Safety and efficacy of transepithelial crosslinking (C3-R/CXL)

Abstract

Baiocchi et al.1 measured stromal riboflavin using a 0.1% riboflavin–20% dextran solution and concluded there are concerns about safety and efficacy of transepithelial crosslinking. Their study has several limitations: The authors admit they have “theoretical indicators” of safety and efficacy. These should not be misinterpreted by the ophthalmic community as a benchmark for future riboflavin penetration studies. More work is needed in this area. The authors evaluated riboflavin in dextran. Dextran has high viscosity (very thick), which has been shown to inhibit penetration.2 Dextran is used in virtually all riboflavin solutions for crosslinking (eg, Ricrolin solution, IROC AG Institut für Refraktive und Ophthalmo-Chirurgie, U.S. Food and Drug Administration Clinical Trial). Doctors who perform transepithelial crosslinking use riboflavin 0.1% with diluted carboxymethylcellulose, not dextran. Compared with dextran, diluted carboxymethylcellulose has low viscosity (very thin like water) and enhanced penetration into stroma,2 which enables riboflavin penetration into stroma, as shown in Figure 1. Note: In Chan et al.,3 the methods section incorrectly stated dextran was used when in fact diluted carboxymethylcellulose was used with riboflavin. While there are no penetration studies comparing riboflavin in dextran versus riboflavin in diluted carboxymethylcellulose, the difference in viscosity of these carrier substances may be a factor.Figure 1: Slitlamp photograph of cornea showing riboflavin (yellow fluorescence) deep in the stroma through intact epithelium facilitated by tetracaine and carboxymethylcellulose.In addition to Chan et al.,3 Kamburoglu and Ertan4 and Pinelli independently found that transepithelial corneal collagen crosslinking (C3-R/CXL) was effective in patients with keratoconus and keratectasia (R. Pinelli, MD, “Corneal Collagen Cross-Linking with Riboflavin (C3-R) Treatment Opens New Frontiers for Keratoconus and Ectasia,” Eyeworld May 2007, pp. 34–36. Available at: http://www.eyeworld.org/article.php?sid=3797. Accessed October 7, 2009). Kamburoglu and Ertan have another study in press. Kamburoglu and Ertan and Pinelli pre-soak patients' corneas with chlorobutanol- or benzalkonium chloride-based anesthetic drops and riboflavin–carboxymethylcellulose drops since preservatives disrupt the corneal epithelium and enhance corneal penetration of topically applied substances through intact epithelium.5,6Figure 1 shows stromal penetration of riboflavin through intact but preservative-induced disrupted epithelium. Pinelli presented laboratory evidence of transepithelial stromal riboflavin penetration (R. Pinelli, MD, “TCCXL: Transepithelial Corneal Collagen X-Linking–Italian Results Tensioactive TCCXL–Preliminary Laboratory Results,” presented at the 4th International Congress of Corneal Cross Linking, Dresden, Germany, December 2008). In his study, he found that the preservative benzalkonium chloride loosened the epithelium, permitting riboflavin to be absorbed through intact epithelium. This principle is not new. We all use it every day. Virtually every large-molecule medicated eyedrop in our field (from glaucoma to antibiotic agent) can penetrate the cornea through intact epithelium with the assistance of a preservative in the eyedrop solution. That is why we do not scrape patients' epithelium when prescribing antiglaucoma medicated drops, for example. It is important to keep in mind that all laboratory and clinical studies that have been performed using riboflavin with diluted carboxymethylcellulose and a preservative indicate that transepithelial corneal C3-R/CXL is effective. It would be helpful if future laboratory studies incorporated the transepithelial crosslinking group with preservative-based anesthetic drops and diluted carboxymethylcellulose.