Francisco Trinco, Joo Feijo, Vtor Maduro, Nuno Alves, Carlos Batalha, Pedro Candelria, Jos Pita-Negro

CENTRO HOSPITALAR DE LISBOA CENTRAL, LISBON - PORTUGAL

Corneal Neovascularization (NV) is the end stage of several corneal diseases. Vascular Endothelial Growth Factor (VEGF) is one of the key mediators of angiogenesis, involved not only in proliferation but also in migration of new vessels. It has been shown to be upregulated in newly vascularized corneas. Anti-VEGF antibodies, such as bevacizumab (Avastin), have been used off-label in ophthalmology, mainly for Age-related Macular Disease.
Topical and perilimbic administration of bevacizumab have been shown to reduce corneal neovascularization in small case series. However their administration was not directed to the neovascularization itself but to the surrounding tissues. To test the safety and efficacy of direct stromal injection of bevacizumab as a targeted therapy.

Table 1. Patient Data

Corneal Opacity CO (1-5) 4 3 3 2 1 2 1 5 4 3 5 1 Follow-up (6 months) t inj (months) 48 7 72 36 3 6 4 13 11 12 >120 8 BCVA NV (-/0/+) 0 0 0 CO (-/0/+) 0 0 0 0 0 0 Patient Perception (at 6 months) VA Photophobia Disease Progression 3 3 4 4 5 5 5 3 4 3 3 5

Eye 1 2 3 4 5 6 7 8 9 10 11 12

Disease

BCVA

No major adverse events were reported during the study. Eyes 1,2, 5, 6, 7, 8 and 11 suffered minor hemorrhage during injection, which had fully reabsorbed by the end of the first week. At the end of the follow-up, no increase in NV or CO was observed in any of the patients. Initial mean BCVA was 0.190.61, which improved to a mean BCVA of 0.320.58. Nevertheless, the eyes studied were very heterogeneous in visual acuity, corneal opacity and neovascularization area and pattern. A subgroup analysis revealed that a subset of patients (eyes 5,6,7,9 and 12), which included all of the traumatic ulcers, did far better than other (eyes 1,2,3, 8 and 11). The former corresponded to the patients who globally had a better baseline BACV (mean BACV = 0.420.38), less corneal opacity (mean CO = 1.82.2) and less time-to-injection (mean tinj = 6.44.6 months). The final visual acuity for this subgroup was 0.70.4. The second subset did not improve in their BCVA but some had a reduction in their NV area (eyes 1,2 and 11). No patients (with the exception of eye 2) had the perception of poorer visual acuity. Most were satisfied with the reduction of symptoms and the evolution of their disease.

HM HM HM 0.1 0.4 Traumatic Ulcer 0.5 0.3 Chemical Burn Exposure Ulcer Herpetic Ulcer Herpetic Keratitis LP 0.1 0.1 LP 0.8

HM HM HM 0.2 0.8 0.8 0.7 LP 0.3 0.1+ LP 0.9

3 2 3 4 5 5 5 3 5 3 3 5

3 3 3 3 4 4 4 3 3 4 3 5

Transplant Rejection

12 eyes (10 patients) were treated with one stromal bevacizumab injection (1.25mg / 0.05mL) in the operating room using a 27G needle: 4 corneal graft rejections, 3 traumatic ulcers, 2 exposure ulcers, 2 herpetic keratites, 1 chemical trauma. We categorized the different eyes by pathology, Best Corrected Visual Acuity (BCVA), NV duration until treatment (tinj) and corneal opacity (CO) at baseline. Patients were followed-up for a 6 month period, complications were monitored and sequential photos were taken to compare the extent of corneal NV. At 6 months we measured BCVA and assessed the degree of CO and NV. Patients were also asked to grade their improvement in visual acuity, photophobia and perception of change in their disease.

1 minimal corneal opacity 5 total corneal opacity

- smaller area + bigger area

1 worse; 3- equal; 5 better / no complaints

Figure 1. Photographs before (X) and 6 months after injection (X) Patients A and B (eyes 2 and 1 respectively), with worse baseline BCVA and CO responded worse to injection. Patients C and D (eyes 5 and 7 respectively) with a less severe baseline BCVA and CO and less time-to-injection had a more significant response.

Targeted therapy with stromal bevacizumab injection provided evidence to be a safe and effective short-term treatment in selected cases with corneal neovascularization. The best results were obtained with subjects who had less severe initial visual acuity, lower degree of corneal opacification and shorter time from the start of neovascularization to injection. In patients where no improvement was seen, no deterioration in pre-existing pathology was reported. Bevacizumab stromal injection may be a useful adjunctive or alternative therapy to conventional treatment in corneal NV. A larger sample size and longer follow-up period is required to evaluate the true efficacy of this treatment. The authors have no financial interests or relationships to disclose.