髙橋 秀徳

[PURPOSE] To investigate whether sub-Tenon injection of triamcinolone acetonide (STTA) combined with anti-vascular endothelial growth factor (VEGF) prolongs the recurrence intervals of macular edema (ME) for chronic retinal vein occlusion (RVO) and to investigate the differences in intraocular inflammatory cytokines between good responders (GRs) and non-responders (NRs). [METHODS] This retrospective, observational study involved 42 eyes of 42 patients with ME due to chronic RVO who had received only anti-VEGF for ≥ 1 year and were transitioned to combination therapy. GRs were defined as patients whose recurrence intervals were prolonged by ≥ 2 weeks compared with patients receiving anti-VEGF alone. Moreover, immediately before starting the combined therapy, aqueous humor was collected and the following inflammatory cytokines were compared between GRs and NRs: CCL11, MCP-3, IP-10, CCL13, G-CSF, GM-CSF, IL-1α, IL-15, IL-4, M-CSF, MMP-9, TNF-α, MCP-1, CXCL-1, CXCL12, IL-8, galectin-1, IFN-γ, IL-12, IL-2, IL-6, MMP-1, PDGF-AA, and VEGF-A. These results were analyzed by nominal logistic regression after stepwise variable selection. [RESULTS] There were 26 eyes (62%) in the GR group. Nominal logistic analyses showed that a higher concentration of IL-1α (P = 0.016) and lower concentrations of IL-5 (P = 0.015), IL-6 (P = 0.022), and galectin-1 (P = 0.015) were significantly associated with the extension of the time from injection to recurrence of ME. [CONCLUSION] Combined anti-VEGF and STTA therapy for chronic RVO was effective in 62% of patients, suggesting the effectiveness of STTA. Higher IL-1α and lower IL-5, IL-6, and galectin-1 were the factors associated with combined treatment effectiveness.

This single-center retrospective cohort study analyzed the 1-year real-world treatment outcomes of 63 consecutive eyes (of 60 patients) with neovascular age-related macular degeneration (nAMD) that were switched from intravitreal brolucizumab (IVBr) to intravitreal faricimab (IVF) and managed on a treat-and-extend regimen with discontinuation criteria. After the switch, patients opted to continue IVF, to switch back to IVBr, or receive photodynamic therapy (PDT). Thirty-eight patients continued IVF, 16 patients were switched back to IVBr, 2 patients received PDT, and 4 patients paused treatment. Best-corrected visual acuity (BCVA), central subfield thickness (CST), subfoveal choroidal thickness (sf-CT), and injection intervals were compared immediately before and 1 year after the initial IVF. Whereas there was no change in BCVA and CST; 0 [- 0.0969 to 0.125, P = 0.58], - 1.5 [- 27.8 to 13.5, P = 0.11] µm, respectively, sf-CT decreased significantly; - 19.5 [- 45.5 to 7.75, P = 0.015] µm. The patients switched back showed no significant change in sf-CT. The injection interval extended significantly in the IVF continuation and the switch-back group (2.0 and 3.0 weeks, respectively; [P = 0.0007 and 0.0078]) in eyes with a pre-switching interval of less than 12 weeks. Faricimab shows promise as a safe and effective alternative to brolucizumab for treating nAMD.

BACKGROUND: This study reports the first cases of scleritis following intravitreal brolucizumab (IVBr) injection for nAMD, emphasizing the need to be aware of the possibility of scleritis following IVBr injections. CASE PRESENTATION: Case 1. A 74-year-old Japanese man with nAMD complained of conjunctivitis and decreased vision in the right eye 8 days after his eighth IVBr injection. Examination revealed scleritis without anterior inflammation. Topical 0.1% betamethasone and 0.3% gatifloxacin eye drops were started. The scleritis worsened in the following 2 weeks and became painful. He underwent sub-Tenon's capsule triamcinolone acetonide (STTA) injection. Two days later, he returned with a complaint of severe vision loss. Fundus examination revealed retinal artery occlusion, vasculitis, and vitreous opacity in the right eye. Vitreous surgery was performed. CASE 2: An 85-year-old Japanese woman with nAMD in the right eye complained of reddening of the eye 27 days after her fifth IVBr injection. Examination showed conjunctivitis and scleritis without anterior inflammation in the right eye. She was started on 0.1% fluorometholone and 0.5% levofloxacin hydrate eye drops. The scleritis worsened in the following 3 weeks. Her treatment was switched to 0.1% betamethasone eye drops. One month later, the scleritis had improved and a sixth IVBr injection was administered. There was no worsening of the scleritis at that time. However, 1 month after a seventh IVBr injection, she complained of severe hyperemia and decreased vision. Fundus examination revealed vitreous opacification. She underwent STTA, and the vitreous opacity improved in 24 days. Case 3. A 57-year-old Japanese man with nAMD complained of pain and decreased vision in the right eye 21 days after a fourth IVBr injection. Examination revealed scleritis with high intraocular pressure but no anterior chamber or fundus inflammation. STTA and topical eye drops were performed. One month later, scleritis improved but visual acuity didn't due to progression of nAMD. CONCLUSIONS: Intraocular inflammation following IVBr injection may progress to the posterior segment. Scleritis can occur after IVBr injection, and topical eye drops alone may not be sufficient for initial treatment. Clinicians should consider the possibility of scleritis in patients with worsening inflammation after IVBr injection.

A new anti-vascular endothelial growth factor agent, brolucizumab, was approved by the United States Food and Drug Administration in 2019. We evaluated whether brolucizumab reduces the treatment burden of neovascular age-related macular degeneration (nAMD) after switching by examining 1-year treatment outcomes in a real-world setting. This retrospective single-institution study included 107 consecutive eyes with nAMD treated with brolucizumab. Among these eyes, 30 with treatment-naïve nAMD and 77 treated with other anti-VEGF agents for more than a year were included. All eyes were managed using a treat and extend (TAE) or modified TAE regimen. The last injection intervals at 52 weeks were 12.9 and 12.1 weeks in the treatment-naïve and switch therapy groups, respectively. Among switch therapy group patients whose pre-switch injection intervals were shorter than 120 days (n = 62 eyes), the injection interval was significantly longer after the switch than before, with a mean difference of 2.7 weeks (P < 0.0001). Intraocular inflammation events occurred in 2 and 7 treatment-naïve and switch therapy patients, respectively. In conclusion, brolucizumab might reduce the treatment burden in patients who required the injection of other anti-VEGF agents with a 120-day interval or shorter, despite a relatively high discontinuation rate due to intraocular inflammation.

PURPOSE: To identify factors associated with intraocular inflammation (IOI) in patients with neovascular age-related macular degeneration (nAMD) treated with brolucizumab. METHODS: In this prospective observational study, we collected aqueous humor samples from 96 eyes of 96 patients receiving treatment with brolucizumab; IOI subsequently developed in 19 eyes of 19 patients. To identify cytokines upregulated in eyes with subsequent development of IOI, we compared the aqueous humor cytokine levels between the IOI and non-IOI groups. We also collected plasma from 20 patients who developed IOI and 20 age- and sex-matched controls to identify differences in plasma biomarkers and the subfraction of CD4+ cells. Using stepwise variable selection and multivariate binary regression analysis, we developed an algorithm that accurately assessed the likelihood of IOI occurrence. RESULTS: The IOI group showed elevated aqueous humor levels of P-selectin (584 vs. 324 pg/mL, P = 0.013), TNF-α (0.89 vs. 0.60 pg/mL, P = 0.018), and IL-1α (2.0 vs. 1.4 pg/mL, P = 0.035) compared with the non-IOI group. Serum MMP-9 concentrations were higher in the IOI group than the non-IOI group (18,310 vs. 13,450 pg/mL, P = 0.029). Furthermore, the percentage of Th2 cells was significantly decreased in the IOI compared with the non-IOI group (3.1% vs. 4.2%, P = 0.013). The receiver operating characteristic curves for the optimal models showed an area under the curve ranging from 0.71 to 0.89, indicating good performance. CONCLUSIONS: The combination of elevated concentrations of multiple aqueous humor cytokines and of serum MMP-9 and a lower number of plasma Th2 cells is associated with brolucizumab-related IOI in patients with nAMD.

PURPOSE: To investigate the incidence of intraocular inflammation (IOI) and its risk factors following intravitreal injections of brolucizumab for neovascular age-related macular degeneration (nAMD) in Japan. METHODS: A total of 1351 Japanese consecutive patients with nAMD who were treated with brolucizumab from May 2020 to May 2022 at 14 institutions were examined. The variables analyzed were the number of brolucizumab injections, time to onset of IOI, and risk factors. RESULTS: IOI developed in 152 eyes (11.3%). Retinal vasculitis and/or retinal occlusion (RV and/or RO) occurred in 53 eyes (3.9%). Ninety-four patients received bilaterally, bilateral IOI occurred in 5 patients (5.3%). Sixteen eyes (1.2%) had irreversible visual acuity loss and nine eyes (0.67%) had visual loss of 3 lines or more due to RV and/or RO. The cumulative IOI incidence was 4.5%, 10.3%, and 12.2% at 30, 180, and 365 days (1-year), respectively. Prior history of IOI (including RV) and/or RO (odds ratio[OR], 5.41; P = 0.0075) and female sex (OR, 1.99; P = 0.0004) were significantly associated with IOI onset. CONCLUSION: The 1-year cumulative incidence of IOI in Japanese nAMD patients treated with brolucizumab was 12.2%. Prior history of IOI (including RV) and/or RO and female sex were significant risk factors.

This prospective, multicentre, interventional study evaluated the efficacy of a modified treat-and-extend (mTAE) aflibercept regimen as personalized therapy for macular oedema (MO) due to central retinal vein occlusion (CRVO). Fifty eyes were studied from 50 patients who were enrolled between November 2016 and July 2019. All patients received intravitreal aflibercept (IVA) injections on an mTAE regimen for 24 months. Primary outcome measures were best-corrected visual acuity (BCVA) and central subfield thickness (CST) at 12 months. Secondary endpoints were BCVA and CST at 24 months. Mean (standard deviation) baseline BCVA (logMAR) and CST were 0.50 (0.51) and 557 (240) µm, respectively. BCVA and CST showed significant improvements at month 12 (0.19 (0.38) and 275 (98) µm, respectively; both p &lt; 0.0001, paired t-test). BCVA and CST also showed significant improvements at 24 months (0.26 (0.50) and 255 (91) µm, respectively, p = 0.0004 and p &lt; 0.0001, paired t-test). The mean numbers of IVA injections and clinic visits over the 24-month study period were 6.2 (3.0) and 10.3 (1.0), respectively. The mTAE regimen of IVA injections for MO due to CRVO was effective in improving BCVA and decreasing CST at 24 months. The mTAE regimen might be an effective personalized therapy for CRVO.

INTRODUCTION: The aim of this study was to investigate the safety and efficacy of a single injection of intravitreal faricimab (IVF) in patients with neovascular age-related macular degeneration (nAMD) who had a prior treatment history. METHODS: A retrospective analysis was conducted on a consecutive cohort of 80 eyes of 75 patients with nAMD who had a prior history of treatment with an injection of anti-vascular endothelial growth factor. Best-corrected visual acuity (BCVA), central subfield thickness (CST), and central choroidal thickness (CCT) were compared before the initial IVF injection and after a treatment interval matching the previous duration. RESULTS: Central choroidal thickness decreased significantly following the IVF injection, but there was no significant change in BCVA or CST. Mean (± standard deviation) BCVA changed from 0.34 ± 0.37 to 0.36 ± 0.40 (P = 0.29), CST changed from 242 ± 72 to 242 ± 82 µm (P = 0.99), and CCT changed from 189 ± 98 to 179 ± 97 µm (P < 0.0001). When the changes were evaluated according to the previous anti-VEGF agent administered, CCT was found to be significantly decreased by 8.7 ± 2.5 µm (P < 0.0001) in eyes previously treated with brolucizumab and by 13.1 ± 3.6 µm (P < 0.0001) in eyes previously treated with aflibercept. No adverse events were observed during the study period. CONCLUSION: Intravitreal faricimab injection is a safe and effective treatment for nAMD in terms of short-term outcomes. Further long-term study is necessary.

PURPOSE: To develop an artificial intelligence (AI) model for estimating best-corrected visual acuity (BCVA) using horizontal and vertical optical coherence tomography (OCT) scans of various retinal diseases and examine factors associated with its accuracy. METHODS: OCT images and associated BCVA measurements from 2,700 OCT images (accrued from 2004 to 2018 with an Atlantis, Triton; Topcon, Tokyo, Japan) of 756 eyes of 469 patients and their BCVA were retrospectively analysed. For each eye, one horizontal and one vertical OCT scan in cross-line mode were used. The GoogLeNet architecture was implemented. The coefficient of determination (R2), root mean square error (RMSE) and mean absolute error (MAE) were computed to evaluate the performance of the trained network. RESULTS: R2, RMSE, and MAE were 0.512, 0.350, and 0.321, respectively. R2 was higher in phakic eyes than in pseudophakic eyes. Multivariable regression analysis showed that a higher R2 was significantly associated with better BCVA (p < 0.001) and a higher standard deviation of BCVA (p < 0.001). However, the performance was worse in an external validation, with R2 of 0.19. R2 values for retinal vein occlusion and age-related macular degeneration were 0.961 and 0.373 in the internal validation but 0.20 and 0.22 in the external validation. CONCLUSION: Although underspecification appears to be a fundamental problem to be addressed in AI models for predicting visual acuity, the present results suggest that AI models might have potential for estimating BCVA from OCT in AMD and RVO. Further research is needed to improve the utility of BCVA estimation for these diseases.

Detection of early clinical keratoconus (KCN) is a challenging task, even for expert clinicians. In this study, we propose a deep learning (DL) model to address this challenge. We first used Xception and InceptionResNetV2 DL architectures to extract features from three different corneal maps collected from 1371 eyes examined in an eye clinic in Egypt. We then fused features using Xception and InceptionResNetV2 to detect subclinical forms of KCN more accurately and robustly. We obtained an area under the receiver operating characteristic curves (AUC) of 0.99 and an accuracy range of 97–100% to distinguish normal eyes from eyes with subclinical and established KCN. We further validated the model based on an independent dataset with 213 eyes examined in Iraq and obtained AUCs of 0.91–0.92 and an accuracy range of 88–92%. The proposed model is a step toward improving the detection of clinical and subclinical forms of KCN.

PURPOSE: To identify the inflammatory cytokine profile in the aqueous humor (AH) of patients with intraocular inflammation (IOI) after intravitreal administration of brolucizumab (IVBr) for neovascular age-related macular degeneration. METHODS: Eight eyes from seven patients with IOI after initial IVBr (IVBrIOI +) were enrolled. Sixteen eyes from 16 patients without IOI after IVBr (IVBrIOI -) and aflibercept (IVA) were used as controls. AH samples were analyzed using a multiplex immunoassay. RESULTS: C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)1, CXCL10, CXCL13, interleukin (IL)-6, IL-8, IL-10, matrix metalloproteinase (MMP)-1, MMP-9, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), intercellular adhesion molecule (ICAM)-1, E-selectin, and P-selectin levels were significantly higher in IVBrIOI + than in IVBrIOI - and IVA. Vascular endothelial growth factor (VEGF) was significantly lower in IVBrIOI - compared to that in IVBrIOI + and IVA. In the IVBrIOI + group, there were significant correlations between CCL2, CXCL1, IL-6, IL-8, IL-10, G-CSF, GM-CSF, ICAM-1, and E-selectin, which also exhibited significant correlations in the IVBrIOI - group. CONCLUSION: The number of inflammatory cytokines increases during IOI, which is associated with type IV hypersensitivity and vascular inflammation. Some cytokines exhibit correlations even in non-inflamed eyes, indicating a subclinical response to IVBr.

Abstract We herein propose a PraNet-based deep-learning model for estimating the size of non-perfusion area (NPA) in pseudo-color fundus photos from an ultra-wide-field (UWF) image. We trained the model with focal loss and weighted binary cross-entropy loss to deal with the class-imbalanced dataset, and optimized hyperparameters in order to minimize validation loss. As expected, the resultant PraNet-based deep-learning model outperformed previously published methods. For verification, we used UWF fundus images with NPA and used Bland–Altman plots to compare estimated NPA with the ground truth in FA, which demonstrated that bias between the eNPA and ground truth was smaller than 10% of the confidence limits zone and that the number of outliers was less than 10% of observed paired images. The accuracy of the model was also tested on an external dataset from another institution, which confirmed the generalization of the model. For validation, we employed a contingency table for ROC analysis to judge the sensitivity and specificity of the estimated-NPA (eNPA). The results demonstrated that the sensitivity and specificity ranged from 83.3–87.0% and 79.3–85.7%, respectively. In conclusion, we developed an AI model capable of estimating NPA size from only an UWF image without angiography using PraNet-based deep learning. This is a potentially useful tool in monitoring eyes with ischemic retinal diseases.