From Cornea and External Diseases, Bascom Palmer Eye Institute, University of Miami, 900 NW 17th Street, Miami, FL 33136.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Sonia H.Yoo, MD, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136.
Blockade of vascular endothelial growth factor (VEGF) with bevacizumab and ranibizumab has been a successful new treatment in decreasing visual morbidity associated with abnormal vascular conditions of the choroid and retina.1–4 More recently, topical anti-VEGF agents have been studied in animals and humans to evaluate their potential in treating abnormal vascularization of the cornea.5–12 A significant decrease in corneal neovascularization was noted with treatment in both animals studies and humans.5–12 Whereas no toxicity was reported with topical therapy in animal models and in retrospective human case series,5–10,12 one prospective study found that 60% of treated eyes developed epithelial erosions.11 In one eye, the erosions progressed to a corneal melt with a resultant desmetocele. We herein describe a second case of corneal melt that occurred in a patient whereas on bevacizumab eye drops, highlighting this potential toxicity of topically applied anti-VEGF agents.
A 75-year-old man noted sudden onset of decreased vision, accompanied by eye redness and pain. He saw a local ophthalmologist who diagnosed a central corneal perforation without an obvious infiltrate. The perforation was temporized with cyanoacrylate glue and a bandage contact lens (BCL) and the patient was sent to Bascom Palmer Eye Institute for further evaluation. On presentation, visual acuity measured light perception in the right eye and 20/20 in the left eye. The right anterior chamber was formed with a central corneal perforation plugged by glue. No obvious infiltrate was noted. B scan ultrasonography demonstrated extensive serous ciliochoroidal detachments without a retinal detachment. Examination of the left eye was unremarkable.
The patient was placed on moxifloxacin eye drops four times a day and oral acyclovir 400 mg twice a day and returned home overseas. He was seen 3 months later at which time visual acuity remained light perception. The BCL and glue were removed and the cornea was noted to have healed with significant central thinning and 360° of peripheral superficial neovascularization (Fig. 1). B scan ultrasonography revealed resolving choroidals and macular thickening. Owing to the central corneal thinning, scarring, and severe irregular astigmatism, a decision was made to perform a penetrating keratoplasty (PKP). Given the marked neovascularization however, the patient was felt to be at high risk for rejection after surgery. Topical bevacizumab eye drops (25 mg/mL, prepared by the Bascom Palmer pharmacy) were commenced four times a day to decrease the neovascularization and perhaps improve prognosis after transplantation. A follow-up visit 1 month later demonstrated a marked decrease in the corneal neovascularization (Fig. 2).
Figure 1. Slit Lamp Photograph of the Right Eye Demonstrating 360° of Superficial Corneal Neovascularization with Central Thinning.
Figure 2. Slit Lamp Photograph of the Right Eye 1 Month After Commencement of Bevacizumab Eye Drops Demonstrating Marked Improvement in Corneal Neovascularization.
The patient underwent a therapeutic PKP and was continued on the bevacizumab eye drops four times a day with the hope that the drug would prevent regrowth of vessels and decrease the risk of graft rejection. Concomitant medications included oral acyclovir, prednisolone acetate 1% 6 times daily, and moxifloxacin 4 times daily. The patient reported doing well until 5 weeks after surgery at which time he noted decreased vision without pain or redness. He continued the bevacizumab eye drops for one week thereafter. On repeat examination 2 weeks after discontinuing the bevacizumab eye drops, the patient was found to have a 70% epithelial defect more than the donor cornea with marked thinning of the donor tissue. Cultures obtained at the time were negative for bacteria, fungi, and herpes virus. The thinning progressed for a period of 2 days and necessitated a repeat therapeutic PKP and Gunderson flap. A rheumatology work-up was negative for an underlying autoimmune condition.
Several groups have studied the effect of topical bevacizumab on corneal neovascularization. Yoeruek et al. studied the ability of topically applied bevacizumab (25 mg/mL administered 5 times daily) to prevent corneal neovascularization and opacification in a rabbit alkali burn model.10 The experiment demonstrated the topically applied bevacizumab can enter the anterior chamber of normal corneas and can reduce corneal damage after an alkali burn. Manzano et al. designed a similar experiment and demonstrated that bevacizumab eye drops (4 mg/mL administered 2 times daily) could decrease the area of corneal neovascularization after chemical injury in a rat model.9 Bock et al. reported that bevacizumab (5 mg/mL administered 4 times daily) decreased both angiogenesis and lymphangiogenesis in a mouse model of suture induced corneal neovascularization.5 Whereas no drug toxicity was noted in these studies, limited safety information can be obtained from animal models as bevacizumab binds poorly to non-primate VEGF.13
The use of topical bevacizumab in humans has been described in 20 eyes of 16 patients.6,7,11,12 Etiologies of vascularization included Steven Johnson syndrome (5 patients), chemical burn (4 patients), post-keratoplasty (2 patients), pterygium (1 patient), trauma (1 patient), mucous membrane pemphigoid (1 patient), herpetic disease (1 patient) and congenital limbal stem cell deficiency (1 patient). In three retrospective studies, the treatment dose ranged from 5 mg/mL to 25 mg/mL, applied 4 or 5 times daily, and the treatment duration ranged from 0.5 months to 6 months (mean 3 months ±1.9).6,7,12 Treatment resulted in a reduction of corneal vessels in all eyes with no reported side effects.
A prospective trial utilizing 12.5 mg/mL of topical bevacizumab, twice daily, for 3 months found that whereas corneal blood vessels regressed in 7 of 10 treated eyes, 6 eyes developed epithelial defects during the second month on treatment. In one patient, the epitheliopathy progressed to stromal thinning and a resultant descemetocele.11 The patient’s corneal neovascularization was secondary to a chemical burn; no previous history of corneal melt was noted. Our patient was treated with bevacizumab 25 mg/mL, 4 times daily. Improvement of neovascularization was seen after 1 month, the recurrent corneal melt occurred after 2 months on treatment. This time course is similar to the one observed by Kim et al.11
Given our patient’s previous history of a corneal perforation, it is unclear whether the bevacizumab eye drops contributed to his recurrent melt. However, this case, along with the 6 reported cases of epitheliopathy, suggests that topically applied bevacizumab may have some associated toxicity. Bevacizumab has known antifibrotic effects10 and may have negative consequences to corneal epithelium and to wound healing. Whereas there is no data to suggest that topical bevacizumab should not be used after corneal transplant surgery, we recommend caution with its use in the immediate postoperative period in patients with a history of a corneal melt until the toxicity of the medication are better characterized.
- Chalam KV, Gupta SK, Grover S, et al. Intracameral Avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol. 2008;18:255–262.
- Scott IU, Edwards AR, Beck RW, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007;114:1860–1867. doi:10.1016/j.ophtha.2007.05.062 [CrossRef]
- Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging. 2007;38:233–237.
- Bashshur ZF, Schakal A, Hamam RN, et al. Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration. Arch Ophthalmol. 2007;125:1357–1361. doi:10.1001/archopht.125.10.1357 [CrossRef]
- Bock F, Onderka J, Dietrich T, et al. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci. 2007;48:2545–2552. doi:10.1167/iovs.06-0570 [CrossRef]
- Bock F, Konig Y, Kruse F, et al. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2008;246:281–284. doi:10.1007/s00417-007-0684-4 [CrossRef]
- DeStafeno JJ, Kim T and . Topical bevacizumab therapy for corneal neovascularization. Arch Ophthalmol. 2007;125:834–836. doi:10.1001/archopht.125.6.834 [CrossRef]
- Hosseini H, Nejabat M, Mehryar M, et al. Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clin Experiment Ophthalmol. 2007;35:745–748. doi:10.1111/j.1442-9071.2007.01572.x [CrossRef]
- Manzano RP, Peyman GA, Khan P, et al. Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br J Ophthalmol. 2007;91:804–807. doi:10.1136/bjo.2006.107912 [CrossRef]
- Yoeruek E, Ziemssen F, Henke-Fahle S, et al. Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol Scand. 2007;86:322–328.
- Kim SW, Ha BJ, Kim EK, et al. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology. 2008;115:e33–38. doi:10.1016/j.ophtha.2008.02.013 [CrossRef]
- Uy HS, Chan PS, Ang RE. Topical bevacizumab and ocular surface neovascularization in patients with stevens-johnson syndrome. Cornea. 2008;27:70–73. doi:10.1097/ICO.0b013e318158f6ad [CrossRef]
- Liang WC, Wu X, Peale FV, et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem. 2006;281:951–961. doi:10.1074/jbc.M508199200 [CrossRef]