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Standard CXL reduces maximum keratometry more than transepithelial CXL
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A meta-analysis of studies comparing standard and transepithelial corneal cross-linking showed that both techniques are safe, but the standard procedure was more effective at decreasing maximum keratometry.
A systematic search through PubMed, the Cochrane Library and Embase identified 1,018 potentially relevant studies, of which only three met the inclusion criteria established by the authors. They included 244 eyes, with 111 eyes treated by standard CXL and 133 eyes treated by transepithelial CXL. The follow-up was from 12 to 24 months.
Maximum keratometry data favored standard CXL, with significantly more reduction in Kmax. Keratometry, the authors noted, indicates the progression or improvement of keratoconus, and the weaker effect of the transepithelial procedure is likely to be the consequence of the lesser riboflavin penetration beyond the epithelial barrier. Because CXL happens through oxygen-dependent pathways, the epithelium may also act as a barrier to oxygen diffusion to the stroma.
“Considering all these factors, the actual transepithelial cross-linking effect may be less deep and less complete at all levels compared to what occurs with equivalent dosing with the epithelium removed,” the authors wrote.
As far as vision gain was concerned, the transepithelial CXL group of eyes had better corrected distance visual acuity improvement, but uncorrected distance visual acuity gain was similar in both groups.
Corneal thickness on the thinnest point was measured to assess safety. With both methods, a similar reduction in corneal thickness, within safety limits, was reported.
The authors said that the power of assessment of this analysis was limited by the low number of studies included and that more pragmatic randomized controlled trials are needed to draw conclusions. – by Michela Cimberle
Disclosures: The authors report no relevant financial disclosures.
Perspective
Back to TopFarhad Hafezi, MD, PhD and Nikki Hafezi, MAS IP ETHZ
According to this study, transepithelial CXL (epi-on) is less effective in decreasing maximum keratometry but is superior in corrected distance visual acuity (CDVA) outcomes and similarly safe. The conclusions drawn by the authors do not change our opinion or current clinical practice, which is epi-off in all standard cases, for the following reasons:
The authors performed a meta-analysis but based on only three trials. They also claim that transepithelial CXL has reported better visual outcomes. Before any conclusions can be drawn, it is important to have a closer look at the data.
The study by Bikbova showed superior CDVA for epi-on only at 12 months, whereas at 24 months, CDVA was comparable in both epi-on and epi-off groups. The study by Soeters specifically states that, “When analyzing the data without the 1-month results, there is no significant difference between the 2 groups.”
Furthermore, the primary goal of CXL is to arrest progression of the disease and not necessarily improving visual acuity. Although the intention to put emphasis on visual acuity is understood, the data obtained from the three studies cannot be compared in a sound manner because the CXL protocols used in the three studies differ substantially. Bikbova and colleagues used the Dresden protocol for both epi-off and epi-on with 10 minutes of iontophoresis. Lombardo and colleagues used the Dresden protocol for the epi-off group but used a different irradiation/time setting of 9 minutes at 10 mW/cm2 for the epi-on group with iontophoresis. Finally, Soeters used the Dresden protocol for both epi-off and epi-on but did not perform iontophoresis in the epi-on group.
This discrepancy is of particular concern because recent research from our group has shown that even changing the irradiation/time parameters while keeping the mode of administration identical (Torres and colleagues, ARVO 2018, accepted) in iontophoresis-mediated epi-on CXL may lead to different results due to the central role of oxygen diffusion. In summary, no conclusion can be drawn using three different studies with three entirely different irradiation/time and riboflavin administration modalities.
In the future, a large randomized controlled trial would provide better evidence and draw more accurate conclusions because the clinical trial protocol (eg, materials, methods, inclusion/exclusion criteria, follow-up, etc.) would be more consistent. LeLorier and co-authors highlighted in a paper published some years ago in the New England Journal of Medicine how often and why there are “discrepancies between meta-analyses and subsequent large randomized, controlled trials.”
Reference:
LeLorier J, et al. N Engl J. Med. 1997;doi:10.1056/NEJM199708213370806.
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