ODs recognize potential of corneal collagen cross-linking

Eye care providers are expressing optimism at the eventual FDA approval of devices for performing corneal collagen cross-linking, but some are still unsure of where the procedure falls within optometric scope of practice.

Corneal collagen cross-linking, widely known as CXL, is currently in clinical trials and is being performed off-label by eye care practitioners throughout the country.

Andrew S. Morgenstern, OD, FAAO, incoming president of the Optometric Council on Refractive Technology and chairman of the New Technology Committee for the American Optometric Association, told Primary Care Optometry News that CXL treats a specific group of disorders.

“Basically, the goal of CXL is to halt the progression of corneal ectatic disease,” he said, “specifically, the big ones such as keratoconus, pellucid marginal degeneration and ectasia as a result of refractive surgery.”

CXL is less a treatment and more an “arrestment,” Marc R. Bloomenstein, OD, FAAO, a member of the PCON Editorial Board, said.

“The intent of cross-linking is to cease the corneal condition from progressing,” Bloomenstein, who practices at the Schwartz Laser Eye Clinic, explained. “We advise any patient with a progressive corneal condition that cross-linking can help maintain a stable and symmetrical corneal topography.”

The excitement surrounding CXL is in large part due to the fact that the procedure represents a way to stop progression, which had not been available to eye care providers previously.

“Absent of transplant, where you remove diseased tissue and replace it with other tissue, it is the only treatment that can halt these diseases,” Morgenstern said. “Others treat the symptoms and sequelae of the disease instead of stopping progression.”

Scott G. Hauswirth, OD, FAAO, a member of the Optometric Council of Refractive Technology and the PCON Editorial Board, said that CXL presents a huge advantage over traditional treatments if performed on patients early in the disease state.

“It can halt the ectatic process and prevent the need for invasive corneal procedures such as a penetrating keratoplasty or deep anterior lamellar keratoplasty,” he said. “In later phases when there is significant corneal irregularity and thinning, it may slow down or halt progression of the ectasia, but the patient is still likely to need some type of visual correction.”

Hauswirth, whose practice has been performing CXL since 2008, continued: “It can also be combined with procedures such as Intacs (AJL Ophthalmic), conductive keratoplasty or even PRK to create a more regular central cornea and lower the amount of higher-order astigmatism.”

Image: Rubinfeld R

Echoing Hauswirth, Arora and colleagues reported in Cornea that CXL demonstrated higher efficacy in terms of topographical and refractive parameters when performed in patients with early keratoconus rather than advanced.

“I do foresee a day where this is FDA approved and permitted by individual state laws, so patients can be identified as having keratoconus in a routine exam and treated with CXL, and the disease never exists in their visual life,” Morgenstern said.

How the procedure works

Hauswirth explained that there are several versions of CXL under investigation in the U.S., but the basics of the procedure are essentially the same.

“The cornea is infused with riboflavin (vitamin B2), and UV light in the 360 nm to 370 nm range is used to create covalent bonding between adjacent collagen fibrils, increasing the tensile strength of the corneal stroma,” he said. “The variations of the process include performing the procedure by denuding the corneal epithelium vs. leaving it in place, or by varying the energy levels of the UV light for faster cross-linking times.”

John A. Hovanesian, MD, FACS, a member of the PCON Editorial Board, said that the treatment typically lasts about an hour, including about 30 minutes for “loading” the cornea with riboflavin and 30 minutes for UV treatment.

“First you anesthetize the eye with drops and then put in a lid speculum with the patient lying down,” Hovanesian said. “After the riboflavin drops, which are colored yellow, absorb into the cornea, you use the UV light to create the cross-linking effect.”

He continued: “Depending on the treatment, some patients may have to use a bandage contact lens. Most patients have some discomfort the night of the treatment and will return to baseline vision in a week.”

Hauswirth said that the UVA exposure is not dangerous.

“At the energy levels used in the traditional CXL procedure, it does not appear that there is a cytotoxic effect on the corneal endothelium, and the amount of UV energy reaching the lens is well below the level needed to induce cataract formation.”

Bloomenstein said that while the duration of the results is still being investigated by the FDA, “it appears that this process should last the entirety of the life of the cornea.”

He said that some patients have needed to have the procedure repeated, however.

Kymionis and colleagues found that CXL was both safe and effective in halting keratoconus over a 5-year follow-up period, according to their study that was published in Cornea.

It is possible that different patients may need unique CXL treatments in order for the results to be permanent, Morgenstern hypothesized.

“Where we’re at now, it’s one-size-fits-all,” he said. “I see a day where we can tailor the procedure to an individual person with an individual problem set.”

Ideal patients for CXL are patients with early stage keratoconus, Hauswirth said.

“Their vision is correctible to 20/25 or 20/30,” he stated. “I would have a hard time persuading a patient who is 20/400 or worse BCVA to have CXL over a deep anterior lamellar keratoplasty or penetrating keratoplasty, because of the potential improvement in visual acuity from the graft.”

“The ideal patient is anyone with progression of a corneal disorder or irregular change to the curvature of the cornea,” Bloomenstein added. “Patients need to have a cornea that is thick enough and without a dense central scar.”

Hauswirth said that the primary miscommunication that he sees regarding the procedure is that patients often think that the treatment will improve their vision.

“While many studies show corneal flattening post-procedure, and many also show improvement in best corrected visual acuity, it is important to phrase the effect of the CXL treatment as an attempt to halt the progression of the disease and not oversell it as improving vision,” he said. “I like to think of it as providing a foundation for technologies that can improve it, but the CXL alone will not.”

Bloomenstein said that while there is not a large change in vision, patients may have more options available to them.

“Patients can often move into a contact lens, such as a Duette (SynergEyes), to improve the quality of the vision,” he said.

Hovanesian acknowledged side effects of the procedure, but said that he considers it safe.

“There are cases where patients develop complications like corneal scarring or infections, but it’s very low,” he said. “It’s less than PRK. We think it’s a pretty safe procedure.”

UV cross-linking is also being investigated for the possible treatment of bacteria, fungi and even Acanthamoeba, Hovanesian said.

“The use of cross-linking in patients with ulceration of the cornea has been studied and found to be effective,” Bloomenstein added. “Cross-linking is a natural process that occurs throughout our lives and thus this procedure is expediting that process. Patients undergoing any corneal refractive surgery may benefit from the increased corneal stability, as will patients with progressive myopia.”

Epi-on vs. epi-off

Hovanesian explained that there are two approaches to CXL, one where the epithelium is removed and one where it is not, commonly known as epi-off and epi-on.

“Epi-off was the original, detailed in the 1996 Dresden protocol,” he said. “The epithelium was removed in order to facilitate treatment. Recent studies have shown that you don’t need to remove the epithelium and that you can achieve the same results with epi-on.”

He said that epi-on offers appealing advantages.

“It’s less trauma to the eye, less healing time, less pain and less chance of infection,” Hovanesian said. “The evidence is compelling, but still debated.”

Several studies have investigated the differences in the two protocols.

Shalchi and colleagues reported in Eye that that epi-on protocols demonstrated less efficacy but fewer complications than epi-off. Additionally, side effects such as haze, scarring, stromal edema and risk of microbial keratitis were only seen in epi-off studies.

Another study, published in Cornea, found that epi-on CXL was as effective as epi-off CXL as well as less painful and with fewer complications, according to Magli and colleagues.

Bloomenstein also sided with epi-on as the preferable protocol.

“I am jaded because I feel the epi-on is the best process since there is no corneal manipulation,” he said.

FDA status

Bloomenstein told PCON that there are quite a few players in the field attempting to bring CXL to market.

“Avedro is the biggest and is the closest to approval, however,” he said.

Morgenstern said that the FDA granted orphan drug status to Avedro’s formulation of riboflavin, but also has to approve the device itself.

“The FDA didn’t say it was an unsafe device, but it was not happy with the methods they used to put data into the study,” Morgenstern explained. “It was a conflict on the quality of the study, not on the device or outcomes.”

Avedro announced in a press release in March 2015 that it received a letter from the FDA in which the agency had “identified a small number of areas of application concerning the device which would require additional information.”

The company stated in the release that it was working to resolve any issues, with the goal of approval as soon as possible.

Hauswirth said that there is a reason why CXL has been approved in Europe, but not in the U.S.

“It speaks to the very conservative approach our FDA has with many items,” he said. “With class action lawsuits there is more responsibility placed on manufacturers of drugs and devices for full disclosure and to provide sometimes excessive amounts of data.”

How will optometry be involved?

In a poll on Healio.com/Optometry, more than 45% of respondents said that they were unsure whether or not CXL falls within their state’s scope of practice for optometry.

David Cockrell, OD, immediate past president of the AOA, told PCON that when CXL receives approval, the ability of optometrists to perform the procedure will vary by state.

“New technology that benefits patients by improving patient care or quality of life is always important to all health care practitioners, including optometry,” he said. “I suspect that this noninvasive procedure may well be within the scope of practice of many, if not most, of our affiliate state practice acts, but I believe it is unlikely that we will see comments by state boards of optometry until the procedure achieves formal approval by the FDA.

“It will depend upon the scope of practice in their state,” he continued. “Some will allow them since it’s not an invasive procedure. Only a very few might be prohibited.”

Cockrell said that it could also depend upon whether optometrists use the epi-on or epi-off technique.

“In most states, ODs are allowed to débride the epithelium to remove a foreign body, and almost all have unrestricted topical medication utilization, so it is very unlikely that epi-on will be disallowed,” he said. “I’m not sure which states will formally authorize the procedure. I think once the procedure is FDA approved, you’ll see some states who say they can authorize it, and some won’t do anything at all and will simply allow the procedure to be incorporated into practice.”

Hauswirth believes that all the aspects of the CXL procedure are within the scope of optometry in most states.

“The energy used is UV light, not a laser source,” he said. “In many surgical practices, much of the work is delegated to technicians, and there are ODs across the country that are performing the procedure already, albeit under the ‘guidance’ of an ophthalmologist.”

Hauswirth said that if CXL is determined to be within optometry’s scope, he does expect significant pushback from ophthalmology.

Bloomenstein said that the clinic he practices with is part of the CXL U.S. FDA clinical trials.

“I would love to perform this in our office when it gets approved for good,” he stated. “As long as the procedure stays epi-on, then I do not see why an OD couldn’t put a drop in an eye and then shine a light on the eye.”

He said that the financial aspect of offering the procedure has yet to be determined.

“However, optometrists see almost 90% of all vision exams and, thus, we see when the cornea is changing,” he said. “It is realistic, but how financially feasible and accessible will be the question.”

Optometrists will need appropriate diagnostic equipment as well as the cross-linking device and access to riboflavin, Morgenstern said.

Image: Hovanesian JA

“The best and simplest device for detection is the Pentacam by Oculus,” he continued. “A device like this is going to be standard optometric equipment in the next 5 to 10 years.”

Hovanesian said that a good way to become involved in CXL now is via the CXL USA website.

“It has a list of providers who are performing the procedure with established protocols,” he stated. “Reach out to who you know on that list or who is close to find an opportunity.”

For optometrists who will be comanaging the procedure, Morgenstern detailed the types of patients to refer.

“Look for anyone with a family history of keratoconus, because all family members should be screened, period,” he said. “Also, patients with irregular astigmatism, vision that’s not correctable to 20/20 or patients with progressive astigmatism or myopia that’s unexplainable. I would rather over-refer false positives than under-refer true negatives. Keratoconus is like glaucoma of the cornea – once you lose vision, you don’t really get it back.”

Hovanesian emphasized that the treatment be made available to those who need it.

“In Europe, it’s considered malpractice not to do CXL on a patient with progressive keratoconus,” he said. “Doctors should be familiar with CXL and be aware of where they can refer.”

Hovanesian continued: “You want to offer this to patients as an option. There is a clear benefit. CXL is clearly good medicine.” – by Chelsea Frajerman Pardes

• References:
• Arora R, et al. Cornea. 2013;32(10):1359-1364.
• Kymionis GD, et al. Cornea. 2014;33(10):1071-1079.
• Magli A, et al. Cornea. 2013;32(5):597-601.
• Salmon HA, et al. Eye. 2015; doi: 10.1038/eye.2015.151.
• Shalchi Z, et al. Eye. 2015;29(1):15-29.

• For more information:
• Marc R. Bloomenstein, OD, FAAO, is a member of the PCON Editorial Board and practices at the Schwartz Laser Eye Clinic. He can be reached at: drbloomenstein@schwartzlaser.
• David Cockrell, OD, is a former president of the American Optometric Association and is in practice in Oklahoma at the Cockrell Eyecare Center with his wife. He can be reached at: DCockrell@CockrellEyecare.com.
• Scott G. Hauswirth, OD, FAAO, is a PCON Editorial Board member who practices in Minnesota. He can be reached at sghauswirth@mneye.com.
• John A. Hovanesian, MD, FACS, is a PCON Editorial Board member and practices at Harvard Eye Associates. He can be reached at: drhovanesian@harvardeye.com.
• Andrew S. Morgenstern, OD, FAAO, is incoming president of the Optometric Council on Refractive Technology, chairman of the New Technology Committee for the American Optometric Association, an optometric subject matter expert/consultant for the DoD/VA Vision Center of Excellence and in practice at the Walter Reed National Military Medical Center in Bethesda, Md. The views discussed in this article are his own and do not reflect the opinion of the U.S. Government, Department of Defense, VA, Vision Center of Excellence or any other U.S. governmental agency or individual. He can be reached at: andrewmorgenstern@gmail.com.

Disclosures: Bloomenstein, Cockrell and Hauswirth report no relevant financial disclosures. Hovanesian is an investigator in the CXLUSA study. Morgenstern is part owner of Bruder Healthcare and an advisory board member for OcuSoft.