Effect of Intralaryngeal Muscle Synkinesis on Perception of Voice Handicap in Patients With Unilateral Vocal Fold Paralysis

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1 The Laryngoscope VC 2017 The American Laryngological, Rhinological and Otological Society, Inc. Effect of Intralaryngeal Muscle Synkinesis on Perception of Voice Handicap in Patients With Unilateral Vocal Fold Paralysis R. Jun Lin, MD; Michael C. Munin, MD; Clark A. Rosen, MD; Libby J. Smith, DO Objectives/Hypothesis: Intralaryngeal muscle synkinesis associated with unilateral vocal fold paralysis (UVFP) is thought to preserve thyroarytenoid-lateral cricoarytenoid muscle complex tone, resulting in a better voice despite the presence of vocal fold paralysis (VFP). This study compares voice handicap in patients with unilateral VFP (UVFP) with and without evidence of adductory synkinesis on laryngeal electromyography (LEMG). Study Design: Retrospective review of LEMG data and Voice Handicap Index-10 (VHI-10) scores of patients diagnosed with permanent UVFP. Methods: LEMG was performed within 1 to 6 months post onset of UVFP. Patients were stratified into two groups: 1) recurrent laryngeal nerve (RLN) neuropathy with synkinesis and 2) RLN neuropathy without synkinesis. Synkinesis was diagnosed when the sniff to phonation maximum amplitude ratio was VHI-10 scores at 6-month follow-up were recorded. Results: Four hundred forty-nine patients with UVFP and who had an LEMG were reviewed. Eighty-three patients met the inclusion criteria, with 16 in group 1 and 67 in group 2. There was no significant difference between the groups with regard to age, timing of LEMG from onset of VFP, number of patients undergoing temporary vocal fold injection or use of offlabel nimodipine. Average VHI-10 scores at 6 months post onset of VFP were for patients with LEMG-identified synkinesis (group 1) and for patients with no LEMG evidence of synkinesis (group 2). This was statistically significant (P 5.02). Conclusions: Patients with unilateral vocal fold paralysis and LEMG evidence of laryngeal synkinesis are more likely to have less perceived voice handicap than those without synkinesis. Key Words: Voice, dysphonia, LEMG, laryngeal electromyophgray, vocal fold paralysis, vocal cord paralysis, voice handicap, voice outcome. Level of Evidence: 4. Laryngoscope, 127: , 2017 INTRODUCTION Intralaryngeal muscle synkinesis (synkinesis) results from misdirected nerve regeneration leading to abnormal reinnervation within the larynx following injury to the recurrent laryngeal nerve (RLN). 1 This phenomenon clinically manifests as persistent vocal fold paralysis secondary to ineffective, unsynchronized muscle activity rather than chronic denervation. The thyroarytenoid-lateral cricoarytenoid (TA-LCA) muscle complex tone is thought to be preserved due to the aberrant reinnervation, which theoretically results in a better voice even in the setting of permanent unilateral From the University of Pittsburgh Voice Center, Division of Laryngology, Department of Otolaryngology Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. (R.J.L., M.C.M., C.A.R., L.J.S.); Department of Physical Medicine and Rehabilitation (M.C.M.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A. Editor s Note: This Manuscript was accepted for publication September 27, Presented at the 136th Annual Meeting of the American Laryngological Association at COSM, Chicago, Illinois, U.S.A. May 18 19, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Libby J. Smith, DO, Department of Otolaryngology, 1400 Locust Street, Building B, Suite 11500, Pittsburgh, PA smithlj2@upmc.edu DOI: /lary vocal fold paralysis (UVFP). Blitzer et al. identified synkinesis in a group of 14 patients with chronic UVFP (i.e., paralysis present for more than 1 year), which was defined as simultaneous muscle unit potentials in both thyroarytenoid (TA) and lateral cricoarytenoid (LCA) muscles on laryngeal electromyography (LEMG). 2 Maronian et al. first proposed the usage of a uniform definition of synkinesis with LEMG. 3 In their study, adductory synkinesis was defined as TA recruitment during a sniff that is greater than or equal to its recruitment seen during phonation, whereas abductory synkinesis was defined as any significant activity of the posterior cricoarytenoid (PCA) muscle with phonation. Statham et al. used abnormal TA-LCA muscle contraction during an abductory task as their definition of synkinesis in the subacute setting (i.e., paralysis present for less than 6 months). 4 Traditionally, laryngeal synkinesis is thought to occur secondary to abnormal reinnervation of the antagonist muscles of the larynx, for example, reinnervation of the adductor muscles by the abductory fibers of the RLN or vice versa. However, recent studies have shown that laryngeal neuroanatomy is more complex than the classic and simplistic description of the intrinsic laryngeal muscles being innervated by the RLN. Connections between the internal branch of the superior laryngeal nerve (SLN) and RLN, the external branch of the SLN

2 and RLN, the internal branch and external branch of the SLN, as well as bilateral RLN contribution to the interarytenoid muscle have been defined. 5 8 Following partial denervation of the RLN, the remaining axons likely expand their territories and reinnervate the laryngeal muscles by collateral sprouting 9,10 onto the other nerves in the vicinity, resulting in reinnervation. Hydman et al. have shown that SLN contributes to reinnervation of the PCA following RLN injury, likely from axon sprouting. 11 LEMG is an excellent test to confirm nerve injury and to determine prognosis in patients with vocal fold paralysis. 12,13 In clinical practice, vocal fold paralysis is commonly considered permanent if there is no motion return by 6 months from injury. 12 A prospective study found that LEMG neuropathic findings, including fibrillation potentials and positive sharp waves with decreased or absent motor unit recruitment, allows for prediction of poor functional outcome with high reliability. 13 LEMG performed more than 2 months from RLN injury has a positive predictive value (PPV) of 97.9%. 14 A more recent study found that quantitative LEMG using turns analysis has a PPV of 100% and negative predictive value (NPV) of 89.5% in anticipating vocal fold motion recovery in the setting of vocal fold paralysis. 15 Furthermore, synkinesis can be diagnosed on LEMG. 3,4 Synkinesis is considered present if there is good motor unit recruitment in the TA- LCA muscle complex during an abductory sniff task. 4 Quantitatively, synkinesis is confirmed if the sniff/phonation ratio of the mean motor unit potential (MUP) amplitude in the TA-LCA muscle complex is greater than An LEMG finding of synkinesis is important due to previous studies linking this finding to reduced likelihood of recovery of purposeful vocal fold motion. This is thought to occur due to pathologic reinnervation between abductor and adductor neurons. 4 In patients with permanent UVFP, their perceived vocal handicap is likely related to the position of the paralyzed vocal fold, the TA-LCA muscle tone, and the compensatory activity of the contralateral TA-LCA muscle complex. In Blitzer et al. s series of 14 patients who had a UVFP for more than 1 year, 7 patients regained good vocalization despite persistent vocal fold paralysis. 2 The remaining 7 patients continued to have a poor voice. No patient-based instrument were available at the time of this study to assess patient perception of voice handicap; thus, assessment of voice quality was subjective. All patients who had regained a good voice had electrical synkinesis, and one out of seven patients with poor voice quality had synkinetic activity on LEMG. Our current study aimed to investigate and compare self-perception of voice handicap in patients with UVFP, with and without electromyographic evidence of synkinesis. MATERIALS AND METHODS Study Design and Subjects This study was approved by the institutional review board (IRB) at the University of Pittsburgh (IRB# PRO ). A retrospective review was performed on adult patients who had undergone diagnostic LEMG between 1 and 6 months from the onset of their RLN injury. All patients had an endoscopic laryngeal examination 6 months after the onset of injury to ensure persistent vocal fold paralysis. Those with vocal fold paresis, bilateral vocal fold motion impairment, cricoarytenoid joint pathology, as well as patients with a known history of central or systemic neurologic disease were excluded. LEMG and Analysis The LEMG was performed by two fellowship-trained laryngologists (L.J.S., C.A.R.). A board-certified electrodiagnostic medicine physician (M.C.M.) was also present to interpret the data. The physician performing the LEMG as well as the one interpreting the data were blinded to the laterality of the patient s vocal fold paralysis. Only information regarding the onset of injury, past medical history, and past surgical history were known to the physicians at the time of LEMG testing. A Synergy EMG machine (Natus Neurology, Middleton, WI) was used, recording motor unit recruitment tracings in synchronization with a surface microphone tracing. All patients received either a 0.5 ml injection of a 50:50 mixture of 1% lidocaine with 1:100,000 epinephrine and bicarbonate, or 3 ml of EMLA (2.5% lidocaine and 2.5% prilocaine) cream over the cricothyroid membrane. A 37- mm concentric needle electrode was utilized in conjunction with a ground electrode placed over the wrist. The concentric needle was inserted through the cricothyroid membrane to locate the TA-LCA muscle complex. Needle position was confirmed by asking patients to perform both a sustained vowel /i/ phonation and a Valsalva maneuver. For spontaneous activities, a sweep speed of 10 ms per division and a gain of 50 lv per division were used. For motor unit analysis, sweep speed was the same but gain was changed to 200 lv per division. Synkinesis testing was performed on all patients who demonstrated normal or mildly to moderately decreased recruitment (11 to 21). The LEMG methodology used for grading motor unit recruitment using an ordinal scale has been previously described, and ranges between 41 or absent recruitment to 11 or mildly decreased activation based on the number of units on the screen and the firing rate of the fastest unit. 13 Synkinesis testing was not performed in patients with severely decreased (31) or absent (41) recruitment because too few motor units were firing to anticipate any volitional vocal fold motion. Synkinesis testing was performed by asking the patient to produce a sustained /i/ at maximal intensity for approximately 3 seconds, briefly pause, and then quickly sniff. 4 Synkinesis was determined to be present if the ratio of mean sniff/phonation MUP amplitude was greater than The methods in this study measured TA-LCA muscle adductory synkinesis. PCA muscle synkinesis, or abductory synkinesis, was not investigated due to the more invasive nature of the technique for inserting the LEMG electrode into the PCA muscle. However, this topic should remain an area for future investigation. Outcomes and Analysis Eligible subjects medical records were reviewed. LEMG reports were reviewed to categorize included subjects into two groups: 1) RLN neuropathy with synkinesis and 2) RLN neuropathy without synkinesis. Patients perception of their voice handicap was measured using the Voice Handicap Index (VHI- 10) 16 at their initial presentation and at the 6-month follow-up. If temporary vocal fold injection was performed prior to 6 months, the final VHI-10 data were collected at least 3 months after the vocal fold injection, after the temporary injectable materials had been absorbed. The following injectable materials were considered temporary, including carboxymethylcellulose (Prolaryn gel), hyaluronic acid (Restylane), and micronized Alloderm tissue (Cymetra). Patients who had permanent vocal fold augmentation procedures before their 6-month follow-up and those with return of motion before their 6-month follow-up were further excluded. Data were analyzed using Stata/SE

3 Fig. 1. Summary of chart review of LEMG patients. LEMG 5 laryngeal electromyography; RLN 5 recurrent laryngeal nerve; SLN 5 superior laryngeal nerve. software (StataCorp, College Station, TX). Comparisons between groups were performed using the two-sample t test with equal variances at a significance level of a RESULTS We retrospectively reviewed 449 consecutive patients with unilateral vocal fold immobility who underwent LEMG at the University of Pittsburgh Voice Center between January 2009 and July Threehundred sixty-five patients were excluded. Reasons for exclusion are provided in Figure 1. A final number of 83 patients were included in the analysis. None of these patients had vocal fold motion recovery by 6 months. Of the included patients, 16 (19%) patients had RLN neuropathy with electrical synkinesis on LEMG and 67 (81%) patients had RLN neuropathy without electrical synkinesis. Patient demographic information as well as the etiologies of their UVFP are listed in Table I. LEMG Timing Patients who had an early LEMG would undergo a second LEMG at a later time. In our study, the second LEMG result was included in the analysis if the patient had undergone two LEMGs. The mean duration between onset of RLN injury and the last LEMG was weeks for the synkinesis group and weeks for the nonsynkinesis group, which was not statistically significantly different (P 5.18) (Table I). VHI-10 The average VHI-10 scores at baseline for the synkinesis group and the nonsynkinesis group were and , respectively. This was not significantly different (P 5.54). At the 6-month follow-up, the average VHI-10 score for the synkinesis group was and for the nonsynkinesis group was The difference between the two groups was statistically significant (P 5.02) (Table II). Vocal Fold Augmentation Procedures In the group with electrical synkinesis (group 1), 88% (14/16) of patients had temporary vocal fold injections (Table III). In the group without electrical TABLE I. Demographic Information of Included Patients. P Value No. of patients 16 (19%) 67 (81%) Gender, male:female 7:9 16:51 Average age at baseline, yr Etiologies of UVFP [no.] Thyroid surgery [10] Thyroid surgery [30] Spine surgery [3] Parathyroid surgery [1] Thoracic/mediastinal surgery [2] Spine surgery [7] Carotid surgery [1] Thoracic/mediastinal surgery [9] Endotracheal intubation [4] Neck surgery [2] Malignancy [1] Idiopathic [13] Mean interval between onset of RLN injury and LEMG, wk Off-label nimodipine therapy 2 (13%) 17 (25%) LEMG 5 laryngeal electromyography; RLN 5 recurrent laryngeal nerve; UVFP 5 unilateral vocal fold paralysis. 1630

4 TABLE II. Voice Outcome of Patients Based on. P Value Mean Baseline VHI-10 scores VHI-10 scores at 6 months post RLN injury * P value.01*.0001* *Statistically significant when P <.05. RLN 5 recurrent laryngeal nerve; VHI-10 5 Voice Handicap Index-10. synkinesis (group 2), 75% (50/67) patients underwent temporary vocal fold injections before their 6-month follow-up. In addition, all of these patients final VHI-10 data were collected at least 3 months after their temporary vocal fold injections and before any permanent vocal fold augmentation procedure was performed. By that time, the temporary injectable materials should have been absorbed and thus should not have affected the final VHI-10 score. Of the patients who had temporary vocal fold injection in the synkinesis group, 14% (2/14) of patients ultimately underwent vocal fold lipoinjection for long-term vocal fold augmentation. None from this group underwent laryngeal framework surgery such as medialization laryngoplasty. Of the patients who had temporary vocal fold injection in the nonsynkinesis group, 24% (12/50) of patients had permanent vocal fold augmentation procedures: 16% (8/50) underwent medialization laryngoplasty and 8% (4/50) underwent vocal fold lipoinjection. Overall, 13% (2/16) of patients in the synkinesis group versus 27% (18/67) of those in the nonsynkinesis group required further permanent vocal fold augmentation procedures (Table III). Two patients (13%) from the synkinesis group and seven patients from the nonsynkinesis group (25%) were started on off-label nimodipine therapy. DISCUSSION Our study found that patients with LEMG evidence of intralaryngeal muscle adductory synkinesis after RLN injury have reduced perceived voice handicap compared to those without synkinesis. Our series has a 19% incidence of synkinesis, which is comparable to previously reported incidences (10% 30%). 3,4 We hypothesize that synkinesis maintains a greater degree of TA-LCA muscle tone, leading to greater muscle bulk and subsequent medialization of the paralyzed vocal fold. Muscle tone is defined as a sustained state of muscle contraction in muscle physiology. 17 Laryngeal muscle tone is a concept that is not well described in laryngology literature and is not a quantifiable measure yet. Synkinesis likely helps to maintain laryngeal muscle tone, and therefore muscle bulk, positioning the paralyzed vocal fold at a more favorable, medialized position for phonation. As a result, patients have a better perception of their voice and are less likely to require permanent vocal fold augmentation. Early vocal fold injection after RLN injury has been suggested to decrease the need for permanent laryngeal framework surgery such as medialization laryngoplasty. Yung et al. found that 26% of patients who underwent vocal fold injection versus 66% of those who did not ultimately required medialization laryngoplasty. 18 Other studies also found that patients who received vocal fold injections less than 6 months from the onset of RLN injury were much less likely to undergo framework surgery than those injected after 6 months. 19,20 These studies suggest that early vocal fold injection for UVFP augments the vocal fold in such a way that it is situated in a more medialized resting position during the time window of synkinetic reinnervation, therefore decreasing the likelihood of requiring future permanent vocal fold augmentation procedures. 20 Our study observed a similar finding in that regardless whether the patient had electromyographic evidence of synkinesis, early vocal fold injection decreased the likelihood for requiring permanent vocal fold augmentation. In addition, the synkinesis group had a significantly lower number of patients undergoing permanent procedures overall, which further supported the concept of a more favorably positioned paralyzed vocal fold due to maintenance of muscle bulk secondary to ongoing muscle innervation. Clinically, off-label nimodipine therapy has been shown to improve recovery rate of purposeful motion in TABLE III. Vocal Fold Augmentation Procedures., N 5 16, N 5 67 Temporary VFI 14 (88%) 50 (75%) Permanent VF augmentation procedures [no.] ML [0], lipoinjection [2] ML [8], lipoinjection [4] Overall 2 (13%) 18 (27%) Permanent VF augmentation procedures [no.] ML [0] (0%), lipoinjection [2] (13%) ML [14] (21%), lipoinjection [4] (6%) ML 5 medialization laryngoplasty; RLN 5 recurrent laryngeal nerve; VFI 5 vocal fold injection. 1631

5 patients with LEMG evidence of significant RLN injury from 20% to 60%. 21 All patients included in this study had no purposeful vocal fold motion recovery by 6 months. We do not know whether nimodipine, given its positive effect on axonal growth, 21,22 could have promoted synkinesis after RLN injury. However, given that small numbers of patients from both groups were started on this medication, nimodipine therapy should not have affected the final results of this study. Limitations This study was limited by its retrospective design. However, strict patient inclusion criteria in terms of timing of LEMG following RLN injury and follow-up were applied so that the data would be reflective of a patient cohort with permanent UVFP. One hundred ninety-four patients (43%) were lost to follow-up before 6 months, and we do not know what proportion of this population had recovery of vocal fold motion. Barriers to patient follow-up care are usually multifactorial, including insurance coverage, travel time and costs, time away from work, as well as caretaker issues. Some of these patients were referred from an outside otolaryngologist for an LEMG, which meant they likely followed-up with their local physician instead of continuing their care at our institution. CONCLUSION Patients with chronic unilateral vocal fold paralysis and LEMG evidence of laryngeal adductory synkinesis are more likely to have improved perception of their voice and therefore less likely to require permanent vocal fold augmentation compared to those without synkinesis. BIBLIOGRAPHY 1. Crumley RL. Laryngeal synkinesis revisited. Ann Otol Rhinol Laryngol 2000;109: Blitzer A, Jahn AF, Keidar A. Semon s law revisited: an electromyographic analysis of laryngeal synkinesis. Ann Otol Rhinol Laryngol 1996;105: Maronian NC, Robinson L, Waugh P, Hillel AD. A new electromyographic definition of laryngeal synkinesis. Ann Otol Rhinol Laryngol 2004;13: Statham MM, Rosen CA, Smith LJ, Munin MC. Electromyographic laryngeal synkinesis alters prognosis in vocal fold paralysis. Laryngoscope 2010;120: Wu BL, Sanders I, Mu, L, Biller HF. The human communicating nerve. An extension of the external superior laryngeal nerve that innervates the vocal cord. Arch Otolaryngol Head Neck Surg 1994;120: Sanders I, Wu BL, Mu L, Li Y, Biller HF. The innervation of the human larynx. Arch Otolaryngol Head Neck Surg 1993;119: Sanudo JR, Maranillo E, Leon X, Mirapeix RM, Orus C, Quer M. An anatomical study of anastomoses between the laryngeal nerves. Laryngoscope 1999;109: Mu L, Sanders I, Wu BL, Biller HF. The intramuscular innervation of the human interarytenoid muscle. Laryngoscope 1994;104 (1 pt 1): Brown MC, Holland RL, Hopkins WG. Motor nerve sprouting. Annu Rev Neurosci 1981;4: Slack JR, Hopkins WG, Williams MN. Nerve sheaths and motoneurone collateral sprouting. Nature 1979;282: Hydman J, Mattsson P. Collateral reinnervation by the superior laryngeal nerve after recurrent laryngeal nerve injury. Muscle Nerve 2008;38: Hirano M, Nosoe I, Shin T, Maeyama T. Electromyography for laryngeal paralysis. In: Hirano M, Kirchner J, Bless D, eds. Neurolaryngology: Recent Advances. Boston, MA: College Hill; 1987: Munin MC, Rosen CA, Zullo T. Utility of laryngeal electromyography in predicting recovery after vocal fold paralysis. Arch Phys Med Rehabilil 2003;84: Wang CC, Chang MH, Virgilio AD, et al. Laryngeal electromyography and prognosis of unilateral vocal fold paralysis a long-term prospective study. Laryngoscope 2014;125: Smith LJ, Rosen CA, Niyonkuru C, Munin MC. Quantitative electromyography improves prediction in vocal fold paralysis. Laryngoscope 2012; 122: Rosen CA, Lee AS, Osborne J, Zullo T, Murry T. Development and validation of the voice handicap index-10. Laryngoscope 2004;114: Johansson B. Myogenic tone and reactivity: definitions based on muscle physiology. J Hypertens Suppl 1989;7:S5 S Yung KC, Likhterov L, Courey MS. Effect of temporary vocal fold injection medialization on the rate of permanent medialization laryngoplasty in unilateral vocal fold paralysis patients. Laryngoscope 2011;121: Alghonaim Y, Roskie M, Kost K, Young J. Evaluating the timing of injection laryngoplasty for vocal fold paralysis in an attempt to avoid future type 1 thyroplasty. J Otolaryngol Head Neck Surg 2013;42: Friedman AD, Burns JA, Heaton JT, Zeitels SM. Early versus late injection medialization for unilateral vocal cord paralysis. Laryngoscope 2010;120: Rosen CA, Smith L, Young V, Krishna P, Muldoon MF, Munin MC. Prospective investigation of nimodipine for acute vocal fold paralysis. Muscle Nerve 2014;50: Gomez TM, Spitzer NC. In vivo regulation of axon extension and pathfinding by growth-cone calcium transients. Nature 1999;397: