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Background/objectives: To compare the prevalence of intra-ocular inflammation (IOI) between brolucizumab and aflibercept in neovascular age-related macular degeneration (nAMD) after intra-vitreal injections (IVI) and to compare the IOI odds ratios (ORs) of both therapies with the prevalence of septic endophthalmitis after IVI that was previously reported in the literature. Methods: A total of 468 IVI of brolucizumab (117 eyes) were compared with 2884 IVI of aflibercept (305 eyes) regarding IOI and occlusive retinal vasculitis (RV) from December 2021 to June 2023 in this retrospective study. The OR was calculated for both anti-VEGF agents and was compared with the relative risk of septic endophthalmitis after IVI. Results: There were four eyes with unilateral IOI related to brolucizumab (3.42%), one presenting uveitis (0.85%), two vitritis (1.71%) and the last one presenting occlusive RV (0.85%), compared with two eyes presenting unilateral IOI (anterior uveitis, 0.66%) and none with RV from the aflibercept cohort. The incidence of IOI per injection with brolucizumab (0.855%) was significantly higher compared with aflibercept (0.069%, p = 0.004). The OR of IOI related to brolucizumab IVI compared with septic endophthalmitis was 20 times greater (1.49 for aflibercept, p = 0.646, versus 20.15 for brolucizumab, p < 0.001). The OR of RV with brolucizumab compared with septic endophthalmitis was 4.6. Conclusion: Data from our department suggest a much higher risk of IOI and occlusive retinal vasculitis after brolucizumab when compared with aflibercept. The risk of IOI and severe sight-threatening complications related to brolucizumab is greater than the risk of septic endophthalmitis after any IVI. [ABSTRACT FROM AUTHOR]

Purpose: To assess the short-term outcomes of intravitreal faricimab (IVF) for previously treated refractory neovascular age-related macular degeneration (nAMD) in a real-world setting. Methods: A retrospective monocentric study including 44 eyes treated with an upload of 4 × monthly intravitreal injections (IVI) of faricimab 6 mg/0.05 mL and followed for 4 weeks after last IVI (16 W). Patients were switched to IVF after treatment with at least three other anti-vascular endothelial growth factors (anti-VEGF). Main outcome measures included best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT) and retinal fluid distribution. Results: 44 eyes of 44 patients with previously treated refractory nAMD (63% males) were included. Mean age was 79 ± 7 years. The total number of previous anti-VEGF before switching to IVF was 32 ± 15 IVIs/eye. BCVA (logMAR) improved significantly from 0.65 ± 0.26 to 0.50 ± 0.23 at 16 W (p <0.01). CMT (µm) decreased significantly from 422 ± 68 to 362 ± 47 at 16 W (p < 0.01). SFCT did not change significantly at 16 W (p = 0.06). The number of eyes with subretinal fluid (SRF) decreased significantly from 29 (65%) to 13 (29%) at 16 W (p =0.001). There were no significant changes regarding the distribution of intraretinal fluid or pigment epithelial detachment (p > 0.05). A complete fluid resolution was achieved in 8 eyes (18%). No adverse events were noticed. Conclusion: In the short term, IVF led to a significant decrease in CMT as well as a significant improvement of BCVA and thus appears to be an effective treatment option for previously treated refractory nAMD without relevant adverse effects. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the potential of microRNAs (miRNAs) in tears, blood, and aqueous humor as biomarkers for predicting treatment response in wet age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy. Methods: In a single-center prospective cohort study, treatment-naïve wet AMD patients and age-matched controls were enrolled. Clinical data and miRNA levels (miR-199a-3p, miR-365-3p, miR-200b-3p, miR-195-5p, miR-335-5p, and miR-185-5p) in tears, blood, and aqueous humor were collected. Treatment response was categorized into responders and non-responders based on visual acuity and central subfield thickness. MiRNA levels were quantified using reverse-transcription PCR. Statistical analyses were performed, including ROC analysis, to evaluate predictive accuracy. Results: Dysregulated miRNA profiles were observed in wet AMD tears and blood compared to controls. Specifically, miR-199a-3p, miR-195-5p, and miR-185-5p were upregulated, while miR-200b-3p was downregulated in tears. All six miRNAs were elevated in wet AMD blood samples. Notably, responders showed higher tear expression of miR-195-5p and miR-185-5p. Combining these miRNAs yielded the highest predictive power (AUC = 0.878, p = 0.006) for anti-VEGF responders. Conclusions: Dysregulated miRNA profiles in tears and blood suggest their potential as biomarkers for wet AMD. MiR-195-5p and miR-185-5p in tears demonstrate predictive value for anti-VEGF treatment responders. This study underscores the non-invasive prediction potential of miRNA tear analysis in wet AMD treatment responses. [ABSTRACT FROM AUTHOR]

Purpose: To assess intra‐ (repeatability) and inter‐observer (reproducibility) variability of laser speckle flowgraphy (LSFG) for retinal blood flow (RBF) measurement in 20 eyes of wild type (C57BL/6J) mice and effect of intravitreal Aflibercept on RBF in optic nerve head (ONH) region of 10 eyes of Ins2 (Akita) diabetic mice. Methods: 'Mean blur rate (MBR)' was measured for all quadrants of tissue area (MT), vessel (MV) and total area (MA) of ONH region. Changes in MT were analysed at each timepoint. Repeatability was evaluated by measuring MBR variability without changing mouse head position, and reproducibility after resetting mouse head position by another operator. Coefficient of repeatability (CR) through Bland–Altman plot method coefficient of variation (COV) and Intraclass correlation coefficient (ICC) was calculated. Intravitreal Aflibercept (1 μg) was administered to Akita eyes and intraocular pressure (IOP) was measured using a tonometer at baseline, day 7, 14, 21 and 28 post‐injection. Hurvich and Tsai's criterion was used. Results: Coefficient of repeatability values of repeatability and reproducibility for all quadrants were within limits of agreement. Reliability was excellent (ICC 0.98–0.99) and reproducibility was moderate to excellent (ICC 0.64–0.96). There was a non‐significant IOP increase in all Akita eyes at Day 28 (p > 0.05), and significant increase in MT in all quadrants at Day 21 and superior, inferior and temporal quadrants at Day 28 (p < 0.05). Conclusion: Laser speckle flowgraphy demonstrates excellent repeatability and moderate to excellent reproducibility in measuring RBF. Intravitreal Aflibercept injection results in a significant increase in MT up to 28 days post‐injection without significant increase in IOP. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to examine and compare the effects of intravitreal bevacizumab injection (IVB) at subfoveal 1500 micron (μm) and submacular 6000 μm in patients with diabetic macular edema (DME). Methods: Fifty eyes of 45 patients with DME who completed six doses of IVB were included in the study group, and 50 eyes of 42 patients who had diabetic retinopathy (DR) but did not receive any treatment were included in the control group. Central macular thickness (CMT), central choroidal thickness (CCT), subfoveal and total choroidal area (TCA), and choroidal vascular index (CVI) were calculated and their changes at zero, three and six months were evaluated. Results: At baseline, CVI was significantly lower in both the subfoveal and total macular areas in the study group (p = 0.004, p = 0.003). In the study group, a significant decrease was observed in CVI between zero and six months in the subfoveal area (p = 0.001). In the submacular area, the decrease in CVI in the study group was significant between zero to three months and zero to six months. There was moderate correlation between measurements of CVI in the subfoveal and total macular areas (r = 0.66, p < 0.001). Conclusion: These findings indicate that intravitreal bevacizumab injection reduces the CVI and the effects of intravitreal anti-VEGF on CVI emerge earlier and more prominently in the submacular 6000 µm area. [ABSTRACT FROM AUTHOR]

Background: Diabetic macular edema (DME) is the primary cause of visual impairment in individuals with diabetes. Anti-vascular endothelial growth factor (VEGF) is the current first-line treatment for DME owing to its effectiveness. However, frequent anti-VEGF injections may be inconvenient for patients. Therefore, this study aimed to investigate whether the addition of subthreshold micropulse laser (SML) to anti-VEGF therapy could reduce the requirement for anti-VEGF injections while maintaining the treatment efficacy for DME. Methods: Clinical trials retrieved from the databases of PubMed, EMBASE, and the Cochrane Library were evaluated to determine the effectiveness of combination treatment with SML and anti-VEGF medication compared with that of anti-VEGF treatment alone. The primary outcome measures were the changes in CMT, best-corrected visual acuity (BCVA), and the total number of intravitreal injections (IVIs). Results: The IVI + SML group revealed a substantial increase in the logarithm of the minimum angle of the resolution BCVA and a reduction in CMT at the 12-month follow-up (BCVA: random-effects; mean difference [MD], −0.05; 95% confidence interval [CI]: −0.10 to −0.01; p-value = 0.28, and CMT: random-effects; MD, −18.27; 95% confidence interval, −27.36 to −9.18; p-value = 0.20). The number of required IVIs in the IVI + SML group was lower than that in the IVI only group (random-effects; MD, −2.22; 95% CI: −3.13 to −1.31; p-value < 0.01). Conclusions: Combining SML therapy with anti-VEGF injections may reduce the total number of injections required, improve VA, and reduce CMT at the 12-month follow-up. Although the included studies used different SML regimens and anti-VEGF agents, this review indicates that the application of additional SML therapy results in positive clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the use of intravitreal anti‐vascular endothelial growth factor (anti‐VEGF) therapy in Norway from 2011 to 2021 and explore how the eye departments organized their injection services. Methods: We combined data from the Norwegian Patient Registry (NPR) with survey responses from Norway's 22 eye departments. The NPR data encompassed all registered intravitreal injection episodes from 2011 to 2021. The survey contained questions about local treatment practices and emphasized neovascular age‐related macular degeneration (nAMD), retinal vein occlusion and diabetic macular edema. Results: A total of 47247 unique patients received 841 646 intravitreal injections in the study period. The number of patients per year increased from 6522 in 2011 to 20 635 in 2021. The number of injections per year increased from 30 926 in 2011 to 125 258 in 2021. The most frequent diagnosis was nAMD. In 2021, the age‐adjusted treatment activity in Norway's 11 counties ranged from 47.8 to 75.5 injections per 1000 inhabitants aged ≥50 years. The use of aflibercept gradually exceeded bevacizumab, but the aflibercept proportion per county ranged from 38 to 82% in 2021. The survey revealed varying treatment practices, local guidelines were often absent, and only half of the departments defined a lower visual limit for initiating or maintaining treatment. Conclusion: The use of intravitreal anti‐VEGF therapy increased considerably from 2011 to 2021, but there was considerable regional variation in treatment activity, drug utilization and organization of injection services. These findings emphasize the need for strengthened governance and national guidelines to ensure equal treatment nationally. [ABSTRACT FROM AUTHOR]

Background: With this study, we investigate the short-term clinical outcomes of patients affected by diabetic macular edema (DME) after switching to intravitreal Faricimab (IVF) in a real-world setting. Methods: We conducted a retrospective chart review on all patients treated for DME with IVF who showed insufficient responses to prior anti-VEGF therapy. Data collected included baseline patient demographics, medical history, best-corrected visual acuity (BCVA), central retinal thickness (CRT) and central retinal volume (CRV). We analyzed functional and structural measures before and after IVF, compared baseline demographics and treatment factors between Faricimab-responders and reduced-responders and assessed influencing factors of the follow-up BCVA and CRT. Results: This study included 25 eyes from 16 patients. After switching to IVF, the mean BCVA showed no significant improvement, changing from 59.4 ± 13.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters at baseline to 61.4 ± 12.8 ETDRS letters at follow-up (p = 0.26). CRT significantly reduced from 414.4 ± 126.3 µm to 353.3 ± 131.1 µm (p < 0.011), and the 3 mm CRV significantly decreased from 2.8 ± 0.5 mm3 to 2.6 ± 0.6 mm3 (p < 0.012). Seven patients met the responder criteria, exhibiting an improvement of at least 5 ETDRS letters and a simultaneous CRT reduction of at least 30 µm. Further analysis showed that higher BCVA at baseline (p < 0.001) was associated with better BCVA following IVF, while higher baseline CRT (p < 0.003), a higher number of prior anti-VEGF agents (p < 0.034) and prior corticosteroid injections (p < 0.019) were associated with greater CRT at follow-up. Conclusions: Following the initial IVF injection series, we observed a clear improvement of anatomical measures. No functional improvement was observed, although visual acuity remained stable. Higher baseline BCVA was associated with better post-IVF BCVA, while higher baseline CRT, a greater number of prior anti-VEGF agents and prior corticosteroid injections were linked to higher CRT post-IVF. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyze the effectiveness of two intravitreal antiangiogenic drugs, ranibizumab and aflibercept, in a Mexican population over a period of 5 years, evaluating the improvement in visual acuity (VA) and central retinal thickness (CRT) in a real-world scenario. This is a retrospective study with subjects diagnosed with diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR), and diabetic macular edema (DME) receiving intravitreal injections of ranibizumab and/or aflibercept. In this study, we analyzed 588 eyes of 294 patients who received intravitreal antiangiogenic injections. The results showed an improvement regardless of antiangiogenic treatment or diagnosis in both VA and CRT. We found that both aflibercept and ranibizumab improved VA, while subjects with DME responded less to antiangiogenic treatment (p < 0.05), and that this difference did not correspond to the CRT measured by OCT. These results support evidence that intravitreal antiangiogenic medications are effective for ophthalmic complications of diabetes in our population; however, damage to visual structures is not reversed in most patients. And that the perception by the patient (VA) and that of the ophthalmologist (CRT) do not completely correlate in our study. [ABSTRACT FROM AUTHOR]

Despite progress in the management of patients with retinal vascular and degenerative diseases, there is still an unmet clinical need for safe and effective therapeutic options with novel mechanisms of action. Recent mechanistic insights into the pathogenesis of retinal diseases with a prominent vascular component, such as retinal vein occlusion (RVO), diabetic retinopathy (DR) and wet age-related macular degeneration (AMD), may open up new treatment paradigms that reach beyond the inhibition of vascular endothelial growth factor (VEGF). Phosphatidylserine (PS) is a novel lipid target that is linked to the pathophysiology of several human diseases, including retinal diseases. PS acts upstream of VEGF and complement signaling pathways. Annexin A5 is a protein that targets PS and inhibits PS signaling. This review explores the current understanding of the potential roles of PS as a target and Annexin A5 as a therapeutic. The clinical development status of Annexin A5 as a therapeutic and the potential utility of PS-Annexin A5 as a theranostic pairing in retinal vascular conditions in particular is described. [ABSTRACT FROM AUTHOR]

To identify factors for meeting prespecified criteria for switching from bevacizumab to aflibercept in eyes with center-involved diabetic macular edema (CI-DME) and moderate vision loss initially treated with bevacizumab in DRCR Retina Network protocol AC. Post hoc analysis of data from a randomized clinical trial. Two hundred seventy participants with one or both eyes harboring CI-DME with visual acuity (VA) letter score of 69 to 24 (Snellen equivalent, 20/50–20/320). Eligible eyes were assigned to receive intravitreal aflibercept monotherapy (n = 158) or bevacizumab followed by aflibercept if prespecified criteria for switching were met between 12 weeks and 2 years (n = 154). Meeting switching criteria: (1) at any time, (2) at 12 weeks, and (3) after 12 weeks. Associations between meeting the criteria for switching and factors measured at baseline and 12 weeks were evaluated in univariable analyses. Stepwise procedures were used to select variables for multivariable models. In the group receiving bevacizumab first, older participants showed a higher risk of meeting the switching criteria at any time, with a hazard ratio (HR) for a 10-year increase in age of 1.32 (95% confidence interval [CI], 1.11–1.58). Male participants or eyes with worse baseline VA were more likely to switch at 12 weeks (for male vs. female: odds ratio [OR], 4.84 [95% CI, 1.32–17.81]; 5-letter lower baseline VA: OR, 1.30 [95% CI, 1.03–1.63]). Worse 12-week central subfield thickness (CST; 10-μm greater: HR, 1.06 [95% CI, 1.04–1.07]) was associated with increased risk of switching after 12 weeks. The mean ± standard deviation improvement in visual acuity after completing the switch to aflibercept was 3.7 ± 4.9 letters compared with the day of switching. The identified factors can be used to refine expectations regarding the likelihood that an eye will meet protocol criteria to switch to aflibercept when treatment is initiated with bevacizumab. Older patients are more likely to be switched. At 12 weeks, thicker CST was predictive of eyes most likely to be switched in the future. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Purpose: To review the risk of systemic adverse events and all-cause mortality following same-day bilateral anti-VEGF injections. Methods: Twelve literature databases were searched for studies on same-session bilateral intravitreal anti-VEGF injections. Studies reporting on systemic adverse events and mortality were included. Data extraction was made independently by two authors and discussed afterwards until consensus was reached. Results: Seven studies were included with a total of 13,406 intravitreal anti-VEGF injections (6703 bilateral injections sessions) given to 689 patients. Across all studies, mean age of patients ranged from 55.7 to 82.5 years, and mean follow-up times ranged from 1.3 to 41 months. Six studies reported on systemic adverse events: Two cases of non-fatal cardiac adverse events were reported after 12,964 injections (6482 bilateral injection sessions) in 626 patients. Four studies reported on death: 12 deaths were recorded after 6233 bilateral injection sessions in a total population of 554 subjects. Conclusions: We suggest that the risk of non-fatal systemic adverse events and death after same-session bilateral anti-VEGF injection is reasonably low, but larger studies with follow-ups of several years are needed to quantify the exact risk. Study registration.: Prospectively registered in PROSPERO, registration ID: CRD42023428254, registration date: 20/05/2023. [ABSTRACT FROM AUTHOR]

Introduction: KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. Methods: C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. Results: KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. Conclusions: Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients. [ABSTRACT FROM AUTHOR]

To report the treatment response of a case of tubercular choroidal granuloma and subretinal abscess with intravitreal anti-vascular endothelial growth factor (anti-VEGF) and moxifloxacin. Retrospective interventional case report. A 34-year-old man presented with bilateral choroidal granuloma and subretinal abscess in one eye. He was a known case of spinal tuberculosis and was on anti-tubercular therapy. Patient was successfully treated with intravitreal injection of anti-VEGF and moxifloxacin. Intravitreal anti-VEGF and moxifloxacin combination may be beneficial in tubercular choroidal granuloma and subretinal abscess. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide and a severe medical and social problem. The steadily increasing number of patients is related to the aging of the population. So far, many factors affecting the development of AMD have been identified, which can be divided into non-modifiable, including genetic factors, age, and sex, and modifiable or environmental factors, such as smoking, poor diet, and hypertension. Early stages of age-related macular degeneration are characterized by fundus drusen and abnormalities in the retinal pigment epithelium. In late stages, geographic atrophy and choroidal neovascularization (CNV) are observed. The treatment of AMD, especially its advanced forms, is very challenging. Intensive research has made it possible to treat advanced stages of the dry form of AMD with pegcetacoplan and avacincaptad pegol, new drugs approved for use in the US. Pegcetacoplan targets the C3 and avacincaptad pegol targets the C5, the pivotal proteins of the complement cascade. The drugs are administered by intravitreal injection. The gold standard for neovascular AMD (nAMD) consists of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs such as bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab. Treatment can be administered according to the fixed, pro-re-nata, and treat-and-extend regimens. The latter seems to have the best effect on improving visual acuity (VA) and the maximum therapeutic benefit. The search continues for the best ways to deliver intravitreal drugs. Current methods include sustained-release implants and hydrogel platforms for drug release, while the most promising future pathways for treating dry and nAMD are stem cell and gene therapy. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the cost-effectiveness of anti–vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of −0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties. • Proliferative diabetic retinopathy (PDR) is a leading cause of visual impairment and blindness in the United Kingdom and worldwide. Anti–vascular endothelial growth factor (anti-VEGF) drugs aflibercept and ranibizumab are recommended by the National Institute for Health and Care Excellence for the treatment of various eye conditions, including diabetic macular edema, and have shown promise as an alternative treatment for PDR. • There is limited evidence on the cost-effectiveness of anti-VEGFs for the treatment of diabetic retinopathy. This study reports discrete event simulation–based cost-effectiveness analysis in which we evaluate the cost-effectiveness of anti-VEGFs compared with panretinal photocoagulation for the treatment of diabetic retinopathy in a UK setting. The analysis leveraged evidence from the AVID individual participant data meta-analysis, which synthesized data from 3 randomized controlled trials evaluating the effectiveness of anti-VEGFs for diabetic retinopathy. • The results of this analysis suggest that anti-VEGFs are unlikely to be a cost-effective treatment option compared with panretinal photocoagulation for treating early PDR in the United Kingdom. This holds across a variety of scenarios, with anti-VEGFs generally associated with higher costs and similar health outcomes over a lifetime time horizon. Important uncertainties remain around the consequences of loss to follow-up, the comparative long-term effectiveness of treatments, and the rates of vision-threatening complications. [ABSTRACT FROM AUTHOR]

In recent years, the progress made in the field of optical coherence tomography has helped to understand the changes in eye layers in patients with exudative age-related macular degeneration (nAMD). Early diagnosis of nAMD, a leading cause of irreversible vision impairment, is helpful. Therefore, we performed a meta-analysis on OCT measurement alterations before and after anti-VEGF therapy in patients with nAMD and controls. We systematically searched Scopus, PubMed, Cochrane, and Web of Science to find articles that measured choroidal and retinal layer changes after anti-VEGF therapy in nAMD Patients. We chose either a fixed-effects or random-effects model based on the assessed heterogeneity level to perform a meta-analysis. In addition, we conducted meta-regression, subgroup analyses, publication bias, and quality assessment for included studies. Thirteen studies were included in the meta-analysis, with 733 total participants. Foveal thickness and subfoveal choroidal thickness (CT) decreased significantly in the first 3 years after injections, except for subfoveal CT in the third year after injection. It also showed that CT at 1500 µm temporal and nasal to the fovea did not significantly change. Our results showed anti-VEGF treatment for nAMD patients was associated with a significant reduction in foveal thickness and subfoveal CT in the first 2 years after treatment. Our analysis did not reveal any correlation between changes in foveal thickness and subfoveal CT with best-corrected visual acuity or other factors. [ABSTRACT FROM AUTHOR]

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars. • Biologics against VEGF are crucial for the treatment of many retinal diseases. • Ophthalmic anti-VEGF reference biologics typically impose high financial burden. • Approved anti-VEGF biosimilars are clinically equivalent to reference products. • Biosimilars can bring substantial benefits to patients and healthcare systems by reducing cost. • Realization of biosimilar benefits depend, in part, on their successful uptake. [ABSTRACT FROM AUTHOR]

Introduction: To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in treatment-naïve age-related macular degeneration (AMD) after faricimab application using optical coherence tomography angiography (OCTA). Methods: Twenty-five eyes of 25 treatment-naïve individuals who underwent intravitreal faricimab injections for neovascular AMD (nAMD) with type 1 MNV were included. Spectral-domain optical coherence tomography (SD-OCT) images and en-face swept-source OCTA images were analyzed, and the percentage of CC flow deficit (FD%), FD average area (FDa) and FD number (FDn) in five progressive 20.0-μm-wide concentric rings (R1, R2, R3, R4 and R5) surrounding the dark halo around the MNV were calculated. Image acquisition was carried out prior to the first faricimab injection (T0) and 1 month after the injection (T1). Results: The topographical sub-analysis revealed noteworthy changes in all rings at T1 compared to T0. There was a notable progressive reduction in FD% at T1 compared to T0 values across all rings, indicating a gradual CC reperfusion following anti-VEGF treatment. Additionally, the average size of FD decreased after the loading phase. Although not reaching statistical significance, there was a progressive reduction in the FDa across all rings. Conclusion: Our study highlights a CC FD reduction following the administration of three consecutive faricimab injections. This effect was detected in all rings surrounding the dark halo. These observations suggest a partial CC reperfusion surrounding the MNV, potentially serving as an indicator for disease regression. [ABSTRACT FROM AUTHOR]

Purpose: To describe a unique case of X-linked Coats'-like retinitis pigmentosa, a form of exudative retinitis pigmentosa, in association with an RPGR variant, and its management with intravitreal anti-vascular endothelium growth factor drugs, along with a peculiar optical coherence tomography finding observed in a late stage of disease. Methods: Case report. Results: A 33-year-old man previously treated with anti-vascular endothelium growth factors for macular edema came to our clinic for bilateral visual loss. A hemizygous RPGR variant (c.2442_2445del) was found and a diagnosis of Coats'-like Retinitis Pigmentosa was made. He was initially treated with carbonic anhydrase inhibitors; when efficacy wore off, he was switched to anti-vascular endothelium growth factor injections in both eyes with improvement. After a year without treatment, VA drastically worsened in both eyes; optical coherence tomography displayed disruption and increased hyper-reflectivity of the inner retinal layers in the right eye. Conclusion: The c.2442_2445del variant is added to a number of known ORF 15 RPGR mutations associated with Coats'like Retinitis Pigmentosa. Anti-vascular endothelium growth factor treatment was successful in blocking visual loss in our patient and withholding treatment had a negative impact on his visual outcome. [ABSTRACT FROM AUTHOR]

Background: Optimal management of colorectal liver metastasis (CRLM) is based on a combination of chemotherapy and surgical resection. The tumor regression grade (TRG) score is a histological scoring system to evaluate response to chemotherapy. The prognosis of a heterogeneous response in cases of multiple metastases has not been evaluated according to the TRG score. Patients and Methods: All patients who underwent liver resection for multiple CRLM after neoadjuvant chemotherapy in two tertiary centers from January 2015 to April 2019 were retrospectively included. Oncological characteristics and outcome between TRG 1–2–3 (good response group), TRG 4–5 (poor response group) and heterogeneous TRG (good and poor TRG among different lesions within the same patient) groups were compared. Results: Among the 327 patients included, 134 (41.0%) had good response (TRG 1–2–3), 120 (36.7%) had poor response (TRG 4–5), and 73 (22.3%) had heterogeneous response. The type and number of cycles of chemotherapy, k-Ras mutational status, and tumor number or size did not differ between the three groups. Use of irinotecan-based and anti-VEGF neoadjuvant therapy was associated with better TRG response [irinotecan-based: hazard ratio (OR) = 1.744; p = 0.045; anti-VEGF neoadjuvant therapy: 2.054; p = 0.005). Overall survival (OS) was higher in the 1–2–3 TRG group than in the heterogeneous TRG group (2-year OS = 81.3% vs. 60.3%, respectively; p = 0.003) and the 4–5 TRG group (2-year OS = 81.3% vs. 55.0%, respectively; p = 0.012) and similar between the heterogeneous and 4–5 TRG groups. Conclusions: The proportion of heterogeneous pathological response according to TRG is 22.3%, and the prognosis is comparable to that of poor pathological response. [ABSTRACT FROM AUTHOR]

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This article explores the evolving role of transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC) in the context of new therapies. Traditionally, TACE has been the standard treatment for intermediate-stage HCC, but the approach has shifted to partial embolization to achieve volume reduction and boost the immune system while preserving liver function. The article also discusses the concepts of TACE failure/refractoriness and TACE unsuitability, and how combining immunotherapy, anti-VEGF therapy, and TACE can be effective in these cases. Additionally, the article explores the benefits of sequential therapy and the use of specific combinations in certain patient populations. Ongoing clinical trials are also mentioned. [Extracted from the article]

Enrico Peiretti,1 Chiara Ascardi,2 Francesco Bandello,3 Francesco Boscia,4 Monica Varano,5 Marta Bartezaghi,2 Lorenzo De Santi,2 Giovanni Staurenghi6 1Clinica Oculistica, San Giovanni di Dio Hospital, Azienda Ospedaliera, Universitaria di Cagliari, Cagliari, Italy; 2Novartis Farma S.p.A, Milan, Italy; 3Department of Ophthalmology, San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; 4Department of Medical Science, Neuroscience and Sense Organs, Eye Clinic, University of Bari, Azienda Ospedaliero-Universitaria Policlinico Bari, Bari, Italy; 5IRCCS G.B. Bietti Foundation, Rome, Italy; 6Eye Clinic, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, ItalyCorrespondence: Enrico Peiretti, Head of the Retina Unit, Eye Clinic, University of Cagliari, Via Ospedale 48, Cagliari, 09100, Italy, Email enripei@hotmail.comPurpose: Limited data is available on treatment satisfaction with the management of wet age-related macular degeneration (wAMD) among patients in Italy. In this cross-sectional real-world study, treatment satisfaction with anti-vascular endothelial growth factor (anti-VEGFs) was assessed in patients with wAMD in Italy.Patients and Methods: This was a non-interventional, cross-sectional survey involving patients with wAMD receiving anti-VEGFs. The survey was administered through a virtual assistant via phone. Patients’ treatment satisfaction was assessed using a newly developed Novartis Tailored Treatment Satisfaction Questionnaire (NVS TTSQ) and the validated Macular Disease Treatment Satisfaction Questionnaire (MacTSQ).Results: Overall, 154 evaluable patients were enrolled in 5 centers across Italy. The mean (SD) age of the patients was 76.8 years (7.01). Overall treatment satisfaction score assessed by NVS TTSQ was 40.50 (7.11), with a mean of 9.97 (1.84) on the information domain and 22.98 (4.57) on the unmet need domain. Patients were satisfied with diagnosis communication (4.99 [1.30]), information provided on treatment administration (4.58 [1.49], range 0– 6), the waiting room (4.40 [1.43]), and management of visits and injections at the center (5.14 [1.12]), general management of maculopathy at the center (5.22 [1.01]). Patients were not satisfied with their independence in terms of disease management (2.56 [2.45]); they would like additional information about the disease (5.38 [1.03]) and to discuss the injection procedures (4.02 [1.94]) with already-treated patients. The overall treatment satisfaction score on MacTSQ scale was 55.84 (10.13).Conclusion: Patients with wAMD are satisfied with the overall management of their disease in Italy. However, patients would like to have more information on prognosis and management of the disease.Keywords: anti-VEGF, patient-reported outcomes, real-world study, treatment satisfaction, treatment satisfaction questionnaire, wAMD

Purpose: To characterize trends in use of and expenditure for the intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept, ranibizumab, and bevacizumab among the population enrolled in Original Medicare from 2014 to 2019. Methods: The Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File was used to extract Medicare Part B fee-for-service outpatient injection claims data submitted by ophthalmologists. Multivariable linear regression models were used to evaluate the association between reimbursement, ophthalmologist availability, and agent administration rate. Results: Between 2014 and 2019, 17,588,995 intravitreal injection claims were filed by 4218 US ophthalmologists. Medicare costs for anti-VEGF injections increased from 2.51 B USD in 2014 to 4.02 B USD in 2019. Increased state-level ophthalmologist availability and incremental increases in average reimbursement amounts were found to be significantly associated with a 6.8-fold variation in 2019 overall anti-VEGF injection rates across states. Conclusions: Medicare injection rates and costs for anti-VEGF injections have both increased between 2014 and 2019, largely driven by increased aflibercept use. There is a significant association between ophthalmologist availability and anti-VEGF injection rate on the state level, suggesting access to care may contribute to the observed state-level disparities in intravitreal injection rates. Further characterization of factors contributing to the state-level variation in injection rates of individual anti-VEGF agents may help inform interventions promoting equitable access to and use of these drugs. [ABSTRACT FROM AUTHOR]

Abstract Introduction KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. Methods C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. Results KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. Conclusions Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients.

Nadyr A Damasceno,1,2 Juliana Angélica Estevão Oliveira,2 Nicolas A Yannuzzi,3 Harry Flynn Jr,3 Mauricio Maia,2 Eduardo F Damasceno,4 Michel Eid Farah2 1HNMD, Hospital Naval Marcilio Dias, Department of Ophthalmology, Rio de Janeiro, RJ, Brazil; 2UNIFESP, Universidade Federal de São Paulo, Department of Ophthalmology, São Paulo, SP, Brazil; 3BPEI, Bascom Palmer Eye Institute, Department of Ophthalmology, Miami, FL, USA; 4UFF, School of Medicine, Universidade Federal Fluminense, Department of Ophthalmology, Niteroi, RJ, BrazilCorrespondence: Eduardo F Damasceno, School of Medicine, Universidade Federal Fluminense, Department of Ophthalmology, Marques Do Paraná 303, Niterói, RJ, 2550-030, Brazil, Email e_damasceno@yahoo.comPurpose: To assess ocular pain in patients undergoing multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) who have previous factors that may influence pain sensitivity.Methodology: This is a prospective, observational, case series study involving patients who underwent multiple (≥ 3) pro re nata intravitreal injections of ranibizumab or aflibercept to treat any cause of chorioretinal vascular disease. Ocular pain was assessed by the numerical analog scale during intravitreal injection. For this study, the main variable was ocular pain and the secondary variables included age, sex, previous history of glaucoma, primary retinal vascular disease, severe dry eye history, trigeminal pain, scleral buckle surgery, collagen diseases, fibromyalgia, severe migraine history, pars plana vitrectomy, scleral thickness measurements, and type of anti-VEGF.Results: In a total of 894 patients, 948 eyes (4822 intravitreal injections), 793 patients (88.6%) had ocular pain sensitivity between no pain to mild pain, 80 patients (8.9%) had moderate ocular pain, 15 patients (1.6%) had severe ocular pain, and 6 patients (0.7%) had extremely severe ocular pain. Patients with severe dry eye (p = 0.01) and previous history of scleral buckle surgery (p = 0.01) showed a significant correlation with ocular pain during intravitreal injection. Pars plana scleral thickness (> 550 um) and diabetic neuropathy were associated with ocular pain but did not meet the criteria for statistical significance (p = 0.09 and p = 0.06, respectively).Conclusion: Dry eye and prior scleral buckle surgery may contribute to pain associated with intravitreal injection. These issues should be taken into consideration in patients undergoing multiple intravitreal injections.Keywords: Ocular pain, multiple intravitreal injections, anti-VEGF, special risk factors

Abstract Introduction To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in treatment-naïve age-related macular degeneration (AMD) after faricimab application using optical coherence tomography angiography (OCTA). Methods Twenty-five eyes of 25 treatment-naïve individuals who underwent intravitreal faricimab injections for neovascular AMD (nAMD) with type 1 MNV were included. Spectral-domain optical coherence tomography (SD-OCT) images and en-face swept-source OCTA images were analyzed, and the percentage of CC flow deficit (FD%), FD average area (FDa) and FD number (FDn) in five progressive 20.0-μm-wide concentric rings (R1, R2, R3, R4 and R5) surrounding the dark halo around the MNV were calculated. Image acquisition was carried out prior to the first faricimab injection (T0) and 1 month after the injection (T1). Results The topographical sub-analysis revealed noteworthy changes in all rings at T1 compared to T0. There was a notable progressive reduction in FD% at T1 compared to T0 values across all rings, indicating a gradual CC reperfusion following anti-VEGF treatment. Additionally, the average size of FD decreased after the loading phase. Although not reaching statistical significance, there was a progressive reduction in the FDa across all rings. Conclusion Our study highlights a CC FD reduction following the administration of three consecutive faricimab injections. This effect was detected in all rings surrounding the dark halo. These observations suggest a partial CC reperfusion surrounding the MNV, potentially serving as an indicator for disease regression.

Abstract Introduction Optimizing treatment protocols for wet age-related macular degeneration (wAMD) is an ongoing challenge, as it involves a delicate balance between achieving therapeutic efficacy and minimizing invasive procedures' frequency. This study aimed to apply the Lean methodology and evaluate the effectiveness of this new setting on intravitreal therapy for wAMD, employing different anti-vascular endothelial growth factors (VEGF) drugs (bevacizumab, brolucizumab, aflibercept, ranibizumab), drawing data from the Bari Intravitreal Injections Registry (BIVIR). Methods This was a retrospective, monocentric, nonrandomized, comparative study. Lean methodology was employed to design the new setting and the BIVIR collected information from electronic medical records. Clinical data of four groups, stratified based on the first-line anti-VEGF agents used, were compared. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) changes were compared between the four groups at 3 and 12 months. Results Out of 4990 eyes and 41,323 intravitreal injections (IVs) recorded in BIVIR, 1421 eyes of 1182 patients were included. The mean number of IVs in first year was 6.1 ± 2.5, with no significant differences among the four subgroups. The mean change in BCVA was + 6.2 letters [95% confidence interval (CI) 5.6–6.8] after two IVs, and + 5.9 (95% CI 5.1–6.8) letters after three IVs; at three months, brolucizumab was associated with a greater mean increase in BCVA than bevacizumab (p = 0.050); aflibercept (p = 0.044) and ranibizumab p = 0.047). At the 1-year follow-up, the mean change was + 6.3 letters (95% CI 5.4–7.2), brolucizumab and ranibizumab were associated with a superior improvement in BCVA compared to aflibercept (p = 0.033). Regarding the CRT, a significant reduction was observed in the subgroup treated with brolucizumab at the 3-month follow-up, compared to bevacizumab (p = 0.003), aflibercept (p = 0.015), and ranibizumab (p

Abstract Objectives The aim of this study was to investigate the retinal morpho‐functional characteristics of patients with neovascular wet age‐related macular degeneration (nAMD) treated with intravitreal injection (IV) of aflibercept (AFL). Methods The study was conducted on 35 patients previously diagnosed with type 1 nAMD who received a fixed‐dosing regimen of aflibercept injections over 12 months. The goal was to assess trends in visual abilities over time by measuring visual acuity (VA), contrast sensitivity (CS), visual evoked potentials (VEPs), and spectral domain‐optical coherence tomography (SD‐OCT). The same psychophysical, electro‐functional, and morphological tests administered at baseline (T0) were repeated 4 to 8 weeks after the last aflibercept injection (Tn), resulting in a total of six examinations. Results At Tn, all subjects exhibited improved VA for both far and near distances compared to values detected at T0. Similarly, VEP amplitude and latency values at Tn showed a greater P100 improvement than those observed at T0. Additionally, the CS examination at Tn demonstrated improvement, particularly at high spatial stimulation frequencies. The Tn SD‐OCT results highlighted a reduction in macular thickness compared to T0 values. Conclusions This exploratory research indicates that intravitreal injections of AFL, following a fixed‐dosing regimen, represent a valuable therapeutic approach for enhancing visual performance. This conclusion is supported by comprehensive statistical analysis of psychophysical, electro‐functional, and morphological examinations within the same group of patients with nAMD, as demonstrated for the first time.

Abstract Purpose The present study tested the hypothesis that repeated anti-VEGF injections are associated with reduced retinal nerve fiber layer (RNFL) and minimum rim width (MRW) of the optic nerve head. Patients and methods Sixty-six patients with a history of intravitreal injections due to neovascular age-related macular degeneration were included. RNFL and MRW were measured using optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany). Results Mean global RNFL was 90.62 μm and both RNFL as well as MRW significantly decreased with advanced age (p = 0.005 and p = 0.019, respectively). Correlating for the number of injections, no significant impact on RNFL was found globally (p = 0.642) or in any of the sectors. In contrast, however, global MRW was significantly reduced with increasing numbers of intravitreal injections (p = 0.012). The same holds true when adjusted for the confounding factor age (RNFL p = 0.566 and MRW p = 0.023). Conclusion Our study shows that repeated intravitreal injections due to choroidal neovascularization seem to have a deleterious effect on MRW but not on RNFL. This suggests that MRW is a more sensitive marker than RNFL for evaluating the effect of frequent intravitreal injections on the optic nerve head since it seems to be the first structure affected.

Abstract Artificial intelligence (AI) has emerged as a transformative technology across various fields, and its applications in the medical domain, particularly in ophthalmology, has gained significant attention. The vast amount of high-resolution image data, such as optical coherence tomography (OCT) images, has been a driving force behind AI growth in this field. Age-related macular degeneration (AMD) is one of the leading causes for blindness in the world, affecting approximately 196 million people worldwide in 2020. Multimodal imaging has been for a long time the gold standard for diagnosing patients with AMD, however, currently treatment and follow-up in routine disease management are mainly driven by OCT imaging. AI-based algorithms have by their precision, reproducibility and speed, the potential to reliably quantify biomarkers, predict disease progression and assist treatment decisions in clinical routine as well as academic studies. This review paper aims to provide a summary of the current state of AI in AMD, focusing on its applications, challenges, and prospects.

Objective: In this study we investigated the efficacy of short-term intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) in treating traumatic submacular hemorrhage. Methods: A total of 115 patients were diagnosed with submacular hemorrhage between 2018 and 2022 at Shenzhen Eye Hospital. In a retrospective analysis, we examined 13 of these patients who presented with submacular hemorrhage and choroidal rupture due to ocular trauma. Eight patients were treated with intravitreal anti-VEGF injection and 5 with oral drugs. We systematically analyzed changes in their ocular conditions pre and post-treatment. The evaluations encompassed best-corrected visual acuity (BCVA), optical coherence tomography, fundus fluorescein angiography, and retinal imaging. Results: The 13 patients diagnosed with submacular hemorrhage comprised of 10 males and 3 female, with their age ranging between 27 and 64 years, with an average age of 38.1 years (standard deviation [SD]: 11.27). A statistically significant reduction in central foveal thickness (CFT) was observed following intravitreal injections of anti-VEGF drugs (P = 0.03). In control group, the CFT was reduced without statistical significance (P = 0.10). The BCVA of the patients in treatment group improved significantly from 1.15 (SD: 0.62. Range: 0.4–2) to 0.63 (SD: 0.59. Range: 0.1–1.6), indicating an average increase of 4.13 lines (SD: 3.36. Range: 0–9) as measured by the visual acuity test using an eye chart (P = 0.01). The difference between baseline visual acuity and final visual acuity was not statistically significant in control group (P = 0.51). Conclusion: Short-term administration of anti-VEGF drugs exhibited significant efficacy in reducing submacular hemorrhage following ocular trauma and enhancing visual acuity. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions To report the incidence of post‐injection endophthalmitis (PIE) and the cumulative risk associated with repeated injections of intravitreal anti‐vascular endothelial growth factor (anti‐VEGF).We employed nationwide registries in Denmark to include all individuals aged ≥40 years who received at least one intravitreal anti‐VEGF injection in 2007–2022. Our primary endpoint PIE was identified using specific diagnostic codes for endophthalmitis and procedure codes for vitreous biopsy within 10 days prior to and 120 days post‐injection. Patients were stratified according to the underlying diagnoses for which they received the treatment. The relative risk (RR) for PIE was calculated between groups based on the number of injections received by the patients.We identified 60 825 patients who received intravitreal anti‐VEGF treatment during study time, with a median age of 77.2 years and females constituting 58.1%. We identified 232 cases of PIE after 1 051 549 injections during follow‐up, resulting in an incidence of 0.022% [95% CI 0.019%–0.025%]. Despite a linear growth in annual anti‐VEGF use, the incidence remained stable at 0.020% [95% CI 0.017%–0.023%] from 2013 to 2022. Compared to patients receiving 1–3 injections, RR for patients receiving 4–20, 21–40, and >40 injections were 0.46 [95% CI 0.34–0.63], 0.32 [95% CI 0.21–0.50], and 0.54 [95% CI 0.36–0.81], respectively. Findings were similar across the different diagnoses.Based on 16 years of nationwide registry data, this study identified a low and stable incidence of PIE. Notably, the highest risk of endophthalmitis was within the first three anti‐VEGF injections. [ABSTRACT FROM AUTHOR]

Objective: To describe the management of diabetic macular oedema (DME) patients from the entire French population between 2012 and 2018. Methods: In this retrospective longitudinal study, we identified adults treated for DME from the French population using the exhaustive French National Health Information database (SNDS), and an algorithm based on diagnosis and procedure codes, and reimbursed treatments. Results: Between 2012 and 2018, we identified 53 584 treated DME patients, who were followed for up to 7 years from DME treatment initiation. Optical coherence tomography (OCT) became the predominant imaging tool to diagnose DME. Only 14% of patients consulted a diabetologist or endocrinologist in the 3 months prior to initiating DME treatment, whereas 84% consulted a general practitioner. The percentage of patients consulting an ophthalmologist declined over time, from 97% of patients in Year 1 (median of 9 consultations), to 46% in Year 7 (median of 7 consultations). The median DME treatment duration with an anti‐VEGF and/or dexamethasone implant treatment was 9 months; 54% of patients had a treatment duration less than 1 year. First‐line treatment was more common with ranibizumab (55% of patients) than with aflibercept (30%), or dexamethasone implant (15%). About 25% of patients who initiated anti‐VEGF treatment switched treatment at least once, while 30% of patients who initiated dexamethasone implant switched to anti‐VEGF treatment at least once. Conclusions: French DME patients seem well‐monitored by their ophthalmologist, but median DME treatment duration was just 9 months. These results emphasise the challenge to manage and treat patients with DME over the long term. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to map the treatment burden for patients with wet age‐related macular degeneration (wAMD). Method: Patients with ongoing treatment with anti‐VEGF for wAMD at a Swedish eye unit underwent a survey about the time spent receiving treatment, caregiver assistance, way of transportation, self‐rated vision and negative experiences associated with the treatment such as discomfort, anxiety or transportation problems. Information about current visual acuity, number of treatments and current treatment intervals were obtained from medical records. Results: The study included 93 patients with an average age of 79.9 years, 68% were women. The average interval between treatments was 7.3 weeks, and 26% had active treatment in both eyes. On average, patients had to spend 2.7 h (2.4–2.9: 95% CI) per treatment and a caregiver assisted the patient in 58% of cases. Caregivers spent on average 2.6 h (2.5–2.8: 95% CI) per visit, and 19% needed to take time off work. The majority (91%) of patients did not experience any transportation problems associated with treatment. A multivariate logistic regression analysis showed a significantly lower odds ratio for discomfort with higher self‐rated vision and a significantly higher odds ratio for discomfort with longer treatment intervals. Discussion: Anti‐VEGF treatment is an effective treatment for wAMD. However, the relatively short treatment intervals place a considerable burden on patients and their relatives regarding time. Although the patients in this study had to spend a lot of time to receive treatment, the majority did not experience any problems associated with treatment. [ABSTRACT FROM AUTHOR]

Purpose: Wet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF). Methods: Bevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent. Results: Bevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies. Conclusions: Bevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections. [ABSTRACT FROM AUTHOR]

To determine the risk of endophthalmitis in eyes undergoing intravitreal injections (IVIs) of anti-VEGF based on cumulative number of injections per eye. Retrospective cohort study. Patients from a single center undergoing IVIs of ranibizumab, aflibercept, or bevacizumab. Eyes were divided into quartiles based on injection number causative of endophthalmitis between January 1, 2011, and June 1, 2022. Interquartile clinical outcomes and cumulative risk of endophthalmitis per injection and per eye. A total of 43 393 eyes received 652 421 anti-VEGF injections resulting in 231 endophthalmitis cases (0.035% per injection, 1 in 2857), of which 215 were included. The cumulative endophthalmitis risk increased from 0.0018% (1 in 55 556) after 1 injection to 0.013% (1 in 7692) after 11 injections (0.0012 percentage point change), versus 0.014% (1 in 7143) after 12 injections to 0.025% (1 in 4000) after 35 injections (0.00049 percentage point change), versus 0.025% (1 in 4000) after 36 injections to 0.031% (1 in 3226) after 66 injections (0.00017 percentage point change), versus 0.031% (1 in 3226) after 63 injections to 0.033% (1 in 3030) after 126 injections (0.000042 percentage point change) (P < 0.001). Likewise, the cumulative endophthalmitis risk per eye increased from 0.028% (1 in 3571) to 0.20% (1 in 500) between injections 1 and 11 (0.018 percentage point change), versus 0.21% (1 in 476) to 0.38% (1 in 263) between injections 12 and 35 (0.0075 percentage point change), versus 0.38% (1 in 263) to 0.46% (1 in 217) between injections 36 and 66 (0.0026 percentage point change), versus 0.46% (1 in 217) to 0.50% (1 in 200) between injections 67 and 126 (0.00063 percentage point change) (P < 0.001). The cumulative endophthalmitis risk per injection and per eye increased with greater number of injections received but appeared to do so at a higher rate during earlier injections and at a lower rate further into the treatment course. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Purpose: This is, to our knowledge, the first network meta-analysis aiming to compare all treatment modalities for myopic choroidal neovascularization (CNV). Methods: After the electronic databases were searched, two independent reviewers screened titles, abstracts, full-texts, and extracted information. Primary endpoints were change in visual outcome and central retinal thickness. We used a network meta-analysis to compare treatment outcomes in the early (≤ 6 months) and late (> 6 months) phase. Results: We included 34 studies (2,098 eyes) in our network meta-analysis. In the early phase, the use of anti-VEGF led to a gain of 14.1 letters (95% CI, 10.8–17.4) compared to untreated patients (p < 0.0001), 12.1 letters (95% CI, 8.3–15.8) to photodynamic therapy (PDT) (p < 0.0001), 7.5 (95% CI, 1.2–13.8) letters to intravitreal triamcinolone acetonide (TCA) (p = 0.019), and − 2.9 letters (95% CI, − 6.0–0.2) to the combination of anti-VEGF and PDT (p = 0.065). In the later phase, these results were largely maintained. There were no significant differences in visual outcomes between patients treated with 1 + PRN and 3 + PRN. However, the 1 + PRN group received 1.8 (SD 1.3), while the 3 + PRN group received 3.2 (SD 0.9) injections within 12 months (p < 0.0001). Conclusion: This network meta-analysis confirms that anti-VEGF is the most effective treatment for myopic CNV using the 1 + PRN treatment strategy. [ABSTRACT FROM AUTHOR]

Introduction: Optimizing treatment protocols for wet age-related macular degeneration (wAMD) is an ongoing challenge, as it involves a delicate balance between achieving therapeutic efficacy and minimizing invasive procedures' frequency. This study aimed to apply the Lean methodology and evaluate the effectiveness of this new setting on intravitreal therapy for wAMD, employing different anti-vascular endothelial growth factors (VEGF) drugs (bevacizumab, brolucizumab, aflibercept, ranibizumab), drawing data from the Bari Intravitreal Injections Registry (BIVIR). Methods: This was a retrospective, monocentric, nonrandomized, comparative study. Lean methodology was employed to design the new setting and the BIVIR collected information from electronic medical records. Clinical data of four groups, stratified based on the first-line anti-VEGF agents used, were compared. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) changes were compared between the four groups at 3 and 12 months. Results: Out of 4990 eyes and 41,323 intravitreal injections (IVs) recorded in BIVIR, 1421 eyes of 1182 patients were included. The mean number of IVs in first year was 6.1 ± 2.5, with no significant differences among the four subgroups. The mean change in BCVA was + 6.2 letters [95% confidence interval (CI) 5.6–6.8] after two IVs, and + 5.9 (95% CI 5.1–6.8) letters after three IVs; at three months, brolucizumab was associated with a greater mean increase in BCVA than bevacizumab (p = 0.050); aflibercept (p = 0.044) and ranibizumab p = 0.047). At the 1-year follow-up, the mean change was + 6.3 letters (95% CI 5.4–7.2), brolucizumab and ranibizumab were associated with a superior improvement in BCVA compared to aflibercept (p = 0.033). Regarding the CRT, a significant reduction was observed in the subgroup treated with brolucizumab at the 3-month follow-up, compared to bevacizumab (p = 0.003), aflibercept (p = 0.015), and ranibizumab (p < 0.001); Aflibercept exhibited a superior effect than ranibizumab (p = 0.001). At 1-year follow-up, aflibercept resulted in a more significant reduction of macular thickness compared to ranibizumab (p = 0.016) while no significant differences were observed among the other drugs. Conclusions: Our practical experience showed the effectiveness of the new setting in the treatment of wAMD. This comparative study at 1 year suggested a predominant brolucizumab efficacy on functional outcomes. In addition, brolucizumab and aflibercept appeared to have similar efficacy in fluid control. [ABSTRACT FROM AUTHOR]

Background: To evaluate the efficacy and safety of Brolucizumab for neovascular age-related macular degeneration (n-AMD) through a systematic review and meta-analysis. Materials and Methods: Cochrane, PubMed, Embase, and Web of Science databases were comprehensively searched for relevant studies. Stata and RevMan5.4 were applied for meta-analysis and risk of bias assessment. Data on the best-corrected visual acuity (BCVA), central subfield thickness (CSFT), presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF), participants with ≥1 serious adverse events, and participants with ≥1 adverse events were analyzed. Results: Six studies were finally included. Meta-analysis showed statistical differences in BCVA [SMD = −0.65, 95% CI [−0.17 to −0.23], P < 0.05], the presence of IRF and/or SRF [RR = 0.67, 95% CI [0.56–0.79], P < 0.05], and the safety of participants with ≥1 serious adverse events [RR = 0.57, 95% CI [0.39–0.84], P < 0.05] between the experimental group and the control group. However, no statistical differences were observed in CSFT [SMD = −1.16, 95% CI [−2.79 to 0.47], P > 0.05] or the safety of participants with ≥1 adverse events [RR = 1.07, 95% CI [0.97–1.17], P > 0.05]. Conclusions: Compared to other anti-VEGF drugs such as Aflibercept and Ranibizumab, intravitreal injection of 6 mg Brolucizumab is more effective and safer for n-AMD, especially in the presence of IRF and/or SRF, and for participants with ≥1 serious adverse events. [ABSTRACT FROM AUTHOR]

Purpose: The German Retina.net ROP registry and its Europe‐wide successor, the EU‐ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries. Methods: Exemplary datasets from the two databases over a 1‐year period each (German Retina.net ROP Registry, 2011, 22 infants; EU‐ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments. Results: The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU‐ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10–12 clock hours in 29% of cases, 2021: 4–6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti‐VEGF therapy in 2021 (86.1%). Within the anti‐VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021. Conclusion: Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti‐VEGF, and within the anti‐VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021. [ABSTRACT FROM AUTHOR]

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]

Purpose: The purpose of the study was to evaluate temporal changes in age‐ and sex‐stratified incidence rates of retinal vein occlusion (RVO) commenced in anti‐vascular endothelial growth factor (anti‐VEGF) treatment, proportion of patients remaining in active anti‐VEGF therapy over time, and to develop a forecasting model for future number of patients with RVO in active anti‐VEGF therapy. Methods: This was a registry‐based study of patients with RVO in the Capital Region of Denmark from commenced in anti‐VEGF therapy from 1 January 2007 to 30 June 2022. Census data were extracted from Statistics Denmark for incidence rate analyses and forecasting data of future demographics. Results: A total of 2641 patients with RVO were commenced in anti‐VEGF therapy, of which 2192 were later discontinued. Number of patients rose dramatically during the first years of introduction of anti‐VEGF therapy, after which growth was slower and followed the demographic changes. Trend analyses revealed that the COVID‐19 epidemics impacted with fewer referrals and more aggressive discontinuation practices. Annual incidence of RVO in 2012–2021 was 13.1 per 100 000 (95% CI: 12.6–13.6 per 100 000). Proportion of patients with RVO remaining in active anti‐VEGF treatment was 55.0%, 40.1%, 30.8% and 12.1% after Years 1, 2, 3 and 8, respectively. According to our forecast, number of patients with RVO in active anti‐VEGF therapy will grow slowly but continually at least until year 2035. Conclusion: Our study reports incidence rates and provides prognostic modelling of number of patients with RVO in anti‐VEGF therapy. [ABSTRACT FROM AUTHOR]

Objectives: This study entailed a weekly analysis of real-world data (RWD) on the safety and efficacy of intravitreal (IVT) faricimab in neovascular age-related macular degeneration (nAMD). Methods: A retrospective, single-centre clinical trial was conducted at the Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland, approved by the Cantonal Ethics Committee of Zurich, Switzerland. Patients with nAMD were included. Data from patient charts and imaging were analysed. The safety and efficacy of the first faricimab injection were evaluated weekly until 4 weeks after injection. Results: Sixty-three eyes with a complete 4-week follow-up were enrolled. Six eyes were treatment-naïve; fifty-seven eyes were switched to faricimab from another treatment. Neither group showed signs of retinal vasculitis during the 4 weeks after injection. Central subfield thickness (CST) and volume (CSV) showed a statistically significant decrease compared to the baseline in the switched group (CST: p = 0.00383; CSV: p = 0.00702) after 4 weeks. The corrected visual acuity returned to the baseline level in both groups. The macular neovascularization area decreased in both groups, but this was not statistically significant. A complete resolution of sub- and intraretinal fluid after 4 weeks was found in 40% (switched) and 75% (naïve) of the treated patients. Conclusions: The weekly follow-ups reflect the structure–function relationship beginning with a fast functional improvement within two weeks after injection followed by a return to near-baseline levels after week 3. The first faricimab injection in our cohort showed a high safety profile and a statistically significant reduction in macular oedema in switched nAMD patients. [ABSTRACT FROM AUTHOR]

Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV. [ABSTRACT FROM AUTHOR]

To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; p = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; p = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate novel, automated biomarkers, pigment epithelial detachment composition indices (PEDCI) in eyes with neovascular age-related macular degeneration (nAMD) undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy through 24 months. Methods: Retrospective analysis of 37 eyes (34 patients) with PED associated with nAMD receiving as-needed anti-VEGF treatment was performed. Best-corrected visual acuity (BCVA) and optical coherence tomography images were acquired at a treatment-naïve baseline and 3-, 6-, 12-, 18-, and 24-month visits. Previously validated automated imaging biomarkers, PEDCI-S (serous), PEDCI-N (neovascular), and PEDCI-F (fibrous) within PEDs were measured. ANOVA analysis and Spearman correlation were performed. Results: Mean BCVA (in logMAR) was 0.60 ± 0.47, 0.45 ± 0.41, 0.49 ± 0.49, 0.61 ± 0.54, 0.59 ± 0.56, and 0.67 ± 0.57 at baseline, 3, 6, 12, 18, and 24 months respectively. Overall, BCVA showed minimal worsening of 0.07 ± 0.54 logMAR (p = 0.07). 13.38 ± 3.77 anti–VEGF injections were given through 24 months. PEDCI-F showed an increase of 0.116, 0.122, 0.036, and 0.006 at months 3, 6, 12, and 18 respectively and a decrease of 0.004 at month 24 (p = 0.03); PEDCI-S showed a decrease of 0.064, 0.130, 0.091, 0.092, and 0.095 at months 3, 6, 12, 18, and 24 respectively (p = 0.16); PEDCI-N showed a decrease of 0.052 at month 3 and an increase of 0.008, 0.055, 0.086, and 0.099 at months 6, 12, 18, and 24 respectively (p = 0.06). BCVA was negatively correlated with PEDCI-F (r = -0.28, p < 0.01), and positively correlated with PEDCI-N (r = 0.28, p < 0.01) and PEDCI-S (r = 0.15, p = 0.03). Conclusion: Longitudinal analysis of PEDCI supports their utility as biomarkers that characterize treatment related effects by quantifying the relative composition of PEDs. [ABSTRACT FROM AUTHOR]

Introduction: This study assessed the European School of Advanced Studies in Ophthalmology (ESASO) classification's prognostic value for diabetic macular edema (DME) in predicting intravitreal therapy outcomes. Methods: In this retrospective, multicenter study, patients aged > 50 years with type 1 or 2 diabetes and DME received intravitreal antivascular endothelial growth factor (anti-VEGF) agents (ranibizumab, bevacizumab, and aflibercept) or steroids (dexamethasone). The primary outcome was visual acuity (VA) change post-treatment, termed as functional response, measured 4–6 weeks post-third anti-VEGF or 12–16 weeks post-steroid injection, stratified by initial DME stage. Results: Of the 560 eyes studied (62% male, mean age 66.7 years), 31% were classified as stage 1 (early), 50% stage 2 (advanced), 17% stage 3 (severe), and 2% stage 4 (atrophic). Visual acuity (VA; decimal) improved by 0.12–0.15 decimals in stages 1–2 but only 0.03 decimal in stage 3 (all p < 0.0001) and 0.01 in stage 4 (p = 0.38). Even in eyes with low baseline VA ≤ 0.3, improvements were significant only in stages 1 and 2 (0.12 and 0.17 decimals, respectively). Central subfield thickness (CST) improvement was greatest in stage 3 (−229 µm, 37.6%, p < 0.0001), but uncorrelated with VA gains, unlike stages 1 and 2 (respectively: −142 µm, 27.4%; − 5 µm, 12%; both p < 0.0001). Stage 4 showed no significant CST change. Baseline disorganization of retinal inner layers and focal damage of the ellipsoid zone/external limiting membrane did not influence VA improvement in stages 1 and 2. Treatment patterns varied, with 61% receiving anti-VEGF and 39% dexamethasone, influenced by DME stage, with no significant differences between therapeutic agents. Conclusion: The ESASO classification, which views the retina as a neurovascular unit and integrates multiple biomarkers, surpasses single biomarkers in predicting visual outcomes. Significant functional improvement occurred only in stages 1 and 2, suggesting reversible damage, whereas stages 3 and 4 likely reflect irreversible damage. [ABSTRACT FROM AUTHOR]