Transepithelial cross-linking may be possible with new riboflavin formula

Methods to enable an epithelium-on stromal diffusion technique are being investigated.

François Malecaze

Transepithelial delivery is the future of cross-linking, but modifications of the current riboflavin formula may still need to be optimized for epithelium-on stromal diffusion, according to a physician.

Cross-linking conventionally entails disepithelialization prior to administration of the photosensitizing agent and ultraviolet irradiation. This is because the corneal epithelium constitutes a barrier against penetration of molecules with a molar mass higher than 100 g/mol. Riboflavin is vitamin B2, a micro-molecule with a molar mass of 376 g/mol, which cannot penetrate the epithelium’s tight junctions.

“This is the reason why we need to scrape off the epithelium prior to administration of conventional riboflavin,” François Malecaze, MD, said at the meeting of the French Society of Ophthalmology in Paris.

However, disepithelialization carries potential complications such as formation of scar tissue, ulceration and infection, he said.

Product available

Several laboratories are currently trying to modify the pharmacokinetics of riboflavin to enhance penetration and allow an epithelium-on technique. One product, Ricrolin TE (transepithelial riboflavin, Sooft), is currently available in Europe.

In this new formula, the presence of the amino alcohol improves bioavailability and, in combination with ethylenediaminetetraacetic acid disodium salt, or EDTA 2Na, enables transepithelial penetration.

Dr. Malecaze explained that the cross-linking technique with this formula is similar to the conventional method. One drop of pilocarpine and one drop of anesthetic are instilled 30 minutes before irradiation. Immediately afterward, one drop of transepithelial riboflavin is instilled every 2 minutes, for a total of at least 16 drops in half an hour. The eye is then exposed to ultraviolet light for 30 minutes, during which transepithelial riboflavin is administered every 5 minutes for a total of five additional drops.

Testing

To ascertain whether transepithelial riboflavin, following epithelial penetration, guarantees sufficient stromal diffusion for effective UV light penetration and collagen cross-linking, animal testing was first performed using biochemical and immunohistochemical methods.

“In rabbit eyes, stromal diffusion was less, approximately half, with transepithelial riboflavin as compared to conventional riboflavin with disepithelialization. In the aqueous humor it was 34% of usual impregnation,” Dr. Malecaze said.

A clinical study was then performed in 40 patients, half of whom were treated with the conventional disepithelialization technique and riboflavin, and half with epithelium-on transepithelial riboflavin.

“Fluorophotometry analysis confirmed the results of animal studies: Ricrolin TE does penetrate through the epithelium and diffuses into the stroma. However, the impregnation of the stroma by the photosensitizing agent is about one-fifth compared to that obtained by conventional riboflavin following removal of the epithelium,” Dr. Malecaze said.

“The next question now is whether this amount of transepithelial diffusion is sufficient to induce cross-linking. We don’t have an answer yet,” he said.

Research is ongoing, and Dr. Malecaze said that the transepithelial method is the future because it induces a satisfactory cross-linking of the collagen fibers.

“Transepithelial means no postoperative pain, faster visual recovery, no complications from disepithelialization and also the ability to perform the procedure outside the operating room,” he said. – by Michela Cimberle

• François Malecaze, MD, can be reached at CHU de Toulouse - Hôpital Purpan, Place du Docteur Baylac - TSA 40031, 31059 Toulouse Cedex 9, France; email: malecaze.fr@chu-toulouse.fr.
• Disclosure: Dr. Malecaze has no relevant financial disclosures.

Joseph Colin

The possibility of performing corneal cross-linking without removal of the epithelium has been a hot topic of discussion during the past years. After initial skepticism, it seems that today most of the keratoconus specialists are moving toward this therapeutic modality.

The advantages of epi-on corneal cross-linking are obvious because of the absence of post-treatment pain, which is very much appreciated by the patients, especially children, and a decrease risk of complications including epithelial healing problems, infectious keratitis and corneal scar formation.

Some preliminary studies have shown that epi-on cross-linking can halt the progression of keratoconus compared with fellow eyes with no treatment. The main question that has to be answered today is the comparative efficiency of epi-on techniques and standard epi-off procedures. Confocal microscopy analysis has demonstrated that corneal cross-linking is much more superficial when using the epi-on technique. If prospective studies can get results that are just as good as the original protocol, epi-on cross-linking will obviously be our first choice for progressive keratoconus.

– Joseph Colin, MD
OSN Europe Edition Editorial Board Member
Disclosure: No products or companies are mentioned that would require financial disclosure.