A Prospective Crossover Trial of Botulinum Toxin Chemodenervation Versus Injection Augmentation for Essential Voice Tremor

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1 The Laryngoscope VC 2017 The American Laryngological, Rhinological and Otological Society, Inc. A Prospective Crossover Trial of Botulinum Toxin Chemodenervation Versus Injection Augmentation for Essential Voice Tremor Christine Estes, MM, MA ; Babak Sadoughi, MD ; Rachel Coleman, MS; Harini Sarva, MD; Elizabeth Mauer, MS; Lucian Sulica, MD Objectives/Hypothesis: Botulinum toxin chemodenervation (BTX) is used to treat essential voice tremor (EVT), but results are not uniformly satisfactory. This study sought to assess the comparative utility of injection augmentation ( for EVT. Study Design: Prospective crossover treatment study. Methods: Patients with EVT underwent BTX. After washout patients underwent IA. Multidimensional assessment carried out prior to and 30 days after each treatment included 1) videostroboscopy graded by the Vocal Tremor Scoring System (VTSS), 2) acoustic and aerodynamic assessment (cepstral peak prominence, cepstral spectral index of dysphonia, cepstral peak prominence fundamental frequency, airflow, peak air pressure and intensity, maximum phonation time, and amplitude/ frequency of tremor), 3) audio-perceptual assessment via Consensus Audio-Perceptual Evaluation of Voice (CAPE-V), and 4) patient self-assessment via Voice Handicap Index-10 (VHI-10) and Percent of Normal Function (PNF) scale. Findings were analyzed via paired t tests and Wilcoxon rank sum tests. Results: Seven patients (five female and two male; mean age 67 years old; range, years old) participated. VTSS grading showed divergent outcomes for certain individual sites of tremor, but without significant differences. Airflow increased following BTX and decreased following IA, and VHI-10 scores indicated slight improvement post-btx ( ), and decline post-ia ( ), although differences were not significant. Only changes in audio-perceptual ratings of loudness achieved significance, which decreased with BTX and increased with IA. Five patients chose to resume BTX; two elected long-term IA. No findings supported patient preferences. Conclusions: IA demonstrated no advantage over BTX in the treatment of EVT. Key Words: Essential tremor, voice tremor, botulinum toxin, injection augmentation, laryngeal injection. Level of Evidence: 2b. Laryngoscope, 128: , 2018 INTRODUCTION Essential voice tremor (EVT) is the phonatory manifestation of essential tremor, an age-related disease of involuntary movement. 1 Symptoms of EVT are the result of action-induced involuntary oscillation of muscles involved in phonation, often beyond those of the larynx itself, creating rhythmic alterations of pitch and loudness. 1 4 Patients with EVT may present with complaints of dysphonia, increased vocal effort, decreased intelligibility and volume, and socioemotional impairment secondary to the condition. From the Sean Parker Institute for the Voice, Department of Otolaryngology Head and Neck Surgery (C.E., B.S., R.C., L.S.), Department of Neurology (H.S.), and Department of Biostatistics and Epidemiology (E.M.), Weill Cornell Medical College, New York, New York, U.S.A Editor s Note: This Manuscript was accepted for publication on August 18, Presented at the 2017 American Laryngological Annual Meeting at the Combined Otolaryngology Spring Meetings, San Diego, California, U.S.A., April 26 30, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Christine Estes, The Sean Parker Institute for the Voice 240 East 59th Street, New York, NY che2013@med.cornell.edu DOI: /lary Botulinum toxin chemodenervation (BTX) of the intrinsic laryngeal adductor muscles is commonly used to manage symptoms of EVT based on the assumption that glottic tremor and the resulting inappropriate glottic aperture cause the greater part of symptoms reported by patients. Results of treatment are not uniformly satisfactory. 1,5 9 In contrast to its action in some cases of spasmodic dysphonia, BTX does not eliminate the involuntary motion, but simply decreases tremor amplitude, sometimes at the cost of compromising glottic closure. As a result, post-treatment vocal function may remain meaningfully impaired; prolonged breathy dysphonia after injection is the most common reason that treatment is abandoned. 1 In addition, BTX cannot be used to treat frequently involved pharyngeal, base of tongue, and other muscles without risk of dysphagia. Based on clinical observations, we hypothesized that glottic insufficiency is an important cofactor in EVT dysphonia. Increased vocal effort as a result of glottic insufficiency may cause more significant muscle activation and greater tremor amplitude in this action-induced movement disorder, and correspondingly more severe symptoms. Injection augmentation ( is a wellestablished treatment for glottic insufficiency in other conditions such as vocal fold paralysis, paresis, or atrophy. Therefore, we hypothesized that IA may reduce 437

2 TABLE I. Study Visit Protocol. Visit Visit Type Visit Timing 1 Baseline assessment 1 BTX treatment Day 1 2 BTX treatment assessment 130 days (Washout period) 3 Baseline assessment 1 IA treatment days 4 IA treatment assessment 130 days BTX 5 botulinum toxin chemodenervation; IA 5 injection augmentation. vocal effort in patients with EVT and provide a treatment alternative to BTX. This study aimed to compare the results of BTX to those of IA in a group of patients with EVT. MATERIALS AND METHODS The Weill Cornell Medical College Institutional Review Board approved this study. Adult patients with EVT were offered enrollment. As with diagnosis of essential tremor overall, diagnosis of EVT is based on clinical criteria. EVT was suspected when patients demonstrated rhythmic fluctuations in vocal intensity and/or pitch. EVT was diagnosed when flexible endoscopic observation revealed periodic involuntary oscillatory motion of the larynx, sometimes extending to the palate and/or pharynx. Patients with laryngeal pathology other than tremor, including other laryngeal movement disorders, were excluded. Subjects were seen for four visits as outlined in Table I. Assessment At each visit subjects underwent multidimensional assessment comprised of videostroboscopic examination, acoustic and aerodynamic assessment, audio-perceptual analysis, and selfassessment of function. Stroboscopic examination was performed via flexible endoscopy. Subjects completed a series of maneuvers to elicit vocal fold motion including abduction, adduction, and lengthening. A laryngologist who did not administer treatment and was blinded to visit type rated severity of tremor using the Vocal Tremor Scoring System (VTSS). 10 Acoustic and aerodynamic measures were obtained by a speech language pathologist (SLP) with speciality and training in voice disorders. For acoustic assessment, subjects produced a sustained /a/ sound at their habitual speaking pitch and loudness and read assessment sentences from the Consensus Audio- Perceptual Evaluation of Voice (CAPE-V) 11 protocol. Tasks were recorded and analyzed using the Analysis of Dysphonia in Speech and Voice (ADSV) and Multi-Dimensional Voice Profile (MDVP) software from the Computerized Speech Lab (Pentax, Montvale, NJ). A handheld microphone 3 inches from the subjects mouths was used for all recordings. The Sustained Vowel and All-Voiced Sentence ( We were away a year ago ) protocols of the ADSV were used to obtain cepstral peak prominence (CPP), cepstral peak prominence fundamental frequency (CPP F0), CPP F0 standard deviation (CPP F0 SD), and cepstral spectral index of dysphonia (CSID). The MDVP was used to obtain amplitude tremor intensity index (ATRI), frequency tremor intensity index (FTRI), amplitude tremor frequency (Fatr), and fundamental frequency tremor frequency (Fftr). CAPE-V analysis was completed by a voice-specialized SLP blinded to visit type. Aerodynamic data were collected using the Phonatory Aerodynamic System (PAS) 6600 (Pentax). Subjects held a facemask coupled to a pneumotachometer with a pressuresensor tube firmly over the nose and mouth, and rested the pressure-sensor tube in the oral cavity above the tongue. They produced sustained /a/ and We were away a year ago, from which mean airflow and mean intensity/loudness were analyzed via the Maximum Sustained Phonation and Running Speech protocols. A string of five consonant-vowel syllables (/pa/) at a comfortable pitch and loudness were analyzed through the Voicing Efficiency protocol to determine mean peak air pressure. Subjects completed the Voice Handicap Index-10 (VHI- 10) 12 and the Percent of Normal Function (PNF) Scale 13 at visits 1 and 3 (see Table I), daily for the following 14 days, and then weekly. Measures at visits 1 and 3 were compared using paired t tests and Wilcoxon signed rank tests to ensure that the effects of BTX did not persist at the time of IA. Descriptive statistics, including mean, standard deviation, median, and range for all measures and for the change from pre- to post-treatment for all measures were reported. Wilcoxon signed rank tests were used to analyze the delta (D) between median scores at visits 1 and 2 (BTX outcome) and between visits 3 and 4 (IA outcome). To compare whether there were significant differences after treatment between BTX and IA, baseline mean scores were first subtracted from post-treatment scores, and then comparative analysis was completed using the Wilcoxon signed-rank test. All analyses were performed in R version for Windows 64-bit (The R Foundation for Statistical Computing, Vienna, Austria), and all tests were two-sided with statistical significance evaluated at the 0.05 a level. Treatment Procedures Botulinum toxin (Botox; Allergan, Dublin, Ireland) was administered via electromyographically-guided percutaneous injection. Subjects were treated with their usual pattern of injections (five bilateral and two unilateral) and dose, or if this was not available, our usual starting dose of 0.83 U in each adductor muscle complex (mean U; range, U), based on our understanding that EVT is a bilateral, approximately symmetric disorder. IA was performed via endoscopically-guided percutaneous injection via the cricothyroid membrane approach in the awake, unsedated subject using buffered hydrogel (RENUGel; Regen Scientific, East Troy, WI). Injections were bilateral in every case. As is routine for augmentation, vocal folds were overinjected to allow for resorption of the aqueous component of the injectable. RESULTS Seven subjects participated in this study. The cohort consisted of five females and two males, with a mean age of 67 years (range, years). Analysis of all measures at visits 1 and 3 (see Table I) demonstrated no statistically significant difference; this ensured that the effects of BTX did not influence post-ia scores. VTSS Analysis Results of VTSS analysis, including individual assessment areas and total score, are shown in Table II. A statistically significant decrease in score was found post-ia for pharyngeal wall tremor (P 5.037). Analysis of other sites of tremor showed some divergence. For instance, tremor of the base of tongue increased post- BTX (0.57 1, D 0.43), but decreased post-ia ( , 438

3 TABLE II. Results of Vocal Tremor Scoring System Analysis. Site of Tremor Visit Mean SD Median Minimum Maximum Value Base of tongue D BTX D IA Larynx D BTX D IA Palate D BTX D IA Pharyngeal walls D BTX D IA Supraglottis D BTX D IA True vocal folds D BTX D IA Total D BTX D IA BTX 5 botulinum toxin chemodenervation; IA 5 injection augmentation; SD 5 standard deviation. D 20.14). Tremor of the palate decreased post-btx ( , D 20.43) and increased post-ia ( , D 0.14). Tremor of the supraglottis decreased post-btx (2.14 1, D 21.14) and decreased post-ia ( , D 0.14). However, when comparing the two treatments, there were no statistically significant differences for individual sites of treatment (Table II) or for total VTSS score (P 5.595). 439

4 Acoustic Analysis Results of acoustic analysis are displayed in Table III. No statistically significant differences were found in post-treatment outcomes or in comparing BTX outcomes to IA outcomes. CSID, a measure of dysphonia severity, decreased to within normal limits with both treatments. IA yielded greater improvement ( , D ) compared to BTX ( , D 29.12). Mean CPP improved post-btx and post-ia (BTX: db, D 0.33; IA: db, D 1.33). Mean CPP F0 decreased post-btx and post-ia (BTX: Hz, D 29.02; IA: Hz, D 25.11), and CPP F0 SD decreased for both (BTX: db, D 21.98; IA: db, D 22.46). Other acoustic measures specific to tremor (Fatr, Fftr, FTRI, ATRI) showed minimal change from baseline to treatment, and no statistically significant differences were found between treatments. Mean FTRI and ATRI were above normal limits at all visits. Aerodynamic Analysis Table IV displays results of aerodynamic analysis. Pre- and post-treatment measures were not statistically significant, nor were differences between treatments. Mean expiratory airflow during sustained /a/ was elevated from normative values across all visits, but increased post-btx and decreased post-ia (BTX: L/s, D 0.11; IA: L/s, D 20.11). Similarly, mean airflow during the all-voiced sentence, We were away a year ago, was elevated across all visits (BTX: 0.32 to 0.38 L/s; IA: L/s), but increased post- BTX (D 0.06) and decreased (D 20.08) post-ia. Mean peak air pressure, an estimate of subglottic pressure, increased both post-btx and post-ia (BTX: cm H 2 O, D 0.94; IA: cm H 2 O, D 0.42). This finding suggested that phonatory effort increased, regardless of treatment. Mean intensity/loudness decreased both post-btx and post-ia (BTX: db, D 21.27; IA: db, D 20.34), and maximum phonation time was below normal limits at all visits and reduced further with both treatments (BTX: seconds, D 23.06; IA: seconds, D 20.66). CAPE-V Analysis Analyses of audio-perceptual outcomes are shown in Tables V and VI. Consistent with airflow measures, mean breathiness increased post-btx (sustained /a/: , D 10.86; sentence: , D 2.14) and decreased post-ia (sustained /a/: , D 20.29; sentence: , D ). No statistically significant differences were found for either treatment (Tables V and VI), or between treatments (/a/: P 5.141, sentence: P 5.089). Although aerodynamic analysis showed decreased intensity/loudness following both treatments, subjects were perceived by a blinded listener to be softer in volume post-btx and louder post-ia. Scores increased (worsened) on sustained /a/ post-btx ( , 440 D 8.43) and decreased (improved) post-ia ( , D 20.29), but without statistical significance for either treatment (Tables V and VI) or when comparing treatments (P 5.553). Similarly, scores on the all-voiced sentence increased (worsened) post-btx ( , D 5.71) and decreased (improved) post-ia ( , D ). A statistically significant reduction in strain in the all-voiced sentence was found post-btx ( , D , P 5.022), but no statistically significant difference was found when comparing treatments (P 5.090). Overall CAPE-V scores were above normal limits at all visits. However, a statistically significant decrease was found for the all-voiced sentence post-btx ( , D 28.29, P 5.035). There were no statistically significant differences in overall scores when comparing treatments (/a/: P 5.150, sentence: P 5.933). Subject Self-Assessment Analysis of subject self-assessment is displayed in Table VII. Scores on the PNF Scale increased (improved) with both treatments (BTX: 40% 45%, D 5%; IA: 34% 44%, D 10%). Statistical significance was not found when comparing pre- and post-treatments (BTX: P 5.400, IA: P 5.094) or when comparing the two treatment outcomes (P 5.313). Mean VHI-10 scores were above normal limits (>11) at all visits. Scores decreased (improved) slightly post-btx ( , D 22.71), but increased (worsened) post-ia ( ; D 4.00). No statistically significant differences were found when comparing treatments (P 5.353). Subject Preferences Two subjects (one male, one female) reported excellent results from IA and chose to repeat IA after study completion. Their outcomes were analyzed against the remaining subjects; no statistically significant differences were found. Although not statistically significant, VHI-10 scores after BTX improved (D 29) for the five individuals who preferred BTX and worsened (D 1 13) for the two individuals who preferred IA (P 5.191). The opposite was not true for IA, as scores worsened slightly after IA for both groups (IA preference [two subjects] 1 2.5; BTX preference [five subjects] 1 4.6; P 5.696). DISCUSSION The first line of treatment for essential tremor is usually pharmacologic. Propranolol and primidone are mainstays in the treatment of essential limb tremor, with documented efficacy in clinical trials in a substantial proportion of patients. Other pharmacologic agents used include methazolamide and gabapentin, albeit with less support in the literature. None of these have proved broadly effective in EVT In this respect, EVT resembles head tremor, another axial tremor, as opposed to extremity tremor.

5 TABLE III. Results of Acoustic Analysis. Measure Visit Mean SD Median Minimum Maximum Value CPP F0 (Hz) D BTX D IA CPP F0 SD D BTX D IA CPP (db) D BTX D IA CSID D BTX D IA Fatr (Hz) D BTX D IA Fftr (Hz) D BTX D IA FTRI (%) D BTX D IA ATRI (%) D BTX D IA ATRI 5 amplitude tremor intensity index; BTX 5 botulinum toxin chemodenervation; CPP 5 cepstral peak prominence; CPP F0 5 cepstral peak prominence fundamental frequency; CPP F0 SD 5 CPP F0 standard deviation; CSID 5 cepstral spectral index of dysphonia; Fatr 5 amplitude tremor frequency; Fftr 5 fundamental frequency tremor frequency; FTRI 5 frequency tremor intensity index; IA 5 injection augmentation; SD 5 standard deviation. 441

6 TABLE IV. Results of Aerodynamic Analysis. Measure Visit Mean SD Median Minimum Maximum Value Mean airflow during voicing (L/s) Mean expiratory airflow / a/ (L/s) Mean peak air pressure (cm H 2 0) D BTX D IA D BTX D IA D BTX D IA Mean loudness (SPL db) D BTX D IA MPT (s) D BTX D IA BTX 5 botulinum toxin chemodenervation; IA 5 injection augmentation; MPT 5 maximum phonation time; SD 5 standard deviation. In the context of equivocal benefit from systemic medication, BTX has become a common treatment for EVT, despite inconsistent and/or incomplete benefit. 1,5 9 An open crossover trial of unilateral versus bilateral BTX injection in patients with EVT 7 showed no statistically significant improvement on acoustic analysis or blinded perceptual evaluation with either treatment. Despite this, eight of 10 patients chose to continue treatment, reporting decreased vocal effort, which was attributed to reduced laryngeal airway resistance. In an open trial study of 15 patients treated with BTX to the thyroarytenoid muscles, and in some cases to the cricothyroid or thyrohyoid muscles, 5 acoustic analysis showed significantly decreased FF0, nearly significant decreases in fundamental frequency (F0) variation, and significant mean improvement on blinded perceptual evaluation, but only 10 patients (67%) reported subjective benefit. A study of 13 patients who underwent dose-randomized BTX and were followed for 6 weeks 6 found significant improvements to F0 variation, blinded perceptual evaluation, and patient self-evaluation. A study of 34 patients with EVT, 16 of whom elected BTX, 1 found that seven (44%) chose to discontinue BTX, citing postinjection breathiness as the reason. More recently, a retrospective review of 16 patients 9 has suggested refinements to BTX treatment protocol, outlining a treatment paradigm dependent upon individualized tremor findings, specifically predominant horizontal or vertical tremor. We hypothesized that glottic insufficiency, appreciated clinically in many patients with EVT, may exacerbate both tremor amplitude, by increasing adductor muscle activation, as well as tremor symptoms, by compounding the effect of the open glottis during that portion of the tremor cycle. We expected that IA would reduce tremor amplitude and improve voice, possibly to a greater extent than weakening muscle with BTX 442

7 TABLE V. Results of CAPE-V Analysis for Sustained /a/. Variable Visit Mean SD Median Minimum Maximum Value Breathiness D BTX D IA Loudness D BTX D IA Pitch D BTX D IA Roughness D BTX D IA Strain D BTX D IA Overall D BTX D IA BTX 5 botulinum toxin chemodenervation; CAPE-V 5 Consensus Audio-Perceptual Evaluation of Voice; IA 5 injection augmentation; SD 5 standard deviation. chemodenervation and thus potentially exacerbating any insufficiency present. Existing studies regarding tremor activation concern extremity involvement, and proved difficult to extrapolate to the larynx because aspects such as weight loading, force tremor, and resistance training were not directly translatable to phonatory vocal fold adduction. In upper extremities, abnormal motor unit entrainment at the frequency of the tremor, excessive agonist activity, inappropriate agonist and antagonist cocontraction, heightened stretch reflex activity, and reduced force steadiness of the digits are all important factors in essential tremor (ET) progression and disability. 20 In a study of 10 ET patients assessing force tremor, a feature of ET that occurs as a result of muscle contraction such a gripping a bag, suggested that the frequency of the tremor was worse at 10% of maximum voluntary contraction than at 60% of maximum voluntary contraction. 21 Another study comparing two groups with ET, one with more motor unit entrainment than the other and one with healthy controls, 443

8 TABLE VI. Results of CAPE-V Analysis for All-Voiced Sentence, We Were Away a Year Ago. Variable Visit Mean SD Median Minimum Maximum Value Breathiness D BTX D IA Loudness D BTX D IA Pitch D BTX D IA Roughness D BTX D IA Strain D BTX D IA Overall D BTX D IA BTX 5 botulinum toxin chemodenervation; CAPE-V 5 Consensus Audio-Perceptual Evaluation of Voice; IA 5 injection augmentation; SD 5 standard deviation. demonstrated that the fluctuations in force and tremor peaks based on spectral analysis were more prominent at lower contraction intensities. 22 As a result of this work looking at force and tremor severity, studies were developed assessing resistance training. Resistance training in small studies has shown to reduce motor unit firing rate variability and upper limb coactivation of muscles, and improve digit force steadiness and intraand intermuscle coordination, resulting in improved motor control in ET. 20 In sum, extremity studies suggest 444 that muscle activation may exert a stabilizing force on tremor, possibly at odds with part of our clinical hypothesis. Our analyses provided some predictable results. Transglottal airflow and breathiness decreased after IA, in contrast to the results of BTX treatment. VTSS analysis showed overall reduction of tremor amplitude with both treatments. However, no findings demonstrated that IA offered superior symptom relief to our subject cohort.

9 TABLE VII. Results of Subject Self-Assessment. Measure Visit Mean SD Median Minimum Maximum Value PNF Scale D BTX D IA VHI D BTX D IA BTX 5 botulinum toxin chemodenervation; IA 5 injection augmentation; PNF 5 Percent of Normal Function; SD 5 standard deviation; VHI-10 5 Voice Handicap Index-10. Despite this, subjects expressed clear preference for one treatment or the other. Two chose to pursue longterm IA, whereas five continued with BTX, yet there were no statistically significant differences found when comparing the two groups. Like other treatment studies for this complicated condition, it appears that current metrics do not capture successful treatment outcomes well. The primary limitation of this study is small sample size, perhaps insurmountable for an uncommon condition in a single center. A larger subject cohort yielding more statistical power is essential to capture limited differences in treatment. The treatment sequence was not randomized, a decision driven by the more predictable washout period of BTX than injectable. This, combined with the fact that subjects had had BTX in the past, may have created high expectations for IA treatment that influenced self-ratings when they were not met; several patients expressed strong disappointment at the final study visit. Finally, treatment (BTX and was administered uniformly. A more individualized methodology might have yielded more significant findings. 9 Our management algorithm for EVT has been detailed elsewhere. 23 In brief, patients who have other troublesome manifestations of essential tremor in addition to EVT are referred for a trial of pharmacologic management. Those for whom EVT is the only complaint are offered a choice of pharmacologic management or BTX. The results of this study leave this unaltered. We reserve a trial of IA for those whose symptom control after BTX remains poor enough to discontinue treatment. Future investigation may examine combined treatment with BTX and IA; IA may help minimize postinjection breathiness and permit more aggressive dosing and possibly more thorough relief. Additionally, for some patients the inclusion of behavioral management may maximize the benefits of treatment and extend them to the context of functional speech production. 24 CONCLUSION EVT remains a functionally limiting manifestation of ET often unresponsive to medication effective in other forms of the disorder and imperfectly treated with BTX. Despite clinically observed glottic insufficiency in some patients, this study reveals no increased benefit from IA in comparison to BTX in a small cohort. EVT remains a treatment challenge; future studies will benefit from improved metrics and larger sample sizes. BIBLIOGRAPHY 1. Sulica L, Louis E. Clinical characteristics of essential voice tremor: a study of 34 cases. Laryngoscope 2010;120: Massey EW, Paulson GW. Essential vocal tremor: clinical characteristics and response to therapy. South Med J 1985;78: Hachinski VC, Thomsen IV, Buch NH. The nature of primary vocal tremor. Can J Neurol Sci 1975;2: Brown JR, Simonson J. Organic voice tremor. A tremor of phonation. Neurology 1963;13: Hertegard S, Grandqvist S, Lindestad PA. Botulinum toxin injections for essential voice tremor. Ann Otol Rhinol Laryngol 2000;109: Adler C, Bansberg S, Hentz J, et al. Botulinum toxin type A for treating voice tremor. Arch Neurol 2004;61: Warrick P, Dromey C, Irish J, Durkin L, Pakiam A, Lang, A. Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: a crossover design study of unilateral versus bilateral injection. Laryngoscope 2000;110: Warrick P, Dromey C, Irish J, Durkin L. The treatment of essential voice tremor with botulinum toxin A: a longitudinal case report. J Voice 2000; 14: Gurey L, Sinclair C, Blitzer A. A new paradigm for the management of essential vocal tremor with botulinum toxin. Laryngoscope 2013;123: Bove M, Daamen N, Rosen C, Wang C, Sulica L, Gartner-Schmidt J. Development and validation of the Vocal Tremor Scoring System. Laryngoscope 2006;116: Kempster G, Gerratt B, Verdolini Abbott K, Barkmeier-Kraemer J, Hillman R. Consensus Auditory-Perceptual Evaluation of Voice: development of a standardized clinical protocol. Am J Speech Lang Pathol 2009; 18: Rosen CA, Lee AS, Osborne J, Zullo T, Murry T. Development and validation of the Voice Handicap Index-10. Laryngoscope 2004;114:

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