• Cornea/External Disease
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    Introduction

    Since Dr. Theo Seiler and colleagues introduced corneal cross-linking (CXL) in 20031, the procedure has gained significant momentum in the treatment of corneal diseases, particularly corneal ectasia. Using a combination of ultraviolet light (UVA) and riboflavin eye drops, corneal cross-linking has taken a relatively simple combination and created an intriguing treatment paradigm for not only corneal ectatic diseases such as keratoconus, but possibly other indications such as infectious keratitis.2 Seiler and colleagues made popular the “Dresden Protocol” specifying the parameters of CXL, which has now blossomed in to a multitude of variations and modifications aimed at reducing complications, side effects and length of the procedure. We will describe the evolution of corneal cross-linking, and examine its future in the treatment of corneal disease.

    The Dresden Protocol

    Seiler and co-workers, developed many of the primary animal models and first clinical trials of corneal cross-linking. Their primary cohort of patients all had keratoconus.  By cross-linking corneal collagen, the group hoped to provide the first treatment for keratoconus that actually halted progression of the disease, instead of simply improving refractive status with rigid gas permeable contact lenses or intracorneal rings. Combining CXL with a refractive treatment would then be the ultimate goal, by both preventing progression and rehabilitating vision.

    The original protocol implemented by Seiler and colleagues remains the standard cross-linking protocol today. Dubbed the “Dresden Protocol”, the technique involves first de-epithelializing the central (> 7mm) cornea. Riboflavin solution (0.1% riboflavin-5-phosphate and 20% dextran T-500) is then applied as a photosensitizer, with an initial 5 minute pre-treatment application followed by additional applications every 5 minutes for the duration of the treatment. The UVA treatment is applied at a 1cm distance for a total of 30 minutes, using 370 nm UVA with an irradiance of 3 mW/cm.1,2

    Seiler and colleagues’ groundbreaking work introduced a number of key corneal changes. Their work in animal models showed significant increases in corneal rigidity following CXL treatments,3 a finding that has been repeated in various clinical trials as well.4 In addition, the diameter of the collagen fibers within the cornea has been shown to increase following CXL treatment, a likely key contributing factor in the arrest of ectasia progression.4 

    Maintaining the Epithelium and Other Protocol Modifications

    While the original work demonstrated CXL to be an apparently safe and well tolerated procedure, a number of side effects and complications were later recognized. For one, epithelial healing could be slowed, leading to an increased risk of infection. Likewise, the large iatrogenic corneal abrasion caused significant pain and discomfort for the initial few days following the procedure. In addition, UVA exposure carried a risk to the corneal endothelium particularly when the corneal thickness dipped below 400 microns, a finding not uncommon in this keratoconus population.5

    Based on these findings, many investigators began exploring “epithelium-on” CXL (Table 1). With the hope of reducing pain, risk of infection and melting, and risk of endothelial toxicity, corneal cross-linking with preservation of the corneal epithelium has been extensively studied with and without adjunctive pharmacologics to increase riboflavin pentration.6 While the depth of the treatment is reduced along with decreased discomfort, the question as to whether the resulting treatment provides the necessary cessation of ectasia progression remains.7

    In addition to “epi-on” treatment protocols, still other modifications of the treatment have been explored. In particular, the lengthy treatment time has been examined with high fluence CXL. By increasing the irradiance of the UVA while shortening the duration, investigators have hoped to mimic results of the original Dresden Protocol in less lengthy procedures, with some protocols shortening treatment times down to 3 minutes.8,9

    Other Indications

    While originally targeted at halting the progression of keratoconus, CXL has subsequently been used in other ectatic disorders. Particularly, the use of CXL in post-LASIK ectasia has also been studied.10 Given the underlying similarity in ectasia, outcomes have likewise been similar in slowing down progression.

    Broader indications for corneal cross-linking may also be on the horizon. Intractable infectious keratitis from a variety of pathogens, including Acanthamoeba or other parasites, mycobacteria, fungus, or bacteria, has been adjunctively treated with some success using CXL. Further investigation into the use of UVA as a photo-activator and riboflavin as a chromophore may help elucidate the role of CXL in infection.11 Additionally, the effect of CXL on reducing stromal edema has been used in the treatment of bullous keratopathy,12 with potential other uses still to be explored.

    Conclusion

    Corneal cross-linking has gained widespread popularity, originating in Europe and now practiced in Asia, South America, and across the globe. As of this week, the procedure was finally approved in the United States. Long term safety and efficacy data continues to be elucidated for CXL, as other novel indications also continue to endorse the concept may have a more permanent place among corneal therapeutics.

     

    Table 1The evolution of corneal cross-linking has led to a number of advances in both treatment regimens and indications of CXL.

    Advancement in CXL

    Impact

    Epithelium-On

    Reduction in pain, risk of infection and melting, and endothelial toxicity, although unclear long term efficacy versus standard epithelium-off protocol.

    Pharmacologic adjunctive therapy

    Used in conjunction with epithelium-on techniques, agents such as benzalkonium chloride and hypotonic riboflavin increased penetration of riboflavin improving efficacy.

    High fluence

    Higher energy over shorter duration led to faster treatments.

    Treatment of post-LASIK ectasia

    Expanded indications to other ectatic diseases with proposed similar efficacy.

    Treatment of infectious keratitis

    Additional treatment modality in the armamentarium against bacterial, fungal, parasitic, and mycobacterial disease.

    Treatment of bullous keratopathy

    Allowed for potential postponement of therapeutic keratoplasty.

     

    References

    1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a–induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620–627.
    2. Iseli HP, Thiel MA, Hafezi F, et al. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea 2008;27:590–594.
    3. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998;66:97–103.
    4. Beshtawi IM, O’Donnell C, Radhakrishnan H. Biomechanical properties of corneal tissue after ultraviolet-A–riboflavin crosslinking. J Cataract Refract Surg 2013;39:451–462.
    5. Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg 2009;35:540–546.
    6. Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in keratoconus. J Refract Surg 2010;26:942–948.
    7. Soeters N, Wisse RPL, Godefrooij DA, et al. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: A randomized controlled trial. Am J Ophthalmol 2015;159:821–828.e3.
    8. Kanellopoulos AJ. Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus. Clin Ophthalmol Auckl NZ 2012;6:97–101.
    9. Shetty R, Matalia H, Nuijts R, et al. Safety profile of accelerated corneal cross-linking versus conventional cross-linking: a comparative study on ex vivo-cultured limbal epithelial cells. Br J Ophthalmol 2015;99:272–280.
    10. Marino GK, Torricelli AAM, Giacomin N, et al. Accelerated Corneal Collagen Cross-linking for Postoperative LASIK Ectasia: Two-Year Outcomes. J Refract Surg 2015;31:380–384.
    11. Hafezi F, Tabibian D, Richoz O. PACK-CXL: Corneal cross-linking for treatment of infectious keratitis. J Ophthalmic Vis Res 2015;10:77.
    12. Wollensak G, Aurich H, Wirbelauer C, Pham D-T. Potential use of riboflavin/UVA cross-linking in bullous keratopathy. Ophthalmic Res 2009;41:114–117.