Comparison of the corneal response to laser in situ keratomileusis with flap creation using the FS15 and FS30 femtosecond lasers

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1 ARTICLE Comparison of the corneal response to laser in situ keratomileusis with flap creation using the FS15 and FS30 femtosecond lasers Clinical and confocal microscopy findings Michael Y. Hu, James P. McCulley, MD, H. Dwight Cavanagh, MD, PhD, R. Wayne Bowman, MD, Steven M. Verity, MD, V. Vinod Mootha, MD, W. Matthew Petroll, PhD PURPOSE: To compare the response of the cornea to laser in situ keratomileusis (LASIK) with flap creation using the IntraLase FS15 or FS30 femtosecond laser (IntraLase Corp.). SETTING: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. METHODS: Twenty-three patients (31 eyes) who had LASIK with flap creation using the FS15 or FS30 laser were assessed by clinical examination and confocal microscopy in a nonrandomized parallel treatment group comparative trial. Eight FS15 patients (15 eyes) were examined preoperatively and 3 months postoperatively, and 14 FS30 patients (15 eyes) were examined 3 months postoperatively. RESULTS: No patient in either group had clinically significant flap interface haze. One FS15 eye and 1 FS30 eye had significant keratocyte activation at the flap interface. The mean difference between the actual flap thickness and intended flap thickness was 16.8 mm G 11.1 (SD) and 13.9 G 7.1 mm in the FS15 group and FS30 group, respectively (P Z.49). The mean measured interface reflectivity was G 88.6 confocal backscatter units (CBU) and G 91.2 CBU, respectively (P Z.15). The mean density of interface particles was 21.4 G 14.8 particles/mm 2 in the FS15 group and 11.0 G 7.1 particles/mm 2 in the FS30 group (P<.05). CONCLUSIONS: Both the FS15 and FS30 lasers provided more reproducible flap thickness and fewer interface particles than previously observed using microkeratomes. The response of corneal keratocytes to intra-lasik was reduced compared with previous results in which higher raster energies were used. Compared with the FS15, there was an apparent reduction in overall interface reflectivity and fewer interface particles with the FS30 laser. J Cataract Refract Surg 2007; 33: Q 2007 ASCRS and ESCRS Laser in situ keratomileusis (LASIK) has been successfully used for more than a decade and is now the most frequently performed refractive surgery procedure in the United States. 1 The most important surgical step in LASIK involves the creation of a 90 to 180 mm thick and 8.0 to 10.0 mm diameter hinged corneal flap. Until recently, the flap has been created with a microkeratome, which relies heavily on surgical skill and microkeratome precision. Flap-related complications can delay recovery of visual acuity and may lead to permanent vision loss. 2 4 Femtosecond laser ablation for LASIK flap creation (intra-lasik) was introduced in late 2001 and is growing rapidly in use. Studies 5 10 show that intra-lasik provides more consistent flap thickness with fewer complications than mechanical microkeratomes and results in better visual outcome in most patients. However, a small subset of patients develop significant corneal haze after intra-lasik, which may be associated with transient light sensitivity; the underlying cause of this haze has been attributed to keratocyte activation and appears to be linked to use of higher raster energies. 11,12 Intra-LASIK entered its second generation with the introduction of the IntraLase FS30 femtosecond laser (IntraLase Corp.), which replaced the IntraLase FS15 femtosecond laser. The FS30 laser generates pulses/second, allowing a faster procedure time, Q 2007 ASCRS and ESCRS Published by Elsevier Inc /07/$dsee front matter 673 doi: /j.jcrs

2 674 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS tighter spot placement, and lower overall energy exposure than to the FS15 laser (15000 pulses/second). The increased speed of the laser decreases suction time for enhanced safety and patient comfort and decreases the time of the procedure. Tighter spot placement produces better dissection quality and a smoother corneal interface and facilitates flap elevation. In addition, it is hypothesized that the lower raster energy will reduce the postoperative inflammatory response and keratocyte activation. Because the FS30 laser is relatively new, its effect on corneal wound healing has not been well documented. In this study, we used clinical data and quantitative 3- dimensional (3-D) confocal microscopy to assess and compare the corneal response to LASIK with flap creation using the FS15 laser and the FS30 laser. PATIENTS AND METHODS Clinical and confocal microscopy assessments were conducted in 30 eyes of 22 patients who had LASIK with flaps created by femtosecond laser ablation using either the FS15 laser or the FS30 laser between May 10, 2005, and February 24, 2006, at the University of Texas Southwestern Medical Center at Dallas, Texas. The femtosecond laser creates focused cavitation spots within the stroma delivered in a raster pattern that begins at a hinge, using an infrared 1053 nm wavelength. 5,6 Five experienced surgeons (H.D.C., S.V., V.M., J.P.M., W.B.) performed the procedures. Corneas were examined clinically and by confocal microscopy through focusing (CMTF) preoperatively (FS15 only) and 3 months postoperatively (FS15 and FS30) to assess interface particles, keratocyte activation, and epithelial and total flap thickness after surgery. 13,14 This study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center, and informed consent was obtained. Laser In Situ Keratomileusis with the FS15 Laser Fifteen myopic eyes (mean attempted correction 5.30 diopters [D] G 1.80 [SD]; range 1.75 to 8.50 D) had LASIK with flap Accepted for publication December 24, From the University of Texas Southwestern Medical School (Hu) and the Department of Ophthalmology (McCulley, Cavanagh, Bowman, Verity, Mootha, Petroll), University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA. No author has a financial or proprietary interest in any material or method mentioned. Supported in part by NIH grants R01 EY (Dr. Petroll), departmental infrastructure grant EY016664, a Lew R. Wasserman Merit award (Dr. Petroll), and an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, USA. Corresponding author: W. Matthew Petroll, PhD, Department of Ophthalmology, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas , USA. matthew. petroll@utsouthwestern.edu. creation using the FS15 laser. The planned flap diameter ranged from 8.9 to 9.4 mm, the planned flap thickness was 115 to 125 mm, the hinge angle was 50 degrees, raster energy was 1.9 or 2.0 mj, the raster line separation was 9 mm, the raster spot separation was 9 to 10 mm, and the side-cut energy was 3.0 to 3.1 mj. All flaps had hinges placed superiorly. A standard intrastromal pocket extending outward from the flap s hinge was also created to facilitate dispersion of the gas layer created by the intra-lasik. The pocket had an angle of 50 degrees and a start depth of 230 mm. Laser In Situ Keratomileusis with the FS30 Laser Fourteen myopic eyes (attempted correction 4.00 G 1.80 D; range 2.00 to 9.25 D) and 1 hyperopic eye (attempted correction C2.50 D) had LASIK with flap creation using the FS30 laser. The planned flap diameter ranged from 8.8 to 9.5 mm, the planned flap thickness was 115 to 120 mm, the hinge angle was 50 degrees, the raster energy was 1.2 mj, the raster line separation was 8 mm, the raster spot separation was 8 mm, and the side-cut energy was 2.4 mj. Hinges were placed superiorly for all flaps, and a standard pocket was created off the resected plane. After flap creation, all eyes were allowed to rest for 10 to 15 minutes to allow absorption of the gases from the microcavitation bubbles. The flap was then separated and reflected superiorly. For photoablation, patients were treated with the Star S4 CustomVue excimer laser (Visx, Inc.) or the LADARVision 4000 custom excimer laser system (Alcon Laboratories). Postoperative Treatment The protocol for steroid treatment was 1 drop of prednisolone acetate (Econopred Plus) every hour for the first 24 hours and then 4 times a day for 4 weeks. Patients also used 1 drop of moxifloxacin hydrochloride (Vigamox) 4 times a day for the first week. Clinical Examination Manifest refraction, uncorrected visual acuity (UCVA), and best spectacle-corrected visual acuity (BSCVA) were measured in each eye. A slitlamp examination was also performed and interface haze assessed. Confocal Microscopy Through Focusing In vivo confocal microscopy was performed using a previously described system 14 consisting of a tandem scanning confocal microscope interfaced to a personal computer (PC). Confocal microscopy through focusing scans were performed using a constant internal lens speed of 160 mm/s, which corresponds to focal plane movement of approximately 64 mm/s. Each scan started at the tip of the objective, went through the full thickness of the cornea, and ended in the anterior chamber of the eye. Two to 3 CMTF scans were performed in each eye. Scans in which significant eye movements were detected were not included in the quantitative analysis. After each CMTF scan, a plot of image intensity versus depth (intensity curve) and the CMTF image stack, its 3-D projection, and side views were immediately displayed on the PC monitor and the data were saved. After the examination, the user could identify images of interest and record their exact z-axis position by moving a cursor along the intensity curve as corresponding images were displayed. The thickness of the corneal epithelium and the LASIK flap were calculated from the intensity curve as previously described. 15 Interface particles were also counted from each CMTF scan and converted to a density measure of particles/mm Individual images from the CMTF scans were evaluated for qualitative assessment of changes in keratocyte morphology and/or reflectivity. The

3 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS 675 area under the CMTF peak corresponding to the flap interface on the intensity curve was calculated as previously described ; this measurement incorporates all factors that might contribute to interface backscatter such as keratocyte activation, edema, interface particles, and debris. The area is expressed in arbitrary confocal backscatter units (CBU), defined as microns pixel intensity Statistical Analysis Normally distributed data are given as mean G standard deviation. All refractions are given as the manifest spherical equivalent. All visual acuities are given as logmar. SigmaStat for Windows (version 3.1, Systat Software, Inc.) was used to perform the statistical analysis. RESULTS Laser In Situ Keratomileusis with the FS15 Laser During the 3-month postoperative clinical examination, no eye was found to have clinically significant haze (ie, haze affecting vision). The mean uncorrected visual acuity (UCVA) was C1.65 G 0.53 logmar preoperatively and C0.24 G 0.33 logmar 3 months postoperatively (Table 1). The mean best spectaclecorrected visual acuity (BSCVA) was 0.04 G 0.06 log- MAR before surgery and C0.03 G 0.14 logmar 3 months postoperatively (P Z.085). At the 3-month postoperative examination, 3 eyes had unreadable CMTF scans as a result of eye movement; thus, quantitative analysis was performed on 12 eyes. In 8 of the 12 eyes, the corneal stroma appeared quiet, with little or no keratocyte activation, and the increase in reflectivity at the interface was subtle (Figure 1). Small, brightly reflective interface particles were observed in most cases (Figure 1, C). In these 8 eyes, the mean total interface reflectivity was G 62.4 CBU and the mean interface particle density was 26.2 G 15.9 particles/mm 2. Keratocyte activation and increased reflectivity at the flap interface were detected by confocal microscopy in 1 patient (1 eye); this patient also had scattered trace haze detected by slitlamp examination. The CMTF 3-D reconstruction from that eye is shown in Figure 2, A.Examination of the images at and around the interface showed brightly reflective keratocytes, suggesting that the cells were activated (Figure 2, B and C, arrows). Quiescent keratocytes were observed above (Figure 2, D) and below (Figure 2, E) the interface. In this eye, the mean total interface reflectivity was CBU and the mean interface particle density was 14.8 particles/mm 2. Three eyes had isolated opacities detected at the flap interface by confocal microscopy; however, the Table 1. Visual acuity before and 3 months after LASIK with the FS15 laser (n Z 15 at all examinations). UCVA (LogMAR) BSCVA (LogMAR) Pt/Eye Preop 3 Mo Postop Change Preop 3 Mo Postop Change 1 OD OS OD OS OD OS OD OD OS OD OS OD OS OD OS BSCVA Z best spectacle-corrected visual acuity; Pt Z patient; UCVA Z uncorrected visual acuity

4 676 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS Figure 1. A: A CMTF stack taken after LASIK with the FS15 laser. The cornea appears quiet, and only a slight increase in reflectivity is detected at the interface. B: Single image taken from the CMTF stack in A at the flap interface. No keratocyte activation is observed, and only 1 interface particle is present (arrow) (bar Z 50 mm). C: Single image taken at the flap interface of another FS15 eye with a higher density of interface particles (arrows). corneas appeared clear on slitlamp examination. These opacities were of unknown origin but were not associated with keratocyte activation (Figure 3). In these 3 eyes, the mean total interface reflectivity was G 33.6 CBU and the mean interface particle density was 10.7 G 5.2 particles/mm 2. Overall, the measured interface reflectivity was higher in the 4 eyes with keratocyte activation or interface opacities than in the other 8 eyes. The measured interface particle density was somewhat lower in these 4 eyes. In all FS15 eyes, the mean interface particle density was 21.4 G 14.8 particles/mm 2 and the mean interface reflectivity was G 88.6 CBU. The mean epithelial thickness was 52.4 G 5.2 mm preoperatively and 53.0 G 2.8 mm 3 months postoperatively (P Z.75); thus, no hyperplasia occurred. The mean difference between the actual flap thickness and intended flap thickness (DIFT) was C16.8 G 11.1 mm; thus, the flaps were slightly thicker than intended. Laser In Situ Keratomileusis with the FS30 Laser At the 3-month postoperative clinical examination, no eye was found to have clinically significant haze. The mean UCVA was C1.29 G 0.34 logmar preoperatively and C0.17 G 0.36 logmar 3 months postoperatively (Table 2). The mean BSCVA was 0.03 G 0.05 logmar preoperatively and 0.02 G 0.08 logmar 3 months postoperatively (P Z.63). Overall, visual results in the FS15 group and FS30 group were comparable. Figure 2. A: A CMTF stack taken after LASIK with the FS15 laser of an eye with keratocyte activation. Note the areas of increased reflectivity surrounding the flap interface. B: Single image taken from the CMTF stack in A at the level of the flap interface. Note highly reflective nuclei (arrows), indicating keratocyte activation. C: Single image from the CMTF stack 10 mm below the flap interface. Note the activated keratocytes (arrows). D: Single image from the CMTF stack taken 20 mm above the flap interface. Quiescent keratocytes are observed (bar Z 50 mm). E: Single image from the CMTF stack taken 20 mm below the flap interface. Quiescent keratocytes are observed.

5 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS 677 Figure 3. A: A CMTF stack taken after LASIK with the FS15 laser in an eye with isolated interface opacities. B: Single image taken from the CMTF stack in A at the level of the flap interface. Note the acellular opacity in the middle of the image (bar Z 50 mm). In 13 of the 15 eyes, the corneal stroma appeared quiet by confocal microscopy, with little or no keratocyte activation at the interface and few interface particles, and the increase in reflectivity at the interface was subtle. A typical CMTF 3-D reconstruction from 1 of the eyes is shown in Figure 4, A. Typical images of the cornea with quiescent keratocytes surrounding the interface are shown in Figure 4, B to D. Small, brightly reflective particles were observed in some eyes (Figure 4, B). In the 13 eyes, the mean total interface reflectivity was 74.6 G 31 CBU and the mean interface particle density was 10.9 G 7.3 particles/mm 2. Keratocyte activation was detected at the flap interface by confocal microscopy in 1 patient (1 eye); however, haze was not detected by slitlamp examination. This is consistent with numerous previous studies demonstrating that confocal microscopy can identify subclinical cellular responses below the threshold of slitlamp detection. The CMTF 3-D reconstruction from that eye is shown in Figure 5, A. Examination of the images at and around the interface showed brightly reflective keratocytes, suggesting the cells were activated (Figure 5, B, arrows). Quiescent keratocytes were observed 20 mm above (Figure 5, C) and 20 mm below (Figure 5, D) the interface. In this eye, the total interface reflectivity was 212 CBU and the interface particle density was 17.7 particles/mm 2. One patient (1 eye) had isolated interface opacities of unknown origin detected at the interface by confocal microscopy (not shown), but the cornea appeared clear by slitlamp examination. In this eye, the total interface reflectivity was 390 CBU and the interface particle density was 5.9 particles/mm 2. Thus, as expected, the interface reflectivity was higher in eyes with greater keratocyte activation or haze patches at the interface. In all FS30 eyes, the mean interface particle density was 11.0 G 7.1 particles/mm 2 and the mean total interface reflectivity was G 91.2 CBU. The particle density was significantly lower than that in the FS15 group (P Z.04) (Table 3). Although not statistically significant, the interface reflectivity was also less in the FS30 group. The mean epithelial thickness was 50.4 G 6.3 mm 3 months postoperatively. The mean DIFT was C13.9 G 7.1 mm; the standard deviation was slightly lower than that measured using the FS15; however, the difference was not statistically significant (Table 3). DISCUSSION Confocal microscopy allows assessment of the cellular response of the cornea to infection, injury, and surgical procedures. Confocal microscopy after photorefractive keratectomy (PRK) shows that the development of clinical corneal haze is correlated with the activation of corneal keratocytes and transformation to a fibroblast or myofibroblast phenotype These activated cells are more reflective than quiescent corneal keratocytes and synthesize extracellular matrix components that also reduce corneal transparency. Keratocyte activation has also been identified by confocal microscopy after microkeratome-assisted LASIK. 20,21 However, the degree of keratocyte activation and clinical haze is markedly less than that induced by PRK. Previous

6 678 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS Table 2. Visual acuity before and 3 months after LASIK with the FS30 laser (n Z 15 at all examinations). UCVA (LogMAR) BSCVA (LogMAR) Pt/Eye Preop 3 Mo Postop Change Preop 3 Mo Postop Change 1 OD OS OS OD OS OS OS OS OS OS OS OS OS OS OS BSCVA Z best spectacle-corrected visual acuity; Pt Z patients; UCVA Z uncorrected visual acuity studies show that intra-lasik provides more consistent flap thickness with fewer complications than traditional microkeratomes and results in better visual outcome in most patients In this study, we used confocal microscopy to compare the corneal response to LASIK with the FS15 and FS30 lasers. An important issue addressed by this study is whether the FS30 and FS15 lasers induce different wound-healing responses. The raster energy used for FS15 was 1.9 to 2.0 mj (raster line separation 9 mm, raster spot separation 9 to 10 mm), while the raster energy used for FS30 was 1.2 mj (raster line separation 8 mm, raster spot separation 8 mm). During the 3-month postoperative clinical examination, no eye in either group was found to have clinically significant haze. This is consistent with our previous study 12 in which haze was sometimes observed at high raster energies (2.6 to 2.7 mj) but not at lower raster energies (1.8 to 2.0 mj) similar to those used in this study. One FS15 patient (1 eye) and 1 FS30 patient (1 eye) had keratocyte activation at the flap interface by confocal microscopy. Thus, the incidence and amount of keratocyte activation were low with both lasers in this study. Quantitatively, the total interface reflectivity in FS15 eyes (mean G 88.6 CBU) was higher than in FS30 eyes (mean G 91.2 CBU), although the difference was not statistically significant. This trend is likely because the FS30 laser uses a lower raster energy. In addition, the FS30 laser uses a smaller step size in the raster pattern and thus may create a smoother surface with less backscattering of light. In corneas in both the FS15 group and FS30 group, the measured backscatter was significantly less than that previously measured after PRK using the same confocal system. 16 We observed highly reflective interface particles in 11 of 12 eyes imaged in the FS15 group and 14 of 15 eyes in the FS30 group. Interface particles of varying sizes and reflectivity after traditional LASIK have

7 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS 679 Figure 4. A: A CMTF stack taken after LASIK with the FS30 laser. The cornea appears quiet, and only a slight increase in reflectivity is detected at the interface. B: Single image taken from the CMTF stack in A at the flap interface. Keratocytes are generally quiescent, and few interface particles are observed (arrows). C: Single image from the CMTF stack taken 20 mm above the flap interface. Quiescent keratocytes are observed. D: Single image from the CMTF stack taken 20 mm below the flap interface. Quiescent keratocytes are observed (bar Z 50 mm). been well documented by confocal microscopy. 15,20,22 26 The particles observed in this study looked nearly identical to those reported after microkeratomeassisted LASIK, and both small and large particles were detected. However, the particle densities with both the FS15 laser and FS30 laser were much lower than those reported after microkeratome-assisted LASIK at similar time points (135 to 400 particles/ mm 2 ). 20,22,23 The particle density in FS30 eyes (11.0 particles/mm 2 ) was significantly lower than that in FS15 eyes (21.4 particles/mm 2 )(P Z.04). Potential sources of the particles include products of cell degradation, particles from the irrigation cannula, debris from sponges or drapes, and dust particles from the air. 20,22,23 A possible explanation of the reduction of interface particles with the FS30 laser is that the flaps were easier to lift and therefore required less surgeon manipulation. Confocal microscopy can be used not only to measure total flap thickness but also to distinguish the epithelial and stromal components of the flap. In this study, the mean DIFT in the FS15 group and the FS30 group was C16.8 G 11.1 mm and C13.9 G 7.1 mm, respectively; thus intra-lasik slightly overcut the flap on average. The DIFT standard deviations for the FS15 laser and FS30 laser (11.1 mm and 7.1 mm, respectively) were on the low end of previous confocal measurements after microkeratome-assisted LASIK, which ranged from 9.5 to 28 mm. 15,20,22,25,26 Although the FS15 group had a standard deviation similar to those in previous intra-lasik studies, the FS30 laser s standard deviation was slightly lower. 5,9,27,28 Both models stand in contrast to microkeratomes, which generally create flaps that are thinner than intended. 15,20,22,25,26 Because our flap-thickness measurements were performed 3 months after surgery, they could have been affected by changes in epithelial thickness that occurred postoperatively. Epithelial hyperplasia after traditional LASIK in the rabbit and human has been

8 680 CONFOCAL ASSESSMENT OF LASIK WITH FS15 AND FS30 LASERS Figure 5. A: A CMTF stack taken after LASIK with the FS30 laser of an eye with keratocyte activation. Note the areas of increased reflectivity at the flap interface. B: Single image taken from the CMTF stack in A at the level of the flap interface. Note highly reflective nuclei (arrows), indicating keratocyte activation. C: Single image from the CMTF stack taken 20 mm above the flap interface. Quiescent keratocytes are observed. D: Single image from the CMTF stack taken 20 mm below the flap interface. Quiescent keratocytes are observed (bar Z 50 mm). reported. 15,26,29 However, epithelial thickness did not change significantly in the FS15 group between the preoperative and 3-month postoperative measurements. In the FS30 group, the mean epithelial thickness at 3 months was 50.4 G 6.3 mm, close to previously Table 3. Summary of FS15 and FS30 confocal microscopy measurements. Parameter FS15 FS30 P Value DIFT (mm) C16.8 G 11.1 C13.9 G Interface particles 21.4 G G (particles/mm 2 ) Interface peak area (pixel intensity) G G DIFT Z difference between actual flap thickness and intended flap thickness established normal epithelial thickness in humans (w51 mm) measured using our instrument. 16 Thus, significant changes in epithelial thickness did not appear to occur in these patients either. CONCLUSION Both the FS15 laser and the FS30 laser created flaps with more reproducible thickness and fewer interface particles than flaps created with mechanical microkeratomes, with a trend toward superiority of the FS30 laser. Clinically significant haze was not detected in this study, and keratocyte activation was rare. Overall interface backscatter was generally less with the FS30 laser, presumably because of its lower raster energy. The FS30 laser also resulted in fewer interface particles than the FS15 laser. Visual results between the FS15 group and the FS30 group were comparable.

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