Corneal Cross-linking

This minimally invasive procedure strengthens the cornea to halt keratoconus progression.

BY ERIC D. DONNENFELD, MD, FAAO

From the time a patient shows the first signs of keratoconus, the disease begins its 10- to 15-year progression of corneal thinning, weakening, distortion and corneal scarring. We apply all the tools at our disposal to preserve vision. Rigid gas permeable contact lenses are key. Intacs corneal implants (Addition Technology, Inc.) are another treatment option. Eventually, some patients must undergo corneal transplants.

But what if instead of battling and adapting to the progression of corneal ectasia, we could actually stop it? Corneal collagen cross-linking (CXL) may have the ability to do just that.

CXL is the only procedure that can strengthen the cornea to stop keratoconus progression, protecting vision and delaying or potentially eliminating the need for a corneal transplant. This cutting edge, minimally invasive keratoconus treatment increases the cornea’s collagen connections (cross-links), thus helping the cornea retain its shape.

Developed in Switzerland nearly 15 years ago, CXL is approved in most countries but is still under investigation in the United States. The biggest sponsor right now for an FDA trial is Avedro, makers of VibeX riboflavin and the KXL System. Several other sponsors such as CXLusa, an international group of eye surgeons, are applying for approval as well. The approval for cross-linking is going through the medication route, so the riboflavin needs to be approved along with the device. The previous study by Peschke GmbH was rejected by the FDA because the riboflavin did not meet the specifics of the FDA. Right now, the Avedro trial has been completed and the FDA is asking for long-term follow up before evaluating the procedure for approval.

Figure 1. Examining the patient at the slit lamp for riboflavin absorption.

The Root of Keratoconus

Keratoconus’ characteristic changes to the shape of the eye occur as the cornea grows thinner and weaker, which in turn is the result of changes to the cornea’s collagen structure. We don’t know why these structural changes occur. One possible cause is that keratoconic eyes can’t repair themselves in the same way that healthy eyes can. This opens the door to free radicals in the cornea, which oxidize and weaken the collagen links.

By strengthening collagen links, CXL is the first keratoconus treatment that goes to the root of the disease. The procedure has very little down side and very promising benefits, making many patients excellent candidates.¹ I recommend CXL for any patient showing progression of ectatic disease whose corneal thickness is at least 400 μm (although exceptions can be made). Young patients are good candidates, as are older patients who have controlled keratoconus. I perform CXL on patients with post-LASIK ectasia as well. CXL patients should have no herpetic infection or corneal scarring.

About 80% of my patients who have undergone CXL have experienced improvement in their best-corrected vision, as well as flattening of the cornea that reduces cylinder.

The CXL Procedure

The CXL procedure combines riboflavin (vitamin B2) drops with exposure to ultraviolet light, which shifts the riboflavin, releasing free radicals and causing collagen lamellae to bond to each other in a process referred to as cross-linking.

First, I instill anesthetic eye drops. The next step is to remove the central 8 mm of the corneal epithelium to allow the riboflavin to penetrate the cornea. I perform manual debridement with a PRK spatula, but two other alternatives are alcohol debridement or using a rotating brush.

After removing the epithelium, I administer one drop of 0.1% riboflavin in the eye every 2 minutes for 30 minutes, at which point I evaluate the eye at the slit lamp to ensure the riboflavin has penetrated the cornea. For the next 30 minutes, I expose the eye to 3.0 mW/cm2 of ultraviolet light, continuing to add riboflavin drops every 2 minutes. Finally, I administer a topical corticosteroid, such as loteprednol 0.5% (Lotemax, Bausch + Lomb), and a fourth-generation fluoroquinolone. Then, I apply a protective bandage contact lens. In addition, I add a topical NSAID such as bromfenac (Bromday, Bausch + Lomb) bid for 3 days.

Patients wear the bandage contact until the epithelium has healed, which generally takes 3 to 5 days. I discontinue the topical antibiotic and NSAID at this time, but continue the topical loteprednol qid for 1 week, tid for 1 week, bid for 1 week and qd for the final week.

The outcomes of CXL begin to show after just 1 week, but the full improvements in corneal integrity occur over the course of several months to several years. One study showed that the K-Max value flattened an average 1.45D to 2.46D at 1 year.² Side effects of the procedure are rare but include sterile and infectious infiltrates similar to those seen following PRK. Rarely, corneal haze can occur but generally resolves after 6 months. In these cases, I continue the topical corticosteroid for an additional month. Patients can return to contact lenses at 1 month after CXL.

Figure 2. Patient undergoing cross-linking with a UV light.

The Future of CXL

I was one of the investigators in the first FDA study for CXL, which was completed several years ago. The results were excellent, but the FDA did not accept the study based on a flaw in the group design. A new FDA study is needed.

Riboflavin-ultraviolet cross-linking is already approved in virtually every country other than the United States. There are several ongoing CXL studies right now, and although it’s hard to project when they will be finished, the common wisdom is that CXL may have FDA approval in about 2 years. My hope is that one day, when CXL is approved, the procedure will prevent many young patients from progressing to need corneal transplantation. ■

References

1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620-627.

2. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24(7):S720-S725.

Eric Donnenfeld, MD, is a clinical professor of ophthalmology at New York University Medical Center and a partner in Ophthalmic Consultants of Long Island in Rockville Centre, N.Y.