Medical Policy: 07.01.72 

Original Effective Date: September 2016 

Reviewed: September 2020 

Revised: September 2020 



This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.


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 measurable 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 only method that currently has FDA approval (as of the printing of this edition) utilizes an instrument manufactured by Avedro, Inc. (Waltham, MA) to deliver ultraviolet light and eye drops containing vitamin B2 (riboflavin). The treatment involves removing the central epithelium (the outermost layer of the cornea) to assure penetration of the eye drops. This is called the ‘epi-off’ or epithelium-off method and is the standard CXL method.


Eye surgeons are testing CXL protocols that do not require disturbing the epithelium (‘epi-on’). These treatments have yet not been shown to be as effective as the epi-off method and have yet to be FDA approved


In review: The two basic types of corneal cross-linking are:

  • Epithelium-off CXL. Epithelium-off CXL (also known as “epi-off”): In 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 for 30 minutes with ultraviolet A 370 nm, a maximal wavelength for absorption by riboflavin, while the riboflavin continues to be applied. The interaction of riboflavin and UVA causes the formation of reactive oxygen species, leading to additional covalent bonds (cross-linking) between collagen molecules, resulting in stiffening of the cornea. Theoretically, by using a homogeneous light source and absorption by riboflavin, the structures beyond a 400-micron thick stroma (endothelium, anterior chamber, iris, lens, retina) are not exposed to an ultraviolet dose that is above the cytotoxic threshold.
  • Epithelium-on CXL. In this procedure (also called transepithelial CXL), the protective corneal epithelium is left intact, requiring a longer riboflavin "loading" time.


The expected result is that the progression of keratoconus stops or is slowed. CXL does not reverse keratoconus changes that have already occurred. That is why this procedure is recommended for those who are recently diagnosed and whose keratoconus is progressing. The procedure is less impactful for those who are no longer experiencing vision changes due to keratoconus.


The initial treatment for keratoconus often consists of hard contact lenses. A variety of kerato-refractive procedures have also been attempted, broadly divided into subtractive and additive techniques. Subtractive techniques include photorefractive keratectomy or laser in situ keratomileusis (LASIK), although generally, results of these techniques have been poor. Penetrating keratoplasty (ie, corneal grafting) is the last line of treatment. About 20% of patients with keratoconus will require corneal transplantation. All of these treatments attempt to improve the refractive errors, but are not disease-modifying.


None of the currently available treatment options for keratoconus reverse the progression of disease and corneal transplantation is the only option available when functional vision can no longer be achieved.


Progressive Disease

According to the Global Consensus on Keratoconus and Ectatic Diseases: abnormal posterior ectasia, abnormal corneal thickness distribution and clinical noninflammatory corneal thinning must be present for a diagnosis of keratoconus. “Ectasia progression” is defined by a consistent change in at least two of the following parameters:

  1. Steepening of the anterior corneal surface
  2. Steepening of the posterior corneal surface
  3. Thinning and/or an increase in the rate of corneal thickness change


Criteria used to establish keratoconus progression in cross-linking clinical trials:

  • Steepest keratometry (Kmax) 1 D increase from baseline
  • Flattest keratometry (Kmin) 1 D increase from baseline
  • Mean keratometry (Kmean) 0.75 D Increase from baseline
  • Corneal apex power 1 D increase from baseline
  • Manifest spherical equivalent 0.5 D difference from baseline
  • Central corneal thickness 2% decrease from baseline


National Guidelines and Position Statements

National Institute for Health and Care Excellence (NICE)

In 2013 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.


The Cornea Research Foundation of America

The Cornea Research Foundation of America contributed to the recent USA Food and Drug Administration (FDA) approval of cross-linking for halting or slowing the progression of keratoconus and corneal ectasia after prior refractive surgery. They enrolled patients in the first USA clinical trials, which began in 2008, and the results of those studies led to the FDA determination that cross-linking is a safe and effective treatment.


Corneal cross-linking involves administering riboflavin (vitamin B2) eye drops and UVA light in carefully selected parameters that strengthen the front layers of the cornea (clear covering of the eye) and avoid damage to the back part of the eye.


Regulatory Status

Currently, the only CXL treatment approved by the Food and Drug Administration is the epithelium-off method. There are no Food and Drug Administration-approved CXL treatments using the epithelium-on method. CXL is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning, such as keratoconus and corneal ectasia following refractive surgery. CXL may also have anti-edematous and antimicrobial properties.


In 2016, riboflavin 5-phosphate in 20% dextran ophthalmic solution (Photrexa Viscous®; Avedro) and riboflavin 5-phosphate ophthalmic solution (Photrexa®; Avedro) were approved by the Food and Drug Administration for use with KXL System in corneal CXL for the treatment of progressive keratoconus and corneal ectasia after refractive surgery.


Prior Approval:

Not applicable



Corneal collagen cross-linking using riboflavin and ultraviolet light with the epithelial off procedure may be considered medically necessary as a one-time treatment of progressive keratoconus in those 14-65 years old.

Progressive keratoconus may be defined by measurement of 1 or more of the following:

  • An increase of 1 D (diopter) in the steepest keratometry value
  • An increase of 1 D (diopter) in regular astigmatism evaluated by subjective manifest refraction
  • A myopic shift (decrease in the spherical equivalent) of 0.50 D (diopter) on subjective manifest refraction
  • A decrease ≥0.1 mm in the back optical zone radius in rigid contact lens wearers where other information was not available.
  • Deterioration in vision, such that adequate functional vision on a daily basis with contact lenses or glasses can no longer be achieved


AND when the following criteria are met:

  • Clear central cornea (without scarring or disease) AND
  • Corneal thickness of at least 400 microns at the thinnest point AND
  • Nonpregnant individuals


Corneal collagen cross-linking is considered investigational for any other indication including when combined with a second refractive procedure (e.g., intrastromal corneal ring segments, PRK or phakic intra-ocular lens implantation) or in disease that does not have evidence of progression.


Corneal collagen cross-linking using the epithelial on procedure is considered investigational


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. Patients over the age of 40, are unlikely to progress but should be monitored for documented progression.


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 (Report medication separately)
  • J2787 Riboflavin 5'-phosphate, ophthalmic solution, up to 3 ml


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
  • Gomes JA, et al. Global consensus on keratoconus and ectatic diseases. Cornea. 2015;34(4):359–69.
  • Andreanos KD, Hashemi K, Petrelli M, Droutsas K, Georgalas I, Kymionis GD. Keratoconus Treatment Algorithm. Ophthalmology and Therapy. 2017;6(2):245-262. doi:10.1007/s40123-017-0099-1.
  • Knutsson KA, Paganoni G, Matuska S, et al. Corneal collagen cross-linking in paediatric patients affected by keratoconus. Br J Ophthalmol. Feb 2018;102(2):248-252. PMID 28655729
  • Hersh PS, Stulting RD, Muller D, et al. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology. Sep 2017;124(9):1259-1270. PMID 28495149
  • Toprak I, Yaylali V, Yildirim C. Visual, topographic, and pachymetric effects of pediatric corneal collagen cross-linking. J Pediatr Ophthalmol Strabismus. Mar 1 2017;54(2):84-89. PMID 27668869
  • National Institute for Health and Care Excellence (NICE). Photochemical corneal collagen crosslinkage using riboflavin and ultraviolet A for keratoconus and keratectasia [IPG466]. 2013


Policy History:

  • September 2020 - Annual Review, Policy Revised
  • September 2019 - Annual Review, Policy Revised
  • September 2018 - Annual Review, Policy Revised
  • 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.


*CPT® is a registered trademark of the American Medical Association.