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Crosslinking: pure wound healing effect?

Is the action of the Cross linking on the cornea purely consequence of epithelial remodeling?

The cornea is made up of 3 main tunics: the epithelium on the surface (about 10% of the total thickness of the cornea), the stroma (about 89.50%) and the endothelium (approximately 0.5%).

The alleged action of the crosslinking (CXL) seat is the corneal stroma, since the corneal epithelium is removed, prior to impregnation of riboflavin and ultraviolet exposure.

Doubts by the author of this site as to the effectiveness of the crosslinkig are based on the fact that the primary purpose for which the technique has been developed to the point is to increase the rigidity of the cornea, to reduce the ability of distension of the corneal tissue is increased in Keratoconus. PRS no published study does highlight one any hardening in patients operated of crosslinking. One recent study has however allowed to save some changes to the Biomechanics of the cornea, but rather in the sense of a 'softening '!

On the other hand, a change morphological has been observed after CXL at the level of the cornea: it is a modest reduction of the maximum keratometry, about one to two diopters.

Cross linking and keratometry

The maximum keratometry is a local data, which provides a relatively limited information. It corresponds to the curvature measured near the corneal apex, performed at the most superficial cornea interface: the tear film that covers the corneal epithelium. By the way, if the CXL is presented as an innovative technique, strength is to recognize that the criteria used to assess its effect are quite obsolete at a time where the corneal topographers are able to provide global clues of curvature and irregularity of the corneal dome.

Any variation of the relief of the cornea affects the keratometry measurement; Thus, a minor change even at the level of the epithelial layer can induce significant modifications of the keratometry.

The CXL isn't the only technique of surgery corneal to induce a change in the keratometry. By sculpting the corneal stroma, refractive surgery with the excimer laser is to change the optical power of the cornea. With the technique of the surface laser (PKR), remove the superficial epithelium (as for the CXL), and then we deliver the excimer photoablation which is intended to change the optical power of the cornea.

Effect of re-growth of the epithelium after CXL

The regrowth of the epithelium after PKR can change the effect printed on the stromal surface, but algorithms used for the issuance of the laser photoablation setting take account of 'medium' effect of epithelial growth.

In simple CXL, there is no withdrawal of the laser stromal tissue: after abrasion of the epithelium and impregnation of a photosensitive agent, the corneal stroma is exposed to ultraviolet light. Assuming that this exhibition has little or no significant effect on corneal rigidity, however, it is certain that epithelial regrowth can alter the topography of the corneal surface.

The following image was obtained in high resolution OCT review, a few months after a Cross linking for a relatively advanced Keratoconus. The patient experienced a decrease of Visual acuity after the cross-linking, because of the occurrence of a haze (reduction of corneal transparency), which resolved in a little more than 3 months. The vertical image reveals a thinning of the epithelial layer next to the corneal apex. This thinning seems the corollary of an effect "relissant" of the corneal epithelium on the distortion underlying stromal layer induced by Keratoconus.

cictrisation epitheliales corneal after CXL

Epithelial remodeling observed at the waning of a crosslinking. Note the relative thinning of the epithelial layer next to the apical region of Keratoconus. Overall, the anterior corneal profile is less tormented than the posterior corneal profile (which does not have a cell coating pluri-stratifie, as is the front). This type of epithelial change is commonly observed in Keratoconus, and more generally the processes that lead to a variation of the corneal relief (refractive surgery, scars, etc.).

The effects of epithelial scarring are also well known in PKR, or in LASIK, especially for strong corrections, where those involved a significant change of the corneal profile (ex: correction of hyperopia).

resurfacing corneal after lasik for hyperopia

Spectacular reshaping after LASIK hypermetropique of the epithelial layer. The correction of hyperopia in LASIK is based on the cut of a flap (which contains the epithelium and superficial stroma) and a sculpture behind the excimer laser. The laser sculpts the cornea to increase its curvature. This implies a peripheral ablation of more and more of the center of the cornea to the periphery, or a "furrow" reaching up to 100 microns is dug. On this example, the epithelium, which is not in contact with the area having undergone the laser photoablation, is is yet bloated several tens micron to "reduce the irregularity" of the peripheral corneal curvature. The mechanism involved in this resurfacing is not well understood. It is certainly put into play at the waning of cross linking, because unlike LASIK, the corneal epithelium is removed during conventional CXL.

Better, they are also documented and implicated in the IOL variations after simple procedures with a therapeutic purpose (PKT). With superficial PKT technique, ablation of ten microns only at the surface of the cornea by laser can explain the changes observed IOL, which are sometimes in the order of a reduction of one to two diopters of the Central curvature after epithelial scarring. These changes explain only the 'hypermetropique shift' observed after PKT.

The law of Munnerlyn, which connects Central depth changes to the changes expected of keratometry, can also be used to calculate the differential thickness necessary to not changing the keratometry such as measured on average after cross linking.

There are only 3 microns of difference in elevation between the Center and the edges of the cornea on the Central 3 mm for occaseionner, this provides a variation of a diopter k (the keratometry is measured in breast of the Central 3 mm).

Healing corneal epithelium CXL

It is enough only to 8 micron of difference between the Center and the edges of the central area of the cornea to change the keratometry to a diopter on a central area. However, the height of an epithelial basal cell is of the order of 5 microns. Changes to the curvature of the cornea after CXL are of the same order that lead to small changes in the epithelial layer.

This value is particularly low compared with the modulating potential of the corneal epithelium. Yet, the CXL on keratometry results seem to implicitly set to the action account a remodeling headquartered the corneal stroma, not the epithelium.

Independently and before any surgery CXL, action remodeling of the epithelium during evolution of Keratoconus is spectacular. After removal of the epithelium. We can observe major topographic changes If you repeated immediately a topography of Bowman layer thus laid bare (5 to 10 dioptres). The plastic virtues of corneal epithelium during evolution of Keratoconus are remarkable: he is able to thin or thicken locally, in order to "smooth" the anterior corneal relief.

OCT high resolution bilateral Keratoconus

Maps of epithelial thickness of the right eye and the left eye of a patient diagnosed with bilateral leratocone. There is an important central thinning (cold colours), next to the apical region of the affected cornea in Keratoconus. This distribution reduces the topographic distortion which would be measured if removing the epithelium of the cornea;

The mechanisms involved are clarified to date, but the repeated action of the eyelids (blinking, that occur thousands of times a day) could play an important role in this resurfacing.

Conclusion: the CXL = simple vector of epithelial remodeling?

These simple findings should lead to consider that since the action of the epithelium on the keratometry precedes the realization of the CXL, and epithelial regrowth is able to strongly influence changes in the corneal relief after CXL. It is legitimate to apply the slight reduction in the keratometry observed in the course of the performance of this technique is the fruit exclusively (or almost exclusively) of simple epithelial remodelling, and not a structural change of the corneal stroma.

This assumption is also compatible with:

-l' lack of measurable corneal hardening after crosslinking.

-l' failure of CXL techniques say "epi - we ', without prior removal of the epithelium, where there has been hardening or significant change k (the epithelium is not removed, are there no regrowth and changing k).

Finally, the stabilizing action supposed on the evolution of the KC (because no demonstrated according to recent reports from the Cochrane Library Study and the health authority, pointing to the weakness of the published studies) could be explained by the fact that the patients operated of CXL are less quick to rub an operated eye: the eye rubbing repeated - or any equivalent mechanical stress - being the main factor of risk (single according to the author of this site) of progression of Keratoconus.


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