Collagen Crosslinking

The corneal collagen crosslinking procedure combines riboflavin (vitamin B2), which is a naturally occurring photosensitizer found in all human cells, with ultraviolet A (UVA) light to strengthen the biomechanical properties of the cornea. Riboflavin alone has no crosslinking effect. Its function as a photosensitizer is to serve as a source for the generation of singlet oxygen and superoxide anion free radicals, which are split from its ring structure after excitation by the UVA irradiation and which then lead to physical crosslinking of the corneal collagen fibers. In the presence of riboflavin, approximately 95% of the UVA light irradiance is absorbed in the anterior 300 µm of the corneal stroma. Therefore, most studies require a minimal corneal thickness of 400 µm after epithelial removal in order to prevent corneal endothelial damage by the 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 collagen crosslinking is that it appears to stabilize the corneal curvature and prevent further steepening and bulging of the corneal stroma. There is no significant change in the refractive index or the clarity of the cornea. The primary clinical application of collagen crosslinking is as a treatment to prevent the progression of keratoconus and post–corneal refractive surgery ectasia.

Corneal collagen crosslinking was first described by Spörl and colleagues in 1997. In the performance of this procedure, riboflavin solution is continually applied to the eye 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 corneal epithelium is generally removed before application of the riboflavin so that riboflavin penetration is increased. Alternative riboflavin formulations and crosslinking techniques that avoid epithelial removal are being evaluated and seem promising.

Corneal collagen crosslinking is approved for use in many countries but not currently in the United States. An FDA clinical trial evaluating collagen crosslinking for the treatment of keratoconus and corneal ectasia is ongoing. In one US clinical trial, all patients with either keratoconus or postLASIK ectasia had their corneal epithelium removed, which 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 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 CDVA 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 best-corrected distance visual acuity in these studies, however.

Figure 7-3 Patient undergoing corneal collagen 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 UV

irradiation to the cornea. (Courtesy of Gregg J. Berdy, MD.)

Complications of corneal collagen crosslinking vary by the technique used for the procedure. They include delayed epithelial healing, corneal haze (which may be visually significant), decreased corneal sensitivity, infectious keratitis, persistent corneal edema, and endothelial cell damage.

Although crosslinking alone seems to be effective in stabilizing corneal ectatic conditions, vision rehabilitation may require additional intervention. Corneal collagen crosslinking has been used successfully in combination with other treatment methods, such as intrastromal corneal ring segments and/or excimer laser photoablation (simultaneously or sequentially) to improve the best-corrected vision in these disorders. Whereas this treatment modality has proved beneficial in the treatment of naturally occurring and laser keratorefractive ectasias, it probably should not be employed to treat ectasia resulting from incisional keratorefractive surgery; cases have been reported of incisional gaping requiring surgical repair after crosslinking of cornea that has undergone prior incisional surgery.

Collagen crosslinking is a very promising treatment modality, and studies are evaluating its place among the options for corneal therapy. In addition to conducting studies employing denuded epithelium for crosslinking, investigators are examining riboflavin penetration across intact epithelium for crosslinking. Additionally, there have been reports of collagen crosslinking employed successfully to treat fungal and bacterial infections of the cornea. This use may represent a potential new application of this technology.

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