Efficacy and Safety of Femtosecond Laser-Assisted Cataract Surgery

Efﬁcacy and Safety of Femtosecond Laser-Assisted Cataract Surgery Compared with Manual Cataract Surgery A Meta-Analysis of 14 567 Eyes

Marko Popovic, MD(C),1 Xavier Campos-Möller, MD,2,3 Matthew B. Schlenker, MD,2,3 Iqbal Ike K. Ahmed, MD, FRCSC2,3,4

Topic: To investigate the efficacy and safety of femtosecond laser-assisted cataract surgery (FLACS) relative to manual cataract surgery (MCS). Clinical Relevance: It is unclear whether FLACS is more efficacious and safe relative to MCS. Methods: A literature search of MEDLINE, EMBASE, and Scopus from 2007 to March 2016 was conducted. Studies containing both FLACS and MCS arms that reported on relevant efficacy and/or safety parameters were included. Weighted mean differences (WMDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. Results: From 2802 screened articles, 14 567 eyes from 15 randomized controlled trials and 22 observational cohort studies were included. For primary visual and refractive outcomes, no statistically significant difference was detected between FLACS and MCS in uncorrected distance visual acuity (WMD, 0.02; 95% CI, 0.04 to 0.01; P ¼ 0.19), corrected distance visual acuity (WMD, 0.01; 95% CI, 0.02 to 0.01; P ¼ 0.26), and mean absolute error (WMD, 0.02; 95% CI, 0.07 to 0.04; P ¼ 0.57). In terms of secondary surgical end points, there was a statistically significant difference in favor of FLACS over MCS for effective phacoemulsification time (WMD, 3.03; 95% CI, 3.80 to 2.25; P < 0.001), capsulotomy circularity (WMD, 0.16; 95% CI, 0.11e0.21; P < 0.001), postoperative central corneal thickness (WMD, 6.37; 95% CI, 11.88 to 0.86; P ¼ 0.02), and corneal endothelial cell reduction (WMD, 55.43; 95% CI, 95.18 to 15.69; P ¼ 0.006). There was no statistically significant difference between FLACS and MCS for total surgery time (WMD, 1.25; 95% CI, 0.08 to 2.59; P ¼ 0.07), capsulotomy circularity using a second formula (WMD, 0.05; 95% CI, 0.01 to 0.12; P ¼ 0.10), and corneal endothelial cell count (WMD, 73.39; 95% CI, 6.28 to 153.07; P ¼ 0.07). As well, there was a significantly higher concentration of prostaglandins after FLACS relative to MCS (WMD, 198.34; 95% CI, 129.99e266.69; P < 0.001). Analysis of safety parameters revealed that there were no statistically significant differences in the incidence of overall complications between FLACS and MCS (RR, 2.15; 95% CI, 0.74 to 6.23; P ¼ 0.16); however, posterior capsular tears were significantly more common in FLACS versus MCS (RR, 3.73; 95% CI, 1.50e9.25; P ¼ 0.005). Conclusions: There were no statistically significant differences detected between FLACS and MCS in terms of patient-important visual and refractive outcomes and overall complications. Although FLACS did show a statistically significant difference for several secondary surgical outcomes, it was associated with higher prostaglandin concentrations and higher rates of posterior capsular tears. Ophthalmology 2016;123:2113- 2126 ª 2016 by the American Academy of Ophthalmology.

Supplemental material is available at www.aaojournal.org.

Today, more than 9.5 million cataract surgeries are performed Manual cataract surgery (MCS) involves the creation of each year worldwide.1 Advances in measurement technology, corneal incisions with a keratome blade, a continuous emergence of phacoemulsification, and invention of foldable curvilinear capsulorrhexis using forceps or a cystotome, and lens designs have lead to increasingly safer and more manual splitting or cracking of the nucleus followed by predictable results. These technologies also have allowed phacoemulsification and cortical aspiration. Although the cataract surgery to become a refractive procedure with current standard of care procedure confers a favorable effi- increasingly precise postoperative refractive results.2 cacy and safety profile, complication rates vary by surgeon

2016 by the American Academy of Ophthalmology http://dx.doi.org/10.1016/j.ophtha.2016.07.005 2113 Published by Elsevier Inc. ISSN 0161-6420/16 Ophthalmology Volume 123, Number 10, October 2016 and setting after MCS, suggesting that a more automated performed (Appendix 1AeC, available at www.aaojournal.org). procedure may achieve more reproducible results.3,4 Reference lists of included articles and pertinent reviews also Femtosecond laser-assisted cataract surgery (FLACS) is were searched. a technology that uses a laser to replace several of the manual steps of cataract surgery with the goal of improving Eligibility Criteria accuracy, safety, and refractive outcomes. Femtosecond Studies were included if they met the following criteria: (1) ran- laser-assisted cataract surgery uses a femtosecond laser to domized controlled trials or prospective or retrospective observa- generate free electrons and ionized molecules, which in turn tional cohort studies; (2) studies that included only patients who produce photodisruption and photoionization of optically underwent cataract surgery; (3) studies that provided safety or ef- transparent tissue through an acoustic shock wave.5 The ficacy data, or both, for both FLACS and MCS study arms; and (4) femtosecond laser is unique because of its shorter pulse studies that accrued more than 5 eyes to each study arm. The time relative to other ophthalmic lasers.6 Theoretically, following exclusion criteria were used in the selection of included lasers with shorter pulse times are able to reduce energy studies: (1) nonpublished articles (e.g., abstracts and conference output significantly for a given effect, thereby reducing proceedings); (2) articles not published in English; (3) articles with repeat data; (4) case reports or small (5 eyes per study arm) case collateral damage to ocular tissues. series; and (5) literature reviews, letters to the editor, correspon- Femtosecond lasers have been used in several different dence, notes, editorials, and forthcoming journal articles. Given stages of cataract surgery, including clear corneal incisions, that existing studies in the published literature were used for this capsulotomy, and lens fragmentation. Femtosecond laser- meta-analysis, institutional review board approval was not neces- assisted cataract surgery was approved for cataract surgery sary. Nonetheless, the study adhered fully to the Declaration of by the United States Food and Drug Administration in Helsinki. 2010.7 By 2013, more than 120 000 eyes globally had undergone FLACS.8 A 2014 survey of new FLACS Study Selection, Data Collection, and Outcome adopters in the United States showed that 30% of cataract Measures patients choose FLACS over conventional MCS.9 Two authors (M.P. and X.C.-M.) examined search results to select Given the increasing interest in FLACS, evidence of safety fi fi pertinent articles for inclusion, rst by title and abstract screening and ef cacy of this technology is needed urgently. In 2013, and then by screening full text articles. Uncertainty in inclusion the Department of Veterans Affairs published a systematic was resolved through consultation with a third author (M.B.S.). review in the gray literature that concluded that there was no The same 2 authors (M.P. and X.C.-M.) extracted the following current benefit in the safety and effectiveness of FLACS baseline demographic and clinical data from each study arm: study relative to MCS.10 Furthermore, they noted that there were design, country of origin, femtosecond laser type, date of inter- significant methodologic concerns in the included studies, vention, number of included eyes, mean cohort age, gender dis- including low sample sizes, unclear study methods, few tribution, mean corrected distance visual acuity (CDVA), and mean randomized controlled trials, issues with patient selection, axial length. In addition, a comprehensive list of intraoperative and and financial conflicts of interest. More recently, the first postoperative outcomes were extracted from included studies and published meta-analysis of FLACS compared with MCS were reported using the following headings: was conducted in 2015 by Chen et al.11 Analyzing a total of 1. Primary visual and refractive outcomes: uncorrected dis- 989 eyes and 9 randomized controlled trials, the authors tance visual acuity (UDVA), CDVA, mean absolute error found a statistically significant improvement for FLACS (MAE) of manifest refraction spherical equivalent. fi over MCS in terms of mean phacoemulsification energy 2. Secondary surgical end points, effective phacoemulsi ca- and effective phacoemulsification time; however, there was tion time, surgery time, balanced salt solution volume, cumulative dissipated energy (CDE), circularity of capsu- no difference for surgical complications. There were fl lotomy or capsulorrhexis, capsule opening diameter, con icting results for visual outcomes, central corneal absolute mean deviation from intended capsule diameter, thickness, and endothelial cell count depending on the intraocular lens (IOL) horizontal and vertical decentration, length of follow-up at which outcomes were compared. central corneal thickness, corneal endothelial cell count and An updated and comprehensive meta-analysis of peer- preoperative to postoperative reduction, total prostaglandin reviewed clinical studies comparing FLACS with MCS is concentration, and mean aqueous flare. needed. This synthesis would be useful to clinicians, policy 3. Safety parameters: overall complications, capsular com- makers, and researchers who are interested in identifying the plications, corneal complications, and pupillary role of FLACS. Thus, we performed a meta-analysis to complications. investigate the comparative efficacy and safety of FLACS In the extraction of data, continuous variables were recorded as relative to MCS in published clinical studies. means standard deviations, whereas categorical variables were reported as percentages of the total sample. If any included study provided acceptable measures of variation that could be converted Methods to a standard deviation (e.g., standard error), these data also were extracted. To facilitate the meta-analysis design, complications Search Strategy were grouped by anatomic site (Table 1, available at www.aaojournal.org). Data for all postoperative outcomes were Using Ovid MEDLINE (2007eMarch 2016, week 2), MEDLINE collected at last follow-up. To ensure balance in the average In-Process and Other Non-Indexed Citations (up to March 18, length of follow-up between comparators, outcomes were extracted 2016), EMBASE (2007e2016, week 12), and Scopus from each included study at the same follow-up period for both (2007eMarch 2016), a systematic search of the literature was FLACS and MCS eyes. If outcome data were repeated in 2 or more

2114 Popovic et al Meta-Analysis of FLACS studies, then data from only 1 study were incorporated into the cohort studies. Furthermore, the significantly increased statistical meta-analysis. Microsoft Excel (Microsoft Corporation, Redmond, power achieved by including observational studies in the meta- WA) was used to manage all identified records and to compile analysis may outweigh the bias from confounding, especially for extracted data. safety outcomes, which are underpowered frequently in randomized controlled trials. Given that a previous report found similar Risk of Bias Assessment effect sizes based on meta-analyses that included observational studies when compared with meta-analyses of randomized To perform an assessment of study quality, 2 authors (M.P. and controlled trials, this meta-analysis included both randomized X.C.-M.) independently completed the Newcastle-Ottawa Quality controlled trials and observational cohort studies.14 Review Assessment Scale (NOS) for included observational studies and Manager version 5.3 (The Nordic Cochrane Centre, The used the guidelines set by the Cochrane Collaboration for ran- Cochrane Collaboration, Copenhagen, Denmark) was used for all domized controlled trials (Appendix 2A-B, available at statistical analyses. No protocol amendments were made for this www.aaojournal.org).12,13 The NOS is an 8-item scale that eval- study. uates study quality based on 3 criteria: patient selection, comparability between treatment arms, and outcomes. To differentiate between high and low risk of bias on the follow-up item of the Results NOS, a threshold of 3 weeks of follow-up was set for all outcomes except intraoperative efficacy and safety parameters. In addition, a Study Inclusions and Demographics conservative estimate of 10% was used for the maximum acceptable loss to follow-up. For randomized controlled trials, 7 aspects Two thousand eight hundred and two records underwent title and of quality assessment were performed: sequence generation, allo- abstract screening. After 2716 exclusions, 86 full texts were cation concealment, blinding of participants, personnel, and screened. Overall, 37 articles were included in the meta-analysis outcome assessors, management of incomplete outcome data, with 7127 eyes undergoing FLACS and 7440 eyes undergoing e completeness of outcome reporting, and other potential threats to MCS (Fig 1; Table 2).2,15 50 Mean baseline age ranged from 58.5 validity. Studies were excluded if they had a high or unclear risk of to 75 years in the FLACS cohort and 56.5 to 74.3 years in the MCS bias in all assessment categories. We also evaluated the rate of cohort (n ¼ 25 studies). In the 17 studies reporting on baseline authorship conflicts of interest and reported funding from industry gender distribution, 1890 of 2901 eyes (65.1%) were those of sponsors. Further, we performed a qualitative synthesis on baseline women in the FLACS cohort and 1694 of 3099 eyes (54.7%) were factors that may have impacted refractive outcomes significantly. those of women in the MCS cohort. Fourteen studies reported on baseline cohort axial length. Across these articles, mean axial Data Synthesis and Analysis length ranged from 23.33 to 25.09 mm in the FLACS cohort and from 23.08 to 26.94 mm in the MCS cohort. A complete list of Weighted mean differences were reported for continuous variables baseline demographic and clinical information is provided on with accompanying 95% confidence intervals. For dichotomous Table 3 (available at www.aaojournal.org). variables, risk ratios and 95% confidence intervals were computed. Using a random effects model in all cases, the inverse variance Quality Assessment method was used for continuous data and the Mantel-Haenszel approach was used for dichotomous outcomes. The weighted Most of the included eyes (12 967 eyes [89.0%]) came from mean was defined as P observational studies (22 studies [59.5%]). There were authorship n w x conflicts of interest in 11 of 22 (50.0%) observational studies and X ¼ Pi¼1 i i n w in 12 of 15 (80.0%) included randomized controlled trials. There i¼1 i was direct funding from industry sponsors in 1 of 22 (4.5%) whereas the weighted standard deviation was represented by vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi observational studies and in 2 of 15 (13.3%) randomized controlled uP trials (Table 3, available at www.aaojournal.org). Assessment of u N w ðx x Þ2 sd ¼ t i¼1 i Pi w : study quality revealed that no included studies had a high or w ’ N ðN 1Þ wi i¼1 unclear risk of bias in all assessment categories (Table 4A, B, N’ available at www.aaojournal.org). However, only 2 of 22 (9.1%) In testing for an overall effect, the number of eyes was used as a observational studies and 1 of 15 (6.7%) randomized controlled weighting variable and comparisons that had a P value of less than trials had a low risk of bias in all categories.25,27,49 For random- 0.05 were deemed statistically significant. Statistical heterogeneity ized controlled trials, omissions in the description of randomization was assessed by computing a chi-square statistic; for this test, only (7/15 [46.7%]), allocation concealment (11/15 [73.3%]), blinding a result of P < 0.05 was considered heterogeneous and was re- of participants and personnel (10/15 [66.7%]), and blinding of ported in the text. Additionally, an I2 measure was computed to outcome assessment (12/15 [80.0%]) may have introduced bias investigate the percentage of variance in the meta-analysis that may into the findings. Analysis of observational studies using the NOS be attributed to heterogeneity. Sources of clinical and methodo- revealed that all articles were of either medium or high quality logic heterogeneity across the included studies also were examined because no study was awarded fewer than 5 stars (range, 5e9 and described qualitatively. Meta-analysis was performed for an stars). Here, omissions in comparator comparability, outcome outcome only if there were appropriate data (i.e., percentage for assessment, and completeness of follow-up may have introduced categorical outcome, mean standard deviation or standard error bias in terms of patient selection, group comparability, and for continuous variable) for at least 2 study arms in each outcome assessment. For instance, only 5 of 22 (22.7%) observa- comparator. After study selection, meta-analysis was performed tional studies attempted to demonstrate comparability of cohorts at regardless of study design. One could argue that only randomized baseline and then attempted to adjust for confounding variables controlled trials should be included because of the high internal (Table 4B, available at www.aaojournal.org). In general, these validity of this study design. However, most randomized controlled adjustments were limited by low sample sizes and a lack of trials in the FLACS literature are unmasked and funded by in- important baseline characteristics that are known to influence dustry, and as such show many of the same biases as observational visual and refractive outcomes.

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Figure 1. Flow diagram illustrating the course of Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) guidelines.

It was also found that certain efﬁcacy end points like CDVA, including variability in the steps of FLACS, differences in FLACS effective phacoemulsiﬁcation time, and CDE showed considerable and MCS platforms, surgical technique and equipment, and in- between-study heterogeneity, thus limiting the interpretability of consistencies in measurement techniques, length of follow-up, the overall effect. There were many causes of heterogeneity, patient populations, and study design (Table 2).

Table 2. Baseline Clinical and Demographic Information

Baseline Parameter No. of Eyes (%) No. of Studies (%) Type of FLACS procedure 6390 (100.0) 33 (100.0) CCIs, fragmentation, capsulotomy15,20,21,24,26,31,35,49,50 2415 (37.8) 9 (27.3) Only CCIs, capsulotomy2,16,34,41 357 (5.6) 4 (12.1) Only capsulotomy, fragmentation23,25,27,28,30,33,37,38,40,43,45e48 3273 (51.2) 14 (42.4) Only capsulotomy17e19,22,36,44 345 (5.4) 6 (18.2) Type of FLACS machine 7054 (100.0) 37 (100.0) LenSx (Alcon Inc, Hünenberg, Switzerland)2,16,19e22,24,26,31,34,41,49,50 929 (13.2) 13 (35.1) LENSAR (LENSAR, Inc, Orlando, FL)28,32,41,44,48 321 (4.6) 5 (13.5) Catalys (Abbott Laboratories, Inc, Abbott Park, IL)15,17,18,29,30,33,35,36,38e40,42,45e47 4458 (63.2) 15 (40.5) Victus (Bausch & Lomb, Inc, Bridgewater, NJ)23,25,37,43 1346 (19.1) 4 (10.8) Type of phacoemulsiﬁcation machine 6614 (100.0) 30 (100.0) Accurus (Alcon, Inc)16,19,22,34 153 (2.3) 4 (13.3) Constellation (Alcon, Inc)31,41 60 (0.9) 2 (6.6) Inﬁniti (Alcon, Inc)2,20,21,24,26,28,32,49,50 1953 (29.5) 9 (30.0) Legacy (Alcon, Inc)17 24 (0.4) 1 (3.3) Megatron (Geuder Group, Heidelberg, Germany)15,18,40,42,47 3458 (52.3) 5 (16.7) Stellaris (Bausch & Lomb, Inc)27,30,33,36e38,43,46,48 966 (14.6) 9 (30.0) Last follow-up (mos) 8185 (100.0) 29 (100.0) <137,40,49,50 408 (5.0) 4 (13.8) 1e32,16e18,20,21,23,25e28,33,35,48 4115 (50.3) 14 (48.3) >319,22,31,32,34,36,38,41,42,46,47 3662 (44.7) 11 (37.9)

CCI ¼ clear corneal incision; FLACS ¼ femtosecond laser-assisted cataract surgery.

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Qualitative synthesis revealed that a variety of potential con- Central Corneal Thickness and Endothelial Cell founding factors may have impacted the results. The following Count Reduction factors were not always measured, reported, compared, or adjusted for: clinical parameters (e.g., preoperative vision, refraction, cata- There was a significant difference in favor of FLACS over MCS in ract density), biometry measurements (e.g., differences in axial average central corneal thickness: after surgery, FLACS corneas length, keratometry, anterior chamber depth, lens thickness), and were thinner by an average of 6.37 mm(P ¼ 0.02; Fig 2N). For surgical planning (e.g., type of IOL, approach to astigmatism endothelial cell count, no significant difference was found in the correction). number of postoperative cells per square millimeter for FLACS eyes relative to MCS eyes (P ¼ 0.07; Fig 2O). At the same time, there was a significantly greater reduction of 55.43 Visual and Refractive Outcomes endothelial cells/mm2 for the MCS comparator before versus ¼ To perform a meta-analysis of visual acuity data from varying after surgery (P 0.006; Fig 2P). studies, the formulae provided by Khoshnood et al51 were used to convert from decimal to logarithm of minimum angle of resolution Prostaglandin Concentration and Mean Aqueous visual acuity. There was no statistically significant difference Flare between FLACS and MCS in terms of postoperative UDVA (P ¼ 0.19; heterogeneity, P ¼ 0.004; I2 ¼ 69%; Fig 2A) or Across 2 studies by the same research team, total prostaglandin CDVA (P ¼ 0.26; heterogeneity, P ¼ 0.004; I2 ¼ 66%; Fig 2B). concentration was greater for eyes receiving FLACS relative to fi MCS (P < 0.001; Fig 2Q). In addition, between-study heteroge- The postoperative MAE also was nonsigni cantly different 2 ¼ < neity was noted for this outcome (P < 0.001; I ¼ 96%). For mean between comparator arms (P 0.57; heterogeneity, P 0.001; fl fi I2 ¼ 75%; Fig 2C). aqueous are, meta-analysis revealed a nonsigni cant difference between comparators (P ¼ 0.28; Fig 2R).

Procedure Time and Energy Safety Analysis On average, meta-analysis revealed that effective phacoemulsi- Analysis of the overall incidence of complications showed that fication time was more than 3 seconds longer for MCS eyes there was no statistically significant difference between compara- compared with eyes undergoing FLACS (P < 0.001; Fig 2D); tors (P ¼ 0.16; Fig 3A); however, there was significant however, total surgery time was nonsignificantly different heterogeneity between studies (P < 0.001; I2 ¼ 95%). The same between comparators (P ¼ 0.07; Fig 2E). Both analyses result was maintained for other end points: capsular showed considerable statistical heterogeneity (P < 0.001; I2 ¼ complications except for posterior capsular tears (P ¼ 0.14; 98% and 97%, respectively). There were no significant heterogeneity, P < 0.001; I2 ¼ 88%; Fig 3B), corneal differences between comparators in terms of balanced salt complications (P ¼ 0.27; heterogeneity, P < 0.001; I2 ¼ 85%; solution volume (P ¼ 0.71; Fig 2F) and total CDE (P ¼ 0.21; Fig 3D), and pupillary complications (P ¼ 0.10; heterogeneity, Fig 2G). P ¼ 0.006; I2 ¼ 81%; Fig 3E). Eyes that underwent MCS had a significantly lower incidence of posterior capsular tears when ¼ Capsulotomy and Capsulorrhexis Parameters compared with those that underwent FLACS (P 0.005; Fig 3C).

Depending on the study, circularity of the removed capsule was Discussion measured in 1 of 2 ways: first, as the normalized ratio of the area of the capsule to the area of a hypothetical disc with a diameter equal to the greatest linear dimension of the capsule,17,35 and second, by The purported efficacy and safety benefits of FLACS rela- using the following formula: circularity ¼ 4p(area/perim- tive to MCS are based on its ability to produce more ac- eter2).34,41,45 In both cases, the ratio is equal to 1 for an ideal circle. curate, reproducible capsulotomies and clear corneal Studies using the first formula found that FLACS extracted a incisions, as well as to reduce the ultrasound energy and significantly more circular capsule by 0.16 units (P < 0.001; intraocular manipulation required for lens fragmentation and Fig 2H). However, this result was not detected in studies using the removal.52e57 second formula because there was no significant difference fi ¼ < 2 ¼ From an ef cacy standpoint, we were unable to detect a between comparators (P 0.10; heterogeneity, P 0.001; I difference between MCS and FLACS for UDVA, CDVA, 99%; Fig 2I). There was no statistically significant difference in terms of and MAE. In reviewing the literature, visual and refractive capsule opening diameter between FLACS and MCS study arms outcomes are the most patient-important end points from a (P ¼ 0.40; Fig 2J); however, this end point also exhibited clinical perspective. However, we do note that our analysis significant heterogeneity (P < 0.001; I2 ¼ 80%). Conversely, was limited to the outcomes that were reported. For future analysis of absolute mean deviation from intended diameter research, an editorial by Hoffer et al58 reminds authors to revealed that FLACS produced capsulotomies that were zero the mean arithmetic error for their study populations, significantly closer to the intended diameter (P ¼ 0.007; Fig to compare median not mean absolute errors, to report 2K). Again, this end point showed heterogeneity (P < 0.001; categorical outcomes of patients within reasonable 2 ¼ I 93%). refractive targets, to report manifest refractions only for Intraocular lens decentration was calculated by using the dis- patients with vision of 20/40 or better, to account for tance between the pupillary axis and the IOL center.19,34 The findings were mixed when decentration parameters were consid- correlation between eyes, and to report the instruments ered: FLACS produced significantly more horizontally centered used to obtain various study measurements. Furthermore, IOLs by an average of 128.84 mm(P < 0.001; Fig 2L); however, we welcome novel studies addressing other measures of vertical decentration was nonsignificantly different between visual quality, including higher-order aberrations, contrast comparators (P ¼ 0.90; Fig 2M). sensitivity, and dysphotopsia. For instance, Mihaltz et al22

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Figure 2. Meta-analysis of the efficacy of femtosecond laser-assisted cataract surgery compared with manual cataract surgery. A, Uncorrected distance visual acuity (logarithm of the minimum angle of resolution [logMAR]). B, Corrected distance visual acuity (logMAR). C, Mean absolute error of manifest refraction spherical equivalent. D, Effective phacoemulsification time. E, Total surgery time. F, Balanced salt solution volume. G, Cumulative dissipated energy. H, Circularity using formula 1. I, Circularity using formula 2. J, Capsule opening diameter. K, Absolute mean deviation from intended capsule diameter. L, Horizontal decentration. M, Vertical decentration. N, Central corneal thickness. O, Corneal endothelial cell count. P, Corneal endothelial cell loss. Q, Total prostaglandin concentration. R, Mean aqueous flare. CI ¼ confidence interval; FLACS ¼ femtosecond laser-assisted cataract surgery; IV ¼ inverse variance; MCS ¼ manual cataract surgery; Random ¼ random effects model; SD ¼ standard deviation. found some evidence that the Strehl ratio and modulation which does not apply to the FLACS capsulotomy.59 Further, transfer function were higher in eyes undergoing FLACS FLACS capsulotomies may not be uniform between patients; relative to MCS. Dick et al60 demonstrated an age-dependent variability in Mixed results were found when examining the ability of capsulotomy size with pediatric FLACS procedures. FLACS to produce more circular capsulotomies. Given the 2 Our meta-analysis also showed that IOLs implanted in definitions that currently exist, it is recommended that future FLACS patients had significantly better horizontal centra- studies standardize the definition of circularity to facilitate tion, presumably because of a more centered and circular better interstudy comparison. When comparing mean devia- capsulotomy. Previous authors have asserted that FLACS tion from the intended diameter, FLACS produced capsu- delivers greater accuracy and precision of the capsulotomy, lotomies that were significantly closer to the intended which may make for a more predictable effective lens posi- diameter relative to MCS. This difference may be attributed tion, thus improving visual and refractive outcomes.53 to variability in surgical technique and the effect of corneal Theoretically, capsule overlap throughout the entire magnification when performing manual capsulorrhexis, circumference of the IOL optic may prevent pea-podding,

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Figure 2. (continued). reducing the risk of myopic shift or astigmatism resulting the pupil. Ideally, the visual axis should be used for from anterior optic displacement and tilt.61e63 Although centration, which can be performed with MCS by using Reddy et al37 found that capsulorrhexis centration was corneal markers that take advantage of Purkinje images to improved signiﬁcantly for FLACS eyes relative to MCS center the capsulorrhexis on the visual axis. In addition, the eyes, so far it is only possible to center the capsulotomy on notion of circularity and centration materially affecting

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Figure 2. (continued). refractive outcomes is still being debated. For instance, in an difference resulting from a consistent capsulotomy. observational study, Okada et al64 did not detect a significant Furthermore, complete capsuleeoptic overlap also has correlation between either circularity or centration with target been shown to reduce the rate of posterior capsular spherical equivalent and cylinder 1 month and 1 year after opacification and dysphotopsia.62,65,66 However, only 1 surgery. Nonsignificant findings in refractive outcomes published study has investigated differences in the rate of may be attributable to numerous sources of error posterior capsular opacification between FLACS and in refractive predictability, including preoperative MCS.48 We encourage future research in this area. measurement, choice of IOL formula, and methods used Although average surgical time was nonsignificantly for prediction error assessment, which could hide any true different between comparators, FLACS produced a shorter

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Figure 3. Meta-analysis of the safety of femtosecond laser-assisted cataract surgery compared with manual cataract surgery. A, Overall incidence of complications. B, Incidence of capsular complications excluding posterior capsular tears. C, Incidence of posterior capsular tears. D, Incidence of corneal complications. E, Incidence of pupillary complications. CI ¼ confidence interval; FLACS ¼ femtosecond laser-assisted cataract surgery; IV ¼ inverse variance; M-H ¼ Mantel-Haenszel approach; MCS ¼ manual cataract surgery; Random ¼ random effects model; SD ¼ standard deviation. *For the Chen et al article, the outlier data from surgeon 5 was excluded. effective phacoemulsification time, which signifies a lower The meta-analysis demonstrated that there was a statis- total amount of energy delivered to the eye.33 Between tically significant difference in favor of FLACS over MCS in studies, differences in surgical equipment, surgeon skill, surgery-induced corneal endothelial cell loss. However, it is patient selection, and definitions of terms may have led to uncertain whether this mean difference of 55.43 cells/mm2 significant heterogeneity in the total procedure time and carries any clinical significance. For instance, this difference effective phacoemulsification time outcomes. At the same may be attributed to instrument bias, given the poor time, the pooled treatment effect of studies reporting on repeatability of specular microscopy. Notwithstanding, cor- CDE showed no significant difference between FLACS and neas were significantly thinner in the early postoperative MCS (Fig 2G). The contradictory results between effective period in patients undergoing FLACS, which may suggest phacoemulsification time and CDE could be explained by less surgically-induced corneal stress. Studies evaluating methodologic variation in the included studies, by corneal endothelial changes after femtosecond LASIK sug- differences in surgical techniques, or by the differential gest that this procedure is safe for the endothelium.68e70 In number of included studies, which may have introduced contrast, a study by Abell et al42 found that eyes undergoing reporting bias into the findings. Another confounding factor FLACS with laser-automated corneal incisions had a greater is between-study variability in energy delivery parameters, endothelial cell loss at 6 months than eyes undergoing which affects the calculation for CDE differently. Specif- FLACS, but with manual corneal incisions (P < 0.001); eyes ically, the formula for calculating CDE assigns only 40% of with 0 effective phacoemulsification time (EPT) and manual the actual torsional effective phacoemulsification time to the incisions had the least endothelial cell loss (P < 0.001). sum, whereas the effective phacoemulsification time for Differences in findings between studies comparing femto- longitudinal ultrasound remains the same.67 second LASIK and FLACS may be explained by the deeper

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Figure 3. (continued).

energy penetration at the level of the endothelium when analysis, 2802 articles).11 Our broader screening strategy performing clear corneal incisions compared with LASIK led to the inclusion of 6 additional randomized controlled flaps.71 trials. These randomized controlled trials, in addition to The safety analysis showed no significant differences be- the inclusion of 22 observational studies, led to an tween FLACS and MCS for overall, capsular, pupillary, and increase in sample size from 989 to 14 567. Our design corneal complications. However, there was a significantly also included additional outcomes not reported previously: greater incidence of posterior capsular tears after FLACS mean absolute error, total surgery time, balanced salt relative to MCS. Given that many of the included studies were solution volume, capsule opening diameter, absolute mean published early after the introduction of FLACS, the surgeon deviation from intended diameter, decentration, total learning curve may have influenced these results. Nonethe- prostaglandin concentration, mean aqueous flare, and less, posterior capsular tears are associated with complica- various complication parameters. tions like retinal detachment, endophthalmitis, and cystoid Beyond efficacy and safety, the cost effectiveness of macular edema. Beyond the evaluated outcomes, there are FLACS is an important consideration that is not addressed also complications unique to femtosecond lasers that have in the present meta-analysis. In their comparative cost- been noted in past case reports, including interface corneal effectiveness analysis of FLACS and MCS, Abell and stromal irregularities, corneal perforation, and incomplete Vote76 reviewed complication rates in the literature. In their laser-assisted capsulotomy and fragmentation resulting from hypothetical cohort of patients between 6 months to 1 year silicone oil in the anterior chamber.72e75 Based on the liter- after cataract surgery, there was a quality-adjusted life-year ature to date, the overall safety profile of FLACS is unfa- gain of 0.06 units for FLACS compared with MCS. How- vorable relative to MCS. However, this result may change as ever, this equated to a cost per quality-adjusted life-year of the femtosecond laser technology and surgeon skill with $102 691, which was not viewed as cost effective. FLACS continues to evolve. Recently, the updated European Registry of Quality Femtosecond laser-assisted cataract surgery was shown Outcomes for Cataract and Refractive Surgery (EUREQUO) to be associated with a significantly greater concentration of case control data concerning the efficacy and safety of intraocular prostaglandins relative to MCS (P < 0.001).29,39 FLACS was presented (Barry P. ESCRS femto laser assisted Schultz et al39 note that, despite the significant cataract surgery (FLACS): case control study. Paper pre- concentrations of prostaglandins synthesized by the iris sented at: 33rd Congress of the ESCRS, September 5e9, and ciliary body, the specific location of prostaglandin 2015; Barcelona). Although the study remains unpublished, release currently is uncertain. They hypothesize that the it is notable for reporting on a large number of eyes (2814 microplasma of gas and water generated by the focused vs. 4987 eyes after FLACS and MCS, respectively) derived FLACS laser spot may trigger the release of from a registry-based database. Their findings corroborate prostaglandins. Prostaglandins have been shown to be the results of the current meta-analysis: higher complication associated with inflammation-induced miosis and may be rates (3.4% vs. 2.3%) and a similar proportion of eyes with a causative factor in the development of cystoid macular an improvement in CDVA (86.0% vs. 89.3%) after FLACS edema and uveitis after cataract surgery.39 relative to MCS. We look forward to the publication of their Comparing the present analysis with the only previous results. meta-analysis in the published literature, we found that the This meta-analysis is the most comprehensive review of previous study screened only 297 articles (present meta- the published literature investigating the efficacy and safety

2122 Popovic et al Meta-Analysis of FLACS of FLACS relative to MCS. As such, the analysis benefits for certain parameters like CDE, capsule opening diameter, from a large sample size (n ¼ 14 567) and a high number of and vertical IOL centration, whereas there was a statistically published studies (n ¼ 37). Further, all included studies significant difference in favor of FLACS for effective contained an MCS arm; based on descriptive statistics, phacoemulsification time, absolute mean deviation from preoperative parameters were comparable between the intended capsule diameter, horizontal IOL centration, and FLACS and MCS cohorts. postoperative central corneal thickness. There was a sig- Despite these advantages, the study is subject to certain nificant difference in favor of MCS in terms of prosta- limitations. In terms of limitations related to the study de- glandin concentration. Safety analysis revealed that FLACS signs of extracted articles, many observational studies were and MCS were nonsignificantly different in the incidence of included (22 of 37 studies [59.5%]; 12 967 of 14 567 eyes overall, capsular, corneal, and pupillary complications; [89.0%]). This may have introduced confounding by indi- however, there was a significant difference in favor of MCS cation, information bias, and selection bias into the findings. over FLACS in the incidence of posterior capsular tears. In Adjusted effect estimates could not be extracted because of general, it is important to consider the clinical significance the limitations in the reporting of individual observational of the measured differences when interpreting these studies, which may have introduced confounding. However, findings. one may hypothesize that the combination of confounding There may be certain clinical scenarios, such as cases in and information bias would skew the results in favor of which a manual capsulorrhexis is harder to perform (e.g., FLACS, a finding that largely was not present in this meta- subluxated lens), in which FLACS may have specific ad- analysis. We found that 15 of 37 (40.5%) included studies vantages.78 Furthermore, there may be applications and disclosed that at least some patients contributed 2 eyes to the modifications of the IOL technology in the future that individual analysis. Of these 15, only 8 (53.3%) noted that may favor FLACS over MCS. Because of the continual patients who contributed 2 eyes were treated independently. evolution of the femtosecond laser technology, it is likely The other 7 (46.7%) studies should have taken into account that there will be continued head-to-head comparisons be- that there is some within-patient correlation between eyes of tween these 2 techniques. We await this evidence and the same patient. For our visual outcome analysis, we re- recommend that a subsequent re-evaluation be performed ported data as they were analyzed in the existing literature, after a significant number of well-designed randomized tri- understanding the limitations of this parametric analysis.77 als are introduced into the literature. Through this process, We encourage future studies to provide broader detail on the authors hope a more definitive conclusion can be their visual outcomes and to consider using clinically reached regarding the role of femtosecond lasers in cataract significant cutoffs in their reporting.58 In terms of surgery. limitations related to the selection of included studies, this meta-analysis considered only published data to ensure Acknowledgments. The authors thank Austin Pereira, Michelle that the rigors of peer review were met for each included Efrosman, and Thomas Berk for their collaboration. article. We recognize that a consequence of this approach is the potential for publication bias (i.e., not including un- References published negative studies). Also, there might have been language bias because the meta-analysis considered only 1. Foster A. Vision 2020: the cataract challenge. Community Eye studies published in English. Finally, in terms of limitations Health 2000;13:17–9. related to variability in clinical reporting, it was difficult to 2. Bali SJ, Hodge C, Lawless M, et al. Early experience with the control for different technologies and surgeon experience femtosecond laser for cataract surgery. Ophthalmology because of a large between-study variance and lack of 2012;119:891–9. reporting of these parameters. There was significant vari- 3. Cullen KA, Hall MJ, Golosinskiy A. Ambulatory Surgery in ability in the duration of reported follow-up in the included the United States, 2006. Hyattsville, MD: National Center for studies; as such, we used the last available follow-up for Health Statistics; 2009:11. analysis of postoperative outcomes. This decision was 4. Bell CM, Hatch WV, Cernat G, Urbach DR. Surgeon volumes 46 and selected patient outcomes in cataract surgery. Ophthal- supported by the work of Conrad-Hengerer et al, who – fi mology 2007;114:405 10. showed that there was no signi cant change in the mean 5. Soong HK, Malta JB. Femtosecond lasers in ophthalmology. refractive spherical equivalent between 1 week and 1 Am J Ophthalmol 2009;147:189–97. month after FLACS and between 1, 2, 3, and 6 months 6. He L, Sheehy K, Culbertson W. Femtosecond laser-assisted after either FLACS or MCS. Our results also showed that cataract surgery. Curr Opin Ophthalmol 2011;22:43–52. there was significant heterogeneity across numerous 7. Baig NB, Cheng GPM, Lam JKM, et al. Intraocular pressure outcomes and that the effect sizes of certain end points profiles during femtosecond laser-assisted cataract surgery. (e.g., corneal thickness) were smaller than the known J Cataract Refract Surg 2014;40:1784–9. variability in the accuracy of measurement. 8. Chen S. Advances in cataract surgery. Available at: http:// In summary, this meta-analysis found that there were no www.optometry.org.au/media/585285/1.9_sat_advances_in_ fi cataract_surgery_chen.pdf. Accessed July 19, 2015. signi cant differences between FLACS and MCS in terms 9. Berdahl JP, Jensen MP. The business of refractive laser of key postoperative visual and refractive outcomes, spe- assisted cataract surgery (ReLACS). Curr Opin Ophthalmol cifically UDVA, CDVA, and MAE. There were mixed re- 2014;25:62–70. sults regarding secondary surgical end points, in which a 10. Quinones A, Gleitsmann K, Freeman M, et al. Benefits and nonsignificant difference between comparators was found harms of femtosecond laser assisted cataract surgery: a

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systematic review. Portland, OR: Evidence-Based Synthesis 28. Krarup T, Holm LM, la Cour M, Kjaerbo H. Endothelial cell Program Center; 2013:1–48. VA-ESP Project no. 05e225. loss and refractive predictability in femtosecond laser-assisted 11. Chen X, Xiao W, Ye S, et al. Efficacy and safety of femto- cataract surgery compared with conventional cataract surgery. second laser-assisted cataract surgery versus conventional Acta Ophthalmol 2014;92:617–22. phacoemulsification for cataract: a meta-analysis of random- 29. Schultz T, Joachim SC, Stellbogen M, Dick HB. Prostaglandin ized controlled trials. Sci Rep 2015;5:13123. release during femtosecond laser-assisted cataract surgery: 12. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa main inducer. J Refract Surg 2015;31:78–81. Scale (NOS) for assessing the quality of nonrandomised studies 30. Conrad-Hengerer I, Schultz T, Jones JJ, et al. Cortex removal in meta-analyses. Available at: http://www.ohri.ca/programs/ after laser cataract surgery and standard phacoemulsification: a clinical_epidemiology/oxford.asp. Accessed July 9, 2015. critical analysis of 800 consecutive cases. J Refract Surg 13. Higgins JP, Green S, eds. Cochrane Handbook for Systematic 2014;30:516–20. Reviews of Interventions. Version 5.1.0. London: Cochrane 31. Mastropasqua L, Toto L, Mastropasqua A, et al. Femtosecond Collaboration; 2011. laser versus manual clear corneal incision in cataract surgery. 14. Shrier I, Boivin JF, Steele RJ, et al. Should meta-analyses of J Refract Surg 2014;30:27–33. interventions include observational studies in addition to ran- 32. Chang JSM, Chen IN, Chan WM, et al. Initial evaluation of a domized controlled trials? A critical examination of underlying femtosecond laser system in cataract surgery. J Cataract principles. Am J Epidemiol 2007;166:1203–9. Refract Surg 2014;40:29–36. 15. Abell RG, Darian-Smith E, Kan JB, et al. Femtosecond laser- 33. Conrad-Hengerer I, Hengerer FH, Schultz T, Dick HB. Effect of assisted cataract surgery versus standard phacoemulsification femtosecond laser fragmentation on effective phacoemulsifica- cataract surgery: outcomes and safety in more than 4000 tion time in cataract surgery. J Refract Surg 2012;28:879–83. cases at a single center. J Cataract Refract Surg 2015;41: 34. Kranitz K, Takacs A, Mihaltz K, et al. Femtosecond laser 47–52. capsulotomy and manual continuous curvilinear capsulorrhexis 16. Filkorn T, Kovacs I, Takacs A, et al. Comparison of IOL parameters and their effects on intraocular lens centration. power calculation and refractive outcome after laser refractive J Refract Surg 2011;27:558–63. cataract surgery with a femtosecond laser versus conventional 35. Palanker DV, Blumenkranz MS, Andersen D, et al. Femto- phacoemulsification. J Refract Surg 2012;28:540–4. second laser-assisted cataract surgery with integrated optical 17. Friedman NJ, Palanker DV, Schuele G, et al. Femtosecond coherence tomography. Sci Transl Med 2010;2:58ra85. laser capsulotomy. J Cataract Refract Surg 2011;37:1189–98. 36. Conrad-Hengerer I, Hengerer FH, Al Juburi M, et al. Femto- 18. Abell RG, Allen PL, Vote BJ. Anterior chamber flare after second laser-induced macular changes and anterior segment femtosecond laser-assisted cataract surgery. J Cataract Refract inflammation in cataract surgery. J Refract Surg 2014;30:222–6. Surg 2013;39:1321–6. 37. Reddy KP, Kandulla J, Auffarth GU. Effectiveness and safety 19. Kranitz K, Mihaltz K, Sandor GL, et al. Intraocular lens tilt of femtosecond laser-assisted lens fragmentation and anterior and decentration measured by Scheimpflug camera following capsulotomy versus the manual technique in cataract surgery. manual or femtosecond laser-created continuous circular cap- J Cataract Refract Surg 2013;39:1297–306. sulotomy. J Refract Surg 2012;28:259–63. 38. Schargus M, Suckert N, Schultz T, et al. Femtosecond laser- 20. 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Optical coherence cataract surgery. J Refract Surg 2011;27:711–6. tomography and 3-dimensional confocal structured imaging 23. Khandekar R, Behrens A, Towerki AEA, et al. Determinants system-guided femtosecond laser capsulotomy versus manual of visual outcomes in femtosecond laser assisted cataract continuous curvilinear capsulorrhexis. J Cataract Refract Surg surgery and phacoemulsification: a nested case control study. 2014;40:2035–43. Middle East Afr J Ophthalmol 2015;22:356–61. 42. Abell RG, Kerr NM, Howie AR, et al. Effect of femtosecond 24. Chen M, Swinney C, Chen M. Comparing the intraoperative laser-assisted cataract surgery on the corneal endothelium. complication rate of femtosecond laser-assisted cataract sur- J Cataract Refract Surg 2014;40:1777–83. gery to traditional phacoemulsification. Int J Ophthalmol 43. Daya SM, Nanavaty MA, Espinosa-Lagana MM. Trans- 2015;8:201–3. leticular hydrodissection, lens fragmentation, and influence on 25. Chee SP, Yang Y, Ti SE. Clinical outcomes in the first two ultrasound power in femtosecond laser-assisted cataract sur- years of femtosecond laser-assisted cataract surgery. Am J gery and refractive lens exchange. J Cataract Refract Surg Ophthalmol 2015;159:714–9. 2014;40:37–43. 26. Takacs AI, Kovacs I, Mihaltz K, et al. Central corneal volume 44. Tackman RN, Kuri JV, Nichamin LD, Edwards K. Anterior and endothelial cell count following femtosecond laser- capsulotomy with an ultrashort-pulse laser. J Cataract Refract assisted refractive cataract surgery compared to conventional Surg 2011;37:819–24. phacoemulsification. J Refract Surg 2012;28:387–91. 45. Schultz T, Joachim SC, Tischoff I, Dick HB. Histologic 27. Conrad-Hengerer I, Al Juburi M, Schultz T, et al. Corneal evaluation of in vivo femtosecond laser-generated capsuloto- endothelial cell loss and corneal thickness in conventional mies reveals a potential cause for radial capsular tears. 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Footnotes and Financial Disclosures

Originally received: March 21, 2016. 2 Department of Ophthalmology and Vision Sciences, University of Tor- Final revision: June 15, 2016. onto, Toronto, Canada. Accepted: July 1, 2016. 3 Prism Eye Institute, Mississauga, Canada. Available online: August 15, 2016. Manuscript no. 2016-573. 4 1 Department of Ophthalmology, Trillium Health Partners, Mississauga, Faculty of Medicine, University of Toronto, Toronto, Canada. Canada.

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Presented at: American Society of Cataract and Refractive Surgery/Amer- Overall responsibility: Popovic, Campos-Möller, Schlenker, Ahmed ican Society of Ophthalmic Administrators Symposium & Congress, May Abbreviations and Acronyms: 2016, New Orleans, Louisiana; and Canadian Ophthalmological Society CCI ¼ clear corneal incision; CDE ¼ cumulative dissipated energy; Annual Meeting & Exhibition, June 2016, Ottawa, Canada. CDVA ¼ corrected distance visual acuity; CI ¼ conﬁdence interval; Financial Disclosure(s): EUREQUO ¼ European Registry of Quality Outcomes for Cataract and The author(s) have made the following disclosure(s): I.I.K.A.: Financial Refractive Surgery; FLACS ¼ femtosecond laser-assisted cataract surgery; support e Alcon (Fort Worth, TX); Abbott Medical Optics (Santa Ana, IOL ¼ intraocular lens; IOP ¼ intraocular pressure; logMAR ¼ logarithm CA); Bausch & Lomb, Inc (Rochester, NY); Carl Zeiss AG (Oberkochen, of the minimum angle of resolution; MAE ¼ mean absolute error; Germany). MCS ¼ manual cataract surgery; NOS ¼ Newcastle-Ottawa Quality Author Contributions: Assessment Scale; RR ¼ relative risk; UDVA ¼ uncorrected distance visual acuity; WMD ¼ weighted mean difference. Conception and design: Popovic, Campos-Möller, Ahmed Correspondence: Analysis and interpretation: Popovic, Campos-Möller, Schlenker, Ahmed Iqbal Ike K. Ahmed, MD, FRCSC, Prism Eye Institute, 3200 Erin Mills Data collection: Popovic, Campos-Möller, Schlenker, Ahmed Parkway, Unit 1, Mississauga, Ontario L5L 1W8, Canada. E-mail: ike. Obtained funding: none [email protected].

Pictures & Perspectives

Merkel Cell Carcinoma of the Eyelid An 81-year-old immunocompetent man presented with a 5-week history of a rapidly growing left upper eyelid lesion (Fig 1, arrow). Eight years prior, he had a Merkel cell carcinoma (MCC) of the left cheek that was treated with repeat wide local excision, limited neck dissection with negative sentinel lymph nodes, and postoperative radiation therapy. Histopathology revealed small blue cells (Fig 2), numerous mitotic ﬁgures, large oval nuclei, prominent nucleoli, and salt and pepper dense chromatin (Fig 3). Merkel cell carcinoma of the eyelids display an aggressive clinical course with a high rate of local recurrence (14%), regional lymph node invasion (20%), and metastasis (5%).

MEISHA L. RAVEN,DO PAUL D. SELID,MD MARK J. LUCARELLI,MD Department of Ophthalmology, University of Wisconsin e Madison, Madison, Wisconsin

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