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Cross-Linking in the USA – Part 2: Best Practice

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Topical, usually with tetracaine or proparacaine, although children and non-cooperative patients may require alternative forms of anaesthesia. CXL using standard (Dresden/FDA-approved) protocols, once riboflavin soaking before UV illumination, followed by 30 minutes of UV-A illumination can take over an hour to complete, so topical anaesthesia will need to be repeatedly administered during the procedure. An additional advantage of topical anaesthesia is that it weakens epithelial bonds, making epithelial removal easier.

Corneal abrasion


Debrided epithelium

Removal of the central 9.0 mm of the corneal epithelium is a crucial step: it enables riboflavin to penetrate into the collagen-rich stroma where the cross-linking reaction occurs. There are multiple options to achieve this:

  • With a blunt instrument (e.g. a hockey knife), used at a shallow angle to avoid damaging Bowman’s membrane
  • A mechanical brush
  • Topical alcohol (similar to how epithelial removal is performed in PRK)


Riboflavin and illumination 

As mentioned above, there are two FDA-approved riboflavin formulations available currently – the isotonic formulation, Photrexa Viscous, and the hypoosomlar formulation, Photrexa, however both are used in the same way. Nevertheless, both solutions should be before performing procedure, as corneal thickness can reduce periproceduralally due to fluid evaporation, and Photrexa use can help swell the cornea.

The cross-linking process is performed as follows:

AC, anterior chamber; q, quaque (every).

Understanding potential complications

The importance of discussing with patients, preoperatively, the potential complications that may arise from the cross-linking procedure (including treatment failure) cannot be underestimated. Complications like corneal haze, scarring, infective keratitis and sterile infiltrates, corneal perforation, photophobia, and excessive flattening with a hyperopic shift are all rare, but possible, issues. Treatment failure can occur, sometimes in as many as 8 in 100 patients, with the most significant risk factor for this being high preoperative maximum keratometry.


Many patients will experience early postoperative stromal haze, but this results from the healing processes that occur in response to the cross-linking procedure. It typically peaks at one month and then stabilizes over the next year. However, around 8% of patients undergoing CXL will experience significant stromal haze that persists for over 1 year, results in a significant decrease in visual acuity, and is resistant to steroid treatment. The Corneal Society’s authors note that “Advanced keratoconus should be considered at a higher risk for haze development after standard epithelium-off cross-linking.”

What causes CXL-induced haze is still unclear, but both in vivo and in vitro confocal microscopy studies have suggested that “CXL results in acute loss of keratocytes in the anterior corneal stroma followed by activated keratocyte repopulation started by 2 months and completed around 6 months”, so it is possible that these activated keratocytes are producing abnormal collagen which might contribute to the development of post-CXL corneal haze.


Strengthening the cornea flattens the cone – CXL gives increases the biomechanical strength of the cornea and more able to counteract the intraocular pressure that presses against the cornea and makes it bulge in the weakest parts. Most eyes experience a 1­–2.6 D flattening of the cornea in the two years after the procedure. Rarely, flattening in the order of 5 D can occur, although this appears to be more common in the corneas of children who have under gone CXL than other patient populations.


Corneal infection – infectious keratitis – in an incredibly rare complication of CXL. One study of CXL performed at a tertiary care center in India (4) performed a retrospective analysis of 2350 procedures reported an incidence of infection of 0.0017%. However rare, it is a severe complication, that risks corneal melting and scarring that result in losses of visual acuity that require corneal transplantation to rectify.

It’s worth noting that only two cases of fungal keratitis (fusarium and microsporidia) and one case of Acanthamoeba have ever been reported. UV irradiation kills both bacteria and fungi, so it’s likely that any corneal infection in this context occurs in the early postoperative period, rather than during surgery. The method of cross-linking and how the UV energy is applied does not appear to affect the infection rates; although there is some indication that infection might be related to the type of epithelial defect present in the cross-linked eye. Most of the time, the offending pathogens are gram-positive bacteria (Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus salivarius, and Streptococcus oralis) although sometimes gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Acanthamoeba keratitis should be considered in any treatment-resistant case, particuarly in patients with poor hygiene and in cases where symptoms (such as pain) are out of proportion to signs.

Management should follow standard procedures for corneal infection treatment: culture and gram stains should be considered for all cases; small, superficial infiltrates can be treated topically with antibiotic monotherapy, but bigger or more unresponsive infiltrates have to be treated more aggressively with multiple agents. Fungal keratitis should be suspected in all cases that do not respond to antibiotic treatment.

Finally, if patients have a history of herpetic disease, then systemic antiviral prophylaxis should be considered before CXL is performed.

Part 3: Off-label applications


The ELZA Institute

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