A Primer on CXL

It is important for eye care professionals to recognize patients who are candidates for corneal collagen crosslinking (CXL). CXL has been shown to significantly reduce the need for corneal grafts.

Keratoconus, a condition characterized by corneal ectasia and irregular astigmatism, occurs in approximately one in 375 individuals, and 10% to 20% of patients diagnosed with keratoconus eventually require a corneal transplant.¹ Researchers in the Netherlands found that the number of corneal transplants in their country dropped by 25% after the introduction of CXL.¹

Based on the results of such studies, CXL has dramatically changed the standard of care for progressive keratoconus, and to a lesser degree postsurgical ectasias.

WHAT IS IT?

In 2016, the FDA approved the KXL system for delivering ultraviolet (UV) light and two riboflavin solutions, Photrexa and Photrexa Viscous (Avedro; now owned by Glaukos). This is still the only FDA-approved system for performing CXL to slow or stop the progression of ectactic diseases. The CXL procedure reduces corneal irregularity, especially in young patients, to minimize the loss of BCVA, the risk of scarring, and therefore the need for corneal transplant.

Pathologic and iatrogenic factors can reduce the quantity of collagen fibrils in the corneal stroma, leading to stromal thinning. When this thinning is extreme, ectasia occurs due to distention of the cornea. CXL causes the formation of links among the remaining collagen fibrils, increasing the biomechanical strength of the corneal stroma. This process was first described at the University of Dresden in the late 1990s.

In the original Dresden study, the researchers demonstrated 2.00 D of flattening of the steepest keratometry readings in 70% of the patients.² The study also found that 100% of the CXL-treated eyes were stable.² Another study showed topographic flattening of 1.6 D.³

THE PROCEDURE

In the CXL procedure, a topical anesthetic is instilled into the eye for patient comfort with the patient lying down. The outer orbit of the eye that is being treated is sterilized with povidone-iodine, and the eye is held open with a lid speculum. In the Dresden protocol, the central 9 mm of corneal epithelium is debrided with a semi-sharp blade to ensure better penetration and homogeneous saturation of riboflavin into the stroma.²

The lid speculum is then removed, and riboflavin, a photosensitizer with an absorption peak 366 nm, is instilled every 2 minutes for 30 minutes. The patient is then checked to ensure that the riboflavin has been absorbed throughout the stromal cornea to a depth of 400 µm and into the anterior chamber before the cornea is exposed to UV light. If this measurement is not achieved, hypotonic riboflavin drops are instilled every 5 to 10 seconds until a minimum of 400 µm corneal depth is achieved. In some cases, this can take an additional 20 minutes.

The stromal cornea is then treated with UV-A radiation for 30 minutes at a wavelength of 365 nm. The photochemical reaction that results causes single oxygen free radicals to form new covalent bonds to stiffen the tissue.² Riboflavin and anesthetic are instilled periodically. The limbus is protected by ensuring that the treatment is centered on the cornea.

After treatment is completed, balanced salt solution is used to irrigate out excess riboflavin. A bandage lens is placed on the eye for 3 to 5 days until the epithelium is healed. Topical antibiotics are prescribed for 1 week and topical steroids for 2 to 3 weeks.⁴

FOLLOW-UP

Continuous follow-up is necessary. The recovery process is similar to that for a patient who has undergone corneal epithelial debridement. The patient may experience pain until the cornea reepithelializes, which averages about 3 to 5 days. Vision may decrease during the first month due to further steepening, thinning, and corneal haze.

Corneal haze is the most common complication after CXL, but it decreases between 3 and 12 months.⁵ In most cases, the cornea will slowly return to baseline after 3 months. Patients should be also seen at 3 to 6 months to ensure that topography and refraction are repeatable. By that time, they may experience an improvement in vision.

Complications of CXL include different epithelial healing rate, eye pain, microbial keratitis, sterile infiltrates, persistent corneal edema or endothelial decompensation, and persistent epithelial defects.⁶ Corneal endothelial decompensation is rare but can occur in patients with significant corneal thinning. This is because of the UV exposure, which can be cytotoxic to the endothelium.⁷ Most patients will have the same or slightly improved BCVA, although a few patients have lost 2 lines or more after CXL.⁷ It is important to note that this finding did not correlate with the patients’ BCVA with contact lenses.

WHO IS A CANDIDATE?

The Avedro CXL system is approved for use in patients 14 years or older with a confirmed diagnosis of progressive keratoconus or postsurgical ectasia and a minimum stromal thickness of 400 µm.

In order to determine if a patient is a candidate for CXL, progression over a 12-month period must be documented. Progression is defined as one of the following:^8-10

• Steepening of the anterior or posterior cornea surface by 1.00 D or more; or
• 10 µm or more loss in thinnest pachymetric point; or
• Change of refractive error by 1.00 D.

A group of expert panelists recommended that at least two of the three criteria below be met before CXL is presented as an option:¹¹

• Progressive steepening of the anterior corneal curvature;
• Progressive steepening of the posterior corneal curvature;
• Progressive thinning from periphery to the thinnest point on the cornea.

Older patients have a slower rate of keratoconus progression, but CXL can still be considered for this patient population.

VARIATIONS

Lombardo et al have described a transepithelial method of CXL in which iontophoresis is used to create a voltage gradient across the cornea to draw riboflavin into the stroma.¹² These authors showed that there were significant improvements in visual and refractive metrics and faster recovery with this method, but less topographic change in comparison with the Dresden protocol. They recommended use of standard CXL for patients younger than 24 years.¹²

Medical insurance covers only the standard Dresden protocol of CXL, approved by the FDA for treatment of keratoconus or of corneal ectasia after refractive surgery. As noted, only the KXL UV system and Photrexa family of riboflavin solutions are approved for these indications.

In addition to the epithelium-off Dresden protocol, Glaukos also manufactures platforms for performing epithelium-on (epi-on) procedures. Epi-on CXL can lead to faster recovery and less postoperative discomfort, but it is not FDA-approved. Nevertheless, some US surgeons are performing epi-on CXL off-label.

In addition, epi-on CXL protocols are being used in other countries. These involve higher doses of UV light with less exposure time. One of the advantages of this approach is that it can be used in corneas as thin as 320 µm, and recovery time is faster.¹³ These procedures have been reported to results in better visual acuity, decreased higher-order aberrations, improved keratometry values, and fewer overall complications.¹³

The Dresden protocol for CXL remains the established standard, especially in the United States due to regulatory approval. Other variants of the Dresden protocol, including performing CXL in combination with Intacs intrastromal corneal ring segments (Addition Technology) and photorefractive keratectomy, are being investigated globally.

CONTACT LENS CHANGES

It is important to educate patients that, after CXL, contact lenses will still be required to give them their best corrected vision. If the patient wore contact lenses preoperatively, he or she may resume contact lens use after 1 month. If the lenses provide a good fit, vision, and comfort, the patient can use the same lenses for the next 3 to 6 months. At that time, the lens parameters can be modified, as there will be little change topographically and refractively. The patient should also be made aware that multiple changes in contact lens prescription can occur throughout the first year postoperatively, for which they will be financially responsible.