Eyeworld

EW CORNEA 70 September 2016 by Maxine Lipner EyeWorld Senior Contributing Writer this was what they had been doing years before with rose bengal and decided to bring it back to life. "This is how we started the animal studies, which showed that it could be an alternative to riboflavin in certain situations," Dr. Melki said, adding that such situations could be in cases where patients have a thinner cornea since the penetration of rose bengal is not as deep as riboflavin. 2 In a study on this, rose bengal was applied to the rabbit cornea and a green light turned on afterward. "When we looked at the amount of crosslinking and compared the two, it was equivalent," Dr. Melki said. In his view, the most obvious advantage of the rose bengal is that it would enable practitioners to treat thinner corneas. "Once you start thinning with keratoconus, after a certain level you're not able to use riboflavin anymore," he said. While some hypo-osmolar solutions can swell the cornea, once you get below a certain level, even that is not go- ing to help, he pointed out. In Dr. Wilson's view, crosslinking will become an important part of many practices and provide a new tool that will further decrease the incidence of penetrating keratoplasty. "That's a good thing because while transplants in patients who need them are a wonderful thing—they restore vision, but they also have a high rate of rejection—it takes a long time for the patient to get useful vision in many cases, and we struggle with problems like abscesses from su- tures breaking or high astigmatism," Dr. Wilson said. "I think the more we can reduce penetrating keratoplasty, the better off we are." EW References 1. Torricelli AA, et al. BAC-EDTA transepithe- lial riboflavin-UVA crosslinking has greater biomechanical stiffening effect than standard epithelium-off in rabbit corneas. Exp Eye Res. 2014;125:114–7. 2. Zhu H, et al. Corneal crosslinking with rose bengal and green light: efficacy and safety evaluation. Cornea. 2016;35:1234–41. Editors' note: Dr. Melki and Dr. Wilson have no financial interests related to their comments. Contact information Melki: melki@bostonlaser.com Wilson: WILSONS4@ccf.org for doctors to practice medicine, he noted. "I'm sure there will be people who decide to have the same for- mulation that we used in our paper made by compounding pharmacies, and they'll use transepithelial," he said, adding that as long as this is just offered as an option and not advertised, this is reasonable. "Physicians can offer patients two options, saying, for example, 'I think they're equally effective at stiffen- ing the cornea, but you'll have less discomfort, less risk of infections and potential for scarring with the transepithelial method,'" he said. In particular, he envisions this approach as helping those with thin corneas. "One of the beauties of the transepithelial technique is we showed that there was only one-third corneal penetration of the level of cell depth in the cornea," Dr. Wilson said, adding that he sees the technique as safer for the endothe- lium. There are ways of swelling the cornea with different agents, but if a patient has a 300-micron cornea, it's still dangerous to do epithelium-off because the physician could knock off the endothelial cells, too, he pointed out. While there are ways to swell the cornea, these can be imprecise, Dr. Wilson stressed. "You can swell the cornea and probably get away with it, but I think in those thin corneas it is a little risky," he said. "I would be inclined, based on what we know now, to use the transepithelial BAK/EDTA method in those patients." Rose bengal alternative Other crosslinking agents may also work for this group of patients. Samir Melki, MD, director, Boston Eye Group, and part-time associate professor, Harvard Medical School, has been investigating the use of rose bengal together with a green light in place of the riboflavin drops and UVA. "That's a study that stems from research that we did back in the late 1990s trying to close corneal incisions with that, and it worked very nicely," he said. "It was only many years later that we realized that what we were actually doing was crosslinking." When use of riboflavin came along, investigators realized that effective. "We picked up all kinds of transepithelial methods and tested them, and the model that we found to be most effective was using BAK and EDTA," he said, adding that neither chemical was as effective by itself at breaking down the epithelial barrier. "I think they have a syner- gistic effect of breaking down that barrier function at least temporar- ily," Dr. Wilson said. "We showed just as much efficacy with the transepithelial technique, as long as we used BAK and EDTA as a barrier breakdown agent, as we did with the epithelium off." In fact, in the first of two studies, Dr. Wilson found that the transepithelial method was actually superior. 1 The follow-up study, however, which included more animals, found that they were equivalent. Even with equivalent efficacy there are many advantages to the transepithelial approach, he stressed. "There is less risk of infection, there tends to be more patient comfort and fewer issues with aggressive wound healing that could pro- duce haze or scarring," Dr. Wilson said. "The general feeling is there should be some level of haze or it didn't work, but if they end up with permanent severe haze, that's not good." Occasionally that happens, but usually that's with epithelium- off techniques, he said. Already there are physicians, especially outside of the U.S., who are using the BAK/EDTA transepi- thelial method. Dr. Wilson expects that while it remains off label, some will begin offering this as an option to patients. Once a treatment is approved, there's a lot of leeway Best practices with riboflavin and other similar agents C rosslinking with riboflavin drops and use of ultravi- olet A (UVA) has proven itself to be an effective method of treating ker- atoconus, as attested by its recent FDA approval. But is this traditional approach the only option? Already there are tweaks to the approach as well as other agents being consid- ered. Here's the latest on some of these new agents and how they are working. Steven E. Wilson, MD, pro- fessor of ophthalmology, Cole Eye Institute, Cleveland Clinic, pointed out that the traditional method for crosslinking involves taking the ep- ithelium off for the treatment with riboflavin drops and UVA. Yet there are investigators like him who have studied approaches that leave the epithelium intact for this same treat- ment. "The problem is that there is such a huge variation in the differ- ent transepithelial techniques, and some of them are effective and some of them are completely ineffective," he said. For example, while many papers have been presented about first applying an anesthetic multiple times to break down the epithelial barrier function before using ribofla- vin, a rabbit study that Dr. Wilson performed showed this to have no effect on the stroma whatsoever. Transepithelial approach However, another technique that Dr. Wilson reviewed was indeed On the crosslinking cusp Pharmaceutical focus At 24 hours after crosslinking, rabbit corneas that underwent standard epi-off treatment in A showed much more cell death than those in B, which underwent epi-on crosslinking with BAK-EDTA. Source: Steven E. Wilson, MD

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