Is an oxygen boost needed to perform efficient epi-on cross-linking?
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Yes, results so far are remarkable
We know from basic science that oxygen plays an important role in the cross-linking reaction.
In the early cases of epi-on, we were able to verify that the major component that was missing was oxygen and that oxygen depletion occurred rapidly. Then we had all the early experiments showing that by increasing oxygen concentration in the environment, we could potentially improve oxygen diffusion across the epithelium, leading to increased stromal oxygen availability for the cross-linking reaction. What we found later on was that, if you combine oxygen boosting with higher energies and more localized treatments, the effect would be even greater. In a study comparing epi-on CXL with the standard procedure and epi-on with customized CXL, boosted with oxygen in both cases, the customized cross-linking group had significantly better results.
Over the last 2.5 years, we have had the privilege to use the oxygen-boosted procedure. What we were able to see is that the demarcation line is at least as deep as it is with the epi-off procedure and in some cases even deeper. This is clear evidence that the cross-linking effect of the treatment penetrates deep into the stroma. Two-year follow-up data, which will soon be published, show stabilization of keratoconus in all cases, often combined with a significant flattening of the cornea. The next step forward will be to refine a customization strategy based on the individual morphological and biomechanical characteristics of each cornea. A truly customized procedure with the augmented effect of oxygen, epi-on and therefore minimally invasive and painless, is our ultimate goal.
Miltos Balidis, MD, PhD, is from Ophthalmica Institute of Ophthalmology and Microsurgery, Thessaloniki, Greece.
Too early to draw an accurate conclusion
Because we still have so much to learn about alternative CXL protocols, trying to dissect out one individual piece of the puzzle, such as oxygen saturation, is fraught with difficulties and, unfortunately, may lead to inaccurate conclusions at this early stage of development.
The first question to answer is whether or not we can perform efficient epi-on CXL equivalent to epi-off CXL. To date, that answer is no. Despite the numerous protocols that have been promoted, none have achieved corneal stabilization equivalent to the standard Dresden protocol when using the same criteria for success (stabilizing maximum keratometry and corrected distance visual acuity) as those in the initial CXL clinical trials. The epithelium provides a barrier to all three primary components of the CXL process: riboflavin saturation, oxygen concentration in the stroma and ultraviolet light. Supplemental oxygen may assist in overcoming one barrier, but it is unlikely that in itself could be sufficient to bring transepithelial CXL on par with epithelial-off protocols.
The second question we need to answer is the actual biomechanical impact of newer CXL protocols. While there is significant evidence of the stiffening effect for standard protocol CXL in vitro, few in vitro studies have been performed for newer protocols. Rather, surrogates for treatment effect are often relied upon, such as the demarcation line. Recent studies have called into question the relevance of the demarcation line, and better, direct biomechanical measurements are needed. While the impact of CXL has been demonstrated using dynamic hysteresis-based techniques, individual results are highly variable, and the techniques are likely not fully representing the biomechanical changes induced by treatment. Brillouin microscopy holds promise as a technique that might yield a better understanding of localized effects of CXL protocols, and these types of direct biomechanical evaluations may prove beneficial in accurately comparing newer CXL protocols to currently established ones.
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Bradley Randleman, MD, is from Cole Eye Institute, Cleveland Clinic.
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