Researchers conducted a Cochrane systematic review of studies that tested the effectiveness and safety of transepithelial (epi-on) corneal crosslinking (CXL) compared with epithelium-off (epi-off) CXL for progressive keratoconus. However, their findings made it difficult to state with confidence whether epi-on CXL confers an advantage over epi-off CXL for patients with progressive keratoconus in regards to stabilization of keratoconus, visual acuity or patient-reported outcomes based on the available data.

The review assessed 13 randomized controlled trials where 567 participants (661 eyes) were included; 11 studies compared non-iontophoresis-assisted transepithelial with epithelium-off CXL. The primary outcome, keratoconus stabilization based on post-operative maximum keratometry (Kmax), was described as an outcome in two studies.

The estimated difference in Kmax means from meta-analysis of 177 eyes in five RCTs indicated that there was no difference between intervention groups in Kmax at 12 months or later. Meta-analysis of keratometry and visual acuity outcomes at 12 months or longer after surgery from two studies that had compared epi-on CXL using iontophoresis provided no conclusive evidence of an advantage over epi-off CXL.

“Because Kmax has been measured using a wide variety of topographic and tomographic devices, reliance on final Kmax value as an outcome measure is inherently problematic,” the researchers said. However, until a better biomarker is found, they still believe the relative change in Kmax is a reasonable proxy for stabilization of progressive keratoconus.

“Because of lack of precision, frequent indeterminate or high risk of bias and inconsistency in methods and outcomes among studies included in this systematic review, it remains to be shown whether transepithelial CXL, or any other approach, confers an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to progression of keratoconus, visual acuity outcomes and patient-reported visual function,” the researchers noted.

Nevertheless, they are hopeful that, with improved trial design methodology and better means of uptake of UVA by the corneal stroma, estimates for outcomes will become more precise and  guide the development of more uniform, effective epi-on techniques.

“Investigators in future studies should correlate clinical assessments of corneal haze, which was observed after epi-off CXL but not after transepithelial CXL and other adverse outcomes with assessments of its visual significance to the patient,” the researchers suggested.

Ng SM, Hawkins BS, Kuo IC. Transepithelial versus epithelium-off corneal crosslinking for progressive keratoconus: findings from a Cochrane systematic review. Am J Ophthalmol. May 25, 2021. [Epub ahead of print].