ELZA’s role in Cross-Linking

Members of ELZA were instrumental in introducing CXL technology into clinical practice. The ELZA member Farhad Hafezi has published over 50 scientific publications on CXL, and is considered a pioneer of the method. In 2014, he was awarded the prestigious Carl Camras Award for Translational Research of ARVO, the International Association for Research in Vision and Ophthalmology, for his translational research in this field.

Prof. Hafezi has co-initiated the International Cross-linking congress, and has co-organized it since its beginnings in 2006. He is the editor of the text book “Corneal Cross-Linking” by Slack.

Besides the scientific expertise, patients from all continents are treated at ELZA, using the latest scientifically proven CXL techniques.

Members of ELZA were the first to apply and describe the use of CXL in postoperative ectasia after LASIK/PRK, in very thin corneas, and for infectious keratitis.


The Chapters

Corneal Cross-Linking (CXL)
CXL in children
CXL in thin corneas
CXL in PMD
CXL in ectasia after LASIK/PRK
Improve vision after CXL

Posts on Cross-Linking published by ELZA


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Corneal Cross-Linking (CXL)

Basically, corneal cross-linking is a technique that uses ultraviolet light-A (UV-A) and riboflavin (Vit B2) to (bio)mechanically stiffen the cornea by increasing the number of cross-links in the stromal collagen.

CXL has been introduced into clinical ophthalmology in 1999, and has since become the gold standard in the treatment of progressive keratoconus.



The effect is almost immediate, and leads to long-term changes in the response of the cornea to mechanical stress. The success rate of CXL, when used adequately, is more than 95%. The biomechanical effect of CXL is used to halt diseases of the cornea like keratoconus, or ectasia after LASIK.

Nowadays, a multitude of variations of the technique exist, and the range of applications has increased. The treating ophthalmologist must not only be familiar with all these new techniques, but must also assess which technique is scientifically sound enough to be applied in every particular case.


Which CXL technique is the best for me?

Dozens of variations of the original CXL protocol exist, and the treating ophthalmologist needs a lot of experience to apply the correct treatment modality. At ELZA, we are constantly solicitated by colleagues from all over the world to give advice on technical settings, treatment protocols, and particular cases. This is why we have created the ELZA recommendations, where we categorize the validity of new cross-linking techniques, based on scientific and clinical evidence. The ELZA recommendations are updated several times per year to reflect advances in the field.




CXL in children


Keratoconus is a disease of the young, and is most often the most aggressive in children (8 to 15 years) and adolescents (10 to 19 years). It is therefore very important to keep the follow-up intervals tight.

Our group has one of the longest-standing experiences in treating children and adolescents. This particular age-group requires particular care and attention, because the risk of postoperative complications like infection may be greatly increased.


A 15-year-old boy presents with a decrease of the visual acuity in his right eye, that had started 3 months before. The left image shows the cornea at the first visit. The patient and his parents were advised to come in again after 4 weeks, but they only showed up after 3 months. The right image shows the massive deterioration after 3 months.


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CXL in thin corneas


The initial CXL protocol established for the treatment of keratoconus sets technical parameters that allow to safely treat a cornea whenever its stromal thickness is 400 µm or more. However, in adcanced cases of keratoconus or PMD, the stroma might be thinner. One way to render these corneas accessible to treatment is to swell the corneas using a special riboflavin solution that is hypo-osmolaric: the solution creates an osmotic gradient, when applied to the cornea, and makes the cornea uptake water, and ultimately swell. This technique was introduced into ophthalmology by a paper of Farhad Hafezi and colleagues in 2009. You will find the manuscript in the posts below.



2008: First treatment of ultrathin corneas in Zurich, Switzerland
A 26-year-old-patient undergoing an epi-off CXL procedure. After removal of the epithelium and application of “normal” iso-osmolaric riboflavin, corneal thickness drops to 325 micrometer, too little to perform safe CXL. In a second step, we applied hypo-osmolaric riboflavin. After 10 additional minutes, the cornea swoll to 407 micrometers, and CXL was performed safely.


Since 2009, a number of strategies have been established to deal with very thin corneas. The ELZA member Farhad Hafezi has helped summarize these techniques (please see posts below), which include CACXL and epithelial island techniques. Which technique to choose in which case, must be assessed for each individual case.

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CXL in PMD (Pellucid Marginal Degeneration)


Pellucid marginal degeneration (PMD) is a disease that belongs to the family of ectatic corneal thinning diseases, similar to keratoconus. In contrast to keratoconus, it starts later in life, usually between 20 and 30 years of age, shows a more peripheral thinning of the cornea, and progresses at any age.




CXL in ectasia after LASIK/PRK


In refractive laser surgery, corneal tissue is removed for every diopter that is corrected. This removal of tissue thins the cornea. A normal cornea does not suffer when a certain amount of tissue is removed. However, when excessive tissue is removed, or when the cornea is compromised through other reasons (hormonal influences, pre-existing disease), then an ectasia may occur after LASIK and PRK, even years after the surgery. This ectasia looks similar to keratoconus and has the same symptoms.

In contrast to keratoconus, ectasia after LASIK and PRK never stops, and may even lead to rupture of the thinned stroma and scar formation. Therefore, CXL should be performed, whenever ectasia after refractive laser surgery occurs.



Until 2007, the only therapeutic option to treat ectasia after LASIK and PRK was corneal transplantation (keratoplasty). This surgery is highly invasive, and carries the risk of rejection.

In 2007, the first patients with ectasia after LASIK were successfully treated by CXL. Ever since, CXL has become the standard of treatment . ELZA is proud to say that its member Farhad Hafezi was the first author of the groundbreaking study that introduced CXL treatment for this disease condition.

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Improve vision after CXL



Contact lenses

A number of different contact lens technologies and materials have been established in the past years to specifically adapt to irregular corneal surfaces. These include soft keratoconus contact lenses, quadrant-specific contact lenses, and mini-scleral and scleral lenses. In the hands of an experienced contact lens fitter, these lenses are highly beneficial to restore vision.

In some cases, contact lenses are not tolerated, and may not be used to improve vision. Here, several other strategies can be applied, either alone, or in combination. Important: contact lenses do not slow down or stop the progression of keratoconus.


CXL plus Excimer Laser (The new Swiss nomogram)

Once the cornea is stabilized, a limited wavefront-guided PRK may be performed using an excimer laser. The aim here is not to make the patient independent of glasses, but to rather make the corneal surface less irregular. The smoother and more regular the corneal surface is, the better vision with glasses may be. In other words, a keratoconus patient might have a visual acuity of 30% before, and a visual acuity of 60-70% after the laser treatment, both while wearing glasses.


The new Swiss nomogram

The sequential approach (CXL first, then PRK one or two years later) makes most sense to us, but there was one major obstacle to this approach: nobody has determined how much corneal tissue is removed by an excimer laser pulse in a cornea, that had been cross-linked previously. Is it just as much tissue as in a non-crosslinked cornea? Or 20% less? Or 40 % more? Not knowing the ablation rate means to become very imprecise regarding the outcome.

In a major study (see below), ELZA’s research affiliates have determined the ablation rate in a previously cross-linked cornea. The study was published in the Journal of Refractive Surgery in 2014: in a previously cross-linked cornea, 12% less tissue is ablated per excimer laser pulse. This knowledge enables us to greatly increase the accuracy of the treatment.


The ELZA members perform CXL first, then the PRK at 12 to 24 months after CXL, because the cornea shows a flattening after CXL that is hard to predict in the individual case. This is called the sequential approach. The pictures to the right show the result of applying the sequential approach to a keratoconus cornea, using the new Swiss nomogram.

This approach is not made to provide freedom from contact lenses. Rather, it can improve best-corrected visual acuity and visual quality with glasses, which allows a patient with keratoconus to wear glasses more often, and be more independent of contact lenses.






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Intrastromal rings (ICRS)

Intrastromal rings redistribute the forces acting on a keratoconus cornea, and may greatly improve the regularity of the surface. The rings do not stop keratoconus progression, and should be combined with a CXL procedure. Members of ELZA were involved in one of the very first large clinical studies using ICRS and CXL.


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Additional intraocular lenses (Phakic lenses, Artisan, ICL)

Sometimes, the regular portion of the astigmatism caused by keratoconus or PMD is surprisingly regular centrally. In these cases, implantation of an additional lens (phakic lens) into the eye may help reduce the refractive error.