Switching to brolucizumab from aflibercept in age-related macular degeneration with type 1 macular neovascularization and polypoidal choroidal vasculopathy: an 18-month follow-up study.

PURPOSE: To assess the effect of switching to brolucizumab from aflibercept on eyes with type 1 macular neovascularization (MNV) and polypoidal choroidal vasculopathy (PCV) at 18 months. METHODS: This study was a retrospective, observational case series that included 19 eyes of 19 patients with type 1MNV and 23 eyes of 22 patients with PCV. We compared the injection intervals, visual acuity, total lesion size, and the number of polypoidal lesions between baseline and 18 months. The correlations between the data including treatment interval, total lesion size, and the number of polyps were also assessed. RESULTS: Treatment intervals were significantly extended; from 7.4 ± 1.4 weeks to 11.6 ± 2.6 weeks for type 1 MNV, p < 0.001; from 6.9 ± 1.3 to 11.7 ± 3.1 weeks for PCV, p < 0.001. In type 1 MNV eyes, strong correlation was found between total lesion size and brolucizumab injection intervals (r = - 0.81; p = 0.0002) and moderate correlation was found between treatment frequency with aflibercept and that with brolucizumab (r = 0.76; p = 0.040). In PCV eyes, we found strong correlation between the number of polyps and brolucizumab treatment frequency (r = - 0.81; p = 0.0016) and moderate correlation between total lesion size and brolucizumab treatment interval (r = - 0.48; p = 0.034). Intraocular inflammation occurred in 2 of 19 eyes (10.3%) with type 1 MNV and 5 of 23 eyes (21.7%) with PCV. CONCLUSION: The properties to extend brolucizumab injection intervals might be the smaller lesion size and lower aflibercept frequency for type 1 MNV and the smaller number of polyps and the smaller size of lesion for PCV.

A ROCK Inhibitor Promotes Graft Survival during Transplantation of iPS-Cell-Derived Retinal Cells.

Currently, retinal pigment epithelium (RPE) transplantation includes sheet and single-cell transplantation, the latter of which includes cell death and may be highly immunogenic, and there are some issues to be improved in single-cell transplantation. Y-27632 is an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of Rho. We herein investigated the effect of Y-27632 in vitro on retinal pigment epithelium derived from induced pluripotent stem cells (iPS-RPE cells), and also its effects in vivo on the transplantation of iPS-RPE cell suspensions. As a result, the addition of Y-27632 in vitro showed suppression of apoptosis, promotion of cell adhesion, and higher proliferation and pigmentation of iPS-RPE cells. Y-27632 also increased the viability of the transplant without showing obvious retinal toxicity in human iPS-RPE transplantation into monkey subretinal space in vivo. Therefore, it is possible that ROCK inhibitors can improve the engraftment of iPS-RPE cell suspensions after transplantation.

Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem (iPS) Cells Suppress or Activate T Cells via Costimulatory Signals.

Human retinal pigment epithelial (RPE) cells derived from induced pluripotent stem (iPS) cells have immunosuppressive properties. However, RPE cells are also known as immunogenic cells, and they have major histocompatibility complex expression and produce inflammatory proteins, and thus experience immune rejection after transplantation. In this study, to confirm the immunological properties of IPS-RPE cells, we examined whether human RPE cells derived from iPS cells could suppress or stimulate inflammatory T cells from uveitis patients via costimulatory signals. We established T cells from patients with active uveitis as target cells and used iPS-RPE cells as effector cells. As a result, cultured iPS-RPE cells inhibited cell proliferation and the production of IFN-γ by activated uveitis CD4+ T cells, especially Th1-type T cells. In contrast, iPS-RPE cells stimulated T cells of uveitis patients. The iPS-RPE cells constitutively expressed B7-H1/CD274 and B7-DC/CD273, and suppressed the activation of T cells via the PD-1 receptor. iPS-RPE expressed these negative costimulatory molecules, especially when RPE cells were pretreated with recombinant IFN-γ. In addition, iPS-RPE cells also expressed B7-H3/CD276 costimulatory molecules and activated uveitis T cells through the B7-H3-TLT-2 receptor. Thus, cultured iPS-derived retinal cells can suppress or activate inflammatory T cells in vitro through costimulatory interactions.

A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models.

Recently, we successfully transplanted an autograft, or major histocompatibility complex (MHC)-matched allografts, from induced-pluripotent-stem-cell-derived retinal pigment epithelial (iPSC-RPE) cells in patients with age-related macular degeneration. However, there was an issue regarding immune rejection after transplantation. In this study, we established a preoperational in vitro "drug-lymphocytes-grafts immune reaction (Drug-LGIR)" test to determine the medication for immune rejection using host immunocompetent cells (lymphocytes) and transplant cells (target iPSC-RPE cells) together with different medications. The adequacy of the test was assessed by in vivo transplantation in monkey models together with medication based on in vitro data. In the results of Drug-LGIR tests, some drugs exhibited significant suppression of RPE cell-related allogeneic reactions, while other drugs did not, and the efficacy of each drug differed among the recipient monkeys. Based on the results of Drug-LGIR, we applied cyclosporine A or local steroid (triamcinolone) therapy to two monkeys, and successfully suppressed RPE-related immune rejections with RPE grafts, which survived without any signs of rejection under drug administration. We propose that our new preoperational in vitro Drug-LGIR test, which specifies the most efficacious medication for each recipient, is useful for controlling immune attacks with personalized treatment for each patient after retinal transplantation.

Short-term results of endovascular surgery with tissue plasminogen activator injection for central retinal vein occlusion.

PURPOSE: To examine the effects of retinal endovascular surgery (REVS) with tissue plasminogen activator injection into the retinal vein in central retinal vein occlusion (CRVO) eyes. METHODS: Sixteen consecutive CRVO patients with macular edema and decreased visual acuity who were referred to Toyama University Hospital between March 2014 and February 2016 were included in this study. Changes in visual acuity (VA) and central retinal thickness (CRT) were evaluated up to 6 months after REVS. Staining and leakage of the retinal veins in fluorescein angiography (FA) was graded in nine patients. RESULTS: Ten of 16 eyes were determined to be non-ischemic while the remaining six were ischemic. The mean logarithm of the minimum angle of resolution (logMAR) of VA was significantly improved from 0.98 ± 0.58 (mean ± standard deviation) at baseline to 0.78 ± 0.61 at 3 months (p = 0.002), and 0.64 ± 0.60 at 6 months (p = 0.003) after REVS. At 6 months, VA was improved in eight eyes (50%), while the other eight (50%) showed no change; none showed worsening. In the 10 eyes with non-ischemic CRVO, the mean VA was significantly improved at 6 months (p = 0.002), whereas no improvement was found in the six eyes with ischemic CRVO, . In all eyes, the mean CRT was significantly improved from 804 ± 343 µm at baseline to 506 ± 304 µm at 2 months (p = 0.014), 332 ± 229 µm at 3 months (p = 0.0001), and 305 ± 235 µm at 6 months (p = 0.00001). The postoperative complications observed were prolonged vitreous hemorrhage in one eye and neovascular glaucoma in two eyes. For postoperative recurrence of macular edema, sub-tenon injection of triamcinolone acetonide was given to five eyes, and intravitreal injection of an anti-VEGF agent was given to five eyes. Pan-retinal photocoagulation was performed on six eyes with ischemic type CRVO. The FA score was significantly improved after REVS (p = 0.018). CONCLUSIONS: REVS using a specially made micro-needle may be a surgical treatment option for non-ischemic CRVO, but it did not seem effective for ischemic CRVO.

The Fluctuation of Intraocular Pressure Measured by a Contact Lens Sensor in Normal-Tension Glaucoma Patients and Nonglaucoma Subjects.

PURPOSE: We compared the fluctuation of intraocular pressure (IOP) in normal-tension glaucoma (NTG) patients and individuals with nonglaucoma eyes. We obtained continuous IOP values using a SENSIMED Triggerfish contact lens sensor. MATERIALS AND METHODS: The eyes of 12 nonglaucoma subjects and 14 NTG patients were examined. In all 26 subjects, the IOP fluctuation was measured continuously for 24 hours with a contact lens sensor. We evaluated the range of IOP fluctuations over the 24-hour period separately for diurnal IOP and nocturnal IOP and identified each subject's maximum value. The range of IOP fluctuation were analyzed, cutoff level of IOP fluctuation was calculated using receiver operating characteristic curve analyses. RESULTS: The mean IOP in the NTG eyes was 11.5±2.4 mm Hg and that in the nonglaucoma eyes was 12.7±2.0 mm Hg, a nonsignificantly difference (P=0.175). The 24-hour range of IOP fluctuations in the NTG group was significantly larger than that of the nonglaucoma group (P=0.007). The percentage of NTG patients who had the peak time of IOP fluctuation during nocturnal sleep was 57.1%, whereas the corresponding rate for the nonglaucoma eyes was 91.7%. The cutoff level of IOP fluctuation for glaucoma was 442 mVeq (sensitivity=1.00; specificity=0.571). CONCLUSIONS: The range of IOP fluctuation was larger in the eyes with NTG than in the nonglaucoma eyes. This larger fluctuation might be one of the reasons underlying the aggravation of the visual field by NTG. Measurements of 24-hour continuous IOP might be one of the useful methods to distinguish NTG from nonglaucoma eyes.

Microperimetric Biofeedback Training Improved Visual Acuity after Successful Macular Hole Surgery.

Purpose. To evaluate the efficacy of setting a preferred retinal locus relocation target (PRT) and performing Macular Integrity Assessment (MAIA) biofeedback training in patients showing insufficient recovery of best corrected visual acuity (BCVA) despite successful closure of an idiopathic macular hole (MH). Methods. Retrospective interventional case series. Nine eyes of 9 consecutive patients with the decimal BCVA of less than 0.6 at more than 3 months after successful MH surgery were included. A PRT was chosen based on MAIA microperimetry and the patients underwent MAIA biofeedback training. BCVA, reading speed, fixation stability, and 63% bivariate contour ellipse area (BCEA) were evaluated before and after the training. Statistical analysis was carried out using paired Student's t-test. Results. PRT was chosen on the nasal side of the closed MH fovea in 8 patients. After the MAIA training, BCVA improved in all patients. The mean logMAR value of BCVA significantly improved from 0.33 to 0.12 (p = 0.007). Reading speed improved in all patients (p = 0.29), fixation stability improved in 5 patients (p = 0.70), and 63% BCEA improved in 7 patients (p = 0.21), although these improvements were not statistically significant. Conclusion. MAIA biofeedback training improved visual acuity in patients with insufficient recovery of BCVA after successful MH surgery.

Impact of obesity on musculoskeletal pain and difficulty of daily movements in Japanese middle-aged women.

OBJECTIVE: To investigate the impact of obesity on musculoskeletal pain and disability, which impairs well-being, associations between body mass index (BMI), frequency of musculoskeletal pain and difficulty of daily movements were assessed in middle-aged women. METHODS: Subjects were 709 Japanese women in a community, aged 40-69. Measured BMI, current smoking habits, frequency of pain (pain score)(rarely (0), occasionally (1) or frequently (2)) during the last 1 month at shoulders, neck, upper back, lower back and legs, difficulty of three daily movements: walking continually for more than a half hour, climbing stairs and sitting on the floor with one's legs bent beneath one another, (score for each movement) (rarely (0), occasionally (1) or frequently (2)) by a questionnaire. The summed score was defined as the difficulty score of daily movements (DS) (0-6). RESULTS: BMI increased significantly with age. Lower back pain (occasionally or frequently) was the most common symptom (40.3%) in the subjects. There was a peak in prevalence of frequent pain of shoulders at age 50. Pain score for legs and DS increased significantly with age. Higher BMI was related to increased prevalence of frequent leg pain and DS (>or=3), but there were no significant associations between age or BMI, and scores of back pain. DS was correlated significantly with pain scores at shoulders, upper back, lower back and legs. After adjustment for age and smoking habit using a logistic regression analysis, odds ratios for frequent pain at legs and DS (>or=3) were 4.02 (CI: 1.83-8.80) and 2.92 (CI: 1.56-5.47), respectively, in the obese women (BMI>or=26.4, n=61), compared with 401 women with normal BMI (20-24). CONCLUSION: Obesity tended to impair well-being through musculoskeletal pain at legs and difficulty of daily movements in Japanese middle-aged women.