Planning Ahead for Collagen Crosslinking

When the technology gets FDA clearance, what will it take to get it up and running in your practice?

By Samantha Stahl, Assistant Editor

Though estimates for an FDA clearance timeframe vary, ophthalmologists are increasingly in agreement about the value of corneal collagen crosslinking (CXL). Already a proven success overseas and up north in Canada, the procedure has become the standard for halting keratoconus and ectasia progression. The UV-A light-activated riboflavin solution preserves corneal strength and, in some cases, increases the patient's visual acuity—an achievement that, at this time, only CXL can boast.

One of the most exciting features of crosslinking, says William Trattler, MD, of Miami, is that with an over 10-year track record of safety in Europe, the technology is continually evolving even without current availability in the US. There are currently multiple clinical trials occurring here, with many more on the way. It is expected that two new crosslinking trials will soon launch up to 70 more investigational sites in the US for both Topcon and Avedro, the companies currently developing technology and pursuing FDA approval. It's safe to say that this promising technology will have vast implications for clinical practice when it finally gets the green light. Here's a preview of how it may play out in your practice.

A 38-year-old male with keratoconus (from left to right): six months after epi-off CXL, preop and his difference map.

An Easy Transition

One big reason for crosslinking's potential success, say proponents, is the low learning curve. Removing the epithelium is something that nearly every ophthalmologist is already familiar with, and for those who already own an excimer laser, it will be relatively easy to incorporate the treatment into practice, says Gregory Pamel, MD, of New York City.

Because the procedure is done with the patient lying down, the practice will need a room that allows the UV light to be properly positioned over the laser bed. Depending on the type of laser the practice has, this setup may already be in place. He also recommends adding the Oculus Pentacam to the office's diagnostic lineup to validate the treatment.

Dr. Pamel, who has been a principle investigator on Topcon's corneal collagen crosslinking clinical trial since July of 2010, says the Pentacam has been used in all the studies to determine the effectiveness of the procedure. The Pentacam software provides Kmax value, which allows surgeons to follow the effect of the treatment with a measurement of the steepest K value measured by the device.

While the learning curve is easy, there are a few pearls that physicians should be mindful of. “Be vigilant about not letting the cornea deteriorate to a point where it thins below a critical thickness of 400 microns. This value was determined to provide the safety from damage to the endothelium from UV light. Also check for the presence of riboflavin in the anterior chamber,” advises Dr. Pamel. He explains that riboflavin serves not only to interact with the UV light to form crosslinks of the collagen molecules, but also to protect the other structures of the eye from the UV light.

Postoperative care is fairly straightforward, with a bandage contact lens placed in the eye and removed three or four days after the procedure—very similar to handling PRK patients. A drop regimen consisting of a steroid, antibiotic and nonsteroidal inflammatory is usually prescribed for two weeks and tapered once the contact lens has been removed. Pain is reported after the procedure for the first day but usually resolves after that. Follow-up is limited, with a check after one week, one month and then three months after. Pentacam measurements should begin at one month. Complications can occur, such as delayed epithelial healing, corneal infiltrates and corneal haze, but they are relatively infrequent.

One of the biggest challenges, however, is managing patient expectations, as many will understandably be keenly interested in the speed and quality of visual recovery. “Patients may focus on the potential improvement in vision that can occur with this procedure or flattening of their cornea—which is up to 70% in some published studies. Vision most likely will get worse before it gets better, so you need to present realistic expectations of what we're trying to accomplish,” says Dr. Pamel. Make patients aware of the slow process—it may take six months or longer to see a change. He emphasizes with patients that the treatment has been shown to halt the progression of keratoconus in a very high percentage of patients. “They feel assured based on the existing published data that this treatment will prevent their condition from getting worse.”

Most refractive surgery suite staff will also be easily trained for crosslinking, says A.J. Kanellopoulos, MD of Athens, Greece and New York City, since most steps are similar to any refractive procedure done on an outpatient basis. He cautions about arranging a protocol for the handling of riboflavin, which is extremely sensitive to sunlight and the light frequencies that are close to sensitizing (370 nm to 480 nm). The solution should be handled in special vials that are not penetrated by light to maintain efficacy.

The instrumentation needs are also very simple, just a lid speculum and an epithelium-removing device before applying the UV light. Dr. Kanellopoulos uses the PTK mode on Alcon's Wavelight Allegretto Wave laser to treat 6.5 mm diameter and 50 µm depth and uses the epithelium as a masking agent to get a more homogenous surface postop. While the first popular UV-emitting devices use a 3 mw wavelength, the past few years have seen devices develop with 5 mw, 10 mw and even 30 mw wavelengths to shorten treatment duration.

Smoothing Surgical Flow

While the technology is promising and the skillset is well within the purview of any anterior segment surgeon, the procedure, including prep work, can take over an hour—a chunk of time most ophthalmologists aren't used to devoting to a single procedure. Making a few simple adjustments to your surgical setup, however, will maintain the usual flow.

“That will probably be the main challenge for physicians—doing the procedure without disrupting their day,” says Dr. Pamel. Luckily, he says there are many ways to set up the procedure and get an effective result.

Designating a specific technician who can calibrate the UV light, set up the surgical room and give the riboflavin solution is crucial, he adds. Though this takes a staff member away from your regular office hours, it will allow physicians to see other patients simultaneously.

“Physicians initially will have to do every step of the procedure to get a sense of their system and how it works in conjunction with other examination rooms. Eventually, however, most physicians will probably train other staff members to do everything other than epithelium removal,” he says. Ideally, the laser suite would be attached to the physician's office, but if that isn't the case, Dr. Pamel recommends converting an exam room and setting up the UV light there as an option.

Growth Opportunity?

CXL strengthens the cornea—will it do the same for your practice?

“Corneal crosslinking has had a very strange upbringing,” says David Muller, PhD, Avedro's CEO. “The initial thought about the potential for crosslinking wasn't very big. There were no serious commercial entities involved for over a decade from when it was first started.” As clinical data developed, however, interest was piqued and enthusiasm increased. Now Dr. Muller foresees crosslinking being a way for doctors to expand their practice in a sensible way, since the technology will allow them to perform LASIK on patients who would ordinarily be borderline cases because their corneas were too thin. Avedro has developed technology that reduces the crosslinking time from an hour to several minutes by increasing the UV-A power.

If the procedure time can be reduced to 15 minutes or less, it may lead to expanded applications other than ectasia. “Although this is a straightforward procedure, there still is a lot to learn about crosslinking and its effects on the biomechanical strength of the cornea. There may come a day when we will add crosslinking to a routine LASIK procedure to prevent the development of ectasia.,” says Dr. Pamel. He hopes to see the treatment evolve sooner rather than later with a different wavelength and novel way of delivering the riboflavin to cut down on procedure time and eliminate the removal of the epithelium.

As the technology continues to evolve and procedure time is reduced, experts predict a wider variety of applications. One hotly debated potential use is as a prophylactic treatment offered to all LASIK patients rather than restricting it to post-LASIK ectasia patients or suspects.

“CXL is done to prevent progression of keratoconus or ectasia, so there currently is no benefit to applying it to a stable cornea,” believes Sheldon Herzig, MD, of Toronto. “CXL may flatten and thin the cornea, causing an unpredictable refractive change,” so he feels it should not be used routinely in all LASIK patients. Dr. Herzig says that young patients with definite keratoconus should be treated as soon as possible without waiting for progression, while older patients should not be treated without evidence of progression. Dr. Trattler adds that while the prophylactic application is a “cool idea,” it is too early to confirm beneficial use.

Others do see a role for this intervention. “Replacing the biomechanical stability reduction that is performed by LASIK with some mode of CXL will make LASIK the absolute preferred procedure for laser refractive surgery in the cornea,” Dr. Kanellopoulos believes.

He says that he is extremely satisfied to see younger investigators focusing on crosslinking as a prophylactic tool for “high risk” LASIK and PRK patients. He has developed a protocol for LASIK patients in which a few drops of riboflavin solution are placed within the LASIK flap for 30 seconds immediately after ablation is finished on the stromal interface. The flap is then repositioned and he irradiates five minutes with 10 mw per square centimeter of UV light. At five years follow up, he has found that the cornea is stable. He believes this method will become especially beneficial as the advent of femtosecond lasers increases the intermixing of laser corneal refractive surgery with cataract surgery.

Future Developments

Dr. Kanellopoulos reports that many investigators have found collagen crosslinking to be beneficial for infectious keratitis, corneal melts and pseudophakic keratopathy. He has introduced the combination of crosslinking with topography-guided PRK as a means of treating significant corneal scars and feels that the treatment may reduce the need for corneal transplantation and subsequent severe corneal blindness.

Dr. Trattler says that epithelium-on treatments have also received a great deal of research attention, since the method provides a quicker recovery time, less risk of infection or epithelial healing problems and less postop pain. Topcon is developing epi-on crosslinking with a new formulation of riboflavin called Ricrolin TE, which according to the manufacturer, Sooft, can penetrate more effectively even without removal of the epithelium.

At the International Congress on Surface Ablation, Femto-Lasers & Cross-Linking this past July in Deer Valley, Dr. Trattler and Roy Rubinfeld, MD, of Chevy Chase, Md., presented that epi-on can be just as effective as epi-off and that technique differences can account for most of the differences in early results that suggested otherwise.

After completing a prospective, non-randomized multi-center study, Dr. Rubinfeld and Dr. Trattler reported that there is a reduced development of corneal haze with epi-on CXL and patients can return to wearing normal contact lenses within days. They also reported that at three months, 50% of eyes treated with epi-on CXL had improved BCVA and increased slightly at six months to 51.7% of all epi-on cases.

The key to success in their study was loading the cornea with riboflavin drops for 60 to 80 minutes, which was followed by 30 minutes of UV light application. In addition to the longer procedure, Dr. Trattler points out that one downside to epi-on is that it cannot be combined with simultaneous topography-guided PRK.

As clinical trials expand, physicians can expect a whole new realm of possibilities to debut for crosslinking in coming years. “As we learn more about the way we perform crosslinking, it is going to become a pivotal tool in manipulating corneal biomechanics,” says Dr. Kanellopoulos. OM