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Purpose Methods Results Conclusions To quantify ellipsoid zone (EZ) loss during anti‐VEGF therapy for neovascular age‐related macular degeneration (nAMD) and correlate these findings with nAMD disease activity using artificial intelligence‐based algorithms.Spectral domain optical coherence tomography (Spectralis, Heidelberg Engineering) images from nAMD treatment‐naïve patients from the Fight Retinal Blindness! (FRB!) Registry from Zürich, Switzerland were processed at baseline and over 3 years of follow‐up. An approved deep learning algorithm (Fluid Monitor, RetInSight) was used to automatically quantify intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelial detachment (PED). An ensemble U‐net deep learning algorithm was used to automated quantify EZ integrity based on EZ layer thickness. The impact of fluid volumes on EZ thickness and late‐stages outcomes were calculated using Wilcoxon rank‐sum tests, a linear mixed model and a longitudinal panel regression model.Two hundred and eleven eyes from 158 patients were included. The mean ± SD EZ loss area in the central 6 mm was 1.81 ± 2.68 mm2 at baseline and reached 6.21 ± 6.15 mm2 at month 36. Higher fluid volumes (top 25%) of IRF and PED in the central 1 and 6 mm of the macula were significantly associated with more advanced EZ thinning and loss compared to the low fluid volume subgroup. The high SRF subgroup in the linear regression model showed no statistically significant association with EZ integrity in the central macula; however, the longitudinal analysis revealed an increased EZ thickness with no additional loss.Intraretinal fluid and PED volumes and their resolution pattern have an impact on alteration of the underlying EZ layer. AI‐supported quantifications are helpful in quantifying early signs of macular atrophy and providing individual risk profiles as a basis for tailored therapies for optimized visual outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Anti-vascular endothelial growth factor (VEGF) is generally given using pro re nata or "treat-and-extend" (T&E) regimens for neovascular age-related macular degeneration (nAMD). Randomized clinical trials have reported that T&E is superior to Pro re nata (PRN), but results from clinical trials may not always be replicated in clinical practice. Real-world data comparing T&E and PRN regimens for nAMD are limited. The objective of this work was to report 24-month outcomes of PRN versus T&E regimens for ranibizumab and aflibercept to treat nAMD in routine clinical practice. Methods: We conducted a retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! Project (FRB). Treatment-naïve eyes starting nAMD treatment with at least three injections using a T&E or PRN regimen were tracked by using the FRB. The primary outcome was the mean change in visual acuity (VA) measured by the number of letters read on a logarithm of the minimum angle of resolution chart at 2 years versus baseline. The secondary outcome was the number of injections at 2 years. Results: From January 1, 2015 to January 31, 2019, 3313 eyes from 2948 patients with nAMD were included: 1243 eyes from 1065 patients were classified as PRN and 2070 eyes from 1935 patients started a T&E regimen. At 24 months, patients on the T&E regimen experienced significantly greater mean (95% confidence interval) improvement in VA than those on PRN (+ 4.2 [3.1, 5.2] vs. + 1.3 [0.1, 2.6] letters; p < 0.001), with more injections (14.9 standard deviation(SD) 4.3) vs. 9.8(SD 4.3); p < 0.001). Conclusions: Eyes treated with a T&E regimen had better VA outcomes from VEGF inhibitors than eyes treated PRN. This large real-world data assessment supports previous data from randomized clinical trials that the T&E regimen delivers better outcomes than PRN. Plain Language Summary: This study focused on comparing two methods of treating neovascular age-related macular degeneration, a common eye condition. The treatments used were ranibizumab and aflibercept. We looked at the reactive "pro re nata" method, where treatment is given sporadically and only when the condition reactivates, and the proactive "treat-and-extend" method, which aims to keep the disease inactive with the fewest treatments at regular intervals. The main aim was to determine which method provides the best vision outcomes over a 24-month period and the frequency of treatment required. We found that the treat-and-extend method resulted in a greater improvement in vision than the pro re nata method, although it did require more injections. This study highlights the effectiveness of the treat-and-extend method for neovascular age-related macular degeneration, suggesting it gets better outcomes despite requiring more injections. [ABSTRACT FROM AUTHOR]

Abstract Introduction Anti-vascular endothelial growth factor (VEGF) is generally given using pro re nata or “treat-and-extend” (T&E) regimens for neovascular age-related macular degeneration (nAMD). Randomized clinical trials have reported that T&E is superior to Pro re nata (PRN), but results from clinical trials may not always be replicated in clinical practice. Real-world data comparing T&E and PRN regimens for nAMD are limited. The objective of this work was to report 24-month outcomes of PRN versus T&E regimens for ranibizumab and aflibercept to treat nAMD in routine clinical practice. Methods We conducted a retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! Project (FRB). Treatment-naïve eyes starting nAMD treatment with at least three injections using a T&E or PRN regimen were tracked by using the FRB. The primary outcome was the mean change in visual acuity (VA) measured by the number of letters read on a logarithm of the minimum angle of resolution chart at 2 years versus baseline. The secondary outcome was the number of injections at 2 years. Results From January 1, 2015 to January 31, 2019, 3313 eyes from 2948 patients with nAMD were included: 1243 eyes from 1065 patients were classified as PRN and 2070 eyes from 1935 patients started a T&E regimen. At 24 months, patients on the T&E regimen experienced significantly greater mean (95% confidence interval) improvement in VA than those on PRN (+ 4.2 [3.1, 5.2] vs. + 1.3 [0.1, 2.6] letters; p

Debdulal Chakraborty,1 Subhendu Boral,1 Tushar Kanti Sinha,1 Arnab Das,1 Angshuman Mukherjee,1 Saptorshi Majumdar,1 Ranabir Bhattacharya,2 Ritobroto Maitra3 1Department of Vitreoretinal Services, Disha Eye Hospitals, Kolkata, West Bengal, India; 2Department of MIS, Disha Eye Hospitals, Kolkata, West Bengal, India; 3Radical Health Tech, New Delhi, IndiaCorrespondence: Debdulal Chakraborty, Department of Vitreoretinal services; Disha Eye Hospitals, Kolkata, West Bengal, India, Tel +91 33 66360000, Email devdc@rediffmail.comPurpose: This study investigates the efficacy of transitioning patients with neovascular age-related macular degeneration (nAMD) from aflibercept (T1) to biosimilar ranibizumab (T2), an approach not previously documented in literature.Methods: In this multicenter observational study, patients over 50 years of age with nAMD were shifted from intravitreal aflibercept (IVI AFL) to biosimilar ranibizumab (B-RBZ) due to financial constraints. This study employed standardized ophthalmological methods to assess visual acuity (VA), central macular thickness (CMT), and subretinal and intraretinal fluid. Statistical analyses included paired t-tests, Wilcoxon signed-rank tests, and linear regression.Results: A total of 29 eyes (12 males and 17 females) were analyzed. Mean age was 72.55 ± 6.43 years. VA improved significantly during T1, with a mean increase from 55.0 ± 10.2 to 70.0 ± 8.5 ETDRS letters at the switch time point (p < 0.01), then a slight decrease to 62.3 ± 8.9 at 12 months (p < 0.05) was noted during T2. The mean CMT decreased notably from 400 ± 50 to 290 ± 45 μm at the switch. The final CMT at 12 months after switching to B-RBZ was 280 ± 40 μm (p < 0.01). There was a significant decrease in the retinal and intra retinal fluid during T1, followed by a gradual increase during T2. A significant correlation (p < 0.05) was noted between the presence of intraretinal fluid and increased injection frequency of B-RBZ.Conclusion: The switch from IVI AFL to IVI B-RBZ in patients with nAMD demonstrated efficacy in maintaining the VA and macular anatomy, with some challenges in fluid management.Keywords: neovascular AMD, aflibercept, biosimilar ranibizumab, subretinal fluid, intraretinal fluid

Purpose: To evaluate the impact of the changes in treatment patterns before, during and after the COVID‐19 pandemic on best‐corrected visual acuity (BCVA) in previously treated neovascular age‐related macular degeneration (nAMD) patients. Methods: A multi‐centre, retrospective, observational study of consecutive nAMD patients during 2019–2021. Data collected included demographics, BCVA, dates of intravitreal anti‐vascular endothelial growth factor (anti‐VEGF) injections and clinic visits. Results: A total of 1652 eyes of 1652 nAMD patients were included, out of which 850 eyes were assessed in 2019 (pre‐COVID‐19), 630 eyes were assessed in 2020 (COVID‐19) and 974 eyes were assessed in 2021 (post‐COVID‐19). During the COVID‐19 period, the mean number of anti‐VEGF injections was significantly lower than the corresponding pre‐COVID‐19 and post‐COVID‐19 periods (5.55 compared to 6.13 and 6.60, respectively p < 0.01). A constant lower ratio of injections per patient/month was observed during COVID‐19 compared to previous and following years, with a notable decline during March–April, reaching a ratio of 0.4 in 2020 versus 0.65 in 2019 and 0.62 in 2021 (p < 0.01). Baseline BCVA (0.825, p < 0.001), number of injections (−0.007, p < 0.001), gender (−0.027, p = 0.037) and age (0.004, p < 0.001) were shown to be significant predictors of final BCVA. Conclusion: During the COVID‐19 period, patients were treated with significantly less intravitreal anti‐VEGF injection compared to the previous year with compensation in the following year. These changes in treatment patterns did not have a significant impact on BCVA outcomes. Age, gender, baseline BCVA and number of injections are predictors of final visual outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background The purpose of the study was to compare the real-world aflibercept treatment and visual outcomes, and to examine the adherence to pandemic guidelines in two groups of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) before and during the first year of the COVID-19 pandemic in Sweden up to the 1-year follow-up. Methods This is a retrospective observational study including 2915 treatment naïve eyes with nAMD. Using data from the Swedish Macula Register (SMR), 1597 eyes initiating treatment between 1 July 2018 and 31 January 2019 (pre-pandemic group) were compared with 1318 eyes starting treatment between 1 February and 31 August 2020 (pandemic group). The eyes were then followed for 1 year ± 2 months, hence the first group was unaffected by the pandemic while the second group was affected. The focus was on baseline characteristics, visual acuity (VA) change from baseline, number of injections, treatment regimen, number of appointments and the frequency and length of appointment delays. The Wilcoxon Signed-Rank Test was used to compare baseline VA to follow-up VA within the respective groups. The Mann-Whitney U-test and Fisher’s exact test were used to compare outcomes between the groups. Results Baseline characteristics were similar between the two groups. The percentage of eyes with an available follow-up VA after 1 year was 58% in the pre-pandemic group vs. 44% in the pandemic group. VA in the pre-pandemic group had increased significantly after 1 year, from 62.2 ± 14.1 letters to 64.8 ± 16.1 letters (n = 921); p

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells in vitro but did not enhance VEGF suppression in mouse eyes in vivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that in vivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear.

Background: The purpose of the study was to compare the real-world aflibercept treatment and visual outcomes, and to examine the adherence to pandemic guidelines in two groups of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) before and during the first year of the COVID-19 pandemic in Sweden up to the 1-year follow-up. Methods: This is a retrospective observational study including 2915 treatment naïve eyes with nAMD. Using data from the Swedish Macula Register (SMR), 1597 eyes initiating treatment between 1 July 2018 and 31 January 2019 (pre-pandemic group) were compared with 1318 eyes starting treatment between 1 February and 31 August 2020 (pandemic group). The eyes were then followed for 1 year ± 2 months, hence the first group was unaffected by the pandemic while the second group was affected. The focus was on baseline characteristics, visual acuity (VA) change from baseline, number of injections, treatment regimen, number of appointments and the frequency and length of appointment delays. The Wilcoxon Signed-Rank Test was used to compare baseline VA to follow-up VA within the respective groups. The Mann-Whitney U-test and Fisher's exact test were used to compare outcomes between the groups. Results: Baseline characteristics were similar between the two groups. The percentage of eyes with an available follow-up VA after 1 year was 58% in the pre-pandemic group vs. 44% in the pandemic group. VA in the pre-pandemic group had increased significantly after 1 year, from 62.2 ± 14.1 letters to 64.8 ± 16.1 letters (n = 921); p < 0.0001. In the pandemic group, VA increased from 61.1 ± 15.8 to 64.9 ± 16.9 (n = 575); p < 0.0001. There was no significant difference in mean VA change between the groups; p = 0.1734. The pre-pandemic group had significantly more delays than the pandemic group, 45% vs. 36%; p < 0.0001. Conclusions: The pre-pandemic and pandemic groups had similar VA gains at 1-year follow-up, but with a reduced number of available VA in the pandemic group. Clinics were able to implement and prioritize injection visits excluding VA measurements, helping to reduce delays and maintain VA gains during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a leading cause of severe vision loss worldwide, with a global prevalence that is predicted to substantially increase. Identifying early biomarkers indicative of progression risk will improve our ability to assess which patients are at greatest risk of progressing from intermediate AMD (iAMD) to vision-threatening late-stage AMD. This is key to ensuring individualized management and timely intervention before substantial structural damage. Some structural biomarkers suggestive of AMD progression risk are well established, such as changes seen on color fundus photography and more recently optical coherence tomography (drusen volume, pigmentary abnormalities). Emerging biomarkers identified through multimodal imaging, including reticular pseudodrusen, hyperreflective foci, and drusen sub-phenotypes, are being intensively explored as risk factors for progression towards late-stage disease. Other structural biomarkers merit further research, such as ellipsoid zone reflectivity and choriocapillaris flow features. The measures of visual function that best detect change in iAMD and correlate with risk of progression remain under intense investigation, with tests such as dark adaptometry and cone-specific contrast tests being explored. Evidence on blood and plasma markers is preliminary, but there are indications that changes in levels of C-reactive protein and high-density lipoprotein cholesterol may be used to stratify patients and predict risk. With further research, some of these biomarkers may be used to monitor progression. Emerging artificial intelligence methods may help evaluate and validate these biomarkers; however, until we have large and well-curated longitudinal data sets, using artificial intelligence effectively to inform clinical trial design and detect outcomes will remain challenging. This is an exciting area of intense research, and further work is needed to establish the most promising biomarkers for disease progression and their use in clinical care and future trials. Ultimately, a multimodal approach may yield the most accurate means of monitoring and predicting future progression towards vision-threatening, late-stage AMD. Plain Language Summary: Age-related macular degeneration, or AMD, is an eye disease that causes vision loss. Worldwide, the number of people with AMD is increasing. It is difficult for doctors to know who, among those with AMD, will get worse and lose some of their sight, and who will not. Researchers are trying to find early signs that predict whether AMD will get worse and ways to track AMD progression over time. These signs are known as "biomarkers." They can be structural (seen in the structures inside the eye), functional (a change in how well someone sees), genetic, or proteins found in the blood. Being able to identify people with AMD that are most at risk of losing their vision will help to make sure they get more frequent review so that interventions can be started quickly before vision is lost permanently. Some structural and functional biomarkers are already well known, while others may be useful and are being intensively researched. Changes in the blood markers need much more research to be useful. Researchers are also looking at how to combine data from different biomarkers. This may be a better way to follow worsening of AMD over time compared to using a single biomarker. In the future, we may also be able to use artificial intelligence to help combine all biomarker data. This is an exciting area of research that will be important to help improve the vision outcomes for people with AMD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a complex and multifactorial disease and a leading cause of irreversible blindness in the elderly population. The anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the management and prognosis of neovascular AMD (nAMD) and is currently the standard of care for this disease. However, patients are required to receive repeated injections, imposing substantial social and economic burdens. The implementation of gene therapy methods to achieve sustained delivery of various therapeutic proteins holds the promise of a single treatment that could ameliorate the treatment challenges associated with chronic intravitreal therapy, and potentially improve visual outcomes. Several early-phase trials are currently underway, evaluating the safety and efficacy of gene therapy for nAMD; however, areas of controversy persist, including the therapeutic target, route of administration, and potential safety issues. In this review, we assess the evolution of gene therapy for nAMD and summarize several preclinical and early-stage clinical trials, exploring challenges and future directions. [ABSTRACT FROM AUTHOR]

Background: The Age-Related Eye Disease Study 2 (AREDS 2) proved the benefit of vitamin and mineral supplementation in preventing advanced age-related macular degeneration (AMD). AREDS 2 supplements are indicated for patients with either bilateral intermediate AMD (AREDS category 3) or unilateral neovascular AMD (AREDS category 4). Aims: The aims of this telephone survey were to identify the rate of adherence of patients to AREDS 2 supplements and the factors associated with non-compliance in these patient groups. Methods: A patient telephone survey was conducted in an Irish tertiary care hospital. Patients were identified by chart review, and their AREDS categorization was reconfirmed. A telephone consultation was conducted with each patient to assess their compliance with the micronutrient supplements. Results: We identified 120 patients who met the AREDS criteria for supplementation. Of these, 103 patients were graded as category 4, and 17 patients were graded as category 3. Almost a fifth (18%) were current smokers. Under two-thirds (60%) of the patients were taking AREDS 2 supplements. Of the remainder, 83% of patients did not recall being advised of their benefit. The cost was cited by 10% of patients as a reason for non-compliance. Conclusion: The ophthalmologist not only has a duty of care to treat the neovascular complications of AMD, but they must also strive to improve patient compliance with AREDS supplements. The cessation of smoking needs to be actively promoted in order to stop preventable vision loss in patients with AMD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a chronic and progressive retinal degenerative disease of the macula that affects the elderly and causes impairment of central vision. AMD is a multifactorial disease that encompasses a complex interplay between aging, environmental risk factors, and genetic susceptibility. Chronic inflammation, lipid deposition, oxidative stress, and impaired extracellular matrix maintenance are strongly implicated in the pathogenesis of AMD. Advanced AMD can be classified into two types: dry and wet. Although dry AMD accounts for the majority of diagnosed cases, wet AMD is responsible for the majority of severe vision loss and usually occurs within weeks or months. Although neovascularization was the most common cause of severe vision loss, geographic atrophy, the most advanced form of dry AMD, can also cause significant vision loss. The medical treatment of neovascular AMD has seen significant progress due to the introduction of vascular endothelial growth factor (anti-VEGF) inhibitors, which have dramatically changed the prognosis of the disease. Research does not prove the need to change treatment methods in every patient, there may be occasions when patients with AMD show a more robust response to one anti-VEGF agent than another. Clinicians may consider alternatives to switching, such as increasing injection frequency, when managing a patient who appears to be unresponsive to therapy. In this regard, it may be helpful to have a patient return for evaluation 1 to 2 weeks after injection with repeat testing to assess whether there has been a reduction in subretinal fluid or retinal edema shortly after anti-VEGF injection.

Abstract Age-related macular degeneration (AMD) is a leading cause of severe vision loss worldwide, with a global prevalence that is predicted to substantially increase. Identifying early biomarkers indicative of progression risk will improve our ability to assess which patients are at greatest risk of progressing from intermediate AMD (iAMD) to vision-threatening late-stage AMD. This is key to ensuring individualized management and timely intervention before substantial structural damage. Some structural biomarkers suggestive of AMD progression risk are well established, such as changes seen on color fundus photography and more recently optical coherence tomography (drusen volume, pigmentary abnormalities). Emerging biomarkers identified through multimodal imaging, including reticular pseudodrusen, hyperreflective foci, and drusen sub-phenotypes, are being intensively explored as risk factors for progression towards late-stage disease. Other structural biomarkers merit further research, such as ellipsoid zone reflectivity and choriocapillaris flow features. The measures of visual function that best detect change in iAMD and correlate with risk of progression remain under intense investigation, with tests such as dark adaptometry and cone-specific contrast tests being explored. Evidence on blood and plasma markers is preliminary, but there are indications that changes in levels of C-reactive protein and high-density lipoprotein cholesterol may be used to stratify patients and predict risk. With further research, some of these biomarkers may be used to monitor progression. Emerging artificial intelligence methods may help evaluate and validate these biomarkers; however, until we have large and well-curated longitudinal data sets, using artificial intelligence effectively to inform clinical trial design and detect outcomes will remain challenging. This is an exciting area of intense research, and further work is needed to establish the most promising biomarkers for disease progression and their use in clinical care and future trials. Ultimately, a multimodal approach may yield the most accurate means of monitoring and predicting future progression towards vision-threatening, late-stage AMD.

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in the aging population, with vascular endothelial growth factor (VEGF) playing a key role. Treatment with recombinant anti-VEGFs is the current standard of care; however, it is only effective for 1–2 months at a time and requires re-administration. Gene therapy could pave the way for stable, long-term expression of therapeutic anti-VEGF with a single dose, reducing the frequency of treatment and potentially improving clinical outcomes. As such, we have developed OXB-203, a lentiviral-based gene therapy encoding the anti-VEGF protein aflibercept. Aflibercept derived from OXB-203 exhibited comparable in vitro binding characteristics to VEGF as recombinant aflibercept. Furthermore, its biological potency was demonstrated by the equivalent inhibition of VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and tubule formation as recombinant aflibercept. In a rat choroidal neovascularization (CNV) model of nAMD, a single subretinal administration of OXB-203 reduced laser-induced CNV lesion areas analogous to an intravitreal bolus of recombinant aflibercept. Finally, in a head-to-head comparative study, aflibercept derived from OXB-203 was shown to be expressed at significantly higher levels in ocular tissues than from an AAV8-aflibercept vector following a single subretinal delivery to rats. These findings support the therapeutic potential of OXB-203 for the management of nAMD.

Abstract Background Cataract and neovascular age-related macular degeneration (nAMD) often co-exist and both contribute to impaired vision. It has been debated whether cataract surgery can increase nAMD activity. The purpose of this retrospective study was to investigate the impact of cataract surgery on visual acuity, treatment intensity for nAMD and macular morphology in patients with on-going treatment for nAMD. Methods Data was obtained from the Swedish Macular Register, the Swedish National Cataract Register, optical coherence tomography (OCT) images and patient charts. All eyes were treated at the Department of Ophthalmology at the County Hospital of Västmanland, Västerås, Sweden. Follow-up was 6 months after surgery. The study was approved by the Swedish Ethical Review Authority. Results In total, 156 patients (168 eyes) were included. The mean age at cataract surgery was 82 (standard deviation, SD 6) years. Both distance and near visual acuity improved after surgery. Distance visual acuity increased from 59 (SD 12) to 66 (SD 15) letters ETDRS (P

Bhim Bahadur Rai,1,2 Deepa Rai,3 Ted Maddess1 1John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; 2Department of Ophthalmology, JDW National Referral Hospital, Thimphu, Bhutan; 3Warrigal Aged Care Facility, Calwell, ACT, AustraliaCorrespondence: Bhim Bahadur Rai, John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, ACT, 2601, Australia, Tel +61 2 61259253, Email bhim.rai@anu.edu.auPurpose: Ocular vascular diseases are common causes of visual impairment and blindness, for which anti-vascular endothelial growth factor (anti-VEGF) is the first-line therapy. Current study describes the profile of patients receiving intravitreal anti-VEGF injections (IVI), and gender variation in Bhutan. The study was designed to inform national health policy.Study Design: Retrospective cross-sectional study.Methods: We reviewed the surgical registers of the vitreoretinal (VR) units across Bhutan over three years. Patient demography, clinical findings, diagnostic tests performed, and diagnoses or indications for IVI were logged. A descriptive analysis was performed.Results: Despite limited availability of anti-VEGF, a total of 381 patients received IVI in operating theatres as mandated by the national guidelines. The majority of patients were males (230, 60.4%, p = 0.004). The mean age was 65.2 ± 13.5 years (range 13 years to 90 years), and a median of 69 years. The majority of the treated eyes (117, 30.7%) had BCVA < 3/60 to light perception (PL), and another 51 eyes (13.4%) had < 6/60 to 3/60. The most common indication for IVI was neovascular age-related macular degeneration (nAMD) (168 cases, 42.2%), followed by retinal vein occlusion (RVO) (132 cases, 34.6%), diabetic macular oedema (DMO) and retinopathy (DR) (50 cases, 13.1%), and myopic choroidal neovascular membrane (11 cases, 0.03%).Conclusion: Limited human resources for managing VR diseases in Bhutan are compounded by economic and geographic challenges. With increasing VR diseases such as nAMD and myopia and complications of systemic diseases such as DR, DMO and RVO, there is a need to improve VR services. Currently, anti-VEGF is procured only for a pooled patients requiring IVI, and patients are lost due to longer waiting periods. Bhutan needs to assess if females are reporting less or are not receiving treatment due to cultural barriers and social stigma.Keywords: anti-VEGF, Bhutan retinal diseases, diabetic macular oedema, intravitreal injection, neovascular AMD, retinal vein occlusion

The editorial discusses new approaches in managing submacular hemorrhages, a vision-threatening complication of neovascular age-related macular degeneration. Various treatment options, including anti-VEGF therapy and surgical interventions, are explored to preserve visual function. The need for individualized treatment plans and ongoing research, such as the TIGER study, to determine optimal approaches for different submacular hemorrhages is emphasized. The integration of tissue plasminogen activator with anti-VEGF therapies shows promise in improving visual outcomes, highlighting the importance of early intervention and continued post-surgery care. [Extracted from the article]

Age-related macular degeneration (AMD) is a leading cause of vision loss among elderly people in developed countries. Neovascular AMD (nAMD) accounts for more than 90% of AMD-related vision loss. At present, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is widely used as the first-line therapy to decrease the choroidal and retinal neovascularizations, and thus to improve or maintain the visual acuity of the patients with nAMD. However, about 1/3 patients still progress to irreversible visual impairment due to subretinal fibrosis even with adequate anti-VEGF treatment. Extensive literatures support the critical role of epithelial-mesenchymal transformation (EMT) of retinal pigment epithelium (RPE) in the pathogenesis of subretinal fibrosis in nAMD, but the underlying mechanisms still remain largely unknown. This review summarized the molecular pathogenesis of subretinal fibrosis in nAMD, especially focusing on the transforming growth factor-β (TGF-β)-induced EMT pathways. It was also discussed how these pathways crosstalk and respond to signals from the microenvironment to mediate EMT and contribute to the progression of nAMD-related subretinal fibrosis. Targeting EMT signaling pathways might provide a promising and effective therapeutic strategy to treat subretinal fibrosis secondary to nAMD.

To determine the incidence of being lost to follow-up (LTFU) and nonpersistence in patients with neovascular age-related macular degeneration (AMD) treated with anti–VEGF injections in the United States. Retrospective cohort study using the IRIS® (Intelligent Research in Sight) Registry data. One hundred fifty-six thousand three hundred twenty-seven treatment-naive patients with neovascular AMD who subsequently were treated with anti-VEGF therapy from 2013 through 2015 and followed up through 2019. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Being LTFU was defined as no follow-up within 12 months from last intravitreal injection. Nonpersistence was defined as no follow-up within 6 months from last intravitreal injection. For neovascular AMD, 11.6% of patients (95% CI, 11.4%–11.7%) were LTFU, and 88.4% of patients were followed up within 12 months. The rate of being LTFU generally was higher with increasing age, with odds of being LTFU greatest for patients between 81 and 84 years of age (OR, 2.51; 95% CI, 2.31–2.74; P < 0.001) compared with patients 70 years of age and younger. Odds of being LTFU for Black or African American patients (OR, 1.32; 95% CI, 1.08–1.61; P = 0.007) were greater than for White patients. Odds of being LTFU were higher for patients with Medicaid insurance (OR, 1.27; 95% CI, 1.01–1.60; P = 0.04) and lower for patients with Medicare Fee-For-Service insurance (OR, 0.69; 95% CI, 0.64–0.74; P < 0.001) than for patients with private insurance. Furthermore, 14.3% (95% CI, 14.1–14.4) of patients were nonpersistent, and 85.7% of patients underwent follow-up within 6 months. Odds of nonpersistence also were greatest among patients between 81 and 84 years of age (OR, 2.13; 95% CI, 1.98–2.29; P < 0.001) compared with patients 70 years of age or younger. Odds of nonpersistence for Black or African-American patients (OR, 1.38; 95% CI, 1.15–1.65; P < 0.001) and Hispanic patients (OR, 1.13; 95% CI, 1.03–1.24; P = 0.009) were greater than odds for White patients. Nearly 1 of 9 patients with neovascular AMD treated with anti-VEGF injections became LTFU, whereas 1 of 7 patients were nonpersistent. Risk factors identified included increasing age, male sex, unilateral involvement, diabetes, Medicaid insurance, and race or ethnicity. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Background: Cataract and neovascular age-related macular degeneration (nAMD) often co-exist and both contribute to impaired vision. It has been debated whether cataract surgery can increase nAMD activity. The purpose of this retrospective study was to investigate the impact of cataract surgery on visual acuity, treatment intensity for nAMD and macular morphology in patients with on-going treatment for nAMD. Methods: Data was obtained from the Swedish Macular Register, the Swedish National Cataract Register, optical coherence tomography (OCT) images and patient charts. All eyes were treated at the Department of Ophthalmology at the County Hospital of Västmanland, Västerås, Sweden. Follow-up was 6 months after surgery. The study was approved by the Swedish Ethical Review Authority. Results: In total, 156 patients (168 eyes) were included. The mean age at cataract surgery was 82 (standard deviation, SD 6) years. Both distance and near visual acuity improved after surgery. Distance visual acuity increased from 59 (SD 12) to 66 (SD 15) letters ETDRS (P < 0.001). Proportion of eyes with normal near visual acuity increased from 12 to 41%. The anti-vascular endothelial growth factor (VEGF) treatment intensity remained unchanged: mean of 3.4 (SD 1.9) and 3.3 (SD 1.7) treatments were given 6 months pre- and postoperatively, respectively. The prevalence of intraretinal fluid (IRF) in the macula increased from 22 to 31% postoperatively, while subretinal fluid, fluid under the pigment epithelium (sub-RPE fluid) and central retinal thickness were unaltered. In eyes with new IRF, improvement in visual acuity and number of anti-VEGF treatments were similar to eyes without new IRF. Conclusion: Cataract surgery improved visual acuity in patients with on-going treatment for nAMD and did not affect anti-VEGF treatment intensity. Macular morphology remained unchanged. The slight increase in intraretinal fluid after surgery was not found to affect visual acuity or anti-VEGF treatment intensity. It is hypothesized that this might indicate that it represents degenerative intraretinal cystic fluid. Key messages: • It has been demonstrated that cataract surgery in eyes with nAMD improves distance visual acuity • In this study in eyes with on-going anti-VEGF treatment for nAMD, cataract surgery improved both distance and near visual function. • Cataract surgery did not affect anti-VEGF treatment intensity over 6 months postoperatively. • A slight increase in new intraretinal fluid, which was observed at 6 months, did not affect neither the visual outcome nor the anti-VEGF treatment intensity after surgery and possibly represents degenerative intraretinal cystic fluid. [ABSTRACT FROM AUTHOR]

Purpose: Patients with extensive submacular hemorrhage (SMH) caused by age-related macular degeneration (AMD) have a poor visual prognosis despite surgical intervention. Systemic blood-thinning drugs, which are commonly prescribed in the same age group, are known to increase the risk of severe hemorrhage in many parts of the body. This study aimed to investigate whether systemic blood-thinning drugs have an impact on the severity of SMH and if there are differences between the different types of blood-thinning medication. Methods: We reviewed the medical records of patients who suffered from surgically treated SMH between 2020 and 2022. All patients received a full ophthalmologic examination upon presentation including best-corrected visual acuity (BCVA) and optical coherence tomography. Other characteristics that were recorded included size of hemorrhage, blood-thinning therapy, and reason for intake. Results: A total of 115 patients with a mean age of 82 years were included in this retrospective analysis. Eighty-three patients (72.2%) were on blood-thinning therapy. The mean size of SMH was 32.01 mm2. Mean BCVA at initial presentation was 1.63 logMAR and 1.59 logMAR 1 year after surgery. The size of SMH was significantly larger in patients on blood-thinning medication (35.92 mm2 vs. 21.91 mm2) (p = 0.001) and their BCVA postoperatively was worse with 1.68 logMAR compared to 1.30 logMAR after 1 year (p = 0.503). Patients with vitamin K antagonists had larger SMH size and worse outcomes regarding BCVA compared to direct oral anticoagulants. Conclusion: Blood thinners in patients with AMD affect the severity of SMH. Consequently, the indication for their intake should be critically evaluated. [ABSTRACT FROM AUTHOR]

Purpose: This study seeks to report the clinical and multimodal imaging findings of eight eyes of seven patients with neovascular age-related macular degeneration (nAMD) who developed bacillary layer detachment (BALAD). Setting/Venue: The patients were analysed at the Western Eye Hospital in London, UK. Methods: The approaches of this research include clinical examinations and multimodal imaging-based description of cases of nAMD with BALAD. Results: We report multimodal imaging findings of bacillary layer detachment (BALAD) in patients with nAMD. Conclusions: A bacillary layer detachment was detected in patients with neovascular age-related macular degeneration. This multimodal imaging finding is not commonly described in the literature for this disease. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a multifactorial genetic disease, with at least 52 identifiable associated gene variants at 34 loci, including variants in complement factor H (CFH) and age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase-1 (ARMS2/HTRA1). Genetic factors account for up to 70% of disease variability. However, population-based genetic risk scores are generally more helpful for clinical trial design and stratification of risk groups than for individual patient counseling. There is some evidence of pharmacogenetic influences on various treatment modalities used in AMD patients, including Age-Related Eye Disease Study (AREDS) supplements, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (anti-VEGF) agents. However, there is currently no convincing evidence that genetic information plays a role in routine clinical care.

Age-related macular degeneration (AMD) is a complex and multifactorial disease and a leading cause of irreversible blindness in the elderly population. The anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the management and prognosis of neovascular AMD (nAMD) and is currently the standard of care for this disease. However, patients are required to receive repeated injections, imposing substantial social and economic burdens. The implementation of gene therapy methods to achieve sustained delivery of various therapeutic proteins holds the promise of a single treatment that could ameliorate the treatment challenges associated with chronic intravitreal therapy, and potentially improve visual outcomes. Several early-phase trials are currently underway, evaluating the safety and efficacy of gene therapy for nAMD; however, areas of controversy persist, including the therapeutic target, route of administration, and potential safety issues. In this review, we assess the evolution of gene therapy for nAMD and summarize several preclinical and early-stage clinical trials, exploring challenges and future directions.

PurposeTo 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).MethodsIn 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.ResultsThirty-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.ConclusionIn 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.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells in vitro but did not enhance VEGF suppression in mouse eyes in vivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that in vivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear.

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]

Currently, there is a wide range of antiglaucoma drugs. Ophthalmologists are faced with the task of choosing certain drugs and their combinations for specific patients. In this regard, studies aimed at studying the effectiveness of treatment, not only in terms of IOP indicators and instrumental research methods, but also in terms of the choice of a particular type of therapy by ophthalmologists, are of great interest. Purpose: to analyze the data obtained in the course of the study of the Russian multicenter scientific program: “Analysis of the assortability of ophthalmologists when choosing therapy within the framework of routine medical care in patients with primary open-angle glaucoma (POAG)”. The large-scale statistical study carried out was based on the study of 197 medical questionnaires from 61 cities of Russia, containing information on 6851 clinical cases. Doctors were asked to fill out a questionnaire based on the results of treatment (at least 2 months), taking into account the following criteria: satisfaction with treatment, adherence to treatment, accessibility, tolerability and ease of use of drugs. Evaluated the use of 5 antiglaucoma drugs of the company Sentiss Russ, belonging to different pharmacological groups: Prolatan (latanoprost), Bimatan (bimatoprost), Brinex-M (brinzolamide); Tisoptan (bimatoprost / timolol maleate), Brinarga (brinzolamide / timolol maleate). During the study, patients were divided into 6 groups depending on the drug used, and also into 3 groups depending on the stage of primary POAG. The data obtained indicate a statically high level of average values when using the point system of all the above criteria when using these drugs. When analyzing the degree of convenience and the level of tolerance of drugs, a tendency towards a decrease in the average scores of these indicators in patients with advanced stage of glaucoma was noted, which may be due to the long-term use of antiglaucoma therapy in this category of patients with changes in the ocular surface. 98.25% of doctors expressed their intention to continue prescribing antiglaucoma drugs from Sentiss Russ.

Colin S Tan,1,2 Wei Kiong Ngo,1,2 Isaac W Chay,1,2 Dominic S Ting,1,2 SriniVas R Sadda3 1National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore; 2Fundus Image Reading Centre, National Healthcare Group Eye Institute, Singapore; 3Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USACorrespondence: SriniVas R Sadda, Doheny Image Reading Center, Doheny Eye Institute, 3623, 1450 San Pablo Street, Los Angeles, CA, 90033, USA, Email sadda@usc.eduAbstract: Neovascular age-related macular degeneration (nAMD) is a common world-wide cause of visual loss. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are an effective means to treat nAMD and reduce its impact on vision compared to either sham treatment or photodynamic therapy. Currently, the approved anti-VEGF drugs include ranibizumab, aflibercept and brolucizumab. In addition, bevacizumab, used as an off-label drug, and has been shown to be effective in treating nAMD. While anti-VEGF agents are effective, its limitations include the requirement for frequent, often monthly injections, and the need for long-term treatment of nAMD. These present significant burdens on the healthcare system and on the patients. In addition, reviews of patients with nAMD treated with anti-VEGF have reported deterioration of vision over time with progression of geographic atrophy. These limitations are partly addressed by exploring different treatment regimens that reduce the frequency of treatments. Newer anti-VEGF drugs have been shown in Phase III clinical trials to have injection intervals as long as 12 or even 16 weeks for a proportion of patients. There is research on newer drugs that affect other pathways, such as the angiopoietin pathway, which may impact nAMD by extending the treatment interval and reducing the burden of treatment. Other measures include the use of sustained-release implants that release the drug regularly over a period of time, and can be refilled periodically, as well as hydrogel platforms that serve to release the drug. The use of biosimilars will also serve to reduce the cost of treatment for nAMD. A new frontier of gene therapy, primarily targeting genes involved in the transduction of retinal cells to produce anti-VEGF proteins intraocularly, also opens a new avenue of therapeutic approaches that can be used for treatment. This review paper will discuss both current treatment options and the newer treatments under development.Keywords: neovascular AMD, anti-VEGF, retina, gene therapy

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.

PurposeAutomated 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.MethodsThirty 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.ResultsNeovascular 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).ConclusionDiffuse 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.

Age-related macular degeneration AMD is one of the leading causes of blindness in the elderly population. An advanced form of AMD known as neovascular AMD (nAMD) is implicated as the main attributor of visual loss among these patients. The hallmark feature of nAMD is the presence of neovascular structures known as choroidal neovascular membranes (CNVs), along with fluid exudation, hemorrhages, and subretinal fibrosis. These pathological changes eventually result in anatomical and visual loss. A type of proangiogenic factor known as vascular endothelial growth factor (VEGF) has been known to mediate the pathological process behind nAMD. Therefore, therapy has transitioned over the years from laser therapy that ablates the lesions to using Anti-VEGF to target the pathology directly. In this work, we provide an overview of current and emerging therapies for the treatment of nAMD. Currently approved Anti-VEGF agents include ranibizumab, aflibercept, and brolucizumab. Bevacizumab, also an Anti-VEGF agent, is used to manage nAMD even though this is an off-label use. While Anti-VEGF agents have provided a favorable prognosis for nAMD, they are associated with a substantial financial burden for patients and the healthcare system, due to their high cost as well as the need for frequent repeat treatments and visits. Emerging therapies and studies aim to extend the intervals between required treatments and introduce new treatment modalities that would improve patients' compliance and provide superior results. [ABSTRACT FROM AUTHOR]

Purpose: To explore the comparative efficacy and safety of higher dose intravitreal bevacizumab, ranibizumab, or aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD). Methods: Retrospective analysis of 37 eyes of 35 patients with treatment-resistant nAMD divided into 3 cohorts based on high-dose treatment received: 3 mg aflibercept, 0.75 mg or 1.0 mg ranibizumab, and 1.8 mg or 2.5 mg bevacizumab. The eyes were analyzed at standardized time points up to 48 months. Included eyes demonstrated active nAMD with persistent exudation on imaging for at least 6 months with at least 4 anti-VEGF injections during this time. Outcomes included change in visual acuity (VA), central retinal thickness (CRT), intraocular pressure (IOP), retinal morphology, adverse event occurrence, and yearly intravitreal injection (IVI) rate. Results: There was no significant difference in VA or IOP change compared to the initiation of high-dose treatment for any agent or comparing between agents at any time point (p > 0.05). CRT improved at month 1, 3, 6, and 12 with all 3 agents (p < 0.05 for all) with a greater CRT reduction seen for ranibizumab than aflibercept at month 6 (p < 0.05), although baseline CRT was greater in the ranibizumab group than the aflibercept group (p < 0.05). Mean absolute CRT was similar at month 6 for all agents (p > 0.05). IVI rates pre- and post-conversion to higher-dose therapy were similar (1 injection per 5.7–6.4 weeks). Mean follow-up was 22.8 months. Conclusions: Higher dose therapy may achieve improved anatomic outcomes and maintain vision, but frequent injections are required to achieve this. There was no detected difference in efficacy or safety between agents. [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]

Purpose: This study seeks to report the clinical and multimodal imaging findings of eight eyes of seven patients with neovascular age-related macular degeneration (nAMD) who developed bacillary layer detachment (BALAD). Setting/Venue: The patients were analysed at the Western Eye Hospital in London, UK. Methods: The approaches of this research include clinical examinations and multimodal imaging-based description of cases of nAMD with BALAD. Results: We report multimodal imaging findings of bacillary layer detachment (BALAD) in patients with nAMD. Conclusions: A bacillary layer detachment was detected in patients with neovascular age-related macular degeneration. This multimodal imaging finding is not commonly described in the literature for this disease.

This study estimated the outcome of delayed intravitreal anti-vascular endothelial growth factor (VEGF) therapy due to the coronavirus (COVID-19) disease pandemic on the prognosis of patients with neovascular age-related macular degeneration (nAMD). This study retrospectively enrolled 57 nAMD patients whose intravitreal anti-VEGF injections were delayed for >2 weeks between February and June 2020. Best-corrected visual acuity (BCVA), central subfield thickness (CST), and anatomical characteristics were evaluated before (baseline), on the day, and at 2, 4, and 6 months after the delayed injection, and risk factors were identified. The average injection interval before and after treatment delay was 3.05 ± 1.45 and 2.41 ± 1.46 months, respectively (p = 0.002). The CST at baseline and on the day of delayed injection was 227.82 ± 62.46 and 267.26 ± 77.74 µm, respectively (p < 0.001). The average BCVA decreased from 0.29 ± 0.29 logMAR (baseline) to 0.38 ± 0.31 logMAR (6 months) (p = 0.001). The maximum subretinal fluid (SRF) height increased from 84.32 ± 89.33 µm (baseline) to 121.38 ± 103.36 µm (6 months) (p = 0.027). A higher baseline maximum SRF height was associated with less SRF height deterioration 6 months later (p < 0.001). Delayed intravitreal anti-VEGF therapy caused by the COVID-19 pandemic has worsened BCVA and residual SRF in nAMD patients after a temporary recovery. The baseline SRF reduce the degree of SRF height deterioration. [ABSTRACT FROM AUTHOR]

Red-green chromatic sensitivity and photopic (cone-mediated) flicker sensitivity showed marked improvement after anti-VEGF treatment. The use of flicker and chromatic sensitivities as potential functional tests to monitor treatment outcomes in age-related macular degeneration highlights the clinical importance. High-contrast visual acuity (VA) is not a sensitive clinical marker in the management of age-related macular degeneration (AMD). Therefore, flicker and chromatic sensitivity changes were assessed following anti-VEGF treatment in subjects with neovascular AMD. Subjects diagnosed with neovascular AMD were recruited. VA was measured using a COMPlog chart. Flicker (in central 5°) and chromatic thresholds (red-green and yellow-blue) were measured using Flicker-plus test and Colour Assessment and Diagnosis (CAD) tests, respectively. Baseline thresholds and foveal thickness were measured on the same day, just before anti-VEGF injection delivery and 5 weeks ± 5 days later. Thirteen subjects (8 males, 5 females) with a mean age of 67.5 ± 8.2 years completed the study. Median VA was not significantly different post-treatment (0.57 logMAR [~6/22: Snellen equivalent], IQR: 0.33) compared to baseline (0.56 logMAR, IQR: 0.33), Wilcoxon matched-pair test, p = 0.55). Median Red-Green thresholds improved significantly post-treatment (22.15 CAD units, IQR: 26.06, n = 9), compared to baseline (24.24 CAD units, IQR: 26.21, p = 0.02). Median photopic and mesopic FMT did not show significant change post treatment compared to baseline (p > 0.01, statistical significance of p-value corrected for multiple comparisons was set to 0.01). Similarly, the foveal thickness was not significantly different at post-treatment visit than baseline (p = 0.53). Red/green sensitivity recovered better than yellow/blue sensitivity, thus, providing insight into recovery mechanisms in AMD and usefulness of these tests as clinical markers in the management of AMD. [ABSTRACT FROM AUTHOR]

Background To study the visual outcomes of neovascular AMD (nAMD) treated with anti‐vascular endothelial growth factor (VEGF) drugs at national level. Methods: Multicenter national database of nAMD eyes treated with anti‐VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) in fixed bimonthly (FB) or treat‐and‐extend (TAE) regimens. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) ETDRS letters at baseline and subsequent visits, number of injections and visits data were collected using a validated web‐based tool (Fight Retinal Blindness!). Results: 1273 eyes (1014 patients) were included, 971 treatment naïve (TN) and 302 previously treated (PT). Baseline VA (mean ± SD) was 57.5 (±19.5) and 62.2 (±17) (p > 0.001), and 24 months final VA was 60.4 (±21.2) and 58.8 (±21.1) (p = 0.326), respectively. Mean VA change at 12/24 months was +4.2/+2.9 letters in TN eyes and +0.1/−3.4 letters in PT eyes (p < 0.001/p < 0.001). The percentage of ≥15 letters gainers/losers at 24 months was 24.8%/14.5% in TN, and 10.3%/15.7% in PT eyes. The median number of injections/visits at 12 months was 7/9 in TN and 6/8 in PT (p = 0.002/p < 0.001) and at 24 months was 11/16 in TN and 11/14 in PT (p = 0.329/p < 0.001). Study drugs included ranibizumab (39.5%), aflibercept (41.2%) and bevacizumab (19.3%). Conclusion: Independent, large‐scale national audits are feasible if committed health care professionals are provided with efficient information technology systems to do them. The results described here represent an adequate measurement of the quality of care delivered nationwide and benchmark the clinical management of nAMD at a country level compared to other real‐world international cohorts. [ABSTRACT FROM AUTHOR]

Purpose: The number of patients receiving anti‐VEGF therapy has increased rapidly since its introduction in Denmark in 2007, placing an enormous pressure on the public healthcare system. In this study, we attempt to describe this growth and identify the factors driving it. Methods: Data on treatment of the entire population of neovascular AMD patients in the Capital Region of Denmark between 2007 and 2019 was retrieved. The age and sex standardized incidences of first time treatment and changes in duration of treatment were analysed. Results: The number of patients in active treatment increased from 576 in 2007 to 3684 in 2019. The growth was initially driven by accumulation of patients continuing anti‐VEGF therapy for extended periods of time (259 patients/year). As larger numbers of patients began to be discharged, the increase slowed to 181 patients/year in late 2010s, with demographic change becoming the main growth driving factor. The incidence of first treatment increased slightly during the study period, mainly for individuals over 85 years. For patients under 85 years, treatment incidences closely followed neovascular AMD incidences from population studies. The likelihood of remaining in anti‐VEGF treatment after the initial injection followed exponential decay curve (t1/2 = 3.6 years). Based on this observation, a model was created to describe the number of patients in active treatment, which accurately described historical data (R2 = 0.999), and forecast a linear growth of 138 patients/year until 2030. Conclusion: Treatment incidences and modelling reported in this study might facilitate a more informed and accurate planning of future ophthalmology services. [ABSTRACT FROM AUTHOR]

Abstract We summarize the most important findings presented at the 2020 angiogenesis, exudation and degeneration symposium in five topic areas: (1) epidemiology of retinal vascular disease and macular degeneration; (2) dry AMD and geographic atrophy; (3) neovascular age-related macular degeneration; (4) drug delivery and devices and (5) diabetic retinopathy.

Objective: To evaluate the incidence of bacillary layer detachment in patients with neovascular age-related macular degeneration (nAMD) and their response to anti-VEGF therapy., Design: Post hoc analysis of the brolucizumab 6-mg and aflibercept 2-mg arms from the HAWK clinical trial, a 48-week, prospective, double-masked, phase III trial., Participants: Participants (n = 652 and 652 eyes) randomized to brolucizumab 6-mg and aflibercept 2-mg arms from HAWK (NCT02307682)., Methods: Spectral-domain OCT scans were obtained at 4-week intervals throughout the HAWK trial and segmented automatically using a proprietary, machine learning-enabled, higher-order feature extraction platform., Main Outcome Measures: The incidence of bacillary layer detachment and effect of anti-VEGF therapy in these eyes on best-corrected visual acuity (BCVA), central subfield thickness (CST), retinal fluid volumes, subretinal hyper-reflective material (SHRM) volume, and ellipsoid zone (EZ) integrity from baseline to week 48., Results: Classic bacillary layer detachment was identified in 7.2% (47/652) of eyes, demonstrating worse BCVA and higher CST, EZ total attenuation, subretinal fluid (SRF), and SHRM volume at baseline than eyes without bacillary layer detachment. Anti-VEGF treatment resulted in resolution of bacillary layer detachment in 97.9% of eyes by week 48. In eyes with bacillary layer detachment, anti-VEGF treatment improved BCVA and decreased SRF and SHRM volume; however, eyes with bacillary layer detachment never reached the level of BCVA improvement as eyes without bacillary layer detachment. A greater proportion of eyes with bacillary layer detachment had high-exudative volatility (increased mean standard deviation after loading dose) of CST, SRF, and total fluid than eyes without bacillary layer detachment (P < 0.05 for each comparison)., Conclusions: Bacillary layer detachment, an OCT signature representing photoreceptor schisis, is identifiable in a notable proportion of eyes with nAMD. Anti-VEGF therapy resulted in a very high proportion of bacillary layer detachment resolution with significantly decreased SRF and SHRM volumes. The majority of eyes with bacillary layer detachment have high-exudative volatility, which may be associated with lower BCVA outcomes. The presence of bacillary layer detachment may provide an important imaging biomarker to be considered for clinical trial inclusion/exclusion based on trial design and therapeutic goals because of its unique behavior., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Neovascular age-related macular degeneration (AMD) can lead to rapid, irreversible vision loss in untreated eyes. While the pathogenesis of neovascular AMD remains incompletely understood, the choriocapillaris has been hypothesized as the initial site of injury. Due to limitations of dye-based angiography, in vivo imaging of the choriocapillaris has been a longstanding challenge. However, the clinical introduction of optical coherence tomography angiography (OCTA) has enabled researchers and clinicians to noninvasively image the choriocapillaris vasculature, allowing the evaluation of the choriocapillaris in eyes with a variety of pathologies. In this perspective, we review important OCTA-based findings regarding choriocapillaris impairment in neovascular AMD and discuss limitations and future directions of OCTA technologies in the context of this disease. [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]

Age-related macular degeneration AMD is one of the leading causes of blindness in the elderly population. An advanced form of AMD known as neovascular AMD (nAMD) is implicated as the main attributor of visual loss among these patients. The hallmark feature of nAMD is the presence of neovascular structures known as choroidal neovascular membranes (CNVs), along with fluid exudation, hemorrhages, and subretinal fibrosis. These pathological changes eventually result in anatomical and visual loss. A type of proangiogenic factor known as vascular endothelial growth factor (VEGF) has been known to mediate the pathological process behind nAMD. Therefore, therapy has transitioned over the years from laser therapy that ablates the lesions to using Anti-VEGF to target the pathology directly. In this work, we provide an overview of current and emerging therapies for the treatment of nAMD. Currently approved Anti-VEGF agents include ranibizumab, aflibercept, and brolucizumab. Bevacizumab, also an Anti-VEGF agent, is used to manage nAMD even though this is an off-label use. While Anti-VEGF agents have provided a favorable prognosis for nAMD, they are associated with a substantial financial burden for patients and the healthcare system, due to their high cost as well as the need for frequent repeat treatments and visits. Emerging therapies and studies aim to extend the intervals between required treatments and introduce new treatment modalities that would improve patients’ compliance and provide superior results.

Purpose: To assess disease stability (absence of intra- and/or subretinal fluid) and the portion of eyes being capable to extend their treatment interval to ≥ 12 weeks in exudative age-related macular degeneration (AMD). Methods: A systematic literature search was performed in NCBI, PubMed, CENTRAL, and ClinicalTrials.gov to identify clinical studies reporting treatment outcomes for ranibizumab, aflibercept, and brolucizumab in exudative AMD under a treat-and-extend protocol and a follow-up of ≥ 12 months. Weighted mean differences and subgroup comparisons were used to integrate the different studies. Results: This meta-analysis refers to 29 published series, including 27 independent samples and 5629 patients. In the pooled group, disease stability was reported in 62.9% and 56.0%, respectively, after 12 and 24 months of treatment, whereas treatment intervals were extended to ≥ 12 weeks in 37.7% and 42.6%, respectively. Ranibizumab, aflibercept, and brolucizumab differed regarding their potential to achieve disease stability (56.3%, 64.5%, and 71.5% after 12, and 50.0%, 52.7% and 75.7% after 24 months; p = < 0.001) and to allow an interval extension to ≥ 12 weeks (28.6%, 34.2%, and 53.3% after 12, and 34.2%, 47.7%, and 41.7% after 24 months; p = < 0.001). Conclusion: The portion of eyes achieving disease stability regressed in the second year, whereas the portion of eyes under a ≥ 12-week interval increased. This discrepancy may reflect the challenges in balancing between under-treatment and a reduced treatment burden. [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.