The Great Debate in CXL: Epi-on Versus Epi-off

Colleagues debate the merits of epithelium-on and epithelium-off corneal collagen crosslinking.

By Andrew S. Morgenstern, OD, FAAO, and Clark Y. Chang, OD, MSA, MSc, FAAO

Epi-on Offers a
Less-invasive Alternative

By Andrew S. Morgenstern, OD, FAAO

A quick note before I begin. Clark Y. Chang, OD, MSA, MSc, FAAO, and I are close colleagues. We frequently lecture together on the topic of this point/counterpoint. We are both executive board members of the International Keratoconus Academy of Eye Care Professionals, or IKA. We also both serve on the executive board of the Optometric Cornea, Cataract, and Refractive Society. We both work in different capacities with TLC Laser Eye Centers. We are both incredibly passionate about corneal ectatic diseases and the methods by which to treat them. I consider him one of my closest and most respected colleagues in eye care.

It is therefore with tremendous respect that I take great pride in disagreeing with his assessment of epithelium-on (epi-on) and epithelium-off (epi-off) corneal collagen crosslinking (CXL). To quote Roy Rubinfeld, MD, inventor of the CXLUSA crosslinking device, “Have you ever used tobramycin/dexamethasone, prednisolone, or erythromycin topically? Did you ever have to take off your patient’s epithelium to get those drugs to penetrate an intact epithelium? Me neither.” So why should we need to remove the epithelium to get riboflavin to absorb into the cornea?

As Dr. Chang states in his accompanying article, some practitioners have “raised clinical concerns regarding epithelial removal in the CXL procedure, primarily due to its association with adverse events such as postoperative pain, delayed visual recovery, microbial infections, corneal haze, corneal scarring, and loss of visual acuity.” To me those are some very serious complications and considerations, not to mention the time patients must spend out of their contact lenses while the epithelium rebuilds itself.

We all know that we are in the infancy of CXL. That is to say, most individuals who undergo the CXL procedure are given the same quantities of riboflavin and light exposure. Unfortunately, the procedure is not generally tailored toward the individual based on level of disease, progression, and/or corneal biomechanics. Some individuals no doubt require less treatment and some more, but we really do not know who they are yet. Also, some individuals will need repeated procedures. The good news is that it is incredibly low risk to perform CXL a second time, especially if the cornea is left intact. And especially in the epi-on fashion.

It is important to note that, at this time, only epi-off CXL is approved on the Avedro device by the US Food and Drug Administration. Epi-on CXL can be performed, but the treating doctor must make the patient or the patient’s parent or guardian aware that it is an off-label procedure.

I will admit that Dr. Chang is correct in his assessment of the disease and the need for a procedure to address it. He and I will continue to professionally disagree on the topic of epi-on versus epi-off CXL, but we do agree on the following statements:

Early detection, especially while the patient’s vision is still good, is crucial to maximize the benefit of CXL and preserve as much vision as possible.

For individuals who are appropriate candidates for CXL, any crosslinking is better than no crosslinking, regardless of the type of procedure.

If you have any questions or wish to learn more about CXL or corneal ectatic diseases such as keratoconus, please visit the IKA website at

Andrew S. Morgenstern, OD, FAAO
• Chief Medical Editor, Advanced Ocular Care and
• optometric subject matter expert, Vision Center of Excellence, Walter Reed National Military Medical Center, Bethesda, Md.; president, Optometric Cornea, Cataract and Refractive Society; executive board member, International Keratoconus Academy; past chairman, American Optometric Association New Technology Committee
• financial interest: none acknowledged


NOTE: The opinions expressed in this article by Dr. Morgenstern are his own and do not reflect the view, opinion, or recommendation of Walter Reed National Military Medical Center, Vision Center of Excellence, US Department of Defense, US Department of Veterans Affairs, Booz Allen Hamilton, or the United States government.

The Epithelium: Barrier to Achieving Maximum Crosslinking Efficacy

By Clark Y. Chang, OD, MSA, MSc, FAAO

Halting the progressive condition keratoconus was not a clinical possibility until Wollensak and colleagues published their initial investigative findings in 2003, describing corneal collagen crosslinking (CXL) as a novel treatment for keratoconus.1 They proposed a CXL technique, now known as the Dresden protocol, that involves epithelial debridement and saturating the exposed stroma with riboflavin prior to exposing the cornea to a carefully calibrated dose of ultraviolet (UV)-A light.

The UV energy level was calculated to be lower than the tolerance threshold of the corneal endothelium, provided that the UV-absorption activities of riboflavin and a minimum corneal thickness of 400 µm were present. The ensuing photooxidative reactions induce formation of covalent bonds within the treated tissue, conferring enhanced biomechanical strength to stabilize a weakening cornea against further deformation. It is worth noting that Wollensak et al not only reported halting keratoconus progression in all treated patients, they also observed postoperative improvement in 70% of study eyes, include a mean reduction of maximum keratometry, or Kmax, by 2.00 D.1,2

Many subsequent clinical trials utilizing this standardized protocol have since reported similar findings of halting keratoconus progression and even improving topographic, refractive, and/or aberrometric profiles.3-5 Due to its proven efficacy and good safety profile, the US Food and Drug Administration last year approved two riboflavin solutions and the KXL System (Avedro) for the treatment of progressive keratoconus.


Notwithstanding this approval, some have raised clinical concerns regarding epithelial removal in the CXL procedure, primarily due to its association with adverse events such as postoperative pain, delayed visual recovery, microbial infections, corneal haze, corneal scarring, and loss of visual acuity.2,6 Therefore, ongoing investigative efforts have focused on improving the transepithelial, or epithelium-on (epi-on), application of CXL. However, even though epithelial debridement increases the risks of some postoperative events, as one would expect from any surgery involving epithelial compromises, such as PRK, clinicians are well equipped with therapeutic tools to manage these episodes after epithelium-off (epi-off) procedures, should they arise.

In comparison with the use of epithelial debridement in epi-off CXL, most transepithelial CXL techniques aim to disrupt epithelial tight junctions in an attempt to provide passageways for riboflavin to enter the stroma. Consequently, the basement membrane is still relatively compromised in transepithelial CXL, albeit for a shorter time course. This explains why symptoms of pain can still occur in some patients, despite best efforts to keep the epithelium intact during CXL. In fact, some studies comparing epi-on and epi-off approaches have found higher pain scores reported in the epi-on CXL group in comparison with the epi-off group.7,8 Such findings may reflect differences in patient education and patients’ postoperative expectations.

The three key ingredients that promulgate the photopolymerization process during CXL are riboflavin, oxygen, and UV-A light. The interaction of these three components in the stroma releases sufficient energy to create singlet oxygen molecules necessary for the formation of new cellular crosslinks. Ideally, the highest CXL reaction rate would be induced if optimum concentrations of all three substrates could be maintained throughout the entire treatment duration. But an intact epithelium, as it appropriately serves its anatomic functions, can negatively interfere with stromal diffusion and homogeneous uptake of these three integral elements.9,10 Therefore, a lower degree of CXL reaction can be anticipated in epi-on procedures.

High concentrations of ascorbate and tryptophan residues in the epithelium absorb some UV light energy, especially wavelengths shorter than 300 nm. Given that the UV-A wavelength used for CXL is typically 365 nm, however, it is more likely that decreased CXL efficacy stems primarily from an intact epithelium blocking riboflavin penetrance and rapid oxygen diffusion into the stroma. Without epithelial debridement, the bioavailability of riboflavin is shifted anteriorly within the stromal tissue, which may cause CXL reactions to predominantly take place at shallower stromal levels in epi-on techniques compared with conventional epi-off CXL.9-12

Animal models corroborate the clinical observations of shallower CXL depth and reduction of biomechanical stiffening by approximately 80% when epithelial debridement is not utilized.9,12,13 In addition, a number of studies investigating the application of transepithelial CXL have reported continued keratoconus progression or earlier CXL regression, often necessitating retreatment with debridement.14-16 One such study even demonstrated a regression rate as high as 50% in pediatric keratoconus patients 2 years after initial transepithelial CXL.16

In a recent meta-analysis of CXL literature, Kmax was shown to be improved or stable in 93.1% of epi-off studies but only 40% of epi-on studies.2 However, the fact that fewer data exist on transepithelial CXL in the literature may be a confounding factor in this finding.


Clinical considerations regarding treatment regression are even more germane in a pediatric population because early onset of keratoconus has been associated with more severe disease staging and rapid progression. And yet, epi-on CXL appears to be a suitable treatment choice for pediatric patients because of the improved comfort during the immediate postoperative phase. Yuksel et al found pain scores to be higher in adult patients than in pediatric patients after CXL,7 but it is easy to understand the advantages of a treatment technique that has less associated discomfort during recovery.

Nonetheless, the goal of performing CXL is to maximally arrest disease progression, not to reduce discomfort. An intact epithelium acts as a barrier to the ultimate therapeutic objective of CXL, and it may lead to concerns about undetected regression, especially when patients are lost to follow-up. Therefore, clinicians must take into account the value of the potential for longer treatment duration with epi-off CXL, as this may translate into the need for fewer retreatments across a patient’s lifetime.

As the science and delivery techniques for epi-on CXL improve with time, it is possible that better efficacy levels will eventually allow us to shift our preference to this mode of CXL without the conundrum of sacrificing efficacy.

1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620-627.

2. Shalchi Z, Wang X, Nanavaty MA. Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus. Eye (Lond). 2015;29(1):15-29.

3. Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014;40(6):345-352.

4. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg. 2011;37(1):149-160.

5. Vinciguerra P, Albè E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116(3):369-378.

6. Dhawan S, Rao K, Natrajan S. Complications of corneal collagen cross-linking. J Ophthalmol. 2011;2011:869015.

7. Yuksel E, Novruzlu S, Ozmen MC, Bilgihan K. A study comparing standard and transepithelial collagen cross-linking riboflavin solutions: epithelial findings and pain scores. J Ocul Pharmacol Ther. 2015;31(5):296-302.

8. Yuksel E. Epithelial on or epithelial off corneal collagen cross-linking: bilateral comparison study. Paper presented at: 19th ESCRS Winter Meeting; February 20-22, 2015; Istanbul.

9. Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg. 2009;35(3):540-546.

10. Richoz O, Hammer A, Tabibian D, Gatzioufas Z, Hafezi F. The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol. 2013;2(7):6.

11. Bottós KM, Schor P, Dreyfuss JL, et al. Effect of corneal epithelium on ultraviolet-A and riboflavin absorption. Arq Bras Oftalmol. 2011;74(5):348-351.

12. Spoerl E, Hoyer A, Pillunat LE, Raiskup F. Corneal cross-linking and safety issues. Open Ophthalmol J. 2011;5:14-16.

13. Hayes S, O’Brart DP, Lamdin LS, et al. Effect of complete epithelial debridement before riboflavin-ultraviolet-A corneal collagen crosslinking therapy. J Cataract Refract Surg. 2008;34(4):657-661.

14. Soeters N, Wisse RP, Godefrooij DA, et al. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol. 2015;159(5):821-828.

15. Kocak I, Aydin A, Kaya F, Koc H. Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus. J Fr Ophtalmol. 2014;37(5):371-376.

16. Caporossi A, Mazzotta C, Paradiso AL, et al. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg. 2013;39(8):1157-1163.

Clark Chang, OD, MSA, MSc, FAAO
• director, cornea specialty lenses, Wills Eye Hospital, Philadelphia
• director, clinical services, TLC Vision, Chesterfield, Mo.
• financial disclosure: travel grant, Avedro