September 2017


Update on Crosslinking
Corneal crosslinking: Fast and furious versus low and slow

by Stefanie Petrou Binder, MD, EyeWorld Contributing Writer

Slit lamp photograph of an eye immediately after epithelium-off CXL. There is a bandage soft contact lens in place. Mild diffuse post-CXL corneal haze and the yellow of the riboflavin can still be seen.

Slit lamp photograph of the same eye 2 weeks after epithelium-off CXL. There is mild diffuse post-CXL corneal haze. Vogt’s striae of keratoconus can be seen at the inferior pupil.
Source: Christopher J. Rapuano, MD

Is using the standard low intensity protocol for corneal crosslinking still the best way to go?

Overall, shorter ophthalmic surgical techniques are preferable and can be far more comfortable for patients, but do they forfeit safety and efficacy? When it comes to corneal crosslinking (CXL), some experts think it might pay to take your time. EyeWorld spoke with two specialists to understand the status of CXL internationally and discuss current viewpoints.
Corneal CXL combines the use of riboflavin (vitamin B2) drops and ultraviolet (UV) light to reshape and stiffen the cornea in patients with corneal ectasias, such as keratoconus, a degenerative non-inflammatory disease of the cornea in which the central or paracentral cornea undergoes progressive thinning and steepening, causing irregular astigmatism. The procedure has been performed in Europe for roughly 15 years, but has only been FDA approved since 2016.

Current paradigm

“Corneal crosslinking internationally has been transformed into the current paradigm for stabilizing progressive keratoconus and ectasia,”1 said John Kanellopoulos, MD, medical director, Institute, Athens, Greece, and clinical professor of ophthalmology, New York University Medical School, New York. “In several parts of the world, the clinical consensus is that it should be used prophylactically in high risk patients, for instance, young patients less than 25 who show even the subtlest clinical signs of keratoconus, such as topographic, topometric, or epithelial mapping irregularities that are consistent with early keratoconus.2 With the FDA approval of corneal crosslinking last year, it is now a globally established procedure for this purpose.”3
Before ophthalmologists can treat keratoconus and decide on surgical or nonsurgical measures, ectasia needs to be defined and physicians require guidelines. Dr. Kanellopoulos referred to the global consensus on keratoconus and ectatic diseases4 that gives definitions and recommendations for the treatment of keratoconus to help physicians navigate their way through the various controversies in diagnosis and management. The global consensus project involved the use of a modified Delphi technique, followed by three questionnaire rounds, as well as face-to-face meetings with 36 expert ophthalmology panelists, to achieve consensus on definition/diagnosis, nonsurgical treatment, and surgical treatment of keratoconus, where a two-thirds majority was required for consensus.
The consensus project defined ectasia progression as a consistent change over time in at least two parameters: steepening of the anterior corneal surface, steepening of the posterior corneal surface, or thinning and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point, which are above the normal variability (noise) of the measurement system. Although progression is often accompanied by a decrease in BSCVA, a change in both UCVA and BSCVA is not required to document progression. The panel agreed that specific quantitative technology and machine-specific data were lacking to further define progression. They recommended that examinations in younger patients be shorter and involve the use of the same measuring platform for consistency.
According to the global consensus panelists, halting disease progression and visual rehabilitation were the two most important goals of nonsurgical therapy. To this end, they advised avoiding eye rubbing but supported the use of topical anti-allergic medications and lubricants. The panelists agreed that there was no direct relationship between keratoconus and dry eye and that preservative-free drops were preferable. The use of contact lenses for aesthetic purposes was contraindicated due to the increased difficulty in contact lens fitting and complications arising from poorly fitting lenses. Rigid contacts were recommended in cases of unsatisfactory vision with glasses.
CXL is indicated in the treatment of keratoconus with documented clinical progression, as well as for eyes with keratoconus that have previously received other forms of corneal surgery. Although the panel did not reach a consensus regarding the use of CXL in subclinical keratoconus, they did agree that as long as there is evidence of progression, there should be no age restriction for CXL in keratoconic eyes.
The wide geographic distribution of the panelists and the fact that some surgical options were more readily available in some countries than others made achieving a consensus for the best surgical option difficult. Next to CXL, anterior lamellar keratoplasty (ALK), specifically descemetic deep ALK, largely indicated by contact lens intolerance, 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 keeping 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 removal and irradiation of 3 mW/cm2 at a dose of 5.4 J/cm2 using 0.1% 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 Dresden protocol. He thinks that while accelerated CXL has its advantages, it may be wise to stick to the standard 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 skittish 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 variability. But there is no doubt that a shorter treatment would be beneficial. I think a 10-minute protocol might be a happy medium.”
Accelerated CXL uses 30 mW/cm2 for a 3-minute duration and is based the Bunsen-Roscoe law of reciprocity that assumes a constant radiant exposure of 5.4 J/cm2. Although 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 complications 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 cylinder to be similar to their preoperative value, if not a little bit less, and thickness should be similar and not thinning over time.”
Faster/higher intensity treatments may not be the answer to improving CXL protocols. A report that evaluated studies using different higher intensity protocols on corneal stiffening found a failure of the Bunsen-Roscoe law of reciprocity 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/cm2 had a reduced biomechanical effect compared to the standard protocol of 3 mW/cm2 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/cm2 gave a similar crosslinking effect when saline-based riboflavin was used, and fluences more than 30 mW/cm2 appeared to have no difference in effect and in sham. Specifically, the 45 mW/cm2 fluence showed no difference 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-refractive 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 showed that higher fluence CXL on the stromal bed in human corneas that were subjected to femto LASIK of –8 D increased the cornea rigidity 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 laboratory simulations provide significant 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.


1. Kanellopoulos AJ, et al. Management of corneal 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 keratoconus diagnosis and progression classification based on evaluation of corneal asymmetry indices, derived from Scheimpflug imaging in keratoconic and suspect cases. Clin Ophthalmol. 2013;7:1539–48.
3. Kanellopoulos AJ, et al. Keratoconus management: long-term stability of topography-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-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus 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.

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