Corneal Cross-Linking

Updated: Jul 17, 2023
  • Author: Manolette R Roque, MD, MBA, FPAO; more...
  • Print


Corneal collagen cross-linking with riboflavin (Vitamin B2) and long-wave ultraviolet A (UV-A) is a surgical treatment for corneal ectasia. Cross-linking (also called C3-R, CXL, CCL, and KXL) is performed to make the cornea more rigid. 

The most common corneal ectasia is keratoconus. Keratoconus has the following characteristics:

  • Generally believed to be non-inflammatory, although there are numerous recent papers published suggesting there may be an inflammatory component
  • Progressive corneal ectasia
  • Increasing irregular astigmatism
  • Loss of best-corrected visual acuity (BCVA) and may lead to surgery
  • Possible scarring and hydrops (acute disruption of Descemet's membrane in the setting of corneal ectasia)
  • Genetic and environmental causes
  • No curative treatment


The main benefit of corneal cross-linking is to halt the progression of corneal ectasia (also known as 'kerectasia' or 'keratectasia'). 

Medical indications

Accepted medical indications for corneal cross-linking include the following:

  • Individuals with keratoconus, with documented progression of corneal ectasia
  • Children with keratoconus, who are eye rubbers
  • Individuals with LASIK-induced corneal ectasia

In post-refractive surgery (LASIK or Radial Keratotomy) ectasia, there are no definitive criteria for progression. Parameters considered include changes in refraction, uncorrected and best-corrected visual acuity, and corneal shape.

Other indications

Other indications for corneal cross-linking include the following:



There are numerous contraindications to corneal cross-linking, and they include the following:

  • Corneal thickness lesser than 400 microns (may cause irreversible damage to the corneal endothelium)
  • Prior herpetic infection (may result in viral reactivation)
  • Concurrent infection (although there now are more scientific papers attesting to the efficacy of cross-linking in sterilizing bacterial and fungal corneal ulcers)
  • Severe corneal scarring or opacification (the results are uneven and unpredictable)
  • History of poor epithelial wound healing
  • Severe ocular surface disease (eg, dry eye)
  • Autoimmune disorders

Poorer results are noted in the following:

  • Aged > 35 years (the cornea is naturally cross-linked by the UVA from sunlight)
  • < 400-micron cornea (possible irreversible endothelial damage)
  • Keratoconus stage III or IV (scarring and opacification)
  • Keratometry > 57 D

Technical Considerations

The commonly used and currenty investigated procedures in clinical practice include the following:

  • Conventional dresden protocol
  • Accelerated corneal cross-linking
  • Transepithelial cross-linking using chemical enhancers
  • Iontophoresis cross-linking


The most consistent results of observational and randomized controlled studies have been that corneal cross-linking induces a small decrease in keratometry values that appears to be maintained over at least a year. This is a significant finding since progressive keratoconus keratometry typically increases over time. Important corneal cross-linking studies include the following:

  • CG Carus University Hospital, Dresden, Germany Study  [1]
  • Siena Eye Cross Study  [2]
  • Australian Study  [3]
  • US FDA Phase III Trials  [4]


Complications of corneal collagen cross-linking include the following:

  • Pain
  • Photophobia
  • Dry eyes
  • Persistent epithelial defect
  • Stromal melt
  • Temporary stromal edema (≤70%) [5]
  • Temporary haze (≤100%) [5]
  • Permanent haze (≤10%) [5]
  • Corneal scarring [5, 6]
  • Sterile infiltrates [5, 6]
  • Infectious keratitis: bacterial/protozoan/herpetic [7, 8, 9]
  • Diffuse lamellar keratitis (DLK) [10]
  • Stromal degeneration
  • Endothelial damage


Epithelium off or on?

Should we do transepithelial crosslinking or not?

  • Shallower demarcation
  • Reduced efficacy

Is it good for children?

  • Centration issues
  • Sedation issues

Higher UV fluence is better?

A shorter operation time may be achieved by means of UV-fluences between 10 to 15 mW/cm2 and riboflavin in HPMC solution.

Shorter operation time results in a shallower demarcation line.