Nambi Nallasamy

Topical Bevacizumab in the Treatment of Corneal Neovascularization Results of a Prospective, Open-Label, Noncomparative Study

OBJECTIVE To study the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization (NV). DESIGN In a prospective, open-label, noncomparative study, 10 eyes from 10 patients with stable corneal NV were treated with topical bevacizumab, 1.0%, for 3 weeks and followed up for up to 24 weeks. MAIN OUTCOME MEASURES The primary safety variables were the occurrence of ocular and systemic adverse events throughout the course of the study. The primary efficacy variables were neovascular area, the area of the corneal vessels themselves; vessel caliber, the mean diameter of the corneal vessels; and invasion area, the fraction of the total corneal area covered by the vessels. RESULTS From baseline visit to the last follow-up visit, mean reductions were 47.1% (standard deviation [SD], 36.7%) for neovascular area, 54.1% (SD, 28.1%) for vessel caliber, and 12.2% (SD, 42.0%) for invasion area. The decreases in neovascular area and vessel caliber were statistically significant (P= .001 and P< .001, respectively). However, changes in invasion area did not achieve statistical significance (P= .19). Visual acuity and central corneal thickness showed no significant changes. Topical bevacizumab was well tolerated with no adverse events. CONCLUSIONS Short-term topical bevacizumab therapy reduces the severity of corneal NV without local or systemic adverse effects. APPLICATION TO CLINICAL PRACTICE Topical bevacizumab provides an alternative therapy in the treatment of stable corneal NV. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00559936.

Effects of topical and subconjunctival bevacizumab in high-risk corneal transplant survival.

PURPOSE To investigate whether corneal graft survival could be improved by topical or subconjunctival bevacizumab in a murine model of vascularized high-risk corneal transplantation. METHODS Before corneal transplantation, intrastromal sutures were placed for 2 weeks in the corneas of BALB/c mice, inducing intense angiogenesis. Allogeneic corneal transplantation was performed using C57BL/6 donor mice. Topical bevacizumab (2.5%) was delivered 3 times a day for 3 weeks in one treatment group, and 0.02 mL (0.5 mg) bevacizumab was injected subconjunctivally at days 0, 4, 8, and 15 after transplantation in the other treatment group. The control group received no treatment. Grafts were examined twice a week for 8 weeks by slit-lamp microscopy and were photographed once a week by slit-lamp digital camera and scored for opacity. For assessment of corneal neovascularization (NV), a quantitative method was used to measure three primary metrics including neovascular area, vessel caliber, and neovessel invasion area. RESULTS Both topical and subconjunctival bevacizumab treatment reduced neovascular area and vessel caliber; however, the regression of corneal NV was more profound when treated subconjunctivally. The mean percentage reduction of neovascular area was 55% (P < 0.05) by week 8 in the subconjunctival treatment group and 33% (P = 0.15) in the topical group. Only subconjunctival bevacizumab treatment resulted in significant regression of neovessel invasion area (P < 0.05). All corneal transplants in both the control and the topical groups were rejected by 4 weeks after transplantation. However, in the subconjunctival treatment group, 33% of corneal grafts survived (P < 0.01). CONCLUSIONS Subconjunctival bevacizumab may offer an adjunctive measure to conventional therapies in preventing graft rejection in high-risk corneal transplantation.

Evidence of Corneal Lymphangiogenesis in Dry Eye Disease A Potential Link to Adaptive Immunity

OBJECTIVE To determine the effect of desiccating stress on corneal angiogenic responses in dry eye disease (DED) using a murine model. METHODS Dry eye was induced in murine eyes using high-flow desiccated air. Corneas were double stained with CD31 (panendothelial marker) and LYVE-1 (lymphatic endothelial marker). Real-time polymerase chain reaction was performed to quantify expression of vascular endothelial growth factors (VEGF-A, VEGF-C, and VEGF-D) and their receptors (VEGFR-2 and VEGFR-3) in the cornea on days 6, 10, and 14. Enumeration of CD11b(+)/LYVE-1(+) monocytic cells was performed in corneas with DED on day 14. Flow cytometric evaluation of the draining lymph nodes in normal mice and mice with DED was performed to determine whether DED is associated with homing of mature (major histocompatibility complex class II(hi)) antigen-presenting cells to the lymphoid compartment. RESULTS Lymphatic vessels unaccompanied by blood vessels were seen growing toward the center of corneas with DED. Significant increases in lymphatic area (P < .001) and lymphatic caliber (P < .02) were seen on day 14 of disease. Lymphangiogenic-specific VEGF-D and VEGFR-3 levels increased earliest on day 6 followed by increased VEGF-C, VEGF-A, and VEGFR-2 levels. Increased recruitment of CD11b(+)/LYVE-1(+) monocytic cells to the cornea and homing of mature CD11b(+) antigen-presenting cells to the draining lymph nodes were also associated with DED. CONCLUSION Low-grade inflammation associated with DED is an inducer of lymphangiogenesis without accompanying hemangiogenesis.

Short-term topical bevacizumab in the treatment of stable corneal neovascularization.

PURPOSE To evaluate the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization. DESIGN Prospective, nonrandomized, interventional case series. METHODS setting: Institutional, multicenter clinical trial. study population: Twenty eyes from 20 patients with stable corneal neovascularization. intervention procedures: Patients were treated with topical 1.0% bevacizumab for 3 weeks and were monitored for a total of 24 weeks. main outcome measures: Primary outcome measures included: neovascular area, defined as the area of the corneal vessels themselves; vessel caliber, defined as the mean corneal vessel diameter; and invasion area, defined as the fraction of the total cornea into which the vessels extended. The occurrence of ocular and systemic adverse events was monitored closely. RESULTS As compared with the baseline visit, patients exhibited a statistically significant improvement in neovascular area by week 6 (P = .007) and in vessel caliber by week 12 (P = .006). At the final visit, neovascular area, vessel caliber, and invasion area were reduced by 47.5%, 36.2%, and 20%, respectively. The decreases in neovascular area and vessel caliber were statistically significant (P < .001 and P = .003, respectively); however, the reduction in invasion area did not reach statistical significance (P = .06). There were no significant changes in the secondary outcomes, and there were no adverse events. CONCLUSIONS Short-term topical bevacizumab treatment reduced the extent of stable corneal neovascularization as measured by neovascular area and vessel caliber with no associated adverse events. Interestingly, the degree of treatment efficacy was inversely proportional to the baseline invasion area.

A Novel Mouse Model for Neurotrophic Keratopathy: Trigeminal Nerve Stereotactic Electrolysis through the Brain

PURPOSE To develop a mouse model of neurotrophic keratopathy by approaching the trigeminal nerve through the brain and to evaluate changes in corneal cell apoptosis and proliferation. METHODS Six- to 8-week-old male C57BL/6 mice underwent trigeminal stereotactic electrolysis (TSE) to destroy the ophthalmic branch of the trigeminal nerve. Clinical follow-up using biomicroscopy of the cornea was performed at days 2, 4, 5, and 7. To confirm the effectiveness of the procedure, we examined the gross nerve pathology, blink reflex, and immunohistochemistry of the corneal nerves. TUNEL-positive apoptotic and Ki-67-positive proliferating corneal cells were evaluated to detect changes from the contralateral normal eye. RESULTS TSE was confirmed by gross histology of the trigeminal nerve and was considered effective if the corneal blink reflex was completely abolished. TSE totally abolished the blink reflex in 70% of mice and significantly reduced it in the remaining 30%. Animals with absent blink reflex were used for subsequent experiments. In these mice, a progressive corneal degeneration developed, with thinning of the corneal epithelium and eventually perforation after 7 days. In all mice, 48 hours after TSE, corneal nerves were not recognizable histologically. Seven days after TSE, an increase in cellular apoptosis in all the corneal layers and a reduction in proliferation in basal epithelial cells were detected consistently in all mice. CONCLUSIONS TSE was able, in most cases, to induce a disease state that reflected clinical neurotrophic keratitis without damaging the periocular structures. Moreover, corneal denervation led to increased apoptosis and reduced proliferation of epithelial cells, formally implicating intact nerve function in regulating epithelial survival and turnover.

Topical Ranibizumab as a Treatment of Corneal Neovascularization

Purpose: To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV). Methods: This was a prospective, open-label, monocentric, uncontrolled noncomparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up period of 16 weeks. The main corneal NV outcome measures were: neovascular area, the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA. Results: Statistically significant decreases in neovascular area (55.3%, P < 0.001), which lasted through 16 weeks, and VC (59%, P < 0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P = 0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted. Conclusions: Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA.

Therapeutic efficacy of topical epigallocatechin gallate in murine dry eye.

Objective: To study the efficacy of topical epigallocatechin gallate (EGCG) for the treatment of dry eye disease (DED). Methods: Seven- to 8-week-old female C57BL/6 mice were housed in the controlled environment chamber to induce DED. Topical 0.01% or 0.1% EGCG, or vehicle, was applied to the eyes of DED mice. Corneal fluorescein staining and the number of corneal CD11b+ cells were assessed in the different groups. Expression of interleukin-1β, tumor necrosis factor-α, chemokine ligand 2, and vascular endothelial growth factor (VEGF)-A/C/D was evaluated by real-time polymerase chain reaction in the corneas at day 9. Corneas were stained for lymphatic vessel endothelial hyaluronan receptor (LYVE)-1 to evaluate lymphangiogenesis, and the terminal transferase dUTP nick end labeling (TUNEL) assay was used to evaluate apoptosis of corneal epithelial cells. Results: Treatment with 0.1% EGCG showed a significant decrease in corneal fluorescein staining compared with the vehicle (24.6%, P = 0.001) and untreated controls (41.9%, P < 0.001). A significant decrease in the number of CD11b+ cells was observed in 0.1% EGCG–treated eyes, compared with the vehicle in the peripheral (23.3%, P = 0.001) and central (26.1%, P = 0.009) corneas. Treatment with 0.1% EGCG was associated with a significant decrease in the corneal expression of interleukin-1β (P = 0.029) and chemokine ligand 2 (P = 0.001) compared with the vehicle and in VEGF-A and VEGF-D levels compared with the untreated group (P = 0.007 and P = 0.048, respectively). EGCG 0.01% also showed a decrease in inflammation at the molecular level but no significant changes in the clinical signs of DED. No cellular toxicity to the corneal epithelium was observed with 0.01% or 0.1% EGCG. Conclusions: Topical EGCG treatment is able to reduce the clinical signs and inflammatory changes in DED by suppressing the inflammatory cytokine expression and infiltration of CD11b+ cells in the cornea.

Ophthalmology Resident Selection: Current Trends in Selection Criteria and Improving the Process

OBJECTIVE To document and assess current ophthalmology resident selection practices as well as to initiate discussion on how best to improve the process. DESIGN Online survey comprising 56 questions. PARTICIPANTS Program directors, chairpersons, or members of the resident selection committee representing 65 United States ophthalmology residency programs accredited by the Accreditation Council on Graduate Medical Education. METHODS Study participants completed an online, anonymous survey consisting primarily of multiple choice questions, with single or multiple answers. MAIN OUTCOME MEASURES Ophthalmology resident selection practices were evaluated and included: screening of applications, interview processes, selection factors, and formation of rank lists; recommendations given to applicants; and respondent satisfaction with the current selection process. RESULTS As a group, survey respondents deemed the following factors most important in resident selection: interview performance (95.4%), clinical course grades (93.9%), letters of recommendation (83.1%), and board scores (80%). Statistical analyses deemed that the best predictors of resident performance are interviews, clinical course grades, recommendation letters, and ophthalmology rotation performance. CONCLUSIONS Ophthalmology resident selection is a relatively subjective process, continuing to rely heavily on cognitive factors. Because these factors are not always indicative of ultimate resident quality, it would be helpful if ophthalmology training programs improved selection practices to discern who most likely will become a successful resident and future ophthalmologist. Long-term studies correlating applicant attributes with residency and postresidency success are needed to recommend guidelines for a more standardized selection process.