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Everything you NEED to know about Corneal Collagen Cross-Linking (CXL)

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Corneal collagen cross-linking is a procedure that can massively benefit patients suffering from corneal disease. Here is what you need to know!

Everything you NEED to know about Corneal Collagen Cross-Linking (CXL)

After years of clinic trials, as of April 18th 2016, Avedro, Inc., an ophthalmic pharmaceutical and medical device company, has received United States FDA approval for Photrexa Viscous, Photrexa, and the KXL System for the treatment of progressive keratoconus.

What are these products? What does this mean to US-based eye care professionals? And most importantly what does this mean for patients?
These products represent a new era in the United States for treating progressive keratoconus. Many eye care professionals are aware of corneal collagen cross-linking (CXL) and that it is used to treat keratoconus but most do not know the goals of treatment, what is involved in the procedure, expectations both on the patient side and the doctor’s side, indications for treatment, or possible complications.
This article will give you a basic understanding of crosslinking and a simple guide to clinical management of a patient undergoing CXL.

About keratoconus

Before we go any further we need to understand more about the FDA approved and primary disease indicated for treatment with CXL, which is progressive keratoconus.
Keratoconus is a bilateral, asymmetric, clinically non-inflammatory, corneal degeneration. The classical presentation of the disease is to have onset in young adults, between the ages of 10-20 years old. This corneal degeneration is the result of biochemical stromal collagen weakening which allows for progressive corneal thinning and results in steepening of the corneal shape. The disease is progressive, and just as the Latin translation of the name suggests (kerato= collagen,cornea , conus = horn,cone), the cornea takes on a conical shape as the disease progresses.
Typically, keratoconus has a so-called life cycle, meaning that progression typically stops above the age of 40. Cases of late onset keratoconus are uncommon but do occur. There is currently no specific genetic factor that is been identified in the current literature, however, there is a preponderance of evidence that keratoconus has a genetic component and multiple associations have been suggested Woodward et al’s recent large scale study.
The most commonly reported prevalence rate for keratoconus is 1 in 2,000; however, this statistic was reported from a study performed by Kennedy et all over 30 years ago and was based simply on detection of scissors reflex and keratometric distortion for the diagnosis of the disease.
Development of more sensitive and advanced technologies for disease detection such a Placido topography and more recently scanning slit or Scheimpflug tomography have allowed for much earlier diagnosis of keratoconus. Subsequent large scale population studies are yet to be published based upon these technologies, but most experts in the field expect prevalence rates to be much higher – perhaps as high as 1 in 500.

Changing management strategies

Up until recently, the traditional management strategy for keratoconus in the United States has been to diagnose the disease when either subjective symptoms or clinically significant objective findings are observed.
This would be followed by visual management with contact lenses (typically with corneal rigid gas permeable lenses) until the disease progressed to a point of contact lens intolerance due to discomfort, fit instability or visual compromise from advanced corneal scarring. At this point, the patient would be referred for corneal transplantation.
This is now an outdated mode of care.
With the advent of corneal cross-linking we now have the ability to halt the progression of keratoconus at a much earlier point along the lifecycle of the disease. CXL has become the standard of care for progressive keratoconus worldwide for some time.
Now with the recent FDA approval of CXL, the United States has joined the rest of the developed world in adopting this contemporary model for keratoconus care. The treatment goal of CXL cannot be over emphasized and that is to halt the progression of the disease. If topographic and/or visual improvement occurs following CXL, that would be a secondary advantage (improved keratometry of 2D or more or improved VA of 2 lines or more has been reported in approximately 25% of patients).
Thus, patients should always be counseled that the purpose of performing the procedure is to stop the progression of keratoconus.

What is cross-linking and how did this procedure come about?

A cross-link is a bond that links one polymer chain to another.
In medical procedures this has been previously used to describe a curing process. Dentistry has used cross-linking for hardening of materials by UV-A illumination to create sealants and other composite fillings. Theo Seiler, MD, PhD, is internationally regarded for his contributions to CXL. His work at the Department of Ophthalmology at Technische Universität of Dresden was the first to suggest applying this cross-linking principle to corneal collagen fibers.
Seiler and his colleagues studied the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation, noting that the combination strengthened corneal stroma.
This effect was obtained by creating new bonds within corneal stroma, a result of the production of activated riboflavin and singlet oxygen. The exact nature of the bonds is unclear, but may be between the collagen fibers and glycosaminoglycans. This early research proved an effective treatment for keratoconus. Seiler then created a standard protocol (The Dresden Protocol) which created standard parameters for the treatment, including riboflavin concentration and penetration, UV fluence, and time of exposure. Standardization was necessary to render the treatment safe and effective.
CXL was first used to treat patients in 1998 in Dresden, Germany.
The results thus far have shown this treatment to be effective and many patients have had a lasting effect (no progression) 3 to 5 years after their initial treatment. The traditional Dresden Protocol calls for removal of the central 8-10mm of corneal epithelium, which is performed with either alcohol and weck-cel sponge or scraped with a blade, and then a 30 min soak (administration of Riboflavin) with 0.1% Riboflavin 20% Dextran solution, followed by a 30 min exposure (illumination with UV-A at 365-370 nm at 3 milliwatts/cm2). After the procedure, a bandage contact lens is placed and topical antibiotic, topical steroid, and topical non-steroidal anti-inflammatory (NSAID) are administered at various intervals daily. After the epithelial defect has resolved, the bandage contact lens is removed and the NSAID is discontinued, and non-preserved artificial tears are added to the regiment.
The topical antibiotic is discontinued at 1 week and the topical steroid is discontinued at 2 weeks. Follow ups to monitor corneal health and curvature are then made at typical 1, 3, 6, and 12-month intervals.
Internationally this has become the standard of care of patients with keratoconus and other forms of corneal ectasia.
In the United States, the FDA had ruled that CXL treatment falls under the drug and device category. Riboflavin (Vitamin B) is commonly found in food products, and is readily available in the US but was not approved for use on the eye until now.

Two main variations to the CXL procedure

Two main variations to the CXL procedure exist: Epithelial Off (Epi-off) CXL, the corneal epithelial layer is removed to expose the anterior stroma bed, and Transepithelial (Epi-on) CXL, where the corneal epithelium is left fully intact.
Epi-off is the classic and proven technique, and it specifically is this technique that has been FDA approved at this point in time. The purposes of removing the epithelial layer are to allow for easier and fuller absorption of riboflavin into the stromal collagen fibers and to remove a possible barrier to UV-A irradiation.
Now within these 2 main forms, there are a variety of variations that can be made and have been utilized internationally and in clinical trials within the United States. Examples include; accelerated techniques which use higher joules and thus shorter UV-A exposure times, iontophoresis which increases the rate of riboflavin absorption, and usage of various solutions of Riboflavin (vitamin B2). Now even beyond the division of Epi-on CXL and Epi-off CXL are combined treatments. These include procedures such as CXL with intracorneal ring segments, CXL with topography guided photorefractive keratectomy, CXL with conductive keratoplasty, CXL with topography guided UV-A illumination, CXL with microwave, and even combinations beyond these. In the United States we are truly at the beginning of a new management paradigm for keratoconus.
The focus of this discussion will be kept limited to the FDA approved Epi-off CXL procedure, which is the recommended method of treating patients. The FDA-approved Avedro devices are the KXL System which will provide the UV-A illumination and Photexra and Photexra Viscous which are different formulations of Riboflavin.
As previously stated, the purpose of CXL is to prevent keratoconus progression; however, it has been documented to have additional positive side effects.
As part of the Avedro CXL trials, Hersh et al reported the following in the article titled “Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results” published in Journal of Cataract and Refractive Surgery 2011, “Collagen crosslinking was effective in improving UDVA (uncorrected distance visual acuity), CDVA (corrected distance visual acuity), the maximum K value, and the average K value. Keratoconus patients had more improvement in topographic measurements than patients with ectasia. Both CDVA and maximum K value worsened between baseline and 1 month, followed by improvement between 1, 3, and 6 months and stabilization thereafter.” Though visual improvement is not the purpose of CXL, it can be noted as a positive or beneficial side effect.

CXL overall has been shown to be safe

The most common complications are associated with the Epi-off procedure, and are associated more with epithelial debridement than the actual procedure itself. These complications include infection, slow healing, and subepithelial haze. These are similar complications as to what is seen in photorefractive keratectomy. As reported from the findings from Hersh and Greenstein et Al, the typical corneal haze is transient and usually resolved between 3 to 12 months after the procedure. The potential complications that can occur due to the UV-A illuminance are cytotoxicity of the corneal endothelium and activation of latent herpetic disease.
A review of the research studies led by Dr. Hersh will cover all clinically relevant aspects of care and comanagement.

Who is a good candidate for CXL?

CXL is FDA-approved for patients with progressive keratoconus.
CXL has other indications such as for progressive corneal ectasia; however, at this time these have not been included in the
FDA-approval. Patients under 40 Years of age, represent the group of patients who are the most likely to progress, these are ideal candidates for CXL. The general consensus among practitioners is to intervene early, stop the disease at it first sign in this higher risk category. The FDA-approval includes patients as young as 14 years old.
Patients over the age of 40, are unlikely to progress and should be monitored for documented progression. If progression is noted, then the patient would be an ideal candidate for cross-linking. Currently there is no specific consensus as to what quantitatively constitutes disease progression. Groups interested in establishing such an important consensus, such as the International Keratoconus Academy among others, are working very hard to achieve this goal.

What should I tell my patients to expect? What should I expect?

The general expectations for KC patients undergoing Epi-off CXL are as follows: the procedure is generally performed one eye at a time and the procedure itself is typically painless and uneventful.
Afterwards most patients report a mild foreign body sensation while wearing the bandage contact lenses. Most patients do note substantial discomfort for the first few hours after the procedure. Although a rare occurrence, some may experience substantial pain for the next few days, and there is currently no way of knowing who will be more predisposed. Vision will be reduced, ie. hazy and/or foggy, and will improve over the first month.
From month 1 to month 3, it is common to have daily fluctuations in vision. From month 3 on, vision typically stabilizes. Contact lens wear should be suspended until 4 weeks after the procedure, with changing curvatures of the cornea, it will be important to reevaluate the patient's current contact lenses as refitting may be indicated. Soft designs and vaulted designs are typically less affected than corneal GP designs. It is important to note that the curvatures of the cornea will continue to change at least over the first 6-month period.

So what does this mean for patients?

Eye care providers will now be able to refer a patient with progressive keratoconus or who is at high risk for progression for CXL treatment and finally be able to stop the deterioration of vision.
This makes KC management much easier as the disease will not progress to the same extremes, thus, visual rehabilitation with contact lenses will be less challenging with less complications. Also, utilization of penetrating keratoplasty in the United States may be significantly lowered, which will alleviate the associated economic burdens to our patients.
Another benefit that is too often overlooked is patient quality of life. A quick review of keratoconus support groups on Facebook will show that many patients are suffering from depression as well as anxiety over their condition. Labiris et al and Cingu et al both found in their respective studies an overall improvement in quality of life after patients with KC were treated with CXL. Cingu specifically found a significant reduction in anxiety. Offor and Hersh found significant improvement in a number of patient subjective vision outcomes after the procedure.

How can I learn more?

The Cornea and Laser Eye Institute and The CLEI Center for Keratoconus, Dr. Hersh’s clinic, will be hosting a series of continued education courses on CXL.
The first lecture will be held May 25th 2016 in New Jersey. For more information please email:
For additional continued education on Keratoconus join the International Keratoconus Academy of Eye Care Professionals (IKA) at The IKA will be hosting continued education at this year's American Optometric Association (AOA) meeting in Boston, Massachusetts and at the American Academy of Optometry meeting in Anaheim, California.


Below is a cost analysis for penetrating keratoplasty. Currently KC is the overwhelming indication for the utilization of penetrating keratoplasty worldwide. Cost-Benefit Analysis of Corneal Transplant, September 2013 Prepared for: Eye Bank Association of America, Submitted by: The Lewin Group, Inc.
“In evaluating costs and benefits of corneal transplant, we examine the medical cost associated with corneal transplantation procedure, which includes the cost of the procedure itself and the cost of care associated with the transplant for three months before and a year after the surgery. We estimate a per-patient average cost of corneal transplant of $16,500; this reflects all related expenses, including corneal tissue, surgeon and anesthesia services, facility costs, pre-operative care, and related services for a year after the transplant. “
“Because transplantation is the treatment of last resort for those suffering from corneal disease or injury, when evaluating benefits, we consider blindness as the alternative to corneal transplant procedure. Therefore, we use costs of blindness as a proxy for the benefits of corneal transplant, and we assume that the benefits will remain with the patient for the remainder of his or her life. Direct medical costs attributed to blindness include medical care and long term care; these average $77,000 over the course of a person’s life. Indirect benefits include avoided cost of lost productivity incurred by the patients due to their reduced income and by their caregiver(s) due to provision of informal care. We estimate that an average person whose vision has been restored through a corneal transplant procedure will avoid about $214,000 in indirect costs over the course of his or her life. This analysis assumes a uniform retirement at age 65, and thus may understate the true cost of lost productivity.“


  1. Chang CY, Hersh PS. Corneal collagen crosslinking: a review of 1-year outcomes. Eye & Contact Lens [Eye Contact Lens], 2014 Nov; Vol. 40 (6), pp. 345-52
  2. Greenstein SA, Hersh PS. Characteristics influencing outcomes of corneal collagen crosslinking for keratoconus and ectasia: implications for patient selection. Journal Of Cataract And Refractive Surgery [J Cataract Refract Surg], 2013 Aug; Vol. 39 (8), pp. 1133-40
  3. Brooks NO, Greenstein S, Fry K, Hersh PS. Patient subjective visual function after corneal collagen crosslinking for keratoconus and corneal ectasia. Journal Of Cataract And Refractive Surgery [J Cataract Refract Surg], 2012 Apr; Vol. 38 (4), pp. 615-9
  4. Greenstein SA, Fry KL, Hersh PS. In vivo biomechanical changes after corneal collagen cross-linking for keratoconus and corneal ectasia: 1-year analysis of a randomized, controlled, clinical trial. Cornea [Cornea], 2012 Jan; Vol. 31 (1), pp. 21-5
  5. Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. Journal Of Cataract And Refractive Surgery [J Cataract Refract Surg], 2011 Jul; Vol. 37 (7), pp. 1282-90
  6. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. Journal Of Cataract And Refractive Surgery [J Cataract Refract Surg], 2011 Jan; Vol. 37 (1), pp. 149-60
  7. Greenstein SA; Fry KL; Bhatt J; Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. Journal Of Cataract And Refractive Surgery [J Cataract Refract Surg], 2010 Dec; Vol. 36 (12), pp. 2105-14
  8. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984; 28:293–322
  9. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiological study of keratoconus. Am J Ophthalmol. 1986; 101:267–73
  10. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42: 297–319
  11. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiological study of keratoconus. Am J Ophthalmol. 1986;101:267–73.
  12. Seiler T, Koufala K, Richt Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet‑a‑induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620‑7.
  13. Kymionis GD, Portaliou DM, Bouzoukis DI, Suh LH, Pallikaris AI, Markomanolakis M, et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007;33:1982‑4.
  14. Yuksel N, Bilgihan K, Hondur AM. Herpetic keratitis after corneal collagen cross‑linking with riboflavin and ultraviolet‑A for progressive keratoconus. Int Ophthalmol 2011;31:513‑5
  15. Holladay JT, Dudeja DR, Koch DD. Evaluating and reporting astigmatism for individual and aggregate data. J Cataract Refract Surg 1998; 24:57–65
  16. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26:385–389
  17. Frigo AC, Fasolo A, Capuzzo C, Fornea M, Bellucci R, Busin M, et al. Corneal transplantation activity over 7 years: changing trends for indications, patient demographics and surgical techniques from the Corneal Transplant Epidemiological Study (CORTES), Transplant Proc. 2015;47:528–35.
  18. Cingu AK, Bez Y, Cinar Y, Turkcu FM, Yildirim A, Sahin A, Tas C, Sir A.Impact of Collagen Cross-linking on Psychological Distress and Vision and Health-Related Quality of Life in Patients With Keratoconus. Eye Contact Lens. 2015 Nov;41(6):349-53.
  19. Labiris G, Giarmoukakis A, Sideroudi H, Gkika M, Fanariotis M, Kozobolis V. Impact of keratoconus, cross-linking and cross-linking combined with photorefractive keratectomy on self-reported quality of life. Cornea. 2012 Jul;31(7):734-9.
  20. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: The Siena Eye Cross Study. Am J Ophthalmol 2010; 149:585–593
  21. Vinciguerra P, Camesasca FI, Albe E, Trazza S. Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg 2010; 26:486–497
  22. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long term results. J Cataract Refract Surg 2008; 34:796–801
  23. Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SPS. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus; one-year analysis using Scheimpflug imaging. J Cataract Refract Surg 2009; 35:425–432
  24. Woodward MA, Blachley TS, Stein JD. The Association Between Sociodemographic Factors, Common Systemic Diseases, and Keratoconus: An Analysis of a Nationwide Health Care Claims Database. Ophthalmology. 2016 Mar;123(3):457-465.
  25. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009; 35: 1358–1362
  26. Avedro Receives FDA Approval for Photrexa® Viscous, Photrexa® and the KXL® System for Corneal Cross-Linking, Waltham, Massachusetts, USA, Apr 18, 2016
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