Corneal Cross-Linking

Updated: Jul 07, 2017
  • Author: Manolette R Roque, MD, MBA, FPAO; more...
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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:

See the list below:

  • generally believed to be non-inflammatory, although there are numerous recent papers published suggesting that 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 scaring 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'). 

The currently accepted medical indications for corneal cross-linking are:

See the list below:

  • individuals with keratoconus, with documented progression of corneal ectasia,
  • children with keratoconus, who are eye rubbers, and
  • individuals with LASIK-induced corneal ectasia.

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

Other indications for corneal cross-linking include:

See the list below:



There are numerous contraindications to corneal cross-linking:

See the list below:

  • Corneal thickness of less than 400 microns (may cause irreversible damage to the corneal endothelium)
  • Prior herpetic infection (may result in viral reactivation)
  • Concurrent infection (although there are now 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 (ex. dry eye)
  • Autoimmune disorders

Poorer results are noted in the following:

See the list below:

  • > 35 years old (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


The most consistent results of observational and randomized controlled studies has 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, inasmuch as progressive keratoconus keratometry typically increases over time. Important corneal cross-linking studies are listed below:

  • C.G. Carus University Hospital, Dresden, Germany Study  [11]
  • Siena Eye Cross Study  [12]
  • Australian Study  [13]
  • US FDA Phase III Trials  [20]


Complications of corneal collagen cross-linking include:

See the list below:

  • temporary stromal edema (< =70%) [14]
  • temporary haze (< =100%) [14]
  • permanent haze (< =10%) [14]
  • corneal scarring [14, 17]
  • sterile infiltrates [14, 17]
  • infectious keratitis: Bacterial/protozoan/herpetic [15, 18, 19]
  • diffuse lamellar keratitis (DLK) [16]


Epithelium Off or On?

Should we do transepithelial crosslinking or not?

  • Shallower demarcation
  • Reduced efficacy

Is it good for children?

Higher UV fluence is better?

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.