Laser in situ keratomileusis (LASIK) is the most common refractive surgery procedure currently being performed in the United States. Although LASIK is generally safe and effective, surgical complications can occur. The most visually significant of these involve problems with the corneal flap. Flap complications have been reported in up to 8% of LASIK procedures and are the most common cause of loss of best corrected visual acuity (BCVA) associated with LASIK.1–5 The etiology of visual loss associated with these types of flap abnormalities is most often irregular astigmatism secondary to scarring and/or epithelial ingrowth.6
The 2 main treatment options for buttonhole or partial flaps are repeating the microkeratome pass after a period of several months4,7 or ablating the surface over the buttonhole flap.6,8,9 There are several disadvantages to repeating the microkeratome pass. Unless a readily identifiable cause of the initial buttonhole is known and corrected, which is usually not the case, a second buttonhole can occur. The new cut can intersect with the initial flap, leading to potential loss of corneal tissue and significant irregular astigmatism. In addition, the waiting period, usually several months and frequently associated with significant anisometropia, can be a cause of considerable patient anxiety. The disadvantage of photorefractive keratectomy (PRK) over an irregular LASIK flap is that there may be a significant risk for developing subepithelial haze and loss of BCVA.10
Mitomycin-C (MMC) is an antibiotic/chemotherapeutic agent with alkylating properties, which enables it to inhibit DNA synthesis.11 It has been used as an adjunct to glaucoma surgery,12 in pterygium surgery,13 in the treatment of corneal intraepithelial neoplasia,14 and most recently as a treatment for PRK haze.15–20 Based on its success in the treatment of symptomatic haze, MMC has been evaluated as a prophylactic agent for the prevention of haze following high-risk PRK.21,22
We hypothesized that surface ablation over a LASIK flap with adjunctive MMC would result in excellent refractive outcomes and minimize the risk for postoperative corneal haze. We report 10 eyes of 10 patients with flap complications who had phototherapeutic keratectomy (PTK)/PRK followed by prophylactic use of MMC (PTK/PRK/MMC) with the intended refractive outcome of emmetropia.
Patients and Methods
Ten patients were pooled from the referral practices of 7 surgeons, including 6 patients referred to our practice over a 2-year period. All had flap complications following attempted LASIK: Six patients had buttonhole flaps, 3 had partial flaps, and 1 developed scarring and haze as a result of a thin flap. Mitomycin-C was prepared by an independent compounding pharmacy in a concentration of 0.2 mg/mL (0.02%). Informed consent was obtained, during which patients were informed of the risks, benefits, investigational “off-label” nature of this treatment, and the possible associated complications.
A minimum of 3 weeks after the initial procedure, transepithelial PTK/PRK was performed using a Visx S2 or S3 excimer laser. The patients were divided into 2 categories for treatment purposes: those with regular corneal topography and those with irregular surfaces. In the subgroup with relatively normal surface topography, such as following a partial flap or a buttonhole flap with no scarring, the epithelium was removed in the central 6.0 mm using the “laser scrape” mode with an epithelial setting of 50 μm. In eyes with an irregular surface, transepithelial PTK with a spot size of 6.0 mm was performed over the central 6.0 mm with a variable total depth. The excimer laser was programmed for a maximum of 1000 pulses, and a variable number of PTK pulses were applied to the irregular surface with the aid of a masking agent such as carboxymethylcellulose sodium 1% (Celluvisc) until the corneal surface was smooth. The masking agent was applied lightly to the surface of the cornea with a Merocel sponge (Medtronic Xomed) and repeated during the procedure based on careful observation of the corneal surface. Serial slitlamp examinations were done to determine the endpoint of the PTK ablation. In both subgroups, once a regular stromal surface had been identified, PRK was performed at 50% to 80% of the most current stable refraction, depending on the degree of scarring and irregularity.
If significant PTK was performed, the amount of (myopic) refractive error programmed was reduced to approximately 50% as the PTK treatment would be expected to induce a hyperopic shift. If no PTK was performed, the programmed sphere was reduced a minimum of 20% to compensate for the inhibitory effect of MMC on corneal wound healing. All eyes received a single intraoperative application of MMC at the conclusion of the PTK/PRK procedure, as previously described.17 A sterile 6.0 mm circular sponge (Merocel corneal light shield, Medtronic Xomed) soaked in MMC (0.02% or 0.2 mg/mL) was applied to the central cornea for 2 minutes. Care was taken to limit MMC exposure to the central 6.0 mm of the corneal surface, avoiding the limbus and sclera. After MMC was applied, the ocular surface was irrigated with 30 mL of balanced salt solution (BSS).
A bandage contact lens was placed for 3 to 5 days until reepithelialization was complete. Patients received a fluoroquinolone antibiotic and prednisolone acetate 1% 4 times a day for 1 week. The antibiotic was discontinued at 1 week, and prednisolone was tapered off and discontinued over the subsequent 3 weeks. Patients were examined 1 day, 1 week, 1 and 3 months, and 1 year postoperatively. Serial examinations were performed to evaluate the presence of corneal haze, and the best spectacle-corrected visual acuity (BSCVA) and uncorrected visual acuity (UCVA).
The mean age of the 5 men and 5 women was 33.6 years. Preoperatively, the mean UCVA was 20/394 (range 20/40 to 20/800) and the mean BSCVA, 20/29 (range 20/20 to 20/50). The median interval between the initial surgery involving the flap complication and the PTK/PRK/MMC treatment was 6 months (range 3 weeks to 5 years). During the interval between the flap complication and the PTK/PRK/MMC procedure, no patient experienced epithelial ingrowth or irregular astigmatism. Postoperatively, the mean UCVA was 20/28 (range 20/20 to 20/40) and the mean BSCVA, 20/21 (range 20/20 to 20/25). No patient had clinical evidence of haze or loss of UCVA or BSCVA. A summary of patient demographics and the clinical course of the patients are shown in Table 1, and a representative clinical course is discussed below. The efficacy of this treatment is shown in Figure 1.
Patient 4, a 32-year-old woman with no significant medical or ocular history and a stable refraction elected to have LASIK for ametropia. The preoperative refraction was −7.25 +2.25 × 90 in the right eye and −6.00 +0.50 × 40 in the left eye. In both eyes, the BSCVA was 20/20. Keratometry was 47.7/45.2 diopters (D) in the right eye and 46.3/45.6 D in the left eye. Central ultrasonic pachymetry was 519 μm and 521 μm, respectively. A corneal flap was attempted in the right eye using a Hansatome microkeratome (Bausch & Lomb) with a 9.5 ring and a 180 μm head. Suction was achieved with the vacuum ring, and intraocular pressure was firm on palpation. The microkeratome pass was uneventful. A buttonhole was noted centrally when the flap was reflected. No laser ablation was applied, and the LASIK procedure in the fellow left eye was canceled.
Postoperatively, prednisolone acetate 1% and ciprofloxacin were prescribed 4 times a day in the right eye for 1 week. Over the next 4 months, the patient's refraction stabilized to −7.50 +2.50 × 90 in the right eye and −5.75 sphere in the left eye. Both eyes had a BSCVA of 20/20. Keratometry was 48.77/44.51 D and 46.41/46.05 D, respectively. The change in keratometry in the right eye was attributed to stromal reaction/scarring. Central ultrasonic pachymetry was 508 μm in the right eye and 525 μm in the left eye. Orbscan topography was normal in both eyes.
The patient consented to PTK/PRK/MMC in the right eye with the Visx Star S3 excimer laser system. As she did not exhibit topographic irregularity or scarring, no PTK was required. The programmed refraction in the right eye was reduced by 16%, from −7.50 sphere to −6.25 sphere, and the full refractive cylinder was entered into the laser for a final programmed refraction of −6.25 +2.50 × 86. The epithelium was removed using the laser-scrape setting at 50 μm followed by the refractive PRK ablation, resulting in an application of 450 pulses to an ablation depth of 99 μm followed by MMC 0.02% application to the central cornea for 2 minutes.
Postoperatively, the patient was treated with ciprofloxacin and prednisolone acetate 1% 4 times daily in the right eye. A bandage contact lens (−0.50 Soflens 66 S/M [Bausch & Lomb]) was placed in the right eye and removed 4 days later after reepithelialization was complete. At 8 months, the UCVA was 20/20 with a plano refraction and no evidence of corneal haze. Because of concerns related to the microkeratome, the patient elected to have laser-assisted subepithelial keratectomy in the left eye with prophylactic MMC. The follow-up was uneventful; at 1 year, the UCVA was 20/20.
Flap complications are associated with a significant potential for loss of BCVA. The optimal technique for the management of patients with flap complications continues to evolve. Transepithelial PTK/PRK has been successful in eliminating the abnormalities associated with partial or buttonhole flaps,6,9,18 and adjunctive MMC has been successful in treating and preventing subepithelial fibrosis in a variety of clinical situations in refractive surgery.15–18 As discussed in the initial report,23 a combination of these techniques may be the optimal way to manage these types of flap complications.
When deciding on the timing of treatment, the surgeon and patient are generally motivated to address the complication early in the postoperative period. However, immediate (ie, same day) surface ablation is reportedly associated with subepithelial fibrosis.17 Jain and coauthors9 report a series of immediate transepithelial PTK/PRK for buttonhole flaps with initial success, but the series was limited by a short follow-up. A concern with the use of immediate treatment includes the possibility of activated stromal keratocytes creating scar tissue. Although prophylactic MMC as described in this series may limit the development of scar tissue even after immediate treatment, the rationale for delaying treatment by several weeks relates to the surface epithelium as well as significant medico-legal issues of informed consent. Wilson18 recommends waiting at least 2 weeks to allow the epithelial surface to normalize and diminish the irregularities of the flap. Although both Jain and Wilson demonstrate initial success with PTK/PRK alone, it is possible that with time, haze due to subepithelial fibrosis will contribute to a loss of BCVA in patients who have surface ablation following attempted LASIK associated with flap complications.3,7,24
Mitomycin-C is an effective adjunct to manage and prevent haze in refractive surgery.15–18,23 As an antimetabolite and chemotherapeutic agent,11 MMC has been used to treat and prevent fibrosis and cell proliferation in a variety of ophthalmic settings for more than 4 decades. Topical MMC has also been used to successfully treat corneal intraepithelial neoplasia/dysplasia (which can share a common clinical appearance with subepithelial fibrosis following refractive surgery).14,25,26 Subepithelial fibrosis, seen clinically as haze, may occur with trauma to Bowman's layer. Mechanical or laser-induced trauma in this area can potentiate the proliferation of stromal keratocytes analogous to uncontrolled neoplastic cellular proliferation, which leads to the deposition of newly generated collagen, proteoglycans, and hyaluronic acid. Clinically, this deposition manifests as haze or scarring, which can contribute to irregular astigmatism and loss of BCVA.27
The transepithelial PTK/PRK technique is performed with minimal manual epithelial debridement. This decreases the likelihood of dislodging the abnormal flap. As the PTK can result in a hyperopic shift, a reduction in the entered treatment is necessary. It is estimated that 48 stationary pulse bursts of PTK will induce approximately 1.0 D of hyperopic shift and ablate approximately 12 μm of corneal stroma. Care must be taken to vary the location of the PTK pulses to limit unwanted hyperopic shifts. In addition, the entered refraction is reduced as MMC may prevent the compensatory wound-healing response seen after PRK, potentially contributing to a more hyperopic outcome if conventional refractive surgery nomograms are used. The PTK procedure is performed only if there is significant topographic irregularity or scarring following the flap complication. In these cases, the programmed spherical correction is reduced to 50% to 80% of the manifest refraction. If there is no surface irregularity or scar, as in our case report, the reduction in sphere is more modest, approximately 15% to 20%, to offset the wound-healing response of MMC. Using this nomogram, the refractive outcomes of this technique were accurate.
In this case series, a single application of MMC was used on the corneal surface after excimer laser ablation with no adverse reactions. Due to varied techniques and dosage regimens, complications following the ophthalmic use of MMC have been reported, especially with scleral applications and chronic topical administration. Although Rubinfeld et al.28 describe a series of MMC-related complications, all the cases involved chronic postoperative instillation of MMC at a higher concentration following pterygium excision. Corneoscleral perforation after use of topical MMC 0.04% 3 times daily for 10 days is reported by Fujitani and coauthors.29 However, there is a case report of corneoscleral melt after a single intraoperative application of MMC for 3 minutes to bare sclera following pterygium surgery.30 The distinguishing feature in these cases is that there was usually a higher concentration of MMC applied to the bare sclera or limbus following pterygium surgery. We believe that application to the avascular central cornea represents a fundamentally different process. Application to the central cornea limits exposure to the limbal vasculature and the stem-cell population that resides there. A single intraoperative dose of MMC 0.02% (0.2 mg/mL) applied to the central cornea for 2 minutes may be a safer method and may decrease the risk for toxicity.17,22,23,31 Care must be taken to prepare MMC as described17 as higher concentrations or longer application times may result in acute corneal endothelial toxicity.
The efficacy and potential side effects of this treatment will be evaluated further with continued long-term follow-up. Our previous experience with MMC in the treatment of subepithelial haze shows it to be indispensable in the treatment of post-PRK haze, eliminating the recurrence of this potentially serious problem. We believe surface ablation with adjunctive MMC will have a significant role in the treatment of LASIK flap complications. We are currently conducting long-term specular microscopy studies to ensure there is no effect on the corneal endothelium, and confocal microscopic studies will help further investigation of the issue of toxicity.
1. Stulting RD, Carr JD, Thompson KP, et al. Complications of laser in situ keratomileusis for the correction of myopia. Ophthalmology 1999; 106:13-20
2. Lin RT, Maloney RK. Flap complications associated with lamellar refractive surgery. Am J Ophthalmol 1999; 127:129-136
3. Tham VM-B, Maloney RK. Microkeratome complications of laser in situ keratomileusis. Ophthalmology 2000; 107:920-924
4. Farah SG, Azar DT, Gurdal C, Wong J. Laser in situ keratomileusis: literature review of a developing technique. J Cataract Refract Surg 1998; 24:989-1006
5. Gimbel HV, Anderson Penno EE, van Westenbrugge JA, et al. Incidence and management of intraoperative and early postoperative complications in 1000 consecutive laser in situ keratomileusis cases. Ophthalmology 1998; 105:1839-1847; discussion by TE Clinch, 1847–1848
6. Kapadia MS, Wilson SE. Transepithelial photorefractive keratectomy for treatment of thin flaps or caps after complicated laser in situ keratomileusis. Am J Ophthalmol 1998; 126:827-829
7. Holland SP, Srivannaboon S, Reinstein DZ. Avoiding serious corneal complications of laser assisted in situ keratomileusis and photorefractive keratectomy. Ophthalmology 2000; 107:640-652
8. Yamanouchi U, Mishima K. [Eye lesions due to mitomycin C instillation after pterygium operation]. [Japanese] Nippon Ganka Kiyo 1967; 18(8):854-861
9. Jain VK, Abell TG, Bond WI, Stevens G Jr. Immediate transepithelial photorefractive keratectomy for treatment of laser in situ keratomileusis flap complications. J Refract Surg 2002; 18:109-112
10. Carones F, Vigo L, Carones AV, Brancato R. Evaluation of photorefractive keratectomy retreatments after regressed myopic laser in situ keratomileusis. Ophthalmology 2001; 108:1732-1737
11. Calabresi P, Chabner BA. Antineoplastic agents. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, eds, Goodman and Gilman's the Pharmacological Basis of Therapeutics, 8th ed. New York, NY, Pergamon Press, 1990; 1247-1248
12. Bindlish R, Condon GP, Schlosser JD, et al. Efficacy and safety of mitomycin-C in primary trabeculectomy; five-year follow-up. Ophthalmology 2002; 109:1336-1341; discussion by GL Spaeth, C Terzidou, A Bhan, 1341–1342
13. Akura J, Kaneda S, Matsuura K, Setogawa A, et al. Measures for preventing recurrence after pterygium surgery. Cornea 2001; 20:703-707
14. Shields CL, Naseripour M, Shields JA. Topical mitomycin C for extensive, recurrent conjunctival-corneal squamous cell carcinoma. Am J Ophthalmol 2002; 133:601-606
15. 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 1991; 109:1141-1146
16. Porges Y, Ben-Haim O, Hirsh A, Levinger S. Phototherapeutic keratectomy with mitomycin C for corneal haze following photorefractive keratectomy for myopia. J Refract Surg 2003; 19:40-43
17. Majmudar PA, Forstot SL, Dennis RF, et al. Topical mitomycin-C for subepithelial fibrosis after corneal refractive surgery. Ophthalmology 2000; 107:89-94
18. Wilson SE. Transepithelial PRK/PTK for treatment of Donut-shaped flaps in LASIK. Refract Surg Outlook Summer 2001
19. Azar DT, Jain S. Topical MMC for subepithelial fibrosis after refractive corneal surgery [letter]. Ophthalmology 2001; 108:239-240
20. Hu H, Liu S, Xia X, et al. Mitomycin C reduces haze formation in rabbits after excimer laser photorefractive keratectomy. J Refract Surg 2001; 17:342-349
21. Winkler von Mohrenfels C, Hermann W, Gabler B, et al. Topisches Mitomycin C zur Rezidivprophylaxe von Haze nach erneuter Excimer-Laser-photorefracktiver Keratektomie (PRK)-Klinische Pilotstudie an 5 Patienten. Klin Monatsbl Augenheilkd 2001; 218:763-767
22. Carones F, Vigo L, Scandola E, Vacchini L. Evaluation of the prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg 2002; 28:2088-2095
23. Lane HA, Swale JA, Majmudar PA. Prophylactic use of mitomycin-C in the management of a buttonholed LASIK flap. J Cataract Refract Surg 2003; 29:390-392
24. Leung ATS, Rao SK, Cheng ACK, et al. Pathogenesis and management of laser in situ keratomileusis flap buttonhole. J Cataract Refract Surg 2000; 26:358-362
25. Yamamoto N, Ohmura T, Suzuki H, Shirasawa H. Successful treatment with 5-fluorouracil of conjunctival intraepithelial neoplasia refractive to mitomycin-C. Ophthalmology 2002; 109:249-252
26. Rozenman Y, Frucht-Pery J. Treatment of conjunctival intraepithelial neoplasia with topical drops of mitomycin C. Cornea 2000; 19:1-6
27. Bechara SJ, Grossniklaus HE, Waring GO III. Subepithelial fibrosis after myopic epikeratoplasty; report of a case. Arch Ophthalmol 1992; 110:228-232
28. Rubinfeld RS, Pfister RR, Stein RM, et al. Serious complications of topical mitomycin-C after pterygium surgery. Ophthalmology 1992; 99:1647-1654
29. Fujitani A, Hayasaka S, Shibuya Y, Noda S. Corneoscleral ulceration and corneal perforation after pterygium excision and topical mitomycin C therapy. Ophthalmologica 1993; 207:162-164
30. Dougherty PJ, Hardten DR, Lindstrom RL. Corneoscleral melt after pterygium surgery using a single intraoperative application of mitomycin-C. Cornea 1996; 15:537-540
31. Rao SN, Majmudar PA, Epstein RJ. Transepithelial PTK/PRK over complicated LASIK flaps [letter]. J Refract Surg 2001; 17:470