BlueCross BlueShield of Tennessee Medical Policy Manual

Corneal Collagen Cross-Linking


Corneal collagen cross-linking (CXL) is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation. A common CXL protocol removes about 8 mm of the central corneal epithelium 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.

CXL is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning such as keratoconus. It has also been evaluated in the treatment of keratitis and ectasia.

Keratoconus is characterized by thinning of the corneal surface and the development of a cone-shaped bulge. This bulging causes refractive errors and deterioration of visual acuity. Keratoconus can be idiopathic or iatrogenic and may be seen as a result of laser in situ keratomileusis (LASIK).


See also:  Intrastromal Corneal Ring Segments (ICRS) for Vision Correction



No UVA devices have received clearance or pre-market approval for the treatment of keratoconus in the U.S. Phase III clinical trials evaluating safety and efficacy are on-going.


American Academy of Ophthalmology. (September, 2007). Refractive errors and refractive surgery preferred practice pattern. Retrieved July 6, 2012 from

BlueCross BlueShield Association. Medical Policy Reference Manual. (4:2015). Corneal collagen cross-linking (9.03.28). Retrieved September 10, 2015 from BlueWeb. (19 articles and/or guidelines reviewed)

Hovakimyan, M., Guthoff, R., & Stachs, O. (2012). Collagen cross-linking: Current status and future trends. Journal of Ophthalmology, Epub 2012.

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)

Leccisotti, A., Aslanides, J., Moore, J, & shah, S. (2012). Keratoconus and keratoectasia: Advancements in diagnosis and treatment. Journal of Ophthalmology, Epub 2012.

Makdoumi, K., Mortensen, J., & Crafoord, S. (October, 2011). Corneal cross-linking for the treatment of keratitis. Cataract and Refractive Surgery Today Europe. Retrieved July 10, 2012 from

National Institute for Health and Clinical Excellence. (2009, November). Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus. Retrieved July 6, 2012 from

National Institute of Health. (June 2012). Vision research: Needs, gaps, and opportunities. Retrieved July 6, 2012 from: - 249k - 07-05-20122012-07-05.

Predmanabhan, P., & Abhishek, D. (2013). Collagen cross-linking in thin corneas. Indian Journal of Ophthalmology, 61 (8), 422-424. Abstract retrieved September 10, 2015 from PubMed database.

Sauer, A., Letscher-Bru, V., Speeg-Schatz, C., Touboul, D., Colin, J., Candolfi, E., et al. (2010). In vitro efficacy of antifungal treatment using riboflavin/UV-A (365 nm) combination and amphotericin B. Investigative Ophthalmology and Visual Science, 51 (8), 3950-3953. (Level 4 Evidence - Independent study)

Sorkine, N., & Varssanoe, D. (2014). Corneal collagen crosslinking: A systematic review. Ophthalmologica, 232 (1), 1-60. Retrieved September 10, 2015 from PubMed database.




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