Abstract
PURPOSE
To identify possible associations with the development of diffuse lamellar keratitis (DLK) after laser in situ keratomileusis (LASIK) with femtosecond laser flap creation.
SETTING
University-based academic practice, Ann Arbor, Michigan, USA.
DESIGN
Case-control study.
METHODS
Myopic LASIK was performed between October 2006 and December 2010 using an Intralase 60 kHz femtosecond laser for flap creation. Preoperative clinical characteristics, treatment parameters, and intraoperative and postoperative complications were recorded. Statistical comparisons were made using t, chi-square, and Fisher exact tests and repeated-measures logistic regression to adjust for inter-eye dependency.
RESULTS
The study enrolled 801 eyes (419 patients). Ninety-nine eyes (12.4%) of 70 patients developed DLK; most cases comprised mild flap interface inflammation and were treated with a routine postoperative antiinflammatory regimen. Twenty-two eyes (2.7%) required more than 1 week of antiinflammatory treatment. There was a statistically significant increase in the incidence of DLK with larger flap diameter (P = .0171), higher side-cut energy (P = .0037), and higher raster energy (P = .0033). Patients with DLK were less likely to achieve corrected distance visual acuity of 20/20 or better 1 day postoperatively (P = .0453). The difference in acuity was no longer present at 1 week. There were no significant associations between the incidence of DLK and preoperative refractive error, flap thickness, ablation depth, or other treatment parameters.
CONCLUSIONS
Diffuse lamellar keratitis after LASIK with femtosecond laser flap creation tended to be mild with little effect on visual acuity. Higher energy level for flap creation and larger flap diameter were associated with an increased risk for DLK.
With the number of laser in situ keratomileusis (LASIK) cases performed in the United States exceeding 630 000 in 2009,1 most eyecare providers are becoming increasingly aware of the complications related to lamellar refractive surgery. Diffuse lamellar keratitis (DLK) is one of the most common postoperative complications of LASIK surgery. It was first described by Smith and Maloney2 in 1998 as a granular white cellular infiltrate within the LASIK flap interface. It represents a sterile inflammatory reaction, usually in the immediate postoperative period. Although most cases resolve, some progress to severe inflammation and permanent scarring.3 Given the potential for serious vision-threatening consequences, vigilance and prompt treatment are required.
The etiology of DLK is not well understood. It has been associated with factors such as bacterial endotoxin,4 chemicals or debris,5 surgical gloves,6 and surgical marking pens.7,8 Patient factors shown to affect the risk for DLK include meibomian gland secretions and peripheral immune infiltrates,9,10 atopy,11 and iatrogenic epithelial defects.12,13 Ultimately, DLK is likely the result of how a patient’s endogenous factors respond to exogenous exposures.14
Diffuse lamellar keratitis after LASIK has been reported to occur at higher frequency with femtosecond laser flap creation than with microkeratome flap creation. The incidence of DLK is estimated to range from 0.2% to 19.4% after femtosecond laser flap creation15–19 and from 0.1% to 7.7% after microkeratome flap creation.18,20–25
With the increased use of the femtosecond laser for flap creation, there is interest in understanding this phenomenon. Studies17–19 have shown that high laser energy levels and the ensuing photodisruption-induced tissue injury and accumulation of gas bubbles can lead to an increased inflammatory response and DLK.
Recently, it was reported that reducing femtosecond energy settings, especially side-cut energy, decreases the incidence for DLK.17–19 Our previous study evaluating the incidence of DLK after LASIK using 3 femtosecond laser frequencies15 found no statistically significant difference between the lasers. However, that study included surgeries with minimal variability in side-cut or bed energy. The purpose of this study was to identify possible associations with the development of DLK after LASIK performed using the same femtosecond laser for flap creation.
PATIENTS AND METHODS
This study, which was approved by the University of Michigan Institutional Review Board, retrospectively reviewed the records of consecutive patients who had myopic LASIK using the Intralase 60 kHz femtosecond laser (Abbott Medical Optics, Inc.) for flap creation between October 2006 and December 2010. The Technolas 217 excimer laser (Bausch & Lomb) was used for stromal ablation in all cases. In bilateral surgeries, the right eye was always treated first with the femtosecond laser and excimer laser.
Preoperative clinical characteristics and treatment parameters as well as intraoperative and postoperative complications were collected and analyzed. The following clinical data were collected: date of LASIK, patient age and sex, presence of meibomian gland dysfunction, history of ocular allergies, corneal thickness, preoperative Schirmer values after topical anesthesia, preoperative intraocular pressure (IOP), and preoperative use of ocular medications. The following treatment data were recorded: optical zone, raster energy, raster spot separation, side-cut energy, intended flap thickness, flap diameter, ablation depth, and treated refractive error. Residual bed thickness was calculated by subtracting the ablation depth and flap thickness from the preoperative corneal thickness. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities were recorded 1 day and 1 week after LASIK.
For patients who developed DLK, the day of onset, DLK grade, treatment, and day of resolution were recorded. The DLK was graded according to the staging described by Linebarger et al.14 as follows: stage 1 = faint white granular infiltrate confined to flap periphery; stage 2 = white granular infiltrate diffusely distributed in flap interface; stage 3 = diffuse white granular infiltrate centrally more confluent and densely clumped; stage 4 = central striae, bullae formation, stromal melting, and permanent scarring.
The standard postoperative treatment protocol involved the use of corticosteroid and antibiotic eyedrops, separately or in combination, starting the day of or the day after surgery, depending on the surgeon’s preference. After the first postoperative week, the eyedrops were stopped. If DLK was detected, more frequent corticosteroids were started and tapered according to the surgeon’s preference and as indicated by the clinical course.
Statistical comparisons between the group that developed DLK and the group with no DLK were performed using t tests for continuous variables and the chi-square or Fisher exact test for categorical variables. Univariate repeated-measures logistic regression models using generalized estimating equations to adjust for inter-eye dependency were used to assess the association between rates of DLK and clinical and treatment variables. A P value less than 0.05 was considered statistically significant. All analyses were performed using SAS software (version 9.2, SAS Institute, Inc.).
RESULTS
Eight hundred one eyes of 419 patients were included in this analysis. Binocular LASIK was performed in 382 patients and monocular LASIK in 37 patients. The mean age of the 232 (55.4) women and 187 men (44.6) was 38 years ± 10 (SD) (range 21 to 72 years). Table 1 shows the demographic data of patients who developed DLK and those who did not develop DLK.
Table 1.
Parameter | No DLK | DLK | P Value* |
---|---|---|---|
Patients (n) | 349 | 70 | — |
Eyes, n (%) | 702 (87.6) | 99 (12.4) | — |
Mean age (y) ± SD | 38.5 ± 10.5 | 38.1 ± 9.4 | .7674 |
Sex, n (%) | .9494 | ||
Female | 193 (55.3) | 39 (55.7) | |
Male | 156 (44.7) | 31 (44.3) |
DLK = diffuse lamellar keratitis
t test for continuous variables; chi-square test for categorical variables
Diffuse lamellar keratitis developed in 99 eyes of 70 patients, 29 bilateral and 41 unilateral (Figure 1). Of the 41 cases of unilateral DLK, 37 occurred after bilateral LASIK; of those cases, 18 (48.7%) involved the right eye and 19 (51.4%) involved the left eye. The overall incidence of DLK was 12.4%. No significant differences in age or sex were found. Preoperative characteristics, including corneal thickness, IOP, presence of allergy or meibomian gland dysfunction, and Schirmer test results, were not significantly different between those who developed DLK and those who did not.
Most cases of DLK represented mild inflammation that required little, if any, additional antiinflammatory treatment for resolution. Of the 99 eyes with DLK, 22 (2.7% of total) required more than 1 week of treatment. In 77 eyes (77.8%), DLK resolved within the first week after LASIK, 9 (9.1%) resolved within 2 weeks, and 13 (13.1%) required up to 1 month of treatment. Table 2 shows the number and percentage of eyes that developed DLK stages 1 to 3. No eye developed stage 4 DLK.
Table 2.
DLK Stage | Frequency (n) | Rate (%) |
---|---|---|
1 | 90 | 11.2 |
2 | 8 | 1.0 |
3 | 1 | 0.1 |
DLK = diffuse lamellar keratitis
An increased incidence of DLK was associated with several femtosecond treatment parameters (Table 3), including larger flap diameter (P = .0171), increased levels of raster energy (P = .0033), and side-cut energy (P = .0037) used for flap creation. There was no difference in the incidence of DLK with variations in flap thickness. However, the flap thickness ranged from 100 to 140 μm only. There were no significant associations between the incidence of DLK and preoperative refractive error, treated refraction, ablation depth, or other treatment parameters.
Table 3.
Parameter | Mean ± SD | P Value* | |
---|---|---|---|
No DLK (n = 702) | DLK (n = 99) | ||
Flap thickness (μm) | 117.0 ± 6.5 | 116.8 ± 7.3 | .4574 |
Flap diameter (mm) | 8.7 ± 0.3 | 8.8 ± 0.2 | .0171 |
Side-cut energy (μJ) | 1.89 ± 0.47 | 2.04 ± 0.20 | .0037 |
Raster energy (μJ) | 1.55 ± 0.20 | 1.62 ± 0.11 | .0033 |
Optical zone (mm) | 6.6 ± 0.4 | 6.5 ± 0.4 | .6659 |
Ablation depth (μm) | 86.6 ± 36.8 | 83.9 ± 38.1 | .7311 |
Residual bed (μm) | 356.1 ± 42.1 | 357.4 ± 37.8 | .8952 |
Treated SE (D) | −3.7 ± 1.8 | −3.8 ± 1.9 | .7806 |
DLK = diffuse lamellar keratitis; SE = spherical equivalent
From generalized estimating equation model adjusting for inter-eye correlation
The postoperative eyedrop regimen was surgeon-dependent and consisted of the use of topical steroids starting on the day of surgery in 371 eyes and starting on the first postoperative day in 282 eyes. When comparing these 2 groups, there was no difference in the incidence of DLK (P = .5193). Patients with DLK were less likely to achieve a CDVA of 20/20 or better on the first postoperative day (P = .0453) (Table 4). Forty-five eyes had minor complications (microstriae, epithelial defect, or small epithelial ingrowth) in the perioperative period; however, they were not associated with the incidence of DLK (P = .1751). There were no major LASIK complications.
Table 4.
Parameter | No DLK, n (%) | DLK, n (%) | OR* | (95% CI) | P Value† |
---|---|---|---|---|---|
UDVA 1 d postop | — | ||||
≥20/20 | 495 (70.6) | 62 (62.6) | 0.75 | 0.26, 2.11 | .5792 |
20/25–20/40 | 182 (26.0) | 31 (31.3) | 0.81 | 0.30, 2.17 | .6745 |
<20/40 | 24 (3.4) | 6 (6.1) | — | — | — |
CDVA 1 d postop | |||||
≥20/20 | 564 (80.7) | 72 (72.7) | 0.37 | 0.14, 0.98 | .0453 |
20/25–20/40 | 129 (18.5) | 24 (24.2) | 0.48 | 0.18, 1.24 | .1304 |
<20/40 | 6 (0.9) | 3 (3.0) | — | — | — |
UDVA 1 wk postop | |||||
≥20/20 | 483 (72.0) | 60 (65.9) | 1.39 | 0.27, 7.27 | .6960 |
20/25–20/40 | 172 (25.6) | 28 (30.8) | 1.52 | 0.28, 8.40 | .6303 |
<20/40 | 16 (2.4) | 3 (3.3) | — | — | — |
CDVA 1 wk postop‡ | |||||
≥20/20 | 579 (86.3) | 76 (83.5) | 0.75 | 0.47, 1.19 | .2158 |
<20/20 | 92 (13.4) | 15 (16.5) | — | — | — |
CDVA = corrected distance visual acuity; CI = confidence interval; DLK = diffuse lamellar keratitis; OR = odds ratio; UDVA = uncorrected distance visual acuity
Calculated versus <20/40 or versus <20/20 for last row
From generalized estimating equation model adjusting for inter-eye correlation
Sample size in the <20/40 range was only 2; thus, the 20/25–20/40 and <20/40 categories were combined.
DISCUSSION
Femtosecond laser–assisted LASIK flap creation has been associated with a higher risk for DLK than microkeratome flap creation.18,19 The precise reasons for the increased incidence of inflammation after femtosecond flap creation are not completely understood. Confocal and histological studies26,27 found greater stromal cell apoptosis, monocyte influx, and a higher wound-healing index with femtosecond laser flap creation than with microkeratome flap creation.
In this study, the overall rate of DLK was 12.4%, which is higher than in some other recent reports of post-LASIK DLK.16–18 This is most likely because of the meticulous notation of the presence of even minimal inflammation in the flap interface in our study population. Only 22 (2.7%) of all eyes required treatment for DLK beyond 1 week postoperatively, which is an incidence more consistent with that reported in the recent literature. Of the cases of DLK in our study, 30 eyes (30.3%) were maintained on the standard topical corticosteroid treatment regimen of 4 times a day and 69 eyes (69.7%) were treated with more frequent corticosteroid eyedrops. Only 3 eyes (3.0%) required oral corticosteroids, and none required surgical flap manipulations for treatment.
Flap diameter was associated with development of DLK in this study. Patients who developed DLK had a larger flap (mean 8.8 ± 0.2 mm; range 8.0 to 9.4 mm) than patients who did not develop DLK (mean 8.7 ± 0.3 mm; range 8.0 to 9.5 mm). This 0.1 mm difference was statistically significant (P = .0171). One possible explanation for this finding is the closer proximity of the larger diameter flaps to the limbus and limbal blood vessels, which could potentially expose the flap to more inflammatory mediators and cells from the limbus. However, we do not necessarily recommend reduction of flap size based on these findings, especially considering the benign appearance of most of our DLK cases and the lack of long-term visual consequences.
We also found a significantly decreased incidence of DLK with decreased femtosecond raster and side-cut energy settings, confirming previous reports of a lower incidence of DLK with reduced energy settings.17–19 Based on the results in previous laboratory studies,26,27 we suspect that lower laser energy settings induce less inflammatory stimulus, leading to fewer inflammatory mediators and less cellular immune response. The exact relationship between laser energy and DLK development, whether a possible linear relationship or a threshold energy level above which DLK would occur, remains to be determined.
Gil-Cazorla et al.18 posit that their low incidence of DLK (0.5%) may be the result of their standard postoperative regimen of corticosteroid eyedrops given 8 times daily for the first postoperative week. In our patient cohort, there was no evidence that earlier postoperative exposure to corticosteroid eyedrops (ie, on the day of surgery) had an effect on the incidence of DLK (P = .5193).
We found no effect of flap thickness on the incidence of DLK (P = .4574). In our previous analysis of factors affecting incidence of DLK after femtosecond LASIK with varied laser frequency,15 we found a higher incidence of DLK with thinner flaps in patients treated with the 30 kHz femtosecond laser. This was not the case in the 60 kHz group in the previous analysis, and the lack of an association between DLK and flap thickness was maintained in the current study.
We found no other preoperative or treatment variables associated with increased risk for DLK. This includes no significant association with preoperative meibomian gland dysfunction or patient atopy, both of which have been found to be associated with an increased risk for DLK in previous studies.9–11
Most cases of DLK in our study were stage 1 or 2 and resolved within 2 weeks with minimal sequelae. Although patients who developed DLK were less likely than those who did not to achieve a 20/20 CDVA 1 day after LASIK (P = .0453), this difference did not persist after 1 day and most patients with DLK (96.7%) achieved a UDVA better than 20/40 by 1 week postoperatively.
Although our study is limited by its retrospective observational design, to our knowledge it is the only one to have found an association between flap diameter and the incidence of DLK. Our study findings suggest that a larger flap diameter is associated with an increased risk for DLK. Our results also confirm the higher incidence of DLK with higher femtosecond energy settings, especially raster and side-cut energy. Finally, we found that DLK after LASIK with femtosecond laser flap creation tends to be mild, with little effect on visual acuity.
WHAT WAS KNOWN
Diffuse lamellar keratitis has been reported to occur at higher frequency with femtosecond LASIK; however, the specific parameters associated with development of DLK are not well understood.
WHAT THIS PAPER ADDS
Larger flap diameter, higher femtosecond raster, and side-cut energy are associated with an increased risk for DLK.
Diffuse lamellar keratitis after LASIK with femtosecond laser flap creation tends to be mild, with little effect on visual acuity.
Acknowledgments
Supported by National Institutes of Health/National Eye Institute grant EY017885 (Dr. Shtein) and a departmental grant from Research to Prevent Blindness, New York, NY, USA.
Footnotes
Presented at the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, USA, May 2011.
Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.
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