11/16/11 Page 1 of 1 BT Injection

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1 Table 2. Evidence for (note that = reported and 0 = not reported). Type of Study Subject Characteristics # Reference Authors Date Sorting Code Case Sing Grou Primary focus Numbeage gendetype of acous meds tx histodiado TPO medic severi physioneuro SES diseasspeec cognhear sensaother Total Candidacy Summary Brin, MF, Fahn, S., Moskowitz, C., Friedman, A., Shale, HM, Greene, PE, Blitzer, A., List, T., Lange, D., Lovelace, RE, McMahon, D. (987), Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Movement Disorders, 2, Brin et al 987 Voice/SD Effect of botox inj on a variety of focal/segmental dystonia on pts injected by authors between ADSD 2 Jankovic, J., Orman, J. (987). Botulinum A toxin for cranialcervical dystonia: a double-blind, placebo-controlled study. Neurology, 37, Jankovic & Orman 987 Voice/SD Effects of botox on blepharospasm & oromandibular dystonia were prime focus, but 3 pts with SD were also injected & studied SD 3 Miller, RH, Woodson, GE, Jankovic, J. (987). Botulinum toxin injection of the vocal fold for spasmodic dysphonia. Archives of Otolaryngology/Head and Neck Surgery, 3, Miller et al 987 Voice/SD Outcome of unilateral laryngeal botox inj for SD Incapacitating SD, not responsive to voice tx 4 Ludlow, CL, Naunton, RF, Sedory, SE, Schulz, GM, Hallett, M. Effects of botox for ADSD in pts who (988). Effects of botulinum toxin injections on speech in had previous RLN surgery with adductor spasmodic dysphonia. Neurology, 38, Ludlow et al 988 Voice/SD return of SD SXs SD; no neuro or psych probs prior to SD onset; stable for 2 years; no surgery for SD; overadduction of cords on laryngoscopy; sx reduction after xylocaine 5 Brin, MF, Blitzer, A., Fahn, S., Gould, W., Lovelace, RE. (989). Adductor Laryngeal Dystonia (Spastic Dystonia): Treatment with Local Injections of Botulinum Toxin (Botox). Movement Disorders, 4, Brin et al 989 Voice/SD Outcome of percutaneous EMG guided laryngeal botox inj into the vocalis muscles for ADSD Pts with clinical dx of ADSD, some who had previous pharmaco tx & 4 who had had or RLN resection. 26 had focal dystonia; remainder had segmental, multifocal or generalized dystonia 6 Ford, CN, Bless, DM, Lowery, JD. (990). Indirect laryngoscopic approach for injection of botulinum toxin in spasmodic dysphonia. Otolaryngology-Head and Neck Surgery, 03, Ford et al 990 Voice/SD The results of indirect laryngoscopic approach to inj botox for ADSD DX of ADSD; complete ORL exam; neuro screening;, incl EMG of vocalis & CT. 7 Jankovic, J., Schwartz, K., & Donovan, DT (990). Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonia and hemifacial spasm. J of Neurology, Neurosurgery, & Psychiatry, 53, Jankovic et al 990 Voice/SD Outcome of botox inj for SD DX of SD (SD type not specified) 8 Ludlow, CL (990). Treatment of speech and voice disorders with botulinum toxin. JAMA, 264 (20), Ludlow 990 Voice/SD Case study of S with SD who underwent laryngeal botox inj Dx of ADSD & failed voice tx, medication, hypnosis, acupuncture, & counseling. Page of

2 Replicability Outcomes Type of Dysarthria Medical Diagnosis Rationale for Treatment eplicabal Informcomple Impairment Activity Limitation Participation Restriction Study Conclusions Psychometric Adequacy chemical denervation to control dystonic spasm Pt questionnaires re improvement and side effects. Yes (pt able to return to graduate school) All 3 pts with dystonic SD and & all 3 with lingual dystonia had sx relief with botox Hyperkinetic (SD) dystonic SD Standard botox rationale, but apparently /3 pts with SD had posterior pharyngeal muscle inj, not TA inj Simple description of improvement, but pt said able to talk on phone for sr time in 9 years Pts with SD improved and could speak freely with only mild hoarseness Hyperkinetic (SD) SD Botox is effective for dystonias; it should be for dystonic SD intrathoracic pressure Pts said to be severely incapacitated Both pts improved without significant complications. The injection can be repeated as outpatient procedure. This is a preliminary report of a promising technique. Hyperkinetic (SD) SD Standard botox rationale for SD % of aperiodic phonation and voice breaks; pitch breaks; sentence duration; indirect laryngoscopy Pt diaries of sxs (? Impairment, not functional) Botox led to sig sx reduction on acoustic measures when it resulted in unilateral vocal cord paralysis. Botox reduces glottal resistance by weakening an adductor muscle but it may not alter pathophysiology of the disorder. Present to some degree Hyperkinetic (ADSD) ADSD Botox for SD because it had been successful in tx other focal dystonias Pt & physician ratings of % of normal speech, ranging from no speech/"full disability" to normal. Pt diaries of weakness, breathiness, choking etc see functional limitation Bilateral low dose laryngeal botox is tx of choice for SD. They report abandoning RLN resection as primary tx because of high recurrence rates. Precise delivery of botox to TA using indirect laryngoscopy to guide the needle should result in more accurate placement without need for EMG monitoring EMG, aerodynamic, acoustic, & videolaryngoscopy Pt ratings of voice & duration of benefit The technique is effective and can be performed in office without EMG guidance. Results comparable to other reports of efficacy of botox for ADSD No reliability data Hyperkinetic (SD) SD Standard Botox rationale Severity rated on 5-point scale by clinicians; pts rated latency of response & time of peak effect after inj; Peak effect rated by pts on 5-pt scale; global rating represented peak effect minus pts for complications; number of weeks of peak effect also rated by pts All 24 pts with SD had very satisfactory result, with avg. of 5 weeks of peak effect. Authors conclude botox inj is safe & effective tx for pts with focal dystonia & hemifacial spasm & SD. Hyperkinetic (SD) SD Standard Botox rationale Perceptual ratings, acoustic data, EMG, & fiberoptic measures. Description of pt social & work limitations & changes after inj Description of pt social & work limitations & changes after inj Botox can significantly improve SD & limitations imposed Page 2 of

3 Classification of Evidence Evidence for Control Reported Risks & Complications AAN Levels Beukelman Levels Raters Comments Pre vs post inj pt comparisons 3/3 Ss had 3 days of mild choking and aspiration IV O SCS This study reports botox inj results for 93 pts with a variety of focal/ segmental dystonias (blepharospasm, torticollis, oromandibular dystonia, limb dystonia, lingual dystonia, & ADSD).Injections were bilateral (2.5 units per cord). For lingual destonia, the genioglossus and hyoglossus were injected. This may be the first large N report of botox results for a variety of dystonias Pre vs post comparison noted IV O SCS This study was primarily focused on botox for blepharospams & cranialcervical/oromandibular dystonia. The reports for SD are treated almost incidentally. No reliability data for SD pts and no formal rating procedures are discussed. This is an early report. Pre vs post comparison Neither pt developed dysphagia or aspiration. IV O SCS This is an early report of botox use. There is little description of speech characteristics & no attempt to rate pre vs post results perceptually or acoustically. Intrathroacic pressure during speech was measured Pts served as own controls from baseline through 3 postinj assessments In adductor patients, mild temporary breathiness (in 35%), coughing on fluids (5%); <% had local pain/sore throat, slight blood tinged sputum, itch, or rash. In abductor patients, mild stridor in ~4%; ~ 0% had dysphagia; side effects usually lasted < III E SS Injections were all unilateral, ranging from 5 to 60 units over 3 injections to get desired result. Avg. duration of benefit was 6 weeks. All pts benefited. Multiple sites were injected and result said better than initial studies with injection at only point on TA Pre vs post-tx ratings. Most frequent were: 45% had period of breathy hypophonia for avg. of 9 days; 22% had mild choking on fluids for avg. of 2 datys. Other side effects were <2% of 95 treatments reported. IV O SCS Scored in nonblinded fashion. Most conservative ratings used to measure improvement. Degree of improvement was 6%. All pts responded to retreatment with longest follow-up to 3.5 years. Avg. duration of benefit was 84 days. Avg. dose was bilat ( per cord). Pre vs post inj using several measures of impairment and disability Breathiness was main side effect (in 9/6). Occasional choking, lasting ~ week (5 pts) IV O SCS All pts rated results favorably. Mean duration of response ~ 2.2 weeks (range = )) with onset of response from -3 days. Good summary of videostrobe results and EMG. Most common EMG abnormalities were tremor & abnormal patterns of motor unit recruitment. Effective dose was less than in other reports, perhaps because of exact placement permitted by technique. Pre vs post inj comparisons Hypophonia or hoarseness in 7 pts & dysphagia in 3. IV O SCS Subject description re SD characteristics not provided; we must take authors' word for the dx of SD and can't be sure if all had ADSD. Pt & clinician ratings presented as group data and are convincing in demonstration of change (although no control group or reliability data reported). This is an early study that demonstrated efficacy of botox for several dystonic conditions. Pre vs post inj comparisons on several measures Not reported IV O CS Single case study documenting improvements assoc with laryngeal botox, including major life style improvements (more social, resumed desired job). Page 3 of

4 9 Ludlow, CL, Naunton, RF, Fujita, M., Sedory, SE. (990). Spasmodic dysphonia: botulinum toxin injection after recurrent nerve surgery. Otolaryngology-Head and Neck Surgery, 02, Ludlow et al 990 Voice/SD c Effects of botox for ADSD in pts who had previous RLN surgery with return of SD SXs ADSD with no psychiatric disorder prior to dx; previous RLN surgery with benefit followed by sx recurrence; no hx of phenothiazine use, no essential tremor or Meige syndrome 0 Blitzer, A., Brin, M. (99). Laryngeal Dystonia: A Series With Review of outcomes in a series of Botulinum Toxin Therapy. Annals Of Otology, Rhinology & >200 Pts treated with botox for Laryngology, 00, Blitzer & Brin 99 Voice/SD various forms of laryngeal dystonia Pts treated with laryngeal botox who had ADSD or ABSD, some who had RLN resection failure Ludlow, CL, Naunton, RF, Terada, S., Anderson, BJ. (99). Successful treatment of selected cases of abductor spasmodic dysphonia using botulinum toxin injection. Otolaryngology- Head and Neck Surgery, 04, Ludlow et al 99 Voice/SD c Effectiveness of botox inj to CT muscle to tx ABSD Dx of ABSD on basis of fiberoptic laryngoscopic exam & EMG & perceptual judgments 2 Rontal, M., Rontal, E., Rolnic, M., Merson, R., Silverman, B., Truong, DD. (99). A Method for the Treatment of Abductor Spasmodic Dysphonia With Botulinum Toxin Injections: A Preliminary Report. Laryngoscope, 0, Rontal et al 99 Voice/SD To describe a technique for injecting the PCA in pts with ABSD Dx of ABSD with no prior surgical tx of SD 3 Truong, DD, Rontal, M., Rolnick, M., Aronson, AE, Mistura, K. (99). Double-Blind Controlled Study of Botulinum Toxin in Adductor Spasmodic Dysphonia. Laryngoscope, 0, Truong et al 99 Voice/SD c Double-blind, randomized, placebo controlled study of effect of botox for ADSD ADSD with agreement of dx by SLP, ORL, & neurologist 4 Blitzer, A., Brin, MF, Stewart, C., Aviv, JE, Fahn, S. (992). Outcome of percutaneous laryngeal Abductor Laryngeal Dystonia: A Series Treated With Botulinum botox inj into the PCA muscles for Toxin. Laryngoscope, 02, Blitzer et al 992 Voice/SD abductor SD Pts with voice characteristic consistent with dx of ABSD. All underwent "comprehensive" neuro, ORL, & Speech Path exams 5 To describe an anatomic approach Green, DC, Ward, PH, Berke, GS, Gerratt, BR. (992). Point- Touch Techniques of Botulinum Toxin Injection For The Treatment of Spasmodic Dysphonia. Annals of Otology, Rhinology, and Laryngology, 0, Green et al 992 Voice/SD to laryngeal botox inj that requires only flexible nasopharyngeal endoscopy & careful eval of anatomic landmarks Dx of ADSD 6 Lees, AJ, Turjanski, N., Rivest, J., Whurr, R., Lorch, M., & Brookes, G. (992). Treatment of cervical dystonia hand spasms and laryngeal dystonia with botulinum toxin. Journal of Neurology, 239, -4. Lees et al 992 Voice/SD Outcome of laryngeal botox for SD pts treated with botox DX of SD; 22 with ADSD; 2 with tremor; with "compensatory adductor tremor." Page 4 of

5 Botox could relieve sx of ADSD that have recurred after RLN surgery EMG, acoustic analysis, & fiberoptic laryngoscopy Significant reductions in all sxs occurred after injection. EMG measures demo sig reductions in % activation levels of both injected & noninjected muscles. Botox was an effective tx of postsurgical sx recurrence in ADSD. No reliability data reported/ Hyperkinetic (SD) laryngeal dystonia Outcomes for what the authors describe is now their tx of choice for laryngeal dystonia. Postinj EMG "in a limited # of Ss, but results not reported Nonblinded subjective ratings on a % scale ranging from "no speech or full disability" to normal speech. Ratings made by patients & physicians. Pts also recorded duration of breathy dysphonia, swallowing probs, & other "notable events." The most conservative ratings were used as the index of % of improvement. Pts derived benefit within hours, with sustained improvement for 2-9 months, with avg. of 4 months. Pts improved to avg. of 90% of normal function. Authors say botox has become their tx of choice for dystonic conditions of the larynx. Hyperkinetic (SD) SD To examine effectiveness of botox for ABSD in selected pts with increased CT muscle activity laryngoscopy, EMG, & acoustic analysis Clinical impression of voice improvement 6/0 pts with CT abnormalities benefited substantially from CT inj on acoustic & clinical impression. Pts with constant breathiness & other (non CT) muscle abnormalities did not benefit. ABSD pts should be examined for CT abnormalities during speech; those with CT abnormalities & mod-severe pitch & voice breaks during speech are best candidates for CT injection Present Hyperkinetic (ABSD) SD Attempt to contribute to effective tx of ABSD by developing technique for inj PCA Acoustic/spectrographic measures of harmonic breakdowns, frequency variation & perturbation Perceptual descriptions of voice Percutaneous with EMG guidance & fiberoptic laryngoscopic monitoring technique that places botox close to PCA muscle (unilaterally), to allow diffusion to PCA is effective in reducing/ eliminating abductor spasms during phonation & improving functional speech communication. To investigate effectiveness of botox (bilateral) for treating SD Acoustic analysis (Fo, Fo range, phonation time, perturbation, & spectrographic analysis Patient self ratings of improvement after injection Botox proved to be effective & safe tx of ADSD.Markedly reduced perturbation, decr Fo frequency range, & improved spectrographic features occurred with botox. Patient ratings of voice improvement sig better than the saline injection group.(saline txd patients noted no change after botox. Hyperkinetic (ABSD) SD Botox for ABSD because it had been successful in tx ADSD reported Pt, physician & SLP ratings of % of normal function, overall severity, breathiness, aphonia, & voice tremor before & after inj ABSD can be safely & effectively treated with percutaneous unilat or bilat PCA botox inj. Avg. improvement was to 70% of normal function (from baseline of 3%), with degree of improvement averaging 39%, with range from 5-85%. Several pts also benefited from cricothyroid inj or type I thyroplasty to max benefit. Acoustic measure of jitter, measure of glottal resistance, & stroboscopic Pt satisfaction & whether they imaging returned for subsequent inj Objective pre & post tx data indicates success for all 3 pts using this inj technique Hyperkinetic (SD) SD Standard Botox rationale Perceptual judgments of voice quality, acoustic analyses of Fo & phonation time, & apparent measures of TA muscle activity - but no quantified data presented Botox inj is a safe & effective method of tx for SD Page 5 of

6 Acoustic measures were blinded to pt ID & testing condition. Pre vs postinj comparisons & comparison to control Ss were made. Not reported III E SS TA injections were on side operated in all pts, with additional inj on side not operated in 2 pts. Inj were repeated at 2-week intervals until a speech benefit or loss of volume occurred. Outcome measures were acoustic measures of pitch breaks, phonatory breaks, & irregular aperiodic phonation. Pts who received bilat inj had greatest benefit. EMG results suggest sx return may be partly assoc with TA innervation on side operated; compensation on side not operated may also be a factor. A good study. Pre vs post injection comparisons, nonblinded. Mild breathy voice beginning on avg. at 3rd day postinj & lasting 4-4 days in 45%. 22% had mild choking on fluids for st several days, but no cases of aspiration. Several hyperventillated & became dizzy trying to speak when hypophonic & several had blood tinged sputum &/or sore throat. One pt had some itching but no rash. They also state that to date no pt had sustained any disability from the injection, or became refractory to injection. IV O SCS The tx protocol was not standard for all pts. Authors report result of the tx as the protocol (e.g., dose level) evolved based on their experience. The report success in some pts who had failed RLN resection. They report success in 8/2 pts with ABSD, with avg. improvement to 57% normal. 0% of pts whose dystonia began in larynx had spread to another body part. 7% had positive family hx of dystonia. This appears to be an early large series report of outcomes with botox for SD. Comparison of change made to normal Ss who did not receive injections Pts who did not benefit had some swallowing difficulties & further loss of loudness III E C 6/9 of their clinic's ABSD pts had predominance of abnormal activation in CT muscles; remainder had probs primarily in PCA muscles. Pre vs post inj changes in voice All pts had postinj breathiness, lasting 2 mo. in 2 pts. No pt had respiratory or swallowing probs. IV O SCS 5/6 pts had reduction in abductor spasms; substantial reduction in speech effort; absence of speech fatigue; disappearance of acoustic evidence of spasms. Benefits lasted 3-6 months. Method for rating speech change not described & acoustic methods not described - Results described in general terms, without quantitative data. Purpose of paper was more to describe the technique than to detail the results. Random assignment to botox vs saline injection group. Blinded evaluation by judges and patients were unaware of tx they received. Excessive breathiness noted in 2 patients, lasting for ~ 2 weeks. One pt had mild bleeding after botox. I E RCS An early study that was well controlled re blinding and randomization of control (placebo) and botox treatments. N was small. Poor S description re age, severity, prior tx, etc. but 3 clinicians agreed on dx of SD. Although data not reported the report indicates that ratings of voice quality by a SLP agreed with patient ratings. Note that postinj ratings and acoustic analyses were done only 4 days postinj, so not likely measures were made at point of optimal benefit. Inj were bilateral with EMG & Laryngoscopic guidance. Pts served as own control in a pre vs post tx comparison 2 pts had transient ( week) exertional stridor & two had transient dysphagia IV O SCS Study includes a description of evolution of the technique from direct laryngoscopy inj to percutaneous. Some pts had unilat inj, some bilat. Some had cricothyroid inj, & 3 also had type I thyroplasty. Study did not report results of neuro, ORL or SLP exams. Not clear if results are based on pt, SLP or physician ratings, or a combination of them. No reliability across raters provided. Pre vs post tx comparison 5/3 pts had period of postinj breathiness ranging from 2-4 weeks. No airway complications or infections or aspiration. All had mild vocal fold edema that resolved. IV O SCS The real purpose of this paper was to describe the injection technique. But all 3 had "increase in fluency" & were pleased; all returned for subsequent inj. Authors provide nice summary of advantages & disadvantages of the technique; one major advantage is that EMG monitoring is not necessary. Results in terms of duration of benefit and side effects seem comparable to those reported for EMG guided techniques. ( as far as can be determined) Temporary pain at site of inj, reduced cough, dry mouth, breathiness & hypophonia & mild swallowing difficulty - generally tolerated well & lg majority of patients wished to continue injections IV O SCS Inadequate subject description and no quantified data provided for any outcome measure. Authors report all 25 pts showed worthwhile benefit" and side effects were "generally tolerable." Intention of article seemed to be to provide a general description of botox outcomes for laryngeal dystonia, cervical dystonia, and hand spasms, rather than to provide convincing data for efficacy. Page 6 of

7 7 Zwirner, P., Murry, T., Swenson, M., Woodson, GE. (992). Effects of Botulinum Toxin Therapy in Patients With Adductor Spasmodic Dysphonia: Acoustic, Aerodynamic, and Videoendoscopic Findings. Laryngoscope, 02, Zwirner et al 992 Voice/SD To documents acoustic, airflow, & videoendoscopic findings, functional status, & their interelationships, before, week & month after unilateral botox inj for ADSD ADSD; unilat botox inj; no previous botox; no other neuro, psychiatric, or speech disorder; no prior surgical mgmt of SD; pre inj, week & month postinj data 8 Adams, SG, Hunt, EJ, Charles, DA, & Lang, AE. (993). Unilateral versus bilateral botulinum toxin injections in spasmodic dysphonia: acoustic and perceptual results. Journal of Otolaryngology, 22, Adams et al 993 Voice/SD c Comparison of results of unilateral vs bilateral laryngeal botox inj for ADSD Dx of ADSD 9 Aronson, AE, McCaffrey, TV, Litchy, WJ, Lipton, RJ. (993). Botulinum Toxin Injection for Adductor Spastic Dysphonia: Patient Self-Ratings of Voice and Phonatory Effort After Three Successive Injections. Laryngoscope, 03, Aronson et al 993 Voice/SD Patient ratings of voice & vocal effort following laryngeal botox for ADSD ADSD of neurologic origin treated with laryngeal botox on 3 consecutive occasions 20 Kobayashi, T., Niimi, S., Kumada, M., Kosaki, H., Hirose, H. (993). Botulinum Toxin Treatment for Spasmodic Dysphonia. Acta Otolaryngologica, 504, Kobayashi et al 993 Voice/SD To report outcome of laryngeal botox inj for SD Dx of SD (adductor or abductor) who received laryngeal botox 2 Whurr, R., Lorch, M., Fontana, H., Brookes, G., Lees, A., Marsden, CD. (993). The use of botulinum Toxin in the treatment of adductor spasmodic dysphonia. Journal of Neurology, Neurosurgery, and Psychiatry, 56, Whurr et al 993 Voice/SD Acoustic & patient rating data in response to percutaneous bilateral laryngeal botox ADSD with or without assoc neuro signs, 7% of whom had previous nonbotox treatments without lasting effects 22 Zwirner, P, Murry, T., & Woodson, GE. (993). Perceptualacoustic relationships in spasmodic dysphonia. Journal of Voice, 7 (2), Zwirner et al 993 Voice/SD c Perceptual parameters in SD prior to & after botox, & relationship between perceptual measures & acoustic parameters known to change after botox Dx of ADSD & tx with botox 23 Zwirner, P., Murry, T., Woodson, GE. (993). A Comparison of Bilateral and Unilateral Botulinum Toxin Treatments for Spasmodic Dysphonia. European Archives of Oto-Rhino- Laryngology, 250, Zwirner et al 993 Voice/SD c To assess efficacy of bilateral or unilateral botox tx for SD Dx of ADSD; st botox inj; no prior Lo surgery; no hx of neuro, psych, or other speech disorder. received unilat inj; 3 received bilat inj 24 Giladi, N., Meer, J., Kidan, C., Greenberg, E., Gross, B., Honigman, S. (994). Interventional Neurology: Botulinum Toxin As A Potent Symptomatic Treatment In Neurology. Israel Journal of Medical Sciences, 30, Giladi et al 994 Voice/SD Report of experience with botox for a variety of CNS disorders, including SD & palatal myoclonus dx of spastic dysphonia Page 7 of

8 Standard unilat laryngeal botox inj for SD Acoustic measures, airflow recordings, & videolaryngoscopy Ratings of functional status re ability to communicate with most severe included career/ employment changes or decreased See functional social interaction limitation Botox inj into TA is effective & safe tx for ADSD. Acoustic measures demo sig voice improvement; airflow rates increase week postinj with almost normal values at month; videolaryngoscopy demo reduced intrinsic laryngeal hyperfunction postinj. Relationships between videoendoscopic findings & acoustic &/or aerodynamic findings were not significant. Change in functional status offered support for the acoustic & physio measures To compare effectiveness and side effects of two accepted approaches (unilateral vs bilateral) to laryngeal botox tx for ADSD. Acoustic measures of vowel duration, Fo, jitter, shimmer, & voice breaks per sec Blinded ratings by 4 SLPs of severity of voice spasms & vocal breathiness using direct magnitude estimation Both types of inj were assoc with sig improvements in SD. Both were assoc with increased vocal breathiness at 2 weeks post-inj. Acoustic measures suggest unilat inj may provide both superior & longer Reliability of perceptual lasting benefits than bilat inj. judgments reported Hyperkinetic (ADSD) ADSD, neurologic (tremor or dystonia) To reduce sx of ADSD with laryngeal botox injection Patient ratings of voice & vocal effort before & at 2 week intervals after transcutaneous botox inj. Testimonial comment within a few case summaries. 80% of pts improved In voice & physical effort at hours after inj. 2. Breathiness/aphonia occurred after 43% of inj, max at 2 weeks post inj. 3. Max improvement in voice was at.9 months & effort at.3 months post inj. 4. Avg. duration of max improvement in voice at.3 mo. 5. Avg. duration before decline was 3.9 mo. for voice & 4.0 mo. for effort.. 6. Avg. duration to request for reinjection was 4.8 mo. Considerable postinj fluctuation within and among pts. Hyperkinetic (SD) SD To document effects of botox on SD, a tx effective for other forms of dystonia Laryngoscopy Pts' subjective judgment of benefit Botox to the TA muscle cords is effective tx for ADSD, but was not effective for 2 pts with ABSD Botox for SD because it had been successful in tx other focal dystonias Acoustic analysis of SD of Fo Patient diaries re degree and duration of benefit Botox is effective method of tx for ADSD, enabling pts to use voice effortlessly & communicate easily. 96% reported improvement in voice, on avg. beginning by day 7 with peak effect lasting 5 weeks (benefits described by pts as reduced # of pitch & voice breaks, increased loudness, reduced effort to speak. SD of Fo was less postinjection than preinjection Hyperkinetic (SD) SD Standard Botox rationale Perceptual measures of OA severity, strained voice, and breathiness; acoustic measures of voice breaks (VBF) & SD of Fo (SDFO). SD voice is perceived as less severe, less strain-strangled, & more breathy week after botox than preinj. Perceptual results were related to VBF & SDFO, parameters known to change after botox. Intr & interjudge reliability data presented for perceptual judgments by 5 SLPs To compare effectiveness and side effects of two accepted approaches (unilateral vs bilateral) to laryngeal botox tx for ADSD. Acoustic measures & airflow recordings Both inj modes resulted in sig improvement of vocal function using objective acoustic & aerodynamic measures. Hyperkinetic (SD) dystonia To report aus' experience with botox for a variety of neuro disorders Pt rating of % of improvement Pts with SD reported 92% improvement. Injection of patient with palatal myoclonus said to be effective Page 8 of

9 Videoendoscopic ratings were blinded Not addressed IV O SCS Uncertain who made ratings of functional status (clinician vs patients). Botox dose depended on severity so varied among pts (this is reasonable re typical clinical practice). The study basically indicates that acoustic & physio & endoscopic measures detect abnormalities before botox and changes after botox in a direction consistent with functional findings. Perceptual judgments were blinded to tx type and time of injection. No indication that Ss were randomly assigned to tx groups Breathiness at 2 weeks postinj was sig greater than preinj ratings for both groups III E C Results demonstrate effectiveness of both treatment approaches & the side effect of breathiness in both. By 6 weeks breathiness was at preinj level so it demonstrates that the side effect is temporary. The acoustic measures identified differences between unilat vs bilat inj whereas the perceptual measures did not. The comparison of unilateral (5 units) vs bilateral (2.5 per side) is probably no longer relevant because patients today receiving unilateral injections rarely get a dose as large as 5 units, in my experience. The study did not address patient satisfaction or ratings of voice, side effects, etc., so we do not learn whether there are differences between the 2 txs in that regard. Pre & postinjection ratings, with multiple postinj ratings after 3 different injections Breathy/aphonia period in 43% of total injections, max. at 2 weeks postinj. IV O Q Variable inj. Protocol re dosage, with some receiving bilat & some unilat inj, & many receiving different dosages on subsequent inj., but this reflected appropriate dose adjustments based on prior results. All data based on pt ratings. Pts represented st 0 to be injected at this institution & au indicated consecutive dosages were "tailored" as experience increased, so variability and duration data may exceed that in practice today (e.g., dosages were higher than typically used today; 20 units unilaterally & 5 units per cord for bilateral inj.). Study points out variability in response across and, most important, within pts. Pre vs postinj judgment of laryngoscopy & pts' pre vs postinj ratings of voice 2 cases were hoarse for 2 weeks. pt was aphonic for 3 weeks. No systemic complications were observed on repeated inj in the series IV O SCS All pts with ADSD showed laryngoscopic or subjective improvements lasting for avg. of 3 months. The 2 pts with ABSD did not improve but the TA was injected. This is a purely descriptive study with little detailing of pt characteristics or the ratings that were made by pts. Pts served as own control in a pre vs post tx comparison 25% had some transitory dysphagia for fluids without aspiration, weak cough, or pain at site of injection. IV O SCS A pre-post comparison study. Authors indicate postinj acoustic analysis are probably conservative because they were often made after peak benefit. Au note that these pts continued with successful injections. Judges blinded to pre vs postinj status & purpose of study. Results compared to a control (non-sd) group Post inj breathiness rated as increased in 2/9) III E C Limited S description but reference given to article in which those characteristics were well summarized (Zwirner et al 99).Post inj ratings done at week postinj, so benefits may have been minimized & measures of breathiness inflated. The study clearly documents perceptual improvement in voice postinj, esp for the measure of OA severity of voice (4/9 pts had decreased severity rating postinj). Ratings of OA severity were still worse than controls post inj, however -- but again, this was at week postinj, so benefits may not yet have reached maximum. Pre inj vs week postinj & month post inj comparisons No aspiration or sig dysphagia, but "tickling" sensation common when swallowing liquids; 54% of bilat pts had swallowing probs vs27% in unilat group III E C It is not clear if Ss were randomized to the 2 tx conditions. The bilat group was more severe prior to tx on several measures; the two groups were equivalent on others. At week the unilat group showed gains on all measures except SNR. In bilat group, values for jitter & SNR were worse at week. Four weeks after inj, bilat group was not sig different from unilat group on measures of VBF & only slightly higher on airflow. Bilat inj resulted in sig improvement at much lower doses than that used in unilat inj (i.e.5-30 vs.5-2 per cord). No perceptual measures from clinicians or pts. No pt satisfaction reported. except for pre vs post injection comparisons dysphagia noted in all 3 pts with SD and in with palatal myoclonus IV O SCS Poor study re control, S description, & outcome measures. The SD portion was embedded within a report of botox results for a wide variety of movement disorders, most with blepharospasm, neck dystonia & limb dystonia (total N = 65) Page 9 of

10 25 Maloney, AP & Morrison, MD (994). A comparison of the efficacy of unilateral versus bilateral botulinum toxin injections in the treatment of adductor spasmodic dysphonia. Journal of Otolaryngology. 23, Comparison of efficacy of unilateral versus bilateral botox inj for ADSD Maloney & Morrison 994 Voice/SD re duration of effect vs side effects of breathiness & swallowing difficulty Dx of ADSD with initial bilat inj of botox who then elected to have at least unilat inj, followed in future by their choice of unilat or bilat injection. Pts with prior RLN resection were excluded. 26 Murry, T, Cannito, MP, & Woodson, GE. (994). Spasmodic dysphonia: Emotional status and botulinum toxin treatment. Archives of Otolaryngology, Head and Neck Surgery, 20, Murry et al 994 Voice/SD c To determine effects of botox inj on measures of depression, anxiety, & somatic complaints in pt with SD Dx of SD; no previous botox tx; sx > year; not under psychiatric care or med dx of mood disorder or depression; no other speech disorder; volunteered to participate; improved postinj by pt self-report & acoustic analysis 27 Rhew, K., Fiedler, D., Ludlow, CL. (994). Technique for injection of botulinum toxin through the flexible nasolaryngoscope. Otolaryngology-Head and Neck Surgery,, Rhew et al 994 Voice/SD c Results of unilateral & bilateral laryngeal botox for ADSD using flexible nasolaryngoscope inj technique ADSD, without h/o speech or voice probs; without h/o prior botox tx or laryngeal surgery; non smokers 28 Adams, SG, Hunt, EJ, Irish, JC, Charles, DA, Language, AE, Durkin, LC, Wong, DLH. (995). Comparison of Botulinum Toxin Injection Procedures in Adductor Spasmodic Dysphonia. Journal of Otolaryngology, 24, Adams et al 995 Voice/SD Comparison of unilateral vs bilateral TA botox injection for ADSD Dx of ADSD based on perceptual, acoustic, aerodynamic, & laryngoscopic signs of adductor vocal spasms 29 Murry, T., Woodson, GE. (995). Combined-Modality Treatment of Adductor Spasmodic Dysphonia with Botulinum Toxin and Voice Therapy. Journal of Voice, 9, Murry & Woodson 995 Voice/SD c Comparison of results for botox for ADSD to botox + subsequent voice tx for ADSD Dx of ADSD; no prior botox tx; no prior RLN resection or other laryngeal surgery; sx > year; no other speech disorder 30 Wong, DLH, Adams, SG, Irish, JC, Durkin, LC, Hunt, EJ, Charlton, MP. (995) Effect of Neuromuscular Activity on the Response to Botulinum Toxin Injections in Spasmodic Dysphonia. Journal of Otolaryngology, 24, Wong et al 995 Voice/SD c Effect on voice outcome of speaking vs silence following percutaneous laryngeal botox injection for SD Pts with SD with no previous laryngeal surgery or hx of laryngeal trauma or CA, or sensitivity to botox or other illness that would preclude safe injection Page 0 of

11 To compare effectiveness of unilat vs bilat inj, both legitimate methods for ADSD. Pt diary ratings of goodness of voice, duration of benefit, of breathiness, & swallowing probs. Phone interview response to query re preference for bilat vs unilat inj & assessment of max voice improvement in response to each. Botox is a useful tx for ADSD. Inj should be initiated using bilateral protocol; if pts experience severe side effects, a unilat inj may be offered with understanding that vocal benefit & duration of effect may be reduced. Bilat inj resulted in 4.7 weeks of benefit, 3.2 weeks of breathiness &.8 weeks of swallowing difficulty. Unilat resulted in.4 weeks of benefit, 2 weeks of breathiness, & 0.9 weeks of swallowing probs. 7% felt bilat inj was superior 29% preferred unilat. Pts consistently & sig rated voice improvement higher after bilat than unilat inj. Men had prolonged benefit with bilat inj; women did not. Hyperkinetic (SD) SD Not a tx study per se. Rationale was to determine if botox tx for Sd would influence depression, anxiety, & somatic complaints. Self-ratings of anxiety, depression, and somatic complaints SD Ss exhibit elevated levels of depression & anxiety preinj. They were sig reduced ~ week postinj & maintained 2 months later. Results suggest that SD pts with elevated depression and anxiety show reduction in those after inj. Present Hyperkinetic (ADSD) ADSD To determine outcome of laryngeal botox using flexible nasolaryngoscope for inj instead of traditional transcutaneous technique. Spectrographic analysis of pitch breaks, phonatory breaks, sentence duration, aperiodicity, & Fo. 2. Videolaryngoscopy to examine changes in mucosal wave. Pt diaries of magnitude & duration of side effects and change relative to preinj voice Flexible nasolaryngoscopic technique is a safe & effective technique for inj botox into laryngeal muscles for tx of SD. Results seem comparable to those reported for other approaches Reliability apparently checked for speech measures but not for videolaryngoscopy Typical rationale for botox. Compare outcomes of unilat vs bilat injection because results of prior studies were inconsistent. max phonation time; SD of Fo; jitter, shimmer; S/N; Fo; voice breaks/sec; spasm severity; breathy voice Standard unilat & bilat botox inj provide equivalent degrees of improvement in sx of ADSD. Bilat inj are assoc. with longer period of Reliability for perceptual excessive phonatory airflow than unilat inj. scaling provided To determine if adjunctive voice tx results in longer period between injections than botox without voice tx. Airflow measures, acoustic analysis Duration between injections was primary outcome measure ADSD is txd most effectively when txd with botox & extrinsic hyperfunctional vocal behaviors are txd with voice tx after injection. Duration between injections was greater for those with voice tx + botox than botox alone, including after a subsequent inj without subsequent voice tx in those initially receiving voice tx Hypothesized that vocalization immediately after inj would increase neuro/metabolic activity of target neurons, and possible enhance botox binding to targets Aerodynamic measures of subglottic pressure, translaryngeal airflow, & laryngeal resistance. Acoustic analysis of Fo, SDFo, shimmer & jitter, Perceptual ratings by SLPs of SN ratio, & max phonation severity of spasm & degree of time breathiness Vocal rest, rather than vocalization for 30 min following botox inj produces a superior & longer lasting response in SD Pts receiving botox. Both groups had breathiness & reduced spasm after inj but nonvocalizing pts had greater reduction in spasm severity at 2 & 0 weeks post inj. Both groups had reduced acoustic abnormalities but nonvocalizers had closer to normal values of max phonation time. Both groups had sig changes in laryngeal resistance, airflow, & variability of airflow but no diffs between groups on aerodynamic measure post inj. Page of

12 Pts served as own control. Swallowing probs & breathiness did occur & are summarized (see Study conclusions) IV O SCS Study based on retrospective chart review & prospective phone interviews. Dose level was empirically determined for each pt but avg. was 2.5 per cord for bilat & 4.5 for unilat (percutaneous inj was used). Analysis based on avg. of 3.3 bilat inj &.5. unilat inj per subject. Pts did not necessarily receive equal # of txs for the 2 methods compared, so results could reflect that bias (e.g., bad result not necessarily due to unilat vs bilat effect may have biased subsequent choice of inj method & stated preference. Measures compared to normal controls. Measures compared at 3 points in time (preinj, week postinj, 2 months postinj). Not addressed III E C Study found depression & anxiety to be elevated in SD pts (in ~ 50% of the group) as compared to controls, but not elevated on measure of somatic complaints. Depression & anxiety reduced after inj to levels well within normal limits, with no pt receiving a score that would suggest referral for psychiatric care. Authors point out that results don't necessarily support a psychogenic cause of SD; results suggest elevated depression & anxiety are result not cause of SD. Acoustic measures were blinded re inj status. Pre vs post inj comparisons. No airway problems, allergic reactions, or serious dysphagia with aspiration. 9 pts had mild swallowing difficulty for avg. of 4 days. 8 had breathiness for avg. of 23 days. 7 had abnormally high pitched voice for avg. of 69 days. III E C Pts were not randomly assigned to unilat vs bilat inj. Optimal inj dose was established for unilat & bilat inj by inj some pts & examining results; unilat in received total of 6 units divided across 2 locations in the TA. Bilat inj were 2 units into one site in each TA. After initial inj some pts had dose adjusted. The inj technique is very well described. Both groups improved comparably in breaks & sentence length. Videolarng showed reduction in asymmetry of movement in both groups. All pts reported improvement & said procedure was tolerable; they were willing to have the technique again. Mean duration of reduced sx was 36 days (90-238), comparable to their reported results with EMG technique. Paper presents very nice summary of advantages and disadvantages of the technique, including relative to percutaneous- EMG technique.. Random assignment of pts to tx groups (unilat vs bilat). 5 control Ss also assessed for comparative purposes. Perceptual ratings were blinded. Breathiness and reduced max phonation time at 2 weeks in both groups at 2 weeks II E C Bilat group had sig greater reduction of max phonation time than the unilat group at 6 weeks. Both groups differed from controls on SDFo, jitter, shimmer, S/N, voice breaks, & spasm severity pre injection. They differed from controls on all acoustic and perceptual measures postinj, except Fo (at all points postinj) and breathiness at 6 weeks. Measures were made preinj and at 2 & 6 weeks postinj. Pts txd with voice tx were also seen after a period of no tx after a second botox injection Not addressed III E C Group assignment was not random; pts who declined voice tx were put in the botox only group, so factors of motivation may be relevant. Although those receiving voice tx were also followed after botox without voice tx, this was not counterbalanced; it would have been better if all pts were followed for a no tx period and then the voice tx study begun This is a good study in the sense that it combines medical & behavioral tx. Results not entirely convincing but impressive enough to warrant work toward clinical trial. Random assignment to treatment groups. Perceptual ratings were blinded to tx group assignment Both groups had sig increase in breathiness at 2 weeks, more so in the nonvocalizing group II E RCS Good study of the comparisons made (vocalizing vs nonvocalizing post inj) that provides general support for the effectiveness of botox in general. The vocalizing group had sig greater laryngeal resistance before injection so it is possible that severity index influenced outcome of comparisons, although there were apparently no sig differences preinj on any other measures. Reliability of perceptual judgments was reported but not reliability of acoustic & aerodynamic measures. Page 2 of

13 3 Wong, DLH, Irish, JC., Adams, SC., Durkin, LC., & Hunt, EJ. (995). Laryngeal image analysis following botulinum toxin injections in spasmodic dysphonia. Journal of Otolaryngology, 24, Wong et al 995 Voice/SD quantification by endoscopic video laryngeal images of pre and post laryngeal botox injection parameters in pts randomized to nonvocalization & vocalization groups postinjection ADSD without prior laryngeal surgery, trauma, CA, RoRx, sensitivity to botox, other laryngeal path, or sig health probs 32 Adams, SG, Durkin, LC, Irish, JC, Wong, DLH, Hunt, EJ. (996). Effects of Botulinum Toxin Type A Injections on Aerodynamic Measures of Spasmodic Dysphonia, Laryngoscope, 06, Adams et al 996 Voice/SD c Effects of bilateral percutaneous laryngeal botox on aerodynamic measures of phonation in pts with ADSD Pts with clinical dx of ADSD 33 Davidson, BJ, Ludlow, CL. (996). Long-Term Effects Of Botulinum Toxin Injections In Spasmodic Dysphonia. Annals of Otology, Rhinology & Laryngology, 05,, Davidson & Ludlow 996 Voice/SD Motor unit characteristics, muscle activation patterns, & cord movement characteristics in injected and noninjected thyroarytenoid muscles receiving botox for ADSD 6-38 mo. Postinj Pts with ADSD who had received 2-7 unilateral TA botox inj, ranging from 0-5 units per inj 34 Fisher, KV, Schere, RC, Owen, AS. (996). Longitudinal Phonatory Characteristics After Botulinum Toxin Type A Injection. Journal of Speech and Hearing Research, 39, Fisher et al 996 Voice/SD Quantification of glottic variability during 0-week period post botox injection Single S with ADSD treated with botox 35 Inagi, K., Ford, CN, Bless, DM, Heisey, Dennis. (996). Analysis of Factors Affecting Botulinum Toxin Results in Spasmodic Dysphonia. Journal of Voice, 0, Inagi et al 996 Voice/SD c Retrospective study of differences in effectiveness of laryngeal botox for ADSD as a function of dosage & site of injection Pts with ADSD with or without a tremor component, all who had > botox injection Koriwchak, M.J., Netterville, J.L., Snowden, T., Courey, M., & Ossof, R.H. (996). Alternating unilateral botulinum toxin type A (Botox) injections for spasmodic dysphonia. Laryngoscope, 06, Koriwchak et. al. Patients with adductor SD dissatisfied with duration or severity of breathy voice following bilat. Botox. All pts had at least 2 bilat & 2 unilat injections Voice/SD Laryngeal Botox Liu, T.C., Irish, J.C., Adams, S.C., Durkin, L.C., & Hunt, E.J. (996). Prospective study of patients' subjective responses to botulinum toxin injection for spasmodic dysphonia. Journal of Otolaryngology, 25, Liu et al 996 Voice/SD c Patients subjective diary responses to effect of unilateral or bilateral laryngeal botox on spasms, hoarseness, breathiness, volume problems, and dysphagia, completed from day before injection through post injection period Dx of SD without previous laryngeal surgery, trauma, or pathology who were medically safe for botox & who completed diary data Page 3 of

14 Hyperkinetic (ADSD) ADSD Laryngeal botox tx, standard with 2 randomly assigned groups, one that read aloud for 30 min postinjection, one that was silent for 30 min postinjection Video image analysis, still frame Quantitative measures of laryngeal images are less sensitive measures (of limited value) of botox tx than perceptual, acoustic or laryngeal aerodynamic measures. Botox as effective tx for ADSD. Purpose was to examine effect of inj on aerodynamic measures assuming tx would be effective Measures of air pressure, avg. airflow, CV of airflow, & laryngeal resistance Aerodynamic measures were useful in assessing voice production in SD. Air pressure, variability of airflow, & laryngeal resistance distinguished SD pts from normal Ss. Avg. airflow, laryngeal resistance, & CV of airflow were useful in tracking effects of tx over Normals were reliable over time (avg. airflow increased, & laryngeal resistance & variability of two testing sessions. No airflow decreased after inj).. They rec that aerodynamic measures be repeated measures for used in future outcome studies. ADSD pts pre-inj. Standard laryngeal botox rationale. This was not a tx study per se. EMG, fiberoptic video Although physiologic effects of botox are reversible, the reinervation process continues past 2 mo. postinj. Motor unit char. differed between inj & noninj muscles & were greater in pts <2 mo. postinj. Asymmatric cord motion was apparent in some pts Standard for bilat laryngeal botox for ADSD. Kinematic & aerodynamic measures to track changes in voice + perceptual ratings of voice by clinicians & patient Change in degree of glottal adduction over time can be observed even when vocal stability is present. Perceptual ratings of voice quality were related to laryngeal measures. Methods used may aid decisions about dose level & sources of perceptual ADSD for given patient No reliability for EGG & aerodynamic data. Reliability of clinician perceptual data were reported (& in some instances, not very good) Hyperkinetic (ADSD) ADSD Standard laryngeal botox tx (peroral) for ADSD with retrospective analysis of injection dose, site, and side on outcome Pt ratings of duration of voice improvement & side effects. Bilat single TA+LCA inj yielded longer intervals between injections than other inj types except bilat multiple TA+LCA inj. 2. Unilat multi TA+LCA inj increased duration of best voice & voice improvement more than did unilat inj of either TA or LCA. 3. For inj of TA, bilat inj prolonged dur of best voice & voice improvement. 4. Patterns of inj did not show sig diffs where both TA & LCA muscles were inj. 5. Variation of inj affected duration of voice improvement & improved duration largely due to prolonged best or optimal voice. MAIN conclusion is that initial tx should be a single unilat inj placed at posterior portion of TA & directed toward LCA so both muscle groups are affected. Unilateral injection hypothesized to reduce duration of breathy interval after botox injection in patient dissatisfied with breathiness Patient diaries rating duration & severity of breathiness and good voice following botox Patient judgments of "effectiveness" of injection. Alternating unilateral injections reduce breathy interval by ~3 days and provide ~ 3.2 more days of strong voice per day of breathy voice than bilateral injections, BUT yield shorter duration of strong voice & higher failure rate (4.9% vs.%). Conclude that alternating injections are useful in SD pts who have difficulty with breathy voice following bilateral injections. 7/8 judged unilateral inj to be effective; preferred bilat inj & returned to it. Hyperkinetic (SD) SD Standard unilateral or bilateral percutaneous botox. Diaries were felt to be valid outcome measure for tx Patient diaries rating duration and magnitude of vocal spasm, hoarseness, breathiness, volume, & swallowing dimensions from pre injection to course of post injection benefits & side effects. Most side effects resolve by 4-6 weeks; spasm relief persists beyond side effects; 84% have spasm relief; unilateral injections have fewer swallowing and loudness side effects than bilat; patient diaries are Patients self ratings over extremely useful outcome measure, and maybe one of the most valid time outcome measure. Page 4 of