How To Compare 3 Year Changes In Corneal Thickness After Photorefractive Keratectomy Or Laser In Situ Keratomileusis

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1 Three-Year Changes in Epithelial and Stromal Thickness after PRK or LASIK for High Myopia Anders Ivarsen, Walther Fledelius, and Jesper Ø. Hjortdal From the Department of Ophthalmology, Århus University Hospital, Århus, Denmark. Supported by the Danish Medical Research Council, Aarhus University Research Foundation, The Institute for Experimental Clinical Research at Århus University, and The Danish Eye Health Society. Submitted for publication September 10, 2008; revised November 6, 2008; accepted March 13, Disclosure: A. Ivarsen, None; W. Fledelius, None; J.Ø. Hjortdal, None The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked advertisement in accordance with 18 U.S.C solely to indicate this fact. Corresponding author: Anders Ivarsen, Department of Ophthalmology, Århus University Hospital, DK-8000 Århus C, Denmark; PURPOSE. To compare 3-year changes in corneal sublayer thickness after photorefractive keratectomy (PRK) or laser in situ keratomileusis (LASIK). METHODS. Forty-six patients with spheroequivalent refraction of 6.0 to 8.0 diopters (D) were randomly assigned to PRK or LASIK. One eye from each patient was included in the study. Examinations included manifest refraction and confocal microscopy through focusing (CMTF) and were performed preoperatively and postoperatively at 1 week and at 1, 3, 6, 12, and 36 months. From CMTF scans, the thicknesses of the central cornea (CT), epithelium (ET), stroma (ST), LASIK flap (FT), and residual stromal bed (BT) were calculated. RESULTS. After LASIK, spheroequivalent refraction averaged 0.76 D by 1 week and 1.19 D by 1 month, with no subsequent significant change. ET increased m within 1 week and remained constant thereafter. ST increased m within 1 year because of increased BT. One week after PRK, refraction averaged 0.23 D and stabilized at 1.42 D by 6 months. By 1 week, ET was reduced by m, reached preoperative thickness by 6 months, and increased further m by 3 years. ST increased m during 1 year, correlating with the postoperative refractive regression. After both procedures, changes in CT also correlated with refractive changes. No other correlations were identified. CONCLUSIONS. PRK and LASIK induce a persistent increase in ET that stabilizes 1 week after LASIK and 1 year after PRK. Stromal regrowth is most pronounced after PRK. After LASIK, regrowth is restricted to the residual stromal bed. Postoperative refractive changes correlate with changes in ST (PRK) and CT (PRK and LASIK) but not with changes in ET. (Invest Ophthalmol Vis Sci. 2009;50: ) DOI: /iovs Laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) remain popular surgical procedures for the correction of myopia. Several studies have demonstrated loss of the initial refractive effect after surgery, 1 5 and corneal wound repair is believed to be a contributing factor in the development of this postoperative refractive regression. 6,7 PRK has been reported to induce more pronounced wound healing than LASIK and has a higher tendency for change in refraction and development of corneal haze. 4,5 A gradual increase in corneal thickness after PRK has been shown in several studies, 8 10 and changes in stromal thickness have been suggested to be responsible for the postoperative refractive instability. 6 Changes in epithelial thickness, however, have also been implicated as a potential cause for myopic regression after PRK. 11,12 In contrast to PRK, changes in the sublayer thickness after LASIK are more unclear, though several reports have shown a persistent increase in epithelial thickness. 8,13,14 In the present study, patients with high myopia were randomly assigned to PRK or LASIK and followed for 3 years with in vivo confocal microscopy to evaluate and compare long-term changes in corneal sublayer thickness. MATERIALS AND METHODS Patients Forty-six patients with spherical equivalent refraction from 6.0 to 8.0 diopters (D) were randomly assigned to PRK or LASIK. All patients had stable myopia for at least 2 years, astigmatism less than 1.5 D, and monocular best spectacle-corrected visual acuity (BSCVA) of at least 0.10 (logmar units). Patients who were pregnant or who had systemic disease or a history of previous ocular disease or surgery were excluded from the study. The study protocol adhered to the Declaration of Helsinki and was approved by the ethics committee of Århus, Denmark. Informed written consent was obtained from all patients. Randomization to PRK or LASIK was performed with random numbers, and only one eye from each patient was included in the study. Twenty-five subjects were randomly assigned to LASIK and 21 to PRK. Retreatment was not allowed within the first year after surgery. Surgery All surgical procedures were performed under topical anesthesia with oxybuprocaine 0.8% (3 drops administered at 5-minute intervals). Two drops of pilocarpine 2% were applied before surgery to facilitate centration of the suction ring. All operations were performed by the same surgeon. In PRK, the epithelium was gently removed in a central 8-mm zone after application of 96% alcohol for 1 to 2 seconds. Excimer laser treatment was performed, and one drop of cyclopentholate 1%, one drop of diclofenac 0.1%, and chloramphenicol ointment were administered. Postoperative treatment consisted of chloramphenicol eye drops (0.5%) three times a day for 1 week and prednisolone eye drops (0.5%) three times a day, gradually tapered over 3 months. In LASIK procedures, a superiorly hinged 9-mm corneal flap was cut with a microkeratome (Supratome; Schwind, Kleinostheim, Germany) with a 130- m cutting head. Laser treatment was performed, and the flap was carefully repositioned. A bandage contact lens (Focus Night and Day; Bausch & Lomb, Rochester, NY) was inserted, and cyclopentholate, diclofenac, and chloramphenicol eye drops (one drop each) were administered. The bandage contact lens was removed 1 day after surgery, and chloramphenicol eye drops were prescribed three times a day for 1 week. Excimer laser photoablation was performed with a flying spot excimer laser (MEL-70 G-scan; Meditec-Aesclepion, Jena, Germany). All treatments were performed in a 6-mm optical zone, and identical nomograms were used for PRK and LASIK surgery. Astigmatism of less Investigative Ophthalmology & Visual Science, May 2009, Vol. 50, No. 5 Copyright Association for Research in Vision and Ophthalmology 2061

2 2062 Ivarsen et al. IOVS, May 2009, Vol. 50, No. 5 than 0.75 D was not specifically treated but was included as part of the spherical correction. Astigmatism from 1.0 to 1.5 D was treated with an attempted astigmatic correction of 1.0 D. Examinations All subjects were examined before surgery and at 1 week and 1, 3, 6, 12, and 36 months after surgery. Examinations included determination of best spectacle refraction and in vivo confocal microscopy. A tandem scanning confocal microscope (Tandem Scanning Corporation, Reston, VA) was used to perform confocal microscopy through focusing (CMTF) for corneal sublayer pachymetry, as previously reported. 15,16 CMTF is a highly precise technique for measurement of corneal sublayer thickness and has an SD of only 2.8 m for stromal thickness measurements in sedated animals. 16 In human subjects, however, precision may be degraded by movement, as previously suggested by McLaren et al. 17 Repeated measurements facilitate the identification of movement-related artifacts. Thus, in the present study, 10 to 20 twoway scans (in and out through the entire cornea) were performed at the corneal apex, followed by careful review for signs of z-axis movement. Subsequent analysis of CMTF scans was performed with custommade software, 16 and thickness measurements were calibrated using polymethylmethacrylate contact lenses with well-defined thickness, as described in a previous study. 16 One patient randomly assigned to PRK was lost to follow-up after 1 month and was excluded from all analyses. During the first year, follow-up was nearly complete apart from follow-up on one LASIK eye at 3 months, three LASIK and two PRK eyes at 6 months, and one PRK eye at 12 months. After 1 year, reoperation was performed in four LASIK eyes and three PRK eyes because of residual myopia, and these patients were excluded from subsequent examinations. By 3 years, 15 LASIK and 14 PRK eyes were available for follow-up. CMTF Measurement Analysis CMTF scans were analyzed by identifying in-focus images of corneal structures (epithelium, subepithelial nerve plexus, most anterior keratocyte layer, LASIK interface, and endothelium). The z-axis positions of these images were then used to calculate corneal sublayer thickness (Fig. 1). Briefly, total corneal thickness was defined as the distance from the epithelial surface to the endothelium. Epithelial thickness was defined as the distance from the epithelial surface to the subepithelial nerve layer or, after PRK, to the intensity peak located at the photoablated stromal surface. Stromal thickness was defined as the difference between total corneal and epithelial thickness. In LASIK-treated corneas, total corneal thickness was further subdivided into flap and residual stromal bed thickness by the LASIK interface that was easily identified by the presence of brightly reflecting particles. 18 Only scans from the photoablation center, defined as the region of minimal stromal thickness, were used for subsequent analyses. Statistical Analysis Corneal thickness measurements before surgery and at 1 week, 1 year, and 3 years were compared using two-tailed paired t-tests with adjustment for multiple comparisons using the Bonferroni technique. Normal distribution was confirmed with the D Agostino- Pearson test. Spherical equivalent refraction at 1 year and 3 years was compared with refraction at 1 week with two-tailed paired t-tests. Changes in refraction from 1 week to 1 or 3 years were correlated to changes in corneal total and sublayer thickness with Pearson correlation coefficient. In all analyses, P 0.05 was considered statistically significant. RESULTS Patients randomly assigned to PRK or LASIK were comparable with respect to all preoperative parameters, including age, best spectacle-corrected visual acuity, spheroequivalent refraction, FIGURE 1. CMTF light intensity profile 3 months after LASIK. Peaks correlate closely with well-defined morphologic features, facilitating the determination of corneal sublayer thickness. keratometry, intraocular pressure, and stromal and epithelial thickness. Preoperative data are summarized in Table 1. Laser In Situ Keratomileusis One week after LASIK, spherical equivalent refraction averaged D. By 1 month, refraction had dropped to D; no further significant change occurred during the first year (Fig. 2). Still, a gradual but insignificant loss of refractive effect was noted from 1 year to 3 years, with refraction averaging D. During the first week, LASIK caused an increase in epithelial thickness of m from the preoperative value of m (paired t-test, P 0.001). At all subsequent time points, epithelial thickness remained increased, with no significant change from 1 week (Fig. 3; Table 2). One week after excimer laser treatment, stromal thickness was reduced to m, which was similar to and correlated with the planned photoablation depth of m (P 0.01; r 0.48, Pearson correlation). Stromal thickness then increased by m, from m at 1 week to m at 1 year after surgery (P 0.001; paired t-test). No significant change occurred between 1 year and 3 years (Fig. 4; Table 2). Flap thickness averaged m 1 week after surgery, with no significant change during the 3-year follow-up (Fig. 5). In contrast, the thickness of the residual stromal bed gradually increased from m by 1 week to m by 3 years (P 0.002; paired t-test; Fig. 5). Changes in corneal sublayer thickness gave rise to an initial reduction in total corneal thickness from m before surgery to m by 1 week, followed by a gradual increase to m by 3 years (P 0.001; paired t-test; Fig. 6). The increase in total corneal thickness from 1 week to 3 years was weakly correlated to the observed change in spheroequivalent refraction (P 0.04; r 0.54, Pearson correlation). No other correlations were identified between change in refraction and changes in corneal sublayer thickness at any time point.

3 IOVS, May 2009, Vol. 50, No. 5 Long-term Changes in Corneal Sublayer Thickness after PRK or LASIK 2063 TABLE 1. Preoperative Characteristics of Patients PRK (n 20) LASIK (n 25) Age (years) 33 8 (range, 23 to 49) 30 7 (range, 21 to 46) BSCVA (logmar units) (range, 0.10 to 0.05) (range, 0.10 to 0.05) Spheroequivalent refraction (D) Keratometry K1 (mm) Keratometry K2 (mm) IOP (mm Hg) Stromal thickness ( m) Epithelial thickness ( m) Photorefractive Keratectomy Spherical equivalent refraction averaged D 1 week after PRK. By 1 year, the average refraction was D, demonstrating a significant loss of refractive effect during the first 12 months (P 0.001, paired t-test; Fig. 2). From 1 year to 3 years, no change in postoperative refraction occurred. In one eye, an initial overcorrection of 2.5 D was observed that was followed by the development of haze and marked regression of the refractive effect. One week after PRK, epithelial thickness averaged m, which was m less than the preoperative value. Epithelial thickness then gradually increased to m by 1 year and m by 3 years (P 0.001; paired t-test), giving a net increase of m over the preoperative thickness (P 0.001; paired t-test; Fig. 3). Thus, changes in epithelial thickness after PRK were more gradual than after LASIK (Table 2). From 1 year to 3 years after surgery, no significant differences were observed between PRK and LASIK. Excimer laser treatment caused a reduction in stromal thickness of m 1 week after PRK, which correlated with the expected photoablation depth of m (P 0.002; r 0.66, Pearson correlation). Stromal thickness then increased by m (P 0.001, paired t-test) from m at 1 week to m at 1 year after PRK. No significant changes were observed from 1 year to 3 years after surgery (Fig. 4). The initial reduction in stromal thickness by 1 week was significantly greater after PRK than after LASIK (Table 2), even though the expected photoablation depth was similar. Subsequent stromal regrowth from 1 week to 1 year after surgery was also significantly greater after PRK than after LASIK (Table 2), but from 1 year to 3 years the change in stromal thickness was similar after both surgical modalities. Total corneal thickness was reduced from m before PRK to m 1 week after excimer laser treatment (Fig. 6). Corneal thickness then gradually increased to m by 1 year (P 0.001; paired t-test), with no significant changes from 1 year to 3 years. The initial reduction and subsequent increase in total corneal thickness was significantly greater after PRK than after LASIK (Table 2). However, changes in total corneal thickness from 1 year to 3 years after surgery were not significantly different between the two procedures. Changes in refraction from 1 week to 1 year after PRK correlated with the increase in total corneal (P 0.002; r 0.68, Pearson correlation; Fig. 7) and stromal thickness (P 0.001; r 0.73, Pearson correlation), indicating that refractive changes were caused, at least in part, by changes in corneal thickness. No other correlations between corneal sublayer thickness and refractive change were identified after PRK. DISCUSSION In the present study, PRK and LASIK both induced increases in epithelial thickness of approximately 15% to 20% that persisted after surgery. In LASIK, the epithelial changes occurred within 1 week and remained unchanged through 3 years (Fig. 3, Table 2). In PRK, per-operative epithelial debridement caused an initial decrease in epithelial thickness, followed by a gradual epithelial thickening over the next 12 months. Thus, PRK and LASIK induced different initial epithelial responses to surgery, though the end point thickness was similar for the two surgical FIGURE 2. Change in average spherical equivalent refraction after PRK or LASIK. FIGURE 3. Change in epithelial thickness after PRK or LASIK.

4 2064 Ivarsen et al. IOVS, May 2009, Vol. 50, No. 5 TABLE 2. Change in Total Corneal, Epithelial, and Stromal Thickness after LASIK or PRK Before to 1 Week 1 Week to 1 Year 1 Year to 3 Years Epithelial thickness ( m) LASIK * * PRK Stromal thickness ( m) LASIK * * PRK Total corneal thickness ( m) LASIK * * PRK * Significant (P 0.05) difference between the two surgical modalities. modalities. In one previous study with CMTF, no changes in epithelial thickness were found 1 year after PRK 6 ; still, other studies have reported an increase in epithelial thickness after PRK 8,11,12 and LASIK. 8,13,14,19 Case reports have demonstrated epithelial hyperplasia with an increased number of cell layers after PRK, 11 whereas the nature of the epithelial changes after LASIK are less clear. It has been suggested that epithelial hyperplasia after refractive surgery may contribute to the loss of the postoperative refractive effect. 11,12,20,21 In the present study, there was no correlation between change in epithelial thickness and change in refraction after PRK or LASIK. This lack of correlation may be attributed to the relatively few patients in each treatment group. After LASIK, however, epithelial thickness had already stabilized by 1 week, whereas the major refractive change was noted between 1 week and 1 month after surgery. This suggested that epithelial changes were not the main cause for refractive instability after LASIK. With respect to PRK, the time course of changes in epithelial thickness and refraction was similar, but, as noted, no correlation between the two parameters could be identified. PRK and LASIK both induced stromal regrowth during the first year after surgery (Fig. 4); however, wound repair after PRK gave rise to significantly more stromal tissue deposition than did LASIK (Table 2), and the increase in stromal thickness correlated with the postoperative loss of refractive effect (Fig. 7). PRK has previously been reported to induce a more aggressive wound-healing response than LASIK and to entail more myopic regression and more haze development. 4,5 Studies have also demonstrated significant amounts of stromal tissue deposition after PRK. 6,8 In contrast, stromal changes after LASIK remain controversial, with one study indicating a minor (insignificant) increase over time, 19 one reporting stability, 8 and one even indicating a decrease in total corneal and stromal thickness. 13 However, the present randomized study is the first to allow a direct comparison of corneal sublayer thickness between LASIK and PRK in human eyes and shows that LASIK causes less stromal tissue deposition than PRK for identical myopic corrections, supporting well-established clinical observations of differences in wound repair (haze development and myopic regression). 4,5,22 Mechanisms leading to more aggressive wound repair after PRK remain unclear. However, in previous studies of rabbit eyes, we demonstrated that the integrity of the epithelial-stromal barrier at the basement membrane level appeared to be of major importance for the gravity of the subsequent stromal wound repair. 23,24 Cell culture studies have supported this observation, 25 as have clinical observations of other surgical approaches that destroy the epithelialstromal barrier. Those approaches include laser subepithelial keratomileusis (LASEK), in which the epithelial sheet is supposedly kept intact but in which haze and myopic regression also may be seen. 26 Interestingly, the stromal regrowth that was observed after LASIK in the present study was found to be localized entirely to the residual stromal bed, whereas flap thickness remained constant through the 3-year follow-up (Fig. 5). This contrasts with our previous observations in rabbit eyes in which LASIK caused stromal regrowth in both flap and residual stroma. 27 The present observation is important in patients who are considered for LASIK retreatment because the thickness of the residual stromal bed is a major safety parameter for the amount of refractive correction that can be applied. 28,29 In contrast to FIGURE 4. Change in stromal thickness after PRK or LASIK. FIGURE 5. Change in flap and residual stromal bed thickness after myopic LASIK.

5 IOVS, May 2009, Vol. 50, No. 5 Long-term Changes in Corneal Sublayer Thickness after PRK or LASIK 2065 FIGURE 6. Change in total corneal thickness after PRK or LASIK. FIGURE 7. Change in refraction from 1 week to 1 year after PRK or LASIK as a function of the increase in total corneal thickness. PRK, changes in stromal thickness after LASIK could not be correlated with changes in postoperative refraction, possibly because of the relatively few patients in both treatment groups. Still, it should be noted that determination of changes in central thickness alone does not allow comprehensive evaluation of the relationship between stromal tissue deposition and refraction. Both PRK and LASIK showed very good correlation between initial changes in stromal thickness and expected photoablation depth. More stromal tissue was removed by PRK than by LASIK (Table 2), even though the nomogram used for the excimer laser photoablation was identical for the two procedures. The reason for the observed difference in the photoablation depth remains unclear, but may be due to differences in stromal hydration at the time of surgery, 30 either because of a longer stromal exposure during epithelial debridement in PRK or because of local variation in stromal hydration with depth. 31 In accordance with the observed difference in the amount of ablated stromal tissue, spheroequivalent refraction by 1 week averaged 0.23 D for PRK and 0.76 D for LASIK. On average, 1 D refractive change required stromal ablation of approximately 12 m during LASIK and 13 m during PRK, in accordance with the expected value fora6mm ablation. 32 Interestingly, this observation suggested that the very large difference between PRK and LASIK in central epithelial thickness by 1 week (Fig. 3; Table 2) did not have any major impact on the refractive result. Once again, this indicates that evaluating thickness changes in only the center of the cornea may be insufficient to estimate postoperative refractive changes. 33 In conclusion, the present study of patients with myopia randomly assigned to PRK or LASIK firmly demonstrates that the two surgical procedures induce different changes in corneal sublayer thickness. Epithelial and stromal wound repair occurs after both PRK and LASIK, but the time course is longer and the amount of tissue deposition is greater after PRK. Still, after 1 year, corneas treated with PRK or LASIK appear to be stable and to have undergone no further significant changes in corneal sublayer thickness. Initial changes in stromal thickness (after PRK) and total corneal thickness (after PRK or LASIK) appear to contribute to postoperative refractive regression. In contrast, the increase in epithelial thickness seems to have no refractive impact. In the present study, all thickness measurements were obtained only in the center of the cornea. To better evaluate the relation between wound repair and postoperative refractive changes, topographic variations in corneal sublayer thickness over time should be determined. Unfortunately, this is not realistic with in vivo confocal microscopy, but it is hoped that future technical development will allow such investigations. References 1. Alio JL, Muftuoglu O, Ortiz D, et al. Ten-year follow-up of photorefractive keratectomy for myopia of more than 6 diopters. Am J Ophthalmol. 2008;145: Kato N, Toda I, Hori-Komai Y, Sakai C, Tsubota K. Five-year outcome of LASIK for myopia. Ophthalmology. 2008;115: , e Rajan MS, O Brart D, Jaycock P, Marshall J. Effects of ablation diameter on long-term refractive stability and corneal transparency after photorefractive keratectomy. Ophthalmology. 2006;113: Hersh PS, Brint SF, Maloney RK, et al. 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