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New strategy of adapted fluence allows for safe cross-linking in thin keratoconus corneas
A nomogram has been developed to customize UVA irradiation, overcoming the need for swelling the cornea.
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A nomogram that customizes UVA fluence allows for safe cross-linking of thin keratoconus corneas. This new method developed by Farhad Hafezi, MD, PhD, and Sabine Kling, PhD, a postdoctoral physicist in his research group, has the potential to make cross-linking accessible to all patients because corneal thickness would no longer be a limitation.
“It simplifies the old method a lot and makes the future so much easier because you don’t have to worry about which solution you use and how thick the cornea is. You just adapt UVA intensity to the cornea,” Hafezi said.
Thin corneas have so far been a limitation in cross-linking, leading to the development of many types of riboflavin solutions, cross-linking protocols and puzzling combinations of different options. The normal user is confused, and many patients with thin corneas are still sent home with nothing done, Hafezi said.
“The idea of swelling the cornea came up in 2009 at the IROC in Zurich because we realized that the 400 µm cutoff excluded many of our patients, and this is how we developed the hypo-osmolar solutions to swell the cornea,” Hafezi said.
Over time, other techniques were proposed: the original transepithelial CXL by Pinelli, contact lens-assisted cross-linking by Jacob and Agarwal, and epithelial island CXL by Mazzotta.
“These four techniques deal with thin corneas and have one thing in common: They try to make the cornea thicker. Of the three factors we can potentially play on, ie, corneal thickness, riboflavin concentration and UVA intensity, we have only tried one because, until recently, we did not know enough on riboflavin distribution, the effect of oxygen on the cornea and UVA intensity. But if you think about it, focusing on UV intensity would make much more sense than changing corneal thickness in every patient,” Hafezi said.
A whole new strategy
Customizing the intensity of UVA radiation for each patient is a new strategy that Hafezi and Kling were able to develop after studying in depth the fundamental role that oxygen plays in corneal cross-linking.
“Those studies allowed us to understand the cross-linking process much better, and Sabine, who is a physicist, was able to create a nomogram for adapting fluence to individual corneal thickness. In 400 µm thick corneas, we use the standard Dresden protocol with a fluence of 5.4 J/cm2, 3 mW/cm2 for 30 minutes or the accelerated protocol with 9 mW/cm2 for 10 minutes. If the cornea is thinner, we use our nomogram to adapt the energy so that the reaction stops at 60 µm to 70 µm from the endothelium. Let’s assume the cornea is 220 µm. I look at my nomogram, and it tells me to use 3 mW/cm2 for a certain amount of minutes (exact numbers known, but subject to validation). If the cornea is 260 µm, it tells me to use 3 mW/cm2 for yet another time and so on. The total fluence changes each time,” Hafezi explained.
The procedure is safe, he said. A prospective study is currently ongoing, and the 26 eyes treated so far have shown good results. The demarcation line was clearly visible at the depth it should be, and there were no problems with the endothelium and no cases of decompensation. Corneas of different thickness were treated, the thinnest at 215 µm of corneal stroma after riboflavin instillation. All procedures were performed epithelium-off, soaking the cornea in hypo-osmolar riboflavin (Ricrolin Plus, Sooft) without removing the speculum.
“This is because the oxygen delivery into the cornea is worse if you can blink and the eyes are closed in between,” Hafezi said.
The study has reached 9 months of follow-up, and safety was demonstrated in the crucial first month after surgery. Efficacy, however, needs to be tested over a longer period of at least 1 year.
“What we know for sure now is that we can treat without danger a thin cornea, but a question remains: Is the effect strong enough to stop the disease in these extremely thin corneas? This we do not know yet. We can just safely perform the maximum amount of CXL and wait to see if we have found the key for treating patients with thin corneas, something we have been long looking for,” Hafezi said. – by Michela Cimberle
- For more information:
- Farhad Hafezi, MD, PhD, can be reached at ELZA Eye Institute, Webereistrasse 2, 8953 Dietikon/Zurich, Switzerland; email: farhad@hafezi.ch.
Disclosure: Hafezi reports no relevant financial disclosures.
Perspective
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Eberhard Spörl, MD, PhD
The standard cross-linking treatment was developed 25 years ago for a fixed fluence (UV irradiance and irradiation time) due to the technical devices and for a stromal thickness larger than 400 µm because in 80% of the keratoconus patients the corneal thickness is 400 µm or greater.
Several possibilities were proposed for treating thin corneas with corneal cross-linking (CXL). The swelling of thin corneas was a milestone to expand the spectrum of CXL to corneas thinner than 400 µm. If the stroma is swollen, the same thickness (300 µm) of the cornea is, even though cross-linked, like in an unswollen cornea. However, after treatment the cornea deswells, and this 300 µm will be changed to a thinner layer. In this technique, you reach a lower CXL effect.
On the other side, it is also possible to reduce the UV fluence according to the stromal thickness, like it is shown in the study by Hafezi. This possibility has been used in thin corneas in special cases before we had the swelling technique. Unfortunately, we did not systematically control the demarcation line in these cases.
With this modification of the application of UV fluence, we can treat thin corneas by CXL. The clinical use will be easier. However, two conditions must be fulfilled: The new nomogram should be published and all users should get it, and the efficacy and safety must be tested in a clinical study at least in two centers to have a high trust in the new treatment procedure. We must also investigate the lowest limit for the corneal thickness because we saw that a thickness of 150 µm of cross-linked tissue is necessary to stabilize the cornea. That means with this technique it should be possible to treat corneas with a stromal thickness of 220 µm (150 µm + 70 µm safety zone) and larger.
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