Corneal collagen cross-linking for thinning of the transparent front part of the eye ('keratoconus')

Review question
Is corneal collagen cross-linking (CXL) a good treatment for slowing down the progression of keratoconus?

Keratoconus is a condition where the transparent front of the eye (cornea) gets thinner and begins to bulge. This leads to vision problems, usually short-sightedness (distant objects appear blurred). The condition is more common in children and young adults and can deteriorate over time. Initially glasses and contact lenses can help. If the disease progresses, the only option may be a corneal transplant.

CXL is a new treatment for keratoconus. The eye doctor removes the outer layer of the cornea, puts in vitamin B2 eye drops, and then treats the eye with ultraviolet A light radiation. This can be done in outpatients and takes about an hour.

Study characteristics
The searches are current to August 2014. We found three randomised controlled trials, which were done in the United States, the United Kingdom, and Australia. A total of 219 eyes were randomly allocated to treatment with CXL or no treatment. In all three studies the surgery was done in the same way. None of the studies included children.

Key results
Eyes treated with CXL were less likely to have problems with progression of bulging compared to eyes that were not treated. However, the studies were small and there were some concerns about the way they were done. It is therefore difficult to say exactly how much the treatment helped. None of the studies reported the risk of eyesight getting worse but, on average, treated eyes had better vision (about 10 letters better) compared to untreated eyes. None of the studies reported on a change in quality of life for the participant. The main adverse effects were inflammation and swelling; this occurred in approximately one in 10 participants.

Quality of the evidence
We judged the quality of the evidence to be very low because of problems in the way the studies were done and reported and the small number of eyes included.

Authors' conclusions: 

The evidence for the use of CXL in the management of keratoconus is limited due the lack of properly conducted RCTs.

Read the full abstract...

Keratoconus is a condition of the eye that affects approximately 1 in 2000 people. The disease leads to a gradual increase in corneal curvature and decrease in visual acuity with consequent impact on quality of life. Collagen cross-linking (CXL) with ultraviolet A (UVA) light and riboflavin (vitamin B2) is a relatively new treatment that has been reported to slow or halt the progression of the disease in its early stages.


The objective of this review was to assess whether there is evidence that CXL is an effective and safe treatment for halting the progression of keratoconus compared to no treatment.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2014), EMBASE (January 1980 to August 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to August 2014), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to August 2014), OpenGrey (System for Information on Grey Literature in Europe) (, the metaRegister of Controlled Trials (mRCT) (, ( and the World Health Organisation International Clinical Trials Registry Platform (ICTRP) ( We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 August 2014.

Selection criteria: 

We included randomised controlled trials (RCTs) where CXL with UVA light and riboflavin was used to treat people with keratoconus and was compared to no treatment.

Data collection and analysis: 

Two review authors independently screened the search results, assessed trial quality, and extracted data using standard methodological procedures expected by Cochrane. Our primary outcomes were two indicators of progression at 12 months: increase in maximum keratometry of 1.5 dioptres (D) or more and deterioration in uncorrected visual acuity of more than 0.2 logMAR.

Main results: 

We included three RCTs conducted in Australia, the United Kingdom, and the United States that enrolled a total of 225 eyes and analysed 219 eyes. The total number of people enrolled was not clear in two of the studies. Only adults were enrolled into these studies. Out of the eyes analysed, 119 had CXL (all using the epithelium-off technique) and 100 served as controls. One of these studies only reported comparative data on review outcomes. All three studies were at high risk for performance bias (lack of masking), detection bias (only one trial attempted to mask outcome assessment), and attrition bias (incomplete follow-up). It was not possible to pool data due to differences in measuring and reporting outcomes. We identified a further three unpublished trials that potentially had enrolled a total of 195 participants.

There was limited evidence on the risk of progression. Analysis of the first few participants followed up to one year in one study suggested that eyes given CXL were less likely to have an increase in maximum keratometry of 1.5 D or more at 12 months compared to eyes given no treatment, but the confidence intervals (CI) were wide and compatible with no effect or more progression in the CXL group (risk ratio (RR) 0.12, 95% CI 0.01 to 2.00, 19 eyes). The same study reported the number of eyes with an increase of 2 D or more at 36 months in the whole cohort with a RR of 0.03 favouring CXL (95% CI 0.00 to 0.43, 94 eyes). Another study reported "progression" at 18 months using a different definition; people receiving CXL were less likely to progress, but again the effect was uncertain (RR 0.14, 95% CI 0.01 to 2.61, 44 eyes). We judged this to be very low-quality evidence due to the risk of bias of included studies, imprecision, indirectness and publication bias but noted that the size of the potential effect was large.

On average, treated eyes had a less steep cornea (approximately 2 D less steep) (mean difference (MD) -1.92, 95% CI -2.54 to -1.30, 94 eyes, 1 RCT, very low-quality evidence) and better uncorrected visual acuity (approximately 2 lines or 10 letters better) (MD -0.20, 95% CI -0.31 to -0.09, 94 eyes, 1 RCT, very low-quality evidence) at 12 months. None of the studies reported loss of 0.2 logMAR acuity. The data on corneal thickness were inconsistent. There were no data available on quality of life or costs. Adverse effects were not uncommon but mostly transient and of low clinical significance. In one trial, 3 out of 12 participants treated with CXL had an adverse effect including corneal oedema, anterior chamber inflammation, and recurrent corneal erosions. In one trial at 3 years 3 out of 50 participants experienced adverse events including mild diffuse corneal oedema and paracentral infiltrate, peripheral corneal vascularisation, and subepithelial infiltrates and anterior chamber inflammation. No adverse effects were reported in the control groups.