Transient light-sensitivity syndrome after laser in situ keratomileusis with the femtosecond laser

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1 J CATARACT REFRACT SURG - VOL 32, DECEMBER 2006 Transient light-sensitivity syndrome after laser in situ keratomileusis with the femtosecond laser Incidence and prevention Gonzalo Muñoz, MD, PhD, FEBO, César Albarrán-Diego, OD, Hani F. Sakla, MD, PhD, Jaime Javaloy, MD, PhD, Jorge L. Alió, MD, PhD PURPOSE: To describe the incidence of transient light-sensitivity syndrome (TLSS) after laser in situ keratomileusis (LASIK) with the femtosecond laser and to identify preventive strategies. SETTING: Hospital NISA Virgen del Consuelo, Valencia, Spain. METHODS: The first 765 eyes operated on with the 15 KHz femtosecond laser were prospectively analyzed for subjective complaints and clinical findings compatible with TLSS. Intraoperative settings, postoperative treatment, and development of complications were analyzed. RESULTS: Overall, TLSS developed in 10 eyes (incidence 1.3%). However, the incidence decreased from 2.8% to 0.4% when aggressive topical steroids were used during the first 3 postoperative days. erative interface inflammation and postoperative use of a low-dose topical steroid regimen were associated with a higher incidence of TLSS. CONCLUSIONS: Transient light-sensitivity syndrome is a relatively uncommon complication related to the use of the femtosecond laser. erative interface inflammation may increase the probability of developing TLSS, whereas an aggressive postoperative steroid regimen seemed to provide protection against it. J Cataract Refract Surg 2006; 32: Q 2006 ASCRS and ESCRS The recently introduced solid-state femtosecond laser creates corneal flaps for laser in situ keratomileusis (LASIK). It uses a 1053 nm infrared wavelength neodymium:glass that deliver microspots to photodisrupt tissue within the corneal stroma, creating cavitation bubbles that expand and coalesce, forming a resection plane. 1 3 The femtosecond laser seems to have advantages over mechanical microkeratomes including improved predictability of the flap thickness and diameter, better flap uniformity, better predictability of hinge position and size, astigmatic neutrality, and reduced incidence of epithelial defects, buttonholes, and cap perforation. 4 5 However, other complications, such as delayed-onset photophobia, corneal folds, and interface inflammation, have been reported. 4,6 The term transient light-sensitivity syndrome (TLSS) has been used to describe a clinical condition characterized by unusual photosensitivity with normal visual acuity several weeks after otherwise uneventful LASIK with the femtosecond laser that typically responds to topical treatment with steroids or cyclosporine. 7 We describe the incidence of TLSS in a cohort of 765 eyes and present possible strategies to prevent it. PATIENTS AND METHODS The first 765 eyes operated on with the femtosecond laser were prospectively analyzed for the incidence of TLSS. The surgeries were performed between July 2004 and September All patients were informed about the details and risks of the LASIK procedure with the femtosecond laser, and written informed consent was obtained in accordance with the Helsinki Declaration. Institutional review board approval was not required for this study. The inclusion criteria for the procedure were older than 18 years of age and a stable refractive history correctable by LASIK. Exclusion criteria included best spectacle-corrected visual acuity (BSCVA) worse than 20/80, scotopic pupil diameter larger than 7.0 mm, cataract, history of uveitis or retinal detachment, corneal Q 2006 ASCRS and ESCRS Published by Elsevier Inc /06/$-see front matter doi: /j.jcrs

2 dystrophy, and glaucoma. The preoperative spherical equivalent (SE) ranged from diopters (D) to C6.00 D. Preoperative evaluation included uncorrected visual acuity (UCVA), BSCVA, manifest and cycloplegic refractions, iris color, pupil diameter (photopic and scotopic), slitlamp biomicroscopy, applanation tonometry, fundus examination, ultrasonic pachymetry, and corneal topography. Intraoperative settings recorded included raster and side-cut energy used for femtosecond laser flap creation, achieved flap diameter and thickness, and presence or absence of an opacified bubble layer. For the patients who developed TLSS, demographic data, reported symptoms, UCVA and BSCVA at the time of TLSS presentation, slitlamp examination, and response to interventions were also recorded. The femtosecond laser procedure has been described. 4 All surgeries were performed by a single surgeon (G.M.) using the 15 KHz IntraLase femtosecond laser (IntraLase Corp.) and the Star S2 excimer laser (Visx, Inc.) at 10 Hz with a 6.5 mm optical zone. Beam calibration was performed at the start of each case. The laser room temperature was maintained at 20 C and the relative humidity at 40% in all cases. The initial settings were an attempted flap diameter of 9.2 mm, flap thickness of 110 mm, pocket width of 2.6 mm with spot separation of 6 mm, hinge angle of 50 degrees, raster energy between 1.8 mm and 2.5 mj with interbeam separation of 11 mm, side-cut angle of 70 degrees, and sidecut energy between 2.3 mj and 3.0 mj. In all the eyes, surgery was planned to leave at least 250 mm of residual stromal bed. The hinge was located in the horizontal meridian (temporal or nasal), and the flap was centered relative to the pupil until a predicted flap of at least 8.8 mm was achieved according to the software of the femtosecond laser. The pattern of bubbles after the femtosecond laser ablation was classified according to the presence or absence of an opacified bubble layer. Immediately after the ablation with the femtosecond laser, the surgical bed was rotated and the patient was positioned under the excimer laser, minimizing the time allowed for absorption of the microcavitation bubbles. The flap was measured with a calipers, and a spatula was used to enter the laser wound in the superior quadrant near the hinge. Once the interface was opened and the flap reflected, central pachymetry was recorded and the excimer laser ablation was performed. Following the procedure, 1 drop of ofloxacin 0.3% (Exocin) and 1 drop of ketorolac tromethamine (Acular) were instilled. When the surgery was bilateral, the same procedure was performed in the fellow eye. Accepted for publication July 11, From the Refractive Surgery Department Centro de Especialidades Marqués de Sotelo and Hospital NISA Virgen del Consuelo (Muñoz, Albarrán-Diego), Valencia, and the Refractive Surgery Department (Muñoz, Sakla, Javaloy, Alió), VISSUM Instituto Oftalmológico de Alicante, Alicante, Spain. Supported by a grant from the Spanish Ministry of Health, Red Temática de Investigación Cooperativa en Oftalmología (ref C 03/13), Subproyecto Cirugía Refractiva y Calidad Visual. No author has a proprietary or financial interest in any material or method mentioned. Corresponding author: Gonzalo Muñoz, Avenida Marqués de Sotelo 5, Planta 2 a, Valencia, Spain. gon.munoz@ ono.com. In the first 153 patients (287 eyes), a low-dose regimen of topical steroids consisting of tobramycin and dexamethasone eyedrops (TobraDex) was used 3 times daily for 7 days. The following 261 patients (478 eyes) received a high-dose regimen of topical steroids consisting of TobraDex 8 times daily for the first 3 days and then 4 times daily for 1 week. Lubricating eyedrops (Acuolens) were used 3 to 4 times daily for 3 months. Patients were examined 1 day, 1 week, and 1 and 6 months after surgery. Data recorded during postoperative visits included UCVA, BSCVA, slitlamp examination, applanation tonometry, and corneal topography. Statistical analysis was performed with the SPSS statistics software package SPSS/Pc 12.0 for Windows. Visual acuity outcomes were transformed into logmar notation for means computation and comparison. The Student t test for 2 samples, the Student t test for paired samples, and the binomial test for binomial variables were used. A P value less than 0.05 was considered statistically significant. RESULTS Of the 414 patients having LASIK with the femtosecond laser, 5 (3 men, 2 women) reported severe light sensitivity in both eyes (n Z 10; 1.3%). The mean age of these patients was 35 years (range 23 to 43 years). Two patients (4 eyes) had hyperopic LASIK, and 3 patients (6 eyes) had myopic LASIK. Table 1 and Figure 1 show the visual acuity and refractive outcomes. All 10 eyes with TLSS had a UCVA of at least 20/25 at the final follow-up. There was no statistically significant difference between the preoperative and postoperative mean BSCVA (P Z.343, paired t test). One eye had lost 1 line of BSCVA by the final follow-up (from 1.0 to 0.9). Table 1. Summary of results of femtosecond LASIK in 10 eyes with TLSS. Before LASIK After LASIK Parameter UCVA, decimal (lines) G SD 0.17 G G 0.55 Range 0.01 to to 1.2 BSCVA, decimal (lines) P Value* d G SD 1.12 G G 0.49 Range 1.0 to to 1.2 UCVA C0.77 G 0.36 C0.01 G 0.06 d (logmar) G SD BSCVA 0.05 G G (logmar) G SD defocus (D) G SD 3.91 G G 0.33 d!0.50 D of defocus (%) 0 80 d UCVA R 20/20 (%) 0 60 d UCVA R 20/25 (%) d Lost 1 line BCVA (%) d 10 d BSCVA Z best spectacle-corrected visual acuity; LASIK Z laser in situ keratomileusis; UCVA Z uncorrected visual acuity *t test for paired samples d 2076 J CATARACT REFRACT SURG - VOL 32, DECEMBER 2006

3 Pre-surgery BCVA Post-surgery UCVA Percentage of Eyes ,3 1,2 1,1 1,0 0,9 0,8 Cumulative Decimal Visual Acuity 0,7 Percentage of Eyes ,3 Pre-surgery BCVA Post-surgery BCVA 1,2 1,1 Cumulative Decimal Visual Acuity Figure 1. Efficacy (top) and safety (bottom) 6 months after femtosecond LASIK in eyes with TLSS. Photophobia presented within 6 to 8 weeks after LASIK and was always bilateral, even in the 3 patients with unilateral diffuse lamellar keratitis (DLK) after surgery. The BSCVA at the time of first photophobia report was nearly within normal limits in all the eyes, ranging between 0.9 and 1.0. On slitlamp examination, the anterior segment was normal with no detectable signs of interface inflammation. Small deposits were present in 3 eyes (30%). Patients were given dexamethasone eyedrops (Maxidex) 6 times a day for 2 weeks; the photophobia improved after a few days of treatment. Figure 2 shows confocal microscopy of activated keratocytes in 3 eyes (30%). In the remaining eyes, confocal microscopy was normal. Photophobia was severe in 4 patients and incapacitating in 1; however, the patient who reported severe bilateral photophobia responded promptly to topical dexamethasone within a few days. Table 2 shows the main characteristics of the eyes that developed TLSS. There were no statistically significant differences between the group of eyes that developed TLSS 1,0 0,9 0,8 0,7 Figure 2. Confocal microscopy image in TLSS showing activated keratocytes at the stromal interface. and the group of eyes that did not develop TLSS in preoperative pachymetry, photopic or scotopic pupil diameter, flap diameter or thickness, or intraoperative settings regarding side-cut energy or raster energy (Table 3). The mean raster energy was 2.4 G 0.1 mj in eyes with TLSS and 2.5 G 0.3 mj in asymptomatic eyes (P Z.154, 2-sample t test). The mean side-cut energy was 2.9 G 0.2 mj and 3.0 G 0.3 mj, respectively (P Z.154, 2-sample t test). In eyes with TLSS, the iris was brown or green brown in 8 eyes (80.0%) and blue in 2 eyes (20.0%). In asymptomatic eyes, the iris was brown or green brown in 629 eyes (83.3%) and blue in 126 eyes (16.7%). There was no statistically significant difference in iris color between the group of eyes that developed TLSS and the group of eyes that did not develop TLSS (P Z.8021, binomial test). Opacified bubble layer formation was seen in 5 eyes (50.0%) that developed TLSS and in 32% of eyes that did not. This difference did not reach statistical significance (P Z.227, binomial test). In the first 287 eyes (153 patients) operated on with the femtosecond laser, in which a low regimen of topical steroids was used, 8 (2.8%) developed TLSS. In the remaining 478 eyes (261 patients), in which a high-dose regimen of topical steroids was used, 2 (0.4%) developed TLSS. This represents a 7-fold decrease in the incidence of TLSS after postoperative topical steroids were increased. The femtosecond laser settings were almost unchanged throughout the study. There was a statistically significant difference in the incidence of use of a low regimen of postoperative steroids between eyes that developed TLSS and eyes that did not (P!.001, binomial test). No intraoperative complications were recorded in the patients with TLSS. However, 3 (30.0%) of the 10 eyes had grade II DLK in the early postoperative period (first J CATARACT REFRACT SURG - VOL 32, DECEMBER

4 Table 2. Characteristics in eyes with TLSS. Eye Preop Thickness Diameter Side-Cut (mj) Raster (mj) OBL Low Steroids No Yes No No Yes No No Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes No Yes Yes Yes No No No No No No 545 G G G G G 0.1 d d d Incidence (%) d d d d d DLK Z diffuse lamellar keratitis; OBL Z opacified bubble layer DLK week). In all cases, the DLK was unilateral and responded well to topical TobraDex every 2 hours for 7 days. The TobraDex was started between 3 and 5 days postoperatively, when the DLK presented. This complication did not require flap lifting. The incidence of DLK in eyes that did not develop TLSS was 3% (23 eyes). There was a statistically significant difference in DLK incidence between eyes with TLSS and eyes without TLSS (P!.001, binomial test). DISCUSSION Several terms have been proposed for the clinical symptoms of extreme light sensitivity with normal vision and unremarkable slitlamp examination 4 to 8 weeks after uneventful femtosecond LASIK. These include TLSS, delayed acute photophobia, track-related iridocyclitis and scleritis syndrome, and good acuity plus photophobia. In TLSS, the slitlamp examination is unremarkable, with normal tear film and no hyperemia, flare, Tyndall effect, or inflammation in the interface. In summary, there are no signs that might explain the cause of the photophobia. Although the etiology of TLSS is unknown, there are clinical clues that point toward an inflammatory origin. Proposed mechanisms include inflammation caused by necrotic cell debris or subproducts of the gas bubbles, cytokines migrating from the flap interface to the perilimbal sclera and iris base, or activated keratocytes in the interface. 7 The femtosecond laser has been associated with a higher postoperative inflammatory reaction and fibrosis adjacent to the flap margin than mechanical microkeratomes. 8 In a recent study of TLSS, Stonecipher et al. 7 observed a 5-fold reduction, from 1% to 0.2%, when the laser energy settings were lowered by 20%. The authors did not describe the postoperative regimen of the steroids used and suggested an inflammatory mechanism for TLSS. In our series, a significant decrease in the incidence of TLSS occurred after we increased the postoperative regimen of steroids while using similar levels of energy in flap creation with the femtosecond laser. The incidence of TLSS dropped 7-fold, from 2.8% (8 of 287 eyes) to 0.4% (2 of 478 eyes), when the postoperative regimen of topical steroids was increased. The use of lower energy settings during Table 3. Comparison between eyes with TLSS and eyes without TLSS. Group n Diameter Mesopic Pupil Photopic Pupil Side-Cut Raster OBL (%) Use of Low Steroids (%) DLK (%) TLSS G G G G G G G No TLSS G G G G G G G P value d.696*.381*.248*.242*.501*.154*.154*.227!.001!.001 s G SD DLK Z diffuse lamellar keratitis; OBL Z opacified bubble layer *Two-sample t test Binomial test 2078 J CATARACT REFRACT SURG - VOL 32, DECEMBER 2006

5 femtosecond laser ablation may prevent keratocyte activation, according to Stonecipher et al. 7 An aggressive postoperative antiinflammatory regimen, as in our series, may have also reduced the activation of keratocytes, explaining the 7-fold decrease in TLSS. It would have been better in terms of our study to increase the steroids only instead of increasing the aminoglycoside and steroids. However, it was easier for patients to use a single bottle of medication, and this procedure was followed to increase compliance. No patient reported increased sensitivity resulting from the increased tobramycin. Confocal microscopy in TLSS may show activated keratocytes; however, the results may be normal, as they were in 7 of the 10 eyes in our study. In our experience, confocal microscopy after femtosecond LASIK in asymptomatic eyes can also show activated keratocytes, suggesting this is a nonspecific finding and activated keratocytes may be present after uneventful photorefractive keratectomy or following normal corneal healing after conventional LASIK with no photophobia. 9,10 Another finding in our study was the relationship between DLK and TLSS. The incidence of DLK in the postoperative period was significantly related to TLSS development. Diffuse lamellar keratitis was 10 times more frequent in eyes that developed TLSS (3 of 10 eyes, 30%) than in eyes that did not develop TLSS (23 of 755 eyes, 3%). This finding suggests that increased inflammation in the postoperative period may increase the incidence of TLSS. Grade II DLK developed unilaterally in 3 patients. Endotoxin-related DLK is almost never unilateral, although it is often highly asymmetric. 11 This suggests that the DLK in the eyes that developed TLSS may not have been the typical endotoxin DLK but was rather another form of inflammation associated with femtosecond energy. Even in cases of unilateral DLK, the patients reported light sensitivity in both eyes, not only in the eye with previous DLK. The hallmark of TLSS is light sensitivity, a subjective complaint that may make it hard for patients to distinguish whether they have TLSS in 1 or both eyes. Some degree of opacified bubble layer was present in 5 eyes (50%) affected by TLSS and in 32% of eyes that did not develop TLSS (no statistically significant difference). In some eyes, an opacified bubble layer forms during femtosecond ablation. The layer is thought to be caused by excessive compression of the cornea by the applanation glass. It has been suggested that decreasing the time from femtosecond laser ablation to flap lifting may reduce the incidence of TLSS. Our study found no differences in iris color, preoperative pachymetry, pupil diameter, flap size, or femtosecond laser energy settings between eyes that developed TLSS and eyes that did not. The differential diagnosis of TLSS should include dryeye syndrome and DLK. Dry eye is common after LASIK with femtosecond lasers or mechanical microkeratomes. Corneal staining is a landmark sign of dry eye, but some patients with TLSS may also have some staining and both clinical pictures may be bilateral. In eyes with TLSS, the photophobia is disproportionate with biomicroscopic findings, even in the presence of moderate corneal staining. Regarding DLK, the presentation may be bilateral, as with TLSS, but interface inflammation is always present, whereas in TLSS, there are no cells at the interface. 11 In TLSS, small particles may be seen at the interface level with confocal microscopy. In DLK, visual acuity may be affected, while in TLSS, the visual acuity remains normal. Both entities respond to topical steroids. Patients presenting with photosensitivity after femtosecond LASIK should be examined for DLK and be monitored for elevated intraocular pressure, especially in myopic eyes receiving high doses of topical steroids. In summary, the combined use of the lowest possible energy and an intensive postoperative regimen of topical steroids for the first few days after femtosecond laser flap creation helped decrease the incidence of TLSS. Further clinical studies may help identify more strategies for the prevention and management of this complication. REFERENCES 1. Nordan LT, Slade SG, Baker RN, et al. 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