The Role of Laser Photocoagulation in Treating Diabetic Macular Edema in the Era of Intravitreal Drug Administration: A Descriptive Review.

Background and Objectives: This study aimed to elucidate the role of laser photocoagulation therapy in the treatment of diabetic macular edema (DME) as an alternative to, or in conjunction with, the first-line treatment, anti-vascular endothelial growth factor (VEGF). Materials and Methods: A comprehensive literature search to identify studies that evaluated the efficacy of laser photocoagulation therapy in the management of DME was performed. The relevant findings of the efficacy of focal/grid laser therapy from data in randomized, controlled trials were synthesized, and the potential of new laser technologies, such as navigated laser systems, pattern scan lasers, and subthreshold lasers, was explored. The usefulness of multimodal imaging-guided laser therapy was also evaluated, with a focus on the potential contribution to anti-VEGF therapy. Results: Focal laser photocoagulation targeting microaneurysms remains an effective therapeutic approach to chronic refractory edema, despite the widespread use of anti-VEGF therapy. To achieve the best possible treatment outcomes, precise identification of microaneurysms is essential. This requires the use of multimodal imaging-guided, highly accurate, minimally invasive coagulation techniques. Subthreshold laser therapy can also reduce the frequency of anti-VEGF injections and minimize treatment burden. Conclusions: Further studies are needed to determine the optimal timing and settings for laser photocoagulation therapy and the potential of new laser technologies in the management of DME. Nevertheless, laser photocoagulation therapy plays an important role in the management of DME, in conjunction with anti-VEGF therapy.

Review of clinical studies and recommendation for a therapeutic flow chart for diabetic macular edema.

Diabetic macular edema (DME), characterized by exudative fluid accumulation in the macula, is the most common form of sight-threatening retinopathy in patients with diabetes. The management of DME has changed considerably in recent years, especially following the development of intravitreal anti-vascular endothelial growth factor therapy which has emerged as a first-line therapy for center-involved DME. Laser treatment, intravitreal steroid therapy, and vitrectomy are also important treatment options for DME. We believe that it is important to choose the most appropriate treatment option for DME based on the clinical evidences, in addition to the careful consideration of individual patients' general or ocular condition, DME characteristics, patients' motivation, and compliance to the treatment in real-world clinical practice. In this review, we have summarized important clinical evidences for the main treatments for DME, presented an expert review for these evidences, and proposed a recommended therapeutic flow chart for DME. We hope that our review of the clinical evidences and the recommended therapeutic flow chart for DME will contribute to better treatment outcome for DME.

Suppression of Retinal Neovascularization by Anti-CCR3 Treatment in an Oxygen-Induced Retinopathy Model in Mice.

PURPOSE: To investigate the association between retinal neovascularization and the CC chemokine receptor-3 (CCR3) in a mouse model of oxygen-induced retinopathy (OIR). METHODS: An OIR model in C57BL/6J mice was used as a retinal neovascularization model. An enzyme-linked immunosorbent assay was performed to evaluate the chronological change in vascular endothelial growth factor A (VEGF-A) and eotaxin expressions. CCR3 and VEGF subtype expression in the retina was examined using real-time RT-PCR, and CCR3, eotaxin, VEGF-A, and CD31 expression was examined immunohistochemically. A CCR3 neutralizing antibody (Ab) was injected into the vitreous humor on both postnatal days 12 (P12) and 14 (P14). Retinal neovascularizations were quantified by measurement of the percentages of neovascular area. RESULTS: The mean eotaxin and VEGF-A protein level was significantly downregulated at P10 and P12 and was significantly upregulated at P14 and P17 (p < 0.05). CCR3 mRNA expression was significantly upregulated at P12 (p < 0.05). VEGF164 mRNA expression was significantly upregulated at P14 (p < 0.05). The areas of vaso-obliteration and neovascularization were significantly suppressed in anti-CCR3 Ab-treated eyes (p < 0.05). Anti-CCR3 Ab treatment suppressed VEGF and eotaxin but not monocyte chemoattractant protein-1. And VEGF 164 mRNA but not VEGF120 mRNA was suppressed by anti-CCR3 Ab treatment. CONCLUSIONS: The present data suggest that anti-CCR3 treatment can suppress retinal neovascularization. Anti-CCR3 treatment may have potential as a new therapy for retinopathies with retinal neovascularization such as diabetic retinopathy and retinopathy of prematurity.

CCR3 is a target for age-related macular degeneration diagnosis and therapy.

Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.

ENLARGEMENT OF FOVEAL AVASCULAR ZONE IN DIABETIC EYES EVALUATED BY EN FACE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To evaluate the area of the foveal avascular zone (FAZ) detected by en face OCTA (AngioVue, Avanti OCT; Optovue) in healthy and diabetic eyes. METHODS: Retrospective chart review of patients who underwent fundus examination including en face OCTA. Eyes with proliferative diabetic retinopathy and history of laser photocoagulation were excluded. The FAZ area in the superficial and deep plexus layers were measured and evaluated using ImageJ software. RESULTS: The FAZ area in the superficial layer was 0.25 ± 0.06 mm² in healthy eyes (n = 19), whereas it was 0.37 ± 0.07 mm² in diabetic eyes without retinopathy (n = 24) and 0.38 ± 0.11 mm² in eyes with diabetic retinopathy (n = 20). Diabetic eyes showed statistically significant FAZ enlargement compared with healthy eyes, regardless of the presence of retinopathy (P < 0.01). The FAZ area in the deep plexus layer was also significantly larger in diabetic eyes than in healthy eyes (P < 0.01). CONCLUSION: Our data suggest that diabetic eyes show retinal microcirculation impairment in the macula even before retinopathy develops. En face OCTA is a useful noninvasive screening tool for detecting early microcirculatory disturbance in patients with diabetes.

Short pulse laser induces less inflammatory cytokines in the murine retina after laser photocoagulation.

AIMS: The purpose of this study was to evaluate the effect of pulse duration on the expression of inflammatory cytokines in the murine retina after laser photocoagulation treatment with a PASCAL(®) pattern scan laser photocoagulator and conventional laser treatment. METHODS: Retinal scatter laser photocoagulation was performed on C57BL/6J mice using a short pulse (10 ms) with a PASCAL laser or conventional settings (100 ms) with a multicolor laser. Eyes were enucleated before treatment (control) and 1 day, 3 days and 7 days after treatment. The levels of inflammatory cytokines (i.e., VEGF, MCP-1, RANTES and IL-6) in the retina/choroid were quantified by an ELISA. The expression patterns of VEGF and macrophages (i.e., F4/80) in the retina/choroid were evaluated by immunohistochemistry. RESULTS: The levels of RANTES, IL-6 and MCP-1 after PASCAL and conventional laser treatments were significantly elevated compared with controls (p < 0.05). Conventional laser treatment, but not PASCAL treatment, resulted in the up-regulation of VEGF. RANTES and IL-6 levels on day 1 and MCP-1 levels on day 3 in the sensory retina were also significantly up-regulated with conventional laser treatment compared with PASCAL treatment (p < 0.05). Immunohistochemical analysis showed that PASCAL treatment was associated with lower VEGF and F4/80 expression levels compared with conventional laser treatment. CONCLUSIONS: Our data suggested that the short pulse duration induced fewer inflammatory cytokines in the sensory retina compared with the conventional pulse duration. Short pulse laser photocoagulation with the PASCAL may prevent macular edema after panretinal photocoagulation.

Intravitreal ranibizumab for patients with neovascular age-related macular degeneration with good baseline visual acuity.

PURPOSE: To report the 1-year results of intravitreal ranibizumab (IVR) injections for neovascular age-related macular degeneration (nAMD) in patients with good baseline visual acuity (VA). METHODS: Thirty-six eyes of 36 patients with nAMD with best-corrected VAs (BCVAs) >0.6 (equal to 0.22 in the logarithm of the minimum angle of resolution unit) were enrolled. IVR was the primary treatment; additional treatment was administered as needed. BCVAs and central retinal thickness (CRT) were measured periodically. RESULTS: The mean number of injections at month 12 was 3.3. The mean BCVAs were 0.11 ± 0.02 at baseline and 0.12 ± 0.03 at month 12, which did not significantly differ. The mean CRT significantly improved from 320 ± 15 to 254 ± 12 µm at month 12 (p < 0.01). Photodynamic therapy was applied in 2 cases because of frequent recurrences. CONCLUSIONS: IVR maintained VA and improved morphological changes in wet AMD with good baseline VA.

[Evaluation of Diabetic Retinopathy with Ultra-wide Field Fluorescein Angiography].

PURPOSE: The ultra-wide field scanning laser ophthalmoscope (Optos 200Tx, Optos, Scotland, UK) provides retinal images of 200 degrees in a single capture which covers more than 80% of the retina. Fluorescein angiography with Optos 200Tx is useful to visualize the microcirculations of peripheral retina. It allows to evaluate peripheral pathology more precisely than conventional fundus photography. The purpose of this study was to evaluate the fluorescein angiography findings of eyes in diabetic retinopathy patients by using ultra-wide field fluoresrein angiography. SUBJECTS AND METHODS: Ultra-wide field fluoresrein angiography was performed on 154 eyes of 77 patients with diabetic retinopathy. We divided the fundus into three zones, the posterior pole, the mid-periphery and the far-periphery. Capillary non-perfusion areas and retinal neovascularization in each zone were evaluated. RESULTS: One hundred thirty eyes (84%) exhibited capillary non-perfusion areas. Ten eyes (7.7%) were found to have a capillary non-perfusion area only in the far-periphery. Seventy two eyes (47%) exhibited retinal neovascularization. Retinal neovascularization was observed most in the mid-periphery (58 eyes; 81%); 8 eyes (11%) were found to have retinal neovascularization in the far-periphery. CONCLUSION: Ultra-wide field fluorescein angiography revealed the microcirculatory disturbance in the peripheral retina of diabetic patients not evident by conventional fundus photography and it was useful for evaluating the status of the diabetic retinopathy.

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.

Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.

[Comparison of outcomes of conventional laser versus pascal laser for diabetic retinopathy].

PURPOSE: To assess the efficacy and outcomes of PASCAL laser versus conventional laser for panretinal photocoagulation (PRP) in the treatment of diabetic retinopathy. METHODS: A retrospective chart review of 26 eyes at Nagoya City University Hospital which had undergone PRP with a follow-up of at least 6 months. The study endpoints were change in visual outcome, central retinal thickness (CRT), laser setting parameters, and total number of PRP and complications. RESULTS: Ten eyes of conventional laser-treated patients and 16 eyes of PASCAL-treated patients were reviewed. There were significant differences in the laser treating parameters between the PASCAL laser treatment and conventional laser treatment in power, duration, number of sessions and total spot counts including additional treatments (p < 0.01). Among the patients who had undergone PRP in the PASCAL group there was an average of 4195 spots, larger than the conventional laser group (p < 0.0001). There were no significant differences between PASCAL group and conventional laser group in complications and in ability to prevent visual loss and CRT. CONCLUSION: Our data suggested that PASCAL laser might need tighter spacing and more total spot counts to achieve an effect equal to traditional conventional laser treatment.

A Case of Posterior Polar Hemispheric Choroidal Dystrophy Successfully Diagnosed With Ultra-Widefield Fundus Autofluorescence and Optical Coherence Tomography Angiography.

We report a case of a 78-year-old man presenting with uncertain visual field loss, ultimately identified as posterior polar hemispheric choroidal dystrophy (PPHCD) using ultra-widefield fundus autofluorescence (FAF) and optical coherence tomography angiography (OCTA). The patient initially reported blurred vision in the left eye and had a previous diagnosis of suspected bilateral normal tension glaucoma based on optic nerve head excavation and static perimetry measurements. Detailed examination revealed suspicious retinal atrophy. Notably, the patient had a tigroid fundus, which complicated the correlation between visual field defect and chorioretinal atrophy. Ultra-widefield FAF highlighted mosaic/patchy hypofluorescent areas, emphasizing this atrophy. OCTA images confirmed choriocapillaris loss in the hemispheric choroidal atrophy and parafoveal atrophy. The combination of these imaging techniques enabled a definitive diagnosis of PPHCD. Long-term follow-up and continued investigation with these imaging modalities may hold promise for a better understanding of disease progression and management in similar cases.

Optimization of individualized faricimab dosing for patients with diabetic macular edema: Protocol for the SWAN open-label, single-arm clinical trial.

PURPOSE: In patients with diabetic macular edema (DME) from YOSEMITE/RHINE, dual angiopoietin-2/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in visual/anatomic improvements with extended dosing. The SWAN trial (jRCTs031230213) will assess the efficacy, durability, and safety of faricimab during the treatment maintenance phase in patients with DME using a treat-and-extend (T&E)-based regimen adapted to clinical practice and the characteristics of patients achieving extended dosing intervals. METHODS: SWAN is a 2-year, open-label, single-arm, interventional, multicenter trial enrolling adults with center-involving DME. All patients will receive three initial faricimab 6.0 mg doses every 4 weeks (Q4W). From week 12 onwards, in patients without active DME, dosing intervals will be extended in 8-week increments up to Q24W. In contrast, patients with active DME (central subfield thickness [CST] >325 µm and intraretinal fluid [IRF] or subretinal fluid [SRF] resulting in vision loss/disease aggravation) will receive a dose within a day and the dosing interval will be shortened by 4 weeks to a minimum of Q8W relative to the previous dosing interval. Recruitment commenced in August 2023 across a planned 16 sites in Japan. RESULTS: The primary endpoint is change in best-corrected visual acuity (BCVA) from baseline at 1 year (averaged over weeks 52, 56, and 60). Key secondary endpoints include: change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire scores over time; proportion of patients with BCVA (decimal visual acuity) ≥0.5, ≥0.7, ≥1.0, or ≤0.1; proportion of patients with absence of DME, and IRF and/or SRF over time. Safety endpoints include incidence/severity of ocular/nonocular adverse events. CONCLUSIONS: The SWAN trial is expected to provide evidence to support individualized faricimab dosing regimens, with the potential to reduce the burden of frequent treatments on patients, caregivers, and healthcare systems.

Efficient delivery of siRNA by atelocollagen in a murine laser-induced choroidal neovascularization model.

PURPOSE: Previous studies have shown that small interfering RNAs (siRNAs) could suppress angiogenesis via stimulation of toll-like receptor-3 (TLR3). The purpose of this study was to determine the efficacy of atelocollagen to deliver siRNA without TLR3 stimulation in the laser-induced choroidal neovascularization (CNV) model. METHODS: CNV was induced by laser injury in C57BL/6J mice and volumes were measured 7 days later. Nontargeted siRNA, 21-nucleotide (nt) siRNA-Luc (Luciferase) and 21-nt siRNA-Vegfa were injected into the vitreous following injury. Atelocollagen was incubated with naked 21-nt siRNAs before injection. To block TLR3 endosomal activity, chloroquine was injected intravitreously after laser injury. RESULTS: The mean CNV volumes were significantly smaller in the naked siRNA-Luc, naked siRNA-Vegfa, or siRNA-Vegfa/atelocollagen complex compared with PBS, atelocollagen or siRNA-Luc/atelocollagen complex-injected mice (p < 0.05). CONCLUSION: These findings demonstrate that atelocollagen may deliver siRNA without nonspecific TLR3 stimulation in the murine laser-CNV model.

[Preference and trends of treatment for diabetic retinopathy in Korea and Japan].

PURPOSE: The difference in preferences and trends of treatment in each country are important to plan an international interventional clinical study in eastern Asia. Accordingly, we compared the preferences and trends in treatment of diabetic retinopathy in Korea and Japan. METHODS: We obtained answers to questionnaires (49 questions) from 91 ophthalmologists of the Korean Retina Society and 120 ophthalmologists of the Japanese Society of Ophthalmic Diabetology in June/July, 2012. Some of the questions were modified from The Preferences and Trends (PAT) survey of American Society of Retina Specialists. RESULTS: The first choice for a patient with vision of 20/25, clinically significant diabetic macular edema and clear evidence of intraretinal fluid on spectral domain OCT were intravitreal anti-vascular endothelial growth factor agent (31%) in Korea and sub-Tenon steroid (22%) in Japan. The management for a patient with refractory neovascular glaucoma who has closed angle and persistent intraocular pressure elevation (>50 mmHg) were glaucoma drainage implant surgery (74%) in Korea and trabeculectomy (57%) in Japan. CONCLUSION: There were differences in preferences and trends of treatment for diabetic retinopathy between Korea and Japan. The differences need to be considered when planning international clinical studies.

Quantitative Evaluation of Fundus Autofluorescence in Laser Photocoagulation Scars for Diabetic Retinopathy: Conventional vs. Short-Pulse Laser.

Short-pulse laser is popular for its advantages like less pain. However, its effectiveness is still debated. The aim of this study was to compare fundus autofluorescence (FAF) luminosity changes of laser photocoagulation scars between the conventional laser (0.2 s) and the short-pulse laser (0.02 s) for diabetic retinopathy. Conventional and short-pulse laser photocoagulations were performed in six and seven eyes, respectively. FAF images were captured at 1, 3, 6, 12, and 18 months after the treatments. To evaluate FAF, individual gray-scale values of the laser scars adjacent to the retinal arcade vessels were recorded; then, the mean gray values of the scars were divided by the luminosity of arcade vein. The average luminosity ratio of laser scars at 1, 3, 6, 12, and 18 months were 1.51 ± 0.17, 1.26 ± 0.07, 1.21 ± 0.03, 0.95 ± 0.11, and 0.89 ± 0.05 with conventional laser and 1.91 ± 0.13, 1.50 ± 0.15, 1.26 ± 0.08, 1.18 ± 0.06, and 0.97 ± 0.04 with short-pulse laser, respectively. Findings suggest the short-pulse laser displayed delayed hypoautofluorescence progression. This implies potential postponement in post-irradiation atrophic changes, as well as metabolic amelioration delay in the ischemic retina, when compared to conventional laser treatment.

Retinal Microvascular Changes after Intravitreal Triamcinolone Acetonide in Diabetic Macular Edema.

Intravitreal injection of triamcinolone acetonide (TA) is essential for clinical treatment in patients who insufficiently respond to vascular endothelial factor inhibitors for diabetic macular edema (DME). The aim of this study was to investigate microvascular changes treated with TA using optical coherence tomography angiography (OCTA). After TA in twelve eyes of eleven patients with central retinal thickness (CRT), there was a 20% or more reduction observed. Visual acuity, the number of microaneurysms, vessel density, and the foveal avascular zone (FAZ) area were compared before and at 2 months after TA. At baseline, the number of microaneurysms was 2.1 ± 1.1 in the superficial capillary plexuses (SCP) and 2.0 ± 1.1 in the deep capillary plexuses (DCP), with a significant decrease post-treatment to 1.0 ± 1.0 for SCP and 0.8 ± 0.8 for DCP (SCP; p = 0.018, DCP; p = 0.008). There was significant enlargement of the FAZ area from 0.28 ± 0.11 mm2 to 0.32 ± 0.14 mm2 (p = 0.041). There was no significant difference in the visual acuity and vessel density of SCP and DCP. Results indicated that OCTA was useful for the evaluation of qualitative and morphological retinal microcirculation and that intravitreal TA may decrease microaneurysms.

Corneal avascularity is due to soluble VEGF receptor-1.

Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth.

Neovascularization in response to tissue injury consists of the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vessels. We reported recently that 21-nt or longer small interfering RNAs (siRNAs) can suppress hemangiogenesis in mouse models of choroidal neovascularization and dermal wound healing independently of RNA interference by directly activating Toll-like receptor 3 (TLR3), a double-stranded RNA immune receptor, on the cell surface of blood endothelial cells. Here, we show that a 21-nt nontargeted siRNA suppresses both hemangiogenesis and lymphangiogenesis in mouse models of neovascularization induced by corneal sutures or hindlimb ischemia as efficiently as a 21-nt siRNA targeting vascular endothelial growth factor-A. In contrast, a 7-nt nontargeted siRNA, which is too short to activate TLR3, does not block hemangiogenesis or lymphangiogenesis in these models. Exposure to 21-nt siRNA, which we demonstrate is not internalized unless cell-permeating moieties are used, triggers phosphorylation of cell surface TLR3 on lymphatic endothelial cells and induces apoptosis. These findings introduce TLR3 activation as a method of jointly suppressing blood and lymphatic neovascularization and simultaneously raise new concerns about the undesirable effects of siRNAs on both circulatory systems.

Mental Status and Feasibility of an Intravitreal Ranibizumab Treat-and-Extend Regimen in Patients with Neovascular Age-Related Macular Degeneration.

INTRODUCTION: Anti-vascular endothelial growth factor (VEGF) therapy is the first-choice treatment for neovascular age-related macular degeneration (nvAMD); however, patients often are burdened physically, financially, and mentally. We investigated the relationship between mental status and feasibility of an intravitreal ranibizumab treat-and-extend (TAE) regimen for nvAMD. METHODS: In this prospective, multicenter study, 75 patients with nvAMD received ranibizumab intravitreally in a TAE regimen. After two monthly injections, the injection intervals were extended step-by-step to 6, 8, 12, and 16 weeks in eyes with dry maculas on optical coherence tomography (OCT) and, if exudation persisted or relapsed, shortened by one step. The best corrected visual acuity (BCVA) measurement and OCT were performed at baseline and on the same days of the scheduled injections. At baseline, all patients completed a survey, the Hospital Anxiety and Depression Scale (HADS), regarding mental burden. At week 52, patients on the TAE regimen for 1 year completed the HADS and a questionnaire designated to assess treatment-associated mental status. RESULTS: Fifty-one patients (68%) completed the 1-year TAE regimen; 24 eyes (32%) discontinued the TAE regimen because of the rescue treatment, difficulty in completing clinical visits, or financial burden. In 51 eyes on the TAE regimen for 1 year, the mean BCVAs improved from 64.3 letters at baseline to 71.6 letters at week 52. The mean anxiety and depression scores on HADS decreased significantly (p < 0.01) after the 1-year treatment. Women tended to have higher anxiety scores, possibly associated with fear of injection and recurrence, while some men had higher depression scores potentially associated with financial burden, difficulty in completing clinical visits, and subsequent interruption of the TAE regimen especially in eyes with low treatment efficacy. CONCLUSIONS: A TAE regimen of intravitreal ranibizumab injections preserves vision in eyes with nvAMD and reduces mental burden associated with disease relapse. TRIAL REGISTRATION: This clinical study was registered retrospectively on December 22, 2014 with the ClinicalTrials.gov identifier NCT02321839.

Impact of the COVID-19 Pandemic on Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in Japan.

Anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME) improves visual acuity. However, repeated injections during routine outpatient visits are required to maintain this effect. The recent sudden global outbreak of coronavirus disease 2019 (COVID-19) had a major impact on daily life, including medical care, such as the provision of VEGF therapy. We retrospectively investigated the relationship between the number of anti-VEGF injections for DME and the number of new COVID-19-positive patients at 23 centers in Japan. We also surveyed ophthalmologists regarding the impact of the COVID-19 pandemic on anti-VEGF therapy. In the third and fourth waves of the pandemic, when the number of infected patients increased, the number of injections significantly decreased. In the first, third, and fourth waves, the number of injections increased significantly during the last month of each wave. Approximately 60.9% of ophthalmologists reported that the number of injections decreased after the pandemic. Of the facilities, 52.2% extended the clinic visit intervals; however, there was no significant difference in the actual number of injections given between before and after the pandemic. Although the number of injections temporarily decreased, Japanese ophthalmologists maintained the total annual number of anti-VEGF injections for DME during the pandemic.