Meta-analysis Gives Edge to Epi-off CXL in Structural Improvements to Cornea

With the FDA set to weigh in soon on potential approval of the epithelium-on crosslinking procedure, interest in the more comfortable alternative is rising, with clinicians wondering whether it provides comparable outcomes. Recently published research in Cornea provides a review on the latest literature examining epi-on and epi-off CXL. The gold standard epi-off procedure demonstrated significantly greater long-term topographical stability in this literature review. Photo: Clark Chang, OD, and Christopher Rapuano, MD. Click image to enlarge. Records from PubMed, Embase and Scopus databases were collected for this study to provide a comprehensive evaluation of each CXL technique. After removing duplicated and inappropriate studies, the researchers analyzed 28 unique articles for their review. Visual and imaging outcomes were examined at baseline and follow-up visits (if available) at six months, one year, two years and three years.“Our findings reinforce that both techniques effectively stabilize disease progression,” reported the authors in their paper, “but epi-off demonstrates greater structural efficacy over time.” Among the 28 studies, 1,764 eyes were treated with either epi-off (49.6%) or epi-on (50.4%) techniques. It was discovered that maximum keratometry measurements, or Kmax, showed flattening at six months for both procedures; however, at two-year follow-up, a significant difference between each technique was found to favor epi-off, which the researchers stated that this explains how patients who had their epithelium removed sustained topographic improvement over time. Additionally, epi-off patients experienced a significant reduction to their central corneal thickness over time compared to epi-on patients.Interestingly, visual acuity changes were similar between both CXL groups. After looking at results throughout each follow-up period, the researchers reported that no statistical significance was found between epi-off and epi-on when examining best-corrected distance visual acuity and uncorrected distance visual acuity.Other relevant factors such as adverse events and patient comfort assessments were not consistently reported among the studies evaluated, but should play a part in the overall assessment of treatment modality. “These findings support a personalized approach in selecting CXL technique based on patient profile and treatment goals,” the paper states.Epi-off CXL “remains the gold standard for long-term stabilization, particularly in younger patients with progressive disease, but it carries a higher risk of complications such as haze, delayed healing, and stromal scarring,” the authors noted. “In contrast, epi-on may be preferable for those prioritizing safety, comfort, and faster recovery, especially in mild to moderate cases, despite ongoing concerns about its long-term efficacy.”In the discussion section of their paper, the researchers suggested that “high-quality randomized controlled trials with long-term data and consistent methodology are needed to confirm structural advantages and better correlate them with functional visual outcomes.” One major limitation to their study was the inclusion of several reports with varying designs, follow-up durations and CXL protocols. Some of the analyzed records coupled keratoconus with other diseases, such as pellucid marginal degeneration. Others focused on anatomical differences, such as central versus peripheral keratoconus. The variations of studies, the researchers noted, complicated the present study’s comparison of epi-off and epi-on CXL.“Subgroup analysis reveals that study design and risk of bias meaningfully influence pooled results, highlighting the need for methodological rigor in the future comparisons,” concluded the authors. “Further research into long-term outcomes and enhanced protocols will be essential in refining CXL strategies for optimal keratoconus management.” Click here for the journal source. Mohammadpour M, Esfandiarifard S, Pourmirbabaei S, et al. A systematic review and meta-analysis comparing epithelium-on and epithelium-off corneal collagen cross-linking in keratoconus management: Integrating new evidence. Cornea. August 22, 2025. [Epub ahead of print]. This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.