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 Relationship Between Artificial Intelligence-Assisted OCT Angiography-Derived Foveal Avascular Zone Parameters and Visual-Field Defect Progression in Eyes with Open-Angle Glaucoma.

Purpose: To investigate clinical factors associated with foveal avascular zone (FAZ) parameters obtained using OCT angiography (OCTA) with assistance from a previously developed artificial intelligence (AI) platform in eyes with open-angle glaucoma (OAG). Design: Retrospective longitudinal. Participants: This study followed up 885 eyes of 558 patients with OAG for ≥ 2 years; all eyes underwent ≥ 5 Humphrey visual-field (VF) tests and had 3.0 × 3.0 mm macular OCTA scans available. Methods: Average total deviation (TD) in the superior, superocentral, inferocentral, and inferior sectors of the Humphrey 24-2 program was calculated. We collected 3.0 × 3.0 mm macular OCTA images from each patient and used a previously developed AI platform with these images to obtain FAZ parameters, including FAZ area, FAZ circularity index (CI), and FAZ perimeter. Multivariable linear mixed-effects models were used to analyze the relationship between FAZ parameters, TD or TD slope in each quadrant, and systemic factors, adjusting for potential confounding factors, including axial length. Main Outcome Measures: Ophthalmic and systemic variables, FAZ parameters, and TD or TD slope in each quadrant. Results: The multivariable model showed that FAZ parameters were correlated with both TD and TD slope in the inferocentral quadrant (ß = -0.244 - 0.168, P < 0.001). Both upper-half and lower-half FAZ parameters were better associated with TD-inferocentral and TD-inferocentral slope than TD-superocentral or TD-superocentral slope in terms of ß size and statistical significance, indicating that there was no evident vertical anatomical correspondence between TD in the central quadrant and FAZ parameters. Foveal avascular zone area enlargement was associated with female gender (ß = 0.242, P = 0.003). Loss of FAZ circularity was associated with both aging and comorbid sleep apnea syndrome (SAS) (yes: 1, no: 0) (ß = -0.188, P < 0.001; ß = -0.261, P = 0.031, respectively). Foveal avascular zone perimeter elongation was associated with aging and female gender (ß = 0.084, P = 0.040; ß = 0.168, P = 0.042, respectively). Conclusions: Artificial intelligence-assisted OCTA-measured FAZ enlargement and irregular shape might be good markers of ocular hypoperfusion and associated inferocentral VF defect progression in eyes with OAG. 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.

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.

The Relationship Between Kiritsu-Meijin-Derived Autonomic Function Parameters and Visual-Field Defects in Eyes with Open-Angle Glaucoma.

PURPOSE: This retrospective cross-sectional study aimed to investigate the association between autonomic parameters measured using the Kiritsu-Meijin device and visual-field defects in patients with open-angle glaucoma. METHODS: A total of 79 eyes of 42 patients with open-angle glaucoma were enrolled in this study. Kiritsu-Meijin testing comprised three phases: sitting, standing, and sitting again (2 min, 2 min, and 1 min, respectively). Continuous electrocardiograms were recorded for five minutes. Autonomic parameters were extracted from the resulting data and analyzed, including activity, balance, reaction, switchover, and recovery; these are five representative parameters derived from Kiritsu-Meijin testing. Correlations between these parameters and mean deviation from Humphrey visual field testing were determined. Additionally, we used a linear mixed-effects model to observe sectoral differences in the relationship between total deviation and the Kiritsu-Meijin parameters. In this study, we focused on superior, central, and inferior total deviations. RESULTS: Significant positive correlations were observed between activity, balance, and recovery and mean deviation values (ß = 0.29-0.38, p < .05). The ß value between activity and inferior total deviation was higher than that between activity and superior total deviation (ß = 0.22, p < .05). Balance did not show any sectoral differences (p > .05). Recovery was more strongly associated with central to inferior total deviation than superior total deviation (ß = 0.17-0.25, p < .05). CONCLUSION: Our findings suggest that in patients with open-angle glaucoma, lower activity and recovery are associated with more severe central and/or inferior visual field defects in the superior quadrant. These results imply that measurements of autonomic function made with the Kiritsu-Meijin device may have clinical utility in the management of glaucoma.

The GPR84 molecule is a mediator of a subpopulation of retinal microglia that promote TNF/IL-1α expression via the rho-ROCK pathway after optic nerve injury.

Resident microglia are important to maintain homeostasis in the central nervous system, which includes the retina. The retinal microglia become activated in numerous pathological conditions, but the molecular signatures of these changes are poorly understood. Here, using an approach based on FACS and RNA-seq, we show that microglial gene expression patterns gradually change during RGC degeneration induced by optic nerve injury. Most importantly, we found that the microglial cells strongly expressed Tnf and Il1α, both of which are known to induce neurotoxic reactive astrocytes, and were characterized by Gpr84high -expressing cells in a particular subpopulation. Moreover, ripasudil, a Rho kinase inhibitor, significantly blunted Gpr84 expression and cytokine induction in vitro and in vivo. Finally, GPR84-deficient mice prevented RGC loss in optic nerve-injured retina. These results reveal that Rho kinase-mediated GPR84 alteration strongly contribute to microglial activation and promote neurotoxicity, suggesting that Rho-ROCK and GPR84 signaling may be potential therapeutic targets to prevent the neurotoxic microglial phenotype induced by optic nerve damage, such as occurs in traumatic optic neuropathy and glaucoma.

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.

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.

The relationship between choroidal blood flow and glaucoma progression in a Japanese study population.

PURPOSE: To determine whether choroidal blood flow (BF) is related to visual field (VF) defect severity and progression in eyes with open-angle glaucoma (OAG). STUDY DESIGN: Retrospective and longitudinal. METHODS: This study comprised 443 eyes of 285 OAG patients who underwent laser speckle flowgraphy (LSFG), optical coherence tomography, and visual-field (VF) testing at baseline. The patients were then observed for at least 2 years and at least 5 reliable VF tests were performed. In the LSFG images, we set regions of interest at the optic nerve head (ONH) and the parapapillary choroid to obtain ONH-tissue mean blur rate (MBR) and choroidal MBR, respectively. We used univariable and multivariable linear mixed-effects models to determine clinical factors associated with choroidal MBR at baseline. We also used a linear mixed-effects model to determine the contribution of ONH-tissue MBR and choroidal MBR to baseline mean deviation (MD) and to MD slope during follow-up, adjusting for potential confounding factors, including circumpapillary retinal nerve fiber layer thickness. RESULTS: Choroidal MBR was associated with age, MD slope, and ONH-tissue MBR (ß = -0.181, P = 0.001; ß = 0.134, P = 0.002; ß = 0.096, P = 0.049, respectively). ONH-tissue MBR was associated with both MD and MD slope (ß = 0.146, P = 0.004; ß = 0.152, P = 0.009, respectively), whereas choroidal MBR was associated only with MD slope (ß = 0.147, P = 0.005). CONCLUSION: LSFG-derived choroidal MBR might be a useful biomarker to predict VF defect progression in a Japanese population.

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.

A lightweight deep learning model for automatic segmentation and analysis of ophthalmic images.

Detection, diagnosis, and treatment of ophthalmic diseases depend on extraction of information (features and/or their dimensions) from the images. Deep learning (DL) model are crucial for the automation of it. Here, we report on the development of a lightweight DL model, which can precisely segment/detect the required features automatically. The model utilizes dimensionality reduction of image to extract important features, and channel contraction to allow only the required high-level features necessary for reconstruction of segmented feature image. Performance of present model in detection of glaucoma from optical coherence tomography angiography (OCTA) images of retina is high (area under the receiver-operator characteristic curve AUC ~ 0.81). Bland-Altman analysis gave exceptionally low bias (~ 0.00185), and high Pearson's correlation coefficient (p = 0.9969) between the parameters determined from manual and DL based segmentation. On the same dataset, bias is an order of magnitude higher (~ 0.0694, p = 0.8534) for commercial software. Present model is 10 times lighter than Unet (popular for biomedical image segmentation) and have a better segmentation accuracy and model training reproducibility (based on the analysis of 3670 OCTA images). High dice similarity coefficient (D) for variety of ophthalmic images suggested it's wider scope in precise segmentation of images even from other fields. Our concept of channel narrowing is not only important for the segmentation problems, but it can also reduce number of parameters significantly in object classification models. Enhanced disease diagnostic accuracy can be achieved for the resource limited devices (such as mobile phone, Nvidia's Jetson, Raspberry pi) used in self-monitoring, and tele-screening (memory size of trained model ~ 35 MB).

A Plant-Derived Antioxidant Supplement Prevents the Loss of Retinal Ganglion Cells in the Retinas of NMDA-Injured Mice.

Purpose: To investigate the effect of plant-derived antioxidant compounds, identified with primary culture screening, on retinal ganglion cell (RGC) survival in mice under excitotoxic conditions. Additionally, to determine the effect of these compounds on the involvement of calpain inactivation. Materials and Methods: Plant-derived antioxidant compounds including hesperidin, crocetin, and Tamarindus indica were administrated orally to C57BL/6J mice. The levels of lipid oxidation and calpain activation were assessed with a TBARS assay and western blotting. RGC survival was evaluated with a TUNEL assay and RBPMS immunostaining after intravitreal injection of NMDA. Results: Plant-derived antioxidant compounds significantly ameliorated the increase in the level of MDA in the retinas after NMDA injury. Cleaved α-fodrin fragments were detected in the NMDA-injured retinas, and these fragments were significantly lower in mice that received the plant-derived antioxidant compounds. The plant-derived antioxidants also ameliorated increases in TUNEL-positive cells and RGC death after NMDA injection. Conclusion: These results indicate that oral administration of plant-derived antioxidant compounds such as hesperidin, crocetin, and Tamarindus indica suppressed RGC death. This oral supplementation decreased lipid oxidation and excessive calpain activation in NMDA-injured retinas. Thus, our newly developed antioxidant supplement has a potential role in neuroprotective treatment for retinal diseases, such as glaucoma.

CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice.

Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

Comparisons between retinal vessel calibers and various optic disc morphologic parameters with different optic disc appearances: The Glaucoma Stereo Analysis Study.

The Glaucoma Stereo Analysis Study (GSAS) is a multicenter collaborative study of the characteristics of glaucomatous optic disc morphology using a stereo fundus camera. This study evaluated the retinal vessel calibers and correlations using GSAS fundus photographs between retinal vessels and 38 optic nerve head (ONH) morphologic parameters comprehensively. In all 240 eyes, the mean central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were 138.4 and 216.5 µm, respectively; the CRAE correlated with age, visual field scores and 19 ONH parameters and CRVE correlated with age, intraocular pressure, visual field scores and 11 ONH parameters. Among the different optic disc appearances including focal ischemia (FI) (n = 53, 22%), generalized enlargement (GE) (n = 53, 22%), myopic glaucoma (MY) (n = 112, 47%), and senile sclerosis (SS) (n = 22, 9%), the CRAE did not differ significantly; CRVE was significantly narrower in SS than in FI and MY. In FI, GE, MY, and SS disc types, CRAE correlated with 3, 14, 9, and 2 ONH parameters, respectively, and CRVE corelated with 9, 0, 12, and 6 ONH parameters, respectively. We confirmed previous observations on the effect of retinal vessel narrowing on glaucomatous changes in the ONH and visual field. The associations between retinal vessel caliber and ONH morphologic parameters vary among different optic disc appearances, suggesting different effects of vascular changes in each disc type.