US corneal cross-linking specialists aim to bridge ‘the innovation gap’ with Europe
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Since its approval in 2016, corneal cross-linking has been gradually gaining popularity in the U.S. Reimbursement issues have been largely overcome, and the procedure is now covered by most insurance companies.
Currently, the FDA allows only the standard epi-off iLink procedure (Glaukos) with 30 minutes of riboflavin instillation (Photrexa Viscous, 0.146% riboflavin 5’-phosphate in 20% dextran ophthalmic solution) and 30 minutes of 3 mW/cm² UV irradiation, the traditional Dresden protocol. However, U.S. ophthalmologists are looking forward to bridging the gap with Europe, where CXL has continued to evolve.
Source: Ann Ostrovsky, MD
“We are looking forward to accelerated protocols (ACXL) because the standard procedure takes a long time, and if the same safety and efficacy can be achieved with a shorter treatment time, that’s what all of us, doctors and patients, will prefer,” OSN Cataract Surgery Board Member Sumit “Sam” Garg, MD, said.
U.S. ophthalmologists are also looking forward to the approval of an “epi-on” technique that is going to be “a huge step forward,” Garg said, and to being actively involved in studying and experiencing oxygen supplementation, pulsed light and many potential variations of the CXL procedure.
“CXL has been an interesting journey for us so far, also in pediatric cases,” Ann Ostrovsky, MD, said. “For the time being, we don’t have a lot of choices because our machines are locked, and even off-label procedures are confined.”
The approval of newer protocols will facilitate the adoption of a case-by-case approach, which is important in patients with keratoconus and even more so in the younger population and in patients with Down syndrome, she said.
Study looks at 9 mW, epi-off ACXL
Eye and Vision recently published a study on the long-term outcomes of accelerated 9 mW corneal cross-linking for early progressive keratoconus. The study was co-authored by specialists in the Siena, Zurich and Dresden groups, European leaders in CXL since the early days.
“In this study, the 9 mW/5.4J/cm² ACXL protocol, that we also named Dresden accelerated protocol, proved to have all the characteristics to become the new gold standard for the management of early progressive corneal ectasia,” Cosimo Mazzotta, MD, PhD, said.
In a case series of 156 keratoconic eyes of 88 consecutive patients with 5 years of follow-up, one of the longest currently reported internationally, this protocol showed statistically significant and stable improvements of uncorrected and corrected distance visual acuity, corneal curvature and corneal higher-order aberrations.
Accelerated protocols are widely used outside of the U.S. and have been investigated in studies, but few of these studies have previously gone beyond a short follow-up.
“For the first time we can provide the definitive evidence, and this is very liberating for all those who have already gone beyond the classic Dresden protocol but did not have the support of long-term data. We used to talk about our shift to accelerated protocols off the record — now we can do it openly,” Mazzotta said.
Comparable efficacy, shorter time, fewer side effects
Accelerating, Mazzotta said, does not mean crashing, and 9 mW is a moderate choice that maintains the efficacy of the 3 mW Dresden protocol but shortens treatment time, improving patient comfort, with the further advantages of less haze and faster visual rehabilitation.
“Shorter UV irradiation on the stroma leads to less inflammation and less activation of fibrotic processes, one of the caveats of the traditional approach. While persistent haze has been reported in 8% to 16% of cases with the Dresden protocol, we had no case at all with the 9 mW,” he said.
All treatments were performed using the international configuration of the Glaukos KXL system under topical anesthesia. Following epithelium removal, dextran-free riboflavin isotonic solution (VibeX Rapid, Glaukos) was instilled for 10minutes. Ultraviolet A irradiation was performed for 10minutes at 9 mW/cm² of UVA power and standard fluence of 5.4J/cm².
“Forty of our patients were pediatric, aged between 14 and 18 years, and they were also stable, with no progression in the 5 years of follow-up,” Mazzotta said.
Anterior segment OCT (AS-OCT) evaluation of the demarcation line at 1 month showed a depth of 332.6 ± 23.6 µm, similar to the depth obtained using the standard 3 mW.
“As shown in a milestone laboratory study by Krueger and Spoerl, high irradiance with equivalent energy exposure has comparable efficacy to standard irradiance in stiffening corneal collagen. This study opened the way to the clinical application of the accelerated protocols,” Mazzotta said.
More extreme acceleration, as shown in laboratory studies, may lead to insufficient oxygen diffusion with consequent decrease of the stiffening effect, visible on AS-OCT as a shallower demarcation line.
“However, the 9 mW/5.4 J/cm² was estimated to have a sufficient oxygen kinetic in the ACXL procedures panorama, definitely ensuring efficacious long-term clinical results,” Mazzotta said.
Supplemental oxygen, customized CXL and epi-on
“Oxygen is the bottleneck of cross-linking,” Theo G. Seiler, MD, said.
In experimental studies, he identified the parameters of a numerical model on oxygen consumption and diffusion and showed that supplemental oxygen increases the oxygen availability during the procedure, allowing a potentially more efficient cross-linking.
Because the epithelium acts as a diffusion barrier for oxygen and consumes additionally a large quantity of oxygen, almost equal to the stroma and endothelium together, oxygen supplementation may be key in addressing the limitations of epi-on CXL.
“Transepithelial cross-linking has remarkable advantages, such as less pain, less inflammation, less haze and faster visual recovery, but if you preserve the epithelium, oxygen diffusion is low in the stroma under atmospheric oxygen concentrations. With supplemental oxygen, the transepithelial approach may become the next gold standard,” Seiler said.
A multicenter, randomized phase 3 pivotal trial evaluated the safety and efficacy of the iLink epi-on procedure with supplemental oxygen. The study has met the primary efficacy endpoint, showing improvement in maximum corneal curvature at 6 months.
Seiler is also involved in a multicenter study analyzing different approaches of tomography-guided customized CXL. Based on the observation that keratoconus goes along with a focal weakening rather than a uniform weakening of the cornea, individual CXL profiles are created in which maximum fluence is focused on the weak area and progressively tapered toward the peripheral non-ectatic region.
“Our study involves multiple sites where we analyze epi-on customized CXL with supplementary oxygen with different irradiation and centration patterns, and the goal is to compare and reach consensus on what protocol is the most efficient,” Seiler said.
Previous studies on epi-off customized CXL have shown improved flattening and regularization of the cornea. Recent publications on customized CXL using a transepithelial approach with intraoperative supplemental oxygen resulted in stabilized keratoconus with the same efficiency as the original Dresden protocol.
“Since then, and since Glaukos is running the approval trial for the transepithelial approach, the whole idea of customization has moved to a transepithelial level in combination with oxygen supplementation. However, in Switzerland, we are also working on the combination of epi-off customized CXL with supplemental oxygen,” Seiler said.
Cross-linking at the slit lamp
Farhad Hafezi, MD, PhD, FARVO, currently performs most of his cross-linking procedures at the slit lamp using the C-Eye device (EMAGine), which can be fitted on a wide range of Haag-Streit and Zeiss slit lamps. The C-Eye can deliver both continuous and pulsed UVA irradiation, allowing for various epi-off and epi-on protocols.
The advantage of performing CXL at the slit lamp is that the procedure is taken out of the operating room and performed in the office, with a significant reduction of costs. The risk for infection is next to zero because the UVA light sterilizes the cornea.
“With every CXL procedure, you don’t only stiffen the cornea, but kill everything that is on the surface, so every keratoconus treatment gives you a sterile cornea at the end,” Hafezi said.
In addition, CXL at the slit lamp is more widely accessible, also in areas of the world where an OR is not available.
“The slit lamp allows for much faster treatment, is ergonomically better for the surgeon, and you can see what you are doing. Ophthalmologists may not be surgeons, but they are all used to the slit lamp,” Hafezi said.
The patient sits on a reclining chair during riboflavin instillation and then sits on a comfortable chair with arm rests at the slit lamp for irradiation. A red fixation light is used to have the patient look at the fixation target with the untreated eye.
“I can look through the slit lamp during the entire procedure, so I have full control of what I am doing,” Hafezi said.
For epi-off procedures, his standard protocol is 9 mW for 10 minutes.
“In some cases, for example a teenager where the disease is very aggressive, we use a 10 J/cm2 approach, 18 mW setting for 9 minutes, which gives even more strengthening. But on average, 9 mW/cm2 for 10 minutes is doing an awesome job and is very good biomechanically,” he said.
Epithelial debridement is also performed at the slit lamp. A cotton swab soaked in ethanol 40% is tapped on the cornea for 70 seconds, and then the epithelium is removed.
Epi-on procedures are more challenging but are the end goal also at the slit lamp. Also, Hafezi recently published a “sub400” protocol for epi-off CXL in ultrathin corneas, which is currently integrated in the C-Eye.
“You need to ensure oxygen availability within the stroma, and you can do this by using supplemental oxygen on the surface but also by pulsing the light, increasing the fluence by 30% and accelerating gently. Mazzotta has shown this very nicely. If you play on these parameters to increase oxygen availability, you don’t need additional oxygen. Our ultimate goal is to do all thicknesses at the slit lamp with no pain, no infection, epi-on,” Hafezi said.
The C-Eye device is not currently approved for use in the U.S.
More opportunities with epi-on
Mazzotta’s nomogram M for transepithelial CXL is currently integrated in the C-Eye. It entailed enhanced fluence pulsed light iontophoresis initially, but the technique can be easily used also with chemically enhanced higher concentrated riboflavin solutions.
“I believe that iontophoresis protocol can be further implemented, and in the meantime, I’m doing a new protocol with 10 minutes of imbibition by enhanced highly concentrated riboflavin solutions. Then I irradiate for 12.58 minutes using 18 mW UVA power, 7 J fluence and pulsed light using the same irradiation parameter of the enhanced fluence pulsed light iontophoresis. There is no need for additional oxygen working at 18 mW, while oxygen supplementation is a must with 30 mW UVA power,” Mazzotta said.
Candidates for transepithelial CXL are, in his view, patients older than 21 years of age or with poor compliance for an epi-off procedure.
“I also treat epi-on in the better eye of some patients who are undergoing epi-off CXL in the in the most severely affected eye. The natural history of keratoconus tells us that the better eye progresses less, so we can use the less aggressive treatment. I often do both eyes on the same day, the worse eye epi-off and the better eye epi-on,” he said.
With this protocol, the epi-on procedure can be used also prophylactically because it is noninvasive, has no complications, in his opinion, and can be performed in outpatient mode, even at the slit lamp.
“If one eye is progressing and the other one is stable, I offer this option to my patients. Not only is it likely to prevent progression, but it does not preclude an epi-off procedure later on, if needed,” Mazzotta said.
“We know that keratoconus, the way it manifests, is not uniform. Some patients are high risk for progression and some progress more slowly, and in these patients, you might want to do an epi-on treatment,” Garg said. “An accelerated epi-on procedure is what we should be aiming at, eventually.”
“We are looking forward to accelerated protocols, to epi-on and to see if and how we should deliver supplemental oxygen. The other interesting twist would be pulsed light, which has also been explored but has not been approved here,” he said.
Photosensitizers for epi-on and thin corneas
Photosensitizers have also evolved to adapt to the changing scenario of CXL, particularly with regard to transepithelial techniques and thin corneas.
“A big improvement was achieved by changing the chromophore carrier from dextran to HPMC, allowing a reduction of the imbibition time from 30 to 10 minutes without inducing corneal thinning. But as the classic solutions with dextran or HPMC do not penetrate the epithelium properly, we needed something to disrupt the tight junctions of the epithelium,” Isaak Fischinger, MD, said.
This was achieved first with Ricrolin TE (Sooft Italia), containing riboflavin 0.1% with the addition of dextran, trometamol and ethylenediaminetetraacetic acid, and with ParaCel (Glaukos), a two-part formulation.
“Part 1 of the kit contains 0.25% riboflavin with HPMC, benzalkonium chloride, EDTA and trometamol, a combination that allows a fast penetration and diffusion into the corneal stroma. You apply this for 4 minutes and then switch to part 2, which is 0.22% riboflavin in BSS,” he said.
For thin corneas, hypo-osmolar solutions were developed, with a swelling effect. The problem is that swelling is unpredictable, Fischinger said, with some corneas swelling just a tiny bit and some corneas by as much as 30%.
“An alternative to modifying stromal thickness or riboflavin concentration is the ‘sub400’ individualized fluence CXL protocol, recently published by Hafezi and co-authors. By modifying UV irradiation time according to the patient’s corneal thickness, the depth of CXL is kept at a safe distance from the endothelium,” Fischinger said.
The study confirmed that CXL with individualized fluence was able to halt keratoconus progression in corneas as thin as 214 µm, with 90% success at 1 year.
Pediatric CXL
Pediatric CXL is approved in the U.S. for children older than 14 years of age.
“I do not know the reasons for this specific age cutoff, but this was the age limit for inclusion for the FDA clinical trial,” Ostrovsky said.
On the other hand, keratoconus does affect children younger than 14 years and tends to be more aggressive when the onset is so early.
“Younger children tend to present with more advanced stage of the disease. They may have a genetic predisposition and strong family history of keratoconus, and some of them have associated conditions that are considered risk factors, including collagen vascular diseases, Down syndrome, Leber congenital amaurosis, blepharitis and allergic syndromes such as vernal conjunctivitis. If progressive disease is not addressed early on, corneal deformation can progress very quickly and necessitate corneal transplantation for visual rehabilitation. Corneal transplantation for this indication has been shown to have higher graft failure rate and worse prognosis in children compared to adults,” she said.
Ostrovsky strongly believes that younger children should have access to this treatment, with the caveat that every pediatric case must be evaluated on a case-by-case basis. Teenagers, who typically have a familial, aggressive disease, are better treated epi-off, but in younger children and in those with Down syndrome, the standard approach may not be feasible.
“Many need general anesthesia, may not be cooperative with postoperative drop administration, and can rub their eyes due to postoperative discomfort, to the point that intervention may cause more harm than benefit,” Ostrovsky said. “We may attempt an epi-off procedure if necessary but must be clear with the families that it is off label. In some cases, it may be even better not to intervene.”
To prevent eye rubbing in children, treating allergic disease and symptomatic blepharitis is important. Educating parents is also critical to creating behavior modifications.
“Many parents don’t know how detrimental eye rubbing can be for the eye,” Ostrovsky said. “I also work with parents to practice eye drop administration before any surgical procedure. I ask them to administer artificial tears regularly until the child feels comfortable and familiar with it and ask them to have the children practice wearing goggles at home in preparation for surgery. As they get used to the goggles, it will be easier to wear them to protect their eyes in the early postoperative period and can hopefully discourage eye rubbing.”
As a physician in the U.S., she said she is grateful to finally be able to offer CXL to her patients but hopes that the current limitations will soon be overcome.
“Having control of each of the variables of the CXL procedure gives great breadth to the types of treatments one could provide and greatly expands the pool of patients who may benefit from the procedure,” she said. “I believe bridging the innovation gap with Europe is essential for the United States and look forward to the results of upcoming trials that may bring us closer in practice with our European colleagues.”
- References:
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- Hafezi F, et al. Am J Ophthalmol. 2021;doi:10.1016/j.ajo.2020.12.011.
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- Mazzotta C, et al. Eye Vis (Lond). 2021;doi:10.1186/s40662-021-00240-8.
- Mazzotta C, et al. J Cataract Refract Surg. 2020;doi:10.1097/j.jcrs.0000000000000347.
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- Seiler TG, et al. Invest Ophthalmol Vis Sci. 2017;doi:10.1167/iovs.17-22426.
- For more information:
- Isaak Fischinger, MD, can be reached at Augentagesklinik Spreebogen, Alt-Moabit 101b, 10559 Berlin, Germany; email: isaak.fischinger@hotmail.com.
- Sumit “Sam” Garg, MD, can be reached at University of California, Irvine, 850 Health Sciences Road, Irvine, CA, 92697-4375; email: gargs@uci.edu.
- Farhad Hafezi, MD, PhD, FARVO, can be reached at ELZA Eye Institute, Webereistrasse 2, 8953 Dietikon/Zurich, Switzerland; email: farhad@hafezi.ch.
- Cosimo Mazzotta, MD, PhD, can be reached at Departmental Ophthalmology Unit, Alta Val d’ Elsa Hospital, Campostaggia, Siena, and Siena Cross-Linking & Refractive Surgery Center, Via Sandro Pertini 7, Monteriggioni 53035, Siena, Italy; email: cgmazzotta@libero.it.
- Ann Ostrovsky, MD, can be reached at NYU Langone Health, Department of Ophthalmology, 222 E. 41st St., 4th Floor, New York, NY 10017; email: ann.ostrovsky@nyulangone.org.
- Theo G. Seiler, MD, can be reached at Insitut für Refraktive und Ophthalmo-Chirurgie (IROC), Stockerstrasse 37, 8002 Zürich, Switzerland; email: theo@seiler.tv.
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