Corneal Healing After Uncomplicated LASIK and Its Relationship to Refractive Changes: a Six-Month Prospective Confocal Study

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Corneal Healing after Uncomplicated LASIK and Its Relationship to Refractive Changes: A Six-Month Prospective Confocal Study

Avni Murat Avunduk, Carl Joseph Senft, Sherif Emerah, Emily D. Varnell, and Herbert E. Kaufman

8,10 PURPOSE. To investigate corneal healing and the factor(s) pos- healing in the living cornea. The most dramatic morpho- sibly responsible for refractive changes after laser in situ kera- logic difference between the pre- and postoperative confocal tomileusis (LASIK). microscopy examination has been reported to occur in kerato- METHODS. Twenty eyes of 10 patients who underwent LASIK cytes that settle immediately behind the flap interface. The oval for myopia were examined clinically and by real-time confocal and brightly reflecting keratocyte nuclei appear larger than preoperative nuclei, and processes can easily be visualized, microscopy for 6 months. Epithelial and posterior stromal 10,11 thicknesses and the thickness of the keratocyte activation zone suggesting that the cells are activated. Keratocyte activa- were measured, and refractive changes were compared with tion was strongest at 1 to 2 weeks and persisted until 3 months after LASIK surgery.11,12 Similarly, activated keratocytes have these values. Keratocyte morphology, flap thickness, and sub- 10,13 basal nerve fiber bundle morphology after LASIK were also been reported after photorefractive keratectomy (PRK). investigated. Neither LASIK nor PRK has been shown superior in efficacy outcomes14,15; however, LASIK has some advantages, such as RESULTS. No significant change was detected over time in epi- minimal postoperative pain, faster clinical and functional re- thelial thickness after LASIK treatment; however, the posterior covery, less regression of refractive status, and less haze for- stromal thickness was found to be significantly higher 1 month mation.14–16 A recent confocal microscopic study revealed after surgery. A slight but statistically significant negative cor- that keratocyte-mediated regrowth of the photoablated stroma relation was detected between the thickness of the keratocyte was a key biological factor responsible for post-PRK refractive activation zone and the spheroequivalent refraction after instability in humans treated with PRK.17 It is logical to think LASIK. The subbasal nerve fiber bundle’s morphology returned that keratocyte activation can be a determining factor for the to its preoperative appearance 6 months after LASIK, but in the refractive changes after LASIK treatment. flap stroma the nerve fiber bundle morphology remained ab- The purpose of this study was to investigate the factor(s) normal at 6 months after LASIK surgery. responsible for the refractive changes after LASIK. For this CONCLUSIONS. A weak but significant negative correlation be- purpose, epithelial thickness, posterior stromal thickness, and tween the thickness of the keratocyte activation zone and the thickness of the keratocyte activation zone were measured spheroequivalent refraction was found after LASIK. The differ- by confocal microscopy, and we sought to establish a correla- ent refractive properties of activated keratocytes may be re- tion between refractive changes and these measurements. We sponsible for the myopic shift after LASIK. Further studies are also investigated keratocyte morphology, flap thickness, and needed to clarify this hypothesis. (Invest Ophthalmol Vis Sci. subbasal nerve fiber bundle morphology after LASIK. 2004;45:1334–1339) DOI:10.1167/iovs.03-1025

ETHODS aser in situ keratomileusis (LASIK) is a relatively new tech- M L nique for correction of myopia. A hinged flap (consisting of Design epithelium, Bowman’s layer, and anterior stroma) is created first, and the exposed stroma is photoablated after the flap is This prospective, interventional cohort study was begun after approval folded back. Although many studies have been published on was obtained from the LSU Health Sciences Center institutional review the clinical outcome after LASIK,1–4 relatively few reports board. Each patient gave written informed consent, and the research address the biological changes associated with the proce- followed the tenets of the Declaration of Helsinki. dure.5–9 The advent of in vivo confocal microscopy has fur- nished us with the means of improving imaging of wound Patients Twenty eyes of 10 patients who underwent LASIK for myopia were included in the study. All eyes had normal anterior ocular segments, Ͻ From the Department of Ophthalmology, LSU Eye Center, Louisi- intraocular pressure ( 20 mm Hg), and fundi. Contact lens wear was ana State University Health Sciences Center, New Orleans, Louisiana. discontinued 2 weeks (soft lenses) or 3 weeks (hard lenses) before the Supported in part by Grant EY02377 from the National Eye Insti- LASIK operation. There were six women and four men (mean age, tute and an unrestricted departmental grant from Research to Prevent 35.4 Ϯ 8.7 years). All patients were 21years of age or older and had Blindness, Inc. stable refractive errors at least 1 year before the laser procedure. Submitted for publication September 17, 2003; revised October Patients who had undergone reoperation, those with diabetes mellitus 30, and December 19, 2003; accepted January 22, 2004. or glaucoma, or those using any topical ophthalmic medication were Disclosure: A.M. Avunduk, None; C.J. Senft, None; S. Emerah, excluded. Patients with corneas thinner than 500 ␮m centrally and/or None; E.D. Varnell, None; H.E. Kaufman, None with a severe systemic disorder that could cause them to miss exami- The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertise- nations were also excluded. ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. The average preoperative spheroequivalent refraction was Corresponding author: Avni Murat Avunduk, Karadeniz Technical Ϫ5.87 Ϯ 3.45 D (range, Ϫ1.75–11.00 D) and the planned ablation University, School of Medicine, Department of Ophthalmology, Trab- depth was 59.8 Ϯ 27.1 ␮m (range, 16–110 ␮m). Each patient was zon 61080, Turkey; [email protected]. examined in the pre- and postoperative period. Preoperative examina-

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FIGURE 1. Three days after LASIK, interface particles, which indicate FIGURE 2. A confocal micrograph taken 1 week after LASIK from the flap interface, were visible (arrow). Scale bar, 100 ␮m. behind the flap interface. The cells with swollen stroma, thick and visible processes, and oval, brightly reflective keratocyte nuclei (arrows) are assumed to be activated keratocytes. Scale bar, 100 ␮m. tions were performed 1 to 3 days before surgery. Postoperative examinations were performed 1day, 3 days, 1 week, 1 month, 3 months, and as the stromal thickness that contained keratocytes with bright nuclei 6 months after surgery. Each examination included latent and manifest and visible processes (Fig. 2). refraction measurement, uncorrected and corrected near and distance visual acuity measurement, slit lamp microscopy, and videokeratogra- Statistical Analysis phy. Confocal microscopic examinations were performed at the preoperative period and 1 week, 1 month, 3 months, and 6 months after Statistical analyses were performed on computer (SPSS for Windows, LASIK. ver. 10; SPSS Sciences, Chicago, IL). Normality was tested by the Shapiro Wilk test. Flap thickness, epithelial thickness, posterior stro- PRK and LASIK Procedures mal thickness, and the thickness of the keratocyte activation zone, and the change in spheroequivalent refraction at different examination All LASIK procedures were performed in eyes under topical anesthesia, points were compared with each other by using a one-way ANOVA using an excimer laser (20/20; VISX, Santa Clara, CA). A corneal flap test. Tukey’s post hoc test was used to detect statistically significant was produced with an automated corneal shaper (ACS) microkeratome differences between values. The correlation between postoperative (ALK-E; Chiron Vision, Irvine, CA). The flap diameter was 8.5 mm and spheroequivalent refraction and the epithelial thickness, posterior stro- the intended thickness was 160 ␮m. Suction was monitored during the mal thickness, and the thickness of the keratocyte activation zone was procedure with a Barraquer tonometer. Patients fixated on a target analyzed by partial correlation. Data are expressed as the mean Ϯ SD, during the ablation. The stromal bed was irrigated with room temper- and the differences are considered statistically significant when P Ͻ ature balanced salt solution before and after flap replacement to elim- 0.05. inate residual debris. The flap was allowed to dry in place for at least 3 minutes to facilitate adhesion at the end of the operation. After the Nerve Fiber Bundles LASIK procedure, the eyes were not occluded. Antibiotic (tobramycin Nerves appeared as long, narrow structures and those longer than 50 0.3%; Tobrex; Alcon, Fort Worth, TX) and corticosteroid (fluoro- ␮m were counted. The nerve fiber bundles located in the subbasal metholone 0.1%; FML; Allergan Inc., Irvine, CA) were prescribed to all region (Fig. 3), in the stromal flap (distance from the most anterior patients, four times a day for the first 5 days. keratocyte to the flap interface), and in the posterior stroma (Fig. 4) were evaluated. A cornea was considered positive when at least one Confocal Microscopy The eyes were examined with a tandem scanning confocal microscope (Advanced Scanning, New Orleans, LA) with a 20ϫ water-immersion objective. Methylcellulose (Goniosol; CIBA Vision Ophthalmics, At- lanta, GA) was used as an optical coupler between the cornea and the tip of the water-immersion objective. The microscope objective lens was disinfected with 70% isopropyl alcohol wipes before and after the examination. Images were displayed in real time on a monitor (Sony Medical Monitor; Sony, San Diego, CA) and recorded through a CCD camera (Kappa Optoelectronics, Gleichen, Germany) onto digital vid- eotape for later playback and analysis. The video images of interest were printed in color (Epson Stylus Color 800; Seiko Epson, Nagano, Japan) without any image enhancement. Video sequences were re- viewed at least twice and evaluated in a masked fashion. From each scan, the flap thickness, defined as the distance between the surface epithelium, and the flap interface, characterized by accu- mulation of interface particles (Fig. 1), were measured. Epithelial thickness, defined as the distance between superficial epithelium and basal epithelial nerve plexus, was also measured, as were posterior FIGURE 3. A confocal micrograph from a patient in the preoperative stromal thickness, defined as the distance between endothelium and period. Arrows: subbasal nerves. During the preoperative examination flap interface, and thickness of the keratocyte activation zone, defined all corneas had a good subbasal nerve plexus. Scale bar, 100 ␮m.

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FIGURE 4. Confocal micrograph of a patient 6 months after LASIK. Arrow: Nerve fiber bundle in the posterior stroma. In this period, we detected nerve fiber bundles in the posterior stroma of 8 (50%) of 16 corneas. LASIK surgery had no significant impact on the number of nerve fiber bundles in the posterior stroma at any examination point. FIGURE 6. The thickness of the keratocyte activation zone decreased Scale bar, 100 ␮m. exponentially 1-week after LASIK. The highest thickness was measured at 1 week after treatment. *Statistically significant differences (P Ͻ 0.05). Error bars, SD. nerve fiber bundle was noted within any of the areas under study. The difference between the preoperative and the postoperative periods was analyzed with a ␹2 test. The differences were considered statisti- keratocytes anterior to the keratome cut (Fig. 5). Nineteen cally significant when P Ͻ 0.05. (95%) of the 20 corneas showed activated keratocytes at 1 week as did 10 (50%) of 20 corneas at 1 month. We were able to detect activated keratocytes 3 months after LASIK surgery in RESULTS 2 (10%) of 20 corneas. We found that the thickness of the keratocyte activation zone at 1 week was 21.54 Ϯ 3.00 ␮m; at One patient did not return for the 3- or 6-month post-LASIK 1 month, 8.75 Ϯ 1.61 ␮m; and at 3 months, 0.65 Ϯ 1.38 ␮m. examinations, and two patients did not return for the 6-month We did not detect any activated keratocytes at 6 months examination. Thus, for the preoperative period, 1 week and 1 (Fig. 6). month after LASIK, we analyzed data from 20 corneas of 10 The mean epithelial thickness was found to be 44.77 Ϯ 6.13 patients, but for the 3-month examination we analyzed data ␮m during the preoperative period. At 1 week after LASIK from 18 corneas of 9 patients, and for the 6-month examination treatment, the mean epithelial thickness was 45.81 Ϯ 7.01 ␮m; we analyzed 16 corneas of 8 patients. All data were distributed at 1 month, 43.06 Ϯ 6.37 ␮m; at 3 months, 46.25 Ϯ 7.26 ␮m; normally. and at 6 months, 44.00 Ϯ 3.85 ␮m. We did not detect any The morphology of the first keratocytes observed behind significant change in epithelial thickness any time point after the flap interface was different from the morphology before LASIK treatment (Fig. 7). surgery. The oval and brightly reflecting keratocyte nuclei and The posterior stromal thickness measured 337.75 Ϯ 18.57 the cell processes could be visualized easily, suggesting that ␮m 1 week after LASIK treatment. One month after surgery, it the cells were activated.10 We did not detect any activated

FIGURE 5. A confocal micrograph taken 1 week after LASIK treatment, from the anterior flap stroma (the stroma in front of the flap interface), shows normal-appearing keratocytes (arrows). No activated keratocyte (with thick and visible processes, and oval, brightly reflec- FIGURE 7. The thickness of the epithelium in the preoperative period tive keratocyte nuclei) were observed in the anterior flap stroma at any and after treatment. LASIK did not have a significant impact on the examination point. Scale bar, 100 ␮m. epithelial thickness.

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nerve fiber bundles in the flap stroma. The difference was statistically significant (P ϭ 0.0005, ␹2 test). When confocal microscopic examination was performed 1 month after LASIK, no corneas had nerve fiber bundles in the flap stroma. The difference between the preoperative percentage and percentage at 1 month was statistically significant (P ϭ 0.00000002, ␹2 test). Three months after LASIK, only 1 cornea showed nerve fiber bundles in the flap stroma (0.4%), which is significantly different from the preoperative finding (P ϭ 0.000018). Six months after the surgery, we detected nerve fiber bundles in the flap stroma of 4 (25%) of 16 corneas, and the difference between this and the preoperative percentage was still significant (P ϭ 0.003, ␹2 test). We detected nerve fiber bundles in the posterior stroma in 8 (50%) of 16 corneas 6 months after LASIK surgery. The percentage of corneas with nerve fiber bundles in the posterior stroma did not change significantly at any examination point.

DISCUSSION FIGURE 8. Posterior stromal thickness increased 1 month after LASIK compared with the 1-week postoperative thickness, but at later time The keratocyte morphology behind the flap interface at 1 week points, no further change was seen. *Statistically significant difference after LASIK operation was different from the preoperative from the 1-week postoperative thickness (P ϭ 0.01). Error bars indi- morphology. We saw many cells with thick and visible pro- cate SD. cesses, and oval, brightly reflective keratocyte nuclei. These cells were assumed to be activated keratocytes.10,18–20 Such was significantly higher (370.42 Ϯ 29.22 ␮m, P ϭ 0.01). At the activated keratocytes have been associated with the healing subsequent examinations, no further significant increase was process in primates after PRK.20,21 The incidence of activated observed. At 3 months after LASIK, the posterior stromal thick- keratocytes diminished after 1 week, but we still detected ness was 365.93 Ϯ 29.69 ␮m and at 6 months, 381.11 Ϯ 30.28 activated keratocytes in 10 of 22 corneas 1 month after LASIK ␮m. Both the 3- and 6-month measurements were significantly surgery. This finding is consistent with the findings of Vesa- higher than the 1-week postoperative value (P ϭ 0.026 and luoma et al.11 P ϭ 0.01, respectively, Fig. 8). Møller-Pedersen et al. demonstrated that activated kerato- The mean spheroequivalent refraction was found to be cyte-mediated rethickening of the photoablated stroma is a key Ϫ0.34 Ϯ 0.18 D one week after treatment. One month after biological factor responsible for post-PRK regression of myo- LASIK treatment, the mean spheroequivalent refraction pia.17 They demonstrated that the corneal rethickening causes changed to the myopic side considerably (Ϫ0.57 Ϯ0. 22 D), myopic regression mediated almost solely by stromal rethick- but the difference did not reach statistical significance (P ϭ ening; only a minor contribution appeared to originate from 0.06). Three months after treatment, the mean spheroequiva- restoration of the postoperative epithelial thickness. In the lent refraction was Ϫ0.56 Ϯ 0.18 D, and at 6 months, Ϫ0.56 Ϯ present study, we found a significant thickening in the poste- 0.24 D (Fig. 9). rior stroma between 1 week and 1 month after surgery. Mean- The mean flap thickness was 145.40 Ϯ 9.55 ␮m 1 week while, the spheroequivalent refraction changed considerably after LASIK. The flap thickness did not change significantly to the myopic side between these time points (Ϫ0.34 vs. between examination points. We did not detect any significant correlation between spheroequivalent refraction and epithelial thickness, when measured at different examination points (r ϭ 0.068, P ϭ 0.650). Similarly, no significant correlation was found between the posterior stromal thickness and the spheroequivalent refraction (r ϭϪ0.099, P ϭ 0.54); however, a slight but statistically significant negative correlation was detected between the thickness of the keratocyte activation zone and spheroequivalent refraction after LASIK (r ϭϪ0.278, P ϭ 0.049). During the preoperative examination, all corneas had a good subbasal nerve plexus. However, 1 week after LASIK, we detected 1 (5%) of 20 corneas with subbasal nerve fiber bundles longer than 50 ␮m. One month after LASIK, one cornea had subbasal nerve fiber bundles longer than 50 ␮m. Three months after, 9 (50%) of 18 corneas showed subbasal nerve fiber bundles. Six months after the surgery, all corneas had subbasal nerve fiber bundles. The ␹2 test revealed significant differences between the percentage of preoperative corneas with subbasal nerve fiber bundles, and the same percentages after LASIK treatment at all examination times except 6 months (all P Ͻ 0.01). Before surgery, we detected that 16 (80%) of 20 corneas FIGURE 9. Mean spheroequivalent refraction changed considerably contained nerve fiber bundles in the anterior stroma, which after LASIK between the 1-week and 1-month examination points, but would correspond with the flap stroma in the post-LASIK the difference is not statistically significant (P ϭ 0.06). At the later period. One week after treatment, only 5 (25%) corneas had examination points, no change occurred. Error bars, SD.

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Ϫ0.57), but the difference did not reach statistical significance. to be thicker with time after LASIK. However, we could not It is logical to think that the posterior stromal rethickening detect such an increase in our study as reported by Erie et al.24 seen 1 month after LASIK was related to the activated kerato- This is not unexpected, because we did not detect any acti- cytes, since the highest value for the thickness of the activated vated keratocytes anterior to the flap cut, and we did not keratocyte zone was found at the 1-week postoperative exam- detect any epithelial thickening after LASIK. ination point, and it is well known that activated keratocytes Six months after LASIK, all our patients had visible subepi- are associated with the healing process after excimer laser thelial nerve fiber bundles in their corneas. Linna et al.26 found treatment.17,21 Normally, it would be expected that a 10- to that subbasal nerve morphology seemed to degenerate from 1 15-␮m rethickening of the posterior stroma produced a 1-D week to 6 months after LASIK and corneal sensitivity returned myopic shift, but the much greater rethickening observed in to normal 6 months after LASIK. However, Lee et al.27 reported the present study created only a small amount of refractive significantly lower numbers of subbasal nerve fiber bundles change. This finding may suggest that the cornea simply swells even 12 months after LASIK compared with the preoperative after LASIK treatment, and anterior curvature does not change values with a superior hinge. Our findings are more consistent despite a high degree of thickening. However, the proposed with the findings of Linna et al.27 The reason for the difference mechanism is just a speculation at this time, because we did between results may be explained by the hinge position, since not have any pachymetry data or corneal curvature measure- most nerves appear to enter the cornea at the nasal and tem- ment to support the hypothesis. poral limbus.28 In our study, the regeneration of the nerves in Mitooka et al.22 reported that, although keratocyte density the flap stroma was not complete up to 6 moths after LASIK, as decreases in the anterior half of the retroablation layer (100- reported earlier.27 We did not find any effect of LASIK on ␮m-thick layer immediately behind the ablation) no decrease posterior stromal nerve fiber bundles, as expected. was detected in the posterior stroma. Pisella et al.23 reported In conclusion, we found a weak but still significant negative slightly different results. Keratocyte density was found to be correlation with the thickness of the keratocyte activation zone increased 8 and 30 days after LASIK compared with the initial and spheroequivalent refraction after LASIK. The different re- value according to the researchers. However, they reported fractive properties of activated keratocytes may be responsible that 3 months after LASIK the keratocyte density was begin- for the myopic shift after LASIK. Further studies with more ning to decrease and returned to the initial value at 6 months. subjects and concomitant corneal curvature analysis will help In the present study, we found that the posterior stromal to explain the underlying mechanism of refractive error shifts thickness was highest at the 1-month examination. The in- that occur after LASIK surgery. crease of the posterior stromal thickness can be caused by activated keratocytes, because the greatest thickness of the References keratocyte activation zone occurred 1 week after LASIK and decreased abruptly thereafter. 1. Fiander DJ, Tayfour F. Excimer laser in situ keratomileusis in 124 Although we did not detect a significant correlation be- myopic eyes. J Refract Surg. 1995;11(suppl):234–238. tween the spheroequivalent refraction and the posterior stro- 2. Salah T, Waring GO III, El-Maghraby A, Moadel K, Grimm SB. mal thickness, we found a weak but significant negative cor- Excimer laser in situ keratomileusis under corneal flap for myopia of 2 to 20 diopters. Am J Ophthalmol. 1996;121:143–155. relation between the thickness of the keratocyte activation 3. Condon PI, Mulhern M, Fulcher T, Foley-Nolan A, O’Keefe M. Laser zone and spheroequivalent refraction. It is difficult to explain in situ keratomileusis for high myopia and myopic astigmatism. this refractive change with activated-keratocyte–mediated re- Br J Ophthalmol. 1997;81:199–206. thickening of the photoablated posterior stroma as caused by 4. Perez-Santonja JJ, Bellot J, Claramonte P, Ismail MM, Alio JL. Laser PRK; because, if this hypothesis were correct, 1-D refractive in situ keratomileusis to correct high myopia. J Cataract Refract change would occur for each 10 to 15 ␮m of rethickening of Surg. 1997;23:372–385. posterior stroma. Thus, the most probable explanation is that 5. Maldonado-Bas A, Onnis R. Results of laser in situ keratomileusis in refractive change is induced by different refractive character- different degrees of myopia. Ophthalmology. 1998;105:606–611. istics of activated keratocytes. However, there may be other 6. Knorz MC, Wiesinger B, Liermann A, Seiberth V, Liesenhoff H. explanations. For example, the anterior and posterior curva- Laser in situ keratomileusis for moderate and high myopia and ture and the refractive index may be shifting at the same time. myopic astigmatism. Ophthalmology. 1998;105:932–940. However, we cannot draw fully justified conclusions, because 7. Amm M, Wetzel W, Winter M, Uthoff D, Ducker GIW. Histopatho- the corneal curvature was not evaluated. Although we do not logical comparison of photorefractive keratectomy and laser in situ keratomileusis. J Refract Surg. 1996;12:677–683. have any data to support this hypothesis directly it is logical to 8. Slowik C, Somodi S, Richter A, Guthoff R. Assessment of corneal think that different cellular characteristics of activated cells alterations by confocal scanning microscopy. Ger J Ophthalmol. may also change their refractive properties. 1997;5:526–531. We did not detect any change in epithelial thickness after 9. Perez-Santonja JJ, Linna TU, Tervo KM, Sakla HF, Alio JL, Tervo LASIK treatment compared with the preoperative thickness. TMT. Corneal wound healing after laser in situ keratomileusis. J 24 Erie et al. reported a significant increase of epithelial thick- Refract Surg. 1998;14:602–609. ness 1 month after LASIK. According to their data, epithelial 10. Møller-Pedersen T, Vogel M, Li HF, Petroll WM, Cavanagh D, Jester thickness did not change thereafter, but remained thicker 12 JV. Quantification of stromal thinning, epithelial thickness, and months after LASIK than before LASIK. We do not know the corneal haze after photorefractive keratectomy using in vivo con- cause of this conflicting result, but we cannot see any reason focal microscopy. Ophthalmology. 1997;104:532–535. for thickening of the epithelium after LASIK treatment. 11. Vesaluoma MH, Perez-Santonja JJ, Petroll WM, Linna T, Alio JL, The ACS keratome significantly undercut corneal flaps as Tervo TMT. Corneal stromal changes induced by myopic LASIK. measured at the 1-week confocal examination after LASIK. No Invest Ophthalmol Vis Sci. 2000;41:369–376. single patient had a flap thickness greater than the base-plate 12. Vesaluoma MH, Petroll WM, Perez-Santonja JJ, Valle TU, Alio JL, Tervo TMT. LASIK flap margin: wound healing and complications thickness. Using ultrasonic pachymetry Perez-Santonja et al.4 ␮ ␮ imaged by in vivo confocal microscopy. Am J Ophthalmol. 2000; reported a mean flap thickness of 114.1 m, with the 160- m 130:564–573. ACS plate. Similarly, but using confocal microscopy, Vesa- 11 25 13. Corbett MC, Prydal JI, Verma S, Oliver KM, Pande M, Marshall J. An luoma et al. reported a mean of 112 ␮m and Gokmen et al. in vivo investigation of the structures responsible for corneal haze reported a mean flap thickness of 133 ␮m with the 160-␮m after photorefractive keratectomy and their effect on visual func- base plate ACS. Vesaluoma et al. reported that the flaps tended tion. Ophthalmology. 1996;103:1366–1380.

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