Keratoconus is an ectatic corneal disease of multifactorial etiology, involving both hereditary and environmental factors (like eye rubbing). It typically appears and progresses during the second through fourth decades of life, then becomes more stable later in life. The cornea stiffens naturally with age, and it has been hypothesized that age-related corneal stiffening explains the stabilization of the condition.

Traditionally, we have prescribed glasses for patients with early keratoconus, fitted contact lenses for eyes that advance to the point at which glasses do not provide good vision, and recommended corneal transplantation when contact lenses no longer provided functional vision. These treatments maximize visual acuity, but they do not address the underlying cause of keratoconus.

Spoerl and associates began to experiment with procedures for stiffening the cornea, with the goal of stopping the progression of keratoconus. They concluded that exposure of a riboflavin-impregnated cornea would be the best strategy for accomplishing this goal without significant complications. Eventually, a protocol was developed that could be applied to humans, minimizing the likelihood of collateral damage from exposure from the cytotoxic effects of the treatment.

In 2003, Wollensak and associates published the first clinical results of 23 eyes of 22 patients with moderate or advanced progressive keratoconus treated by riboflavin–ultraviolet A (UVA) corneal collagen cross-linking (CXL). They observed flattening of the corneal curvature, improvement in vision, and a decrease in myopia. This publication has been followed by confirmatory reports from around the world and a prospective, controlled clinical trial.

Complications of the procedure are rare, including infectious keratitis, sterile infiltrates, corneal scarring, nonhealing epithelial defects, and corneal edema. All of these complications are a result of epithelial removal, except corneal edema, which is a result of endothelial damage. Damage to corneal epithelial stem cells from exposure to UVA and riboflavin may contribute to corneal complications.

As we gain more experience with this novel technology, the question of which eyes should be treated and which eyes should be followed obviously arises. The answer to this question should be based on the complication rate of the procedure, the likelihood of benefit if treatment is undertaken, the likely result if treatment is withheld, and the longevity of treatment benefit.

The print literature, common knowledge, and unpublished experiences of ophthalmologists performing CXL around the world is remarkably similar, and complications resulting in visual loss are unusual, probably occurring in 1% to 3% of the cases. These complications can be minimized by selecting patients with corneas more than 400 μm thick, prescribing prophylactic postoperative antibiotics, and following patients closely for complications.

The profession seems to be divided at this point between those who believe CXL should be performed at the time of diagnosis of keratoconus and those who believe it should be reserved for eyes that demonstrate progression.

Vinciguerra and associates report the results of CXL in 40 eyes of 40 consecutive children aged 9 to 18 years with rapidly progressive keratoconus. They noted a decrease in corneal curvature, increase in visual acuity, and improvement in objective measures of corneal optical qualities. No complications were observed. Interestingly, the authors were able to deliver treatment without general anesthesia, even in this young age group.

These data support the safety and efficacy of CXL in a pediatric population with severe, advancing keratoconus that would be likely to progress to the point at which contact lenses and probably penetrating keratoplasty would be indicated.

One must ask whether it is necessary and appropriate to require progression before recommending CXL or whether the likelihood of progression is so great for eyes with keratoconus in this age group that treatment at the time of diagnosis is more appropriate than permitting eyes to progress in severity before CXL is recommended. Is the risk of visually significant complications from CXL greater than the risk of visual loss from progression of keratoconus? These are questions that should be addressed as we become more familiar with this technology and its capabilities. The report of Vinciguerra and associates suggests that the use of CXL may be appropriate at the time of diagnosis in young patients with keratoconus.

What does the future hold? First, we can expect expansion of the indications for CXL. We already know that CXL reduces the amount of water that a cornea can hold, so CXL can delay or eliminate the need for keratoplasty in eyes with endothelial dysfunction. CXL inhibits enzymatic degradation of the cornea, so it is a potential treatment for corneal melting disorders. Cytotoxic effects of the riboflavin-UVA interaction can be used to treat infectious keratitis that is unresponsive to traditional antibiotics. CXL can also be used to treat corneal ectasia after LASIK and to pretreat eyes at risk for it.

In fact, if one considers the indications for keratoplasty in the United States, it is possible to estimate that CXL, used to its fullest capabilities, could conceivably avoid the need for 50% of the keratoplasty procedures now performed in the United States.

The classical Dresden protocol described in Vinciguerra’s paper requires 30 minutes to saturate the cornea with riboflavin and 30 minutes of UVA exposure to obtain the desired effect. The epithelium is a barrier to the passage of riboflavin into the corneal stroma. Current treatment protocols require either the removal of the epithelium or exposure of the epithelium to an agent that increases permeability. Commercially available products now enhance passage of riboflavin through the intact epithelium, increasing the safety of the procedure, but probably with a reduction in the depth of cross-linking.

Early basic laboratory studies of CXL demonstrated that a riboflavin-impregnated cornea will stiffen in the presence of sunlight. This raises the possibility that a topical form of riboflavin might allow penetration of drug to the stroma without damaging the epithelium, allowing the medial treatment of corneal ectasia.

CXL is a truly revolutionary treatment that addresses the underlying defect in eyes with ectatic corneal disease. It has the potential to prevent almost 50% of the corneal transplants performed in the United States, and the contribution of Vinciguerra and associates is a significant advancement of our ability to understand its capabilities.