Corneal Cross-Linking

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:

• Pellucid marginal degeneration
• Terrien marginal degeneration
• Corneal infection

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

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.