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Collagen cross-linking a great advancement for surgeons, patients
 Richard L. Lindstrom |
The application of collagen cross-linking for the treatment of keratoconus, post-corneal refractive surgery ectasia and sight-threatening infectious keratitis/keratolysis is either extremely promising or a part of your everyday practice as a corneal surgeon, depending on where you live in the world.
Collagen cross-linking is another example of the innovation cycle at work. We have always known that the cornea stiffens with age. Those of us who do corneal transplants and work with eye banks know that a child’s donor cornea is unmanageably floppy with nearly no rigidity whereas the older donor cornea has significant rigidity, retaining its shape when exposed to the rigors of trephination and transplantation. The difference between the two is years of aging and exposure to environmental ultraviolet light, resulting in collagen cross-linking and increased rigidity, reduced elasticity and enhanced capability to counteract the IOP and externally applied forces that result in progressive corneal ectasia.
The brilliance of Theo Seiler, MD, and his team in postulating that the natural corneal cross-linking that occurs with age, which causes most keratoconus eyes to stabilize by age 50, might be accelerated and used to prevent ectasia progression, is another example of disruptive invention at work. Experimenting in his laboratory with several known methods of enhancing collagen cross-linking, Dr. Seiler and his group found that the combination of epithelial removal, saturation of the cornea with the nontoxic vitamin riboflavin to enhance ultraviolet light absorbance in the corneal stroma to protect the endothelium, lens epithelium and retina, and exposure to an external ultraviolet light source resulted in rapid acceleration of corneal cross-linking and a stiffer cornea that is more resistant to progressive ectasia.
In Europe, a couple of years of laboratory research and a couple more years of carefully conducted clinical trials resulted in CE mark regulatory approval and access to an amazingly effective treatment for a heretofore untreatable disease for millions of people — all at a reasonable investment cost. Other countries, including our neighbors in Canada and Mexico, have also achieved regulatory approval, and hundreds of Americans are being referred every month from U.S. surgeons to their colleagues in these countries for this sight-saving treatment.
Today, 10 years after commercialization in Europe and many millions of dollars later, clinical trials are under way in the U.S. The initial company our group at Minnesota Eye Consultants partnered with to perform clinical trials, one of the pioneers in Europe, was soon bankrupted by the extraordinary U.S. regulatory costs. Since that time, we have found a better capitalized partner, Topcon, and have resumed enrolling patients in U.S. Food and Drug Administration-approved clinical trials. Others have developed protocols using single surgeon- or multiple surgeon-sponsored FDA-approved clinical trials. Still another group, believing that its patients are being irrevocably harmed by lack of access to this technology, is treating patients quietly by prescription. While other countries evaluate ways to improve the outcomes, expand the indications and reduce the morbidity and invasiveness of the procedure to their patients’ immense benefit, we in the U.S. remain saddled with a regulatory pathway that ensures first approval, if attained, remains years and millions of dollars away. In addition, the treatment method approved will be outdated and will require off-label application to allow state-of-the-art therapy.
Major investments in collagen cross-linking to support the enormous costs of FDA approval in America are difficult to attract as the return on investment is unlikely to be significant. In my mind, in the best interests of our patients, we must find a more rational way to bring advances such as corneal collagen cross-linking to the American patient. Meanwhile, in the more enlightened countries of the world, the promise of this technology is exploding.
The combination of radiofrequency reshaping of the cornea to reduce astigmatism and/or defocus with conductive keratoplasty or alternative methods of energy application followed by collagen cross-linking are extremely exciting. The combination of cross-linking and PRK or cross-linking and Intacs (Addition Technology) is already helping many patients globally. Less invasive methods of treatment, with epithelium on vs. epithelium off, promise to simplify the surgeon and patient experience. Progressive hyperopic shift after radial keratotomy, often associated with advancing astigmatism, also shows signs of being at least partially responsive. Sight-threatening infectious keratitis and/or corneal melting disorders unresponsive to medical therapy also appear to benefit, both through killing the infectious agents when present with the ultraviolet light and reducing keratolysis of the remaining corneal tissue by cross-linking and toughening the remaining stromal fibrils.
In the era of growing MSRA, MRSE and other pathogens resistant to our available antimicrobials, and with investment in new antibiotics at a standstill because of regulatory costs and time to approval, this is an extremely positive development. In my opinion, collagen cross-linking is a major advance in the ophthalmic surgeon’s ability to treat sight-threatening corneal ectasia and infectious keratitis/keratolysis, regardless of cause. We can only hope and pray that patients and surgeons worldwide gain access to this technology in time to save the thousands who cannot afford to travel abroad for therapy and are not close to or eligible for a clinical trial.