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Subspecialties Cornea / Ocular Surface

Time to Drop the Debate

In the CXL space, epi-on CXL (or transepithelial CXL) has been a source of controversy for years – and a healthy amount of skepticism surrounds the approach. This intense skepticism likely stems from the history of CXL, which began back in the late 1990s with Theo Seiler, Michael Mrochen and colleagues at The University of Dresden, Germany. After demonstrating riboflavin-UVA corneal collagen crosslinking in porcine and rabbit eyes after epithelium removal (1)(2), they went on to show promising epi-off results in a pilot study in humans with moderate or advanced progressive keratoconus (3). But why was the epithelium removed? According to personal communications with Michael Mrochen and others, despite a self-evident preference to leave the epithelium intact, making CXL a non-invasive procedure, it was primarily because there was no formulation or technology available to adequately load riboflavin into the stroma through the epithelium. Instead, a technique from photoreactive keratectomy (PRK) was used: they surgically removed the protective epithelium and applied the riboflavin directly to the deeper layers of the cornea... And the rest is history. Epi-off CXL became the “norm.”

Traditional epi-off CXL is a typically safe and effective procedure, but there are well-documented complications including corneal edema, infectious keratitis, delayed epithelial healing, corneal haze, stromal scars and even corneal perforation – nearly all of which derive from the surgical removal of the epithelium. Additionally, removal of the epithelium is painful for patients, and re-epithelialization can take at least a week during which they may require opioids for pain management. Recovery of pre-operative vision can take at least one month or longer. Would most patients prefer to have their epithelium removed, suffer worsened vision, be in substantial pain and at risk of complications such as infection, perforation, scarring and haze, and effectively ‘out of commission’ for weeks per eye – or undergo an equally effective non-invasive procedure that consists essentially of ‘eyedrops and sunlight,’ returning to work the next day? The advantages of performing CXL with the epithelium intact is clear, so why aren’t people more accepting of an epi-on approach?

I believe false promises in the rather stormy history of epi-on CXL are to blame. The procedure wasn’t approved in the US by the FDA until 2016, so Europe has largely led the way in CXL – and it’s been quite a frustrating experience. I live part time in Europe and have observed CXL’s development from the beginning. When the epi-on approach first came around; everyone was excited about it – all the while hoping that a less-disruptive, safer approach might be forthcoming. And indeed, over the years, there have been many attempts to develop an effective epi-on procedure, from various commercial formulations to different devices designed to disrupt the epithelium – and even a “scratching” technique (a “happy” medium between removing the epithelium and leaving it intact). Europe is a wonderful place for innovative technology, and many of its ophthalmic surgeons were excited by the products and systems that they believed would more safely and conveniently strengthen corneas to protect against vision loss – only to find to their great dismay that they didn’t. No commercial transepithelial CXL has been definitively proven to work long term. In many cases, exciting six-month data turned into unacceptably high failure rates with many patients progressing and losing vision one to two years after the procedure – it turned out that 24 months post-surgery was the real test (4, 5). Trying epi-on approaches in an effort to better treat their patients, only to see ectatic disease progress under their care must have caused frustration if not also guilt and anger to these pioneering surgeons, so it is easy to understand why epi-on skepticism persists and has even increased.

But when people use the term “epi-on,” do they mean the 10 approaches that haven’t worked or the one approach with scientifically validated potential? I have heard that Robert Machemer performed almost a dozen failed vitrectomies before he found success. Do people say “vitrectomy doesn’t work?” No, because it was the first dozen approaches that didn’t work. And that’s why I refer to “epi-on versus epi-off” as the great non-debate; this discussion is a red herring leading nowhere. We should be open to scientifically evaluating any approach that achieves the best outcomes for patients. Previous epi-on approaches may not have worked well, but we have developed a new approach – and we are seeing extremely promising long-term study results.

As a corneal surgeon in 2009, having observed CXL being performed in Europe, I organized a group of innovative surgeons across the US (CXLUSA) to find a way to reduce the number of corneal transplants in their respective states. Back then, we were performing epi-off CXL under Institutional Review Board (IRB) approvals just like everybody else. Why? Because we didn’t believe epi-on approaches worked. But that didn’t stop us from seeking improved, non-invasive corneal strengthening treatments for our patients. And because our IRB protocols allowed us substantial freedom in terms of iterations, we were able to test different modifications; concentrations, pH, osmolarity, excipients, and more – we performed literally dozens of modifications to the protocol whilst staying in the range of approvals as part of a group effort. Through much communication between our investigators and many procedures, we have developed a new way to perform epi-on CXL: the CXLUSA methodology. The main differences between previously-trialed epi-on methodologies and our approach include the riboflavin formulation itself, a novel non-iontophoretic delivery system and the light diameter. We also use a patented, pulsed UV light cycle, which allows molecular oxygen – the rate-limiting reagent of the crosslinking reaction – to be replenished in the stroma during the dark cycle.

Using our approach, we have found in our multicenter study transepithelial treatments we can consistently load riboflavin into the stroma in 10–20 minutes. In ex vivo rabbit cornea studies (performed by an independent laboratory), adequate riboflavin loading was consistent with that of epi-off stromal concentration (≥15 µg/mg). Loading was observed in as little as 10 minutes through slit lamp examination, and chromatography and mass spectrometry analysis confirmed a four-fold greater concentration of riboflavin with our formulation than commercially-available alternatives (6). Earlier this year at the American Society of Cataract and Refractive Surgeons (ASCRS) annual meeting, we presented results from 592 eyes with keratoconus (n=512) and ectasia (n=80) that received our procedure between October 7, 2013 and April 26, 2016 (7). The results are promising: at 12 and 24 months after surgery, we saw improvements in five parameters (corrected distance visual acuity, uncorrected visual acuity, Kmax, higher order aberrations and coma), and we saw no progression, even among the 48 pediatric eyes (≤18 years) (7). Adverse events of hydrops, scleritis and disciform edema were reported from one eye each, but were not related to the treatment.

In conclusion, we believe that our novel approach works – and we’re thrilled with the results we’re achieving because it means we’re able to perform a safer and more comfortable procedure for our patients. We have submitted our findings for publication, and our next goal is to proceed through the regulatory process so that more patients in the future might be able to benefit from an effective epi-on CXL approach. It hasn’t been easy to reach where we are now after eight years of research – there have been many hurdles, not least the ongoing skepticism. However, I believe the tide is slowly turning and that more people in the field are willing to accept the idea of an epi-on CXL approach once they see the scientific in vitro and clinical study data. The fact that there are many other groups investigating transepithelial CXL is testament to this. I think it is time to ‘drop the debate,’ because it is not about epi-on or epi-off; it is about what is best for our patients and which approach works best with the least discomfort and risks.

Rubinfeld reports that he holds equity in CurveRight, LLC; CXLOphthalmics, LLC; and CXLUSA, LLC.

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  1. E Spoerl et al., “Induction of cross-links in corneal tissue”, Exp Eye Res, 66, 97–103 (1998). PMID: 9533835.
  2. E Spoerl et al., “[Studies on the stabilization of the cornea in rabbits”], Ophthalmologe, 97, 203–206 (2000). PMID: 10789179.
  3. G Wollensak et al., “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus”, Am J Ophthalmol, 135, 620–627 (2003). PMID: 12719068.
  4. A Caporossi et al., “Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results”, J Cataract Refract Surg, 39, 1157–1163 (2013). PMID: 23790530
  5. N Soeters et al., “Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial”, Am J Ophthalmol, 159, 821–828 (2015). PMID: 25703475.
  6. RS Rubinfeld et al. “Quantitative analysis of trans-epithelial corneal riboflavin loading”. Paper presented at International CXL Congress; December 4-5, 2015; Boston, MA, USA.
  7. RD Stulting et al., “Corneal crosslinking without epithelial removal”. Oral presentation at the annual meeting of the American Society of Cataract and Refractive Surgeons; May 5–9, 2017; Los Angeles, CA, USA.
About the Author
Roy Rubinfeld

Roy Rubinfeld is Clinical Associate Professor at MedStar Georgetown University/Washington Hospital Center, and Medical Director of Re:Vision, Rockville, Maryland and Fairfax, Virginia, USA.

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