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

## TL;DR

This study compares three corneal cross-linking methods for treating keratoconus, finding conventional methods most effective for long-term results.

## Contribution

The study provides a systematic review comparing three CXL protocols for progressive keratoconus, highlighting their efficacy and safety profiles.

## Key findings

- Conventional epi-off CXL showed the best long-term keratometric stabilization and visual acuity preservation.
- Accelerated CXL protocols had similar short-term outcomes but less durability over time.
- Transepithelial approaches with enhancements achieved results closer to conventional methods in some cases.

## Abstract

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 (<5%). Transient corneal haze occurred more frequently following conventional epi-off CXL (approximately 40-70%) than accelerated protocols (approximately 20-47%), while serious complications, including infectious keratitis, remained rare (approximately 0.001-0.5%).

Conclusion: Conventional epi-off CXL has the strongest evidence for durable keratometric stabilization and visual acuity preservation in progressive keratoconus. Accelerated protocols offer similar short-term efficacy with improved treatment efficiency, while enhanced transepithelial approaches may be appropriate for selected patients prioritizing reduced invasiveness and postoperative discomfort, with potential trade-offs in long-term durability.