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Evolving cross-linking techniques treating wider range of keratoconus patients
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Corneal cross-linking, or CXL, is enjoying its 10th anniversary of broad clinical use since the pioneering work of Seiler and Mrochen. In most parts of the world, CXL is approved, available and standard of care for treating the patient with keratoconus. In the U.S., CXL is still not approved by the U.S. Food and Drug Administration, but many of us are hoping this will change in 2015 if Avedro is successful in achieving approval for the so-called standard epithelium-off Dresden protocol.
The world consensus is that CXL is the treatment of choice for mild to moderate keratoconus with documented progression. Still controversial, but gaining many advocates worldwide, is the position that every patient with even the earliest findings of keratoconus should be offered CXL.
In our practice at Minnesota Eye Consultants with four cornea-trained specialists, we have participated in CXL clinical trials for nearly 8 years, starting with the classical Dresden protocol in studies sponsored by Peschke and Topcon and evolving to an investigator-sponsored clinical trial using a proprietary epithelium-on protocol with CXLUSA for just over 2 years.
With the epithelium-on technique, we have been impressed enough with the safety and efficacy to now recommend the procedure to any patient over the age of 10 years with definite topographic changes consistent with keratoconus. We do not believe it is necessary to wait for documented progression but instead offer this alternative to all patients with documented keratoconus. A few patients still elect to be carefully monitored for progression before being treated, and we always offer this alternative, but most select treatment at even the earliest stages of keratoconus. If any of us had a child or close relative diagnosed with keratoconus, we would all treat immediately.
The goal, of course, is to prevent progression of keratoconus. In some patients, we achieve some corneal flattening and improved topography, but this cannot be predicted or relied upon. When caught early, with only topographic changes, most patients with keratoconus still correct to 20/25 or better with spectacles or a soft contact lens. All of us who treat keratoconus patients on a regular basis would love to arrest the disease at that stage. I personally always recommend bilateral treatment in these early-stage patients, even when there are minimal findings in the least affected eye.
Our current treatment protocol using an epithelium-on approach allows bilateral treatment and has low risk with rapid visual recovery. Those patients who progress despite therapy can be re-treated. There will be some treatment failures, and if progression is documented after three repeated epithelium-on CXL, I would offer the patient an epithelium-off treatment, which can generate a more significant CXL response. To date, I have not yet experienced this situation.
Consensus is growing that we should treat the patient as early as possible to arrest the disease and maintain good vision. Today in the U.S., about 20% of corneal transplants, or approximately 10,000 per year, are performed for keratoconus so advanced that scarring is present or vision cannot be rehabilitated with any contact lens. I anticipate that in 20 years, thanks to CXL, a keratoplasty for keratoconus will be a historical footnote. So, while techniques will continue to evolve and become less invasive, CXL is becoming the treatment of choice for mild to moderate keratoconus as soon as the diagnosis is made.
Because many, if not most, of these keratoconus patients in the U.S. are contact lens wearers under the care of an optometrist, this message needs to be shared with our OD colleagues through appropriate education. Cooperative management of these patients, most of whom will return to the OD for spectacle or contact lens care and long-term follow-up, is a critical need and will encourage referral.
The next challenge is what to do with the patient with severe keratoconus. We have many of these to treat because CXL was not available when they were younger and at an earlier stage of disease. These patients usually have corneas with maximum keratometry readings higher than 60 D, significant irregular and regular astigmatism of more than 4 D, and a central corneal thickness less than 400 µm. Most have central corneal striae and, in many cases, frank central corneal scars. Classical CXL in these patients puts the patient at risk for endothelial damage from the intense ultraviolet light with corneal decompensation or progressive central opacity.
Several approaches are being investigated, including swelling the cornea with hypotonic solutions and using a soft contact lens to increase the distance from the surface of the contact to the endothelium. In our practice, we have found a combination of epithelium-on CXL and pulsed ultraviolet light application has allowed us to treat many of these patients safely. In some severe cases, we are treating the patient initially with conductive keratoplasty (CK), either alone or in combination with Intacs (Addition Technology). These treatments, based on our experience, are best done 1 day to 1 month before the CXL treatment and not consecutively on the same day. The ideal delay between the treatments is still being investigated, and there is much to learn, but we are impressed that with a combination of CK, Intacs and epithelium-on CXL with pulsed UV light delivery that we can salvage many severe keratoconus patients and help them avoid a deep lamellar or penetrating keratoplasty. We have also found that treatment 12 months later with excimer laser phototherapeutic keratectomy can further enhance visual function.
Thus, many of our patients with more advanced disease now undergo staged procedures, starting with CK with or without Intacs, following a few days to a few weeks later with epithelium-on pulsed light CXL and finishing a year later with a PTK/PRK. Some of these patients still require a keratoplasty, but many achieve significant improvement in their uncorrected, spectacle corrected and contact lens corrected vision.
Allowing a patient who could only be corrected with a rigid gas permeable or scleral contact lens to see well with a soft lens or even spectacles is a life-changing experience for an advanced keratoconus patients. In some moderate keratoconus patients, we have even achieved functional spectacle and contact lens independent vision. Thus, we are evolving from a therapeutic CXL in which the goal is to simply stabilize the cornea to a refractive CXL in which we can also enhance visual function and reduce dependence on glasses and contact lenses.
The CXL keratoconus treatment evolution is still in its infancy but is exciting, holding much promise for not only the keratoconus patient, but perhaps in the future also the patient with a simple refractive error who desires a safe, effective and minimally invasive treatment.