Research Review

Corneal Neovascularization in Contact Lens Practice

BY LORETTA B. SZCZOTKA-FLYNN, OD, PHD, MS, FAAO

Corneal neovascularization is a concern when fitting patients with contact lenses after keratoplasty, interstitial keratitis, significant ocular trauma, chemical burns, limbal stem cell deficiency, or even low-Dk/t contact lens wear. Irregular corneas such as those mentioned above are classically prescribed high-Dk GP corneal lenses, which provide as much oxygen transmissibility and tear exchange as possible.

More recently, high-Dk scleral lenses have been used with increasing frequency. However, despite the best lens fit, corneal vascularization can persist with new vessel formation secondary to the underlying pathology. Most new vessel formation is termed angiogenesis, referring to the sprouting or splitting of new vessels from pre-existing vessels at the corneoscleral limbal vascular plexus (as opposed to vasculogenesis, or de novo formation of blood vessels).

This review summarizes epidemiology, pathogenesis, consequences, and potential new treatments for corneal angiogenesis, which every specialty contact lens fitter should be aware of as they monitor such patients.

How Neovascularization Occurs

The cornea is avascular under normal homeostatic conditions—which is considered "corneal angiogenic privilege"—as opposed to other vascularized tissues in the human body. Corneal avascularity is actively maintained by the expression of many redundant antiangiogenic mechanisms and results in transparent tissue and optimal vision.

However, sight-threatening complications occur when the balance between angiogenic and anti-angiogenic factors shift toward angiogenic molecules such as vascular endothelial growth factor (VEGF). Corneal neovascularization ultimately reduces visual acuity by inducing stromal edema, cellular infiltration, lipid deposition, hemorrhage, and scarring (Stevenson et al, 2012).

Managing Neovascularization in Corneal Transplant Patients

For contact lens fitters, the most common presentation of corneal neovascularization occurs after corneal transplantation. About 40,000 corneal transplants are performed in the United States annually (Eye Bank Association of America Annual Report, 2012) Abnormal angiogenesis can be evoked from suture-induced inflammation and alloimmune responses (Dana et al, 1995).

Corneal neovascularization is a known risk for graft rejection as it removes the angiogenic privilege. In fact, the risk of corneal graft rejection has been correlated with the number of corneal quadrants that exhibit neovascularization (Bachman et al, 2010). The abnormal vessels allow increased afferent and efferent access to graft alloantigens, priming the immune system for rejection (Dana, 2006).

When presented with someone for contact lens fitting who has a vascularized graft, I first evaluate whether the vessels are old and established or new and active. Established vessels do not depend on VEGF anymore for proliferation (Keonig et al, 2009) and produce overall fewer inflammatory factors. My goal in lens fitting at this point is to prevent any change or increased stimulus that would re-activate vessel progression. The vessels are usually thin, superficial, and don't cross the graft host-junction. I often consider small-diameter, high-Dk corneal lenses or larger scleral lenses that sit well past the limbus (18.2mm or larger).

Active vessels are usually located in the deeper stroma, appear engorged, often cross the graft-host junction, and under slit lamp evaluation can even appear to be pumping blood. In such a cornea, I suggest discussing treatments with the corneal surgeon that may stop or reverse the active vessel growth while, or prior to, initiating contact lens fitting. I usually try corneal, high-Dk GP lenses first. Large scleral lenses are also an option, but you should make every effort to avoid any limbal engorgement as this is a potent stimulus to very rapid angiogenesis. I also avoid piggyback fits and hybrid lenses that have low-Dk soft skirts, which contribute to hypoxia at the limbus.

Treatment Options

Several medical therapies exist for controlling neovascularization. Topical steroids are the standard medical treatment for active corneal neovascularization associated with corneal transplantation. Inflammation is a characteristic shared by all etiologies of corneal neovascularization (Stevenson et al, 2012), as inflammatory cells are not only rich in VEGF but also cytokines, chemokines, and other inflammatory mediators that promote the angiogenic cascade. Therefore, topical steroids suppress the development of inflammatory-mediated neovascularization, but not stable corneal neovascularization.

Non-steroidal anti-inflammatory drugs (NSAIDs) play a similar role as they inhibit the production of prostaglandins in the angiogenic cascade. However, they are less utilized due to variable efficacy and occasional side effects in patients who have ocular surface disease.

Laser-induced photocoagulation and photodynamic therapy have also been used to treat corneal neovascularization, but both are limited by the stimulation and release of pro-angiogenic factors that promote the development of collateral circulation (Stevenson et al, 2012). Combining these treatments with angiogenesis-specific inhibitors, such as anti-VEGF treatment, may overcome these limitations.

VEGF and Topical Anti-VEGF Therapy VEGF is upregulated in inflamed corneas, and it promotes several steps of angiogenesis such as endothelial cell proliferation, migration, and capillary tube formation (Keonig et al, 2009). There are multiple members of the VEGF family including VEGF-A, VEGF-B, VEGF-C, and VEGF-D.

Animal models have demonstrated that topical or subconjunctival administration of the anti-VEGF treatments ranibizumab (Lucentis) or bevacizumab (Avastin, both Genentech), are effective medications in the treatment of corneal neovascularization. Bevacizumab is humanized monoclonal antibody blocking VEGF-A, which was initially approved for metastatic colon cancer. Ranibizumab is a high affinity antibody fragment produced by recombinant DNA technology that blocks all the isoforms of VEGF (Turkcü et al, 2013). These agents have proven valuable in the treatment of retinal conditions such as neovascular age-related macular degeneration and diabetic retinopathy.

Topical and subconjunctival ranibizumab treatment has been assessed in an experimental corneal neovascularization model in rats. The percentage of the corneal neovascularization area and the number of vessels in all treatment groups were significantly lower compared to the control group (Turkcü et al, 2013). The inhibitory effects of topical and subconjunctival bevacizumab on corneal neovascularization were also assessed in a rat model in which, histologically, each treatment group had fewer vessels compared to the control group (Öner et al, 2012).

In humans, off-label uses of topical ranibizumab and bevacizumab in the treatment of corneal neovascularization have also been studied. Koenig et al (2009) showed that off-label topical bevacizumab therapy against corneal neovascularization was generally well-tolerated for up to 12 months. Bevacizumab eye drops inhibited corneal neovascularization and led to a reduction of the vessel diameter. Stevenson et al (2012) have also shown that both ranibizumab and bevacizumab demonstrated clinical utility in the control of corneal neovascularization.

These findings clearly indicate that ranibizumab and bevacizumab are promising and effective future treatments for corneal neovascularization, especially when combined with other therapies. Of course, appropriate precautions must be observed as side effects ranging from epitheliopathies, descemetocele, persistent epithelial defects, and neurotrophic keratopathies are possible (Keonig et al, 2009). Managing the contact lens fit to avoid an additional stimulus to vascularization in addition to these potential new therapies can help minimize sight-threatening corneal neovascularization. CLS

For references, please visit www. clspectrum.com/references.asp and click on document #217.

Dr. Szczotka-Flynn is a professor in the Departments of Ophthalmology & Visual Sciences and Epidemiology & Biostatistics at Case Western Reserve University and director of the Contact Lens Service at University Hospitals Case Medical Center Eye Institute. She is also the director of the Coordinating for the CPTS Study. She receives research funding from Alcon and Vistakon.