Variations of CCL procedures include the original Dresden protocol procedure, transepithelial CCL, accelerated CCL, and combined techniques. All have several prerequisites in common. The primary goal of the first stage of therapy is to allow sufficient riboflavin to diffuse into the cornea. In the initial studies, riboflavin was not able to penetrate an intact epithelium, and so the standard Dresden protocol required epithelial removal in order to allow riboflavin to rapidly penetrate into the stroma. However, newer formulations of riboflavin have been shown to penetrate intact epithelium and may have the additional advantage of faster healing, faster visual recovery, less pain, and lower incidence of complications. Studies are investigating the use of iontophoresis via an electrical charge gradient to allow for more complete penetration of riboflavin through the epithelium.
Once riboflavin has adequately diffused into the cornea, the second component of the CCL procedure is exposure to UVA light. The standard Dresden Protocol calls for 30-minute exposure to 370 nm UVA with an irradiance of 3 mWcm–2 for a total of 5.4 J/cm2. Newer accelerated protocols attempt to decrease the duration of UVA exposure, while maintaining the same exposure (ie, 30 min at 3 mWcm–2 is equivalent to 3 min at 30 mWcm–2 or 10 min at 9 mWcm–2). Table 7-1 reviews steps in the Dresden protocol.
Transepithelial corneal crosslinking
Postoperative discomfort, possible delayed epithelial healing, infection, stromal haze, and corneal melting represent the disadvantages of epithelial debridement that have led surgeons to explore transepithelial CCL. The reported clinical outcomes are promising. Experimental studies, however, have shown a significantly lower efficacy of transepithelial CCL compared to the standard epithelium-off approach due to the low epithelial permeability of riboflavin. Chemical agents such as benzalkonium chloride, trometamol, and ethylenediaminetetraacetic acid, as well as the use of hypotonic riboflavin solution without dextran, may to enhance riboflavin’s penetration. The use of iontophoresis and partial disruption of the superficial epithelial layers also enhance riboflavin’s penetration through the epithelium.
No matter which approach is used, stromal saturation with riboflavin is crucial and should always be visualized (Fig 7-4) before the UVA irradiation. Some researchers claim that, even with a sufficient stromal concentration of riboflavin, the effect of the transepithelial CCL may be decreased due to the attenuation of UVA radiation by the epithelium. That would imply that UVA energy may need to be increased or otherwise modulated beyond the current level of 5.4 J/cm2 when the epithelium is kept intact.
Table 7-1 Dresden Protocol
Figure 7-4 Full-thickness, homogeneous stromal penetration of riboflavin during epitheliumon (Epi-On) corneal crosslinking. Adequate riboflavin penetration is of paramount clinical importance prior to ultraviolet A light application.
(Courtesy of Roy S. Rubinfeld, MD, MA.)
Baiocchi S, Mazzotta C, Cerretani D, et al. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg. 2009;35(5): 893–899.
Bottos KM, Schor P, Dreyfuss JL, Nader HB, Chamon W. Effect of corneal epithelium on ultraviolet-A and riboflavin absorption. Arq Bras Oftalmol. 2011;74(5):348–351.
Filippello M, Stagni E, O’Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg. 2012;38(2):283–291.
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.
Kissner A, Spoerl E, Jung R, Spekl K, Pillunat LE, Raiskup F. Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/Riboflavin corneal collagen cross-linking. Curr Eye Res. 2010;35(8):715–721.
Stojanovic A, Zhou W, Utheim TP. Corneal collagen cross-linking with and without epithelial removal: a contralateral study with 0.5% hypotonic riboflavin solution. Biomed Res Int. 2014; 2014:619398. Epub 2014 Jun 22.
Accelerated corneal crosslinking
New-generation lamps have been developed to shorten the duration of UVA irradiation. Some offer fixed treatment times of 10 and 5 minutes with the use of a power of 10 and 18 mW/cm2. Other systems allow a wide range of adjustable times (1–30 minutes) with a UV power of 3 to 45 mW and increased maximum irradiance to 10 J/cm2. Kanellopoulos reported that the use of higher-fluence UVA for a shorter time (7 mW/cm2 for 15 minutes) is safe and effective. He found that this approach achieves similar clinical results to the Dresden protocol in terms of stabilizing ectasia.
In some cases, patients do not achieve visual acuity improvement sufficient to provide functional vision after CCL treatment. Ophthalmologists, therefore, have attempted to combine CCL with various refractive surgical techniques (see Chapter 12). The implantation of intracorneal ring segments with sequential or subsequent CCL treatment has proven effective. The limited use of topography-guided transepithelial PRK followed by CCL has also been shown to improve visual acuity and stabilize keratoconus. Same-day PRK followed by CCL appears to be superior to sequential PRK after CCL, and the former has been widely used as the Athens protocol. Combining CCL with the implantation of a phakic toric intraocular lens safely and effectively corrects myopic astigmatism in eyes with mild to moderate keratoconus. The triple procedure of CCL combined with topography-guided PRK to regularize the corneal shape and the implantation of a phakic intraocular to optimize the refraction may rehabilitate the patient’s vision with a higher predictability of the refractive outcome compared with CCL combined with topography-guided PRK alone.
Güell JL, Morral M, Malecaze F, Gris O, Elies D, Manero F. Collagen crosslinking and toric iris-claw phakic intraocular lens for myopic astigmatism in progressive mild to moderate keratoconus. J Cataract Refract Surg. 2012;38(3):473–484.
Kamburoglu G, Ertan A. Intacs implantation with sequential collagen cross-linking treatment in postoperative LASIK ectasia. J Refract Surg. 2008;24(7):S726–729.
Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg. 2009;25(9): S812–818.
Stojanovic A, Zhang J, Chen X, Nitter TA, Chen S, Wang Q. Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration. J Refract Surg. 2010;26(2):145–152.
Complications of CCL may include delayed epithelial healing, corneal haze (which may be visually significant), decreased corneal sensitivity, infectious keratitis, persistent corneal edema, and endothelial cell damage.
Corneal crosslinking is a very promising treatment modality, and studies are evaluating its place among the options for corneal therapy. In addition to conducting studies employing denuded epithelium for crosslinking, investigators are examining riboflavin penetration across intact epithelium for crosslinking. In addition, there have been reports of CCL employed successfully to treat fungal and bacterial infections of the cornea. This use may represent a potential new application of this technology.
Excerpted from BCSC 2020-2021 series: Section 13 - Refractive Surgery. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.