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Abstract This retrospective study evaluated the real-world safety and effectiveness of switching to intravitreal brolucizumab for refractory neovascular age-related macular degeneration (nAMD). A total of 81 patients who received brolucizumab injections as switch therapy were followed for more than 3 months. A good response was defined as better anatomical improvement or extended injection intervals compared with previous anti-vascular endothelial growth factor (VEGF) treatment over a mean follow-up period of 41.4 weeks. Approximately 82.7% of patients showed a good response after switching. After 1 year, patients showed significant visual gains (+ 6.6 letters, p = 0.006) and central retinal thickness reductions (− 112.6 µm, p

Abstract To investigate angiographic characteristic features of diabetic choroidopathy, as well as choroidal vascular density (CVD) and fractal dimension (CFD) in diabetic eyes and controls using ultra-widefield (UWF) indocyanine green angiography (ICGA). All patients underwent UWF fluorescein angiography and ICGA. Using imageJ software, CVD and CFD was analyzed. SFCT was assessed using spectral-domain optical coherence tomography. The image parameters were compared based on the DR stage and the presence of diabetic macular edema (DME). One-hundred six eyes from 63 patients (59.11 ± 16.31 years; male [%]: 23 [36.5%]) were included in the DM group, and 40 eyes from 22 subjects were included in the control group. The DM group had a mean age of 59.11 ± 16.31 years and a mean HbA1c percentage of 7.72 ± 1.28%. The most common ICGA findings of DC were choroidal hyperpermeability (57.5%), hypofluorescent spots (48.1%). Salt and pepper pattern (19.8%), inverted inflow phenomenon (3.8%), choroidal arterial tortuosity (24.5%), and late choroidal non-perfusion (6.6%) were more common in advanced DR. The CVD, CFD, and SFCT increased as the DR severity progressed. The DME group had a significantly higher CFD and SFCT than the non-DME group (P

Abstract Background To identify factors associated with microvascular recovery after intravitreal bevacizumab or panretinal photocoagulation (PRP) in diabetic retinopathy (DR). Methods We retrospectively reviewed 320 eyes/patients with DR treated with intravitreal bevacizumab and/or PRP. Two consecutive fluorescein angiographies (FAs) of each eye were compared. The number of microaneurysms and the area of capillary non-perfusion were calculated automatically using ImageJ software. Microvascular recovery was defined as a marked reduction in the numbers of microaneurysms (

Abstract To investigate hemodynamic changes in macula-off rhegmatogenous retinal detachment (RRD) and its impact on visual prognosis by comparing with central serous chorioretinopathy (CSC). Using optical coherence tomography angiography (OCTA), vascular density in the superficial capillary plexus and deep capillary plexus (DCP) was retrospectively compared with that in contralateral unaffected eyes in macula-off RRD and CSC eyes. In RRD eyes, pre- and postoperative ultra-widefield (UWF) fluorescein angiography (FA) were obtained to analyze vascular changes. In OCTA, both macula-off RRD and CSC eyes showed less density in macular DCP, compared to the unaffected fellow eyes. Compared to CSC, eyes affected by macula-off RRD showed a reduction in DCP vascular density and an increase in foveal avascular zone area, although it had a much shorter macular detachment period. In macula-off RRD, less density of DCP was strongly correlated with longer duration of detachment, greater ellipsoid zone disruption, and poor visual recovery. In UWF-FA, detached retina showed capillary hypoperfusion, venous stasis and leakage, which were improved after reattachment. In conclusion, macular capillary loss of flow, which was associated with photoreceptor disruption, correlated with duration of detachment in RRD. Early reattachment and reperfusion are required for minimizing macular vasculature and photoreceptor damage in macula-off RRD.

PurposeTo evaluate the clinical characteristics of myopic choroidal neovascularization (mCNV) according to peripapillary atrophy (PPA) and optic disk tilt and to explore whether those myopic disk deformations are associated with the prognosis of mCNV.MethodsPatients with subfoveal mCNV who received intravitreal bevacizumab injection and followed for ≥3 years were included. PPA was quantified as area of the ß-zone PPA/disk area ratio (PDR) and optic disk tilt as the tilt ratio (the longest/shortest disk diameter). We compared the clinical characteristics in terms of PDR and tilt ratio and identified the poor prognostic factors using Logistic regression and Cox proportional hazard model.ResultsAmong 80 eyes of 80 patients, 29 (36.30%) eyes developed macular atrophy during 80.71 ± 34.76 months. PDR and tilt ratio are strongly correlated with each other (P = 0.004). Higher PDR showed significant correlations with longer axial length (P = 0.013), worse baseline and final VA (P = 0.007 and P = 0.047), and thinner subfoveal choroidal thickness (P = 0.039), while higher tilt ratio showed significant correlations only with longer axial length (P = 0.036). High PDR was also an independent risk factor for both macular atrophy (OR = 2.257, P < 0.001) and poor visual outcome (HR = 1.174, P = 0.007), while high disk tilt ratio was not.ConclusionSubfoveal mCNV with higher ß-zone PPA area/disk area ratio had worse functional and structural outcomes.

ObjectiveTo investigate the associations between the macular microvasculature assessed by optical coherence tomography angiography (OCTA) and subclinical atherosclerosis in patients with type 2 diabetes.MethodsWe included patients with type 2 diabetes who received comprehensive medical and ophthalmic evaluations, such as carotid ultrasonography and OCTA at a hospital-based diabetic clinic in a consecutive manner. Among them, 254 eyes with neither diabetic macular edema (DME) nor history of ophthalmic treatment from 254 patients were included. The presence of increased carotid intima-media thickness (IMT) (>1.0 mm) or carotid plaque was defined as subclinical atherosclerosis. OCTA characteristics focused on foveal avascular zone (FAZ) related parameters and parafoveal vessel density (VD) were compared in terms of subclinical atherosclerosis, and risk factors for subclinical atherosclerosis were identified using a multivariate logistic regression analysis.ResultsSubclinical atherosclerosis was observed in 148 patients (58.3%). The subclinical atherosclerosis group were older (p < 0.001), had a greater portion of patients who were men (p = 0.001) and who had hypertension (p = 0.042), had longer diabetes duration (p = 0.014), and lower VD around FAZ (p = 0.010), and parafoveal VD (all p < 0.05). In the multivariate logistic regression analysis, older age (p ≤ 0.001), male sex (p ≤ 0.001), lower VD around FAZ (p = 0.043), lower parafoveal VD of both superficial capillary plexus (SCP) (p = 0.011), and deep capillary plexus (DCP) (p = 0.046) were significant factors for subclinical atherosclerosis.ConclusionThe decrease in VD around FAZ, and the VD loss in parafoveal area of both SCP and DCP were significantly associated with subclinical atherosclerosis in patients with type 2 diabetes, suggesting that common pathogenic mechanisms might predispose to diabetic micro- and macrovascular complications.

Purpose: To describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD). Design: Identical, global, double-masked, randomized, controlled, phase 3 clinical trials. Participants: Adults with treatment-naïve nAMD. Methods: These trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients’ disease activity. Main Outcome Measures: Rationale for trial design and PTI approach. Results: The TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden. Conclusions: The innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients' disease activity while fulfilling health authority requirements for potential registrational efforts.

Abstract Background To report the clinical course and outcomes of adjunctive dexamethasone implants in patients with atopic dermatitis (AD) and retinal detachment (RD) undergoing vitrectomy and silicone oil tamponade. Methods This retrospective, interventional case series included AD patients with RD and various degrees of proliferative vitreoretinopathy (PVR) who were scheduled to undergo vitrectomy. Following total vitrectomy and retinopexy, silicone oil tamponade was performed. Finally, an intraocular dexamethasone implant was injected intravitreally. Anatomical and functional outcomes were assessed at 12 months, and extended follow-up data were also collected. Results Seven eyes from six patients (five male, one female) were included. The median age was 29 (range, 20–38) years. Preoperatively, six eyes were pseudophakic, two eyes had a history of previous vitreoretinal surgery, and one had uveitis. Postoperatively, best-corrected visual acuity improved in two eyes, worsened in one, and remained similar in four. Retinal attachment was maintained in all eyes at 12 months. The major complication was an increase in postoperative intraocular pressure in six eyes, requiring either medical or surgical treatment. During the extended follow-up period (15–37 months), retinas remained attached in all eyes and stable visual acuity was maintained in five. Conclusions Injection of an intraoperative dexamethasone implant to silicone oil-filled eyes appears tolerable and may be beneficial in the surgical management of AD patients with RD and PVR.

Purpose. Retinitis pigmentosa (RP) shows great diversity between genotypes and phenotypes, and it is important to identify the causative genes. This study aimed to analyze the molecular profiles, associated ocular characteristics, and progression of RP in Korean patients. Methods. All the genetic variants in patients with RP, identified using targeted next-generation sequencing (NGS) with a panel of 88 RP-related genes between November 2018 and November 2019, were retrospectively reviewed. All the patients underwent comprehensive ophthalmological evaluations, and their clinical and family histories were recorded. The best-corrected visual acuity (BCVA) deterioration and photoreceptor disruption progression rates were determined based on the major causative mutational genes using nonlinear mixed models, and the differences among them were investigated using the interaction effect. Results. Among the 144 probands, 82 variants in 24 causative genes were identified in 77 families (53.5%). Most of the RP cases were associated with autosomal recessive variants (N = 64 (44.4%)), followed by autosomal dominant (N = 10 (6.9%)) and X-linked variants (N = 3 (2.1%)). The four most frequently affected genes were EYS (N = 15 (10.4%)), USH2A (N = 12 (8.3%)), PDE6B (N = 9 (6.3%)), and RP1 (N = 8 (5.6%)). Epiretinal membranes and cystoid macular edema were frequently noted in the patients with USH2A (75.0%) and PDE6B (50.0%) variants, respectively. During the follow-up period, the BCVA and photoreceptor disruption changes were significantly different among the patients carrying the four common causative genes (P=0.014 and 0.034, resp.). Patients with PDE6B variants showed faster BCVA changes (0.2 LogMAR/10 years), and those with USH2A variants showed the fastest ellipsoid zone disruptions (−170.4 µm/year). Conclusion. In conclusion, our genetic analysis using targeted NGS provides information about the prevalence of RP-associated mutations in Korean patients. Delineating clinical characteristics according to genetic variations may help clinicians identify subtype features and predict the clinical course of RP.

Introduction To evaluate the effects of intravitreal aflibercept injection on retinal nonperfusion in patients with diabetic retinopathy (DR) using ultrawide field (UWF) fluorescein angiography (FA).Research design and methods Thirty-eight eyes of 38 consecutive patients with DR and substantial retinal nonperfusion (nonperfusion index (NPI): nonperfused/total gradable area >0.2) without macular edema were included in this prospective case series. Monthly injections of 2 mg aflibercept were given for 6 months. UWF-fundus photography and UWF-FA images were acquired at baseline, 6 months, and 12 months and evaluated by 2 masked, independent graders for the extent of retinal nonperfusion and vascular leakage. Twenty untreated fellow eyes were analyzed as controls.Results Inter-grader agreement was strong (r=0.875) for NPI measurements. NPI was 0.46±0.10 at baseline; NPI was decreased to 0.43±0.08 (p=0.015) after 6 monthly injections of aflibercept and then slightly increased to 0.44±0.09 (p=0.123) after 6 months of observation. Vascular leakage also significantly decreased by 21.0% at 6 months (p=0.010). Untreated fellow eyes did not show significant changes in NPI and vascular leakage during follow-up. Reduction in retinal nonperfusion was associated with severe nonproliferative diabetic retinopathy (NPDR) (vs PDR, OR 19.119, p=0.025) and higher leakage index (per 0.1, OR 15.152, p=0.020).Conclusions Intensive aflibercept treatment was effective in reducing retinal capillary nonperfusion in patients with DR without macular edema. Severe NPDR and profound vascular leakage were significantly associated with retinal reperfusion after aflibercept treatment.Trial registration number NCT03006081.

Introduction Anti-vascular endothelial growth factor (VEGF) agents are used worldwide for advanced-stage diabetic retinopathy (DR). In contrast, apart from blood glucose control, there are no specific treatments that can limit the progression of early-stage DR that starts with pericyte loss and the destruction of the blood–retinal barrier. Here, we examined the efficacy of aflibercept, a potent anti-VEGF agent, against early-DR pathologies in a murine model of streptozotocin (STZ)-induced DR.Research design and methods STZ was intraperitoneally administered in 8-week-old C57BL/6N male mice. After 4 weeks, the mice were divided into aflibercept-treated and saline-treated groups. Eight weeks after the STZ injection, vascular permeability/leakage was measured with fluorescein angiography in live mice. At 4, 6, and 8 weeks after the STZ injection, the eyes were enucleated, flat-mounted, and stained for platelet-derived growth factor receptor-β to assess pericyte abundance, CD45 to assess leukocyte recruitment, and fluorescein isothiocyanate dextran to assess perfusion. VEGF levels were quantified in each group. The effects of aflibercept on pericyte number, perfusion status, and leukocyte recruitment/accumulation on mice with diabetes retina were evaluated.Results Our murine model successfully replicated the salient pathologies of DR such as pericytes loss, hyperpermeability, and perfusion blockage. Interestingly, numerous leukocytes and leukocyte clumps were found in diabetic retinal capillaries, especially in the non-perfused border area of the retina, suggesting a possible mechanism for non-perfusion and related pericyte damage. Treatment with aflibercept in mice with diabetes inhibited the upregulation of VEGF and the associated adhesion molecules while reducing the defects in perfusion. Aflibercept also attenuated pericyte loss in the diabetic retina.Conclusion VEGF inhibition through aflibercept treatment decreased leukocyte recruitment and aggregation, perfusion blockage, retinal hypoperfusion, and hyperpermeability in mice with diabetes and ultimately attenuated pericyte loss. Our findings suggest that anti-VEGF strategies may prove useful as possible therapies for limiting the progression of early-stage DR.

Purpose. To identify the clinical characteristics and risk factors for secondary choroidal neovascularization (CNV) in central serous chorioretinopathy (CSC). Methods. In this retrospective study, we included a total of 108 eyes in 106 CSC patients. Group A was defined as patients initially diagnosed with CSC who developed secondary CNV, and group B was defined as patients who did not develop secondary CNV. Clinical and demographic characteristics, optical coherence tomography (OCT) findings at CSC diagnosis and OCT angiography (OCTA) at the time of secondary CNV diagnosis, were compared between the groups. Results. Thirty-one eyes had CNV (group A) and 77 eyes did not (group B). The mean age of group A was higher than that of group B (52.28 ± 6.87 vs. 46.78 ± 9.45 years; P

Abstract Background To describe a case of highly suspected primary intraocular lymphoma (PIOL) in a patient using etanercept for the treatment of rheumatoid arthritis. Case presentation A 50-year-old female patient presented with decreased vision in her left eye that lasted for a week. She had a 15-year history of seropositive rheumatoid arthritis (RA), and had been taking weekly etanercept for the preceding 8 months. Funduscopic examination and SD-OCT showed a swollen ellipsoid zone (EZ) and a retinal pigment epithelium (RPE) irregularity of the right eye. We also noted EZ disruption and a RPE irregularity in the left eye. As subretinal infiltration was aggravated in the right eye after the initial treatment, we completed a vitrectomy. Vitreous cytology revealed PIOL with positive CD20 immunostaining. She was treated with serial intravitreal methotrexate injections and systemic chemotherapy. After the treatment, subretinal infiltration and subRPE deposits were decreased in the right eye with no evidence of recurrence in either eye. Conclusions This case suggests a potential relationship between immunosuppression with anti-TNFα medication, and increased risk for lymphoma, especially in patients with underlying rheumatologic disorders and especially in patients with suspected chronic refractory uveitis.

Abstract Background To evaluate the inhibitory effects of aflibercept on the growth and subretinal invasion of retinoblastoma. Methods Xenotransplantation and orthotopic mouse models were created by injecting Y-79 cells subcutaneously and intravitreally, respectively. After induction of retinoblastoma, animals were intraperitoneally injected with aflibercept (25 mg/kg body weight) or saline twice a week for 3 weeks. Tumor size was measured weekly and compared between the two groups. At 4 weeks, animals were sacrificed and an immunohistochemical examination was conducted to compare the microvascular density and degree of apoptosis between groups. In addition, the degree of choroidal invasion was also analyzed in the orthotopic xenotransplantation model. A co-culture system of Y-79 or WERI-Rb-1 cells and human umbilical vein endothelial cells (HUVECs) was used for in vitro experiments, and the anti-angiogenic effect of aflibercept was evaluated by analyzing cell numbers. Results In the Y-79 xenotransplantation model, aflibercept treatment significantly inhibited tumor growth at 4 weeks versus baseline compared with saline-injected mice (188.53 ± 118.53 mm3 vs. 747.87 ± 118.83 mm3, respectively, P

Loss of pericytes, an early hallmark of diabetic retinopathy (DR), results in breakdown of the blood-retinal barrier. Endoplasmic reticulum (ER) stress may be involved in this process. The purpose of this study was to examine the effects of ursodeoxycholic acid (UDCA), a known ameliorator of ER stress, on pericyte loss in DR of streptozotocin- (STZ-) induced diabetic mice. To assess the extent of DR, the integrity of retinal vessels and density of retinal capillaries in STZ-induced diabetic mice were evaluated. Additionally, induction of ER stress and the unfolded protein response (UPR) were assessed in diabetic mice and human retinal pericytes exposed to advanced glycation end products (AGE) or modified low-density lipoprotein (mLDL). Fluorescein dye leakage during angiography and retinal capillary density were improved in UDCA-treated diabetic mice, compared to the nontreated diabetic group. Among the UPR markers, those involved in the protein kinase-like ER kinase (PERK) pathway were increased, while UDCA attenuated UPR in STZ-induced diabetic mice as well as AGE- or mLDL-exposed retinal pericytes in culture. Consequently, vascular integrity was improved and pericyte loss reduced in the retina of STZ-induced diabetic mice. Our findings suggest that UDCA might be effective in protecting against DR.

We investigated the relationship between the peripapillary retinal nerve fiber layer and peripapillary retinal thickness in patients with diabetic macular edema. Fifty eyes (group I) with non-proliferative diabetic retinopathy and diabetic macular edema receiving intravitreal anti-VEGF injection, and 90 eyes (group II) without diabetic macular edema were included in this case-control study. The peripapillary retinal nerve fiber layer thickness, peripapillary retinal thickness, and a new retinal nerve fiber layer index using a modeled relationship between the two parameters were evaluated with spectral-domain optical coherence tomography, at baseline and at the 6-month follow-up. In group I, the peripapillary retinal nerve fiber layer thickness decreased from 126.4 μm at baseline to 117.6 μm at 6 months (p < 0.001), while the peripapillary retinal thickness decreased from 376.0 μm at baseline to 359.6 μm at 6 months (p < 0.001) after intravitreal anti-VEGF injection. In group II, however, both the parameters remained stable at the 6-month follow-up (100.7 to 102.1 μm and 311.1 to 316.2 μm, respectively, and all p > 0.01). Analysis with the new index to adjust for retinal edema showed no significant change from baseline to 6 months in both groups (p = 0.593 and p = 0.101, respectively). The peripapillary retinal nerve fiber layer thickness is strongly affected by the peripapillary retinal thickness. Therefore, the measured changes in peripapillary retinal nerve fiber layer thickness may not represent the real gain or loss of the retinal nerve fiber layer. Therefore, the new retinal nerve fiber layer index, which corrects for the component of macula edema, could be a better means of assessing the changes of peripapillary retinal nerve fiber layer thickness in patients with diabetic macular edema.

To evaluate the effect of metformin on vascular changes in oxygen-induced retinopathy (OIR) in mouse, and to elucidate the possible underlying mechanism.OIR mice were treated with metformin by intraperitoneal injection from postnatal day 12 (P12) to P17 or P21. At P17 and P21, vessel formation and avascular areas were assessed using retinal flat mounts. Levels of vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assays, and the effects of metformin on VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) were assessed. The effects of metformin on the levels of Flk1 (VEGF receptor-2) and phosphorylated Flk1 (pFlk1) were measured by Western blotting (HUVECs) and immunohistochemistry (retinal tissue).Retinal morphologic changes were analyzed between two groups (saline-treated OIR; metformin-treated OIR). Metformin treatment did not change the extent of avascular areas at P17. However, at P21, when OIR pathology was markedly improved in the saline-treated group, OIR pathology still remained in the metformin-treated OIR group. VEGF expression levels did not differ between metformin- and saline-treated OIR groups at P17 and P21, but Flk1 levels were significantly reduced in the metformin group compared with saline-treated OIR group. Moreover, metformin inhibited VEGF-induced cell proliferation and decreased levels of Flk1 and pFlk1, consistent with the interpretation that metformin inhibits vascular growth by reducing Flk1 levels.Metformin exerts anti-angiogenesis effects and delays the normal vessel formation in the recovery phase of OIR in mice, likely by suppressing the levels of Flk1.

Purpose. To analyze causes and prognosis of acute-onset preoperatively unknown origin vitreous hemorrhage (VH). Methods. This study included patients who underwent vitrectomy for acute-onset preoperatively unknown origin VH. The underlying causes of VH, which were identified after vitrectomy, were analyzed. And overall visual prognosis of unknown origin VH was analyzed. Risk scoring system was developed to predict visual prognosis after vitrectomy. Results. 169 eyes were included. Among these, retinal vein occlusion (RVO), retinal break, and age-related macular degeneration (AMD) were identified in 74 (43.8%), 50 (29.6%), and 21 (12.4%) patients, respectively. After vitrectomy, logMAR BCVA significantly improved from 1.93±0.59 to 0.47±0.71. However, postoperative BCVA in AMD eyes were significantly poorer than others. Poor visual prognosis after vitrectomy was associated with old age, poor preoperative vision in both eyes, and drusen in the fellow eye. Conclusions. RVO, retinal break, and AMD are the most common causes of acute-onset preoperatively unknown origin VH and the most common causes of VH change with age. The visual prognosis of unknown origin VH is relatively good, except among AMD patients. Older patients with poor preoperative BCVA in both eyes and patients with AMD in the fellow eye are at a higher risk of poor visual prognosis following vitrectomy.

A 55-year-old female presented with bilateral progressive retinal vasculitis. She was on systemic and intravitreal steroids on the basis of uveitis work-up result (negative result including rapid plasma reagin), but her visual acuity continued to deteriorate to light perception only. Ocular examination showed retinal vasculitis, multiple yellow placoid lesions and severe macula edema in both eyes. Repeated work-up revealed positivity of fluorescent treponemal antibody-absorption in serum and subsequently in cerebrospinal fluid. Ocular syphilis was diagnosed. And intravenous penicillin G resulted in rapid resolution of vasculitis and macular edema. To avoid delay in the diagnosis of ocular syphilis, high index of suspicion and repeating serological tests (including both treponemal and non-treponemal tests) are warranted.