The therapeutic modality known as corneal collagen cross-linking has intrigued surgeons for several years now, as it’s shown potential for stabilizing some corneas that may have been on the road to corneal transplants without such treatment. Recently, researchers outside of the United States and one of the companies behind several cross-linking devices, Avedro, have begun investigating the ability of cross-linking to create a refractive change in corneas that are otherwise healthy. Here’s a look at what they’ve found so far.

PiXL
The technique and technology being investigated by Avedro is known as photorefractive intrastromal cross-linking, or PiXL; it uses the company’s KXL II device, which features an active eye tracker.

Teaneck, N.J., surgeon Peter Hersh, MD, who is on the medical advisory board for Avedro, says the treatment needs both the energy to make the tissue alteration and the ability to put the energy in the proper place. “What PiXL does is take advantage of the fact that when you make isolated focal or topography-guided changes in corneal biomechanics, it can change the corneal shape and give a refractive outcome,” he explains. “The equipment needs to have the ability to change treatment sizes, powers and patterns, as well as the ability to have an eye tracker so it can put the treatment in the right position.

“PiXL can be approached in a couple of ways,” Dr. Hersh continues. “First, in irregular corneas and those with keratoconus, a surgeon can treat the cone itself, or treat the corneal topography, so to speak, by doing a focal application over the cone. Typically, this is a graded application, meaning there’s more UV energy delivered right over the cone, and it gradually grades out or blends as you move away from the tip of the cone. You can take this concept a step further: If you focally treat the center of the cornea with customized patterns, you can get correction of modest amounts of myopia, hyperopia and astigmatism.” Dr. Hersh says PiXL treatments usually use higher levels of energy delivered centrally than are used in standard cross-linking. “For instance, where it’s standard to use 5.4 mJ for cross-linking, we are looking at doubling or tripling this in a graded pattern for the treatment of irregular cornea PiXL patients and refractive PiXL patients,” he avers. “We don’t know what powers are optimal yet, but that’s the thinking.”

John Kanellopoulos, MD, of Athens, Greece, has used PiXL in some patients so far in his practice and describes the myopic protocol: “The light profile is a very small-diameter beam of 4 mm placed at the corneal apex with a very high level of UV light at the magnitude of 15 mJ and a fluence of 45 mW/cm2,” he says. “And it uses a riboflavin solution of 0.25%, which is about three times more than the standard solution used in the Dresden protocol. The hyperopic profile is more of a doughnut shape 1-mm wide starting at 4 mm or 6 mm, similar in appearance to a hyperopic excimer ablation. The depth of the treatment in an endothelium-off treatment is deeper, extending to about 60 percent of corneal thickness. In epithelium-on treatments, it extends to a third or half of the corneal thickness.”

PiXL’s Performance
Though PiXL is proving to have an effect, some surgeons say that, like any new procedure, nomograms need to be worked out in order to increase the procedure’s predictability.

The Czech Republic’s Pavel Stodulka, MD, PhD, has performed PiXL on 10 patients. “I’ve performed it in two patient groups,” he says. “I’ve done it in keratoconus patients and in patients with low myopic refractive surprises after IOL implantation. Both the predictability and efficacy were quite low in both groups. Our best case was a 52-year-old pseudophakic lady with a refraction of -1.25 -0.25 x 0 and uncorrected distance visual acuity of 0.1 [20/200] and best-corrected distance acuity of 1.0 [20/20]. She became [20/20] uncorrected a month after PiXL treatment. She was an outstanding case, but we didn’t get any other similar result. Corneal haze wasn’t really a problem and we didn’t see any PiXL-specific complications.”

Matthias Elling, MD, senior physician at Ruhr University Bochum in  Germany, is a researcher in a study of 33 PiXL eyes with six months of follow-up. “We observed that if patients had -3 D preop, we weren’t able to reach emmetropia completely,” he says. “But in lower myopes we came nearer to it. The refractive outcome is stable, and the median uncorrected acuity is 0.8 [20/25] postop. So, the early results show it’s possible to do a refractive treatment with cross-linking, and we’re able to correct up to 2 D.”

Dr. Kanellopoulos sees potential in the procedure but has run into the variability, as well. “In our patients, 80 percent were within 0.5 D of intended correction up to a year postop,” he says. “We didn’t see any adverse effects or complications, with the exception of one case in the epithelium-on group developing a small epithelial defect, and some epithelium-off cases having a delayed epithelialization. The only issue of relative concern was that we did encounter a few young patients who had a minimal refractive effect, even though a higher refractive effect was anticipated. For instance, one 34-year-old woman, in whom 2 D of correction was planned via a transepithelial treatment, only achieved 0.5 D. This procedure has proven its feasibility but needs further study to refine a nomogram.”

Dr. Hersh says the procedure’s predictability is a result of a host of factors. “These are very early studies,” he says. “And they’ve shown fairly reproducible results. Postop, on average, surgeons are getting 1.25 to 1.5 D of correction with these treatments. These are patients who start out -1 or -2 or so. Yes, some people are getting more correction than others, just as they did in the early days of PRK. I think centration of the treatment is ultimately an issue, as is proper alignment and proper registration. Clearly, since you’re trying to meticulously place the treatment energy, all of these will be important components.”

Singapore surgeon Jerry Tan, who has experience with cross-linking, thinks that PiXL’s biggest hurdle may be current procedures. “I have used the technology and I think it will work,” he says. “However, treatment times and healing times are too long. Currently, LASIK is very fast and accurate—making a LASIK flap takes 10 seconds and treating a low myope takes five to 10 seconds. How can you get any faster than that? Plus, LASIK patients see very well after a few hours with hardly any discomfort. PiXL has a tough act to follow.”  REVIEW

Drs. Hersh and Kanellopoulos are consultants to Avedro. Drs. Stodulka, Elling and Tan have no financial interest in the products mentioned.