Corneal Crosslinking

Corneal crosslinking (CCL) was first described by Seiler, Spörl, and colleagues in 1997 as the “Dresden protocol.” CCL involves the use of a riboflavin (vitamin B2) solution plus exposure to ultraviolet A (UVA) light. The activated riboflavin causes collagen fibrils in tissue to form strong chemical bonds with adjacent fibrils. In the cornea, as in the skin, crosslinking of collagen can occur naturally, due to oxidative deamination within the end chains of the collagen molecule. In addition, other pathways can lead to crosslinking of collagen.

Most systems of corneal crosslinking employ oxidation through the release of oxygen free radicals. Riboflavin serves as a source for the generation of singlet oxygen and superoxide anion free radicals, which are split from its ring structure after excitation by UVA irradiation. It is this interaction of oxygen free radicals generated by the combination of riboflavin and exposure to UVA light that allows for crosslinking of collagen and increase corneal rigidity. In the presence of riboflavin, approximately 95% of the UVA light irradiance is absorbed in the anterior 300 μm of the corneal stroma. Therefore, a minimal corneal thickness of 400 μm after epithelial removal is recommended so as to avoid corneal endothelial damage by UVA irradiation. Thinner corneas may be thickened temporarily with application of a hypotonic riboflavin formulation prior to UVA treatment.

Although there may also be a slight flattening of the cornea, the most important effect of CCL is to stabilize the corneal curvature and prevent further steepening and bulging of the cornea in patients with ectatic conditions. There is no significant change in the refractive index or the clarity of the cornea. The primary clinical application of CCL is to prevent the progression of keratoconus and post–corneal refractive surgery ectasia.

In the Dresden protocol, riboflavin solution is continually applied to the de-epithelialized cornea for 30 minutes (in most studies), and the riboflavin is then activated by illumination of the cornea with UVA light for 30 minutes, during which time application of the riboflavin solution continues. The resultant corneas were shown to be nearly 300% stiffer and more resistant to enzymatic digestion. Investigation also proved that the treated corneas contained higher molecular weight polymers of collagen due to fibril crosslinking. Safety studies showed that the endothelium was not damaged by the treatment if proper UV irradiance was maintained and if the corneal thickness exceeded 400 μm. This type of cross-linking is commonly referred to as “epithelium-off ” or “epi-off ” CCL. Alternative riboflavin formulations and crosslinking techniques that avoid epithelial removal are being evaluated and seem promising.

CCL has rapidly become a first-line treatment for keratoconus throughout the world and was approved by the FDA in April 2016 for the treatment of progressive keratoconus and ectasia. Human studies of UV-induced CCL began in 2003 in Dresden, and early results were promising. The initial pilot study enrolled 16 patients with rapidly progressing keratoconus and all patients stopped progressing after treatment. In addition, 70% had flattening of their steep anterior corneal curvatures (decreases in average and maximum keratometric values), and 65% had an improvement in visual acuity. There were no reported complications.

In a clinical trial in the United States, all patients with keratoconus or post-LASIK ectasia had their corneal epithelium removed. This was followed by a 30-minute application of riboflavin (0.1% diluted in 20% dextran) every 2 minutes, and a subsequent 30-minute UVA treatment (365 nm; 3 mW/cm² irradiation), with concomitant administration of topical riboflavin as a photosensitizer (Fig 7-3). Two control groups—sham and fellow eye—were included in the study, and all patients were monitored for 1 year. Treated eyes initially showed a slight steepening of the cornea with a decrease in best-corrected visual acuity (BCVA; also called corrected distance visual acuity, CDVA), followed by corneal flattening of approximately 1.00–2.00 D, which peaked at between 1 and 3 months after crosslinking. In addition to a reduction in corneal cylinder, a transient compaction of the cornea and an increase in BCVA were observed. There appears to be stabilization in most treated eyes. Some eyes may require re-treatment, and there have been rare cases of loss of 2 or more lines of BCVA in these studies, however.

Figure 7-3 Patient undergoing corneal crosslinking. A, Patient preparing to undergo crosslinking of the cornea immediately prior to riboflavin application. B, After topical administration, the riboflavin fluoresces during application of ultraviolet irradiation to the cornea.

(Courtesy of Gregg J. Berdy, MD.)

• Spörl E, Huhle M, Kasper M, Seiler T. [Increased rigidity of the cornea caused by intrastromal cross-linking]. Ophthalmologe. 1997;94(12):902–906. German.

• Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–627.

Excerpted from BCSC 2020-2021 series: Section 13 - Refractive Surgery. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.