Safeguarding the Cornea

Cross-linking on the verge

An update on the treatment that could help prevent corneal transplants.

By Robert Murphy

Corneal cross-linking, the treatment in which riboflavin is administered in conjunction with ultraviolet A, is poised to take its place as the preeminent treatment available to U.S. keratoconus sufferers. “It’s a technology that not only stops the progression of keratoconus, but often results in improvement in corneal shape and improvement in vision,” says William Trattler, MD, of the Center for Excellence in Eye Care in Miami, who participated in clinical trials in 2007. “It’s a game-changing surgery.”

Avedro Inc., of Waltham, Mass., has developed a cross-linking system and sponsored FDA clinical studies. In late February, an FDA advisory panel recommended approval of Photrexa/KXL, a combination system of riboflavin, irridated with UVA light issued from the KXL electric system.

Figure 1: Patient undergoing accelerated cross-linking using the Avedro CXL system.

U.S. surgeons who have performed the procedure off-label are cautiously optimistic. “I think it’s going to be an absolutely major, landmark improvement,” says Eric Donnenfeld, MD, of Ophthalmic Consultants of Long Island, in Garden City, N.Y., and a professor of ophthalmology at New York University. “My goal is that keratoconus some day will be like polio in that we eradicate it in our country through the use of cross-linking.”

COLLAGEN CROSS-LINKING

A review

Keratoconus is characterized by a progressive steepening of the cornea as it grows thinner and weaker due to changes in its collagen structure. Free radicals in the cornea oxidize and weaken the collagen links. The natural course of the disease conduces to an ever-greater progression of corneal steepening and eventual scarring. Collagen cross-linking is designed to halt this process.

Theodore Seiler, MD, PhD, developed cross-linking in 1997. He found that treatment with riboflavin (vitamin B2) and ultraviolet radiation brought about greater corneal stiffness. UV itself tends to form cross-links within collagen through a time-consuming photobiologic process; riboflavin acts as a photosensitizing and photoactivating agent to speed this up. Their interaction within the collagen and intracellular matrix of the stroma strengthens the cornea.

“Since keratoconus and corneal ectasia are inherently biomechanical, where the cornea is inherently steep, there’s a tendency for continued elevation and distortion over time,” says Peter S. Hersh, MD, of The Cornea and Laser Eye Institute-Hersh Vision Group in Teaneck, N.J., and professor and director of the Cornea and Refractive Surgery Division at Rutgers Medical School. “Strengthening the cornea, would diminish the progression of the disease.”

In traditional corneal cross-linking, the clinician removes the central 8 mm of the patient’s corneal epithelium to allow riboflavin to penetrate the cornea. The clinician-researcher then instills a drop of riboflavin every two minutes for 30 minutes. This is followed by application of ultraviolet radiation with continued drops every two minutes. Postoperatively, the patient receives topical antibiotic, steroid and nonsteroidal anti-inflammatory agents, plus a bandage contact lens; some patients require an oral narcotic such as Vicodin (acetaminophen and hydrocodone) for discomfort. (A growing shift to transepithelial cross-linking all but eliminates this side effect and offers other benefits; see sidebar.)

Where it stands today

Cross-linking is approved and performed in virtually every developed nation except one — the United States. “To my knowledge, this has been the case for at least five years,” Dr. Donnenfeld says. Clinical trials performed in 2007, in which he participated, showed good outcomes, he points out, but the FDA objected to the formulation of the riboflavin and did not approve the procedure at the time.

POSITIVE OUTCOMES

Clinical trial success

Investigators participating in the U.S. multicenter clinical trials of cross-linking report promising outcomes in terms of the study’s primary endpoint, maximum corneal curvature (k-max) by corneal topography and other criteria. “In our trial, the endpoint we were trying to achieve was the change in maximum keratometry reading of greater than 1 diopter comparing preop to postop, compared to placebo,” says Vance Thompson, MD, of Vance Thompson Vision in Sioux Falls, S.D.; a professor of ophthalmology at the University of South Dakota Sanford School of Medicine and principal investigator of the Avedro clinical trials. “That primary endpoint was more than met.”

Dr. Hersh participated in the phase III FDA clinical trials of cross-linking and published his outcomes in the Journal of Refractive Surgery in 2001.¹ His study population included patients age 14 years or older with axial keratometry patterns consistent with keratoconus. They had corrected distance visual acuity worse than 20/20 and a diagnosis of progressive keratoconus. Forty-nine eyes received cross-linking and were monitored for one year. In addition to these keratoconus patients, the study also included 22 eyes of patients with post-LASIK ectasia. Patients were compared with a sham control group and a fellow-eye control group.

The changes in uncorrected distance visual acuity (UDVA) were not considered statistically significant at one month, three months, or six months, but were considered statistically significant at 12 months (P = 0.04). UDVA improved by two or more Snellen lines in 18 eyes; six eyes lost two or more Snellen lines of UDVA.¹

The mean corrected distance visual acuity improved significantly over one year (-0.13 + 0.21 log MAR; P < 0.001). It remained unchanged at one month (0.006 + 0.18 log MAR; P = 0.81), then improved significantly between one and three months (-0.07 + 0.14 logMAR; P = 0.001) and again between three and six months (-0.06 + 0.12 logMAR; P < 0.001). It leveled off between six and 12 months. At 12 months, the change in the mean corrected distance visual acuity was statistically significant (P < 0.001). The mean corrected distance visual acuity improved by two or more Snellen lines in 15 eyes.¹

Effects on keratometry

The study also looked at maximum keratometry (K). Among the keratoconus eyes receiving cross-linking, there was a 2.00 D decrease in the mean maximum K value between preoperatively and 12 months postoperatively (P = 0.002). There was a significant increase between baseline and one month (mean change: 1.33 + 3.03 D; P = 0.003). There was a significant decrease in the mean maximum K value between one and three months (mean change: -1.70 + 2.66 D; P = 0.001), and again between three and six months (mean change: -0.94 + 3.22 D; P = 0.046). No significant change was observed between six and 12 months. The maximum K value decreased by 2.00 D or more in 22 eyes and remained unchanged in 28 eyes. It increased by 2.00 D or more in three eyes.1 (For additional details of the study, go to www.ophthalmologymanagement.com.)

PATIENT SELECTION

Calling all keratoconus patients?

If patients with the greatest corneal steepening are those who stand most to benefit from cross-linking, the next question is: For whom should this procedure be offered, and at what point in the course of a patient’s keratoconus?

“Our major goal is to stop the progression of the disease,” Dr. Donnenfeld says. “And all groups of patients, mild, moderate, severe, all had their disease stop progressing. The improvement of vision was greatest in the worst cases, but that doesn’t mean we should only do this in the worst cases; we should do it in all cases. There is evidence that suggests that it’s worth offering it because you can see improvement so they wouldn’t need a corneal transplant.”

He continued. “Any patients who are showing progression should be offered it right away. Any keratoconus has a deleterious effect on the quality of vision, and these patients have an overwhelmingly high risk of progressing. And because the risks of the procedure are so low and the benefits are great, my level of treatment is very small. I do these patients very early on when they develop the disease,” Dr. Donnenfeld says.

Take the offensive

In 33 years of surgical practice in Fairfield, N.J., keratoconus expert Theodore Perl, MD, has performed more than his share of corneal transplants. Medical director of the Keratoconus Center of New Jersey, Dr. Perl doesn’t wait for progression in keratoconus before recommending cross-linking to his young patients; he takes a proactive approach and performs it off-label.

“Some people say, let’s only treat people when we have signs of progression, but that’s not really what we’re doing anymore,” Dr. Perl says. Young patients in particular, he notes, can begin progressing at any minute. Should the surgeon tell the patient to return in six months, there’s the risk of a 17-year-old coming back in that time with more advanced keratoconus. “The cross-linking won’t undo the damage that’s happened,” Dr. Perl notes. “So it’s something that we want to do prophylactically in these patients. We know the natural history if you don’t treat them, for most of them, and it’s not a good one. I’m saying, get it done.”

ON THE HORIZON

Further developments just ahead

Investigators are looking to improve outcomes through the use of corneal topography to better target UV radiation for optimal therapeutic effect. European ophthalmologists are already doing this successfully. “One of the exciting areas in the wings is topography-guided cross-linking,” Dr. Hersh says. “So, just as there is topography-guided LASIK, it may be that if we use cross-linking focally to treat the cone in keratoconus, that we get a more robust result, delivering more energy to the more-affected areas of the cone and less energy to the less-affected areas.” Early results from Europe, he notes, have been encouraging.

Since most patients will require vision correction following cross-linking anyway, it makes sense to explore its use in conjunction with PRK, LASIK and Intacs (Figure 2). One key unresolved question is whether to do these concomitantly with, or separately from, cross-linking. Further work will be needed to answer this question.

Figure 2: A 26-year-old male with progressive keratoconus right eye, wanted to stop progression and improve vision. Pre-operative acuity was 20/150 and Max K in this eye was 47.33. Three months later, uncorrected acuity in this eye improved to 20/25 and Max K was reduced to 44.38. This patient underwent combined Intacs and collagen cross-linking in the same session.
COURTESY: YARON S. RABINOWITZ, MD

Cross-linking may be used for vision correction. We may yet see the dawn of refractive cross-linking. “Studies are being undertaken using cross-linking to correct low degrees of nearsightedness and farsightedness,” Dr. Hersh reports.

New promise for keratoconus

A patient’s frustration with poor vision rubs off on anyone caring for the person. Their anguish is acutely felt, especially if there’s little you can do to remedy the matter. This is why corneal surgeons are excited about cross-linking.

“This has been a very anxiety-provoking diagnosis for many patients,” Dr. Thompson says. “And it’s been frustrating to not be able to cure it. So, to me, it’s a game-changer in that it will serve an unmet need in our country for keratoconus patients. And that will be one of the highlights that I will see in my career.” OM

REFERENCES

DISCLOSURES: Dr. Trattler has an interest in PXLO, a company introducing epi-on, or transepithelial, cross-linking, in the US. Dr. Hersh and Dr. Thompson are members of the Avedro medical advisory board.