Comparative Efficacy and Safety of Conventional Dresden, Transepithelial, and Accelerated Corneal Collagen Cross-Linking Protocols for Progressive Keratoconus: A Systematic Review

OBJECTIVE: The objective of this study was to compare the efficacy and safety of conventional Dresden, transepithelial (epithelium-on), and accelerated corneal collagen cross-linking (CXL) protocols for the treatment of progressive keratoconus. METHODS: A systematic review of 84 studies was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Study screening and data extraction were supported by AI-assisted tools with full manual verification. Extracted outcomes included keratometric stabilization, visual acuity, endothelial cell density (ECD), complications, corneal thickness changes, and biomechanical or surrogate markers. RESULTS: Conventional epithelium-off (epi-off) CXL demonstrated the most consistent long-term keratometric stabilization and visual acuity preservation, with mean Kmax flattening of approximately 1.0-2.3 D at 12-36 months and durability extending up to five years in long-term datasets, alongside corrected distance visual acuity improvements of approximately 0.10-0.23 logMAR. Accelerated CXL protocols achieved comparable short-term outcomes (approximately 0.8-1.5 D Kmax flattening at 6-12 months) but exhibited greater variability in durability at longer follow-up. Standard transepithelial approaches generally produced smaller effects, although enhanced epi-on protocols incorporating oxygen supplementation or modified riboflavin delivery achieved keratometric stabilization approaching epi-off outcomes in selected studies (approximately 1.5-1.7 D flattening). Across all protocols, endothelial cell density was preserved, with changes typically within physiologic variability (