In recent years, corneal cross-linking (CXL) has been touted to be a highly effective procedure for “stabilizing” corneal thinning disorders and other indications, such as the treatment of microbial keratitis and bullous keratopathy, as well as in tandem use as an adjunct with refractive procedures, including LASIK and PRK.1 However, several issues remain in debate.

The Procedure
What’s the best way to deliver the UV light to the cornea with riboflavin curing? While trans-epithelial treatment is well tolerated and the patient experience is better than when the epithelium is removed, do we achieve the same therapeutic effect? Treatment via epithelial removal has been to date the standard to assure adequate penetration of riboflavin and UV.

Delivery platforms vary somewhat depending on the device and instructions used—the aperture size may limit its expected outcome to stabilize the cornea, especially with thinning disorders like Pellucid’s marginal degeneration (where the thinning extends to the periphery of the cornea well beyond the 9mm treatment zone). Delivering UV energy to the cornea can be performed using a one-shot approach, or it can be titrated over time. Studies looking at this important issue of how best to apply the therapy will take time to sort out.

Who are the best candidates for CXL and what age group should be treated? The earliest age at which the procedure can be used is debatable since keratoconus often affects adolescents and young adults. The disease doesn’t progress forever, so at what age would the procedure no longer be beneficial? An argument can be made that intervention may be helpful even without signs of progression, because lamellar “strengthening” may make even an older cornea stiffer.

Using CXL may have a prophylactic benefit with refractive surgery candidates, especially in those with a family history of corneal thinning. CXL may become common with any surface ablation procedure to help modulate corneal biomechanics.1 Should we consider surface ablation in forme fruste keratoconus patients?

Combining CXL and corneal Intacs is an interesting concept. Each procedure has its own list of indications and may actually provide additional support or “strengthening” effects to an unstable cornea. Applying UV light with riboflavin is an attractive treatment option for other diseases, including microbial keratitis with melts and bullous keratopathy.

How long will a patient benefit from treatment? Reports from Europe indicate that multiple titrated applications may be required. Michael Smolek, Ph.D., and colleagues have shown that cohesive strength (stiffness) of the cornea varies by location.2 In keratoconus, the weakest areas correspond to the topographically steepest area (inferior and central).2 Perhaps the weakest area will need to be treated differently for maximum effect.

Adverse Events and Long-Term Concerns
We also have unanswered questions relative to side effects such as endothelial toxicity. Are we going to see premature cataracts or retinal morphology later in life?

The FDA has granted Avedro, Inc. orphan drug status for 0.1% riboflavin ophthalmic solution (VibeX) for use with its KXL system for corneal collagen crosslinking (trans-epithelial) to treat keratoconus.3 An additional application has been filed for use in patients with ectasia following refractive surgery.3

How this moves through the approval process is a popular subject for discussion. The FDA wants to continue to provide reasonable assurance of safety and efficacy before giving approval even though orphan drug status has been granted. The Avedro and Topcon devices will undergo additional scrutiny with a cohort of patients followed for at least 12 months.

CXL has the potential for significant benefits in treating patients with corneal thinning disorders and may be used routinely to provide prophylactic benefits in higher-risk patients who undergo refractive surgery. In time, the unanswered questions should be properly vetted, and practitioners will be able to add such treatment options for their most troublesome patients.

RCCL References available at