ORIGINAL CONTRIBUTION. Botulinum Toxin Type A for Treating Voice Tremor

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1 ORIGINAL CONTRIBUTION Botulinum Toxin Type A for Treating Voice Charles H. Adler, MD, PhD; Stephen F. Bansberg, MD; Joseph G. Hentz, MS; Lorraine O. Ramig, PhD; Eugene H. Buder, PhD; Kristi Witt, MS; Brian W. Edwards, MA; Kari Krein-Jones, MS; John N. Caviness, MD Background: Voice tremor, like spasmodic dysphonia and other tremor disorders, may respond to botulinum toxin type A injections. Objective: To evaluate the safety and efficacy of botulinum toxin type A injections as treatment for voice tremor. Design: A randomized study of doses of botulinum toxin type A with weeks of follow-up. Setting: A single-site tertiary care center. Participants and Methods: Thirteen subjects (11 women, men; mean age, years) with voice tremor and no spasmodic dysphonia or head, mouth, jaw, or facial tremor were entered into this study. Patients received 1. U (n=),. U (n=), or. U (n=) of botulinum toxin type A in each vocal cord. All patients were evaluated at baseline and postinjection at weeks,, and. Main Outcome Measures: The primary outcome measure was the patient tremor rating scale, with secondary measures including patient-rated functional disability, response rating scale, independent randomized tremor ratings, and acoustical measures. Results: All patients at all dose levels noted an effect from the injection. The mean time to onset of effect was. days (range, 1- days). For all patients combined, mean tremor severity scale scores (rated by patients on a -point scale) improved 1. points at week, 1. points at week, and 1. points at week. Measures of functional disability, measures of the effect of injection, independent ratings of videotaped speech, and acoustic measures of tremor also showed improvement. The main adverse effects at all doses were breathiness and dysphagia. Conclusion: Voice tremor improves following injections of botulinum toxin type A. Arch Neurol. 00;1:1-10 Author Affiliations: Parkinson s Disease and Movement Disorders Center, Department of Neurology (Drs Adler and Caviness, Mss Witt and Krein-Jones, and Mr Edwards), Department of Otorhinolaryngology (Dr Bansberg), Department of Biostatistics (Mr Hentz), Mayo Clinic Scottsdale, Scottsdale, Ariz; Department of Communication Disorders and Speech Science, University of Colorado at Boulder (Dr Ramig); School of Audiology and Speech-Language Pathology, University of Memphis, Memphis, Tenn (Dr Buder). Financial Interest: Dr Adler has previously received research funding and honoraria from Allergan. ESSENTIAL TREMOR IS A VERY common movement disorder that has an increased incidence with age. 1, Essential tremor most often affects the hands and head, and although voice tremor is not as common, it can be very embarrassing and disabling. Voice tremor can be isolated or associated with tremor of other body parts, and it must be distinguished from spasmodic dysphonia, a dystonic disorder of the larynx., Treatments for essential tremor include oral medications and surgery. Oral medicationsarepartiallybeneficialforhandandhead tremor but not very effective for voice tremor., Surgicalintervention,suchasthalamotomy and thalamic stimulator implantation, is recommended for medicationrefractory patients., However, these treatments are primarily recommended for hand tremor, with some reports showing benefit forvoicetremor. BotulinumtoxintypeAinjections (BoNT-A) (Botox; Allergan, Irvine, Calif) are considered the treatment of choice for laryngeal dystonia, and they are beneficial for hand and head tremors. -1 Three small studies 1-1 and one case report 1 have found some benefit of BoNT-A for voice tremor. We present a randomized dose, randomizedobjectivevideo,andrandomizedobjective audio assessment trial of BoNT-A injections for the treatment of voice tremor. METHODS Thirteen consecutive subjects with voice tremor without spasmodic dysphonia or head, mouth, jaw, or facial tremor, who were willing to receive BoNT-A injections, were entered into this study between 1 and 000, after they signed writteninformedconsentformsapprovedbythemayo Clinic Institutional Review Board. Patients with head, mouth, and jaw tremors were excluded because these tremors can result in tremuloussoundingvoices.otherexclusioncriteriaincluded age less than 1 years, known neuromuscular junction disorders, concurrent treatment with dantrolene sodium or aminoglycosides, concurrent signs of parkinsonism, and previous treatmentwithbont-a. Thepresenceoflimbortrunk (REPRINTED) ARCH NEUROL / VOL 1, SEP 00 1 Downloaded From: on 1//01 00 American Medical Association. All rights reserved.

2 Table. Change From Baseline Severity, for All Dose Groups Combined Change From Baseline No. of Patients Mean (SD) Mean (SD) P Value % Confidence Interval Patient-rated tremor severity scale Baseline 1.00 (0.) Week 1 1. (0.) 1. (1.1) to 0. Week 1 1. () 1. (1.).00. to 0. Week (1.11) 1. (1.).001. to 0. Patient-rated functional disability scale Baseline 1.1 (0.) Week 1.0 (0.) 0. (1.1). 0. to 0. Week 1 1. (0.) (1.1) to 0. Week 1 0. (0.) 1. (1.1) to 0. Patient-rated effect of injection Week 1 1. (.0) to. Week 1.0 (1.) to. Week 1. (1.) to. Investigator-rated tremor severity based on videotape review Baseline 1.1 (0.) Week (0.) 1. () to 0. Week 1 1. (0.) 0. (0.1) to 0. Week (0.) 0.0 (0.) to 0. Fundamental frequency tremor (log-transformed percent modulation) Baseline (0.) Week 1.1 (0.) 0. (0.). 0. to 0.0 Week (0.1) 0. (0.0).0 1 to 0.0 Week 11 (0.) 0. (0.).0 0. to 0.01 tremor did not exclude patients. Women were excluded if they were pregnant, nursing, or had an unprotected risk of pregnancy. At baseline, all patients completed the tremor severity scale (0 [no tremor] to [severe tremor]) 1 and a functional disability scale (0 [none] to [severe, unintelligible speech]); the patients were videotaped and underwent videolaryngostroboscopy. severity was also rated by the physician. Vocal tasks were recorded onto reel-to-reel audiotapes via headset microphones. Videotape and audiotape segments included the patient reading a standardized paragraph as well as performing a sustained ah. Patients taking concurrent tremor medications were instructed not to change the dose or frequency of treatment during the duration of the study; also, new medications could not be given. Botulinum toxin type A was reconstituted with normal saline at a concentration of. U/0.1 ml and was injected percutaneously under electromyographic guidance with a -in - gauge needle through the cricothyroid membrane. 0 At the time of injection, patients were randomized to receive 1. U,. U, or. U into each vocal cord. These doses were chosen based on previous reports 1,1 and because. U was the starting dose used in our office at that time for patients with adductor spasmodic dysphonia. Randomization was accomplished by the treating physician randomly choosing the dose from 1 identical treatment kits created prior to study initiation. Neither the patient nor any of the individuals assessing treatment response were made aware of the treatment allocation (assessments were performed by blinded videotape or acoustical review). Patients were reassessed at weeks,, and. They were asked to rate their vocal tremor response to BoNT-A injection on a scale from + (marked improvement) to (marked worsening). Adverse events were recorded at each visit and rated as mild, moderate, or severe. All videotape segments from all the patients (at baseline and the follow-up visits) were randomized; then they were dubbed onto a master tape by an independent video specialist using a randomization list provided by the statistician. These segments were then reviewed and independently rated by blinded investigators. A total of video segments were rated (1 patients, visits per patient). Sample size was determined prior to beginning the study, butthestudywasterminatedafterweenrolledonly1oftheplanned 1 subjects because of very slow enrollment. The decision to terminate the study was made prior to unblinding the data. The modulographic method was used for acoustic assessment of tremor. 1 The analysis produces low-frequency spectrograms of modulations in fundamental frequency (f 0 ) and intensity parameters. There were a total of measures. For each parameter, there are ordinarily domains of analysis that use different bandwidths of Fourier analysis: (1) wow, from 0.1- to -Hz modulations; () tremor, from - to -Hz modulations; and () flutter, modulations from to 0 Hz. The modulogram is preferable to the measures used in previous tremor treatment studies 1, because a wide range of specific modulation frequencies can be examined distinctly. Audio recordings were digitized and transferred to a blinded laboratory group for acoustic analysis to assess modulations of f 0 in the tremor domain ( to Hz). Files were first submitted to amplitude and pitch determination algorithms in the CSpeechSP environment to extract intensity and f 0. Some phonations were essentially aphonic and hence unanalyzable for f 0. Severely tremulous phonations exhibited frequent voice breaks. To construct a continuous record, simple interpolations were used across gaps in f 0 but only when such gaps spanned less than a complete tremor cycle. Special accommodations were also made for very short (- to -second) phonations by omitting wow analysis (which normally requires more than seconds of continuous phonation). This was acceptable because the primary interest in this population was in the tremor domain of to 0 Hz. The extracted acoustic parameters of these phonations were submitted to the modulogram procedure. 1 Outcomes are summarized by calculating an instability metric as the product of a frequency-specific modulation (percent variation around mean level) times the proportion of phonation time affected by that modulation. The modulogram supports these selections by displaying a histogram of cumulated magnitudes for each instability tape; typically, the mode of the histogram represents the chief in- (REPRINTED) ARCH NEUROL / VOL 1, SEP Downloaded From: on 1//01 00 American Medical Association. All rights reserved.

1 0.1 0. 0. 0. 0.0.1.. 1. 0. 0 1 1 1 Hz 0 1 1 1. 1. 1 0..... 1 Decibel 0 0 0 0 0 1 1 1 1 1 1 Hz Fundamental Frequency 00 0 0 0 0 Figure 1.

Each set contains a plot of the acoustic parameter across time and low-frequency spectrograms depicting modulations in the parameter: 1 for tremor frequencies (- Hz) and 1 for flutter frequencies (-0

3 Hz Decibel Hz Fundamental Frequency Figure 1. Modulogram of sustained phonation by a patient with essential tremor, pretreatment. Upper panels depict variations in intensity; lower panels depict fundamental frequency. Each set contains a plot of the acoustic parameter across time and low-frequency spectrograms depicting modulations in the parameter: 1 for tremor frequencies (- Hz) and 1 for flutter frequencies (-0 Hz). Gray scales to the left index the modulation depths in the percent of mean level. Histograms to the right show time-collapsed cumulative summaries of the modulations. stability in that domain. In this application, the primary interest was in the instability of f 0 in the tremor domain. However, apparently unrelated wow modulations were often observed to leak into the tremor panel. Hand inspection of each modulogram was performed to check for this artifact. Whenever the dominant instability within a tremor display was attributable to leakage from a lower frequency wow and a higher tremordomain frequency produced a clear mode, that tremor frequency was instead reported. This technique guaranteed that the pretreatment and posttreatment samples were being compared for the same type of distinctly tremulous component. Changes from baseline were assessed by using the paired t test for the primary outcome measure (patient tremor rating) and secondary outcome measures (patient disability rating, videotape ratings, BoNT-A response rating, and acoustic measures). The dose-response relationships were quantified by using the slope of the linear regression model for the change from baseline to dose. A % confidence interval (CI) was calculated for the slope of each regression line to assess the margin of error for the dose-response relationship. The pairwise correlations among the video scores from the raters were quantified using the Pearson correlation coefficient, and the overall interrater reliability was calculated using the intraclass correlation coefficient. All P values were for -sided tests. RESULTS The mean age was years (range, -1 years), with 11 women and men. Five of the 1 patients had concomitant mild-moderate bilateral postural or terminal tremors, and 1 had unilateral arm tremor. Concomitant tremor medications included propranolol (n=), primidone (n=1), and clonazepam (n=). Five patients received BoNT-A 1. U/cord, received. U/cord, and received. U/cord. All patients completed the entire study. All patients at all dose levels perceived some effect from the BoNT-A injection, mean time to onset being. days (range, 1- days). Mean patient ratings of the tremor severity scale for all dose groups combined (baseline, ) improved 1. points at week, 1. points at week, and 1. points at week (Table). The scores improved in all dose groups at all time points. Patient-rated functional disability (baseline,.1) improved 0. points at week, 1.1 points at week, and 1. points at week, for the combined group data (Table). Patient-rated effect from the BoNT-A injection showed benefit (Table). (REPRINTED) ARCH NEUROL / VOL 1, SEP Downloaded From: on 1//01 00 American Medical Association. All rights reserved.

0. 0.1 0. 0. 0.1 0.0 1. 1. 0. 0. 0.1. 1. 1. 0. 0. 0. 0.1 0. 0. 0.1 0.0 1. 1. 0. 0. 0.1. 1. 1. 0. 0. Wow Wow Decibel Fundamental Frequency 0 1 1 1 Hz 1. 0. 0 1 0 0 0 1 1 1 1 1 1 Hz 1. 0. 0 0 0 10 10 0 0 0 1 1 1 1.

4 Wow Wow Decibel Fundamental Frequency Hz Hz Cumulative Magnitude Cumulative Magnitude Figure. Modulogram of sustained phonation by the same patient depicted in Figure 1, weeks after a botulinum toxin type A injection of. U. This modulogram includes panels for wow frequencies (0.1- Hz). Note that gray scales are adjusted from Figure 1. The mean ± SD scores for all video segments rated were.1 ± for rater 1,. ± 0. for rater, and. ± 0.1 for rater. The correlation among reviewers was excellent, with a correlation coefficient greater than 0.0 and an interrater reliability of % (% CI, 0 to ). The independent randomized tremor ratings revealed significant improvement for the combined data at all time points (Table). The most sensitive acoustic measure was the logtransformed percent modulation. These results (in original modulation units) indicate that at the main tremor frequencies (usually - Hz), patients exhibited f 0 modulations on the order of % of their mean levels. These levels decreased to about half that level at weeks, to about % modulation depth at weeks, and to about % modulation depth at weeks. Average levels observed in control subjects (previously published data), however, were on the order of 1%. 1 Figure 1 and Figure display modulograms of one patient s phonations before and weeks after a.-u injection. Figure 1 omits wow panels to accommodate the short phonation. High-magnitude modulations are evident in the tremor and flutter panels, but the most relevant of these is a - to -Hz tremor of f 0 (reflected in a clear histogram mode to the right of the f 0 panel). Figure illustrates that in this patient the treatment was very effective weeks postinjection. The f 0 tremor is still evident at to Hz, but relatively high-magnitude instabilities remain at lower frequencies. The sample was too small to assess a dose-response relationship within the range of doses studied. At week, tremor severity scale scores improved by 0.0 points/ unit of BoNT-A (% CI, 0. to 0.), functional disability scale scores changed 0.1 points/unit (% CI, 1.1 to 0.), effect of injection scores increased 0. (REPRINTED) ARCH NEUROL / VOL 1, SEP Downloaded From: on 1//01 00 American Medical Association. All rights reserved.

5 points/unit (% CI, 0. to 1.), and videotape scores changed 0.1 points/unit (% CI, 0. to 0.). The main adverse effects at all doses were breathiness and dysphagia. At week, 11 of 1 patients had breathiness, and of1haddysphagia;allbut1improvedbyweek.patients rated these adverse effects as mild-severe in intensity, and they were most severe at week. Two patients experienced hoarseness, 1 excess phlegm, 1 fatigue, and 1 a cough. COMMENT Voice tremor can be a very disabling disorder that responds poorly to oral medications but well to botulinum toxin injections. While the severity of voice tremor averaged of in this study, many of the more severely affected patients withvoicetremorwereexcludedbecauseofconcurrenthead or jaw tremor, so results cannot be generalized to these patients. Improvement was significant for patient-rated tremor severity and functional disability and for tremor severity as rated by blinded reviewers. Improvement in voice tremor was of a similar degree as that found in patients with adductor spasmodic dysphonia ; this could extend the indications for botulinum toxin injections in terms of tremor disorders. 1 Becausethisstudydidnotincludeaplaceboarm, we cannot entirely rule out the possibility that improvement was due to regression to the mean or the physical nature of the injection into the vocal cord. This study also assessed the interrater reliability for videotape reviews of vocal tremor severity using the tremor severity scale. 1 The correlation and interrater reliability among all raters was excellent. Videotape reviews are therefore an excellent means for determining treatment effects because they can be randomized and independently rated. While we cannot rule out some placebo effect on the subjective ratings, these videotape results support a definite beneficial effect of the botulinum toxin injections. This was also the first study to use a frequencyspecific acoustic measure of tremor severity. The acoustic measures revealed that some voice modulation remains after the treatment, but the tremor-specific frequencies were often affected most directly by the treatment. As described in Methods, lower-frequency modulations can dominate an assessment of overall f 0 instability unless this assessment is focused on a specific frequency. The results of our study show that BoNT-A is a promising treatment for voice tremor, and further controlled studies should be pursued. Accepted for Publication: February, 00. Correspondence: Charles H. Adler, MD, PhD, Parkinson s Disease and Movement Disorders Center, Department of Neurology, Mayo Clinic Scottsdale, 100 E Shea Blvd, Scottsdale, AZ (cadler@mayo.edu). AuthorContributions: Studyconceptanddesign: Adler, Bansberg, Ramig, and Edwards. Acquisition of data: Adler, Bansberg, Witt, Edwards, Krein-Jones, and Caviness. Analysis and interpretation of data: Adler, Bansberg, Hentz, Ramig, and Buder. Drafting of the manuscript: Adler, Hentz, Buder, and Edwards. Critical revision of the manuscript for importantintellectualcontent: Adler, Bansberg, Hentz, Ramig, Buder, Witt, Krein-Jones, and Caviness. Statistical expertise: Hentz and Buder. Obtained funding: Adler. Administrative, technical, and material support: Bansberg, Hentz, and Krein-Jones. Study supervision: Adler, Bansberg, and Buder. Funding/Support: This study was funded by a grant from the Mayo Foundation, Rochester, Minn. Acknowledgment: We thank Bruce Pope for creating the randomized videotape; Alan Zinsmeister, PhD, for initial assistance with study design; and Jose Hernandez and Melissa Garafalo for assistance with data analysis. This article is dedicated to the memory of Brian Edwards. REFERENCES 1. Hubble JP. Essential tremor: diagnosis and treatment. In: Adler CH, Ahlskog JE, eds.parkinson sdiseaseandmovementdisorders:diagnosisandtreatmentguidelines for the Practicing Physician. Totowa, NJ: Humana Press; 000:-.. Dogu O, Sevim S, Camdeviren H, et al. Prevalenceofessentialtremor: door-to-door neurologic exams in Mersin Province, Turkey. Neurology. 00;1: Massey EW, Paulson GW. Essential vocal tremor: clinical characteristics and response to therapy. South Med J. 1;:-1.. Findley LJ, Gresty MA. Head, facial, and voice tremor. In: Jankovic J, Tolosa E, eds. Advances in Neurology: Facial Dyskinesias. Vol. New York, NY: Raven Press; 1:-.. Koller WC, Glatt S, Biary N, Rubino FA. Essential tremor variants: effect of treatment. Clin Neuropharmacol. 1;:-0.. Hubble JP, Busenbark KL, Wilkinson S, et al. Effects of thalamic deep brain stimulation based on tremor type and diagnosis. Mov Disord. 1;1:-1.. Kumar R, Lozano AM, Sime E, Lang AE. Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor. 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A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology. 001;: Ludlow CL, Sedory SE, Fujita M, Naunton RF. Treatment of voice tremor with botulinum toxin injection. Neurology. 1;(suppl 1):.. Brin MF, Blitzer A, Stewart C, et al. Laryngeal botulinum toxin (botox) injections in 1 patients with laryngeal movement disorders: spasmodic dysphonia, adult stuttering and essential voice tremor. Mov Disord. 1;(suppl 1):. 1. Warrick P, Dromey C, Irish JC, 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. 000; 1: Warrick P, Dromey C, Irish J, Durkin L. The treatment of essential voice tremor with botulinum toxin A: a longitudinal case report. J Voice. 000;1: Aronson AE, Ramig LO, Winholtz WS, Silber SR. Rapid voice tremor, or flutter, in amyotrophic lateral sclerosis. Ann Otol Rhinol Laryngol. 1;1: Adler CH. Botulinum toxin treatment of movement disorders. In: Gilman S, Goldstein GW, Waxman SG, eds. Neurobase. rd ed. San Diego, Calif: Arbor Publishing; Buder EH, Strand E. Quantitative and graphic acoustic analysis of phonatory modulations: the modulogram. J Speech Lang Hear Res. 00;:-0.. Hertegard S, Granqvist S, Lindestad PA. Botulinum toxin injections for essential voice tremor. Ann Otol Rhinol Laryngol. 000;:0-0.. CSpeechSP [computer program]. Madison, Wis: University of Wisconsin- Madison; 1. (REPRINTED) ARCH NEUROL / VOL 1, SEP Downloaded From: on 1//01 00 American Medical Association. All rights reserved.

Isolated vocal tremor as a focal phenotype of essential tremor: a retrospective case review

Isolated vocal tremor as a focal phenotype of essential tremor: a retrospective case review Patel and Frucht Journal of Clinical Movement Disorders (2015) 2:4 DOI 10.1186/s40734-015-0016-5 RESEARCH ARTICLE Open Access Isolated vocal as a focal phenotype of essential : a retrospective case review