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Reassessing transepithelial corneal crosslinking

Rubinfeld, Roy S. MD, MA; Caruso, Ciro MD; Ostacolo, Carmine PharmD

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Journal of Cataract & Refractive Surgery: April 2019 - Volume 45 - Issue 4 - p 535-536
doi: 10.1016/j.jcrs.2019.01.036
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We read with great interest the timely and clinically important meta-analysis by Kobashi, et al.1 comparing transepithelial and epithelium-off (epi-off) corneal crosslinking (CXL) for corneal ectasia. Several transepithelial techniques have been published, and various comparisons have been made to epi-off approaches. Although a definitive comparison has not been established, we believe transepithelial CXL is nearing maturity and that a future standard transepithelial technique will have some distinguishing features identified in the review. A recent assessment of keratoconus prevalence, at 1 in 375, highlights the importance of this discussion.

The authors identified 2 features that match our decade-long experience assessing dozens of permutations of transepithelial CXL approaches. First, with a notable exception (see below), not one of these transepithelial techniques has been shown in large-scale or long-term studies to have the same efficacy against the progression of keratoconus as the original epi-off Dresden protocol.2 We believe the variety of transepithelial techniques noted in the review indicates the cause—incomplete optimization of the mechanisms by which riboflavin and ultraviolet light interact with oxygen in the cornea.

Second, in optimizing our transepithelial system and applying it to larger samples of patients, we have found greater changes in visual acuity and smaller changes in maximum keratometry (K) values than typically reported in similar studies of epi-off CXL. For inclusion in the analysis, the authors wisely included degradation in visual acuity in their definition of progression. Although the definition varies, this one addresses the large variability of keratometry in keratoconic eyes (as much as 2.4 diopters within 5 minutes).3 The single exception we take to the authors’ conclusions is the implied primacy of the maximum K value as an efficacy parameter. Visual acuity is also an important marker of efficacy and arguably more clinically relevant.

One clinical study not included in the meta-analysis was recently published in this journal,4 reporting on 592 eyes treated with a patented proprietary transepithelial crosslinking system (CXL Ophthalmics LLC). The mean corrected and uncorrected distance visual acuities improved by 1.0 Snellen lines and 1.5 Snellen lines, respectively, 1 year and 2 years postoperatively (P < .0001). The keratoconus did not progress in any eye, and there was no loss of effect between 1 year and 2 years postoperatively. Animal research on this system showed adequate loading of the corneal stroma,5 which Kobashi et al.1 correctly identified as a key efficacy-limiting factor. We believe that this clinical study is the largest of its kind and represents an important step toward establishing a mature effective alternative to epi-off CXL. It solves problems noted in the authors’ review but exhibits a favorable safety profile and salutary effect on visual acuity.

We commend the authors on their excellent work and seek to point out the constantly changing landscape of CXL. We believe recent peer-reviewed publications and supporting basic science research clearly show that optimized transepithelial CXL can stop the progression of corneal ectasia and consequent vision degradation inherent in keratoconus and that because of the adverse events associated with epithelium removal, transepithelial CXL will be ultimately favored.


1. Kobashi H, Rong SS, Ciolino JB. Transepithelial versus epithelium-off corneal crosslinking for corneal ectasia. J Cataract Refract Surg. 2018;44:1507-1516.
2. 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.
3. Rubinfeld RS, Littner R, Trattler WB, Rocha K, Talamo J, Lindstrom RL. Pentacam HR criteria for curvature change in keratoconus and postoperative LASIK ectasia [letter]. J Refract Surg. 2013;29:666. reply by RL Epstein, Y-L Chiu, G Epstein, 666–667.
4. Stulting RD, Trattler WB, Woolfson JM, Rubinfeld RS. Corneal crosslinking without epithelial removal. J Cataract Refract Surg. 2018;44:1363-1370.
5. 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.