髙橋 秀徳

Purpose: This study aimed to characterize inflammatory cytokine profiles in recurrent retinal vein occlusion (RVO) and to describe subtype- and phase-specific patterns relative to controls. Methods: This was retrospective study conducted from September 2010 to September 2022 at the Japan Community Healthcare Organization Tokyo Shinjuku Medical Center and Jichi Medical University. Aqueous humour (AqH) was collected immediately before intravitreal bevacizumab, ranibizumab or aflibercept injections from patients with RVO. We included an acute group (RVO onset within 3 months) and a recurrent group (patients with disease duration of >= 1 year). Using a multiplex cytokine assay, we measured the concentrations of nine cytokines and VEGF. The results were compared with controls after adjusting for sex, age, axial length, and posterior vitreous detachment. Results: AqH samples from 30 acute branch RVO (BRVO), 31 recurrent BRVO, 25 acute central RVO (CRVO), 20 recurrent CRVO, and 81 cataract surgery eyes without retinal disease (as controls) were used. In recurrent BRVO, MCP-1, CXCL13, and CCL11 levels were significantly lower than those in control eyes (all, P < 0.05). Similarly, in recurrent CRVO, MCP-1, CXCL12, CXCL13, CCL11, and CXCL1 levels were significantly reduced compared with controls (all, P < 0.05), whereas IL-6 levels were significantly elevated (P < 0.05). In acute RVO, cytokine alterations compared with controls were limited. Acute BRVO showed decreased MCP-1, CXCL13, and CCL11 levels (all, P < 0.05), while acute CRVO exhibited increased IL-6 and IP-10 levels (all, P < 0.05). Conclusions: Inflammatory cytokine profiles in recurrent RVO differ between BRVO and CRVO and are characterized by reduced levels of multiple inflammatory cytokines compared with controls. These findings highlight distinct inflammatory features of recurrent RVO and provide a basis for future studies investigating disease progression and treatment resistance.

This study investigated the one-year real-world clinical outcomes of intravitreal faricimab (IVF) in treatment-na & iuml;ve neovascular age-related macular degeneration (nAMD) and its association with aqueous humor cytokine profiles. Thirty-four eyes of 32 nAMD patients, who received initial IVF at Jichi Medical University were included. These eyes showed significant improvements in central retinal subfield thickness (CST), central choroidal thickness (CCT), and best-corrected visual acuity (BCVA) one year post-IVF (all P < 0.01). Among 24 measurable cytokines, only VEGF-Awas significantly higher in eyes with a dry macula at week 16 (P = 0.0030). Three cytokines were significantly higher in eyes with longer injection interval. Higher levels of galectin-1 and VCAM-1, and lower levels of P-selectin, were correlated with greater CST reduction (P = 0.020, 0.0061, and 0.012, respectively). Conversely, five cytokines including Ang-1 were correlated with greater BCVA improvement (all P < 0.05). In conclusion, an anatomical perspective faricimab demonstrated anatomical efficacy for VEGF-driven nAMD in the loading phase, while multiple cytokines associated with vascular instability or fibrosis appear to contribute to its durability. Notably, Ang-1 may be linked to visual improvement, suggesting that the neurotrophic effects ofAng-1 could be enhanced byAng-2 inhibition.

Highlights What are the main findings? Deep learning models using fundus and OCT images showed limited ability to predict intraocular cytokine concentrations, with overall low R2 values across approaches. Including demographic and clinical features did not improve model performance compared with image-only inputs. What is the implication of the main finding? The findings suggest that cytokine levels may not be strongly reflected in retinal image features alone. Further refinement of model design and incorporation of additional modalities may be needed to achieve reliable prediction.Highlights What are the main findings? Deep learning models using fundus and OCT images showed limited ability to predict intraocular cytokine concentrations, with overall low R2 values across approaches. Including demographic and clinical features did not improve model performance compared with image-only inputs. What is the implication of the main finding? The findings suggest that cytokine levels may not be strongly reflected in retinal image features alone. Further refinement of model design and incorporation of additional modalities may be needed to achieve reliable prediction.Abstract The relationship between retinal images and intraocular cytokine profiles remains largely unexplored, and no prior work has systematically compared fundus- and OCT-based deep learning models for cytokine prediction. We aimed to predict intraocular cytokine concentrations using color fundus photographs (CFP) and retinal optical coherence tomography (OCT) with deep learning. Our pipeline consisted of image preprocessing, convolutional neural network-based feature extraction, and regression modeling for each cytokine. Deep learning was implemented using AutoGluon, which automatically explored multiple architectures and converged on ResNet18, reflecting the small dataset size. Four approaches were tested: (1) CFP alone, (2) CFP plus demographic/clinical features, (3) OCT alone, and (4) OCT plus these features. Prediction performance was defined as the mean coefficient of determination (R2) across 34 cytokines, and differences were evaluated using paired two-tailed t-tests. We used data from 139 patients (152 eyes) and 176 aqueous humor samples. The cohort consisted of 85 males (61%) with a mean age of 73 (SD 9.8). Diseases included 64 exudative age-related macular degeneration, 29 brolucizumab-associated endophthalmitis, 19 cataract surgeries, 15 retinal vein occlusion, and 8 diabetic macular edema. Prediction performance was generally poor, with mean R2 values below zero across all approaches. The CFP-only model (-0.19) outperformed CFP plus demographics (-24.1; p = 0.0373), and the OCT-only model (-0.18) outperformed OCT plus demographics (-14.7; p = 0.0080). No significant difference was observed between CFP and OCT (p = 0.9281). Notably, VEGF showed low predictability (31st with CFP, 12th with OCT).

PurposeTo evaluate aqueous flare values in patients with neovascular age-related macular degeneration (nAMD) receiving anti-vascular endothelial growth factor (VEGF) therapy, including brolucizumab.MethodsThis retrospective study included 101 patients treated with intravitreal anti-VEGF injections at Jichi Medical University Hospital from March to July 2021. Aqueous flare values were measured in both affected and fellow eyes. The number of treated eyes was 28 for aflibercept and 73 for brolucizumab. Flare values were compared between affected and fellow eyes, and associations with age, gender, drug type, number of injections, disease duration, and time since last injection were analyzed. We also measured flare values from pre-filled syringes.ResultsIn unilateral treatment cases, brolucizumab-treated eyes had significantly higher aqueous flare values than fellow eyes (6.7 vs. 6.2 photon counts/ms, P = 0.0032), while no significant difference was observed with aflibercept (6.9 vs. 6.7 pc/ms, P = 0.55). Flare values increased significantly with age in the brolucizumab group (P = 0.0076) but not in the aflibercept group (P = 0.56). The number of brolucizumab injections did not alter flare values. Multivariate analysis identified age as the only significant factor associated with increased aqueous flare. The mean (standard deviation) flare values measured from pre-filled syringes were 430 (15.6) pc/ms for Beovu (R) (brolucizumab) and 161.8 (31) pc/ms for Eylea (R) (aflibercept).ConclusionIn nAMD, aqueous flare values were higher in brolucizumab-treated eyes and increased with age but were unaffected by the number of injections. Different flare values of each drug might affect the aqueous flare values within hours after injection.

Purpose To develop and evaluate a novel artificial intelligence (AI)-derived metric for detection of early ectasia by leveraging spatiotemporal biomechanical data derived from dynamic cornea videos only. Design Multi-center cross-sectional case-control retrospective study. Participants A total of 451 eyes from 451 patients from two centers with both Pentacam and Corvis ST (Oculus Optikgeräte, Germany) examinations. Methods The training dataset included 167 normal (N) patients with stable eyes post laser vision correction (LVC), 83 normal topography eyes with very asymmetric ectasia (VAE-NT), and better eye from 64 patients with bilateral keratoconus (i.e., mild keratoconus; MKC). The external validation dataset included 68, 33, and 36 patients from the N, VAE-NT, and MKC groups, respectively. Extensive spatial and temporal pixel-level analysis of corneal displacement, stromal grey-scale changes, and thickness variations from Corvis ST video frames was performed to identify a novel risk score with best detection of early ectasia (combined VAE-NT and MKC). Findings were further validated using various approaches based on the external dataset. Main Outcome Measures Area under the receiver operating characteristics curve (AUC), accuracy, specificity, and sensitivity for detecting early ectasia. Results The novel AI-derived index achieved an area under the receiver operating characteristics curve (AUC) of 0.995 with accuracy, sensitivity and specificity of 96%, 97% and 96%, respectively, outperforming all Pentacam and Corvis tomography, topography, biomechanics, and combined indices such as Belin/Ambrósio Enhanced Ectasia Display (BAD-D), Corvis Biomechanical Index (CBI), and Tomographic and Biomechanical Index (TBI). Conclusions The AI-derived index based on spatio-temporal corneal biomechanical data outperformed existing instrument’s topographic, tomographic, and biomechanical indices, in detecting ectasia. This novel metric offers a clinically meaningful enhancement in early diagnosis and management of corneal ectasia disease.

Retinal breaks are critical lesions that can cause retinal detachment and vision loss if not detected and treated early. Automated, accurate delineation of retinal breaks in ul-tra-widefield fundus (UWF) images remains challenging. In this study, we developed and validated a deep learning segmentation model based on the PraNet architecture to localize retinal breaks in break-positive cases. We trained and evaluated the model using a dataset comprising 34,867 UWF images of 8,083 cases. Performance was assessed using image-level segmentation metrics, including accuracy, precision, recall, Intersection over Union (IoU), dice score, and centroid distance score. The model achieved an accuracy of 0.996, precision of 0.635, recall of 0.756, IoU of 0.539, dice score of 0.652, and centroid distance score of 0.081. To our knowledge, this is the first study to present pixel-level segmentation of retinal breaks in UWF images using deep learning. The proposed PraNet-based model showed high accuracy and robust segmentation performance, highlighting its potential for clinical application.

Purpose: This report aims to present a case of the retinal nerve fiber layer (NFL) thinning, in which the progression of thinning was slowed following optic nerve-carotid artery decompression surgery. Observations: A 41-year-old ophthalmologist incidentally noticed a generalized thinning of NFL in his left eye using optical coherence tomography (OCT). Five years earlier, the OCT showed only mild thinning. While visual acuity and visual fields were normal, the patient reported a blurriness. The MRI revealed an ectatic and tortuous left internal carotid artery compressing the left optic nerve. Due to the lack of reports on the correlation between NFL thickness and visual acuity, an internal review was conducted. We searched for cases with a progression from healthy visual acuity to blindness, and in the only case identified, we investigated the correlation between NFL thickness and visual acuity. Applying this correlation, it was predicted that the patient would lose vision by age 48. As a result, the patient decided to receive decompression surgery. Following the surgery, the rate of NFL thinning significantly slowed from -1.9 µm / year to -0.57 µm / year (p < .0001). At the current age of 48, the patient’s corrected visual acuity is 20/16, and visual field remains normal. The predicted onset of blindness has been postponed by 10 years. Conclusions and Importance: We report a case in which compression of the optic nerve by the internal carotid artery was observed in a patient with retinal nerve fiber layer (NFL) thinning. A slowing of NFL thinning was noted following surgical decompression.

AIは2012年の深層学習技術実用化により、ヒトを超える画像識別能を獲得した。その能力は各種画像診断プログラムとなって医療においても実用化されている。AIによる画像変換技術は各種画質向上プログラムとして実用化され、医用画像の高精細化と、放射線にあっては低線量化に役立っている。近年はchatGPTなどで知られる各種生成AIの性能が実用に達し、医療においてはカルテの自動記載が始まっている。演者はAIの画像識別能がヒトを超えた2015年からAIの研究を始めた。大学発ベンチャーを設立し2製品の認証を得た。それら経験と、網膜光干渉断層像から視野を推測することで視野検査を両眼30分から2秒にする開発中AIを、自験例として紹介する。アメリカ食品医薬品局(FDA)は既に数百のAI医療機器プログラムを承認しており、それらは放射線科領域が主体であり、プラットフォーム化している。日本も数年遅れながら同様に医療AIが当たり前になっていくだろう。

[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 &#x2265;&#x2009;1 year and were transitioned to combination therapy. GRs were defined as patients whose recurrence intervals were prolonged by &#x2265;&#x2009;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-1&#x3b1;, IL-15, IL-4, M-CSF, MMP-9, TNF-&#x3b1;, MCP-1, CXCL-1, CXCL12, IL-8, galectin-1, IFN-&#x3b3;, 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-1&#x3b1; (P&#x2009;=&#x2009;0.016) and lower concentrations of IL-5 (P&#x2009;=&#x2009;0.015), IL-6 (P&#x2009;=&#x2009;0.022), and galectin-1 (P&#x2009;=&#x2009;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-1&#x3b1; 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.