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Purpose: To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation., Design: Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil., Participants: Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft., Methods: Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks., Main Outcome Measure: The 52-week endothelial immune rejection rate., Results: Ninety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis., Conclusions: In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation., Design: Multicenter, double-masked, randomized, placebo-controlled phase III study., Participants: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180., Main Outcome Measures: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL., Results: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related., Conclusions: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether peripheral corneal neovascularization in bullous keratopathy (BK) is due to conjunctivalization, a sign of limbal stem cell deficiency., Design: Observational case-control study., Participants: Sixteen BK patients., Methods: Patients were divided into 2 groups: BK without peripheral neovascularization [NV(-) group; 5 patients, 5 eyes] and BK with neovascularization [NV(+) group; 11 patients, 13 eyes]. Evidence of conjunctivalization was evaluated by periodic acid-Schiff staining of impression cytology samples from the peripheral vascularized cornea. The 2 groups' durations of disease also were compared. Penetrating keratoplasty (PK) was performed in all 16 cases, and the 2 groups' durations of reepithelialization after PK were compared., Main Outcome Measures: Presence of goblet cells using impression cytology, duration of BK, and duration of postoperative reepithelialization., Results: Goblet cells were found on the peripheral corneal surface in all eyes in the NV(+) group. However, all eyes in the NV(-) group were negative for goblet cells (P<0.0001). Duration of disease was 14.4+/-5.4 months in the NV(-) group and 66.2+/-65.5 months in the NV(+) group (P = 0.030). Duration of postoperative epithelialization was 6.2+/-2.2 days in the NV(-) group and 28.8+/-36.5 days in the NV(+) group (P = 0.046)., Conclusion: Conjunctivalization of the peripheral cornea and delayed postoperative epithelialization in BK patients with NV suggest the presence of limbal stem cell deficiency in such patients. Patients with long-standing disease were found to be more prone to neovascularization. For this reason, early surgery may lead to a better surgical outcome.

Background: Conventional treatment of corneal stromal vascularization is often inadequate. The authors developed a rabbit model of corneal stromal vascularization, treated it with laser photocoagulation, and then studied the histopathology., Methods: A reproducible model of corneal stromal vascularization was developed in albino rabbits by injecting sodium hydroxide into the corneal stroma. Corneal stromal vascularization was produced in both eyes of 13 rabbits, and treated after stabilization at 5 weeks with 577-nm yellow dye laser in 1 eye of each rabbit. Seven rabbits were followed for 6 months with corneal angiography and photography, and the corneal stromal vascularization quantified with a grid. The other 6 rabbits were killed at 1, 4, 8, 24, 48 hours, and 6 days after laser photocoagulation and examined by light and transmission electron microscopy., Results: Stable corneal stromal vascularization was observed in the anterior and midstroma for at least 6 months in the model. Laser photocoagulation reduced corneal stromal vascularization significantly compared with the controls (P < or = 0.05), resulting in 40.7% +/- 5.0%, 45.3% +/- 3.3%, and 34.9% +/- 5.2% (mean +/- standard error of the mean) reduction at 2, 4, and 6 months, respectively. Maximum inflammatory cell infiltrates were detected at 8 hours after laser photocoagulation, which diminished markedly at 6 days. The stroma of unlasered eyes showed no inflammatory cells and considerably more patent blood vessels than the lasered eyes. In the lasered eyes, transmission electron microscopy showed damaged vascular endothelial cells, extravasated erythrocytes, haphazardly arranged collagen fibrils, thrombus formation, and ghost vessels in the stroma. No damage was observed in the deep corneal stroma or endothelium in the lasered eyes., Conclusion: Laser photocoagulation is effective in reducing corneal stromal vascularization in this model for at least 6 months. It does not damage the deeper stroma or endothelium.

The authors treated corneal neovascularization in 25 eyes of 23 patients with corneal laser photocoagulation using 577 nm yellow light. Four groups of patients were treated: patients with corneal neovascularization and active graft rejection (group 1); patients with neovascularization before penetrating keratoplasty (PK) (group 2); lipid keratopathy patients with opacification and/or focal edema threatening the visual axis (group 3); and patients with extensive corneal neovascularization, who were not candidates for PK (group 4). Area of neovascularization and clinical outcome were monitored. After corneal laser photocoagulation, there was a statistically significant reduction in the neovascularized area in group 1 from 32% of corneal area to 10%, and in group 3 from 46% to 27%. All five patients in group 1 had resolution of their graft rejection. In group 3, there was a reduction in the area of corneal opacification from 59% of corneal area to 52%. This difference was not statistically significant. Seven of nine patients in group 3 had stabilization or improvement in their vision over a mean of 9.3 months follow-up. There was no significant change in neovascularized area in groups 2 and 4. In group 2, no rejection reactions occurred over a mean of 5.6 months follow-up after PK. In group 4, corneal laser photocoagulation was disappointing.