Fig. 5.6 Eye drops with antisense oligonucleotides against IRS-1 given twice daily were shown to significantly inhibit progressive corneal neovascularization in a randomized, multicenter European phase II trial [30]. After additional treatment with GS101 eye drops, (b) there is marked regression of corneal neovessels compared to baseline (a)

Summary for the Clinician

•Current treatment options for actively growing corneal vessels include steroids, anti-VEGFs, and anti-IRS-1 eye drops.

•Anti-VEGFs such as Avastin and Lucentis given as eye drops reliably block active corneal neovascularization and also minimize vessel diameters of remaining vessels.

•Main side effects of topical anti-VEGF therapy at the ocular surface are neurotoxicity as well as delayed epithelial and stromal wound healing.

•Anti-IRS-1 eye drops given twice daily have been shown in phase II trial to safely and effectively inhibit corneal neovascularization.

•Main treatment option for mature feeder vessels is fine needle diathermy combined with topical anti-VEGFs. Main drawback is the high rate of reperfusion if disease is still active.

Treatment Options for Mature Corneal Vessels

Angioregressive therapies allow to regress preformed pathologic corneal blood vessels. Whereas the regression of novel, newly outgrown blood vessels (in the socalled “pruning-phase” [31]) can be achieved by removal of angiogenic agents such as VEGF, older and more mature and pericyte-covered vessels do not depend on angiogenic signaling any longer [31]. Induction of regression of these mature vessels is more complex, and would have to involve anti-VEGF strategies combined with agonists of the vascular endothelial TIE2 receptor (Angiopoetin 2). The regression phase for immature vessels again is very short, so that, e.g., removal of a loose suture or a hypoxia-inducing contact lens has to be performed very early after the onset of vessel outgrowths to cause regression of the new vessels. Since the mechanisms responsible for maintenance of lymphatic vessels are poorly understood, so

Fig. 5.7 Combined fine needle diathermy with subconjunctival Avastin and postoperative topical Avastin eye drops reliably occludes large mature feeder vessels prior to transplantation. This “preconditioning” should promote subsequent corneal graft survival [34]. Left: preoperatively; middle: 1 month after cautery and Avastin subconjunctivally and right: after 15 months

far no approach to pharmacologically regress lymphatic corneal vessels is known. Fortunately, lymphatic vessels in the cornea seem to regress spontaneously after the (inflammatory) stimulus subsides [22]. Angioocclusive approaches are useful, e.g. to prevent intraoperative bleeding during keratoplasty in vascularized high-risk eyes or to stop leakage into the cornea out of these blood vessels and to “precondition” such corneas for subsequent keratoplasty. Besides the more experimental approach of corneal photodynamic therapy, fine needle diathermy is a reliable, cost-effective, and quick treatment option. Corneal vessels are either directly cauterized or a suture needle is placed into/next to the vessel and the needle tip is then cauterized [32]. By combining that therapy with subconjunctival anti-VEGFs (e.g., Avastin) and postoperative Avastin eye drops (5 mg/ml; 5x/day for 10 days), the recurrence rate can be reduced significantly ([34]; Fig. 5.7).

Safety Profile of Anti-VEGFs at the Ocular Surface

What about the safety of topical neutralization of VEGF at the ocular surface? Although the limited evidence from published off-label clinical use of anti-VEGF therapies (primarily Bevacizumab) as well as from in vivo and in vitro safety studies suggest this specific antiangiogenic approach to be safe, several potential complications have to be kept in mind and observed thoroughly in futures studies. If one deducts potential side effects from the known physiological functions of VEGF in the cornea or in the anterior segment of the eye, several potential side effects come into play, especially given the “non-angiogenic” effects of VEGF that is its neurotrophic effect, its role in wound healing and inflammation:

(a)“Neurotrophic keratopathy”: the cornea is one of the most densely innervated tissues of the human body and we know now that VEGF is a potent neurotrophic growth factor. Physiologically, there is trace amounts of VEGF found in normal avascular corneas so that VEGF in that avascular cornea also might have a neurotrophic effect. Therefore, it may well be that a long-term anti-VEGF strategy at the cornea may reduce corneal innervation, thus leading to neurotrophic keratopathy or impaired corneal nerve regeneration.