Epithelium-on Corneal Collagen Cross-Linking with Hypotonic Riboflavin Solution in Progressive Keratoconus

Abstract

Introduction: Epithelium-off cross-linking (epi-off CXL) has long been established as the gold standard treatment for progressive keratoconus. Several protocols for epithelium-on (epi-on) CXL have been proposed to help reduce post-operative pain and facilitate visual recovery, but there is no epi-on treatment approach that is currently approved in the United States. The hydrophilic and macromolecular characteristics of conventional epi-off riboflavin formulations may create clinical challenges for absorption through an intact epithelium. This study investigates the clinical efficacy of a dextran-free hypotonic riboflavin ophthalmic solution (Photrexa, Glaukos, Burlington, MA, USA), approved for epi-off CXL, in a novel epi-on CXL protocol. Methods: Twenty-five eyes of 17 patients were treated in this prospective, single-arm study using a hypotonic riboflavin formulation without dextran and low irradiance UVA (3mW/ cm 2 ) for epi-on CXL. Visual acuity, as well as refractive and keratometry outcomes, were observed over 12 months. Results: At 12 months, Kmax was stable with no clinically or statistically significant change from a mean pre-op of 55.4D to 55.9D (p=0.13). Uncorrected and best corrected logMAR visual acuity significantly improved from 0.77 to 0.62 and from 0.17 to 0.12, respectively. There were no significant adverse safety events. Conclusion:Patients who underwent epi-on CXL with dextran-free hypotonic riboflavin demonstrated improvements in uncorrected and best corrected visual acuity with stable keratometry at 12 months post-operatively. The efficacy is consistent with other epi-on studies to date but remains lower than standard epi-off CXL. New technologies, including supplemental oxygen and transepithelial riboflavin ophthalmic solutions, are currently under clinical evaluation and may offer a path forward for epi-on CXL in the USA.

Oxygen-supplemented and topography-guided epithelium-on corneal crosslinking with pulsed irradiation for progressive keratoconus

“…12,13 Clinical modifications such as benzalkonium chloride and other permeability enhancers, hypo-osmolar riboflavin solutions, and substituting conventional dextran viscosity agents with hydroxypropylmethyl cellulose, among others, may reduce this resistance to riboflavin molecules, improve UV-A diffusion, and consequently augment the efficacy of epi-on CXL. 12,[14][15][16][17] According to a recent meta-analysis by D'Oria et al, epion CXL techniques (without oxygen supplementation) have similar efficacy in halting the progression of KC as epioff CXL techniques as well as visual, topographic, endothelial, and pachymetry parameters; however, epi-on CXL has added benefits such as increasing comfort and less epithelial healing-related complications. 18 A few studies have mentioned the incidence of diffuse punctate keratitis after epi-on CXL, which might require application of a soft contact lens for a few days, hence undermining the added benefit of epithelial preservation.…”

“…12,13 Clinical modifications such as benzalkonium chloride and other permeability enhancers, hypo-osmolar riboflavin solutions, and substituting conventional dextran viscosity agents with hydroxypropylmethyl cellulose, among others, may reduce this resistance to riboflavin molecules, improve UV-A diffusion, and consequently augment the efficacy of epi-on CXL. 12,14–17…”

Oxygen-supplemented transepithelial-accelerated corneal crosslinking with pulsed irradiation for progressive keratoconus: 1 year outcomes

“…Additionally, using BAC permeability enhancer, hypo-osmolar riboflavin solutions, substituting conventional Dextran ophthalmic viscosity agent agent with HPMC, removing the mucin tear layer from the epithelial surface with a sterile sponge, and rinsing away excess riboflavin solution on the corneal surface prior to UV-A irradiation have been shown to improve epion CXL outcomes. 16,[18][19][20]26 Despite these epi-on CXL procedural modifications, a recent meta-analysis review still indicated reduced efficacy with epi-on CXL when compared with the conventional epi-off CXL. 32 In another study, retreatment was required in one third of the study eyes treated with the epi-on procedure.…”

“…Riboflavin corneal absorption was not confirmed during this study but was assumed based on previous studies. 26,27…”

“…Riboflavin corneal absorption was not confirmed during this study but was assumed based on previous studies. 26,27 During the O 2 epi-on CXL procedure, a single-use, wearable oxygen delivery device (Boost Goggles, Glaukos Corp.), connected to a humidified, medical grade oxygen source, was used to create a hyperoxic, periocular environment for the treated cornea. The oxygen level within the Boost Goggles was verified using a noninvasive oxygen sensor to be more than 90% and preferably at 95% prior to initiating UV-A emission, and the oxygen flow was maintained between 1.5 and 2 L per minute throughout the treatment procedure.…”