Development of late-onset subepithelial corneal haze after laser-assisted subepithelial keratectomy with prophylactic intraoperative mitomycin-c

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1 J CATARACT REFRACT SURG - VOL 32, SEPTEMBER 2006 Development of late-onset subepithelial corneal haze after laser-assisted subepithelial keratectomy with prophylactic intraoperative mitomycin-c Case report and literature review Mujtaba A. Qazi, MD, Troy W. Johnson, OD, Jay S. Pepose, MD, PhD We present a case of dense, visually significant reticular haze that developed approximately 17 months after uneventful laser-assisted subepithelial keratectomy with mitomycin-c (MMC). The patient was successfully treated with manual debridement coupled with phototherapeutic keratectomy and intraoperative MMC. J Cataract Refract Surg 2006; 32: Q 2006 ASCRS and ESCRS Laser-assisted subepithelial keratectomy (LASEK) offers an alternative technique of laser vision correction for individuals who are not ideal candidates for laser in situ keratomileusis (LASIK) based on corneal curvature, central corneal pachymetry, orbital anatomy, or the presence of corneal dystrophies or surface irregularity. Laser-assisted subepithelial keratectomy improves the safety of refractive procedures and can provide visual outcomes similar to those of photorefractive keratectomy (PRK) and LASIK. 1 4 However, several potential side effects have been described with LASEK, including the development of visually significant corneal haze. 5 The term haze is used to describe alterations in corneal transparency caused by refractive surgery. 6 Corneal haze Accepted for publication April 5, From the Pepose Vision Institute (Qazi, Pepose); the Department of Ophthalmology and Visual Sciences (Qazi, Pepose), Washington University School of Medicine; and the University of Missouri School of Optometry (Johnson), St. Louis, Missouri, USA. Supported in part by research grants from the Midwest Cornea Research Foundation, St. Louis, Missouri, USA. No author has a financial or proprietary interest in any product mentioned. Corresponding author: Jay S. Pepose, MD, PhD, Pepose Vision Institute, Baxter Road, Suite 205, Chesterfield, Missouri 63017, USA. jpepose@peposevision.com. and associated myopic regression, with potential loss of best corrected visual acuity (BCVA), have been attributed to aggressive wound healing involving an influx of stromal keratocytes and replacement with extracellular matrix (ECM) elements. 7 9 It is postulated that preserving an epithelial flap along with the basement membrane structure over an ablated stromal bed reduces the risk for corneal haze and regression compared with the risk with PRK. Basic science and clinical investigations attribute the protective mechanism of the LASEK flap to the reduction in: stromal infiltration of tear-film cytokines, the release of preformed cytokines from damaged corneal epithelia, and subepithelial keratocyte apoptosis. Transient, mild corneal haze can occur after LASEK but usually fades after several months with minimum sequelae. Lin et al. 10 show that deeper ablations increase the risk for haze formation. We have reported that corneal haze after LASEK (without prophylactic mitomycin-c [MMC]) can evolve into reticular anterior scarring resulting in loss of BCVA. 11 Attempts to mitigate the risk for haze formation after LASEK involve the prophylactic use of topical MMC intraoperatively. Mitomycin-C is an alkylating agent 12 that inhibits proliferation of subepithelial keratocytes. 13,14 The prophylactic use of intraoperative topical MMC has become routine for many surgeons in cases of high correction or deep ablation with LASEK. Its use, however, does not eliminate the risk for haze formation. We report Q 2006 ASCRS and ESCRS Published by Elsevier Inc /06/$-see front matter doi: /j.jcrs

2 a patient who developed significant subepithelial haze more than 1 year after LASEK with intraoperative MMC. This was successfully treated by manual debridement, phototherapeutic keratectomy (PTK), and intraoperative MMC. CASE REPORT A 23-year-old Asian man was evaluated for laser refractive correction of high compound myopic astigmatism before the availability of phakic intraocular lenses in the United States. The preoperative BCVA was 20/16 in each eye, with a manifest refraction of in the right eye and in the left eye (Table 1). The keratometric readings in the right and left eye by Orbscan (Bausch & Lomb, Inc.) were 43.8/42.1@4 and 43.9/42.5@163, respectively. The central corneal thickness by 50 MHz ultrasonic pachymetry (Cornea-Gauge Plus, Sonogage) was 523 mm in the right eye and 517 mm in the left eye. Due to the large refractive error and thinner than average corneas, LASEK was recommended after the potential risks, benefits, and alternatives had been discussed. The patient had bilateral, sequential LASEK with the Star S2 excimer laser (193 nm, 160 mj/cm 2 ; Visx, Inc.) using a large optical zone (6.5 mm) with a blend of approximately 8.0 mm in both eyes. The epithelial flap was created after ethanol 20% (dehydrated ethyl alcohol) was applied for 30 seconds. The total ablation depth was 155 mm in the right eye and 151 mm in the left eye, according to the laser platform. Following laser application, MMC 0.02% was applied to the central cornea with a presoaked Merocel sponge (Becton Dickinson) for 2 minutes and then irrigated copiously with balanced salt solution (BSS). After the epithelial flap was repositioned, a soft bandage lens was placed in each eye. The patient was treated with topical ciprofloxacin 0.3% (Ciloxan) 4 times daily in each eye for 1 week, with preservative-free artificial tears and oral analgesics as needed. On day 1, the binocular visual acuity was 20/100 with wellcentered bandage contact lenses bilaterally. At 4 days, the contact lenses were removed and the uncorrected visual acuity (UCVA) was 20/200 in the right eye and 20/80 in the left eye. Irregular epithelium was noted in both eyes without areas of sloughing, and there were no signs of subepithelial haze. At this time, prednisolone acetate (Econopred Plus 1%) was prescribed 4 times daily, with a plan to begin tapering after 1 month. At 1 month, trace corneal haze was noted in both eyes. The haze completely resolved by the 10-week visit, at which time the UCVA was 20/20 in both eyes. The topical steroid was discontinued 14 weeks postoperatively. The patient was seen at 17 months with a complaint of a gradual, painless decrease in vision in the left eye over the previous 2 to 3 weeks. The UCVA was 20/20 in the right eye and 20/40 in the left, with a BCVA of 20/32 in the left eye. Biomicroscopy of the right eye was unremarkable, but there was dense central subepithelial haze (grade 4/4) in the left eye, with dimensions of 2.4 mm 3.2 mm, obscuring iris details. Topical steroids (Pred Forte 1%) 4 times a day and cyclosporine (Restasis 0.05%) 2 times a day were prescribed in the left eye. At the next follow-up visit, 19 months postoperatively, there was no improvement in UCVA or BCVA in the left eye. Manual debridement with MMC 0.02% and PTK was therefore scheduled for the left eye. After informed consent had been obtained, gentle debridement (Crescent blade, Alcon, Inc.) was used to manually remove most of the central haze. Phototherapeutic keratectomy (6.0 mm diameter) was then performed with the Visx Star 3 laser to polish the stromal surface using carboxymethylcellulose 1.0% (Celluvisc) as a masking agent. A Merocel sponge soaked with MMC 0.02% was placed over the central cornea for 2 minutes. After the cornea was copiously irrigated with BSS, a soft contact lens was applied. On day 1, topical Econopred Plus 1% and moxifloxacin hydrochloride 0.5% (Vigamox) were prescribed 4 times a day in the left eye. The UCVA was 20/125 in the left eye, and C1 haze was noted (Figure 1). Once again, the topical steroid was gradually tapered over several months. Topical Restasis twice a day in the left eye and oral vitamin C 500 twice a day were also prescribed. The UCVA improved to 20/32 by the 3-month postdebridement visit, with trace residual haze observed on biomicroscopy (Figure 2). At 11 months, the patient s last recorded visit, the UCVA was 20/16 in the right eye and had improved to 20/25 in the left eye with a manifest refraction of Table 1. Timeline of dense subepithelial haze formation after LASEK with adjuvant, single-dose intraoperative mytomycin C (MMC) 0.02% Left Eye UCVA BSCVA Spherical Equivalent Haze Preoperative 20/CF 20/ months post LASEK 20/16 20/16 Plano 0 9 months post LASEK 20/16 20/16 Plano C months post LASEK 20/40 20/ C4 11 months post debridement/mmc/ptk 20/25 20/25 Plano C0.5 UCVA Z uncorrected visual acuity, BSCVA Z best spectacle-corrected visual acuity, CF Z counting fingers, PTK Z phototherapeutic keratectomy Figure 1. One day after manual debridement plus intraoperative MMC and PTK, residual reticular subepithelial haze (grade C1) is seen centrally J CATARACT REFRACT SURG - VOL 32, SEPTEMBER 2006

3 Figure 2. Further resolution of haze 3 months after manual debridement with intraoperative MMC and PTK. C (BCVA 20/25). The patient denied any significant complaints, and only mild haze was noted. DISCUSSION Corneal haze after photoablation is a well-documented risk and has been widely investigated. Most series involving the treatment of low to moderate myopia with LASEK without prophylactic MMC describe low levels (0% to 13%) of haze formation, generally peaking at the third postoperative month and resolving by the twelfth month. 1,3 5,15 20 Other series involving the treatment of moderate to high myopia report visually significant haze formation in 8% to 10% of LASEK eyes. 21,22 Kim et al. 23 report 7.5% of 146 eyes (mean preoperative spherical equivalent of 8.01 diopters [D] [SD]) with C3 haze, 17.8% with C2 haze, and 31.5% with C1 haze 12 months after LASEK. Lin et al. 10 show that the duration of haze after LASEK depended on the severity of the haze: C1 haze resolved after months, while C2 haze resolved after months. Haze formation peaked at 3 months in their cohort of 90 LASEK eyes. In LASEK, a viable epithelium is believed to limit keratocyte transformation into cells actively involved in the production of ECM and collagen. 3,5,7,9,24 Transmission electron microscopy of the LASEK flap shows an intact epithelial cellular layer, with some discontinuity and irregularities in the basement membrane. 3 Gabler et al. 25 observe that the corneal epithelial flap remained vital for up to 45 seconds while exposed to alcohol 20%. The plane of alcohol-assisted dissection of the epithelial layer was between Bowman s and the lamina densa. Several authors have determined that surgically induced injury to the corneal epithelium plays a significant role in subsequent subepithelial fibrosis. Nakamura et al. 26 have demonstrated subepithelial haze after LASIK if the epithelium is denuded intraoperatively. Epithelial disruption results in the release of preformed cytokines and secretion of newly formed cytokines, including interleukin-1, transforming growth factor (TGF)-b, interleukin 6, and epidermal growth factor. 7,27 29 These cytokines mediate epithelial keratocyte interactions, initiating epithelial regeneration and keratocyte apoptosis. 27 The actions of cytokines, enzymes such as metalloproteinases, inflammatory cells, and free radicals in the subepithelial stroma disrupt the highly organized matrix of collagen fibrils, leading to alteration of corneal clarity. 30,31 The wound modulating properties of the epithelial flap were observed in white leghorn chick eyes that had LASEK. 32 Less keratocyte apoptosis was seen in the central superficial stroma than in the peripheral stroma, perhaps because the epithelial flap served as a plug and barrier against the influx of tear cytokines into the central stroma. An albino rabbit model comparing LASEK and PRK showed that at higher ablations ( 7.00 D), LASEK induced less keratocyte apoptosis, myofibroblast transformation, and chondroitin sulfate synthesis. 33 Laube et al. 34 confirmed less keratocyte apoptosis in rabbit eyes after LASEK than after PRK. In another animal model of PRK, amniotic membrane application to the stromal bed reduced subepithelial haze grading by reducing the expression of IL Lee et al. 16 correlate lower haze gradings with lower tear fluid transforming growth factor-b1 in the early days after LASEK than after PRK. In clinical studies, Carones et al. 2 show lower haze rates in eyes deepithelialized with alcohol 20% than in those deepithelialized manually, presumably because of less disruption of the epithelial cell layer. Lee et al. 16 show lower haze rates at 1 month in LASEK eyes, with alcohol-assisted flap formation, than in PRK eyes. Autrata and Rehurek 36 confirm lower haze grading in 108 LASEK eyes than in 108 PRK eyes 1 to 24 months after surface ablation. Risk factors for the development of corneal haze after photoablation include large treatments, 10 atopy, autoimmune conditions, 37 or high ultraviolet (UV) radiation. Our patient did not have a history significant for these risk factors except deep ablation. Lin et al. 10 found that if the ablation depth/corneal thickness ratio was greater than 0.18, there was a higher chance of developing 1C haze or more. They also identified an ablation depth of 100 mm or deeper as increasing the risk for haze formation. J CATARACT REFRACT SURG - VOL 32, SEPTEMBER

4 Using their criteria, our patient would have had a greater than 92.5% chance of developing corneal haze of at least 1C. However, according to the findings in several of the above-cited studies, we would most likely have observed haze within the first 6 months. Our case revealed the onset of advanced haze 16 to 17 months postoperatively. The patient denied local trauma, corneal erosion, or acute conjunctivitis. He had been wearing UV-protective sunglasses on a regular basis and had been using topical lubricants as needed. As such, the etiology of the late-stage haze formation remains unidentified. Intraoperative strategies to reduce the risk for postoperative haze formation aim to limit epithelial injury. With alcohol-assisted techniques, this requires keeping the exposure time of alcohol to a minimum, as higher concentrations and duration of exposure lead to a reduction in the number of viable cells in the epithelial flap. In our experience, 18% to 20% alcohol for 20 seconds provides safe and complete epithelial flap creation. Vinciguerra et al. 38 recommend the butterfly LASEK technique with smoothing to minimize epithelial trauma and haze formation. This involves the retraction of both halves of the alcohol-assisted epithelial sheet from the center to the periphery, along with the application of a hyaluronic acid masking agent that is removed with PTK. An alcohol-free technique in which a methylcellulose gel is used to create the epithelial sheet. 5,20 Pallikaris et al. 39 report the use of an automated epikeratome to form the epithelial flap, with preservation of normal epithelial and basement membrane structure, 40 in which 97% of eyes had trace haze grading or less 3 months after photoablation. Additionally, intraoperative, single-dose MMC has been used as adjuvant therapy to prevent haze formation after LASEK. The long-term effects of using this drug for corneal prophylaxis are unknown. Frequent topical use of MMC is associated with significant ocular toxicity, including scleral melt. 41 A single intraoperative application of MMC has the advantages of full compliance, minimum side effects, and controlled drug delivery. Carones et al. 42 randomized 60 consecutive PRK eyes (preoperative myopia range 6.00 to D) into 2 groups: 1 received a 2-minute intraoperative application of MMC (0.2 mg/ml) and the other did not. They conclude that the prophylactic MMC group had lower haze rates (0% of MMC eyes versus 63% of control eyes with haze higher than C1 at 6 months), better UCVA and BCVA results, and more accurate refractive outcomes than those achieved in the control group. Camellin 43 reports that the use of a brushstroke of intraoperative MMC 0.01% after alcohol-assisted LASEK with smoothing significantly decreased subepithelial haze compared with a control group that did not receive intraoperative MMC. He cautions, however, that the use of MMC was associated with greater overcorrection and higher corneal surface aberrations at 1 month and 1 year. Kottler and Dick 44 recommend MMC use in LASEK enhancements. The question of repeated use of MMC remains unanswered and needs to be fully discussed during the informed consent process. A concentration- and duration-dependent effect on stromal keratocyte density has been shown in rabbit eyes following a single application of MMC, with greater MMC exposure affecting deeper stromal layers 45 and endothelium. 46 However, Lee et al. 47 report no statistically significant decrease from preoperative level in endothelial cell densities measured by specular microscopy in 1011 human eyes following PRK with intraoperative MMC. To limit the potential risks of MMC exposure, they adjusted the exposure time of intraoperative MMC as a function of ablation depth and used an annular-shaped sponge for paracentral application of MMC, as originally described by Jain et al. 48 Koch reserves repeat MMC for patients who developed haze during their initial surface ablation procedure, eyes with corneal surgery prior to the initial surface ablation, and enhancement procedure ablation depth greater than 20 mm (D.D. Koch, MD, Second Surface Ablation with MMC, Journal of Cataract & Refractive Surgery Today, February 2006, pages 53 54). Postoperative pharmacologic strategies to reduce the risk for post-lasek haze involve the use of topical corticosteroids, nonsteroidals, and ascorbic acid, among others. 5,9,20 Topical and systemic ascorbate have been shown to reduce the deleterious effects of UV-radiation exposure and free-radical injury to corneal tissue Camellin 1 advocates the use of topical autologous serum 4 times daily for 1 week if the LASEK flap is disrupted, and Yee and Yee 20 apply autologous serum intraoperatively and postoperatively. Lee et al. 52 report that fixing a strip of amniotic membrane at the inferior limbus immediately after LASEK in 94 eyes resulted in shorter reepithelialization times, better refractive and visual outcomes, and lower corneal haze than in eyes that had a bandage contact lens only. Additional modalities such as keratocyte apoptosis blockers 29 and vector gene therapy 53 may assist with the treatment of subepithelial haze after LASEK in the future. Once haze has developed, surgical management is similar to that after PRK Partal et al. 19 report 1 eye of a 27- year-old woman with a preoperative spherical equivalent of 7.25 D and an ablation depth of 178 mm who developed C2 to 3 haze that was treated with PTK and MMC with reduction of haze on subsequent visits. Camellin 1 reports an eye in which the epithelium sloughed 2 days after LASIK and the cornea later developed C4 haze, which was treated with repeat LASEK plus PTK. Mirza et al. 11 illustrate the use of manual debridement coupled with PTK and intraoperative MMC for the treatment of subepithelial scarring after LASEK. The present case highlights the use of the same strategy in a young patient who developed haze 1576 J CATARACT REFRACT SURG - VOL 32, SEPTEMBER 2006

5 despite the intraoperative use of MMC and an aggressive postoperative topical steroid regimen. The identification of late-onset corneal haze after LASEK despite the use of intraoperative MMC poses the question of the causative agents or mechanisms of this phenomenon. One could argue that the use of MMC itself could alter the timeline for introduction of apoptotic cytokines, resulting in a delayed response. Randomized masked prospective controlled trials are needed to fully evaluate the efficacy and safety of routine prophylactic use of intraoperative MMC during LASEK, as well as the optimum concentration and duration of treatment. However, such trials may require a large enrollment to give the study sufficient power in light of the relatively low incidence of haze without prophylaxis following LASEK and an acceptable beta (type II) error limit. 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