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Cross-linking: A milestone in the management of keratoconus
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First developed by Theo Seiler and his team in Zurich in 1993, corneal collagen cross-linking, or CXL, was progressively adopted as a technique in the first decade of this century by several corneal specialists in Europe, gaining wide popularity over a relatively short period of time.
CXL represents, to date, the only effective way to slow down or stop the progression of keratoconus by strengthening the collagen fibers in the cornea. As shown by several studies, it is a relatively harmless procedure with a high rate of efficacy. Stabilization of the disease is obtained in approximately 90% of cases, and a mean decrease of 2 D in maximum keratometry is achieved, with a mean gain of two lines of vision in a number of eyes. CXL indications have gradually broadened, maintaining the notion of progressive keratoconus as one of the basic criteria. Progression can be functional and/or physical, as objectively shown by topography, pachymetry or corneal aberrometry. CXL plays a critical role in the management of progressive keratoconus because it is the only treatment capable of stabilizing the disease without preventing the use of refractive treatments, such as rigid contact lenses and intracorneal rings.
The aim of CXL is to create bridges between the collagen fibers and the proteoglycans present in the extracellular matrix of the corneal stroma in order to increase the rigidity of the anterior cornea. This reaction, which occurs naturally with age in the human eye, is accelerated by the CXL procedure: The ultraviolet A (UVA) rays are used as catalyzers, while riboflavin is used as a photosensitizer. Because riboflavin cannot spontaneously penetrate an intact epithelial barrier, the classic CXL technique entails de-epithelialization before riboflavin imbibition for 30 minutes, followed by UVA light irradiation with a dose parameter of 3 mW/cm2 for a further 30 minutes.
The main side effects are pain in the first 48 hours after treatment and pseudo-haze with consequent decrease of vision, which may last for a maximum of 3 months. Complications are rare and encompass endothelial decompensation in thin corneas of less than 400 µm, infectious keratitis and stromal opacities.
Most of the ongoing research focuses on possible ways to avoid de-epithelialization in order to prevent side effects and improve treatment comfort. Transepithelial CXL has been explored as a possibility; shorter treatment times and a modified UVA irradiation profile have also been proposed.
Several ways of performing transepithelial CXL have been investigated in the past few years. The first attempts were made by using a modified hypo-osmolar riboflavin solution that could potentially penetrate the cornea through the epithelium. Several enhancers were added to the original formulation, such as polyethylene glycol, lysine, benzalkonium chloride and peptide NC-1059. Currently, the only molecule on the market that allows us to perform transepithelial CXL is Ricrolin TE (Sooft), which uses a combination of two enhancers: the amino alcohol TRIS and ethylenediaminetetraacetic acid. Clinical studies have produced contradictory results. While some report good results, others do not. However, all of them agree that transepithelial riboflavin penetration is less as compared with epithelium-off procedures. An alternative way of performing transepithelial CXL is by using iontophoresis, a noninvasive method of facilitating riboflavin penetration with the aid of low-intensity electrical current. Preclinical results are encouraging, but clinical evaluation of medium- and long-term stabilization of the disease is needed.
Attempts to improve the CXL procedure by shortening the time of UVA irradiation have also been made in recent years. They are based on the assumption that the induced biomechanical stiffening of the cornea is proportional to the total quantity of energy delivered and not to its power. Therefore, an equivalent result could theoretically be obtained by increasing power and reducing time, taking into account that there is a threshold beyond which increased irradiation power is not associated with increased stiffening. Several companies are currently working on this concept and offer devices that allow a surgeon to perform CXL in 3 minutes or 9 minutes. The first clinical trials report efficacy of the accelerated procedure, but there is no prospective, randomized trial demonstrating the non-inferiority of the accelerated UVA treatment compared with the classic procedure.
The modulation of the irradiation profile is another direction in which CXL advancements are moving. The idea is to tailor the irradiation profile to the individual preoperative cornea, based on topography and optical coherence tomography, or according to fluorescence measurements.
The association of these parameters will hopefully allow us to improve results, reduce unwanted effects and procedure times, offer better comfort for patients and broaden the indication of CXL.
- For more information:
- François Malecaze, MD, an OSN Europe Edition Board Member, is Professor and Chairman of Ophthalmology at Purpan University Hospital, Toulouse, France. He can be reached at Hôpital Purpan Place du Docteur Baylac - TSA 40031, 31059 Toulouse Cedex, France; +33-5-6177-7752; fax: +33-5-6177-7796; email: malecaze.fr@chu-toulouse.fr.
Disclosure: Malecaze has no relevant financial disclosures.