Corneal collagen cross-linking revolutionised treatment for keratoconus patients when it was introduced in the late 1990s, but it was a one-size-fits-all approach. Two decades later, capabilities have taken a significant leap, reducing risks and improving patient outcomes.
The primary goal of corneal collagen cross-linking (CXL) has always been to halt the progression of ectasia, with the most common progressive ectatic disease of the cornea being keratoconus. Widely recognised as a safe and effective procedure, most patients with keratoconus in Australia today are treated with CXL.
Dr Brendan Cronin at the Queensland Eye Institute (QEI) is an early adopter of a new CXL protocol (or technique), seizing the advantage it offers his keratoconus patients, who he describes as predominantly in their late teens or early 20s, and male.
For years, the epithelium-off (epi-off) CXL protocol has been the standard, but Cronin hopes more Australian corneal specialists in Australia will switch to the newer oxygen-enhanced epithelium-on (epi-on) CXL protocol, and adopt new topography-guided technology that can customise treatment to the shape of each individual cornea.
QEI was the first clinic in Australia to offer new topography-guided CXL treatment to keratoconus patients, which has not reached the tipping point of becoming mainstream – yet.
“We have now combined oxygen-enhanced epithelium-on CXL with our topography-guided system – the only one in Australia – for over a year. This means people can have their corneal topography and vision improved with faster recoveries, without even having their epithelium removed. It’s definitely the way forward in cross-linking,” Cronin says.
Cross linking timeline
Corneal collagen cross-linking was first developed in 1997 by a team at Dresden University of Technology in Germany, with the first clinical applications following in 1998.
Prior to its introduction, the conservative therapeutic approach for keratoconus involved fitting hard contact lenses to improve best corrected visual acuity. The only treatment that slowed progression was to control ocular allergies and stop eye rubbing. These measures still play a role in keratoconus management but don’t halt progression or improve corneal topography.
By contrast, CXL aimed to strengthen the cornea through a chemical reaction, a combination of riboflavin (vitamin B2) and ultraviolet (UV) light, to strengthen the crosslinks between the collagen fibres within the stromal layer.
Although several variations of CXL emerged, the most commonly used and studied was a traditional method called the Dresden epi-off technique, according to Keratoconus Australia. The technique, which gets its name from human studies of UV-induced CXL in Dresden in 2003, became the most widely adopted protocol, and remained so for 15 years, regarded by many as the gold standard.
In the Dresden protocol, the cornea is anesthetised, the epithelium is removed, and the corneal stroma is saturated with riboflavin for 30 minutes.
After the first 30 minutes, the irradiation of the cornea for another 30 minutes begins with UVA light of 3 mW/cm2 for a total of UVA fluence of 5.4 J/cm2. During this time, additional riboflavin is instilled to the corneal stroma every five minutes.
In the shadows of the popular Dresden protocol, scientific and technological advances helped create various modifications to cross-linking techniques, experimenting with key factors including riboflavin formulations, fluence rates, removing the epithelium or leaving it in place, and treatment time.
Researchers were aiming to create the same results of safety and efficacy in the clinical application of CXL in less time and with less patient discomfort.
Cronin says the epithelium is approximately 50 microns thick, and researchers found that soaking the corneal stroma in riboflavin and exposing it to UV light with the epithelium on proved difficult because 50 microns will absorb UV and it won’t go into the stroma.
“It’s like trying to get a suntan with sunscreen on. You need exposure to stronger UV light for a longer period of time,” he says, adding he now chills riboflavin to four degrees to help reduce the sunburn-like pain of CXL.
Further research led to the development of ‘accelerated’ CXL, which still involved removing the epithelium, but saturating the cornea in riboflavin for 10 minutes (a third of the time compared to the Dresden protocol) and exposing the cornea to an increased power of UV light (up to 30mW of power).
This accelerated technique led to another discovery.
“The CXL chemical reaction depends on oxygen. When the power, or strength, of UV light is increased, it uses up oxygen in the corneal stroma, preventing cross-linking from occurring. We need to pump in oxygen, to maintain an adequate level of oxygen,” Cronin says.
New and improved techniques
Each new discovery has nudged CXL protocol forward but a significant leap in technology has resulted in a new school of CXL that doesn’t require removing the epithelium.
The new techniques include oxygen-enhanced epi-on CXL, topography- guided epi-on CXL, and combined topography-guided transepithelial PRK and CXL.
Massachusetts-based Avedro, now owned by Glaukos, has been a frontrunner in this space. Its iLink V technology is the first and only FDA- approved corneal cross-linking procedure that slows or halts progressive keratoconus. Glaukos’ iLink V platform (previously known as Boost) allows surgeons to perform oxygen-enhanced epi-on CXL. Its Mosaic platform for topography-guided CXL is currently under limited commercial release, with QEI home to the only one in Australia.
Which treatment a patient receives depends on the individual.
“Oxygen-enhanced epi-on CXL technique uses oxygen to enhance the collagen cross-linking effect in the cornea for a safer procedure, a faster visual recovery and better patient outcomes,” Cronin explains.
“Topography-guided epi-on treatments plug in a map of the patient’s keratoconus, and the machine applies more UV light to steeper parts of the cornea, effectively customising CXL to each individual patient.”
The goal of the third treatment option, combined topography-guided transepithelial PRK and CXL, is to synergise the effects of the two treatments.
Although expensive, Cronin says no other ophthalmic instrumentation comes comes close to iLink V CXL technology.
“We are already performing the new oxygen-enhanced procedure but the Glaukos FDA study results should be released in the next 12 months on this protocol, seeing it go mainstream.”
Growing confidence
Ophthalmic surgeon Dr Nikhil Kumar has been performing oxygen-enhanced epi-on CXL using Glaukos’ iLink V platform at Vision Clinic Sydney for 12 months and commenced his first cases using this protocol at Chatswood Private Hospital in April this year.
Prior to adopting this newer cross-linking technique, he was treating keratoconus patients with the Dresden protocol for about 11 years, and then progressed to the ‘accelerated’ epi-off approach.
“From my perspective, the ideal solution is to be cross-linking without removing the epithelium, because removing the epithelium increases the risk of infection, inflammation, and corneal melt,” Kumar says.
“Those complications are significant and vision threatening if they occur. Despite performing the Dresden protocol – which involves removing the epithelium – for many years, I’ve always been concerned about the potential complications that can arise from removing the epithelium.”
Kumar is aware that for his patients, the act of cross-linking produces pain, and removing the epithelium only compounds that, but there hasn’t been a better alternative – until now.
He has conscientiously followed the evidence-based literature on cross- linking, and says a transepithelial approach – leaving the epithelium intact – trialled several years ago generated discussion but was ultimately flawed and didn’t appear to be equally as effective as the traditional epi-off method.
When he learned of the new oxygen-enhanced protocol, he says it intuitively made sense, and consulting with surgeons at the QEI, who had already adopted it, gave him confidence in its efficacy to the degree that he too invested to offer the procedure to his patients.
“My observations are anecdotal but the anterior stromal demarcation line – the measure of the depth of effect of cross-linking – is deeper than for those patients who had traditional epi-off cross-linking,” Kumar says, noting that patients undergoing the newer procedure also appear to be in less postoperative discomfort.
“It’s a revelation, and it fills me with confidence.”
He says leaving the epithelium on is a leap forward in a procedure that is aiming to improve visual function while being minimally invasive – and ultimately avoiding a corneal transplant – but scientific evaluation of the data is critical.
“Obtaining current evidence is essential. Glaukos is taking time to gather more data before introducing this new protocol to the wider market,” he says.
“It’s a significant leap in cross-linking, and it appears to achieve an excellent penetrative effect, to instil in me the confidence to offer it to patients.”
Although Kumar has not yet taken the next step of offering topography- guided CXL to his patients, he is considering it, and says he is excited for the future of cross-linking.
“If safe and effective, topography-guided cross-linking could become the gold standard of CXL for corneal ectasia; hopefully that can be achieved.”
Data is king
Melbourne cataract and anterior segment specialist Dr Alex Ioannidis divides his time between the Vision Eye Institute Clinics, Retina Specialists Victoria and the Mornington Specialist Eye Clinic.
He is aware of the oxygen-enhanced protocol, which he says looks promising as a potential future technique that may become mainstream once published data supports its use.
He currently performs the conventional Dresden epi-off protocol on his keratoconus patients.
“Oxygen-enhanced cross-linking is a very interesting concept, as it potentially enhances the chemical reaction between riboflavin and UV. I’m currently waiting for more data to be published on this treatment,” he says.
“This is a very exciting development in the field. Leaving the epithelium on also reduces the risk of infection in the cornea, and would significantly reduce post-treatment pain which typically occurs in the first 24-48 hours after epi-off cross-linking.”
“We are therefore potentially looking at a painless procedure with oxygen enhanced epi-on treatments.”
“The reason we are currently removing the epithelium is that riboflavin poorly penetrates this natural barrier, and the effect of the treatment has been limited.”
Another limiting factor to performing cross-linking has been severe thinning of the cornea. In the past cross-linking wasn’t recommended for patients if their cornea was too thin, generally less than 400 microns as there was a concern about possible endothelial damage.
“Hence it is important to diagnose and treat patients before the disease progresses to a very advanced stage,” Ioannidis says.
Surgeons are now dealing with keratoconus in its earlier stages because there is more awareness from the public, optometrists and ophthalmologists. Ioannidis has had to perform CXL on a 14-year-old patient, and that patient five years later has stable vision and no further progression detectable on topography.
“The fact we now have a treatment – cross-linking – has improved awareness and a sense of clinical suspicion when patients present to their optometrist with changing vision,” he says.
“Optometrists are getting better at detecting and referring cases to ophthalmologists because they know that a safe and proven treatment exists for this condition.”
It is also a more accessible procedure after a Medicare Benefits Schedule item was introduced in May 2018, providing a significant rebate, Ioannidis says.
Far and fewer cornea transplants
Vast improvement in CXL technology and better patient outcomes is having a flow on effect on corneal transplants.
In the February issue of Insight, director of the Lions Eye Donation Service Dr Graeme Pollock said keratoconus used to be the most common reason for requiring a donor cornea in Australia – but now it’s Fuch’s dystrophy.
Cronin used to preform two corneal grafts or transplants for keratoconus every week – now he performs just a few a year.
“It’s really rare to graft someone for keratoconus. This is partly due to better CXL results but also because optometrists have invested more heavily in detecting keratoconus earlier, resulting in patients undergoing CXL in their late teens and in early 20s,” Cronin says.
“The contact lenses we use to treat keratoconus have also improved out of sight, utilising today’s 3D scan technology to create custom-made contact lenses,” he says.
More reading
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Advances in treating corneal disease – Feature
QEI clinic unveils new cross-linking technology for corneal procedure
