Effect of magnification error and axial length on circumpapillary capillary density and retinal nerve fiber layer thickness.

This study aimed to evaluate the effect of magnification error and axial length (AL) on circumpapillary capillary density (cpCD) and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) in healthy eyes. Seventy-two healthy eyes of 72 subjects with AL 24.7 ± 1.5 mm (range: 20.9-28.0 mm) were enrolled in this retrospective cross-sectional study and underwent optical coherence tomography angiography scanning. Magnification corrected measurement areas were obtained using AL upon which corrected cpCD, cpRNFLT values were determined. Relationships between AL and the percentage difference between corrected and uncorrected values (ΔcpCD, ΔcpRNFLT) as well as the effect of AL on magnification corrected cpCD, cpRNFLT were evaluated. ΔcpCD significantly increased with AL in the global, inferior nasal and superior nasal sectors (all p < 0.001). ΔcpRNFLT significantly increased with AL in global and all sectors (all p < 0.001) and the correlations were significantly stronger than that of ΔcpCD-AL in all sectors (all p < 0.001). Corrected cpCD did not associate with AL while corrected cpRNFLT demonstrated a significant positive association with AL in the global (p = 0.005) and temporal sector (p < 0.001). Magnification error led to a significant underestimation of cpCD in eyes with longer AL although its underestimation and the effect of AL was smaller in comparison to that of cpRNFLT.

Neuroprotective effect of omidenepag on excitotoxic retinal ganglion cell death regulating COX-2-EP2-cAMP-PKA/Epac pathway via Neuron-Glia interaction.

Glutamate excitotoxicity is involved in retinal ganglion cell (RGC) death in various retinal degenerative diseases, including ischemia-reperfusion injury and glaucoma. Excitotoxic RGC death is caused by both direct damage to RGCs and indirect damage through neuroinflammation of retinal glial cells. Omidenepag (OMD), a novel E prostanoid receptor 2 (EP2) agonist, is a recently approved intraocular pressure-lowering drug. The second messenger of EP2 is cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). In this study, we investigated the neuroprotective effects of OMD on excitotoxic RGC death by focusing on differences in cAMP downstream signaling from the perspective of glia-neuron interactions. We established a glutamate excitotoxicity model in vitro and NMDA intravitreal injection model in vivo. In vitro, rat primary RGCs were used in an RGC survival rate assay. MG5 cells (mouse microglial cell line) and A1 cells (astrocyte cell line) were used for immunocytochemistry and Western blotting to evaluate the expressions of COX-1/2, PKA, Epac1/2, pCREB, cleaved caspase-3, inflammatory cytokines, and neurotrophic factors. Mouse retinal specimens underwent hematoxylin and eosin staining, flat-mounted retina examination, and immunohistochemistry. OMD significantly suppressed excitotoxic RGC death, cleaved caspase-3 expression, and activated glia both in vitro and in vivo. Moreover, it inhibited Epac1 and inflammatory cytokine expression and promoted COX-2, pCREB, and neurotrophic factor expression. OMD may have neuroprotective effects through inhibition of the Epac pathway and promotion of the COX-2-EP2-cAMP-PKA pathway by modulating glia-neuron interaction.

Diagnostic criteria of anterior segment swept-source optical coherence tomography to detect gonioscopic angle closure.

AIMS: To compare the diagnostic performance of 360° anterior segment optical coherence tomography assessment by applying normative percentile cut-offs versus iris trabecular contact (ITC) for detecting gonioscopic angle closure. METHODS: In this multicentre study, 394 healthy individuals were included in the normative dataset to derive the age-specific and angle location-specific normative percentiles of angle open distance (AOD500) and trabecular iris space area (TISA500) which were measured every 10° for 360°. 119 healthy participants and 170 patients with angle closure by gonioscopy were included in the test dataset to investigate the diagnostic performance of three sets of criteria for detection of gonioscopic angle closure: (1) the 10th and (2) the 5th percentiles of AOD500/TISA500, and (3) ITC (ie, AOD500/TISA500=0 mm/mm2). The number of angle locations with angle closure defined by each set of the criteria for each eye was used to generate the receiver operating characteristic (ROC) curve for the discrimination between gonioscopic angle closure and open angle. RESULTS: Of the three sets of diagnostic criteria examined, the area under the ROC curve was greatest for the 10th percentile of AOD500 (0.933), whereas the ITC criterion AOD500=0 mm showed the smallest area under the ROC (0.852) and the difference was statistically significant with or without adjusting for age and axial length (p<0.001). The criterion ≥90° of AOD500 below the 10th percentile attained the best sensitivity 87.6% and specificity 84.9% combination for detecting gonioscopic angle closure. CONCLUSIONS: Applying the normative percentiles of angle measurements yielded a higher diagnostic performance than ITC for detecting angle closure on gonioscopy.

Crystalline lens nuclear age prediction as a new biomarker of nucleus degeneration.

BACKGROUND: The crystalline lens is a transparent structure of the eye to focus light on the retina. It becomes muddy, hard and dense with increasing age, which makes the crystalline lens gradually lose its function. We aim to develop a nuclear age predictor to reflect the degeneration of the crystalline lens nucleus. METHODS: First we trained and internally validated the nuclear age predictor with a deep-learning algorithm, using 12 904 anterior segment optical coherence tomography (AS-OCT) images from four diverse Asian and American cohorts: Zhongshan Ophthalmic Center with Machine0 (ZOM0), Tomey Corporation (TOMEY), University of California San Francisco and the Chinese University of Hong Kong. External testing was done on three independent datasets: Tokyo University (TU), ZOM1 and Shenzhen People's Hospital (SPH). We also demonstrate the possibility of detecting nuclear cataracts (NCs) from the nuclear age gap. FINDINGS: In the internal validation dataset, the nuclear age could be predicted with a mean absolute error (MAE) of 2.570 years (95% CI 1.886 to 2.863). Across the three external testing datasets, the algorithm achieved MAEs of 4.261 years (95% CI 3.391 to 5.094) in TU, 3.920 years (95% CI 3.332 to 4.637) in ZOM1-NonCata and 4.380 years (95% CI 3.730 to 5.061) in SPH-NonCata. The MAEs for NC eyes were 8.490 years (95% CI 7.219 to 9.766) in ZOM1-NC and 9.998 years (95% CI 5.673 to 14.642) in SPH-NC. The nuclear age gap outperformed both ophthalmologists in detecting NCs, with areas under the receiver operating characteristic curves of 0.853 years (95% CI 0.787 to 0.917) in ZOM1 and 0.909 years (95% CI 0.828 to 0.978) in SPH. INTERPRETATION: The nuclear age predictor shows good performance, validating the feasibility of using AS-OCT images as an effective screening tool for nucleus degeneration. Our work also demonstrates the potential use of the nuclear age gap to detect NCs.

Contributing factors for intraocular pressure control in patients with mostly normal-tension glaucoma after initial Ex-PRESS drainage device implantation.

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.

Cost-effectiveness analysis of prophylactic laser peripheral iridotomy for primary angle-closure suspect in Japan.

BACKGROUND/OBJECTIVES: This study aimed to compare the cost-effectiveness of prophylactic laser peripheral iridotomy (LPI) with that of observation for primary angle-closure suspect (PACS) in Japan. SUBJECTS/METHODS: A Markov model was developed to compare the costs and utilities of prophylactic LPI with those of observation of 40-year-old patients with PACS. In the model with a yearly cycle over a 20-year time horizon, the disease was postulated to irreversibly progress from PACS to primary angle closure, followed by primary angle-closure glaucoma, unilateral blindness, and bilateral blindness. The parameters were estimated mainly based on a recent randomised controlled trial and analyses of Japanese claims data. The incremental cost-effectiveness ratio was estimated from the healthcare payer's perspective and evaluated at the willingness-to-pay 5 million Japanese Yen per quality-adjusted life-year. The observation period and the age at entry into the cohort was changed to account for a variety of clinical courses in sensitivity analyses. We conducted one-way deterministic sensitivity analysis and probabilistic sensitivity analysis with Monte Carlo simulations with 10 000 iterations. RESULTS: The incremental cost-effectiveness ratio of LPI was 2,287,662 Japanese Yen (14,298 pounds sterling) per quality-adjusted life-year, which was below the willingness-to-pay threshold. The ratios were approximately 4 and 8 million in the 15-year and 10-year time horizons, respectively. Increasing the age at entry had little influence on the incremental cost-effectiveness ratio. The deterministic and probabilistic sensitivity analyses indicated that the results were robust. CONCLUSIONS: Our results indicate that prophylactic LPI for middle-aged patients with PACS is cost-effective in Japan.

Factors associated with visual field or structure progression occurring first in a prospective study on patients with untreated open-angle glaucoma with normal intraocular pressure.

BACKGROUND/OBJECTIVES: To identify factors associated with disc/retina deterioration in stereo fundus photographs preceding that of the visual field (VF), as determined with a Humphrey Field Analyzer (HFA) (Structure First deterioration) and factors associated with the latter preceding the former (Field First deterioration) in open-angle glaucoma (OAG) with lower normal intraocular pressure (IOP). SUBJECTS/METHODS: Prospective cohort study. Ninety eyes of 90 patients with OAG and a baseline IOP < 15 mmHg participated in a 5-year prospective study without treatment. IOP measurements and HFA 24-2 Swedish Interactive Test Algorithm Standard tests were performed every 3 months, and fundus photographs were obtained every 6 months. VF deterioration was determined by Guided Progression Analysis and deterioration of disc/retina was determined on stereophotographs by an independent committee. A multivariable Cox proportional hazard model was used to identify factors associated with Structure First deterioration, and with Field First deterioration. RESULTS: The average baseline age and mean deviation were 53.9 ± 9.8 years and -2.8 ± 2.8 dB, respectively. During the 5-year follow-up, the probability of Field First deterioration was 49% ± 6.6% (standard error) and that of Structure First deterioration was 33% ± 6.4% (P = 0.062, log-rank test). Disc hemorrhage (DH) prior to the event (P = 0.006) was associated with Structure First deterioration, and older age was associated with Field First deterioration (P = 0.040). CONCLUSIONS: In OAG eyes with lower normal IOP, DH was significantly associated with Structure First deterioration, and age was significantly associated with Field First deterioration.

Synergic effects of EP2 and FP receptors co-activation on Blood-Retinal Barrier and Microglia.

Macular edema (ME) is caused with disruption of the blood-retinal barrier (BRB) followed by fluid accumulation in the subretinal space. Main components of the outer and inner BRB are retinal pigment epithelial (RPE) cells and retinal microvascular endothelial cells, respectively. In addition, glial cells also participate in the functional regulation of the BRB as the member of 'neurovascular unit'. Under various stresses, cells in neurovascular units secrete inflammatory cytokines. Neuroinflammation induced by these cytokines can cause BRB dysfunction by degrading barrier-related proteins and contribute to the pathophysiology of ME. Prostaglandins (PGs) are crucial lipid mediators involved in neuroinflammation. Among PGs, a novel EP2 agonist, omidenepag (OMD) acts on not only the uveoscleral pathway but also the conventional pathway, unlike F prostanoid (FP) receptor agonists. Moreover, the combination use of the EP and the FP agonist is not recommended because of the risk of inflammation. In this study, we investigated effects of OMD and latanoprost acid (LTA), a FP agonist, on BRB and microglia in vitro and in vivo. To investigate the function of outer/inner BRB and microglia, in vitro, ARPE-19 cells, human retinal microvascular endothelial cells (HRMECs), and MG5 cells were used. Cell viability, inflammatory cytokines mRNA and protein levels, barrier morphology/function, and microglial activation were evaluated using proliferation assays, qRT-PCR, ELISA, immunocytochemistry, trans-epithelial electrical resistance, and permeability assay. Moreover, after vitreous injection into the mouse, outer BRB morphology, glial activation, and cytokine expression were assessed. Each OMD and LTA alone did not affect the viability or cytokines expression of the three types of cells. In ARPE-19 cells, the co-stimulation of OMD and LTA increased the mRNA and protein levels of inflammatory cytokines (IL-6, TNF-α, and VEGF-A) and decreased the barrier function and the junction-related protein (ZO-1 and ß-catenin). By contrast in HRMECs, the co-stimulation affected significant differences in the mRNA levels of some cytokine (IL-6 and TNF-α) but enhanced the barrier function. In MG5 cells, the cytokines mRNA and size of Iba1-expressed cell were increased. A non-steroidal anti-inflammatory inhibited the barrier dysfunction and the junction-related protein downregulation in ARPE-19 cells and activation of MG5 cells. Also in vivo, the co-stimulation induced outer BRB disruption, cytokine increase, and retinal glial activation. Therefore, the co-stimulation of EP2 and FP induced the inflammatory cytokine-mediated outer BRB disruption, the enhanced inner BRB function, and the microglial activation. The BRB imbalance and the intrinsic prostaglandin production may be involved in OMD-related inflammation.