Stromal remodeling and lenticule thickness accuracy in small-incision lenticule extraction: One-year results

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ARTICLE

Stromal remodeling and lenticule thickness accuracy in small-incision lenticule extraction: One-year results Nikolaus Luft, MD, PhD, Siegfried G. Priglinger, MD, Michael H. Ring, PhD, Wolfgang J. Mayer, MD, Anna S. Mursch-Edlmayr, MD, Thomas C. Kreutzer, MD, Matthias Bolz, MD, Martin Dirisamer, MD

Purpose: To prospectively characterize the stromal thickness changes during the first year after myopic small-incision lenticule extraction using spectral-domain optical coherence tomography (SD-OCT). Setting: Department of Ophthalmology, Kepler University Hospital, Linz, Austria. Design: Prospective case series. Methods: This study evaluated eyes that had small-incision

Postoperatively, the stromal thickness showed a significant decrease during the first 6 weeks, which amounted to a mean of 10.4 G 6.3 mm at the apex (P < .001). Subsequently, the central stroma thickened by a mean of 8.8 G 5.9 mm up until the 1-year follow-up (P < .001). One year postoperatively, the mean observed central stromal thickness reduction was 18.7 G 5.7 mm smaller than the planned lenticule thickness. This difference was smallest 6 weeks postoperatively (mean 9.8 G 7.8 mm).

lenticule extraction to treat myopia or myopic astigmatism. A highresolution SD-OCT system (RS 3000 Advance) in conjunction with a custom image-segmentation algorithm was applied to directly measure stromal thickness within the central 5.0 mm corneal zone. Measurements were obtained preoperatively and postoperatively at 1 day, 1 week, 6 weeks, 3 months, 6 months, and 1 year.

Conclusions: Significant anatomic changes in the corneal stroma were detected during the first year after small-incision lenticule extraction. The achieved lenticule thickness was systematically lower than planned, and the mismatch was more pronounced with higher lenticule thickness. Refractive outcomes did not appear to be influenced by lenticule thickness accuracy.

Results: The study enrolled 42 eyes of 21 patients. The mean surgical refractive correction was 4.94 diopters G 1.75 (SD).

J Cataract Refract Surg 2017; 43:812–818 Q 2017 ASCRS and ESCRS

A

proposed advantage of small-incision lenticule extraction (SMILE, Carl Zeiss Meditec AG) over femtosecond laser–assisted laser in situ keratomileusis (LASIK) is in its all-femtosecond laser approach, which overcomes potential sources of variability associated with excimer laser ablation (eg, corneal hydration status,1 environmental temperature, or relative humidity2). In fact, a range of prospective studies has confirmed the accuracy of small-incision lenticule extraction with regard to the cutting precision of the refractive lenticule. Predominantly, cap-thickness precision has been assessed in multiple studies using very high-frequency-ultrasound (VHF-US) and spectral-domain optical coherence tomography (SD-OCT).3–7 In contrast, only 1 previous study by

Reinstein et al.8 has assessed lenticule thickness accuracy. Surprisingly, in this study using VHF-US, a systematic discrepancy in lenticule thickness was detected with the achieved central stromal thickness reduction being on average 8 mm lower than the attempted 3 months postoperatively. The authors concluded that this difference might be related to a postoperative expansion of the central stroma caused by corneal biomechanical changes after smallincision lenticule extraction rather than to actual systematic errors in laser cutting accuracy or measurement errors. Postoperative changes in stromal thickness (also referred to as stromal remodeling) in terms of an expansion of the peripheral stroma are known to occur after LASIK.9 In agreement with these observations, Dupps and Roberts9

Submitted: October 7, 2016 | Final revision submitted: December 29, 2016 | Accepted: March 26, 2017 From the Department of Ophthalmology (Luft, Mursch-Edlmayr, Bolz) and the Ars Ophthalmica Study Center (Luft, Ring, Mursch-Edlmayr, Bolz), Kepler University Hospital, Linz, Austria; University Eye Hospital (Luft, Priglinger, Mayer, Kreutzer, Dirisamer), Ludwig-Maximilians-University, Munich, Germany. Presented at the XXXIV Congress of the European Society of Cataract and Refractive Surgeons, Copenhagen, Denmark, September 2016. Corresponding author: Martin Dirisamer, MD, Department of Ophthalmology, Ludwig-Maximilians-University, Mathildenstraße 8, 80336 Munich, Germany. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.

0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.03.038

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found thickening of the peripheral (unablated) stroma after excimer laser phototherapeutic keratectomy in an ex vivo study of human donor eyes. The authors concluded that these biomechanical corneal stromal changes could be a potential source of refractive variability in the early period after LASIK and photorefractive keratectomy.9 With regard to small-incision lenticule extraction, a range of studies has evaluated the postoperative changes to the ultrastructural and biomechanical properties of the cornea using confocal microscopy10,11 and a dynamic bidirectional applanation device.12–15 The body of evidence on the anatomic (ie, stromal thickness) changes after smallincision lenticule extraction, however, is sparse and limited to the central cornea.8 In the present work, we set out to study the temporal dynamics of corneal stromal remodeling throughout the first postoperative year after small-incision lenticule extraction. We used a high-resolution SD-OCT system in conjunction with a custom B-scan analysis algorithm that was applied to directly measure stromal thickness in the central 5.0 mm zone. Using the identical setup, our group recently characterized the corneal epithelial remodeling reaction after small-incision lenticule extraction.16 The secondary aim of this study was to assess lenticule thickness accuracy in small-incision lenticule extraction and to elucidate its potential effects on refractive outcomes.

thickness was 140 mm. For the extraction of the lenticule, a 4.0 mm incision was created using the femtosecond laser at the superotemporal position (at 45 degrees or 135 degrees). After the lenticule was created by the laser, the incision was opened and the lenticule separated from the surrounding stroma by breaking the remaining tissue bridges using a thin blunt spatula. After extraction of the lenticule with a pair of forceps and inspection for completeness, the stromal pocket was thoroughly flushed with a balanced salt solution and residual fluid was removed by applying gentle pressure on the cap with a triangular sponge swab. Postoperatively, all patients were prescribed dexamethasone 0.1% and tobramycin 0.3% eyedrops (Tobradex) 6 times daily for 1 week. Afterward, rimexolone 1.0% eyedrops (Vexol) were given 4 times daily and then tapered over 1 month. In addition, patients used preservative-free lacrimal substitutes as individually required.

PATIENTS AND METHODS

Spectral-Domain Optical Coherence Tomography Measurements Preoperatively and at all subsequent follow-up timepoints, corneal stromal thickness measurements of the central 5.0 mm zone were taken using a high-resolution SD-OCT system (RS 3000 Advance, Nidek Co., Ltd.). The device is equipped with an anterior segment adaptor lens and captures B-scan images with an axial resolution of 4 mm, a transversal resolution of 7.8 mm, and a scanning speed of 53 000 A-scans per second. Four 8.0 mm B-scans were acquired along the 0-degree, 45-degree, 90-degree, and 135-degree corneal meridians. Ten B-scans were acquired on each meridian and automatically averaged by the onboard software to 1 B-scan image. Three consecutive OCT scans were taken of each eye, and the highest quality scan was selected for further analysis. It was ensured that each scan was centered on the corneal vertex reflex, which appears as a central hyperreflective artifact on the B-scan image while the patient is focusing on the central fixation target. For further analysis, all OCT images were exported and a custom image-segmentation algorithm was used to determine stromal thickness at 17 regions of interest as follows: at the corneal vertex as well as paracentral (1.25 mm) and midperipheral (2.5 mm) on either side of the 4 meridional scans (Figure 1). Stromal thickness

This prospective observational study recruited patients who were scheduled for small-incision lenticule extraction for the treatment of myopia or myopic astigmatism. Patients with a history of corneal injury or surgery or any other present contraindication to corneal refractive surgery (eg, keratoconus) were excluded from participation in the study. Written informed consent was obtained from all patients after the nature of the study had been explained. All research adhered to the tenets outlined in the Declaration of Helsinki, and the study protocol was approved by the local ethics committee (Ethikkommission des Landes Ober€osterreich, Austria). Surgical Technique and Postoperative Treatment Regimen All small-incision lenticule extraction procedures were performed by the same surgeon (S.G.P.) using the Visumax 500 kHz femtosecond laser (Carl Zeiss Meditec AG). The principles of the small-incision lenticule extraction procedure have been described in detail.17 In this study, a laser spot spacing of 4.5 mm and a laser cut energy of level 32 (corresponding to 160 nJ) were used. In all cases, an optical zone of 6.5 mm was created and the programmed cap

Preoperative and Postoperative Assessments During the 4 weeks preceding surgery, all patients received a comprehensive clinical examination including medical history, slitlamp biomicroscopy, Goldmann applanation tonometry, dilated fundus evaluation, corneal tomography, and dry-eye screening. Moreover, the manifest and cycloplegic refractions were measured using the Jackson cross-cylinder method. The corrected distance visual acuity (CDVA) was determined using the Early Treatment Diabetic Retinopathy Study charts at 4 m. Postoperative followup visits were scheduled at 1 day, 1 week, 6 weeks, 3 months, 6 months, and 1 year. Manifest and cycloplegic refractions as well as CDVA measurements were taken from the 1-week follow-up visit onward because tear-film instability can introduce considerable variation in these parameters during the first postoperative days.

Figure 1. Overview of the semiautomated SD-OCT B-scan segmentation algorithm. The anterior (yellow circular segments) and posterior (red circular segments) corneal surface was detected automatically. At 5 locations (vertex, 1.25 mm, and 2.50 mm to each side), stromal thickness was semiautomatically measured orthogonally to the anterior corneal surface (solid green lines) by manual delineation of the epithelium– Bowman layer boundary (blue asterisks). In the same manner, central epithelial thickness was determined adjacent to the corneal vertex reflex (dotted green line) to exclude these specular reflections from the measurements.

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of the 1.25 mm zone and the 2.5 mm zone was defined as the mean thickness at all 8 paracentral and midperipheral measurement locations, respectively. In addition, measurements of central epithelial thickness in the vicinity of the central hyperreflective vertex reflex were obtained (Figure 1). The principles of the semiautomated image-analysis software have been outlined in detail.18 A previous study18 found this method has high repeatability and reproducibility in determining epithelial thickness and stromal thickness profiles in normal corneas and in corneas after small-incision lenticule extraction; a majority of eyes analyzed in the present study were also evaluated in this previous study. Statistical Analysis All statistical analysis was performed using R Statistical Software (version 3.3.0, R Foundation for Statistical Computing) together with the add-on software packages GEE and GEEPACK. When appropriate, descriptive data were presented as the mean G SD (and range). A P value less than 0.05 was defined to indicate statistical significance. The generalized estimating equation (GEE) model represents an extension of the general linear regression model. It provides an adequate statistical approach to account for the presence of correlated observations in data (ie, paired-eye data).19 A linear GEE model with adjustment for multiple comparisons (Bonferroni correction) was used to assess the changes in the manifest refraction spherical equivalent (MRSE), stromal thickness, and epithelial thickness between multiple postoperative timepoints. Generalized estimating equation regression modeling was applied to assess the correlation between the planned and the achieved lenticule thickness and to study the relationships between lenticule thickness accuracy, baseline characteristics (eg, preoperative stromal thickness), and refractive outcomes (eg, deviation from planned refraction). Pearson correlation coefficients were calculated to assess the correlation of stromal remodeling between paired eyes of patients.

RESULTS The study comprised 42 myopic eyes of 21 patients (9 men and 12 women) with a mean age of 33 years G 6 (SD) (range 25 to 46 years). The mean SE of the surgical refractive correction was 4.94 G 1.75 diopters (D) (range 8.5 to 2.0 D). No intraoperative or postoperative complications were encountered during the 1-year follow-up. Visual and Refractive Outcomes

Table 1 shows baseline and follow-up values for the uncorrected distance visual acuity, CDVA, and MRSE. Of 147 visits (7 visits per patient), 6 visits were incomplete; 2 patients missed the 1-week follow-up visit, and 4 patients missed the 6-week follow-up visit. Hence, 95.9% of all visits were complete. Postoperative Stromal Remodeling

Central stromal thickness was highest on the first postoperative day (mean 407.2 G 29.8 mm) (Figure 2, A). Subsequently, central stromal thickness decreased by a mean of 10.4 G 6.3 mm until the minimum was reached 6 weeks postoperatively (396.8 G 32.2 mm) (P ! .001). Thereafter, a continuous increase in the mean central stromal thickness of 8.8 G 5.9 mm was observed until the 1-year follow-up (405.6 G 32.5 mm) (P ! .001). In the 1.25 mm zone (Figure 2, B), stromal thickness also attained the maximum on the first day after small-incision lenticule extraction (mean 431.7 G 29.1 mm) and decreased significantly by a Volume 43 Issue 6 June 2017

Table 1. Visual and refractive outcomes. Timepoint Preoperative Mean G SD Range Postoperative 1 week Mean G SD Range 6 weeks Mean G SD Range 3 months Mean G SD Range 6 months Mean G SD Range 1 year Mean G SD Range

UDVA (LogMAR)

CDVA (LogMAR)

MRSE (D)

0.02 G 0.05 0.10, 0.10

5.09 G 1.78 8.75, 2.00

0.02 G 0.13 0.10, 0.16

0.00 G 0.10 0.1, 0.16

0.27 G 0.35 1.00, C0.63

0.05 G 0.08 0.18, 0.05

0.07 G 0.09 0.18, 0.20

0.18 G 0.30 1.13, C0.38

0.07 G 0.07 0.18, 0.05

0.07 G 0.09 0.18, 0.20

0.20 G 0.28 1.00, C0.25

0.07 G 0.08 0.18, 0.10

0.10 G 0.06 0.18, 0.10

0.24 G 0.30 1.13, C0.25

0.05 G 0.09 0.20, 0.15

0.11 G 0.06 0.20, 0.00

0.25 G 0.36 1.13, C0.38

NA NA

CDVA Z corrected distance visual acuity (spectacle); MRSE Z manifest refraction spherical equivalent; NA Z not applicable; UDVA Z uncorrected distance visual acuity

mean of 11.3 G 7.0 mm to the detected minimum at the 6-week time point (420.4 G 31.6) (P ! .001). Similarly, in the 2.5 mm zone (Figure 2, C), stromal thickness was highest on 1 day (mean 485.5 G 31.9 mm) and thereafter showed a mean decrease of 6.9 G 9.3 mm until 6 weeks postoperatively (478.6 G 33.6 mm) (P ! .001). In contrast to the central cornea, stromal thickness remained stable after 6 weeks in the 1.25 mm corneal zone and 2.5 mm corneal zone (P Z .06 and P Z .99, respectively). Lenticule Thickness Accuracy

The mean attempted central thickness of the extracted refractive lenticule stated in the femtosecond laser readout was 95.0 G 24.6 mm (range 53 to 143 mm). One year postoperatively, the achieved central stromal thickness reduction was less than the attempted in all 42 eyes by a mean of 18.7 G 5.7 mm (range C6 to C33 mm). The difference between the attempted and achieved lenticule thickness was smallest at the 6-week timepoint (mean 9.8 G 7.8 mm; range 5 to C30 mm). This mismatch was closely correlated between paired eyes of patients (R Z 0.719, P Z .001). A close correlation between the attempted and achieved central stromal thickness reduction was observed (P ! .001) (Figure 3). Nevertheless, the slope of the regression line of 0.89 indicated that the difference between the attempted and achieved lenticule thickness was greater with higher lenticule thickness and, thus, higher myopic correction. The GEE regression modeling confirmed that the discrepancy between the attempted and achieved lenticule thickness was significantly dependent on the amount of surgical refractive correction (P Z .017) (Figure 4, A). In contrast, the preoperative central stromal thickness was not a significant determinant (P Z .10) (Figure 4, B). Refraction

Seven patients (33.3%) opted for mini-monovision with a planned refraction of 0.50 D or 0.75 D in the

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Figure 3. Correlation between planned and achieved central stromal thickness reduction (ie, central lenticule thickness). The red dotted line indicates a slope of 1, and the black dotted lines show the 95% CI.

months after small-incision lenticule extraction, the epithelium had thickened by 11.3% (mean 5.9 G 3.3 mm; range 0.7 to 11.4 mm) (P ! .001). No significant changes in central epithelial thickness were observed after the 3-month timepoint (P Z .99). In total, the central epithelial thickness increased by a mean of 6.2 G 3.3 mm (range 0.9 to 12.5 mm) over the 1-year follow-up.

Figure 2. Time course of stromal thickness readings during the first postoperative year (A) at the corneal apex, (B) the 1.25 mm zone, and (C) the 2.50 mm zone. The 95% confidence intervals (CIs) are represented by the error bars.

nondominant eye. Hence, the overall mean planned refraction was slightly myopic ( 0.15 G 0.27 D; range 0.88 to 0.00 D). At 1 year, the mean refractive predictability (calculated as the difference between predicted and achieved MRSE) was 0.11 G 0.31 D (range 0.75 to 0.63 D). The MRSE was closest to the planned refraction 6 weeks postoperatively with a mean predictability of 0.05 G 0.24 D (range 0.38 to C0.50 D). No statistically significant postoperative change in the MRSE was observed between the 1-week, 6-week, 3-month, 6-month, and 1-year follow-up visits (P Z .11) (Table 1). The difference between the planned and achieved lenticule thickness was not associated with refractive overcorrection or undercorrection (P Z .33) (Figure 5). Epithelial Thickness Changes

Preoperatively, the mean epithelial thickness at the corneal apex was 52.2 G 2.6 mm (range 47.4 to 57.9 mm). Three

DISCUSSION The present study found significant corneal stromal thickness changes during the first year after myopic smallincision lenticule extraction. Applying SD-OCT, we detected a decrease in stromal thickness over the central 5.0 mm zone during the first 6 postoperative weeks that appeared to be attributable to the resolution of postoperative corneal edema. Moreover, the central stroma showed continuous thickening from 6 weeks to 1 year postoperatively, an observation that might be indicative of biomechanical stromal remodeling. Previously, only Tay et al.5 had assessed the dynamics of corneal anatomic changes after small-incision lenticule extraction. In their study based on SD-OCT, the total corneal thickness along the horizontal meridian remained stable between 1 week and 6 months postoperatively. Nevertheless, the results in their study should be interpreted with care because the measurements included the corneal epithelium, which is known to show significant thickening after smallincision lenticule extraction.6,8,16,18 In the present study, we used a high-resolution anterior segment SD-OCT system in conjunction with a semiautomated B-scan image segmentation algorithm. This setup enables direct measurements of the stromal and epithelial thickness over the central 5.0 mm zone with excellent repeatability and reproducibility.18 Our group recently used the same setup to characterize the corneal epithelial remodeling subsequent to small-incision lenticule extraction.16 Volume 43 Issue 6 June 2017

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Figure 5. Dependency of refractive predictability (ie, relative deviation from planned refraction) on lenticule thickness accuracy (ie, planned and achieved central stromal thickness reduction).

Figure 4. Associations of central lenticule thickness accuracy (ie, planned and achieved central stromal thickness reduction) with (A) planned lenticule thickness and (B) preoperative central stromal thickness.

We believe that this study is the first to assess lenticule thickness accuracy in small-incision lenticule extraction using SD-OCT. Because the peripheral lenticule thickness is not known, this analysis was limited to the central lenticule thickness. At the 1-year timepoint, the femtosecond laser readout overestimated the central lenticule thickness (on average by 19 mm) in all 42 study eyes. Of all postoperative timepoints, the smallest discrepancy between the planned and achieved lenticule thickness was 6 weeks after surgery, with a mean overestimation of approximately 10 mm. However, remarkable interindividual differences were observed, with a range of 5 to C30 mm. Of note, the mismatch was closely correlated between paired eyes of the same patient. Our findings are in good agreement with the VHF-US study performed by Reinstein et al.,8 who reported a mean 8.2 G 8.0 mm (range 8 to 29 mm) overestimation of the central lenticule thickness measured 3 months postoperatively. A range of potential sources of this discrepancy Volume 43 Issue 6 June 2017

has been elaborated in detail.8 In short, systematic errors in laser cutting accuracy for 1 of the 2 interfaces of the lenticule can be widely excluded because the precision of the Visumax femtosecond laser in creating LASIK flaps has been well established,20–22 as has its accuracy in creating interfaces in small-incision lenticule extraction (independent of depth).4 Moreover, measurement errors seem unlikely to be a causative factor. Instead, the hypothesis has been proposed that stromal remodeling might be the root cause for the observed discrepancy between the planned and achieved lenticule thickness. As an underlying mechanism, Reinstein et al.8 put forward that the central stroma might expand after small-incision lenticule extraction as a result of tension release of the stromal collagen lamellae disrupted during the creation of the lenticule. The findings in this present study may agree with this theory because we observed significant stromal remodeling in terms of continuous central thickening of approximately 9 mm between 6 weeks and 1 year postoperatively. Following this hypothesis, it would also be expected for there to be a larger discrepancy between the planned and achieved lenticule thickness with higher refractive correction and, hence, a greater amount of stromal collagen layers being disrupted by the lenticule. Indeed, in additional support of the central stromal expansion hypothesis, we found this association to be statistically significant. Nevertheless, we believe that several additional factors remain to be discussed. First, keratocyte-mediated wound healing in the laser-cut interface might be a source of postoperative stromal thickening. Even though the woundhealing reaction after small-incision lenticule extraction was found to be less pronounced than after LASIK in the rabbit model,23 intense keratocyte activity in the interface layer was observed after small-incision lenticule extraction in a human in vivo study.11 A second potentially influential factor is stromal hydration. We suggest that the stromal thinning of approximately 10 mm observed during the first 6 weeks after small-incision

STROMAL REMODELING AFTER SMALL-INCISION LENTICULE EXTRACTION

lenticule extraction was attributable to the resolution of the postoperative corneal edema. Thus, the lenticule thickness accuracy night have been underrated in the earlier postoperative period because of the potential bias resulting from postoperative stromal edema. In the end, however, the question arises as to why the relatively large mismatch between the planned and achieved central stromal thickness reduction did not appear to diminish the refractive precision of the small-incision lenticule extraction procedure. For example, the 2 eyes with the largest mismatch between the planned and achieved lenticule thickness (O30 mm) achieved an outcome of nearly plano. Because the small-incision lenticule extraction lenticule is thickest in the center, we hypothesize that decentration of the lenticule in relationship to the corneal vertex might have caused an overestimation of the mismatch between the planned and achieved central stromal thickness reduction. The average decentration of the small-incision lenticule extraction lenticule has been reported to between 0.17 mm and 0.32 mm,24–26 although it can range up to more than 1.1 mm.24 However, the effect of lenticule decentration on refractive outcomes is believed to be small because the postoperative topographic maps in small-incision lenticule extraction show larger optical zones than after LASIK.25 Further research seems warranted to determine the actual potential causes of the apparent mismatch between the planned and achieved lenticule thickness in small-incision lenticule extraction. Such causes include postoperative stromal remodeling (including wound healing in the interface), decentration of the treatment zone, and stromal edema. With respect to the refractive stability of small-incision lenticule extraction, we observed no significant refractive alterations throughout the first postoperative year. Nevertheless, the refractive predictability was most favorable 6 weeks postoperatively, when the lenticule thickness accuracy was highest. Furthermore, the central stromal expansion observed between 6 weeks and 1 year coincided with a mild (nonsignificant) myopic regression. These observations indicate that stromal remodeling might be a contributor to long-term refractive regression after small-incision lenticule extraction. Further research is needed to substantiate this hypothesis. Stromal thickness in the 1.25 mm zone and 2.5 mm zone remained stable after 6 weeks in the present study. The reasons for stromal remodeling after small-incision lenticule extraction apparently being accentuated or limited to the corneal apex remain to be elucidated. A further beneficial field of study would be the peripheral lenticule thickness accuracy in small-incision lenticule extraction. However, at present, the manufacturer of the dedicated femtosecond laser platform has not provided data on the properties other than those in the central lenticule. A limitation is that this study evaluated stromal thickness changes within the 5.0 mm corneal zone despite the optical zone of 6.5 mm created during small-incision lenticule extraction. However, precise and repeatable measurements of peripheral corneal sublayer pachymetry are challenging, and part of these difficulties might be inherent in the planar scanning patterns used in currently available

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SD-OCT systems.27 Moreover, the SD-OCT setup used in this study did not permit segmentation of the laser-cut interface, which presented as a relatively blurred hyperreflective structure confined to the peripheral stroma. Hence, this study was incapable of analyzing the precision and stability of cap thickness or residual stromal bed thickness. Further limitations include the small sample and the absence of a control group (eg, femtosecond laser–assisted LASIK) as well as that no objective means of measuring refraction (eg, wavefront aberrometry) were used. Furthermore, the stromal pocket was flushed with a balanced salt solution subsequent to the removal of the lenticule, which might have added to postoperative stromal hydration. Hence, our results may not be representative of other surgical techniques that do not include flushing the stromal pocket. To conclude, this SD-OCT–based study characterized the anatomic changes in the corneal stroma during the first year after small-incision lenticule extraction. During the first 6 postoperative weeks, considerable stromal thinning was detected in the 5.0 mm corneal zone, presumably as a result of the resolution of postoperative edema. Furthermore, this study found evidence of central stromal expansion during the remaining first postoperative year. Among other factors, such as stromal hydration and lenticule decentration, the observed stromal remodeling might be the reason for the relatively large mismatch between the planned and achieved lenticule thickness, which was more pronounced with higher lenticule thickness. Refractive results were stable during the first postoperative year and, in our hands, the refractive predictability of small-incision lenticule extraction did not appear to be influenced by lenticule thickness accuracy.

WHAT WAS KNOWN  As shown by VHF-US, the planned central lenticule thickness in small-incision lenticule extraction seems to be systematically greater than the actually achieved central stromal thickness reduction.  Postoperative changes in stromal thickness, as encountered after LASIK, have been suspected to be the origin of this stromal thickness inaccuracy in small-incision lenticule extraction.

WHAT THIS PAPER ADDS  Considerable postoperative stromal remodeling in terms of initial stromal thinning followed by a subsequent central stromal expansion occurred during the first year after smallincision lenticule extraction.  The mismatch between the planned and achieved central stromal thickness reduction correlated with the thickness of the extracted lenticule.

REFERENCES 1. Dougherty PJ, Wellish KL, Maloney RK. Excimer laser ablation rate and corneal hydration. Am J Ophthalmol 1994; 118:169–176 2. Schena E, Silvestri S, Franzesi GT, Cupo G, Carito P, Ghinelli E. Theoretical model and design of a device to reduce the influence of environmental factors on refractive surgery outcomes. Conf Proc IEEE Eng Med Biol Soc 2006; 1:343–346

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3. Ozgurhan EB, Agca A, Bozkurt E, Gencer B, Celik U, Cankaya K_I, Demirok A, Yilmaz OF. Accuracy and precision of cap thickness in small incision lenticule extraction. Clin Ophthalmol 2013; 7:923–926. Available at: http://www.ncbi. nlm.nih.gov/pmc/articles/PMC3665570/pdf/opth-7-923.pdf. Accessed April 19, 2017 4. Reinstein DZ, Archer TJ, Gobbe M. Accuracy and reproducibility of cap thickness in small incision lenticule extraction. J Refract Surg 2013; 29:810–815 5. Tay E, Li X, Chan C, Tan DT, Mehta JS. Refractive lenticule extraction flap and stromal bed morphology assessment with anterior segment optical coherence tomography. J Cataract Refract Surg 2012; 38:1544–1551 6. Vestergaard AH, Grauslund J, Ivarsen AR, Hjortdal JØ. Central corneal sublayer pachymetry and biomechanical properties after refractive femtosecond lenticule extraction. J Refract Surg 2014; 30:102–108 7. Zhao J, Yao P, Li M, Chen Z, Shen Y, Zhao Z, Zhou Z, Zhou X. The morphology of corneal cap and its relation to refractive outcomes in femtosecond laser small incision lenticule extraction (SMILE) with anterior segment optical coherence tomography observation. PLoS One 2013; 8:e70208. Available at: http://www.plosone.org/article/fetchObject.action?uriZinfo% 3Adoi%2F10.1371%2Fjournal.pone.0070208&representationZPDF. Accessed April 19, 2017 8. Reinstein DZ, Archer TJ, Gobbe M. Lenticule thickness readout for small incision lenticule extraction compared to Artemis three-dimensional very high-frequency digital ultrasound stromal measurements. J Refract Surg 2014; 30:304–309 9. Dupps WJ Jr, Roberts C. Effect of acute biomechanical changes on corneal curvature after photokeratectomy. J Refract Surg 2001; 17:658–669 10. Agca A, Ozgurhan EB, Yildirim Y, Cankaya KI, Guleryuz NB, Alkin Z, Ozkaya A, Demirok A, Yilmaz OF. Corneal backscatter analysis by in vivo confocal microscopy: fellow eye comparison of small incision lenticule extraction and femtosecond laser-assisted LASIK. J Ophthalmol 2014:265012. Available at: http://downloads.hindawi.com/journals/joph/2014/265012. pdf. Accessed April 19, 2017 11. Liu M, Zhang T, Zhou Y, Sun Y, Wang D, Zheng H, Liu Q. Corneal regeneration after femtosecond laser small-incision lenticule extraction: a prospective study. Graefes Arch Clin Exp Ophthalmol 2015; 253:1035–1042 12. Kamiya K, Shimizu K, Igarashi A, Kobashi H, Sato N, Ishii R. Intraindividual comparison of changes in corneal biomechanical parameters after femtosecond lenticule extraction and small-incision lenticule extraction. J Cataract Refract Surg 2014; 40:963–970 13. Wang B, Zhang Z, Naidu RK, Chu R, Dai J, Qu X, Yu Z, Zhou H. Comparison of the change in posterior corneal elevation and corneal biomechanical parameters after small incision lenticule extraction and femtosecond laserassisted LASIK for high myopia correction. Cont Lens Anterior Eye 2016; 39:191–196. Available at: http://www.contactlensjournal.com/article/ S1367-0484(16)30005-4/pdf. Accessed April 19, 2017 14. Wang D, Liu M, Chen Y, Zhang X, Xu Y, Wang J, To C-h Liu Q. Differences in the corneal biomechanical changes after SMILE and LASIK. J Refract Surg 2014; 30:702–707 15. Wu D, Wang Y, Zhang L, Wei S, Tang X. Corneal biomechanical effects: small-incision lenticule extraction versus femtosecond laser–assisted laser in situ keratomileusis. J Cataract Refract Surg 2014; 40:954–962 16. Luft N, Ring MH, Dirisamer M, Mursch-Edlmayr AS, Kreutzer TC, Pretzl J, Bolz M, Priglinger SG. Corneal epithelial remodeling induced by small incision lenticule extraction (SMILE). Invest Ophthalmol Vis Sci 2016; 57:OCT176–OCT185. Available at: http://iovs.arvojournals.org/article. aspx?articleidZ2535985. Accessed April 19, 2017

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17. Sekundo W, Kunert KS, Blum M. Small incision corneal refractive surgery using the small incision lenticule extraction (SMILE) procedure for the correction of myopia and myopic astigmatism: results of a 6 month prospective study. Br J Ophthalmol 2011; 95:335–339 18. Luft N, Ring MH, Dirisamer M, Mursch-Edlmayr AS, Pretzl J, Bolz M, Priglinger SG. Semiautomated SD-OCT measurements of corneal sublayer thickness in normal and post-SMILE eyes. Cornea 2016; 35:972–979 19. Fan Q, Teo Y-Y, Saw S-M. Application of advanced statistics in ophthalmology. Invest Ophthalmol Vis Sci 2011; 52:6059–6065. Available at: http://iovs.arvojournals.org/article.aspx?articleidZ2186999. Accessed April 19, 2017 20. Ahn H, Kim J-K, Kim CK, Han GH, Seo KY, Kim EK, Kim TI. Comparison of laser in situ keratomileusis flaps created by 3 femtosecond lasers and a microkeratome. J Cataract Refract Surg 2011; 37:349–357 21. Issa A, Al Hassany U. Femtosecond laser flap parameters and visual outcomes in laser in situ keratomileusis. J Cataract Refract Surg 2011; 37:665–674 22. Ju W-K, Lee J-H, Chung T-Y, Chung E-S. Reproducibility of LASIK flap thickness using the zeiss femtosecond laser measured postoperatively by optical coherence tomography. J Refract Surg 2011; 27:106–110 23. Dong Z, Zhou X, Wu J, Zhang Z, Li T, Zhou Z, Zhang S, Li G. Small incision lenticule extraction (SMILE) and femtosecond laser LASIK: comparison of corneal wound healing and inflammation. Br J Ophthalmol 2014; 98:263– 269. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913294/ pdf/bjophthalmol-2013-303415.pdf. Accessed April 19, 2017 24. Lazaridis A, Droutsas K, Sekundo W. Topographic analysis of the centration of the treatment zone after SMILE for myopia and comparison to FS-LASIK: subjective versus objective alignment. J Refract Surg 2014; 30:680–686 25. Li M, Zhao J, Miao H, Shen Y, Sun L, Tian M, Wadium E, Zhou X. Mild decentration measured by a Scheimpflug camera and its impact on visual quality following SMILE in the early learning curve. Invest Ophthalmol Vis Sci 2014; 55:3886–3892. Available at: http://iovs.arvojournals.org/article. aspx?articleidZ2128950. Accessed April 19, 2017 26. Reinstein DZ, Gobbe M, Gobbe L, Archer TJ, Carp GI. Optical zone centration accuracy using corneal fixation-based SMILE compared to eye trackerbased femtosecond laser-assisted LASIK for myopia. J Refract Surg 2015; 31:586–592 27. Reinstein DZ, Yap TE, Archer TJ, Gobbe M, Silverman RH. Comparison of corneal epithelial thickness measurement between Fourier-domain OCT and very high-frequency digital ultrasound. J Refract Surg 2015; 31:438–445. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596531/pdf/ nihms-726292.pdf. Accessed April 19, 2017

Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned.

First author: Nikolaus Luft, MD, PhD University Eye Hospital, Ludwig-MaximiliansUniversity, Munich, Germany