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Peer Review | Mar/Apr '14

Corneal Collagen Crosslinking in the Literature: An Update

Applications of corneal collagen crosslinking (CXL) have evolved into a diverse number of uses in the past few years. Since the last Peer Review article on advances in CXL1 was published in the first issue of MillennialEYE, recent strides have been made to refine the procedure and improve outcomes. This article will focus on a few key updates in CXL applications, namely management of keratoconus, hyperopic LASIK, and microbial keratitis.

For review, CXL is a procedure that creates stiffening of the stroma by photochemically enhancing covalent bonds between collagen fibrils caused by riboflavin drops reacting with ultraviolet A (UVA) light.2 Under topical anesthesia, the corneal epithelium is usually removed to increase riboflavin penetration. Riboflavin is then placed on the cornea for a period of time, after which the stroma is exposed to UVA light in various intervals, with additional riboflavin and hydration given in between sequences.2,3


Keratoconus, affecting roughly one in 1,000 people, is a progressive condition in which the cornea thins and becomes cone-shaped over time.2 The only current treatment targeted toward prevention of disease progression is CXL.2,4

A recent advancement from the traditional CXL protocol is a newer rapid CXL treatment protocol that has emerged in order to allow shortened UVA exposure time. Despite shorter UVA exposure, the overall total energy used is similar because the rapid protocol uses increased irradiance.4 In a recent randomized, controlled trial comparing conventional CXL with rapid CXL, results were similar with respect to improvement in BCVA, reduction of maximum K, and halt in ectasia progression. Of note, endothelial cell loss was lower in the rapid CXL group.5

Transepithelial CXL, in which the epithelium is left intact and riboflavin is delivered with greater epithelial permeability by various chemicals, is also currently being tested.4 By keeping the epithelium intact, the risk of haze and infection ideally should decrease, thereby allowing improved patient comfort. The outcomes are still controversial, as a recent retrospective review comparing transepithelial CXL with conventional CXL has shown limited benefit in the newer method with respect to halting the progression of keratoconus.6 However, a group from Toulouse, France, recently published promising results using iontophoresis for transepithelial CXL in a rabbit model.7 This technology seems to allow for better riboflavin penetration and improved effectiveness of CXL.


Hyperopic LASIK has been long known to have high risk of regression over the first few postoperative years. In an effort to prevent such regression, there has been an attempt to prophylactically treat these patients with CXL. Kanellopoulos and Kahn reported a prospective controlled study of 34 patients who underwent topographic-guided hyperopic LASIK, with one eye randomly selected to receive simultaneous rapid-protocol CXL.8 Interestingly, eyes that did not receive CXL showed a statistically significant greater amount of regression than the fellow eye. Another recent report with a much smaller cohort (five eyes) showed similar results.9

These studies have shown that not only is adjuvant corneal crosslinking with riboflavin application under the flap followed by UV light safe when combined with hyperopic LASIK, but also that it seems to be effective in preventing the eventual corneal flattening and regression that occurs after hyperopic LASIK.


Despite new-generation antimicrobials, there are a growing number of unfortunate multiresistant organisms causing corneal ulcers that can be difficult to treat. There have been several case reports of using nucleotide-disrupting qualities of CXL to treat microbial keratitis, but a comprehensive meta-analysis was recently published on all such reports.10 The analysis identified 104 eyes with infectious keratitis, of which 57% cases were bacterial, 12% fungal, 7% acanthamoeba, and 25% unknown. The mean time to reepithelialization after CXL treatment was 20.7 ±28.1 days (range, 3 to 145 days). The overall analysis suggested a trend toward stopping corneal melting in 85% of eyes. The conclusion was favorable for the use of CXL for infectious keratitis, but the study called for more comprehensive and prospective studies.

A prospective clinical trial of 40 eyes with advanced microbial keratitis and corneal melt was recently published.11 Twenty-one eyes underwent CXL along with antimicrobial therapy, while the control group (19 eyes) received antimicrobial therapy alone. The average time until healing was not found to be significantly shortened by CXL. However, there were no corneal perforations (three in the control group) or recurrence (one in the control group) in the CXL group. This study suggests that CXL may be useful as an adjuvant therapy to help prevent corneal melting and other complications associated with advanced microbial keratitis.


Complication rates for CXL were extensively studied in a prospective manner by a Swiss group. In 117 eyes that underwent CXL for keratectasia, there was a 2.9% complication rate, defined as having lost 2 or more Snellen lines. The study authors identified age older than 35 years as a risk factor for complication and high preoperative maximum K reading >58.00 D as a risk factor for CXL failure.3

Although a relatively safe procedure, CXL has some theoretical and reported complications. CXL causes some death of keratocytes from the UVA treatment and could potentially affect endothelial cells if the cornea is too thin.2 In addition, corneal haze often occurs and extends into the anterior stroma.3 This haze, however, does not always affect BCVA.2 Microbial keratitis is a risk given the epithelial defect created during the procedure. However, the infection would most likely develop in the postoperative period because UVA treatment kills microbes.3 Other complications reported include corneal burn, corneal edema, and sterile keratitis.2


Over the past decade, CXL has been shown to be an effective and relatively safe treatment for a variety of corneal diseases. However, these studies have limited follow-up, and the long-term effects of this procedure must be actively studied. Currently, CXL is not approved in the United States, but, given favorable international results, this may change as more data are amassed.

1. Yeu E. What’s New with Corneal Collagen Crosslinking? MillennialEYE. 2013;1(1).

2. Asri D, Touboul D, Fournie P, et al. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg. 2011;37(12):2137-2143.

3. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35(8):1358-1362.

4. Gore DM, Shortt AJ, Allan BD. New clinical pathways for keratoconus. Eye (Lond). 2013;27(3):329-339.

5. 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. 2012;6:97-101.

6. Kocak I, Aydin A, Kaya F, Koc H. Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus [published online ahead of print March 25, 2014]. J Fr Ophtalmol. doi:10.1016/j.jfo.2013.11.012.

7. Cassagne M, Laurent C, Rodrigues M, et al. Iontophoresis transcorneal delivery technique for transepithelial corneal collagen crosslinking with riboflavin in a rabbit model [published online ahead of print March 18, 2014]. Invest Ophthalmol Vis Sci. doi:10.1167/iovs.13-12595.

8. Kanellopoulos AJ, Kahn J. Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. J Refract Surg. 2012.28(11):S837-840.

9. Aslanides IM, Mukherjee AN. Adjuvant corneal crosslinking to prevent hyperopic LASIK regression. Clin Ophthalmol. 2013;7:637-641.

10. Alio JL, Abbouda A, Valle DD, Del Castillo JM, Fernandez JA. Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthalmic Inflamm Infect. 2013;3(1):47.

11. Said DG, Elalfy MS, Gatzioufas Z, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting [published online ahead of print February 25, 2014]. Ophthalmology. doi:10.1016/j.ophtha.2014.01.011.

Gargi Khare Vora, MD

Gargi Khare Vora, MD, is a cornea fellow in the Cornea, Refractive Surgery, and External Disease Service at Duke Eye Center in Durham, North Carolina. Dr. Vora may be reached at gargi.vora@duke.edu.

Preeya K. Gupta, MD

Preeya K. Gupta, MD, is an Assistant Professor of Ophthalmology, Cornea & Refractive Surgery, at Duke Eye Center in Durham, North Carolina. Dr. Gupta may be reached at preeya.gupta@duke.edu.