Corneal crosslinking (CXL) with riboflavin (vitamin B2) and UVA light delays or halts the progression of corneal ectasia by increasing the strength and rigidity of the corneal covalent collagen bonds. This direct interaction between riboflavin and UV light creates oxygen free-radicals that are consumed by reactive corneal proteins, thus creating and stabilizing the proteoglycans and collagen bonds.¹

Bottom line: no need for corneal transplantation in keratoconus.

While corneal ectasia, the noninflammatory steepening and thinning of the corneal stroma, is most commonly associated with keratoconus and therefore the primary beneficiary of CXL, other causes of ectasia and corneal diseases (LASIK, pellucid marginal degeneration, bullous keratopathy and corneal infections)^2,3 could also benefit from CXL or a version of it.

AN UNDERESTIMATED PREVALENCE?

The incidence and prevalence of keratoconus have likely been underestimated. A 48-year epidemiological study of the prevalence of keratoconus in Olmstead County, Minn., indicated 54.5 cases per 100,000.⁴ A 2016 database study of keratoconus in the Netherlands revealed an estimated prevalence of 265 cases per 100,000, a five-fold increase over previous statistics.⁵ Extrapolating both these rates of prevalence to the current U.S. population, keratoconus has the potential to negatively impact the life of between 178,000 and 865,000 Americans.⁶ The average age at onset is 15.39 ± 3.95 years with progression in the 20s and stabilization in the early 40s.⁷ Because keratoconus affects young people, the average lifetime ophthalmic cost alone of the disease is substantial, estimated to be approximately $25,168.⁸

New diagnostic modalities have enabled detection of early corneal changes or ‘forme fruste’ disease.⁹ According to Christopher Rapuano, MD, director of the Corneal Service at the Will’s Eye Hospital in Philadelphia, “Physicians are able to make the diagonisis of keratoconus earlier which is more relevant because there is now an effective method of treatment.” He emphasized that keratoconus is a multifactorial process with genetic, environmental and social factors associated, but the most important preventive measure is to stop eye rubbing.

PATIENT SELECTION CRITERION

“By its very nature, keratoconus is a progressive disease, so CXL is indicated at diagnosis, regardless of age,” says John Berdahl, MD, from Sioux Falls, S.D. He has been involved with corneal cross-linking since 2011, through participation in clinical trials leading to the first cross-linking approved treatment.

According to the 2015 Global Delphi Panel of Keratoconus and Ectatic Diseases, in which Dr. Rapuano participated, CXL is most effective when used early on a progressing cornea and the fellow eye, even in the absence of progression. The panelists concluded that true unilateral disease does not exist.² If the patient is too young and the corneal stroma too plastic, the procedure may need to be repeated.

Published case studies, however, have shown success following retreatment. Moorfields Eye Hospital in London, UK set the upper age limit for CXL at 40 years of age at which point the corneal collagen becomes naturally stiffer with diminished progression.¹⁰

APPROVAL — FINALLY

In April 2016, the FDA approved the KXL system (Avedro) for CXL, which emits continuous UVA radiation at a wavelength of 365 nm at an intensity of 3 mW/cm², with riboflavin 5’-phosphate sodium photoenhancers, Photrexa 0.146% and Photrexa 0.146% viscous in 20% dextran for CXL in progressive keratoconus.¹¹ Two months later, CXL received subsequent approval for ectasia following refractive surgery.

Approval followed three controlled clinical studies on a total of 205 patients with progressive keratoconus and 179 patients with corneal ectasia following LASIK. The studies demonstrated the safety and effectiveness of CXL to reduce and maintain the corneal curvature over a 12-month period compared to sham controls.¹¹

In 2015, the department of Ophthalmology at the University Hospital in Dresden, Germany, published its 10-year results of CXL involving the 9-mm, epithelial-off Dresden protocol using 0.15 isotonic riboflavin in 20% dextran and 3 mW/cm² for 30 minutes. The small study involving 34 eyes of 24 patients showed that CXL was effective in halting keratoconus and achieving long-term stabilization. The mean apical keratometry (K) values were 61.5 D preoperatively and 55.3 D 10 years postoperatively, with a mean improvement of corrected distance visual acuity of 0.14 logMAR. Two eyes required retreatment due to progression, both with subsequent stabilization. One eye had a permanent stromal corneal scar, and 13 eyes had asymptomatic persistent haze.¹²

INDICATIONS FOR CXL

Kashif Baig, MD, in Ottawa, Canada, has performed almost 950 CXL procedures since its approval by Health Canada in 2011. The majority were keratoconus patients; however 2.5% were postrefractive ectasia cases secondary to LASIK, PRK and RK procedures; in the latter particularly to minimize patients’ daily visual fluctuations.

Because UV light has antimicrobial properties, Dr. Baig and colleagues have used CXL for infectious keratitis. “It is particularly effective at halting bacterial infections, but also in select viral and fungal cases,” Dr. Baig says. CXL is generally used in conjunction with anti-infective therapy, but photo-activated chromophore for infectious keratitis (PACK-CXL) may have a place as first-line therapy in treating antimicrobial-resistant infections.^13,14

Bullous keratopathy is a dysfunction of the corneal endothelium resulting in edema and possible opacification. Patients present with pain and photophobia. Traditional treatment is hypertonic saline, topical steroids and bandage contact lenses, while in advanced cases penetrating keratoplasty or automated lamellar keratectomy may be required.¹⁵

CXL has been shown to compact the cornea, decreasing edema. A 2015 study in Pakistan on 24 eyes that were treated with accelerated CXL of 9mW/cm² for 10 minutes revealed a mean central corneal thickness decrease of 112.75 ± 52.32 µm with decreased symptomology.¹⁶ The beneficial effects of CXL on bullous keratopathy may be short lived, however, due to continued aqueous influx from endothelial decompensation.

RISK FACTORS AND RECOMMENDATIONS

A corneal thickness of 400 µm or greater is required for CXL, otherwise there is risk of endothelial cell loss. Some have attempted CXL in thinner corneas using hypo-osmolar riboflavin diluted with 0.9% sodium chloride to induce cornel swelling, but found the threat to the endothelium increases.¹⁷ The endothelial damage threshold is an irradiance of 0.35 mW/cm², which is approximately twice the amount that reaches the corneal endothelium when using the epithelium-off Dresden protocol.¹⁸ If cross-linking a thin cornea, accelerated CXL is recommended due to decreased penetration. Using 2% pilocarpine prior to CXL constricts the pupil, thus minimizing UV exposure to the posterior pole.

Contraindications include but aren’t limited to corneal scarring, poor wound healing, concurrent autoimmune disease and previous herpetic corneal ulcers. CXL has resulted in herpetic ulceration of the cornea without known prior corneal infection. It’s possible the introduction of UVA radiation can stimulate the herpes simplex virus in a previously unaffected cornea.¹⁹

ACCELERATED CXL

The resultant photochemical reaction in CXL is dependent upon the total energy dose delivered to the cornea. In theory, 3 mW/cm² for 30 minutes is equivalent in safety and effectiveness to 9 mW/cm² for 10 minutes and 18 mW/cm² for five minutes at a constant energy dose of 5.4 J/cm².²⁰ Accelerated CXL, more easily tolerated by patients, is generally considered 9 mW/cm² for 10 minutes. The irradiance may be pulsed or continuous. Pulsed UV light may improve efficiency by allowing for diffusion of oxygen during the pauses, producing a deeper demarcation line.²¹ Accelerated CXL has not been FDA approved.

A 2015 study comparing 19 eyes of patients who received the standard treatment for 30 minutes to 19 eyes that received accelerated treatment for five minutes revealed that overall, standard CXL delivered a more effective flattening of the cornea.²²

EPI ON VS. EPI OFF

Epithelium-off CXL complications are directly tied to debridement, which is achieved with brush removal or by 50 µm phototherapeutic keratectomy. Recovery is attained with a bandage contact lens. Transepithelial, or epithelium-on CXL, despite a less painful recovery, is not as effective with only about one-third the amount of stromal penetration and a greater risk of progression, says Yaron Rabinowitz, MD, a corneal and refractive surgeon in Beverly Hills, Calif. A literature review comparing epithelium-on to epithelium-off results showed a mean reduction in Kmax of -0.82 D after a year when the epithelium was removed in 91% of the studies, while the epithelium-on procedure gave a median progression of 0.6 D in Kmax in 75% of the studies.²³

Better riboflavin penetration or a photoenhancer substrate with a smaller molecular weight is required for epithelium-on CXL to be successful. Iontophoresis uses an electrical gradient to drive the negatively charged riboflavin molecules across the intact epithelium to enhance penetration.²⁴ One-year results of a prospective comparative study of epithelium-on CXL with iontophoresis to epithelium-off CXL showed fewer aberrations and fewer incidence of stromal opacities and no further progression. The reduction in Kmax, however, was only -0.31 ± 1.87 D with epi-on compared to -1.05 ± 1.51 D with epi-off.²⁵

COMBINATION THERAPIES

Dr. Rabinowitz has done more than 700 CXL procedures under an investigational device exemption, comparing CXL to CXL in conjunction with intracorneal ring segments (Intacs). The primary goal of CXL is not to improve visual acuity but to halt progression, he says. “The purpose of using Intacs is to flatten the steeper part of the cornea, reducing astigmatism while improving vision and contact lens tolerance. Expectations must be managed carefully, because 20% to 30% of people who have the combination procedure do not achieve improved acuity.”

Lasik Xtra, LASIK and CXL combined for the treatment of hyperopia, is in use in more that 50 countries, but not the United States. The goal is to strengthen the cornea, lowering enhancement rates and preventing iatrogenic ectasia. Kanellopoulous and Kahn, in Greece, reported approximately 0.5 D less refractive regression in a cohort of 34 hyperopic patients who received Lasik Xtra in one eye and LASIK without CXL in the contralateral eye.²⁶ Less myopic refractive shift was also shown after two years with Lasik Xtra in a cohort of 140 eyes, 65 who received myopic Lasik Xtra as compared to the 75 eyes that received LASIK alone.²⁷

Photorefractive intrastromal crosslinking (PiXL) uses CXL to topographically target and differentially correct refractive error in low myopia. A prospective trial of 39 eyes divided into two groups demonstrated a mean uncorrected acuity of 20/20 at 12 months. A second study used a transepithelium approach, showing a mean reduction in myopia of 0.75 D after nine months.²⁸

CXL as an adjunct to refractive treatment is still in its infancy. The benefits are not yet known and the cost may be prohibitive. Some of those interviewed said that keratoconus CXL can cost at minimum $3,000 per patient.

CONCLUSION

Early diagnosis of keratoconus and bilateral treatment with CXL with riboflavin and UVA are essential to preventing vision loss. They have been proven to delay or halt ectasia progression by strengthening corneal collagen bonds, preventing the need for corneal transplantation. FDA approval of accelerated CXL and LASIK Xtra as well as better riboflavin penetration for epithelium-on procedures will make CXL a mainstay for the treatment for other corneal disorders including infectious keratitis and bullous keratopathy. OM

For references, see the online version of this article.

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