**5. Management**

Corneal neovascularization is one of the main risk factor for immune rejection after corneal transplantation. Healthy cornea is devoid of blood vessels and is said to be immune privileged. When corneal grafts are placed into an avascular recipient corneal bed (*low risk keratoplasty*) the two year survival rate approaches 90% under cover of steroids.

The survival rates of corneal grafts placed over vascularized recipient beds (*high risk keratoplasty*) decrease significantly. Even in low risk setting, mild angiogenesis develops after keratoplasty and increase risk of immune graft rejection. For this reason aggressive treatment of neovascularization may be necessary prior to corneal transplant surgery to ensure lower risk of graft rejection.

Various antiangiogenic agents may be used in management of post keratoplasty graft rejection:


Corticosteroids and systemic immunosuppression remain an important aspect in prevention of post keratoplasty graft rejection. Corticosteroids inhibit macrophages that release growth

Topical Bevacizumab Therapy in Graft Rejection After Penetrating Keratoplasty 131

factor. They also prevent intercellular adhesion leading to leukocyte adhesion and migration. They can slow the progression of neovascularization, but cannot stabilize or

Vascular endothelial growth factor inhibitors are emerging as the new pharmacological therapy in the management of post keratoplasty graft rejection. Anti-VEGF agent has been found to be effective in reducing corneal vascularization (Fig. 1). Currently available anti-

 **Bevacizumab (Avastin**) Bevacizumab is a humanized monoclonal antibody that inhibits all active isoforms of VEGF and is approved by USFDA since February 2004 for

**Ranibizumab (Lucentis)** Ranibizumab is also a humanized monoclonal antibody

 **Pegaptanib (Macugen)** Pegaptanib is a synthetic oligonucleotide that binds the pathologic isoform of VEGF, which is VEGF 165 and this binding, happens

Efficacy of bevacizumab therapy has been highlighted in several studies. Manzano et al 6 in an experimental study on rats showed that a concentration of 4 mg/mL bevacizumab limits corneal neovascularization. Dastjerdi et al7 in their study used 1% bevacizumab for 3 weeks in 10 eyes of 10 patients and followed them up to 24 weeks. They found that short-term topical bevacizumab therapy reduced the severity of corneal neovascularization without local or systemic adverse effects. Chen et al8 used subconjunctival injection of bevacizumab in doses 0.25-2.5 mg twice per week for 2 to 8 weeks in rabbits and concluded that it is effective in preventing corneal neovascularization in acute phase of various kinds of corneal inflammation. Carrasco 9 reported the use of bevacizumab in an 81-year old woman with corneal neovascularization secondary to herpetic stromal keratitis. Treatment with subconjunctival bevacizumab showed regression of corneal neovascularization. Bock et al10 in their study used topical bevacizumab (5x/day; 5 mg/ml) for 15 days in corneal neovascularization of various cause and concluded that it inhibits corneal

**5.2 Role of bevacizumab in the treatment of corneal vascularization after keratoplasty**  Efficacy of bevacizumab therapy has been highlighted in several studies. Schollmayer et al11 performed a retrospective case series study of nine eyes of nine patients with corneal transplant and neovascularization. Five eyes were administered topical bevacizumab 5 mg/ml 4 times daily for a month. Three eyes were administered bevacizumab subconjunctivally 2.5 mg/0.1 ml and one eye was administered bevacizumab both topically as well via subconjunctival route. After a follow up of 6 months, it was concluded that topical and subconjunctival bevacizumab is effective in regressing neovascularization in

Saxena et al12 used topical bevacizumab (4 mg/4 ml) in dose of one drop twice daily for 15 days in a patient of corneal graft rejection and did a follow up after 1 month, 6 month and 9 months. After 1 month, his BCVA improved to 20/120 from finger counting 1meter. Corneal vascularization and stromal haze regressed. After 6 months, his BCVA improved to 20/60

reverse the process.

VEGF agents include:

extracellular.

keratoplasty patients.

treatment of metastatic colorectal cancer.

fragment highly related to bevacizumab structurally.

**5.1 Role of bevacizumab in the treatment of corneal vascularization** 

neovascularization without obvious corneal epithelial side effects.

A

B

Fig. 1. Effect of topical bevacizumab in a case of corneal neovascularization**.** A. Pretreatment: Corneal vascularization and stromal haze is visible. B. Post-treatment: Marked regression in corneal vascularization and stromal haze has resulted.

A

B

Fig. 1. Effect of topical bevacizumab in a case of corneal neovascularization**.** A. Pretreatment: Corneal vascularization and stromal haze is visible. B. Post-treatment: Marked

regression in corneal vascularization and stromal haze has resulted.

factor. They also prevent intercellular adhesion leading to leukocyte adhesion and migration. They can slow the progression of neovascularization, but cannot stabilize or reverse the process.

Vascular endothelial growth factor inhibitors are emerging as the new pharmacological therapy in the management of post keratoplasty graft rejection. Anti-VEGF agent has been found to be effective in reducing corneal vascularization (Fig. 1). Currently available anti-VEGF agents include:

