Sector-specific Association of Intraocular Pressure Dynamics in Dark-room Prone Testing and Visual Field Defect Progression in Glaucoma.

PURPOSE: To investigate sectoral differences in the relationship between intraocular pressure (IOP) dynamics during dark-room prone testing (DRPT) and visual field (VF) defect progression in primary open-angle glaucoma (POAG) patients. DESIGN: Retrospective, longitudinal study. PARTICIPANTS: This retrospective study included 116 eyes of 84 POAG patients who underwent DRPT and had at least 5 reliable VF tests conducted over a more than 2-year follow-up period. We excluded eyes with mean deviation worse than -20 dB or a history of intraocular surgery or laser treatment. METHODS: Average total deviation (TD) was calculated in the superior, central, and inferior sectors of the Humphrey 24-2 or 30-2 program. During DRPT, IOP was measured in the sitting position, and after 60 minutes in the prone position in a dark room, IOP was measured again. The relationship between IOP change during DRPT, IOP after DRPT, and TD slope in each quadrant was analyzed with a linear mixed-effects model, adjusting for other potential confounding factors. MAIN OUTCOME MEASURES: Total deviation slope in each quadrant, IOP change during DRPT, and IOP after DRPT. RESULTS: Intraocular pressure after DRPT and IOP change during DRPT were 18.16 ± 3.42 mmHg and 4.92 ± 3.12 mmHg, respectively. Superior TD slope was significantly associated with both IOP after DRPT (ß = -0.28, P = 0.003) and IOP change during DRPT (ß = -0.21, P = 0.029), while central (ß = -0.05, P = 0.595; ß = -0.05; P = 0.622) and inferior (ß = 0.05, P = 0.611; ß = 0.01, P = 0.938) TD slopes were not. CONCLUSION: Dark-room prone testing might be a useful test to predict the risk of superior VF defect progression in eyes with POAG. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The association between intraocular pressure dynamics during dark-room prone testing and intraocular pressure over a relatively long-term follow-up period in primary open-glaucoma patients.

PURPOSE: To investigate the relationship between the dynamics of intraocular pressure (IOP) during dark-room prone testing (DRPT) and IOP over a relatively long-term follow-up period. METHODS: This retrospective study enrolled 84 eyes of 51 primary open-angle glaucoma patients who underwent DRPT for whom at least three IOP measurements made using Goldmann applanation tonometry were available over a maximum follow-up period of two years. We excluded eyes with a history of intraocular surgery or laser treatment and those with changes in topical anti-glaucoma medication during the follow-up period. In DRPT, IOP was measured in the sitting position, and after 60 min in the prone position in a dark room, IOP was measured again. In this study, IOP fluctuation refers to the standard deviation (SD) of IOP, and IOP max indicates the maximum value of IOP during the follow-up. The relationship between these parameters was analyzed with a linear mixed-effects model, adjusting for clinical parameters including age, gender, and axial length. RESULTS: IOP increased after DRPT with a mean of 6.13 ± 3.55 mmHg. IOP max was significantly associated with IOP after DRPT (ß = 0.38; p < 0.001). IOP fluctuation was significantly associated with IOP change in DRPT (ß = 0.29; p = 0.007). CONCLUSION: Our findings suggest that short-term and relatively long-term IOP dynamics are associated. Long-term IOP dynamics can be predicted by DRPT to some extent.

Reduced glutathione level in the aqueous humor of patients with primary open-angle glaucoma and normal-tension glaucoma.

Glaucoma is a leading cause of blindness worldwide in older people. Profiling the aqueous humor, including the metabolites it contains, is useful to understand physiological and pathological conditions in the eye. In the current study, we used mass spectrometry (MS) to characterize the aqueous humor metabolomic profile and biological features of patients with glaucoma. Aqueous humor samples were collected during trabeculectomy surgery or cataract surgery and analyzed with global metabolomics. We included 40 patients with glaucoma (32 with POAG, 8 with NTG) and 37 control subjects in a discovery study. VIP analysis revealed five metabolites that were elevated and three metabolites that were reduced in the glaucoma patients. The identified metabolomic profile had an area under the receiver operating characteristic curve of 0.953. Among eight selected metabolites, the glutathione level was significantly decreased in association with visual field defects. Moreover, in a validation study to confirm the reproducibility of our findings, the glutathione level was reduced in NTG and POAG patients compared with a cataract control group. Our findings demonstrate that aqueous humor profiling can help to diagnose glaucoma and that various aqueous humor metabolites are correlated with clinical parameters in glaucoma patients. In addition, glutathione is clearly reduced in the aqueous humor of glaucoma patients with both IOP-dependent and IOP-independent disease subtypes. These findings indicate that antioxidant agents in the aqueous humor reflect glaucomatous optic nerve damage and that excessive oxidative stress may be involved in the pathogenesis of glaucoma.

DPP-4 Inhibitors Attenuate Fibrosis After Glaucoma Filtering Surgery by Suppressing the TGF-ß/Smad Signaling Pathway.

Purpose: This study investigated the effect of dipeptidyl peptidase-4 inhibitors (DPP-4is) on fibrosis after glaucoma filtering surgery with clinical data and an in vitro model that used transforming growth factor-ß (TGF-ß) to induce human Tenon's fibroblast (HTF) fibrosis. Methods: The medical records of 41 eyes of 35 patients with diabetes with neovascular glaucoma (NVG) who received initial trabeculectomy were retrospectively reviewed. The surgical success rate was compared between cases that received (n = 23) and did not receive (n = 18) DPP-4i treatment for diabetes. The antifibrotic effects of linagliptin (a DPP-4i) were evaluated with quantitative real-time PCR for fibrosis markers (α-smooth muscle actin, collagen Iα, and fibronectin), a scratch assay, and a collagen gel contraction assay of primary cultured HTFs treated with TGF-ß1 and linagliptin. Western blotting analysis was performed to evaluate the levels of phosphorylated Smad2 and Smad3 in the presence of linagliptin. Results: The Kaplan-Meier curve for bleb survival was higher in patients who received DPP-4is (P = 0.017, log-rank test). The in vitro experiments demonstrated that treatment with linagliptin attenuated the elevated levels of fibrosis markers induced by TGF-ß1 in HTFs. Linagliptin treatment also prevented the migration and gel contraction of HTFs. Linagliptin inhibited the phosphorylation of Smad2 and Smad3, which is the canonical pathway of TGF-ß signaling. Conclusions: The current study indicates the potential effect of DPP-4is for maintaining bleb function after glaucoma filtering surgery in patients with diabetes with NVG. Our results demonstrate that linagliptin attenuates fibrotic change in HTFs by inhibiting TGF-ß/Smad signaling.

Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

Comparing Surgical Outcomes in Neovascular Glaucoma between Tube and Trabeculectomy: A Multicenter Study.

OBJECTIVE: To compare the surgical outcomes between Baerveldt glaucoma implant (BGI) surgery and trabeculectomy with mitomycin C for patients with neovascular glaucoma (NVG). DESIGN: Retrospective clinical cohort study at 5 clinical centers in Japan. PARTICIPANTS: Patients treated with trabeculectomy or BGI for NVG between April 1, 2012, and December 31, 2019, at 5 clinical centers were recruited. METHODS: The inclusion criteria were age ≥ 20 years and having NVG. The exclusion criteria were eyes with no light perception vision and with previous tube-shunt surgery. If both eyes in the same patient satisfied the inclusion criteria, the eye that was treated first was investigated. We included 100 eyes undergoing BGI surgery and 204 eyes undergoing trabeculectomy. MAIN OUTCOME MEASURES: The primary outcome was surgical success or failure, with failure being defined according to 3 criteria: < 20% reduction of the preoperative intraocular pressure (IOP) or criterion A (IOP > 21 mmHg), criterion B (IOP > 17 mmHg), or criterion C (IOP > 14 mmHg). Cases of reoperation, a loss of light perception vision, or hypotony were also considered failures. RESULTS: The probability of success was significantly higher in patients undergoing BGI surgery than in those receiving trabeculectomy for criteria A (P < 0.01) and B (P = 0.01). Trabeculectomy was significantly associated with surgical failure in the multivariable analysis for criterion A (hazard ratio, 1.70) and criterion B (hazard ratio, 1.50). The overall incidence of postoperative complications was similar between the 2 groups. Reoperations for glaucoma were required significantly more frequently in the trabeculectomy group than in the BGI surgery group (20.1 % vs. 5.0%; P < 0.01). CONCLUSIONS: Baerveldt glaucoma implant surgery had a higher success rate compared with trabeculectomy in patients with NVG for a target IOP < 21 mmHg or < 17 mmHg. The rates of postoperative complications were similar between both surgical procedures. Additional glaucoma surgery was required more frequently after trabeculectomy than after BGI surgery.

Noninferiority of Microhook to Trabectome: Trabectome versus Ab Interno Microhook Trabeculotomy Comparative Study (Tram Trac Study).

PURPOSE: To elucidate the noninferiority of ab interno microhook trabeculotomy (µTLO) using a recently developed reusable stainless spatula-type microhook device to incise the trabecular meshwork to Trabectome (Neomeix, Inc) surgery in terms of the 1-year postoperative outcomes of Japanese patients with glaucoma by means of propensity score analyses. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: We enrolled 553 and 392 patients who underwent Trabectome surgery and µTLO, respectively, between January 2014 and March 2020 at 10 facilities. METHODS: Logistic regression analysis was conducted to calculate the propensity score, which indicates the likelihood of treatment assignment (Trabectome or µTLO). We set the following factors as outcome-related covariates: age, sex, facility, glaucoma disease types, preoperative intraocular pressure (IOP), glaucoma drug score, mean deviation of Humphrey visual field test results, antithrombotic drug use, the presence or absence of combined cataract surgery, and incision range of the trabecular meshwork (1 or 2 quadrants). We analyzed 4 different methods (matching, inverse probability of treatment weighting [IPTW], stratification, and regression adjustment) using the propensity score. We set 15% as the noninferiority margin based on previous Trabectome meta-analysis results. MAIN OUTCOME MEASURES: The primary outcome was surgical success at 1 year after surgery. We defined surgical success as satisfying all 3 criteria: (1) IOP within 5 to 21 mmHg, (2) IOP reduction of 20% or more from preoperative IOP, and (3) no additional glaucoma surgery. RESULTS: The 95% confidence interval of risk difference of surgical failure in µTLO in reference to Trabectome surgery was -12.1% to +9.5% in matching, -12.7% to +11.1% in IPTW, -12.2 to +7.0 in stratification, and -9.7% to +8.1% in regression adjustment, all of which fell within the predetermined noninferiority margin of 15%. CONCLUSIONS: Surgical success of µTLO at 1 year after was not inferior to that of Trabectome surgery.

Anterior-Segment Optical Coherence Tomography for Predicting Postoperative Outcomes After Trabeculectomy.

PURPOSE: To determine whether anterior-segment optical coherence tomography (AS-OCT) can be used to predict post-trabeculectomy bleb outcomes. MATERIALS AND METHODS: We divided 58 eyes of 47 trabeculectomy patients into success or failure groups based on their status at 12 months after surgery. We then compared various AS-OCT measurement parameters between the two groups at 1 and 2 weeks and 1, 3, 6, and 12 months. We also analyzed the early post-trabeculectomy bleb parameters with multiple logistic regression, stepwise multiple regression, and the receiver operating characteristic (ROC) curve, to evaluate the power of these parameters to predict long-term outcomes. RESULTS: Intraocular pressure 3 or more months after trabeculectomy was significantly lower in the success group than the failure group (all: P < 0.0016). Cleft volume was significantly higher 6 or more months after trabeculectomy in the success group than the failure group (P = 0.0027 and <0.0016). Reflectivity of the bleb wall was significantly higher in the failure group than the success group at 2 weeks and all later time points (all: P < 0.0016). Reflectivity of the bleb wall at 2 weeks after trabeculectomy was a risk factor for failure, with an odds ratio (OR) for failure of 2.48 (95% confidence interval, 1.31-4.68, increasing per 10 AU). The area under the ROC curve for reflectivity of the bleb wall at 2 weeks after trabeculectomy was 0.775 when the cutoff value was set at 122.8, with sensitivity, specificity, and OR of 78.3%, 80.0%, and 14.4, respectively. A stepwise multiple regression analysis showed that reflectivity of the bleb wall at 2 weeks was an independent factor indicating postoperative bleb survival period (ß = -0.39, P = 0.007). CONCLUSIONS: Reflectivity of the bleb wall, measured by AS-OCT, may be an early post-trabeculectomy predictor of bleb outcome.

Characteristics of cases needing advanced treatment for intractable Posner-Schlossman syndrome.

BACKGROUND: In Posner-Schlossman syndrome (PSS), which is characterized by recurrent unilateral attacks of ocular hypertension. Surgical treatment is sometimes necessary because intraocular pressure (IOP) cannot be controlled with anti-glaucoma medications. To identify the clinical features of Posner-Schlossman syndrome (PSS) indicative of the need for intraocular pressure (IOP)-controlling surgery. METHODS: This study was a retrospective case-series analysis of the clinical charts of 33 patients diagnosed with PSS, who underwent surgery to control IOP or received medication only. Various clinical factors were compared between the surgical and medication groups. RESULTS: The surgical group had a higher corneal endothelial cell (CEC) density loss (p < 0.05), higher maximum IOP (p < 0.01), greater visual field loss (p < 0.01) and higher positive number for cytomegalovirus (CMV) (p < 0.001) than the non-surgical group. Eighteen of the 33 patients had a high CEC reduction ratio. Of these 18, 16 required glaucoma surgery. CONCLUSIONS: PSS patients with a higher CEC reduction ratio, higher maximum IOP, greater visual field loss and higher positive number for CMV in the aqueous humor tended to be more likely to require progressive treatment, such as glaucoma surgery.

In vivo cellular imaging of various stress/response pathways using AAV following axonal injury in mice.

Glaucoma, a leading cause of blindness worldwide, is instigated by various factors, including axonal injury, which eventually leads to a progressive loss of retinal ganglion cells (RGCs). To study various pathways reportedly involved in the pathogenesis of RGC death caused by axonal injury, seven pathways were investigated. Pathway-specific fluorescent protein-coded reporters were each packaged into an adeno-associated virus (AAV). After producing axonal injury in the eye, injected with AAV to induce RGC death, the temporal activity of each stress-related pathway was monitored in vivo through the detection of fluorescent RGCs using confocal ophthalmoscopy. We identified the activation of ATF6 and MCP-1 pathways involved in endoplasmic reticulum stress and macrophage recruitment, respectively, as early markers of RGC stress that precede neuronal death. Conversely, inflammatory responses probed by NF-κB and cell-death-related pathway p53 were most prominent in the later phases, when RGC death was already ongoing. AAV-mediated delivery of stress/response reporters followed by in vivo cellular imaging is a powerful strategy to characterize the temporal aspects of complex molecular pathways involved in retinal diseases. The identification of promoter elements that are activated before the death of RGCs enables the development of pre-emptive gene therapy, exclusively targeting the early phases of diseased cells.

Characteristics of patients with primary open angle glaucoma and normal tension glaucoma at a university hospital: a cross-sectional retrospective study.

BACKGROUND: The characteristics of glaucoma patients and their response to therapy may differ by institution, region and country. Therefore, clinicians should understand the distinctiveness of their patients. Here, we profile primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients at a major university hospital in Japan. METHODS: This study included 523 eyes from 523 POAG and NTG patients who underwent full clinical ophthalmologic evaluations at Tohoku University Hospital. Clinical characteristics such as age, sex, visual acuity, intraocular pressure, Humphrey field analyzer-measured mean deviation (MD) and MD slope were collected retrospectively. MD slope was calculated from MD data that included the first baseline measurement of MD and 4 subsequent, consecutive, reliable measurements of MD. Refractive error was analyzed in a subgroup with no history of refractive surgery, including intraocular lens implantation. Patient characteristics were analyzed separately in the groups of patients with low (<15 mmHg) and high IOP (≥15 mmHg) and in the groups with MD slope ≥-1.0 and <-1.0 dB/year. RESULTS: Mean age, visual acuity (median), IOP, pre-treatment IOP (from patient history), refractive error and MD were 61.7 ± 12.5 years, -0.08 (interquartile range -0.08 to 0.05) LogMAR, 13.87 ± 3.37 mmHg, 18.35 ± 6.26 mmHg, -4.48 ± 3.81 diopters and -11.73 ± 8.83 dB, respectively. POAG and NTG patients had significant differences in mean age (63.4 ± 12.4 vs. 60.7 ± 12.5 years, P < 0.01), visual acuity, IOP (14.95 ± 4.20 vs. 13.21 ± 2.54 mmHg, P < 0.01) and MD (-13.85 ± 9.32 vs. -10.45 ± 8.27 dB, P < 0.01). Interestingly, MD slope was slightly steeper in the low-IOP group than in the high-IOP group, although the difference was not statistically significant (-0.85 vs. -0.70 dB/year, P = 0.31). Baseline MD was significantly worse in the group with MD slope <-1.0 dB/year than in the group with MD slope ≥-1.0 dB/year (-11.56 vs. -7.64 dB/year, P < 0.01). CONCLUSIONS: We identified characteristics of glaucoma patients at a university hospital that may reflect the specialized nature of such an institution.

Characteristics of uveitic glaucoma and evaluation of its surgical treatment.

PURPOSE: To investigate the characteristics of uveitic glaucoma (UG) and evaluate surgical treatments. METHODS: This study examined a retrospective, nonrandomized comparative interventional case series of 105 UG patients (141 eyes) followed between April 1, 2001 and July 30, 2014 at the outpatient clinic of Tohoku University Hospital. The study group included 47 patients (47 eyes) who underwent glaucoma surgery: trabeculectomy, trabeculotomy, and trabectome surgery. The analysis used Kaplan-Meier life tables, with surgical failure defined as intraocular pressure ≧21 mmHg or the need for additional glaucoma surgery. RESULTS: UG patients represented 9.73% of our database of glaucoma patients. The mean follow-up period was 40.32±32.53 months. Seventy-one patients had granulomatous uveitis (67.62%) and 34 had nongranulomatous uveitis (32.38%). The causes of uveitis included sarcoidosis (n=25), Behçet's disease (n=11), Vogt-Koyanagi-Harada disease (n=9), Posner-Schlossman syndrome (n=12), herpes simplex virus infectious uveitis (n=7), acute anterior uveitis (n=5), intermediate uveitis (n=4), scleritis (n=4), inflammatory bowel disease (n=4), varicella zoster virus uveitis (n=2), and others (n=6). An additional 16 patients were diagnosed with idiopathic UG. Surgical success rates were 82.86% for trabeculectomy, 62.50% for trabeculotomy, and 75.00% for trabectome. Significant risk factors for surgical failure included male sex (P=0.02), age less than 45 years (P=0.0009), nongranulomatous uveitis (P=0.04), and postoperative inflammation (P=0.01). CONCLUSION: Young male patients with nongranulomatous uveitis had a significant risk of surgical failure. Moreover, prolonged postoperative inflammation created a susceptibility to surgical failure, indicating the importance of postoperative inflammation reduction.

Critical role of calpain in axonal damage-induced retinal ganglion cell death.

Calpain, an intracellular cysteine protease, has been widely reported to be involved in neuronal cell death. The purpose of this study is to investigate the role of calpain activation in axonal damage-induced retinal ganglion cell (RGC) death. Twelve-week-old male calpstatin (an endogenous calpain inhibitor) knockout mice (CAST KO) and wild-type (WT) mice were used in this study. Axonal damage was induced by optic nerve crush (NC) or tubulin destruction induced by leaving a gelatin sponge soaked with vinblastine (VB), a microtubule disassembly chemical, around the optic nerve. Calpain activation was assessed by immunoblot analysis, which indirectly quantified the cleaved α-fodrin, a substrate of calpain. RGCs were retrogradely labeled by injecting a fluorescent tracer, Fluoro-Gold (FG), and the retinas were harvested and flat-mounted retinas prepared. The densities of FG-labeled RGCs harvested from the WT and CAST KO groups were assessed and compared. Additionally, a calpain inhibitor (SNJ-1945, 100 mg/kg/day) was administered orally, and the density of surviving RGCs was compared with that of the vehicle control group. The mean density of surviving RGCs in the CAST KO group was significantly lower than that observed in the WT group, both in NC and in VB. The mean density of surviving RGCs in the SNJ-1945-treated group was significantly higher than that of the control group. The calpain inhibitor SNJ-1945 has a neuroprotective effect against axonal damage-induced RGC death. This pathway may be an important therapeutic target for preventing this axonal damage-induced RGC death, including glaucoma and diabetic optic neuropathy and other CNS diseases that share a common etiology.