A MEK inhibitor arrests the cell cycle of human conjunctival fibroblasts and improves the outcome of glaucoma filtration surgery.

Better agents are needed to improve glaucoma filtration surgery outcomes compared to current ones. The purpose of this study is to determine whether mitogen-activated protein kinase kinase (MEK) inhibitors can effectively arrest the cell cycle of human conjunctival fibroblasts (HCFs) and inhibit the formation of fibrosis and scarring following glaucoma filtration surgery. A cell counting kit­8 assay revealed that the MEK inhibitor PD0325901 exhibited concentration-dependent growth inhibition of HCFs. Quantitative PCR, immunocytochemistry, and western blotting demonstrated decreased expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and increased expression of p27 in HCFs treated with PD0325901. Flow cytometry indicated that PD0325901 arrested the cell cycle of HCFs in the G0/1 phase. The cell-migration assay showed that HCF migration rate was significantly suppressed by PD0325901 exposure. Rabbits were divided into PD0325901-treatment and control groups, and glaucoma filtration surgery was performed. Although intraocular pressure did not differ between PD0325901-treatment and control groups, bleb height was greater in the treatment group. Histopathological evaluation revealed that fibrotic changes were significantly attenuated in the PD0325901-treatment group compared to the control group. In conclusion, the MEK inhibitor impedes HCF proliferation via cell-cycle arrest and may be beneficial for glaucoma filtration surgery by reducing bleb scarring.

Outcomes of Filtering Surgery Versus Clear Lens Extraction in Young Patients With Angle-Closure Glaucoma.

PURPOSE: To compare the effect of filtering surgery versus clear lens extraction in young patients with medically uncontrolled angle-closure glaucoma (ACG). DESIGN: Retrospective, nonrandomized, comparative, interventional study. METHODS: We reviewed the medical charts of patients with the following scenarios: (1) age ≤40 years; (2) diagnosis of ACG without cataract, including primary angle-closure glaucoma (PACG), nanophthalmic ACG, and ACG combined with retinal dystrophies; and (3) ACG undergoing filtering surgery or clear lens extraction. The main outcomes including intraocular pressure (IOP), number of medications, best-corrected visual acuity, and severe complications were extracted at the postoperative early (within 1 week) and late stage (>3 months) follow-up. RESULTS: Data from 160 eyes of 130 young patients with ACG were available. Eyes with 76 PACG, 12 nanophthalmic ACG, and 26 ACG with retinal diseases underwent filtering surgery, whereas eyes with 22 PACG, 12 nanophthalmic ACG, and 12 ACG with retinal diseases received clear lens extraction. Overall, filtering surgery and clear lens extraction resulted in significant but comparable IOP and drug reductions at the postoperative late stage in each ACG subgroup, with similar complete success rates between 2 treatments (all P > .05). Regarding the safety, filtering surgery and patients with retinal diseases were independent factors associated with postoperative malignant glaucoma (P < .05 in both multivariable logistic regression models). CONCLUSIONS: This study highlights that the efficacy of clear lens extraction is comparable to that of filtering surgery in medically uncontrolled ACG in young patients, but clear lens extraction is safer, especially for young patients with ACG comorbid with retinal diseases.

Incidence of glaucoma filtration surgery from disease onset of open-angle glaucoma.

AIMS: To investigate the rate and risk factors of undergoing glaucoma filtration surgery (GFS) in patients with newly diagnosed open-angle glaucoma (OAG). METHODS: This is a population-based historic cohort study, consisting of 9420 patients older than 45 years diagnosed with OAG during 1997-2010. Follow-up spanned from 1997 to 2017. We obtained data for trabeculectomy (TRE), deep sclerectomy (DS), and glaucoma drainage implant (GDI) surgeries from national administrative healthcare registers by hospital billing data. We plotted the cumulative incidence of GFS and carried out a multivariate Poisson regression analysis adjusted for age, sex, hospital district, systemic comorbidities, and the number of IOP-lowering drugs. We reported incidence rate ratios (IRR) with 95% confidence intervals (CI) for GFS after the onset of OAG. RESULTS: The cumulative incidence of GFS at 5 years from OAG onset was 3.1% and at 10 years 5.4%. Age over 80 years at baseline was associated with lower GFS incidence (IRR 0.51, CI 0.31-0.84). The number of IOP-lowering drugs in the first 2 years of treatment correlated with the risk of GFS increasing from (IRR 3.23, CI 2.32-4.50) for two drugs, (IRR 7.44, CI 5.28-10.47) for three and to (IRR 14.95, CI 10.38-21.52) for four drugs. CONCLUSION: This study characterized the treatment path of OAG from diagnosis to surgical intervention refining the role of GFS among glaucoma therapies.

MiR-29b Downregulation by p53/Sp1 Complex Plays a Critical Role in Bleb Scar Formation After Glaucoma Filtration Surgery.

Purpose: To investigate the function and mechanism of tumor protein p53 in pathological scarring after glaucoma filtration surgery (GFS) using human Tenon's fibroblasts (HTFs) and a rabbit GFS model. Methods: The expression of p53 in bleb scarring after GFS and transforming growth factor-ß (TGF-ß)-induced HTFs (myofibroblasts [MFs]) was examined by western blot and immunochemical analysis. The interaction between p53 and specificity protein 1 (Sp1) was investigated by immunoprecipitation. The role of p53 and Sp1 in the accumulation of collagen type I alpha 1 chain (COL1A1) and the migration of MFs was evaluated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), wound healing, and Transwell assay. The regulatory mechanisms among p53/Sp1 and miR-29b were detected via qRT-PCR, western blot, luciferase reporter assay, and chromatin immunoprecipitation assay. The therapeutic effect of mithramycin A, a specific inhibitor of Sp1, on scarring formation was evaluated in a rabbit GFS model. Results: p53 was upregulated in bleb scar tissue and MFs. p53 and Sp1 form a transcription factor complex that induces the accumulation of COL1A1 and promotes the migration of MFs through downregulation of miR-29b, a known suppressor of COL1A1. The p53/Sp1 axis inhibits miR-29b expression by the direct binding promoter of the miR-29b gene. Mithramycin A treatment attenuated bleb scar formation in vivo. Conclusions: The p53/Sp1/miR-29b signaling pathway plays a critical role in bleb scar formation after GFS. This pathway could be targeted for therapeutic intervention of pathological scarring after GFS. Translational Relevance: Our research indicates that inhibition of p53/Sp1/miR-29b is a promising therapeutic strategy for preventing post-GFS pathological scarring.

Minimally Invasive Glaucoma Surgery: Latest Developments and Future Challenges.

The development of minimally invasive glaucoma surgeries (MIGSs) was intended to provide safe and modestly efficacious modalities for early intervention of mild-to-moderate glaucoma, with minimal trauma and rapid recovery. They were mainly ab interno procedures that reduce intraocular pressure by facilitating the aqueous outflow by bypassing the trabecular meshwork resistance, reinforcing the uveoscleral flow via the supraciliary space, and reducing aqueous production by the ciliary body. While the cumulating evidence helps shape the role of the available MIGS, the exponential new development and advancement in this field has expanded the territory of MIGS. Apart from developing subconjunctival MIGS filtration devices (Xen gel stent and PRESERFLO MicroShunt), there is a tendency to revisit the "traditional" MIGS for alternative use and to modify the procedures with consideration of the fundamental aqueous outflow physiology. Combined MIGS has also been suggested, based on the theory that their different mechanisms may provide additive or synergistic effects. The advancement of laser procedures is also promising and could supplement unmet needs along the glaucoma treatment algorithm. This review examines the broad array of MIGS, updates the recent findings, discusses their potential alternative applications, and explores future challenges.

[Review by the French Glaucoma Society on the roles of new surgical techniques in glaucoma]. / Mise au point de la Société française du glaucome sur la place des nouvelles techniques chirurgicales dans le glaucome.

The surgical management of glaucoma has been enriched in recent years by the arrival of new surgical techniques as a group known as MIGS (minimally invasive glaucoma surgery). The objective of these new techniques is to reduce intraocular pressure (IOP) while limiting the risk of complications of conventional filtering surgery and allowing faster visual recovery. MIGS can be classified into three main categories depending on the route used to promote the outflow of aqueous humor: the trabecular route, the suprachoroidal route and the subconjunctival route. MIGS using the subconjunctival route are also called minimally invasive bleb surgery (MIBS). These new techniques do not replace conventional filtering surgery, which remains the gold standard technique, but now offer new alternatives for the surgical management of glaucoma patients in combination with cataract surgery or as stand-alone procedures.

A machine learning approach to predict the glaucoma filtration surgery outcome.

This study aimed at predicting the filtration surgery (FS) outcome using a machine learning (ML) approach. 102 glaucomatous patients undergoing FS were enrolled and underwent ocular surface clinical tests (OSCTs), determination of surgical site-related biometric parameters (SSPs) and conjunctival vascularization. Break-up-time, Schirmer test I, corneal fluorescein staining, Meibomian gland expressibility; conjunctival hyperemia, upper bulbar conjunctiva area of exposure, limbus to superior eyelid distance; and conjunctival epithelial and stromal (CET, CST) thickness and reflectivity (ECR, SCR) at AS-OCT were considered. Successful FS required a 30% baseline intraocular pressure reduction, with values ≤ 18 mmHg with or without medications. The classification tree (CT) was the ML algorithm used to analyze data. At the twelfth month, FS was successful in 60.8% of cases, whereas failed in 39.2%. At the variable importance ranking, CST and SCR were the predictors with the greater relative importance to the CART tree construction, followed by age. CET and ECR showed less relative importance, whereas OSCTs and SSPs were not important features. Within the CT, CST turned out the most important variable for discriminating success from failure, followed by SCR and age, with cut-off values of 75 µm, 169 on gray scale, and 62 years, respectively. The ROC curve for the classifier showed an AUC of 0.784 (0.692-0.860). In this ML approach, CT analysis found that conjunctival stroma thickness and reflectivity, along with age, can predict the FS outcome with good accuracy. A pre-operative thick and hyper-reflective stroma, and a younger age increase the risk of FS failure.

[Attaching importance to the health economic evaluation of minimally invasive glaucoma surgery].

Compared to traditional filtration surgery, minimally invasive glaucoma surgery (MIGS) offers several advantages, including smaller incisions, more effective intraocular pressure reduction, higher safety levels, fewer surgical complications, faster postoperative recovery, and reduced postoperative use of antiglaucoma drugs. MIGS has gained rapid popularity both domestically and internationally due to its easier operation, shorter learning curve, and reduced operation time. Considering the current clinical promotion of MIGS and the application of health economic evaluation in the glaucoma field, this article proposes the need for an emphasis on the health economic evaluation of MIGS. Conducting research in this area will provide valuable insights for related clinical diagnosis and treatment, medical pricing, and medical insurance payment, and help to further disseminate MIGS, so as to offer clinical benefits, which are aligned with national conditions and economic viability.

Suture manipulation post-trabeculectomy: A practical guide.

Background: Trabeculectomy is the gold standard filtration surgery for diverting aqueous from anterior chamber to the subconjunctival space. More than the surgery, postoperative follow-ups and management of the blebs play a critical role in the long-term success. This video is aimed at showing the real-world management of blebs postoperatively. Purpose: This video will serve as a practical guide to the postoperative management of trabeculectomy blebs with specific focus on the suture manipulation. Synopsis: This video will demonstrate various suturing techniques of trabeculectomy and their manipulation in the postoperative period. Complications related to each will be discussed. Highlights: We demonstrate how to place and remove, releasable, and fixed sutures. We also address the practical points on why and when to remove the sutures. Suture-related complications and their management have been shown along with practical examples. Video Link: https://youtu.be/2WFQJAPyOvY.

Effects of Ripasudil, a Rho-Kinase Inhibitor, on Scar Formation in a Mouse Model of Filtration Surgery.

PURPOSE: Glaucoma is a leading cause of blindness worldwide. Characteristic changes occur in the optic nerve and visual field of patients with glaucoma; optic nerve damage can be mitigated by lowering intraocular pressure. Treatment modalities include drugs and lasers; filtration surgery is necessary for patients with insufficient intraocular pressure reduction. Scar formation often contributes to glaucoma filtration surgery failure by increasing fibroblast proliferation and activation. Here, we examined the effects of ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, on postoperative scar formation in human Tenon's fibroblasts. METHODS: Collagen gel contraction assays were used to compare contractility activity among ripasudil and other anti-glaucoma drugs. The effect of Ripasudil in combination with other anti-glaucoma drugs and transforming growth factor-ß (TGF-ß), latanoprost and timolol-induce contractions were also tested in this study. Immunofluorescence and Western blotting were used to study the expression of factors relating scarring formation. RESULTS: Ripasudil inhibited contraction in collagen gel assay and reduced α-smooth muscle actin (SMA) and vimentin (scar formation-related factors) expression, which was inversely promoted by latanoprost, timolol or TGF-ß. Ripasudil also inhibited contraction on TGF-ß, latanoprost and timolol-induced contraction. Furthermore, we investigated the effects of ripasudil on postoperative scarring in a mouse model; ripasudil suppressed postoperative scar formation by altering the expression of α-SMA and vimentin. CONCLUSIONS: These results suggest that ripasudil, ROCK inhibitor may inhibit excessive fibrosis after glaucoma filtering surgery vis inhibition the transdifferentiation of tenon fibroblast into myofibroblast and may have a potential effect as anti-scarring for glaucoma filtration surgery.

Clinicopathological features of corneal invasion by filtering bleb.

PURPOSE: To describe the clinicopathological characteristics and explore the possible etiology of cornea invasion by filtering bleb (CIFB) after filtering surgery. METHODS: We reviewed 22 patients treated for CIFB between March 2005 and March 2022. The patients were followed up for more than 1 year. Slit-lamp examination, optical coherence tomography (OCT), ultrasound biomicroscopy, and histopathological examination were performed to observe the morphology of the bleb and depth of corneal invasion. Depending on the severity of the lesion, treatments consisting of local massage, acupuncture separation, or surgical resection were administered. RESULTS: The mean age of the patients was 56.3 ± 8.8 years. All patients underwent filtering surgery in the moderate or advanced stage of glaucoma. The filtering bleb was closely connected with the cornea, and its posterior boundary was locally adhered. Forward displacement of the internal opening of the filtering bleb was found in 4 of 7 surgically treated patients. OCT and pathological examination showed that the filtering blebs invaded the corneal stroma. Removal of the adhesion of the posterior boundary of the filtering bleb by different treatment methods successfully improved the patients' conditions. CONCLUSION: Filtering blebs can invade the corneal stroma. Adhesion of the posterior boundary and forward displacement of the internal opening of the filtering bleb are the possible causes of CIFB. Removal of the adhesion of the posterior boundary of the filtering bleb can halt the progression of CIFB.

Analysis of the Systemic Exposure of Mitomycin C Used in Glaucoma Filtering Surgery Among Women in the Reproductive Age Group.

PURPOSE: Systemic absorbtion of topically applied mitomycin C (MMC) during trabeculectomy needs to be evaluated to look for any systemic toxicity, which might be a major concern in certain conditions like pregnancy. METHODS: After obtaining ethical committee clearance, female patients in the reproductive age group undergoing trabeculectomy with MMC were included. Pregnant/lactating patients, patients with any systemic illness were excluded. During trabeculectomy, 0.02% MMC was applied subconjunctivally for 2 min and then washed. Blood samples were withdrawn at 1, 2, 4, 8, 12, and 24 hrs after the surgery and analyzed of MMC levels using Liquid chromatography-tandem mass spectroscopy (LC-MS/MS). RESULTS: The mean age of the participants was 29 ± 12 years. MMC was not detected in any of the plasma samples analyzed as it was less than the detection limit (<1.56 ng/mL) of the employed LC-MS/MS assay. CONCLUSION: It can be deduced that the systemic absorption of MMC is negligible or the plasma concentration is less than 1.56 ng/ml (1000 times less than the concentration where systemic toxicity was not observed).

The anti-scar effect of tyrosine-kinase inhibitor nintedanib in experimental glaucoma filtration surgery in rabbits.

PURPOSE: To investigate the efficacy of nintedanib on preventing postoperative scar in formation following glaucoma filtering surgery (GFC) in rabbits in comparison with Mitomycin-C (MMC). DESIGN: Experimental Animal Study. METHODS: 24 New Zealand rabbits were divided randomly into 3 groups as Sham, Nindetanib and MMC(n = 8). Limbal-based trabeculectomy was performed on the right eyes of the rabbits. Left eyes that did'nt undergo surgery were included in the control group (n = 8). Following surgery, Intraocular pressures (IOP), postoperative complications and morphological changes in the bleb were evaluated. On the 28th day, eight eyes from each group were enucleated and histologically and immunohistochemically analyzed. Matrix metalloproteinase-2 (MMP-2), Transforming Growth Factor-1 (TGF-B1) and alpha-smooth muscle actin (a-SMA) were evaluated. RESULTS: It was observed that nintedanib has no side effects and reduces subconjunctival fibrosis. Postoperative IOP values in the Nindetanib group were lower than the other groups (p < 0.05). The longest bleb survival was observed in the Nintedanib group and the shortest in the Sham group (p < 0.001). Conjunctival vascularity and inflammation was reduced in the Nintedanib group compared to the Sham group (p < 0.05). The highest subconjunctival fibrosis was observed in the Sham group and the least in the Nintedanib group (p < 0.05). Although the fibrosis score was found lower in the Nintedanib group compared to the MMC(p > 0.05). α-SMA TGF-ß1, MMP-2 expressions were similar in Nintedanib and MMC groups (p > 0.05), however, it was observed that significantly decreased in both groups compared to Sham group (p < 0.05). CONCLUSION: It has been observed that Nindetanib suppress fibroblast proliferation Thus, It may be a drug that can prevent subconjunctival fibrosis in GFC.

Penetrating canaloplasty in angle-closure glaucoma secondary to iridocorneal endothelial syndrome following multiple failed filtering surgeries: A case report.

RATIONALE: Angle-closure glaucoma secondary to iridocorneal endothelial syndrome (ICE) is challenging to treat, especially in patients who have already undergone multiple surgical procedures. Long-term success is difficult to achieve with traditional filtration surgery again. This case report describes a novel nonbleb-dependent surgery for managing such a young patient. PATIENT CONCERNS: A 30-year-old male with glaucoma secondary to ICE was referred to West China Hospital, Sichuan University for uncontrolled intraocular pressure following multiple failed filtering surgeries under maximum topical antiglaucoma medications in his right eye. DIAGNOSES: The patient was diagnosed with angle-closure glaucoma secondary to ICE in the right eye based on a series of ophthalmic examinations. INTERVENTIONS: Penetrating canaloplasty was performed to manage glaucoma secondary to ICE in the right eye. OUTCOMES: The patient's visual acuity improved, the intraocular pressure was reduced to 11 to 15 mm Hg through 30 months of follow-up, and no antiglaucoma medication or additional surgical procedures were needed. LESSONS: Penetrating canaloplasty could be considered as an option for the treatment of refractory angle-closure glaucoma secondary to ICE with extensive angle adhesion.

Review of glaucoma management in France.

PURPOSE: To conduct a review of glaucoma management in France. METHOD: A 15-question survey was sent to ophthalmologists listed in the journal Réalités Ophtalmologiques and the Syndicat National des Ophtalmologues de France. RESULTS: 459/471 responses were analyzed. Gonioscopy was performed by 64.7% of respondents with a Goldmann three-mirror lens, by 51.4% with a four-mirror lens, and 8.2% preferred to perform the procedure with anterior segment imaging. The visual field was reported to be interpreted without difficulty by 87.8% of the practitioners, and 54.0% utilize a progression software. Ultrasound biomicroscopy was reported to be interpreted without difficulty by 20.0% of practitioners. In cases of severe ocular hypertonia with flat bleb in early postoperative trabeculectomy, 61.7% chose ocular massage as a first-line treatment, 52.9% chose laser suture lysis, 50.5% utilized needling, and 24.8% employed hypotonizing eyedrops. In case of severe ocular hypertonia with flat bleb in early postoperative deep sclerectomy, 53.2% chose goniopuncture as their first treatment, 34.4% employed needling, 31.8% utilized ocular massage, and 23.3% chose hypotonizing eyedrops. The selective laser trabeculoplasty is used as soon as the diagnosis is made by 37.5%, in association with a mono or dual therapy by 93.2%, after trying different combinations of eyedrops by 45.5%, when the visual field deteriorates despite a normalized intraocular pressure by 46.6%, and in cases of hypertonia after filtering surgery by 19.2%. Concerning management for primary angle-closure glaucoma, 80.8% considered peripheral iridotomy, and 18.7% utilized cataract surgery. CONCLUSION: The diversity of responses concerning glaucoma management should draw attention to the need for standardized practices.

New glaucoma drainage implants available to glaucoma surgeons.

PURPOSE OF REVIEW: Glaucoma drainage device (GDD) implantation surgery is commonly performed by glaucoma specialists to treat complex and refractory glaucomas. Relative safety and efficacy data from randomized controlled trials conducted in the last two decades have sparked the interest in GDDs as possible surgical options earlier in the course of the disease than has traditionally been practiced. However, until recently, advances in the design and techniques of GDD surgery have fallen short of this increasing interest. RECENT FINDINGS: Most recently, new GDDs that possess novel design features have become available to glaucoma specialists. Two of these new devices are the Ahmed ClearPath and the Paul glaucoma implant. These devices have demonstrated promising outcomes that are comparable to those of traditional implants. Additionally, given their unique respective features, these devices may streamline surgical technique due to ease of insertion and afford better safety and efficacy outcomes in certain patients. SUMMARY: The recent introduction of new GDDs has been long awaited by glaucoma surgeons. Although early results are promising, long-term data and comparison of outcomes to those of traditional filtering surgery and commonly implanted devices are needed before these devices can be the new standard of care in glaucoma tube shunt surgery.

Effects of topical docosahexaenoic acid on postoperative fibrosis in an animal model of glaucoma filtration surgery.

PURPOSE: The aim of this study was to evaluate docosahexaenoic acid (DHA) as a potential antifibrotic agent after glaucoma filtration surgery (GFS) in rats. METHODS: A total of 36 10-week-old Brown Norway rats underwent GFS. Animals were equally divided into three groups: a control group, a DHA group and a mitomycin C (MMC) group. Intraocular pressure (IOP) was measured using a dynamic rebound tonometer, and a photograph of the surgical site was taken on days 1, 3, 7, 10, 14 and 17. The incorporation of DHA into fibroblasts was evaluated by gas chromatography. The expression of alfa-smooth muscle actin (α-SMA) and Smad proteins was assessed by Western blotting. RESULTS: IOP decreased after surgery in animals from the three groups on day 1 after surgery. Over time, IOP remained lower in the DHA and MMC groups than in the control group (median [interquartile range] 8.0 [7.0-8.0] and 8.0 [7.3-8.0] mmHg vs. 9.0 [8.0-9.0] mmHg, respectively; p < 0.001). Bleb area in the DHA and MMC groups remained larger than that of the control group from day 7 to day 14 (3.9 [2.9-5.2] and 3.5 [2.3-4.4] mm2 vs. 2.3 [2.0-2.8] mm2 , respectively; p = 0.0021). We did not observe any change in DHA concentrations in the fibroblasts of the DHA group compared with the other groups. CONCLUSION: The impact of DHA on IOP and bleb area was similar to that of MMC. The mechanisms of action of DHA in rat eye fibroblasts deserve further investigation.