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TOPIC: This systematic review and meta-analysis investigates the efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) injections compared to surgical intervention in improving visual acuity (VA) and reducing complications for patients with submacular hemorrhage (SMH) due to neovascular age-related macular degeneration (AMD). CLINICAL RELEVANCE: Determining the optimal intervention for SMH in AMD is crucial for patient care. METHODS: We included studies on anti-VEGF injections or surgical interventions for SMH in AMD from 7 databases, searched up to May 2024. Data extraction and quality assessment were done by two independent reviewers. Certainty of evidence was assessed GRADE approach. Meta-analysis employed random-effects models. Primary outcomes were pooled mean logMAR VA difference (initial examination minus last follow-up VA) and adverse events rates. RESULTS: A total of 43 observational studies were included: 21 (960 eyes) on anti-VEGF and 22 (455 eyes) on surgery. Comparisons were made across separate studies due to lack of head-to-head studies. Meta-analysis included 11 anti-VEGF studies (444 eyes) and 12 surgical studies (195 eyes) for VA outcomes. The mean difference (MD) in VA was -0.16 (95%CI: -0.26,-0.07) for anti-VEGF and -0.36 (95%CI: -0.68,-0.04) for surgery, with no significant difference between groups (X2=1.70, df =1, p=0.19). Heterogeneity was high in surgical studies (I2=96.2%, tau2=0.23, p<0.01) and negligible in anti-VEGF studies (I2=7%, tau2=0.003, p=0.38). GRADE certainty was moderate for anti-VEGF and low for surgery. Anti-VEGF had lower rates of cataract (0% vs 4.6%), proliferative vitreoretinopathy (PVR, 0.1% vs 2.0%), and retinal detachment (RD, 0.1% vs 10.6%), but similar rates of recurrent hemorrhage (5.4% vs 5.3%). Complications were summarized descriptively due to zero cell problem. CONCLUSION: Both anti-VEGF and surgery treat SMH in AMD with similar VA outcomes but different safety profiles. Anti-VEGF is preferred for less severe hemorrhage, while surgery is suited for extensive hemorrhage. Despite uncertain comparative VA outcomes, treatment should be guided by clinical judgment and patient factors.
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BACKGROUND: To evaluate the impact of reimbursement criteria change on the utilization pattern of anti-vascular endothelial growth factor (anti-VEGF) among patients with wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) separately in Taiwan. METHODS: An interrupted time series analysis (ITSA) was performed using Taiwan's National Health Insurance (NHI) database, and patients with wAMD or DME diagnosis at the first injection of anti-VEGF agents was identified from 2011 to 2019. The outcome of interest was treatment gaps between injections of anti-VEGF. This outcome was retrieved quarterly, and the study period was divided into three phases in wAMD (two criteria changed in August 2014 [intervention] and December 2016 [intervention]) and two phases in DME (three consecutive criteria changed in 2016 [intervention]). Segmented regression models adjusted for autocorrelation were used to estimate the change in level and the change in slope of the treatment gaps between each anti-VEGF injection. RESULTS: The treatment gaps between each anti-VEGF injection decreased from 2011 to 2019. The cancellation of the annual three needles limitation was associated with significantly shortened treatment gaps between the third and fourth needles (wAMD change in level: -228 days [95% CI -282, -173], DME change in level: -110 days [95% CI -141, -79]). The treatment gap between the fifth and sixth needles revealed a similar pattern but without significant change in DME patients. Other treatment gaps revealed considerable change in slopes in accordance with criteria changes. CONCLUSION: This is the first nationwide study using ITSA to demonstrate the impact of reimbursement policy on treatment gaps between each anti-VEGF injection. After canceling the annual limitation, we found that the treatment gaps significantly decreased among wAMD and DME patients. The shortened treatment gaps might further link to better visual outcomes according to previous studies. The different impacts from criteria changes can assist future policy shaping. Future studies were warranted to explore whether such changes are associated with the benefits of visual effects.
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Inibidores da Angiogênese , Retinopatia Diabética , Análise de Séries Temporais Interrompida , Edema Macular , Fator A de Crescimento do Endotélio Vascular , Humanos , Edema Macular/tratamento farmacológico , Edema Macular/economia , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/economia , Masculino , Feminino , Inibidores da Angiogênese/economia , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Taiwan , Idoso , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/economia , Injeções Intravítreas , Mecanismo de Reembolso , Pessoa de Meia-Idade , Programas Nacionais de Saúde/economia , Programas Nacionais de Saúde/estatística & dados numéricos , Ranibizumab/economia , Ranibizumab/uso terapêutico , Ranibizumab/administração & dosagem , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Age-related macular degeneration (AMD) is a progressive retinal degenerative disease that is implicated as one of the leading causes of visual impairment in the elderly population. Vascular endothelial growth factor (VEGF) has been identified as the main driver of AMD, and various therapeutics have revolutionized the treatment and management of neovascular AMD (nAMD) with favorable visual and anatomical outcomes. AREAS COVERED: Physicians have a variety of approved therapeutics in their arsenal for patients with varying disease progression and patient-specific needs, with the ultimate goal of achieving optimal visual and anatomic outcomes. The literature search was conducted using PubMed, Google Scholar, and sources from companies' websites, allowing us to locate findings recently presented at conferences. EXPERT OPINION: Scientific advancements in the field have led to newly approved therapeutics and devices, such as the port-delivery system with ranibizumab (PDS), and further investigation is ongoing in the realm of gene therapy for retinal diseases. In addition to efficacy and durability, newer agents must have comparable safety profiles to older agents in order to be used broadly. These options introduce a level of complexity in nAMD treatment; however, physicians to personalize treatment to improve vision in nAMD patients and reduce treatment burden overall.
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Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation.
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This report presents a unique case of a 77-year-old diabetic male patient with bilateral central serous chorioretinopathy (CSCR), who was receiving multiple bilateral intravitreal injections for a presumed diagnosis of wet age-related macular degeneration (AMD). The fundus examination did not show any signs of AMD or diabetic retinopathy (DR). The spectral domain optical coherence tomography (OCT) revealed bilateral subretinal fluid. The neovascular membrane was not visible on OCT angiography. Fundus fluorescein angiography (FFA) confirmed the absence of choroidal neovascularization (CNV). Notably, this represents a unique case of an elderly patient with CSCR mimicking occult CNV.
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CLINICAL RELEVANCE: The challenges of establishing retinal screening programs in rural settings may be mitigated by the emergence of deep-learning systems for early disease detection. BACKGROUND: Deep-learning systems have demonstrated promising results in retinal disease detection and may be particularly useful in rural settings where accessibility remains a barrier to equitable service provision. This study aims to evaluate the real-world performance of Thirona RetCAD for the detection of referable diabetic retinopathy and age-related macular degeneration in a rural Australian population. METHODS: Colour fundus images from participants with known diabetic retinopathy or age-related macular degeneration were randomly selected from ophthalmology clinics in four rural Australian centres. Grading was confirmed retrospectively by two retinal specialists. RetCAD produced a quantitative measure (0-100) for DR and AMD severity. The area under the ROC curve (AUC) was calculated. Sensitivity, specificity, and positive and negative predictive values were calculated at a pre-defined cut-point of ≥50. RESULTS: A total of 150 images from 82 participants were included. The mean age (SD) was 64.0 (12.8) years. Seventy-nine (52.7%) eyes had evidence of referable DR, while 54 (36.0%) had evidence of referable AMD. The AUC for referable DR detection was 0.971 (95% CI 0.950-0.936) with a sensitivity of 86.1% (76.8%-92.0%) and a specificity of 91.6% (82.8%-96.1%) at the pre-defined cut-point. Using the Youden Index method, the optimal cut-point was 41.2 (sensitivity 93.7%, specificity 90.1%). The AUC for the detection of referable AMD was 0.880 (0.824-0.936). At the pre-defined cut-point sensitivity was 88.9% (77.8%-94.8%) and specificity was 66.7% (56.8%-75.3%). The optimal cut-point was 52.6 (sensitivity 87.0%, specificity 75.0%). CONCLUSION: RetCAD is comparable with but does not outperform equivalent deep-learning systems for retinal disease detection. RetCAD may be suitable as an automated screening tool in a rural Australian setting.
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Non-exudative choroidal and/or macular neovascularizations (NV) represent nowadays a common finding in different retinal disorders. The introduction of non-invasive techniques such as structural optical coherence tomography (OCT) and OCT angiography (OCTA) allowed for easy detection and follow-up of non-exudative NVs. Recognized as a distinct entity, these lesions demonstrate a high variability in terms of pathophysiology, morphology, and prognostic implications. In the absence of a consensus regarding correct classification of subtypes of non-exudative NVs, accurate management through strict follow-up strategies and prompt treatment is required. In this review we offer a comprehensive overview of the non-exudative NV spectrum in various retinal diseases aiming to provide a deeper insight into this clinical entity.
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PURPOSE: This study aimed to investigate the association between the CC-cytokine ligand-2 (CCL2) 2518A/G (rs1024611) single nucleotide polymorphism (SNP) and susceptibility to age-related macular degeneration (AMD). METHODS: PubMed, Embase, Web of Science, and other databases were searched for articles published before August 24, 2023. After searching, data extraction, and quality assessment, meta-analysis and trial sequential analysis were conducted using RevMan 5.4, Stata 17.0, and TSA 0.9.5.10 Beta software. Combined OR, P values, and 95% confidence intervals (CIs) were calculated. Sensitivity analysis, subgroup analysis and publication bias assessment were also performed. RESULTS: Six articles, comprising 1186 cases and 1124 controls, were included. No significant statistical difference was found in six main outcomes. However, due to observed heterogeneity and high sensitivity, subgroup analysis was performed, revealing statistically significant differences across different regions. No significant publication bias was observed. Trial sequential analysis suggested the need for additional follow-up case-control studies to further validate the findings. CONCLUSION: The CCL2 gene 2518A/G (rs1024611) polymorphism is associated with AMD susceptibility. Among Caucasian populations in West Asia and Europe, the G allele is protective against AMD, whereas in East and South Asia, it poses a risk factor.
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Quimiocina CCL2 , Predisposição Genética para Doença , Degeneração Macular , Polimorfismo de Nucleotídeo Único , Humanos , Degeneração Macular/genética , Quimiocina CCL2/genéticaRESUMO
PURPOSE: To investigate aqueous humor cytokine levels in neovascular age-related macular degeneration (nAMD) patients with subretinal fibrosis and to explore the relationship between cytokine levels and disease severity. METHODS: The aqueous humor samples were collected from 16 eyes with subretinal fibrosis due to nAMD (SRFi group), 33 eyes with nAMD without subretinal fibrosis (nAMD group) and 28 eyes with cataract patients (control group). Clinical samples were analyzed for 5 cytokines,including vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), transforming growth factor-α (TGF-α), platelet-derived growth factor-BB (PDGF-BB). RESULTS: Aqueous humor cytokines VEGF and bFGF were significantly higher in nAMD patients than controls (all P < 0.05), and VEGF, bFGF and TGF-α levels were significantly higher in SRFi patients than controls (all P < 0.05). No significant differences in 4 cytokine levels were observed between nAMD and SRFi patients in aqueous humor. We also identified a positive correlation between the aqueous humor levels of IL-6 and VEGF in the SRFi group, while bFGF and TGF-α in the nAMD group. Moreover, VEGF levels were strongly related to BCVA, and bFGF levels were positively related to the maximum thickness of subretinal hyperreflective material (SHRM) in fibrosis due to nAMD. CONCLUSION: VEGF and bFGF levels in aqueous humor were elevated in macular neovascularization with and without subretinal fibrosis. TGF-α levels exclusively differed in neovascular AMD with fibrosis. Cytokines are distributed differently and play a synergistic role in different stages (angiogenesis and fibrogenesis) of nAMD. The bFGF levels could predict the negative prognosis in fibrosis due to nAMD.
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Humor Aquoso , Citocinas , Fibrose , Humanos , Humor Aquoso/metabolismo , Masculino , Feminino , Idoso , Fibrose/metabolismo , Citocinas/metabolismo , Degeneração Macular Exsudativa/metabolismo , Degeneração Macular Exsudativa/diagnóstico , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos , Acuidade Visual , AngiofluoresceinografiaRESUMO
Neovascular age-related macular degeneration (nARMD) is an important cause of visual impairment and blindness in the elderly, with choroidal neovascularization in the macula as the main pathological feature. The onset of nARMD is closely related to factors including age, oxidative stress, and lipid metabolism. Vascular endothelial growth factor (VEGF) is an important factor contributing to nARMD as well as choroidal neovascularization and retinal leakage formation. At present, anti-VEGF therapy is the only treatment that improves vision and halts disease progression in most patients, making anti-VEGF drugs a landmark development for nARMD treatment. Although intravitreal injection of anti-VEGF drugs has become the first-line treatment for nARMD, this treatment has many shortcomings including repeated injections, poor or no response in some patients, and complications such as retinal fibrosis. As a result, several new anti-VEGF drugs are being developed. This review provides a discussion of these new anti-VEGF drugs for the treatment of nARMD.
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INTRODUCTION: This study evaluated the cost-effectiveness of anti-vascular endothelial growth factor (VEGF) therapies for subtypes of neovascular age-related macular degeneration (nAMD) from the societal perspective, and for any nAMD from the patient perspective in Japan. METHODS: A Markov model was developed to simulate the lifetime transitions of a cohort of patients with nAMD through various health states based on the involvement of nAMD, the treatment status, and decimal best-corrected visual acuity. Ranibizumab biosimilar was compared with aflibercept from the societal perspective regardless of treatment regimen for the analysis of three subtypes (typical nAMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP)). Two analyses from the patient perspective focusing on the treat-and-extend regimens were performed, one with a cap on patients' copayments and one without. Ranibizumab biosimilar was compared with branded ranibizumab, aflibercept, aflibercept as the loading dose switching to ranibizumab biosimilar during maintenance (aflibercept switching to ranibizumab biosimilar), and best supportive care (BSC), for patients with any nAMD. RESULTS: In the subtype analyses, ranibizumab biosimilar when compared with aflibercept resulted in incremental quality-adjusted life years (QALYs) of - 0.015, 0.026, and 0.009, and the incremental costs of Japanese yen (JPY) - 50,447, JPY - 997,243, and JPY - 1,286,570 for typical nAMD, PCV, and RAP, respectively. From the patient perspective, ranibizumab biosimilar had incremental QALYs of 0.015, 0.009, and 0.307, compared with aflibercept, aflibercept switching to ranibizumab biosimilar, and BSC, respectively. The incremental costs for ranibizumab biosimilar over a patient lifetime excluding the cap on copayment were estimated to be JPY - 138,948, JPY - 391,935, JPY - 209,099, and JPY - 6,377,345, compared with branded ranibizumab, aflibercept, aflibercept switching to ranibizumab biosimilar, and BSC, respectively. CONCLUSIONS: Ranibizumab biosimilar was demonstrated as a cost-saving option compared to aflibercept across all subtypes of nAMD, irrespective of the perspectives considered.
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Ferrous ion accumulation and lethal oxidative stress mediate irreversible retinal pigment epithelial (RPE) cell ferroptosis and subsequent photoreceptor degeneration, a potential key pathogenic factor in the onset of dry age-related macular degeneration (dAMD), causing irreversible vision loss in the global elderly population. However, currently, no effective interventional treatment strategy exists in clinical practice. Herein, lesion site-targeted melanin-like nanoparticles, named ConA-MelNPs, are designed as a novel ferroptosis inhibitor for retinal degenerative diseases. ConA-MelNPs possessed chelating iron ion characteristics, alleviating severe mitochondrial damage caused by oxidative stress and protecting RPE cells from ferroptosis induced by sodium iodate (NaIO3). In a preclinical dAMD mouse model, a single intravitreal injection of ConA-MelNPs yielded significant responses in electroretinograms and visually-driven optomotor responses in visually impaired mice, resisting the challenge posed by secondary NaIO3-induced injuries, with the long-term sustainability of its therapeutic effect. Mechanistically, ConA-MelNPs achieve a therapeutic effect by interrupting the detrimental cascade involving "RPE cell ferroptosis, lethal oxidative stress, and microglial proinflammatory activation," affording the restoration of retinal homeostasis. The synthesized ConA-MelNPs demonstrated good biosafety, with no detected ophthalmic or systemic side effects. Collectively, ConA-MelNPs are proposed as a promising therapeutic option for atrophic retinal diseases such as dAMD.
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PURPOSE: This review focuses on extensive macular atrophy with pseudodrusen-like appearance (EMAP), a recently described maculopathy presenting with pseudodrusen-like lesions and chorioretinal atrophy more pronounced in the vertical axis. METHODS: Narrative review of the literature published until May 2024. RESULTS: The early onset age of EMAP (50-55 years) and its distinctive natural history, which includes night blindness followed by severe vision loss, differentiate it from atrophic age-related macular degeneration (AMD). A clear pathogenesis has not been determined, but risk factors include female gender and complement system abnormalities (altered levels of C3 and CH50). Moreover, lifelong exposure to pesticides has been suggested as risk factor for direct neuronal degeneration involving rods and cones. In the early phase of the disease, reticular pseudodrusen-like lesions appear in the superior perifovea and tend to coalescence horizontally into a flat, continuous, reflective material localized between the retinal pigmented epithelium and Bruch's membrane. Over time, EMAP causes profound RPE and outer retinal atrophy in the macular area, with a recent classification reporting a 3-stages evolution pattern. Blue autofluorescence showed rapidly evolving atrophy with either hyperautofluorescent or isoautofluorescent borders. Significant similarities between the diffuse-trickling phenotype of geographic atrophy and EMAP have been reported. Macular neovascularization is a possible complication. CONCLUSION: EMAP is specific form of early-onset atrophic macular degeneration with rapid evolution and no treatment. Further studies are needed to assess the best management.
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We provide an overview of the expanding literature on the role of cytokines and immune mediators in pathophysiology of age-related macular degeneration (AMD). Although many immunological mediators have been linked to AMD pathophysiology, the broader mechanistic picture remains unclear with substantial variations in the levels of evidence supporting these mediators. Therefore, we reviewed the literature considering the varying levels of supporting evidence. A Medical Subject Headings (MeSH) term-based literature research was conducted in September, 2023, consisting of the MeSH terms "cytokine" and "Age-related macular degeneration" connected by the operator "AND". After screening the publications by title, abstract, and full text, a total of 146 publications were included. The proinflammatory cytokines IL-1ß (especially in basic research studies), IL-6, IL-8, IL-18, TNF-α, and MCP-1 are the most extensively characterised cytokines/chemokines, highlighting the role of local inflammasome activation and altered macrophage function in the AMD pathophysiology. Among the antiinflammatory mediators IL-4, IL-10, and TGF-ß were found to be the most extensively characterised, with IL-4 driving and IL-10 and TGF-ß suppressing disease progression. Despite the extensive literature on this topic, a profound understanding of AMD pathophysiology has not yet been achieved. Therefore, further studies are needed to identify potential therapeutic targets, followed by clinical studies.
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Cell adhesion to the extracellular matrix and its natural outcome of cell spreading, along with the maintenance of barrier activity, are essential behaviors of epithelial cells, including retinal pigment epithelium (RPE). Disruptions in these characteristics can result in severe vision-threatening diseases such as diabetic macular edema and age-related macular degeneration. However, the precise mechanisms underlying how RPE cells regulate their barrier integrity and cell spreading are not fully understood. This study aims to elucidate the relative importance of upper glycolytic components in governing these cellular behaviors of RPE cells. Electric Cell-Substrate Impedance Sensing (ECIS) technology was utilized to assess in real-time the effects of targeting various upper glycolytic enzymes on RPE barrier function and cell spreading by measuring cell resistance and capacitance, respectively. Specific inhibitors used included WZB117 for Glut1 inhibition, Lonidamine for Hexokinase inhibition, PFK158 for PFKFB3/PFK axis inhibition, and TDZD-8 for Aldolase inhibition. Additionally, the viability of RPE cells was evaluated using a lactate dehydrogenase (LDH) cytotoxicity assay. The most significant decrease in electrical resistance and increase in capacitance of RPE cells were observed due to dose-dependent inhibition of Glut1 using WZB117, as well as Aldolase inhibition with TDZD-8. LDH level analysis at 24-72 h post-treatment with WZB117 (1 and 10 µM) or TDZD-8 (1 µM) showed no significant difference compared to the control, indicating that the disruption of RPE functionality was not attributed to cell death. Lastly, inhibition of other upper glycolytic components, including PFKFB3/PFK with PFK158 or Hexokinase with Lonidamine, did not significantly affect RPE cell behavior. This study provides insights into the varied roles of upper glycolytic components in regulating the functionality of RPE cells. Specifically, it highlights the critical roles of Glut1 and Aldolase in preserving barrier integrity and promoting RPE cell adhesion and spreading. Such understanding will guide the development of safe interventions to treat RPE cell dysfunction in various retinal disorders.
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Glicólise , Epitélio Pigmentado da Retina , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/citologia , Glicólise/efeitos dos fármacos , Humanos , Transportador de Glucose Tipo 1/metabolismo , Hexoquinase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Impedância Elétrica , Fosfofrutoquinase-2/metabolismo , Fosfofrutoquinase-2/antagonistas & inibidoresRESUMO
Purpose: To evaluate the readability, accountability, accessibility, and source of online patient education materials for treatment of age-related macular degeneration (AMD) and to quantify public interest in Syfovre and geographic atrophy after US Food and Drug Administration (FDA) approval. Methods: Websites were classified into 4 categories by information source. Readability was assessed using 5 validated readability indices. Accountability was assessed using 4 benchmarks of the Journal of the American Medical Association (JAMA). Accessibility was evaluated using 3 established criteria. The Google Trends tool was used to evaluate temporal trends in public interest in "Syfovre" and "geographic atrophy" in the months after FDA approval. Results: Of 100 websites analyzed, 22% were written below the recommended sixth-grade reading level. The mean (±SD) grade level of analyzed articles was 9.76 ± 3.35. Websites averaged 1.40 ± 1.39 (of 4) JAMA accountability metrics. The majority of articles (67%) were from private practice/independent organizations. A significant increase in the public interest in the terms "Syfovre" and "geographic atrophy" after FDA approval was found with the Google Trends tool (P < .001). Conclusions: Patient education materials related to AMD treatment are often written at inappropriate reading levels and lack established accountability and accessibility metrics. Articles from national organizations ranked highest on accessibility metrics but were less visible on a Google search, suggesting the need for visibility-enhancing measures. Patient education materials related to the term "Syfovre" had the highest average reading level and low accountability, suggesting the need to modify resources to best address the needs of an increasingly curious public.
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Background: Age-related Macular Degeneration (AMD) poses a growing global health concern as the leading cause of central vision loss in elderly people. Objection: This study focuses on unraveling the intricate involvement of Natural Killer (NK) cells in AMD, shedding light on their immune responses and cytokine regulatory roles. Methods: Transcriptomic data from the Gene Expression Omnibus database were utilized, employing single-cell RNA-seq analysis. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and single-cell regulatory network inference and clustering (SCENIC) analysis were applied to reveal the regulatory mechanisms of NK cells in early-stage AMD patients. Machine learning models, such as random forests and decision trees, were employed to screen hub genes and key transcription factors (TFs) associated with AMD. Results: Distinct cell clusters were identified in the present study, especially the T/NK cluster, with a notable increase in NK cell abundance observed in AMD. Cell-cell communication analyses revealed altered interactions, particularly in NK cells, indicating their potential role in AMD pathogenesis. HdWGCNA highlighted the turquoise module, enriched in inflammation-related pathways, as significantly associated with AMD in NK cells. The SCENIC analysis identified key TFs in NK cell regulatory networks. The integration of hub genes and TFs identified CREM, FOXP1, IRF1, NFKB2, and USF2 as potential predictors for AMD through machine learning. Conclusion: This comprehensive approach enhances our understanding of NK cell dynamics, signaling alterations, and potential predictive models for AMD. The identified TFs provide new avenues for molecular interventions and highlight the intricate relationship between NK cells and AMD pathogenesis. Overall, this study contributes valuable insights for advancing our understanding and management of AMD.
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Purpose: To report a case of a full-thickness macular hole (FTMH) associated with a retinal pigment epithelium (RPE) tear after anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nvAMD), which was successfully closed by vitreous surgery. Observations: A 73-year-old man with nvAMD in the right eye received an intravitreal aflibercept injection due to enlarged pigment epithelial detachment. However, 2 days after the third injection, the patient experienced a sudden decline in vision. An FTMH with a tear in the underlying RPE was detected. The FTMH was closed using vitrectomy combined with the inverted internal limiting membrane (ILM) flap technique. Conclusions and Importance: Our case highlights a rare complication of both an FTMH and an RPE tear after anti-VEGF therapy. Vitrectomy, with the inverted ILM flap technique, proved effective in closing the FTMH despite the complexity of the case.
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Purpose: To evaluate the feasibility and outcomes of implanting the Smaller-Incision New-Generation Implantable Miniature Telescope (SING IMT) in pseudophakic patients affected by late-stage dry AMD. Subjects: Five pseudophakic patients' eyes with stable dry AMD were suitable for SING IMT implantation. Four eyes were excluded because of previous YAG laser capsulotomy. Patients underwent preoperative assessments, including visual acuity measurements and OCT scans. Methods: Surgical procedures were performed under peribulbar anesthesia, with careful IOL removal and SING IMT implantation. Postoperative follow-up was conducted at regular intervals to monitor visual acuity, device positioning and complications. Results: Postoperative outcomes demonstrated improvements in visual acuity for most patients with an average gain in CDVA (Corrected Distance Visual Acuity) and CNVA (Corrected Near Visual Acuity) of 16,8 ± 10,2 and 13,8 ± 7,4 ETDRS letters, respectively. Limited complications have been observed. In one case, we observed dislocation of the device into the vitreous chamber, which we managed through vitrectomy and scleral fixation of the SING IMT using GoreTex suture. Conclusions: Despite being traditionally contraindicated for pseudophakic patients, SING IMT implantation in selected cases yielded favorable outcomes, indicating potential benefits for this population. Further research with larger sample sizes and longer follow-up periods is warranted to refine patient selection criteria and optimize surgical techniques.
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Purpose: To evaluate the safety of subretinal injection of cord blood platelet-rich plasma (CB-PRP) and its possible effect in eyes affected by geographic atrophy (GA) associated with dry age-related macular degeneration (d-AMD). Design: Interventional, open-label study started in January 2021 with follow-up at 12 months (the Si.Cord Study). This study was a single-center, nonrandomized, sequential-assigned clinical trial conducted in Rome, Italy, at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (ClinicalTrials.gov NCT04636853). Participants: Thirteen patients (26 eyes) with bilateral d-AMD-related GA were enrolled. One eye from each patient (with more advanced GA) underwent CB-PRP treatment, and the fellow eye was considered the control. All patients participated in follow-up at 12 months. Intervention: All 13 eyes received 23-gauge (G) vitrectomy and subretinal injection of CB-PRP using a 41-gauge needle. Main Outcomes and Measures: Best-corrected visual acuity (BCVA) with ETDRS letters, central macular thickness using OCT, and atrophic area measured on en face OCT images were assessed at baseline, 1, 3, 6, and 12 months. Results: The BCVA in the treated group was 34.46 ± 20.8 ETDRS at baseline, 40.84 ± 20.52 at 1 month, 40.07 ± 20.34 at 3 months, 39.38 ± 19.84 at 6 months, and 35.84 ± 18.38 at 12 months. In the untreated group, the BCVA was 53 ± 21.1 ETDRS letters at baseline, 51.54 ± 20.99 at 1 month, 46.62 ± 19.47 at 3 months, 46.85 ± 18.58 at 6 months, and 43.92 ± 17.97 at 12 months (2-way analysis of variance: interaction of treatment by eye or time, P = 0.084). Central macular thickness did not show a significant intereye difference at 12 months (P = 0.97). The atrophic geographic areas tended to increase in both treated and fellow eyes at 12 months (P < 0.0001). No inflammatory reaction, endophthalmitis, retinal detachment, uveitis, or other complications due to the subretinal injection of CB-PRP were observed during the follow-up. Conclusions: Subretinal injection of CB-PRP could be safely used for d-AMD in its GA form. Despite its safety, a larger cohort of patients, and probably a new way of administration, will be needed to understand whether the CB-PRP could have a role in the GA treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.