Corneal Collagen Cross-linking

Number 9.03.28

Effective Date June 19, 2014

Revision Date(s) 06/09/14; 05/13/13

Replaces N/A



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

Related Policies




Policy Guidelines



There are no specific CPT codes for this treatment, it may be reported using:



Unlisted procedure, anterior segment of eye



Corneal collagen cross-linking (CXL) is a photochemical procedure that is being evaluated as a method to stabilize the cornea in patients with progressive keratectasia such as keratoconus and pellucid marginal degeneration. CXL may also have anti-edematous and antimicrobial properties and has been evaluated for the treatment of corneal edema, bullous keratopathy and infectious keratitis.


Corneal 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 for 30 minutes with 370 nm UVA, a maximal wavelength for absorption by riboflavin, together with the continued application of 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. Theoretically, by using a homogeneous light source and absorption by riboflavin, the structures beyond a 400 -micron thick stroma (endothelium, anterior chamber, iris, lens, and retina) are not exposed to a UV dose that is above the cytotoxic threshold.

CXL is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning such as keratoconus. CXL may also have anti-edematous and antimicrobial properties.

Keratoconus is a bilateral dystrophy that is characterized by progressive ectasia (paracentral steepening and stromal thinning) that impairs visual acuity. The progression of keratoconus is highly variable. Initial treatment often consists of hard contact lenses. A variety of keratorefractive procedures have also been attempted, broadly divided into subtractive and additive techniques. Subtractive techniques include photorefractive keratectomy or LASIK, but in general, results of these techniques have been poor. Implantation of intrastromal corneal ring segments (see Related Policies) is an additive technique in which the implants are intended to reinforce the cornea, prevent further deterioration, and potentially obviate the need for a penetrating keratoplasty. A penetrating keratoplasty (i.e., 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. In contrast, CXL has the potential to slow the progression of disease.

Pellucid marginal degeneration is a noninflammatory progressive degenerative disease, typically characterized by bilateral peripheral thinning (ectasia) of the inferior cornea. Deterioration of visual function results from the irregular astigmatism induced by asymmetric distortion of the cornea, and visual acuity typically cannot be restored by using spherocylindrical lenses. Rigid gas permeable contact lenses may be used to treat pellucid marginal degeneration. Intrastromal ring segment implantation, crescentic lamellar keratoplasty, penetrating keratoplasty, and corneal wedge excision have also been proposed.

Regulatory Status

No UVA devices have received clearance or premarket approval for the treatment of keratoconus in the U.S. A search of online site shows ongoing Phase III safety and efficacy trials of UV-A Illumination Systems by Topcon Medical (VEGA) and Avedro Inc. (KXL or UV-X). The U.S. Food and Drug Administration (FDA) has granted Avedro Inc., a priority review of their new drug application (NDA) for the riboflavin ophthalmic solution/KXL II™ system as an orphan drug (<200,000 individuals affected in the U.S.). If approved, Avedro would have 7 years of market exclusivity in the U.S. On March 18, 2014, FDA sent Avedro a complete response letter in which the agency identified a number of areas of the application which require additional information. The KXL II™ system is currently approved for use in Europe.



Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application





This policy was created in 2012 and updated periodically using the MEDLINE database. The most recent literature update was performed through February 7, 2014.

Natural History of Keratoconus

The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study is a multi-center long-term observational study of the natural history of keratoconus. Two reports were published from the CLEK study in 2006 that showed slow changes over 7 years of follow-up. (1, 2) Davis et al. reported changes in high- and low-contrast visual acuity from 953 patients (1,855 eyes). (1) Over a period of 7 years, there was a decrease of 2 high- and 4 low-contrast letters. High-contrast visual acuity decreases of 10 or more letters occurred in 19.0% of patients; low-contrast visual acuity decreases of 10 or more letters occurred in 30.8% of patients. McMahon et al. reported longitudinal changes in corneal curvature over 8 years of follow-up in 1,032 patients. (2) The slope for First Definite Apical Clearance Lens (FDACL) was 0.18 diopters (D) per year, and the slope for flatter keratometric reading (Flat K) was 0.20 D per year. These translated into mean increases of 1.44 D in FDACL and 1.6 D in Flat K during the 8-year follow-up period. Close to 25% of patients had projected increases of 3 D or more in FDACL, while 24% had projected increases of 3 D or more in Flat K.

Evidence Review

Evidence on whether corneal collagen cross-linking (CXL) improves health outcomes for patients with progressive keratoconus consists of 4 controlled trials, 3 of which are randomized. In addition, there are uncontrolled trials that report on longer-term outcomes of the procedure. The main health outcome for CXL treatment is improvement, or stabilization, of visual acuity. Other outcomes commonly reported in trials of CXL include physiologic measures, such as the steepness of the corneal curvature and/or the manifest refraction spherical equivalent (MRSE). These are intermediate outcomes that may corroborate whether improvements in visual acuity correlate with physiologic changes, and which may or may not be adequate surrogates for true health outcomes.

Controlled Trials

Wittig-Silva et al. reported the first randomized controlled trial (RCT) of corneal CXL in 2008. (3) Three-year results were published in 2014.(4) Recruitment for the trial was completed in 2009 with 50 eyes randomized to CXL and 50 randomized to untreated control. To be eligible for enrollment, clear evidence of progression of the ectasia over the preceding 6 to 12 months was required. Progression was confirmed if at least one of the following criteria were met: an increase of at least 1.00 D in the steepest simulated keratometry reading (K-max); an increase in astigmatism determined by manifest subjective refraction of at least 1.00 D; an increase of 0.50 D in MRSE; or a 0.1 mm or more decrease in back optic zone radius of the best fitting contact lens. At the time of analysis for the 2008 report, 20 eyes had reached 1-year follow-up.

The 3-year results included 46 CXL and 48 control eyes. Last observation carried forward was used for 26 eyes, including 17 eyes from the control group with progressive disease that underwent compassionate use CXL or corneal transplantation. In the CXL group there was a flattening of Kmax by -1.03 D, compared with an increase in Kmax of 1.75 in the control group. One eye in the CXL group progressed by more than 2.0 D, compared with 19 eyes in the control group. Uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) improved in the CXL-treated eyes at 1, 2, and 3 years. In control eyes, UCVA was significantly reduced at 36 months and there was a trend of a decrease in BCVA (p=.10). The difference between the groups in UCVA was statistically significant. Follow-up is continuing through 5 years.

One-year outcomes of a crossover RCT were reported in 2011 from a U.S. Food and Drug Administration (FDA)‒regulated multi-center trial of the UV-X system (IROC). (5) Included in the study were 71 eyes of 58 patients 14 years of age or older with a diagnosis of progressive keratoconus or corneal ectasia, an inferior-superior ratio greater than 1.5 on topography mapping, and a BCVA worse than 20/20. If the cornea was thinner than 400 microns, hypotonic riboflavin was administered to swell the stroma. Patients were randomized to CXL or a control treatment consisting of 60 minutes of topical riboflavin alone with the light not turned on. Patients were aware of the treatment assignment, and the control patients crossed over to CXL treatment after the 3-month follow-up visit. With CXL, BCVA improved significantly at the 3-, 6-, and 12-month follow-up visits (from 20/45 at baseline to 20/34 at 12 months). There was a significant decrease in the maximum, average, flat, and steep K values during follow-up. Manifest astigmatism and MRSE did not change significantly. In the control group, there were no statistically significant changes in best corrected distance visual acuity (BCDVA), manifest astigmatism, MRSE, maximum, average or steep K values or corneal astigmatism at the 1-month and 3-month follow-up. A limitation of this trial is that the study design does not allow comparison of CXL and sham treatment over longer than 3 months.

In 2012, another publication from the randomized crossover trial described above reported on subjective visual function. (6) There were a total of 107 eyes (76 patients) with progressive keratoconus (n=71) or corneal ectasia (n=36). At 1 year after CXL, there were significant improvements in reading difficulty, diplopia, halo, and foreign body sensation in the keratoconus group. There was little to no correlation between the subjective and objective measures of vision and keratoconus progression. In addition to the limitation created by controls crossing over to active treatment after 3 months, there is a strong potential for bias in subjective measures when participants are not masked to treatment condition.

Also in 2012, Renesto et al. reported results of a randomized trial that compared CXL versus 1 month of riboflavin eye drops in 39 eyes of 31 patients with keratoconus. (7) After 3 months, all patients received intrastromal corneal ring segments (ICRS; see Related Policies). Patients were evaluated at 1 and 3 months after treatment with CXL or riboflavin, and then at 1, 3, 6, 12, and 24 months after ICRS insertion. There was no significant difference between the 2 groups for UCVA, BCVA, or in 3 topographic parameters (flattest-K, steepest K, and average keratometry) throughout the 24-month follow-up.

Coskunseven et al. reported a within subject comparison of CXL in 38 eyes of 19 patients with progressive keratoconus in 2008. (8) The eye of each patient that progressed more in the previous 6 months was treated with CXL, while the fellow (other) eye served as the control. At baseline, the treated eyes showed worse UCVA and BCVA, higher spherical equivalent refraction, cylinder, and maximal curvature (K-max), and lower pachymetry. Intraocular pressure (IOP) and endothelial cell count did not differ significantly between the treated and untreated eyes. At 9-months follow-up, CXL-treated eyes showed a significant decrease (less myopic) in spherical equivalent refraction (-1.03 D) cylinder (-1.04 D) and K-max (-1.57 D); these measures did not change significantly in untreated eyes (-0.03 D, -0.01 D, and +0.04 D, respectively). UCVA and BCVA increased in CXL-treated eyes (+0.06 and +0.10, respectively) and decreased in untreated eyes (-0.08 and -0.06, respectively). There was an increase in IOP from 9 to 11 mm Hg in CXL-treated eyes.

Uncontrolled Studies

In 2008, Raiskup-Wolf et al. reported outcomes of 241 eyes (130 patients) treated with CXL, with a minimum of 6 months follow-up. (9) This was out of a total of 488 eyes (272 patients) with progressive keratoconus and a corneal thickness of at least 400 microns treated at their center in Germany. Progression was indicated by either an increase in maximum K of 1.00 D in 1 year, patient report of deteriorating visual acuity, or the need for new contact lens fitting more than once in 2 years. Follow-up examinations were performed at 1, 6, and 12 months, and then annually. The mean follow-up was 26 months with a range of 12 months (n=142) to 6 years (n=5). In the first year (n=142), steepening (K-max) improved or remained stable in 86% of eyes, and BCVA improved by at least 1 line in 53% of the eyes. Three years after treatment (n=33), K-max improved by a mean of 2.57 D in 67% of eyes while BCVA improved by at least 1 line in 58% of eyes. This study is limited by the retrospective nature of the study and the low number of cases with extended follow-up.

Twelve-month results from 142 eyes treated with CXL from the French National Reference Center for Keratoconus were reported in 2011. (10) Inclusion criteria for this retrospective study were confirmed keratoconus, central corneal thickness greater than 400 microns, disease progression proven by previous central keratometry reports, and subjective loss of vision (loss of >2 lines in 1 year or keratometry increasing more than 1.0 D in 6 months or 2.0 D in 12 months). Stable visual acuity was defined as a 1-line change in BCVA, improvement was defined as a 2-line gain of BCVA, and failure was a 2-line loss in BCVA. Progression was defined as an increase of more than 1.0 D in K-max in 6 months or of more than 2.0 D in 12 months. Out of 142 eyes enrolled in the study, 6-month follow-up was available for 104 (73.2%), and 12-month follow-up was available for 64 (45.1%). At 12 months after treatment, the BCVA had stabilized in 31 of the 64 eyes (47.6%), improved in 26 eyes (40%) and decreased in 8 eyes (12%). Keratoconus progression had stopped in 42 eyes (68.8%), and the K-max value had decreased by more than 2.0 D in 13 eyes (21.3%). There was a 7% complication rate in the total sample, with 5 eyes (3.5% of 142 or 7.8% of 64) losing more than 2 Snellen lines of visual acuity. Indicators of failure were preoperative K-max greater than 58.0 D, age older than 35 years, and female gender. This retrospective study is also limited by the low percentage of patients available at 12-month follow-up.

A 2010 publication from the Siena Eye Cross Study reported a 52.4 month mean follow-up (range, 48-60 months) on their first 44 keratoconic eyes treated with CXL. (11) Included in the study were 44 patients between 10 and 40 years of age with disease progression in the previous 6 months, minimum corneal thickness of 400 microns in the thinnest point, topographic mean K value less than 55 D, clear cornea by slit-lamp examination, and absence of eye infections, herpetic clinical history, autoimmune disease, and pregnancy. Follow-up evaluations were performed at 1, 2, 3, 6, 12, 24, 36, 48, and 60 months after CXL. Topographic analysis showed a mean K reading reduction of -1.96 D after 1 year, -2.12 D after 2 years, -2.24 D after 3 years, and -2.26 D after 4 years of follow-up. By comparison, in fellow eyes untreated for the first 24 months, the mean K value increased by 1.2 D at 1 year and 2.2 D at 2 years. In treated eyes, UCVA improved by a mean of 2.41 lines after 12 months, 2.75 lines after 24 months, 2.80 lines after 36 months, and 2.85 lines after 48 months. There was no significant decrease in endothelial cell density, central corneal thickness, or IOP over follow-up. Temporary side effects included stromal edema in the first 30 days (70% of patients) and temporary haze (9.8% of patients). No persistent side effects were observed.

A 2012 publication from the Siena CXL Pediatrics trial reported 12- to 36 -month follow-up after CXL in 152 patients aged 18 years or younger with keratoconus progression. (12) Visual acuity increased by an average of 0.15 Snellen lines, whereas a clinically relevant change is generally considered to be 2 Snellen lines.

Adverse Events

Reported adverse events are relatively uncommon, but precise rates of adverse events are not available because of the lack of large studies with long-term follow-up. Adverse events reported to date include corneal endothelial damage, stromal haze, corneal melt, keratitis, gaping of corneal incisions, and corneal scarring.(13-15)

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 physician specialty society and 1 academic medical center (2 reviewers) while this policy was under review in 2012. The input from all reviewers was mixed, noting the limited literature and lack of FDA approval for this procedure, although there are ongoing FDA-regulated clinical trials. The reviewers also commented on the lack of alternatives to slow the progression of disease and that data indicate that the procedure is safe and effective enough to offer to patients with adequate informed consent under an investigational protocol.

Ongoing Clinical Trials

A search of online site in February 2014 identified 30 open trials of corneal CXL. Some of the randomized controlled studies of CXL for keratoconus include:

  • An industry-sponsored multi-center sham controlled trial of the KXL system with riboflavin (NCT01344187). The study will evaluate the change in maximum corneal curvature at 6 and 12 months after active and sham treatment. The study began August 2011, has completed enrollment with a target of 226 patients, and has a completion date of December 2014.
  • A randomized comparison of 3 intensities with the KXL system (NCT01459679). The study began in 2012, has an estimated enrollment of 4,000 patients, and a completion date of December 2014.
  • A randomized comparison of CXL or sham in 130 patients with keratoconus (NCT00626717). The primary outcome measures are keratoconus progression and endothelial cell loss at 3 years. This study is listed as completed as of January 2013.
  • A Phase III trial of the Vedera KXS Microwave System combined with CXL compared with CXL alone (NCT01672814). The study has an estimated enrollment of 130 patients with completion expected August 2014.
  • A Phase III noninferiority trial comparing iontophoretic vs standard riboflavin for CXL (NCT01868620). The study has an estimated enrollment of 162 patients with completion expected in May 2016.
  • A multicenter, randomized, placebo-controlled evaluation of the safety and efficacy of the KXL System with VibeX (Riboflavin Ophthalmic Solution vs. placebo) for CXL in eyes with keratoconus (NCT01972854). The study sponsor is Avedro. The study began in 2013 and has an estimated enrollment of 206 patients. Completion is expected in March 2016.
  • A Phase III randomized trial of CXL for the treatment of keratoconus and pellucid marginal degeneration (NCT01604135). The study is sponsored by university hospitals in Sweden and has an estimated enrollment of 200 patients. Completion is expected in May 2015.

Also identified on is the German Corneal Cross-Linking Registry (NCT00560651). Goals of the registry are to gather long-term results of CXL, detect rare complications and side effects, and evaluate efficacy in a large number of patients. There is an estimated enrollment of 7,500 patients with a study completion date of November 2012. The status of this study is unknown.


Corneal cross-linking (CXL) is a treatment for progressive keratoconus and other forms of corneal ectasia. There is evidence from a number of small randomized controlled trials (RCTs) that CXL leads to short-term improvements in visual acuity compared with untreated eyes, and results from 1 trial have reported that benefits are maintained at 2 to 3 years’ follow-up. However, due to the variable natural history of keratoconus, there is a need for prospective RCTs with larger numbers of patients that are followed over many years to determine whether CXL improves longer-term outcomes. Several trials are ongoing, and results from these other trials are expected soon. Longer-term outcomes from large cohorts will also be useful to evaluate potential long-term complications of this new treatment approach. Although one device is currently under Food and Drug Administration (FDA) review for a humanitarian device exemption (HDE), no CXL devices have received FDA approval at this time. Pending FDA approval of the HDE, CXL is considered investigational.

Practice Guidelines and Position Statements

In 2013 the National Institute for Health and Care Excellence issued an Interventional Procedure Guideline (IPG 466) (16) that replaced the 2009 IPG 320. The new IPG now stratifies their recommendations for corneal CXL as follows:

“Most of the published evidence on photochemical corneal collagen crosslinkage (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”.

Information on corneal cross-linking and ongoing trials is provided by the National Keratoconus Foundation.(17)

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.



  1. Davis LJ, Schechtman KB, Wilson BS et al. Longitudinal changes in visual acuity in keratoconus. Invest Ophthalmol Vis Sci 2006; 47(2):489-500.
  2. McMahon TT, Edrington TB, Szczotka-Flynn L et al. Longitudinal changes in corneal curvature in keratoconus. Cornea 2006; 25(3):296-305.
  3. Wittig-Silva C, Whiting M, Lamoureux E et al. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg 2008; 24(7):S720-5.
  4. 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 2014.
  5. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg 2011; 37(1):149-60.
  6. Brooks NO, Greenstein S, Fry K et al. Patient subjective visual function after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg 2012; 38(4):615-9.
  7. Renesto Ada C, Barros Jde N, Campos M. Impression cytologic analysis after corneal collagen cross-linking using riboflavin and ultraviolet-A light in the treatment of keratoconus. Cornea 2010; 29(10):1139-44.
  8. Coskunseven E, Jankov MR, 2nd, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg 2009; 25(4):371-6.
  9. Raiskup-Wolf F, Hoyer A, Spoerl E et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34(5):796-801.
  10. Asri D, Touboul D, Fournie P et al. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 2011; 37(12):2137-43.
  11. 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 2010; 149(4):585-93.
  12. Caporossi A, Mazzotta C, Baiocchi S et al. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea 2012; 31(3):227-31.
  13. 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 2011; 31(4):309-19.
  14. Gokhale NS. Corneal endothelial damage after collagen cross-linking treatment. Cornea 2011; 30(12):1495-8.
  15. Abad JC, Vargas A. Gaping of radial and transverse corneal incisions occurring early after CXL. J Cataract Refract Surg 2011; 37(12):2214-7.
  16. National Institute for Health and Clinical Excellence (NICE). 2013. Available online at: Last accessed May, 2014.
  17. National Keratoconus Foundation. Crosslinking. Available online at: Last accessed May, 2014
  18. Blue Cross and Blue Shield Association. Corneal Collagen Cross-Linking. Medical Policy Reference Manual, Policy 9.03.28, 2013.








Unlisted procedure, anterior segment of eye









New policy, add to Vision section. New policy created with literature review through January 2012; clinical input reviewed; considered investigational.


Update Coding Section – ICD-10 codes are now effective 10/01/2014.


Update Related Policies. Delete 9.03.05 as it was archived.


Replace policy. Policy updated with literature review through January 29, 2013; references 5, 6, 11 added and references reordered; policy statement unchanged. Remove Related Policy 9.03.14 as it was archived.


Annual Review. Policy updated with literature review through February 7, 2014; reference 4 added; policy statement unchanged. CPT 66999 added to coding section; it previously appeared only within the Policy Guidelines section.

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