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Corneal Crosslinking for
Keratoconus and LASIK Complications

By William Trattler, MD

Corneal collagen crosslinking (CXL) was developed in 1998 by Theo Seiler, MD, and has been shown in numerous clinical trials to strengthen the eye's clear surface (cornea) through the application of riboflavin, a form of vitamin-B2, followed by treatment with ultraviolet A (UV-A) light.

The two basic types of corneal crosslinking are:

• Epithelium off, which means the thin layer covering the eye's surface is removed, allowing for faster penetration with liquid riboflavin.
• Transepithelial corneal crosslinking (epithelium on) is where the corneal epithelial surface is left intact, which requires a longer riboflavin loading time.

Crosslinking with riboflavin and UV-A light has proven to be a first-line treatment for people with eye conditions such as keratoconus, pellucid marginal degeneration and corneal weakness (ectasia) after LASIK.

While crosslinking is used in virtually every country around the world, it is still in the FDA approval process in the United States. Both Avedro and Topcon are working to get their brands of riboflavin drops and UV light sources approved by the FDA. As well, many other single-center and multicenter clinical trials are evaluating CXL in the U.S.

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)

Corneal crosslinking can also be used in combination with other technologies, with the goal of improving the visual results more rapidly. Tiny plastic inserts known as Intacs, which are surgically implanted within the cornea, have been shown to work well with crosslinking. Surface laser vision correction guided by corneal topography has also proven to be a useful technology.

Another technology, currently under development, uses microwave energy to flatten the cornea, and this may one day prove to be effective when combined with crosslinking.

Who Are the Best Candidates for Corneal Crosslinking?

Multiple systems for corneal crosslinking have received approval in Europe. Since these systems are widely available there, the goal is to identify patients with corneal ectactic disorders such as keratoconus or pellucid marginal degeneration early in the disease process and treat them before they develop significant vision loss from ectasia.

Once they have received crosslinking, in most cases their corneal shape will either remain stable or actually improve. This can provide patients with improved visual acuity and improved ability to wear contact lenses.

Other potential applications of corneal crosslinking include the treatment of corneal ulcers that are non-responsive to topical antibiotics. Studies have found that the combination of riboflavin plus the UV light can be effective for eradicating a variety of corneal infections.

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.

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. Transepithelial Corneal Crosslinking

One of the big questions that some clinicians are researching is whether transepithelial CXL can provide similar results to crosslinking procedures where the epithelium has been removed.

In Europe, a special riboflavin formulation has been developed that helps facilitate transepithelial CXL, called Ricolin TE. 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.*

The advantages of transepithelial CXL are reduced risks of infection, corneal haze and delays in epithelial healing. While outcomes with epithelial-off CXL tend to be significantly better in younger candidates than in people older than 35**, this difference does not appear to be an issue with transepithelial CXL.*** Transepithelial CXL also allows for quicker visual recovery and less discomfort.

Novel Eye Procedure Helps Win Olympic Gold Medal

U.S. Olympic bobsledding champion Steve Holcomb overcame a heartbreaking diagnosis of legal blindness that threatened to rob him forever of his lifelong dream of winning an Olympic gold medal.

Holcomb had progressive keratoconus, a thinning of his cornea that caused irregularities on his eye's surface to continually worsen.

After undergoing corneal collagen crosslinking and implantation of an ICL, Steve Holcomb could see so well that he led his team to an Olympic gold medal victory in bobsledding. (Video: NBC Nightly News)

By 2007, his vision had degraded so rapidly that numerous ophthalmologists told Holcomb his only hope for restoring at least some sight was to undergo a corneal transplant. And this meant Holcomb could never again participate in the jarring sport of bobsledding, because his eyes could be injured.

He and Olympic team members searched for another answer and discovered that Beverly Hills ophthalmologist Brian Boxer Wachler had been performing a procedure that might save his eyesight.

Holcomb received an application of liquid riboflavin that was then activated by UV-A light. This was the transepithelial (epithelium-on) type of corneal crosslinking. Dr. Boxer Wachler followed up with implantation of a special contact lens (ICL), which further improved Holcomb's vision.

In February 2010, at the Winter Olympics in Vancouver, Holcomb and teammates rode a bobsled nicknamed the "Night Train" down icy slopes straight to an Olympic gold medal — the first in bobsledding for the United States in 62 years. (Watch video.)

Dr. Boxer Wachler sat in the stands to cheer on his patient. And because of the enormous publicity surrounding the event, Dr. Boxer Wachler has officially changed the name of his transepithelial corneal crosslinking technique to the Holcomb C3-R. It is the first medical procedure named for an Olympic athlete. (Watch video from the program The Doctors, which describes the procedure as well as its renaming.)(Watch video from the program The Doctors, which describes the procedure as well as its renaming.)

"His story is one of triumph over adversity," said Dr. Boxer Wachler, who also is a member of AllAboutVision.com's editorial board.

Dr. Boxer Wachler admits he had some harsh critics in the early years of using the procedure off label. And as far as he knows, he was the only U.S. eye surgeon using the treatment when he first developed the technique in 2003.

"Someone once told me that a pioneer is someone who goes out into the wilderness, and then comes back with arrows in his back," Dr. Boxer Wachler joked. But he saw the results and believed in what he was doing.

Critics have also disputed his argument that the epithelium should be left on the corneal surface to greatly reduce pain, accelerate healing, protect against infection and reduce the possibility of complications such as corneal haze.

While in some studies transepithelial crosslinking produced less effective results than techniques involving removal of the epithelium, Boxer Wachler said that the solution he uses loosens the eye's surface enough to allow penetration by the riboflavin. He said he also uses a more liquid consistency of the riboflavin than what was tested in other studies, to make sure the substance penetrates the cornea.

William Trattler, MD, a Miami ophthalmologist and the reviewer of this article, is participating in clinical trials that explore both methods of corneal crosslinking. He said the method Boxer Wachler uses appears to produce identical results to the epithelium-off method of CXL while significantly improving patient comfort and safety.

"My position on the epithelium-on method is that it is more comfortable and has a more rapid return of vision, while producing similar visual results," Trattler said. "Plus, it is minimally invasive." — M.H.

Current Status of Clinical Trials for Corneal Crosslinking

Current clinical trials in the United States include:

• Epithelial-off CXL for progressive keratoconus, sponsored by Avedro.
• Epithelial-off CXL for keratoconus and ectasia, sponsored by Topcon Medical Systems.
• Multicenter epithelial-on CXL study conducted by the CXL-USA Study Group.

If you are interested in participating in a U.S. clinical trial, visit our access page for the clinical trials database operated by the National Institutes of Health, and type in a search for corneal crosslinking.

Information displayed there will show you where research sites are located and if investigators are still actively recruiting candidates.

You should be prepared to pay from $2,500 to $4,000 per eye for the crosslinking procedure. It is not covered by insurance, because it is still considered investigational in the United States.

[Page updated September 2012]