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To report the frequency of hyphema after PRESERFLO ® MicroShunt (PMS) surgery using double-step knife in patients with glaucoma and to investigate its relationship with the tube insertion position. Glaucoma patients who underwent PMS surgery were reviewed. Hyphema was defined as visible hemorrhage in the anterior chamber. The insertion position of PMS was confirmed via gonioscopy. Patient backgrounds in the hyphema and non-hyphema groups were compared, and the course of visual acuity (VA), intraocular pressure (IOP), and time to resolution of hyphema were investigated. 65 of 66 eyes were eligible for consideration. Hyphema had occurred in 23 (35%) eyes. At the end of surgery, anterior chamber bleeding was observed under the microscope in 8 of 23 cases (35%). The tube fixation position was on the scleral spur (25 eyes), on the trabecular meshwork (27 eyes), on the Schwalbe line (10 eyes) and on the corneal side (3 eyes). There was no significant difference of the site of tube insertion between the two groups. All cases of hyphema spontaneously resolved within a few weeks, with stable IOP and recovered VA. It is worth noting that in PMS surgery using the double-step knife, hyphema may occur high frequency even if the tube insertion site is accurately positioned. Patients should be informed of the risk of hyphema before the surgery., Competing Interests: Declarations Competing interests The authors declare no competing interests. Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s).)

Purpose: Topical prostaglandin analogues are commonly used to treat patients with glaucoma, but may cause periocular and periorbital complications known as prostaglandin-associated periorbitopathy syndrome (PAPS)., Methods: A literature review was conducted on PAPS. Given the lack of consensus on grading PAPS, glaucoma specialists from Asia convened to evaluate current PAPS grading systems and propose additional considerations in grading PAPS., Results: Existing grading systems are limited by the lack of specificity in defining grades and consideration for patients' subjective perception of symptoms. Patient-reported symptoms (e.g., via a self-assessment tool) and additional clinical assessments (e.g., exophthalmometry, lid laxity, differences between tonometry results, baseline measurements, and external ocular photographs) would be beneficial for grading PAPS systematically., Conclusions: Effective management of PAPS could be facilitated by a common clinical grading system to consistently and accurately diagnose and characterise symptoms. Further research is required to validate specific recommendations and approaches to stage and monitor PAPS.

Purpose: Minimally invasive glaucoma surgery is safer and effective surgical modality for patients with glaucoma. To compare the effect of axial length (AL) on the surgical outcomes of combined cataract surgery and ab interno trabeculotomy (phaco-LOT), a retrospective, non-randomized comparative study was performed., Methods: In total, 458 eyes of 458 open-angle glaucoma patients who underwent phaco-LOT and were followed-up without any intervention for at least 6 months were enrolled. All were divided into a long-AL group (AL ≥ 26.0 mm, 123 eyes) and a not-long-AL group (AL < 26.0 mm, 335 eyes). The principal outcomes were the changes in intraocular pressure (IOP) and medication scores. We also sought a correlation between postoperative IOP spike and hyphema., Results: Significant postoperative reductions in IOP and medication scores were apparent in all subjects. The IOP reductions were significant at all timepoints in the not-long-AL group, but not until 1 month postoperatively in the long-AL group, and the IOP change was significantly lower in the long-AL group from postoperative day 1 to 3 months. On subanalysis of subjects by age, the microhook used, the pre-operative IOP, and the medication score, a significantly higher incidence of IOP spike was observed in the long-AL group in weeks 1 and 2 (both p < 0.05), but this did not correlate with hyphema status, implying that a different mechanism was in play., Conclusion: Phaco-LOT was effective regardless of AL, but the postoperative IOP decrease was lower and the early postoperative incidence of IOP spike was higher in long-AL eyes., (© 2023. The Author(s).)

The primary treatment for glaucoma, the most common cause of intermediate vision impairment, involves administering ocular hypotensive drugs in the form of topical eye drops. Observing real-time changes in the drugs that pass through the cornea and reach the anterior chamber of the eye is crucial for improving and developing safe, reliable, and effective medical treatments. Traditional methods for measuring temporal changes in drug concentrations in the aqueous humor employ separation analyzers such as LC-MS/MS. However, this technique requires multiple measurements on the eyes of various test subjects to track changes over time with a high temporal resolution. To address this issue, we have developed a measurement method that employs boron-doped diamond (BDD) microelectrodes to monitor real-time drug concentrations in the anterior chamber of the eye. First, we confirmed the electrochemical reactivity of 13 antiglaucoma drugs in a phosphate buffer solution with a pH of 7.4. Next, we optimized the method for continuous measurement of timolol maleate (TIM), a sympathetic beta-receptor antagonist, and generated calibration curves for each BDD microelectrode using aqueous humor collected from enucleated porcine eyes. We successfully demonstrated the continuous ex vivo monitoring of TIM concentrations in the anterior chambers of these enucleated porcine eyes. The results indicate that changes in intracameral TIM concentrations can be monitored through electrochemical measurements using BDD microelectrodes. This technique holds promise for future advancements in optimizing glaucoma treatment and drug administration strategies.

Purpose: Animal models of ocular hypertension (OH) have been developed to understand the pathogenesis of glaucoma and facilitate drug discovery. However, many of these models are fraught with issues, including severe intraocular inflammation and technical challenges. Lysophosphatidic acid (LPA) is implicated in trabecular meshwork fibrosis and increased resistance of aqueous outflow, factors that contribute to high intraocular pressure (IOP) in human open-angle glaucoma. We aimed to elevate IOP by increasing expression of the LPA-producing enzyme autotaxin (ATX) in mouse eyes., Methods: Tamoxifen-inducible ATX transgenic mice were developed. Tamoxifen was administered to six- to eight-week-old mice via eye drops to achieve ATX overexpression in the eye. IOP and retinal thickness were measured over time, and retinal flat-mount were evaluated to count retinal ganglion cells (RGCs) loss after three months., Results: Persistent elevation of ATX expression in mouse eyes was confirmed through immunohistochemistry and LysoPLD activity measurement. ATX Tg mice exhibited significantly increased IOP for nearly two months following tamoxifen treatment, with no anterior segment changes or inflammation. Immunohistochemical analysis revealed enhanced expression of extracellular matrix near the angle after two weeks and three months of ATX induction. This correlated with reduced outflow facility, indicating that sustained ATX overexpression induces angle fibrosis, elevating IOP. Although inner retinal layer thickness remained stable, peripheral retina showed a notable reduction in RGC cell count., Conclusions: These findings confirm the successful creation of an open-angle OH mouse model, in which ATX expression in the eye prompts fibrosis near the angle and maintains elevated IOP over extended periods.

Better agents are needed to improve glaucoma filtration surgery outcomes compared to current ones. The purpose of this study is to determine whether mitogen-activated protein kinase kinase (MEK) inhibitors can effectively arrest the cell cycle of human conjunctival fibroblasts (HCFs) and inhibit the formation of fibrosis and scarring following glaucoma filtration surgery. A cell counting kit‑8 assay revealed that the MEK inhibitor PD0325901 exhibited concentration-dependent growth inhibition of HCFs. Quantitative PCR, immunocytochemistry, and western blotting demonstrated decreased expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and increased expression of p27 in HCFs treated with PD0325901. Flow cytometry indicated that PD0325901 arrested the cell cycle of HCFs in the G0/1 phase. The cell-migration assay showed that HCF migration rate was significantly suppressed by PD0325901 exposure. Rabbits were divided into PD0325901-treatment and control groups, and glaucoma filtration surgery was performed. Although intraocular pressure did not differ between PD0325901-treatment and control groups, bleb height was greater in the treatment group. Histopathological evaluation revealed that fibrotic changes were significantly attenuated in the PD0325901-treatment group compared to the control group. In conclusion, the MEK inhibitor impedes HCF proliferation via cell-cycle arrest and may be beneficial for glaucoma filtration surgery by reducing bleb scarring., (© 2024. The Author(s).)

Purpose: To investigate factors associated with the severity of prelaminar schisis (PLS) in heathy subjects and glaucoma patients., Design: Prospective cross-sectional study., Methods: A total of 217 eyes of 217 subjects (110 normal eyes and 107 open angle glaucoma eyes) were studied. Frequency and severity of PLS were compared between normal and glaucomatous eyes. Multivariate logistic models were used to assess factors associated with the severity of PLS. Factors considered were age, axial length, glaucomatous damage indices, Bruch membrane opening (BMO) and anterior scleral canal opening parameters, tractional forces (posterior vitreous staging and presence of Bergmeister papilla), circumpapillary choroidal thickness, lamina cribrosa (LC) parameters, and peripapillary scleral (PPS) angle., Results: The frequency of PLS was 70.9% in normal eyes and 72.0% in glaucomatous eyes. There was no difference in frequency and severity between the groups. The presence of Bergmeister papilla was the strongest predictor of a more severe PLS in both normal and glaucomatous eyes (odds ratio [OR] + 9.78, 12.5; both P < .001). A larger PPS angle in normal eyes (OR = 1.19; P = .003) and a larger BMO area and a deeper LC depth in glaucomatous eyes (OR = 1.08, 1.05; both P = .038) were associated with severity of PLS., Conclusions: The severity of PLS was strongly associated with the presence of Bergmeister papilla, suggesting a traction-related phenomenon. Correlation of PLS severity with larger BMO area and deeper LC depth, which are optic nerve head structures associated with glaucoma, suggested its possible relationship with glaucomatous damage., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the postoperative intraocular pressure (IOP) control and identify the factors associated with failure of initial Ex-PRESS surgery in patients with open-angle glaucoma for 3 years., Methods: A total of 79 patients with medically uncontrolled open-angle glaucoma (55 normal-tension glaucoma and 24 primary open-angle glaucoma) were enrolled. All patients underwent Ex-PRESS implantation (including combined cataract surgery). The outcome measure was the survival rate using life table analysis, the failure was defined as IOP of > 18 mmHg (criterion A), > 15 mmHg (criterion B) or > 12 mmHg (criterion C) and/or IOP reduction of < 20% from baseline (each criterion) without any glaucoma medications. The Cox proportional hazards model was used to identify risk factors for IOP management defined as the above criterion.  RESULTS: The mean preoperative IOP was 19.3 ± 5.8 mmHg. At 36 months, the mean IOP was 11.8 ± 3.6 mmHg with a mean IOP change of 7.5 mmHg (reduction rate 39.0%). The cumulative probability of success was 58% (95%CI: 42-64%) (criterion A), 48% (95%CI: 37-59%) (criterion B) and 30% (95%CI: 20-40%) (criterion C). In multivariate analyses, factors that predicted poor IOP control included the intervention of bleb needling after 6 months after the surgery (HR: 2.43; 95%CI: 1.35-4.37; P = 0.032). Transient hypotony was observed in 4 patients., Conclusion: The implementation of bleb needling after Ex-PRESS surgery in the late postoperative period was suggested to be the main risk factor for achieving lower IOP., (© 2023. The Author(s).)

Purpose: Understanding the practice patterns and costs of glaucoma care in real-world clinical settings is important for optimizing medical expenses. However, glaucoma treatment trends and associated costs in Japan are unknown. We aimed to unveil glaucoma treatment trends and costs using a large administrative claims database in Japan., Study Design: Retrospective cohort study., Methods: We included patients diagnosed with glaucoma between April 2014 and March 2021 using the DeSC database. We calculated the frequencies and costs of antiglaucoma eyedrops, incisional or laser procedures, and ophthalmic examinations stratified by fiscal year and age. In the year-by-year analyses, the age distribution was standardized based on the 2020 distribution., Results: A total of 841,747 patient-years (429,051 patients) were included. The number of prescribed eyedrops significantly increased and the fixed-combination eyedrops proportion decreased with age. Trabeculectomy frequency decreased, and that of laser trabeculoplasty increased during the observation period. The frequencies of both incisional and laser procedures peaked in the 75-79 age group. In 2020, 16.1 bottles of eyedrops per patient-year were prescribed, and 15.9 incisional surgeries and 11.3 laser therapies were performed per 1000 patient-years. Intraocular pressure measurement and visual field testing were performed 6.5 times and 2.0 times per patient-year, respectively. The total direct cost of glaucoma treatment was 55,139 yen (US $399.5) per patient-year, of which medications accounted for 44.2%, ophthalmic examinations for 47.4%, and incisional or laser procedures for 8.4%., Conclusion: These results may be useful for understanding glaucoma treatment trends and costs in Japan., (© 2023. Japanese Ophthalmological Society.)

Purpose: The purpose of this study was to investigate risk factors for progression in the superior and inferior hemi-visual fields (hemi-VFs) and the corresponding hemi-disc/retinas in eyes with normal tension glaucoma (NTG)., Methods: A 5-year prospective follow-up of 90 patients with NTG with untreated intraocular pressure (IOP) consistently ≤ 15 mm Hg was conducted. The IOP and Humphrey Perimeter measurements and disc/retina stereo-photographs were taken every 3 and 6 months, respectively. Risk factors for progression in the superior and inferior hemi-VFs and in the superior and inferior hemi-disc/retinas were investigated., Results: The mean total deviation values decreased at -0.50 ± 0.76 and -0.13 ± 0.34 dB/year in the superior and inferior hemi-VFs, respectively (P < 0.001). In the superior hemi-VF, the risk factor for faster progression was greater long-term IOP fluctuation (P = 0.022). In the inferior hemi-VF, the risk factors were disc hemorrhage (DH), greater myopic refraction, body mass index (BMI), and vertical cup-to-disc ratio (v-C/D; P < 0.05). The progression probability was 47.7 ± 6.0 and 17.7 ± 4.7% at 5 years in the superior and inferior hemi-disc/retinas respectively (P < 0.001), and DH was a risk factor for progression in both (P = 0.001)., Conclusions: In NTG eyes, greater BMI, myopia, and v-C/D are characteristic risk factors for faster progression in the superior half of the optic nerve head (ONH), whereas long-term IOP fluctuation is the significant risk factor in the inferior half of the ONH, whereas DH is a risk factor in both., Translational Relevance: Different risk factors were identified in superior and inferior hemifields in NTG eyes.

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We thus hypothesised that IVT-Ngb may also be neuroprotective in experimental glaucoma (EG) by mitigating optic nerve (ON) astrogliosis and microgliosis as well as structural damage. In this study using a microbead-induced model of EG in six Cynomolgus primates, optical coherence imaging showed that Ngb-treated EG eyes had significantly less thinning of the peripapillary minimum rim width, retinal nerve fibre layer thickness, and ON head cupping than untreated EG eyes. Immunohistochemistry confirmed that ON astrocytes overexpressed Ngb following Ngb treatment. A reduction in complement 3 and cleaved-caspase 3 activated microglia and astrocytes was also noted. Our findings in higher-order primates recapitulate the effects of neuroprotection by Ngb treatment in rodent EG studies and suggest that Ngb may be a potential candidate for glaucoma neuroprotection in humans.

Purpose: To elucidate which swept-source optical coherence tomography (OCT)-derived optic nerve head (ONH) parameters are associated with longer axial length (AXL) in healthy myopic eyes., Design: Prospective cross-sectional observational study., Methods: Two hundred eleven healthy eyes of 140 participants (96 emmetropic-mild myopic [AXL: 22.2-24.5 mm], 83 moderately myopic [24.5-26.0 mm], and 32 highly myopic [26.0-27.4 mm] eyes) were enrolled. Bruch membrane opening (BMO), anterior scleral canal opening (ASCO) area and ovality, minimum rim width, parameters defining misalignment between the BMO and ASCO planes, OCT-defined region of perineural canal retinal epithelium atrophy and externally oblique choroidal border tissue, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), circumpapillary choroidal thickness (cpChT), lamina cribrosa parameters, and peripapillary scleral (PPS) angle were calculated from BMO-centered radial scans reconstructed from 3D raster scans. Multivariate linear mixed models were used to elucidate ONH parameters that are independently associated with AXL., Results: Longer AXL was associated with a greater misalignment between ASCO and BMO planes, larger region of externally oblique choroidal border tissue, thinner cpChT, larger PPS angle, larger ASCO area, and thicker cpRNFLT (all P < .040 after Bonferroni's correction for number of included explanatory variables)., Conclusions: A greater misalignment between BMO and ASCO planes, thinner choroid, a more posteriorly bowed PPS, an enlargement of ASCO, and thicker cpRNFLT were each associated with longer AXL. An enhanced understanding of these AXL-associated configurations should provide essential information to improve our ability to detect glaucoma-induced ONH morphology in myopic eyes., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prcis: Diagnostic or antiglaucoma drug records in the Japanese claims data showed a high validity in identifying glaucoma patients. Specific subtypes were identified with high specificity and negative predictive values but low sensitivity and positive predictive values., Purpose: Despite the widespread use of administrative claims data in epidemiological research on glaucoma, only a few studies have investigated the validity of the methods in defining patients with glaucoma using diagnoses and drug records. We aimed to evaluate the validity of these algorithms in identifying patients with glaucoma using the Japanese claims data., Methods: Two ophthalmologists independently reviewed the medical charts and administrative claims data of 500 randomly selected patients who visited the Department of Ophthalmology of an academic hospital in 2019. We constructed 12 algorithms to identify patients with any type and specific subtypes of glaucoma using the claims records of diagnosis, antiglaucoma drugs, and visual field tests. We regarded the diagnosis of glaucoma based on the medical charts as the reference standard and calculated the sensitivity, specificity, and positive and negative predictive values of each algorithm based on the claims data., Results: The algorithms of ≥1 diagnostic record per year and ≥1 antiglaucoma drug record per year exhibited sensitivities of 94.6% and 89.2%, respectively, and specificities of 88.9% and 98.3%, respectively. An increase in the frequency of records resulted in a decreased sensitivity and slightly increased specificity. The addition of visual field tests did not improve the validity. The algorithms for specific subtypes of glaucoma exhibited high specificity and relatively low sensitivity., Conclusion: Diagnostic or antiglaucoma drug records in the Japanese claims data were useful for identifying patients with glaucoma. Researchers should select identification algorithms based on the study design., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Visual field (VF) testing in combination with a specialized VF analysis software is critical for characterizing and monitoring visual loss in glaucoma. Although performing glaucoma progression analysis requires original VF data rather than printouts or image files, extent of VF data transfer between referring and referred ophthalmologists is unclear. Here, we surveyed glaucoma specialists who belong to the Japan Glaucoma Society (JGS)., Methods: An internet survey of daily practice patterns regarding electronic VF data transfer at the time of glaucoma referrals (referring/referred) was sent to all 50 JGS board members. The survey consisted with 11 questionnaires, and the response rate was 100%., Results: The respondents included 33 university hospital ophthalmologists (66%) (Q1), and those scattered throughout Japan (Q2). All respondents used Humphrey Visual Filed Analyzer (HFA) (Q3) and at least one of a VF progression analysis software (Q4). Ten respondents (20%) actively transferred electronic VF data, while 40 (80%) did not (Q5). The major reasons for not actively transferring data electronically were that there was no support for data transfer by neighboring (n = 26, 65%) and/or own (25, 63%) institutes (Q6). All 40 inactive respondents responded that electronic data transfer is ideal (Q7). All 10 active respondents transferred data using USB flash memory (Q8). Of the 10 active respondents, seven (70%) reported that the percentage of referral letters accompanying electronic VF data in a format that allows for progression analysis from the beginning was less than 25% (Q9). When the referral letters did not accompany the electronic VF data, four (40%) reported that they further requested the data transfer in < 25% of cases (Q10). When the 10 active respondents were requested to transfer data, six (60%) had experienced rejection due to various reasons (Q11)., Conclusion: An internet survey showed that 80% of the JGS board members were not actively transferring VF data mainly because of the absence of a system in place at institutions for sending and receiving data, although they feel that the electronic VF data transfer is ideal. The results provide basic data for future discussions on the promotion of the VF data transfer., (© 2023. The Author(s).)

Purpose: Prostaglandin-associated periorbitopathy in patients with glaucoma is reportedly not caused by EP2 agonist, but it has been a cosmetic problem with prostaglandin F receptor (FP) agonists. In this study, patients with prostaglandin-associated periorbitopathy on FP agonists were switched to EP2 agonist and changes were investigated. Methods: Patients complaining of prostaglandin-associated periorbitopathy were included. The FP agonist was switched to EP2 agonist (omidenepag isopropyl), and patients were followed up for 7 months. Frontal photographs were taken at every visit, and objective changes in deepening of the upper eyelid sulcus were assessed by three observers. Subjective questionnaires (self-awareness of deepening of the upper eyelid sulcus, eyelid/peri-eyelid skin pigmentation, eyelash elongation, and conjunctival hyperemia) were acquired at the start and the endpoint. Factors associated with the change of prostaglandin-associated periorbitopathy were investigated using logistic regression analysis. Results: Included were 23 eyes of 23 patients (17 women; 60.6 years). At 7 months, objective deepening of the upper eyelid sulcus improved by 76%. The subjective questionnaires showed that deepening of the upper eyelid sulcus improved in 95%, eyelid/peri-eyelid skin pigmentation in 76%. The less extent of myopia was a significant factor in the eyes with improved eyelid/peri-eyelid skin pigmentation. After switching, no change in intraocular pressure or visual acuity was observed ( P  ≥ 0.22). Conclusion: Switching to omidenepag isopropyl increased patient satisfaction and might be the first step to lightening deepening of the upper eyelid sulcus and eyelid/peri-eyelid skin pigmentation. It was suggested that pigmentation may be more easily improved in nonmyopic eyes.

Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-knock-in (Mettl23+/G and Mettl23G/G) and -knockout (Mettl23+/- and Mettl23-/-) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor α target gene that was critical for RGC homeostasis through the negative regulation of NF-κB-mediated TNF-α and IL-1β feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

Purpose: To evaluate the effectiveness of MicroPulse ® transscleral laser therapy (MP-TLT) using both the original and revised MicroPulse P3 ® delivery probes in patients with refractory glaucoma., Study Design: Retrospective study METHODS: We analyzed the data of patients with refractory glaucoma who underwent MP-TLT with the original and with the revised MicroPulse P3 ® Delivery Device from January 2018 to December 2020 at the University of Tokyo Hospital and who were followed up for 3 months. Patients' demographics, preoperative and postoperative intraocular pressure (IOP), medication scores, best-corrected visual acuity (BCVA), and complications were analyzed., Results: This study enrolled 40 patients in both probe groups. At baseline, the mean IOP was 31.1 mmHg in the original group and 29.2 mmHg in the revised group, and it decreased to 22.6 mmHg and 21.6 mmHg after 3 months, respectively (paired t-test p=0.001, 0.001). No significant difference was noted between the number of medications and BCVA at baseline and 3 months in either probe group (paired t-test, p>0.05). Nor were any serious complications observed., Conclusion: MP-TLT using the revised MicroPulse P3 ® Delivery Device for the treatment of refractory glaucoma was effective in reducing IOP across glaucoma types with an excellent safety profile and was well-tolerated by the patients., (© 2022. Japanese Ophthalmological Society.)

Among increasing eye diseases, glaucoma may hurt the optic nerves and lead to vision loss, the treatment of which is to reduce intraocular pressure (IOP). In this research, we introduce a new concept of the surgery simulator for Minimally Invasive Glaucoma Surgery (MIGS). The concept is comprised of an anterior eye model and a fluidic circulatory system. The model made of flexible material includes a channel like the Schlemm's canal (SC) and a membrane like the trabecular meshwork (TM) covering the SC. The system can monitor IOP in the model by a pressure sensor. In one of the MIGS procedures, the TM is cleaved to reduce the IOP. Using the simulator, ophthalmologists can practice the procedure and measure the IOP. First, considering the characteristics of human eyes, we defined requirements and target performances for the simulator. Next, we designed and manufactured the prototype. Using the prototype, we measured the IOP change before and after cleaving the TM. Finally, we demonstrated the availability by comparing experimental results and target performances. This simulator is also expected to be used for evaluations and developments of new MIGS instruments and ophthalmic surgery robots in addition to the surgical training of ophthalmologists., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To evaluate the histological changes associated with, and the potential mechanisms of, intraocular pressure (IOP) reduction by micropulse cyclophotocoagulation (MP-CPC) in rabbit eyes., Methods: MP-CPC was performed on the right eyes of Dutch belted rabbits, whereas the left eyes served as controls. The laser power settings were 250, 500, 750, 1000, 1500, and 2000 mW, 10 seconds per sweep, 100 seconds in total. IOP, outflow facility, and uveoscleral outflow tract imaging, using a fluorescent tracer, were examined at one week after MP-CPC. Changes of morphology and protein expressions in the outflow tissues, conjunctiva, and sclera were also evaluated., Results: Significant reductions in IOP after MP-CPC were observed at 500 to 1000 mW (P = 0.036 and P = 0.014, respectively). The pre-MP-CPC IOP was 11.35 ± 0.41 mm Hg. At one week after surgery, the respective IOP values in the eyes treated at 500 mW and 1000 mW were 9.45 ± 0.49 mm Hg and 7.4 ± 0.27 mm Hg, respectively. Severe ciliary body damage was observed at 1500 to 2000 mW. MMP1-3 and fibronectin expression levels in the outflow tract and ciliary body were upregulated after MP-CPC. The α-smooth muscle actin (α-SMA) was upregulated at higher power levels. MP-CPC significantly increased uveoscleral outflow, whereas the outflow facility did not change. The α-SMA, collagen, and fibronectin were significantly upregulated in the subconjunctiva and sclera., Conclusions: Reactive fibrotic responses were observed in the outflow tract, conjunctiva, and sclera after MP-CPC. A potential mechanism of IOP reduction by MP-CPC in pigmented rabbit eyes may involve increased uveoscleral outflow related to MMP upregulation.

Purpose: We aimed to analyze the changes in the visual cortex of a ferret model of ocular hypertension (OH) using cytochrome oxidase (CO) staining., Study Design: Experimental., Methods: OH was induced in 9 ferrets by means of injection of cultured conjunctival cells into the anterior chamber of the right eye. Three ferrets were used as the controls. CO staining was performed to assess the metabolic intensity at the II-III and IVC layers of the visual cortex., Results: The intensities of CO staining in the right and left II-III layers of the primary visual cortex (V1) in the OH ferrets were 39.8 ± 10.3 and 41.9 ± 9.2 arbitrary units, respectively. In the control ferrets, the intensity was 88.1 ± 8.1 arbitrary units. The intensity of CO staining of the II-III layers obtained from the OH eyes was significantly lower than that from the control eyes (unpaired t test, P < .01). The intensities of CO staining in the right and left IVC layers of V1 in the OH ferrets were 60.3 ± 12.8 and 60.0 ± 13.5 arbitrary units, respectively. In the control ferrets, the intensity was 111.4 ± 9.6 arbitrary units. The CO staining intensity of the IVC layer obtained from the OH eyes was significantly lower than that from the control eyes (unpaired t test, P < .01)., Conclusion: The CO staining intensity was reduced in the visual cortex from OH eyes. This study revealed that OH causes metabolic change in the visual cortex., (© 2022. Japanese Ophthalmological Society.)

Purpose: To clarify recent trends in glaucoma surgery in Japan, including minimally invasive glaucoma surgery., Study Design: Retrospective cohort study., Methods: We used the Diagnostic Procedure Combination database, a nationwide administrative database in Japan. Patients who underwent glaucoma-related procedures were included. We calculated the number of surgeries stratified by procedures and age categories. We also investigated the number of glaucoma-related procedures in combination with cataract surgery., Results: From fiscal years 2011 to 2019, we identified 134,331 glaucoma-related procedures at 720 hospitals. The total number of glaucoma-related procedures increased by 215% from 6516 in 2011 to 20,569 in 2019. The numbers of filtering surgeries, trabeculotomies, and glaucoma drainage devices with plates [GDD(p +)] procedures significantly increased (P = 0.002, 0.002, and 0.006, respectively), whereas the number of cyclocryotherapy procedures significantly decreased (P = 0.002). The number of iStent procedures increased by 49% from 371 in 2018 to 551 in 2019. The ≥ 65 year age group accounted for > 80% of the iStent procedures. In the 0 to 14 year age group, trabeculotomy accounted for about 70% of the procedures, and the GDD(p +) procedure became the second most common procedure after trabeculotomy because of the decrease in filtering surgeries. Among combination surgeries, trabeculotomy was most frequently performed. The proportion of combination surgery increased, especially in trabeculotomy., Conclusions: The total number of glaucoma-related procedures increased throughout the observation period. Before 2017 filtering surgery was the most common procedure, whereas trabeculotomy was most common after 2018. The proportion of trabeculotomies performed in combination with cataract surgery continuously increased., (© 2022. Japanese Ophthalmological Society.)

Intraocular pressure reduction is the only available and evidence-based medical therapy for glaucoma. Currently, the first-line eye drops are prostaglandin analogues including latanoprost, travoprost, bimatoprost, and tafluprost. These drugs stimulate intraocular prostanoid false positive (FP) receptors and reduce intraocular pressure by increasing mainly uveoscleral aqueous outflow. For 2 decades since latanoprost was launched, no drug has been comparable in its efficacy. In 2018, a prostanoid EP2 agonist, omidenepag, was launched in Japan. Current FP agonists and EP2 agonists indicate comparable intraocular pressure reduction by stimulating prostanoid FP or EP2 receptors. However, their safety profiles are quite different because of the differences between the intracellular signaling pathways through their own receptors. Including these commercially available FP and EP2 receptor agonists, prostanoid receptors have a large potential to control intraocular pressure. In this review I will trace the history and development of FP and EP2 receptor agonists from their original function, and explain their potential as first-line drugs including elucidation of their efficacy and safety., (© 2021. Japanese Ophthalmological Society.)

To compare the short-term surgical effectiveness and safety profile of trabeculotomy ab externo and ab interno with microhook in terms of the recovery of visual acuity. A retrospective chart review was performed on patients who underwent trabeculotomy combined with phacoemulsification and lens implantation at Asahi General Hospital, with 6 months of follow-up. The patients treated by trabeculotomy were classified into two groups depending on the surgical procedures: ab interno with Tanito microhook (TMH) and ab externo with rigid probe trabeculotome (LOT). The demographics, preoperative and postoperative intraocular pressure (IOP), number of medications (Med), best-corrected visual acuity (BCVA), surgical-induced astigmatism (SIA), and postoperative complications were analyzed at pre-operation, and 1 week and 1-6 months post-operation. Fifty-two eyes of 38 Japanese patients underwent TMH and 42 eyes of 32 patients underwent LOT. The decreases in IOP and Med from the baseline were significant at all time points in both groups (p < 0.001), but there were no significant differences between the two groups. BCVA improved significantly in TMH and LOT after the operation (p < 0.001). BCVA and SIA significantly improved, mostly at 1 week in TMH, compared with LOT (p = 0.02 and 0.003). Hyphema and IOP spike exceeding 30 mmHg (spike) occurred in 11% and 6% of participants in TMH, and 33% and 26% of participants in LOT, respectively. Hyphema and IOP spike occurred more frequently in the LOT than in the TMH group (p = 0.01 and 0.005). Ab interno trabeculotomy showed similar IOP-lowering effects as ab externo, but had less postoperative complications., (© 2021. The Author(s).)

Introduction: We aimed to evaluate the additional effects and safety of a Rho-associated protein kinase (ROCK) inhibitor, ripasudil hydrochloride hydrate, in Japanese patients with primary open-angle glaucoma (POAG) with an intraocular pressure (IOP) of at most 15 mmHg undergoing prostaglandin F 2α (FP) receptor agonist monotherapy (FP monotherapy)., Methods: In this prospective observational study, 30 Japanese patients with POAG and IOP of at most 15 mmHg (mean age 59.4 years; 10 men) who were undergoing FP monotherapy in both eyes were administered an additional dose of ripasudil hydrochloride hydrate (GLANATEC ophthalmic solution 0.4%: ripasudil) in one eye. The following factors were investigated at 1 and 3 months after the initiation of ripasudil treatment: (1) magnitude of change in IOP between the treated and contralateral untreated eyes, (2) number of treated eyes showing 20% and 30% IOP reduction, (3) IOP difference between treated and contralateral untreated eyes, and (4) safety during the treatment period. Both (1) and (3) were analyzed using the mixed-effect model for repeated measurements., Results: The treated eyes showed significant reduction in IOP at 1 month (- 1.92 mmHg, P < 0.001) and 3 months (- 1.81 mmHg, P < 0.001). In contrast, contralateral untreated eyes did not show IOP reduction at 1 month (0.53 mmHg, P = 0.016) and 3 months (0.38 mmHg, P = 0.15). IOP reduction of - 20% and - 30% was achieved in 9 (30%) and 3 (10%) treated eyes, respectively. There were significant differences in IOP between the treated and contralateral untreated eyes at 1 month (- 2.46 mmHg, P < 0.001) and 3 months (- 2.20 mmHg, P < 0.001). Two patients experienced local adverse events (facial edema, one patient at week 1; blepharitis, one patient at 1 month); they recovered quickly after stopping ripasudil administration., Conclusion: In patients with POAG with an IOP of at most 15 mmHg undergoing FP monotherapy, the addition of ripasudil resulted in significant IOP lowering at 1 and 3 months. Ripasudil could be used to enhance the outcome of FP monotherapy., Trial Registration: Registered UMIN ID: UMIN000030742., (© 2021. The Author(s).)

Purpose: To investigate the outcomes of fornix-based trabeculectomy in Japanese patients with glaucoma based on more than five years of preoperative data., Study Design: Retrospective case series METHODS: This study consisted of 35 eyes of 35 Japanese glaucoma patients (mean age: 60.6, standard deviation (SD) 11.5 years) who received initial fornix-based trabeculectomy from a single ophthalmology clinic, with one or more reliable visual field test results per year from at least five years before and after the surgery. Measurements included postoperative mean intraocular pressure (IOP), standard deviation of IOP, medication scores, mean deviation slope, and total deviation slope were evaluated based on preoperative data. The relationship between mean IOP, SD-IOP and the visual field (VF) deterioration speed was also analysed., Results: The mean follow-up period before surgery was 6.15 (SD 0.97) years and post surgery it was 5.95 (SD 0.63) years. The preoperative mean IOP of 14.6 (SD 2.3) mmHg significantly decreased to 9.2 (SD 2.2) mmHg (P <.001). The preoperative medication score 2.7 (SD 0.5) significantly decreased to 0.1 (SD 0.4, P <.001). The preoperative MD slope of -0.52 (SE 0.047) dB/year significantly improved to -0.31 (SE 0.14) dB/year (P <.01), with improvement in the superior hemifield (P ≤.018). Inferior hemifield (P >.10) did not follow the trend. Neither mean IOP nor SD-IOP correlated with the VF deterioration speed., Conclusions: Fornix-based trabeculectomy is an acceptable procedure for initial surgical management of glaucoma, especially for maintenance of superior VF.

Purpose: We previously reported the presence of multidrug-resistant staphylococci on the ocular surface of glaucoma patients using prostaglandin analog drops for more than 1 year. Here, we investigated the effect of benzalkonium chloride (BAC) on these multidrug-resistant staphylococci., Methods: Staphylococcus epidermidis was isolated from the conjunctival sacs of 32 eyes of 32 patients comprised of 13 eyes treated with 0.005% latanoprost (Xalatan; Xa group) and 19 eyes treated with 0.004% travoprost (Travatan Z; Tz group). The minimum inhibitory concentrations (MICs) of prostaglandin analogs and BAC were measured. The presence of efflux pump genes was analyzed using polymerase chain reaction., Results: No difference was found in the MIC values of prostaglandin analogs. In contrast, the MIC values of BAC were significantly higher for the isolates from the Xa group than for those from the Tz group (2.02 vs. 1.02 µg/mL; P = 0.001). One proton-motive efflux gene, qacC/smr , was detected more frequently in the Xa isolates than in the Tz isolates ( P < 0.001). The prevalence of methicillin resistance was correlated with the presence of qacC/smr ( P = 0.010), and the MIC of BAC was significantly correlated with the detection of qacA/B and qacC/smr sequences ( P = 0.03 and P < 0.001, respectively)., Conclusions: The long-term use of eye drops containing BAC might select BAC-resistant S. epidermidis harboring qacC/smr ., Translational Relevance: These findings suggest that the long-term use of eye drops containing BAC might be inappropriate in terms of avoiding antimicrobial resistance., Competing Interests: Disclosure: J. Lee, None; T. Iwasaki, None; S. Ohtani, None; H. Matsui, None; R. Nejima, None; Y. Mori, None; F. Kagaya, None; A. Yagi, None; A. Yoshimura, None; H. Hanaki, None; M. Aihara, None; K. Miyata, None, (Copyright 2020 The Authors.)

Purpose: We aimed to investigate the toxicity of 6 fixed-combination drugs for glaucoma therapy using human corneal epithelial sheets (HCES)., Study Design: Experimental., Materials and Methods: We used 6 kinds of commercially available fixed-combination drugs: latanoprost/carteolol (LAT/CAR), latanoprost/timolol (LAT/TIM), tafluprost/timolol (TAF/TIM), travoprost/timolol (TRA/TIM), brinzolamide/timolol (BRZ/TIM), and dorzolamide/timolol (DRZ/TIM) including different preservatives. The cell viability and barrier function of the HCES after exposure to the eye drops for 10 or 30 minutes were assessed using the WST-1 assay and transepithelial electrical resistance (TEER) measurements, respectively. The HCES were also evaluated using hematoxylin and eosin (HE) staining and transmission electron microscopy., Results: The cell viability significantly decreased in the HCES treated with LAT/TIM or DRZ/TIM after 10 and 30 minutes and in those treated with BRZ/TIM after 30 minutes. The barrier function increased significantly in the HCES treated with LAT/CAR. Histologically, the HCES were damaged after treatment with LAT/TIM, BRZ/TIM, or DRZ/TIM for 30 minutes. Transmission electron microscopy indicated narrow intercellular spaces and multiple intercellular junctions in the HCES treated with LAT/CAR, TAF/TIM, or TRA/TIM. The HCES treated with DRZ/TIM, BRZ/TIM, or LAT/TIM contained cytoplasmic vacuoles and collapsed cellular structures., Conclusion: Glaucoma fixed-combination eye drops demonstrated a different toxic effect on the cell viability, barrier function, and morphologic changes of HCES.

To examine whether autotaxin (ATX) in the aqueous humor causes elevated intraocular pressure (IOP) in patients with Posner-Schlossman syndrome (PSS). ATX and transforming growth factor beta (TGF-β) in the aqueous humor were quantified in PSS patients. The expression of ATX and TGF-β in cytomegalovirus (CMV)-infected-human trabecular meshwork (hTM) cells was examined. Biological changes in hTM cells and monkey Schlemm's canal endothelial (SCE) cells cultured in the conditioned medium of CMV-infected hTM cells were analyzed. The expression of ATX and TGF-β1 was upregulated in the aqueous humor of CMV-positive PSS patients, and the level of ATX in the aqueous humor was positively correlated with IOP. CMV infection upregulated ATX and TGF-β1 in hTM cells. The conditioned medium induced fibrotic changes in hTM cells and reduced SCE permeability, which was attenuated by an ATX inhibitor, a lysophosphatidic acid receptor antagonist, and a Rho kinase inhibitor. ATX in the aqueous humor induced by CMV infection may trigger elevated IOP. Modulating ATX activity may be a novel treatment modality for PSS.

Purpose: To clarify the prevalence of secondary glaucoma (SG) and its speed of progression in patients with herpes simplex virus (HSV)-anterior uveitis (AU), varicella zoster virus (VZV)-AU, and cytomegalovirus (CMV)-AU., Methods: In total, 170 patients with herpetic AU were enrolled in this retrospective observational case series. Patients with visual field (VF) defects and glaucomatous disc abnormalities were diagnosed with SG. Moreover, the speed of SG progression was defined as decreasing mean deviation (MD) values per year. SG prevalence and annual MD-value decrease were compared among the three types of herpetic AU., Results: SG prevalence was 16%, 9%, and 72% in patients with HSV-AU, VZV-AU, and CMV-AU, respectively. Patients with CMV-AU had the highest SG prevalence (odds ratio = 3.15; 95% confidence interval = 1.15-8.65; P < 0.05). Furthermore, the annual MD-value change was significantly higher in SG caused by CMV-AU than in that caused by HSV/VZV-AU (-2.6 ± 2.4 dB/year and -0.45 ± 0.54 dB/year, respectively; P < 0.05)., Conclusions: Our results demonstrated that patients with CMV-AU may have a higher risk and faster speed of progression of SG than patients with HSV/VZV-AU. Therefore, clinicians should monitor glaucoma onset and VF-defect progression in patients with CMV-AU.

Glaucoma is a chronic optic neuropathy that leads to visual field loss. Elucidating the mechanisms underlying glaucoma is essential for developing new treatments, such as neuroprotective drugs. Various glaucoma models based on the induction of intraocular pressure (IOP) elevation have been established for use in glaucoma studies. However, the time-dependent pathological changes accompanying IOP elevation have not been fully elucidated. In this study, rat conjunctival fibroblasts were injected into the anterior chamber of rat eyes, and IOP elevation was induced for 28 days. Glaucomatous signs such as optic nerve head cupping, retinal thinning, glial activation and apoptotic signaling in the retina were obvious in the cell-injected eyes on the 14th day after injection. The pattern of retinal ganglion cell (RGC) loss differed by the magnitude of IOP elevation. The number of RGCs decreased by 37.5% in eyes with IOP lower than 50 mmHg (Under-50) and by 88.0% in those with IOP higher than 50 mmHg (Over-50) 28 days after cell injection. The RGC counts were correlated with IOP in the Under-50 group but not in the Over-50 group. Our model may contribute to the investigation of pathogenic mechanisms of glaucoma and the development of new glaucoma treatments.

Purpose: The present study aimed to investigate the effectiveness of adjunctive therapy involving the Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitor ripasudil in lowering intraocular pressure (IOP) in patients with different subtypes of glaucoma, on the basis of the time of IOP measurement STUDY DESIGN: Retrospective study METHODS: In total, 58 patients who underwent adjunctive therapy with ripasudil at a single institution were included. They were classified into a primary open-angle glaucoma (POAG) group, an exfoliation glaucoma (XFG) group, and a secondary glaucoma associated with uveitis, or steroid glaucoma (SG), group. The average IOPs within 6 months before (pre-IOP) and after (post-IOP) the addition of ripasudil were compared among the 3 groups. The IOP values of the morning-visit and afternoon-visit groups were also compared to reflect the peak effectiveness of ripasudil., Results: The IOP reductions in the POAG (n = 38), XFG (n = 6), and SG (n = 14) groups were -1.1, +0.5, and +0.5 mmHg, respectively. Significant reductions in IOP were observed in the POAG group (P = .014). The IOP reductions in the POAG morning-visit and afternoon-visit groups were -1.9 and +0.5 mmHg, respectively. IOP was significantly reduced in the morning-visit POAG group after treatment with ripasudil (P = .002). The IOP values measured during morning visits were lower than those measured during afternoon visits (IOP reduction: -1.3 mmHg; P = .011)., Conclusions: The findings of the present study indicate that ripasudil is effective as an adjunctive therapy for lowering IOP in patients with POAG; these reductions are more significant when measured closer to the time of peak effectiveness.

We explored the potential relevance of aqueous lysophosphatidic acid (LPA) and autotaxin (ATX) levels on postoperative outcomes of trabeculectomy, and the effects of ATX on fibrotic response in cultured human conjunctiva fibroblast (HCF) cells. We enrolled 70 glaucomatous eyes which underwent trabeculectomy, and quantified aqueous LPA and ATX. Those eyes were followed up for 12 months, and postoperative filtering blebs were evaluated using anterior segment optical coherence tomography. Also, the ATX-induced fibrotic changes in HCFs and the effects of an ATX inhibitor were assessed. Measured aqueous ATX and LPA levels were significantly different between glaucoma subtypes. In multivariate analyses, aqueous ATX levels were significantly correlated with the presence of needlings at 1, 3, 6 and 12 months after surgery. Exfoliative glaucoma, whose ATX level was significantly high, showed significantly increased numbers of needlings and a lower cumulative success rate without needlings. An in vitro study showed that fibrotic changes were upregulated by ATX treatment in HCFs, which was significantly suppressed by an ATX inhibitor. We presently demonstrate that aqueous ATX may be a prognostic factor affecting the fibrotic response in HCFs and bleb formation, and inhibition of ATX could be a therapeutic target after trabeculectomy.

Purpose: To investigate the clinical characteristics of Japanese patients with scleritis STUDY DESIGN: Retrospective study METHODS: The clinical records of 123 patients with scleritis, who presented to the University of Tokyo Hospital between January, 2004 and December, 2015, were retrospectively reviewed., Results: The cohort comprised 55 men and 68 women (mean age, 57.8±16.4 years), of which 76 showed anterior diffuse scleritis, 17 showed anterior nodular scleritis, 10 showed anterior necrotizing scleritis, and 20 showed posterior scleritis. The underlying etiology was identified in 39 patients. Autoimmune diseases were present in 32 patients, including eight with rheumatoid arthritis, seven with antineutrophil cytoplasmic antibody-associated vascular disease, and six with relapsing polychondritis. Ocular hypertension was the most common ocular complication (41%), followed by anterior chamber cells (38%). Fifty-three percent of patients required systemic immunosuppressive medication. Systemic corticosteroids were the most commonly used medication (45%), followed by methotrexate (11%). A, decrease in vision was observed in one-third of patients with anterior necrotizing scleritis or posterior scleritis, of which secondary glaucoma and optic neuritis were the major causes., Conclusion: Autoimmune diseases were present in 26% of patients. One-third of patients with anterior necrotizing scleritis or posterior scleritis experienced decreased vision, mostly due to secondary glaucoma and optic neuritis. Therefore, controlling intraocular pressure by methods such as administration of steroid-sparing immunosuppressive medication and appropriate treatment for posterior scleritis are essential for scleritis treatment.

Purpose: To examine clinical outcomes following an initial trabeculectomy with mitomycin-C for secondary glaucoma associated with uveitis in Behçet disease (BD) patients., Design: Retrospective interventional case series., Patients and Methods: Twenty-two eyes in 18 patients with uveitic glaucoma (UG) associated with Behçet disease who underwent an initial trabeculectomy with mitomycin-C between January 1996 and August 2014 were retrospectively reviewed. The main outcome measures were intraocular pressure (IOP) control, persistence of a filtering bleb, incidence of postoperative complications, and preopertaive and postoperative frequency of uveitic attacks. We analyzed persistence rates using Kaplan-Meier life tables based on 3 definitions of target IOP control (≤21, ≤18, ≤15 mm Hg) and filtering bleb persistence., Result: The persistence rates of postoperative IOP at ≤21, ≤18, and ≤15 mm Hg at 5 years after surgery were 76.1%, 71.5%, and 68.1%, respectively, whereas that of a filtering bleb was 54.4%. Hypotony as a postoperative complication was observed in 4 (18.2%) cases. No significant difference was observed between the preoperative and postoperative frequency of uveitic attacks (1.36±1.15 vs. 0.95±1.49 times/y, P=0.16). There was 1 case in which recurrence of uveitis after surgery caused a loss of filtering bleb, which required a reoperation., Conclusions: At 5 years after surgery, the persistence rate of postoperative IOP control (≤21 mm Hg) was 76.1% and that of a filtering bleb was 54.4%. The frequency of uveitis recurrence did not significantly increase after surgery. Attention must be paid to avoid such recurrence to maintain the filtering bleb.

Purpose: To investigate levels of sphingosine-1-phosphate (S1P) in aqueous fluid samples taken before and after filtration surgery and S1P-induced human conjunctival fibroblast (HCF) responses., Methods: Levels of S1P and its related sphingophospholipids in aqueous fluid obtained immediately before and after filtration surgery were determined by liquid chromatography-tandem mass spectrometry. HCFs were used for all in vitro experiments. The expression of five S1P receptor subtypes in HCFs was examined by quantitative real-time PCR. The effect of S1P and receptor-specific antagonists on HCF viability and cell migration was assessed by WST-1 assay and scratch migration assay, respectively. Differentiation to myofibroblasts and extracellular matrix production was evaluated by examining changes in F-actin, α-smooth muscle actin (αSMA), and collagen expression with immunocytochemistry, Western blotting, and collagen accumulation assay, respectively., Results: No significant S1P levels in the aqueous fluid samples were detectable immediately before surgery, but postoperative levels of several lysophospholipids, including S1P, dehydro-S1P, and sphingosine, were significantly increased to bioactive concentrations in aqueous fluid in the blebs (P < 0.0001). mRNA expression of the three main S1P receptor subtypes was detected in HCFs. Although S1P levels did not influence HCF proliferation, S1P enhanced cell migration, which could be inhibited by the S1P2 antagonist JTE 013. F-actin, αSMA, and collagen expression was significantly increased by S1P stimulation and was reduced by JTE 013., Conclusions: Bioactive S1P concentrations were present in the aqueous fluid at the end of filtration surgery. S1P activated HCFs via S1P2 receptors. These results revealed the potential of S1P2 antagonists in preventing scarring after glaucoma filtration surgery.

Purpose: Ｗe conducted a survey to evaluate the current status of glaucoma-related medical data management and standardization, aiming to improve the development of glaucoma care and research in Japan. Materials and methods: The survey was performed as a paper-based questionnaire of 14 universities that both participate in the glaucoma-related data standardization committee, established by the Japan Glaucoma Society in 2014, and actively perform glaucoma care. Results: All enrolled university hospitals installed an electronic hospital information system and used any of three ophthalmology-limited electronic chart systems. However, only 30.8% of the hospitals established a data extraction system from an electronic medical chart system, and only 14.3% could practically apply medical data for secondary research purposes. In all, 35.7% of the hospitals operate a medical cooperation system with local medical institutions and 42.9% electronically managed medical data inside their departments. Conclusion: This survey clarified the current state of medical data management and standardization.

Glaucoma optic neuropathy (GON) is a condition where pathogenic intraocular pressure (IOP) results in axonal damage following retinal ganglion cell (RGC) death, and further results in secondary damage of the lateral geniculate nucleus (LGN). Therapeutic targets for glaucoma thus focus on both the LGN and RGC. However, the temporal and spatial patterns of degeneration and the mechanism of LGN damage have not been fully elucidated. Suitable and convenient ocular hypertension (OH) animal models with binocular vision comparable to that of monkeys are strongly needed. The ferret is relatively small mammal with binocular vision like humans - here we report on its suitability for investigating LGN. We developed a new method to elevate IOP by injection of cultured conjunctival cells into the anterior chamber to obstruct aqueous outflow. Histologically, cultured conjunctival cells successfully proliferated to occlude the angle, and IOP was elevated for 13 weeks after injection. Macroscopically, the size of the eye gradually expanded. Subsequent enlargement of optic nerve head cupping and atrophic damage of LGN projected from the OH eye were clearly observed by anterograde staining with cholera toxin B. We believe the ferret may be a promising OH model to investigate secondary degeneration of central nervous system including LGN.

Objective: To examine effects of long-term topical anti-glaucoma medications on meibomian gland morphology and function and assess their relationship with slit-lamp findings., Methods: This was a cross-sectional observational case series of 31 patients with glaucoma (mean age ± standard deviation, 65.0 ± 13.0 years; mean duration of eye drop use, 7.9 ± 6.0 years) treated with topical anti-glaucoma drugs in only one eye for more than 1 year: 13 receiving prostaglandin analogues (PGs) alone, eight receiving β-blockers alone, and ten receiving multiple treatments. Untreated contralateral eyes served as controls. Lid margin (lid margin abnormality score: 0-4) and superficial punctate keratopathy (SPK score: 0-1) were observed with a slit lamp. Upper and lower eyelids were turned over to observe meibomian glands using non-contact meibography. Meibomian gland loss was scored for each eyelid from grade 0 (no loss of meibomian glands) through grade 3 (loss >2/3 of total meibomian gland area). Meibomian lipid content (meibum) was scored (meibum score: 0-3)., Results: Treated eyes had significantly higher scores for lid margin abnormality (P= 0.001), SPK (P< 0.001), meibo-score (P< 0.001), and meibum (P< 0.001) than control eyes. Tear film break-up time (BUT) was significantly shorter in treated eyes than in control eyes (P= 0.001). Schirmer values were significantly lower in treated eyes than in control eyes (P= 0.0039). Subgroup analysis indicated a significantly higher meibo-score in eyes treated with PGs (P= 0.0046) and in eyes treated with β-blockers (P= 0.0231) than in the corresponding controls., Conclusions: Long-term anti-glaucoma eye drop use affects meibomian gland morphology and function.

Purpose: To establish an animal model for the easy assessment of pressure-dependent damage to retinal ganglion cells (RGCs) using the B6.Cg-TgN(Thy1-CFP)23Jrs/J transgenic mouse strain (CFP mouse), which expresses cyan fluorescent protein (CFP) in RGCs, and to evaluate pressure-dependent RGC death., Methods: In 20 CFP mice, right eyes were selected to receive laser-induced ocular hypertension eye and the contralateral eyes remained untouched to serve as controls. Intraocular pressure (IOP) was measured each week in both eyes using the microneedle method up to 8 weeks. Based on the line plot of time (x) and IOP (y) in laser-treated and control eyes, the area surrounded by both lines (∫ΔIOP(y) dx) was calculated as a surrogate value of the pressure insult. At 9 weeks, eyes were enucleated and RGCs expressing CFP were evaluated histologically in retinal whole mounts. The correlation between pressure insult and RGC density was evaluated in the whole eye, three concentric regions, and four quadrants., Results: Laser-treated eyes showed a significantly higher IOP than control eyes from 1 to 7 weeks (p<0.01). The pressure insult and the RGC density showed a significant negative correlation (y=-0.070x+97.2, r=0.75, p=0.0008). Moreover, the central, middle, and peripheral areas measured from the optic disc and each of four retinal quadrant areas also showed significant negative correlations. Our data demonstrate that each retinal area was almost evenly damaged by IOP elevation., Conclusions: Laser photocoagulation causes a chronic elevation of IOP in CFP mice. The use of CFP mice enabled us to easily evaluate pressure-dependent RGC damage. This glaucomatous CFP mouse model may contribute to the molecular analysis of neurodegeneration and the development of neuroprotective drugs for glaucoma with a great increase in experimental efficiency.

Purpose: Recent studies have indicated that accumulation of amyloid β(1-42) (Aβ(1-42)), which is associated with the progression of Alzheimer disease, may also be responsible for retinal ganglion cell death in glaucoma. The purpose of this study was to investigate the expression and localization of Aβ(1-42) in the retina and the optic nerve head (ONH) of monkeys with experimental glaucoma., Methods: Five cynomolgus monkeys with a glaucomatous left eye at 4, 9, 11, 15, and 24 weeks after laser photocoagulation treatment were studied by immunohistochemical methods. Another two cynomolgus monkeys with a glaucomatous left eye at 133 weeks after laser photocoagulation treatment were used to measure Aβ(1-42) concentrations in the retina by enzyme-linked immunosorbent assay., Results: At 11 to 24 weeks after the laser photocoagulation treatment, Aβ(1-42) was upregulated in the nerve fiber layer (NFL) and the ganglion cell layer (GCL) of the retina and the ONH, but the expression of amyloid precursor protein decreased in the NFL and ONH from levels at 9 weeks. The localizations of Aβ(1-42) were merged in glial fibrillary acidic protein-positive astroglial cells but not phosphorylated neurofilament heavy- or nonphosphorylated neurofilament heavy-positive axons in the retina and the ONH. Likewise, Aβ(1-42) concentrations in the retina of monkeys increased in the chronic stage of glaucoma., Conclusions: These findings indicate that the upregulation of Aβ(1-42) after an intraocular pressure elevation could apply to monkeys since the structure of the ONH is more similar to humans than that of rodents.

We investigated whether endoplasmic reticulum (ER) stress was involved in the pathophysiological mechanisms underlying neuronal death of the lateral geniculate nucleus (LGN) after intraocular pressure (IOP) elevation. Five cynomolgus monkeys, four with a glaucomatous left eye after laser photocoagulation treatment and one normal monkey, were studied. At 4, 11, 15 and 24 weeks after the laser photocoagulation treatment, the numbers of LGN neurons and atrophy were immunohistochemically evaluated using anti-parvalbumin-antibody, which was used to specifically label relay neurons connecting to the visual cortex. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, polyubiquitin, and production of ER stress-related proteins, such as the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and C/EBP-homologous protein (CHOP), were also measured using in situ hybridization and immunostaining. Loss of neurons and/or neuronal atrophy in layers 1, 4 and 6 of the LGN on the contralateral side were observed at 4-24 weeks after the laser photocoagulation treatment. Furthermore, the retinal input from the high IOP eye projected to layers 2 (magnocellular layer), 3 and 5 (parvocellular layer) on the ipsilateral side. Neuronal damage was also confirmed in these layers. In the LGN region, TUNEL-positive cells, polyubiquitin, p-eIF2α and CHOP were also detected at 11-24 weeks after the laser photocoagulation treatment. These findings indicate that ER stress may play a pivotal role in neuronal death of the LGN after IOP elevation., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Purpose: Normal tension glaucoma (NTG) is a subtype of glaucoma in which intraocular pressure is within the statistically normal range. NTG may be associated with an immune disorder. The aim of this study was to determine whether specific alleles in the human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 genes correlated with NTG in Japanese patients., Methods: We genotyped the HLA-DRB1 and HLA-DQB1 alleles in 113 Japanese patients with NTG and in 184 healthy Japanese control subjects using the polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) Luminex method. We assessed the allelic diversity in patients and controls., Results: There were no statistically significant differences in the allele frequency of HLADRB1 and HLA-DQB1 between NTG patients and control subjects, and no HLA-DRB1-HLA-DQB1 haplotypes demonstrated any significant association with NTG., Conclusions: Our findings suggest that HLA-DRB1 and HLA-DQB1 polymorphisms have no significant effect on the development of NTG in Japanese patients.

Animal models are indispensable for glaucoma research, because intraocular pressure (IOP) regulation, IOP reduction by ocular hypotensive drugs, and chronic progressive glaucomatous optic neuropathy stem from the eye and its adnexa. The mouse, an excellent animal model available as transgenic mice which are an outstanding experimental tool, has been recently applied for glaucoma research. Many regulating factors such as diurnal variation, body position, and clock genes have been elucidated since accurate measurements of mouse IOP have been published in this decade. These advances were followed by clarification of the molecular mechanism of IOP reduction by eye drops and of the aqueous humor dynamics using transgenic mice. Now, the pathogenesis of glaucomatous optic neuropathy is being investigated using glaucoma mouse models and transgenic mice expressing fluorescent proteins in retinal ganglion cells. By comparing the differences between mouse and human eyes, the mechanism of IOP regulation and retinal ganglion cell damage will be gradually revealed.

Purpose: To investigate the correlation between conjunctival vasculature factors and two types of functional bleb shape, cystic and diffuse, formed after trabeculectomy with limbal-based conjunctival flaps., Methods: Eighty-five eyes of glaucoma patients were consecutively enrolled. After 6 months, functioning blebs were classified as either cystic or diffuse. For each bleb type, the presence of neovascularized vessels in the dissected area (NVc) or the nondissected area (NVi), an avascular area (AVA), or a posterior tarsal artery (PTA) feeding the conjunctiva was analyzed., Results: In 62 eyes with functioning blebs, there were 54 cystic and eight diffuse blebs. AVA was present in 96.3% of the cystic and 25.0% of the diffuse blebs. NVc was present in 100% of the cystic and 62.5% of the diffuse blebs, and NVi in 96.3% of the cystic and 12.5% of the diffuse blebs. A PTA was present in 87.5% of the diffuse blebs, but in only 3.7% of the cystic blebs. AVA, NVi, and NVc were significantly more frequent in cystic blebs, whereas a PTA was more frequent in diffuse blebs. The presence of a PTA in the blebs was negatively related to the presence of AVA, NVc, or NVi., Conclusions: Avoidance of damage to the PTA during conjunctival dissection might facilitate the formation of a diffuse filtration bleb. The conjunctival vasculature should be considered to avoid cystic avascular bleb formation in trabeculectomy with limbal-based flaps.

Purpose: To investigate the distribution of intraocular pressure (IOP) measured by Goldmann applanation tonometry (GAT) and factors correlating with IOP, with special attention to age, in a large sample of ophthalmologically normal Japanese subjects., Methods: A total of 7313 subjects (2847 male, 4466 female) were selected as a normal Japanese sample. The following exclusion criteria applied: abnormal results suggestive of any eye diseases in slit-lamp examination, fundus photography or visual field testing using frequency-doubling technology; corrected visual acuity < 0.7, and contact lens wear within 1 week of study examinations. All subjects were sourced from the Eye Disease Screening Service in Tajimi City, which carried out a screening programme between September 2000 and October 2001. All data, including subject age, gender, body mass index (BMI), systolic blood pressure (BP), laterality, refraction, corneal radius and IOP measured with GAT were collected from subject records. Central corneal thickness (CCT) was measured by SP-2000P specular microscopy. Levels of IOP and correlating factors were statistically analysed., Results: Average IOP was 14.1 +/- 2.3 mmHg (mean +/- standard deviation; n = 7313 x 2). Mean IOP levels in male and female subjects were 14.1 +/- 2.3 mmHg and 14.1 +/- 2.2 mmHg, respectively. There was no difference in IOP between male and female subjects. Multiple regression analysis indicated that IOP had negative correlations with age, corneal radius and refraction (p < 0.0001), and positive correlations with CCT, systolic BP and BMI (p < 0.0001)., Conclusions: In a large-scale population of ophthalmologically normal Japanese subjects, IOP measured by GAT was significantly and negatively correlated with age. It was also negatively correlated with corneal radius and refraction, and positively with CCT, systolic BP and BMI.

Glaucoma, a progressive optic neuropathy due to retinal ganglion cell (RGC) degeneration, is one of the leading causes of irreversible blindness. Although glaucoma is often associated with elevated intraocular pressure (IOP), IOP elevation is not detected in a significant subset of glaucomas, such as normal tension glaucoma (NTG). Moreover, in some glaucoma patients, significant IOP reduction does not prevent progression of the disease. Thus, understanding IOP-independent mechanisms of RGC loss is important. Here, we show that mice deficient in the glutamate transporters GLAST or EAAC1 demonstrate spontaneous RGC and optic nerve degeneration without elevated IOP. In GLAST-deficient mice, the glutathione level in Müller glia was decreased; administration of glutamate receptor blocker prevented RGC loss. In EAAC1-deficient mice, RGCs were more vulnerable to oxidative stress. These findings suggest that glutamate transporters are necessary both to prevent excitotoxic retinal damage and to synthesize glutathione, a major cellular antioxidant and tripeptide of glutamate, cysteine, and glycine. We believe these mice are the first animal models of NTG that offer a powerful system for investigating mechanisms of neurodegeneration in NTG and developing therapies directed at IOP-independent mechanisms of RGC loss.

Hypoxia-induced retinal ganglion cell (RGC) death has been implicated in glaucomatous optic neuropathy. However, the precise mechanism of death signaling and how neuroprotective agents affect it are still unclear. The aim of this study is to characterize the mechanisms of hypoxia-induced apoptosis of cultured purified RGCs and to study the neuroprotective effects of beta-adrenergic antagonists. Rat RGCs were purified utilizing a modified two-step immuno-panning procedure. First, the extent of apoptosis in RGCs under hypoxia was quantified. Next, the effects of glutamate-channel antagonists (MK801 or DNQX), Bax inhibiting peptide (BIP), and beta-adrenergic antagonists (betaxolol, nipradilol, timolol or carteolol) on hypoxia-induced RGC death were investigated by the cell viability assay. Third, the effects of beta-adrenergic antagonists on hypoxia-induced increase of intracellular calcium concentrations ([Ca(2+)](i)) and the additional effect of NO scavenger to nipradilol were evaluated. Apoptotic RGC percentages under hypoxia were significantly increased compared to the control. The viability of RGCs under hypoxia was not affected by MK801 or DNQX, whereas it was increased in a dose-dependent manner with exposure to BIP, and to betaxolol, nipradilol, timolol, but not to carteolol. These effective beta-adrenergic antagonists showed no significant change in hypoxia-induced [Ca(2+)](i) levels. The NO scavenger alleviated neuroprotective effect by nipradilol. In conclusion, purified RGC damage induced by hypoxia involves Bax-dependent apoptotic pathway, but mostly independent of glutamate receptor-mediated excitotoxicity. Betaxolol, timolol and nipradilol showed a protective effect against hypoxia-induced RGC death, which was thought to be irrelevant either to calcium channel or beta-adrenoceptor blocking effects.

Purpose: To assess the relationship between regional variation of axon loss and optic nerve head anatomy in laser-induced experimental glaucoma in the mouse., Methods: Experimental glaucoma was induced unilaterally in eight NIH Swiss black mice. Intraocular pressure (IOP) was measured for 12 weeks, and the mice were killed. The eyes were enucleated, and both optic nerves were dissected and processed conventionally for electron microscopy. Low- and high-magnification images of the optic nerve cross sections 300 microm posterior to the globe were collected systematically and masked before analysis. For each nerve, cross-sectional area was measured in low-magnification micrographs. Axon number and density were determined in the high-magnification micrographs. Loss of axonal density was compared between the superior and inferior and nasal and temporal areas of the optic nerve cross section. Additional cross-section micrographs were collected at 10- or 20-microm intervals throughout the optic nerve head., Results: In the treated (glaucoma) eyes, mean IOP was 44% higher than that in the control eyes. The optic nerve cross-sectional area, mean axonal density, and total axonal number were significantly less than those in the control eyes (P < 0.01 for each). Axon loss in the superior optic nerve was greater than in the inferior optic nerve in each glaucomatous eye (P = 0.012). The ratio of axonal density in the superior and inferior optic nerve (superior-to-inferior [S/I] ratio) in all treated eyes was <1.0 and significantly lower than that in the control eyes (P = 0.012). The central retinal vessels occupied approximately 20% of the central optic nerve head cross-sectional area, gradually shifted position ventrally as they progressed toward the scleral foramen (the mouse does not have a lamina cribrosa), and exited the inferior retrobulbar optic nerve adjacent to the posterior of the globe., Conclusions: Ocular hypertension in the mouse eye sufficient to cause optic nerve damage induces preferential loss of superior optic nerve axons. Optic nerve axon loss appeared less among the axons that were near the major optic nerve blood vessels at the scleral foramen. Topographic differences in optic nerve axon loss should be considered when evaluating optic nerve damage in experimental laser-induced glaucoma in the mouse.

Purpose: To determine whether central corneal thickness (CCT) is a risk factor for visual field loss development among patients diagnosed with preperimetric glaucomatous optic neuropathy (GON)., Design: Observational cohort study., Methods: The study included 98 eyes of 98 patients with GON, with a mean follow-up time of 4.3 +/- 2.7 years. Diagnosis of GON was based on masked assessment of optic disk stereophotographs. All patients had normal standard automated perimetry visual fields at baseline. Criteria for visual field abnormality were derived from a prior study. Several clinical factors (CCT, intraocular pressure, vertical cup-to-disk ratio, refraction, age, gender, family history of glaucoma, high blood pressure, cardiovascular disease, and migraine) were investigated to ascertain whether there is an association with development of repeatable visual field loss. Cox proportional hazards models were used to obtain hazard ratios (HR) and identify factors that predicted which individuals developed glaucomatous visual field loss during the follow-up period., Results: Thirty-four patients (35%) developed repeatable visual field abnormality during follow-up. In multivariate analysis, risk factors that predicted the development of visual field loss were a thinner CCT (adjusted HR = 1.62/40 microm thinner; P =.023; 95% confidence interval [CI]: 1.07-2.45), higher baseline intraocular pressure (adjusted HR = 1.07/mm Hg; P =.022; 95% CI: 1.01-1.14), and larger baseline vertical cup-to-disk ratio (adjusted HR = 1.63/0.1 larger; P =.009; 95% CI: 1.13-2.35). The mean +/- standard deviation CCT of GON patients who developed visual field loss was 543 +/- 36 microm compared with 565 +/- 35 microm of those who did not develop visual field abnormalities (P =.005, Student t test)., Conclusions: Central corneal thickness is a risk factor for development of visual field loss among patients diagnosed with preperimetric GON. It is important to consider CCT when establishing target intraocular pressure of patients with GON.