Corneal collagen cross-linking
Corneal collagen cross-linking with riboflavin (vitamin B2) and UV-A light (also known as CXL, C3-R, CCL and KXL ), better known as Cross-linking, is a parasurgical treatment for corneal ectasia such as keratoconus.
It was first developed in Germany in 1998 and clinical trials have been in course since the same year; in Italy routine interventions have been successfully performed since 2005, while in the USA clinical trials commenced only in 2008. The procedure, with epithelium removed, is approved for use throughout Europe and Canada.
On 24 February 2015, amid concerns about study data and labeling, a joint panel of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) and Ophthalmic Devices Panel (OP-MDAC) recommended approval of Avedro’s combined riboflavin ophthalmic solutions (Photrexa and Photrexa Viscous) and ultraviolet light irradiation (KXL system) for corneal collagen cross-linking. In March 2015, FDA decided not to approve the Avedro's new drug application, identifying areas of the application concerning the device which require additional information.
The cross-linking involves a one-time application of riboflavin solution to the eye that is activated by illumination with UV-A light for approximately 30 or less minutes. The riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea, which recovers and preserves some of the cornea's mechanical strength. The corneal epithelial layer is generally removed to increase penetration of the riboflavin into the stroma.
Patients that are considered for treatment must undergo an extensive clinical workup, including computerized corneal topography, endothelial microscopy, ultrasound pachymetry, b-scan sonography, keratometry and biomicroscopy.
Epithelium-Off (Dresden protocol)
The standard cross-linking technique, also called Dresden protocol (CXL) requires the removal of central 9 nm of corneal epithelium layer (epi-off), followed by 30 minutes of riboflavin administration, subsequently, UVA light is applied for 30 minutes.
In transepithelial or epithelium-on (epi-on) cross-linking technique, the corneal epithelium layer is left intact. Brian Boxer Wachler was the first to perform transepithelial crosslinking in 2004. in this technique, because the epithelium is not removed, riboflavin loading requires more time than with epi-off techniques.
In Pocket Cross-linking Riboflavin is injected directly into the target tissue (corneal stroma) via a corneal pocket in order to bypass the epithelium, which is left intact. Therefore, the treatment is both, effective and painless. In conventional epi-off technique the epithelium is removed which makes the procedure effective but painful. Transepithelial cross-linking, where the epithelium, which is a significant barrier for Riboflavin administration, is not removed and the Riboflavin has to pass through the epithelium in order to get it into the target tissue (corneal stroma) is painful but the effectiveness is discussed controversially.
In accelerated cross-linking (also known as ACXL, KXL ), UVA exposure time is reduced to less than 3 minutes, this is achieved by increasing the UVA power and reducing the exposure time, thereby maintaining the same energy on the eye as standard cross-linking while reducing cross-linking time.
Combination with refractive eye surgeries
Cross-linking is not intended to correct vision, thus it is usually combined with refractive eye surgeries such as photorefractive keratectomy and intrastromal corneal ring segments. Cross-linking can also be used to avoid post-LASIK ectasia and to improve refractive outcomes.
Corneas normally become thinner after LASIK because the excimer laser used removes tissue. This effect is more marked when higher degrees of spectacle power or larger optical zones are treated. In a small percentage of cases, this thinning causes the cornea to bulge forwards and become distorted in a condition called corneal ectasia. In a similar manner to keratoconus, corneal collagen cross-linking has been found to benefit patients with post-LASIK corneal ectasia as well. However, when cross-linking is performed only after the cornea becomes distorted, vision remains blurry even though the disease is stabilised. Simultaneously crosslinking corneal collagen with LASIK ('LASIK Xtra') aims to strengthen the cornea at the point of surgery and may be useful in cases where a very thin cornea is expected after the LASIK procedure. This would include cases of high spectacle power and patients with thin corneas before surgery. By strengthening the cornea and preventing its distortion, the patient avoids the risk of blurred vision which is experienced if ectasia is treated only after it happens. Definitive evidence that the procedure can reduce the risk of corneal ectasia will only become available a number of years later as corneal ectasia, if it happens, usually occurs in the late post-operative period. Some have also questioned the cost effectiveness of this procedure for preventing corneal ectasia, since corneal ectasia is a very rare complication and there may be many cases treated unnecessarily. Recently, it has been found that LASIK Xtra adds stability to hyperopic treatments and may also do the same for very high myopic treatments. As a result, some centers outside the USA are already performing LASIK Xtra routinely in such cases.
Corneal Collagen Cross-linking may also be combined with other treatments to improve corneal strength or optical refraction. Successful treatment methods include Mini Asymmetric Radial Keratotomy (MARK), corneal ring segment inserts (Intacs or Ferrara rings), topography-guided laser, or Keraflex. Corrective lenses are normally required after these treatments, but with smaller, more normalized prescriptions. Increased corneal symmetry allows for more comfortable contact lens wear, often of daily disposable lenses. These newer methods have an important role in limiting deterioration of vision, increasing unaided and uncorrected vision, and strongly reducing the case for corneal transplantation.
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|40x40px||Wikimedia Commons has media related to corneal collagen crosslinking.|
- Corneal Collagen Cross-Linking on National Keratoconus Foundation website.
- Corneal Collagen Cross-Linking on EyeWiki from the American Academy of Ophthalmology
- US FDA clinical trials for Corneal Collagen Cross-Linking for Keratoconus