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Severe corneal epithelial sloughing during laser in situ keratomileusis as a presenting sign for silent epithelial basement membrane dystrophy

Pérez-Santonja, Juan J. MD, FEBO; Galal, Ahmed MD, PhD; Cardona, Carmen MD, PhD; Artola, Alberto MD, PhD; Ruíz-Moreno, José M. MD; Alió, Jorge L. MD, PhD

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Journal of Cataract & Refractive Surgery: October 2005 - Volume 31 - Issue 10 - p 1932-1937
doi: 10.1016/j.jcrs.2005.06.041
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Abstract

Epithelial basement membrane dystrophy (EBMD), also known as map-dot-fingerprint or Cogan microcystic dystrophy, is the most common corneal dystrophy, with an estimated prevalence of 5% to 18%.1 Although EBMD is a bilateral disorder, it may be asymmetric. The classic biomicroscopic findings of EBMD are maplike subepithelial geographic opacities (maps), intraepithelial microcysts (dots), and subepithelial ridges resembling fingerprints.2–5 The basic histopathologic findings in EBMD are multiple laminations of basement membrane, underdeveloped hemidesmosomes, and an absence of anchoring fibrils.3,4 All these findings result in poor adherence of the corneal epithelium to Bowman's layer. In these patients, even minor trauma to the corneal surface may dislodge the poorly attached epithelium and lead to recurrent corneal erosions.

Patients with EBMD are predisposed to epithelial sloughing/defects during the microkeratome pass in laser in situ keratomileusis (LASIK), subsequent wound-healing problems, and multiple complications in the postoperative period.6 Epithelial defects during LASIK have also been associated with the type of microkeratome used and poor irrigation of the corneal surface before the microkeratome pass, although some authors have hypothesized the presence of undiagnosed or subclinical basement membrane dystrophy as a cause for some of these epithelial defects during LASIK.7,8

We report the occurrence of severe corneal epithelial sloughing/defects during LASIK as the first presenting sign for subclinical EBMD in corneas described as being clinically normal.

PATIENTS AND METHODS

This noncontrolled retrospective case series reviewed the medical records of all patients with a diagnosis of large epithelial sloughing/defect (more than 9.0 mm2 or 20% of flap surface) during LASIK who were operated on by 1 surgeon (J.J.P-S.) at the Cornea and Refractive Surgery Unit at Alicante Institute of Ophthalmology from January 1, 1995, to December 31, 2004. All those who presented normal corneas on clinical examination before LASIK and EBMD changes after LASIK surgery were included in the study. Patients signed written informed consent forms allowing anonymous use of their data for this or other studies.

A uniform LASIK technique using the ALK-E (Chiron Vision), BD K-3000 (Becton and Dickinson), or M2 (Moria) microkeratome and the Technolas C-LASIK 217 excimer laser (Bausch & Lomb) was performed during the study period.9 Postoperatively, a therapeutic contact lens was inserted at the end of the procedure and all patients were treated with a topical antibiotic, a steroid, and artificial tears. The treatment duration and dose were modified individually depending on the clinical course.

All the eyes had a preoperative and postoperative basic examination, including measurement of uncorrected (UCVA) and best corrected visual acuity, manifest and cycloplegic refractions, slitlamp microscope examination, pachymetry, videokeratography, and indirect ophthalmoscopy. All patients were examined on the first postoperative day, at 1 week, and at 1 month. The frequency of subsequent follow-up examinations was at the surgeon's discretion, according to the status of the corneal flap and visual acuity, although all patients were also examined 3 and 12 months after surgery.10 The postoperative course and complications were also recorded.

SPSS 10.0.7 (SPSS Inc.) was used for data collection and statistical analysis. A P value less than 0.05 was considered statistically significant.

RESULTS

The medical records of 5670 LASIK procedures were reviewed, and epithelial sloughing/defects larger than 20% of flap surface were found in 18 eyes (0.32%). Eleven of these 18 eyes (6 patients; 61.1%) presented normal corneas on biomicroscopic examination before LASIK and EBMD changes after LASIK and were included in this study. The mean age of the 5 men and 1 woman was 35 years ± 6.1 (SD) (range 25 to 43 years). All patients were myopic or had myopic astigmatic before surgery. The first 3 patients had simultaneous bilateral LASIK, the following 2 patients had sequential bilateral LASIK (1 week apart), and the last patient had LASIK in 1 eye and photorefractive keratectomy in the fellow eye. The ALK-E microkeratome was used in 6 of 11 eyes (54.5%), the M2 in 4 of 11 eyes (36.3%), and the BD K-3000 in 1 of 11 eyes (9%). All cases completed a minimum follow-up period of 12 months.

Visual and refractive outcomes in the eyes included in this study are illustrated in Figures 1 and 2, respectively. Mean preoperative UCVA was 20/500 (0.04 ± 0.02), and after surgery, mean UCVA significantly increased to 20/34 (0.59 ± 0.26) at 1 month, 20/31 (0.64 ± 0.24) at 3 months, and 20/27 (0.74 ± 0.21) at 12 months (paired Student t test, P<.0001). No significant differences were observed in postoperative UCVA (paired Student t test, P>.1). Mean preoperative best spectacle-corrected visual acuity (BSCVA) was 20/22 (0.9 ± 0.16); after surgery, BSCVA changed to 20/26 (0.76 ± 0.19) at 1 month, 20/24 (0.85 ± 0.15) at 3 months, and 20/21 (0.94 ± 0.1) at 12 months. The BSCVA worsened 0.14 at 1 month (0.1 = 1 line) compared with preoperative values (paired Student t test, P = .002). Three-month and 12-month postoperative BSCVAs were not significantly different from preoperative values (paired Student t test, P = .234 at 3 months, P = .295 at 12 months). There was a significant improvement in BSCVA between 1 and 3 months after surgery (paired Student t test, P = .039), and also between 3 and 12 months (paired Student t test, P = .013). At the last examination, BSCVA loss was observed in 1 of 11 eyes (9%) (1 Snellen line), with no affected eye losing 2 or more Snellen lines of BSCVA. The safety index was 1.04, and the efficacy index was 0.82.

Figure 1.
Figure 1.:
Time course of UCVA and BCVA. Values are means and standard deviations.
Figure 2.
Figure 2.:
Time course of spherical equivalent. Values are means and standard deviations.

Three months after surgery, 9 of 11 eyes (81.8%) were within ±1.00 diopter (D) of emmetropia and 6 of 11 (54.5%) were within ±0.5 D. One year after surgery, 10 of 11 eyes (91%) were within ±1.00 D and 7 of 11 (63.6%) within ±0.5 D of emmetropia. Although 2 patients were undercorrected by more than 1 D 3 months after surgery, only 1 patient decided to have LASIK retreatment.

None of the 11 eyes had a history of recurrent corneal erosions or corneal signs of basal membrane dystrophy before surgery. During the microkeratome pass in the 11 eyes, partial (4 of 11 eyes) and total (7 of 11 eyes) epithelial sloughing/defect occurred. All epithelial defects healed between 2 and 5 days.

During the early postoperative period, paracentral isolated nests of epithelium in the interface were observed in 1 of 11 eyes (9%), which spontaneously decreased with time. Diffuse lamellar keratitis (DLK) stage I to II developed in 6 of 11 eyes (54.5%). Treatment with topical steroids was intensified in these patients. Map-dot-fingerprint dystrophy signs developed in 6 of 11 eyes (54.5%), the intraepithelial microcysts (dots) being the most common sign. Flap microfolds were observed in 2 of 11 eyes (18.2%) and were visually significant. Flap lifting with hydration with deionized water within 1 week of the original procedure was the treatment used in these patients.

Between 1 and 3 months after surgery, the slitlamp examination revealed map-dot-fingerprint dystrophy signs in 6 of 11 eyes (54.5%), peripheral epithelial ingrowth in 8 of 11 (72.7%), and flap melting in 3 of 11 (27.3%). In 2 eyes, surgery to remove the epithelial ingrowth from the interface was necessary, although small epithelial sheets persisted (Figure 3).

Figure 3.
Figure 3.:
A: Slitlamp photograph showing epithelial ingrowth 1 month after LASIK. B: Same eye 1 month after removal of epithelial ingrowth (2 months after LASIK).

At the final follow-up, basal membrane dystrophy signs were present in 2 of 11 eyes (18.2%) (Figure 4), peripheral epithelial ingrowth in 8 of 11 (72.7%), and flap melting in 4 of 11 (36.4%). In all eyes, flap melting developed on an epithelial ingrowth area. Both epithelial ingrowth and stromal melting were peripheral disorders and did not affect the visual acuity at the last follow-up. Table 1 illustrates the complications that occurred after surgery.

Figure 4.
Figure 4.:
Slitlamp photograph showing maplike subepithelial geographic opacities (maps) in the upper cornea 1 year after LASIK.
Table 1
Table 1:
Intraoperative and postoperative complications (N = 11).

DISCUSSION

The underdeveloped hemidesmosomes and the absence of anchoring fibrils in patients with EBMD lead to poorly adherent epithelium and an increased risk for recurrent corneal erosion.3,4,8 In these patients, even minor trauma to the corneal surface may dislodge the poorly attached epithelium.

Patients with EBMD are at higher risk for epithelial complications during LASIK because of mechanical trauma from the sliding motion of the microkeratome head over the corneal surface. Recently, Dastgheib et al.6 reported that patients with EBMD are predisposed to epithelial sloughing during the microkeratome pass in LASIK, and this may lead to flap distortion, epithelial ingrowth, flap keratolysis, and corneal scarring.

In addition to EBMD, epithelial defects during LASIK have been associated with several risk factors, such as age, corneal thickness, skin type, microkeratome type, and poor irrigation before the microkeratome pass.8,11 However, some authors have hypothesized the presence of undiagnosed or subclinical basement membrane dystrophy as a cause for some of these epithelial defects, particularly large ones, during LASIK.7,8 In this study, we report the occurrence of large intraoperative epithelial sloughing/defects as the first diagnostic sign for silent EBMD during LASIK.

Our study shows that subclinical EBMD is an important cause of large epithelial sloughing/defects during LASIK because approximately 60% of all large epithelial defects appeared in normal corneas on biomicroscopic examination before LASIK but with EBMD signs after surgery. To prevent such a complication, it is important to examine the cornea carefully during the preoperative evaluation for refractive surgery. During slitlamp evaluation, a meticulous examination of the corneal epithelium should be performed by direct, tangential, and retroillumination, especially when the pupil is dilated. Observation for negative staining of fluorescein dye with cobalt blue illumination may also be helpful in the diagnosis. However, it is important to realize that clinical signs in asymptomatic eyes may be absent, and EBMD may be missed despite meticulous examination, as shown in our study. If classic signs of EBMD are found, a surface ablation (photorefractive keratectomy) should be considered.

Our study also shows a high risk for significant sloughing of the epithelium in the second eye when such sloughing occurs in the first eye. We were unable to prevent epithelial problems in the second eye using either simultaneous or sequential bilateral LASIK. A surface ablation (photorefractive keratectomy) should be considered in the fellow eye if significant sloughing occurs in the first eye, as in the case of our last patient.

Dastgheib et al.6 reported epithelial complications during LASIK and subsequent wound-healing problems in patients with clinical EBMD. They found that epithelial sloughing developed during LASIK in 81% of patients with clinical EBMD and that these patients were predisposed to multiple complications in the postoperative period. Epithelial ingrowth beneath the flap was observed in 46% of eyes, all of which required interface epithelium removal, and isolated nests of epithelial ingrowth were observed in 15% of eyes. Flap melting or keratolysis occurred in 31% of eyes with epithelial sloughing.

In our series, sloughing/defect of corneal epithelium occurred during LASIK in all eyes, and all patients were known to have EBMD after LASIK. Therefore, LASIK was the precipitating factor for the clinical presentation of this silent form of EBMD. Our study also shows that these patients are predisposed to multiple complications in the postoperative period. The main early postoperative complications were DLK and flap microfolds. Between 1 and 3 months postoperatively, and also 1 year after surgery, peripheral epithelial ingrowth and flap melting were the most common complications.

Diffuse lamellar keratitis, which is characterized by invasion of inflammatory cells into the LASIK interface, occurred in 6 of 11 eyes (54.5%) in our study. The incidence of DLK after primary LASIK is highly variable (between 0.06% and 3%).12 This complication has not been reported after LASIK in patients with clinical EBMD,6 but it was observed in the early postoperative course in 91% of eyes with intraoperative epithelial defects during LASIK.7 Although the relationship between epithelial defects and DLK has been described,7,13 the level of association found in our study is high and confirms this finding. Because DLK occurred in 54.5% of eyes in our series despite postoperative treatment with topical steroids, and because steroids are known to reduce the intensity of the inflammatory response,7 the nonuse of steroids might have led to higher grades of DLK. Therefore, the use of steroid drops and careful observation seem mandatory in cases of epithelial sloughing/defects after LASIK.

Microfolds requiring flap repositioning have been observed in 0.4% of eyes in primary LASIK patients,12 although they were not found after LASIK in patients with clinical EBMD.6 We observed flap microfolds in 18% of eyes, which required flap lifting and hydration with hypotonic solution. Microfolds were completely eliminated with this approach, and vision was recovered. Every effort should be made to eliminate flap microfolds as soon as they are identified and deemed to be visually significant so that permanent irregular astigmatism can be prevented because the longer microfolds are present, the more difficult they are to eliminate.12

Epithelial ingrowth is a well-known complication after LASIK with a highly variable incidence between 0.3% and 9%.9,14,15 Epithelial ingrowth after LASIK in patients with clinical EBMD has been observed in 46% of eyes.6 In our series, epithelial ingrowth within the interface occurred in 8 of 11 eyes (72%) and surgical removal was required in 2 eyes. The etiology of this epithelial ingrowth is uncertain, but epithelial sloughing/defects may cause mild flap edema with elevation of the flap margin, which may create a space for epithelial cells to migrate from the flap perimeter into the interface.6,12 It is recommended to aggressively remove a sheet of interface epithelium, continuous with surface epithelium, if the sheet is causing visual symptoms, producing irregular astigmatism or flap melting.12 Isolated nests of epithelium in the interface may be observed because they will often spontaneously degenerate without visual symptoms.

Flap keratolysis or melting has been reported in 0% to 5.7% of eyes after primary LASIK,9 and in 31% of eyes after LASIK in patients with clinical EBMD and intraoperative epithelial sloughing.6 In our study, flap melting was observed in 3 of 11 eyes (27.3%) between 1 and 3 months after surgery and in 4 of 11 eyes (36.4%) at the final follow-up. In all eyes, flap melting developed on an epithelial ingrowth sheet. Production of enzymes, such as proteases, by the epithelium has been postulated to cause flap keratolysis,16 but if this were the only mechanism, one would expect some necrosis of the stromal bed, too. Interference of metabolic exchange between the aqueous humor and the flap by the epithelial ingrowth sheet has also been suggested as a cause for flap melting.12 Although the proper management of this complication is still poorly known, it is recommended to lift the flap with epithelium debridement when significant areas of epithelial ingrowth are present.9

Our study demonstrates that visual acuity development is prolonged after surgery. The restoration of BSCVA took several months, with a significant decrease 1 month after surgery followed by a slow, continuous, and significant improvement up to 12 months after surgery. At the last examination, BSCVA loss was observed in only 9% of eyes (1 Snellen line), with no affected eye losing more than 1 Snellen line of BSCVA. Our results are in agreement with those of Mirshahi and coauthors'7 retrospective study of 22 LASIK cases complicated by intraoperative epithelial defects. Similarly, the refractive results in our series seem to have been negatively influenced at the midterm follow-up, as suggested by the low percentage of eyes within ±0.5 D of emmetropia 3 months after surgery in comparison with primary LASIK.17,18 Moreover, 2 eyes (18.2%) were undercorrected by more than 1 D, although only 1 patient decided to have LASIK retreatment for residual myopia. These results are similar to those found by Mulhern and coauthors19 and Mirshahi and coauthors,7 who demonstrated that eyes affected by intraoperative epithelial defects have a larger deviation from emmetropia.

Because the estimated incidence of EBMD is at least 5% in the general population,1 it is clear that most of the patients with undetected EBMD have LASIK with no complications.20 However, those patients with classic and symptomatic EBMD are predisposed to epithelial sloughing during LASIK and postoperative complications, and this procedure should not be recommended.6,21 In our series, large epithelial sloughing/defects were found in 0.32% of all LASIK procedures, and 61% of them occurred in patients with subclinical and undetected EBMD. In these patients, the microkeratome pass was enough of a precipitating factor for the clinical presentation of silent EBMD, indicating that the corneal epithelium is not sufficiently attached. For this reason, when facing a large epithelial sloughing/defect during LASIK in the first eye, the surgeon should expect similar behavior in the fellow eye and LASIK should not be performed. Photorefractive keratectomy should be considered and discussed with the patient because it eliminates the risk for epithelial sloughing and its postoperative-related complications when the abnormal basement membrane is discarded.

In summary, our study shows that subclinical EBMD is an important cause of large epithelial sloughing/defects during LASIK. Moreover, it also shows that LASIK is the precipitating factor for the clinical presentation and diagnosis of this silent form of EBMD. Patients with subclinical EBMD and intraoperative epithelial sloughing/defects are predisposed to multiple complications in the postoperative period, including DLK, flap microfolds, epithelial ingrowth, and flap melting, which require close follow-up and proper management. Restoration of visual acuity takes longer than expected, and both the surgeon and patient should be aware of it. Our study also shows a high risk for significant sloughing of the epithelium in the second eye when it occurs in the first eye, and neither simultaneous nor sequential LASIK can prevent it. Although most patients with undetected EBMD have LASIK with no complications, when a large epithelial sloughing/defect occurs in the first eye, similar behavior should be expected in the fellow eye and LASIK should not be performed. Photorefractive keratectomy, which is refractive and therapeutic at the same time, should be considered and discussed with the patient.

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