Is Glaucoma a Two-Pressure-Related Optic Neuropathy? A Systematic Review and Meta-Analysis.

Objectives: To review the current literature related to the correlation between translaminar pressure difference (TLPD) and glaucoma. Materials and Methods: In this article, we conducted a literature review using MEDLINE via PubMed, Cochrane Eyes and Vision, and Google Scholar from 01/01/2010 to 31/12/2022. Search terms included "glaucoma", "intraocular pressure", "translaminar cribrosa pressure gradient/difference", "intracranial pressure", and "cerebrospinal fluid pressure". Of 471 results, 8 articles were selected for the meta-analysis. Results: Our meta-analysis demonstrated significantly higher intraocular pressure, lower cerebrospinal fluid pressure (CSFp), and greater TLPD in high-tension and normal-tension glaucoma groups compared to healthy groups. Conclusion: The differences in CSFp and TLPD between glaucoma and healthy people detected in current studies suggests a potential relationship between TLPD and glaucoma.

The Effect of Yoga on Intraocular Pressure Using the "iCare HOME2" Tonometer.

BACKGROUND: Various yoga positions may have an unfavorable impact on intraocular pressure (IOP) and may therefore be seen as a potential risk factor for the progression of glaucoma. The new "iCare HOME2" is a handheld self-tonometer for IOP measurements outside clinical settings. This is the first study to evaluate the immediate effect of common yoga postures on the IOP of healthy and glaucomatous eyes using the "iCare HOME2" self-tonometer and to compare the time of IOP recovery in both groups. METHODS: This is a single-center, prospective, observational study including 25 healthy and 25 glaucoma patients performing the following yoga positions: "legs up" (Viparita Karani), "bend over" (Uttanasana), "plough pose" (Halasana), and the "down face dog" (Adho Mukha Svanasana) for 90 s each, with a 2-min break in between. IOP was measured with the "iCare HOME2" before, during, and after each position. RESULTS: IOP significantly increased in all eyes in all positions (p < 0.05), showing no statistically significant difference between healthy or glaucomatous eyes (p > 0.05). The mean rise in IOP in healthy subjects was 1.6 mmHg (SD 1.42; p = 0.037), 14.4 mmHg (SD 4.48; p < 0.001), 7.5 mmHg (SD 4.21; p < 0.001), and 16.5 mmHg (SD 3.71; p < 0.001), whereas in glaucoma patients, IOP rose by 2.8 mmHg (SD 2.8; p = 0.017), 11.6 mmHg (SD 3.86; p < 0.001), 6.0 mmHg (SD 2.24; p < 0.001), and 15.1 mmHg (SD 4.44; p < 0.001) during the above listed yoga positions, repsectively. The highest increase in IOP was seen in the down face position, reaching mean IOP values above 31 mmHg in both study groups. IOP elevation was observed immediately after assuming the yoga position, with no significant change during the following 90 s of holding each pose (p > 0.05). All IOP values returned to baseline level in all individuals, with no significant difference between healthy and glaucoma participants. CONCLUSION: Our data show that common yoga positions can lead to an acute IOP elevation of up to 31 mmHg in healthy as well as glaucoma eyes, with higher IOP values during head-down positions. Given that IOP peaks are a major risk factor for glaucomatous optic neuropathy, we generally advise glaucoma patients to carefully choose their yoga exercises. If and to what extent practicing yoga leads to glaucoma progression, however, remains unclear and warrants further research.

Iris neovascularization and neurotrophic keratopathy following ultrasound cycloplasty in refractory glaucoma: case series.

BACKGROUND: Ultrasound cycloplasty is a noninvasive surgery used to reduce intraocular pressure in patients with glaucoma, with fewer severe complications. This report presents several cases of iris neovascularization and neurotrophic keratopathy following ultrasound cycloplasty. CASE PRESENTATION: Six patients diagnosed with refractory glaucoma underwent ultrasound cycloplasty at our clinic. Three cases developed iris neovascularization at postoperative day 3, week 2 and week 4 respectively, with intraocular pressure ranging from 12 to 24 mmHg. The other three cases developed neurotrophic keratopathy at postoperative week 3, week 6 and week 8 which completely healed within 60 days. CONCLUSIONS: Iris neovascularization and neurotrophic keratopathy can be triggered after ultrasound cycloplasty, which are uncommon and self-limited but potentially vision-threatening. Preoperative risk assessment and regular postoperative follow-up are recommended to manage complications effectively.

Glaucoma progression due to refraining examination amid the pandemic of COVID-19.

PURPOSE: Some patients refrained from seeking an ophthalmologist due to the anxiety and morbidity associated with the coronavirus disease (COVID-19) pandemic. We investigated progressive visual field defects in patients with glaucoma who refrained from ophthalmological examinations. METHODS: This was a retrospective study. We analyzed data from 886 patients with glaucoma who visited Inouye Eye Hospital in June 2022 and were followed-up prior to January 2020. We examined the number of times patients canceled visits between January 2020 and May 2022 due to coronavirus concerns. We assessed the mean deviation (MD) values of the Humphrey Visual Field Assessment (HFA) program 30-2 SITA Standard values after visit interruptions for worsening beyond the MD values predicted by the MD slope. Factors influencing this difference were analyzed using logistic regression analysis. RESULTS: The study included 374 men and 512 women. The mean age was 68.7 ± 12.0 years. Visit interruptions occurred in 146 patients (16.5%), with 95 (65.1%) rescheduling once, 27 (18.5%) twice, and 24 (16.4%) three or more times. Among 90 patients who underwent HFA regularly, 50 (55.6%) experienced worse-than-expected MD values and 12 (13.3%) deteriorated by 2 dB or more. Longer interruptions and high intraocular pressure before interruption worsened the MD values by 2 dB or more. CONCLUSION: Patients with glaucoma with visit interruptions due to the pandemic should be monitored for the progression of visual field impairment.

Outcomes of iStent inject combined with cataract surgery in Asian eyes: Australian data from the Fight Glaucoma Blindness international registry.

PURPOSE: To analyse real-world outcomes in Asian eyes of iStent inject, a second-generation trabecular micro-bypass stent, combined with phacoemulsification. METHODS: This is a multi-centre, observational study of glaucomatous Asian eyes that have undergone iStent inject implantation combined with cataract surgery. Patient data were extracted from the Fight Glaucoma Blindness! Registry. Outcome measures included those of IOP reduction, glaucoma medication reduction, and adverse events including the need for secondary surgery. RESULTS: 123 eyes of 86 patients with a mean age of 68.4 ± 9.3 years underwent iStent inject implantation with phacoemulsification. At baseline, the mean ± SD preoperative intraocular pressure (IOP) was 16.0 ± 4.4 mmHg, and the mean preoperative number of topical glaucoma medications was 1.9 ± 1.4. At 12 months 30.8% of eyes demonstrated a reduction in IOP greater than 20%, the mean IOP reduction was 12.5% with an additional reduction of 0.7 glaucoma medications. 40% of eyes were using no medications at 12 months compared to 16.3% preoperatively. 8.2% of eyes required a subsequent procedure within the 12-month follow-up window. CONCLUSION: iStent inject implantation combined with phacoemulsification in Asian eyes showed a reduction of IOP and glaucoma medication use in a real-world clinical setting. The safety profile of the device is good with minimal adverse outcomes, however, a subset of patients required secondary procedures within the 12 month follow up.

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway.

BACKGROUND: NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. METHODS: Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2 -/- mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O2-) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. RESULTS: We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. CONCLUSIONS: Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

Evaluation of Optic Nerve Head Microcirculation in Open-Angle Glaucoma Patients with Unilateral Visual Field Defect.

INTRODUCTION: Microcirculation of optic nerve head (ONH) in open-angle glaucoma (OAG) patients with unilateral visual field (VF) loss has yet to be fully investigated, especially the perimetrically unaffected fellow eyes. METHODS: Thirty-eight OAG patients with VF defect in one eye and normal VF in the other eye, and thirty-one healthy participants were analyzed. All participants underwent laser speckle flowgraphy (LSFG), spectral-domain optical coherence tomography (SD-OCT) imaging, and VF test for further analyses. LSFG measurements included mean blur rate in all area of ONH (MA), big vessel area of ONH (MV), and tissue area of ONH (MT). SD-OCT parameters included circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macula thicknesses. The difference of LSFG and SD-OCT indices between glaucoma patients and healthy controls were compared. The diagnostic accuracy was analyzed with the areas under the receiver operating characteristic curves (AROCs). RESULTS: Global cpRNFL thickness and macular thickness in unaffected eyes of OAG patients were higher than their fellow eyes and lower than healthy eyes. MA and MV in healthy eyes and unaffected eyes were significantly higher than in affected eyes. MT in unaffected eyes of OAG patients was higher than in their fellow affected eyes but lower than in healthy eyes. The AROCs were highest for cpRNFL (0.925), followed by macular thickness (0.838), and MT (0.834). CONCLUSIONS: ONH microcirculation in perimetrically unaffected fellow eyes was decreased in OAG patients with unilateral VF loss. LSFG can detect changes of ONH in high-risk eyes before detectable VF damage, which may reflect the vascular pathophysiology for glaucoma.

Mesenchymal Stromal Cells from Human Wharton's Jelly Modulate the Intraocular Immune Response in a Glucocorticoid Hypertension Model: An Exploratory Analysis.

INTRODUCTION: Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells. Recent research suggests immunological changes such as cytokine imbalance may affect its pathophysiology. This implies that immunomodulation, like that of mesenchymal cells, could be a potential therapeutic avenue for this disease. However, the effects of intravitreal injections of human Wharton's jelly-derived mesenchymal stromal cells (hWJ-MSCs) on intraocular immune response have not been assessed in ocular hypertension (OH) models. METHODS: We explored this by measuring cytokine levels and expression of other markers, such as glial fibrillary acidic protein (GFAP) and T cells, in 15 randomly divided New Zealand rabbits: G1: OH, G2: hWJ-MSCs, and G3: OH+hWJ-MSCs. We analyzed the aqueous humor (IL-6, IL-8, and TNF-α) and vitreous humor (IFN-γ, IL-10, and TGF-ß) using ELISA and flow cytometry (cell populations), as well as TCD3+, TCD3+/TCD4+, and TCD3+/TCD8+ lymphocytes, and GFAP in the retina and optic nerve through immunohistochemistry. RESULTS: We found a decrease in TNF-α, IL-6, IFN-γ, IL-10, and IL-8 in G3 compared to G1 and an increase in TGF-ß in both G2 and G3. TCD3+ retinal infiltration in all groups was primarily TCD8+ rather than TCD4+ cells, and strong GFAP expression was observed in both the retina and optic nerves in all groups. CONCLUSION: Our results suggest that cellular and humoral immune responses may play a role in glaucomatous optic neuropathy and that intravitreal hWJ-MSCs can induce an immunosuppressive environment by inhibiting proinflammatory cytokines and enhancing regulatory cytokines.

Comparative posterior corneal profile of keratoconus hydrops versus Haab's striae in congenital glaucoma.

Keratoconus eyes develop corneal decompensation more often compared to eyes with primary congenital glaucoma (PCG) following Descemet's membrane (DM) tear. This study was conducted to compare the posterior corneal morphology in areas with DM breaks with regards to DM and pre-Descemet's layer (PDL) between the two. In this cross-sectional comparative study, anterior segment optical coherence tomography (AS-OCT) scans of the posterior cornea of advanced keratoconus eyes with hydrops ( n = 12), PCG eyes with Haab's striae ( n = 15), and healthy control eyes ( n = 14) were compared for DM-PDL morphology. These were further corroborated by the histopathology of corneal buttons from keratoconus ( n = 14) and PCG ( n = 13) cases obtained following penetrating keratoplasty and compared with controls (enucleated retinoblastoma globes, n = 6) on light microscopy and collagen IV immunostaining. AS-OCT showed a thicker median DM/PDL complex in PCG (80 µm) versus keratoconus eyes (36 µm, P = 0.01; Kruskal-Wallis test). The median height and length of detached DM-PDL were significantly more in keratoconus versus PCG (145 µm, 1766.1 ± 1320.6 µm vs. 26.5 µm, 453.3 ± 303.2 µm, respectively, P = 0.012; Kruskal-Wallis test). Type-1 DM/PDL detachment (seen as a characteristic taut chord) in keratoconus (90%) was the most common morphological pattern versus intracameral twin protuberance (92%) following DM breaks in PCG. Histopathology confirmed thicker DM in PCG (median: 63.4 µm) versus keratoconus eyes (median: 33.2 µm) or controls (27.1 µm) ( P = 0.001; Kruskal-Wallis test). Greater height/length of DM/PDL detachment compounded by poor healing response (lower DM/PDL thickness) probably causes more frequent corneal decompensation in keratoconus eyes when compared to PCG eyes following DM tears.

Chamber shallowing technique for challenging DMEK cases: Tucking cellulose spears under the speculum to augment posterior pressure.

Some anterior chambers do not readily shallow because of insufficient posterior pressure and/or very deep anterior chamber anatomy, which can make unscrolling descemet membrane endothelial keratoplasty (DMEK) tissue more challenging with an unmodified tap technique. We present a hands-free method for augmenting posterior pressure by temporarily tucking cellulose sponges under the blades of the eyelid speculum. The sponges transfer some of the eyelid speculum's weight onto the bulbar surface posterior to the iris, thereby indenting the sclera and causing the iris diaphragm to bulge further forward. This hands-free technique can transform a potentially challenging DMEK case into a more straightforward one by facilitating both a shallow anterior chamber and a bimanual unscrolling technique. However, it only works in bicameral eyes with a vitreous body (e.g., an eye with penetrating keratoplasty, vitreous syneresis, and axial myopia) and will not work in unicameral eyes after vitrectomy (e.g., an eye with an Anterior Chamber Intraocular Lens (ACIOL)).

Risk Factors for Progression of Primary Open-Angle Glaucoma with Lower Normal Intraocular Pressure.

INTRODUCTION: This study aimed to investigate intraocular pressure (IOP)-independent factors associated with the progression of primary open-angle glaucoma (POAG) with IOP ≤15 mm Hg. METHODS: POAG patients with maximum IOP ≤15 mm Hg at the Kyoto University Hospital between January 2011 and August 2021 were retrospectively enrolled. We evaluated effects of various factors on the rate of mean deviation (MD) changes in the visual field (VF) examinations using a linear mixed model. These factors included hypertension, diabetes mellitus (DM), hyperlipidemia (HL), cardiovascular disease, arrhythmia, disc hemorrhage, sleep apnea syndrome, orthopedic diseases, and malignant tumors. RESULTS: In total, 98 eyes from 68 patients were included. The baseline MD was -9.74 ± 7.85 dB. The mean rate of MD change and IOP during the observation period were -0.28 ± 0.04 dB/year and 11.8 ± 1.0 mm Hg, respectively. Comorbidity of DM or HL showed a significant positive association with the rate of MD change (ß = 0.35, p = 0.0006 and ß = 0.18, p = 0.036, respectively) in the model adjusted for age, sex, axial length, mean IOP, and standard deviation of IOP during the observation period. However, no significant association of DM or HL was found after adjusting for central corneal thickness. CONCLUSION: This study suggests that DM or HL is associated with VF deterioration in glaucoma with lower IOP, but the association may be due to differences in IOP characteristics.

Clinical Characteristics of Microcystic Macular Edema in Chronic Primary Angle-Closure Glaucoma and Primary Open-Angle Glaucoma Patients.

INTRODUCTION: This study investigated the clinical characteristics of and risk factors for microcystic macular edema (MME) in patients with chronic primary angle-closure glaucoma (CPACG) and primary open-angle glaucoma (POAG). METHODS: This retrospective observational study included 1,588 eyes from 926 glaucoma inpatients and analyzed the patients' basic demographic information, visual field parameters, macular scans, and peripapillary retinal nerve fiber layer thickness. RESULTS: Our findings were that the incidence rate of MME was 3.97% (34/857) in CPACG and 5.88% (43/731) in POAG. MME was predominantly diagnosed at an advanced stage in CPACG (almost 100%) compared to POAG (93.02%). MME was most frequently involved in the inferior (83.12%) quadrant of the peri-macular region in both CPACG and POAG. Risk factors for MME occurrence in CPACG and POAG included lower visual field mean deviation (OR = 1.14, 95%: CI 1.05-1.24, p = 0.003; OR = 1.14, 95% CI: 1.06-1.21, p < 0.001) and younger age (OR = 0.92, 95% CI: 0.88-0.96, p < 0.001; OR = 0.96, 95% CI: 0.93-0.99, p = 0.003), while female sex (OR = 0.30, 95% CI: 0.11-0.84, p = 0.022) reduced the MME occurrence in POAG. CONCLUSION: MME could develop in both CPACG and POAG patients, occurring earlier in POAG. The inferior peri-macular region is commonly affected. Younger age and poorer visual field are risk factors for MME in glaucoma patients.

Differentiating Ischemic Optic Neuropathy from Glaucoma Using Diagnostic Tests.

INTRODUCTION: Anterior ischemic optic neuropathy (AION) can mimic glaucoma and consequently cause difficulties in differential diagnosis. The purpose of this paper was to summarize differences in diagnostic tests that can help perform a correct diagnosis. METHODS: The search strategy was performed according to the PRISMA 2009 guidelines, and four databases were used: MEDLINE, Embase, Web of Science, and Cochrane. Totally, 772 references were eligible; 39 were included after screening with respect to inclusion criteria that included English language and published in the 20 years before search date. RESULTS: Ninety percent (n = 35) of included studies used optical coherence tomography (OCT). Glaucomatous eyes had a significantly greater cup area, volume and depth, cup-to-disk ratio, a lower rim volume and area, and a thinner Bruch's membrane opening-minimum rim width. Retinal nerve fiber layer (RNFL) thinning in glaucomatous eyes occurred primarily at the superotemporal, inferotemporal, and inferonasal sectors, while AION eyes demonstrated mostly superonasal thinning. Glaucoma eyes showed greater macular ganglion cell layer thickness, except at the inferotemporal sector. OCT angiography measurements demonstrated a significant decrease in superficial and deep macular vessel density (VD) in glaucoma compared to AION with similar degree of visual field damage; the parapapillary choroidal VD was spared in AION eyes compared to glaucomatous eyes. CONCLUSION: By use of OCT imaging, optic nerve head parameters seem most informative to distinguish between glaucoma and AION. Although both diseases affect the RNFL thickness, it seems to do so in different sectors. Differences in structure and vascularity of the macula can also help in making the differential diagnosis.

The efficacy of XEN gel stent implantation in glaucoma: a systematic review and meta-analysis.

BACKGROUND: Xen is a device for minimally invasive glaucoma surgery, and is used to treat POAG, pseudoexfoliative or pigmentary glaucoma, as well as refractory glaucoma. The efficacy of XEN in treating glaucoma remains to be confirmed and clarified. Hence, we conducted a systematic review and meta-analysis to examine the efficacy and associated complication of XEN implantations. METHODS: We conducted a literature search in PubMed, EMBASE, the Cochrane Library of Systematic Reviews, Web of Science, China National Knowledge Infrastructure, WanFang and SinoMed databases to identify studies, published before May 15, 2021, which evaluated XEN in glaucoma, and parameters for measurements included intra-ocular pressure (IOP), number of anti-glaucoma medications (NOAM), and bleb needling rate. We compared the measurements of XEN-only procedure between phaco-XEN and trabeculectomy, and we also did sub-analysis based on time points, glaucoma types, ethnics, etc. Sensitivity analyses and publication bias were conducted for evaluating bias.This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) reporting guideline. RESULTS: We identified 78 eligible studies, analysis revealed obvious IOP reduction after XEN stent implantation (SMD: 1.69, 95% CI 1.52 to 1.86, p value < 0.001) and NOAM reduction (SMD: 2.11, 95% CI 1.84 to 2.38, p value < 0.001). Sub-analysis showed no significant difference with respect to time points, ethnicities, and economic status. No significant difference was found between XEN treatment effect on POAG and PEXG eyes and between pseudo-phakic and phakic eyes. Also no significant difference was found between XEN and phaco-XEN surgery in terms of IOP after surgery (SMD: -0.01, 95% CI -0.09 to 0.08, p value 0.894). However, NOAM (after publication bias correction) and bleb needling rate (RR: 1.45, 95% CI 1.06to 1.99, p value 0.019) were lower in phaco-XEN group compared to XEN only group. Compared to trabeculectomy, XEN implantation had similar after-surgery IOP, however bleb needling rate (RR: 2.42, 95% CI 1.33 to 4.43, p value 0.004) was higher. CONCLUSION: Our results confirmed that XEN is effective in lowering both IOP and NOAM till 48 months after surgery. It is noteworthy that XEN implantation leads to higher needling rate, compared to phaco-XEN or trabeculectomy. Further research, studying complications of XEN on non-European ethnicities, especially on Asian, are in urgent need before XEN is widely applied.

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

A20 Attenuates the Fibrotic Response in the Trabecular Meshwork.

Although the extracellular matrix (ECM) in trabecular meshwork (TM) cells is known to be important in intraocular pressure (IOP) regulation, the molecular mechanisms involved in generating a glaucomatous environment in the TM are not completely understood. Recently we identified a molecular pathway, transforming growth factor beta 2 (TGFß2)-toll-like receptor 4 (TLR4) signaling crosstalk, as an important regulator of glaucomatous damage in the TM, which contributes to fibrosis. Here we evaluate a novel molecular target, A20, also known as tumor necrosis factor alpha-induced protein 3 (TNFAIP3), which may help to block pathological TGFß2-TLR4 signaling. Primary human TM cells were analyzed for A20 message and for A20 and fibronectin protein expression after treatment with TGFß2. A20 message increased when the TLR4 pathway was inhibited in TM cells. In addition, TGFß2, a known inducer of fibrosis, increased fibronectin expression, while at the same time decreasing the expression of A20. We then overexpressed A20 in TM cells in order to test the effect on treatment with TGFß2, lipopolysaccharide (LPS), or cellular fibronectin extra domain A (cFN-EDA). Importantly, overexpression of A20 rescued the fibrotic response when TM cells were treated with TGFß2, LPS, or cFN-EDA. In situ hybridization was used to probe for A20 RNA expression in age-matched control (C57BL/6J) mice and mice that constitutively express the EDA isoform of fibronectin (B6.EDA+/+). In this novel mouse model of glaucoma, A20 RNA was increased versus age-matched control mice in a cyclic manner at 6 weeks and 1 year of age, but not at 8 months. Overall, these data suggest that A20 may work through a negative feedback mechanism attenuating the ability of TGFß2-TLR4 signaling to induce fibrosis.

The Roles Played by FP/EP3 Receptors During Pressure-lowering in Mouse Eyes Mediated by a Dual FP/EP3 Receptor Agonist.

Purpose: We investigated the intraocular pressure (IOP)-lowering effect of topical sepetaprost (SPT), a dual agonist of the FP and EP3 receptors. We explored whether certain receptors mediated the hypotensive effect of SPT and outflow facility changes in C57BL/6 mice (wild-type [WT]) and FP and EP3 receptor-deficient mice (FPKO and EP3KO mice, respectively). Methods: IOP was measured using a microneedle. Outflow facility was measured using a two-level, constant-pressure perfusion method. Results: SPT significantly reduced IOP for 8 hours after administration to WT mice. The 2-hour IOP reductions afforded by latanoprost were 15.3 ± 2.5, 1.8 ± 2.0, and 12.3 ± 2.4% in WT, FPKO, and EP3KO mice, respectively; the SPT figures were 13.6 ± 2.1, 5.9 ± 2.7, and 6.6 ± 2.6%, respectively. Latanoprost-mediated IOP reduction was significantly decreased in FPKO mice, and SPT-mediated IOP reduction was reduced in both FPKO and EP3KO mice. At 6 hours after administration, latanoprost did not significantly reduce the IOP in any tested mouse strain. SPT-mediated IOP reduction was reduced in both FPKO and EP3KO mice. IOP reduction at 6 hours was significantly higher after simultaneous administration of selective FP and EP3 receptor agonists, but IOP did not fall on administration of (only) a selective EP3 receptor agonist. SPT significantly increased outflow facility in WT mice, but less so in FPKO and EP3KO mice. Conclusions: The IOP-lowering effect of SPT lasted longer than that of latanoprost. Our data imply that this may be attributable to augmented outflow facility mediated by the FP and EP3 receptors.

Morphologic Changes in the Lamina Cribrosa Upon Intraocular Pressure Lowering in Patients With Normal Tension Glaucoma.

Purpose: The purpose of this study was to investigate whether the lamina cribrosa (LC) curve changes in response to intraocular pressure (IOP) reduction following administration of topical ocular hypotensive eye drops in eyes with normal tension glaucoma (NTG). Methods: Ninety-three eyes of 93 patients with treatment naïve NTG at initial examination and with ≥20% reduction from baseline IOP following administration of topical ocular hypotensive eye drops were included. Serial horizontal B-scan images of the optic nerve head (ONH) were obtained from each eye using enhanced depth imaging spectral domain optical coherence tomography (OCT) before and 1 year after IOP-lowering treatment. The LC curvature in each eye was assessed by measuring the LC curvature index (LCCI) in horizontal OCT B-scan images obtained at three (superior, central, and inferior) locations spaced equidistantly across the vertical optic disc diameter before and after IOP-lowering treatment. We evaluated the OCT detectible change in the LC curvature based on the interval change of LCCI to exceed the intersession standard deviation of 1.96 times and factors associated with the magnitude of the LCCI change in the eyes showing significant LC change. Results: IOP decreased from 15.7 ± 2.5 mm Hg at baseline to 11.2 ± 1.7 mm Hg after topical glaucoma medication. Among the 93 subjects, 62 (66.7%) eyes showed the significant reduction of the LCCI (interssetional change over 1.5) after the treatment; greater interssessional change of the LCCI after IOP reduction was associated with younger age (P = 0.020) and larger baseline LCCI (P < 0.001). Conclusions: The OCT detectible changes in LC curvature occurred in response to a modest decrease in the IOP in the naïve NTG eyes. The therapeutic benefit of these changes need to be assessed in longitudinal studies.