Analysis aqueous humor lipid profile of neovascular glaucoma secondary to diabetic retinopathy and lipidomic alteration response to anti-VEGF treatment.

The objective of this study was to examine the lipid spectrum of aqueous humor (AH) in patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy and to investigate the lipid alteration response to anti-vascular endothelial growth factor (anti-VEGF) treatment. Lipidomic analysis using ultra-high performance liquid chromatography-tandem mass spectrometry was conducted to compare the lipid profiles of the AH in NVG patients with those of a control group. Lipid changes in the AH of NVG patients before and after intravitreal conbercept injections were also evaluated. The identification of lipids showing differential expression was accomplished through both multivariate and univariate analyses. This study included 13 NVG patients and 20 control subjects. Based on LipidSearch software, 639 lipid species across 33 lipid classes were detected in the participants' AH. The combination of univariate and multivariate statistical analyses yielded 53 differentially expressed lipids (VIP >1 and P < 0.05). In addition, 9 lipids were found to be differentially expressed before and after the intravitreal conbercept injections in the NVG patients. Significant alterations in the metabolic pathways of glycerophospholipid and glycerolipid exhibited notable changes. Our results highlighted the lipid changes in patients' AH in relation to the progression of NVG, and indicated that the modified lipids could potentially be utilized as therapeutic targets for NVG.

Benefits of a combined surgical technique for patients with secondary neovascular glaucoma.

OBJECTIVE: Aim: To assess the effectiveness and safety of the proposed surgical technique for treating secondary neovascular glaucoma. PATIENTS AND METHODS: Materials and Methods: We examined 28 eyes of 28 patients (16 women and 12 men), aged 46}7,2 years, with secondary neovascular glaucoma. All patients underwent a comprehensive ophthalmological examination before and during treatment. Two-stage treatment was applied to all patients. At the first stage - performed an advanced technique of non-penetrating deep sclerectomy while administering anti-VEGF (anti-vascular endothelial growth factor) intravitreal or intracameral injections. At the second - we performed externalization of Schlemm's canal followed by YAG laser trabeculectomy. Statistical analysis of the results was used the SPSS v. 11.0, MedStat v.15.1 software package for medical and biological research. RESULTS: Results: The proposed surgical technique, leads to a gradual decrease in intraocular pressure (IOP) and regression of the iris and anterior chamber angle neovascularization. The postoperative course was uneventful for all the patients. In the early postoperative period, the IOP was observed to be normalized in all the eyes. The IOP ranged from 12 to 16 mm Hg. The neovascularization regression occurred (in 100 % of cases) within 5-7 days. CONCLUSION: Conclusions: Gradual reduction of IOP reduces intraoperative complications. Intravitreal or intracameral injections of anti-proliferative agents contribute to the regression of neovascularization and further gradual reduction of IOP. Performing a laser trabeculectomy in the area where a non-penetrating deep sclerectomy was previously performed creates new pathways for the outflow of intraocular fluid from the anterior chamber and reduces the risks of reintervention.

Anti-vascular endothelial growth factor for neovascular glaucoma.

BACKGROUND: Neovascular glaucoma (NVG) is a potentially blinding, secondary glaucoma. It is caused by the formation of abnormal new blood vessels, which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) medications are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGF medications for the control of intraocular pressure (IOP) in NVG. OBJECTIVES: To assess the effectiveness of intraocular anti-VEGF medications, alone or with one or more types of conventional therapy, compared with no anti-VEGF medications for the treatment of NVG. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register); MEDLINE; Embase; PubMed; and LILACS to 19 October 2021; metaRegister of Controlled Trials to 19 October 2021; and two additional trial registers to 19 October 2021. We did not use any date or language restrictions in the electronic search for trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of people treated with anti-VEGF medications for NVG. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for trials, extracted data, and assessed risk of bias, and the certainty of the evidence. We resolved discrepancies through discussion. MAIN RESULTS: We included five RCTs (356 eyes of 353 participants). Each trial was conducted in a different country: two in China, and one each in Brazil, Egypt, and Japan. All five RCTs included both men and women; the mean age of participants was 55 years or older. Two RCTs compared intravitreal bevacizumab combined with Ahmed valve implantation and panretinal photocoagulation (PRP) with Ahmed valve implantation and PRP alone. One RCT randomized participants to receive an injection of either intravitreal aflibercept or placebo at the first visit, followed by non-randomized treatment according to clinical findings after one week. The remaining two RCTs randomized participants to PRP with and without ranibizumab, one of which had insufficient details for further analysis. We assessed the RCTs to have an unclear risk of bias for most domains due to insufficient information to permit judgment.   Four RCTs examined achieving control of IOP, three of which reported our time points of interest. Only one RCT reported our critical time point at one month; it found that the anti-VEGF group had a 1.3-fold higher chance of achieving control of IOP at one month (RR 1.32, 95% 1.10 to 1.59; 93 participants) than the non-anti-VEGF group (low certainty of evidence). For other time points, one RCT found a three-fold greater achievement in control of IOP in the anti-VEGF group when compared with the non-anti-VEGF group at one year (RR 3.00; 95% CI:1.35 to 6.68; 40 participants). However, another RCT found an inconclusive result at the time period ranging from 1.5 years to three years (RR 1.08; 95% CI: 0.67 to 1.75; 40 participants).  All five RCTs examined mean IOP, but at different time points. Very-low-certainty evidence showed that anti-VEGFs were effective in reducing mean IOP by 6.37 mmHg (95% CI: -10.09 to -2.65; 3 RCTs; 173 participants) at four to six weeks when compared with no anti-VEGFs.  Anti-VEGFs may reduce mean IOP at three months (MD -4.25; 95% CI -12.05 to 3.54; 2 studies; 75 participants), six months (MD -5.93; 95% CI -18.13 to 6.26; 2 studies; 75 participants), one year (MD -5.36; 95% CI -18.50 to 7.77; 2 studies; 75 participants), and more than one year (MD -7.05; 95% CI -16.61 to 2.51; 2 studies; 75 participants) when compared with no anti-VEGFs, but such effects remain uncertain. Two RCTs reported the proportion of participants who achieved an improvement in visual acuity with specified time points. Participants receiving anti-VEGFs had a 2.6 times (95% CI 1.60 to 4.08; 1 study; 93 participants) higher chance of improving visual acuity when compared with those not receiving anti-VEGFs at one month (very low certainty of evidence). Likewise, another RCT found a similar result at 18 months (RR 4.00, 95% CI 1.33 to 12.05; 1 study; 40 participants).  Two RCTs reported the outcome, complete regression of new iris vessels, at our time points of interest. Low-certainty evidence showed that anti-VEGFs had a nearly three times higher chance of complete regression of new iris vessels when compared with no anti-VEGFs (RR 2.63, 95% CI 1.65 to 4.18; 1 study; 93 participants). A similar finding was observed at more than one year in another RCT (RR 3.20, 95% CI 1.45 to 7.05; 1 study; 40 participants).  Regarding adverse events, there was no evidence that the risks of hypotony and tractional retinal detachment were different between the two groups (RR 0.67; 95% CI: 0.12 to 3.57 and RR 0.33; 95% CI: 0.01 to 7.72, respectively; 1 study; 40 participants). No RCTs reported incidents of endophthalmitis, vitreous hemorrhage, no light perception, and serious adverse events. Evidence for the adverse events of anti-VEGFs was low due to limitations in the study design due to insufficient information to permit judgments and imprecision of results due to the small sample size. No trial reported the proportion of participants with relief of pain and resolution of redness at any time point. AUTHORS' CONCLUSIONS: Anti-VEGFs as an adjunct to conventional treatment could help reduce IOP in NVG in the short term (four to six weeks), but there is no evidence that this is likely in the longer term. Currently available evidence regarding the short- and long-term effectiveness and safety of anti-VEGFs in achieving control of IOP, visual acuity, and complete regression of new iris vessels in NVG is insufficient. More research is needed to investigate the effect of these medications compared with, or in addition to, conventional surgical or medical treatment in achieving these outcomes in NVG.

A systematic review and meta-analysis of randomised controlled trials in the management of neovascular glaucoma: absence of consensus and variability in practice.

PURPOSE: Neovascular glaucoma (NVG) is characterised by neovascularisation of the angle and therefore elevated intraocular pressure (IOP). This results in progressive optic neuropathy and loss of visual acuity. Treatment aims to reduce IOP in order to prevent optic nerve damage. A systematic review was completed synthesising results from randomised control trials (RCTs) comparing interventions for the management of NVG and their efficacy and safety. METHODS: Data was sourced from Web of Science, Embase and Medline after 1st January 2000. The primary outcome measures were mean IOP at follow-up and success rate. The secondary outcomes included mean IOP lowering medications and total complications. A meta-analysis was completed on comparative studies using Revman (version 5.4). RESULTS: For the two studies comparing Ahmed glaucoma valve (AGV) + pan-retinal photocoagulation (PRP) vs AGV + PRP + intra-vitreal bevacizumab (IVB), there was no difference in mean IOP or odds of success from the meta-analysis. From the 4 studies examining the utilisation of anti-vascular endothelial growth factor (anti-VEGF), one study showed lower mean IOP at 1 (p = 0.002) and 3 months (p = 0.033) for IVB vs sham injection. In the 2 studies studying transcleral diode laser (TDL), there were no significant findings. From the 4 studies looking at trabeculectomy (trab), lower mean IOP at 6 (p = 0.001), 9 (p = 0.01), 12 (p = 0.02) and 18 months (p = 0.004) was shown for intra-vitreal ranibizumab (IVR) + PRP + visco-trabeculectomy vs IVR + PRP + trab, and a significantly lower mean IOP was present in the Baerveldt group vs trab at 6 months (p = 0.03). In the 2 studies investigating the AGV, there was a lower mean IOP at 1 month (p = 0.01) in the AGV + triamcinolone (TCA) group. The risk of bias was low for 4 studies, high for 4 studies and 6 studies had some concerns. CONCLUSION: This is the first meta-analysis of RCTs in the management of neovascular glaucoma. The lack of high-quality evidence contributes to the lack of consensus in managing NVG. Our results highlight modern treatment strategies and the need for better powered RCTs with long-term follow-up in order to establish optimal treatment modalities and true patient outcomes.

RISK FACTORS FOR SURGERY OR BLINDNESS IN NEOVASCULAR GLAUCOMA EYES TREATED WITH ANTI-VEGF INJECTIONS BY A RETINA SPECIALIST.

PURPOSE: To determine baseline patient characteristics that predict the need for glaucoma surgery or blindness in eyes with neovascular glaucoma (NVG) despite intravitreal antivascular endothelial growth factor therapy. METHODS: This is a retrospective cohort study of patients with NVG who had not previously received glaucoma surgery and were treated with intravitreal antivascular endothelial growth factor injections at the time of diagnosis, from September 8, 2011, to May 8, 2020, at a large, retina subspecialty practice. RESULTS: Of 301 newly presenting NVG eyes, 31% required glaucoma surgery and 20% progressed to no light perception vision despite treatment. Patients with intraocular pressure >35 mmHg ( P < 0.001), two or more topical glaucoma medications ( P = 0.003), worse than 20/100 vision ( P = 0.024), proliferative diabetic retinopathy ( P = 0.001), eye pain or discomfort ( P = 0.010), and new patient status ( P = 0.015) at the time of NVG diagnosis were at a higher risk of glaucoma surgery or blindness regardless of antivascular endothelial growth factor therapy. The effect of panretinal photocoagulation was not statistically significant in a subgroup analysis of patients without media opacity ( P = 0.199). CONCLUSION: Several baseline characteristics at the time of presentation to a retina specialist with NVG seem to portend a higher risk of uncontrolled glaucoma despite the use of antivascular endothelial growth factor therapy. Prompt referral of these patients to a glaucoma specialist should be strongly considered.

[Changes of cytokines in the aqueous humor of neovascular glaucoma at the angle-closure stage].

Objective: To evaluate the concentration of cytokines in the aqueous humor of neovascular glaucoma (NVG) patients at the angle-closure stage in different treatment periods and its relationship with recurrence. Methods: A prospective case-control study. Angle-closure stage NVG patients who came to Peking University Third Hospital from September 2018 to September 2019 were enrolled and followed-up for at least 12 months. Patients received triple sequential therapy, including anti-vascular endothelium growth factor (VEGF) injection, trabeculectomy, and panretinal photocoagulation. The aqueous humor before anti-VEGF treatment, before trabeculectomy, and during recurrence was collected. Multiplex bead immunoassay was applied to measure the concentration of 45 cytokines including VEGF, interleukin (IL), and chemokine. The relevant data were compared with the values of 25 proliferative diabetic retinopathy (PDR) patients and 24 age-related cataract patients undergoing phacoemulsification as controls. The concentration of cytokines was presented as M (Q1, Q3). The nonparametric Kruskal-Wallis H test was applied to compare the cytokine concentration between the NVG group and controls. The difference between the recurrence and non-recurrence groups was compared with the Mann-Whitney U test. Results: The average age of NVG patients was (60±11) years, and there were 22 males and 10 females. No significant differences were found in age and gender between the NVG group and the two control groups (both P>0.05). The median concentrations of VEGF in the NVG group before anti-VEGF treatment, before trabeculectomy, and after recurrence were 2 151.3 (1 433.1, 4 280.0) ng/L, 655.4 (287.3, 836.3) ng/L and 2 003.4 (1 603.1, 2 468.9) ng/L respectively. The concentrations of VEGF before anti-VEGF treatment and after recurrence in the NVG group were significantly higher than the PDR group [453.8 (189.9, 595.8) ng/L] and the cataract group [143.5 (112.7, 269.8) ng/L] (all P<0.05). The median concentration of programmed cell death protein ligand 1 (PD-L1) was 38.9 (22.4, 50.6) ng/L before anti-VEGF treatment, higher than that in the PDR group [12.0 (6.3, 20.1) ng/L] and the cataract group [14.6 (11.4, 19.3) ng/L]. The median concentration of fractalkine was 242.7 (189.0, 306.7) ng/L, higher than that in the PDR group [131.1 (119.1, 157.6) ng/L] and the cataract group [116.7 (10.2, 135.9) ng/L]. The median concentration of IL-7 was 18.0 (12.0, 32.7) ng/L, higher than that in the PDR group [7.7 (2.0, 10.8) ng/L] and the cataract group [3.3 (1.9, 6.8) ng/L]. The median concentration of eotaxin was 84.0 (52.4, 122.7) ng/L, higher than that in the PDR group [26.6 (17.1, 72.3) ng/L] and the cataract group [7.1 (5.6, 14.8) ng/L]. The median concentration of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was 3.6 (2.8, 6.4) ng/L, higher than that in the cataract group [1.1 (0.3, 2.3) ng/L]. All the differences were statistically significant (all P<0.05). There were no significant differences between the NVG and control groups in other cytokines or other treatment periods (all P>0.05). Six NVG patients suffered recurrence during the follow-up. The baseline concentration of IL-7 of these patients [10.5 (8.4, 16.0) ng/L] was significantly lower than that in patients who did not have recurred disease [22.7 (15.7, 34.1) ng/L] (Z=-2.74, P<0.01). Conclusions: In the angle-closure stage of NVG patients, the concentrations of VEGF, PD-L1, fractalkine, IL-7, eotaxin, and TRAIL in the aqueous humor significantly increase during the onset of disease. Lower IL-7 may indicate a recurring tendency.

Comparison of conbercept and ranibizumab combined mitomycin C-augmented trabeculectomy for neovascular glaucoma.

PURPOSE: To compare the efficacy and security of conbercept and ranibizumab combined with trabeculectomy and panretinal photocoagulation for neovascular glaucoma (NVG). METHODS: One hundred and sixty patients with NVG were randomly divided into a conbercept group comprised of 80 patients and a ranibizumab group comprised of 80 patients. The postoperative and preoperative visual acuities, intraocular pressures frequency of anti-glaucoma medications, and surgical complications were recorded. The expressions of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (FLT-1), and placenta-like growth factor (PLGF) in the aqueous humor were determined using an enzyme-linked immunosorbent assay. Examining the fundus and obtaining photographs used indirect ophthalmoscopy. Kaplan-Meier and log-rank analyses estimated the success rates. RESULTS: All patient follow-up periods were at 1 year. The differences observed in IOP and the frequencies of anti-glaucoma medications at various follow-up time points were not statistically significant (all P > 0.05). The differences observed in both the group visual acuities at various follow-up time points were not statistically significant (P > 0.05). Rates of surgery complications were 18.75% and 25.00% in the conbercept group and ranibizumab group, respectively. The expressions of VEGF, FLT-1, and PLGF significantly decreased (all P < 0.05). The recurrence percentages were 30.00% and 36.25% after conbercept and ranibizumab treatment, respectively. CONCLUSION: The conbercept effects were similar with that of ranibizumab. Intravitreal injection of conbercept was effective for NVG treatment, which provides a new therapeutic drug for NVG treatment.

Anti-vascular endothelial growth factor for neovascular glaucoma.

BACKGROUND: Neovascular glaucoma (NVG) is a potentially blinding, secondary glaucoma. It is caused by the formation of abnormal new blood vessels, which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) medications are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGF medications for the control of intraocular pressure (IOP) in NVG. OBJECTIVES: To assess the effectiveness of intraocular anti-VEGF medications, alone or with one or more type of conventional therapy, compared with no anti-VEGF medications for the treatment of NVG. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register); MEDLINE; Embase; PubMed; and LILACS to 22 March 2019; metaRegister of Controlled Trials to 13 August 2013; and two additional trial registers to 22 March 2019. We did not use any date or language restrictions in the electronic search for trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people treated with anti-VEGF medications for NVG. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for trials, extracted data, and assessed risk of bias, and the certainty of the evidence. We resolved discrepancies through discussion. MAIN RESULTS: We included four RCTs (263 participants) and identified one ongoing RCT. Each trial was conducted in a different country: China, Brazil, Egypt, and Japan. We assessed the trials to have an unclear risk of bias for most domains due to insufficient information. Two trials compared intravitreal bevacizumab combined with Ahmed valve implantation and panretinal photocoagulation (PRP) with Ahmed valve implantation and PRP. We did not combine these two trials due to substantial clinical and statistical heterogeneity. One trial randomised participants to receive an injection of either an intravitreal anti-VEGF medication or placebo at the first visit, followed by non-randomised treatment according to clinical findings after one week. The last trial randomised participants to PRP with and without ranibizumab, but details of the study were unavailable for further analysis. Two trials that examined IOP showed inconsistent results. One found inconclusive results for mean IOP between participants who received anti-VEGF medications and those who did not, at one month (mean difference [MD] -1.60 mmHg, 95% confidence interval [CI] -4.98 to 1.78; 40 participants), and at one year (MD 1.40 mmHg, 95% CI -4.04 to 6.84; 30 participants). Sixty-five percent of the participants with anti-VEGF medications achieved IOP ≤ 21 mmHg, versus 60% without anti-VEGF medications. In another trial, those who received anti-VEGF medications were more likely to reduce their IOP than those who did not receive them, at one month (MD -6.50 mmHg, 95% CI -7.93 to -5.07; 40 participants), and at one year (MD -12.00 mmHg, 95% CI -16.79 to -7.21; 40 participants). Ninety-five percent of the participants with anti-VEGF medications achieved IOP ≤ 21 mmHg, versus 50% without anti-VEGF medications. The certainty of a body of evidence was low for this outcome due to limitations in the design and inconsistency of results between studies. Post-operative complications included anterior chamber bleeding (3 eyes) and conjunctival hemorrhage (2 participants) in the anti-VEGF medications group, and retinal detachment and phthisis bulbi (1 participant each) in the control group. The certainty of evidence is low due to imprecision of results and indirectness of evidence. No trial reported the proportion of participants with improvement in visual acuity, proportion of participants with complete regression of new iris vessels, or the proportion of participants with relief of pain and resolution of redness at four- to six-week, or one-year follow-up. AUTHORS' CONCLUSIONS: Currently available evidence is uncertain regarding the long-term effectiveness of anti-VEGF medications, such as intravitreal ranibizumab or bevacizumab or aflibercept, as an adjunct to conventional treatment in lowering IOP in NVG. More research is needed to investigate the long-term effect of these medications compared with, or in addition to, conventional surgical or medical treatment in lowering IOP in NVG.

Ahmed glaucoma valve implantation versus suprachoroidal silicone tube implantation following the injection of bevacizumab into the anterior chamber in patients with neovascular glaucoma.

PURPOSE: This study compared the efficacy and safety of Ahmed glaucoma valve (AGV) implantation versus suprachoroidal silicone tube (SST) implantation after the injection of bevacizumab into the anterior chamber in patients with neovascular glaucoma. METHODS: Patients were randomly assigned to undergo AGV or SST implantation. Bevacizumab was injected into the anterior chamber at a dosage of 1.25 mg/0.1 mL, 1 week before surgery. Intraocular pressure (IOP) control, complication, and success rates were compared between the groups. Success was defined as a final IOP > 5 mmHg, < 22 mmHg with or without any antiglaucoma drug. RESULTS: A total of 23 patients were enrolled in the study, including 13 (56.5%) in the AGV group (group 1) and 10 (43.5%) in the SST group (group 2). The mean baseline IOP was 42.0 ± 9.1 mmHg in group 1 and 39.5 ± 10 mmHg in group 2 (p > 0.05). The mean IOP was 16.9 ± 7.0 mmHg in group 1 and 12.5 ± 6.7 mmHg in group 2 on the first day after surgery. After a mean follow-up period of 19.4 ± 5.2 months, success was achieved in 12 (92.3%) patients in group 1 and in 1 (10%) patient in group 2. There was a statistically significant difference in terms of the success rate between groups (p < 0.05). Complications included hyphema in three (23%) patients, obstruction of the AGV tube by iris tissue in one (7.7%) patient, and tube exposure in one patient (7.7%) in group 1. Suprachoroidal silicone tube dislocation to the anterior chamber was observed in one (10%) patient in group 2. CONCLUSION: AGV implantation after the injection of bevacizumab into the anterior chamber had a higher success rate than SST implantation. Complications were seen more frequently in the AGV group.

What is the impact of intravitreal injection of conbercept on neovascular glaucoma patients: a prospective, interventional case series study.

BACKGROUND: The aim of the present study was to evaluate the efficacy and safety of intravitreal conbercept combined with trabeculectomy and panretinal photocoagulation for neovascular glaucoma (NVG). METHODS: Fifty patients (54 eyes) with NVG were included in this prospective study. Fifty-two eyes initially underwent intravitreal conbercept (0.5 mg/0.05 ml) treatment followed by trabeculectomy and panretinal photocoagulation. Preoperative and postoperative best-corrected visual acuity (BCVA), intraocular pressure (IOP), the number of antiglaucoma medications, and surgical complications were recorded. The levels of VEGF-A, TGF-ß1 and PLGF in aqueous humour samples collected during surgery were measured by enzyme-linked immunosorbent assay (ELISA). Light microscopy and transmission electron microscopy were used to observe the surgically excised trabecular tissue; enucleation was performed in 2 eyes, and light microscopy was used as the histopathological control. RESULTS: The follow-up period after trabeculectomy was 1 year. Of the 52 eyes, 39 completed 1 year of follow-up, and 13 were lost to follow-up. Recurrence of iris neovascularization was observed in 5 eyes, 9 had hyphema, 16 had filter-bled scarring, and no eye had complications attributable to the drug. The mean IOP was reduced from 48.1 ± 14.2 to 23.2 ± 8.7 mmHg, and the mean number of antiglaucoma medications used decreased from 3.0 (3.0, 4.0) to 1.0 (0.0, 1.0) after 1 year (both P < 0.05). The complete success rate was 76.9, 76.9, 71.0, 51.6, and 32.3% at 1 week, 1 month, 3 months, 6 months and 12 months, respectively, when the cut-off IOP was 18 mmHg. After patients underwent intravitreal injection, the concentrations of VEGF-A and TGF-ß1 in the aqueous humour in NVG patients decreased from 168.8 ± 13.4 and 159.6 ± 15.4 pg/ml to 160.2 ± 7.6 and 151.9 ± 2.3 pg/ml, respectively (both P < 0.05). Light microscopy revealed neovascularization regression in the iris in specimens treated with intravitreal conbercept. Electron microscopy revealed trabecular endothelial cell degeneration in the conbercept-treated specimens. CONCLUSIONS: Our initial findings suggest that intravitreal conbercept is an effective treatment for managing NVG that has fewer short-term postoperative complications. TRIAL REGISTRATION: Current Controlled Trials ChiCTR1800019918 , 8 December 2018, retrospectively registered.

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR-proNGF pathway.

Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.

Intravitreal bevacizumab for neovascular glaucoma in uveal melanoma treated by proton beam therapy.

BACKGROUND: To evaluate the efficacy of bevacizumab on reduction of the enucleation rate and control of intraocular pressure (IOP) in neovascular glaucoma (NVG)-complicating proton beam therapy for UM and to identify the determinants of the efficacy of bevacizumab. METHODS: Retrospective comparative study of patients with rubeosis following proton therapy for uveal melanoma. Patients were divided into two groups: a bevacizumab group and a control group which comprised two subgroups: panretinal photocoagulation (PRP)/cryotherapy and observation subgroups. Bevacizumab was administered by three intravitreal injections at 1-month intervals. A second series of injections was administered when necessary. Data concerning IOP and the secondary enucleation rate were collected and compared between the two groups. Univariate and multivariate analyses were performed to determine predictive factors of response to bevacizumab. RESULTS: A total of 169 patients who developed rubeosis following proton therapy between 2006 and 2016 were included: 44 patients in the bevacizumab group and 125 in the control group (38 in the PRP/cryotherapy subgroup and 87 in the observation subgroup). The two groups presented the same baseline characteristics apart from hypertension, retro-equatorial site, and proximity of the optic disk, which were more frequent in the control group, while initial retinal detachment and larger tumor volume were more frequent in the bevacizumab group. After a mean follow-up of 31 months, IOP was less than 21 mmHg in 54.54% of patients after IVB versus 72.7% before treatment (p = 0.06). Statistical analysis did not reveal any statistically significant reduction of the enucleation rate in the bevacizumab group compared to the observational group, whereas the PRP/cryotherapy group showed better eye retention rate (p = 0.15). No enucleation was performed when IOP was < 21 mmHg before IVB. Multivariate analysis identified initial IOP < 21 mmHg and UM situated away from the macula as predictive factors of good response to bevacizumab. CONCLUSION: Despite the improvement of IOP level, intravitreal bevacizumab (IVB) did not reduce the overall enucleation rate in NVG following proton beam therapy. Nevertheless, this treatment was effective in the early phases of NVG or as preventive treatment. PRP remains a valid treatment for NVG.

Efficacy of intravitreal ranibizumab combined with Ahmed glaucoma valve implantation for the treatment of neovascular glaucoma.

BACKGROUND: Neovascular glaucoma is a refractive glaucoma. Recently, anti-VEGF factors have been used alone or in combination for the treatment of neovascular glaucoma. However, the medium- and long-term efficacy of such drugs remains to be evaluated. This study was to determine the efficacy of intravitreal ranibizumab combined with Ahmed glaucoma valve implantation for the treatment of neovascular glaucoma. METHODS: In this prospective non-randomized study, 43 neovascular glaucoma patients (43 eyes) were assigned to receive either 0.5 mg intravitreal ranibizumab for three to 14 days before Ahmed glaucoma valve implantation (injection group, n = 21) or Ahmed glaucoma valve implantation alone (control group, n = 22). The patients were followed up for six to 12 months. Differences in surgical success rate, intraocular pressure, best corrected visual acuity, anti-glaucoma medications and postoperative complications were compared between the two groups. Surgical success was defined as IOP > = 6 mm Hg and < = 21 mm Hg, with or without the use of anti-glaucoma medications, and without severe complications or reoperation. RESULTS: Of the 43 patients, 40 completed the 6-month follow-up and 37 completed the 1-year follow-up. Success rate was 73.7% vs. 71.4% at six months and 72.2% vs. 68.4% at 12 months in the injection group and the control group respectively. No significant difference was noted between the two groups (six months: P = 0.87, 12 months: P = 1.00). There were no significant differences in the two groups with respect to intraocular pressure, best corrected visual acuity, anti-glaucoma medications or postoperative complications at six months or 12 months. CONCLUSIONS: Single intravitreal ranibizumab (0.5 mg) before surgery has no significant effect on the medium- or long-term outcomes of neovascular glaucoma treated with Ahmed glaucoma valve implantation. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR-OOC-14005709, Trial registration date: 2014-12-01).

Anti-VEGF treatment is the key strategy for neovascular glaucoma management in the short term.

BACKGROUND: To present a comprehensive approach for the management of patients with neovascular glaucoma (NVG) aiming to preserve visual function and complement pan-retinal photocoagulation (PRP) by anti-vascular endothelial growth factor (anti-VEGF) treatment and anti-glaucoma surgery. METHODS: This study includes a prospective, interventional case series. A process flow chart for NVG management was designed. Totally 50 patients (51 eyes) with NVG were included. Of these, 43 patients (44 eyes) completed the treatment process. Patients were divided into central retinal vein occlusion (CRVO) and proliferative diabetic retinopathy (PDR) groups according to their original diagnosis. Intraocular pressure (IOP), visual function, and the status of iris and angle neovascularization were recorded before and after treatment. RESULTS: Patients were followed up for 6-30 months (mean 12.2 months). The IOP of all 44 patients was effectively controlled and was significantly less after treatment (16.68 ± 4.69 mmHg) than before treatment (42.59 ± 9.44 mmHg, P < 0.05). Thirty-nine eyes displayed controlled IOP (≤21 mmHg) after treatment. Visual acuity improved, to some extent, in 32 eyes (72.9 %), and 12 eyes (27.3 %) had a visual acuity better than 0.1. There was no significant difference in IOP between the PDR and CRVO groups at the end of follow-up (P = 0.8657), but the visual acuity in the PDR group was much better than that in the CRVO group (P = 0.0079). CONCLUSIONS: A comprehensive therapy for NVG can effectively control IOP and preserve visual function in patients by anti-VEGF injection and anti-glaucoma surgery.

Aflibercept for the treatment of neovascular glaucoma.

BACKGROUND: Neovascular glaucoma (NVG) is a potentially blinding disease associated with ocular ischaemia. Use of an anti-vascular endothelial growth factor agent has been reported as a treatment option for NVG. The purpose of this study was to investigate initial results regarding the treatment of NVG with intravitreal aflibercept. DESIGN: This study employed a prospective, interventional case series study design. PARTICIPANTS: Patients with newly diagnosed stage 1 or 2 neovascular glaucoma were eligible to participate in this study. METHODS: Four patients with newly diagnosed stage 1 or 2 NVG were treated with intravitreal aflibercept at the time of diagnosis, with planned repeat injection at 4 weeks, 8 weeks and then every 8 weeks thereafter up until 52 weeks after study initiation. MAIN OUTCOME MEASURES: Primary outcomes were regression of neovascularization of the iris and angle (NVI, NVA). Secondary outcome measurements included visual acuity and intraocular pressure (IOP). RESULTS: Intravitreal aflibercept resulted in rapid regression of NVI and NVA. IOP was stable or reduced in all patients at the 52-week study visit. CONCLUSIONS: These results suggest that intravitreal aflibercept may be an effective treatment for stage 1 and 2 NVG, resulting in rapid and sustained regression of NVI and NVA as well as control of IOP. Further research is needed to determine the full duration of effect and the optimal dose and timing of administration.

Short-term effect of intravitreal ranibizumab on intraocular concentrations of vascular endothelial growth factor-A and pigment epithelium-derived factor in neovascular glaucoma.

BACKGROUND: This study aims to evaluate concentrations of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF)-A in aqueous of patients with neovascular glaucoma prior to, and shortly after, an intravitreal ranibizumab injection. DESIGN: Interventional comparative study. PARTICIPANTS: The study included patients undergoing an intravitreal ranibizumab injection about one week before anti-glaucomatous surgery (study group) or who underwent routine cataract surgery (control group). METHODS: Aqueous and blood samples were collected at the occasions of intravitreal injections, anti-glaucomatous surgery or cataract surgery. They were analysed by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Concentrations of PEDF and VEGF-A in aqueous. RESULTS: At baseline, concentrations VEGF-A (3698 ± 2105 pg/mL vs. 233 ± 98 pg/mL) and PEDF (18.9 ± 11.9 ug/mL vs. 2.2 ± 0.6 ug/mL) were higher (P < 0.001) in the study group (n = 20 patients) than control group (n = 20 patients). The VEGF-A/PEDF concentration ratio was higher in the study group (396 ± 554 vs. 110 ± 49; P = 0.02). One week after the ranibizumab injection, iris neovascularization had completely regressed in 17 (85%) eyes, and VEGF-A concentration decreased significantly (P < 0.001) to 184 ± 130 pg/mL. The PEDF concentration remained unchanged (19 ± 12 ug/mL). The VEGF-A/PEDF concentration ratio decreased to 13.2 ± 13.6. Plasma concentrations of VEGF-A and PEDF did not differ significantly between both groups (P = 0.65 and P = 0.15, respectively) nor were they significantly correlated with the aqueous concentrations (all P > 0.15). CONCLUSIONS: Aqueous concentrations of VEGF-A and PEDF were significantly elevated in eyes with neovascular glaucoma. Within one week after intravitreal injection of ranibizumab, VEGF-A concentration decreased to subnormal levels, while the PEDF concentration remained unchanged and the VEGF-A/PEDF ratio decreased.

[Effect of Intravitreal Bevacizumab Injection on Iris and Iridocorneal Angle Neovascularization in Neovascular Glaucoma].

Neovascular glaucoma is a serious complication associated with retinal ischemic changes, which increase the production of vascular endothelial growth factor. Vascular endothelial growth factor has been implicated as a key molecule in the development of newly formed vessels and neovascular glaucoma. Intravitreal injection of bevacizumab, a full-length humanized anti-vascular endothelial growth factor monoclonal antibody, leads to a dramatic regression of the new iris and iridocorneal angle vessels on slitlamp examination. However, anterior segment angiography reveals that bevacizumab does not cause a regression of the neovascular vessels themselves but reduces vascular permeability while newly formed vessels are still present in the iris and iridocorneal angle. This review focuses on the pathology and diagnosis of neovascula glaucoma and the effect of intravitreal bevacizumab on the iris and iridocorneal angle neovascularization.

[Application of anti-VEGF agents in treatment of neovascular glaucoma and anti-scarring in filtering surgery].

Neovascular glaucoma (NVG) is a group of secondary glaucoma which led by a variety of diseases that have anoxia or ischemia to the retina. Some studies have found that the etiology was related to the vascular endothelial growth factor (VEGF). At present, anti-VEGF as a treatment method to NVG, has become an important advance in the field of glaucoma research, which established a new way to improve the prognosis. This review mainly focused on the pathophysiologic basis and clinical research of NVG, fundamental research and applications about four kinds of anti-VEGF agents (Bevacizumab, Ranibizumab, Pegaptanib and Aflibercept) and application of treatment of NVG and anti-scarring in filtering surgery. The review also provided references for the clinical treatment of NVG and improving the success rate of operation.

Topical bevacizumab for neovascular glaucoma: a pilot study.

BACKGROUND/AIMS: Bevacizumab (Avastin), an anti-vascular endothelial growth factor drug, has been successfully used in recent years to treat ocular pathologies, mostly by intravitreal administration. The aim of this study was to investigate the safety and efficacy of topically applied bevacizumab for the treatment of neovascular glaucoma (NVG). METHODS: Patients with NVG were treated with topical bevacizumab (25 mg/ml) 4 times daily during 2 weeks. The following parameters were evaluated at baseline and on days 3, 7 and 14: visual acuity, slit-lamp examination, intraocular pressure (IOP), heart rate and systemic blood pressure. Iris neovascularization was documented using slit-lamp color photos at baseline and on day 14. RESULTS: Eight eyes of 8 patients with NVG were evaluated. After the 2-week treatment, mean IOP was lowered from 34.9 mm Hg (SD 12.8) at baseline to 28.8 mm Hg (SD 9.9) on day 14, representing a mean reduction of 6.1 mm Hg (17.5%). Three patients had clinical regression of their iris neovascularization. Ocular adverse events were transient and included mild upper eyelid swelling, mild exacerbation of superficial punctate keratitis and mild corneal epithelial bullae in an already edematous cornea. There were no serious systemic adverse events. CONCLUSIONS: Topical application of bevacizumab may lower IOP and result in regression of neovascularization in patients with NVG.

Comparative efficacy and safety of different anti-VEGF agents combined with different delivery methods for neovascular glaucoma: a systematic review and Bayesian network meta-analysis.

OBJECTIVE: To compare the efficacy and safety of different anti-vascular endothelial growth factor (VEGF) agents combined with different delivery methods for neovascular glaucoma (NVG). DESIGN: Systematic review and Bayesian network meta-analysis (NMA). DATA SOURCES: PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, ISRCTN and Chinese databases including the China National Knowledge Infrastructure, China Science Periodical Database (Wanfang Database), VIP Journal Integration Platform and China Biology Medicine Database were searched from inception to 5 September 2022. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that investigated the treatment of NVG using different anti-VEGF agents combined with various methods of drug administration, without any language limitations. All patients included underwent panretinal laser photocoagulation and there were no restrictions on prior glaucoma surgery. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed the risk of bias. Random-effect Bayesian NMA was conducted to compare the efficacy and safety and rank priority of anti-VEGF regimens. The source of heterogeneity and the related factors affecting the stability of the results were also explored. CINeMA (Confidence in Network Meta-Analysis) was used to assess the certainty of evidence. RESULTS: Our analysis included 17 RCTs involving a total of 1311 eyes from 1228 patients. We examined five different treatment regimens, which used three different anti-VEGF drugs. The following treatments showed a significant decrease in intraocular pressure (IOP) compared with the control group at 1 month after glaucoma surgery: simultaneous intravitreal and intracameral injection of conbercept (ICCIVC) (mean difference (MD)=-11.56, 95% credible interval (CrI) -20.8 to -2.24), intravitreal injection of conbercept (MD=-8.88, 95% CrI -13.93 to -3.78), intravitreal injection of ranibizumab (MD=-7.62, 95% CrI -10.91 to -4.33) and intravitreal injection of bevacizumab IVB) (MD=-5.51, 95% CrI -10.79 to -0.35). The surface under the cumulative ranking curve (SUCRA) analysis indicated that ICCIVC (82.0%) may be the most effective regimen in reducing IOP. In terms of safety, there were no statistically significant differences among the interventions. According to the SUCRA analysis, ICCIVC (68.0%) was considered the safest choice with the fewest complications. Subgroup and meta-regression analyses showed that mean age was the main source of heterogeneity. Sensitivity analysis demonstrated the robustness of the study results. CONCLUSION: ICCIVC was more effective and safer than other anti-VEGF regimens for NVG. Simultaneous intravitreal and intracameral injection was found to be the best route of administration, and conbercept was found to be the superior drug selection when compared with ranibizumab and bevacizumab. PROSPERO REGISTRATION NUMBER: CRD42022309676.