Corneal Collagen Cross-Linking

Medically Reviewed by: Brian S. Boxer Wachler, MD

Corneal collagen cross-linking (CXL) is a minimally invasive procedure that strengthens the predominant inner layer of the cornea (stroma). It is used to treat progressive keratoconus and corneal ectasia, which is a rare but significant complication of LASIK eye surgery.

The process of the cross-linking procedure includes using ultraviolet (UV) light to spur the development of new and stronger bonds in the corneal collagen tissues. A type of riboflavin eye drop is placed on the eye during the procedure to accelerate and enhance the effects of the UV light.

CXL was first used on human eyes in 1998 and currently is approved for use in Canada and throughout Europe. The procedure is not yet approved in the United States and is under investigation by the U.S. Food and Drug Administration to determine its safety and efficacy. Early studies have shown the treatment to be highly effective.

What is Corneal Collagen?

The human cornea has five layers. The outermost layer is called the epithelium, which protects the eye from bacteria and other micro-organisms, much like the outer layer of skin on your body (epidermis). The epithelium accounts for about 10 percent of the overall thickness of the cornea.

Corneal layers under the epithelium (from outermost to innermost) are: Bowman's layer, stroma, Decemet's membrane, and the corneal endothelium. Of these, the stroma is the thickest layer, accounting for roughly 90 percent of the overall thickness of the cornea.

The transparent stroma is responsible for the structural integrity of the cornea, and it consists of roughly 200 layers of tiny connective tissue fibers called collagen fibers, which consist mainly of protein. It is the orderly arrangement of these collagen fibers that keep the cornea clear and maintain the shape of the front of the eye.

If bonds between collagen fibers break or there is insufficient corneal thickness to keep the collagen fibers in order—such as in keratoconus and post-LASIK ectasia—the cornea bulges forward due to the normal pressure inside the eye (intraocular pressure or IOP).
This causes increasing myopia and irregular astigmatism that eventually cannot be corrected with eyeglasses.

In severe cases, loss of the orderly arrangement of collagen fibers in the corneal stroma can lead to loss of clarity of the cornea (scarring), permanent vision loss and the need for a corneal transplant to restore vision.  

How Does Corneal Collagen Cross-Linking Work?

Corneal collagen cross-linking (also called corneal crosslinking with riboflavin, or CXL) establishes new bonds ("cross-links") between collagen fibers within the stroma. This increases the stability of the front of the eye and thereby halts or reverses problems caused by keratoconus and post-LASIK ectasia.

The riboflavin (vitamin B2) eye drops used in the CXL procedure sensitize the corneal tissue to UV light, which causes new bonds to form between collagen fibers through a process called photo-oxidation.

The amount of UV light is carefully controlled to prevent damage to the eye from exposure to too much UV radiation during CXL.

The CXL Procedure

The corneal cross-linking with riboflavin procedure consists of the following steps:

1. Numbing eye drops are applied to the eye for comfort.
2. The epithelium is gently removed so the riboflavin can easily penetrate the corneal stroma.
3. Riboflavin eye drops are applied and allowed to soak into the stromal tissue.
4. Controlled UV light is applied to the eye, usually for about 30 minutes. (During the UV exposure, additional riboflavin eye drops are applied at regular intervals.)
5. At the end of treatment, a bandage contact lens is applied to the eye and the eye is patched overnight.

Because your eye will be numbed with anesthetic eye drops, you won't feel the need to blink frequently during the CXL procedure.

Your eye doctor will examine your eye the following day to make sure it is healing properly and several additional follow-up exams will be performed to monitor your progress. Generally, the corneal epithelium grows back within a few days.

You also will be prescribed antibiotic and anti-inflammatory eye drops for use after the procedure to reduce the risk of post-surgical complications and make your eye more comfortable during the healing process.

Variations of the CXL procedure—called transepithelial CXL or Holcomb C3-R Crosslinking—where the epithelium is left intact during the riboflavin/UV treatment are used by some eye doctors. Your doctor can discuss the pros and cons of these variations of the procedure during your pre-treatment consultation.

In some cases, CXL is combined with implantation of intrastromal corneal ring segments (such as Intacs) for the correction of keratoconus.

Safety and Effectiveness of Corneal Cross-Linking

In most cases, a single CXL treatment is sufficient to halt the progression of keratoconus or post-LASIK corneal ectasia and improve vision and corneal shape.

In one long-term study of CXL for the treatment of keratoconus that included 23 eyes with moderate or advanced keratoconus, corneal collagen cross-linking with riboflavin effectively halted the progression of keratoconus for a follow-up period spanning 4 years.

In another long-term study that had a maximum follow-up of 6 years, the corneal curvature of keratoconic eyes decreased significantly in the first three years after CXL treatment and a majority of treated eyes had significant improvement in best-corrected visual acuity.

In a study of transepithelial CXL for progressive keratoconus published in 2011, evaluation of the treated eyes 18 months after the cross-linking procedure showed significant improvements in uncorrected and corrected visual acuity and improved corneal shape (flattening of the corneal apex).

Another recent study evaluated the outcomes of CXL for the treatment of both keratoconus and post-LASIK ectasia. In this study, the treatment group underwent the standard CXL procedure and the control group received riboflavin eye drops only (without UV light exposure).

Results of the study showed corneal collagen cross-linking with riboflavin improved uncorrected and corrected visual acuity and corneal shape over the 1-year follow-up period, compared with eyes treated with riboflavin eye drops alone. The eyes with keratoconus had more improvement in corneal topography than eyes affected by post-LASIK ectasia.      

In a French study of 142 keratoconic eyes published in December 2011, at one year after CXL, progression of keratoconus had stopped in 69 percent of eyes, and the steepest curve of the cornea had decreased by more than 2.0 diopters in 13 eyes (21 percent). Corrected distance visual acuity had improved in 40 percent of treated eyes, stabilized in 48 percent, and decreased in 12 percent. The overall complication rate (with vision loss) was 3.5 percent.

Vision After Cross-Linking

While these and other studies show corneal collagen cross-linking is safe and effective for the treatment of both keratoconus and post-LASIK ectasia and typically improves visual acuity, some residual nearsightedness and astigmatism usually remain after CXL, requiring correction with eyeglasses, contact lenses or refractive surgery.

Also, it is common for eyes affected by keratoconus or post-LASIK ectasia to be unable to attain 20/20 best-corrected visual acuity, even after CXL treatment.

Your eye doctor can evaluate your specific condition, determine if you are a good candidate for the CXL procedure, and advise you of the expected outcome of your corneal collagen cross-linking procedure.

Resources:
1. Corneal collagen cross-linking. Cataract & Refractive Surgery Today. September 2009.
2. Corneal collagen cross-linking. Middle East African Journal of Ophthalmology. January-March 2010.
3. Riboflavin/ultraviolet-A-induced collagen crosslinking for the correction of keratoconus. American Journal of Ophthalmology. May 2003.
4. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. Journal of Cataract & Refractive Surgery. February 2006.
5. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. Journal of Cataract & Refractive Surgery. May 2008.
6. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. Journal of Cataract & Refractive Surgery. January 2011.
7. Transepithelial corneal collagen crosslinking: bilateral study. Journal of Cataract & Refractive Surgery. Published online ahead of print November 20, 2011.
8. Holcomb C3-R - proprietary, non-surgical corneal crosslinking. Boxer Wachler Vision Institute website. Accessed December 19, 2011.
9. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. Journal of Cataract & Refractive Surgery. December 2011.

Note: This information is for general education purposes only. It is not to be used as a substitute for medical advice from your eye doctor or refractive surgeon.

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About the Reviewer

Brian S. Boxer Wachler, MD, is a Board-certified ophthalmologist and multi-published book author in private practice in Beverly Hills, CA. Often referred to as “America’s TV Eye Doctor,” Dr. Boxer Wachler has a stellar reputation for excellence amongst his peers who have elected him as one of the “World’s Best Refractive Surgeons.”

Dr. Boxer Wachler (or Dr. Brian as his patients affectionately call him) has devoted his career to vision correction, with expertise spanning an array of conditions and treatments, including cataract surgery, FortifiedLASIK™, the treatment of keratoconus and more. To learn more about Dr. Brian, visit his keratoconus specialty website at https://keratoconusinserts.com/

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