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JAMA Otolaryngology–Head & Neck Surgery | Original Investigation

Powering the Gracilis for Facial Reanimation A Systematic Review and Meta-analysis of Outcomes Based on Donor Nerve

Peter M. Vila, MD, MSPH; Dorina Kallogjeri, MD, MPH; Lauren H. Yaeger, MA, MLIS; John J. Chi, MD, MPHS

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IMPORTANCE Free gracilis transfer for dynamic reanimation in chronic facial paralysis is the gold standard, but there remains a need to better understand outcomes with respect to the donor nerve. OBJECTIVE To characterize outcomes in adults undergoing primary gracilis transfer for facial paralysis stratified by donor nerve used for neurotization. DATA SOURCES Search strategies were used in Ovid MEDLINE (1946-2019), Embase (1947-2019), Scopus (1823-2019), Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (1997-2019). STUDY SELECTION Inclusion and exclusion criteria were designed to capture studies in adults with unilateral chronic facial paralysis undergoing single-paddle free gracilis transfer. All study types were included except case reports. Abstracts and full texts were reviewed in duplicate. Of 130 unique citations, 10 studies including 295 patients were included after applying inclusion and exclusion criteria. Data were analyzed between November 2018 and December 2019. DATA EXTRACTION AND SYNTHESIS PRISMA guidelines were followed. The Newcastle-Ottawa scale was used to assess study quality, and the Cochrane Risk of Bias tool was used to assess risk of bias. Independent extraction by 2 authors (P.M.V. and J.J.C.) was performed. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Owing to heterogeneity in reporting of facial reanimation outcomes, we first performed a systematic review, and then compiled available outcomes for meta-analysis. Outcomes studied for meta-analysis were oral commissure excursion and facial symmetry. RESULTS Meta-analysis of masseteric nerve (MN) (n = 56) vs cross-facial nerve graft (CFNG) (n = 52) in 3 retrospective studies showed no statistical heterogeneity between these studies ( I 2 = 0%), and the standardized mean difference (SMD) was greater for MN (0.55; 95% CI, 0.17 to 0.94). Meta-analysis of angles of symmetry in 2 retrospective studies comparing MN (n = 51) to CFNG (n = 47) both at rest (−0.22; 95% CI, −0.63 to 0.18) and with smiling (−0.14; 95% CI, −0.73 to 0.46) were better with MN, though the difference was not statistically significant. CONCLUSIONS AND RELEVANCE Owing to heterogeneity in reported outcomes from facial reanimation, we were unable to make definitive conclusions regarding the optimal donor nerve. Establishing a reporting standard at peer-reviewed journals to improve results reporting is one method to allow for improved collaboration in the future. Standardizing follow-up times, assessing spontaneity in an objective and reproducible fashion, and use of consistent outcome measures would allow for future meta-analyses and better understanding of options for facial reanimation.

Author Affiliations: Department of Otolaryngology–Head & Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri (Vila, Kallogjeri); Bernard Becker Medical Library, Washington University School of Medicine in St Louis, St Louis, Missouri (Yaeger); Division of Facial Plastic & Reconstructive Surgery, Department of Otolaryngology–Head & Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri (Chi). Corresponding Author: John J. Chi, MD, MPHS, Barnes-Jewish West County Hospital, 1020 N Mason Rd, Medical Building 3, Ste 205, St Louis, MO 63141 (johnchi@wustl.edu).

JAMA Otolaryngol Head Neck Surg . 2020;146(5):429-436. doi:10.1001/jamaoto.2020.0065 Published online March 26, 2020.

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F acial paralysis is a devastating condition with a cas cade of downstream effects, including negative effects on quality of life. 1 The resulting disfigurement greatly impacts patients by adversely affecting their social interac tions, leading to anxiety, depression, social avoidance, and so cial isolation, primarily owing to the inability to express emotion. 2 In themodern era, an increasingly common option for dynamic lower facial reanimation in chronic facial paraly sis is free gracilis muscle transfer. Since its initial description by Harii et al 3 in 1976 using the deep temporal nerve to power the transplantedmuscle, various donor nerves have been pro posed, including a cross-facial nerve graft (CFNG), 4 hypoglos sal or spinal accessory nerves, 5 masseteric nerve (MN), 6 and most recently, using both the masseteric and a CFNG. 7 Recommendations fromexperienced centers regarding the optimal donor nervehavebeenmixed. Somehave reported that older patients do not have as good of a result with a CFNG, 8 but the use of the CFNG may lead to better spontaneity of smile. 9 There is some evidence that excursion may be better with the MN, presumably because the axon count is higher compared with a CFNG, which requires 2 neurroraphies. 10,11 Others have recommended using both a CFNG and the MN to provide both spontaneity and excursion. 12-14 Despite calls to standardize assessment of postoperative outcomes to allow better comparison between studies using validatedmeasures, however, results continue to be reported in a heterogenous fashionwithmany different outcomemea sures used. 15,16 Recent additions such as the FACEgram software, 17 the FaCE instrument, 18 and the FACIAL CLIMA system 19 areobjective, validated instruments, but because they are relatively new, they have not seen widespread use. There remains a need to better understand outcomes such as excur sion, symmetry, and spontaneity of smile with respect to the various donor nerves available. With this inmind, we performed a systematic review and meta-analysis of outcomes fromgracilismuscle transfer for fa cial reanimation in adults, with attention to the donor nerve. The question guiding this studywas: in adults undergoing pri mary gracilis transfer for facial paralysis, what are the out comes stratified by the donor nerve used for neurotization? Methods This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for System atic Reviews and Meta-Analyses (PRISMA) guidelines. 20 This study was exempt from our university institutional review boardbecause it useddata frompublished literature. Datawere analyzed between November 2018 and December 2019. Search Strategy and Study Selection No review protocol was published for this study. Using the PICOS (Population, Intervention, Comparator, Outcome, Study design) framework for this systematic review, the population of interest was adults aged 18 years or older with chronic fa cial paralysis, the interventionwas free gracilis transfer for fa cial reanimation, the comparatorwas the nerve(s) used to neu

rotize the gracilis, the outcomewas themeasure used to report postoperative results, and the study designwas all study types except case reports. A medical librarian created search strategies for the con cepts of facial paralysis, gracilis muscle transfer, and facial reanimation in multiple electronic databases including Ovid MEDLINE (1946-2019), Embase (1947-2019), Scopus (1823-2019), Cochrane Central Register of Controlled Trials (CENTRAL), andClinicalTrials.gov (1997-2019). All search strat egies were completed November 8, 2018, and resulted in 116 unique citations. An updated literature search was com pleted on December 23, 2019, and identified 14 additional unique citations. Fully reproducible search strategies for each database can be found in eTable 1 in the Supplement. Ab stracts and full texts were reviewed independently in dupli cate (P.M.V. and J.J.C.), and disagreements were resolved by consensus. At the abstract review stage, we excluded studies for the following reasons: (1) reviewarticle and not original re search, (2) did not use the gracilis flap for reanimation, (3) pe diatric study, (4) duplicate publication, (5) cadaver study, (6) revision surgery, (7) bilateral facial paralysis, (8) used a double paddle gracilis flap, and (9) non-English language. At the full text review stage, we excluded studies for the follow ing reasons: (1) pediatric studies, (2) did not report objective outcome measures, (3) revision surgery, (4) full text was not available, (5) did not separate adult and pediatric data, (6) case report, (7) duplicate publication, (8) incomplete paralysis, and (9) review article ( Figure 1 ). Studies that did not report objec tive outcome measures were excluded owing to the inherent heterogeneity in reporting the result. Data Extraction and Quality Assessment The primary outcomes of interestwere the postoperative smile outcomes reported in the study, and the nerve(s) used to neu rotize the gracilis free flap. Study design, location, and length of follow-up were also assessed. If data were not available in the published article, authors were contacted via e-mail. A modified version of the Cochrane Collaboration’s Risk of Bias Tool was used. 21 Because none of the included studies were randomized clinical trials, the domains specific to random ized trials (sequence generation, allocation concealment) were marked as not applicable. The Newcastle-Ottawa scale 22 was Key Points Question In adults undergoing primary gracilis transfer for facial paralysis, what are the outcomes, stratified by donor nerve used for neurotization? Findings In this systematic review and meta-analysis, we found that use of the masseteric nerve may be associated with improved oral commissure excursion compared with the cross-facial nerve graft, but many incompatible outcomes were reported in the included studies. Meaning The masseteric nerve may be associated with the best excursion in facial reanimation with gracilis free transfer, but reporting of results from facial reanimation surgery must be standardized.

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used to assess study quality, graded independently by 2 authors (P.M.V. and J.J.C.).

Figure 1. Flow Diagram of Studies Through Systematic Review

116 Abstracts identified through computerized and manual search on November 8, 2018

Statistical Analysis Descriptive statisticswere used for studies included in the sys tematic review that were unable to be summarized in meta analysis owing toheterogeneityof outcomemeasures. Random effectsmeta-analyseswere performed toquantifymean excur sionandsymmetrywithsmilingandat restwiththeMNvsCFNG instudies thatusedtheFACEgram. Theeffect sizewas calculated usingthestandardizedmeandifferences incentimeters.All analy ses were performed in Stata statistical software (version 14.1, StataCorp) andMicrosoft Excel (version 15.2, Microsoft). Results The search strategy resulted in 130 unique citations. After ap plying inclusion and exclusion criteria, 10 studies were in cluded in our systematic review (Figure 1). The Table describes the characteristics of the included studies. Eight were retrospective cohort studies, and 2 were case series. The studies came from all over the world, includ ing Italy, Germany, Spain, Taiwan, South Korea, Japan, Bos ton, Massachusetts, and Baltimore, Maryland. Eight studies scored 8 of 9 on the Newcastle-Ottawa scale, and 2 studies scored 7 of 9 on the scale, indicating all studies were of good quality. All studies lost a point in the comparability category because there were no controls and the studies were all retro spective, and 2 studies 13,24 lost another point in the selection category due to including both flaccid and nonflaccid paraly sis patients in their study. Follow-up time ranged from 6 months for patients reanimated with MN, and 12 months for CFNG, to over 40months. One study 23 did not explicitly state length of follow-up. Six studies 7,12,23,25,26,28 were rated as hav ing an unclear risk of bias, 2 studies 11,27 had a low risk of bias, and 1 study 24 had a high risk of bias. The only study 24 with a high risk of bias was rated as such because the outcome as sessment was unblinded and relied entirely on assessment from the surgeon. Because the data used in themeta-analysis came from studies with either low or unclear risk of bias, we do not believe the risk of bias is sufficient to affect the inter pretation of the results (eTable 2 in the Supplement). Excursion and Symmetry All 10 studies examined excursion and symmetry as an out comemeasure. Reportedmeasures included the distance from themidline lower lip to the oral commissure as calculatedwith FACEgram 17 software (4 studies 11,25-27 ); Terzis and Noah grade, 29 a combined aesthetic and functional scale ranging from 1 (poor) to 5 (excellent) based on standard photographic analysis by an observer (4 studies 7,24,26,28 ); FACIAL CLIMA, 10 an automated measurement software program based on in frared photographic analysis (1 study 12 ); distance between the tragionandoral commissureon lateral photography (1 study 10 ); and the Sunnybrook Facial Grading System, 30 a validated scor ing systemused to evaluate symmetry at rest andwithmove ment, as well as synkinesis (1 study 25 ).

116 Abstracts screened

74 Abstracts excluded 23 Review articles

12 Duplicate publications 5 Cadaver studies 4 Revision surgery 3 Bilateral facial paralysis 1 Double paddle gracilis 1 Not English language 13 Did not use gracilis 12 Pediatric studies

42 Full texts screened

33 Full texts excluded 12 Pediatric studies

3 Full text not available 3 Did not separate pediatric and adult data 1 Case report 7 Did not report objective outcome measures 4 Revision surgery

1 Duplicate publication 1 Incomplete paralysis 1 Not original research study

9 Studies included in review, search repeated December 23, 2019

14 Additional full texts screened

13 Full texts excluded 4 Did not separate pediatric and adult data

2 Duplicate data 2 Nonhuman studies

1 Not original research study 1 Case report

10 Studies included in review

3 Studies included in meta-analysis

Because 4 studies 11,25-27 reported outcomes using the FACEgram, we chose to use thismeasure formeta-analysis. Of the 4 studies reporting results, only FACEgram results for MN and CFNG were reported. Unfortunately, 1 study 26 reported combined results for patientswhounderwent eitherMNorMN combined with the CFNG, and was thus excluded from the meta-analysis. Thus, meta-analysis of MN (n = 56) vs CFNG (n = 52) showed no heterogeneity between the 3 studies 11,25,27 ( I 2 = 0%), and excursionwas greaterwith themasseteric nerve (0.55 mm; 95% CI, 0.17-0.94) ( Figure 2 ). Angles of symmetry were only reported in 2 of these studies, 11,25 and thus a meta analysis was performed for these 2 studies with MN (n = 51) vs CFNG (n = 47). Heterogeneitywas low( I 2 = 37.5%at rest, 0% with smiling). Angles of symmetry at rest (−0.14; 95%CI, −0.73 to 0.46) and with smiling (−0.22; 95% CI, −0.62 to 0.18) were better with MN, though the differences were not statistically significant ( Figure 3 ).

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Table. Summary of Studies Reporting Outcomes for Gracilis Muscle Transfer a

Reported Postoperative Outcome Measures Excursion and Symmetry Spontaneity

Newcastle Ottawa

Score (of 9)

Length of Follow-up 9 mo for MN; 18 mo for CFNG

Study Design Location

No. of Stages

Mean Age, y

Other

Source Bhama et al, 11 2014 Biglioli et al, 7 2012 Biglioli et al, 7 2012 Braig et al, 23 2017

Donor Nerve

Retro spective cohort

Boston, Massachusetts

66 MN; 52 CFNG; 6 MN + CFNG; 1 ipsilateral VII

Single for MN; double for CFNG

35.0 FACEgram NA

NA

8

NA

18 mo

8

Case series

Milan, Italy

4 MN + CFNG Single

49.4 Terzis and Noah Grade

Recorded movement during funny movie Recorded movement during funny movie

NA

12 mo

8

Single

42.3 Terzis and Noah Grade

Milan, Italy

10 MN; 40 latissimus (excluded)

Retro spective cohort Retro spective cohort Retro spective cohort Retro spective cohort Retro spective cohort Retro spective cohort Retro spective cohort

NA

Revision rate

20 mo

8

36.2 Tragion

Freiburg, Germany

14 MN; 8 CFNG Single for MN; double for CFNG

commissure distance

NA

>40 mo

8

Hontanilla et al, 12 2016

Single

43.6 FACIAL CLIMA

Questionnaire, funny home video

Pamplona, Spain

36 MN; 30 contralateral MN transfer (excluded) 18 dominant VII branch

Lin et al, 24 2011

Taoyuan, Taiwan

Single

43

Terzis and Noah Grade

NA

NA

>24 mo

7

8

NA

FaCE survey

<6 mo for MN; 12-18 mo for CFNG

37.8 FACEgram, Sunnybrook Facial Grading Scale 46.6 FACEgram, Terzis and Noah Grade

Boston, Massachusetts

8 MN; 12 CFNG Single for MN; double for CFNG

Lindsay et al, 25 2014

Oh et al, 26 2019

NA

NA

15 mo

8

Single for both

Seoul, South Korea

3 MN; 7 MN + CFNG (combined both groups in results) 5 MN; 6 CFNG; 3 MN + CFNG; 14

43.5 FACEgram NA

Revision rate

Not stated 8

Oyer et al, 27 2018 Uehara et al, 13 2018

Single for MN; double for CFNG

Baltimore, Maryland

temporalis (excluded)

Physician observation

CMAP >12 mo

7

Case series

Oita, Japan

6 MN + CFNG Single

56.7 Oral

commissure excursion, angle measurement

Abbreviations: CFNG, cross-facial nerve graft; CMAP, compound motor unit action potential; MN, masseteric nerve; NA, not applicable. a Discrepancies in reported numbers of patients in each group due to patients being excluded from analysis.

Figure 2. Meta-analysis of Studies Assessing Oral Commissure Excursion After Reanimation With Gracilis Powered by Cross-Facial Nerve Graft vs Masseteric Nerve

Favors Cross Facial Nerve

Favors Masseteric Nerve

Weight, %

Study

SMD (95% CI)

Bhama et al, 11 2014

0.68 (0.22 to 1.14)

71.62

Lindsay et al, 25 2014

0.34 (–0.56 to 1.24)

18.57

Oyer et al, 27 2018

0.05 (–1.19 to 1.29)

9.82

Overall a

0.55 (0.17 to 0.94)

100

–2

–1

SMD (95% CI) 0

1

2

SMD indicates standardized mean difference.

to fill out a questionnaire to determine whether they ob served spontaneous smiling. One study 13 did not use any objective measures, and reported the results of physician observation during follow-up visits. Two retrospective studies 12,28 found that 1 of 10 (10%) and 20of 36 patients (56%)

Spontaneity Four studies 7,12,13,28 including 56 patients examined the rate of achieving a spontaneous smile. Three studies 11,25,28 showed patients a funny movie, and observed them for spontaneity, graded as yes vs no. One study 12 also asked family members

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Figure 3. Meta-analysis of Studies Assessing Facial Symmetry

Favors Cross Facial Nerve

Favors Masseteric Nerve

At rest A

Weight, %

Study

SMD (95% CI)

Bhama et al, 11 2014

0.07 (–0.38 to 0.51)

69.25

Lindsay et al, 25 2014

–0.59 (–1.51 to 0.32)

30.75

Overall a

–0.14 (–0.73 to 0.46)

100

–2

–1

SMD (95% CI) 0

1

2

Favors Cross Facial Nerve

Favors Masseteric Nerve

Smiling B

Weight, %

Study

SMD (95% CI)

Lindsay et al, 25 2014 Bhama et al, 11 2014

–0.13 (–0.58 to 0.32)

80.81

–0.61 (–1.53 to 0.31)

19.19

SMD indicates standardized mean difference. Studies of smile (A) at rest and (B) while smiling after reanimation with gracilis powered by cross-facial nerve graft vs masseteric nerve.

Overall a

–0.22 (–0.62 to 0.18)

100

–2

–1

SMD (95% CI) 0

1

2

fromtheFACEgram. Thoughwewereunable toperformameta analysis onstudies reporting results onsmile spontaneityowing toheterogeneity in reportedoutcomemeasures, 100%of the 10 patients included in this systematic reviewachieved spontane itywithmassetericnerveplusCFNG,whereas fewer thanhalf of the46patientswhounderwentmassetericnervealoneachieved spontaneity.Roughlyonequarterofpatientsunderwent thinning of the flap postoperatively in the 2 studies 24,27 that reported re vision rates. Given that our study includedcase series and retro spective cohort studies, this constitutes level 3a evidence. 32 The 3 major categories of outcome measures reported in the included studies were excursion, symmetry, and sponta neity. Unfortunately, despite calls to standardize reporting of results after facial reanimation surgery, there continue to be disparate outcomemeasures reported in the literature. Otolo gists faced a similar problem in the reporting of hearing out comes after surgery, limiting the ability to perform meta analyses on published data. They addressed that barrier by creating aminimumreporting standard, put forth by theHear ing Committee of the American Academy of Otolaryngology– Head and Neck Surgery, and recommended that researchers publish results inwhatever format they desired, as long as the minimum standard was included. 33 This reporting standard was subsequently endorsed by other major peer-reviewed journals, 34 but not without generating some controversy from the American Academy of Audiology, for example. 35 This was followed by the proposal of a reporting standard formiddle ear implants, 36 suggesting that researchers are benefiting from a minimum reporting standard. A reporting standard has also beenmentioned as amethod to improve the transparency and quality of published research. 37 An analogous standard could be developed for reporting outcomes of facial reanimation sur gery, to allow for better collaboration andmeta-analysis of fu ture studies. This reporting standard could include agreed-on measures of these 3 categories—excursion, symmetry, and spontaneity.

achieved spontaneity with the masseteric nerve. In 2 case series 7,13 including 4 and 6 patientswithmasseteric nerve plus CFNG, 4of 4 (100%) and6of 6patients (100%) achieveda spon taneous smile. Additional Outcome Measures Four studies examined other outcome measures. These mea sures included secondary revision rates for thinning of the gracilis for flap bulkiness (2 studies 24,27 ); the FaCE scale, 31 a validated patient-reported outcome measure focused on fa cial impairment and disability (1 study 14 ); and the compound motor action potential (CMAP), an electromyographic mea sure that allows for quantitative assessment ofmuscle strength (1 study 12 ). Though several studies excluded patients who un derwent secondary revisionof thegracilis flap, the2 studies 23,27 that did report cited a rate ranging from 23% to 29%. Postop erative thinning of the flap, while decreasing excursion, may help improve symmetry in patients with excessive pull. Of the 7 studies 7,11,13,23,24,27,28 that reported flap survival, 213 of 218 flaps survived (97.7%). One study 27 reported 2 infections in 14 flaps, 1 in the face, and 1 in the donor site. Discussion Thissystematicreviewandmeta-analysis included295adultsun dergoing freegracilismuscle transfer for facial reanimation from 10studiesdone around theworld. It is encouraging that all stud ies included in this systematic reviewandmeta-analysiswereof high quality. Unfortunately, the meta-analysis was limited ow ing to the heterogeneity of reporting, whichprecluded our abil ity tomake definitive conclusions regarding the optimal choice ofdonornerve.However, ourmeta-analysisof 3studieswith108 patients showed that excursionmaybe superiorwithmasseteric nerve comparedwithCFNG. Symmetrywas not found tobedif ferent between the2groups in the2 studies reporting angledata

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Consistent with prior studies, our results support the use of themasseteric nerve and CFNG together, rather than either alone, as the best option for neurotizing the gracilis flap for fa cial reanimation in adults. Several experienced facial reani mation surgeons have postulated that achieving spontaneity is only likely with use of the CFNG. 9,27,38,39 Unfortunately, as noted in the past by several independent groups, the limita tion of CFNG may be the decreased axon count that reaches the transplantedmuscle aftermultiple anastomoses. 40,41 Thus, the added robust axonal input from themasseteric nervemay help augment the excursion beyond what the CFNG can achieve alone. 10,11,41,42 Though the mechanism for this phe nomenon is not known, the previously described “babysit ter” procedure is one possible explanation. 43 Aswith the origi nally described “minihypoglossal” graft during the first stage of a CFNG, themasseteric nervemay serve this purpose by pro viding neural input while the CFNG is maturing. Though our meta-analysis was limited to the masseteric nerve and CFNG, there is some compelling evidence that the masseteric nerve may be the best nonfacial nerve to use for this purpose. Researchers have theorized that, owing to the proximity of the smile and jaw-clenching areas of control in the premotor and primary motor area, it may be easier for pa tients to achieve spontaneity after reinnervationwith themas seteric nerve. 44,45 In addition, there is normal activation of the masseteric nerve during smiling, 46 which further supports the case for the masseteric nerve because this is the gesture used to trigger a smile by patients after reanimationwith this nerve. Opportunities for Future Research It is clear from our systematic review that spontaneity is the most heterogeneously reported measure in facial reanima tion. Unfortunately, noexistingpatient-reportedoutcomemea sure addresses this specific issue of standardizing how spon taneity is measured. A standard protocol for measuring spontaneity postoperatively would likely require a video as sessment with independent, blinded raters, and would re quire a patient to fall within a defined upper limit for the amount of time allowed to elapse after exposure to a smile stimulus to be called spontaneous. Hadlock’s group has pro posed a smile spontaneity assay to address this problem, and recently showed that the correlation between the assay and clinician-graded spontaneity was unfortunately quite low (R = 0.35). 47,48

A related issue is that of preoperative patient factors such as age and severity of paralysis. Though facial reanimation sur geons would likely agree that younger age is a positive prog nostic factor for subsequent spontaneity, and a nonflaccid pa ralysis will likely have a better result than a flaccid paralysis owing to better postoperative resting tone, neither of these fac tors are well-controlled for in published studies. As reporting standards improve over time, we expect that the impact of age, flaccidity, and other patient factors will become better under stood in a more quantitative fashion. Limitations Despite a thorough systematic search, our study is some what limited in that there were a small number of donor nerve options to use for our meta-analysis, which precluded our ability to make definitive conclusions. Unfortunately, we were limited to previously published studies, which do not capture all the possible donor nerves that have been used in facial reanimation with alternative techniques. For example, others have obtained successful outcomes with a hypoglos sal nerve transfer. 9,49,50 Because those studies did not use a gracilis free flap, however, they were excluded from this study. In addition, our meta-analyses were largely driven by the study by Bhama et al 11 because it was the largest of the included studies. Furthermore, all of the studies included in our meta-analyses were done in the United States at 1 of 2 centers. Though this does limit the generalizability of our findings, this helps to highlight the need for compatible out come measures and improved results reporting in facial reanimation. Conclusions Owing to the heterogeneity in reported outcomes from facial reanimation, we were unable to make definitive conclusions regarding the optimal donor nerve for this purpose. Establish ing a reporting standard at peer reviewed journals to improve results reporting is onemethod to allow for improved collabo ration in the future. Standardizing follow-up times, assessing spontaneity in an objective and reproducible fashion, and use of consistent outcomemeasures would allow for futuremeta analyses and better understanding of options for facial reani mation for this challenging patient population.

2 . Bradbury ET, Simons W, Sanders R. Psychological and social factors in reconstructive surgery for hemi-facial palsy. J Plast Reconstr Aesthet Surg . 2006;59(3):272-278. doi:10.1016/j.bjps.2005.09. 003 3 . Harii K, Ohmori K, Torii S. Free gracilis muscle transplantation, with microneurovascular anastomoses for the treatment of facial paralysis. a preliminary report. Plast Reconstr Surg . 1976;57 (2):133-143. doi:10.1097/00006534-197602000 00001 4 . O’Brien BM, Franklin JD, Morrison WA. Cross-facial nerve grafts and microneurovascular free muscle transfer for long established facial

ARTICLE INFORMATION Accepted for Publication: January 10, 2020.

Statistical analysis: Vila, Kallogjeri. Administrative, technical, or material support: Chi. Study supervision: Vila, Chi. Conflict of Interest Disclosures: Dr Kallogjeri reported grants from Potentia Metrics outside the submitted work. No other disclosures were reported. REFERENCES 1 . Nellis JC, Ishii M, Byrne PJ, Boahene KDO, Dey JK, Ishii LE. Association among facial paralysis, depression, and quality of life in facial plastic surgery patients. JAMA Facial Plast Surg . 2017;19(3): 190-196. doi:10.1001/jamafacial.2016.1462

Published Online: March 26, 2020. doi:10.1001/jamaoto.2020.0065

Author Contributions: Drs Vila and Chi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Vila, Chi. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Vila, Chi. Critical revision of the manuscript for important intellectual content: Vila, Kallogjeri, Yaeger .

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Powering the Gracilis for Facial Reanimation

reanimation. Arch Facial Plast Surg . 2012;14(4):277 282. doi:10.1001/archfacial.2012.111 18 . Bhama P, Gliklich RE, Weinberg JS, Hadlock TA, Lindsay RW. Optimizing total facial nerve patient management for effective clinical outcomes research. JAMA Facial Plast Surg . 2014;16(1):9-14. three-dimensional quantitative analysis for evaluation of facial movement. J Plast Reconstr Aesthet Surg . 2008;61(1):18-30. doi:10.1016/j.bjps. 2007.03.037 20 . Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med . 2009;151(4):264-269, W64. 21 . Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2011; Version 5.1.0:http://handbook.cochrane.org. Accessed February 22, 2016. 22 . Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2009; http://www.ohri.ca/programs/clinical_ epidemiology/oxford.asp. Accessed February 22, 2016. 23 . Braig D, Bannasch H, Stark GB, Eisenhardt SU. Analysis of the ideal muscle weight of gracilis muscle transplants for facial reanimation surgery with regard to the donor nerve and outcome. J Plast Reconstr Aesthet Surg . 2017;70(4):459-468. doi:10.1016/j.bjps.2016.12.005 24 . Lin CH, Wallace C, Liao CT. Functioning free gracilis myocutaneous flap transfer provides a reliable single-stage facial reconstruction and reanimation following tumor ablation. Plast Reconstr Surg . 2011;128(3):687-696. doi:10.1097/ PRS.0b013e318221db14 25 . Lindsay RW, Bhama P, Weinberg J, Hadlock TA. The success of free gracilis muscle transfer to restore smile in patients with nonflaccid facial paralysis. Ann Plast Surg . 2014;73(2):177-182. doi:10.1097/SAP.0b013e3182a0df04 26 . Oh TS, Kim HB, Choi JW, Jeong WS. Facial reanimation with masseter nerve-innervated free gracilis muscle transfer in established facial palsy patients. Arch Plast Surg . 2019;46(2):122-128. doi: 10.5999/aps.2018.00717 27 . Oyer SL, Nellis J, Ishii LE, Boahene KD, Byrne PJ. Comparison of objective outcomes in dynamic lower facial reanimation with temporalis tendon and gracilis free muscle transfer. JAMA Otolaryngol Head Neck Surg . 2018;144(12):1162-1168. doi:10.1001/jamaoto.2018.1964 28 . Biglioli F, Colombo V, Tarabbia F, et al. Recovery of emotional smiling function in free-flap facial reanimation. J Oral Maxillofac Surg . 2012;70(10): 2413-2418. 29 . Terzis JK, Noah ME. Analysis of 100 cases of free-muscle transplantation for facial paralysis. Plast Reconstr Surg . 1997;99(7):1905-1921. doi:10.1097/00006534-199706000-00016 30 . Coulson SE, Croxson GR, Adams RD, O’Dwyer NJ. Reliability of the “Sydney,” “Sunnybrook,” and “House Brackmann” facial grading systems to assess voluntary movement and synkinesis after facial nerve paralysis. Otolaryngol Head Neck Surg . doi:10.1001/jamafacial.2013.1382 19 . Hontanilla B, Aubá C. Automatic

2005;132(4):543-549. doi:10.1016/j.otohns.2005.01. 027 31 . Kahn JB, Gliklich RE, Boyev KP, Stewart MG, Metson RB, McKenna MJ. Validation of a patient-graded instrument for facial nerve paralysis: the FaCE scale. Laryngoscope . 2001;111(3):387-398. doi:10.1097/00005537-200103000-00005 32 . OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. 2011. http://www.cebm.net/index.aspx?o=5653. Accessed March 20, 2015. 33 . Gurgel RK, Jackler RK, Dobie RA, Popelka GR. A new standardized format for reporting hearing outcome in clinical trials. Otolaryngol Head Neck Surg . 2012;147(5):803-807. doi:10.1177/ 0194599812458401 34 . Welling DB, Stewart MG. Minimal reporting standard for reporting hearing outcomes. Laryngoscope . 2013;123(2):303. doi:10.1002/lary. 23858 35 . Carlson DL. American Academy of Audiology response to Gurgel et al. Otolaryngol Head Neck Surg . 2013;149(2):349-350. doi:10.1177/ 0194599813491706 36 . Maier H, Baumann U, Baumgartner WD, et al. Minimal reporting standards for active middle ear hearing implants. Audiol Neurootol . 2018;23(2):105 115. doi:10.1159/000490878 37 . Munafò MR, Nosek BA, Bishop DVM, et al. A manifesto for reproducible science. Nature Human Behaviour . 2017;1:0021. 38 . Faria JC, Scopel GP, Busnardo FF, Ferreira MC. Nerve sources for facial reanimation with muscle transplant in patients with unilateral facial palsy: clinical analysis of 3 techniques. Ann Plast Surg . 2007;59(1):87-91. doi:10.1097/01.sap.0000252042. 58200.c3 39 . Terzis JK, Olivares FS. Long-term outcomes of free-muscle transfer for smile restoration in adults. Plast Reconstr Surg . 2009;123(3):877-888. doi:10.1097/PRS.0b013e31819ba316 40 . Rayment R, Poole MD, Rushworth G. Cross-facial nerve transplants: why are spontaneous smiles not restored? Br J Plast Surg . 1987;40(6):592-597. doi:10.1016/0007-1226(87) 90153-6 41 . Snyder-Warwick AK, Fattah AY, Zive L, Halliday W, Borschel GH, Zuker RM. The degree of facial movement following microvascular muscle transfer in pediatric facial reanimation depends on donor motor nerve axonal density. Plast Reconstr Surg . 2015;135(2):370e-381e. doi:10.1097/PRS. 0000000000000860 42 . Okazaki M, Kentaro T, Noriko U, et al. One-stage dual latissimus dorsi muscle flap transfer with a pair of vascular anastomoses and double nerve suturing for long-standing facial paralysis. J Plast Reconstr Aesthet Surg . 2015;68(6):e113-e119. doi:10.1016/j.bjps.2015.02.013 43 . Terzis JK, Tzafetta K. “Babysitter” procedure with concomitant muscle transfer in facial paralysis. Plast Reconstr Surg . 2009;124(4):1142-1156. doi:10.1097/PRS.0b013e3181b2b8bc 44 . Buendia J, Loayza FR, Luis EO, Celorrio M, Pastor MA, Hontanilla B. Functional and anatomical basis for brain plasticity in facial palsy rehabilitation using the masseteric nerve. J Plast Reconstr Aesthet Surg . 2016;69(3):417-426. doi:10.1016/j.bjps.2015. 10.033

palsy. Br J Plast Surg . 1980;33(2):202-215. doi:10.1016/0007-1226(80)90013-2 5 . Terzis JK, Noah EM. Dynamic restoration in Möbius and Möbius-like patients. Plast Reconstr Surg . 2003;111(1):40-55. doi:10.1097/00006534 200301000-00007 6 . Singham J, Manktelow R, Zuker RM. Möbius syndrome. Semin Plast Surg . 2004;18(1):39-46. doi:10.1055/s-2004-823122 7 . Biglioli F, Colombo V, Tarabbia F, et al. Double innervation in free-flap surgery for long-standing facial paralysis. J Plast Reconstr Aesthet Surg . 2012; 65(10):1343-1349. doi:10.1016/j.bjps.2012.04.030 8 . Gur E, Stahl S, Barnea Y, et al. Comprehensive approach in surgical reconstruction of facial nerve paralysis: a 10-year perspective. J Reconstr Microsurg . 2010;26(3):171-180. doi:10.1055/s-0029-1242139 9 . Gousheh J, Arasteh E. Treatment of facial paralysis: dynamic reanimation of spontaneous facial expression-apropos of 655 patients. Plast Reconstr Surg . 2011;128(6):693e-703e. doi:10.1097/ PRS.0b013e318230c58f 10 . Hontanilla B, Marre D, Cabello A. Facial reanimation with gracilis muscle transfer neurotized to cross-facial nerve graft versus masseteric nerve: a comparative study using the FACIAL CLIMA evaluating system. Plast Reconstr Surg . 2013;131(6):1241-1252. doi:10.1097/PRS. 0b013e31828bd4da 11 . Bhama PK, Weinberg JS, Lindsay RW, Hohman MH, Cheney ML, Hadlock TA. Objective outcomes analysis following microvascular gracilis transfer for facial reanimation: a review of 10 years’ experience. JAMA Facial Plast Surg . 2014;16(2):85-92. doi:10.1001/jamafacial.2013.2463 12 . Hontanilla B, Cabello A. Spontaneity of smile after facial paralysis rehabilitation when using a non-facial donor nerve. J Craniomaxillofac Surg . 2016;44(9):1305-1309. doi:10.1016/j.jcms.2016.06. 031 13 . Uehara M, Shimizu F. The distal stump of the intramuscular motor branch of the obturator nerve is useful for the reconstruction of long-standing facial paralysis using a double-powered free gracilis muscle flap transfer. J Craniofac Surg . 2018;29(2): 476-481. doi:10.1097/SCS.0000000000004064 14 . Watanabe Y, Akizuki T, Ozawa T, Yoshimura K, Agawa K, Ota T. Dual innervation method using one-stage reconstruction with free latissimus dorsi muscle transfer for re-animation of established facial paralysis: simultaneous reinnervation of the ipsilateral masseter motor nerve and the contralateral facial nerve to improve the quality of smile and emotional facial expressions. J Plast Reconstr Aesthet Surg . 2009;62(12):1589-1597. doi:10.1016/j.bjps.2008.07.025 15 . Niziol R, Henry FP, Leckenby JI, Grobbelaar AO. Is there an ideal outcome scoring system for facial reanimation surgery? A review of current methods and suggestions for future publications. J Plast Reconstr Aesthet Surg . 2015;68(4):447-456. doi:10.1016/j.bjps.2014.12.015 16 . Hadlock T. Standard outcome measures in facial paralysis: getting on the same page. JAMA Facial Plast Surg . 2016;18(2):85-86. doi:10.1001/ jamafacial.2015.2095 17 . Hadlock TA, Urban LS. Toward a universal, automated facial measurement tool in facial

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Research Original Investigation

Powering the Gracilis for Facial Reanimation

47 . Iacolucci CM, Banks C, Jowett N, et al. Development and validation of a spontaneous smile assay. JAMA Facial Plast Surg . 2015;17(3):191-196. doi:10.1001/jamafacial.2015.0083 48 . Dusseldorp JR, van Veen MM, Guarin DL, Quatela O, Jowett N, Hadlock TA. Spontaneity assessment in dually innervated gracilis smile reanimation surgery. JAMA Facial Plast Surg . 2019; 1-7. doi:10.1001/jamafacial.2019.1090 49 . Hontanilla B, Marré D. Comparison of hemihypoglossal nerve versus masseteric nerve

45 . Garmi R, Labbé D, Coskun O, Compère JF, Bénateau H. Lengthening temporalis myoplasty and brain plasticity: a functional magnetic resonance imaging study. Ann Chir Plast Esthet . 2013;58(4): 271-276. doi:10.1016/j.anplas.2013.03.002 46 . Schaverien M, Moran G, Stewart K, Addison P. Activation of the masseter muscle during normal smile production and the implications for dynamic reanimation surgery for facial paralysis. J Plast Reconstr Aesthet Surg . 2011;64(12):1585-1588. doi:10.1016/j.bjps.2011.07.012

transpositions in the rehabilitation of short-term facial paralysis using the Facial Clima evaluating system. Plast Reconstr Surg . 2012;130(5):662e-672e. doi:10.1097/PRS.0b013e318267d5e8 50 . Kochhar A, Albathi M, Sharon JD, Ishii LE, Byrne P, Boahene KD. Transposition of the intratemporal facial to hypoglossal nerve for reanimation of the paralyzed face: the VII to XII transposition technique. JAMA Facial Plast Surg . 2016;18(5):370-378. doi:10.1001/jamafacial.2016. 0514

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Facial Plastic Surgery & Aesthetic Medicine Volume 24, Number 4, 2022 ª American Academy of Facial Plastic and Reconstructive Surgery, Inc. DOI: 10.1089/fpsam.2021.0207

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ORIGINAL INVESTIGATION

Facial Nerve

The Tinel Sign and Myelinated Axons in the Cross-Face Nerve Graft: Predictors of Smile Reanimation Outcome for Free Gracilis Muscle Transfer? Jacqueline J. Greene, MD, * , { Zoe Fullerton, MD, Nate Jowett, MD, and Tessa Hadlock, MD

Abstract Introduction: During a two-stage free gracilis muscle transfer (FGMT) to restore smile to patients with facial paralysis, some surgeons assess nerve regeneration through the cross-face nerve graft (CFNG) with the Tinel sign and a nerve biopsy. Objective: To test whether ultimate smile reanimation outcomes are correlated with (1) the Tinel sign or (2) myelinated axons of the biopsied CFNG at the time of FGMT. Methods: Retrospective case series was performed at a tertiary care facial nerve center. Dynamic smile out comes were quantified with Emotrics analysis of pre- and postoperative photographs. Results: Of the 113 FGMT surgeries by CFNG performed since 2002, 92 patients had pre- and postoperative photo-documentation. Most patients (89%, N = 82) had a positive Tinel sign at the time of FGMT; however, 14 patients with positive Tinel signs were deemed failures. Interestingly, 4 patients with a negative Tinel sign went on to have successful dynamic outcomes and 16 patients lacking myelinated axons in their CFNG biopsy ultimately achieved successful smile outcomes. Conclusion: Although the majority of patients had a positive Tinel sign and myelinated axons in the CFNG at the time of FGMT, the presence or absence of either factor did not predict ultimate smile outcome in this series.

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longer time until muscle innervation, 2 and has a slightly lower success rate (84% vs. 92% when driven by the mas seteric nerve 2–5 ). This difference is likely related to the longer distance required for the regenerating nerve. Although there are currently no tests that predict ulti mate success of FGMT by CFNG, the presence of the Tinel sign (a referred sensation to the contralateral face elicited by tapping on the distal end of the CFNG) has

Introduction Free gracilis muscle transfer (FGMT) was introduced in 1976 by Harii et al. 1 and is a well-accepted smile reanima tion procedure for longstanding or irreversible facial paralysis. 1,2 Innervating the gracilis muscle with the con tralateral facial nerve through a cross-face nerve graft (CFNG) provides the most natural and spontaneous smile, but usually requires a two-stage approach (Fig. 1),

Department of Head and Neck Surgery-Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. { Current affiliation: Department of Surgery, Facial Nerve Center, University of California, San Diego, La Jolla, California, USA.

*Address correspondence to: Jacqueline J. Greene, MD, Department of Head and Neck Surgery-Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, 9th Floor Facial Nerve Center, Boston, MA 02114, USA, Email: j2greene@health.ucsd.edu

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the average axonal regeneration rate (1.8 mm/day), 9 many patients are not tested until the time of FGMT. It is cur rently unclear whether the presence of the Tinel sign at the time of FGMT denotes sufficient nerve regeneration through the CFNG to reinnervate the gracilis muscle, and thus predict smile reanimation outcomes. At the time of FGMT, the presence of myelinated axons can sometimes be detected in a biopsy of the distal tip of the CFNG and they are thought to be a positive predictor for dy namic smile outcome. Myelin sheaths are actually individ ual Schwann cells enwrapping each axon and may be readily visualized using light microscopy on appropriately stained thin sections in uninjured sensory and motor axons of the peripheral nervous system. Regenerating axons in contrast, such as those traversing a CFNG, may lack myelin sheaths and typically require electron microscopy for visualization and quantification. 14 Nerve histomorphometry (axon count, density, myelin thickness, etc.) has often been reported as a measure of successful nerve regeneration in animal nerve stud ies, 10–13 although published data of regenerating human nerve histomorphometry are limited. One key study used electron microscopy to investigate CFNG biopsies in 30 patients who underwent free pectoralis muscle transfer for facial reanimation. 22 Interestingly, they found a small proportion of small diameter myelinated axons and an abundance of unmyelinated axons and par tially myelinated axons in the CFNG, however, long-term

been historically used to deduce neural penetration through the CFNG and thus potential success (Fig. 1). The Tinel sign is named after Dr. Jules Tinel, a French neurologist who attributed the referred ‘‘tingling’’ phe nomenon to regenerating axons in 1915 after serving as a military physician during the First World War, although a German neurologist Dr. Paul Hoffman published his de scription of the ‘‘percussion test’’ the same year. 7 Hoffman reasoned that sensory, not motor, axons were responsible for the sign and that a positive sign meant motor functional return was possible but not guaranteed. 7,8 Although the site of the Tinel sign migrates as the axons regenerate through a CFNG and has been used to estimate Meaning: There are currently no tests that predict success of smile reanimation surgery and further research to assess suc cessful nerve regeneration is needed. KEY POINTS Question: Is it possible to predict whether a smile reanimation surgery will be successful by nerve biopsy or by a clinical test where light tapping on the face creates a referred tingling sen sation (the Tinel sign)? Findings: Most patients undergoing smile reanimation sur gery will have both a positive Tinel sign and myelinated axons in a nerve biopsy, but this does not uniformly guarantee success; in addition, a negative Tinel sign or lack of myelinated axons in the nerve biopsy does not predict failure.

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Fig. 1. Two-stage facial reanimation surgery can restore a spontaneous smile to patients with facial paralysis. The importance of the Tinel sign and myelinated axons in the distal CFNG as predictors of ultimate smile reanimation is unclear. (A) In the first stage, a CFNG is coapted to a healthy facial nerve branch to smile musculature without a distal hook-up. Neural regeneration through the CFNG takes 6–9 months. The presence of the Tinel sign has been historically used to determine the extent of neural penetration through the CFNG (elicited by tapping on the distal end of the CFNG, resulting in a referred sensation to the coaption site [marked by an asterisk]). (B) In the second stage, a free gracilis muscle is transferred to the paralyzed hemiface with vessel anastomosis and nerve coaption to the CFNG. A biopsy of the distal CFNG is done at this time to assess for the presence of myelinated axons. Reinnervation and movement of the gracilis muscle typically begins 10–12 months after this point, resulting in a bilateral spontaneous smile. CFNG, cross-face nerve graft.