A New Era for CXL

Changing mindsets on treatment timing and technique expected to improve outcomes for keratoconus patients. Cheryl Guttman Krader reports from ASCRS Cornea Day 2021, Las Vegas, USA.

Cheryl Guttman Krader

Posted: Friday, October 1, 2021

Changing mindsets on treatment timing and technique expected to improve outcomes for keratoconus patients. Cheryl Guttman Krader reports from ASCRS Cornea Day 2021, Las Vegas, USA.

The first published paper describing corneal cross-linking (CXL) as an effective treatment for progressive keratoconus appeared in 2003. The procedure has been commercially available in Europe for more than a decade and five years in the United States. Now, Parag A Majmudar MD says, the time has come for two major paradigm shifts in the use of CXL for keratoconus.

“We should be thinking about treating keratoconus at the earliest possible stage. I don’t think there is any other way to tackle the problem. And while we are challenging this status quo, the second paradigm shift will be to adopt the epi-on approach. In 10 years, I foresee we will not be doing epi-off CXL,” Dr Majmudar reported.


Dr Majmudar observed the controversy over which is the better technique for CXL, epi-on or epi-off, has been raging for years. Proponents of epi-off CXL argue it is the more effective of the two, but Dr Majmudar contended that conclusion is debatable considering recent data for the epi-on procedure.

“What is not debatable is the epi-on technique is better for the patient and the surgeon because it reduces the risk of infection and scarring and is associated with faster recovery, allowing patients an earlier return to normal life,” he added.

Dr Majmudar proposed that even if one accepts the idea that epi-off CXL is 100% effective and the epi-on technique is only 80% effective, the difference between treatments is likely inconsequential if the paradigm shifts to very early keratoconus treatment.

“With aggressive screening done by primary eye care providers, we can be catching keratoconus when it is just beginning. And with early diagnosis, we can treat keratoconus when the cone is minimal,” he said.

“Then, even if epi-on is a slightly weaker procedure, it will probably have enough effect to provide adequate stability and maintain the good vision present with early keratoconus.”


Research in recent years has revealed that one key to achieving better efficacy with epi-on CXL is to ensure adequate oxygen in the cornea. Thus, a treatment protocol was designed for the commercially available iLink system (Glaukos) that uses supplemental oxygen. Recently reported results from a phase three randomised, placebo-controlled clinical trial investigating this approach showed the study met its primary endpoint comparing treatment groups for change from baseline to six months in maximum corneal curvature (Kmax).

Dr Majmudar told attendees of his experience performing epi-on CXL with the investigational EpiSmart system (CXL Ophthalmics). It improves oxygen availability in the cornea through pulsed delivery of the UVA light, which, compared to continuous irradiation, allows time for oxygen to replenish in the corneal stroma. As another feature, the proprietary riboflavin formulation used in the procedure contains sodium iodide that results in oxygen formation, which may enhance the effectiveness of the cross-linking procedure.

Phase three studies to support registration of the epi-on EpiSmart system in the United States are in progress. A 2018 paper observed two years of follow-up for 512 eyes treated for keratoconus, forme fruste keratoconus, or post-LASIK ectasia. The published results reported the EpiSmart procedure was associated with significant improvements in mean Kmax, total higher order aberrations, and coma (Stulting RD, et al, J Cataract Refract Surg. 2019; 44 (11): 1363–1370).

“Kmax decreased more than 1D in three times as many eyes as it increased more than 1D, and that difference was highly statistically significant. Furthermore, no eyes treated with the epi-on system progressed in two years, and there was no loss of effect comparing results from evaluations at one and two years.”


Dr Majmudar proposed that in the future, CXL may be performed using drops alone without UVA light. IVMED-80™ (iVeena Delivery Systems), a topical drop that induces CXL by enhancing lysyl oxidase activity in the cornea, is under investigation in clinical trials that have generated some promising early results.

Accelerated CXL protocols that improve patient flow while possibly also reducing risk of haze and allowing faster visual rehabilitation may also be coming.

Reflecting on the current and future developments, Dr Majmudar concluded his talk by stating that CXL is at the dawn of a new era. Addressing his audience of American ophthalmologists, Dr Majmudar noted many international colleagues are already moving towards implementing the new techniques.

“I think we will start seeing significant improvements in our paediatric patients who will be uniformly screened earlier for keratoconus and treated at its earliest onset. The repercussions for these patients in terms of improved quality of life will be immense. So, let’s start thinking about changing how we think about keratoconus and CXL.”

Parag A Majmudar MD is Associate Professor of Ophthalmology, Rush University, Chicago, Illinois, USA

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