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New protocols for corneal cross-linking promisingly address limitations, complications
Today, so-called conventional corneal collagen cross-linking has become the gold standard to halt the course of progressive keratoconus. In this photoreticulation technique, the collagen fibers are bonded with the surrounding corneal matrix. Chemical toxicity leads to keratocyte and nerve fiber apoptosis and subsequently to a progressive renewal of the intracorneal cellular networks. Over time, both biochemical and biological mechanisms allow biomechanical stabilization of the anterior part of the cornea.
Nevertheless, in a small number of cases, dramatic complications occur, such as infections, sterile keratitis or endothelial depletions. These negative outcomes are mainly correlated with the need to remove the epithelium (epi-off CXL), failure of the healing process, or inappropriate toxicity of the hyperactive free radicals spreading too much and too close to the endothelium layer.
Thus, many alternative protocols have been proposed to soak the epithelium with riboflavin without epithelium removal (epi-on CXL). Riboflavin can pass through the tight epithelium junctions with the help of additive enhancers solutions, such as TRIS, BAK and EDTA, thanks to a transcorneal-induced electric field called iontophoresis, or perhaps, in the near future, with the contribution of laser-induced forward transfer technology.
Thus, many alternative protocols have been proposed to soak the epithelium with riboflavin without epithelium removal (epi-on CXL). Riboflavin can pass through the tight epithelium junctions with the help of additive enhancers solutions, such as TRIS, BAK and EDTA, thanks to a transcorneal-induced electric field called iontophoresis, or perhaps, in the near future, with the contribution of laser-induced forward transfer technology. Here, the best argument is the subtle amount of keratocyte apoptosis usually observed with in vivo corneal confocal microscopy after most of the epi-on protocols. The second limitation is the shielding effect of the epithelial layer when the cornea is lightened with the UVA source, due to limited permeability and retention of the riboflavin photoactivator. The epithelial layer, about 40 μm to 50 μm thick, might theoretically absorb almost 20% of the UVA irradiation and furthermore will not play any role in the corneal stiffening. Unfortunately, there are not yet enough publications focusing on this concern and providing relevant recommendations.
In the near future, epi-on CXL will still try to challenge epi-off procedures. At the same time, both approaches will need to address the fact that keratoconus is a corneal focal biomechanical disease in which an inappropriate localized gradient of stiffness can lead to progressive thinning and bulging. The consequent progressive corneal ectasia, involved in the so-called biomechanical circle of worsening, is supposed to be stopped or reversed by biomechanical therapies such as CXL, as well as intracorneal ring segment insertion. Based on this theory, there is no longer a rationale for treating the whole cornea with the same dose of photo-induced collagen reticulation. Focal island CXL or topography-guided CXL are recent emerging strategies to refine the conventional CXL approach. Elastography-based and guided procedures should be possible in the coming years, using optical scattering (Brillouin shift microscopy) or ultrafast mechanical waves imaging technologies (optical coherence tomography or ultrasound).
The issue of thin corneas is usually addressed by using hypotonic riboflavin solutions with epi-off CXL in order to allow the posterior stroma to swell and push back the endothelium layer from the surface to perform CXL more securely. The mechanism is not well known, and there are few papers about efficacy. One can image that collagen bonding could be less efficient if water is excessive in the stromal matrix. The other obvious possibility is to use epi-on CXL.
Because CXL is a dynamic process that needs to control the riboflavin concentration spatially and over time, further technological advancements are required to achieve the goal of customized CXL. This approach will enable us to treat corneas thinner than 400 μm, adding safety to the procedure without compromising efficacy.
In this issue of OSN Europe Edition, ophthalmologists gives us the opportunity to update our knowledge about these encouraging new CXL protocols for keratoconus treatment, with a special focus on thin corneas.
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David Touboul, MD, PhD, OSN Europe Edition Board Member, can be reached at the Centre National de Référence du Kératocône (CRNK), CHU de Bordeaux, Place Amélie Raba-Léon, Bordeaux, 33000, France; email: david.touboul@chu-bordeaux.fr or toubould@gmail.com.
Disclosure: Touboul has no relevant financial disclosures.