Eyeworld

EW FEATURE 76 Update on crosslinking • September 2017 showed that higher fluence CXL on the stromal bed in human corneas that were subjected to femto LASIK of –8 D increased the cornea rigidi- ty over 100% and had no effect on the flap versus controls. The control cases showed a significant decrease in cornea stability due to the tissue removal." Dr. Kanellopoulos said both prospective clinical studies and lab- oratory simulations provide signif- icant evidence that higher fluence and routine LASIK can increase the adhesion between the LASIK flap and the underlying stromal bed and may significantly reinforce the underlying stromal bed rigidity. "This may be considered the single most adverse effect as far as cornea biomechanics and LASIK procedures are concerned, which to date is the most common laser refractive surgery procedure performed in the cornea," he said. EW References 1. Kanellopoulos AJ, et al. Management of cor- neal ectasia after LASIK with combined, same- day, topography-guided partial transepithelial PRK and collagen cross-linking: the Athens protocol. J Refract Surg. 2011;27:323–31. 2. Kanellopoulos AJ, et al. Revisiting keratoco- nus diagnosis and progression classification based on evaluation of corneal asymmetry indices, derived from Scheimpflug imaging in keratoconic and suspect cases. Clin Ophthal- mol. 2013;7:1539–48. 3. Kanellopoulos AJ, et al. Keratoconus management: long-term stability of topog- raphy-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). J Refract Surg. 2014;30:88–93. 4. Gomes JA, et al. Global consensus on keratoconus and ectatic diseases. Cornea. 2015;34:359–69. 5. Kanellopoulos AJ, et al. Collagen cross-link- ing (CCL) with sequential topography-guided PRK: a temporizing alternative for kerato- conus to penetrating keratoplasty. Cornea. 2007;26:891–5. 6. Mrochen M. Current status of accelerated corneal cross-linking. Indian J Ophthalmol. 2013;61:428–9. Editors' note: Dr. Rapuano has financial interests with Avedro. Dr. Kanellopoulos has no financial interests related to his comments. Contact information Kanellopoulos: thanos@laservision.gr Rapuano: cjrapuano@willseye.org restriction for CXL in keratoconic eyes. The wide geographic distribu- tion of the panelists and the fact that some surgical options were more readily available in some coun- tries than others made achieving a consensus for the best surgical op- tion difficult. Next to CXL, anterior lamellar keratoplasty (ALK), specif- ically descemetic deep ALK, largely indicated by contact lens intoler- ance, and penetrating keratoplasty (PK), mostly done in eyes with significant corneal scarring, were the most frequent surgical modalities used in the surgical treatment of keratoconus. 5 According to Christopher J. Rapuano, MD, Wills Eye Hospital, Philadelphia, who was a global consensus panel member, CXL has moved the timing of treatment intervention to much earlier in the disease process. "We do not delay therapeutic treatments until there is significant loss of vision anymore, which is what makes early diagnosis so much more important and our work to establish a consensus very relevant. In terms of the surgery, the worldwide standard for CXL is the original Dresden protocol involving 30 minutes of UV treatment with the epithelium off. There are many variations on crosslinking done both in the U.S. and around the world. One of the biggest variations is keep- ing the epithelium on or removing it prior to riboflavin application. There are proponents for each. Epi- on is more comfortable and has less risk. Currently, however, the only procedure approved by the FDA is the epi-off protocol. The majority of the literature around the world demonstrates that epi-off seems to work better than epi-on. Another variation in CXL causing much debate revolves around duration and intensity," Dr. Rapuano said. Fast and furious or low and slow The aim of using different protocols is to optimize control of the CXL process and improve predictability for the best clinical outcomes. The FDA approved CXL using the Avedro system (Waltham, Massachusetts) with the Dresden protocol, which involves a 9 mm epithelium remov- al and irradiation of 3 mW/cm 2 at a dose of 5.4 J/cm 2 using 0.1% Corneal continued from page 74 riboflavin every 1–2 minutes for 30 minutes. Irradiation is performed once 400 µm is met or exceeded on ultrasound pachymetry, and is performed for 30 minutes. Dr. Rapuano performs CXL in his practice according to the Dres- den protocol. He thinks that while accelerated CXL has its advantages, it may be wise to stick to the stan- dard protocol for the time being. His unpublished results, however, on higher intensity CXL treatments revealed good short-term outcomes. "In my experience with faster/higher intensity treatments, the protocols included a 2-minute and 40-second treatment, a 4-minute treatment, and an 8-minute treatment. The patients we followed seemed to do well in all treatment groups. I do not have a sense that any one protocol worked better than the other," Dr. Rapuano said. "The faster/higher intensity treatments were easier for the patients than the current 30-minute treatments. On the other hand, if the patient was a little skit- tish and kept looking around during a short treatment, with the light not centered on the cornea for 10–20 seconds, we could have lost 10% of our treatment, whereas almost nothing gets lost in a 30-minute treatment. I think that I am getting a more consistent treatment with a 30-minute protocol and less vari- ability. But there is no doubt that a shorter treatment would be bene- ficial. I think a 10-minute protocol might be a happy medium." Accelerated CXL uses 30 mW/ cm 2 for a 3-minute duration and is based the Bunsen-Roscoe law of reciprocity that assumes a constant radiant exposure of 5.4 J/cm 2 . Al- though a number of current studies are using accelerated protocols with encouraging results, it is too early to evaluate the short-term outcomes. "We need to see results for at least 1 year. Anything else is too early," Dr. Rapuano said. "You can see compli- cations in a lot less than a year but not the efficacy of the procedure. It is best to follow outcomes for 5 years to understand if the keratometry readings look stable, like the Kmax, but also astigmatism and corneal thickness. You want Kmax and cyl- inder to be similar to their preopera- tive value, if not a little bit less, and thickness should be similar and not thinning over time." Faster/higher intensity treat- ments may not be the answer to improving CXL protocols. A report that evaluated studies using differ- ent higher intensity protocols on corneal stiffening found a failure of the Bunsen-Roscoe law of reciproc- ity for short illumination time and high intensities, probably due to the complex photochemistry involved in CXL. 6 The same report discussed the role of oxygen consumption in higher intensity treatments, which was consumed too quickly with new oxygen not able to diffuse into the stroma. The report maintained that the clinical benefits of increasing the intensity and reducing the treatment time were still not known, claiming that one might even expect reduced efficacy based on the in vitro results. The report concluded that higher intensity treatments of more than 10 mW/cm 2 had a reduced biome- chanical effect compared to the standard protocol of 3 mW/cm 2 for 30 minutes. Based on the evidence, a reduction in the treatment time by simply increasing the intensity might not lead to the same level of efficacy of stopping the progression of corneal ectasia. In contrast to this study, Dr. Kanellopoulos has found that faster/ higher intensity protocols can be beneficial. "One of our studies looked at in vitro human corneas, not porcine corneas, showing that fluences of 3–30 mW/cm 2 gave a similar crosslinking effect when saline-based riboflavin was used, and fluences more than 30 mW/cm 2 appeared to have no difference in ef- fect and in sham. Specifically, the 45 mW/cm 2 fluence showed no differ- ence in sham," he said. More studies with long-term results are needed to further validate these data. Post-refractive use Relevant to many medical practices is the use of corneal CXL in post-re- fractive patients. According to Dr. Kanellopoulos, "The application of corneal crosslinking and corneal laser surgery has been considered experimental. However, there have been several in vivo and in vitro studies establishing the crosslinking effect of higher fluence crosslinking applied in combination with LASIK. Also, evaluating this model in vitro and using bidirectional tensiometry

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