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Epi-on vs. epi-off debate will improve cross-linking procedure
Since its introduction by Seiler and Spoerl in 1997, corneal collagen cross-linking has proven to be safe and effective for improving the biomechanical stability of eyes with keratectasia. For many years, the Dresden protocol involving epithelial debridement has been the gold standard. But the disadvantages of epithelial debridement, including infection, postoperative pain, delayed epithelial healing, stromal haze and corneal melting, have led to the development of transepithelial cross-linking.
The epi-off technique
The standard epi-off protocol, also called the Dresden protocol, involves removal of 9 mm of the corneal epithelium followed by saturation of the corneal stroma using 0.1% isotonic riboflavin solution in 20% dextran. After adequate riboflavin absorption, the cornea is irradiated with ultraviolet A 5.4 J/cm2 or 3 mW/cm2 for 30 minutes. Various refinements in epithelial removal have been introduced and involve the use of debridement burrs, alcohol solutions, phototherapeutic keratectomy or an epithelial disruptor. The minimal thickness of corneal stroma to be cross-linked must be at least 400 µm.
The epi-on technique
The epi-on technique was originally described by Brian Boxer Wachler in 2004 and then by Roberto Pinelli. Other authors, too, have described the favorable but limited effects of epi-on in keratectatic eyes. Many variations of the treatment protocol have been described. Kanellopoulos and colleagues demonstrated that cross-linking using a femtosecond laser facilitated creation of an intrastromal pocket to apply the 0.1% riboflavin, showing promising preliminary results.
Challenges of the epi-on technique
One of the major challenges is the time taken to load the cornea with riboflavin when performing a transepithelial approach. This results in prolonging the procedure time by 30 to 50 minutes. One method to help with transepithelial riboflavin loading is a procedure described by Filippello and colleagues, in which a flat silicone ring is applied to the corneoscleral limbus to keep the corneal surface in contact with the riboflavin.
Although the results of epi-on have been promising, the effect appears to be less pronounced than in epi-off. Experimental studies have shown a lower efficacy of epi-on due to the lower epithelial permeability of riboflavin and possible interference with transmission of the ultraviolet light. Comparative studies of biomechanical and histological changes after cross-linking with and without epithelial debridement have demonstrated that without epithelial debridement, the biomechanical effect of cross-linking is reduced by approximately one-fifth compared with complete removal of the epithelium.
Various methods to enhance riboflavin penetration are being attempted, such as the use of hypertonic riboflavin solution without dextran and the use of chemical enhancers such as benzalkonium chloride, trometamol and ethylenediaminetetraacetic acid. Partial epithelial removal has been suggested; however, this results in a limited and non-homogeneous uptake of riboflavin and, therefore, diminished efficacy of collagen cross-linking.
Limitations of the epi-on technique
Epi-on cannot be combined with simultaneous procedures involving epithelial debridement, such as topography-guided PRK. Although it is a safe treatment option to slow progression of keratectasia, it can be associated with some complications and failure. There are no specific criteria to define treatment failure, but diminution of best corrected visual acuity improvement and increased keratometry readings at 1 year have been described. Koller et al used Scheimpflug imaging to assess progression and failure. An increase in maximum keratometry by 1 D over the preoperative values was deemed a failure. Complication rate was defined as a decrease of two or more Snellen lines of corrected distance visual acuity at 1 year follow-up. In this study, the complication rate was 2.9% and failure rate was 7.6%. Postoperative complications included corneal ulcers, corneal haze, stromal scarring (seen more in advanced disease), endothelial cell density loss (in thin corneas below 400 µm) and corneal melt.
The debate: On or off
The debate over epi-on vs. epi-off is important because it will ultimately make the procedure better. If surgeons gain the ability to perform combined topography-guided PRK and cross-linking, then the epi-off approach would be natural. If cross-linking is combined with Intacs (Addition Technology) to reshape the cornea, then an epi-on approach would make sense. In cases in which cross-linking is performed alone, the epi-on technique would be preferable.
References:
Bakke EF, et al. J Cataract Refract Surg. 2009;doi:10.1016/j.jcrs.2009.03.023.
Filippello M, et al. J Cataract Refract Surg. 2012;doi:10.1016/j.jcrs.2011.08.030.
Kanellopoulos AJ. J Refract Surg. 2009;doi:10.3928/1081597X-20090901-02.
Kanellopoulos AJ, et al. J Refract Surg. 2011;doi:10.3928/1081597X-20101105-01.
Koller T, et al. J Cataract Refract Surg. 2009;doi:10.1016/j.jcrs.2009.03.035.
Leccisotti A, et al. J Refract Surg. 2010;doi:10.3928/1081597X-20100212-09.
Raiskup F, et al. Ocul Surf. 2013;doi:10.1016/j.jtos.2013.01.003.
For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; +852-3997-3266; fax: +852-3996-8212; email: dennislam.gm@gmail.com.
Disclosure: The authors have no relevant financial disclosures.