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Kobashi, Hidenaga MD, PhD

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Journal of Cataract & Refractive Surgery: April 2019 - Volume 45 - Issue 4 - p 536
doi: 10.1016/j.jcrs.2019.02.040
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As Rubinfeld et al. mentioned in their letter, a long-term prospective case series by Caporossi et al.1 found transepithelial CXL showed keratoconus instability in cases of progressive keratoconus; however, they did not compare the efficacy with that in the epi-off Dresden protocol. Stulting et al.2 also reported that the new transepithelial CXL halted the progression of corneal ectasia in a 2-year prospective observational follow-up study, as evident by an improvement in visual acuity and a decrease in maximum K values. Our review was limited to randomized controlled trials (RCTs) comparing transepithelial CXL and epi-off CXL in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.3

We agree that visual acuity is clinically important because these parameters might reflect the patients’ satisfaction with the CXL treatment. The maximum K value is arguably the most popular parameter when considering keratoconus progression, although it is not very reproducible. Which parameter is the most reliable for the evaluation of progression in eyes with keratoconus is debatable. According to the previous clinical trial for U.S. Food and Drug Administration approval, the primary and secondary efficacy criteria were the change in the maximum K value and in visual acuity, respectively.4

As for the concentrations of riboflavin in cornea, the corneal epithelium prevents absorption of topical riboflavin. Previous studies5,6 found that the concentration of riboflavin in the epithelium-on cornea was much lower than in the epi-off cornea in vivo. Rubinfeld et al.7 reported that the new transepithelial CXL system achieved higher corneal stromal concentrations of riboflavin than a commercially available transepithelial CXL system. Longer term follow-up and controlled trials of transepithelial CXL using different protocols are necessary to optimize the efficacy of the procedure. Our meta-analysis confirmed the variety in transepithelial techniques, such as concentrations and impregnations of riboflavin, in each trial. We emphasize that our meta-analysis provides more powerful evidence than individual RCTs alone.


1. Caporossi A, Mazzotta C, Paradiso AL, Baiocchi S, Marigliani D, Caporossi T. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg. 2013;39:1157-1163.
2. Stulting RD, Trattler WB, Woolfson JM, Rubinfeld RS. Corneal crosslinking without epithelial removal. J Cataract Refract Surg. 2018;44:1363-1370.
3. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. 2011
4. Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK., on behalf of the United States Crosslinking Study Group. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology. 2017;124:1259-1270. erratum, 1878.
5. Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg. 2009;35:893-899.
6. Mastropasqua L, Nubile M, Calienno R, Mattei PA, Pedrotti E, Salgari N, Mastropasqua R, Lanzini M. Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. Am J Ophthalmol. 2014;157:623-630.
7. Rubinfeld RS, Stulting RD, Gum GG, Talamo JH. Quantitative analysis of corneal stromal riboflavin concentration without epithelial removal. J Cataract Refract Surg. 2018;44:237-242. erratum, 523.
© 2019 by Lippincott Williams & Wilkins, Inc.