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    Research Update 576


    Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial.

    Eye (London, England). 2023 Mar 24.

    Patel SS, Lally DR, Hsu J, Wykoff CC, Eichenbaum D, Heier JS, Jaffe GJ, Westby K, Desai D, Zhu L, Khanani AM.

    Background/objectives: To assess the safety and efficacy of avacincaptad pegol (ACP), a C5 inhibitor, for geographic atrophy (GA) secondary to age-related macular degeneration (AMD) over an 18-month treatment course.

    Subjects/methods: This study was an international, prospective, randomized, double-masked, sham-controlled, phase 2/3 clinical trial that consisted of 2 parts. In part 1, 77 participants were randomized 1:1:1 to receive monthly intravitreal injections of ACP 1 mg, ACP 2 mg, or sham. In part 2, 209 participants were randomized 1:2:2 to receive monthly ACP 2 mg, ACP 4 mg, or sham. The mean rate of change of GA over 18 months was measured by fundus autofluorescence.

    Results: Compared with their respective sham cohorts, monthly ACP treatment reduced the mean GA growth (square root transformation) over 18 months by 28.1% (0.168 mm, 95% CI [0.066, 0.271]) for the 2 mg cohort and 30.0% (0.167 mm, 95% CI [0.062, 0.273]) for the 4 mg cohort. ACP treatment was generally well tolerated over 18 months, with most ocular adverse events (AEs) related to the injection procedure. Macular neovascularization (MNV) was more frequent in both 2 mg (11.9%) and 4 mg (15.7%) cohorts than their respective sham control groups (2.7% and 2.4%).

    Conclusions: Over this 18-month study, ACP 2 mg and 4 mg showed continued reductions in the progression of GA growth compared to sham and continued to be generally well tolerated. A pivotal phase 3 GATHER2 trial is currently underway to support the efficacy and safety of ACP as a potential treatment for GA.

    DOI: 10.1038/s41433-023-02497-w


    Associations and Prognostic Significance of Fluctuations in Diabetic Retinopathy Severity in Eyes Treated for Diabetic Macular Edema.

    Ophthalmologica 2023 Mar 30.

    Cicinelli MV, Gregori G, Rabiolo A, Tombolini B, Barresi C, Pignatelli F, Lattanzio R, Bandello F.

    Introduction: The aim of our study was to investigate factors associated with diabetic retinopathy (DR) severity fluctuations in patients undergoing intravitreal injections for diabetic macular edema and to explore risk factors for proliferative DR (PDR).

    Methods: We graded ultra-widefield fundus photography imaging at each visit using the Early Treatment Diabetic Retinopathy Study severity scale (DRSS). We calculated the deviation from the mode (DM) of DRSS values as a proxy of DR severity fluctuations, and we analyzed its clinical associations with linear models. We computed risk factors for PDR with Cox hazard models. We included the DRSS area-under-the-curve (AUC) of DRSS scores as a covariate in all analyses. RESULTS: We included 111 eyes with median follow-up of 44 months. Higher DRSS-AUC values (b=+0.03 DRSS DM for unitary DRSS/month increase, p=0.01) and a higher number of anti-VEGF injections (b=+0.07 DRSS DM for injection, p=0.045) were associated with wider DR severity fluctuations. Higher DRSS-AUC values (HR=1.45 for unitary DRSS/month increase, p=0.001) and wider DR severity fluctuations (HR=22.35 4th quartile vs. 1st-3rd quartile of DRSS DM, p=0.01) were risk factors for PDR.

    Discussion/Conclusion: Patients with larger DR variability in response to intravitreal injections may be at higher risk of DR progression. We advocate attentive follow-up in these patients to recognize PDR early.

    DOI: 10.1159/000530417

    Visual acuity time in range: a novel concept to describe consistency in treatment response in diabetic macular oedema

    Eye (London, England). 2023 Mar 28

    Kozak I, Pearce I, Cheung CMG, Machewitz T, Lambrou GN, Molina D, Suleiman L, Youssef H, Bressler NM

    Objective: To assess ‘time in range’ as a novel measure of treatment response in diabetic macular oedema (DMO).

    Methods: This post hoc analysis of the Protocol T randomised clinical trial included 660 individuals with centre-involved DMO and best-corrected visual acuity (BCVA) letter score ≤78-≥24 (approximate Snellen equivalent 20/32-20/320). Study participants received intravitreal aflibercept 2.0 mg, repackaged (compounded) bevacizumab 1.25 mg, or ranibizumab 0.3 mg given up to every 4 weeks using defined retreatment criteria. Mean time in range was calculated using a BCVA letter score threshold of ≥69 (20/40 or better; minimum driving requirement in many regions), with sensitivity analyses using BCVA thresholds from 100 to 0 (20/10 to 20/800) in 1-letter increments. RESULTS: Time in range was defined as either the absolute or relative duration above a predefined BCVA threshold, measured in weeks or as a percentage of time, respectively. Using a BCVA letter score threshold of ≥69 (20/40 or better), the least squares mean time in range (adjusted for baseline BCVA) in Year 1 was 41.2 weeks with intravitreal aflibercept, 4.0 weeks longer (95% CI: 1.7, 6.3; p = 0.002) than bevacizumab and 3.6 weeks longer (1.3, 5.9; p = 0.004) than ranibizumab. Overall, mean time in range was numerically longer for intravitreal aflibercept for all BCVA letter score thresholds between 92 and 30 (20/20 to 20/250). In the Day 365-728 analysis, time in range was 3.9 (1.3, 6.5) and 2.4 (0.0, 4.9) weeks longer with intravitreal aflibercept vs bevacizumab and vs ranibizumab (p = 0.011 and 0.106), respectively.

    Conclusion: BCVA time in range may represent another way to describe visual outcomes and potential impact on vision-related functions over time for patients with DMO and provide a better understanding, for physicians and patients, of the consistency of treatment efficacy.

    DOI: 10.1038/s41433-023-02507-x

    Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab.

    Ophthalmology. 2023 Mar 27.

    MacCumber MW, Wykoff CC, Karcher H, Adiguzel E, Buxy Sinha S, Vishwakarma S, LaPrise A, Igwe F, Freitas R, Ip MS, Zarbin MA.

    Purpose: To evaluate factors associated with anti-VEGF injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab.

    Design: Retrospective observational cohort study.

    Participants: Adults in the US-based Intelligent Research in Sight (IRIS) Registry with nAMD who switched from another anti-VEGF agent (treatment-experienced) to brolucizumab-only treatment for at least 12 months in the time period of 10/08/2019 through 11/26/2021.

    Methods: Univariate and multivariable analyses were used to examine associations of demographic and clinical characteristics with the likelihood of interval extension following switch to brolucizumab therapy.

    Main Outcome Measures: Eyes were classified as either “extenders” or “non-extenders” at 12 months. “Extenders” were eyes that achieved (i) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the pre-switch interval (time between the last known prior anti-VEGF injection and first [“index”] brolucizumab injection) and (ii) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months compared with VA at index.

    Results: Of the 2015 eyes among 1890 patients that switched to brolucizumab, 1186 eyes (58.9%) were “extenders”. In univariate analyses, demographic and clinical characteristics were comparable between extenders and non-extenders, except that extenders had a shorter pre-switch interval compared with non-extenders (mean 5.9 ± 2.1 versus 10.1 ± 7.6 weeks, respectively). The multivariable logistic regression model showed that a shorter pre-switch interval was significantly and positively associated with interval extension with brolucizumab therapy (adjusted odds ratio 5.6 for pre-switch interval of <8 weeks compared with ≥8 weeks; 95% confidence interval 4.5-6.9; P <0.001), and that eyes with an index VA of 40-65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories.

    Conclusions: Length of the pre-switch treatment interval was the characteristic most strongly associated with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter pre-switch intervals) showed the greatest extensions when switching to brolucizumab. With careful consideration of the benefits/risks, brolucizumab may be a valuable treatment option for patients whose treatment burden is higher due to the need for frequent injections.

    DOI: 10.1016/j.ophtha.2023.03.017


    Assessing the structure of the posterior visual pathway in bilateral macular degeneration.

    Scientific reports. 2023 Mar 27;

    Brown HDH, Gale RP, Gouws AD, Vernon RJW, Airody A, Hanson RLW, Baseler HA, Morland AB

    Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

    DOI: 10.1038/s41598-023-31819-x

    Hyperreflective band in the ganglion cell layer in retinitis pigmentosa.

    Retina. 2023 Mar 29.

    Alessio A, Alessandro A, Lorenzo B, Elena C, Alessandro B, Filippo C, Giacomo C, Francesco B, Ottavio C, Maurizio BP.

    Purpose: To describe a sign that takes the form of a continuous hyperreflective band within the thickness of the ganglion cell layer (GCL), thus dubbed the “hyperreflective ganglion cell layer band” (HGB), which we detected in a fraction of patients affected by retinitis pigmentosa (RP).

    Methods: Retrospective, cross-sectional, observational study. Optical coherence tomography (OCT) images of RP patients examined between May 2015 and June 2021 were retrospectively reviewed for the presence of HGB, epiretinal membrane (ERM), macular hole and cystoid macular edema (CME). The ellipsoid zone (EZ) width was also measured. A subgroup of patients underwent microperimetry in the central 2°,4° and 10°.

    Results: One hundred forty-four eyes from 77 subjects were included in the study. HGB was present in 39 (25.3%) RP eyes. Mean best-corrected visual acuity (BCVA) was 0.39 ± 0.05 logMAR (approximately 20/50 Snellen equivalent) and 0.18 ± 0.03 logMAR (approximately 20/32 Snellen equivalent) in eyes with and without HGB, respectively (p < 0.001). The two groups did not differ with regard to EZ width, mean 2°, 4° and 10° retinal sensitivity, and prevalence of CME, ERM and macular hole. The multivariable analysis showed the presence of HGB to be a predictor of poorer BCVA (p<0.001).

    Conclusions: HGB is an OCT finding detectable in approximately a quarter of RP eyes and is associated with a poorer visual function. In the discussion, we speculate about possible morphogenetic scenarios to explain this observation.

    DOI: 10.1097/IAE.0000000000003801


    Association between sight-threatening eye diseases and death by suicide in South Korea: a nationwide population-based cohort study.

    Ophthalmology. 2023 Mar 29:

    Ha A, Kim SH, Kang G, Yoon HJ, Kim YK.

    Objective: Although associations between visual impairment (VI) and suicide are posited, specific risks across the sight-threatening eye disease (STED) spectrum remain to be assessed. We determined whether individuals with STED die more often by suicide than do other people and assessed the temporal associations.

    Design: A nationwide population-based cohort study PARTICIPANTS: All persons aged 40 years or older and registered as living in South Korea from 2010 through 2020.

    Methods: Persons diagnosed with STEDs (i.e., glaucoma, exudative age-related macular degeneration [AMD], diabetic retinopathy [DR]) were identified in the Korean National Health Insurance (NHI) service database. Both NHI health checkup records and the National Disability Registration were utilized for coexisting severe VI. Death by suicide was defined as diagnostic codes as recorded in the Korea National Statistical Office. Incidence rate ratios (IRRs) were estimated by Quasi-Poisson regressions, and were adjusted for socio-demographics, comorbidity, psychiatric diagnoses, and VI. The temporal relationship between time since first STED diagnosis and suicide risk was determined by identifying STED patients newly diagnosed during the period 2010 to 2011.

    Main Outcome Measures: The IRR of death by suicide in people with STED relative to those without

    Results: Of the 2.8 million people (45% males) observed for 24300969 person-years, 13205 died by suicide. Among them, 34% (n=4514) had had a STED diagnosis, for a suicide rate of 69 per 100000 person-years (95% CI, 67-72), relative to 51 per 100000 person-years (95% CI, 50-52) for non-STED individuals. People with STED had an adjusted IRR of 1.33 (95% CI, 1.26-1.41) relative to those without. The largest excess adjusted IRR of suicide mortality was that for DR (1.40, 95% CI, 1.29-1.52). For exudative AMD, the adjusted IRR was 1.20 (95% CI, 1.04-1.39), while for glaucoma, the corresponding value was 1.09 (95% CI, 1.02-1.17). With coexisting severe VI, the IRR for any STED was 1.49 (95% CI, 1.29-1.73). The highest suicide HR was between the 3rd and 6th months post-diagnosis (5.33; 95% CI, 4.59-6.20).

    Conclusion: In South Korea between 2010 and 2020, a significantly higher suicide rate was evident among those with diagnosed STED than for persons not so diagnosed.

    DOI: 10.1016/j.ophtha.2023.03.018


    Dietary nutrient intake and cognitive function in the Age-Related Eye Disease Studies 1 and 2.

    Alzheimer’s & dementia: the journal of the Alzheimer’s Association 2023 Mar 20.

    Keenan TDL, Agrón E, Chew EY;

    Introduction: The objective was to analyze associations between dietary intake of multiple nutrients and altered cognitive function and/or decline.

    Methods: Observational analyses of participants (n = 6334) in two randomized trials of nutritional supplements for age-related macular degeneration: Age-Related Eye Disease Study (AREDS) and AREDS2.

    Results: In AREDS, for 4 of 38 nutrients examined, higher intake quintiles were significantly associated with decreased risk of cognitive impairment on the Modified Mini-Mental State test (<80): β-carotene, copper, docosahexaenoic acid, and insoluble fiber. In AREDS2, for 13 of 44 nutrients, higher intake quintiles were associated with decreased risk on the Telephone Interview Cognitive Status-Modified (<30). Rate of cognitive decline over up to 10 years was not significantly different with higher intake of any nutrient.

    Discussion: Higher dietary intake of multiple nutrients, including specific vitamins, minerals, carotenoids, fatty acids, and fiber, was associated with lower risk of cognitive impairment but not slower decline in cognitive function.

    DOI: 10.1002/alz.13033


    Effects of acupuncture on age-related macular degeneration: A systematic review and meta-analysis of randomized controlled trials.

    PLoS One. 2023 Mar 23;

    Sun W, Zhao Y, Liao L, Wang X, Wei Q, Chao G, Zhou J.

    Background: In recent years, an increasing number of patients with age-related macular degeneration (AMD) have received acupuncture treatment, but there has been no systematic review to evaluate the effect of acupuncture on patients with AMD.

    Purpose: This meta-analysis aims to review the clinical efficacy of acupuncture in the treatment of AMD.

    Methods: Randomized controlled trials up to September 4, 2022 were searched in the following

    databases: PubMed, Ovid Medline, Embase, Cochrane Library, The Chinese National Knowledge Infrastructure Database, VIP, Wanfang, and SINOMED. Two reviewers independently performed literature screening and data extraction. RevMan 5.4 was used for the meta-analysis.

    Results: Nine of the 226 articles were finally included. A total of 508 AMD patients (631 eyes) were enrolled, including 360 dry eyes and 271 wet eyes. The results showed that acupuncture alone or as an adjunct therapy improved both the clinical efficacy and best-corrected visual acuity (BCVA) of AMD patients and reduced their central macular thickness. The certainty of the evidence ranged from “low” to “very low”.

    Conclusion: There is no high-quality evidence that acupuncture is effective in treating patients with AMD; patients with dry AMD may benefit from acupuncture treatment. Considering the potential of acupuncture treatment for AMD, it is necessary to conduct a rigorously designed randomized controlled trials to verify its efficacy.

    DOI: 10.1371/journal.pone.0283375

    Age-related macular degeneration.

    Lancet (London, England) 2023 Mar 2

    Guymer RH, Campbell TG.

    Age-related macular degeneration is an increasingly important public health issue due to ageing populations and increased longevity. Age-related macular degeneration affects individuals older than 55 years and threatens high-acuity central vision required for important tasks such as reading, driving, and recognising faces. Advances in retinal imaging have identified biomarkers of progression to late age-related macular degeneration. New treatments for neovascular age-related macular degeneration offer potentially longer-lasting effects, and progress is being made towards a treatment for atrophic late age-related macular degeneration. An effective intervention to slow progression in the earlier stages of disease, or to prevent late age-related macular degeneration development remains elusive, and our understanding of underlying mechanistic pathways continues to evolve.

    DOI: 10.1016/S0140-6736(22)02609-5