratified Cox proportional analysis showed that relative to the comparison cohort, the adjusted hazard ratio for neovascular AMD during 5-year follow-up was 2.68 (95% CI: 1.55-4.66) for patients who had undergone cataract operation. We censored those who died during follow-up period and adjusted for patients' monthly income, geographical location, urbanization level, diabetes, hypertension, cardiovascular disease and hyperlipidaemia. CONCLUSION: This study demonstrated epidemiological evidence of a link between cataract surgery and neovascular AMD during a 5-year follow-up period.

Effect of Dietary Supplementation With Lutein, Zeaxanthin, and ω-3 on Macular Pigment: A Randomized Clinical Trial.

Importance: Nutritional uptake of lutein, zeaxanthin, and ω-3 polyunsaturated fatty acids may increase macular pigment optical density (MPOD) and thereby protect against the development of age-related macular degeneration (AMD). Objectives: To estimate the efficiency of dietary supplementation containing lutein, zeaxanthin, ω-3 polyunsaturated fatty acids, and vitamins to increase the density of macular pigment in first-generation offspring of parents with neovascular AMD. Design, Setting, and Participants: This study was a randomized clinical trial (Lutein Influence on Macula of Persons Issued From AMD Parents [LIMPIA]) with a 6-month treatment period, followed by a 6-month follow-up period. Analyses were based on the intent-to-treat principle. The setting was 2 university hospitals in France (at Bordeaux and Dijon) from January 2011 (first participant first visit) to February 2013 (last participant last visit). The analysis was conducted from January to November 2016. Participants were 120 individuals free of any retinal ocular disease. They were first-generation offspring of parents with neovascular AMD. Interventions: Participants were randomized in a 1:1 ratio to receive either 2 daily dietary supplementation capsules or placebo for 6 months. Main Outcomes and Measures: The primary assessment criterion was the evolution of MPOD after 6 months of supplementation (value of both eligible eyes) measured using the modified MPD-Visucam 200 (Carl Zeiss Meditec) and the modified Heidelberg Retina Angiograph (Heidelberg Engineering) (HRA) at 0.98° eccentricity. The statistical analysis was adjusted for hospital and for risk factors. Results: Overall, 120 participants (60 in each group) were included, and 239 eyes were analyzed (119 in the lutein plus zeaxanthin [L + Z] group and 120 in the placebo group). Their mean (SD) age was 56.7 (6.6) years, and 71.7% (n = 86) were female. A statistically significant increase in plasma lutein and zeaxanthin was shown in the L + Z group after 3 months and 6 months of treatment compared with the placebo group. However, the difference between groups in the evolution of MPOD measured by HRA 0.98° eccentricity between 6 months and baseline was 0.036 (95% CI, -0.037 to 0.110) (P = .33). Conclusions and Relevance: Among first-generation offspring of parents with neovascular AMD in the LIMPIA trial, MPOD as measured with the modified HRA and the MPD-Visucam was not modified after 6 months of lutein and zeaxanthin dietary supplementation despite plasma levels showing continuous exposure to lutein and zeaxanthin. Further research is necessary to understand the mechanism of absorption and metabolism of these nutrients in the macula, the best way to measure MPOD, and the clinical benefit for the patients. Trial Registration: clinicaltrials.gov Identifier: NCT01269697.

Automated Grading of Age-Related Macular Degeneration From Color Fundus Images Using Deep Convolutional Neural Networks.

Importance: Age-related macular degeneration (AMD) affects millions of people throughout the world. The intermediate stage may go undetected, as it typically is asymptomatic. However, the preferred practice patterns for AMD recommend identifying individuals with this stage of the disease to educate how to monitor for the early detection of the choroidal neovascular stage before substantial vision loss has occurred and to consider dietary supplements that might reduce the risk of the disease progressing from the intermediate to the advanced stage. Identification, though, can be time-intensive and requires expertly trained individuals. Objective: To develop methods for automatically detecting AMD from fundus images using a novel application of deep learning methods to the automated assessment of these images and to leverage artificial intelligence advances. Design, Setting, and Participants: Deep convolutional neural networks that are explicitly trained for performing automated AMD grading were compared with an alternate deep learning method that used transfer learning and universal features and with a trained clinical grader. Age-related macular degeneration automated detection was applied to a 2-class classification problem in which the task was to distinguish the disease-free/early stages from the referable intermediate/advanced stages. Using several experiments that entailed different data partitioning, the performance of the machine algorithms and human graders in evaluating over 130 000 images that were deidentified with respect to age, sex, and race/ethnicity from 4613 patients against a gold standard included in the National Institutes of Health Age-related Eye Disease Study data set was evaluated. Main Outcomes and Measures: Accuracy, receiver operating characteristics and area under the curve, and kappa score. Results: The deep convolutional neural network method yielded accuracy (SD) that ranged between 88.4% (0.5%) and 91.6% (0.1%), the area under the receiver operating characteristic curve was between 0.94 and 0.96, and kappa coefficient (SD) between 0.764 (0.010) and 0.829 (0.003), which indicated a substantial agreement with the gold standard Age-related Eye Disease Study data set. Conclusions and Relevance: Applying a deep learning-based automated assessment of AMD from fundus images can produce results that are similar to human performance levels. This study demonstrates that automated algorithms could play a role that is independent of expert human graders in the current management of AMD and could address the costs of screening or monitoring, access to health care, and the assessment of novel treatments that address the development or progression of AMD.

Epilutein for Early-Stage Age-Related Macular Degeneration: A Randomized and Prospective Study.

PURPOSE: The hypothesis that oral supplementation of the epilutein/lutein combination could augment the macular pigment optical density (MPOD) in patients with age-related macular degeneration (AMD) was tested. METHODS: In a prospective randomized interventional study, 40 consecutive patients with early-stage AMD were recruited. After a 2-week run-in period, patients were randomly treated with a daily oral administration of 8 mg epilutein and 2 mg lutein (group 1) or 10 mg lutein (group 2) for 2 months. At baseline (BL) and 1-month (M1) and 2-month visits (M2), all patients underwent a complete ophthalmological examination, including measurement of MPOD in a 7° area (Visucam 200; Carl Zeiss Meditec, Milan, Italy). Xanthophylls were quantified in plasma, as well as the HDL, non-HDL, and erythrocyte fractions at each study visit. RESULTS: Twenty-one patients (mean age 69.4 ± 6.7 years, 35 eyes) were included in group 1. Mean MPOD was 0.203 ± 0.02 optical density units (ODU) at BL, and increased to 0.214 ± 0.04 ODU at M1 (p = 0.008) and 0.206 ± 0.03 ODU at M2 (p = 0.04). Sixteen patients (mean age 72.0 ± 6.3 years, 29 eyes) were included in group 2. Mean MPOD was 0.215 ± 0.03 at BL, which reduced to 0.202 ± 0.03 ODU at M1 (p = 0.003) and 0.207 ± 0.02 ODU at M2 (p < 0.001). A rise in the systemic level of total xanthophylls was observed at M1 for both groups. At M2, total xanthophylls were significantly increased only in group 1 and decreased in group 2. CONCLUSION: In patients with early-stage AMD, the administration of lutein in combination with epilutein was associated with an increased MPOD compared to the administration of lutein alone.

Dietary Intakes of Eicosapentaenoic Acid and Docosahexaenoic Acid and Risk of Age-Related Macular Degeneration.

PURPOSE: To evaluate the associations between intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the intermediate and advanced stages of age-related macular degeneration (AMD). DESIGN: Prospective cohort study. PARTICIPANTS: We followed 75 889 women from the Nurses' Health Study and 38 961 men from the Health Professionals Follow-Up Study who were at least 50 years old, from 1984 to 2012 and 1986 to 2010, respectively. Cohort participants are mostly white (≥95%). METHODS: We assessed dietary intake by a validated food frequency questionnaire (FFQ) at baseline and every 4 years. We calculated cumulative average intakes of EPA and DHA from FFQs and also computed predicted erythrocyte and plasma scores directly from food intake using regression models. Cox proportional hazards models were used to compute the associations with AMD outcomes. MAIN OUTCOME MEASURES: We confirmed 1589 incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse, owing primarily to AMD, by medical record review. RESULTS: For intermediate AMD, the pooled hazard ratio (HR) between the 2 cohorts for DHA comparing the extreme quintiles of intake was 0.78 (95% confidence interval [CI], 0.66-0.92; P trend, 0.008) and for EPA + DHA was 0.83 (95% CI, 0.71-0.98; P trend, 0.03). The pooled HR for fatty fish, comparing ≥5 servings per week to almost never, was 0.61 (95% CI, 0.46-0.81; P trend, <0.001). For advanced AMD, the pooled HR for DHA was 1.01 (95% CI, 0.84-1.21; P trend, 0.75) and for fatty fish was 0.80 (95% CI, 0.59-1.08; P trend, 0.11). Secondary analyses using predicted erythrocyte and plasma scores of EPA and DHA yielded slightly stronger inverse associations for intermediate AMD and similar results for advanced AMD. CONCLUSIONS: Higher intakes of EPA and DHA may prevent or delay the occurrence of visually significant intermediate AMD. However, the totality of current evidence for EPA and DHA and advanced AMD is discordant, though there was no association with advanced AMD in the present study.

The design and implementation of a study to investigate the effectiveness of community vs hospital eye service follow-up for patients with neovascular age-related macular degeneration with quiescent disease.

IntroductionStandard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.MethodsThe Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant's judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.DiscussionThis trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.

The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9.

PURPOSE: To evaluate the association of statin use with progression of age-related macular degeneration (AMD). DESIGN: Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years. METHODS: Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed. MAIN OUTCOME MEASURES: Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). RESULTS: Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD. CONCLUSIONS: Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the majority of previous studies. Statins have been demonstrated to reduce the risk of cardiovascular disease, but our data do not provide evidence of a beneficial effect on slowing AMD progression.

Age-Related Macular Degeneration and Risk of Degenerative Dementia among the Elderly in Taiwan: A Population-Based Cohort Study.

PURPOSE: To investigate the relationship between age-related macular degeneration (AMD) and future development of Alzheimer's disease (AD) or senile dementia. DESIGN: A longitudinal case-control study using the Taiwan National Health Insurance Research Database. PARTICIPANTS: From 2001 to 2009, the newly diagnosed AMD cases aged ≥65 years in the database were recruited as the AMD cohort (n=4993). Of those, there were 540 with and 4453 without exudative AMD diagnoses. Subjects without any AMD, matched for age, gender, and time of enrollment, were randomly sampled as the control cohort (n=24,965) for comparison. METHODS: Alzheimer's disease/senile dementia-free survival analysis was assessed using a Kaplan-Meier method. Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of AD or senile dementia for the 2 cohorts after adjusting for preexisting comorbidities and number of clinical visits. MAIN OUTCOME MEASURES: The first-ever diagnosis of AD or senile dementia during the observation period. RESULTS: Of the 29 958 sampled subjects, 1589 (5.3%) were diagnosed with AD or senile dementia during a mean follow-up period of 4.4 years, including 294 (5.9%) from the AMD cohort and 1295 (5.2%) from the control cohort. The incidence of AD or senile dementia was higher in patients with AMD than in the controls (P=0.044), with an HR of 1.44 (95% confidence interval [CI], 1.26-1.64) after adjusting for covariates. The stratified analysis showed that the adjusted HR for AD or senile dementia was 1.35 (95% CI, 0.89-2.06) for exudative AMD versus the controls and 1.44 (95% CI, 1.26-1.65) for nonexudative AMD versus the controls. CONCLUSIONS: This study provides large-scale, population-based evidence that AMD, especially nonexudative AMD, is independently associated with an increased risk of subsequent AD or senile dementia development.

Omega-3 supplementation combined with anti-vascular endothelial growth factor lowers vitreal levels of vascular endothelial growth factor in wet age-related macular degeneration.

PURPOSE: To determine the influence of omega-3 supplementation on vitreous vascular endothelial growth factor A (VEGF-A) levels in patients with exudative age-related macular degeneration (wet AMD) receiving intravitreal anti-VEGF treatment. DESIGN: Prospective, randomized, open-label, single-center, clinical trial, consecutive interventional case series. METHODS: The study included 3 cohorts with wet AMD and a control group with epiretinal membrane or macular hole. Twenty wet AMD patients being treated with anti-VEGF were randomized to daily supplementation of antioxidants, zinc, and carotenoids with omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid; group 1, n = 10) or without omega-3 fatty acids (group 2, n = 10). They were compared with an anti-VEGF treatment-naïve wet AMD group (group 3, n = 10) and an epiretinal membrane or macular hole group (group 4, n = 10). Primary outcome was vitreal VEGF-A levels (at the time of anti-VEGF injection). Secondary outcomes were plasma VEGF-A and central foveal thickness. Patients with new submacular hemorrhage or any other treatment within 3 months were excluded. Final analyses included 9, 6, 7, and 8 patients in groups 1 through 4, respectively. RESULTS: Patients receiving omega-3s (group 1) had significantly lower levels of vitreal VEGF-A (141.11 ± 61.89 pg/mL) when compared with group 2 (626.09 ± 279.27 pg/mL; P = .036) and group 3 (735.48 ± 216.43 pg/mL; P = .013), but similar levels to group 4 (235.81 ± 33.99 pg/mL; P = .215). All groups showed similar values for plasma VEGF-A and central foveal thickness measurements. CONCLUSIONS: This study demonstrated that omega-3 supplementation combined with anti-VEGF treatment is associated with decreased vitreal VEGF-A levels in wet AMD patients.