Regional Biomechanical and Topographic Changes after Transepithelial vs. Epithelium-off Continuous Accelerated Corneal Cross-linking in Keratoconus: Updated Stress-Strain Index as a Superior Biomarker

Purpose: To compare regional biomechanical and topographic outcomes between transepithelial (Epi-on) and epithelium-off (Epi-off) continuous accelerated corneal cross-linking (ACXL) in keratoconus. Design: A retrospective cohort study. Subjects: Seventy-seven keratoconic eyes were included: 45 with Epi-on ACXL and 32 with Epi-off ACXL. Methods: All eyes underwent ACXL (10 mW/cm ², 7.2 J/cm ²). Pentacam HR and Corvis ST measurements were obtained preoperatively (pre), and at 1 month (pos1m), and 6 months (pos6m) postoperatively. The SSIv2m, M, and J ₀, J ₄₅ were evaluated across central (0–3 mm), paracentral (3–6 mm), and peripheral (6–9 mm) regions. Correlated measurements were analyzed using generalized estimating equations for regional and longitudinal data, and generalized linear models for intergroup comparisons, with both absolute (Δ) and relative changes (Δ%) evaluated. Main Outcome Measures: Regional changes in SSIv2 _m, M, J ₀, and J ₄₅ were analyzed across central (0–3 mm), paracentral (3–6 mm), and peripheral (6–9 mm) regions preoperatively and at 1 and 6 months postoperatively. Results: At 6 months, SSIv2 _m increased significantly in all regions of the Epi-off ACXL group (greatest centrally), whereas the Epi-on group showed no consistent change. ΔSSIv2 _m between preoperative and pos6m was significantly greater in Epi-off ACXL than Epi-on ACXL across all regions (central: P < 0.01; paracentral and peripheral: P < 0.05). Central flattening (negative ΔM) was significant in the Epi-off ACXL group (P < 0.001) and exceeded that in Epi-on ACXL (P < 0.001). No significant changes were detected in J ₀ or J ₄₅. Δ%SSIv2 _m exceeded Δ%M in the paracentral and peripheral (paracentral: P < 0.01; peripheral: P < 0.05) regions after Epi-off ACXL. Conclusions: Epi-off ACXL induces stronger and more durable biomechanical stiffening and central flattening than Epi-on ACXL. Biomechanical parameters, particularly SSIv2, were more sensitive than curvature-based metrics for detecting regional treatment effects. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.