Comparative features of superior versus inferior hemisphere microvasculature dropout in open-angle glaucoma.

PURPOSE: This study aimed to investigate differences in microvasculature dropout (MvD) between the superior and inferior hemispheres in glaucoma patients. STUDY DESIGN: Retrospective and cross-sectional. METHODS: Fifty-eight eyes of 58 open-angle glaucoma patients (age 61.12 ± 10.19 years, mean deviation - 7.32 ± 6.36 dB) were included. MvD was detected with en face images from swept-source optical coherence tomography angiography. Blood flow at the optic nerve head was measured with laser speckle flowgraphy, represented as the mean blur rate in tissue (MBRT). Logistic and linear regression models adjusted for age, intraocular pressure, axial length, and circumpapillary retinal nerve fiber layer thickness were used to investigate the relationship between various factors and MvD angle in each hemisphere. RESULTS: The presence of inferior MvD was related to peripapillary atrophy-ß area (odds ratio = 14.10 [2.49-234.00], P = 0.019). Superior MvD angle was significantly related to MBRT in the superior quadrant (ß = -0.31 [- 0.60 - -0.02], P = 0.037). Inferior MvD angle was significantly related to peripapillary atrophy-ß area (ß = 0.49 [0.21-0.77], P = 0.001). CONCLUSIONS: Only superior MvD demonstrated a significant relationship with reduced ocular blood flow. In contrast, inferior MvD was associated with mechanical stress. These findings may suggest a potential difference in pathophysiology between superior and inferior MvD.

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 Effect of ß-Blocker Eye Drops on Pulse Rate, Ocular Blood Flow, and Glaucoma Progression: A Retrospective Longitudinal Study.

INTRODUCTION: Our study was conducted to determine factors associated with the effectiveness of a ß-blocker eye drop add-on in altering pulse rate (PR) in glaucoma patients. METHODS: This retrospective study examined 236 eyes of 138 patients who received a ß-blocker eye drop add-on during follow-up. Patients were included if at least one PR measurement was available both before and after the add-on was started. We collected data on ophthalmic parameters: longitudinal PR; longitudinal choroidal blood flow, represented by laser speckle flowgraphy-measured mean blur rate (MBR); and diacron-reactive oxygen metabolites (d-ROMs). We used a multivariable linear mixed-effects model to investigate the effectiveness of the ß-blocker eye drop add-on in altering PR and examined factors contributing to a larger PR alteration after the add-on was started by analyzing the effect on PR of the interaction term between the add-on and clinical factors. We used the k-means method to classify the patients. RESULTS: The ß-blocker eye drop add-on reduced PR (- 7.61 bpm, P < 0.001). Female gender, higher PR when the add-on was started, lower central corneal thickness, and a higher d-ROM level were associated with greater reduction in PR (P < 0.05). In a cluster of patients with these clinical features, choroidal MBR increased by + 3.42% when we adjusted for change over time; MD slope, which represents the speed of glaucoma progression, improved by + 0.64 dB/year (P < 0.05). CONCLUSIONS: We identified a glaucoma subgroup in which PR decreased, choroidal blood flow increased, and glaucoma progression slowed after a ß-blocker eye drop add-on was started.

Factors associated with intrachoroidal cavitation and sinkhole formation in eyes with glaucomatous visual-field defects.

PURPOSE: To investigate factors associated with intrachoroidal cavitation (ICC) and sinkhole formation in eyes with glaucomatous visual-field defects. METHODS: This retrospective, cross-sectional study enrolled a total of 2808 eyes of 1482 patients who were diagnosed/treated for glaucoma and underwent swept-source optical coherence tomography (OCT). We first determined the prevalence of ICCs and sinkholes and their locations. Next, we selected one eye from each patient and compared the clinical characteristics of eyes with and without ICCs. Finally, in eyes with ICCs, we compared the clinical characteristics of eyes with and without sinkholes. Blood flow (BF), represented by laser speckle flowgraphy-measured tissue-area mean blur rate (MBR), was measured in the temporal optic nerve head (ONH), temporal peripapillary chorioretinal atrophy (PPA) zone, and in the ICC zone. ICC area and angle were analyzed in OCT en-face images. Mean deviation and total deviation in the central area (TD-central) were measured with Humphrey visual-field testing. RESULTS: A total of 86 eyes (3.1%) had ICCs and 52 eyes (1.9%) had sinkholes. ICC eyes had a lower spherical equivalent and longer axial length (AL) than non-ICC eyes (P < 0.05). Patients with eyes with sinkholes were more elderly and had worse best-corrected visual acuity, worse TD-central, a larger ICC, and lower tissue-area MBR in the temporal ONH, temporal PPA zone, and ICC zone (P < 0.05). CONCLUSION: In eyes with glaucoma, AL elongation might be linked to ICC formation. Sinkhole formation might be associated with ICC enlargement, impaired ocular BF, and impaired retinal structure and function involving the central area.

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.

A ginger extract improves ocular blood flow in rats with endothelin-induced retinal blood flow dysfunction.

The aim of this study was to investigate the effect of a ginger extract on optic nerve head blood flow (ONH BF) under endothelin-1 (ET-1) stimulation. Using laser speckle flowgraphy, we measured ONH BF in brown Norway rats. To establish the ONH BF impairment profile under ET-1 stimulation, we administered an intravitreal injection of ET-1 under anesthesia. We then gave the ginger extract sublingually to assess its effect on ONH BF in both normal and ET-1-induced ischemic conditions. Post ET-1 injection, there were no significant changes in parameters including intraocular pressure or systemic factors. ONH BF showed a dose-dependent decline after ET-1 injection, with a significant reduction after a 2.50 pmol ET-1 dose. Sublingual administration of the ginger extract significantly improved ONH BF in both normal and ET-1-stimulated rats. This suggests that our newly developed supplement for improving ONH BF has a potential role in retinal ischemic diseases, including glaucoma.

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.

Predictive potential of optical coherence tomography parameters for the prognosis of decreased visual acuity after trabeculectomy in open-angle glaucoma patients with good vision.

BACKGROUND: Trabeculectomy (trab) is the most effective surgical procedure for lowering IOP and preventing glaucoma progression. However, decline in best-corrected visual acuity (BCVA) is one of the most serious postoperative complications of trab. Here, we investigated methods to predict decreased BCVA after trab in glaucoma patients with good preoperative BCVA. METHODS: This study included 35 eyes of 35 open-angle glaucoma (OAG) patients (male / female: 21 / 14, age: 64.0 ± 9.7 years old, preoperative intraocular pressure: 15.9 ± 5.4 mmHg, mean deviation: -18.1 ± 5.6 dB) with preoperative BCVA of 0.7 or better who underwent trab and were observed for more than 12 months. As a preoperative analysis, we measured temporal quadrant circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and ganglion cell complex thickness in a central strip between the disc and fovea (csGCCT), an area that corresponds to the location of the papillomacular bundle (PMB) in swept-source optical coherence tomography (OCT). We defined BCVA decline as a loss of more than 3 lines of BCVA after 12 months. Measurement parameters were compared between the BCVA-decline group and the non-BCVA-decline group. RESULTS: BCVA decline was detected in 11 cases (31.4%) 12 months after trab. There was a statistically significant difference in axial length (P = 0.049). A single logistic analysis showed that the BCVA-decline group had significantly lower cpRNFLT than the non-BCVA-decline group (27.7 ± 8.0 µm vs. 45.1 ± 5.3 µm, P < 0.001, cut-off value: 33.4 µm), as well as lower csGCCT (72.4 ± 7.7 µm vs. 87.5 ± 5.1 µm, P = 0.002, cut-off value: 82.3 µm). Multivariable logistic analysis showed that the BCVA-decline group had significantly lower temporal quadrant cpRNFLT (P < 0.001) and lower middle csGCCT (P < 0.001) compared to the non-BCVA-decline group. CONCLUSIONS: Lower temporal quadrant cpRNFLT and middle csGCCT, OCT scan areas that correspond to the location of the PMB, might be biomarkers that predict BCVA decline after trab in OAG patients with good vision.

Factors Associated With Visual Acuity Decline in Glaucoma Patients With Loss of Ganglion Cell Complex Thickness.

Purpose: To investigate the association between ocular/systemic factors and visual acuity decline in glaucoma patients with loss of ganglion cell complex thickness (GCCT). Methods: In 515 eyes of 515 patients with open-angle glaucoma (mean age, 62.6 ± 12.8 years; mean deviation, -10.95 ± 9.07 dB), we used swept-source optical coherence tomography to measure macular GCCT in sectors classified as corresponding to circumpapillary retinal nerve fiber layer clock-hour sectors from 7 o'clock (inferotemporal) to 11 o'clock (superotemporal). We calculated Spearman's rank correlation coefficient between each sector and best-corrected visual acuity (BCVA), determined cutoff values for BCVA decline (<20/25), and used multivariable linear regression models to determine the correlation between BCVA and biological antioxidant potential (BAP), corneal hysteresis (CH), and temporal-tissue optic nerve head blood flow (represented by temporal mean blur rate, or MBR-T). Results: Macular GCCT corresponding to the 9 o'clock sector had the highest correlation with BCVA (Rs = -0.454; P < 0.001) and a cutoff of 76.17 µm (area under the receiver operating characteristic curve = 0.891; P < 0.001). Subjects below this cutoff (N = 173) showed significant correlations between BCVA and age, BAP, CH, and MBR-T (ß = 0.192, P = 0.033; ß = -0.186, P = 0.028; ß = -0.217, P = 0.011; and ß = -0.222, P = 0.010, respectively). Conclusions: Multiple factors are involved in BCVA decline in patients with glaucoma with decreased macular GCCT. This suggests that evaluating BCVA may require assessing multiple factors. Translational Relevance: Multiple factors contribute to BCVA decline.

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.

Glutathione trisulfide prevents lipopolysaccharide-induced retinal inflammation via inhibition of proinflammatory cytokine production in glial cells.

We aimed to investigate the impact of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammation in retinal glia. Inflammatory responses in mouse-derived glial cells and Wistar rat retinas were stimulated with administration of LPS. Cell survival and proinflammatory cytokine production were examined using the Calcein-AM assay, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Retinal microglia were visualized with immunohistochemistry for Iba1. Administration of LPS (10 µg/mL) or GSSSG (less than 100 µM) did not affect survival of cultured primary Müller cells and established microglial cells (BV-2). RT-qPCR and ELISA indicated that GSSSG inhibited LPS-induced gene upregulation and protein secretion of proinflammatory cytokines in these glial cells and rat retinas. GSSSG inhibited LPS-induced activation of TGF-ß-activated kinase 1 (TAK1), which is an upstream kinase of NF-κB, in BV-2 cells. Finally, in vivo experiments indicated that intravitreal administration of GSSSG but not its relative glutathione disulfide (GSSG) inhibited LPS (500 ng)-induced accumulation of Iba1-immunopositive microglia in rat retinas. Taken together, GSSSG has the potential to prevent pathogenesis of inflammation-associated ocular diseases by inhibiting proinflammatory cytokine expression in retinal glial cells.

A quality management system aiming to ensure regulatory-grade data quality in a glaucoma registry.

BACKGROUND: Disease/patient registries are underutilized despite their multiple advantages over clinical trials in the clinical evaluation of drugs, such as the capacity for long-term curation, provision of patient outcome data in routine clinical practice, and provision of benchmark data for comparison. Ensuring the fit-for-purpose quality of data generated from such registries is important to informing regulatory decision making. Here, we report the construction of a quality management system aiming to ensure regulatory-grade data quality for a registry of Japanese patients with glaucoma to evaluate long-term patient outcomes. METHODS: The quality management system was established by reference to the risk-based approach in the ICH-E6 (R2) recommendations. The following three-component approach was taken: establishment of governance, computerized system validation (CSV), and implementation of risk assessment and control. Compliance of the system with the recommendations of regulatory guidelines relevant to use of the registry was assessed. RESULTS: Governance by academic collaboration was established. This was followed by the development of a total of 15 standard operating procedures, including CSV, data management, monitoring, audit, and management of imaging data. The data management system was constructed based on a data management plan, which specified data/paper flow and data management procedures. The electronic data capture (EDC) system was audited by an external vendor, and configured and validated using the V-model framework as recommended in the GAMP5 guideline. Informed consent, eligibility assessment and major ophthalmology measurements were determined as Critical to Quality (CTQ) factors. A total of 22 risk items were identified and classified into three categories, and operationalized in the form of a risk control plan, which included training sessions and risk-based monitoring. The glaucoma registry addressed most quality recommendations in official guidelines issued by multiple health authorities, although two recommendations were not met. CONCLUSIONS: We established and configured a quality management system for a glaucoma registry to ensure fit-for-purpose data quality for regulatory use, and to curate long-term follow-up data of glaucoma patients in a prospective manner.

Reduced Plasma BDNF Levels in Normal Tension Glaucoma Compared to Open Angle Glaucoma.

PRCIS: The study suggests that a low level of systemic BDNF may contribute to the pathogenesis of glaucoma in an IOP-independent manner. AIMS: To evaluate differences in systemic brain-derived neurotrophic factor (BDNF) levels between primary open angle glaucoma (POAG) patients and normal tension glaucoma (NTG) patients. METHODS: This study collected blood samples from 260 NTG patients, 220 age-matched POAG patients, and 120 age-matched cataract patients (as controls). BDNF levels were measured with an antibody-conjugated bead assay system (Luminex). RESULTS: We found that plasma BDNF levels in the NTG group were significantly lower than in the POAG and cataract control groups. There was no significant difference between the POAG and cataract groups. CONCLUSION: This result suggests that a low level of systemic BDNF may contribute to the pathogenesis of glaucoma in an IOP-independent manner.

Long-Term Surgical Outcomes and Possible Postoperative Complication with Severe Corneal Endothelial Cell Loss After Trabeculectomy for Cytomegalovirus-Associated Anterior Uveitis with Secondary Glaucoma.

PURPOSE: We assess long-term surgical outcomes after an initial trabeculectomy for cytomegalovirus-associated anterior uveitis with secondary glaucoma (CMV-SG). METHODS: We retrospectively reviewed the medical records of 16 eyes of 15 patients with CMV-SG and 157 eyes of 157 patients with primary open-angle glaucoma. The average follow-up period was approximately 3 years. Surgical success was defined as intraocular pressure (IOP) below 18 mmHg and at least 20% lower than baseline. RESULTS: Kaplan-Meier survival analysis revealed that bleb survival rates were not significantly different in the CMV-SG and POAG groups (P = 0.75). Bullous keratopathy occurred in 2 of 16 eyes with CMV-SG postoperatively but did not occur in the POAG group. The corneal endothelial cell density decreased by 34.2 ± 22.7% in the CMV-SG group during an average follow-up period of 2.7 ± 2.0 years. CONCLUSION: Trabeculectomy effectively controlled IOP in CMV-SG, but attention must be paid to corneal endothelial cell loss.

Development of an anti-oxidative intraocular irrigating solution based on reactive persulfides.

Anti-oxidative intraocular irrigating solutions (IISs) based on reactive persulfides, such as oxidized glutathione disulfide (GSSG), are commonly used worldwide. However, even with GSSG-based IISs, it has been shown that oxidative stress can occur during surgery, posing a risk to intraocular tissues. This study compared two IISs: one containing GSSG and one containing an oxidized glutathione trisulfide (GSSSG). Experimental in vivo irrigation with the IISs in rabbits showed that there was less leakage into the anterior chamber of rabbit serum albumin during perfusion with a 300-µM GSSSG IIS than with a 300-µM GSSG IIS. Experimental in vivo cataract surgery in rabbits showed that aqueous flare was suppressed 3 days after surgery with a 600-µM GSSSG IIS, but not with a 300-µM GSSSG or 300-µM GSSG IIS. Furthermore, an in vitro experiment, without any live tissue, showed that reactive oxygen species were suppressed more strongly with a 600-µM GSSSG IIS than with a 300-µM GSSG IIS. Thus, this study found that novel IISs based on GSSSG had anti-inflammatory and anti-oxidative effects during and after intraocular surgery and may decrease the rate of complications after surgery.

Clinical characteristics of glaucoma patients with various risk factors.

BACKGROUND: Glaucoma is multifactorial, but the interrelationship between risk factors and structural changes remains unclear. Here, we adjusted for confounding factors in glaucoma patients with differing risk factors, and compared differences in structure and susceptible areas in the optic disc and macula. METHODS: In 458 eyes with glaucoma, we determined confounding factors for intraocular pressure (IOP), central corneal thickness (CCT), axial length (AL), LSFG-measured ocular blood flow (OBF), which was assessed with laser speckle flowgraphy-measured mean blur rate in the tissue area (MT) of the optic nerve head, biological antioxidant potential (BAP), and systemic abnormalities in diastolic blood pressure (dBP). To compensate for measurement bias, we also analyzed corrected IOP (cIOP; corrected for CCT) and corrected MT (cMT; corrected for age, weighted retinal ganglion cell count, and AL). Then, we determined the distribution of these parameters in low-, middle-, and high-value subgroups and compared them with the Kruskal-Wallis test. Pairwise comparisons used the Steel-Dwass test. RESULTS: The high-cIOP subgroup had significantly worse mean deviation (MD), temporal, superior, and inferior loss of circumpapillary retinal nerve fiber layer thickness (cpRNFLT), and large cupping. The low-CCT subgroup had temporal cpRNFLT loss; the high-CCT subgroup had low cup volume. The high-AL subgroup had macular ganglion cell complex thickness (GCCT) loss; the low-AL subgroup had temporal cpRNFLT loss. The high-systemic-dBP subgroup had worse MD, total, superior, and inferior cpRNFLT loss and macular GCCT loss. The low-BAP subgroup had more male patients, higher dBP, and cpRNFLT loss in the 10 o'clock area. The high-OBF subgroup had higher total, superior and temporal cpRNFLT and macular GCCT. CONCLUSIONS: Structural changes and local susceptibility to glaucomatous damage show unique variations in patients with different risk factors, which might suggest that specific risk factors induce specific types of pathogenesis and corresponding glaucoma phenotypes. Our study may open new avenues for the development of precision medicine for glaucoma.

Deep Learning-Based Noise Reduction Improves Optical Coherence Tomography Angiography Imaging of Radial Peripapillary Capillaries in Advanced Glaucoma.

PURPOSE: We applied deep learning-based noise reduction (NR) to optical coherence tomography-angiography (OCTA) images of the radial peripapillary capillaries (RPCs) in eyes with glaucoma and investigated the usefulness of this method as an objective analysis of glaucoma. METHODS: This cross-sectional study included 118 eyes of 94 open-angle glaucoma patients (male/female = 38/56, age: 56.1 ± 10.3 years). We used OCTA (OCT-HS100, Canon) and built-in software (RX software, v. 4.5) to perform NR and calculate RPC vessel area density (VAD) and skeleton vessel length density (VLD). We also examined NR's effect on reproducibility. Finally, we assessed the vascular structure (PRCs)/function relationship at different glaucoma stages with Spearman's correlation. RESULTS: Regardless of NR, RPC parameters had excellent coefficients of variation (1.7-4.1%) in glaucoma patients and controls, and mean deviation (MD) was significantly correlated with VAD (NR: r = 0.835, p < 0.001; non-NR: r = 0.871, p < 0.001) and VLD (NR: r = 0.829, p < 0.001; non-NR: r = 0.837, p < 0.001). For mild, moderate, and advanced glaucoma, the correlation coefficients between MD and VLD were 0.366 (p = 0.028) 0.081 (p = 0.689), and 0.427 (p = 0.017) with NR and 0.405 (p = 0.014), 0.184 (p = 0.360), and 0.339 (p = 0.062) without NR, respectively. CONCLUSION: Denoised RPC images might have the potential for a closer structural/functional relationship, in which the floor effect of retinal nerve fiber layer thickness affects measurements. Deep learning-based NR promises to improve glaucoma assessment.

Correlation Between Enlargement of Retinal Nerve Fiber Defect Angle in En Face Imaging and Visual Field Progression.

Purpose: Retinal nerve fiber layer defects (RNFLDs) become enlarged with glaucoma progression. We measured the RNFLD angle and investigated whether it was correlated with deterioration of the visual field in patients with glaucoma. Methods: This study included 84 eyes of 84 patients with open-angle glaucoma (mean deviation [MD] = -6.51 ± 5.91 dB, follow-up period = 2.82 ± 0.74 years) with the RNFLDs, who underwent en face swept-source optical coherence tomography (SS-OCT) wide scans (12 × 9 mm) at least 6 times. The RNFLD angle was measured as the intersection between the RNFLD and a circle centered on the disc with a radius half the distance between the disc and the fovea. Slopes for the RNFLD angle, macular ganglion cell layer thickness (GCCT), and circumpapillary RNFL thickness (cpRNFLT) were compared with the MD slope, as measured with the Humphrey field analyzer 24-2 program. Results: The correlation coefficients with MD slope were -0.67 for the RNFLD angle slope (P < 0.001), 0.15 for the macular GCCT slope (P = 0.163), and 0.04 for the cpRNFLT slope (P = 0.719). The RNFLD angle tended to increase as the number of disc hemorrhage occurrences increased (rs = 0.31, P = 0.004). The RNFLD angle slope also had good predictive power for glaucoma progression (area under the receiver operating characteristic curve = 0.88, 95% confidence interval = 0.81-0.95). Conclusions: We found that the RNFLD angle slope was more closely associated with the MD slope than were other OCT parameters. This suggests that measurement of the RNFLD angle with en face OCT images could be effective in evaluating glaucoma progression. Translational Relevance: Our study provides a method for monitoring glaucoma progression with SS-OCT.

Glutathione Trisulfide Prevents Lipopolysaccharide-induced Inflammatory Gene Expression in Retinal Pigment Epithelial Cells.

We investigated the effects of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammatory gene expression in immortalized ARPE-19, and primary human and mouse retinal pigment epithelial (RPE) cells. Sulfane sulfur molecules were significantly increased in GSSSG-treated ARPE-19 cells. GSSSG prevented the LPS-induced upregulation of interleukin (IL)-1ß, IL-6, and C-C motif chemokine ligand 2 (CCL2) in ARPE-19/primary RPE cells. Moreover, GSSSG prevented the activation of the nuclear factor-kappa B p65 subunit, and promoted the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LPS-treated ARPE-19 cells. ERK1/2 inhibition prevented the GSSSG-mediated inhibition of LPS-induced IL-6 and CCL2 upregulation. Additionally, ERK1/2 activation prevented the upregulation of these genes in the absence of GSSSG. Knockdown of HMOX1 or NRF2, known as anti-oxidative genes, did not affect the activity of GSSSG in the context of LPS stimulation. These findings suggest that GSSSG attenuates LPS-induced inflammatory gene expression via ERK signaling hyperactivation, independently of the NRF2/HMOX1 pathway.