Comparison of Epithelium-Off Versus Transepithelial Corneal Collagen Cross-Linking for Keratoconus: A Systematic Review and Meta-Analysis

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To systematically compare standard epithelium-off corneal collagen cross-linking (SCXL) and transepithelial corneal collagen cross-linking (TECXL) for treating keratoconus.


PubMed, EMBASE, the Cochrane Library, the US trial registry (, VIP Database, Wanfang Databse, and China National Knowledge Infrastructure searches up to February 2017 were conducted. Primary outcomes were changes at 1 year in uncorrected distance visual acuity, maximum keratometry (Kmax), and mean keratometry (mean K). Secondary outcomes were changes at 1 year in corrected distance visual acuity, mean refractive spherical equivalent, central corneal thickness, endothelial cell density, and the occurrence of adverse events.


Eight studies with a total of 455 eyes were included. For primary outcomes, SCXL showed a greater reduction in mean K [standardized mean difference (SMD) 0.28; 95% confidence interval (CI), 0.03–0.53; P = 0.03] compared with TECXL. Subgroup analysis indicated that SCXL had a comparable effect on reducing mean K with TECXL protocols using chemical enhancers (SMD 0.05; 95% CI, −0.36 to 0.45; P = 0.82) but a greater reduction in mean K compared with TECXL with current iontophoretic protocols (SMD 0.43; 95% CI, 0.10–0.75; P = 0.01). For the other outcomes, there were no statistically significant differences.


With the exception of less reduction in mean K with current iontophoretic protocols, analysis of the limited number of comparative studies available seems to demonstrate that SCXL and TECXL have a comparable effect on visual, refractive, pachymetric, and endothelial parameters at 1 year after surgery. Further follow-up is required to determine whether these techniques are comparable in the long-term.

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