Effects of Combination Therapy with Intravitreal Ranibizumab and Tissue Plasminogen Activator for Neovascular Age-Related Macular Degeneration.

Background: Subretinal hyper-reflective material (SHRM) sometimes causes vision loss in spite of anti-vascular endothelial growth factor (VEGF) therapy in eyes with neovascular age-related macular degeneration (nvAMD). We evaluated the impacts of combination therapy with intravitreal ranibizumab (IVR) and tissue plasminogen activator (tPA) in eyes with nvAMD accompanying SHRM. Methods: In total, 25 eyes of 25 patients (16 men and 9 women, 76.7 years old), who underwent IVR/tPA for nvAMD with SHRM and were followed up for at least 12 months, were retrospectively reviewed. In total, 15 eyes were treatment-naïve and 10 eyes had previous treatment for nvAMD. Results: In total, 16 eyes had type 2 macular neovascularization (MNV), 5 eyes type 1 MNV with fibrovascular pigment epithelial detachment and 4 eyes polypoidal choroidal vasculopathy. At month 12, SHRM regressed or reduced in 18 eyes (72%) and the best-corrected visual acuity (BCVA) improved in 6 eyes (24%) and was unchanged in 14 eyes (56%), while the mean BCVA was just stabilized. The mean central retinal thickness, macular volume and SHRM thickness significantly improved from 408 µm to 287 µm, from 11.9 mm3 to 9.6 mm3, from 369 µm to 165 µm, respectively (p < 0.01). Conclusions: The combination therapy with IVR/tPA for nvAMD with SHRM may help preserve vision by prompt regression of SHRM.

Long-Term Prognosis of Patients with Polypoidal Choroidal Vasculopathy Treated with Photodynamic Therapy.

We evaluated the long-term prognosis of the eyes of patients with polypoidal choroidal vasculopathy (PCV) treated with photodynamic therapy (PDT). In total, 60 eyes of 57 patients diagnosed with PCV and treated with PDT were reviewed retrospectively in real-world settings. The best-corrected visual acuity (BCVA), central retinal thickness (CRT), anatomical findings (vision-threatening findings), and treatment history were assessed. In total, 38 eyes underwent PDT as the initial treatment (initial PDT group) and 22 eyes underwent PDT as a rescue treatment (rescue PDT group). In the initial PDT group, 11 eyes (29%) did not require additional therapy throughout the observation period and maintained good BCVA. A total of 27 eyes (71%) underwent additional treatments and the mean BCVA was only stabilized for 2 years; thereafter, decreased vision occurred even with additional treatments. In the rescue PDT group, 22 eyes (95%) required additional treatment. Hard exudate, serous pigment epithelial detachment, and the total vision-threatening score were related to worse BCVA. Initial PDT may be effective in about 30% of cases with preservation of good vision and no need for additional treatment. However, patients with received rescue PDT needed additional treatment in most cases and the vision decreased in many cases.

Differences in clinical characteristics and treatment outcomes of submacular hemorrhage caused by age-related macular degeneration and retinal macroaneurysms: A multicenter survey from the Japan Clinical Retina Study (J-CREST) group.

PURPOSE: To evaluate the clinical characteristics, treatment trends, and visual prognosis of submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (nAMD) and retinal arterial macroaneurysm (RAM). METHODS: This retrospective study enrolled 187 Japanese patients with SMH at 10 institutions from 2015 to 2018. Medical records including SMH etiology, best-corrected visual acuity (BCVA), fundus photographs, optical coherence tomography images, and selected treatments were analyzed. RESULTS: Major causes of SMH were typical nAMD (tnAMD) (18%), polypoidal choroidal vasculopathy (PCV) (50%) and RAM (29%). Age, male/female ratio, baseline BCVA, central retinal thickness, and involved retinal layers were significantly different between etiologies (all P<0.0001). Treatment with anti-vascular endothelial growth factor drugs with and without intravitreal gas injection was chosen for half of eyes in the tnAMD and PCV groups, whereas vitrectomy was performed in 83.7% of eyes with RAM. The final BCVA improved significantly from baseline in the PCV and RAM groups (P = 0.0009, P<0.0001) and final BCVA was significantly better in the PCV group at a level similar to the other groups (P = 0.0007, P = 0.0008). BCVA improvement from baseline was significantly greater in the RAM group compared with the tnAMD (P = 0.0152) and PCV (P = 0.017) groups. Multivariate analysis revealed better final BCVA was significantly associated with younger age (P = 0.0054), better baseline BCVA (P = 0.0021), RAM subtype (P = 0.0446), and no tnAMD (P = 0.001). CONCLUSIONS: The characteristics of, and treatment strategy for, SMH were different between the underlying diseases. Anti-vascular endothelial growth factor treatment with or without expansile gas was mainly chosen for SMH in tnAMD and PCV, whereas vitrectomy with gas was the most common treatment for RAM, and the higher rate for vitrectomy might result in the greater BCVA improvement in the RAM group than in the other groups. Final BCVA was better in PCV, RAM, and tnAMD, in that order, because patients with PCV were younger and had better baseline BCVA.

A multicentre study of the risk factors associated with recurrence of central serous chorioretinopathy.

PURPOSE: To investigate potential clinical and multimodal imaging factors in central serous chorioretinopathy (CSC) recurrence. METHODS: The study was performed at nine Japanese medical institutions for patients who had experienced an active CSC episode. Demographic data and medical history were reviewed retrospectively. Significant differences in chronic manifestation, leakage site, leakage point number, leakage intensity, choroidal hyperpermeability, central retinal thickness (CRT) and subfoveal choroidal thickness were analysed between the recurrence and non-recurrence groups. RESULTS: In total, 538 eyes (538 patients) diagnosed with CSC (402 men, 136 women; mean age: 53.4 ± 11.9 years) were enrolled. Among them, 253 eyes (47.0%) developed ≥1 recurrence (follow-up: 15.9 ± 13.5 months, range 3-86 months). Univariate and multivariate analyses indicated that a history of corticosteroid use (odds ratio [OR], 5.52; 95% confidence interval [CI], 1.39-21.92; p = 0.015), bilateral disease (OR, 3.94; 95% CI, 1.47-10.6; p = 0.007), chronic manifestations (OR, 7.12; 95% CI, 2.93-17.28; p < 0.001), non-intense fluorescein leakage (OR, 3.34; 95% CI, 1.44-7.75; p = 0.005) and initial CRT (OR, 0.997; 95% CI, 0.993-0.999; p = 0.049) were significantly associated with CSC recurrence. Receiver operating characteristic curves were created, and the area under the curve for the multivariate logistic regression model of these five factors was 0.814. CONCLUSION: Patients with CSC who received corticosteroids and had bilateral disease, chronic manifestation, non-intense fluorescein leakage on fluorescein angiography or a relatively thinner CRT should be closely monitored to identify whether they are at high risk of recurrence.

Risk factors and characteristics of central serous chorioretinopathy with later development of macular neovascularisation detected on OCT angiography: a retrospective multicentre observational study.

OBJECTIVE: To identify the risk factors and characteristics of central serous chorioretinopathy (CSC) with subsequent macular neovascularisation (MNV) detected on optical coherence tomography angiography (OCTA). METHODS AND ANALYSIS: We included patients from six institutions who were initially diagnosed with CSC and subsequently did or did not develop MNV detected by OCTA. Potential influencing factors were identified by evaluating the patients' baseline demographics, multimodal fundus imaging, treatment options, recurrence and outcomes in both groups. RESULTS: We enrolled 176 eyes in 152 patients (112 men, 40 women; mean age: 52.1±10.4 years) with a mean follow-up of 30.4±16.3 months. Secondary MNV was present in 23 eyes (13.1%), and non-MNV was observed in 153 eyes (86.9%) by OCTA. Multivariate analysis revealed that older age (OR 1.06; 95% CI 1.01 to 1.11; p=0.014), chronic CSC (OR 3.05; 95% CI 1.12 to 8.30; p=0.029), leakage sites within the fovea on fluorescein angiography (OR 7.60; 95% CI, 1.89 to 30.48; p=0.004) and recurrent fluid within the first year (OR 5.12; 95% CI 1.66 to 15.77; p=0.012) were risk factors for subsequent MNV. Moreover, eyes with CSC complicated with MNV were characterised by poor visual acuity and low complete fluid resolution rates. CONCLUSION: The factors associated with MNV secondary to CSC were older age, higher rates of chronic CSC and recurrence, and foveal leakage points on fluorescein angiography.

A case of Nd:YAG laser-induced traumatic macular hole with good visual prognosis after vitrectomy with inverted internal limiting membrane technique.

PURPOSE: To report an accidental case of traumatic macular hole caused by Nd:YAG laser in a dermatology clinic. OBSERVATIONS: A 24-year-old woman sustained a laser injury to her right eye while practicing a dermatologic treatment using a Nd:YAG laser without wearing protective goggles. She noticed sudden-onset and progressing visual loss in her right eye and consulted an ophthalmologist 2 days after injury. The best-corrected visual acuity (BCVA) of her right eye decreased to 20/133. Fundus examination showed white parafoveal flecks with a central retinal hemorrhage and underlying serous retinal detachment. The retinal sensitivity in this lesion deteriorated. Two weeks later, a full-thickness macular hole (FTMH) developed in the affected eye. She was referred to Nagoya City University Hospital where the laser damage described was observed. The BCVA was 20/67. She underwent pars plana vitrectomy performed using the inverted internal limiting membrane (ILM) flap technique and gas tamponade. One week postoperatively, the FTMH closed, the BCVA in her right eye improved to 20/50, and the retinal sensitivity in the macular area mostly improved. The BCVA gradually improved and reached 20/25 9 months after the injury. CONCLUSIONS AND IMPORTANCE: Protective goggles must be worn when using an Nd:YAG laser in the laboratory or clinical setting. In the unfortunate event of a FTMH, early vitrectomy with an inverted ILM flap technique can be helpful to achieve a good visual prognosis.

Background Factors Affecting Visual Acuity at Initial Visit in Eyes with Central Retinal Vein Occlusion: Multicenter Study in Japan.

PURPOSE: To determine the baseline characteristics of patients with central retinal vein occlusion (CRVO) that were significantly associated with the best-corrected visual acuity (BCVA) at the initial examination. METHODS: This was a retrospective multicenter study using the medical records registered in 17 ophthalmological institutions in Japan. Patients with untreated CRVO (≥20-years-of-age) who were initially examined between January 2013 and December 2017 were studied. The patients' baseline factors that were significantly associated with the BCVA at the initial examination were determined by univariate and multivariate linear regression analyses. RESULTS: Data from 517 eyes of 517 patients were analyzed. Univariate analyses showed that an older age (r = 0.194, p < 0.001) and the right eye (r = -0.103, p < 0.019) were significantly associated with poorer BCVA at the initial visit. Multivariate analyses also showed that an older age (ß = 0.191, p < 0.001) and the right eye (ß = -0.089, p = 0.041) were significantly associated with poorer BCVA at the initial visit. CONCLUSIONS: The results indicate that an older age, a known strong factor, and the right eye were significantly associated with poorer BCVA at the initial visit to the hospital. These results suggest that functional and/or anatomical differences between the right and left eyes may be involved in these results.

Remote screening of diabetic retinopathy using ultra-widefield retinal imaging.

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.

Tilted Disc Syndrome Associated with Serous Retinal Detachment: Long-term Prognosis. A Retrospective Multicenter Survey.

PURPOSE: This study evaluated the long-term visual prognosis of a serous retinal detachment (SRD) secondary to tilted disc syndrome with or without an SRD at the final visit and the interventions. DESIGN: A retrospective, observational case series. METHODS: This was a multicenter study with an enrollment of 48 eyes of 41 treatment-naïve patients (14 men, 27 women) in whom tilted disc syndrome-related SRD was diagnosed at the first visit. Investigators at each institution decided whether to observe the patients without interventions or to treat with intravitreous injections of antivascular endothelial growth factor agents, photodynamic therapy, or both therapies combined. The patients were followed for at least 12 months. Main outcome measurements were changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline. RESULTS: Analyses of all eyes showed improvement from baseline when BCVA was measured (P < 0.0001), although last BCVA was similar to BCVA at baseline (P = 0.46). CRT significantly improved from that at baseline at the final visit (P < 0.0001). When eyes with or without SRD at the final visit were analyzed, baseline BCVAs (P = 0.22) were similar, whereas BCVA (P = 0.05) and last BCVA (P = 0.005) were significantly better in eyes without SRD. When eyes with or without the interventions were analyzed, baseline (P = 0.70), best (P = 0.99), and last (P = 0.70) BCVAs were similar. Last CRT significantly decreased from baseline CRT in eyes that had undergone interventions (P < 0.0001). CONCLUSIONS: The visual prognosis of SRD secondary to tilted disc syndrome was better when SRD resolved but was not influenced by the treatments.

Automated Detection of Macular Diseases by Optical Coherence Tomography and Artificial Intelligence Machine Learning of Optical Coherence Tomography Images.

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.

In vitro drusen model - three-dimensional spheroid culture of retinal pigment epithelial cells.

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.

Experimental proliferative vitreoretinopathy in rabbits by delivery of bioactive proteins with gelatin microspheres.

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.

Tissue Plasminogen Activator as an Antiangiogenic Agent in Experimental Corneal Neovascularization in Rabbits.

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.

Indocyanine Green Angiography-Guided Focal Laser Photocoagulation for Diabetic Macular Edema.

PURPOSE: To evaluate the usefulness of indocyanine green angiography (ICGA) to detect leaking spots and the effectiveness of ICGA-guided focal laser photocoagulation in eyes with diabetic macular edema (DME). METHODS: Ten eyes (8 patients) with diffuse DME diagnosed using fluorescein angiography (FA) and refractory to a sub-Tenon injection of triamcinolone acetonide (STTA), grid laser photocoagulation, or both were enrolled. FA and ICGA were performed using the Heidelberg Retina Angiograph 2. Hyperfluorescent spots on early-phase FA and on early- and late-phase ICGA were superimposed onto the macular thickness map measured by optical coherence tomography (OCT) and counted to calculate the spot density in the area with or without macular edema (ME). ICGA-guided focal laser photocoagulation was carried out. In 7 eyes, STTA was simultaneously performed. The central macular thickness (CRT) and macular volume (MV) were measured by OCT. RESULTS: On early-phase FA, 4.8 ± 2.3 and 2.3 ± 1.5 hyperfluorescent spots/disk area were observed inside and outside the ME, respectively. In contrast, the spot density was significantly decreased to 1.8 ± 0.9 inside the ME and was only 0.3 ± 0.4 outside the ME on late-phase ICGA (p < 0.01). The mean follow-up period after ICGA-guided photocoagulation was 19.0 months. The mean best-corrected visual acuity improved significantly from 0.77 ± 0.34 logarithm of the minimum angle of resolution at baseline to 0.52 ± 0.37 at the last visit (p < 0.01). Both CRT and MV significantly decreased (p < 0.01). Recurrence of DME was observed in 4 eyes: 3 eyes were treatable only with STTA and 1 required additional ICGA-guided laser photocoagulation. CONCLUSIONS: ICGA may be useful to detect leaking spots responsible for DME, enabling less invasive focal laser photocoagulation even in some of the eyes with diffuse DME.