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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.

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AIMS: To study the possibility of constructing a remote interpretation system for retinal images. METHODS: An ultra-widefield (UWF) retinal imaging device was installed in the internal medicine department specializing in diabetes to obtain fundus images of patients with diabetes. Remote interpretation was conducted at Nagoya City University using a cloud server. The medical data, severity of retinopathy, and frequency of ophthalmologic visits were analyzed. RESULTS: Four hundred ninety-nine patients (mean age, 62.5 ± 13.4 years) were included. The duration of diabetes in 240 (48.1%) patients was less than 10 years and 433 (86.7%) patients had a hemoglobin (Hb) A1c below 8%. Regarding the retinopathy severity, 360 (72.1%) patients had no diabetic retinopathy (NDR), 63 (12.6%) mild nonproliferative retinopathy (NPDR), 38 (7.64%) moderate NPDR, 13 (2.6%) severe NPDR, and 25 (5.0%) PDR. Two hundred forty-one (48.3%) patients had an ophthalmologic consultation within 1 year, 104 (20.8%) had no history of an ophthalmologic consultation. DR was not present in 86 (82.7%) patients who had never had an ophthalmologic examination, 30 (78.9%) patients with severe NPDR or PDR had had an ophthalmologic visit within 1 year. The frequency of ophthalmic visits was correlated negatively with age, diabetes duration, HbA1c, and severity of retinopathy. CONCLUSION: Remote interpretation of DR using UWF retinal imaging was useful for retinopathy screening. During the COVID-19 pandemic, a remote screening system that can ensure compulsory social distancing and reduce the number of ophthalmic visits can be a safe system for patients and clinicians.

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PURPOSE: Although optical coherence tomography (OCT) is essential for ophthalmologists, reading of findings requires expertise. The purpose of this study is to test deep learning with image augmentation for automated detection of chorioretinal diseases. METHODS: A retina specialist diagnosed 1,200 OCT images. The diagnoses involved normal eyes (n=570) and those with wet age-related macular degeneration (AMD) (n=136), diabetic retinopathy (DR) (n=104), epiretinal membranes (ERMs) (n=90), and another 19 diseases. Among them, 1,100 images were used for deep learning training, augmented to 59,400 by horizontal flipping, rotation, and translation. The remaining 100 images were used to evaluate the trained convolutional neural network (CNN) model. RESULTS: Automated disease detection showed that the first candidate disease corresponded to the doctor's decision in 83 (83%) images and the second candidate disease in seven (7%) images. The precision and recall of the CNN model were 0.85 and 0.97 for normal eyes, 1.00 and 0.77 for wet AMD, 0.78 and 1.00 for DR, and 0.75 and 0.75 for ERMs, respectively. Some of rare diseases such as Vogt-Koyanagi-Harada disease were correctly detected by image augmentation in the CNN training. CONCLUSION: Automated detection of macular diseases from OCT images might be feasible using the CNN model. Image augmentation might be effective to compensate for a small image number for training.

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Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50 years of age in many developed countries. Drusen are yellowish extracellular deposits beneath retinal pigment epithelium (RPE) found in aging eyes and considered as a biomarker of AMD. However, the biogenesis of drusen has not been elucidated. We reported previously that multicellular spheroids of human RPE cells constructed a well-differentiated monolayer of RPE with a Bruch's membrane. We determined that RPE spheroids exhibited drusen formation between the RPE and Bruch's membrane with expression of many drusen-associated proteins, such as amyloid ß and complement components, the expression of which was altered by a challenge with oxidative stress. Artificial lipofuscin-loaded RPE spheroids yielded drusen more frequently. In the current study, we showed that drusen originates from the RPE. This culture system is an attractive tool for use as an in vitro drusen model, which might help elucidate the biogenesis of drusen and the pathogenesis of related diseases, such as AMD.

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Proliferative vitreoretinopathy (PVR) is a challenging pathological condition, often causing failure of retinal detachment surgery. The purpose of this study was to evaluate the feasibility of a delivery system of bioactive proteins using anionic and cationic gelatin microspheres and to establish a new PVR model in rabbits by intraocular sustained delivery of basic fibroblast growth factor (bFGF) and interferon-beta (IFNß). Anionic and cationic gelatin microspheres were prepared and immersed in bFGF and IFNß solution, respectively, to yield a polyion complex between gelatin matrix and a bioactive protein. The bFGF-impregnated microspheres were injected into the subretinal space in rabbit eyes. At week 2, the IFNß-impregnated microspheres also were injected into the same space. Control eyes received gelatin microspheres without bFGF or IFNß, or both. The eyes then were observed for 8 weeks by ophthalmoscopy, fundus photography, and fluorescein angiography. The eyes also were evaluated histologically. In the group with both bFGF and IFNß, the number of eyes with more severe PVR increased over time. Histologic examination showed retinal folds. In contrast, no proliferative changes were seen in any control groups. Subretinal implantation of bFGF and IFNß-impregnated gelatin microspheres induced reproducible PVR in rabbit eyes. This study guaranteed delivery of bioactive proteins with gelatin microspheres.

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AIMS: Anti-vascular endothelial growth factor agents effectively treat age-related macular degeneration and myopic choroidal neovascularization (CNV). Tissue plasminogen activator (tPA), a fibrinolytic compound, is used as an adjuvant to displace submacular hemorrhage and to treat type 2 CNV. The purpose of this study was to investigate in in vitro and in vivo experiments the antiangiogenic impact of tPA itself. METHODS: The impact of tPA on the proliferation of human umbilical vein endothelial cells (HUVECs) was assessed by an XTT assay [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide]. A basic fibroblast growth factor-impregnated gelatin hydrogel sheet was implanted into the rabbit cornea to induce corneal neovascularization. Immediately postoperatively, tPA or buffered saline solution (control) was injected intravitreally. RESULTS: The growth and viability of the HUVECs were unaffected by tPA at clinical concentrations. In the control group, the mean lengths of the new vessels were 1.0 ± 0.41, 1.6 ± 0.75, and 3.6 ± 2.1 mm at weeks 1, 2, and 4, respectively. In contrast, tPA significantly (p < 0.01) reduced the corneal neovascularization. CONCLUSION: Although tPA has no direct impact on the vascular endothelial cells in vitro, the fibrinolytic effects of tPA might markedly suppress neovascularization in vivo.

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PURPOSE: To study the association between the distributions of microaneurysms detected by en face optical coherence tomography angiography (OCTA) and diabetic macular edema (DME). METHODS: The study design was a retrospective chart review of 27 patients (33 eyes) with DME. The eyes were scanned using OCTA (6 × 6 mm) and spectral-domain (SD) OCT macular cube. Each of the images of the capillary plexus was overlaid onto the image of the topographic map, and the densities of the microaneurysms were measured by ImageJ software. The association between the distribution of microaneurysms and macular edema was evaluated. RESULTS: For microaneurysms in areas with and without edema, 77.3 ± 8.1% of these microaneurysms were located in the deep capillary plexuses (DCP). However, in areas of edema where the retinal thickness was more than 400 µm, 91.3 ± 9.1% of the microaneurysms were found in the DCP. This difference was statistically significant (P < 0.001). In the macular edema area, there was a significantly higher density of microaneurysms in the DCP compared to the superficial capillary plexuses (1.71/mm2 vs. 0.17/mm2, P < 0.001). There was also a significant correlation between the macular volume and the density of microaneurysms in the DCP in edema (r = 0.63, P < 0.001). CONCLUSIONS: Our study demonstrated a high proportion of microaneurysms in the DCP, as well as a novel association between the distributions of microaneurysms detected by OCTA and DME. Results also indicated that microaneurysms located in the DCP contribute to the pathogenesis of DME.

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PURPOSE: Fibrovascular scar formation related to subfoveal type 2 choroidal neovascularization (CNV) often causes severe vision loss in eyes with age-related macular degeneration. The authors assessed additional impacts of intravitreal tissue plasminogen activator (tPA), a fibrinolytic compound, combined with intravitreal ranibizumab (IVR) on subfoveal type 2 CNV. METHODS: Eight eyes of eight patients with type 2 CNV underwent intravitreal injections of ranibizumab and tPA (IVR/tPA) (40 kIU). Twelve eyes of 12 patients with type 2 CNV were treated with only IVR injections, as the control group. For retreatment, IVR was performed as needed. The best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) and macular volume (MV) on optical coherence tomography were recorded periodically for 6 months. RESULTS: The subretinal fibrinous and fibrovascular tissue complex regressed or contracted immediately after administration of IVR/tPA in contrast to IVR monotherapy. The total numbers of IVR injections did not differ significantly between the two groups. The mean logarithm of the minimum angle of resolution BCVA in the combination therapy group improved significantly from 0.72 at baseline to 0.51 at month 6 and was superior to that in the monotherapy group (0.70-0.79). The improvements of the mean CRT and MV in the combination therapy group were superior to the monotherapy group. No tPA-related complications developed. CONCLUSIONS: tPA may have a specific ability to regress already formed subretinal fibrinous and fibrovascular tissue complexes in eyes with type 2 CNV, potentially increasing the chances of visual improvement through a synergistic relationship with anti-VEGF therapies.

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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.

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