In 2003, Wollensak et al. first reported that corneal crosslinking (CXL) is effective in reducing the corneal curvature and improving the visual acuity of patients with progressive keratoconus (KC).¹

CXL involves saturating the corneal stroma with riboflavin and then exposing it to ultraviolet light. The interaction of riboflavin molecules with UVA light stimulates the formation of covalent bonds between collagen molecules among themselves and proteoglycan molecules among themselves, increasing the tensile strength of the cornea.²

Riboflavin solutions available at the time of the initial report in 2003 would not penetrate the corneal epithelium, so the central corneal epithelium was removed to allow passage of topically applied riboflavin into the corneal stroma prior to UVA light exposure.

CXL Approval in the US

I obtained a physician-sponsored IND for CXL with epithelial removal (Epi-OFF CXL) and, on January 5, 2008, performed the first case of CXL in the United States as part of a clinical trial that eventually led to FDA approval of the Epi-OFF procedure by Avedro on April 15, 2016.³ I continued to perform Epi-OFF CXL experimentally as part of other clinical studies for the next 5 years.

The study that led to FDA approval of epi-OFF CXL showed an average flattening of 1.6 D of Kmax at 1 year in the treatment group of keratoconus eye with 31% flattening more than 2 D.³ However, Epi-OFF CXL has a number of potential consequences as well. It causes severe pain, which can persist for up to 1 week after treatment, can lead to corneal haze,⁴ can delay return of preoperative visual acuity for weeks to months after treatment, can lead to sterile infiltrates that are seen in up to 7.6% of eyes,⁴ and causes visually significant corneal scarring in 2.9% of eyes.⁴ There are multiple published reports of infectious keratitis after Epi-OFF CXL due to gram-positive bacteria, gram-negative bacteria, fungi, herpes simplex virus, Acanthamoeba, and even Microsporidia. The incidence of infectious keratitis has been reported to be 0.3% in one study and 1.3% in another.⁵ Epi-OFF CXL can even lead to corneal perforation with severe visual loss and the need for emergent corneal transplantation.⁵

Where CXL is Headed

In 2013, I had the opportunity to participate in a physician-sponsored clinical trial of CXL without epithelial removal (Epi-ON CXL). The technology was very different from that published by others, who first reported enthusiastic results but later noted progression of KC between years 1 and 2 postoperatively.^6,7 Importantly, it included a method of determining the amount of riboflavin that had reached the corneal stroma and pulsed light that allowed oxygen, which enhances cross-linking, to diffuse into the stroma during the dark phase of UVA exposure.⁸

We eventually published the results of Epi-ON CXL performed on 592 eyes of 363 patients at our practice, 49 of whom were less than 19 years old and very likely to progress.⁹ We did not note progression in any eyes, which we defined as an increase of more than 1 D Kmax and loss of more than 1 line of CDVA. Extended follow-up showed no loss of effect between 1 and 2 years postoperatively. Importantly, we did not observe any complications from the CXL procedure.

Studies are ongoing to maximize corneal stabilization with Epi-ON protocols. Glaukos, which now owns Avedro, has completed enrollment in a pivotal Phase 3 clinical trial to evaluate the safety and efficacy of a system for epi-on corneal cross-linking to treat progressive KC.

Epi-ON CXL is clearly the way of the future. Performed with an effective protocol, it can produce outcomes at least as good as those of Epi-OFF CXL, without the possibility of complications. I look forward to the day when an effective Epi-ON procedure is approved by the FDA and widely available in the United States. CP

References:

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. Zhang Y, Conrad AH, Conrad GW. Effects of ultraviolet-A and riboflavin on the interaction of collagen and proteoglycans during corneal cross-linking. J Biol Chem. 2011;286(15):13011-13022.
3. Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK. United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment. Ophthalmology. 2017;124(9):1259-1270.
4. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35(8):1358-1362.
5. Maharana PK, Sahay P, Sujeeth M, et al. Microbial Keratitis After Accelerated Corneal Collagen Cross-Linking in Keratoconus. Cornea. 2018;37(2):162-167.
6. Caporossi A, Mazzotta C, Paradiso AL, Baiocchi S, Marigliani D, Caporossi T. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg. 2013;39(8):1157-1163.
7. Soeters N, Wisse RP, Godefrooij DA, Imhof SM, Tahzib NG. 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 e823.
8. Rubinfeld RS, Stulting RD, Gum GG, Talamo JH. Quantitative analysis of corneal stromal riboflavin concentration without epithelial removal. J Cataract Refract Surg. 2018;44(2):237-242.
9. Stulting RD, Trattler WB, Woolfson JM, Rubinfeld RS. Corneal crosslinking without epithelial removal. J Cataract Refract Surg. 2018;44(11):1363-1370.

 

DR. STULTING is director of the Stulting Research Center, Woolfson Eye Institute, Professor of Ophthalmology, Emeritus, Emory University, past President of the American Society of Cataract and Refractive Surgery (ASCRS), past director of the Eye Bank Association of America (EBAA), past editor-in-chief of Cornea, and an editorial board member of the Journal of Cataract and Refractive Surgery.