To Link or Not to Link: CXL Discussion at ESCRS Matures as Procedure’s Use Grows

By Linda Roach

Corneal collagen cross-linking (CXL) stayed securely in the spotlight at the 2012 meeting of the European Society of Cataract and Refractive Surgeons (ESCRS) in Milan this month, as researchers and clinicians wrestled with clinical issues that are emerging as CXL transitions into wider use.

In papers, posters and symposia, speakers described a multitude of ways in which they are modifying their riboflavin/ultraviolet A cross-linking protocols to reduce postoperative pain, possibly improve CXL outcomes and enable expansion of the accepted indications for CXL.

Several presentations in Milan also reported successfully combining cross-linking with some form of surgical refractive correction. With such treatment, patients receive CXL to stabilize and flatten their corneas, plus photorefractive keratectomy (PRK), intrastromal ring segments or LASIK to neutralize residual astigmatism and correct spherical error. The studies largely consisted of retrospective examination of a series of patients’ outcomes, not the prospective, randomized, controlled clinical trials that could help ophthalmologists rule out untoward complications.

Taking the Long View

Clinicians still do not know if there might be long-term damage to limbal stem cells from the UVA treatments, said Jörg H. Krumeich, MD, a keratoconus expert who practices at his outpatient surgery hospital in Bochum, Germany.

“The first number we need to have to justify cross-linking is the amount of UV light that does not harm the stem cells or allows them to recover. This certainly is true in particular when using this procedure in children,” Dr. Krumeich said.

Indeed, as the ESCRS meeting approached in early September, the website of the British Journal of Ophthalmology published a research paper suggesting that UVA delivered during cross-linking treatments might send some limbal cells down a biochemical path toward apoptosis.¹ And in June, Italian scientists warned that 1.5 mW/cm² is the maximum level of UVA energy that should be used during transepithelial CXL.² However, the latest generation of UVA light sources are about six times more powerful than that.

The ESCRS presentations revealed wide variability from surgeon to surgeon and country to country in how and why CXL is used, with no definitive resolution of these differences in sight, said William B. Trattler, MD, a refractive surgeon at the Center for Excellence in Eye Care in Miami, Fla.

“I attended a number of the different cross-linking courses to get a feel for what’s going on in Europe,” he said.

For his part, after performing hundreds of CXL procedures, Dr. Trattler and his colleagues who participated in a 15-center U.S. clinical trial have come down on the epithelium-on side of the debate regarding whether removing the corneal epithelium is required with CXL.

European Preference No. 1: Epi-Off

“We have 2 ½ years of experience with epi-on treatments, and we’re doing everything we can to convince our international colleagues to consider epi-on. But my impression is that most of the surgeons in Europe continue to believe in epi-off– except for Italy, which appears to have a preference for epi-on,” Dr. Trattler said.

Even if transepithelial CXL stiffens the cornea slightly less than the epi-off version does, it is less painful and eliminates the risks of haze, delays in epithelial healing and infection, Dr. Trattler said.

He is an investigator for CXLUSA, an independent, physician-sponsored clinical trial in which surgeons are using a nonophthalmic UV-light source for CXL. (The device has the correct UVA parameters, but it lacks FDA approval for other medical uses.) In a paper he presented at ESCRS, Dr. Trattler reported that CXL patients with gains of two or more lines in UCVA or BSCVA at six months or one year after the procedure had more preoperative corneal astigmatism, a lower preop spherical equivalent, and worse preoperative UCVA and BSCVA than lower responders.³

European Preference No. 2: Younger Patients

The European ophthalmic surgery community also is conservative in its CXL patient selection, Dr. Trattler found.

“If patients are over the age of about 25, European surgeons do not recommend treating unless they document progression,” he said. “The surgeons in Europe largely view cross-linking as a prevention measure to stop or slow progression and not as a therapeutic treatment to make patients see better.

“I was in a course where Dr. [A. John] Kanellopoulos was teaching, and he asked the audience if they would treat a 45-year-old patient with stable keratoconus. Out of about 100 people, I was the only person who raised my hand,” Dr. Trattler said.

The variation in how CXL is being performed and on whom is making it difficult to develop consensus on what is best for patients, said Michael Mrochen, PhD, professor of medical optics and physics at the Swiss Federal Institute of Technology Zurich in Switzerland. Outcomes from available clinical studies usually cannot be directly compared, he said.

“Clear study guidelines for comparing new treatment modalities are missing here,” Dr. Mrochen said. “Another big drawback is that, at the moment, we are missing guidelines for how to report cross-linking outcomes. Second, we always rely on a secondary measure – corneal topography – rather than looking directly at the corneal biomechanical changes.”

Measurement Conundrum

There is no clinical system available today for directly measuring the impact of CXL. As a result, researchers present their results differently and use different metrics to measure success, he said. “There’s good research going on by respected clinical groups around the world. But I’m not aware of any commercially available device to do this. So we can’t compare outcomes,” Dr. Mrochen said.

He is president and research director for IROC Innocross, a Zurich-based company that sells cross-linking products. It has CE Mark approval to market a second-generation corneal cross-linking device with a UVA beam that is shaped to deliver light evenly across the curved cornea. It delivers 9 mW/cm² of UVA.

There has been a trickle of case reports in the literature and at meetings of complications, such as scarring, postoperative infection, persistent haze, corneal edema and endothelial failure after epithelium-off cross-linking. In Milan, one presentation provided the details of two CXL patients who each developed a deep stromal scar several months after corneal cross-linking for keratoconus.⁴

Pathway to Apoptosis?

The British Journal of Ophthalmology study reported on the work of a research group in Bangalore, India, that cultured human limbal epithelial cells (LECs) and exposed them to UVA radiation with and without the presence of riboflavin. Cells were irradiated with a standard cross-linking dose: intensity of 3.0 ± 0.3 mW/cm², emitting a total energy dose of 5.4 J/cm² at a wavelength of 365 nm UVA.

The goal was to learn more about the biochemical pathways activated by the exposure, said senior author Debashish Das, PhD, a researcher at the Stem Cell Research Laboratory of Narayana Nethralaya, a specialty eye hospital in Bangalore.

“So far, people have been mainly speculating about what the impact or lack of impact on LECs might be from the UVA light used in corneal cross-linking. Most studies have looked at cell morphology, which does not tell you what is going on at a molecular level inside the limbal cells,” Dr. Das said.

His group’s study found that UVA exposure downregulated a known anti-apoptotic gene in cells that had not been treated with riboflavin and upregulated a pro-apoptotic gene. Pretreating cells with 0.1% riboflavin blocked most of the downregulation (92.9 percent) and halved the percentage of the LECs in which pro-apoptosis genes were upregulated (1.01 vs. 2.29 percent, P = 0.02). Riboflavin did not completely prevent UVA-induced damage.

Other analyses showed that 9 percent of LECs were limbal stem cells, and these were preferentially affected with UVA exposure. No one knows what level of UVA exposure would prevent them from being able to transdifferentiate later when needed for corneal scar repair, Dr. Das said.

Limbal Exposures Might Be Low

Dr. Trattler said he is “not that worried” about this issue, because the UVA beam has a smaller diameter than the limbus. So the only direct exposure limbal cells would receive would be incidental, he said.

“The key is how much UVA do you need for there to be an impact on the cells,” he said. “Our beam is 8 mm. It really stays pretty centered. Sure, patients may move their eyes at times during the procedure, but no one is going to get a full 30 minutes of UVA exposure to the limbus. The cumulative time might be one or two minutes.”

Even that can be prevented by using a limbal shield during the procedure, Dr. Mrochen said.

Amar Agarwal, MBBS, MS, FRCS, FRCOphth, a Chennai, India, surgeon and the president of ISRS, said he tries not to overuse cross-linking, because it is not without risk. He recommends deciding whether or not to use it on a case-by-case basis.

“We should remember that cross-linking, though very good, has its own complications,” he said. “The treatment we give should not be worse than the disease itself.”

Financial Interests

Dr. Krumeich has no financial interests to declare.

Dr. Trattler is a consultant for Abbott Medical Optics, Inc.; Allergan, Inc.; Aton Pharmaceuticals; CXLUSA; EyeGate Pharma; Inspire Pharmaceuticals; LensAR; QLT Phototherapeutics, Inc.; TearScience; and WaveTec Vision. He receives grant support or lecture fees from AMO, Allergan, Bausch + Lomb, Inspire, Ista Pharmaceuticals, QLT, Rapid Pathogen Screening and WaveTec. He has equity interest in CurveRight.

Dr. Mrochen is president and research director for IROC Innocross.

Dr. Agarwal is a consultant for AMO, Bausch + Lomb Surgical and STAAR Surgical Co. He receives royalties from SLACK Inc., and Thieme Medical Publishers, Inc., and he owns Dr. Agarwal’s Pharma.

References

1. Matalia H, Shetty R, Dhamodaran K, Subramani M, Arokiaraj V, Das D. Potential apoptotic effect of ultraviolet-A irradiation during cross-linking: a study on ex vivo cultivated limbal epithelial cells. Br J Ophthalmol. 2012;96:1339-1345.

2. Caruso C, Barbaro G, Troisi S, Pacente L, Del Prete A. UV-A rays absorption in human corneas before and after trans-epithelial riboflavin application: An experimental Study. Paper presented at: 2nd Joint International Congress of Refr@ctive.online and SICSSO (Societa Italiana Cellule Staminall e Superficie Oculare); June 28, 2012; Rome.

3. Trattler W, Rubinfeld R, Kaiser C, et al. Retrospective evaluation of patients with a strong response to epithelial-on corneal collagen cross-linking (CXL). Paper presented at: XXX Congress of the ESCRS; Sept. 11, 2012; Milan, Italy.

4. Kato N, Saiki M, Negishi K, Tsubota K. Delayed onset deep corneal stromal scar after corneal cross-linking. Paper presented at: XXX Congress of the ESCRS; Sept. 11, 2012; Milan, Italy.