IN 2016, the U.S. Food and Drug Administration (FDA) approved a procedure for corneal cross-linking (CXL) that requires removal of the corneal epithelium (epi-off) to allow for appropriate corneal saturation of riboflavin. It was reported on a review of outcomes from a multicenter, prospective, randomized, sham-controlled clinical trial in support of an FDA New Drug Application for that CXL procedure that Kmax flattened by 1.6D and best-corrected visual acuity (VA) improved by an average of 5.7 logMAR letters (Greenstein and Hersch, 2021). Additionally, corneal topography, ocular aberrations, and subjective visual function improved after this epi-off system of CXL.  

The most commonly reported adverse event after epi-off CXL was stromal haze, with a rate of 57%. However, at 12 months, only two eyes had remaining stromal haze, and one eye in the keratoconus treatment group (of 102 treated eyes) had a stromal scar. Post CXL treatment, there was worsening of VA and steepening of the cornea for one month. This was followed by stabilization between one and three months and improvement between three and 12 months after treatment. 

DEVELOPMENTS IN TRANSEPITHELIAL (“EPI-ON”) CXL 

To treat the earliest forms of keratoconus prior to significant vision loss, there needs to be a treatment method that significantly reduces procedure risk while achieving efficacy. Transepithelial, commonly termed “epithelium on (epi-on)” CXL, involves the administration of riboflavin without the need to remove the corneal epithelium prior to the application of UV light exposure. The advantages of this form of CXL include reduced risk associated with the removal of the epithelium, reduced post-treatment discomfort, and rapid visual recovery. 

Early limitations of epi-on CXL were due to reduced efficacy associated with limited riboflavin corneal penetration through an intact epithelium (Vilares-Morgado et al, 2024; Nath et al, 2021). Newer riboflavin formulations appear to have addressed that issue.

Another study described the use of a unique formulation of riboflavin that contained sodium iodide, which acted as an active pharmaceutical ingredient (API) along with other procedural elements that optimized riboflavin penetration. This resulted in a transepithelial technique that effectively halted keratoconus progression (Stulting et al, 2018). Epstein and colleagues (2023) reported on a phase 2 clinical trial utilizing this methodology: 1,605 keratoconus subjects were treated with a drug-device combination epi-on cross-linking system. Researchers reported robust improvements in VA sustained over 12 months in a keratoconus population (not known to spontaneously regress), including a large subset of subjects 21 years old or younger, with minimal adverse events. The authors felt the results supported this method as a safer, noninvasive CXL technique to arrest the progression of keratoconus.

PEDIATRIC KC AND CXL

A retrospective study looked at keratoconus children ages 9 to 19 and found a disease progression rate of 88% (Chatzis and Hafezi, 2012). Additionally from this study, the investigators proposed that documenting progression was not mandatory and that CXL should be performed at diagnosis in the pediatric population. Others stated that keratoconus is likely to be more aggressive in the pediatric population, with a higher risk of progression and visual loss (Polido et al, 2022). Following a literature review supporting the efficacy of CXL in the pediatric population, they emphasized the importance of early treatment and an individualized approach to management. 

SUMMARY 

Keratoconus is a progressive disease with significant visual and quality of life implications. CXL can slow progression of the disease in a very high proportion of patients. Safe and effective CXL treatment predicates the importance of early disease diagnosis. 

REFERENCES

1. Godefrooij DA, de Wit GA, Uiterwaal CS, Imhof SM, Wisse RP. Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study. Am J Ophthalmol. 2017 Mar;175:169-172.

2. Harthan JS, Gelles JD, Block SS, et al. Prevalence of Keratoconus Based on Scheimpflug Corneal Tomography Metrics in a Pediatric Population From a Chicago-Based School Age Vision Clinic. Eye Contact Lens. 2024 Mar 1;50:121-125.

3. Greenstein SA, Hersh PS. Corneal Crosslinking for Progressive Keratoconus and Corneal Ectasia: Summary of US Multicenter and Subgroup Clinical Trials. Transl Vis Sci Technol. 2021 Apr 29;10:13.

4. Vilares-Morgado R, Ferreira AM, Cunha AM, et al. Transepithelial Accelerated Crosslinking for Progressive Keratoconus: A Critical Analysis of Medium-Term Treatment Outcomes. Clin Ophthalmol. 2024 Feb 8; 18:393-407.

5. Nath S, Shen C, Koziarz A, et al. Transepithelial versus Epithelium-off Corneal Collagen Cross-linking for Corneal Ectasia: A Systematic Review and Meta-analysis. Ophthalmology. 2021 Aug;128:1150-1160.

6. Stulting RD, Trattler WB, Woolfson JM, Rubinfeld RS. Corneal crosslinking without epithelial removal. J Cataract Refract Surg. 2018 Nov;44:1363-1370. 

7. Epstein RJ, Belin MW, Gravemann D, Littner R, Rubinfeld RS. EpiSmart Crosslinking for Keratoconus: A Phase 2 Study. Cornea. 2023 Jul 1;42:858-866.

8. Chatzis N, Hafezi F. Progression of keratoconus and efficacy of corneal collagen cross-linking in children and adolescents. J Refrac Surg. 2012;28:753-758. 

9. Polido J, Dos Xavier Santos Araújo ME, Alexander JG, Cabral T, Ambrósio R Jr, Freitas D. Pediatric Crosslinking: Current Protocols and Approach. Ophthalmol Ther. 2022 Jun;11:983-999.

Errata