Corneal Collagen Cross-Linking
Corneal collagen cross-linking (CXL) is a photochemical procedure used in the treatment of progressive keratoconus and corneal ectasia. Keratoconus is a naturally occurring dystrophy of the cornea characterized by progressive deformation (steepening) of the cornea while corneal ectasia is keratoconus that occurs after refractive surgery. Both lead to functional loss of vision and need for corneal transplantation. The goal of keratoconus treatment is to reshape the abnormal cornea into a normal dome-like shape, which allows light entering the eye to focus on the retina, improving current visual function and preventing additional vision loss.
CXL is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation. Currently the only CXL method approved by the Food and Drug Administration (FDA) is the epithelium-off method. Using this method, about 8 mm of the central corneal epithelium is removed under topical anesthesia to allow better diffusion of the photosensitizer riboflavin into the stroma. Following de-epithelialization, a solution with riboflavin is applied to the cornea (every 1-3 minutes for 30 minutes) until the stroma is completely penetrated. The cornea is then irradiated with UVA at a maximal wavelength to allow for absorption by riboflavin. The interaction of riboflavin and UVA causes the formation of reactive oxygen species, leading to additional covalent bonds (cross-linking) between collagen molecules that results in stiffening of the cornea.
Another method being evaluated is the epithelium-on method (also known as epi-on or transepithelial). With this method, the corneal epithelial surface is left intact or is partially disrupted and a longer riboflavin loading time is required. This method is still under investigation.
Corneal collagen cross-linking may be considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Corneal collagen cross-linking for the treatment of other conditions/diseases, including use of the epithelium-on (epi-on or transepithelial) method, is considered investigational.
Corneal collagen cross-linking is considered medically appropriate if ALL of the following are met:
Treatment is indicated for ANY ONE of the following conditions:
Corneal ectasia after refractive surgery
Failure of conservative treatment (e.g., spectacle correction, rigid contact lens)
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In 2016, riboflavin 5’-phospate in 20% dextran ophthalmic solution (Photrexa Viscous®; Avedro) and riboflavin 5’-phosphate ophthalmic solution (Photrexa®; Avedro) were approved by the U.S. Food and Drug Administration for use with KXL System in corneal collagen cross-linking for the treatment of progressive keratoconus and corneal ectasia after refractive surgery.
American Academy of Ophthalmology (AAO). Preferred Practice Pattern. (2018). Corneal estasia. Retrieved March 1, 2019 from https://www.aao.org.
BlueCross BlueShield Association. Evidence Positioning System. (3:2018). Corneal collagen cross-linking (9.03.28). Retrieved March 1, 2019 from http://www.evidencepositioningsystem.com. (27 articles and/or guidelines reviewed)
Kanellopoulos, A. (2012). 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. Clinical Ophthalmology, 2012 (96), 97-101. (Level 3 evidence)
Khattak, A., Nakhli, F., & Cheema, H. (2015). Corneal collagen crosslinking for progressive keratoconus in Saudi Arabia: one-year controlled clinical trial analysis. Saudi Journal of Ophthalmology, 29, 249-254. (Level 2 evidence)
Lang, S., Messmer, E., Geerling, G., Mackert, M., Brunner, T., et al. (2015). Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus. BMC Ophthalmology, 2015, 15:78. (Level 2 evidence)
McAnena, L., Doyle, F., & O’Keefe, M. (2016). Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmologica, 2016 Sep 28 [Epub ahead of print]. Abstract retrieved March 10, 2017 from PubMed database.
Meiri, Z., Keren, S., Rosenblatt, A., Sarig, T., Shenhav, L., & Varssano, D. (2016). Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis. Cornea, 35 (3), 417-428. Abstract retrieved March 10, 2017 from PubMed database.
National Institute for Health and Clinical Excellence. (2013, September). Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia. Retrieved July 21, 2016 from www.nice.org.uk.
O’Brart, D.P. (2016). Corneal collagen crosslinking for corneal ectasias: a review. European Journal of Ophthalmology, 2016 Dec 6 [Epub ahead of print]. Abstract retrieved March 10, 2017 from PubMed database.
Padmanabhan, P, Rachapalle, R., Rajagopal, R., Natarajan, R., Iyer, G., Srinivasan, B., et al. (2016). Corneal collagen cross-linking for keratoconus in pediatric patients- long term results. Cornea, 2016 Dec 1 [Epub ahead of print]. Abstract retrieved March 10, 2017 from PubMed database.
Papaioannou, L., Miligkos, M., & Papathanassiou, M. (2016). Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea, 35 (1), 62-71. Abstract retrieved March 10, 2017 from PubMed database.
Poli, M., Lefevre, A., Auxenfans, C., & Burillon, C. (2015). Corneal collagen cross-linking for the treatment of progressive corneal ectasia: 6-year prospective outcome in a french population. American Journal of Ophthalmology, 160 (4), 654-662. Abstract retrieved November 4, 2016 from PubMed database.
Rush, W.W., & Rush, R.B. (2016). Epithelium-off versus transepithelial corneal collagen crosslinking for progressive corneal ectasia: a randomized and controlled trial. The British Journal of Ophthalmology, 2016 Jul 7 [Epub ahead of print]. Abstract retrieved March 10, 2017 from PubMed database.
Sorkine, N., & Varssanoe, D. (2014). Corneal collagen crosslinking: A systematic review. Ophthalmologica, 232 (1), 1-60. (Level 1 evidence)
U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Summary review, application number 203324Orig2s000. Retrieved March 10, 2017 from http://www.accessdata.fda.gov.
Winifred S. Hayes, Inc. Medical Technology Directory. (2018, December). Conventional corneal collagen cross-linking for treatment of LASIK-related ectasia. Retrieved March 1, 2019 from www.Hayesinc.com/subscribers. (42 articles and/or guidelines reviewed)
Winifred S. Hayes, Inc. Medical Technology Directory. (2018, February). Corneal cross-linking for treatment of keratoconus. Retrieved March 1, 2019 from www.Hayesinc.com/subscribers. (66 articles and/or guidelines reviewed)
ORIGINAL EFFECTIVE DATE: 11/10/2012
MOST RECENT REVIEW DATE: 4/11/2019
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