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Updated: Feb 6, 2026

Three Different Protocols of Corneal Collagen Crosslinking in Keratoconus: Conventional, Accelerated and Iontophoresis
Published on: November 12, 2015
Epi-Off versus Epi-On Corneal Collagen Cross-Linking in Keratoconus Patients: A Comparative Study through 2-Year
F Cifariello1,2, M Minicucci3, F Di Renzo1
1Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
Aim:
To evaluate two different techniques of cross-linking: standard epithelium-off (CXL epi-off) versus transepithelial (CXL epi-on) cross-linking in patient with progressive keratoconus.
Methods:
Forty eyes from 32 patients with progressive keratoconus were prospectively enrolled from June 2014 to June 2015 in this nonblinded, randomized comparative study. Twenty eyes were treated by CXL epi-off and 20 by CLX epi-on, randomly assigned, and followed for 2 years. All patients underwent a complete ophthalmologic testing that included uncorrected and best corrected visual acuity, central and peripheral corneal thickness, corneal astigmatism, simulated maximum, minimum, and average keratometry, corneal confocal microscopy, Schirmer I and break-up time (BUT) tests, and the Ocular Surface Disease Index. Intra- and postoperative complications were recorded. The solution used for CXL epi-off comprised riboflavin 0.1% and dextran 20.0% (Ricrolin), whereas the solution for CXL epi-on (Ricrolin TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with a UV-X system at 3 mW/cm2.
Results:
In both groups, a significant improvement in visual function (Group 1: baseline 0.36 ± 0.16 logMAR, two-year follow-up 0.22 ± 0.17 logMAR, p=0.01; Group 2: baseline 0.32 ± 0.18 logMAR, 2-year follow-up 0.27 ± 0.19 logMAR, p=0.01) was recorded. Keratometry remained unchanged in both groups. The mean corneal thickness showed a significant reduction (mean difference of corneal thickness: -55 micron and -71 micron, resp.). One-month after treatment, OSDI© reached 13.56 ± 2.15 in Group 1 (p=0.03) and 11.26 ± 2.12 in Group 2 (p=0.04). At confocal microscopy, abnormal corneal nerve alterations were found in both groups. Fibrotic reaction (43.75%) and activated keratocyte (62.6%) were more commonly recorded in Group 1 than in Group 2 (25.0% and 18.75%), with p=0.668 and 0.356, respectively.
Conclusion:
Our findings demonstrate that both procedures are able to slow keratoconus progression. Both treatment modalities are equivalent in terms of results and related complications. CXL epi-on technique is preferable to CXL epi-off since it preserves the corneal thickness and improves visual acuity, also reducing the postoperative ocular discomfort during the study period.
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