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BackgroundTo report on the optic nerve sheath diameter (ONSD) in patients with normal-tension glaucoma (NTG) compared with controls without known optic nerve (ON) or intracranial disease.MethodsIn 18 patients with NTG (mean age 64.9±8.9 years; 7 women and 11 men), CT of the orbit was performed. 17 age- and gender-matched patients without ON or intracranial disease, who underwent CT of the orbits for non-ophthalmological reasons, served as controls. The widest intraorbital ONSD in axial sections was measured using a standardised technique. Study design: unmasked. Statistical analysis was performed using an independent two-tailed t Test and the non-parametric Spearman correlation test.ResultsONSD was significantly (p<0.001) increased in NTG patients (right side: mean 7.9±0.9 mm SD; left: 8.0±1.1 mm) compared with controls (right: 6.3±0.5 mm; left: 6.1±0.6 mm). Neither the NTG nor the control group had a significant difference in ONSD between males and females or between right and left sides.ConclusionsAn increased ONSD is generally associated with increased intracranial pressure; however, ONSDs in a group of NTG patients also were significantly increased compared with controls. ON sheath compartmentation and thinning of the ON sheath are two possible explanations for an increase in the ONSD in patients with NTG.

Chronic glaucoma is a multifactorial disease among which oxidative stress may play a major pathophysiological role. We conducted a systematic review and meta-analysis to evaluate the levels of oxidative and antioxidative stress markers in chronic glaucoma compared with a control group. The PubMed, Cochrane Library, Embase and Science Direct databases were searched for studies reporting oxidative and antioxidative stress markers in chronic glaucoma and in healthy controls using the following keywords: \"oxidative stress\" or \"oxidant stress\" or \"nitrative stress\" or \"oxidative damage\" or \"nitrative damage\" or \"antioxidative stress\" or \"antioxidant stress\" or \"antinitrative stress\" and \"glaucoma\". We stratified our meta-analysis on the type of biomarkers, the type of glaucoma, and the origin of the sample (serum or aqueous humor). We included 22 case-control studies with a total of 2913 patients: 1614 with glaucoma and 1319 healthy controls. We included 12 studies in the meta-analysis on oxidative stress markers and 19 on antioxidative stress markers. We demonstrated an overall increase in oxidative stress markers in glaucoma (effect size = 1.64; 95%CI 1.20-2.09), ranging from an effect size of 1.29 in serum (95%CI 0.84-1.74) to 2.62 in aqueous humor (95%CI 1.60-3.65). Despite a decrease in antioxidative stress marker in serum (effect size = -0.41; 95%CI -0.72 to -0.11), some increased in aqueous humor (superoxide dismutase, effect size = 3.53; 95%CI 1.20-5.85 and glutathione peroxidase, effect size = 6.60; 95%CI 3.88-9.31). The differences in the serum levels of oxidative stress markers between glaucoma patients and controls were significantly higher in primary open angle glaucoma vs primary angle closed glaucoma (effect size = 12.7; 95%CI 8.78-16.6, P < 0.001), and higher in pseudo-exfoliative glaucoma vs primary angle closed glaucoma (effect size = 12.2; 95%CI 8.96-15.5, P < 0.001). In conclusion, oxidative stress increased in glaucoma, both in serum and aqueous humor. Malonyldialdehyde seemed the best biomarkers of oxidative stress in serum. The increase of some antioxidant markers could be a protective response of the eye against oxidative stress.

Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOC(Y437H) mice. Analysis of adult Tg-MYOC(Y437H) mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure [IOP], retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOC(Y437H) mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOC(Y437H) mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients.

Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% dexamethasone led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, dexamethasone-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model. Dexamethasone induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented dexamethasone-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1 , ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus ( r  = −0.62, P  = 5.30 × 10 −5 ) but not between CCT and primary open-angle glaucoma ( r  = −0.17, P  = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation. Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.

Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.

Background: Prostaglandin analogues are effective ocular hypotensive agents and are being used increasingly in the treatment of elevated intraocular pressure (IOP). These agents are typically dosed once daily. Objectives: A pilot study was conducted to evaluate the duration of travoprost's IOP-lowering efficacy up to 84 hours after the final dose in patients with open-angle glaucoma. A follow-up study was conducted to compare diurnal IOP control with travoprost and latanoprost over a 44-hour period. Methods: In the open label pilot study, patients received 0.004% travoprost in both eyes at 8 pm daily for 2 weeks. After 2 weeks, IOP was measured before administration of the last daily dose, every 4 hours thereafter for 36 hours, and 60 and 84 hours after the last dose, with no additional ocular hypotensive medication given. In the controlled, double-masked, parallel-group, follow-up study, patients were randomized to self-administer 1 drop of the marketed doses of 0.004% travoprost or 0.005% latanoprost in both eyes at 8 pm daily for 2 weeks. At the end of this period, patients returned to the facility at ∼8 pm for IOP measurement and administration of the final dose of study medication. IOP was then measured at 4-hour intervals for 44 hours after the last dose, with no additional ocular hypotensive medication given. Results: The pilot study included 21 patients (67% female, 33% male; age range, 35–81 years) with open-angle glaucoma. IOP values were significantly below baseline at all time points up to 84 hours after the final dose of travoprost ( P < 0.001). The follow-up study enrolled 35 patients, 1 of whom was excluded for missing data; thus, the intent-to-treat analysis included 34 patients (68% female, 32% male; age range, 36–72 years). At the unmedicated eligibility visit, mean IOP over 24 hours ranged from 21 to 26 mm Hg in each treatment group. After 2 weeks of treatment and 24 hours after the last dose, mean (SD) IOP was 13.1 (2.1) mm Hg (change from eligibility visit, −10.4 [2.7] mm Hg) in the travoprost group and 16.0 (3.1) mm Hg (change from eligibility visit, −7.1 [2.4] mm Hg) in the latanoprost group. The difference in change from baseline was statistically significant between treatment groups ( P = 0.006). Travoprost lowered IOP significantly at all time points throughout the 44-hour period after the last dose (mean IOP, ≤18 mm Hg; P < 0.001) and was statistically superior to latanoprost at 8 pm before the last dose ( P = 0.041) and 24 hours after the last dose ( P = 0.006). Latanoprost showed greater IOP-lowering efficacy compared with travoprost 4 hours after the last dose ( P = 0.040). IOP reductions were significantly different from zero at all time points with both treatments ( P ≤ 0.001). Conclusions: The results of the pilot study suggest that travoprost produces reductions in IOP that may be sustained for up to 84 hours after dosing. The results of the follow-up study suggest that both prostaglandin analogues significantly lower IOP from baseline in patients with open-angle glaucoma and provide excellent diurnal IOP control throughout a 24-hour period.

To compare parapapillary choroidal microvascular (PPCMv) densities between myopic eyes with and without glaucoma. In this retrospective study, OCTA images (4.5 × 4.5 mm) were obtained using a commercial spectral-domain OCTA system. PPCMv density was calculated in inner and outer annuli using customized software. Marginal model of generalized estimating equations was established to adjust for confounding factors and intraclass correlations. This study included 35 myopic eyes with glaucoma (MG), 96 non-myopic eyes with glaucoma (NMG) matched for visual field mean deviation, 37 myopic eyes without glaucoma (MNG), and 73 control eyes from three tertiary centers. The participant ages were (mean [standard deviation, SD]) 57.43 [11.49], 60.40 [10.07], 52.84 [9.35], and 54.74 [12.07] years. Inner and outer annular PPCMv densities (mean [SD]) decreased in the following order: control (0.15 [0.04] and 0.12 [0.04]), MNG (0.14 [0.08] and 0.12 [0.08]), NMG (0.09 [0.05] and 0.07 [0.04]), and MG (0.09 [0.04] and 0.07 [0.03]). The mean differences in PPCMv density between glaucoma groups (NMG and MG) and the control group (mean difference [95% confidence interval]) were -0.06 (-0.08 to -0.04, P < 0.001 for inner whole annular PPCMv density in NMG vs control) and -0.07 (-0.10 to -0.04, P < 0.001 for inner whole annular PPCMv density in MG vs control), consistent across all regions of interest (ROIs). No significant interaction was observed between glaucoma and myopia after adjustment for potential confounders (P > 0.112). Parapapillary choroidal microvascular density attenuation tends to be greater in eyes with glaucoma than in eyes with myopia.

Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.

Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK / SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1 and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy. Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1 , or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.