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Purpose: This study was conducted to determine the morphological and functional retinal changes in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal bevacizumab 1.25 mg.Methods: This was a prospective, nonrandomized, interventional study. Eighteen eyes of 18 subjects with nAMD were treated with intravitreal bevacizumab (1.25 mg) injection. Subjects underwent complete ophthalmic evaluation which included visual acuity, slitlamp examination, tonometry, binocular ophthalmoscopy, optical coherence tomography (OCT), and MP1 microperimetry before the intravitreal injection and the follow-up at 1 and 3 months. Test of significance such as Chi-squared test, paired ttest and oneway analysis of variance (ANOVA) linear trend were used to compare the pre- and post-anti-VEGF outcomes. Intraclass correlation was done to assess the intra observer variability.Results: Mean retinal sensitivity had increased from 3.77 ± 3.13 dB at baseline to 4.93 ± 2.42 dB at 3 months (P = 0.05). Visual acuity improved from 0.62 ± 0.36 at baseline to 0.52 ± 0.36 at 1 month and 0.48 ± 0.34 at 3-month followup, but overall change was not significant (P = 0.40). There was a significant reduction in central foveal thickness (CFT) from 274.61 ± 117.95 at baseline to 179.83 ± 84.18 at 1 month and 179.00 ± 126.55 at 3-month follow-up (P = 0.013).Conclusion: Intravitreal bevacizumab (1.25 mg) injection in nAMD improves retinal function, quantified by retinal sensitivity, scotoma characteristics, fixation stability by MP 1 microperimetry and morphological parameters quantified by CFT in SDOCT. These changes show the effectiveness of treatment with intravitreal bevacizumab in nAMD. [ABSTRACT FROM AUTHOR]

Purpose: To compare the 12 months visual and anatomical outcomes of treatment‐naïve neovascular age‐related macular degeneration (nAMD) patients diagnosed by optical coherence tomography angiography (OCT‐A) compared with fluorescein angiography (FA)/indocyanine green angiography (ICGA), after anti‐VEGF treatment in a real‐world setting. Methods: Monocentric, observational, parallel‐group study of nAMD patients diagnosed with either FA/ICGA or non‐invasive OCT‐A methods. Patients were treated with a fixed dosing regimen of intravitreal ranibizumab or aflibercept and followed up for 12 months. Primary outcomes were the 12 months functional (BCVA) and anatomical (CST reduction) gains between the two groups. The stratification of BCVA and CST gains by type of neovascular lesion and by anti‐VEGF treatment was also assessed. Results: Seventy‐two patients received FA/ICGA for the initial diagnosis of nAMD, while 73 received OCT‐A. Overall, the mean BCVA gain at 12 months was 11.5 ± 9.6 letters. There were no statistically significant differences between the invasive and non‐invasive imaging groups in BCVA gain (p = 0.87) or CST reduction (p = 0.76). No statistically significant outcome differences between different lesion types and the two drugs were observed. Conclusion: In a real‐world setting, nAMD patients diagnosed with OCT‐A showed meaningful improvements in visual and anatomical parameters during 12 months of treatment, without significant differences with those diagnosed by invasive modalities. [ABSTRACT FROM AUTHOR]

Many studies over the past 20 years have pursued the goal of preventing or deferring progression from early and intermediate age-related macular degeneration (AMD) to advanced AMD. The onset of neovascular AMD has been used as a primary endpoint in some prophylactic clinical trials because it is easy to assess and relatively well-defined. Nevertheless, the use of this endpoint for assessing progression of AMD lacks validation. The aims of this paper are to review the current practice of clinical trials investigating the prevention of progression of early or intermediate AMD to neovascular AMD, so-called prophylactic trials, as well as identify ongoing efforts to standardize endpoints and select the ideal population for such studies. [ABSTRACT FROM AUTHOR]

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. Post hoc analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. 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. 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. Progression to late AMD, geographic atrophy (GA), neovascular AMD, and (separate analyses) large drusen. 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, β-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, β-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. 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. [ABSTRACT FROM AUTHOR]

The long-term clinical outcome of adjuvant stereotactic radiotherapy (SRT) in neovascular age-related macular degeneration (nAMD) patients was evaluated. This case-control study included patients with unilateral nAMD, who underwent SRT complementary to standard anti-VEGF treatment. Only patients with monthly follow-up over at least three years were considered. Number of intravitreal injections, visual acuity (VA), central retinal thickness (CRT), and subfoveal choroidal thickness (SFCT) were evaluated and compared to baseline as well as to an age- and gender-matched control group, who received anti-VEGF monotherapy. Twenty patients were irradiated and had complete follow-up. Cumulatively, SRT patients needed significantly less injections than non-irradiated ones over three years (14 vs. 18, p ​= ​0.014), while median VA did not show statistically significant changes (0.4 logMAR at baseline to 0.65 logMAR at final follow-up, p ​= ​0.061). CRT remained steady, but SFCT showed a continuous thinning of almost 50 ​μm (p ​= ​0.031) in irradiated patients over three years. Multiple linear regression analysis revealed that SFCT and VA at time of irradiation are significant prognostic factors of VA change in SRT patients over the following three years (F(2,17) ​= ​23.946, p<0.001, R2 of 0.738). SRT significantly reduced the cumulative anti-VEGF treatment burden over three years, however, this was mainly driven by the results of the first year after irradiation. A thinner SFCT at time of irradiation was associated with poorer visual outcome. While further research and investigation are warranted to elucidate the underlying pathogenesis, SFCT could be a potential biomarker when evaluating a patient's suitability for SRT. [ABSTRACT FROM AUTHOR]

Abstract Background Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes. Methods CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA. Results Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups. Conclusions Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. Key messages: Lactate and lipoprotein profile are associated with the active phase of AMD and CNV development. Lactate is a relevant and functional metabolite correlated with AMD progression. Modulating lactate through pyruvate dehydrogenase kinase led to a decrease of CNV progression. Pyruvate dehydrogenase kinase is a new therapeutic target for neovascular AMD. [ABSTRACT FROM AUTHOR]

Introduction: Despite consistent use of anti-vascular endothelial growth factor (anti-VEGF), prognosis of large, fovea-involving submacular hemorrhage (SMH) has remained guarded, particularly in patients with neovascular age-related macular degeneration. Areas covered: This review provides an update on management of SMH, with particular focus on the role of anti-VEGF therapy and surgical management of thick, large, and/or subfoveal SMH. A literature search and meta-analysis of studies published from January 2010 to February 2019 was performed to evaluate outcomes of eyes with SMH following management with either medical treatment (i.e. anti-VEGF monotherapy) or a combined surgical approach of pars plana vitrectomy, subretinal tPA with or without subretinal air, pneumatic displacement, and anti-VEGF. The surgical techniques are summarized, with emphasis on novel surgical techniques described in the past decade. Prognostic factors associated with, and potential indications for, choice of management approach were evaluated. Expert commentary: SMH represents a continuing treatment challenge. Anti-VEGF monotherapy is a reasonable approach in patients with small, thin, and localized hemorrhage. Combination vitrectomy, tPA, pneumatic displacement, and anti-VEGF may be effective in managing thick, large SMH in some cases. While no consensus exists on optimal treatment algorithm, choice of medical or surgical therapy should be tailored to each patient. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate ganglion cell complex (GCC) thickness in patients with neovascular age-related macular degeneration (AMD) who underwent aflibercept injection by using optical coherence tomography (OCT). Methods:The study included 28 eyes of 28 patients with neovascular AMD who had at least 6 months of follow-up following 3-dose anti-VEGF injection. Central macular thickness (CMT) and GCC thickness were evaluated with SD-OCT. Visual acuity, intraocular pressure, CMT, GCC thickness were recorded at the first month, 3 months and 6 months after the injection. Results:The mean age of the patients was 71.9 ± 7.2 (55-82) years. Best corrected visual acuity (logMAR) before injection was 0.90±0.24, at third month it was 0.32±0.22 idi (p=0.005). Before injection the mean CMT was 383.75 ± 28.6 µm, it was 267 ± 67 µm in the 6th month (p = 0.001). Mean GCC thickness was 93.20 µm before injection and 92.56 µm at 6 months. (P = 0.250) Conclusion: It was found that intravitreal Aflibercept injection did not have a significant effect on GCC thickness after 6 months of follow-up. Aflibercept is an effective, reliable treatment option in the treatment of neovascular AMD. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate treatment outcome at 12 months in eyes with neovascular age‐related macular degeneration (nAMD) treated with antivascular endothelial growth factor (anti‐VEGF) injections according to either pro re nata (PRN)‐ or treat‐and‐extend (TE)‐regimen in one clinical setting in Sweden. Methods: Data were obtained retrospectively from the Swedish Macula Register, optical coherence tomography‐database and electronic patient charts. The study included 443 eyes; 223 PRN‐ and 220 TE‐treated eyes. Baseline (BL) characteristics and follow‐up data at 6 and 12 months were collected. Statistical regression analysis was performed to evaluate association between treatment strategy and visual outcome at 12 months. Results: Baseline (BL) characteristics were well balanced between cohorts. Visual acuity at 12 months was higher in TE‐cohort 66.5 (13.1) compared to PRN‐cohort 60.1 (17.6) (p = 0.000). Visual improvement at 12 months was +5.2 (11.8) and +1.2 (12.7) letters Early Treatment Diabetic Retinopathy Study (ETDRS) in TE‐ and PRN‐cohorts, respectively (p = 0.002). Number of administered injections at 12 months was 10.2 (2.1) and 6.3 (2.1) in the two cohorts (p = 0.000). Statistical analysis demonstrated a strong association between TE treatment strategy and improvement in visual acuity at 12 months. Conclusion: Eyes treated according to TE had better visual outcome at 12 months. The results indicate that treatment according to proactive TE‐regimen is superior to treatment according to PRN‐regimen in clinical routine care of nAMD. [ABSTRACT FROM AUTHOR]

Purpose: To determine the proportion of treatment-experienced eyes with exudative age-related macular degeneration successfully treated with every-4-week aflibercept that can be kept dry on fixed every-8-week aflibercept injections (maintenance). Methods: In this retrospective chart review, we evaluated our cohort of patients treated with a treatment paradigm for CNV in AMD. Initially, patients were treated with bevacizumab or ranibizumab and switched to every-4-week aflibercept when therapeutic responses were not durable or were suboptimal. Maintenance every-8-week therapy was initiated when the retina was completely dry on every-4-week aflibercept therapy. The primary outcome measure was recurrence of exudation on optical coherence tomography (OCT) during maintenance. Results: Thirty-six eyes of 31 consecutive patients with median age of 79 years (range, 65–89) were included. Maintenance was started after a median of 34 (range, 8–88) injections. Recurrence was observed in 20 eyes (55%). Of these, 11 eyes (31%) reactivated at 8 weeks. Median time to failure of maintenance schedule was 40 weeks by Kaplan-Meier analysis. Baseline demographic and anatomic characteristics were not associated with failure of maintenance schedule. Conclusion: In treatment-experienced eyes that respond completely to every-4-week aflibercept, maintenance therapy with every-8-week injections can only temporarily maintain anatomic success with the majority of eyes developing recurring activity. This regimen fails early in one third of eyes and has a median effective duration of 40 weeks. Aflibercept appears to be inadequate to maintain control of exudation in most eyes in at least half of eyes undergoing long-term therapy. [ABSTRACT FROM AUTHOR]

Purpose: The main objective of this study was to assess choroidal thickness (CT) changes during an exudative recurrence of age-related macular degeneration (AMD). Methods: A real-life prospective non-interventional 9-month study was conducted in two centers in consecutive patients with exudative AMD between November 2016 and July 2017. CT was measured manually in both eyes based on enhanced-depth imaging spectral-domain optical coherence tomography at different follow-up visits scheduled in the morning. Results: A total of 134 patients were included. Ninety-five patients presented at least one episode, defined by a follow-up visit under controlled condition (dry retina) followed by a visit for exudative recurrence. A total of 119 episodes were analyzed. The mean CT change in the treated eye was + 8.45 ± 13.52 μm (p < 0.001) and + 5.62 ± 14.77 μm (p = 0.009) respectively in the subfoveal area and nasal area. No significant change in CT was observed in the fellow eye. No significant association between CT changes and treatment, number of intravitreal injections, and blood pressure was observed. Conclusion: CT increased in case of exudative recurrence of neovascular AMD. The increase was mild but significant. Thus, CT could be used as a monitoring criterion, like the central retinal thickness, in AMD management. [ABSTRACT FROM AUTHOR]

Purpose: To assess mean change in visual acuity (VA) overall and stratified by baseline VA after 1 and 2 years' treatment with aflibercept in a real‐life setting. Methods: This was an observational cohort study using nationwide data from the Swedish Macula Register. Treatment‐naïve patient eyes with wet age‐related macular degeneration and prescribed aflibercept from January 2013 to December 2014 were followed for 1 year (2478 eyes) or 2 years (831 eyes) to assess VA. Eyes were grouped by baseline VA. Results: Mean number of injections in patients treated according to label (72%) versus patients treated not according to label was 8.0 ± 1.5 versus 4.4 ± 0.8 (p < 0.0001) at 1 year, and 12.5 ± 3.2 versus 7.3 ± 1.9 (p < 0.0001) at 2 years. Among all eyes, mean VA increased from 61.3 ± 13.4 Early Treatment Diabetic Retinopathy Study letters at baseline to 64.5 ± 15.6 at 1 year and 65.1 ± 15.1 letters at 2 years. At 2 years, eyes with good baseline vision (≥70 letters) lost a mean of 2.4 ± 11.3 to 72.3 letters, eyes with intermediate baseline VA (36–69 letters) gained 5.7 ± 14.1 to 62.7 letters, and eyes with poor baseline VA (≤35 letters) gained 13.2 ± 18.3 to 41.0 letters. Also at 2 years, 75% of treated eyes were stable or had improved VA. Among eyes with intermediate baseline VA, near vision was significantly better among those treated according to label versus not according to label at 3 (p = 0.019), 6 (p = 0.0002) and 12 months (p ≤ 0.0001). Conclusion: While gain in vision was especially pronounced in eyes with poor baseline VA, good baseline VA was important for best prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Automated segmentation of retinal layers by spectral-domain optical coherence tomography (SD-OCT) is usually erroneous in the presence of retinal diseases. The purpose of this study is to report the changes in ganglion cell complex (GCC) comprising retina nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) in neovascular age-related macular degeneration (AMD) patients by manually correcting the automated segmentation errors.Methods: Thirty eyes of 30 patients with new-onset choroidal neovascularization secondary to neovascular AMD and 30 eyes of 30 healthy subjects were included. The inner retinal thicknesses were measured using early treatment diabetic retinopathy circle in the central 1 mm (fovea) and surrounding 3 mm diameter (parafovea) after checking the accuracy of automated segmentation lines. Manual segmentation was done to ensure the accurate segmentation, when needed.Results: Neovascular AMD patients had thicker mean RNFL, GCL, IPL, and GCC thicknesses within the fovea compared to healthy eyes (p = 0.04, p = 0.001, p = 0.032, and p = 0.005, respectively). In the parafoveal area, among the thickness-related measurements, the only significant difference was a thicker mean RNFL (p = 0.002).Conclusion: Diffuse thickening of inner retinal layers in neovascular AMD may overestimate actual GCC thickness within fovea. This pseudo-increase in GCC thickness and inner retinal layers in general likely does not reflect more cells or tissue, but rather diffuse edema which leads to a falsely increased reading of layer thickness. Such false readings may also make the assessment of other conditions that lead to reduced inner retinal layer thickness such as glaucoma, optic nerve disease, or retinovascular occlusions more difficult. [ABSTRACT FROM AUTHOR]

Purpose:: To evaluate intravitreal bevacizumab every 2 weeks (biweekly) in refractory neovascular age-related macular degeneration (nAMD).Study design:: Retrospective study.Methods:: A retrospective study of consecutive nAMD patients unresponsive to monthly intravitreal anti-vascular endothelial growth factor (VEGF) switched to 3-4 biweekly injections.Results:: Twenty-seven eyes of patients aged 82.08  ± 6.85 years were included. Prior to the 2-week interval bevacizumab injections, 74.1% (n=20) were treated with both bevacizumab and ranibizumab, 11.1% (3 eyes) also received aflibercept and 14.8% (4 eyes) had received prior treatment of monthly bevacizumab (average number of injections 21.5 ± 6.7). Best corrected visual acuity (BCVA) remained stable between baseline (logMAR 0.72± 0.60) and follow-up (0.76± 0.66) (p=0.41). Mean central macular thickness and macular volume did not change significantly between baseline and follow-up (p=0.35 and p=0.60, respectively). Six eyes (22.2%) showed morphologic anatomic improvements, while 19 eyes (70.4%) were stable and two eyes (7.4%) deteriorated from baseline. Subretinal fluid completely resolved in 3 of the eyes and improved in the other 3 eyes and in this group (22.2%) both central macular thickness (326.2 ± 101.4 versus 297.5 ± 97.2, p=0.002) and macular volume (8.69 ± 1.69 versus 8.22 ± 1.43, p=0.03) were significantly reduced. No adverse events were observed in any of the treated eyes.Conclusion:: This study demonstrates that biweekly bevacizumab injections are effective in nearly one-quarter of nAMD non-responders with no adverse events reported. Switching earlier, rather than later, to this low cost modality may be of benefit for a portion of non-responders to conventional treatment. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Although intravitreal injection of anti-VEGF antibodies and VEGF Trap have significant clinical benefits, the complications of intravitreal injection, drug resistance and patient compliance still need to be concerned. In this study, the effects of an orally administered multi-targeted tyrosine kinase inhibitor (Lenvatinib, E7080) were evaluated in vitro and in vivo on neovascular AMD mouse model. The results showed that E7080 effectively inhibited the proliferation, migration and tubule formation of human choroidal microvascular endothelial cells (HCMECs), and suppressed the angiogenesis of zebrafish subintestinal vessels without causing malformation. The anti-angiogenic effect of E7080 on the laser-induced choroidal neovascularization (CNV) mouse model by oral administration of 10 mg/kg/day was observed. The fluorescein angiography showed CNV leakage area in treatment group vs control group was 3.407 ± 0.2939 vs 5.202 ± 0.9001 ( P  = .0133) at day 7th post laser-induced CNV, 1.138 ± 0.4334 vs 3.122 ± 0.3466 ( P  = .0064) at day 14th, 1.401 ± 0.6577 vs 2.781 ± 0.9815 ( P  = .00262) at day 21th respectively. Moreover, pharmacokinetics analysis in rat retina showed that E7080 rapidly penetrated the blood-retina barrier to retina through oral administration. The T 1/2 in retina was 3.81 ± 0.77 h, the T max was 4.60 ± 0.73 h, the AUC 0-∞ was 110448.51 ± 18532.51 h*ng/g after a single dose administration analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In conclusion, our study suggested that orally administered E7080 can be a novel therapeutic strategy for neovascular AMD. [ABSTRACT FROM AUTHOR]

Purpose To present Swedish Macula Register (SMR) data regarding treatment of neovascular age-related macular degeneration (AMD) in clinical practice since 2008. Methods A retrospective register-based study was conducted. Evaluation of baseline demographics, visual outcome and number of injections during this period is presented. Results Mean age at diagnosis was 79 ± (SD) 8 years; 65% were female. The proportion of patients with <2 months' duration of symptoms increased from 26% in 2008 to 41% in 2014 (p = 0.001). Mean visual acuity (VA) at baseline increased from 54.3 ± 15.0 early treatment diabetic retinopathy study (ETDRS) letters in 2008 to 57.8 ± 15.6 letters in 2014 (CI95 2.6; 4.3; p < 0.001). Mean VA after 1 year of treatment increased from 57.8 ± 17.7 ETDRS letters for patients who started the treatment in 2008 to 62.8 ± 16.4 ETDRS letters in patients starting treatment in 2014 (CI95 2.67; 4.64; p < 0.001). During all study years, the proportion of patients with an improvement in VA of between 5 and 15 letters was around 30%, while 14% had VA improvement of more than 15 letters. The mean number of injections during the first treatment year increased from 4.3 ± 1.9 in 2008 to 5.9 ± 2.9 in 2014 (CI95 1.40; 1.67; p < 0.001). Seven-year follow-up of 322 eyes showed a mean change of −1 letters from baseline, with a mean of 21 injections for the entire period. Conclusion The duration of symptoms before treatment decreased, while VA at baseline and after 1 year of treatment increased over the years and so did the number of injections. Long-term follow-up demonstrated stable VA. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to analyze mortality in patients treated with bevacizumab for wet AMD.Methods: We conducted a retrospective case-control study between patients who received intravitreal injections of bevacizumab as the sole treatment for exudative AMD between September 2008 and October 2014 (n = 5385) and age and gender matched controls (n = 10,756). All individuals included in the study were reviewed for sociodemographic data and comorbidities. Survival analysis was performed using adjusted Cox regression, using relevant adjusted variables.Results: During follow-up (maximum: 73 months), 1063 (19.7%) individuals after bevacizumab died compared with 1298 (12.1%) in the control group (P < .001). After adjusted Cox survival regression, mortality differed significantly between the groups, Odds ratio = 1.69, (95% C.I. 1.54-1.84), P < .001.Conclusions: We found an increased long-term mortality in individuals with wet AMD treated with bevacizumab compared to a same age and gender group without wet AMD. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this project was to evaluate the role of MR antagonists as an adjunct in patients with neovascular age-related macular degeneration (AMD) who have chronic subretinal fluid. Methods: Inclusion criteria were patients with a diagnosis of neovascular AMD, who had completed at least six anti-VEGF injections, and had persistent subretinal fluid (SRF) on optical coherence tomography (OCT). Treatment with oral eplerenone was initiated and dose titrated according to protocol. Results: 23 patients were included in the study (mean age = 54.6, 52.2% female, 47.8% male). 13 of the 23 patients had predominantly chronic subretinal fluid without large PEDs. In this subgroup, mean initial central macular thickness (CMT) prior to starting oral eplerenone was 305.3 μm, and mean injection interval was 40.25 days. Mean final CMT after at least 3 months of adjunctive eplerenone treatment was 240.6 μm and mean injection interval with adjunctive treatment was 54.61 days. Mean extension of the injection interval after commencing oral eplerenone was 14.36 days. Conclusions: These findings suggest oral MR antagonists may have a role as an adjunctive treatment in neovascular AMD, and may be particularly useful in dehydration of the subretinal space in the setting of chronic subretinal fluid. Further research is needed in randomized controlled trials to elucidate the precise role of oral MR antagonists in neovascular AMD. [ABSTRACT FROM AUTHOR]

Purpose To examine the outcome after cataract surgery in patients with neovascular age-related macular degeneration (AMD) treated with intravitreal anti-vascular endothelial growth factor (VEGF) injections in routine clinical practice. Methods We extracted information about patients recorded in electronic databases managing anti-VEGF injections and cataract surgery. We compared Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity and frequency of anti-VEGF injections before and after cataract surgery. Results We identified 89 eyes from 89 patients who had cataract surgery after being treated with a median of 10 (range 3-36) anti-VEGF injections for neovascular AMD. Visual acuity improved by a mean of 7.1 [95% confidence interval (CI) 4.6-9.6] ETDRS letters in the first 6 months after cataract surgery. The need of anti-VEGF injections did not change after cataract surgery with an average of 1.5 in the 6 months before surgery versus 1.7 in the 6 months after surgery (p = 0.25). Visual improvement was greater in patients when the time from latest injection to cataract surgery was lower. Conclusions Cataract surgery improves vision in patients undergoing treatment for neovascular AMD. Cataract surgery was not associated with an increased need for anti-VEGF treatment and patients who were in active anti-VEGF treatment had better visual outcomes than patients who had cataract surgery after long injection-free periods. [ABSTRACT FROM AUTHOR]

Background: With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a "one size fits all" to an "individualised" approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 μm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD.Methods/design: This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab "intensive" treatment (complete resolution of IRF and SRF) or ranibizumab "relaxed" treatment (resolution of IRF or >200 μm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment.Discussion: This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol.Trial Registration: Trial Registration Number: NCT01972789. Date of registration: 24th October 2013. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of ranibizumab on visual acuity (VA) following a 3-year treatment period for patients diagnosed with wet age-related macular degeneration. To establish whether baseline VA and injection frequency influence visual outcomes. Patients and methods: Retrospective review of 70 patients (76 eyes) treated with 0.5 mg intravitreal ranibizumab for 3 consecutive months, and pro re nata thereafter (three + pro re nata protocol), over a 3-year period. VA was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts at baseline, 12, 24, and 36 months. The number of injections administered at the end of years 1, 2, and 3 were also recorded. Eyes were stratified according to baseline VA, as well as the number of injections administered at the end of year 1. Linear regression analysis determined the relationship between VA and both baseline VA and injection frequency. P<0.05 was considered statistically significant. Results: At 36 months, VA improved by a mean of 5.3 ETDRS letters (P=0.002), with 29% of eyes (n=22) demonstrating a clinically significant improvement in VA (gain of ≥15 ETDRS letters). Improvements in VA from baseline to 36 months were inversely proportional to the baseline VA (R=0.414, P=<0.001). A positive correlation was observed between injection frequency and change in VA from baseline to 36 months (R=0.244, P=0.036). Conclusion: Mean improvement in VA is inversely proportional to baseline VA, and directly proportional to injection frequency. [ABSTRACT FROM AUTHOR]

Purpose The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age-related macular degeneration (wet AMD) in daily practice. Methods The HELIOS study was a 2-year prospective, observational, open-label, multicentre study involving 14 sites. Patients with wet AMD were enrolled and observed for a period of 24 months. The data were collected at baseline and at the visits closest around the time-points 3, 6, 12, 18 and 24 months after inclusion. Results Treatment with ranibizumab resulted in prevention of vision loss. The mean ETDRS score increased from 45.1 letters at baseline to 48.5 letters at 24 months. This was achieved with a mean of 7.8 injections over 24 months. Stabilization of visual acuity was also reflected by the scores on the quality of life EQ-5D questionnaire, which did not significantly change over the study period. The more subjective EQ- VAS questionnaire showed an overall improvement. The VFQ-25 questionnaire was also mostly stable over time. After 24 months, 32.2% of the patients gained ≥1 letter and 17.1% gained >15 letters. Patients completing the loading phase were better responders, as demonstrated by increased long-term visual acuity. In addition, ranibizumab was well tolerated and had a safety profile commonly seen in routine clinical practice. Conclusion This study demonstrates that also in daily practice ranibizumab was effective in preventing vision loss over a period of 24 months. No new safety findings were identified. [ABSTRACT FROM AUTHOR]

Objective: To compare the macular pigment optical density (MPOD) among Filipinos with and without agerelated macular degeneration (AMD). Methods: Consecutive patients with AMD and without posterior segment disease were recruited into the study Baseline MPOD measurements using an autofluorescence spectrometer were obtained. MPOD in the 0.5 degree retinal eccentricity and the average of 3 measurements (MPOD Max) was the primary outcome measure. Results: 120 patients, aged 50 to 80 years, were included into 3 groups: group 1 (n=40) without retinal disease, group 2 (n=40) with non-neovascular AMD, and group 3 (n=40) with neovascular AMD. The mean baseline MPOD were: 0.382 ± 0.10 DU for group 1, 0.333 ± 0.07 DU for group 2, and 0.283 ± 0.07 DU for group 3. Significant differences were present comparing the MPOD values of the 3 groups. Conclusion: Eyes without retinal disease had higher MPOD than those with early non-neovascular or neovascular AMD. [ABSTRACT FROM AUTHOR]

The ocular compartment presents distinct challenges for drug delivery. For the scope of this review, the authors focus on two specific diseases of the posterior segment of the eye including age related macular degeneration (AMD) and diabetic macular edema for which current successful treatments include protein-based molecules delivered into the eye via repeat intravitreal injection. Distinct from the neovascular form of AMD, a large unmet need remains in the advanced dry form of AMD. In consideration of the next wave of biotherapeutics for intraocular application, combination targeted agents are expected. Here the authors review technologies to engineer dual targeting into protein-based therapeutics for intravitreal delivery with an additional aim of minimizing systemic exposure after intraocular injection. In the summary the authors highlight two of these forms, DAPRin and Fab'2, as important to monitor closely as bispecifics for ocular therapy development. [ABSTRACT FROM AUTHOR]

. Purpose: Quantification of short-term progression of active neovascular age-related macular degeneration and correlation with 1-year outcome. Methods: Sixty-five patients with newly diagnosed treatment-naive active subfoveal choroidal neovascularization (CNV), who had participated in clinical trials testing anti-vascular endothelial growth factor therapy, were retrospectively assessed. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA), Spectral Domain Optical Coherence Tomography (SD-OCT) and fluorescein angiography (FA) were performed twice during the pretreatment period. Changes in BCVA, central retinal thickness (CRT), average macular thickness (AMT) and leakage area were documented within this pretreatment period for all patients and for lesion type I (occult CNV, n = 42) and type II (classic CNV, n = 23). Three-month and 1-year BCVA were then correlated with the pretreatment period. Results: The pretreatment period was 19 ± 3 days (range: 2-108). Neither type I nor type II lesions showed a significant BCVA decrease or CRT/AMT increase during this period. On FA, mean leakage area increased significantly during the pretreatment period: in the pooled group from 5.50 ± 0.62 (screening) to 7.60 ± 0.86 mm2 (baseline) (p < 0.0001), in type II from 4.65 ± 0.90 to 7.83 ± 1.62 mm2 (p < 0.01) and in type I from 6.08 ± 0.85 to 7.45 ± 0.96 mm2 (p < 0.0001). The mean increase in leakage area per day was 0.046 ± 0.02 mm2, p = 0.034. Type II showed a daily growth of 0.09 ± 0.08 mm2 (p < 0.042) and type I 0.045 ± 0.008 mm2 per day (p < 0.0001). However, neither leakage area increase nor pretreatment period was correlated with 3-month or 1-year BCVA outcome. Conclusions: SD-OCT and BCVA testing did not reveal deterioration during the pretreatment period. However, the leakage area progressed rapidly. Despite the rapid increasing leakage area, the 19-day waiting period was not associated with a poorer visual outcome at 3 months and 1 year. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology.Methods: In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months.Results: Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002).Conclusions: Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes.Methods: CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA.Results: Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups.Conclusions: Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients. [ABSTRACT FROM AUTHOR]

Background: Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. Methods: In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Results: Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Conclusion: Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy. [ABSTRACT FROM AUTHOR]