A significant number of patients treated with photorefractive keratectomy (PRK) for moderate to high myopia subsequently develop subepithelial scarring (haze). The etiology of the haze following PRK is thought to be the disorderly deposition of collagen and ground substances (glycosaminoglycans) in the corneal stroma during the wound-healing phase. As in any wound-healing process, the cornea exhibits various stages of cellular response that result in tissue remodeling. Histologic studies have documented that following PRK, stromal keratocytes undergo apoptosis to a depth of 50 to 200 µm. New keratocytes repopulate the area within several days, but these cells are associated with the disorderly deposition of collagen and ground substances that result in clinical haze. The degree to which this occurs most likely depends on the cumulative laser energy delivered, as well as patients' individual healing characteristics.
Corneal haze following PRK may occur several years after the procedure, which is the reason that it has remained a significant problem despite the procedure's continued decline. Haze is generally responsive to steroids, but reappears promptly once the steroids are discontinued. Various treatment strategies have been proposed for recurrent corneal haze, including Thiotepa and other chemical agents, with mixed results. Our group has had extensive experience with mitomycin C (MMC) in the treatment of post-PRK haze, and we feel that its safety and efficacy profile offers distinct advantages.1
EXPANDING APPLICATIONS
MMC is an antibiotic derived from the fungus, Streptomyces. By virtue of its DNA cross-linking capability, it is a potent inhibitor of DNA synthesis. Talamo et al2 first suggested its use in wound-healing modulation following PRK in their study entitled “Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids.”
My colleagues and I initially attempted to use MMC on a patient who developed subepithelial fibrosis following radial keratotomy (RK) in both eyes. The scars in this patient were removed by surgical debridement several times in each eye, with recurrence in each eye. MMC (0.02%) was initially applied as a topical medication four times daily for several weeks. The patient developed a recurrence however, and additionally had mild toxic side effects. We then changed our approach by using a single, intraoperative application of MMC. The rationale was that by delivering only the required amount directly to the tissue in question, we could increase efficacy and decrease any toxic side effects of the medication. This approach worked dramatically in improving both corneal clarity and best-corrected visual acuity (BCVA).
We then postulated that MMC might play a similar role in the treatment of post-PRK haze, although the severity of the scarring after PRK is generally much greater than that following RK. In an early case, a limited debridement of the scar resulted in incomplete scar removal, because MMC does not remove the scar itself, but only prevents its recurrence. Subsequent patients treated with MMC for post-PRK haze fared much better, experiencing near-total eradication of the scar and significantly improved BCVA.
CLINICAL TESTING
Currently in our series, 24 eyes of 21 patients have undergone successful treatment for post-PRK haze with MMC. Corneal clarity and BCVA improved in all patients, and there were no toxic side effects. We believe that the single, intraoperative application of MMC is the primary reason for the absence of adverse reactions in this procedure. Although complications of MMC after a single application have been reported,3 the majority of those cases involved higher concentrations delivered to the limbal region (because the cases used MMC as an adjunct to pterygium excision). The majority of complications following limbal application may be due to induced ischemia of the limbal vasculature, which may initiate the inflammatory cascade and release the proteolytic and collagenolytic enzymes responsible for corneoscleral melting. Our application is considerably different in that the avascularity of the central cornea may prevent this adverse phenomenon. In addition, care is taken to irrigate residual MMC from the ocular surface, limbus, and fornices following the application. According to correspondence I have received from numerous ophthalmologists, this procedure has been performed successfully on a number of patients internationally without evidence of toxicity.
We believe that prophylactic mitomycin C may offer significant benefits in various facets of refractive surgery in 2001 and beyond. In conjunction with Francesco Carones, MD, of Milan, Italy, we are currently conducting a prospective evaluation of the role of prophylactic MMC for preventing corneal haze following PRK for high myopia. Patients with a refractive error of -6 D or greater who were not eligible for LASIK were recruited for the study. To date, 50 eyes have been enrolled. After an average 8 months of follow-up (range, 1 to 14 months), no eyes have developed corneal haze. Because of the nature of corneal haze, longer follow-up will determine whether this treatment is successful.
LOOKING AHEAD
LASEK, or laser-assisted subepithelial keratomileusis, offers the faster visual rehabilitation and decreased discomfort of LASIK in a PRK-style surface ablation. Conventional wisdom states that by replacing the epithelial “flap,” LASEK will prohibit haze by preventing the release of proinflammatory mediators into the corneal stroma. However, I believe that LASEK may still be plagued by late-onset corneal haze, although perhaps not to the same degree as PRK. If one accepts this hypothesis, the case can be made for prophylactic MMC treatment following LASEK. At this time, I have treated four LASEK eyes with prophylactic MMC for high myopia. The follow-up data are less than 3 months old, so meaningful conclusions are premature.
Another potential application of prophylactic MMC is for patients who have sustained flap complications during LASIK. It is well known that certain flap complications, such as buttonholed flaps, may be difficult to treat with conventional PRK immediately after LASIK because of the high propensity for corneal haze formation. In fact, one of the first patients I treated with MMC had undergone LASIK for -9.00 D myopia, which resulted in a buttonhole flap. Her surgeon immediately performed PRK through the defective flap, and she subsequently developed 4+ reticular haze and BCVA of 20/400. Unfortunately, waiting the recommended 3 to 6 months before attempting a LASIK re-cut may cause haze and irregular astigmatism, which might preclude any surgical intervention until customized ablations can be performed. In cases such as these, transepithelial phototherapeutic keratectomy (PTK)/PRK, as described by Wilson, et al,4 followed by prophylactic MMC, may help treat the residual refractive error as well as prevent the onset of corneal haze which otherwise is extremely likely. To date, one case of a buttonholed flap has been treated with PTK/PRK and prophylactic MMC, resulting in a BCVA of 20/20 and a clear cornea during 6 months of follow-up.
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 has no financial interest in any product or technology discussed herein. He may be reached at (312) 942-5300; pamajmudar@chicagocornea.com1. Majmudar PA, Forstot SL, Nirankari VS, et al: Topical mitomycin-C for subepithelial fibrosis after refractive corneal surgery. Ophthalmol 107:89-94, 2000
2. Talamo JH, Gollamudi S, Green WR, et al: Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids. Arch Ophthalmol 109:1141-1146, 1991
3. Rubinfeld RS, Pfister RR, Stein RM, et al: Serious complications of topical mitomycin C after pterygium surgery. Ophthalmol 99:1647-1654, 1992
4. Kapadia MS, Wilson SE: Transepithelial photorefractive keratectomy for treatment of thin flaps or caps after complicated laser in situ keratomileusis. Ophthalmol 126:827-829, 1998
