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FDA approval of topography-guided PRK brings additional benefits to small subset of patients
In many respects, 2013 is the year of collagen crosslinking and topography-guided PRK in a review of surgical technique highlights.
By Lynda Charters; Reviewed by Peter S. Hersh, MD, and Jonathan Talamo, MD
This year has seen exceptional activity surrounding collagen CXL (CXL)-both by itself and as an adjunctive technique for treating keratoconus and potentially for treating refractive errors.
The results of the original U.S. multicenter CXL trial are working their way through the FDA approval process. Peter S. Hersh, MD, is hopeful that the approval decision will be forthcoming in the near future.
“The outcomes looked very encouraging, and I hope that we might know more in the New Year,” said Dr. Hersh, director, Cornea and Laser Eye Institute, Hersh Vision Group, Teaneck, and clinical professor of ophthalmology, and chief, Cornea and Refractive Surgery, Rutgers -New Jersey Medical School, Newark, NJ.
That study assessed the standard CXL technique with a 3-mW ultraviolet light source and a 30-minutes riboflavin “soak” for the treatment of keratoconus and corneal ectasia. The study included 293 eyes with keratoconus and 219 eyes with corneal ectasia that underwent the CXL procedure to evaluate the ability of the technology to stabilize the progressive diseases.
“Other potential benefits of the technique also became apparent,” Dr. Hersh said.
Researchers found a significant difference in 1-year outcomes between the treated eyes and the sham-treated control eyes. In the keratoconus eyes treated with CXL, investigators found a significant improvement and flattening of the corneal topography by 1.6 D compared with continued disease progression in the untreated group.
Considering this and the low-risk profile, as well as long-term results internationally, the procedure seems to be safe and effective for treating keratoconus and ectasia, Dr. Hersh noted.
An evaluation of his patient cohort of about 100 patients that is part of the U.S. multicenter trial found:
Subjective improvements were also reported on patient-completed questionnaires, he said.
Based on the results in this patient cohort, Dr. Hersh and associates reported outcomes that might be predictive of improvement.
“We observed that patients with keratometry readings of 55 D or more before treatment and patients with correctable vision of 20/40 or worse were more likely to have improvements in topography and visual acuity outcomes,” he said.
They published their findings in Cataract and Refractive Surgery (2013;39:1133-1140).
Dr. Hersh also discussed the various avenues into which CXL is evolving.
Three multicenter clinical trials of CXL that are sponsored by Avedro Inc. are currently ongoing in the United States. One study of accelerated CXL in which the power was increased to 30 mW was completed.
“The initial 6-month results of that randomized study are encouraging with improvement in the treatment group compared with the control group,” Dr. Hersh said.
Another study was started recently in which accelerated CXL with a pulsing technique is being assessed-i.e., rather than using continuous wavelight, the light is pulsed (on for 1 second and off for 1 second).
“The presence of oxygen is important for one pathway of the CXL process, and oxygen is rapidly depleted during ultraviolet exposure,” Dr. Hersh said. “With the pulse technique, additional oxygen is able to diffuse into the stroma during the dark phase.”
The hope is that with more oxygen availability, the CXL strengthening effect will become more robust, he noted.
Another study is currently evaluating the potential for CXL as an adjunct to LASIK, specifically in patients who have more than 2 D of hyperopia.
“The goal is enhanced stability of the hyperopic corrections over time, with improvement of our LASIK outcomes” he explained.
Surgeons in Europe are beginning to use topography-guided CXL. The dosage of the ultraviolet light is patterned by corneal topography.
Dr. Hersh explained that a new system has an eye-tracking modality (KXL II System for Accelerated CXL, Avedro Inc.). This allows the surgeon to apply the light at graded powers over specific locations on the cornea, as guided by corneal topography.
“The early results are encouraging with substantial improvements in topography achieved in patients with keratoconus,” Dr. Hersh said. “Also, of great interest is the use of CXL for treatment of simple refractive errors.”
Early results in patients with simple myopia and astigmatism show that different treatment patterns and ultraviolet energies possibly can correct low degrees of myopia and astigmatism.
“This is very exciting from the refractive surgery standpoint,” Dr. Hersh said.
Also, in Europe and elsewhere, CXL has been used as an adjunct to implantation of Intacs (Addition Technology) and as an adjunct to topography-guided PRK in patients with ectasia and keratoconus.
Dr. Hersh also is involved in a study in his clinic in which he and his colleagues are using microwave treatments with CXL.
“Some patients treated in this study have had [more than] 15 D of flattening, with one very happy patient improving from counts fingers to 20/25 uncorrected over the first year after treatment,” Dr. Hersh said.
Although the FDA in the United States has not yet approved CXL, the procedure is almost universally accepted around the world as the first-line treatment for keratoconus, particularly in patients with progressive disease and in younger patients.
“The current issues in refractive surgery are the indications for CXL and the various clinical approaches of the technology and their efficacies,” said Jonathan Talamo, MD, associate clinical professor of ophthalmology, Harvard Medical School, Boston.
Recently, there has been increasing interest in “epithelium-on” CXL, in which the corneal epithelium is left on when the riboflavin is applied in contrast to the standard CXL in which the epithelium is removed (“epithelium-off”).
In the epithelium-on procedure, the riboflavin requires more time to penetrate into the cornea. Although now, loading times are becoming shorter as newer and more concentrated solutions with proprietary additives are being developed that facilitate penetration deeper into the corneal stroma without scraping the epithelium, Dr. Talamo said.
“This more rapid penetration is important because the patient comfort is increased, the visual recovery is faster, and the incidence of complications is reduced dramatically without the need for epithelial healing,” he said.
Much of the controversy surrounding epithelium-on and epithelium-off procedures is about efficacy.
Some histologic, microscopy, and optical coherence tomography studies have reported evidence regarding cell death in the cornea associated with the application of ultraviolet light. With the epithelium-on procedure, cell death is not evident, less evident, or evident to a more shallow corneal depth, Dr. Talamo noted.
“The argument by proponents of epithelium-off CXL is that the desired effect is not reaching the deep layers of the cornea or the effect might not be as complete or long-lasting,” Dr. Talamo said.
He also noted that the literature on this topic is contradictory.
In a multicenter study, CXL-USA, in which Dr. Talamo is participating, there is a large body of epithelium-on data that suggests that the procedure is effective and in many cases equally effective to that of the epithelium-off procedure.
About one-half of the studies in the peer-reviewed literature show that the procedure is effective, and the other half that it is not.
“The variable results probably have more to do with a lack of consistency with making sure that the cornea is loaded with riboflavin and a lack of understanding about the appropriate parameters for establishing the dose of the ultraviolet light, that is, continuous delivery or fractionated delivery,” Dr. Talamo explained.
The answers to these questions are still forthcoming, but there seems to be a groundswell of opinion in the direction of the epithelium-on procedure. Especially when doing CXL in conjunction with other procedures, which is the approach that will truly deliver refractive changes to patients with keratoconus, healing problems may increase if the epithelium is scraped off,” he commented.
Peter S. Hersh, MD
Dr. Hersh is the medical monitor for Avedro Inc.
Jonathan Talamo, MD
Dr. Talamo is co-chairman of the medical advisory board for and a consultant to CXL Ophthalmics.
“The big news of 2013 has been the approval by the FDA of topography-guided PRK (Wavelight Allegretto Laser, Alcon Laboratories) in the United States. I am very excited by this,” said Jonathan Talamo, MD, associate clinical professor of ophthalmology, Harvard Medical School, Boston.
Though wavefront-guided treatment is very effective for the vast majority of cases, Dr. Talamo explained, there is a small subset of patients who will benefit greatly from topography-guided PRK-such as patients who have corneal irregularities after previous surgeries or those with corneal topographic asymmetries that will leave the patients with HOAs.
Wavefront-guided treatments are based on the wavefront profile of the entire eye, which, Dr. Talamo noted, may be harder to measure reproducibly and may not reflect abnormalities in the cornea alone but may reflect lenticular aberrations, which can change over time.
He soon hopes to be involved in a clinical trial of topography-guided PRK and CXL to treat keratoconus.
“Topography-guided technology is going to be very helpful to surgeons in the United States,” Dr. Talamo said.
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