Treatment of dense subepithelial corneal haze after laser-assisted subepithelial keratectomy

Treatment of dense subepithelial corneal haze after laser-assisted subepithelial keratectomy M. Azim Mirza, MD, Mujtaba A. Qazi, MD, Jay S. Pepose, MD, PhD We report a case of dense and visually significant corneal haze after laserassisted subepithelial keratectomy (LASEK). Visually significant corneal haze after LASEK can be successfully treated with manual debridement and intraoperative mitomycin-C. J Cataract Refract Surg 2004; 30:709–714  2004 ASCRS and ESCRS

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aser-assisted subepithelial keratectomy (LASEK) improves the safety of refractive procedures and can provide visual outcomes similar to those with photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) (M. Cimberle, “LASEK May Offer the Advantages of Both LASIK and PRK,” Ocular Surgery News, March 1, 1999, page 28).1–4 The term corneal haze has been used since 19885 to describe alterations in corneal transparency caused by the reflection or scattering of light after refractive surgery. The relationship between corneal haze and regression has been well documented in the PRK literature, (ie, as a result of aggressive wound healing, with epithelial hyperplasia and stromal remodeling, subsequent corneal refractive power increases resulting in a myopic shift).5–9 While the preservation of an epithelial flap and its basement membrane components2 over an ablated stromal bed may modify the risk for corneal haze and

Accepted for publication August 21, 2003. From the Pepose Vision Institute (Mirza, Qazi, Pepose), and the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine (Qazi, Pepose), St. Louis, Missouri, USA. Presented at the International Society of Refractive Surgery Fall Refractive and Cataract Symposium, Orlando, Florida, USA, October 2002. Supported in part by the Midwest Cornea Research Foundation, St. Louis, Missouri, USA. None of the authors has a financial or proprietary interest in any material or method mentioned. Reprint requests to Jay S. Pepose, MD, 16216 Baxter Road, Suite 205, Chesterfield, Missouri 63017, USA.  2004 ASCRS and ESCRS Published by Elsevier Inc.

regression, investigators are increasingly aware of haze formation after LASEK, particularly in cases with a higher attempted correction (R.W. Yee, MD, First International LASEK Congress, Houston, Texas, USA, March 2002). Mild and transient corneal haze after this procedure is sometimes observed but typically fades after several months with minimal or no vision-disturbing sequelae. We found that dense haze can evolve into reticular, anterior stromal scarring, resulting in loss of best corrected visual acuity (BCVA). We report a patient who developed significant subepithelial haze after LASEK, which was successfully treated by manual debridement, intraoperative mitomycin-C (MMC), and phototherapeutic keratectomy (PTK).10

Case Report A 21-year-old Asian man with a history of seasonal allergies was evaluated for laser vision correction of compound myopic astigmatism. His nasopharyngeal allergy symptoms were treated with oral loratadine (Claritin威) 10 mg daily. The patient did not have significant ocular or dermatologic findings related to the seasonal allergies. The preoperative best spectacle-corrected visual acuity (BSCVA) was 20/20 in each eye, with manifest refractions of ⫺7.25 ⫺2.25 ⫻ 28 in the right eye and ⫺7.75 ⫺2.50 ⫻ 162 in the left eye. The central corneal power was 46.00/43.87 ⫻ 10 in the right eye and 46.50/43.75 ⫻ 164 in the left eye. Ultrasonic central corneal pachymetry was 490 ␮m in each eye. Because of relatively thin corneas, a recommendation for LASEK was made. The patient had bilateral LASEK with a Visx Star S2 excimer laser (193 nm, 160 mJ/cm) and a large optical zone (6.5 mm) treatment. An epithelial flap was created after application of ethanol 20% (dehydrated ethyl alcohol) for 0886-3350/04/$–see front matter doi:10.1016/S0886-3350(03)00521-2

CASE REPORTS: MIRZA

Figure 1. (Mirza) Slitlamp view of the right eye 6 months after LASEK shows dense, central subepithelial opacification.

40 seconds. The total ablation depth was 104 ␮m in the right eye and 108 ␮m in the left eye. After repositioning of the epithelial flap, a soft contact lens (Soflens威 66, Bausch & Lomb) was placed as a masking agent in each eye. The initial postoperative regimen included topical ciprofloxacin 0.3% (Ciloxan威) 4 times a day for 1 week, oral analgesics as needed, and frequent local application of cold compresses. The patient continued daily use of Claritin. On the first postoperative day, binocular vision was 20/20 with well-positioned contact lenses. On postoperative day 4, the contact lenses were removed. The UCVA was 20/50 in the right eye and 20/32 in the left eye. Mild, central epithelial irregularity and mild subepithelial haze were greater in the right eye than in the left eye. Prednisolone acetate 1% (Pred Forte威) was started 4 times a day in both eyes, with a plan to taper off the medication over several months. The subepithelial haze worsened, and a comanaging physician placed the patient on frequent topical dexamethasone 0.1% (Decadron威) in the right eye by the third postoperative month. A ⫺4.00 diopter (D) sphere correction was prescribed for the right eye. The patient was seen again at our institution on the sixth postoperative month with progressive, gradual loss of visual acuity in the right eye. The right eye UCVA had deteriorated to counting fingers, which improved to 20/50 with a refraction of ⫺9.25 D sphere. The UCVA was 20/20 in the left eye with a manifest refraction of ⫺0.25 ⫺0.75 ⫻ 90 (BSCVA 20/20). Biomicroscopy revealed a dense region of subepithelial opacification in the right eye (Figure 1), with a central 2.40 mm component obscuring all iris details (4⫹/4). Focal 1⫹ subepithelial haze was noted in the left eye. After informed consent was obtained, manual debridement (Crescent knife, Alcon, Inc.) followed by intraoperative MMC 0.02% application for 2 minutes with a 6.0 mm circular sponge was performed to restore BSCVA in the right eye. A bandage contact lens (BCL) was placed 710

Figure 2. (Mirza) The right cornea during a second debridement with MMC procedure: A: Manual debridement. B: After application of MMC 0.02%.

over the right eye after the procedure, and topical Ciloxan and Pred Forte 1% 4 times a day each were started on postoperative day 1. The BCL was removed after adequate reepithelialization on postoperative day 4. The UCVA in the right eye 3 weeks after initial debridement was 20/80, with a dry refraction of ⫺2.75 ⫺0.50 ⫻ 155 (BSCVA 20/20). Residual 1⫹ haze was seen on slitlamp examination. The patient was maintained on a monthly Pred Forte 1% taper. Four months after the initial debridement with MMC treatment, with the patient remaining on topical steroids once a day, the UCVA had decreased to 20/125 in the right eye. The BSCVA in the right eye was 20/25 with a ⫺3.75 ⫺0.75 ⫻ 25 correction. Residual central haze (1⫹ to 2⫹) in the right eye was observed. Thirteen months after the initial LASEK and 5 months after initial debridement and MMC treatment, the patient had a second manual debridement procedure (Figure 2). Biomicroscopy immediately after debridement revealed an irregular stromal surface, with 0.5⫹ to 1⫹ residual central

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Figure 3. (Mirza) Anterior elevation maps of the right eye. A: 6 months post-LASEK and before debridement. B: After the second debridement and MMC.

haze. Phototherapeutic keratectomy (14 pulses with a 6.00 mm beam, Visx Star S3) was performed to smoothen the stromal surface, using carboxylmethylcellulose 1.0% (Celluvisc威) as a masking agent. A 6.00 mm circular sponge soaked with MMC 0.02% was placed over the central cornea for 2 minutes. After copious irrigation with balanced salt solution (BSS威), a soft contact lens was applied. Topical Ciloxan and Pred Forte 1% 4 times a day each were started on postoperative day 1. The UCVA after contact lens removal on the fourth day was 20/50 with a refraction of ⫺2.00 D sphere (BSCVA 20/30). Speckled staining, along with trace central haze, was noted in the right eye. The patient was examined again 3 months after the second debridement and MMC procedure. The patient was using loteprednol 0.5% (Lotemax威) in the right eye twice a day. The UCVA was 20/32 in the right eye and 20/20 in the left eye. The manifest refraction was ⫹0.75 ⫺0.75 ⫻ 105 (BSCVA 20/25) in the right eye. Postoperative videokeratography (Orbscan威 II, Bausch & Lomb), when compared with predebridement measurements, demonstrated central corneal flattening in the right eye and a return to a relatively oblate topographic pattern typically seen after laser vision correction (Figure 3). Although postoperative HartmannShack aberrometry (Zywave威, Bausch & Lomb) was unattainable prior to debridement, there was a reduction in total

wavefront aberrations by 50% comparing data collected before and 3 months after the second debridement/MMC procedure (Figure 4). Biomicroscopy revealed 1⫹ patchy central haze in the right eye. Discrete specks of 1⫹ subepithelial haze in the left eye were unchanged from previous examinations. The topical steroid was gradually tapered and discontinued. The patient had uncorrected binocular visual acuity of 20/20⫹ and did not require further vision corrective aids. The clinical course is summarized in Table 1.

Discussion A key event after excimer photoablation is epithelial injury, regardless of technique used, which triggers the release of cytokines by the lacrimal gland and corneal epithelium. Epithelial–keratocyte interactions initiate epithelial regeneration and keratocyte apoptosis.11 This is accompanied by inflammatory cell infiltration, which further mediates corneal injury directly through free radical formation and indirectly through the release of additional cytokines. The cytokine milieu, particularly Interleukin-1 (IL-1) and transforming growth factor (TGF)-␤,11,12 promotes the transformation of keratoTable 1. Temporal changes in vision, myopic regression, and slitlamp grading after sequential manual debridement and intraoperative MMC procedures.

Figure 4. (Mirza) Hartmann-Shack aberrometry after the first and second debridement procedures. T RMS ⫽ total root mean square; 2 O RMS (second order RMS) ⫽ defocus ⫹ astigmatism; H O RMS (higher order RMS) ⫽ Third to fifth order root mean square; 6 to 7 and 12 are coefficient values of individual Zernike terms.

Spherical BSCVA Equivalent (D) Haze

Right Eye

UCVA

Preoperative

20/CF

20/20

–8.38

0

6 months post LASEK

20/CF

20/50

–9.25

4⫹

4 months post scrape/MMC 1 20/125

20/25

–3.50

3⫹

3 months post scrape/MMC 2 20/32

20/25

⫹0.38

1⫹

BSCVA ⫽ best spectacle-corrected visual acuity, CF ⫽ count fingers; UCVA ⫽ uncorrected visual acuity

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cytes at the borders of the ablation zone into myofibroblasts, which migrate into the subepithelial space. These highly reflective cells and the atypical matrix elements that they synthesize combine to reduce light transmission.13 Once the epithelial defect is healed, there is a shift in the cytokines expressed by mature epithelial cells, with disappearance of myofibroblasts and a return to quiescent keratocytes with normal morphology. Metalloproteinases14 then assist in remodeling stromal tissue, restoring a more orthogonal arrangement of collagen fibrils. Any imbalance, particularly prolonged delay in epithelial healing or sloughing of the epithelial sheet, in this complex process of wound healing may shift the equilibrium toward subepithelial haze formation. Patients with a larger attempted correction,8,9,15–17 atopy, autoimmune conditions,18 or high ultraviolet (UV) radiation exposure19 may have a higher risk for corneal haze after excimer photoablation. Our patient had a history of seasonal allergies but was not atopic and had no evidence of autoimmune disease or prolonged UV exposure. The timing of haze formation after LASEK is similar to that in PRK. Claringbold4 notes trace haze in 13.00% of 222 eyes 3 months after LASEK (mean myopia ⫺4.89 D, 6.0 mm ablation zone, Visx Star S2), with resolution in all cases by 12 months. Another series20 (n ⫽ 58, mean myopia ⫺7.80 D, Alcon Autonomous) reports 8.00% of eyes with visually significant haze after LASEK. A retrospective review of 62 eyes (mean myopia ⫺7.96 D, Visx Star S2) at our center, with at least a 3-month follow-up after LASEK, demonstrates a haze rate of 47.00%, with almost all receiving only the lowest grading. Three eyes (4.80%) had a haze grading ⬎2, of which 1 eye (reported herein) required surgical intervention because of BSCVA loss. The higher haze rate in our series appears to be related to greater attempted correction, and supports the findings of Yee (R.W. Yee, MD, First International LASEK Conference, Dallas, Texas, USA, 2001), who identified an ablation depth ⬎100 ␮m, as in our patient, and/or an ablation depth to corneal thickness ratio ⬎0.18 as independent risk factors for haze formation after LASEK. Several studies correlate the severity of epithelial trauma to the degree of subsequent anterior stromal hypocellularity,11,21,22 presumably because more cytokines are released and can access stromal receptors to induce keratocyte apoptosis and myofibroblast activa712

tion. Nakamura and coauthors23 have, in fact, demonstrated subepithelial fibrosis after LASIK when the epithelium is denuded intraoperatively. This has implications for LASEK, where an epithelial flap is maintained to protect the ablated stromal surface. Marshall (J. Marshall, PhD, First International LASEK Congress, Houston, Texas, USA, March 2002) suggests that modification of epithelial regeneration patterns via formation of a central epithelial flap may shift the timeline for introduction of apoptotic cytokines outside the susceptibility period of stromal fibroblasts. Tseng (S.C.G. Tseng, MD, PhD, First International LASEK Congress, Houston, Texas, USA, March 2002) notes that some constituents of the basement membrane and subepithelial region after LASEK are also found in amniotic membranes and may inhibit haze formation. These considerations may explain the observation by Carones and coauthors1 of lower haze rates (P ⫽ 0.04) in human eyes treated with the excimer laser after deepithelialization using alcohol 20% versus those deepithelialized manually. This result is corroborated by Lee et al.24 in a prospective study comparing LASEK and PRK in the same patient in whom haze scores were significantly lower at 1 month (P ⫽ 0.005) in LASEK eyes. Strategies for the prevention and treatment of postLASEK haze are often extensions of our experience with haze after PRK.14,21,25–28 Further developments in LASEK flap creation, such as the use of methylcellulose (M. Piechocki, “Alcohol-Free LASEK Procedure Proves Effective in Pilot Study,” Ocular Surgery News, June 1, 2002, pages 27–28) to dissect free an epithelial flap or microkeratome-assisted (D. Angelucci, “New Technology May Combine Benefits of PRK and LASIK, Eye World, March 2003, page 45) epithelial flap formation may offer more protection by preserving the integrity of epithelial cells and basement membrane components. While most of these agents or techniques have been used on a prophylactic basis, Majmudar et al.29 illustrate the use of MMC as an adjunct to debridement for the treatment of subepithelial scarring after refractive corneal surgery. They describe a 2-minute intraoperative application of MMC 0.02% after epithelial and stromal debridement that resulted in recovery of BSCVA and prevented recurrence of subepithelial fibrosis. We report a 21-year-old patient with high myopia and seasonal allergies who developed significant haze

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after LASEK that was successfully treated with debridement plus intraoperative MMC and excimer PTK. Delayed epithelial healing in the right eye marked the early postoperative course. Since it is not possible to predict which eyes after LASEK may manifest delayed wound healing or loss of the epithelial sheet, our report raises the question of whether topical intraoperative MMC should be considered for prophylactic use for patients at higher risk for haze, such as those requiring ablations of ⬎100␮m or ablation depth to total corneal thickness ratios of ⬎0.18. The long-term use of topical MMC may be associated with significant ocular toxicity, including scleral melt.30 A single intraoperative application of MMC has the advantages of full compliance, minimal side effects, and controlled drug delivery.31 We prophylactically use a 2-minute application of MMC 0.02% to the stromal bed for all cases of LASEK ⫺6.00 D or higher. We have not observed adverse intraoperative events or a significant delay in epithelial healing postoperatively, and we have not modified our nomogram when using intraoperative MMC. A randomized masked controlled prospective study of prophylactic MMC in 1 eye of LASEK patients would be of benefit, so that the decision to use mitomycin prophylactically is grounded in evidence. In summary, the complex wound healing response of the cornea has important implications in refractive surgery. The end result is variable stromal remodeling and epithelial hyperplasia associated with myopic regression and haze. Although the specific cellular events of corneal wound healing after LASEK remain unclear, it is speculated that the epithelial flap protects the bare surface of the stroma and prevents the influx of cytokines and inflammatory cells from the tears, reducing the apoptotic and inflammatory insult to the stroma. Experimental and clinical investigations must confirm this. While several researchers have identified keratocyte apoptosis blockers, further investigations are needed to determine the efficacy of topical agents32 and vector gene therapy33 for the management of postsurgical corneal haze. Controlled clinical trails may reveal the benefits of surgical techniques that further preserve epithelial integrity or of earlier and more uniform use of modulating agents such as corticosteroids, ascorbate, autologous serum, MMC, IL-1 inhibitors, TGF-␤ inhibitors, or

amniotic membrane factors. Careful selection parameters must be developed to guide recommendations for LASEK that weigh risk–benefit profiles versus alternative nonexcimer techniques (eg, the use of a pseudophakic lens, phakic lens, or corneal inlay implantation). Techniques used to address visually significant corneal haze may effectively restore visual acuity.

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