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Seeking alternatives to CXL protocol for stromal saturation


Chemical enhancements to riboflavin solution aim to overcome need for epithelial debridement


Chemical enhancement may enable stromal imbibition without epithelial removal. Further study is needed to establish the efficacy of corneal collagen crosslinking with these methods.


By Cheryl Guttman Krader; Reviewed by Jesper Hortjdal, MD, PhD

Aarhus, Denmark-Currently, complete debridement of the corneal epithelium is the most effective technique for ensuring proper imbibition of the corneal stroma with riboflavin when performing collagen crosslinking (CXL).

However, chemical modification of the riboflavin solution is showing promise as an approach for enabling transepithelial CXL, said Jesper Hortjdal, MD, PhD.

“The creation of an epithelial defect to perform CXL is associated with pain along with risks of keratitis and haze,” said Dr. Hjortdal, professor of ophthalmology, Aarhus University Hospital, Denmark. “These drawbacks have generated interest in developing alternative techniques for delivering riboflavin while reducing the epithelial lesion.

“Chemical modifications of the riboflavin solution aim to loosen tight junctions between epithelial cells, and some methods have shown promise,” Dr. Hjortdal said. “However, they should not be used routinely until their safety and efficacy have been studied in further detail.”

Discussing studies on riboflavin penetration into the cornea, Dr. Hjortdal noted that research conducted by his group and others confirm that there is insufficient riboflavin penetration through the intact epithelium when the 0.1% riboflavin solution used in standard CXL is applied. For example, using confocal microscopy to determine riboflavin penetration depth, Dr. Hjortdal and colleagues found that even after complete epithelial removal, a reasonably high concentration of riboflavin was achieved only in the anterior 200 µm of the cornea.

Alternative to epithelial debridement

Scraping of the epithelium has been investigated as an alternative to total epithelial debridement. Results of an in vitro study by Alhamad et al. showed poor penetration into the stroma if the standard riboflavin solution was applied after manual epithelial scraping. However, riboflavin absorption into the stroma was achieved when the applied solution was enhanced with EDTA and trometamol.

Bakke and colleagues conducted a clinical trial evaluating riboflavin solution application to the cornea after incomplete epithelial removal with an excimer laser. Based on examination at the slit lamp to determine riboflavin penetration, they found saturation into the stroma was achieved using the PTK technique.

However, patients who underwent the procedure had more pain than a comparator group treated with mechanical full-thickness epithelial removal, and it took longer to achieve corneal saturation. Additionally, the efficacy of the procedure is unknown as the investigators did not report any postoperative follow-up data.

Preclinical models

Using an animal model and biomechanical testing after CXL to investigate treatment efficacy, Wollensak and colleagues reported that an epithelium-on technique of CXL using a riboflavin solution containing proxymetacaine and benzalkonium chloride (BAC) increased Young’s modulus. However, the effect was only one-fifth that achieved using the standard epithelial-off CXL technique. In contrast, Kissner et al. found the increase in Young’s modulus was similar comparing animal eyes undergoing the standard protocol and those treated with an intact epithelium and riboflavin with 0.02% BAC.

In another preclinical model, Raiskup et al. found a hypoosmolar riboflavin solution containing BAC enhanced riboflavin penetration through the intact epithelium, but the effect was still lower than that achieved with the standard treatment.

Dr. Hjortdal noted there are no randomized controlled clinical trials comparing epithelium-on and epithelium-off techniques of CXL, and cohort studies of epithelium-on techniques report conflicting results. In one trial, Filipello et al. reported good results where eyes were treated with a riboflavin solution containing trometamol and EDTA.

However, in a study using riboflavin solution prepared with proparacaine and a low concentration of BAC (0.005%), Koppen et al. found the outcomes were less effective than what might be achieved with standard CXL.

Jesper Hjortdal, MD, PhD

E: jesper.hjortdal@dadlnet.dk

Dr. Hjortdal has no relevant financial interests to disclose. This article was adapted from Dr. Hjortdal’s presentation during Refractive Surgery 2012 at the annual meeting of the American Academy of Ophthalmology.


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