Refining Protocols for Corneal Cross-Linking

With further refinement, this outpatient procedure could reduce the number of corneal transplantations in keratoconus patients

In the spring of 2016, after more than a dozen years of clinical experience outside of the United States, the FDA approved corneal cross-linking (CXL) for keratoconus, a non-inflammatory progressive ectasia of the cornea that affects approximately 1 in 2,000 individuals in the U.S.1 In European countries, where cross-linking has been in use for more than a decade, research is not only revealing a significant reduction in the number of corneal transplants performed for keratoconus but also strongly suggesting that this reduction is due in part to the growing number of corneal cross-linking procedures performed to address keratoconus.2

While a trend toward fewer corneal transplants for patients with keratoconus also has been reported in the U.S.,3 most data used to identify this trend were obtained before 2016, so it is still too early to say if CXL has played a role. Yet, many experts anticipate that this procedure will indeed help to halt the disease progression in keratoconus that necessitates corneal transplantation.

As cornea specialists continue to gain experience with CXL, their focus is on refining the protocols and techniques used during and after the procedure. The pros and cons of performing CXL after the corneal epithelium has been removed (‘epi-off’ versus ‘epi-on’) have long been a subject of debate among experts around the world. Likewise, there is still a lack of consensus regarding the best techniques for enhancing vision after CXL. Long-term outcomes will play a critical role in guiding future practice, as will the results of newer cross-linking studies.

The results of one such study,4 which examines the value of topography-guided ablation after cross-linking, were published this past August. Lead author Alanna Nattis, DO, of Lindenhurst Eye Physicians & Surgeons, talked with The Ophthalmic ASC about this study and about her practice on Long Island.

Bringing Cross-linking to a New York Surgery Center

“Cross-linking has unquestionably added another revolutionary technology to the field of cornea and refractive surgery,” suggests Dr. Nattis, whose earliest experience with the cross-linking procedure came during her fellowship training.

“During my fellowship, I saw how valuable cross-linking was for patients with keratoconus. It enables surgeons to not only prevent progression of the condition, but also provide options for visual improvement after cross-linking. At our practice, patients did not have access to cross-linking before I joined. I really pushed to offer the procedure, because I felt we needed to make this technology available to patients who otherwise might have to travel a long distance to undergo cross-linking.”

Because CXL is still a relatively new procedure, the percentage of clinicians who prefer to perform CXL in a surgery center versus an office remains to be seen. Dr. Nattis, who prefers an ophthalmic ASC setting, says she can see advantages to both settings.

“I think it’s great to perform this procedure in a controlled environment, in a quiet room with the patient, myself, and an OR nurse. In my experience, patients feel comfortable knowing that the procedure is being done in a very controlled, sterile environment. Furthermore, being in an ophthalmic ASC allows access to sterilized instrument packs for each procedure, without the burden of having to transport them to and from the office setting,” says Dr. Nattis.

“On the other hand, I can see why doing this procedure in an office might offer a certain degree of flexibility. For example, if a technician is trained and able to place riboflavin eye drops on the patient’s eye(s), the physician can be with other patients, while still in the vicinity, until the next part of the procedure. I prefer to stay with my patients, so I perform the entire procedure myself; being in an ophthalmic ASC works best for me. The decision really depends on physician preference and also what may be most convenient for the patient.”

Regardless of outpatient surgical setting, Dr. Nattis notes that it is critically important to educate patients to ensure that they are prepared for the procedure.

“I explain to my patients that cross-linking is a very successful, FDA-approved outpatient procedure that will help to stop their keratoconus from getting worse,” says Dr. Nattis. “I let patients know I will follow them very closely after the procedure to ensure that they heal properly, and I explain that antibiotic and steroid eye drops will be part of an eye drop regimen afterward. I make sure they understand that healing will happen slowly, and that although they may have discomfort initially, they should start to feel better in about 4 to 7 days. I also tell patients that vision can fluctuate slightly for 3 to 6 months after the procedure. And, of course, I counsel patients about their options for visual enhancement after cross-linking, which can vary considerably depending on the individual.”

Visual Enhancement After CXL: Study Results

The lack of a clear treatment algorithm for visual enhancement after CXL prompted Dr. Nattis and colleagues to conduct their recently published study, which supports the use of topography-guided custom PRK for patients with keratoconus following CXL. The authors note that because of the irregular contour of the cornea and the focal thinning that can persist after CXL, conventional or wavefront-optimized excimer laser ablations are usually not recommended.

“Initially, when topography-guided ablation was FDA approved, it was for patients undergoing routine laser-vision correction surgeries,” Dr. Nattis says. “However, many refractive surgeons saw the procedure as an opportunity to treat corneal irregularities, such as those in keratoconus patients. I’ve been fortunate to see how topography-guided PRK can visually rehabilitate patients after cross-linking, especially those who could not comfortably wear glasses or tolerate contact lenses.”

Both conventional and wavefront-guided laser therapies, which work by removing considerably more corneal tissue to create a more spherical cornea, can present obstacles in eyes with high refractive errors or significant corneal irregularities. Topography-guided ablation allows the clinician to save as much as one-third more tissue. Yet appropriate patient selection is important, says Dr. Nattis, and is based in part on an accurate preoperative image of the cornea.

“Of course, patients should only undergo this procedure if it is safe for them,” says Dr. Nattis, “They need to have a sufficiently thick cornea, no corneal scarring, and they need to demonstrate corneal and refractive stability for at least 3 to 6 months after cross-linking. In appropriate patients, the beauty of the topography-guided custom PRK is that it is able to treat the different peaks and valleys of the keratoconic cornea. It permits hyperopic ablation in flatter areas of the cornea and a myopic ablation in steeper areas of the cornea, which can smooth the cone present in keratoconus.”

Dr. Nattis and her colleagues note that PRK and CXL have been performed simultaneously with success; however, they believe it is important to allow the cornea to stabilize between treatments.

“We have seen that the cornea continues to flatten and change for at least several months after cross-linking,” says Dr. Nattis. “So we felt the best surgical planning would involve ensuring that keratometric and refractive values were stable before proceeding. We feel that this is the safest approach.”

It’s important to note that for most of the patients in the study who underwent cross-linking prior to FDA approval of the Avedro system, CXL was performed using the Peschke Trade CCL-VARIO 365 system.

“The Peschke cross-linking system is used widely throughout Europe and has provided excellent results,” notes Dr. Nattis. “Some physicians used Peschke in the US prior to the FDA approval of Avedro, but now, it seems Avedro use has become more prevalent. We use the Avedro system in our practice.”

Reimbursement Issues

To help outpatient facilities navigate the somewhat complex process of seeking reimbursement for cross-linking, the American Academy of Ophthalmology provides useful, detailed information on its website ( ). As noted, although there has been fairly rapid adoption of positive cross-linking coverage polices throughout the U.S., the existence of a CPT code does not ensure coverage under Medicare or commercial payers.

“Even though the FDA approved cross-linking in April 2016, getting commercial insurance carriers to cover it is a challenge,” says Lisa D’Andrea, practice administrator at Lindenhurst Eye Physicians and Surgeons. The procedure code for cross-linking is temporary so coverage is determined on a case-by-case basis. More often than not, patients end up paying out of pocket for it.”

As of September 2018, there is still no formal policy in the state of New York, where Dr. Nattis practices.

“We are working to change that,” says D’Andrea. “We feel it’s important to get cross-linking on the insurance carrier’s radar. The way to do that is to keep requesting prior authorizations, keep submitting claims, and keep appealing denied claims. It’s time consuming but it’s worth it to make this technology available to our patients.”

CMS recently issued a preliminary decision to establish a product-specific Healthcare Common Pro-cedure Coding System J code for Photrexa (Avedro) drug formulations. This is noteworthy, since claims submitted with a product-specific J code are generally processed more efficiently than claims using a miscellaneous code (J3490), which requires manual review. CMS is expected to announce its final decision in November, with new or revised codes becoming effective on Jan. 1, 2019.

Until then, ophthalmic ASCs and other outpatient settings will likely benefit by checking updates that appear on websites hosted by AAO and Avedro.

Looking Forward: The Need for More Research

The study conducted by Dr. Nattis and colleagues also offered valuable experience with a modified ‘epi-on’ procedure. The Avedro KXL system is approved for use with an epi-off technique; however, Avedro anticipates the completion of a phase-3 ‘epi-on’ clinical trial of a new drug/device combination for CXL in 2020.

“Our study is not the first to show that ‘epi-on’ techniques are effective,” says Dr. Nattis. “I think what we really need is a head-to-head trial to compare visual and keratometric results 12 months after cross-linking in patients who undergo ‘epi-on’ and ‘epi-off’ procedures. Many physicians are concerned about how deeply the riboflavin can penetrate the cornea in epi-on procedures. In our study, we used a modified ‘epi-on’ approach, which may have allowed slightly deeper riboflavin penetration than traditional ‘epi-on’ techniques.”

Dr. Nattis and her coauthors also note that more research into corneal biomechanics and remodeling after topography-guided PRK is needed and may help clinicians obtain optimum results.

“We also think it’s important to better understand the relationship between epithelial remodeling and refractive outcomes after CXL, with both modified epi-on and standard epi-off approaches,” says Dr. Nattis. “Measurements of corneal flattening in a head-to-head trial would help determine which cross-linking strategy provides a better surgical foundation before PRK treatment,”

Dr. Nattis adds that she and her colleagues will continue to monitor and evaluate all of the patients who participated in their study. She also looks forward to participating in new CXL research, for which she will perform all CXL procedures in an ophthalmic ASC. ■


  1. Asimellis G, Kaufman EJ. Keratoconus. NCBI Bookshelf; StatPearls [Internet]. Last updated: December 2017. Available at:
  2. Godefrooij DA, Gans R, Imhof SM, Wisse RP. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking. Acta Opthalmol. 2016;94(7):675-678.
  3. Sarezky D, Orlin SE, Pan W, VanderBeek BL. Trends in corneal transplantation in keratoconus. Cornea. 2017;36(2):131-137.
  4. Nattis A, Donnenfeld ED, Rosenberg E, Perry HD. Visual and keratometric outcomes of keratoconus patients after sequential corneal crosslinking and topography-guided surface ablation: Early United States experience. 2018; J Cataract Refract Surg. 2018:44(8):1003-1011.