Corneal Cross-linking (CXL):
For Keratoconus Treatment and
LASIK-Related Corneal Ectasia
Corneal cross-linking (CXL) is an in-office eye procedure that strengthens the cornea if it's been weakened by keratoconus, other corneal disease, or (rarely) a complication of LASIK surgery. Alternative and brand names for the procedure include corneal crosslinking, corneal collagen crosslinking, C3-R, CCL and KXL.
The minimally invasive CXL procedure involves applying liquid riboflavin (vitamin B2) to the surface of the eye, followed by treatment with a controlled application of ultraviolet light, to eliminate corneal ectasia.
The two basic types of corneal cross-linking are:
- Epithelium-off CXL. In this type of cross-linking procedure, the thin outer layer (epithelium) of the cornea is removed to allow the liquid riboflavin to more easily penetrate the corneal tissue.
- Epithelium-on CXL. In this procedure (also called transepithelial CXL), the protective corneal epithelium is left intact, requiring a longer riboflavin "loading" time.
Corneal crosslinking also can be combined with other procedures for keratoconus treatment. For example, combining CXL with implanting tiny arc-shaped corneal inserts called Intacs has been shown to help reshape and stabilize the cornea in more advanced cases of keratoconus.
Current Status of CXL in the United States
Corneal collagen cross-linking is performed in many countries, but the procedure has not yet gained FDA approval for use by eye doctors in the United States.
The aim of corneal crosslinking is to strengthen the cornea by increasing the number of "anchors" that bond collagen fibers together. (Diagram: Boxer Wachler Vision Institute)
In June 2015, Boston-based pharmaceutical and medical device company Avedro announced the sale of its 500th corneal cross-linking device outside of the United States and said that approximately 200,000 patient eyes have undergone treatment with the company's Photrexa/KXL System for corneal crosslinking.
Earlier in the year, Avedro announced it received a response from the FDA concerning the company's application for approval of its crosslinking system in the U.S., in which the agency identified areas in the application that require additional information before approval could be granted. None of the FDA's concerns pertained to the safety or efficacy of the procedure demonstrated in clinical trials, according to the company, and in a press release issued in March 2015, Avedro said the company is "diligently working to resolve these outstanding questions with the goal of making this vital treatment available (in the U.S.) as soon as possible."
Avedro's Photrexa/KXL System received orphan status from the FDA in 2011, which means the treatment will have seven years of market exclusivity in the United States once approved.
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Who Are the Best Candidates for Corneal Crosslinking?
Corneal crosslinking is most effective if it can be performed before the cornea has become too irregular in shape or there is significant vision loss from keratoconus or other causes of corneal ectasia. If applied early, CXL typically will stabilize or even improve the shape of the cornea, resulting in better visual acuity and an improved ability to wear contact lenses.
Other potential applications of CXL include the treatment of corneal ulcers that are unresponsive to treatment with topical antibiotics. Studies also have found that corneal cross-linking can be effective for eradicating a variety of corneal infections.
SEE ALSO: Ask the Eye Doctor About Keratoconus >
Some surgeons have also reported reasonable results in improving the stability of the cornea in people who have undergone radial keratotomy, an incisional refractive procedure from the 1980s and 1990s. Crosslinking appears to work best for those who are experiencing daily fluctuations in their vision.
People who are considering vision correction procedures such as LASIK also might eventually be pre-treated with corneal crosslinking to strengthen the eye's surface before undergoing an excimer laser ablation that reshapes the cornea.
What To Expect During and After a Corneal Crosslinking Procedure
During preliminary examinations, your eye doctor will measure the thickness of your cornea and make sure you are a good candidate for the procedure. You also will need to have a routine eye exam to assess your visual acuity and general eye health. And your doctor will perform mapping of your cornea (called corneal topography) to determine the level of your eye condition.
Layers of the cornea. Corneal crosslinking strengthens bonds in the stroma of the cornea, which is the layer from which tissue is removed during LASIK surgery.
The crosslinking procedure takes 60 to 90 minutes in most cases. If you are receiving epithelial-off crosslinking, your surgeon will place you in a reclining position and remove the epithelial layer from your cornea. Riboflavin eye drops will then be placed.
If you are receiving epithelial-on crosslinking, you are placed in a reclining position, and riboflavin drops are started. After enough time has passed (depending on the technique), the surgeon will evaluate your eye to ensure that the cornea has sufficient riboflavin present.
The corneal thickness will be checked, and then the UV light will be applied for up to 30 minutes.
In some cases, a bandage contact lens will be placed. Topical antibiotic and anti-inflammatory drops will be prescribed.
With both epithelial-off and epithelial-on CXL, studies have found that 99 percent of patients will remain stable or achieve improvement in the corneal shape, which is highly significant for people with progressive keratoconus that otherwise might lead to blindness.
Epithelium-off vs. Epithelium-on CXL
One of the big questions that some clinicians are researching is whether epithelium-on (transepithelial) CXL can provide similar results to crosslinking procedures where the epithelium has been removed.
In Europe, a special riboflavin formulation (Ricrolin TE) has been developed that helps riboflavin penetrate the corneal epithelium more easily to facilitate epithelium-on CXL. In the United States, investigators are evaluating the effectiveness of transepithelial CXL, and to date these researchers have reported visual results that are similar to those of epithelial-off CXL.
Advantages of epithelium-on CXL include reduced risk of infection, less corneal haze and fewer delays in epithelial healing. And though some studies show outcomes with epithelial-off CXL tend to be significantly better in younger candidates than in people older than age 35, this difference does not appear to be an issue with transepithelial CXL. Epithelium-on CXL also allows for quicker visual recovery and less discomfort.
How To Get CXL Prior to FDA Approval
If you have keratoconus or corneal ectasia, it may be possible for you to undergo corneal cross-linking treatment in the United States prior to official FDA approval by participating in a clinical trial designed to evaluate the safety and effectiveness of the procedure.
If you are interested in participating in a study of this sort, visit our access page for the clinical trials database operated by the National Institutes of Health, and type "corneal cross-linking" in the search box on the page to obtain information about current CXL trials, research site locations, and if investigators are still actively recruiting candidates.
Another option is to travel to a location outside the United States to have corneal cross-linking performed in a country where the procedure has full regulatory approval. For example, CXL has been approved in Canada since 2008 and has been available even longer in several western European countries. An eye doctor who specializes in keratoconus treatment in the United States can advise you regarding his or her preferred international clinics where CXL is performed and usually can perform follow-up exams for you here at home.
Another possibility might be to have corneal cross-linking performed by a qualified eye doctor on an off-label basis. "Off-label" is the term used to describe when a drug or medical device is used for a purpose for which it does not yet have regulatory approval. Off-label use of drugs and medical devices is legal in the United States, provided certain conditions are met and the patient is fully informed and agrees to the treatment.
Before proceeding with CXL (or C3-R, CCL, KXL, or any other type of corneal cross-linking procedure) for keratoconus, corneal ectasia or other conditions, consult with your eye doctor so you fully understand the approval status, legality, risks, contraindications and possible side effects of the procedure.
Cost of Corneal Cross-Linking
Be prepared to pay from $2,500 to $4,000 per eye for a corneal cross-linking procedure. CXL usually is not covered by health insurance, because it is still considered an investigational procedure in the United States.
Cross-linking platform denied FDA approval - for now. Ophthalmology Innovation Summit (OIS) Eye on Innovation e-newsletter. April 2015.
Avedro announces receipt of complete response letter from FDA for corneal cross-linking NDA. Press release issued by Avedro, Inc. in March 2015.
Multicenter evaluation of trans-epithelial versus epithelial-off corneal collagen crosslinking (CXL) for keratoconus and post-LASIK ectasia. Poster 363, American Academy of Ophthalmology Annual Meeting. October 2011.
Evaluation of epithelial-on corneal collagen crosslinking in patients ages 35 or older. E-Poster 101325, International Society of Refractive Surgery Annual Meeting. October 2011.
Collagen corneal cross linking. Presentation by Ramon Naranjo-Tackman, MD, at Cornea Day 2011 sponsored by the American Society of Cataract and Refractive Surgery. March 2011.
Corneal collagen crosslinking: promises and problems. British Journal of Ophthalmology. December 2010.
Complication and failure rates after corneal crosslinking. Journal of Cataract & Refractive Surgery. August 2009.
Marilyn Haddrill also contributed to this article.
[Page updated November 2015]