The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc.

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1 The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc. The Electrophysiology of Thyroid Surgery: Electrophysiologic and Muscular Responses With Stimulation of the Vagus Nerve, Recurrent Laryngeal Nerve, and External Branch of the Superior Laryngeal Nerve Whitney Liddy, MD; Samuel R. Barber, MS; Matteo Cinquepalmi; Brian M. Lin, MD; Stephanie Patricio, BS; Natalia Kyriazidis, BS, MS; Carlo Bellotti, MD; Dipti Kamani, MD; Sadhana Mahamad, MD; Henning Dralle, MD; Rick Schneider, MD, PhD; Gianlorenzo Dionigi, MD; Marcin Barczynski, MD, PhD; Che-Wei Wu, MD, PhD; Feng Yu Chiang, MD; Gregory Randolph, MD Objectives/Hypothesis: Correlation of physiologically important electromyographic (EMG) waveforms with demonstrable muscle activation is important for the reliable interpretation of evoked waveforms during intraoperative neural monitoring (IONM) of the vagus nerve, recurrent laryngeal nerve (RLN), and external branch of the superior laryngeal nerve (EBSLN) in thyroid surgery. Study Design: Retrospective chart review. Methods: Data were reviewed retrospectively for thyroid surgery patients with laryngeal nerve IONM from January to December, EMG responses to monopolar stimulation of the vagus/rln and EBSLN were recorded in bilateral vocalis, cricothyroid (CTM), and strap muscles using endotracheal tube-based surface and intramuscular hook electrodes, respectively. Target muscles for vagal/rln and EBSLN stimulation were the ipsilateral vocalis and CTM, respectively. All other recording channels were nontarget muscles. Results: Fifty surgical sides were identified in 37 subjects. All target muscle mean amplitudes were significantly higher than in nontarget muscles. With vagal/rln stimulation, target ipsilateral vocalis mean amplitude was 1,095.7 lv (mean difference range to 21,078 lv, P <.0001). For EBSLN stimulation, target ipsilateral CTM mean amplitude was 6,379.3 lv (mean difference range 526,222.6 to 26,362.3 lv, P <.0001). Target muscle large-amplitude EMG responses correlated with meaningful visual or palpable muscular responses, whereas nontarget EMG responses showed no meaningful muscle activation. Conclusions: Target and nontarget laryngeal muscles are differentiated based on divergence of EMG response directly correlating with presence or absence of visual and palpable muscle activation. Low-amplitude EMG waveforms in nontarget muscles with neural stimulation can be explained by the concept of far-field artifactual waveforms and do not correspond to a true muscular response. The surgeon should be aware of these nonphysiologic waveforms when interpreting and applying IONM during thyroid surgery. Key Words: Thyroid surgery, electrophysiology, electromyography, intraoperative neural monitoring, vagus, recurrent laryngeal nerve, external branch of the superior laryngeal nerve. Level of Evidence: 4 Laryngoscope, 127: , 2017 INTRODUCTION Intraoperative neural monitoring (IONM) of the vagus, recurrent laryngeal nerve (RLN), and external branch of the superior laryngeal nerve (EBSLN) provides additional functional information during thyroid surgery to supplement knowledge of anatomy and surgical expertise. Anatomical and functional studies of laryngeal nerves have shown that the vagus/rln is the primary innervator of intrinsic laryngeal muscles except for the cricothyroid muscle (CTM), which is innervated Additional supporting information can be found in the online version of this article. From the Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A. (W.L., S.R.B., M.C., B.M.L., S.P., N.K., D.K., S.M., G.R.); Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, U.S.A. (W.L., B.M.L., D.K., G.R.); Surgery of Thyroid and Parathyroid Operative Unit, Sapienza University of Rome, S. Andrea Hospital, Rome, Italy (M.C., C.B.); Department of General, Visceral, and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (H.D., R.S.); Endocrine Surgery Research Center, Department of Surgical Sciences, University of Insubria, Varese, Italy (G.D.); Department of Endocrine Surgery, Jagiellonian University College of Medicine, Krakow, Poland (M.B.); Department of Otorhinolaryngology Head and Neck Surgery, Kaohsiung Medical University Hospital, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (C.-W.W., F.Y.C.); and Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (F.Y.C.). Editor s Note: This Manuscript was accepted for publication May 16, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Whitney Liddy, MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA Whitney_Liddy@meei.harvard.edu DOI: /lary

2 artifactual. Surgeons should be mindful of these artifactual waveforms, as they can present a source of potential confusion when interpreting IONM during central neck surgery. MATERIALS AND METHODS Study Population This retrospective study (protocol ID: H) was approved by the Human Studies Committee (HSC) at Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. Medical records were reviewed for patients within the Nerve Monitoring Data Repository (HSC protocol: H). Patients included were adults who underwent surgical procedures of the anterior neck with IONM of laryngeal nerves performed as standard of care from January to December Preoperative laryngeal examinations for all consented patients demonstrated normal glottic function. Perioperative laryngeal examination was performed in alignment with the American Academy of Otolaryngology Improving Voice Outcomes After Thyroid Surgery guidelines. 5 Collected information included demographic data, type and laterality of procedure, and IONM data. Fig. 1. Setup for intramuscular bipolar electrode placement. CC 5 contralateral cricothyroid muscle; IC 5 ipsilateral cricothyroid muscle; IS 5 ipsilateral strap. by the EBSLN. 1 These findings correlate with IONM during thyroid surgery, with visual contraction of the ipsilateral vocal cord during vagal/rln stimulation and ipsilateral CTM contraction with EBSLN stimulation. Intraoperative electromyographic (EMG) studies supplement and support these observations, with guidelines for the use of both EBSLN and vagal/rln IONM published by the International Neural Monitoring Study Group (INMSG). 2,3 Correlation of physiologically important EMG waveforms with demonstrable muscle activation is important for reliable interpretation of IONM data. Confusion can ensue when intraoperative EMG waveforms are recorded in isolation from true muscular response. For years, IONM small waveform EMG activity has been noted in the contralateral vocal cord without actual contralateral cord movement during ipsilateral RLN stimulation. 4 Conversely, uncertainty can also arise when regional muscle contraction is observed intraoperatively without neural stimulation. Direct stimulation of local muscle fibers with resultant regional contraction could be confused with neural stimulation of a branch of the RLN or EBSLN during thyroid surgery IONM if EMG morphology is not interpreted correctly. This study aims to confirm the differential innervation of laryngeal muscles by merging both visual and palpable target muscle activation with intraoperative stimulation of the vagus/rln and EBSLN systems during IONM. Small EMG waveforms demonstrated in nontarget muscles with intraoperative neural stimulation can be seen as a consequence of the recording electrode format. These small waveforms do not correlate with muscular contraction, and thus are considered Intraoperative Neural Monitoring Technique General anesthesia was used without paralytic agents except for an initial dose of 1 to 2 mg/kg of succinylcholine at induction. The NIM-Neuro 3.0 Monitoring System (Medtronic, Jacksonville, FL) was utilized for IONM with size 7.0 or 8.0 endotracheal tubes for intubation. IONM procedure, protocol, and EMG modality parameters were in accordance with the INMSG standards. 1,2 Stimulation of the vagus, RLN, and EBSLN was performed via a Prass Slim Monopolar Stimulator Probe (Xomed, Medtronic) at a supramaximal intensity of 2 ma, a rate of 4 Hz, and pulse width of 100 microseconds. EMG recording electrodes were bilateral bipolar surface electrodes (for vocalis) and intramuscular hook electrodes placed in the ipsilateral and contralateral CTM and ipsilateral strap muscles (Fig. 1). Recorded responses had an event threshold of 100 lv and a stimulation rejection artifact set at 1.2 milliseconds. All impedances were <5 kx in all channels with impedance imbalance of <1 kx prior to baseline recordings. All surgeries were performed by the senior author (G.R.). For each surgical side, four stimulation trials were performed at each of the three sites (vagus, RLN, and EBSLN) to calculate mean EMG amplitudes and latencies for all responses. The vagus nerve was identified and stimulated at the level of the thyroid, and the RLN was visually identified and stimulated within the thyroid bed at the second tracheal ring, below the laryngeal entry site. The EBSLN was identified and stimulated in the sternothyroid-laryngeal triangle, just below the laryngeal insertion site of the sternothyroid muscle. 6,7 Muscular response was assessed in the following way in all patients. With stimulation of the given nerve, the CTM and strap musculature were visually observed for corresponding muscle contraction, and glottic muscular response was determined by palpation of the posterior larynx to assess for contraction of the posterior cricoarytenoid muscle (PCA; i.e., determination of laryngeal twitch). 8 In a subset of patients, video laryngoscopy was performed to obtain direct glottic cordal/vocalis muscular response (see Supporting Video in the online version of this article). With vagal/rln or EBSLN stimulation, the target muscle for the given nerve was identified based on large-amplitude EMG response coupled with visual or palpable muscle activation. 765

3 Fig. 2. Stimulation of the recurrent laryngeal nerve and/or vagus nerve causes resultant contraction of the ipsilateral vocalis muscle, whereas stimulation of the external branch of the superior laryngeal nerve causes resultant contraction of the ipsilateral cricothyroid muscle. Statistical Analysis The mean EMG amplitude (in microvolts) for each muscle group was calculated from four stimulation trials of each nerve (vagus, RLN, and EBSLN). Mean amplitudes between target and nontarget muscles were compared, expressed as a mean difference and standard deviation of the mean difference. A paired t test compared mean target muscle responses to mean nontarget muscle responses. All probability values were two-sided, with 95% confidence intervals calculated for both the mean difference in amplitude between target and nontarget muscle responses and the standard deviation of the mean difference. Probability values <.05 were considered statistically significant. SAS software (v 9.4, SAS Institute; Cary, NC) was used to perform all statistical analyses. RESULTS A total of 50 surgical sides (26 left, 24 right) were evaluated in 37 patients. Mean age was 56.6 years, with 31 females and six males. For each side, muscular responses from the bilateral vocalis, bilateral cricothyroid, and ipsilateral strap muscles were evaluated TABLE I. Laryngeal Electromyographic Amplitudes With Stimulation of the Vagus/RLN and EBSLN. Variable Mean Amplitude, lv Mean Difference, lv, Target vs. Nontarget Muscle SD of Mean Difference 95% CI of Mean Difference 95% CI of SD P* Vagus/RLN stimulation Target muscle Ipsilateral vocalis 1,095.7 Nontarget muscle Ipsilateral CTM , , <.0001 Contralateral vocalis , , <.0001 Contralateral CTM , ,172.5, , <.0001 Ipsilateral strap , ,203.8, , <.0001 EBSLN stimulation Target muscle Ipsilateral CTM 6,379.3 Nontarget muscle Ipsilateral vocalis , , ,480.3, 24, ,651.5, 5,470.4 <.0001 Contralateral vocalis , , ,554.6, 25, ,660.1, 5,483.2 <.0001 Contralateral CTM , , ,578.6, 25, ,670.6, 5,499.0 <.0001 Ipsilateral strap , , ,628.2, 25, ,675.2, 5,505.9 <.0001 *Paired t test. CI 5 confidence interval; CTM 5 cricothyroid muscle; EBSLN 5 external branch of the superior laryngeal nerve; RLN 5 recurrent laryngeal nerve; SD 5 standard deviation. 766

4 Fig. 3. Mean electromyographic (EMG) amplitudes with vagal/recurrent laryngeal nerve (RLN) and external branch of the superior laryngeal nerve (EBSLN) stimulation. CTM 5 cricothyroid muscle. during stimulation of the vagus, RLN, and EBSLN. Nerves were stimulated with a current of 2 ma and were identified electrically and visually. The target muscle for vagal/rln stimulation was the ipsilateral vocalis muscle based on large EMG amplitudes and presence of laryngeal twitch (Fig. 2). The target muscle for EBSLN stimulation was the ipsilateral CTM based on large EMG amplitudes and correlated muscular contraction (Fig. 2). In contrast, nontarget muscle groups showed small EMG amplitudes and a concomitant lack of muscular contraction. Quantitative Laryngeal EMG Data With vagal/rln stimulation, mean EMG amplitude of the target muscle ipsilateral vocalis response for all 50 sides was 1,095.7 lv (Table I, Fig. 3). In comparison, nontarget muscle groups showed much smaller EMG amplitudes with a mean amplitude of lv (ipsilateral CTM), lv (contralateral vocalis), 45.3 lv (contralateral CTM), and 17.7 lv (ipsilateral straps). Mean differences in EMG amplitudes between the target muscle ipsilateral vocalis response and nontarget muscle responses were lv (ipsilateral CTM), lv Fig. 4. (A) Laryngeal twitch can be palpated with a finger placed on the posterior aspect of the larynx during recurrent laryngeal nerve (RLN) or vagal stimulation. (B) Stimulator probe points to the left RLN in the photo. 767

5 TABLE II. Comparison of Visible Twitch, Palpable Contraction, and Significant Electrophysiologic Response Between Muscle Groups During Electrical Stimulation of the RLN/Vagus Nerve Versus the EBSLN. Variable Visible Twitch* Palpable Contraction* Significant Electrophysiologic Response Vagus/RLN stimulation Target muscle Ipsilateral vocalis Yes Yes Yes Nontarget muscle Contralateral vocalis No No No Ipsilateral CTM No No No Contralateral CTM No No No Ipsilateral strap No No No EBSLN stimulation Target muscle Ipsilateral CTM Yes Yes Yes Nontarget muscle Ipsilateral vocalis Yes No No Contralateral CTM No No No Contralateral vocalis No No No Ipsilateral strap No No No *See Supporting Video. CTM 5 cricothyroid muscle; EBSLN 5 external branch of the superior laryngeal nerve; RLN 5 recurrent laryngeal nerve. (contralateral vocalis), 21,048.4 lv (contralateral CTM), and 21,078.0 lv (ipsilateral straps). This mean difference was robust between target and nontarget muscle groups, with statistical significance in all muscle groups (P <.0001; Table I). With EBSLN stimulation, mean EMG amplitude of the target muscle ipsilateral CTM response for all 50 sides was 6,379.3 lv (Table I, Fig. 3). Mean EMG amplitudes for nontarget muscle groups were much smaller at lv (ipsilateral vocalis), 85.4 lv (contralateral vocalis), 65.0 lv (contralateral CTM), and 17.0 lv (ipsilateral straps). Mean differences in amplitude compared to the target ipsilateral CTM were all statistically significant (P <.0001) for nontarget muscles, including 26,222.6 lv (ipsilateral vocalis), 26,294.0 lv (contralateral vocalis), 26,314.3 lv (contralateral CTM), and 26,362.3 lv (ipsilateral straps; Table I). (either visibly or on laryngeal palpation). This lack of muscular contraction or activation of nontarget muscles was associated with an observed low-amplitude EMG waveform (Table II). With EBSLN stimulation, the target muscle ipsilateral CTM displayed visible twitch of the muscle fibers in all cases (see Supporting Video, Fig. 5). This correlated with a significant electrophysiologic response that contrasted with small EMG waveforms observed with nontarget muscles (vocalis, contralateral CTM, and strap muscles). With the exception of a small demonstrable twitch of the anterior portion of the ipsilateral vocalis Muscular Responses The large-amplitude EMG response of the target muscle for both the vagus/rln and EBSLN systems was correlated with a meaningful muscular response through visualization and/or palpation of target muscle activation. This was in stark contrast to a lack of any visual or palpable nontarget muscle activation. In addition to large-amplitude EMG responses with vagal/rln stimulation, laryngeal twitch was also palpable with a finger placed on the posterior aspect of the larynx sensing the PCA muscle contraction in all cases. The target muscle ipsilateral vocalis was also noted to contract with visible twitch in all cases where intraoperative direct laryngoscopy was performed (see Supporting Video, Fig. 4). Nontarget muscles including the contralateral vocalis, CTM, and strap muscles did not contract Fig. 5. Visualization of target muscle ipsilateral cricothyroid (black dashed line) twitch with external branch of the superior laryngeal nerve (white dashed line) stimulation (see Supporting Video). 768

6 muscle (as visualized on direct laryngoscopy), no visible twitch or palpable contraction of the PCA, contralateral CTM, contralateral vocalis, or strap muscles was observed (see Supporting Video, Table II). DISCUSSION With multiple recording electrodes in and around the larynx, a variety of waveforms have been observed during intraoperative stimulation of the vagus/rln and EBSLN in thyroid surgery, leading to confusion as to the meaning and significance of these waveforms. For example, when the RLN is stimulated a confirmatory EMG response is expected from the ipsilateral vocal cord. However, when EMG waveforms are also recorded from surrounding laryngeal muscles not innervated by the RLN, confusion and uncertainty can arise over EMG interpretation during IONM and over neural innervation of the larynx. We provide data to enhance appropriate interpretation of EMG waveforms through both comparison of EMG response amplitudes and confirmation of a meaningful EMG response with real-time visual or palpable muscle activation. For both the vagus/rln and EBSLN systems, primary target and nontarget laryngeal muscles can be appreciated. Through both observation of regional electrophysiologic waveform responses and detection of gross observable muscular responses, we show that the ipsilateral vocalis is the primary target muscle with vagus/rln stimulation given 1) high-amplitude EMG and 2) isolated and discrete contraction. This study also confirms that for EBSLN stimulation, the ipsilateral CTM is the primary target muscle given 1) high-amplitude EMG and 2) isolated and discrete contraction. For both the vagus/rln and EBSLN systems, EMG amplitudes of primary target muscles are significantly higher than the measurable but low-amplitude responses from other regional, nontarget, noncontracting laryngeal muscle groups. Target musculature, then, is the primary innervated muscle that produces the highest EMG amplitude and is the sole muscle grossly contracting with nerve stimulation. Nontarget musculature, although demonstrating a small but recordable EMG waveform, fails to contract with neurostimulation. This small EMG waveform is physiologically irrelevant. A prime example of a nontarget muscle with vagal/rln stimulation is the contralateral vocal cord. Here, although a contralateral vocalis waveform is present, it is significantly smaller than the ipsilateral muscle, and only the ipsilateral side contracts with neurostimulation during real-time glottic observation. The observed contralateral waveform is an artifact, a distant measurement of the ipsilateral cord s physiologic electrical muscular event that we term a far-field recording. Contraction of the ipsilateral vocalis (and absence of contralateral contraction) with vagal/rln stimulation is confirmed by direct visualization with intraoperative laryngoscopy (see Supporting Video). Palpation of the posterior aspect of the larynx also confirms PCA activation with vagal/rln stimulation but not with EBSLN stimulation. 1 Such muscular response is not observed in nontarget muscles including the CTM and strap musculature. With EBSLN (but not vagal/rln) stimulation, palpable and visual ipsilateral CTM contraction confirms primary target muscle activation. In practical terms, this method for confirming identification of the vagus/rln or EBSLN by demonstrating both a high-amplitude EMG response and an isolated palpable or visual contraction of the target muscle allows the surgeon using IONM to reliably ignore small physiologically meaningless EMG waveforms and feel confident in his/her appropriate identification of the nerve. This allows for correct interpretation of IONM, which in turn leads to more effective and efficient intraoperative decision making. Neurophysiologic and anatomic fundamentals are paramount to correctly interpreting EMG morphology. In a discussion of intralaryngeal neural anatomy, it is important to discuss the human communicating nerve (HCN). 1 The HCN facilitates electrical EBSLN activity to the anterior one-third of the ipsilateral vocal cord, as seen in both humans and canines. 3,7,9,10 In a prospective multicenter study of 22 patients, Darr et al. demonstrated successful evoked glottic waveforms in 100% of patients with EBSLN stimulation, with response amplitudes about one-quarter of that with RLN stimulation (recorded with surface glottis electrodes). 7 In a prospective study of 72 patients, Potenza et al. demonstrated reliable nonartifactual glottic EMG responses in 80% of cases with EBSLN stimulation, with amplitudes onethird of those seen with RLN stimulation. 6 Perceived glottic anterior cordal twitch with ipsilateral EBSLN stimulation (see Supporting Video, Fig. 5) is believed to result primarily from CTM activation (which moves the thyroid cartilage relative to the cricoid cartilage) with perhaps a limited contribution from anterior vocalis muscle response. The existence of the HCN implies there is joint EBSLN/RLN innervation of the anterior third of the vocal cord but does not represent any connection between the RLN and CTM. With the acknowledged lack of innervation of nontarget laryngeal muscle groups by a given laryngeal nerve, why then are low-amplitude EMG responses demonstrated with stimulation of that nerve? With vagal/ RLN stimulation, we see small detectable waveforms in the contralateral vocalis, bilateral CTM, and ipsilateral strap muscle. The size of these nontarget muscle amplitudes is significantly less than the ipsilateral vocal cord. Of note, even the ipsilateral straps show smallamplitude EMG waveforms. We of course appreciate there is no RLN to strap muscle connection. For EBSLN stimulation, we see small but measurable waveforms in the contralateral CTM, bilateral vocalis, and ipsilateral straps. Again, we have a definable waveform in the ipsilateral strap with EBSLN stimulation without known EBSLN strap muscle innervation. These responses, overall, are not associated with visual or palpable muscle activation and can be thought of as artifactual. Generally, the contralateral EMG response is smaller than the ipsilateral response. Furthermore, that both responses occur with short latencies argues against a contralateral vagal reflex and favors an artifactual EMG response

7 In the neurophysiology literature, the concept of artifactual EMG responses from neighboring muscle groups is expressed in discussions of surface EMG crosstalk, where the EMG signal detected over a nonactive muscle is generated by a nearby activated muscle EMG recordings treat the monitored muscle as a volume conductor, with response amplitude composed of signals not only from the monitored muscle but also from surrounding muscles and ambient electrical noise, without discrimination between sources. 14 Both nearfield potentials (signal obtained with the recording electrode close to the source) and far-field potentials (signal obtained with the recording electrode far from the source) are recorded. 15 Near-field potentials reflect electrical activity from the specific muscle being recorded and are higher in amplitude than far-field potentials, which are small and more difficult to interpret, as they are net potentials from multiple sources. 16 Our construct for nontarget muscle small-amplitude EMG waveforms that fail to correspond to meaningful muscular contraction can, therefore, be explained by the concept of farfield artifactual waveforms. 4,17 Placing surface electrodes over the middle of a muscle rather than peripherally, increasing the distance between electrodes, or using smaller size electrodes minimizes crosstalk. 14 In one study, EMG recordings from leg muscle surface electrodes demonstrated crosstalk signals accounting for up to 16% of the amplitude at the target muscle site. 12 Given the significantly closer proximity of intrinsic laryngeal muscles compared to lower extremity muscle groups, crosstalk or far-field artifactual waveforms maintain a dominant presence in regional recording channels. Use of intramuscular electrodes, such as those for the CTM and straps in this and other laryngeal studies, helps to minimize crosstalk and signal contamination by far-field artifactual waveforms. 16 However, bipolar intramuscular electrodes will still pick up any potential within range of adjacent dipole interactions. In our study, intramuscular electrodes were used for CTM and strap muscle EMG recordings, whereas endotracheal tube laryngeal surface electrodes were used for vocalis EMG recordings. Whereas some studies have suggested higher recorded amplitudes with intramuscular as compared to surface electrodes, 18 other studies utilizing laryngeal EMG have shown excellent correlation between the two. 4 Our observations of EMG latencies showed no differences between target muscle and nontarget muscle groups in response to the same train of stimulation. If true responses were present in nontarget muscles, the onset latency at which the motor endplates would undergo excitation would vary based on the lengths, diameters, and conduction properties of their respective motor branches. That latencies were equivalent in this study additionally supports that responses in nontarget muscle groups correspond to crosstalk from the target muscle group. Additionally, any reflex response to explain coactivation of nontarget groups would have significantly delayed latencies due to the time necessary for an antidromic volley back toward the brainstem before the signal can travel down the efferent motor limb This is not consistent with our observation of equivalent latencies. Lastly, direct stimulation of muscle fibers can result in their contraction, circumventing neural stimulation. For example, a localized inferior constrictor twitch can be visualized with direct stimulation of muscle fibers without stimulation of the adjacent EBSLN. This localized response is in the absence of an evoked glottic waveform and CTM twitch. These localized falsepositive contractions can also be seen with direct stimulation of the straps or esophageal muscle fibers adjacent to the RLN. 4,17 Our algorithm for confirming direct neural stimulation with both high EMG amplitude response and visual or palpable muscle twitch of the primary target muscle encourages surgeons to focus on the meaningful neurophysiologic connections of the vagus/rln and EBSLN. This helps the surgeon to recognize localized false-positive EMG muscle contractions when mapping and preserving the RLN and EBSLN during central neck surgery. In a small series of 13 patients undergoing laryngectomy, Martin-Oviedo et al. describe a small EMG response in the CTM following RLN stimulation in seven patients, although no visualized CTM contraction was reported. 19 Matsuoka et al. suggest the presence of reverse innervation of the CTM by the RLN through the HCN in a series of 50 patients during thyroid surgery with IONM. 20 The authors report both visual contraction of the CTM and EMG responses in up to 40% of cases during vagus or RLN stimulation (with 34% of cases showing either visual contraction or EMG response but not both). However, the median ratio of EMG amplitude after RLN stimulation in the CTM compared to the EBSLN was only 8.5%, and the methodology for distinguishing gross contraction of anterior laryngeal muscles from true CTM contraction was not described. 20 In this study, no cases demonstrated significant CTM EMG response or contraction with vagal/rln stimulation (see Supporting Video, Fig. 5). The functional roles of known RLN/superior laryngeal nerve (SLN) anastomoses have been debated in the literature. Anatomical studies of the HCN showed an association between the EBSLN and distal RLN in the region of the anterior vocal cord in up to 85% of cases. 21,22 However, it is important to understand that presence of the HCN implies joint SLN/RLN innervation of the anterior third of the vocal cord and not any connection between the RLN and CTM. Our study suggests that nontarget muscle, low-grade, nonphysiologic, far-field EMG waveforms should not be interpreted as evidence for an RLN to CTM connection. The addition of IONM in central neck surgery provides valuable, real-time information regarding the course and functional status of the vagus/rln and EBSLN. However, the correct interpretation and reliable use of IONM depends on the surgeon s understanding of potential troubleshooting pathways in an underlying context of laryngeal neuroanatomic relationships. For example, with stimulation of the RLN our results support an expected robust ipsilateral vocalis EMG waveform in combination with a palpable laryngeal twitch. In the setting of a low-amplitude EMG response, palpation

8 of laryngeal twitch is a useful adjunct for troubleshooting that helps confirm correct identification of the RLN and points to possible issues with IONM equipment. The authors recognize that multiple muscular electrodes outside of vocalis surface electrodes are not standard for IONM. The use of additional electrodes in this study, in combination with palpation and visualization of muscle contraction, helps to define physiologically important and unimportant EMG waveforms that can be obtained during IONM and cautions the surgeon to be mindful of artifactual, nonphysiologic responses. CONCLUSION We conclude that for both vagal/rln and EBSLN systems, target and nontarget laryngeal muscles are present and are differentiated based on divergence of EMG responses directly correlating with the presence or absence of visual and palpable muscle activation. Lowamplitude EMG waveforms seen in nontarget muscles can be explained by the concept of far-field artifactual waveforms and do not demonstrate a corresponding true muscular response. The surgeon should be aware of these nonphysiologic artifactual EMG responses when interpreting and applying IONM during thyroid and central neck surgery. BIBLIOGRAPHY 1. Randolph G. Surgical anatomy and monitoring of the recurrent laryngeal nerve. In: Randolph G, ed. Surgery of the Thyroid and Parathyroid Glands. Philadelphia, PA: Saunders; 2013: Randolph GW, Dralle H, Abdullah H, et al. Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement. Laryngoscope 2011; 121(suppl 1):S1 S Barczynski M, Randolph GW, Cernea CR, et al. External branch of the superior laryngeal nerve monitoring during thyroid and parathyroid surgery: International Neural Monitoring Study Group standards guideline statement. Laryngoscope 2013;123(suppl 4):S1 S Randolph G. Intraoperative electrophysiologic monitoring of the recurrent laryngeal nerve during thyroid and parathyroid surgery: experience with 1381 nerves at risk. Accepted in laryngoscope, June Chandrasekhar SS, Randolph GW, Seidman MD, et al. Clinical practice guideline: improving voice outcomes after thyroid surgery. Otolaryngol Head Neck Surg 2013;148:S1 S Potenza AS, Phelan EA, Cernea CR, et al. Normative intra-operative electrophysiologic waveform analysis of superior laryngeal nerve external branch and recurrent laryngeal nerve in patients undergoing thyroid surgery. World J Surg 2013;37: Darr EA, Tufano RP, Ozdemir S, Kamani D, Hurwitz S, Randolph G. Superior laryngeal nerve quantitative intraoperative monitoring is possible in all thyroid surgeries. Laryngoscope 2014;124: Randolph GW, Kobler JB, Wilkins J. Recurrent laryngeal nerve identification and assessment during thyroid surgery: laryngeal palpation. 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