Effects of slit lamp-delivered retinal laser photobiomodulation in a rat model of choroidal neovascularization.

Neovascular age-related macular degeneration, also known as exudative or wet age-related macular degeneration, is the leading cause of blindness in the developed world. Photobiomodulation has the potential to target the up-stream hypoxic and pro-inflammatory drivers of choroidal neovascularization. This study investigated whether photobiomodulation attenuates characteristic pathological features of choroidal neovascularization in a rodent model. Experimental choroidal neovascularization was induced in Brown Norway rats with laser photocoagulation. A custom-designed, slit-lamp-mounted, 670 nm laser was used to administer retinal photobiomodulation every 3 days, beginning 6 days prior to choroidal neovascularization induction and continuing until the animals were killed 14 days later. The effect of photobiomodulation on the size of choroidal neovascular membranes was determined using isolectin-B4 immunohistochemistry and spectral domain-optical coherence tomography. Vascular leakage was determined with fluorescein angiography. The effect of treatment on levels of vascular endothelial growth factor expression was quantified with enzyme-linked immunosorbent assay. Treatment with photobiomodulation was associated with choroidal neovascular membranes that were smaller, had less fluorescein leakage, and a diminished presence of inflammatory cells as compared to sham eyes. These effects were not associated with a statistically significant difference in the level of vascular endothelial growth factor when compared to sham eyes. The data shown herein indicate that photobiomodulation attenuates pathological features of choroidal neovascularization in a rodent model by mechanisms that may be independent of vascular endothelial growth factor.

Factors associated with loss to follow-up in patients with advanced age-related macular degeneration: A telehealth recall initiative.

INTRODUCTION: Patients with advanced age-related macular degeneration (AMD) frequently experience loss to follow-up (LTFU), heightening the risk of vision loss from treatment delays. This study aimed to identify factors contributing to LTFU in patients with advanced AMD and assess the effectiveness of telephone-based outreach in reconnecting them with eye care. METHODS: A custom reporting tool identified patients with advanced AMD who had not returned for eye care between 31 October 2021 and 1 November 2022. Potentially LTFU patients were enrolled in a telephone outreach programme conducted by a telehealth extender to encourage their return for care. Linear regression analysis identified factors associated with being LTFU and likelihood of accepting care post-outreach. RESULTS: Out of 1269 patients with advanced AMD, 105 (8.3%) did not return for recommended eye care. Patients LTFU were generally older (89.2 ± 8.9 years vs. 87.2 ± 8.5 years, p = 0.02) and lived farther from the clinic (25 ± 43 miles vs. 17 ± 30 miles, p = 0.009). They also had a higher rate of advanced dry AMD (26.7% vs. 18.5%, p = 0.04) and experienced worse vision in both their better-seeing (0.683 logMAR vs. 0.566 logMAR, p = 0.03) and worse-seeing (1.388 logMAR vs. 1.235 logMAR, p = 0.04) eyes. Outreach by a telehealth extender reached 62 patients (59%), 43 through family members or healthcare proxies. Half of the cases where a proxy was contacted revealed that the patient in question had died. Among those contacted directly, one third expressed willingness to resume eye care (20 patients), with 11 scheduling appointments (55%). Despite only two patients returning for in-person eye care through the intervention, the LTFU rate halved to 4.4% by accounting for those patients who no longer needed eye care at the practice. CONCLUSIONS: There is a substantial risk that older patients with advanced AMD will become LTFU. Targeted telephone outreach can provide a pathway for vulnerable patients to return to care.

Evaluation of training, patient and practitioner perspectives on community-based monitoring of patients with stable age-related macular degeneration compared to hospital-based care: The FENETRE study report no. 1.

PURPOSE: Describe the development, delivery, acceptability and evaluation of a modular training programme for community-based, non-medical practitioners monitoring patients with quiescent neovascular age related macular degeneration (QnAMD). Also, report on a qualitative process evaluation conducted during the pilot phase of a randomised control trial (the FENETRE Study) exploring patient and practitioner acceptability of community-based QnAMD care relative to hospital-based care. METHODS: Learning outcomes from The College of Optometrists' Medical Retina higher qualifications and the Royal College of Ophthalmologists' Common Clinical Competency Framework were used to develop a competency framework for QnAMD care. Training was delivered online, comprising six asynchronous lectures followed by two synchronous case-based discussion webinars, with an accredited assessment of 24 case vignettes. An anonymous evaluation survey was conducted with the first two FENETRE cohorts (n = 38). Separately, we undertook a qualitative process evaluation, sampling purposively in four hospitals and five community-based practices, interviewing nine patients and eight practitioners. RESULTS: Survey responses (n = 26) showed community optometrists were very satisfied (n = 12; 46%) or satisfied (n = 14; 54%) with the training; feedback reflected by qualitative process evaluation data. Overall, optometrists also felt either confident (n = 15; 58%) or very confident (n = 8; 31%) in conducting AMD monitoring appointments following training, a finding also corroborated by interview data from optometrists participating in the initial pilot phase roll-out. Optometrists identified patient convenience and alleviating pressures in hospital care as the primary reasons for acceptability of community pathways. Data from patients entering community practices suggested they largely found this at least as safe and convenient as hospital care, although some patients randomised to hospital care perceived that as safer. CONCLUSION: This pilot study has shown the development and implementation of a collaborative community monitoring model is feasible, with satisfaction from community optometrists for training and accreditation, and broad acceptance for the pathway by both patients and practitioners.

Altered proportion of CCR2+ and CX3CR1+ circulating monocytes in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

BACKGROUND: We investigated the expression of chemokine receptors CCR2 (C-C chemokine receptor) 2 and CX3CR1 (C-X3-C receptor 1) on circulating monocyte subsets in patients with neovascular age-related macular degeneration (AMD) and patients with polypoidal choroidal vasculopathy (PCV). METHODS: We recruited patients with neovascular AMD, patients with PCV and age-matched healthy controls for this prospective case-control study. All participants underwent comprehensive clinical examination and imaging. Freshly sampled venous blood was prepared for flow cytometry, where we determined the proportion of CCR2+ - and CX3CR1+ -positive cells in monocyte subsets identified using monocyte identification and subgrouping surface markers CD14, CD16 and HLA-DR. RESULTS: Patients with neovascular AMD had significantly increased proportion of CCR2+ and CX3CR1+ non-classical monocytes. PCV type 1 was associated with significantly increased CCR2+ and CX3CR1+ in all monocyte subsets when compared to PCV type 2. CONCLUSIONS: Neovascular AMD is associated with increased expression of angiogenesis-associated chemokine receptors in the pro-inflammatory non-classical monocytes. PCV differs from neovascular AMD immunologically and show immunological heterogeneity across angiographic subtypes.

Androgen Deprivation Therapy and Newly Developed Neovascular Age-Related Macular Degeneration Risk in Patients with Prostate Cancer.

Background/Objectives: to evaluate the association between androgen deprivation therapy (ADT) and newly developed neovascular age-related macular degeneration (AMD) in patients with prostate cancer. Methods: We identified 228,803 men from the nationwide claims database in the Republic of Korea diagnosed with prostate cancer between 1 August 2009 and 31 December 2018 and followed until April 2021. Cases were defined as those newly diagnosed with neovascular AMD during follow-up. Cases were matched with controls based on age, index date, and follow-up duration, at a case-to-control ratio of 1:4. Adjusted odds ratios (aORs) of incident neovascular AMD associated with ADT were estimated using conditional logistic regression. Results: The main analysis included 1700 cases and 6800 controls, with a median follow-up of 3.42 years. ADT was associated with a reduced risk of incident neovascular AMD in patients with prostate cancer (aOR = 0.840; 95% confidence interval [CI], 0.743-0.951; p = 0.0058) in the multivariable analysis. A cumulative ADT duration less than 1 year was associated with a reduced risk of neovascular AMD (aOR = 0.727; 95% CI, 0.610-0.866; p = 0.0004); however, no association was observed when the duration of ADT was between 1 and 2 years (aOR = 0.862; 95% CI, 0.693-1.074; p = 0.1854) or more than 2 years (aOR = 1.009; 95% CI, 0.830-1.226; p = 0.9304). Conclusions: In patients with prostate cancer, medical castration for less than a year is associated with a reduced risk of incident neovascular AMD. These results suggest that androgens are involved in the pathogenesis of neovascular AMD.

Real-life neovascular AMD treatment considering reimbursement in Turkiye: One-year comparison of switching to intravitreal ranibizumab or aflibercept after treatment failure with three loading intravitreal bevacizumab injections.

OBJECTIVE: To compare one-year anatomical and functional results of switching to an on-label intravitreal anti-vascular endothelial growth factor (anti-VEGF) agent (intravitreal ranibizumab [IVR] or aflibercept [IVA]) after treatment failure with three loading doses of off-label intravitreal bevacizumab (IVB), which is mandatory in the treatment of neovascular age-related macular degeneration (nAMD) to get reimbursement from Social Security Institution in Turkiye. METHODS: This comparative, real-life, retrospective cohort study included treatment-naïve nAMD patients treated starting with three loading doses of IVB, switched to three loading doses of IVR and IVA due to treatment failure after IVB loading, and followed up one year with a treat-and-extend (T&E) protocol with 2-week extension/shortening intervals. The primary outcomes were changes in best-corrected visual acuity (BCVA; logMAR) and central macular thickness (CMT, µm) one year after the switch, and the secondary outcomes were maximum treatment intervals, number of injections, and disease activity rates. RESULTS: The mean age (72.9±8.2 and 72.2±6.7, p=0.677) and gender (60.0% and 47.4% females, p=0.398) were similar among the IVR (35 eyes/patients) and IVA (38 eyes/patients) groups. The median BCVA and CMT were significantly improved during the study period (p<0.001) with no significant intergroup differences. The ratio of 4-, 6-, 8-, 10-, and 12-week maximum treatment intervals were 28.6%, 17.1%, 14.3%, 8.6%, and 31.4% in the IVR, and 13.2%, 15.8%, 21.1%, 15.8%, and 34.2% in the IVA group (p=0.492). The median (IQR) number of injections in the IVA group (8 [7-9]) was significantly lower than the IVR group (9 [8-12]) during the one-year T&E period (p=0.026). The disease activity rates were 34.3% and 26.4% one month (p=0.610) and 37.1% and 21.1% one year (p=0.195) after the switch in IVR and IVA groups. CONCLUSION: This real-life comparison study indicates that, after the treatment failure with three loading doses of IVB, switching to either on-label anti-VEGF agent can be regarded as comparable considering functional and anatomical results. However, although maximum treatment intervals were not significantly different, fewer injections were required with aflibercept during the one-year T&E follow-up period.

Off-Label Use of Bevacizumab in Patients Diagnosed with Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly people. Current pharmacological treatment in vascular AMD includes anti-VEGF agents, such as ranibizumab and aflibercept. Additionally, the off-label use of bevacizumab has been shown to be effective and has a lower cost, making it an interesting pharmacological approach; however, there is no consensus about its use. Therefore, this systematic review and meta-analysis aims to evaluate the efficacy, safety, and efficiency of bevacizumab in AMD patients. METHODS: This review only focused on randomized controlled clinical trials published in 2010 in the MEDLINE database that compared the effect of bevacizumab with ranibizumab. The risk of bias in each included study was assessed using the CASP Randomised Clinical Trials checklist. RESULTS: Twelve studies were included for qualitative synthesis, and nine of them were considered for meta-analysis. Bevacizumab-treated patients showed a significantly reduced neovascularization in a longer spectrum of time; however, they had a higher incidence of endophthalmitis than those treated with ranibizumab. Regarding efficiency, the mean number of administrations was reduced in the treatment with bevacizumab in comparison to ranibizumab. CONCLUSIONS: Clinical evidence demonstrates that bevacizumab has efficacy and safety profiles comparable with ranibizumab; however, it is relatively more efficient.

"Application and accuracy of artificial intelligence-derived large language models in patients with age related macular degeneration".

INTRODUCTION: Age-related macular degeneration (AMD) affects millions of people globally, leading to a surge in online research of putative diagnoses, causing potential misinformation and anxiety in patients and their parents. This study explores the efficacy of artificial intelligence-derived large language models (LLMs) like in addressing AMD patients' questions. METHODS: ChatGPT 3.5 (2023), Bing AI (2023), and Google Bard (2023) were adopted as LLMs. Patients' questions were subdivided in two question categories, (a) general medical advice and (b) pre- and post-intravitreal injection advice and classified as (1) accurate and sufficient (2) partially accurate but sufficient and (3) inaccurate and not sufficient. Non-parametric test has been done to compare the means between the 3 LLMs scores and also an analysis of variance and reliability tests were performed among the 3 groups. RESULTS: In category a) of questions, the average score was 1.20 (± 0.41) with ChatGPT 3.5, 1.60 (± 0.63) with Bing AI and 1.60 (± 0.73) with Google Bard, showing no significant differences among the 3 groups (p = 0.129). The average score in category b was 1.07 (± 0.27) with ChatGPT 3.5, 1.69 (± 0.63) with Bing AI and 1.38 (± 0.63) with Google Bard, showing a significant difference among the 3 groups (p = 0.0042). Reliability statistics showed Chronbach's α of 0.237 (range 0.448, 0.096-0.544). CONCLUSION: ChatGPT 3.5 consistently offered the most accurate and satisfactory responses, particularly with technical queries. While LLMs displayed promise in providing precise information about AMD; however, further improvements are needed especially in more technical questions.

The Efficacy, Safety, and Efficiency of the Off-Label Use of Bevacizumab in Patients Diagnosed With Age-Related Macular Degeneration: Protocol for a Systematic Review and Meta-Analysis.

BACKGROUND: Age-related macular degeneration (AMD) is recognized as the leading cause of vision loss in older people. Considering the phenomenon of aging societies worldwide, the prevalence of AMD is expected to increase gradually in the future. AMD can be divided into early, intermediate, and late stages, with the early and intermediate stages being mainly asymptomatic, and the late stage being classified as geographic atrophy, neovascular AMD, or both. Current pharmacological treatments for neovascular AMD include anti-vascular endothelial growth factor agents, such as ranibizumab, pegaptanib, and aflibercept. Additionally, it has been reported that the off-label use of intravitreally administered bevacizumab is effective. It is also lower cost than other agents, which makes it an interesting pharmacological approach. OBJECTIVE: This review aims to evaluate the efficacy, safety, and efficiency of bevacizumab for the treatment of neovascular AMD. METHODS: This review will only consider randomized controlled clinical trials that compare the use of bevacizumab with another pharmacological agent or a placebo in patients aged 50 years and older who are diagnosed with vascular AMD. It will exclude studies that include participants diagnosed with polypoidal choroidal vasculopathy or retinal angiomatous proliferation. To identify and select relevant articles, we will develop a highly sensitive search strategy and apply it in MEDLINE via the PubMed platform. Upon selection of the studies and analysis of the titles, abstracts, and full texts, the results will be presented according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis and extraction of the data will be performed by 2 independent reviewers. Risk of bias will be evaluated with the Critical Appraisal Skills Programme (CASP) checklist. Finally, the same reviewers will also perform a quality assessment of the included studies with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. RESULTS: The search strategy, after the application of the inclusion and exclusion criteria, identified 15 randomized clinical trials, which are currently being analyzed. This project has no funding and it has been developed by a multidisciplinary research team of pharmacologists and orthoptists. The study was initiated in May 2021 and it is expected to conclude by the end of 2023. CONCLUSIONS: This review will provide a synthesis of current information and underlying evidence about the off-label use of bevacizumab in neovascular AMD. It will provide a clearer vision of a possible new pharmacological approach, as well as the most suitable treatment designs, for the treatment of neovascular AMD. TRIAL REGISTRATION: PROSPERO CRD42021244931; https://tinyurl.com/p6m5ycpk. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38658.

Classification of dry and wet macular degeneration based on the ConvNeXT model.

Purpose: To assess the value of an automated classification model for dry and wet macular degeneration based on the ConvNeXT model. Methods: A total of 672 fundus images of normal, dry, and wet macular degeneration were collected from the Affiliated Eye Hospital of Nanjing Medical University and the fundus images of dry macular degeneration were expanded. The ConvNeXT three-category model was trained on the original and expanded datasets, and compared to the results of the VGG16, ResNet18, ResNet50, EfficientNetB7, and RegNet three-category models. A total of 289 fundus images were used to test the models, and the classification results of the models on different datasets were compared. The main evaluation indicators were sensitivity, specificity, F1-score, area under the curve (AUC), accuracy, and kappa. Results: Using 289 fundus images, three-category models trained on the original and expanded datasets were assessed. The ConvNeXT model trained on the expanded dataset was the most effective, with a diagnostic accuracy of 96.89%, kappa value of 94.99%, and high diagnostic consistency. The sensitivity, specificity, F1-score, and AUC values for normal fundus images were 100.00, 99.41, 99.59, and 99.80%, respectively. The sensitivity, specificity, F1-score, and AUC values for dry macular degeneration diagnosis were 87.50, 98.76, 90.32, and 97.10%, respectively. The sensitivity, specificity, F1-score, and AUC values for wet macular degeneration diagnosis were 97.52, 97.02, 96.72, and 99.10%, respectively. Conclusion: The ConvNeXT-based category model for dry and wet macular degeneration automatically identified dry and wet macular degeneration, aiding rapid, and accurate clinical diagnosis.

Burden of disease assessment in patients with neovascular age-related macular degeneration in Spain: Results of the AMD-MANAGE study.

BACKGROUND/AIMS: The present study evaluates the burden of neovascular age-related macular degeneration (nAMD) to Healthcare System and patients, describing the management and treatment effectiveness in routine clinical practice in Spain. METHODS: Observational, non-interventional, cross-sectional, retrospective (24 months), multicentre study including patients who started treatment with licensed vascular endothelial growth factor inhibitors (anti-VEGF) for nAMD with a minimum follow up of 24 months. RESULTS: 126 evaluable patients were included with mean (SD) age of 79.1 (7.5) years. From diagnosis, it took a mean (SD) of 0.5 (0.5) months for the first treatment. Throughout 24 months, mean (SD) number of visits per patient was 16.0 (5.0), 9.4 (4.3) associated intravitreal injection. There were 1186 injection visits, 53.6% of them only with injection and 46.3% with injection and tests. After loading phase, preferred treatment regimens were T&E (46.0%), PRN (44.4%), fixed regimen (4.0%), and others (5.6%). Total number of visits in patients with T&E and PRN were 16.5 (5.7) and 15.5 (4.7), respectively. After complete loading phase, mean (SD) time between two consecutive treatment injections was 2.2 (1.6) months. 27.8% patients underwent a treatment change, being lack of response the most frequent reason to change (43.2%). Mean (SD) best-corrected visual acuity change was 2.1 (15.9) letters at 24 months. CONCLUSION: This study showed an important burden to Healthcare System and patients related to monitoring visits. More efficacious and longer lasting treatments could be useful to increase treatment intervals, thus reducing the burden of patients and caregivers and the use of healthcare resources.

A hypothetical therapeutic effect of light peripheral panretinal photocoagulation in neovascular age-related macular degeneration.

Background: Vascular endothelial growth factor (VEGF) is a significant modulator of ocular angiogenesis, including that of neovascular age-related macular degeneration (nAMD). Intravitreal injection of anti-VEGF is the benchmark treatment for most retinal vascular diseases, including nAMD, diabetic maculopathy, and macular edema secondary to retinal venous occlusion. Anti-VEGF treatment is a high-frequency, time-consuming, non-cost-effective therapy, especially in countries and regions with limited resources. This treatment is easily restricted, and in practice, maintaining long-term periodic care is challenging for patients. Hypothesis: Light peripheral panretinal photocoagulation (PPRP) is applied in a mild form (barely visible mild light gray mark) anterior to the equator so as not to jeopardize the visual field. PPRP lessens the ischemia that causes neovascularization and decreases the metabolic demand in the peripheral retina. PPRP reduces serum angiopoietin-2 and VEGF levels in patients with type 2 diabetes mellitus with proliferative diabetic retinopathy. We propose using light PPRP to suppress VEGF secretion, aiming to attenuate the VEGF drive and halt choroidal neovascular growth in eyes with nAMD. Our regimen is based on two concepts: first, nAMD is a diffuse or generalized disease that affects the posterior segment; and second, PPRP is very effective in regressing diabetic retinopathy. PPRP has reportedly been successful in cases of macular edema (diabetic or following venous occlusion) resistant to VEGF antagonists. Light PPRP may be used as prophylaxis, adjunctive treatment, or monotherapy in nAMD when intravitreal injections of VEGF antagonists are not feasible. Conclusions: The established light PPRP therapy could be promising as a one-time, cost-effective therapy or prophylaxis in patients with nAMD or at high risk. This proposed modality could be suitable for patients who have injection phobia or prefer a one-time affordable therapy to the long-term monthly visits to retinologists. Future trials are necessary to verify the safety and efficacy of this proposed treatment modality in selected patients with nAMD.

Non-invasive testing for early detection of neovascular macular degeneration in unaffected second eyes of older adults: EDNA diagnostic accuracy study.

BACKGROUND: Neovascular age-related macular degeneration is a leading cause of sight loss, and early detection and treatment is important. For patients with neovascular age-related macular degeneration in one eye, it is usual practice to monitor the unaffected eye. The test used to diagnose neovascular age-related macular degeneration, fundus fluorescein angiography, is an invasive test. Non-invasive tests are available, but their diagnostic accuracy is unclear. OBJECTIVES: The primary objective was to determine the diagnostic monitoring performance of tests for neovascular age-related macular degeneration in the second eye of patients with unilateral neovascular age-related macular degeneration. The secondary objectives were the cost-effectiveness of tests and to identify predictive factors of developing neovascular age-related macular degeneration. DESIGN: This was a multicentre, prospective, cohort, comparative diagnostic accuracy study in a monitoring setting for up to 3 years. A Cox regression risk prediction model and a Markov microsimulation model comparing cost-effectiveness of the index tests over 25 years were used. SETTING: This took place in hospital eye services. PARTICIPANTS: Participants were adults (aged 50-95 years) with newly diagnosed (within the previous 6 weeks) neovascular age-related macular degeneration in one eye and an unaffected second (study) eye who were attending for treatment injections in the first eye and who had a study eye baseline visual acuity of ≥ 68 Early Treatment Diabetic Retinopathy Study letters. INTERVENTIONS: The index tests were Amsler chart (completed by participants), fundus clinical examination, optical coherence tomography, self-reported vision assessment (completed by participants) and visual acuity. The reference standard was fundus fluorescein angiography. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity and specificity; the performance of the risk predictor model; and costs and quality-adjusted life-years. RESULTS: In total, 552 out of 578 patients who consented from 24 NHS hospitals (n = 16 ineligible; n = 10 withdrew consent) took part. The mean age of the patients was 77.4 years (standard deviation 7.7 years) and 57.2% were female. For the primary analysis, 464 patients underwent follow-up fundus fluorescein angiography and 120 developed neovascular age-related macular degeneration on fundus fluorescein angiography. The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)], fundus clinical examination [53.8 (44.8 to 62.5); 97.6 (95.3 to 98.9)], Amsler [33.7 (25.1 to 43.5); 81.4 (76.4 to 85.5)], visual acuity [30.0 (22.5 to 38.7); 66.3 (61.0 to 71.1)] and self-reported vision [4.2 (1.6 to 9.8); 97.0 (94.6 to 98.5)]. Optical coherence tomography had the highest sensitivity across all secondary analyses. The final prediction model for neovascular age-related macular degeneration in the non-affected eye included smoking status, family history of neovascular age-related macular degeneration, the presence of nodular drusen with or without reticular pseudodrusen, and the presence of pigmentary abnormalities [c-statistic 0.66 (95% confidence interval 0.62 to 0.71)]. Optical coherence tomography monitoring generated the greatest quality-adjusted life-years gained per patient (optical coherence tomography, 5.830; fundus clinical examination, 5.787; Amsler chart, 5.736, self-reported vision, 5.630; and visual acuity, 5.600) for the lowest health-care and social care costs (optical coherence tomography, £19,406; fundus clinical examination, £19,649; Amsler chart, £19,751; self-reported vision, £20,198; and visual acuity, £20,444) over the lifetime of the simulated cohort. Optical coherence tomography dominated the other tests or had an incremental cost-effectiveness ratio below the accepted cost-effectiveness thresholds (£20,000) across the scenarios explored. LIMITATIONS: The diagnostic performance may be different in an unselected population without any history of neovascular age-related macular degeneration; the prediction model did not include genetic profile data, which might have improved the discriminatory performance. CONCLUSIONS: Optical coherence tomography was the most accurate in diagnosing conversion to neovascular age-related macular degeneration in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Economic modelling suggests that optical coherence tomography monitoring is cost-effective and leads to earlier diagnosis of and treatment for neovascular age-related macular degeneration in the second eye of patients being treated for neovascular age-related macular degeneration in their first eye. FUTURE WORK: Future works should investigate the role of home monitoring, improved risk prediction models and impact on long-term visual outcomes. STUDY REGISTRATION: This study was registered as ISRCTN48855678. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 8. See the NIHR Journals Library website for further project information.

Wet age-related macular degeneration is the leading cause of sight loss in older people. It is diagnosed using fundus fluorescein angiography, which involves photographing the retina after the injection of a dye into a vein in the arm, which may result in allergic reactions. Many people with wet age-related macular degeneration in one eye will also develop it in their second eye. To avoid regular fundus fluorescein angiography, non-invasive tests are used to routinely monitor for wet age-related macular degeneration in the second eye of patients with wet age-related macular degeneration already in one eye. We studied five commonly used and easily performed non-invasive tests to see which best detected the onset of wet age-related macular degeneration. The five tests were: self-report of visionself-completion of an Amsler charta standard sight testexamination of the retina by a specialistoptical coherence tomography, which is a non-invasive scan of the central retina. If any tests suggested wet age-related macular degeneration, fundus fluorescein angiography was performed to compare results. In total, 552 hospital eye clinic patients who had wet age-related macular degeneration in only one eye took part. Over a 3-year period, wet age-related macular degeneration developed in the second eye in 145 people (26%), of whom 120 had undergone fundus fluorescein angiography. In 25 people with wet age-related macular degeneration, fundus fluorescein angiography was not carried out for safety reasons or because the patient did not want to undergo it. Of all the tests, only optical coherence tomography was good at detecting wet age-related macular degeneration correctly (92% sensitivity) and at detecting those who did not have wet age-related macular degeneration (88% specificity). All other tests either did not detect wet age-related macular degeneration consistently when it occurred or gave a false positive result when it had not occurred. This study confirmed that optical coherence tomography detected wet age-related macular degeneration correctly in the second eye of people with wet age-related macular degeneration in their first eye, and may offer cost saving for the NHS.

Topical Triamcinolone Acetonide-Loaded Liposome Formulation Used as an Adjuvant to Intravitreal Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration.

Novel strategies have been developed to reduce or avoid intravitreal injections (IVTs) of the antiangiogenic (ranibizumab (RBZ)) and anti-inflammatory (triamcinolone acetonide (TA)) agents used to treat vitreoretinal diseases. One of the strategies includes liposomes. This study evaluated the safety and efficacy of a topical triamcinolone-loaded liposome formulation (TALF) as an adjuvant to intravitreal RBZ therapy in treatment- naïve patients with neovascular age-related macular degeneration (nAMD). Subjects were randomly assigned to the RBZ-TALF or the RBZ-pro re nata (RBZ-PRN) groups. Patients from the RBZ-TALF group were instructed to apply TALF for 12 months after a single dose of RBZ. Patients from the RBZ-PRN group received three monthly RBZ-IVTs. Retreatment with RBZ was considered in the case of nAMD reactivation. Regarding safety, non-ocular abnormalities were observed during TALF therapy. Concerning efficacy, non-significant differences were identified in terms of visual acuity or central foveal thickness when the RBZ-PRN and RBZ-TALF groups were compared. It is worth noting that the average number of RBZ injections was significantly lower in the RBZ-TALF group (2.5 ± 1.4 vs. 6.1 ± 1.3 IVTs; p = 0.0004). Therefore, TALF used as an adjuvant to RBZ reduces the need for RBZ-IVT retreatment with optimal visual and anatomic results.

Hypo-angiogenesis: a possible pathological factor in the development of dry age-related macular degeneration and a novel therapeutic target.

Background: Angiogenesis causes severe vision loss in patients with exudative or wet forms of age-related macular degeneration (AMD). The pathogenesis involves upregulation of several proangiogenic factors, particularly the vascular endothelial growth factor (VEGF). Contrary to the pathogenesis of exudative AMD, molecular events leading to the development of dry AMD remain unclear. Dry AMD is characterized by loss of the retinal pigment epithelium (RPE). The mechanism that triggers RPE cell loss remains unclear. Choriocapillaris development is absent in mice with RPE-specific deletion of VEGF. Moreover, in later life, background VEGF secretion promotes the survival of the RPE and maintains choriocapillaris integrity. Hypothesis: We hypothesized that reduced synthesis of VEGF (hypo-angiogenesis) or abnormalities in its receptors, VEGF receptor-1 (VEGFR1) and VEGFR2, may be involved in the pathogenesis of non-exudative AMD or dry AMD. If the concept of hypo-angiogenesis as a driver for dry AMD is proven, treatment with VEGF or induction of angiogenesis could be considered. Similar attempts at therapeutic angiogenesis have been actively investigated in cardiac and limb ischemia. Conclusions: The reasons for a patient developing exudative AMD or dry AMD remain poorly understood. Nevertheless, targeting increased VEGF production in patients with exudative AMD using anti-VEGF drugs is highly efficacious in preserving vision. Similarly, dry AMD may be a manifestation of reduced VEGF synthesis (hypo-angiogenesis) and subsequent decreased RPE cell survival. Experimental studies exploring the possibility of reduced VEGF secretion and/or increased receptor resistance/abnormality could pave the way for clinical trials of angiogenesis to treat dry AMD.

Novel Association of High C-Reactive Protein Levels and A69S at Risk Alleles in Wet Age-Related Macular Degeneration Women.

Purpose: To explore the relationship between plasma C-reactive protein (CRP) levels, the main ARMS2 gene single nucleotide polymorphism (SNP), and gender in patients with neovascular age-related macular degeneration (wet AMD). Methods: Our study included 131 patients with wetAMD [age-related eye disease study (AREDS) category 4] and 153 control participants (AREDS category 1) from two Spanish retinal units. CRP levels were determined on blood samples by high-sensitivity ELISA assay. According to their CRP level, subjects were categorized into three well-established CRP categories: low (<1.00 mg/L, L-CRP), moderate (1-2.99 mg/L, M-CRP), and high (>3.00 mg/L, H-CRP). Genomic DNA was extracted from oral swabs using QIAcube (Qiagen, Hilden, Germany) and the A69S; rs10490924 of ARMS2 gene was genotyped by allelic discrimination with validated TaqMan assays (Applied Biosystems, Foster City, CA, USA). Univariate and multivariate logistic regression adjusted for age was used to analyze the genomic frequencies and to calculate odds ratio (OR) using SNPStats software. Results: Considering CRP risk categories, H-CRP group showed a significant [OR 4.0 (1.9-8.3)] association with wetAMD compared to L-CRP group. The risk genotypes of A69S (TT) SNPs showed an association with wetAMD risk [OR 14.0 (4.8-40.8)]. Interestingly, the gender stratification of the CRP categories showed a significant increase in CRP levels in wetAMD women compared with control women [OR 6.9 (2.2-22.3)] and with wetAMD men [OR 4.6 (1.3-16.9)]. In addition, the subgroup analysis of CRP within A69S genotype and gender showed a link in women between the A69S and CRP levels in the AMD group compared to controls [OR 4.2 (1.4-12.6)]. Conclusion: Our study shows, for the first time, that a different genetic association related with gender could contribute to AMD risk. As a consequence, the risk of female gender in the different CRP levels and A69S SNP frequencies could be taken into consideration to the established risk relationship of high levels of CRP and its association with risk A69S genotype.

A Retrospective Analysis of the Real-Life Utilization of Ranibizumab in Patients with Wet Age-Related Macular Degeneration from Portugal.

INTRODUCTION: Anti-vascular endothelial growth factor therapy has revolutionized the treatment of wet age-related macular degeneration; however, it is important to monitor actual use of ranibizumab and related treatment outcomes in routine practice. MATERIAL AND METHODS: This was a retrospective, observational study to monitor the 2-year outcomes following ranibizumab treatment for wet age-related macular degeneration in Portugal. Patients treated between January 2009 and December 2009 were retrospectively evaluated. All decisions were made by the treating physician in accordance with their usual routine clinical practice. The primary assessment was mean change in visual acuity score using Early Treatment Diabetic Retinopathy Study or Snellen equivalent. RESULTS: A total of 128 patients with wet age-related macular degeneration were analyzed (mean age 79.4 years; mean visual acuity score 54.2 letters). Mean change in visual acuity score from baseline was -1.6 letters (n = 82) at year one and -5.1 letters (n = 72) at year two. The mean number of ranibizumab injections was 3.8 (year one) and 1.6 (year two). On average, patients attended 8.6 and 5.0 visits and optical coherence tomography was used in 75.0% of patients in year one and in 56.3% of patients in year two, respectively. DISCUSSION: Despite a relatively high number of visits, including monitoring visits and use of optical coherence tomography - guided therapy, few injections were administered and visual acuity was not improved. CONCLUSION: These findings indicate that as-needed treatment resulted in under-dosing in a real-life setting in Portugal. Such limitations may also be related to increasing numbers of patients, resulting in clinic saturation.

Introdução: A terapeutica com anti-factor de proliferação endotelial vascular revolucionou o tratamento da degenerescência macular da idade exsudativa; no entanto, é importante monitorizar o uso em contexto real do ranibizumab e os resultados associados ao tratamento na prática clínica corrente. Material e Métodos: Este foi um estudo observacional, retrospetivo, para monitorizar os resultados de dois anos, após o tratamento com ranibizumab para a da degenerescência macular da idade exsudativa em Portugal. Os doentes tratados entre janeiro de 2009 e dezembro de 2009 foram avaliados retrospetivamente. Todas as decisões foram tomadas pelo médico responsável pelo tratamento, em conformidade com a respetiva prática clínica corrente. A avaliação primária foi a alteração média na melhor acuidade visual corrigida utilizando a tabela ETDRS (Early Treatment of Diabetic Retinopathy Study) ou Snellen equivalente. Resultados: Foi analisado um total de 128 doentes com degenerescência macular da idade exsudativa (idade média de 79,4 anos; média de acuidade visual de 54,2 letras). A alteração média na melhor acuidade visual corrigida desde a situação basal foi de -1,6 letras (n = 82) no ano um e -5,1 letras (n = 72) no ano dois. O número médio de injeções de ranibizumab foi de 3,8 (ano um) e 1,6 (ano dois). Em média, os doentes tiveram entre 8,6 e 5,0 consultas e foi utilizada a tomografia de coerência ótica em 75,0% dos doentes no ano um e em 56,3% dos doentes no ano dois, respetivamente. Discussão: Apesar do número de consultas relativamente elevado, incluindo consultas de monitorização e de utilização de terapêutica guiada por tomografia de coerência ótica, foram administradas poucas injeções e não houve melhoria na acuidade visual. Conclusão: Em Portugal, num contexto real, estes achados indicam que o tratamento consoante as necessidades resultou numa dosagem insuficiente. Essas limitações também podem estar associadas ao número crescente de doentes, o que resulta numa saturação clínica.

Real world evidence of use of anti-VEGF therapy in Denmark.

OBJECTIVE: This study evaluates real-world evidence regarding the frequency of anti-vascular-endothelial-growth-factor (VEGF) injections during the first year of therapy of treatment-naïve patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME) and retinal vein occlusion (RVO) from the Danish National Patient Registry. There was a switch in anti-VEGF treatment for naïve nAMD patients during the study period, following the introduction of aflibercept, which was expected to reduce the injection frequency relative to ranibizumab due to a perception of prolonged treatment duration of aflibercept. METHODS: All treatment-naïve nAMD, DME or RVO patients who received an intravitreal injection in Denmark from 1 January 2012 to 31 July 2015 were eligible for inclusion. Patients were required to have been treated for at least one year and, for nAMD, to have received at least three injections during the first four months of treatment. Patients were allocated to half-year groupings (2012/1 to 2014/1) based on registration of their first intravitreal injection. Injection frequency during the first year of treatment was calculated for each group and t-tests investigated whether injection frequencies changed over time. RESULTS: In treatment naïve nAMD patients (n = 500), the mean (SD) number of anti-VEGF injections increased significantly from 6.04 (1.71) in 2012/1 to 6.73 (1.62) in 2014/1 (p = .001; 2012/1 and 2012/2 vs. 2014/1) across all treatments. A similar trend was found for DME patients (n = 76) from 2012/1 to 2014/1 and RVO patients (n = 82) from 2012/2 to 2014/1, with mean injection frequencies increasing significantly from 5.14 (2.29) to 5.93 (1.98) (p = .007), and from 4.83 (1.21) to 6.08 (1.55) (p = .024), respectively. Post hoc sensitivity analysis also found a significant increase in injection frequency in nAMD patients who did not receive a loading phase (4.55 in 2012/1 and 5.05 in 2014/1; p = .006; n = 616). CONCLUSIONS: In contrast to the decrease in injection frequency predicted with a switch to aflibercept treatment for nAMD, our study showed that injection frequencies increased significantly from 2012 to 2014 in patients initiating therapy across the three diseases.

Follow-up after surgery for hemorrhagic AMD.

INTRODUCTION: The long-term functional results of macular hematoma (MH) surgery in exudative AMD are often limited. The goal of this study was to compare visual outcomes of monthly versus bimestrial follow-up in these patients. METHODS: Retrospective, interventional case series. Population : 21 eyes of 21 patients with SMH associated with exudative AMD. INCLUSION CRITERIA: first SMH associated with exudative AMD, with 1-year postoperative follow-up. EXCLUSION CRITERIA: blood located exclusively underneath the retinal pigment epithelium on OCT imaging, SMH due to different etiology, lost to follow-up, ≤5 postoperative visits and a different surgical protocol as described. Patients were divided into two groups according to the number of postoperative visits (number of intravitreal injections [IVT] combined with the number of consultations, only one visit was recorded when IVT and consultation occurred on the same day) during the 1-year postoperative follow-up: group 1 had ≥11 visits (n=8); group 2 had 6 to 10 visits (n=13). All eyes underwent vitrectomy with subretinal injection of recombinant tissue plasminogen activator, fluid-gas exchange and anti-VEGF intravitreal injection. The main outcome was change in best-corrected visual acuity (BCVA). RESULTS: Considering visual acuity (VA) change between 1-month and 1-year postoperative follow-up examinations, group 1 had statistically significant greater VA changes (logMAR -0.29±0.44 vs logMAR 0.42±0.73; P=0.016; P=0.016). In patients that had exudative recurrences (ER), group 1 received more anti-VEGF IVT than group 2 (P=0.045). CONCLUSION: Our results showed that monthly follow-up, between the IVT series, is highly recommended to preserve postoperative VA in patients undergoing surgery for SMH associated with AMD.

Three-dimensional Segmentation of Retinal Cysts from Spectral-domain Optical Coherence Tomography Images by the Use of Three-dimensional Curvelet Based K-SVD.

This paper presents a new three-dimensional curvelet transform based dictionary learning for automatic segmentation of intraretinal cysts, most relevant prognostic biomarker in neovascular age-related macular degeneration, from 3D spectral-domain optical coherence tomography (SD-OCT) images. In particular, we focus on the Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) system, and show the applicability of our algorithm in the segmentation of these features. For this purpose, we use recursive Gaussian filter and approximate the corrupted pixels from its surrounding, then in order to enhance the cystoid dark space regions and future noise suppression we introduce a new scheme in dictionary learning and take curvelet transform of filtered image then denoise and modify each noisy coefficients matrix in each scale with predefined initial 3D sparse dictionary. Dark pixels between retinal pigment epithelium and nerve fiber layer that were extracted with graph theory are considered as cystoid spaces. The average dice coefficient for the segmentation of cystoid regions in whole 3D volume and with-in central 3 mm diameter on the MICCAI 2015 OPTIMA Cyst Segmentation Challenge dataset were found to be 0.65 and 0.77, respectively.