Article Date: 6/1/2012

corneal cross-linking
corneal cross-linking

CXL: Strengthening the Ties That Bind

Now in FDA trials, corneal collagen cross-linking has been shown to slow the progression of keratoconus and post-LASIK corneal ectasia in European studies.

Frank Giardina, O.D., F.A.A.O., Santa Maria, Calif.

For years, optometrists have remained limited in their options to effectively treat or otherwise manage significant keratoconus and post-LASIK corneal ectasia.

RGP contact lenses can improve visual acuity in many keratoconus patients, but the condition often progresses to require corneal transplantation to restore useful vision.1 The condition’s relentless course occasions the need for vision-prescription upgrades with paradoxically poorer outcomes through time.

Corneal ectasia post-refractive surgery is yet another keratic malformation for which better treatments have long been sought.

At the far end of the treatment-invasiveness spectrum for both conditions lies corneal transplantation, which comes with advantages and drawbacks. An effective, yet minimally invasive, treatment for keratoconus and corneal ectasias has long stood as an unmet need.

Into this clinical scenario arrives a relatively novel treatment approach called corneal collagen cross-linking (CXL). Developed at Germany’s Technische Universität Dresden, the mildly invasive procedure essentially involves epithelial debridement; the topical instillation of a photosensitizing riboflavin (vitamin B2) eye drop; and UVA light exposure.2 Besides an anesthetic eye drop, the clinician may wish to administer a mild sedative to quiet jangled nerves prior to treatment.

Already tested, approved and widely used for many years in Europe, the procedure is currently being investigated in FDA clinical trials (see “Update of U.S. Clinical Studies,” page 49). Earlier studies and European clinical experience to date indicate CXL is a safe and effective treatment that halts the progression of keratoconus and post-LASIK corneal ectasia by improving the cornea’s biomechanical stability.

Indications for CXL

A normal cornea has cross-links between its collagen fibers that allow it to maintain its habitual shape. Keratoconus is a naturally occurring non-inflammatory corneal ectasia in which the collagen fibers weaken, leading to progressive central-corneal thinning and steepening. The condition afflicts about one in 750 Americans.2 The central-corneal narrowing and distention result in increased myopia, irregular astigmatism and eventual loss of best-spectacle-corrected visual acuity.1

Post-LASIK corneal ectasia is likewise characterized by central thinning (iatrogenic) and visually detrimental bulging.

Together, refractory keratoconus and post-LASIK corneal ectasia comprise the second-leading indications for corneal transplantation, accounting for 15% of these procedures.1 (Infectious keratitis from various pathogens tops the list.)

Corneal transplants, however, can produce serious adverse events that may threaten vision and diminish the patient’s quality of life during recovery, with lost work time and perhaps permanent lifestyle changes.

The alternative: CXL.

How cross-linking works

Corneal collagen cross-linking — first performed in the United States in 2008 by Emory University’s R. Doyle Stulting, M.D., Ph.D. — strengthens the collagen cross links that serve as natural anchors within the cornea. The 30-minute office-based treatment begins with a topical anesthetic to the cornea, after which the surgeon debrides 7mm of the central epithelium to allow uniform diffusion of riboflavin into the stroma.

The clinician then applies a 0.1% solution of riboflavin to the denuded cornea. Also known as vitamin B, riboflavin is a readily absorbed micronutrient required for numerous cellular processes. In this case, it works as both a photosensitizer and UV blocker. With the patient’s eye held open with a speculum, the surgeon irradiates the cornea using UVA light with an irradiance of 3mW/cm2 and a wavelength of 370nm for 30 minutes.

After the procedure, an antibiotic ointment blankets the cornea until it has re-epithelialized, usually within one week. Healing is generally unremarkable, with the exception of slight transient stromal edema until re-epithelialization occurs.

The risk of cataract formation and retinal damage secondary to UV radiation is evidently minimal. In the presence of riboflavin, 94% of UVA radiation is absorbed in the cornea’s anterior 400ųm; without riboflavin, only 32% is absorbed within this depth.1 Therefore, CXL is not recommended for corneas thinner than 400ųm.

Comanagement of CXL

Optometrists are in an excellent position to comanage patients who have progressive keratoconus or post-LASIK corneal ectasia and would therefore, may benefit from CXL.

Comanagement preoperatively calls for choosing appropriate patients and educating them on the procedure.

To do this, you must perform corneal topography to assess the cornea (both pre-and post-surgically). Also, you must measure the corneal thickness by pachymetry, ruling out those thinner than 400ųm. Careful biomicroscopy of the cornea is necessary as well.

The best time to treat keratoconus and other corneal ectasias is before astigmatism becomes severe and vision has been lost.2 Early detection and timely referral for treatment yield the best results. Those with very poor preoperative vision may benefit from CXL; however, the treatment’s results for patients with advanced keratoconus have been less successful.2

Postoperatively, you must look for these possible complications via slit lamp.

Stromal haze. Some patients may experience steroid-resistant stromal hazing within two or three months after treatment. It’s usually minor, with little effect on visual acuity.

Stromal demarcation. Sometimes, a stromal demarcation line appears about two weeks after treatment. This may occur due to changes in the refractive index or reflection properties of the treated vs. untreated corneal tissue.

Corneal collagen cross-linking results in flatter keratometry readings and, therefore, better uncorrected and corrected visual acuity. It does not necessarily eliminate the need for glasses or contact lenses. That said, postoperative corneas are easier to fit in contact lenses.

Update of U.S. Clinical Studies

The FDA has acceded to three U.S. clinical trials to evaluate the safety and efficacy of corneal collagen cross-linking for those with keratoconus or post-LASIK corneal ectasia.1

The first is a physician-sponsored Investigational New Drug (IND) clinical trial initiated in 2008 by Emory University’s R. Doyle Stulting, M.D., Ph.D., the study’s principal investigator. Two multicenter studies — one for progressive keratoconus and the other for corneal ectasia — are sponsored by the Swiss-based company (Peschke Meditrade), which makes a UV-illumination system commonly used in the procedure and are being used at 10 U.S. sites.

Designed to enroll 160 patients in both, the multicenter studies are randomized, controlled clinical trials wishing to determine the safety and effectiveness of Peschke Meditrade’s UV-X Illumination System for CXL. The studies are comparing the effect of riboflavin/UVA light (the CXL group) to that of riboflavin alone. At three-to-six months, subjects with no contraindications have the option to receive the procedure in their fellow untreated eye. Controls have the same alternative. All eyes are followed for 12 months following treatment.

While CXL remains under investigation in the United States, results from earlier international clinical trials revealed it halts the progression of keratoconus and post-LASIK corneal ectasia.1 Beneficial outcomes: improved corneal stability, increased flattening, and better vision. The effects appear to be long-term, as some patients in the European studies have been followed up to eight years after treatment.

Hope for misshapen corneas

Corneal collagen cross-linking (CXL) is a new and exciting treatment for keratoconus and other forms of corneal ectasia.

O.D.s are ideally positioned to comanage these patients. Remember: Early detection of treatable keratoconus and post-LASIK corneal ectasia and prompt CXL referral are likely to yield the best outcomes. You have the tools, the knowledge and the patients. Keep an eye out for U.S. clinical study outcomes and regulatory action. OM

1. NKCF: National Keratoconus Foundation. US Corneal Collagen Crosslinking Study. (Accessed 5/12).

2. CXLUSA Online. FAQs About Treatment Options for Keratoconus. (Accessed 6/5/12’)

Dr. Giardina is the area doctor for First Sight Vision Services. To comment on this article, e-mail optometricmanagement@

Optometric Management, Volume: 47 , Issue: June 2012, page(s): 48 49 74