Comparison of epithelium-off versus iontophoresis-assisted transepithelial corneal collagen cross-linking in keratoconus: a systematic review and meta-analysis.

background / purposeKeratoconus is a progressive corneal ectasia characterized by stromal thinning and protrusion, leading to irregular astigmatism and visual impairment. To mitigate these issues, iontophoresis-assisted transepithelial corneal collagen cross-linking (I-CXL) was developed to enhance riboflavin penetration while preserving the epithelium, aiming for comparable biomechanical effects with fewer adverse events. This systematic review and meta-analysis aim to compare the efficacy and safety of iontophoresis-assisted transepithelial corneal collagen cross-linking (I-CXL) and standard epithelium-off corneal collagen cross-linking (S-CXL) in the management of keratoconus.

methodsThis systematic review and meta-analysis was registered with PROSPERO (ID: CRD420251091187). PubMed, Web of Science, CENTRAL (Cochrane Central Register of Controlled Trials), ClinicalTrials.gov, Google Scholar, and DOJA were searched from inception until August 2025. Risk of bias was assessed using the Cochrane Risk of Bias Tool for randomized controlled trials and Newcastle-Ottawa Scale (NOS) for observational cohort studies. Meta-analysis was conducted using Review Manager (RevMan) version 5.4 (Cochrane Collaboration). A random-effects model was used to assess heterogeneity across studies.

results14 studies with a total of 629 patients were included, with10 incorporated into the quantitative analysis. Pooled analysis showed no significant difference between S-CXL and I-CXL in K-max reduction (mean difference MD = 0.52 D; 95% CI = [- 0.20, 1.23]; P = 0.16). I-CXL had more improvement in UCVA and BCVA, but without statistical significance (UCVA MD =  - 0.03 logMAR; P = 0.30; BCVA MD =  - 0.01 logMAR; P = 0.57). there was no significant difference between the two in terms of ECC, CCT, and TPT. I-CXL was associated with less adverse events and better patient comfort.

conclusionBoth S-CXL and I-CXL are effective in halting keratoconus progression. S-CXL offered better corneal flatting, whereas I-CXL achieved better visual acuity parameters with less side effects and better patient comfort. Due to the high heterogeneity, lack of long-term trials, especially on pediatric population, further research is required.