Corneal Collagen Cross Linking (CXL): A Review

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IntroductionTreatments for conditions affecting the biomechanical strength of the cornea, until now, have been limited to treatment of the consequences of progressive weakness of the cornea such as inserts (Intacs or Ferrara rings) and corneal grafting (Deep anterior Lamellar or Penetrating Keratoplasty). Neither addresses the basic defect within the cornea.Corneal collagen crosslinking (CXL) is a treatment designed to increase the rigidity and structural integrity of the cornea, preventing progression to end-stage disease.Keratoconus is a common condition, affecting 1 in 2000 of the population. It typically affects the young, presenting in adolescence with distorted vision. It is a noninflammatory, degenerative disorder of the cornea, characterized by stromal thinning and conical ectasia, resulting in irregular astigmatism and associated visual loss.1It is usually an isolated condition; however, commonly recognized associations include Down syndrome, Leber congenital amaurosis, and connective tissue disorders. Atopy, eye rubbing, and hard contact lenses have also been reported to be highly associated with this disorder, and 6% to 8% of reported cases have a positive family history or show evidence of familial transmission.1,2 Recent biochemical assays and immunohistological studies of corneas with keratoconus suggest that the loss of corneal stroma after digestion by proteolytic enzymes could be caused by increased levels of proteases (matrix metalloproteinase) and other catabolic enzymes3 or decreased levels of proteinase inhibitors (TIMP-1).4 Clinical observations, topographic studies, and preliminary segregation analyses of families of patients with keratoconus suggest that genes play a major role in the etiology of keratoconus.5–8 The heterogenous nature of the disease suggests that different genetic subtypes might result from different mutations and that not all families with keratoconus will follow classical mendelian patterns of inheritance.Pioneering research work by Morishige et al9 in which high energy, short pulsed femtosecond lasers are used to generate signals in a process termed second harmonic generation (SHG) specifically from collagen, were able to obtain high-resolution 3-dimentional images of collagen and showed in normal cornea that anterior stroma collagen lamellae are highly interwoven and that “sutural” lamellae that insert to Bowman layer are present. In keratoconus corneas these “sutural” lamellae are lost.In the majority of keratoconic patients, vision may be restored through the use of hard contact lenses. In cases of advanced disease, Intacs inserts have been reported to be effective in decreasing the corneal steepening and astigmatism and improving visual acuity in patients with keratoconus10–12 but it cannot stop further progressive ectasia. The progressive changes are the result of weakened collagen that leads to the herniation of the cone. In 20% of the patients corneal transplantation is inevitable owing to inadequate contact lens fitting, contact lens intolerance, and corneal scarring. This is a major ophthalmic surgical procedure with a risk of 1 in 500 of blindness. Keratoconus remains one of the most common indications for corneal transplant surgery.13–16Riboflavin (vitamin B2)/ultraviolet A (UVA) (370(nm) corneal collagen cross linkage is a new therapeutic modality, which is the first treatment available to stabilize the keratoconic process.17 Early in vitro studies by Spoerl et al in 1997, showed the potential and advantages of Riboflavin/UVA treatment to safely increase the stability of the cornea by artificial cross-linking without the disadvantages of other cross-linking agents for example glutaraldehyde and Karnovsky solution,18 such as scarring, decompensation, and toxicity.

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