Conventional Versus Accelerated Collagen Cross-Linking for Keratoconus

Abstract: Collagen cross-linking (CXL) is a procedure that primarily aims to increase corneal stiffness. Although used for a variety of conditions, it is most commonly applied to the treatment of keratoconus. Collagen cross-linking involves irradiation of the cornea with ultraviolet A (UVA) irradiation after it has been soaked with riboflavin (vitamin B), a photosensitizer. In conventional treatment, based on the Dresden protocol, a minimum corneal thickness threshold of 400 &mgr;m is recommended and UVA (370 nm) irradiation of 3 mW/cm2 irradiance is applied for 30 min, resulting in a cumulative dose of 5.4 J/cm2. Evidence presented in this review shows that conventional CXL stabilizes the vision and corneal topographic parameters in the majority of treated patients, with only a small failure rate. It has a good safety profile with no endothelial cell loss and a small risk of corneal infiltration and infection. To reduce the treatment duration, accelerated protocols of similar efficacy have been sought. In accelerated protocols, UVA irradiation of higher irradiance, typically 9 mW/cm2, is applied for a shorter time, typically 10 min. The evidence, limited to small studies with short follow-up, shows that they may also stabilize the vision and the ectasia, with no additional safety concerns highlighted. Randomized controlled studies are, however, required to confirm the encouraging results and noninferiority to conventional treatment.

[1]  Yasin Cinar,et al.  Comparison of accelerated and conventional corneal collagen cross-linking for progressive keratoconus , 2014, Cutaneous and ocular toxicology.

[2]  Yasin Cinar,et al.  Accelerated corneal collagen cross-linking for progressive keratoconus , 2014, Cutaneous and ocular toxicology.

[3]  G. Snibson,et al.  A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. , 2014, Ophthalmology.

[4]  P. A. Mattei,et al.  Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. , 2014, American journal of ophthalmology.

[5]  Friedrich Paulsen,et al.  Distribution of Young's Modulus in Porcine Corneas after Riboflavin/UVA-Induced Collagen Cross-Linking as Measured by Atomic Force Microscopy , 2014, PloS one.

[6]  F. Hafezi,et al.  The Biomechanical Effect of Corneal Collagen Cross-Linking (CXL) With Riboflavin and UV-A is Oxygen Dependent. , 2013, Translational vision science & technology.

[7]  F. Hafezi,et al.  Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. , 2013, Journal of refractive surgery.

[8]  B. Derby,et al.  Biomechanical properties of human corneas following low- and high-intensity collagen cross-linking determined with scanning acoustic microscopy. , 2013, Investigative ophthalmology & visual science.

[9]  A. Fotouhi,et al.  Corneal collagen cross-linking with riboflavin and ultraviolet a irradiation for keratoconus: long-term results. , 2013, Ophthalmology.

[10]  F. Hafezi,et al.  Corneal collagen cross-linking for ectasia after LASIK and photorefractive keratectomy: long-term results. , 2013, Ophthalmology.

[11]  F. Raiskup,et al.  Corneal crosslinking with riboflavin and ultraviolet A. Part II. Clinical indications and results. , 2013, The ocular surface.

[12]  F. Raiskup,et al.  Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. , 2013, The ocular surface.

[13]  R. McDonald,et al.  Long-term follow-up of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linking to halt the progression of keratoconus , 2013, British Journal of Ophthalmology.

[14]  Jeremy Wernli,et al.  The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. , 2013, Investigative ophthalmology & visual science.

[15]  B. Seitz,et al.  Morphological and Immunohistochemical Changes After Corneal Cross-Linking , 2013, Cornea.

[16]  N. Efron,et al.  Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. , 2012, Journal of refractive surgery.

[17]  A. Kanellopoulos,et al.  Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. , 2012, Journal of refractive surgery.

[18]  L. Buzzonetti,et al.  Transepithelial corneal cross-linking in pediatric patients: early results. , 2012, Journal of refractive surgery.

[19]  F. Hafezi Significant visual increase following infectious keratitis after collagen cross-linking. , 2012, Journal of refractive surgery.

[20]  A. Kanellopoulos Long-term safety and efficacy follow-up of prophylactic higher fluence collagen cross-linking in high myopic laser-assisted in situ keratomileusis , 2012, Clinical ophthalmology.

[21]  D. Mathysen,et al.  Refractive and topographic results of benzalkonium chloride–assisted transepithelial crosslinking , 2012, Journal of cataract and refractive surgery.

[22]  D. O’Brart,et al.  Transepithelial corneal collagen crosslinking: Bilateral study , 2012, Journal of cataract and refractive surgery.

[23]  J. Zárate,et al.  Treatment of Fungal Keratitis From Fusarium Infection by Corneal Cross-Linking , 2012, Cornea.

[24]  A. Kanellopoulos Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus , 2012, Clinical ophthalmology.

[25]  N. Gokhale Corneal Endothelial Damage After Collagen Cross-Linking Treatment , 2011, Cornea.

[26]  Michael Mrochen,et al.  Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. , 2011, Investigative ophthalmology & visual science.

[27]  Ramón Gutiérrez-Ortega,et al.  Keratopathy After Cross-linking for Keratoconus , 2011, Cornea.

[28]  M. Mannis,et al.  Riboflavin/Ultraviolet A Corneal Collagen Cross-linking for the Treatment of Keratoconus: Visual Outcomes and Scheimpflug Analysis , 2011, Cornea.

[29]  D. O’Brart,et al.  A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus , 2011, British Journal of Ophthalmology.

[30]  G. Conrad,et al.  Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking* , 2011, The Journal of Biological Chemistry.

[31]  Karim Makdoumi,et al.  Infectious Keratitis Treated With Corneal Crosslinking , 2010, Cornea.

[32]  M. Díaz-Llopis,et al.  Fusarium keratitis 3 weeks after healed corneal cross-linking. , 2010, Journal of refractive surgery.

[33]  A. Leccisotti,et al.  Transepithelial corneal collagen cross-linking in keratoconus. , 2010, Journal of refractive surgery.

[34]  Jatin N Ashar,et al.  Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for Keratoconus in Italy: the Siena eye cross study. , 2010, American journal of ophthalmology.

[35]  T. Seiler,et al.  Corneal infiltrates after corneal collagen cross-linking. , 2010, Journal of refractive surgery.

[36]  N. Sharma,et al.  Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. , 2010, Journal of cataract and refractive surgery.

[37]  Tos T. J. M. Berendschot,et al.  Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. , 2009, American journal of ophthalmology.

[38]  J. Marshall,et al.  Effect of epithelial retention and removal on riboflavin absorption in porcine corneas. , 2009, Journal of refractive surgery.

[39]  Theo Seiler,et al.  Complication and failure rates after corneal crosslinking , 2009, Journal of cataract and refractive surgery.

[40]  G. Kymionis,et al.  Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. , 2009, Journal of cataract and refractive surgery.

[41]  J. Alió,et al.  Microbial keratitis after corneal collagen crosslinking. , 2009, Journal of cataract and refractive surgery.

[42]  P. Rama,et al.  Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use. , 2009, Journal of cataract and refractive surgery.

[43]  C. Cursiefen,et al.  Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. , 2009, Journal of cataract and refractive surgery.

[44]  C. Mazzotta,et al.  Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. , 2008, American journal of ophthalmology.

[45]  Eberhard Spoerl,et al.  Collagen crosslinking with riboflavin and ultraviolet‐A light in keratoconus: Long‐term results , 2008, Journal of cataract and refractive surgery.

[46]  T. Seiler,et al.  Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis , 2007, Journal of cataract and refractive surgery.

[47]  G. Kymionis,et al.  Diffuse lamellar keratitis after corneal crosslinking in a patient with post-laser in situ keratomileusis corneal ectasia. , 2007, Journal of cataract and refractive surgery.

[48]  Cristina Tommasi,et al.  Treatment of Progressive Keratoconus by Riboflavin-UVA-Induced Cross-Linking of Corneal Collagen: Ultrastructural Analysis by Heidelberg Retinal Tomograph II In Vivo Confocal Microscopy in Humans , 2007, Cornea.

[49]  G. Lang [Cross linking]. , 2007, Klinische Monatsblatter fur Augenheilkunde.

[50]  Theo Seiler,et al.  Increased resistance of crosslinked cornea against enzymatic digestion , 2004, Current eye research.

[51]  T. Seiler,et al.  Endothelial cell damage after riboflavin–ultraviolet‐A treatment in the rabbit , 2003, Journal of cataract and refractive surgery.

[52]  T. Seiler,et al.  Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. , 2003, American journal of ophthalmology.

[53]  E. Spoerl,et al.  Induction of cross-links in corneal tissue. , 1998, Experimental eye research.

[54]  D G Pitts,et al.  Ocular effects of ultraviolet radiation from 295 to 365 nm. , 1977, Investigative ophthalmology & visual science.