Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes For peer review only

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1 Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes Journal: BMJ Open Manuscript ID bmjopen-0-00 Article Type: Research Date Submitted by the Author: -Dec-0 Complete List of Authors: Wu, Wenjing Wang, Yan; Zhang, Hui; Zhang, Jiamei; Li, Hua; Dou, Rui; <b>primary Subject Heading</b>: Ophthalmology Secondary Subject Heading: Ophthalmology Keywords: Cataract and refractive surgery < OPHTHALMOLOGY, Corneal and external diseases < OPHTHALMOLOGY, Ophthalmology < SURGERY

2 Page of BMJ Open Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes Wenjing Wu, Ph.D., Yan Wang, M.D, Ph.D.,Hui Zhang, Ph.D., Jiamei Zhang, M.D. Hua Li, M.D, Rui Dou, M.D, Tianjin Eye Hospital & Eye Institute, Tianjin Ophthalmology and Visual Science Key Laboratory, Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 0000, China Corresponding author: Yan Wang, Professor. Add: No. Gansu Rd, Heping District, Tianjin 0000, China wangyan@vip.sina.com Tel: Fax: -- ext. 0. Mob: 00

3 Page of Abstract Objective: To determine whether the long-term visual outcomes of the SMILE surgery is consistent with the short-term results in the high myopic eyes. Design: Retrospective case-control study of data collected from August, 0, until August, 0. Setting: Single Refractive surgery center. Participants: This study totally enrolled eyes. Sixty-five eyes of subjects ( female / male) in the high myopic group (MRSE -.0D), eyes of subjects ( female/ male) in the control group (MRSE<-.0D). The inclusion criteria were subjects who had follow-ups at day, week, month,, months and year postoperatively together with the manifest refraction, uncorrected and corrected distance visual acuity (UDVA / CDVA). There were no statistically significant differences between the high myopic groups and the control group on the patients gender, age, or cylindrical diopter, preoperatively (P=0., P=0.0, P=0.,respectively). Primary and secondary outcome measures: The UDVA, refractive stability, safety index (the postoperative CDVA / the preoperative CDVA), the predictability (the percentage of eyes within ± 0.0D). Results: In both groups, the long-term ( months postoperatively) UDVA and safety index were significantly better than these results at day (high myopic group: P=0.0, P<0.00; control group: P<0.0, P<0.00), the long-term predictability showed no significant difference with the short-term results (P=.00 in both groups).

4 Page of BMJ Open In high myopic eyes, the long-term MRSE was slightly but significantly worse than the short term result (P=0.0). However, the postoperative MRSE showed no differences from day to year (P=0.) in the control group. Conclusions: The long-term visual outcomes were better than the short-term results after the SMILE surgery in terms of the visual acuity and safety. However, the high myopic eyes suffered from slight regression in long-term, which may be valuable for the adjustment of the nomagram to correct high myopia. Keywords: small incision lenticule extraction; high myopia; long-term; short-term Strengths and limitations of this study Early visual and refractive outcomes of small incision lenticule extraction (SMILE) have been quite intensively investigated, the results are encouraging, but the long-term observations of the SMILE procedure is far from established, whether the long-term results is consistent with the short-term results remain to be clarified. Moreover, the long term results of the high myopic eyes, which is a major concern in the prognosis of the patient, has not so far been fully elucidated.

5 Page of Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes Introduction Small incision lenticule extraction (SMILE) is a new keratorefractive procedure to correct myopia and astigmatism.[, ] The short-term clinical results of the SMILE surgery have been quite intensively investigated in the past several years. [-0]A major concern of the SMILE surgery today is the long-term clinical results especially in the high myopic eyes. [, ] Some studies reported the one-year outcomes of the SMILE surgery[-], however, the high myopic eyes were not analyzed separately. Although Hjortdal J and Kim, JR recently published the observations of the SMILE surgery in high myopic eyes,[, ] the long-term studies of the SMILE surgery in the high myopic eyes are far from established. It is still not well explored whether the long-term visual outcomes were consistent with the short-term results in the high myopic eyes after the SMILE surgery. This may be important to answer patients concerns of the regression after SMILE surgery clinically. Hence, this study was performed to investigate the short-term and long-term visual outcomes of the SMILE procedure especially in the high myopic eyes, we not only compared the differences on the refraction, but also on the visual recovery, safety and predictability. Materials and Methods Ethics Statement This study was approved by the Institutional Review Board of Tianjin Eye Hospital

6 Page of BMJ Open and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all patients. Subjects We reviewed the clinical charts of the subjects who underwent the SMILE surgery in the refractive center of Tianjin Eye Hospital from August, 0 to August, 0. The inclusion criteria were subjects who had follow-ups at day, week, month,, months and year postoperatively together with the manifest refraction, uncorrected and corrected distance visual acuity (UDVA / CDVA) examinations. This study totally enrolled myopic eyes. They were divided into two groups according to their preoperative MRSE. eyes of subjects ( female / male) in the high myopic group (MRSE -.0D), eyes of subjects ( female/ male) in the control group (MRSE<-.0D). In the high myopic group, the patient s age was.±. years (mean ± SD), ranging from to years ; the preoperative MRSE was -.0± 0. D, ranging from.0 to.0 D, the sphere was -.±0. D, ranging from -. D to -. D, and the cylinder was -0.±0. D, ranging from 0.00 to.0 D. In the control group, the patient age was.±. years, ranging from to years. The preoperative MRSE were -.±0. D, ranging from. to. D, the sphere was -.±.0 D, ranging from 0 to -.0 D, the cylinder was -0.±0. D, ranging from 0.00 to.d. There were no statistically significant differences between the high myopic groups and the control group on the patients gender, age, or cylindrical diopter, preoperatively, P=0., P=0.0, P=0.,respectively. Surgical Technique

7 Page of The experienced surgeon (Y.W.) performed all the SMILE surgeries. The Visumax femtosecond laser system (Carl Zeiss Meditec AG) with a repletion rate of 00 khz was used for this procedure. The intended cap thickness was 0 µm, the diameter of the optical zone was.0 to. mm. All side-cut angles were 0 degrees. The target refraction was ±0.D. The surgical procedure was under topical anaesthesia with - drops oxybuprocaine eye drops for minutes (Benoxil, Santen, Inc., Japan). A standard eyelid speculum was used to keep the eye open, the patient eye was positioned under curved contact glass of the femtosecond laser and fixated on a blinking target. The suction was applied when the center of pupil was centered to the contact lenses. The posterior of the refractive lenticule was created from the periphery to the center of the cornea with a 0-degree cordial length vertical edge of the refractive lenticels. The anterior surface of the refractive lenticels was created from the center to the periphery, and at last the small incision was created at the o clock position with the cordial length ranging from to mm. After laser treatment, our patented spatula was used to break the remaining tissue bridges and lose the stromal lenticels, which was then grasped with a pair of forceps and removed. All patients received drop of topical ofloxacin 0.% (Tarivid; Santen, Inc., Osaka, Japan) and drop of diclofenac (Voltaren Ophtha) at the end of the procedure. After that, topical ofloxacin 0.% (Tarivid; Santen, Inc., Osaka, Japan) was applied times daily for days postoperatively, 0.% fluorometholone (Flumetholon; Santen, Inc., Osaka, Japan) were applied times per day for weeks and then tapered over months. Preoperative and postoperative assessments

8 Page of BMJ Open The subjects had eye examinations including the manifest refraction, UDVA, CDVA, history of refractive stability, slit-lamp evaluation, dilated fundoscopy and the corneal topography, preoperatively. The postoperative follow-up was scheduled at day, week, month,, and months postoperatively including the examinations of the manifest refraction, UDVA, and CDVA. The UDVA and CDVA were measured using a standard Snellen visual acuity chart. Statistical Analysis Statistical analysis was performed using the SPSS statistical software (ver.0.0, Chicago, USA). The normality of all data samples was checked with the Kolmogorov-Smirnov test. The comparisons between the groups for normally distributed data were made using the Student t test (two-tailed). The Mann-Whitney rank-sum test was used for non-normally distributed data between the two independent groups, the Kruskal Wallis test was used to determine any significant differences among the non-normally distributed multiple groups. Differences were considered to be statistically significant when the P value was less than 0.0. Results Visual Recovery The visual recovery indicates the changes of the uncorrected distance visual acuity (UDVA) with time after the SMILE surgery. The UDVA was 0.±0., 0.±0.,.0±0.,.0±0.,.0±0., 0.±0. in the high myopia group at day, week, month,, and months, postoperatively. The UDVA was 0.±0.,.00 ±0.,.0±0.,.0±0.,.0±0.,.0±0. in the control group at day,

9 Page of week, month,, and months, respectively. There were statistically significant differences of the UDVA in the high myopic eyes from day to year after the SMILE surgery (P=0.00, the Kruskal-Wallis test). The long-term UDVA (one year) was significant better than the result at early stage (day), P=0.0, shown in Figure A. In the low to moderate myopic group, the UDVA was also better at year than at day (P=0.0, Figure B). The Figure C suggested that although the UDVA showed no statistically significance between the high myopic eyes and the control group at day (P=0., the Mann-Whitney Test), week (P=0.), month (P=0.) or months (P=0.), the UDVA was significantly lower in the high myopia group than the control group at and months (P=0.0, P=0.0). Refractive Stability Refractive stability depicts the changes of the MRSE with time after the SMILE surgery. The MRSE was -0.0±0.,-0.0±0.0,-0.0±0.,-0.0±0.,-0. ±0.0, -0.±0. in the high myopia group at day, week, month,, and months, postoperatively. The MRSE was -0.0±0.,-0.0±0.,-0.0±0., -0.0±0.,-0.0±0., -0.0±0. in the control group at day, week, month,, and months, respectively. It showed statistically significant differences from day to year in the high myopia group (P<0.00, the Kruskal-Wallis test), the absolute value of the MRSE was significantly higher at year than the results at day, week, or month, (Figure A, P=0.0, P=0.00, P=0.0 respectively). However, the postoperative MRSE showed no differences from day to year in the control

10 Page of BMJ Open group (P=0., the Kruskal-Wallis test). It stabled within day after surgery, Figure B. The MRSE was significantly worse in the high myopia group than the control group at year after the SMILE surgery, (P<0.00, the Mann-Withney U test, shown in Figure C). There were no significant differences between the two groups at day, week, month, months or months, P=0., P=0.0, P=0. P=0., P=0.0, respectively. Safety The safety index defined as the postoperative CDVA / the preoperative CDVA. The safety index was in the high myopic group at day, week, month,, and months, postoperatively. The safety index was.0±0.,.0±0.,.0± 0.,.±0.,.±0.,.±0.. In the control group, the safety index was.0±0.,.0±0.,.0±0.,.±0.,.±0.,.±0. at day, week, month,, and months, respectively. In both the high myopic group and the control group, there were significant differences of the safety index among the different postoperative times (P<0.00 for the two groups, the Kruskal-Wallis test), shown in Figure. The safety index was significantly better long-term ( months and year) after the SMILE surgery than the early stage ( day) in both groups. There were no significant differences of the safety index between the high myopia group and the control group at day, week, month,, or months (P=0., P=0., P=0., P=0., P=0.0, P=0., respectively, the Mann-Withney U test).

11 Page 0 of Predictability In both groups, the percentages of eyes within ±0.0D showed no significant difference between day and year follow-up (P=.00, Chi-Square Test), Figure. Moreover, the percentage of eyes within ±0.0 D showed no significant differences between the two groups for all follow-up visits ( day: P=.000, week: P=.000, month: P=0.00, months: P=0., months: P=0.0, year: P=0., the Mann-Withney U test). Figure shows the regression line within the plot of the actual correction achieved versus the attempted refractive correction year postoperatively. The regression line for the high myopic eyes (Figure A) could be expressed using the following equation (R =0.), Achieved SE (D)=0. Attempted SE (D)+0.D, () The regression line for the low to moderate myopic eyes (Figure B) expressed using the following equation (R =0.), Achieved SE (D)=0. Attempted SE (D)-0.0, () As explained by Equation and and shown in Figure C, the high myopic eyes tend to be under corrected at year after operation. Discussion In order to find the visual differences of the SMILE surgery between long-term and short-term especially in the high myopic eyes, the present study not only investigated the refractive stability from day to year, but also studied the visual recovery, safety and predictability between day and year after the SMILE surgery. Moreover, 0

12 Page of BMJ Open this study analyzed the high myopic eyes separately and showed that the SMILE surgery could offer as satisfied visual outcomes as in the low to moderate myopic eyes. This may be important clinically and indicate that SMILE surgery could provide as safe outcomes for the high myopic eyes as in the low to moderate myopic eyes even year postoperatively. In addition to the better safety results, the long-term visual acuity was better than the short-term results in the high myopic eyes after the SMILE surgery. The results shows that the SMILE surgery could provide a better visual acuity and safety results year postoperatively both in the high myopia eyes and low to moderate myopic eyes. There were no differences of the safety results between the two groups even after long-term observations. However, it is still important to detect a keratoconus-suspect cornea or a subclinical keratoconus/forme fruste keratoconus as a contraindication to the SMILE surgery for the safety concerns. [-0] In terms of the myopic refraction, the high myopic eyes showed a tendency of slightly regression at months after SMILE procedure, which lead to the slightly worse results than the low to moderate myopic eyes. It may be associated with the thicker refractive lenticule extracted in the high myopic eyes, the smaller optical zone which was originally selected to limit depth of tissue removed especially in the high myopic eyes with thinner corneal thickness, and the corneal healing responses.[] The epithelial hyperplasia, weak corneal biomechanics are also supposed to be associated with the slightly myopic regression in the high myopic eyes after the SMILE surgery. [, ] It still needs further investigations on the regressions long-term after the

13 Page of SMILE surgery, which may be valuable for the adjustment of the nomagram to correct high myopia. In terms of the predictability, the short-term predictability is similar with the long-term results both in the high myopic and the low to moderate myopic eyes. Water Sekundo[] reported % eyes were within ±0.0 D at months after the SMILE surgeries, and it is % in a study by Alper Agca []. Recently, Jae Ryun Kim reported % of the high myopic eyes and.% of the low to moderate myopic eyes were within ±0.0 D one-year after the SMILE surgery.[] Our results were comparable with those published studies and these investigations together suggested that the SMILE procedure showed good predictability in both groups even long-term after operation. There are some limitations in the present study. The present study mainly investigated the differences of the visual outcomes of the SMILE surgery between long-term and short-term. Future studies are needed to determine the differences on the corneal biomechanics, or the high order aberrations, which is now being investigated in our group. In summary, the long-term visual outcomes were better than the short-term results after the SMILE surgery in terms of the visual acuity and safety. The long-term predictability remained similar with the early stage. However, the high myopic eyes suffered from slight regression in long-term, which may be valuable for the adjustment of the nomagram to correct high myopia. Acknowledgments Grants and financial support: This study was supported by research grants from the

14 Page of BMJ Open National Nature Science Foundation of China (Grant No. 0. to Y.W.) and Tianjin Research Program of Application Foundation and Advanced Technology (JCZDJC00). Author contributions: WWJ performed the study, participated in the design and drafted the manuscript. ZH, ZJM, LH and DR helped to draft the manuscript and performed the statistical analysis. ZH, ZJM, LH and DR conducted the long-term observation and participated in the examination and acquisition of data. WY conceived of the study, participated in the design, revised the manuscript and gave final approval of the version for publication. All authors read and approved the final manuscript. Competing interests: None of the author has a financial or proprietary interest in any material or method mentioned in the manuscript. Data sharing statement: No additional data are available.

15 Page of References:. 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 month prospective study. The British journal of ophthalmology 0, ():-.. Shah R, Shah S, Sengupta S: Results of small incision lenticule extraction: All-in-one femtosecond laser refractive surgery. Journal of cataract and refractive surgery 0, ():-.. Hjortdal JO, Vestergaard AH, Ivarsen A, Ragunathan S, Asp S: Predictors for the outcome of small-incision lenticule extraction for Myopia. Journal of refractive surgery 0, ():-.. Vestergaard A, Ivarsen AR, Asp S, Hjortdal JO: Small-incision lenticule extraction for moderate to high myopia: Predictability, safety, and patient satisfaction. Journal of cataract and refractive surgery 0, (): Agca A, Demirok A, Cankaya KI, Yasa D, Demircan A, Yildirim Y, Ozkaya A, Yilmaz OF: Comparison of visual acuity and higher-order aberrations after femtosecond lenticule extraction and small-incision lenticule extraction. Contact lens & anterior eye : the journal of the British Contact Lens Association 0, ():-.

16 Page of BMJ Open Ang M, Mehta JS, Chan C, Htoon HM, Koh JC, Tan DT: Refractive lenticule extraction: transition and comparison of surgical techniques. Journal of cataract and refractive surgery 0, 0():-.. Ganesh S, Gupta R: Comparison of visual and refractive outcomes following femtosecond laser- assisted lasik with smile in patients with myopia or myopic astigmatism. Journal of refractive surgery 0, 0():0-.. Ivarsen A, Asp S, Hjortdal J: Safety and complications of more than 00 small-incision lenticule extraction procedures. Ophthalmology 0, ():-.. Ivarsen A, Hjortdal J: Correction of myopic astigmatism with small incision lenticule extraction. Journal of refractive surgery 0, 0(): Kamiya K, Shimizu K, Igarashi A, Kobashi H: Visual and refractive outcomes of femtosecond lenticule extraction and small-incision lenticule extraction for myopia. American journal of ophthalmology 0, ():- e.. Alio JL, Muftuoglu O, Ortiz D, Artola A, Perez-Santonja JJ, de Luna GC, Abu-Mustafa SK, Garcia MJ: Ten-year follow-up of photorefractive keratectomy for myopia of more than - diopters. American journal of ophthalmology 00, ():-.. Alio JL, Muftuoglu O, Ortiz D, Artola A, Perez-Santonja JJ, de Luna GC, Abu-Mustafa SK, Garcia MJ: Ten-year follow-up of photorefractive keratectomy for myopia of less than - diopters. American journal of ophthalmology 00, ():-.

17 Page of Sekundo W, Gertnere J, Bertelmann T, Solomatin I: One-year refractive results, contrast sensitivity, high-order aberrations and complications after myopic small-incision lenticule extraction (ReLEx SMILE). Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 0, ():-.. Xu Y, Yang Y: Small-incision lenticule extraction for myopia: results of a -month prospective study. Optometry and vision science : official publication of the American Academy of Optometry 0, ():-.. Zhang J, Wang Y, Wu W, Xu L, Li X, Dou R: Vector analysis of low to moderate astigmatism with small incision lenticule extraction (SMILE): results of a -year follow-up. BMC ophthalmology 0, :.. Pedersen IB, Ivarsen A, Hjortdal J: Three-Year Results of Small Incision Lenticule Extraction for High Myopia: Refractive Outcomes and Aberrations. Journal of refractive surgery 0, ():-.. Kim JR, Kim BK, Mun SJ, Chung YT, Kim HS: One-year outcomes of small-incision lenticule extraction (SMILE): mild to moderate myopia vs. high myopia. BMC ophthalmology 0, :.. El-Naggar MT: Bilateral ectasia after femtosecond laser-assisted small-incision lenticule extraction. Journal of cataract and refractive surgery 0, ():-.. Wang Y, Cui C, Li Z, Tao X, Zhang C, Zhang X, Mu G: Corneal ectasia. months after small-incision lenticule extraction. Journal of cataract and

18 Page of BMJ Open refractive surgery 0, (): Mastropasqua L: Bilateral ectasia after femtosecond laser-assisted small-incision lenticule extraction. Journal of cataract and refractive surgery 0, ():-.. 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 00, (0):-0.. Lohmann CP, Reischl U, Marshall J: Regression and epithelial hyperplasia after myopic photorefractive keratectomy in a human cornea. Journal of cataract and refractive surgery, ():-.. Wu W, Wang Y: The Correlation Analysis between Corneal Biomechanical Properties and the Surgically Induced Corneal High-Order Aberrations after Small Incision Lenticule Extraction and Femtosecond Laser In Situ Keratomileusis. Journal of ophthalmology 0, 0:.

19 Page of Figure Legends Figure The UDVA in the high myopic eyes (A) and the control group (B) after the SMILE surgery, comparisons of the UDVA between the two groups (C). **P<0.0, *P<0.0. UDVA=uncorrected distance visual acuity, SMILE: small incision lenticule extraction Figure. Refractive stability. The plots of the MRSE against time in the high myopia (green line, A), and the control group (blue line, B), comparison of the MRSE between the two groups (C). MRSE: manifest refraction spherical equivalent. The height of the box indicates the upper and lower quartiles. The bars in the box indicate the maximum and minimum range of the results; the error bar in the line chart indicates the standard deviation. **P<0.0, *P<0.0. Figure. The safety index in the high myopic eyes (green line, A) and the control group (blue line, B) at day, week, month,, and months after the SMILE surgery. The height of the box indicates the upper and lower quartiles. The bars in the box indicate the maximum and minimum range of the results. **P<0.0, *P<0.0. Figure. Bar graph showing the percentage of eyes within ±0. D, ±0.0 D, ±.00 D, and±.0 D of the target refraction at day, week, month,, months and year

20 Page of BMJ Open after the SMILE surgery in the high myopic eyes (green bar) and the low to moderate myopic eyes (blue bar). SMILE: small incision lenticule extraction Figure. Predictability: Scatter plot of the absolute value of the attempted MRSE changes plotted against the achieved MRSE changes at year in the high myopic eyes (green circle, A) and the low to moderate myopic eyes (blue circle, B). MRSE: manifest refraction spherical equivalent.

21 Page 0 of Figure The UDVA in the high myopic eyes (A) and the control group (B) after the SMILE surgery, comparisons of the UDVA between the two groups (C). **P<0.0, *P<0.0. UDVA=uncorrected distance visual acuity, SMILE: small incision lenticule extraction xmm (00 x 00 DPI)

22 Page of BMJ Open Figure. Refractive stability. The plots of the MRSE against time in the high myopia (green line, A), and the control group (blue line, B), comparison of the MRSE between the two groups (C). MRSE: manifest refraction spherical equivalent. The height of the box indicates the upper and lower quartiles. The bars in the box indicate the maximum and minimum range of the results; the error bar in the line chart indicates the standard deviation. **P<0.0, *P<0.0. xmm (00 x 00 DPI)

23 Page of Figure. The safety index in the high myopic eyes (green line, A) and the control group (blue line, B) at day, week, month,, and months after the SMILE surgery. The height of the box indicates the upper and lower quartiles. The bars in the box indicate the maximum and minimum range of the results. **P<0.0, *P<0.0. x0mm (00 x 00 DPI)

24 Page of BMJ Open Figure. Bar graph showing the percentage of eyes within ±0. D, ±0.0 D, ±.00 D, and±.0 D of the target refraction at day, week, month,, months and year after the SMILE surgery in the high myopic eyes (green bar) and the low to moderate myopic eyes (blue bar). SMILE: small incision lenticule extraction xmm (00 x 00 DPI)

25 Page of Figure. Predictability: Scatter plot of the absolute value of the attempted MRSE changes plotted against the achieved MRSE changes at year in the high myopic eyes (green circle, A) and the low to moderate myopic eyes (blue circle, B). MRSE: manifest refraction spherical equivalent. xmm (00 x 00 DPI)

26 Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes: retrospective cohort study Journal: BMJ Open Manuscript ID bmjopen-0-00.r Article Type: Research Date Submitted by the Author: -Apr-0 Complete List of Authors: Wu, Wenjing Wang, Yan; Zhang, Hui; Zhang, Jiamei; Li, Hua; Dou, Rui; <b>primary Subject Heading</b>: Ophthalmology Secondary Subject Heading: Ophthalmology Keywords: Cataract and refractive surgery < OPHTHALMOLOGY, Corneal and external diseases < OPHTHALMOLOGY, Ophthalmology < SURGERY

27 Page of BMJ Open Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes: retrospective cohort study Wenjing Wu, Ph.D., Yan Wang, M.D, Ph.D.,Hui Zhang, Ph.D., Jiamei Zhang, M.D. Hua Li, M.D, Rui Dou, M.D, Tianjin Eye Hospital & Eye Institute, Tianjin Ophthalmology and Visual Science Key Laboratory, Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 0000, China Corresponding author: Yan Wang, Professor. Add: No. Gansu Rd, Heping District, Tianjin 0000, China wangyan@vip.sina.com Tel: Fax: -- ext. 0. Mob: 00

28 Page of Abstract Objective: To determine whether the long-term visual outcomes of the SMILE surgery is consistent with the short-term results in the high myopic eyes. Design: Retrospective cohort study of data collected from August, 0, until August, 0. Setting: Single Refractive surgery center. Participants: This study totally enrolled eyes. Sixty-five eyes of subjects ( female / male) in the high myopic group (MRSE -.0D), eyes of subjects ( female/ male) in the control group (MRSE<-.0D). The inclusion criteria were subjects who had follow-ups at day, week, month,, months and year postoperatively together with the manifest refraction, uncorrected and corrected distance visual acuity (UDVA / CDVA). There were no statistically significant differences between the high myopic groups and the control group on the patients gender, age, or cylindrical diopter, preoperatively (P=0., P=0.0, P=0.,respectively). Primary and secondary outcome measures: The UDVA, refractive stability, safety index (the postoperative CDVA / the preoperative CDVA), the predictability (the percentage of eyes within ± 0.0D). Results: In both groups, the long-term ( months postoperatively) UDVA and safety index were significantly better than these results at day (high myopic group: P=0.0, P<0.00; control group: P<0.0, P<0.00), the long-term predictability showed no significant difference with the short-term results (P=.00 in both groups).

29 Page of BMJ Open In high myopic eyes, the long-term MRSE was slightly but significantly worse than the short term result (P=0.0). However, the postoperative MRSE showed no differences from day to year (P=0.) in the control group. Conclusions: The long-term visual outcomes were better than the short-term results after the SMILE surgery in terms of the visual acuity and safety. However, the high myopic eyes suffered from slight regression in long-term, which may be valuable for the adjustment of the nomagram to correct high myopia. Keywords: small incision lenticule extraction; high myopia; long-term; short-term Strengths and limitations of this study Many previous studies investigated the early visual and refractive outcomes of small incision lenticule extraction (SMILE), the long-term observations of the SMILE procedure is far from established. This is a long-term study including the visual recovery, refractive stability, safety and predictability. Moreover, the long-term result of the high myopic eyes, which is a major concern in the prognosis of the patient, has not been well studied. We compared the long-term visual outcomes between high myopic eyes and the low to moderate myopic eyes. We also assessed whether the long-term results are consistent with the short-term results in high myopic eyes. This study did not assess the long-term differences of the myopic eyes after SMILE surgery on the corneal biomechanics, or the high order aberrations. In addition, this study sample is quite small, future studies with larger samples still needed to confirm these results.

30 Page of Short-term and long-term visual outcomes of the small incision lenticule extraction (SMILE) surgery in high myopic eyes: retrospective cohort study Introduction Small incision lenticule extraction (SMILE) is a new keratorefractive procedure to correct myopia and astigmatism.[, ] The short-term clinical results of the SMILE surgery have been quite intensively investigated in the past several years. [-0]A major concern of the SMILE surgery today is the long-term clinical results especially in the high myopic eyes. [, ] Some studies reported the one-year outcomes of the SMILE surgery[-], however, the high myopic eyes were not analyzed separately. Although Hjortdal J and Kim, JR recently published the observations of the SMILE surgery in high myopic eyes,[, ] the long-term studies of the SMILE surgery in the high myopic eyes are far from established. It is still not well explored whether the long-term visual outcomes were consistent with the short-term results in the high myopic eyes after the SMILE surgery. This may be important to answer patients concerns of the regression after SMILE surgery clinically. Hence, this study was performed to investigate the short-term and long-term visual outcomes of the SMILE procedure especially in the high myopic eyes, we not only compared the differences on the refraction, but also on the visual recovery, safety and predictability. Materials and Methods Ethics Statement This study was approved by the Institutional Review Board of Tianjin Eye Hospital

31 Page of BMJ Open and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all patients. Subjects This is a retrospective cohort study. We reviewed the clinical charts of the subjects who underwent the SMILE surgery in the refractive center of Tianjin Eye Hospital from August, 0 to August, 0. The inclusion criteria were subjects who had follow-ups at day, week, month,, months and year postoperatively together with the manifest refraction, uncorrected and corrected distance visual acuity (UDVA / CDVA) examinations. This study totally enrolled myopic eyes. They were divided into two groups according to their preoperative MRSE. eyes of subjects ( female / male) in the high myopic group (MRSE -.0D), eyes of subjects ( female/ male) in the control group (MRSE<-.0D). Theoretically, it is better to compare the visual outcomes among low myopic eyes, moderate myopic eyes and high myopic eyes. But clinically, most of the subjects underwent the corneal refractive surgery had high myopia or moderate myopia. Only a few eyes with low degree of myopia had the surgery. So we put the low myopia and moderate myopia together as the control group. In the high myopic group, the patient s age was.±. years (mean ± SD), ranging from to years ; the preoperative MRSE was -.0±0. D, ranging from.0 to.0 D, the sphere was -.±0. D, ranging from -. D to -. D, and the cylinder was -0.±0. D, ranging from 0.00 to.0 D. In the control group, the patient age was.±. years, ranging from to years. The preoperative MRSE were -.±0. D, ranging from. to

32 Page of D, the sphere was -.±.0 D, ranging from 0 to -.0 D, the cylinder was -0.±0. D, ranging from 0.00 to.d. There were no statistically significant differences between the high myopic groups and the control group on the patients gender, age, or cylindrical diopter, preoperatively, P=0., P=0.0,P=0.,respectively. Surgical Technique The experienced surgeon (Y.W.) performed all the SMILE surgeries. The Visumax femtosecond laser system (Carl Zeiss Meditec AG) with a repletion rate of 00 khz was used for this procedure. The intended cap thickness was 0 µm, the diameter of the optical zone was.0 to. mm. We slightly decreased the optical zone to save more tissue and also to reduce the risk of the keratoectasia in the high myopic eyes with thinner corneal thickness. Meanwhile, the low mesopic pupil sizes of the subjects were all smaller than the optical zones. All side-cut angles were 0 degrees. The target refraction was ±0.D. The surgical procedure was under topical anaesthesia with - drops oxybuprocaine eye drops for minutes (Benoxil, Santen, Inc., Japan). A standard eyelid speculum was used to keep the eye open, the patient eye was positioned under curved contact glass of the femtosecond laser and fixated on a blinking target. The suction was applied when the center of pupil was centered to the contact lenses. The posterior of the refractive lenticule was created from the periphery to the center of the cornea with a 0-degree cordial length vertical edge of the refractive lenticels. The anterior surface of the refractive lenticels was created from the center to the periphery, and at last the small incision was created at the o clock

33 Page of BMJ Open position with the cordial length ranging from to mm. After laser treatment, our patented spatula was used to break the remaining tissue bridges and lose the stromal lenticels, which was then grasped with a pair of forceps and removed. All patients received drop of topical ofloxacin 0.% (Tarivid; Santen, Inc., Osaka, Japan) and drop of diclofenac (Voltaren Ophtha) at the end of the procedure. After that, topical ofloxacin 0.% (Tarivid; Santen, Inc., Osaka, Japan) was applied times daily for days postoperatively, 0.% fluorometholone (Flumetholon; Santen, Inc., Osaka, Japan) were applied times per day for weeks and then tapered over months. Preoperative and postoperative assessments The subjects had eye examinations including the manifest refraction, UDVA, CDVA, history of refractive stability, slit-lamp evaluation, dilated fundoscopy and the corneal topography using a rotating Scheimpflug Camera (Pentacam HR, Oculus, Wetzlar, Germany),preoperatively. The postoperative follow-up was scheduled at day, week, month,, and months postoperatively including the examinations of the manifest refraction, UDVA, and CDVA. The UDVA and CDVA were measured using a standard Snellen visual acuity chart. The qualified readings preoperatively and postoperatively were accepted for statistical analysis. Statistical Analysis Statistical analysis was performed using the SPSS statistical software (ver.0.0, Chicago, USA). The normality of all data samples was checked with the Kolmogorov-Smirnov test. The comparisons between the groups for normally distributed data were made using the Student t test (two-tailed). The Mann-Whitney

34 Page of rank-sum test was used for non-normally distributed data between the two independent groups, the Kruskal Wallis test was used to determine any significant differences among the non-normally distributed multiple groups. Differences were considered to be statistically significant when the P value was less than 0.0. Results Visual Recovery The visual recovery indicates the changes of the uncorrected distance visual acuity (UDVA) with time after the SMILE surgery. The UDVA was 0.±0., 0.±0.,.0±0.,.0±0.,.0±0., 0.±0. in the high myopia group at day, week, month,, and months, postoperatively. The UDVA was 0.±0.,.00 ±0.,.0±0.,.0±0.,.0±0.,.0±0. in the control group at day, week, month,, and months, respectively. There were statistically significant differences of the UDVA in the high myopic eyes from day to year after the SMILE surgery (P=0.00, the Kruskal-Wallis test). The long-term UDVA (one year) was significant better than the result at early stage (day), P=0.0, shown in Figure A. In the low to moderate myopic group, the UDVA was also better at year than at day (P=0.0, Figure B). The Figure C suggested that although the UDVA showed no statistically significance between the high myopic eyes and the control group at day (P=0., the Mann-Whitney Test), week (P=0.), month (P=0.) or months (P=0.), the UDVA was significantly lower in the high myopia group than the control group at and months (P=0.0, P=0.0).

35 Page of BMJ Open Refractive Stability Refractive stability depicts the changes of the MRSE with time after the SMILE surgery. The MRSE was -0.0±0.D,-0.0±0.0D,-0.0±0.D,-0.0±0.D, -0.±0.0D, -0.±0.D in the high myopia group at day, week, month,, and months, postoperatively. The MRSE was -0.0±0.D,-0.0±0.D,-0.0 ±0.D,-0.0±0.D,-0.0±0.D, -0.0±0.D in the control group at day, week, month,, and months, respectively. It showed statistically significant differences from day to year in the high myopia group (P<0.00, the Kruskal-Wallis test), the absolute value of the MRSE was significantly higher at year than the results at day, week, or month, (Figure A, P=0.0, P=0.00, P=0.0 respectively). However, the postoperative MRSE showed no differences from day to year in the control group (P=0., the Kruskal-Wallis test). It stabled within day after surgery, shown in the Figure B. The MRSE was significantly worse in the high myopia group than the control group at year after the SMILE surgery, (P<0.00, the Mann-Withney U test, shown in Figure C). There were no significant differences between the two groups at day, week, month, months or months, P=0., P=0.0, P=0. P=0., P=0.0, respectively. Safety The safety index defined as the postoperative CDVA / the preoperative CDVA. The safety index was in the high myopic group at day, week, month,, and months, postoperatively. The safety index was.0±0.,.0±0.,.0±

36 Page 0 of ,.±0.,.±0.,.±0.. In the control group, the safety index was.0±0.,.0±0.,.0±0.,.±0.,.±0.,.±0. at day, week, month,, and months, respectively. In both of the high myopic group and the control group, there were significant differences of the safety index among the different postoperative times (P<0.00 for the two groups, the Kruskal-Wallis test), shown in Figure. The safety index was significantly better long-term ( months and year) after the SMILE surgery than the early stage ( day) in both groups. There were no significant differences of the safety index between the high myopia group and the control group at day, week, month,, or months (P=0., P=0., P=0., P=0., P=0.0, P=0., respectively, the Mann-Withney U test). Predictability In both groups, the percentages of eyes within ±0.0D showed no significant difference between day and year follow-up (P=.00, Chi-Square Test), Figure. Moreover, the percentage of eyes within ±0.0 D showed no significant differences between the two groups for all follow-up visits ( day: P=.000, week: P=.000, month: P=0.00, months: P=0., months: P=0.0, year: P=0., the Mann-Withney U test). Figure shows the regression line within the plot of the actual correction achieved versus the attempted refractive correction year postoperatively. The regression line for the high myopic eyes (Figure A) could be expressed using the following equation (R =0.), 0

37 Page of BMJ Open Achieved SE (D)=0. Attempted SE (D)+0.D, () The regression line for the low to moderate myopic eyes (Figure B) expressed using the following equation (R =0.), Achieved SE (D)=0. Attempted SE (D)-0.0, () As explained by Equation and and shown in Figure C, the high myopic eyes tend to be under corrected at year after operation. Complications Neither group has the visually threatening complications. No cases of epithelial ingrowth, severe diffuse lamellar keratitis, or keratoectasia were seen at any time during the one -year observation period. Discussion In order to find the visual differences of the SMILE surgery between long-term and short-term in the high myopic eyes, the present study not only investigated the refractive stability from day to year, but also studied the visual recovery, safety and predictability between day and year after the SMILE surgery. Moreover, this study analyzed the high myopic eyes separately and showed that the SMILE surgery could offer as satisfied visual outcomes as in the low to moderate myopic eyes. This may be important clinically and indicate that SMILE surgery could provide as safe outcomes for the high myopic eyes as in the low to moderate myopic eyes even year postoperatively. In addition to the better safety results, the long-term visual acuity was better than the short-term results in the high myopic eyes after the SMILE surgery. The results shows

38 Page of that the SMILE surgery could provide a better visual acuity and safety results year postoperatively both in the high myopia eyes and low to moderate myopic eyes. There were no differences of the safety results between the two groups even after long-term observations. However, it is still important to detect a keratoconus-suspect cornea or a subclinical keratoconus/forme fruste keratoconus as a contraindication to the SMILE surgery for the safety concerns. [-0] In terms of the myopic refraction, the high myopic eyes showed a tendency of slightly regression at months after SMILE procedure, which lead to the slightly worse results than the low to moderate myopic eyes. It may be associated with the thicker refractive lenticule extracted in the high myopic eyes, the smaller optical zone which was originally selected to limit depth of tissue removed in the high myopic eyes with thinner corneal thickness, and the corneal healing responses.[] The epithelial hyperplasia, weak corneal biomechanics are also supposed to be associated with the slightly myopic regression in the high myopic eyes after the SMILE surgery. [, ] It still needs further investigations on the regressions long-term after the SMILE surgery, which may be valuable for the adjustment of the nomagram to correct high myopia. Moreover, some professors suggested that myopic regression is an issue of surface refractive procedures, specifically in high myopias. And it is clinically important to compare the differences among the SMILE surgery, traditional LASIK surgery with the mechanical blade, femto-lasik and PRK surgeries in high myopic eyes, which may be determined in our future studies. In terms of the predictability, the short-term predictability is similar with the

39 Page of BMJ Open long-term results both in the high myopic eyes and the low to moderate myopic eyes. Water Sekundo[] reported % eyes were within ±0.0 D at months after the SMILE surgeries, and it is % in a study by Alper Agca []. Recently, Jae Ryun Kim reported % of the high myopic eyes and.% of the low to moderate myopic eyes were within ±0.0 D one-year after the SMILE surgery.[] Our results were comparable with those published studies and these investigations together suggested that the SMILE procedure showed good predictability in both groups even long-term after operation. There are some limitations in the present study. The present study mainly investigated the differences of the visual outcomes of the SMILE surgery between long-term and short-term. Future studies are needed to determine the differences on the corneal biomechanics, or the high order aberrations. As the optical zone varied with the degree of the myopia and the corneal thickness, it may limit our future studies on the on the corneal biomechanics, and the high order aberrations. In addition, this study sample is quite small, future studies with larger samples still needed to confirm our results. In summary, the long-term visual outcomes were better than the short-term results after the SMILE surgery in terms of the visual acuity and safety. The long-term predictability remained similar with the early stage. However, the high myopic eyes suffered from slight regression in long-term, which may be valuable for the adjustment of the nomagram to correct high myopia.

40 Page of Acknowledgments Grants and financial support: This study was supported by research grants from the National Nature Science Foundation of China (Grant No. 0. to Y.W.) and Tianjin Research Program of Application Foundation and Advanced Technology (JCZDJC00). Author contributions: WWJ performed the study, participated in the design and drafted the manuscript. ZH, ZJM, LH and DR helped to draft the manuscript and performed the statistical analysis. ZH, ZJM, LH and DR conducted the long-term observation and participated in the examination and acquisition of data. WY conceived of the study, participated in the design, revised the manuscript and gave final approval of the version for publication. All authors read and approved the final manuscript. Competing interests: None of the author has a financial or proprietary interest in any material or method mentioned in the manuscript. Data sharing statement: No additional data are available.

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