February 14, 2019
11 min read

Corneal cross-linking for keratoconus an option for patients of all ages

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Corneal cross-linking should be considered as a viable treatment for patients of all ages with keratoconus due to its ability to halt or slow progression of the disease, even before a corneal transplant in most cases.

Keratoconus is a progressive disease that causes corneal thinning and distortion that can lead to vision loss if untreated. It tends to be more progressive in younger patients but slows down as patients age. If caught early, treatment can halt progression of the disease, OSN Cornea/External Disease Board Member Kenneth A. Beckman, MD, FACS, said.

Corneal cross-linking is usually the best treatment for patients with keratoconus if they are viable candidates for the procedure. Cross-linking stops progression of keratoconus and has the capability to flatten the cornea, reversing some of the damage already caused by the disease, Beckman said.

Kenneth A. Beckman, MD, FACS
Along with cost, education is another hurdle that needs to be overcome to spread the benefits of cross-linking and scleral lenses for the treatment of keratoconus, according to Kenneth A. Beckman, MD, FACS.

Source: Kenneth A. Beckman, MD, FACS

Delaying treatment, as many ophthalmologists and optometrists suggested patients do in the past, is no longer the best course of action. It is important to halt progression of the disease as soon as possible, before it begins to affect a patient’s vision, Beckman said. Because of advancements in scleral lens technology, patients who undergo cross-linking and are then properly fit with scleral lenses can experience improved vision and corneal remodeling.

“We’re informing the community that patients detected with early keratoconus are the best patients for corneal cross-linking. You shouldn’t sit on them anymore. We’re starting to see optometrists and general ophthalmologists refer patients who still have excellent vision for cross-linking. Cross-linking is at its best in these early patients because it stops progression. It stiffens up the cornea and stops it from getting worse,” he said.

Prior treatment protocol suggested patients with more advanced keratoconus undergo a corneal transplant procedure when their spectacle corrected vision began to decline. While a corneal transplant for keratoconus can potentially result in improved best corrected visual acuity, the rehabilitation after a transplant can take from months to more than a year as sutures are slowly removed. Transplants also require continued care and the use of long-term topical steroids, which can increase risk for cataract formation and glaucoma, OSN Technology Section Editor William B. Trattler, MD, said.

“Corneal transplant surgery treats keratoconus, but it does not prevent keratoconus. Even if they have a transplant, keratoconus will continue to be present in the cornea. The cornea can continue to stretch, and keratoconus can reoccur,” Trattler said.


A corneal transplant treats the central part of the cornea, but keratoconus remains in the periphery and may spread and redevelop in the future, according to the National Keratoconus Foundation.

William B. Trattler, MD
William B. Trattler

Cross-linking indications

Corneal cross-linking works by infusing and saturating the corneal stroma with riboflavin and using ultraviolet light to initiate a cross-linking reaction within the cornea. The process strengthens and stiffens the cornea and can slow or halt the progression of keratoconus.

Corneal cross-linking, approved by the FDA in 2016, is indicated for progressive keratoconus in adults and post-LASIK ectasia. It is not approved for stable keratoconus, according to a 2018 study in Cornea.

The only FDA-approved system is from Avedro. An off-label use of the system needs to be noted in an informed consent document and the patient’s medical record, according to the American Academy of Ophthalmology.

Corneal cross-linking does not preclude a patient from undergoing a corneal transplant later in life. Cross-linking can stabilize the cornea in a patient with keratoconus in preparation for a transplant later in life, OSN Pediatrics/Strabismus Board Member Erin D. Stahl, MD, said.

“There is a theoretical benefit to stabilizing the future graft-host junction in the peripheral cornea of young people with keratoconus in preparation for future transplant stability. These patients may have less astigmatism and peripheral changes after transplant,” Stahl said.

Erin D. Stahl, MD
Erin D. Stahl

In the past, optometrists and general ophthalmologists who detected keratoconus in a young patient with 20/20 vision would not set a course of treatment right away. The typical treatment involved monitoring the patient closely for several years until vision began to decline and then setting a course of treatment, which was usually a corneal transplant, Beckman said.

“These patients would be followed and eventually their vision would decrease to 20/25 and eventually 20/30, and then they’d need hard contacts. Before you knew it, they’d be 30 years old and in need of a corneal transplant. We want to avoid that,” Beckman said.

Treat early

Undergoing treatment as soon as possible can halt progression of keratoconus sooner. In a prospective, double-center, observational clinical study published in the Journal of Refractive Surgery, 25% of patients who waited a mean interval of 84.8 days for treatment showed evidence of disease progression. The patients experienced a change in maximum corneal curvature within the cone area of at least 1 D on a tangential map.

According to the study, patients who experienced disease progression during the waiting period were younger, with a mean age of 22.2 years, compared with those who did not show evidence of progression, with a mean age of 25.4 years. Patients younger than 18 years had a significantly greater incidence of progression during the waiting period.


Long-term cross-linking benefits

Corneal cross-linking should be discussed and considered for every patient with keratoconus, according to Alanna Nattis, MD, FAAO, of Lindenhurst Eye Physicians and Surgeons in New York. However, a surgeon must determine if a patient is a viable candidate to undergo the procedure.

According to a study in Cornea, patients with herpetic keratitis, significant corneal scarring, neurotrophic keratopathy, autoimmune disorders, pregnancy, and severe dry eye may not be good candidates.

“If a patient has a very thin cornea, corneal scarring, a history of herpetic disease or a history of poor epithelial healing, they’re not a candidate for cross-linking. If so and they need to have a transplant, they’re probably better with just that,” Nattis said.

Alanna Nattis, MD, FAAO
Alanna Nattis

On the other hand, patients with a history of herpes simplex virus or neurotrophic keratopathy are not ideal candidates for a corneal transplant either, as graft survival is significantly reduced with these preoperative conditions, Trattler said.

Younger patients can benefit from delaying corneal transplantation and undergoing cross-linking to see if corneal remodeling is possible. Cross-linking combined with scleral contact lenses could lead to improved visual acuity for a longer period of time, Parag A. Majmudar, MD, president and chief medical officer of Chicago Cornea Consultants, said.

Treating keratoconus with cross-linking at the earliest possible diagnosis, provided that the condition is progressing or is likely to progress, should be the prescribed course of action for these patients. There is no reason to wait until keratoconus reaches an advanced state, as early cross-linking can lead to corneal stabilization and allow for maintenance of good corrected or even uncorrected visual acuity, he said.

Cross-linking candidates

Parag A. Majmudar, MD
Parag A. Majmudar

Cross-linking can be safely performed in patients with advanced keratoconus if the minimum corneal thickness parameters are respected. Additionally, advances in scleral lens technology have expanded treatment opportunities for advanced keratoconus patients, Majmudar said.

“Once the patient becomes a graft candidate, the corneal shape has likely deteriorated to the point where contact lens fitting is not practical. In that setting, corneal cross-linking is not likely to be of much value, as maintaining corneal shape at that degree of advanced keratoconus would not allow the patient functional vision,” he said.

A patient with a very thin cornea or a dense central scar should forgo cross-linking in favor of a corneal transplant. If these conditions are met, cross-linking has several theoretical benefits for younger keratoconus patients, Stahl said.

“There is often much better vision than expected with the combination of corneal remodeling after corneal cross-linking and scleral contact lenses. In these cases, the patients can avoid a transplant,” she said.


Age does not matter

Older patients can also benefit from cross-linking despite the myth that all keratoconus stops progressing at a certain age, Majmudar said.

While most patients do experience a slowdown of their keratoconus progression in their mid-40s and 50s, progression has been documented in patients older than 50 years of age, he said.

“The decision to perform cross-linking should be based on individual circumstances. Furthermore, if cross-linking can achieve corneal remodeling and improve the corneal shape, it can benefit the older patient, especially if cross-linking is performed well in advance of cataract surgery as it may allow for improved keratometry readings and better post-cataract surgery visual acuity,” he said.

Scleral lens technology

Older patients can improve after cross-linking if they are also fitted properly with a good scleral lens. The advancements in scleral lens technology have led to improvements in visual acuity after cross-linking, Trattler said.

The last 5 to 7 years have resulted in a much broader growth of scleral lens technology. If fitted correctly, even patients with the most irregular-shaped corneas can experience 20/25 or even 20/20 best corrected vision. Patients who have not benefited from traditional rigid gas permeable lenses could experience better outcomes if properly fitted with scleral lenses, he said.

“It’s a revolutionary technology for patients with keratoconus,” Trattler said.

According to a 2015 study in Clinical Ophthalmology, scleral lenses are either air ventilated or fluid ventilated to provide oxygen to the ocular surface without compromising physiology. The lenses only have bearing on the sclera, with the diameter of the lens being 15 mm or greater.

Scleral contact lenses can offer a stable platform for adjustment of design to improve visual quality. According to a 2017 Journal of Ophthalmology study, patients with keratoconus fitted with scleral lenses showed an 88% improvement in visual acuity. In the study, visual acuity progressed from 0.68 logMAR to 0.15 logMAR 6 months after proper scleral lens fitting.

Scleral lens fitting

To be effective, patients need to be fitted for scleral lenses by an experienced scleral lens fitter, Trattler said.

“The fitting is definitely challenging. There are going to be differences in the ability of scleral lens fitters in providing this technology to patients with moderate to advanced keratoconus. The ones who are more experienced can be very successful in providing scleral lenses to very irregular-shaped corneas. They can even utilize custom molds of the eyes,” Trattler said.

Fitting of a scleral lens becomes more complicated when keratoconus is more advanced or in patients with an irregularly shaped sclera, such as when a pterygium is present. A 2015 Clinical Ophthalmology study found that unlike rigid gas permeable lenses, scleral lens fitting is not aided by corneal topography.


Because the scleral lens rests on the sclera, according to the study, proper alignment is key for obtaining a proper fitting lens.

Scleral lens fitters have access to new technology to help fit lenses to patients. Trattler said the EyePrintPRO (EyePrint Prosthetics) is a new piece of technology that creates custom prosthetic scleral shells by using an impression molding process for creating the lenses. The program matches the contours of the eye in patients who cannot successfully fit in traditional scleral lenses.

EyePrint technicians use a high-tech computerized topographical scanner to capture the precise curvatures of the patient’s entire ocular surface and create an impression of the cornea and sclera. The impression is used to create a custom-fitted prosthetic scleral cover shell. The BostonSight PROSE is another technology that is a custom-designed scleral lens.

Cost and insurance

The cost of cross-linking and scleral lenses can come into consideration when patients are deciding on a course of treatment, Stahl said.

“There is a financial aspect for cross-linking. It can be expensive for the patient and often is not covered by insurance. In some cases, a transplant may be the only choice if the patient cannot afford the cost of cross-linking. As we get wider and more robust insurance coverage for corneal cross-linking, I believe that the appropriate cases will be treated prior to transplant,” she said.

The cost is an “elephant in the room” and has been a barrier for even the most appropriate cross-linking eligible patients. Cross-linking has traditionally not been covered by insurance, and when the price of riboflavin increased, it became an expensive procedure, Beckman said.

A 2016 letter to the editor in the Journal of Refractive Surgery estimated corneal cross-linking costs patients a mean total of $1,929.47 per eye.

Insurance companies are beginning to cover the procedure, and CMS issued product-specific J codes for Photrexa formulation (riboflavin 5’-phosphate ophthalmic solution) and Photrexa Viscous (riboflavin 5’-phosphate in 20% dextran ophthalmic solution), the only FDA-approved drugs for use in cross-linking. This is helping to make the procedure more accessible for patients, Beckman said.

The need to educate

Along with cost, education is another hurdle that needs to be overcome to spread the benefits of cross-linking and scleral lenses for the treatment of keratoconus, Beckman said.

“Many optometrists don’t have topography, so they may not even pick it up. If you have a patient who has a lot of astigmatism or it’s irregular or progressing, you should think about sending them for topography. By the time you see clinical signs on the cornea, such as thinning or the striae on the cornea, they’re going to be advanced,” Beckman said.


It can be a delicate issue for surgeons who do not have access to cross-linking when faced with a patient who would benefit from the procedure. Losing a patient or being bypassed on a referral network is concerning, but referring the patient to another surgeon who has access to the technology is the correct move, Beckman said.

While a young patient undergoing a corneal transplant and wearing a contact lens could improve their vision to 20/20, they may have also benefited from attempting cross-linking as a first step, Beckman said.

“There is a good chance that if they underwent cross-linking and were put into a scleral lens, they would have had the same vision as a corneal transplant, but their eye would still have its natural integrity,” he said.

“Even a more advanced patient, that appears to be at transplant level, may actually be a good candidate for cross-linking first, if their cornea is still optically clear. Cross-linking may stabilize their cornea, and then a scleral contact may allow excellent vision without needing a transplant. In addition, there is minimal risk to the procedure that would not be corrected if the patient eventually needs a transplant,” Beckman said.

Surgeons need to be aware that this is a minimally invasive route for rehabilitating patients with keratoconus without surgery. Cross-linking combined with properly fitted scleral lenses can provide outstanding visual outcomes, Trattler said. – by Robert Linnehan

Disclosures: Beckman reports he is a consultant for Avedro. Majmudar reports he is an investigator in the CXL-USA trial and an investor in CXL Ophthalmics. Nattis reports no relevant financial disclosures. Stahl reports she is a consultant for Avedro. Trattler reports he has a financial interest in Avedro and CXL Ophthalmics.

Click here to read the POINTCOUNTER, “What characteristics are needed to be a good candidate for cross-linking for keratoconus?