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Cross-Linking in the USA – Part 1: Patient and Riboflavin Selection

Cross-Linking in the USA

Corneal cross-linking (CXL) in the USA is a relatively recent phenomenon, although it’s a technique that was first used in Europe back in 1998 for the treatment of keratoconus (1), and is now used to treat a wide range of corneal ectasias (such as Terrien Marginal Degeneration and post-LASIK ectasia). But until April 2016, any cross-linking performed in the USA was off-label. In other words, before this date, CXL was an unapproved procedure; it would not be covered by health insurance, and the risk of any adverse events would potentially be borne by the surgeon.

What changed in 2016 was the FDA’s approval of one cross-linking light source (Avedro’s KXL device) and two riboflavin solutions (20% Dextran ophthalmic solution 0.146% [Photrexa Viscous] and Riboflavin 5’-phosphate ophthalmic solution 0.146% [Photrexa], both Avedro). Suddenly, corneal surgeons across the USA could offer CXL and be reimbursed from it by health insurers ­– and started to do so.

CXL in the USA cross-linking cornea paper cover pageThe challenge therefore is to close the knowledge and experience gap between surgeons new to the technique in the USA, and surgeons in Europe, some of whom have well over a decade’s worth of experience performing CXL. With that in mind, cross-linking leaders from Europe (Farhad Hafezi, Jose Gomes and Beatrice Cochener) and North America (Michael Belin, and Rajesh Rajpal) and Asia (Li Lim) in the Cornea Society worked together to bridge that gap, resulting in the publication “Corneal Cross-Linking: Current USA Status” being published in the journal, Cornea, in the latter half of 2018 (2).

What was their advice?

Pick the right patient

Progression, progression, progression! CXL’s primary indication is for the treatment of progressive keratoconus in adults (and the treatment of postoperative ectasia). Keratoconus typically progresses until people are in their fourth decade, whereupon it slows or even stops. The CXL procedure isn’t without risk (see below), so received wisdom is that CXL is only performed in patients when their keratoconus starts to progress. Post-LASIK ectasia is by definition, progressive, so unless there is a compelling reason not to, early cross-linking should be performed.

Cross-linking in the USA riboflavin photrexa syringe

Pick the right riboflavin

At the time of writing, the US has only two riboflavin solutions available – “regular” riboflavin with Dextran (Photrexa Viscous) and hypoosomolaric riboflavin (Photrexa). The latter solution is typically used to swell thin corneas to a thickness ≥400 µm before UV irradiation is applied (it’s believed corneas need to have a stromal thickness of ≥400 µm to protect corneal the endothelial cells below the stroma from damage from the UV irradiation performed during the procedure.

Internationally, there’s far more to choose from – another 24, to be precise. Many of these are 0.1% riboflavin formulations (with or without dextran), but there are another six transepithelial (epi-on) formulations listed which typically contain compounds that should loosen epithelial junctions with the intention of letting more riboflavin penetrate through the epithelium and into the stroma. There are another four 0.1% riboflavin solution in HPMC (which results in a more hydrated cornea and a shallower cross-linked volume (3), and can significantly reduce the loading time it takes to achieve yellow anterior chamber flare [which needs to be achieved before UV irradiation can commence]). Internationally, there are another three riboflavin formulations that are more concentrated than the FDA-approved 0.14%, and these are typically used after LASIK flap creation, where the solution is applied to the stromal surface under the flap (as opposed to the corneal surface). The higher concentration of riboflavin is thought to act as a UV shield, decreasing the amount of UV light that might reach the corneal endothelium.

Part 2: Following best practice


1. Wollensak G, Spoerl E, Seiler T. Riboflavin / ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003; 135 (5): 620-7.
2. Belin MW, Lim L, Rajpal RK, Hafezi F, Gomes JAP, Cochener B, Corneal Cross-Linking: Current United States Status: Report From the Cornea Society. Cornea. 2018; 37 (10): 1218-1225.
3. Ehmke T, Seiler TG, Fischinger I et al. Comparison of Corneal Riboflavin Gradients Using Dextran and HPMC Solutions. J Refract Surg. 798-802: 32 (12); 2016th


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