When it comes to corneal cross-linking (CXL), every single one of us is currently in the “epi-off” camp. Why? Because corneal ectasias like keratoconus need to be dealt with effectively – and, if CXL is the right approach to take for an ectatic cornea, then performing epi-off (rather than epi-on) CXL is almost always the right choice. It’s the collagen in the corneal stroma that needs to be cross-linked; riboflavin, UV-A light and oxygen need to reach the stroma to do that, but the corneal epithelial cells form a very effective barrier to riboflavin penetration and oxygen diffusion (2). That’s why the original Dresden protocol required epithelial cell debridement (3). It’s also why no epithelial-sparing – epi-on – method has come close to the effectiveness of epi-off CXL – even iontophoresis, where a small electric current is applied to enhance riboflavin penetration (4). We would all love to be able to perform an effective epi-on procedure for our patients – such an approach promises patients less pain, a reduced risk of infection and transient haze, faster recovery, easier post-procedural aftercare and more… But we don’t, because we won’t risk having to repeat the surgical procedure at a later date and having patients suffer progression from that delay. Epi-on CXL, despite all of the advances in riboflavin formulations and delivery methods, still isn’t as effective as epi-off CXL in terms of cross-linking the cornea, adding biomechanical strength, and crucially, halting the progression of corneal ectasia. Nothing the CXLUSA group have presented to date has convinced us otherwise.

Our first concern comes down to the fundamentals of the scientific method. The CXLUSA investigators have presented one-year data (5) from 341 keratoconic eyes that suggest significant improvements in uncorrected visual and corrected distance visual acuity (UCVA and CDVA) of 0.5 and 1.0 lines, respectively, a -0.45 D improvement in Kmax, and data from 217 eyes suggesting an almost 30 percent reduction in higher order aberrations (HOA) and coma (5)(6). But there was no control group – a huge concern – and these results do not come close to what can be achieved with epi-off CXL (7). And let’s not forget that science is based on a simple principle: publish your methods and let others repeat your experiment and confirm your data. In the CXLUSA consortium’s case, the important missing factor is the nature of their bespoke riboflavin solution. The formulation remains a mystery, and other sites have not been supplied with the solution so that they may try and repeat the experiment. Until that happens, the validity of their results will remain in doubt.