What surgical procedure works best to slow the progression of keratoconus (an eye disease)?

Why is this question important?
Keratoconus is a disease that affects the thin, clear outer layer of the eye, known as the cornea. Normally, the cornea is dome-shaped. In people with keratoconus, the cornea slowly thins, and a cone-shaped bulge develops in the center of the cornea. The disease usually begins between the ages of teens and 40, and persists throughout life. It causes blurry or distorted vision that may not be improved by wearing glasses and may result in perforation of the cornea and other visual problems.

Treatments such as glasses and contact lenses can be used to improve the vision of people with keratoconus. However, these do not slow the progression of the disease. The only treatment known to slow disease progression is ‘corneal collagen crosslinking’ (CXL).

CXL is a surgical procedure that aims to strengthen the cornea and prevent further thinning. It involves shining ultraviolet A (invisible) light rays onto eyes that have been treated with eye drops containing riboflavin (a vitamin). When the light rays meet the riboflavin, new links form between the fibers that make up the cornea.

There are two types of CXL. One type requires the removal of the cells on surface of the cornea, to make it easier for the riboflavin to reach the cornea. This procedure is called ‘epithelium-off CXL’. The other type does not require the removal of these cells. This procedure is called ‘transepithelial CXL’. Surgeons who carry out this procedure can use chemicals to help riboflavin penetrate the cells on the surface of the cornea. They can also deliver riboflavin to the cornea using a small electrical current (iontophoresis).

Epithelium-off CXL is the more commonly used procedure. However, transepithelial CXL could have advantages, such as faster healing and less patient discomfort. We reviewed the evidence to find out which of these two procedures is more beneficial and less risky for people with keratoconus.

How did we identify and evaluate the evidence?
We searched the medical literature for studies that compared epithelium-off CXL against transepithelial CXL. Then we compared the results and summarized the evidence from all the studies. We rated our confidence in the evidence, based on factors such as study methods and sizes, and the consistency of findings across studies.

What did we find?
We found 13 studies with a total of 567 people. The studies took place in Europe, the Middle East, India, Russia, and Turkey. The shortest studies lasted six months, and the longest study lasted more than three years. Eleven studies compared transepithelial CXL without iontophoresis against epithelium-off CXL. Three studies compared transepithelial CXL with iontophoresis against epithelium-off CXL.

Transepithelial CXL without iontophoresis compared to epithelium-off CXL

We do not know if one procedure is better than the other for preventing progression of keratoconus or visual loss because too few robust studies have compared the effects of these two CXL methods.

Evidence from four studies suggests that corneal hazing (clouding of the cornea) or scarring are probably more common with epithelium-off CXL.

Transepithelial CXL with iontophoresis compared to epithelium-off CXL

Evidence from two studies suggests that there may be little to no difference between the two procedures in changes to vision clarity. We do not know if one procedure is better than the other to prevent progression of keratoconus because two few robust studies have compared the two methods.

The evidence does not suggest that one procedure leads to more unwanted events than the other. However, our confidence in this evidence is low, because it is based on three studies that did not use robust methods.

What does this mean?
Due to a lack of robust evidence, we do not know if epithelium-off CXL or transepithelial CXL is better for slowing keratoconus progression.

Adverse events such as corneal hazing or scarring are probably more common with epithelium-off CXL than with transepithelial CXL without iontophoresis.

We need more and larger studies to strengthen the evidence. These should compare the benefits and the risks of different CXL procedures. Studies should aim to follow patients for more than 12 months, so that long-term effects can be compared as it can take at least that much time for corneal tissue to heal from any procedure.

How-up-to date is this review?
The evidence in this Cochrane Review is current to January 2020.

Authors' conclusions: 

Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs. 

Read the full abstract...

Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening.

Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process.

Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze.


To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus.

Search strategy: 

To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020.

Selection criteria: 

We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus.

Data collection and analysis: 

We used standard Cochrane methodology.

Main results: 

We included 13 studies with 661 eyes of 567 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention.

Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI −0.11 to 2.09; 5 studies; 177 eyes; I2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14).

Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI −0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported.

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