Medical Policy: 07.01.72 

Original Effective Date: September 2016 

Reviewed: September 2017 



Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.



Corneal cross-linking (CXL) is an in-office eye procedure that is said to strengthen or stabilize the cornea if it's been weakened by keratoconus, other corneal disease, or a complication of LASIK surgery. During the procedure, riboflavin is applied to the epithelized or de-epithelialized cornea followed by exposure to UV light. Using riboflavin as a photosensitizer and ultraviolet-A (UVA) to increase the formation of intra and interfibrillar covalent bonds by photosensitized oxidation thus, resulting in a measureable stiffening of corneal tissue. This treatment has also been used to treat infectious corneal ulcers and in combination with other treatments, such as intracorneal ring segment implantation.


Alternative and brand names for the procedure include corneal crosslinking, corneal collagen crosslinking, C3-R, CCL and KXL.


The two basic types of corneal cross-linking are:

  • Epithelium-off CXL. In this type of cross-linking procedure, the thin outer layer (epithelium) of the cornea is removed to allow the liquid riboflavin to more easily penetrate the corneal tissue.
  • Epithelium-on CXL. In this procedure (also called transepithelial CXL), the protective corneal epithelium is left intact, requiring a longer riboflavin "loading" time.

The main health outcome for corneal CXL treatment is improvement, or stabilization, of visual acuity.

National Guidelines and Position Statements

In 2013 the National Institute for Health and Care Excellence (NICE)  issued an Interventional Procedure Guideline (IPG 466)

The  IPG stratifies their recommendations for corneal CXL as follows: “Most of the published evidence on photochemical corneal collagen cross-linkage (CXL) using riboflavin and ultraviolet A (UVA) for keratoconus and keratectasia relates to the technique known as 'epithelium-off' CXL'. 'Epithelium-on (transepithelial) CXL' is a more recent technique and less evidence is available on its safety and efficacy. Either procedure (epithelium-off or epithelium-on CXL) can be combined with other interventions, and the evidence base for these combination procedures (known as 'CXL-plus') is also limited. Therefore, different recommendations apply to the variants of this procedure, as follows:

  • 1.1 Current evidence on the safety and efficacy of epithelium-off CXL for keratoconus and keratectasia is adequate in quality and quantity. Therefore, this procedure can be used provided that normal arrangements are in place for clinical governance, consent and audit.
  • 1.2 Current evidence on the safety and efficacy of epithelium-on (transepithelial) CXL, and the combination (CXL-plus) procedures for keratoconus and keratectasia is inadequate in quantity and quality. Therefore, these procedures should only be used with special arrangements for clinical governance, consent and audit or research….”

In 2016, the FDA approved Avedro’s cross-linking system for progressive keratoconus. The approval was unique, as it is a combination drug and device approval. The approval includes Avedro's Photrexa Viscous and Photrexa, which are riboflavin solutions used with the KXL System during the procedure.


Prior Approval:


Not applicable



Corneal collagen cross-linking is considered investigational for all indications.


Collagen cross-linking treatment is not a cure for keratoconus, rather, it aims to slow or even halt the progression of the condition. The main aim of this treatment is to arrest progression of keratoconus, and thereby prevent further deterioration in vision and the need for corneal transplantation. In regards to completed studies the overall quality of the evidence was judged to be very low primarily due to downgrading the evidence due to risk of bias in the included studies, imprecision, indirectness and publication bias. The short term outcomes appear promising but more evidence is needed to determine if long term outcomes are achieved and the need for corneal transplantation is actually halted.


Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 0402T  Collagen cross-linking of cornea (including removal of the corneal epithelium and intraoperative pachymetry when performed)


Selected References:

  • National Institute for Health and Clinical Excellence (NICE) Photochemical Corneal Collagen Cross-Linkage Using Riboflavin and Ultraviolet A for Keratoconus and Keratectasia, IPG466 2013
  • Gkika M, Labiris G, Kozobolis V. Corneal collagen cross-linking using riboflavin and ultraviolet-A irradiation: a review of clinical and experimental studies. Int Ophthalmol. Aug 2011;31(4):309-319. PMID 21847678
  • Caporossi A, Mazzotta C, Baiocchi S, et al. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea. Mar 2012;31(3):227-231. PMID 22420024
  • Papaioannou L, Miligkos M, Papathanassiou M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea. Jan 2016;35(1):62-71. PMID 26509768
  • Sykakis E, Karim R, Evans JR, et al. Corneal collagen cross-linking for treating keratoconus. Cochrane Database Syst Rev. 2015;3:CD010621. PMID 25803325
  • Coskunseven E, Jankov MR, 2nd, Hafezi F, Atun S, Arslan E, Arslan GD. Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus. Cataract Refract Surg. 2009;35:2084–91.
  • Raiskup F, Theuring A, Pillunat LE, et al. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. Jan 2015;41(1):41-46. PMID 25532633
  • U.S. Food and Drug Administration Briefing package: Riboflavin opthalmic solution/KXL system for the treatment of progressive keratoconus or corneal ectasia following refractive surgery 2015
  • Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. Apr 2010;149(4):585-593. PMID 20138607
  • Wittig-Silva C, Chan E, Islam FM, et al. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. Apr 2014;121(4):812-821. PMID 24393351
  • Papaioannou L, Miligkos M, Papathanassiou M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea. Jan 2016;35(1):62-71. PMID 26509768
  • National Keratoconus Foundation Corneal Crosslinking Sites in the US
  • Chunyu T, Xiujun P, Zhengjun F, et al. Corneal collagen cross-linking in keratoconus: a systematic review and meta-analysis. Sci Rep. 2014;4:5652. PMID 25007895
  • Vazirani J, Basu S. Keratoconus: current perspectives. Clin Ophthalmol 2013; 7:2019.
  • Sykakis E, Karim R, Evans JR, et al. Corneal collagen cross-linking for treating keratoconus. Cochrane Database Syst Rev 2015
  • Avedro Inc. Photorexa® Viscous and Photorexa® Prescribing Label.
  • Center for Drug Evaluation and Research: FDA. Summary Review: Application Number 203324Orig2s000.
  • Meiri Z, Keren S, Rosenblatt A, et al. Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis. Cornea. Mar 2016;35(3):417-428. PMID 26751990
  • McAnena L, Doyle F, O'Keefe M. Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmol. Sep 28 2016. PMID 27678078


Policy History:

  • September 2017 - Annual Review, Policy Renewed
  • September 2016 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.


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