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Clinical implications of corneal cross-linking


Now that we have CXL , it is imperative for clinicians to incorporate new technologies that can help us achieve disease detection at the earliest clinical stage prior to onset of visual symptoms.

Corneal cross-linking (CXL) is globally considered to be the only evidence-validated method to halt or slow down the progression of corneal ectatic disorders. CXL has gained wide acceptance as a front-line treatment for keratoconus and ectasia outside of  the U.S., and the long-awaited approval of CXL from U.S. Food and Drug Administration (FDA) was granted in April 2016.

This is a landmark event in the landscape of eye care, and I have invited some of the most recognized clinical experts on this subject to discuss the clinical implications of this important development: Drs. Clark Chang, Andrew Morgenstern, and Jim Owen. It is worth noting that they do not have any financial interest in today’s topic.

Cross-linking indication and approval

Dr. Tullo: What are the FDA indications of CXL per its recent approval? 

Dr. Chang: The FDA approval on CXL is unique in that the approval is granted for a specific drug/device combination, both of which are manufactured by Avedro.1 In this case, the device component is the KXL system and the drug component refers to the two particular riboflavin formulations. These two riboflavin ophthalmic solutions can be differentiated by the presence of Dextran-Photrexa Viscous contains Dextran solution, whereas Photrexa does not. Per FDA indication, Photrexa Viscous and Photrexa are meant to be used together with KXL system for CXL treatment in patients with progressive keratoconus.

Dr. Tullo: That is indeed a very interesting FDA labelling. Are there different clinical applications for Photrexa Viscous and Photrexa?   

Dr. Morgenstern: Both riboflavin formulations contain the same amount of riboflavin molecules (1.20g/ml), but the solution osmolarity differs due to the addition or subtraction of Dextran. Photrexa Viscous contains Dextran, which gives it an osmolality of 301–339 mOsm/kg, whereas Photexa that does not contain Dextran is more hypo-osmolar with an osmolality of 157–177 mOsm/kg. If a cornea dehydrates to thinner than 400 µm during the initial riboflavin loading process, then the hypotonic Photrexa will be used to rehydrate cornea to a minimum of 400 µm prior to proceeding with CXL treatment via the KXL system.

Dr. Tullo: What is the significance behind this 400 µm guideline?

Dr. Owen: It has been shown that CXL treatment depth penetrates into stromal tissue up to approximately anterior 300 µm. Therefore, by maintaining a corneal thickness of 400 µm or greater prior UV light exposure, investigators believe that CXL becomes a safe procedure whereby the UV energy that may interact with corneal endothelium or may enter intraocular space is then lower than the actual tissue damage threshold. In fact, some long-term studies have proven this point by showing the lack of endothelial decompensation, lenticular-related changes, and retinal damages after CXL treatments.2


Cross-linking protocol

Dr. Tullo: Speaking of long-term studies, we know that there has been more than one CXL protocol investigated in the last 10 to 15 years with most of them showing good clinical success immediately after each type of treatment protocol. Does FDA approval include the clinical uses of various clinical CXL methodologies?

Figure 1. Cornea loaded with riboflavin. Image courtesy of Avedro.

Dr. Chang: The study data that was submitted to and reviewed by FDA included only those clinical trials following the Dresden protocol, so the FDA CXL approval is currently intended only for use with the same CXL delivery methodology. This method included four simple steps:

• Epithelial debridement: Remove approximately central 9 mm zone using topical anesthesia and standard aseptic technique

• Riboflavin loading phase: Use Photrexa Viscous to saturate corneal stroma with riboflavin by instilling one drop every two minutes for 30 minutes. The presence of Photrexa Viscous in cornea and anterior chamber is examined via biomicroscopy prior to moving forward (Figure 1)

• Corneal pachymetry: Proceed with UV exposure only if pachymetry shows 400 µm or greater; otherwise, Photrexa is instilled one drop every two minutes until 400 µm is reached

• UV exposure phase: While continuing to instill Photrexa Viscous every two minutes and topical anesthesia periodically, KXL system is centered over the treatment zone to emit wavelength of 365nm at 3mW/cm2 for 30 continuous minutes. Each treatment is carefully controlled so all eyes receive the same standardized treatment dose, which is the reason why the current FDA approval is so specific.

Dr. Tullo: That is starting to make a great deal of clinical sense now. What does the current FDA approval mean for patients with keratoconus in the U.S.?

Dr. Morgenstern: The efficacy in this procedure was clear: to arrest or slow down disease progression with good safety. After all of the 25 European Union countries approved CXL in late 2006, U.S. patients still did not have access to CXL. When the first multicenter CXL trials were launched in 2008, there was still very limited access due to geographical exclusions for patients who needed this procedure (many patients had to travel to Europe or Canada to receive CXL treatment).

In the U.S., a CXL study group was formed later on to help widen patient access to those living in the U.S. since many lived in fear of losing their vision due to this progressive disease-and many experts believe that the prevalence rate for keratoconus is greater than the conventionally quoted rate of 1:2000. Therefore, CXL will now be more readily available for the thousands who suffer from diseases such as progressive keratoconus in U.S.

However, it is still in a very early phase post-approval, so there is still only a limited amount of devices currently on the market, and an insurance code is not available yet. Avedro is working on manufacturing about 100 more KXL units by the end of 2016.


Choosing cross-linking candidates

Dr. Tullo: I hope that more clinics will be able to offer CXL soon to patients who need this procedure. Under the current FDA indications, who are the good and poor candidates for CXL?   

Dr. Owen: Current FDA label indicates CXL for use in patients who are identified with progressive keratoconus. Therefore we will have to become more astute in monitoring patients so we can identify good candidacy at the earliest sign of clinical progression.

Because it is not known if CXL negatively affects reproductive capacity or causes fetal harm, recommendations for CXL should not be made for pregnant women. Also, there is no data on the presence of Photrexa Viscous and Photrexa in human milk or their effects on breastfed infants. The benefits of CXL in a lactating or nursing mother should be weighed against the potential and yet unknown effect on the development of the infants.

In addition, given the corneal thickness guideline previously alluded to by Dr. Chang for the Dresden protocol, serious considerations should be given prior to making CXL recommendations under the current FDA label to patients with thinner corneas. This is another good reason to detect disease as early as possible.

Managing keratoconus patients

Dr. Tullo: With the availability of an FDA-approved CXL protocol in place, what should be the role of optometrists in managing patients with keratoconus or ectasia?

Dr. Chang: Prior to the advent of CXL treatment, all symptomatic keratoconus patients were managed with the similar clinical doctrine of being provided with the necessary refractive management- be it glasses or contact lenses- and patients are offered options of keratoplasty if such prescribed refractive corrections fail. Under this conventional model in which momentum of progression cannot be altered, we did not have to place clinical emphasis on early objective detection.

However, now that we have CXL , it is imperative for clinicians to incorporate new technologies that can help us achieve disease detection at the earliest clinical stage prior to onset of visual symptoms.


Examples of such clinical tools are elevation-based corneal tomography (i.e., Oculus Pentacam or Bausch + Lomb Orbscan), corneal biomechanical strength measurements (i.e., Reichert Ocular Response Analyzer or Oculus Corvis), and wavefront aberrometry (i.e., Tracey Technologies iTrace). This new management approach not only allows optometrists to provide recommendations on timely intervention to stabilize and preserve patients’ maximum visual functions but also will ensure longevity in the refractive correction tools that we prescribe to our patients. In time, we will witness a trend of less keratoplasty utilizations. Some experts even propose that CXL may eliminate the future need for keratoplasty in keratoconus patients.3   

Dr. Tullo: That is great news. Although I do not hesitate in recommending corneal transplants when clinically necessary up to this point, we all know that there are refractive challenges in visually rehabilitating a post-graft patient. What are the typical natural courses in the post-operative phase of CXL? 

Dr. Morgenstern: Dr. Chang has written extensively on this subject, including publishing in peer-reviewed scientific journals, so I would recommend our optometric colleagues to look up his work. The data from his clinical trials show a general trend of worsening in various study parameters during the initial month immediately after CXL, such as reduced vision, steepening in Kmax, pachymetric thinning, and corneal haze. However, these clinical attributes typically return to baseline by the three-month study follow up with continual improvement up to one year.4

The multicenter data submitted for FDA review reflects the same trends Dr. Chang’s study center noted as well.5 The majority of adverse events reported resolved during the first month, while events such as corneal epithelium defect, corneal striae, punctate keratitis, photophobia, dry eye and eye pain, and decreased visual acuity took up to six months to resolve, and corneal opacity or haze took up to 12 months to resolve. I do want to point out that in 1–2 percent of patients, corneal epithelium defect, corneal edema, corneal opacity, and corneal scar continued to be observed at 12 months.

Dr. Tullo: Thank you for such in-depth analysis. How do ODs find a CXL center offering FDA-approved CXL protocol?

Dr. Owen: On its website, Avedro has a list of its study sites  as well as affiliated clinical sites that will be offering the FDA-approved CXL treatment. However, there are also other investigation sites that will continue to perform CXL procedures under and in accordance with American IRB-approved protocols. One example would be the CXL U.S. study sites that Dr. Morgenstern has brought up in a previous discussion. Other good resource organizations include International Keratoconus Academy as well as National Keratoconus Foundation.


Dr. Tullo: I would like to thank Drs. Clark Chang, Andrew Morgenstern, and Jim Owen for sharing their expertise in managing keratoconus and ectasia patients. CXL is an exciting new clinical topic that has many more dimensions that we can discuss in leading our effort to improve current standard of care. I highly encourage all eye care professionals to adopt the new management approach to move toward early keratoconus detection by incorporating new clinical technologies as discussed within this article.   


1. Avedro website. Avedro Receives FDA Approval for Photrexa Viscous, Photrexa and the KXL System for Corneal Cross-Linking, WALTHAM, Mass: Avedro, Inc., 18 April 2016. Available at: http://avedro.com/press-releases/avedro-receives-fda-approval/. Accessed 07/07/16.

2. Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. 2015 Jan;41(1):41-6.

3. Hashemi H, Seyedian MA, Miraftab M, Fotouhi A, Asgari S. Corneal collagen cross-linking with riboflavin and ultraviolet a irradiation for keratoconus: long-term results. Ophthalmology. 2013 Aug;120(8):1515-20.

4. Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014 Nov;40(6):345-52

5. Hersh PS. Safety of Corneal Collagen Cross-linking. Presented at: Joint Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Device Panel of the Medical Devices Advisory Committee; 2015, Feb 24; Silver Spring, MD.

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