In this article we review the latest innovations in the treatment CrossLinking (CXL) for Keratoconus and other indications, how it has improved and how it can be combined with other procedures. The points to develop are:

  • Classic Procedure (Dresden Protocol)
  • New Indications
  • New aspects on the technique of CrossLinking

    • Maintain or remove the corneal epithelium
    • Increased  power at the UVA (Ultra Violet Light) source
  • Combination of Techniques

    • Intrastromal Rings and CXL
    • Excimer Laser and CXL
    • Phakic Lenses and CXL
    • Triple procedure


One of the key topics in ophthalmology today is the treatment of Keratoconus (if you want to know what Keratoconus is about, click here (, a corneal ectasia that in no time has gone from considering a corneal transplantation, with “uncertain” results to a versatile treatment which seeks not only to control the disease but also to improve vision, to the point of eventually eliminating the need for glasses.

We currently have combined different procedures that allow downright spectacular results. One such treatment would be the CrossLinking (CXL), aimed at slowing the progression of the disease.

We shall recall that the CXL dates from 1997 but had not been used in a standardized way until 2007, following what has been called the protocol of Dresden, which was to remove the corneal epithelium (9 mm in diameter), saturation of the corneal stroma with a 0.1%  isotonic riboflavin solution and 20% dextran, instilling 1 eye drop every 2 minutes for 30 minutes and after checking into the slit lamp that complete saturation was achieved, it was proceeded to irradiation with UVA to 5.4J / cm2  (3 mW / cm2) for 30 minutes longer. With these parameters, it was pretended to  “harden” the cornea in order to prevent progression of the ectasia. The main indication was Keratoconus (primary ectasia) or secondary ectasias to refractive surgery, especially those that appeared after LASIK.

What has changed in the CXL in recent years? Basically there are new indications, the technique has been modified, has reduced the treatment time and finally, we have more experience in the CXL combination with other procedures.


The CXL is currently being used in the treatment of degenerative cornea diseases such as bullous keratopathy, where corneal edema, usually secondary to endothelial failure, causes the accumulation of fluid beneath the epithelium, forming “blisters” that distort vision and cause pain when removed by the touch of the eyelids. By CXL, an increase in the rigidity of the cornea occurs, the stromal collagen fibers form bridges and cohere preventing the passage of liquid from the endothelium to the epithelium, thereby preventing the formation of blisters.

Another indication that is gaining popularity is the treatment of corneal infections, especially those that do not respond well to conventional treatments or as in the case of acanthamoeba, there is no fully effective drug. In these cases, the CXL has proven efficient to eliminate these microorganisms.

Other indications are corneal ulcers, corneal tissue modification in transplantation and refractive treatment currently in orthokeratology. After modifying the corneal structure by means of the lenses used in orthokeratology (overnight), the CXL would try ​​that this effect would last over time, and would not be reversible within a few days, as it is at present. The first experiments look very promising but, in my humble opinion, I think there are other refractive methods more effective and safer.



For a better understanding, changes in methodological trends can be analyzed in different sections.

3.1 Keep or remove the corneal epithelium.

It is one of the discussions that appeared almost from the beginning and still continue to arise. Although there are several studies that demonstrate the need to remove the corneal epithelium to achieve a good saturation of the corneal stroma with riboflavin, there is clinical evidence that raise questions. Yet, most importantly in recent months, it is the development of methods and variations in the molecule’s riboflavin that can enhance the penetration keeping the epithelium.

Why is it important to keep the epithelium? Basically because most complications are related to the epithelial removal that could be pain, delays in the regeneration of the epithelium, infection, haze, or even corneal melting cases. All these situations have led to attempt to maintain the epithelium but, as we said above, experimental studies show that the epithelium is a major barrier to the penetration of riboflavin.

A first step of improvement was “lifting” the epithelium, as we do in the technique of EpiLASIK, replacing it after finishing the UVA irradiation. It tries to minimize pain and protect against infections and corneal haze. The results have not been very encouraging so far and the technology to perform the EpiLASIK is a must .

Currently, certain substances are used that applied on the epithelium facilitate the penetration of riboflavin, such as benzalkonium chloride, ethylenediaminetetraacetic acid or tromethamine, based on the breakage of the cell junctions and on partial loss of epithelial cells, thereby reducing the barrier of the epithelium. The results show a better penetration and part of the epithelium is being preserved. Yet, not all corneas respond the same way to these substances; thus it becomes difficult to standardize the method.

Alternatively, riboflavin, not mixed with dextran, can be used, because this latter has a very large molecule that hinders the penetration; whereas riboflavin alone has a smaller molecule. Presently there are studies that show it is possible to use just riboflavin and getting both a good permeability and maintaining the epithelium.

The most recent contribution is the use of iontophoresis methods to improve penetration, especially when combined with the partial removal of the epithelium, only from its surface layers. The studies show a very important decrease in the complications and a very effective saturation of the stroma.

3.2 Increased power at the UVA source

Compared to the 3 mW / cm 2 of the initial Dresden protocol , UV lamps have emerged that reach up to 45 mW and 10 J/cm2 (Peschke Meditrade, IROC Innocross or Avedro Inc.), which reduces the exposure time and improve riboflavin penetration even through the corneal epithelium.

When power of 45 mW and 10 J/cm2 is applied, time of exposure goes down from 30 to only 1 minute. Kanellopoulos published studies with 7 mW / cm 2 during 15 minutes, with results similar to those obtained with the Dresden protocol, in regard to stabilization of the corneal ectasia. The problem we encounter with these more powerful UV sources is that it increases the phototoxic effect and therefore it is essential to implement the protocol strictly.


Patients who suffer from keratoconus or ectasia secondary to LASIK have a double problem; first, the evolutionary process of corneal deformation and second, poor quality of vision, which makes indeed necessary the use of glasses or contact lenses and still it is not achieved a  “useful” vision in many cases, therefore one solution consists of combining therapies aimed at slowing the progression of the disease, in this case (the CXL), with other techniques to improve visual quality, such as corneal implants segments in the stroma, refractive laser treatment (PRK or LASIK) or a phakic lens implant.

4.1 Intrastromal segments and CXL

Intrastromal segments help improving the geometry of the cornea, and focusing the apex of astigmatism that appears in these cases as well as aberrations secondary to corneal deformation. Its effectiveness has long been established, with over 10 years experience and now with new designs that allow partly correct refractive defects. Several surgeons advocate performing the implantation of the segments and if the goal is achieved, then performing CXL treatment to “fix” these changes by increasing corneal rigidity.

4.2 Excimer Laser and CXL

Although it seems a contradiction to apply laser on a weakened cornea, even in cases that previously LASIK was performed, the combination of laser with the CXL, appears as an effective and safe technique, and so it is referred by those specialists who are doing this combination. As it usually happens, it is not applicable to all cases, but in patients whose cornea has a sufficient thickness and where refractive treatment is not more than 4 or 5 diopters, it has been found possible both actions at the same laser surgical act: to eliminate or at least significantly reduce, the refractive problem secondary to deformation of the cornea and to make the CXL. Different authors report very good results, with significant improvements in vision and no changes occurred in the corneal ectasia, with follow up tests to 5 years.

4.3 Phakic lenses

The third option is to combine the CXL with a lens that is implanted inside the eye, in the anterior chamber or posterior chamber, to correct the refractive defect. As astigmatism is most significantly the key default in refractive issues, lenses must be those that allow the combination of spherical graduation with a cylinder, that is toric lenses.

The results are encouraging but not all cases can be treated with this combination,; it would exclude those with corneal apex decentration. In such cases, a triple procedure would be required (we will look at it next). Or,  mavbe phakic lenses are enough by their own, because once in place, thanks to the material they are made of, its optic zone may be modified through the action of UV radiation that “molds” it specifically in each case, treating the refractive default and the aberrations in a personalized way.

4.3 Triple procedure

There are cases where the degree of evolution of the patient or the complexity of the cornea requires the combination of three options. It often begins with the implantation of intrastromal segments, followed by CXL to prevent the development of ectasia and, if a remaining refractive default is not improved with glasses or contact lenses, a phakic intraocular lens is implanted. The results are very encouraging with a significant visual improvement, especially considering the fact that it is the most complex group of patients.

Another indicated alternative is one that combines the laser to improve the refractive issue, with simultaneous CXL to control ectasia and, if a refractive default is yet not improved with glasses or contact lenses, a phakic intraocular lens is implanted.

I would like to finish this article by recalling the importance of regular eye check ups. The optometrist is the first step to detect vision loss with a significant change of graduation, especially astigmatism, not improved with new eyeglasses; finding out probably an incipient keratoconus  and then referring the patient to the ophthalmologist, who has the necessary means to confirm the disease and to treat it properly. As we have seen, medical progress is important and in order to achieve a fully effective treatment, it is necessary to be an experienced ophthalmologist in this disease, to be able to fully and accurately advise those who suffer from it.

Área Oftalmológica Avanzada offers largely both the technology and the experience of professionals in this field to counsel and treat those patients with keratoconus or other corneal ectasias.

cornea - normal & keratoconus

cornea – normal & keratoconus



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