Epi-Off Versus Epi-On: the Conversation Continues

With a worldwide incidence of patients with keratoconus being one in 700 to 750 adults and keratoconus suspects being one in 223 pediatrics,^1,2 optometrists must understand the threat of ectasia—progressive weakening of the cornea post-refractive surgery—and be aware of any new solutions to halt the progression of this condition. Patients with progressive keratoconus have corneal stromal thinning with steepening and protrusion, which often manifests clinically during the teen years and into the twenties, leading to the development of increasing myopia and astigmatism. Over time, as the cornea warps, the astigmatism becomes irregular, leading to further decreased BCVA and a reduced quality of life.³ This doesn’t have to be the case, however, if a diagnosis is made early and treatment is initiated swiftly. Below is a breakdown of our approved treatment options.

CROSSLINKING

Epi-Off Procedures

In 2016, epithelial-off (epi-off) corneal crosslinking (CXL) received FDA approval for progressive keratoconus and refractive ectasia to slow or stop progression and is still the only FDA-approved CXL method.^4,5 Epithelial removal is beneficial because the corneal epithelium creates a barrier against riboflavin penetration and can reduce its effectiveness.

The first step is to create a central 7 mm to 9 mm epithelial defect through debridement. Then, 0.1% riboflavin ophthalmic solution (Photrexa, Glaukos) or 0.1% riboflavin ophthalmic solution/20% dextran (Photrexa Viscous, Glaukos) is applied to the cornea for 30 minutes. Next, the cornea is exposed to 30 minutes of ultraviolet type A (UVA) light (370 nm) while the riboflavin/dextran drops are continuously instilled every 3 to 5 minutes (Figure). Combining riboflavin with UVA light creates covalent bonds, stiffening the cornea. Oxygen is the catalyst that keeps the reaction going. To finish the procedure, a bandage contact lens is applied, and the patient is started on a postoperative regimen of topical antibiotic alone or plus steroid.

Crosslinking is now performed regularly in the United States with a 95% success rate, defined as less than 2.00 D of maximum keratometry (Kmax) steepening over 1 year.⁴ The phase 3 FDA clinical trials concluded that uncorrected visual acuity, corrected visual acuity, and maximum K value all improved 1 year after treatment and that CXL has a good safety profile.

One study reported that 81.8% of eyes with keratoconus had stable topography and 50% of eyes with refractive ectasia had stable topography 10 years post-epi-off CXL. The study also stated, “The BCVA also was stable in 84.2% of the entire cohort, in 100% of the keratoconic eyes, and in 62.5% of the ectasia eyes.”⁶

Despite epi-off’s success, removing the epithelium leads to increased postoperative discomfort and transient reductions in acuity for several days.⁴ Bandage contact lenses are placed for comfort, and typically removed at the 1-week follow-up, when the epithelium is closed. Patients may experience worse vision immediately after the procedure and can expect to notice stabilization around 4 to 8 weeks. Complete visual recovery can take 3 to 6 months and tends to fluctuate during this time.

Epi-On Procedures

To combat postoperative pain, extended procedure time, and slower visual recovery, epithelial-on (epi-on) CXL procedures have begun to enter the conversation. Keeping the epithelium intact promotes a quicker recovery and reduces postoperative discomfort and complications, such as scarring and corneal haze.

Numerous trials have detailed the alteration of riboflavin formulations to penetrate an intact epithelium and alter UVA delivery through accelerated and pulsed methods. Various methods for riboflavin absorption into the stroma while maintaining epithelial integrity include applying topical anesthetics, changing the concentration of riboflavin, increasing the application time of riboflavin, partial epithelial disruption, and iontophoresis. Due to the negative charge and hydrophilicity of riboflavin, iontophoresis could help move it through the hydrophobic corneal epithelium.

Recently, a phase 3 trial was conducted for Epioxa (Glaukos), an epi-on approach to crosslinking. This multicenter, randomized, placebo- and sham-controlled trial involved 312 eyes to evaluate the safety and efficacy of stabilizing Kmax in progressive keratoconus.⁷ Epioxa is a protocol designed for improved riboflavin corneal penetration, pulsed UVA irradiation with a shorter exposure time, and increased levels of oxygen supplementation. Significant efficacy was demonstrated with a Kmax treatment difference of -1.00 D (0.20 D flattening in the treatment group compared with 0.80 D steepening in the control group) from baseline to 12 months. Overall, the procedure showed good tolerance levels with no reports of systemic effects, changes in corneal endothelial cell counts, or serious adverse ocular side effects.⁷

COMPARE AND CONTRAST

For epi-on crosslinking to surpass epi-off, there needs to be a consistent protocol. Once this happens and the success rates and potential drawbacks are further explored, epi-on will be a great addition to stalling ectasia progression. The advantages to the epi-on approach with decreased pain, potential for reducing infection rates and scarring, and quicker visual recovery are hard to pass up for both patient and practitioner. The importance of efficacy cannot be overlooked, and that will be the largest hurdle for epi-on. Until further studies are completed to test the efficacy of epi-on, epi-off crosslinking will remain the gold standard.