Corneal Applications for Anti-VEGF Agents

By BALA AMBATI, MD, PHD

Ophthalmologists are well aware of the different causes of corneal neovascularization (Figure 1). Clinical studies have proven that bacterial infections, improper contact lens wear, injury, and rejection of corneal transplants are all contributing factors. When considering treatment of corneal decompensation, it is important to consider that the eye’s transparent optical axis requires exquisite vascular compartmentalization and that the cornea is surrounded by the heavily vascular limbus. Normal corneal avascularity depends on vascular endothelial growth factor (VEGF) receptor 1. This article outlines why anti-VEGF agents are ideal treatments for corneal decompensation.

BEVACIZUMAB

Why It Works
VEGF is a key mediator of angiogenesis, therefore, bevacizumab (Avastin; Genentech, Inc.) is an ideal treatment for corneal decompensation, because it is a humanized anti-VEGF. Bevacizumab was initially FDA approved for use in colon cancer. Six years ago, it became commonly used for age-related macular degeneration, diabetic retinopathy, and neovascular glaucoma. Between 2007 and 2010, over 40 studies have been conducted for corneal neovascularization in a total of 152 eyes with penetrating keratoplasty, deep anterior lamellar keratoplasty, pterygium, recurrent pterygium, Stevens-Johnson syndrome, herpes simplex virus, neurotrophic keratopathy, and filamentary keratitis. There rarely were episodes of epithelial dysfunction, and there were multiple reports showing nontoxicity to human cells in vitro. However, it should be noted that intravitreal injections reportedly cause temporary corneal edema or subepithelial infiltrates, although these have not been reported with topical or subconjunctival use.

Side Effects
Bevacizumab’s side effects include stroke and heart disease, so its use in patients with those conditions should be approached with caution. Although there have not been reports of significant toxicity to the cornea from subconjunctival application, injections in the subconjunctival site have been reported to cause temporary corneal edema and sometimes subepithelial infiltrates, but those side effects seem to resolve on their own.

Overall, bevacizumab has been reported as safe with no observed toxicity. It is effective for the treatment of acute neovascularization, especially in the setting of graft rejection to treat and reverse acute transplant rejection. When the agent is used to treat chronic neovascularization, it requires long-term therapy and multiple injections. Ghost vessels, however, may persist. Bevacizumab may also have a role as an adjunct to improve the prognosis for future or concurrent penetrating keratoplasty by reducing the risk of angiogenesis, a key risk for neovascularization. Based on published reports, topical treatment should consist of 1.25% to 5% of bevacizumab, twice a day, for a duration determined by the clinician. Topical treatment should be administered subconjunctivally (2.5 mg/0.1 mL) on a monthly basis, adjacent to the area of neovascularization.

PERSONAL EXPERIENCE

I administered one to five injections of 2.5 mg of bevacizumab in 24 eyes on a monthly basis. This was done to treat penetrating keratoplasty rejection in 10 eyes; lamellar keratoplasty in three; keratitis, ichthyosis, and deafness syndrome in one; astigmatic keratotomy-associated corneal neovascularization in one; neurotrophic keratopathy in five; and chemical burn in four. Twenty eyes showed improvement, as evidenced by partial regression of vessels or the presence of ghost vessels and increase in more than 1 line of Snellen visual acuity. Three eyes showed no change. No patient was lost to follow-up, and there were no adverse outcomes related to the subconjunctival injection of bevacizumab.

Three cases in particular stand out. In one, a 21-year-old man presented to my clinic with acute graft projection. He had undergone a corneal transplant due to trauma 2 or 3 years prior to presentation. He had a very vigorous vascular front, crossing into the corneal transplant. I administered a subconjunctival injection of bevacizumab at the 6-o’clock position adjacent to the vascular front. By 3 days postoperatively, nearly complete resolution of corneal neovessels and restoration of excellent visual acuity were observed. In a second case, a 50-year-old woman presented with a long-standing history of herpetic neurotrophic disease and 20/200 visual acuity. I gave five injections of bevacizumab, administered over the course of 5 months. The patient achieved a modest improvement but not a complete regression of vessels. In the third case, a 40-year-old man presented with a rejected corneal transplant. Approximately 2 weeks after the graft’s rejection onset and 1 week after treatment with bevacizumab, regression of corneal vascularization and improved clarity in the corneal transplant were observed (Figure 2).

CONCLUSION

The use of bevacizumab on the ocular surface is safe. It is effective in acute corneal neovascularization, but chronic vascular conditions do not respond as well. The drug is most useful to treat graft rejection, chemical burn, and other acute causes of neovascularization.

Bala Ambati, MD, PhD, is an associate professor at The University of Utah, John Moran Eye Center, in Salt Lake City. He acknowledged no financial interest in the product or company mentioned herein. Dr. Ambati may be reached at bala.ambati@utah.edu.