As corneal collagen crosslinking continues to gain traction as a method of keratoconus management, clinicians are re-evaluating ways to refine the procedure and improve patient outcomes. In this second part of Optometry Advisor’s 3-part series, Courtney Dryer, OD, discusses the epi-on corneal collagen crosslinking procedure and its implications for optometry should it receive US Food and Drug Administration approval and become a routine part of clinical practice.
Corneal collagen crosslinking (CXL) has become a standard treatment for progressive corneal ectasia due to keratoconus.1 The procedure not only hardens the cornea and stabilizes disease progression, it also preserves vision, improves corneal topography, allows for better contact lens fit, and prevents the need for keratoplasty.2,3 Currently, CXL is the only keratoconus treatment proven to halt progression, and only the epi-off procedure, which involves the removal of the corneal epithelium, is approved by the US Food and Drug Administration (FDA).3,4
Risks Associated With Epi-Off CXL
The epi-off CXL procedure has improved quality of life for patient with keratoconus since its introduction in 2003.5 While it is a simple and relatively safe procedure, it presents certain risks including an increased risk of corneal infection, subepithelial haze, and sterile corneal infiltrates.4 Additionally, epi-off CXL carries a small risk of viral reactivation, corneal melting, infectious ulceration, and the development of permanent stromal scars.6
Severe ocular pain, which may be the result of primary afferent nerve injury and inflammation, is not uncommon following the procedure. However, chronic pain persisting more than 1 year following surgery has not been reported. Researchers attribute this to a rapid healing of the superficial corneal wound and positive anti-inflammatory changes in the tear film following CXL.7 While symptoms such as dry eye, foreign body sensation, and photophobia are common following many ocular surface procedures, these symptoms are often absent following CXL.7
The Epi-On Alternative
Epi-on, or transepithelial CXL, is a variation of the original procedure and does not require the epithelium to be removed.2 The technique avoids severing the sub-basal nerve plexus and is associated with less postsurgical pain. However, the difference in pain scores and the need for analgesics between patients receiving the epi-off and epi-on procedures loses significance after only a few days. 7
The clinical advantages of epi-on CXL include increased comfort and reduced risk of complications such as delayed epithelial healing, persistent stromal haze, and infectious keratitis.4,5 By leaving the epithelium intact, the patient may also experience a quicker recovery and be able to resume contact lens wear within 1 week.7
The Efficacy of Epi-On CXL
Despite these advantages, hurdles must be cleared in order to receive FDA approval and implement the epi-on procedure as part of routine clinical practice. Riboflavin, which is used as a photosensitizer, does not easily diffuse into the stroma due to corneal epithelial tight junctions.9 The epithelium also blocks 20% of the administered UV light.5
Studies demonstrate that stromal concentrations of riboflavin increase with exposure time only when the epithelium is removed. A riboflavin concentration of 15 μg/g is obtained for ultraviolet A-induced CXL only in epi-off procedures after riboflavin is applied every 2 minutes for at least 10 minutes. 10, 11
Despite this apparent shortcoming, investigators maintain that adding chemical enhancers to the riboflavin formulation can increase its ability to penetrate the epithelium.3 Benzalkonium chloride, gentamicin and ethylenediamine tetra-acetic acid (EDTA) have all been used to enhance permeability.12, 13
Other research suggests that the epi-off and epi-on procedures demonstrate similar efficacy in keratoconus management. A comparative 2-year follow-up study indicated both procedures were able to slow keratoconus, but the epi-on CXL technique was preferable because of its ability to preserve corneal thickness, improve visual acuity, and reduce postoperative ocular discomfort.1
Another investigation found that epi-on CXL can halt disease progression in corneas as thin as 302 nm and may offer faster visual recovery than the epi-off method. Study participants reported discomfort for only 24 hours post-operatively, with blurred vision for 2 to 3 days.8
Epi-on CXL significantly improves maximum keratometry (Kmax) values and uncorrected distance acuity over 1 year, according to another report.14 Patients who underwent epi-on CXL with dextran-free hypotonic riboflavin showed improvements in both uncorrected and corrected visual acuity with stable keratometry at 12 months following surgery — which is consistent with other epi-on studies, but demonstrates lower efficacy than the epi-off procedure.15
Still, other studies show conflicting results. One such investigation suggests that epi-on and epi-off CXL have comparable effects on visual acuity, topography, pachymetry, and endothelial parameters.4 And 1 report indicates there is a higher improvement in corrected distance visual acuity (CDVA) with the epi-on procedure.5
As research continues to highlight both the benefits and shortcomings of the epi-on CXL procedure, new technologies, including supplemental oxygen and transepithelial riboflavin ophthalmic solutions, are currently under clinical evaluation and may be the future of epi-on CXL in the United States.15
The Optometrist’s Role in Performing Epi-On CXL
Since CXL is currently a procedure reserved for ophthalmologists, optometrists would need extensive training in order to safely and effectively perform the procedure. The epi-on procedure that is presently used involves removal of the corneal epithelium, saturation of the cornea with 0.1% riboflavin solution, and administration of ultraviolet-A (UVA) in 370 wavelengths with 3 mW/cm2 power, 1 cm away from the cornea. The procedure often requires 2 hours of chair time, but an accelerated procedure can shorten treatment time.17
The epi-on procedure will be similar, without debridement, and may require more intense light and an alternative riboflavin formation to help with penetration. State licensure will likely determine whether optometrists can perform the epi-on procedure. But for now, the optometrist’s role is to detect early disease, monitor progression, and make timely referrals for surgery. Optometrists may comanage keratoconus along with an ophthalmologist and provide postoperative contact lens care.
Will the FDA Approve the Epi-On Procedure?
It is possible the FDA will grant approval for epi-on CXL. Currently, the iLink® (Glaukos) epi-off procedure is the only FDA-approved protocol for collagen cross-linking. Glaukos announced positive phase 3 trial results in early 2021 for its epi-on procedure.16 The epi-on procedure achieved its primary efficacy outcome of demonstrating a Kmax treatment effect of -1 D at 6 months vs a placebo (P =.0004). This included a 0.2 diopter (D) improvement in Kmax in the treatment arm and a 0.8 D worsening in Kmax in the placebo arm.16 These results suggest that epi-on treatment can halt or slow keratoconus progression.
Epi-on CXL has several advantages over epi-off CXL including reduced pain and ocular complications. However, studies assessing the procedure’s efficacy on halting keratoconus progression and improving visual acuity show conflicting results. As researchers seek improvements to the epi-on procedure, the FDA’s approval hangs in the balance.
- Cifariello F, Minicucci M, Di Renzo F, et al. Epi-off versus epi-on corneal collagen cross linking in keratoconus patients: a comparative study through 2-Year follow-up. J Ophthalmol. 2018:4947983. doi:10.1155/2018/4947983
- Yuksel E, Cubuk MO, Yalcin NG. Accelerated epithelium-on or accelerated epithelium-off corneal collagen cross-linking: contralateral comparison study. Taiwan J Ophthalmol. 2020;10(1):37-44. doi:10.4103/tjo.tjo_11_19
- Agarwal R, Jain P, Arora R. Complications of corneal collagen cross-linking. Indian J Ophthalmol. 2022;70(5):1466-1474. doi:10.4103/ijo.IJO_1595_21
- Henriquez MA, Hernandez-Sahagun G, Camargo J, Izquierdo L Jr. Accelerated epi-on versus standard epi-off corneal collagen cross-linking for progressive keratoconus in pediatric patients: five years of follow-up. Cornea. 2020;39(12):1493-1498. doi:10.1097/ICO.0000000000002463
- D’Oria F, Palazón A, Alio JL. Corneal collagen cross-linking epithelium-on vs. epithelium-off: a systematic review and meta-analysis. Eye Vis (Lond). 2021;8(1):34. doi:10.1186/s40662-021-00256-0
- Ghanem VC, Ghanem RC, de Oliveira R. Postoperative pain after corneal collagen cross-linking. Cornea. 2013;32(1):20-4. doi:10.1097/ICO.0b013e31824d6fe3
- Van der Valk Bouman ES, Pump H, Borsook D, et al. Pain mechanisms and management in corneal cross-linking: a review. BMJ Open Ophthalmol. 2021;6(1):e000878. doi:10.1136/bmjophth-2021-000878
- Stulting RD, Trattler WB, Woolfson JM, Rubinfeld RS. Corneal crosslinking without epithelial removal. J Cataract Refract Surg. 2018;44(11):1363-70. doi:10.1016/j.jcrs.2018.07.029
- Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg. 2009;35(3):540-6. doi:10.1016/j.jcrs.2008.11.036
- Dong Z, Zhou X. Collagen cross-linking with riboflavin in a femtosecond laser-created pocket in rabbit corneas: 6-month results. Am J Ophthalmol. 2011;152(1):22-27. e1. doi:10.1016/j.ajo.2011.01.010
- Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg. 2009;35(5):893-9. doi:10.1016/j.jcrs.2009.01.009
- Chang S, Chi R, Wu C, Su M. Benzalkonium chloride and gentamicin cause a leak in corneal epithelial cell membrane. Exp Eye Res. 2000;71(1):3-10. doi:10.1006/exer.2000.0849
- Majumdar S, Hippalgaonkar K, Repka M. Effect of chitosan, benzalkonium chloride and ethylenediaminetetraacetic acid on permeation of acyclovir across isolated rabbit cornea. Int J Pharm. 2008;348(1):175-8. doi:10.1016/j.ijpharm.2007.08.017
- Hersh PS, Lai MJ, Gelles JD, Lesniak SP. Transepithelial corneal crosslinking for keratoconus. J Cataract Refract Surg. 2018;44(3):313-22. doi:10.1016/j.jcrs.2017.12.022
- Beckman KA. Epithelium-on corneal collagen cross-linking with hypotonic riboflavin solution in progressive keratoconus. Clin Ophthalmol. 2021;15:2921-2932. doi:10.2147/OPTH.S318317
- Glaukos Announces Positive Phase 3 Trial Results for iLink™ Epi-on Investigational Therapy That Met the Primary Efficacy. Bloomberg Business. Published February 25, 2021. Accessed October 13, 2022. https://www.bloomberg.com/press-releases/2021-02-25/glaukos-announces-positive-phase-3-trial-results-for-ilink-epi-on-investigational-therapy-that-met-the-primary-efficacy
- Touboul D, Efron N, Smadja D, Praud D, Malet F, Colin J. Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. J Refract Surg. 2012;28(11):769-76. doi:10.3928/1081597X-20121016-01