- Email: [email protected]
Epithelial-defect-masquerade syndrome after laser in situ keratomileusis
Epithelial-defect-masquerade syndrome after laser in situ keratomileusis Characteristic clinical findings and visual outcomes Dimitri T. Azar, MD, Amy Scally, OD, Sadeer B. Hannush, MD, Sarkis Soukiasian, MD, Mark Terry, MD Purpose: To describe a potentially serious complication of laser in situ keratomileusis (LASIK) that can masquerade as a persistent epithelial defect. Setting: Refractive surgery centers in academic institutions. Methods: Charts of 4 eyes in which epithelial-defect-masquerade syndrome was diagnosed were reviewed to determine the time to diagnosis and the presence of associated features that may have contributed to the delay in diagnosis. Clinical findings and outcomes of medical and surgical intervention were recorded. Results: All eyes developed an epithelial defect involving the edge of the flap during surgery. The diagnosis of epithelial ingrowth was delayed because of the presence of stromal edema (n ⫽ 4), diffuse lamellar keratitis (n ⫽ 3), and contraction of the flap leading to gutter widening (n ⫽ 4). Epithelial ingrowth was diagnosed 5, 7, 15, and 60 days after LASIK. All eyes satisfied the following criteria: convexity of the peripheral epithelium at the edge of the flap associated with light reflections at the end of the flap, fluorescein pooling in the gutter, stromal edema, reduced best spectacle-corrected visual acuity (⬍20/60 in 3 eyes), and partial healing of the epithelial defect limited to the flap hinge. One eye developed stromal scarring and ulceration that required fortified antibiotics. Surgical repair included epithelial scraping after the flap was lifted and ironing followed by placement of a contact lens after surgery. The epithelial defect healed 5, 7, 21, and 24 days after surgery. The final uncorrected visual acuity ranged from 20/15 to 20/100. Conclusions: Epithelial ingrowth following LASIK-associated epithelial defects may masquerade as stromal edema associated with a persistent epithelial defect. A high index of suspicion for epithelial ingrowth is essential to avoid a delayed diagnosis, which can result in irreversible visual loss due to stromal melting and infectious keratitis. J Cataract Refract Surg 2003; 29:2358–2365 2003 ASCRS and ESCRS
L
aser in situ keratomileusis (LASIK) is among the most commonly performed ophthalmic surgical procedures. As experience with this procedure has increased, the incidence of vision-threatening complications has decreased. One serious complication of LASIK
Accepted for publication March 12, 2003. Reprint requests to Dimitri T. Azar, MD, Corneal and Refractive Surgery Services, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts, USA. E-mail: [email protected]. 2003 ASCRS and ESCRS Published by Elsevier Inc.
that remains is epithelial ingrowth.1–15 It is associated with an epithelial defect involving the flap edge.10–14 The presence of an epithelial defect is generally attributable to the shearing forces of the microkeratome and often resolves without serious complications. Recent reports show a high association between an epithelial defect and diffuse lamellar keratitis (DLK) and reduced visual acuity.16–18 The epithelial defect may be associated with flap wrinkles and stromal edema.5,10,11,13 Intraoperative recognition of an epithelial defect, repositioning of loose epithelium, use of a contact lens, and flap suturing 0886-3350/03/$–see front matter doi:10.1016/S0886-3350(03)00333-X
EPITHELIAL-DEFECT-MASQUERADE SYNDROME
Table 1. Clinical findings, treatment, and visual outcomes in epithelial-defect-masquerade syndrome. Patient Parameter
1
2
3
4
Age (y)/sex
53/M
29/F
27/M
46/M
⫹
⫹
⫹
⫹
UCVA before diagnosis
20/400
N/A
20/30
CF @ 4 ft
BSCVA before diagnosis
20/200
20/80
20/25
20/400
Time between LASIK and final diagnosis (d)
5
60
7
15
DLK
Slitlamp diagnostic features
⫹
⫹
⫹
–
Center sparing
–
–
–
–
Center involved
⫹
⫹
⫹
⫹
Stromal melting
–
⫹
–
⫹
Flap wrinkles
–
–
⫹
–
Bacterial keratitis
–
⫹
–
–
Early flap elevation
⫹
–
⫹
–
Epithelial scraping
⫹
⫹
⫹
⫹
Therapeutic soft contact lens application
⫹
⫹
⫹
⫹
Need for retreatment
–
⫹
⫹
–
Final UCVA
20/30
20/100
20/15
20/20
Final BSCVA
20/20
20/60
20/15
20/20
BSCVA ⫽ best spectacle-corrected visual acuity; CF ⫽ counting fingers; DLK ⫽ diffuse lamellar keratitis; N/A ⫽ not available; UCVA ⫽ uncorrected visual acuity; ⫹ ⫽ present; – ⫽ not present
may enhance epithelial wound healing and minimize epithelial ingrowth. In this report, we describe the clinical features, treatment, and outcomes of epithelial ingrowth after intraoperative epithelial defects associated with LASIK that masqueraded as stromal edema and persistent epithelial defects. Although the association of epithelial defects and epithelial ingrowth is known to LASIK surgeons, to our knowledge, this is the first report of epithelial-defect-masquerade syndrome as a surgical complication of LASIK, with characteristic clinical findings, outcomes, and treatment alternatives.
Patients and Methods The charts of 4 eyes (4 patients) in which epithelial ingrowth was diagnosed after LASIK associated with epithelial defects were reviewed. The time between surgery and final diagnosis was recorded. The factors that may have contributed to the delayed diagnosis were investigated; these included the possible association of stromal edema, DLK, flap-edge contraction, stromal folds, and anterior chamber inflammation. The clinical findings were recorded to determine common potential pathognomonic features and possi-
ble pathologic sequelae. The interval between diagnosis and surgery and the type of surgical interventions were recorded. The visual outcomes after treatment were determined.
Results Table 1 summarizes the age, sex, clinical findings, and possible etiology of the 4 patients. All eyes had an epithelial defect reaching the flap edge immediately after surgery; the persistent defect and stromal edema obscured early diagnosis of epithelial ingrowth. Healing of the epithelial defect was incomplete in the region of the subsequent diagnosis of ingrowth. In all eyes, the edge of the defect coincided with the flap margin for more than 3 clock hours and the peripheral epithelium showed a pathognomonic convexity at the flap margin (Figure 1, top). This was seen with slitlamp biomicroscopy as an arcuate light reflex along the margin of the flap overlying the ingrown epithelium. Fluorescein staining showed characteristic patterns of pooling at the junction of the swollen stromal flap and the inwardly directed epithelium (Figure 1, bottom right). The best spectacle-corrected visual acuity (BSCVA) was worse in 3 eyes at the time of diagnosis (⬍20/60);
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Table 2. Recommended diagnostic and therapeutic approach in epithelial-defect-masquerade syndrome. Diagnostic features Microkeratome-related epithelial defect Epithelial defect edge involving flap margin Delayed reepithelialization Stromal edema, DLK, and/or ulceration of the flap Convexity of peripheral epithelium at flap edge Fluorescein pooling at flap edge overlying ingrown epithelium Confocal microscopic findings of cells in the interface
Figure 1. (Azar) Top: Diagramatic illustration of epithelial-defect-
Therapeutic approach
masquerade syndrome after LASIK showing the characteristic epithelial convexity adjacent to the stromal edema in the inferior half of the LASIK flap. Bottom left : Clinical appearance of epithelial-defect-masquerade syndrome. Bottom right: Fluorescein staining showing an epithelial defect at the edge of the flap and arcuate fluorescein pooling below the defect corresponding to the peripheral region of the epithelial ingrowth.
Early flap lifting Extensive epithelial flap scraping Diagnostic cultures of specimen if bacterial keratitis suspected Flap repositioning, ironing, and possible suturing Therapeutic soft contact lens application Postoperative steroids and antibiotics
in 1 eye, it was 20/25. In 1 eye, stromal melting developed and ulceration complicated by bacterial keratitis required fortified antibiotics. Surgical repair included flap lifting, epithelial scraping on both sides of the interface, repositioning the flap, and ironing the resultant folds. A therapeutic soft contact lens was applied in all eyes. The epithelial defects healed within 7, 21, 24, and 5 days in patients 1, 2, 3, and 4, respectively. Reoperation was necessary in 2 eyes. The final uncorrected visual acuity (UCVA) and BSCVA improved by 3 to 8 and by 2 to 9 Snellen lines, respectively. Table 2 summarizes our diagnostic and therapeutic approach to the management of persistent epithelial-defect-masquerade syndrome after LASIK.
Case Reports Case 1 A 53-year-old man had LASIK in the left eye 5 days before presentation and was referred because of a persistent epithelial defect and flap edema that did not respond to topical treatment with prednisolone acetate, ofloxacin, and 5% sodium chloride solution. Laser in situ keratomileusis was performed using an LSK-1 microkeratome and a Visx 20/20 laser and was complicated by intraoperative epithelial abrasion in the center of the cornea extending to the flap edge. The patient complained of blurred vision, pain, and irritation, especially on blinking, since the surgery. He had difficulty opening his eyes and complained of severe glare. The preoperative refractive error was ⫺2.00 ⫺0.50 ⫻ 100 in the right eye and ⫺2.00 in the left eye. 2360
Careful observation for recurrent epithelial ingrowth DLK ⫽ diffuse lamellar keratitis
On presentation, the patient’s UCVA was 20/20 in the right eye. In the operated left eye, the UCVA was 20/400, improving to 20/200 only with pinhole. Slitlamp examination showed evidence of a large geographic defect extending from the edge of the flap to the hinge, sparing the superior and inferior margins of the flap. This was associated with 3⫹ flap edema and surface irregularities. The temporal epithelium exhibited characteristic convexity suggestive of ingrowth. Epithelial-defect-masquerade syndrome was diagnosed. The patient was treated by lifting the flap and scraping the epithelial cells on the stromal bed and the posterior layer of the flap; this was performed successfully. Corneal scraping and cultures were obtained, a therapeutic contact lens was applied at the end of the procedure, and prednisolone acetate and ofloxacin were started 4 times daily. The next day, the patient reported significant improvement in vision and symptoms. The UCVA was 20/80, improving to 20/30 with pinhole. The epithelial defect decreased over the following 3 days. Early DLK was visible on day 3 and was managed by removing the contact lens and increasing the topical corticosteroids to every 2 hours. The UCVA improved to 20/50 by day 4. All cultures and scrapings obtained at the time of surgery were negative. The steroid drops were tapered and the antibiotics discontinued. One month after surgery, the UCVA was 20/40⫺2, improving to 20/25⫺3 with ⫺0.25 ⫺0.75 ⫻ 95. Trace haze was evident at the temporal edge of the flap. The central cornea was clear, but microstriae could be seen with retroillumination. Artificial tears were continued.
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Six months after surgery, the UCVA was 20/30, improving to 20/20 with ⫺0.50. The haze at the flap margin and the microstriae were still visible. The patient was happy with the visual outcomes and the monovision results. Corneal topography showed an area of peripheral flattening that contributed to slight surface irregularity and was consistent with mild peripheral stromal melting.
Case 2 A 29-year-old woman had LASIK complicated by loose epithelium that extended to the flap edge in both eyes. The preoperative refractions were 20/20 with ⫺1.25 sphere in the right eye and 20/20 with ⫺1.25 ⫹1.00 ⫻ 172 in the left eye. The preoperative central keratometry was 41.61/ 42.55 ⫻ 88 and 40.90/41.82 ⫻ 180, respectively. Bandage contact lenses were placed in both eyes. On the first postoperative day, there were small abrasions in both eyes. The UCVA was 20/70 in the right eye and 20/30 in the left eye. The left eye healed without complications; at 1 week, the UCVA was 20/20. Small epithelial microcysts were observed on the flap surface in the right eye. The BSCVA in the right eye did not improve beyond 20/50 in the first 3 weeks despite punctal plug insertion. The central epithelium was debrided, and a bandage contact lens was placed. Tobramycin 4 times daily and prednisolone acetate every 2 hours were started. Three days after scraping, there was increased pain and redness and decreased visual acuity. Flap shrinkage, stromal melting, and interface infection were suspected. Ofloxacin was started every 30 minutes, and prednisolone acetate was increased to every hour. The patient was seen by another physician, who obtained corneal cultures (by scraping) and performed a subconjunctival injection of tobramycin (Ancef威). Fortified vancomycin and fortified gentamicin drops were also started. The flap was left in place and the patient followed closely. Cultures grew Streptococcus viridans. The pain decreased, the infiltrate decreased with therapy, and the medications were tapered. The patient was examined 2 months after LASIK and 1 month after scraping. The BSCVA in the right eye was 20/80. Slitlamp examination showed a white and quiet eye, but the flap was retracted with an epithelial defect, a white flap edge, and thinned periphery (Figure 1, bottom right). Epithelial ingrowth masquerading as an epithelial defect and stromal ulceration were diagnosed. The flap was lifted, and an epithelial membrane was excised from the bed and flap. The necrotic stromal tissue of the inferonasal flap was removed; the residual LASIK flap was sutured in place, and a bandage contact lens was placed. Three weeks after flap surgery, the UCVA was 20/60, improving to 20/40 with pinhole; all sutures were removed. Seven weeks after suture removal, the UCVA was 20/100, improving to 20/60 with ⫺0.25 ⫹2.75 ⫻ 105. Corneal topography showed evidence of irregular astigmatism. A gas-permeable contact lens was prescribed, which improved visual acuity to 20/15⫹1.
Case 3 A 27-year-old man had uneventful sequential bilateral LASIK for a refractive error of ⫺3.75 diopters (D) in the right eye and ⫺3.65 D in the left eye using a Summit Apex Plus威 laser and an SKBM microkeratome (Alcon Laboratories, Inc.). One day postoperatively, the patient complained of minimal foreign-body sensation in the left eye that began the preceding evening. The UCVA was 20/25⫺3 in the right eye and 20/30⫺2 in the left eye. The BCVA was 20/20 with ⫹0.75 ⫺0.50 ⫻ 12 and 20/25 with ⫹0.75 ⫺0.50 ⫻ 22, respectively. The right eye was unremarkable. There was superior flap slippage in the left eye with parallel fixed folds extending toward the superotemporal flap margin (Figure 2, A and B). The flap in the left eye was lifted, and epithelial ingrowth was noted inferiorly and removed. To remove the fixed folds sequentially, the flap was bimanually stretched and the surface mechanically stroked with a Merocel威 sponge (Medtronic Solan); the epithelium over the area of the folds was removed by stroking, and the stroma was hydrated using sterile water. The flap was floated into position and allowed to dry, and a bandage contact lens (Protek, Bausch & Lomb) was placed. Postoperatively, the patient was instructed to use ofloxacin 0.3% and fluorometholone 0.1% every 2 hours. The following day, the flap was well positioned with no folds noted; focal areas of epithelial haze and flap edema were noted, and the bandage contact lens was in position. Two days after flap repositioning, the patient complained of slight irritation in the left eye. The conjunctiva was not inflamed. There was increased superior and temporal flap edema and grade 2 to 3 DLK 2.0 to 3.0 mm from the flap margin. Minimal anterior chamber reaction was noted. Rimexolone 1% ophthalmic suspension was initiated every 2 hours, and ofloxacin 0.3% was continued. The following day (3 days after flap lifting), a crescent-shaped epithelial defect on the temporal flap edge was noted overlying localized flap edema (Figure 2, C and D). Prednisolone acetate 1% and oral prednisone at 80 mg/day was initiated. The epithelial defect failed to heal. Epithelial-defect-masquerade syndrome was suspected, and the flap was relifted 6 days after flap repositioning. Epithelial ingrowth of 1.0 to 2.0 mm was noted in the periphery of the bed. This was removed and the interface irrigated, but the epithelial ingrowth recurred. It was retreated by retracting the epithelium onto the peripheral cornea and partially redraping the flap after it had been repositioned to prevent epithelial regrowth. Three days later, the UCVA was 20/30⫹2 with minimal peripheral epithelial ingrowth but persistent stromal haze. Two months after the procedure, the UCVA was 20/20⫺2 with ⫹1.25 ⫺0.50 ⫻ 33. Four months after the procedure, the UCVA was 20/15⫺2 with ⫹1.00 ⫺0.50 ⫻ 25. Interface and stromal haze had decreased.
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Figure 2. (Azar) After LASIK using a horizontal microkeratome, striae are seen by direct slitlamp illumination (A ). The horizontal striae are better appreciated by negative staining with fluorescein (B ). Following treatment of the striae, epithelial-defect-masquerade syndrome occurred as evidenced by stromal swelling (C) and an epithelial defect in the flap (D ) overlying the area of ingrown epithelium.
Case 4 A 46-year-old man had LASIK in both eyes 15 days before the initial presentation. He was referred because he developed keratopathy in the left eye that was thought to be secondary to herpes zoster but did not respond to topical or oral antiviral medication (Figure 3). At the initial presentation, the patient’s medications included trifluridine and erythromycin ointment in the left eye and oral valacyclovir 1000 mg 3 times a day. The patient complained of persistent foreign-body sensation, pain, and decreased visual acuity in the left eye. The visual acuity was 20/25 in the right eye and counting fingers at 4 feet in the left eye. Slitlamp examination of the right eye revealed a well-positioned LASIK flap with a superonasal hinge, minimal surface staining, an anterior stromal scar in the superonasal quadrant, and no interface changes. Slitlamp examination of the left eye revealed a 90% epithelial defect over the LASIK flap, which had a superotemporal hinge. Multiple filaments were noted on the surface, with early stromal melt. Epithelial-defect-masquerade syndrome was diagnosed. The flap edge was loosely adherent (Figure 4, A and B), and epithelial ingrowth covered the bed, overlying the pupillary zone (Figure 4, C and D). The patient agreed to proceed
with debridement and repositioning of the flap with multiple 10-0 nylon sutures (Figure 5, A). A therapeutic bandage contact lens was placed and a punctal plug inserted in the inferior left punctum. The medication regimen was modified to include systemic steroids and topical antibiotic agents. The goals were to prevent infection, control inflammation, prevent epithelial ingrowth, and rehabilitate the patient visually. Five days after the debridement and flap repositioning, the LASIK flap was almost completely reepithelialized. The interface remained clear with no evidence of epithelial ingrowth after suture removal (Figure 5, B).
Discussion In this report, we document an uncommon complication of LASIK surgery in which the diagnosis of epithelial ingrowth was delayed. This syndrome displays characteristic clinical features and, if left untreated, may result in irreversible visual loss. The diagnostic features listed in Table 2 were present in all 4 patients. We believe the presence of stromal edema and DLK may interfere with early diagnosis
Figure 3. (Azar)
Epithelial-defectmasquerade syndrome following LASIK displaying DLK (left) and an epithelial defect involving the entire LASIK flap (right).
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Figure 4. (Azar) Close examination of the LASIK flap edge demonstrates the loose adhesion of the flap (A ). As the flap is retracted, epithelial ingrowth becomes more evident (B ). Following flap elevation, cobalt-blue filter (C ) and diffuse illumination (D ) demonstrate the extent of epithelial ingrowth.
because these findings may obscure clear visualization of the ingrown sheet of epithelial cells. The role of confocal microscopy in these patients is not known. It
Figure 5. (Azar) Postoperative photographs of the cornea showing sutures that were placed after debridement and flap repositioning to enhance wound healing and to minimize the recurrence of epithelial ingrowth (A ). When there is no evidence of an epithelial defect or epithelial ingrowth, the sutures are carefully removed (B ).
may facilitate the diagnosis and prevent delays in proper diagnosis and treatment.5 We did not suture all the flaps in these patients. Repositioning, ironing, and contact lens application after scraping may not be sufficient to prevent epithelial regrowth into the interface. Suturing the flap may add another protective barrier against regrowth, and we think it may be necessary in this situation. The sutures remain for 3 to 5 days before they are removed. We have described an experimental model of intrastromal epithelial accretion after excimer concentric keratectomy.19,20 In this rabbit model, neither central flap nor laser treatment was necessary to induce epithelial migration into the stroma. Our findings show that the conditions for epithelial migration in the rabbit are (1) a stromal-gaping incision or an ablation that creates a deep orthogonal stromal edge (⬎80 m) in which the central stroma is elevated relative to the periphery, (2) a surface epithelial defect, and (3) central stromal edema. These 3 requirements were satisfied in our patients with epithelial-defect-masquerade syndrome after LASIK. Long-term follow-up of rabbits showed that the central stroma undergoes slow melting, primarily as a result of the action of gelatinase B (MMP-9) produced by the migrating epithelial cells.21 A similar outcome was noted in 2 of the patients. An important feature of epithelial ingrowth is that it may be subtle and can be mistaken for fibrosis, DLK, and debris. The diagnosis of epithelial ingrowth in these situations is often delayed. In addition, the extent of
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epithelial ingrowth after LASIK, which is often underestimated, is best appreciated using retroillumination. The management of isolated asymptomatic epithelial islands is usually limited to observation. In contrast, symptomatic epithelial ingrowth, progressive ingrowth, and ingrowth communicating with the peripheral epithelium require more aggressive management. Lifting the flap and scraping the undersurface of the flap and the stromal bed should be performed in these situations. An attempt to redirect remnants of the ingrown epithelium toward the flap surface may reduce the chance of a local recurrence. The use of a therapeutic soft contact lens may also reduce the likelihood of this. In recalcitrant cases of epithelial-defect-masquerade syndrome associated with stromal edema and/or a deep gutter at the flap margin, suturing the flap may be necessary to avoid recurrences. We have used a technique of deliberate epithelial defect formation to treat eyes with recalcitrant flap wrinkles after LASIK. All eyes were noted to have localized stromal edema in the area of the debridement. We believe the primary mechanism by which the wrinkles are reversed may be related to the resultant stromal hydration and its effect on stretching the reorientation of the collagen fibers. In these eyes, we have consistently avoided extending the defect to the flap margin to avoid epithelial downgrowth and we have not induced epithelial ingrowth. In summary, a high index of suspicion of epithelial ingrowth is necessary in patients with delayed reepithelialization and persistent epithelial defects after LASIK to avoid a delay in the diagnosis of epithelial ingrowth. Recognizing the distinct clinical findings and characteristic predisposing factors can lead to an early diagnosis of epithelial-defect-masquerade syndrome after LASIK. Early surgical intervention may avoid irreversible visual loss due to stromal melting, ulceration, and infectious keratitis.
References 1. Sun C-C, Chang S-W, Tsai RRF. Traumatic corneal perforation with epithelial ingrowth after laser in situ keratomileusis. Arch Ophthalmol 2001; 119:907–909 2. Brahma A, McGhee CNJ, Craig JP, et al. Safety and predictability of laser in situ keratomileusis enhancement by flap reelevation in high myopia. J Cataract Refract Surg 2001; 27:593–603 2364
3. Waring GO III. Epithelial ingrowth after laser in situ keratomileusis [letter]. Am J Ophthalmol 2001; 131: 402–403 4. Haw WW, Manche EE. Treatment of progressive or recurrent epithelial ingrowth with ethanol following laser in situ keratomileusis. J Refract Surg 2001; 17:63–68 5. Vesaluoma MH, Petroll WM, Pe´rez-Santonja JJ, et al. Laser in situ keratomileusis flap margin: wound healing and complications imaged by in vivo confocal microscopy. Am J Ophthalmol 2000; 130:564–573 6. Lumba JD, Hersh PS. Topography changes associated with sublamellar epithelial ingrowth after laser in situ keratomileusis. J Cataract Refract Surg 2000; 26:1413– 1416 7. Wang MY, Maloney RK. Epithelial ingrowth after laser in situ keratomileusis. Am J Ophthalmol 2000; 129: 746–751 8. Walker MB, Wilson SE. Incidence and prevention of epithelial growth within the interface after laser in situ keratomileusis. Cornea 2000; 19:170–173 9. Wright JD Jr, Neubaur CC, Stevens G Jr. Epithelial ingrowth in a corneal graft treated by laser in situ keratomileusis: light and electron microscopy. J Cataract Refract Surg 2000; 26:49–55 10. Leung ATS, Rao SK, Lam DSC. Traumatic partial unfolding of laser in situ keratomileusis flap with severe epithelial ingrowth. J Cataract Refract Surg 2000; 26: 135–139 11. Lam DSC, Leung ATS, Wu JT, et al. Management of severe flap wrinkling or dislodgment after laser in situ keratomileusis. J Cataract Refract Surg 1999; 25:1441– 1447 12. Lyle WA, Jin GJ. Interface fluid associated with diffuse lamellar keratitis and epithelial ingrowth after laser in situ keratomileusis. J Cataract Refract Surg 1999; 25: 1009–1012 13. Kapadia MS, Wilson SE. Transepithelial photorefractive keratectomy for treatment of thin flaps or cap after complicated laser in situ keratomileusis. Am J Ophthalmol 1998; 126:827–829 14. Lim JS, Kim EK, Lee JB, Lee JH. A simple method for the removal of epithelium grown beneath the hinge after LASIK. Yonsei Med J 1998; 39:236–239 15. Daneshvar H, Brownstein S, Mintsioulis G, et al. Epithelial ingrowth following penetrating keratoplasty: a clinical, ultrasound biomicroscopic and histopathological correlation. Can J Ophthalmol 2000; 35:222–224 16. Johnson JD, Harissi-Dagher M, Pineda R, et al. Diffuse lamellar keratitis: incidence, associations, outcomes, and a new classification system. J Cataract Refract Surg 2001; 27:1560–1566 17. Linebarger EJ, Hardten DR, Lindstrom RL. Diffuse lamellar keratitis: diagnosis and management. J Cataract Refract Surg 2000; 26:1072–1077
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18. Shah MN, Misra M, Wilhelmus KR, Koch DD. Diffuse lamellar keratitis associated with epithelial defects after laser in situ keratomileusis. J Cataract Refract Surg 2000; 26:1312–1318 19. Jain S, Chamon W, Stark WJ, et al. Intrastromal epithelial accretion follows deep excimer annular keratectomy. Cornea 1996; 15:248–257 20. Azar DT, Hahn TW, Jain S, et al. Matrix metalloproteinases are expressed during wound healing after excimer laser keratectomy. Cornea 1996; 15:18–24 21. Maeda M, Vanlandingham BD, Ye H, et al. Immunoconfocal localization of gelatinase B expressed by migrating intrastromal epithelial cells after deep annular excimer keratectomy. Curr Eye Res 1998; 17:836–843
From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School (Azar, Scally), Boston, Massachusetts, Wills Eye Hospital, Jefferson Medical College (Hannush), Philadelphia, Pennsylvania, Lahey Eye Institute (Soukiasian), Peabody, Massachusetts, and Devers Eye Institute (Terry), Portland, Oregon, USA. Supported in part by the New England Corneal Transplant Research Fund, Research to Prevent Blindness Lew R. Wasserman Merit Award, and Massachusetts Lions Eye Research Award (D.T.A.). None of the authors has a financial interest in any product mentioned.
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L
aser in situ keratomileusis (LASIK) is among the most commonly performed ophthalmic surgical procedures. As experience with this procedure has increased, the incidence of vision-threatening complications has decreased. One serious complication of LASIK
Accepted for publication March 12, 2003. Reprint requests to Dimitri T. Azar, MD, Corneal and Refractive Surgery Services, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts, USA. E-mail: [email protected]. 2003 ASCRS and ESCRS Published by Elsevier Inc.
that remains is epithelial ingrowth.1–15 It is associated with an epithelial defect involving the flap edge.10–14 The presence of an epithelial defect is generally attributable to the shearing forces of the microkeratome and often resolves without serious complications. Recent reports show a high association between an epithelial defect and diffuse lamellar keratitis (DLK) and reduced visual acuity.16–18 The epithelial defect may be associated with flap wrinkles and stromal edema.5,10,11,13 Intraoperative recognition of an epithelial defect, repositioning of loose epithelium, use of a contact lens, and flap suturing 0886-3350/03/$–see front matter doi:10.1016/S0886-3350(03)00333-X
EPITHELIAL-DEFECT-MASQUERADE SYNDROME
Table 1. Clinical findings, treatment, and visual outcomes in epithelial-defect-masquerade syndrome. Patient Parameter
1
2
3
4
Age (y)/sex
53/M
29/F
27/M
46/M
⫹
⫹
⫹
⫹
UCVA before diagnosis
20/400
N/A
20/30
CF @ 4 ft
BSCVA before diagnosis
20/200
20/80
20/25
20/400
Time between LASIK and final diagnosis (d)
5
60
7
15
DLK
Slitlamp diagnostic features
⫹
⫹
⫹
–
Center sparing
–
–
–
–
Center involved
⫹
⫹
⫹
⫹
Stromal melting
–
⫹
–
⫹
Flap wrinkles
–
–
⫹
–
Bacterial keratitis
–
⫹
–
–
Early flap elevation
⫹
–
⫹
–
Epithelial scraping
⫹
⫹
⫹
⫹
Therapeutic soft contact lens application
⫹
⫹
⫹
⫹
Need for retreatment
–
⫹
⫹
–
Final UCVA
20/30
20/100
20/15
20/20
Final BSCVA
20/20
20/60
20/15
20/20
BSCVA ⫽ best spectacle-corrected visual acuity; CF ⫽ counting fingers; DLK ⫽ diffuse lamellar keratitis; N/A ⫽ not available; UCVA ⫽ uncorrected visual acuity; ⫹ ⫽ present; – ⫽ not present
may enhance epithelial wound healing and minimize epithelial ingrowth. In this report, we describe the clinical features, treatment, and outcomes of epithelial ingrowth after intraoperative epithelial defects associated with LASIK that masqueraded as stromal edema and persistent epithelial defects. Although the association of epithelial defects and epithelial ingrowth is known to LASIK surgeons, to our knowledge, this is the first report of epithelial-defect-masquerade syndrome as a surgical complication of LASIK, with characteristic clinical findings, outcomes, and treatment alternatives.
Patients and Methods The charts of 4 eyes (4 patients) in which epithelial ingrowth was diagnosed after LASIK associated with epithelial defects were reviewed. The time between surgery and final diagnosis was recorded. The factors that may have contributed to the delayed diagnosis were investigated; these included the possible association of stromal edema, DLK, flap-edge contraction, stromal folds, and anterior chamber inflammation. The clinical findings were recorded to determine common potential pathognomonic features and possi-
ble pathologic sequelae. The interval between diagnosis and surgery and the type of surgical interventions were recorded. The visual outcomes after treatment were determined.
Results Table 1 summarizes the age, sex, clinical findings, and possible etiology of the 4 patients. All eyes had an epithelial defect reaching the flap edge immediately after surgery; the persistent defect and stromal edema obscured early diagnosis of epithelial ingrowth. Healing of the epithelial defect was incomplete in the region of the subsequent diagnosis of ingrowth. In all eyes, the edge of the defect coincided with the flap margin for more than 3 clock hours and the peripheral epithelium showed a pathognomonic convexity at the flap margin (Figure 1, top). This was seen with slitlamp biomicroscopy as an arcuate light reflex along the margin of the flap overlying the ingrown epithelium. Fluorescein staining showed characteristic patterns of pooling at the junction of the swollen stromal flap and the inwardly directed epithelium (Figure 1, bottom right). The best spectacle-corrected visual acuity (BSCVA) was worse in 3 eyes at the time of diagnosis (⬍20/60);
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Table 2. Recommended diagnostic and therapeutic approach in epithelial-defect-masquerade syndrome. Diagnostic features Microkeratome-related epithelial defect Epithelial defect edge involving flap margin Delayed reepithelialization Stromal edema, DLK, and/or ulceration of the flap Convexity of peripheral epithelium at flap edge Fluorescein pooling at flap edge overlying ingrown epithelium Confocal microscopic findings of cells in the interface
Figure 1. (Azar) Top: Diagramatic illustration of epithelial-defect-
Therapeutic approach
masquerade syndrome after LASIK showing the characteristic epithelial convexity adjacent to the stromal edema in the inferior half of the LASIK flap. Bottom left : Clinical appearance of epithelial-defect-masquerade syndrome. Bottom right: Fluorescein staining showing an epithelial defect at the edge of the flap and arcuate fluorescein pooling below the defect corresponding to the peripheral region of the epithelial ingrowth.
Early flap lifting Extensive epithelial flap scraping Diagnostic cultures of specimen if bacterial keratitis suspected Flap repositioning, ironing, and possible suturing Therapeutic soft contact lens application Postoperative steroids and antibiotics
in 1 eye, it was 20/25. In 1 eye, stromal melting developed and ulceration complicated by bacterial keratitis required fortified antibiotics. Surgical repair included flap lifting, epithelial scraping on both sides of the interface, repositioning the flap, and ironing the resultant folds. A therapeutic soft contact lens was applied in all eyes. The epithelial defects healed within 7, 21, 24, and 5 days in patients 1, 2, 3, and 4, respectively. Reoperation was necessary in 2 eyes. The final uncorrected visual acuity (UCVA) and BSCVA improved by 3 to 8 and by 2 to 9 Snellen lines, respectively. Table 2 summarizes our diagnostic and therapeutic approach to the management of persistent epithelial-defect-masquerade syndrome after LASIK.
Case Reports Case 1 A 53-year-old man had LASIK in the left eye 5 days before presentation and was referred because of a persistent epithelial defect and flap edema that did not respond to topical treatment with prednisolone acetate, ofloxacin, and 5% sodium chloride solution. Laser in situ keratomileusis was performed using an LSK-1 microkeratome and a Visx 20/20 laser and was complicated by intraoperative epithelial abrasion in the center of the cornea extending to the flap edge. The patient complained of blurred vision, pain, and irritation, especially on blinking, since the surgery. He had difficulty opening his eyes and complained of severe glare. The preoperative refractive error was ⫺2.00 ⫺0.50 ⫻ 100 in the right eye and ⫺2.00 in the left eye. 2360
Careful observation for recurrent epithelial ingrowth DLK ⫽ diffuse lamellar keratitis
On presentation, the patient’s UCVA was 20/20 in the right eye. In the operated left eye, the UCVA was 20/400, improving to 20/200 only with pinhole. Slitlamp examination showed evidence of a large geographic defect extending from the edge of the flap to the hinge, sparing the superior and inferior margins of the flap. This was associated with 3⫹ flap edema and surface irregularities. The temporal epithelium exhibited characteristic convexity suggestive of ingrowth. Epithelial-defect-masquerade syndrome was diagnosed. The patient was treated by lifting the flap and scraping the epithelial cells on the stromal bed and the posterior layer of the flap; this was performed successfully. Corneal scraping and cultures were obtained, a therapeutic contact lens was applied at the end of the procedure, and prednisolone acetate and ofloxacin were started 4 times daily. The next day, the patient reported significant improvement in vision and symptoms. The UCVA was 20/80, improving to 20/30 with pinhole. The epithelial defect decreased over the following 3 days. Early DLK was visible on day 3 and was managed by removing the contact lens and increasing the topical corticosteroids to every 2 hours. The UCVA improved to 20/50 by day 4. All cultures and scrapings obtained at the time of surgery were negative. The steroid drops were tapered and the antibiotics discontinued. One month after surgery, the UCVA was 20/40⫺2, improving to 20/25⫺3 with ⫺0.25 ⫺0.75 ⫻ 95. Trace haze was evident at the temporal edge of the flap. The central cornea was clear, but microstriae could be seen with retroillumination. Artificial tears were continued.
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Six months after surgery, the UCVA was 20/30, improving to 20/20 with ⫺0.50. The haze at the flap margin and the microstriae were still visible. The patient was happy with the visual outcomes and the monovision results. Corneal topography showed an area of peripheral flattening that contributed to slight surface irregularity and was consistent with mild peripheral stromal melting.
Case 2 A 29-year-old woman had LASIK complicated by loose epithelium that extended to the flap edge in both eyes. The preoperative refractions were 20/20 with ⫺1.25 sphere in the right eye and 20/20 with ⫺1.25 ⫹1.00 ⫻ 172 in the left eye. The preoperative central keratometry was 41.61/ 42.55 ⫻ 88 and 40.90/41.82 ⫻ 180, respectively. Bandage contact lenses were placed in both eyes. On the first postoperative day, there were small abrasions in both eyes. The UCVA was 20/70 in the right eye and 20/30 in the left eye. The left eye healed without complications; at 1 week, the UCVA was 20/20. Small epithelial microcysts were observed on the flap surface in the right eye. The BSCVA in the right eye did not improve beyond 20/50 in the first 3 weeks despite punctal plug insertion. The central epithelium was debrided, and a bandage contact lens was placed. Tobramycin 4 times daily and prednisolone acetate every 2 hours were started. Three days after scraping, there was increased pain and redness and decreased visual acuity. Flap shrinkage, stromal melting, and interface infection were suspected. Ofloxacin was started every 30 minutes, and prednisolone acetate was increased to every hour. The patient was seen by another physician, who obtained corneal cultures (by scraping) and performed a subconjunctival injection of tobramycin (Ancef威). Fortified vancomycin and fortified gentamicin drops were also started. The flap was left in place and the patient followed closely. Cultures grew Streptococcus viridans. The pain decreased, the infiltrate decreased with therapy, and the medications were tapered. The patient was examined 2 months after LASIK and 1 month after scraping. The BSCVA in the right eye was 20/80. Slitlamp examination showed a white and quiet eye, but the flap was retracted with an epithelial defect, a white flap edge, and thinned periphery (Figure 1, bottom right). Epithelial ingrowth masquerading as an epithelial defect and stromal ulceration were diagnosed. The flap was lifted, and an epithelial membrane was excised from the bed and flap. The necrotic stromal tissue of the inferonasal flap was removed; the residual LASIK flap was sutured in place, and a bandage contact lens was placed. Three weeks after flap surgery, the UCVA was 20/60, improving to 20/40 with pinhole; all sutures were removed. Seven weeks after suture removal, the UCVA was 20/100, improving to 20/60 with ⫺0.25 ⫹2.75 ⫻ 105. Corneal topography showed evidence of irregular astigmatism. A gas-permeable contact lens was prescribed, which improved visual acuity to 20/15⫹1.
Case 3 A 27-year-old man had uneventful sequential bilateral LASIK for a refractive error of ⫺3.75 diopters (D) in the right eye and ⫺3.65 D in the left eye using a Summit Apex Plus威 laser and an SKBM microkeratome (Alcon Laboratories, Inc.). One day postoperatively, the patient complained of minimal foreign-body sensation in the left eye that began the preceding evening. The UCVA was 20/25⫺3 in the right eye and 20/30⫺2 in the left eye. The BCVA was 20/20 with ⫹0.75 ⫺0.50 ⫻ 12 and 20/25 with ⫹0.75 ⫺0.50 ⫻ 22, respectively. The right eye was unremarkable. There was superior flap slippage in the left eye with parallel fixed folds extending toward the superotemporal flap margin (Figure 2, A and B). The flap in the left eye was lifted, and epithelial ingrowth was noted inferiorly and removed. To remove the fixed folds sequentially, the flap was bimanually stretched and the surface mechanically stroked with a Merocel威 sponge (Medtronic Solan); the epithelium over the area of the folds was removed by stroking, and the stroma was hydrated using sterile water. The flap was floated into position and allowed to dry, and a bandage contact lens (Protek, Bausch & Lomb) was placed. Postoperatively, the patient was instructed to use ofloxacin 0.3% and fluorometholone 0.1% every 2 hours. The following day, the flap was well positioned with no folds noted; focal areas of epithelial haze and flap edema were noted, and the bandage contact lens was in position. Two days after flap repositioning, the patient complained of slight irritation in the left eye. The conjunctiva was not inflamed. There was increased superior and temporal flap edema and grade 2 to 3 DLK 2.0 to 3.0 mm from the flap margin. Minimal anterior chamber reaction was noted. Rimexolone 1% ophthalmic suspension was initiated every 2 hours, and ofloxacin 0.3% was continued. The following day (3 days after flap lifting), a crescent-shaped epithelial defect on the temporal flap edge was noted overlying localized flap edema (Figure 2, C and D). Prednisolone acetate 1% and oral prednisone at 80 mg/day was initiated. The epithelial defect failed to heal. Epithelial-defect-masquerade syndrome was suspected, and the flap was relifted 6 days after flap repositioning. Epithelial ingrowth of 1.0 to 2.0 mm was noted in the periphery of the bed. This was removed and the interface irrigated, but the epithelial ingrowth recurred. It was retreated by retracting the epithelium onto the peripheral cornea and partially redraping the flap after it had been repositioned to prevent epithelial regrowth. Three days later, the UCVA was 20/30⫹2 with minimal peripheral epithelial ingrowth but persistent stromal haze. Two months after the procedure, the UCVA was 20/20⫺2 with ⫹1.25 ⫺0.50 ⫻ 33. Four months after the procedure, the UCVA was 20/15⫺2 with ⫹1.00 ⫺0.50 ⫻ 25. Interface and stromal haze had decreased.
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Figure 2. (Azar) After LASIK using a horizontal microkeratome, striae are seen by direct slitlamp illumination (A ). The horizontal striae are better appreciated by negative staining with fluorescein (B ). Following treatment of the striae, epithelial-defect-masquerade syndrome occurred as evidenced by stromal swelling (C) and an epithelial defect in the flap (D ) overlying the area of ingrown epithelium.
Case 4 A 46-year-old man had LASIK in both eyes 15 days before the initial presentation. He was referred because he developed keratopathy in the left eye that was thought to be secondary to herpes zoster but did not respond to topical or oral antiviral medication (Figure 3). At the initial presentation, the patient’s medications included trifluridine and erythromycin ointment in the left eye and oral valacyclovir 1000 mg 3 times a day. The patient complained of persistent foreign-body sensation, pain, and decreased visual acuity in the left eye. The visual acuity was 20/25 in the right eye and counting fingers at 4 feet in the left eye. Slitlamp examination of the right eye revealed a well-positioned LASIK flap with a superonasal hinge, minimal surface staining, an anterior stromal scar in the superonasal quadrant, and no interface changes. Slitlamp examination of the left eye revealed a 90% epithelial defect over the LASIK flap, which had a superotemporal hinge. Multiple filaments were noted on the surface, with early stromal melt. Epithelial-defect-masquerade syndrome was diagnosed. The flap edge was loosely adherent (Figure 4, A and B), and epithelial ingrowth covered the bed, overlying the pupillary zone (Figure 4, C and D). The patient agreed to proceed
with debridement and repositioning of the flap with multiple 10-0 nylon sutures (Figure 5, A). A therapeutic bandage contact lens was placed and a punctal plug inserted in the inferior left punctum. The medication regimen was modified to include systemic steroids and topical antibiotic agents. The goals were to prevent infection, control inflammation, prevent epithelial ingrowth, and rehabilitate the patient visually. Five days after the debridement and flap repositioning, the LASIK flap was almost completely reepithelialized. The interface remained clear with no evidence of epithelial ingrowth after suture removal (Figure 5, B).
Discussion In this report, we document an uncommon complication of LASIK surgery in which the diagnosis of epithelial ingrowth was delayed. This syndrome displays characteristic clinical features and, if left untreated, may result in irreversible visual loss. The diagnostic features listed in Table 2 were present in all 4 patients. We believe the presence of stromal edema and DLK may interfere with early diagnosis
Figure 3. (Azar)
Epithelial-defectmasquerade syndrome following LASIK displaying DLK (left) and an epithelial defect involving the entire LASIK flap (right).
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Figure 4. (Azar) Close examination of the LASIK flap edge demonstrates the loose adhesion of the flap (A ). As the flap is retracted, epithelial ingrowth becomes more evident (B ). Following flap elevation, cobalt-blue filter (C ) and diffuse illumination (D ) demonstrate the extent of epithelial ingrowth.
because these findings may obscure clear visualization of the ingrown sheet of epithelial cells. The role of confocal microscopy in these patients is not known. It
Figure 5. (Azar) Postoperative photographs of the cornea showing sutures that were placed after debridement and flap repositioning to enhance wound healing and to minimize the recurrence of epithelial ingrowth (A ). When there is no evidence of an epithelial defect or epithelial ingrowth, the sutures are carefully removed (B ).
may facilitate the diagnosis and prevent delays in proper diagnosis and treatment.5 We did not suture all the flaps in these patients. Repositioning, ironing, and contact lens application after scraping may not be sufficient to prevent epithelial regrowth into the interface. Suturing the flap may add another protective barrier against regrowth, and we think it may be necessary in this situation. The sutures remain for 3 to 5 days before they are removed. We have described an experimental model of intrastromal epithelial accretion after excimer concentric keratectomy.19,20 In this rabbit model, neither central flap nor laser treatment was necessary to induce epithelial migration into the stroma. Our findings show that the conditions for epithelial migration in the rabbit are (1) a stromal-gaping incision or an ablation that creates a deep orthogonal stromal edge (⬎80 m) in which the central stroma is elevated relative to the periphery, (2) a surface epithelial defect, and (3) central stromal edema. These 3 requirements were satisfied in our patients with epithelial-defect-masquerade syndrome after LASIK. Long-term follow-up of rabbits showed that the central stroma undergoes slow melting, primarily as a result of the action of gelatinase B (MMP-9) produced by the migrating epithelial cells.21 A similar outcome was noted in 2 of the patients. An important feature of epithelial ingrowth is that it may be subtle and can be mistaken for fibrosis, DLK, and debris. The diagnosis of epithelial ingrowth in these situations is often delayed. In addition, the extent of
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epithelial ingrowth after LASIK, which is often underestimated, is best appreciated using retroillumination. The management of isolated asymptomatic epithelial islands is usually limited to observation. In contrast, symptomatic epithelial ingrowth, progressive ingrowth, and ingrowth communicating with the peripheral epithelium require more aggressive management. Lifting the flap and scraping the undersurface of the flap and the stromal bed should be performed in these situations. An attempt to redirect remnants of the ingrown epithelium toward the flap surface may reduce the chance of a local recurrence. The use of a therapeutic soft contact lens may also reduce the likelihood of this. In recalcitrant cases of epithelial-defect-masquerade syndrome associated with stromal edema and/or a deep gutter at the flap margin, suturing the flap may be necessary to avoid recurrences. We have used a technique of deliberate epithelial defect formation to treat eyes with recalcitrant flap wrinkles after LASIK. All eyes were noted to have localized stromal edema in the area of the debridement. We believe the primary mechanism by which the wrinkles are reversed may be related to the resultant stromal hydration and its effect on stretching the reorientation of the collagen fibers. In these eyes, we have consistently avoided extending the defect to the flap margin to avoid epithelial downgrowth and we have not induced epithelial ingrowth. In summary, a high index of suspicion of epithelial ingrowth is necessary in patients with delayed reepithelialization and persistent epithelial defects after LASIK to avoid a delay in the diagnosis of epithelial ingrowth. Recognizing the distinct clinical findings and characteristic predisposing factors can lead to an early diagnosis of epithelial-defect-masquerade syndrome after LASIK. Early surgical intervention may avoid irreversible visual loss due to stromal melting, ulceration, and infectious keratitis.
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3. Waring GO III. Epithelial ingrowth after laser in situ keratomileusis [letter]. Am J Ophthalmol 2001; 131: 402–403 4. Haw WW, Manche EE. Treatment of progressive or recurrent epithelial ingrowth with ethanol following laser in situ keratomileusis. J Refract Surg 2001; 17:63–68 5. Vesaluoma MH, Petroll WM, Pe´rez-Santonja JJ, et al. Laser in situ keratomileusis flap margin: wound healing and complications imaged by in vivo confocal microscopy. Am J Ophthalmol 2000; 130:564–573 6. Lumba JD, Hersh PS. Topography changes associated with sublamellar epithelial ingrowth after laser in situ keratomileusis. J Cataract Refract Surg 2000; 26:1413– 1416 7. Wang MY, Maloney RK. Epithelial ingrowth after laser in situ keratomileusis. Am J Ophthalmol 2000; 129: 746–751 8. Walker MB, Wilson SE. Incidence and prevention of epithelial growth within the interface after laser in situ keratomileusis. Cornea 2000; 19:170–173 9. Wright JD Jr, Neubaur CC, Stevens G Jr. Epithelial ingrowth in a corneal graft treated by laser in situ keratomileusis: light and electron microscopy. J Cataract Refract Surg 2000; 26:49–55 10. Leung ATS, Rao SK, Lam DSC. Traumatic partial unfolding of laser in situ keratomileusis flap with severe epithelial ingrowth. J Cataract Refract Surg 2000; 26: 135–139 11. Lam DSC, Leung ATS, Wu JT, et al. Management of severe flap wrinkling or dislodgment after laser in situ keratomileusis. J Cataract Refract Surg 1999; 25:1441– 1447 12. Lyle WA, Jin GJ. Interface fluid associated with diffuse lamellar keratitis and epithelial ingrowth after laser in situ keratomileusis. J Cataract Refract Surg 1999; 25: 1009–1012 13. Kapadia MS, Wilson SE. Transepithelial photorefractive keratectomy for treatment of thin flaps or cap after complicated laser in situ keratomileusis. Am J Ophthalmol 1998; 126:827–829 14. Lim JS, Kim EK, Lee JB, Lee JH. A simple method for the removal of epithelium grown beneath the hinge after LASIK. Yonsei Med J 1998; 39:236–239 15. Daneshvar H, Brownstein S, Mintsioulis G, et al. Epithelial ingrowth following penetrating keratoplasty: a clinical, ultrasound biomicroscopic and histopathological correlation. Can J Ophthalmol 2000; 35:222–224 16. Johnson JD, Harissi-Dagher M, Pineda R, et al. Diffuse lamellar keratitis: incidence, associations, outcomes, and a new classification system. J Cataract Refract Surg 2001; 27:1560–1566 17. Linebarger EJ, Hardten DR, Lindstrom RL. Diffuse lamellar keratitis: diagnosis and management. J Cataract Refract Surg 2000; 26:1072–1077
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18. Shah MN, Misra M, Wilhelmus KR, Koch DD. Diffuse lamellar keratitis associated with epithelial defects after laser in situ keratomileusis. J Cataract Refract Surg 2000; 26:1312–1318 19. Jain S, Chamon W, Stark WJ, et al. Intrastromal epithelial accretion follows deep excimer annular keratectomy. Cornea 1996; 15:248–257 20. Azar DT, Hahn TW, Jain S, et al. Matrix metalloproteinases are expressed during wound healing after excimer laser keratectomy. Cornea 1996; 15:18–24 21. Maeda M, Vanlandingham BD, Ye H, et al. Immunoconfocal localization of gelatinase B expressed by migrating intrastromal epithelial cells after deep annular excimer keratectomy. Curr Eye Res 1998; 17:836–843
From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School (Azar, Scally), Boston, Massachusetts, Wills Eye Hospital, Jefferson Medical College (Hannush), Philadelphia, Pennsylvania, Lahey Eye Institute (Soukiasian), Peabody, Massachusetts, and Devers Eye Institute (Terry), Portland, Oregon, USA. Supported in part by the New England Corneal Transplant Research Fund, Research to Prevent Blindness Lew R. Wasserman Merit Award, and Massachusetts Lions Eye Research Award (D.T.A.). None of the authors has a financial interest in any product mentioned.
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