Whenever a new concept or technique is formulated, there are several questions that must be answered satisfactorily in order to gauge its feasibility. What is the need for the new treatment? Is it effective? Is it safe? These key questions are often raised about the prophylactic use of mitomycin C (MMC) in refractive surgery, particularly regarding its routine use following PRK and LASEK in an effort to decrease the incidence of late-onset corneal haze.
DO WE NEED SUCH A TREATMENT?
How do we define the problem? We are all aware of the propensity of high levels of excimer laser energy to cause subepithelial fibrosis, or “haze” in the cornea (Figure 1). This type of haze is thought to be closely correlated with the total amount of energy delivered to the cornea (and therefore corresponds most often to higher levels of myopic correction), and is known to be a late-onset event. In many cases, the development of visually significant haze can occur years after the original procedure. The resulting haze can have a tremendous impact on visual quality, often reducing the BCVA to levels at which activities of daily living are significantly compromised.
What is the incidence of this visually disabling haze? Unfortunately, there is no good answer to that question. Studies of the results of PRK in moderate to high myopia report the incidence of haze as ranging from 2% to 90%, depending on the series.1,2 It is true that most of these studies were performed using early-generation excimer lasers, which did not have as homogenous a beam profile as current lasers, and therefore an argument can be made that the incidence of haze is less than it had been previously. However, the notion that corneal haze cannot occur with the current crop of excimer lasers is completely unfounded. In addition, some proponents of LASEK believe that haze is not a feature of this modified PRK procedure. However, we know that the incidence of haze following LASEK is far from “zero,” as cases already exist. I have seen two patients in consultation who developed significant haze following LASEK procedures performed using a flying-spot excimer laser. Undoubtedly, the etiology of and propensity for an individual to develop haze is multifactorial. Clearly, this is the uncertain environment in which refractive surgeons are working.
THE ISSUE OF EFFICACY
If we accept the premise that there is a problem (ie, the potential of corneal haze), the next concern that must be addressed is one of efficacy. My involvement over the past 5 years in the use of MMC for the treatment of pre-existing haze following PRK has certainly placed me in a biased position. MMC, if used in the exact manner as my colleagues and I described,3 has been extremely successful in preventing haze recurrence and restoring corneal clarity in many patients with haze, who would have otherwise required lamellar or penetrating keratoplasty. The natural progression was to use MMC in a preventive manner. My colleagues and I surmised that if MMC limited the ability of previously activated keratocytes from depositing recurrent scar tissue, it may inhibit the keratocytes from becoming “hyper-reactive” in the first place. This, we believed, could decrease the likelihood of corneal haze in highly myopic patients who might be predisposed to it following PRK. We first began using MMC in this manner 2 years ago.
A prospective study by Carones et al4 presented at the 2001 AAO meeting in New Orleans, Louisiana, in which one eye was randomized to PRK alone and the fellow eye to PRK with MMC, showed a significant benefit in using MMC. The overwhelming success that has been seen with MMC, not only in our hands, but also worldwide, underscores the efficacy of this treatment.
THE SAFETY FACTOR
The final and perhaps most important principle in the analysis of a new technique is safety. Even the most successful treatment is meaningless if there is a significant risk of toxicity, or an unacceptably high incidence of adverse effects. The potential complications of MMC have been well chronicled throughout the literature. However, based on our practice's experience, and coupled with the pooled experiences of many notable and respected researchers throughout the world, it is my belief that MMC, if used exactly in the manner that my colleagues and I originally described, is a safe, adjunctive treatment. This application is fundamentally different than other ocular uses of MMC for several reasons.
Because MMC is applied in a single dose and avoids the limbal region, I believe that the incidence of toxic effects should be low. The majority of complications that have been reported with MMC have occurred following limbal application for indications such as pterygium surgery. In this setting, complications are likely due to ischemia of the limbal vessels, which may initiate an inflammatory cascade that could potentially lead to a corneoscleral melt.
In this technique, the surgeon applies prophylactic MMC to the central cornea, taking meticulous care to ensure that the MMC does not contact the peripheral cornea and limbus. Because the limbal stem cells are protected from MMC exposure, the epithelium would be expected to regenerate at a rate comparable to patients who have not received MMC. This is in fact true; not a single case of delayed re-epithelialization has been reported. As delayed re-epithelialization is a known etiologic factor in the progression of corneal melting, one would expect that in its absence, the incidence of complications would be low.
ANECDOTAL REPORTS OF CORNEAL MELTING
Strict adherence to the concentration (0.02%) and duration (2 minutes) of MMC will significantly reduce the risk of toxicity. Among all cases in which MMC has been used in refractive surgery patients, either as a therapeutic or a prophylactic agent, there has not been a single case of toxicity when administered in strict accordance with our protocol. I am aware of two anecdotal reports of corneal melting following the prophylactic use of MMC in refractive surgery.
In the first case, the surgeon used MMC 0.2% for several weeks. Of course, this is 10 times the concentration that is recommended, and in addition, long-term postoperative instillation enables MMC to have excessive and unnecessary contact with the conjunctiva and limbus for a prolonged period of time.
In the second case, which involved the prophylactic use of MMC in LASEK, the consulting surgeon knew none of the intra- and postoperative details; certainly improper preparation of MMC, and/or poor surgical technique cannot be excluded as causes of the corneal melt. Robin Beran, MD, from Columbus, Ohio, believes that the prophylactic use of MMC in LASEK may lead to a higher incidence of complications, as MMC may be sequestered within the epithelial flap (personal communication, May 2002). Although this is certainly a possibility, further investigation is required to determine what type of toxicity may result in that setting, and how long MMC might remain there. In theory, the epithelial flap in LASEK is completely replaced within 1 week. Radioactive labeling studies in an experimental model may help to answer some of these questions. In our practice, we are collecting specular microscopic data in an effort to determine the impact of MMC treatment on the corneal endothelium.
HOW SAFE IS THE “SOLUTION?”
There is no question that the prophylactic use of MMC involves a potentially toxic agent. What each of us must decide for ourselves is the actual incidence of haze (“the problem”), and based on existing knowledge, how safe and effective this “solution” appears to be. We are currently limiting the prophylactic use of MMC to patients undergoing PRK or LASEK, with greater than -6.0 D of myopia, or with a predicted ablation depth of 75 µm or greater. Certainly, longer follow-up and treatment of greater numbers of patients will help support the validity of this technique.
Parag A. Majmudar, MD, is an Assistant Professor of Ophthalmology at Rush Medical College in Chicago, Illinois, and is in private practice with Chicago Cornea Consultants, Ltd. Dr. Majmudar may be reached at (847) 882-5900; firstname.lastname@example.org
1. Shah SI, Hersh PS: Photorefractive keratectomy for myopia with a 6-mm beam diameter. J Refract Surg. 12:341-346, 1996
2. Helmy SA, Salah A, Badawy TT, Sidky AN: Photorefractive keratectomy and laser in situ keratomileusis for myopia between 6.00 and 10.00 diopters. J Refract Surg 12:417-421, 1996
3. Majmudar PA, Forstot SL, Nirankari VS et al: "Topical Mitomycin-C for Subepithelial Fibrosis after Refractive Corneal Surgery, Ophthalmol 107:89-94, 2000.
4. Carones F, Vigo L, Scandola E, Brancato R: "Evaluation of prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy," Presented at the American Academy of Ophthalmology Annual Meeting, New Orleans, LA, November 2001