Often referred to as CXL, the technique of crosslinking (corneal collagen cross-linking) is proposed to the patient to increase the stiffness of the cornea in case of keratoconus Evolutionary. Despite its growth in ophthalmology in recent years, no significant increase in corneal stiffness could be demonstrated in patients using this technique, whatever its type of realization (removal of the epithelium: Epi off CXL, non-removal of the epithelium,: Epi on CXL, or diffusion by iontophoresis of riboflavin in the corneal stroma) , etc.). This should be enough to make the Controversial CXL.
It is legitimate to issue a doubts when its real effectiveness on corneal Biomechanics and to discuss his interest in the management of Keratoconus (see here), as well as this Article written in the light of very recent data.
If the crosslinking fails to harden the cornea, its effect on corneal topography is mainly the result of SCAR changes of the corneal surface (remodeling of corneal epithelium). It is relatively small in magnitude and clinically significant (one to two diopters).
These facts which should stimulate critical thinking, and question the scientific rigour put into play to judge the merits of the realization of the corneal crosslinking in human clinic, are gathered in a Recent publication.
Numerous clinical examples showing that there is no need to perform a CXL procedure to stabilise the evolution of a keratoconus are gathered on the site: https://defeatkeratoconus.com/
What did the cross linking?
Cross linking (or CXL) is a chemical reaction that aims to create covalent bonds between atoms or molecules (e.g., polymer chains). These additional bindings between the atoms concerned (referred to as collagen cross-linking) then in principle provide increased stiffness to the material or treated fabric. Like any chemical cross-linking reaction (creation of interatomic bonds), it requires an energetic input (ultraviolet light in the case of the corneal CXL), a substrate, and time. The vulcanization of rubber, or the creation of polymers used in dentistry are examples of realization using cross linking.
The goal of the cross linking is to harden the treated fabric.
The technique of "crosslinking" thus requires an energy intake that can be made in the form of heat or radiation by particles (ex: electrons, or photons). Also some reactions require the addition of a chemical agent (molecule): "cross linking agent. More energy and substrate, the cross linking takes time. Finally, changes in the mechanical properties of the substances "cross linked" depend on the density of links created.
Cross linking of the cornea
The thickness of the corneal wall consists of two main tissue layers: epithelium, on the surface, which is a stratified cluster layer and the stroma (composed of interlaced collagen lamellae). Collagen fibers are themselves made up of different types of collagen fibrils. In the case of the cornea, the crosslinking reaction aims to achieve additional chemical bonds (Covalent bonds) between the fibrils of collagen in the corneal stroma.
It is important to bear in mind that before anything else, the Crosslinking is a technique thought and designed to harden corneal collagen. Its effectiveness must thus be judged on the yardstick of this reinforcement. There is currently a drift to present the CXL as a technique capable of inducing some corneal remodeling, beneficial to the vision of the patients operated. The study of literature reveals that the Visual benefit of cross linking is low and not significant With regard to degradation inflicted by corneal deformation. On average, the resulting camber reduction does not exceed one-and-a-half diopter, and is due to scarring of the cornea (epithelial regrowth).
The crosslinking technique for corneas with Keratoconus was originally proposed by the team of Dr. Theo Seiler (Zurich, Switzerland). It requires the addition of a molecule of Riboflavin (also called vitamin B2) and irradiation of corneal tissue by ultraviolet photons A ()UVa). Riboflavin must impregnate the corneal stroma; Irradiated by UVA (particularly energetic radiation), this molecule generates free radicals containing oxygen, which would be responsible for the creation of covalent bonds. Oxygen radicals (e.g. peroxide, oxygen ions) are highly reactive because they have free electron pairs; These electrons are then available to form covalent chemical bonds.
However, they are responsible for a oxidative stress, and are Toxic to living cells like the kératocytes of the corneal stroma. The intimate chemical mechanisms put into play by the corneal cross linking are not yet accurately known.
If the solidification of the cornea has been measured in vitro (on animal corneas, laboratory) no increase of corneal rigidity has been measured vivo (on human corneas, treated for a keratoconus). This point for the least surprising, and which should lead to questioning the real effectiveness of cross linking, will be developed infra.
It may be trivial to mention that The CXL reaction itself stops as soon as the corneal stroma impregnated with riboflavin is no longer irradiated by UV-A (i.e. when the UV lamp is turned off, usually after 30 minutes, but there are variants and forms of CXL that are called "accelerated"). However, some relate the late topographical variations with the collagen cross-linking procedure itself. This could be a form of Magical thought", but in reality, late changes in the curvature of the cornea (late and modest, far from what should be obtained to regularize the geometry of the cornea and make the keratoconus disappear) are linked to Non-specific scar remodeling phenomena. These kinds of scarring variations are observed in many corneal surgical procedures, or various ailments such as infections, interstitial keratitis, etc.
Surgical technique of crosslinking
The classic technical achievement of the crosslinking requires the removal of the epithelium of the cornea (such as in surface laser refractive surgery or "PKR"), and the impregnation of the underlying stromal tissue (the thickness of which must be at least 400 microns) by riboflavin. Drops containing riboflavin in suspension are instilled at regular intervals for 30 minutes. A ultralviolet radiation (360 nm, 3 MW/cm) is then delivered at a distance of 5 cm on the bare corneal stroma. After the intervention occurs a superficial epithelial healing phase.
This Healing certainly explains to her only topographic changes measured after cross linking (Opinion of the author of this site which derives from the logical arguments mentioned above, and that many clinical and experimental results reinforce). In fact, one observes for example the same type of change after procedures to therapeutic target (PKT: This technique also involves the removal of the epithelium, followed by the application of a superficial photoablation of a few microns, and an epithelial scarring that is of magnitude comparable to that which can be observed after CXL, in a context less inflammatory, however).
While the goal of the CXL is to stiffen the cornea (which is unfortunately not obtained in clinical practice), the existence of changes (topographic)weak(, of the order of 2 diopters) allows developers of this technique to convince himself of his 'efficiency '.
More recently, techniques consisting of to permeate the cornea of riboflavin without removal of the epithelium have been proposed (ex: iontophoresis, which allows you to migrate the molecules of riboflavin through the epithelium under the action of an electric field). Their effectiveness seems as bad on the corneal rigidity than the classic technique with desepithelialisation, but the changes observed in terms of corneal topography are also this time not significant (the absence of withdrawal of the epithelium probably explaining the modesty of the results observed in the corneal shape change).
These results strongly suggest that theEs epithelial changes explain the topographical changes observed after CXL, which are therefore not specific to this technique, and would also occur in the course of any technique involving removal and regrowth of the epithelium.
If the cornea is particularly thinned by the evolution of keratoconus, cross linking may be toxic to the endothelial cell layer. These cells are located at the deep face of the cornea and charged with keeping the corneal tissue in a state of relative dehydration. The'Activating free radicals in the deep layers of the cornea can be a source of endothelial cell death, with the risk of corneal edema. An éSufficient minimum thickness of cornea must be measured before proposing a CXL. It should be pointed out that the cornea is generally finer after the cross linking is attained, which is not a guarantee of the efficiency of the technique.
Finally, variations consisting of a cross linking accelerated, where UV radiation is more intense but brief have been proposed: their effectiveness is comparable (anywhere on the Biomechanics of corneal, partial on the topography of the corneal surface); they are essentially designed to simplify the operating procedure but do not bring not much more that the classic technique.
The long-term effects of cross linking are still unknown, as well as the sustainability of the hardening effect envisaged, as there is a physiological corneal remodel.
Indications of the crosslinking
If you believe in the effectiveness of the crosslinking, it makes sense to offer part of Keratoconus SCALABLE, Since the issue claimed by this technique, because they cannot demonstrate an any hardening is to slow down the evolution of Keratoconus.
From the point of view of the author of this site, Keratoconus is probably linked intimately to the realization of repeated eye rubbing, who are more likely to explain the corneal deformation that dystrophy involving purely Biomolecular mechanisms. One external mechanical force (friction) seems necessary at the outbreak of the disease, and to stop its progression, it appears logical to do more exercise (stop rubbing your eyes).
Unfortunately, there an abusive tend to offer this technique from the discovery of a beginner same Keratoconus. Similarly, improper indication of cross linking are unfortunately sometimes found, for example in patients over 30 years, for which the evolution of Keratoconus is null,.. .except well heard if patients continue to vigorously rub the eyes.
Proposing a cross linking after 35 years does not fall under any scientific evidence because the keratoconus is little or more evolutionary (... it is unfortunately very possible that one day it is the same regardless of the age of the patient). Indeed, a balance between the mechanical stress (frictions) and the loss of elasticity of the corneal tissue is reached. This may be different for rare and late forms of keratoconus, which sometimes occur when the patient concerned began to rub his eyes very frequently and vigorously in adulthood (occupation exposed with eye irritants, very prolonged work on screen, appearance of marked dryness of the eye, etc.).
The argument opposed by supporters of the cross linking against abstention is that"Please do something"... However, cross linking does not have the characteristics and safety of a placebo, as this technique is potentially aggressive for corneal tissue. The crosslinking consists of a powerful oxidative reaction, of which we know the potential deleterious effects on biological tissues, and whose rate of complication is far from negligible, ... as well as the cost to the patient. The argument put forward is that if the lenses or some procedures are able to restore all or part of the visual function, It is necessary to stop the evolution of the Keratoconus. The patients who are legitimately worried and uninformed are very sensitive to this speech and are very positive about the realization of a technique supposed to stop their disease and are willing to disburse sometimes consequent sums for it.
In fact, patients with keratoconus, and their loved ones, are often very worried, and seekers of an intervention that could if not cure them, at least curb the evolution of the disease, which explains the ease with which this technique of CXL is accepted. As underlined by the reference study of the Cochrane Bookstore published in 2015, however, there is No studies able to demonstrate that the CXL delay the cornea transplant. The published studies do not have a statistical value because there is no control group, and the evaluation criteria used for the monitoring of keratoconus are insufficiently accurate. That the realization of the CXL delays the graft is a view of the mind, and sometimes a bias related to the fact that the doctors who realize the CXL naturally delay the indication of a graft to the discourse of it. Furthermore, it is possible that a beneficial effect of the CXL is to stop the eye rubbing: But the latter can and should rather be obtained without it being necessary to carry out a relatively invasive gesture for a corneal tissue already put to evil by the repetition of a mechanical trauma sometimes violent (especially for patients who rub with the hard part of the knuckles of the fingers).
The scalability of the keratoconus must be confirmed by the corneal topography. The realization of good quality topographical and tomographic examinations is crucial: it is preferable to perform several measurements at each visit because the repeatability of the topographic measure is lower in case of keratoconus. In addition, the scalability of the keratoconus must be judged on a beam of criteria, and not a single topographic criteria Like the simulated keratometry (SIM-K). At best, a differential topographic map, which is a relatively easy to interpret objective examination.
It is not lawful, even if one is convinced of a speed bump effect, propose a crosslinking during the first visit after discovery of a Keratoconus regardless of its stage. There are indeed non-evolutionary forms of keratoconus, in particular the infra-clinical forms (including the Keratoconus fruste). These forms are often encountered in atopic patients, who have rubbed their eyes at certain periods of their existence and have stopped or severely reduced these frictions.
In proven forms of Keratoconus. It doesn't help (for the patient at least) to a cross linking If the Keratoconus evolves more.
Repeat that after 30/35 years, the majority of the Keratoconus no longer evolve (except for repeated vigorous rubbing of the eyes). Conversely, repeated eye rubbing practice can quite provoke a deformation (often called "ectasia" of the corneal wall) and even after 30 years.
Rather than prescribing a CXL in haste, and presenting this need as "urgent", it is crucial to explain to the patient that it is absolutely necessary to stop rubbing the eyes, that are very often (always?) patients with Keratoconus. Patients should also be questioned about how to sleep and to avoid prolonged eye cuts at night (patients sleeping on the belly or on the side, head in the pillow, in orbital support on one hand or forearm, etc.). Some times of the day are conducive to often unconscious friction: in the morning when waking up, in the shower, in front of the screen (work supported), in the evening at bedtime. The make-up is sometimes carried out in a somewhat "violent" way for the corneas, and it is often observed in women who remove their makeup with vigour some contact deformations (usually little pronounced, because the gesture is performed only once a day).
Rigorous monitoring of patients with Keratoconus teaches that stopping friction is enough to stop the evolution of the keratoconus. This reinforces, if not, demonstrates the hypothesis of a causal mechanism of eye rubbing. This assertion can be simply verified by consulting the case gathered on the site Defeatkeratoconus.com. This unique collection of unsorted observations provides eloquent examples of the role of friction, of the sleep position, in the genesis of the Keratoconus, and of the beneficial and stabilizing effect obtained by the simple cessation of these frictions (case are available Here).
Finally, a minimum of objectivity and scientific spirit should lead to realize that the results of the cross linking are questionable, in particular on the biomechanical plan (see below "") The crosslinking in question« ). The methodology used in the studies to evaluate the cross linking does not assert the superiority of this technique on a "placebo", or even the absence of any therapy to freinatrice aiming! Many forms of Keratoconus are not spontaneous progression beyond some time of evolution, in the absence of repeated local trauma (always eye rubbing).
It is absolutely true thatin VITRO, there is a "hardener" of the crosslinking effect: it is generated for animal or free of Keratoconus corneas. But in VIVOthe hardener of the crosslinking effect could never be highlighted, which is for the least surprising because the crosslinking has as purpose than to crosslink the corneal stroma to modify the visco-elastic properties.
The measurable effects of the CXL could be that induced by a epithelial remodeling (rather than anterior stromal), that is to say a superficial scarring reaction. There is also often a more or less discreet clouding in the superficial anterior stroma, which can induce Visual discomfort to fog type called "haze".
Depending on the importance of the opacity, simple Visual discomfort or greater functional disabilities can be observed.
So in summary:
After CXL of corneal collagen, some late flattening case (reduction of corneal curvature) were reported, but they are not specific to this technique And were also reported after episodes of keratitis or inflammation of the cornea stroma. Changes in corneal curvature observed after CXL (most often of low amplitude, 1-2 D) are probably related to Scar reshuffles of the most superficial tunic of the cornea (epithelium), and do not have much to do with the consequences of any hardening of the corneal stroma (which has never been measured after this technique in vivo, whereas the solidification of the cornea is the raison of a cross linking technique!)).
The Keratoconus is often associated with (most likely caused by) to repeated and vigorous eye rubbing (made with the phalanges, harder than the pads of the fingers), aggravating the distortion and ruptures between the collagen fiber linking corneal slats, and creating (supposed) of Covalent chemical bonds can probably not truly repair the real natural links, or restore the harmonious spatial organization of the collagen fibers.
The author of this site is convinced of the need for external physical trauma to explain the onset and evolution of Keratoconus: eye rubbing repeated are frequently complained, but in some rarer forms, night compression extended by hand or pillow seems associated with forms United or bilateral Keratoconus (the "hugging pillow" syndrome). Patients who sleep on their stomach or side are more exposed to this form of Keratoconus. These Keratoconus usually have a particular topography (marked peripheral camber).
Subtract the corneal dome at the physical external factors likely to jeopardize the biomechanical rigidity is the first step to consider when the discovery of an evocative form of beginner Keratoconus, or a proven Keratoconus. The termination of the eye rubbing (or any trauma repeated on the corneal dome) is enough in my experience based on monitoring of hundreds of eyes to stop the evolution of Keratoconus.
It is never urgent to perform a crosslinking. It may not even be appropriate to do so.
This page lists scientific arguments To justify the Skepticism of the author of this site, which nis not a grief mind, but endowed with critical mind and intellectual probity. It is also intended to Reassure patients with Keratoconus To which the following lines are specifically addressed:
-Never forget that you can stop the evolution of the corneal distortion by never rubbing your eyes vigorously. It's not your fault if you have a keratoconus, information about the eye rubbing and their dangers is unfortunately almost non-existent outside this site and a few others. The ophthalmological community as a whole continues to consider the keratoconus as a genetic disorder whose mechanisms are misunderstood, and that the disease of the ocular tissue is linked to local constitutional and/or inflammatory phenomena. It is difficult to combat the certainties that have been inculcated for decades, and it will take time to evolve the understanding and acceptance of the mechanical character of the keratoconus. Many teams are dedicated to the search for genes, molecular mechanisms that could only explain the disease. It is not necessarily easy for researchers involved in the search for pointy biomolecular mechanisms to admit that corneal deformation may simply be the result of repetition of local trauma (friction): However, this explanation is the most obvious and able to account for what is encountered during the keratoconus.
– The critical arguments developed against the CXL are supported by logical findings and it is entirely possible to verify in the medical literature (see the link to the article in English). If your ophthalmologist has strongly recommended the CXL, it is very likely that he did so by being convinced of the benefit of this technique. Take several opinions, and use your critical mind.
– this page does not promote any competitor or alternative product. No more rubbing your eyes costs nothing, if it is sometimes a lot of willpower.
NB February 7, 2014: the hypothesis of an effect of corneal epithelium has been confirmed by a study conducted through the use of technology OCT spectral domain; the study cut eye who "received" a CXL before and after intervention shows no changes at the level of the stroma (where the CXL is supposed to Act) but changes in the epithelial layer (explaining the topographical changes reported after CXL):
If you believe in the merits of the CXL, its realization, however, is not possible to propose it for all patients, and there is against conventional signs for the CXL. In case of thin cornea, the risk is that endothelial toxicity (the endothelium is the deepest layer of the cornea: his injury caused an irreversible oedema), do not realize cross linking If the affected cornea in Keratoconus has a Center thickness less than 400 microns at the Center. Any active scar lesion is also a contraindication.
Finally, remember that the cross linking is not indicated in case of no evolutionary Keratoconus, and in case of progressive form, is it necessary to check that evolution continues even when the patient stops rubbing the eyes. The realization of a cross linking with the discovery of a Keratoconus in an adult is often an indication of abuse. Some medical recommendations suggest to propose a CXL to any patient young (ex 18), before checking the Keratoconus progresses. In the (extensive) experience of the author of this site, the eye rubbing strict stop to stop evolution of Keratoconus. On the other hand, and despite the linking cross, Keratoconus is still progressing when it rubs his eyes.
Results of the cross linking
The clinical results suggest the occurrence of a stabilization (but not a regression or healing) of Keratoconus and corneal ectasies.
Actually, the number of published studies are of insufficient to demonstrate a statistically significant the CXL jams evolution of Keratoconus. Cross linking does not allow healing of Keratoconus; even if the studies were sufficiently robust, limited in time of this technique back would not yet say that there is a stabilizing effect of the cross linking to medium and long term. Moreover,. There are many no evolutionary forms of Keratoconuswhich does not necessarily conclude the effectiveness of cross-linking in case of stabilization after realization of this technique.
In particular, the strict eye digital friction stop just in most part of the case to stop the evolution of Keratoconus in young adults. Repeat in the echoing of the Cochrane study, onlyNo well constructed statistical studies to demonstrate that the CXL stops more evolution of Keratoconus than the judgment of the eye rubbing, or spontaneous evolution that would have had the disease in the absence of treatment.
Topographic changes (comparison of corneal topography before and after cross linking) have been observed. initial increase of camber (linked to the removal of the epithelium and the likely unmasking of the geometry of the layer of Bowman) before later reduced it. However, this reduction is low amplitude in terms of deformation caused by Keratoconus (a little less 2 diopters on average, while Keratoconus can increase the keratometry 10 to 20 diopters). In a recent study, the Central corneal curve (keratometry) and theastigmatism corneal declined 0.16±2.20 and 0.10±1.69 D)see the summary of the study). Improving vision is on average close to a line of best corrected Visual acuity and modest. These results are comparable to those that could be hope in stripping the cornea of his epithelium, by creating a local inflammatory reaction, and observing the effects of epithelial growth over the cornea.
The complications of the cross linking have been reported: local inflammation (haze), infections corneal (corneal abscess), and lesions endothelial (the endothelium is the deepest layer of the cornea, which can cause an irreversible oedema). In the most serious case a melting stromal (Central necrosis of the cornea) may be observed. The reported rate of complications is generally between 2 and 3 percent.
Still emphasize an important point and too often overlooked: there is a technique simple and devoid of risk (and the financial cost is zero for the patient...) to avoid advancing a Keratoconus: convince the patient to stop rubbing your eyes. Some case, after stopping eye rubbing, observed some regularization of the cornea curve (small amplitude, about 1d, but which appears to be real and not related to fluctuations of measures, and probably related to the reduction of Inflammation induced by friction and some epithelial regularization).
The repeated and vigorous eye rubbing are a cause proven scalability for Keratoconus, which often causes an overwhelming urge to rub the eyelids, as tears spread less well on the distorted cornea, there are inflammatory factors associated with Keratoconus at the level of the ocular surface.
These data support the questioning of the effectiveness of the cross linking.
The video follows (in English), recorded at the Congress of the French society of Ophthalmology 2015, summarizes the reasons that make that skepticism should be the rule for cross linking: http://www.healio.com/Ophthalmology/cornea-external-disease/news/online/%7B909f9158-4926-4bac-9016-c673992ccf59%7d/video-speaker-discusses-issues-with-cross-linking
The Cross-linking of corneal collagen has been Designed to solidify the cornea Patients with Progressive form of keratoconus, but no evidence of corneal hardening has ever been observed in patients with keratoconus who have undergone this technique. Proponents of the latter usually reject the lack of evidence of clinical efficacy on measuring instruments, which would not be sufficiently effective to measure this hardening. These instruments perfectly measure the corneal "softening" following the presence and evolution of a keratoconus, or corneal surgery, or a corneal pathology responsible for reducing the corneal stiffness (e.g., corneal edema). If the cornea hardened significantly after CXL, this hardening would be highlighted, at least in a trendy way on large numbers, under the basic principle in physics of reversibility of a phenomenon with the arrow of time.
The stakes of the CXL shifted towards the supposed stabilization of the keratoconus, and the reduction of the central curvature of the cornea. There is no well constructed statistical study to validate the formal evidence of a slowdown in the evolution of keratoconus, as there are many spontaneously non-evolutionary forms. The studies focus on small samples, without a quality control group, without taking into account the lesser repeatability of measures to judge progression and/or Al stabilization.
The results of these studies are unfortunately interpreted with a bias characterized by a priori favorable, without the effectiveness of this technique being questioned: when the expected results are not at the rendezvous (no hardening measured), the authors blame the measuring instruments considering that there is necessarily a hardening, but that it is not measurable. I leave it to the reader to appreciate the scientific value of this type of interpretation.
The changes observed after CXL with respect to the alteration of the corneal curvature are Low amplitude and non-specific, related to the Remodeling the epithelium of the cornea.
The relative success for the practice of this technique of CXL in patients with Keratoconus is explained by the request of these patients, anxious once the diagnosis has been made, as well as the "economic" aspects of the gains it generates in the industrial (sale of riboflavin and consumable ampoules) and of course the surgeons (most believe in the virtues of the CXL , but some refuse to question its effectiveness when it is challenged, and sweep away from a hand of the striking, simple and obvious arguments.
In addition to the absence of biomechanical amendment vivo, further indirect evidence of the ineffectiveness of the CXL exist:
- total ineffectiveness of the CXL without epithelial removal (the scar nonspecific mechanisms are not put into play)
- Inefficacy of CXL techniques by iontophoresis, yet quite able to penetrate the reactive agents in the cornea, and which should react to UV radiation which easily crosses the epithelial layer.
Keratoconus is not a condition that evolves in capricious and unpredictable ways. The keratoconus is the direct consequence of repeated eye rubbing. The diagnosis of keratoconus should be investigated in relation to the habits of eye rubbing, and the position of the head during sleep, in order to stop the possible irritations and eye trauma associated with prolonged compression and Contamination by irritants (allergens, mites, microbial germs, etc.). Stopping the eye rubbing, and keeping the orbits at distances from the pillow (sleeping on the back rather than the belly or the side) are much more effective a priori on the main causal mechanism of the keratoconus than a physico-chemical reaction whose issue is not obtained in clinical practice. It is not necessary to add a physico-chemical stress to a cornea victim of repeated mechanical stress...