February 14, 2019
4 min read

Therapeutic, refractive uses await CXL

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The six fellowship-trained cornea specialist partners and I at Minnesota Eye Consultants are deeply engaged in corneal cross-linking.

More than a decade ago, we participated in the Peschke clinical trial that provided the data leading to FDA approval for Avedro. We then participated in a similar trial sponsored by Topcon that was never submitted for approval. Both of these trials utilized the classical epithelium-off so-called Dresden protocol developed by Theo Seiler, MD, PhD, and his associates. We then joined the CXLUSA clinical trial and participated in the development and study of an epithelium-on approach designed by Roy Rubinfeld, MD. Since Avedro obtained FDA approval, we adopted its technology. We are also participating in the Avedro-sponsored FDA clinical trial evaluating epithelium-on CXL for keratoconus and post-LASIK ectasia. We remain convinced that an epithelium-on approach will be the future of CXL.

Much learning has occurred in the past 20 years as CXL has evolved, and of course many questions remain. In the following commentary, I would like to share a few of my learnings and humbly admit that a number of them may be proven wrong over the next decade.

First, I believe keratoconus, keratoconus suspect and post-LASIK ectasia are more common than classical textbooks suggest. The old teaching is 1:2,000 population, which would be about 360,000 in the U.S. Because we are usually treating both eyes, that is 700,000-plus eyes, a significant number, but I think the prevalence of patients who would benefit from CXL is much higher. Not all of these patients would be eligible for third-party pay, and some would be cash pay, but the number of potential patients is much higher than 1:2,000.

If we add in all of the patients who present for laser refractive surgery who are rejected for treatment based on an atypical corneal topography, the number of patients who might benefit from CXL increases significantly. Most laser centers reject at least 10% to 15% of patients for atypical topography or thin pachymetry. While the patient presenting for laser refractive surgery may be a unique subpopulation, if 10% of the 40% of patients in the U.S. with myopia have an atypical topography or thin cornea, that is 4% of the population, or 14.4 million. I believe CXL followed by PRK or maybe SMILE would allow these usually highly motivated patients to safely undergo laser vision correction. In addition, many of the patients who have undergone RK in the past with significant hyperopic drift and diurnal refraction fluctuation might also benefit from CXL with or without PRK. As I think broadly, including the private-pay patient, I do not think it is too bold to suggest that as many as 1:200 rather than 1:2,000 of the population might benefit from CXL. In addition, CXL is showing promise as a treatment for low refractive errors, especially hyperopia and early presbyopia. If that indication pays off, the opportunity for CXL grows exponentially.


The second thought that I would like to share is that while therapeutic CXL with a goal to stabilize refractive error in keratoconus is a wonderful advance, most patients I see would prefer to have me improve their refractive status, not just stabilize them. In thinking about this and talking with colleagues, I have started to talk about two types of CXL: therapeutic CXL (TCXL) and refractive CXL (RCXL). In TCXL, we are treating a disease state, and in my opinion, third-party payment is appropriate. In RCXL, we are combining a therapeutic treatment with a refractive treatment. The refractive portion is appropriate for cash pay, similar to the premium IOL reimbursement approach.

Today, for select patients, I am finding Intacs (Addition Technology), conductive keratoplasty (CK) off label and PRK/PTK to be useful treatments in combination with CXL to enhance many patients’ refractive status. While there is much to be learned, my current criteria for offering RCXL to the patient are quite simple. If I am and/or the patient is happy with their current refractive status, I simply proceed with TCXL. If the patient would like their presenting refractive error improved upon and accepts the risks and costs after careful informed consent, I am willing to try to help them. Again, it is similar to standard cataract surgery vs. patients who choose to pay extra for a refractive correction. In RCXL as I do it, the refractive procedures, including Intacs, CK and PRK/PTK, are done at a separate time than the TCXL.

My current favorite procedure is a CXL quadruple procedure. I perform Intacs, sometimes adding a few spots of CK to reduce astigmatism as a combined procedure in our office laser suite. I then wait 2 to 4 weeks and perform CXL. I allow the eye to heal for 12 to 18 months. At 12 to 18 months, for select patients who have a refractive error that allows good vision with correction or who have disabling anisometropia, I have had good success with PRK/PTK. This approach has generated some positive outcomes for patients, and I have as yet had no patients who have developed new progression of their keratoconus after a conservative PRK/PTK done 12 to 18 months after CXL.

I have seen progression in post-LASIK ectasia patients, but these are more difficult eyes to stabilize with TCXL. I am still willing to treat these eyes with PRK/PTK if they have a disabling refractive error even though they may progress, as I do not believe the flap adds any meaningful structural strength to the cornea, and the PRK/PTK is on the flap only. I limit my treatment in all eyes to 40 µm or less corneal tissue removal.


Even after 20 years of broad usage and hundreds of extraordinarily bright surgeons and scientists applying their best thoughts to help patients with CXL, we remain with many unanswered questions. Investment in CXL remains limited, with only one company with significant funding and another consortium with limited funding in the U.S. working to advance the field. I remain hopeful that one of our major strategic corporate partners will recognize that RCXL greatly expands the opportunity inherent in TCXL. With adequate capitalization, our progress in this field could be accelerated to the benefit of many.

Disclosure: Lindstrom reports he has financial interests in Avedro, CorneaGen CXLO, Refractec and Johnson & Johnson Vision.