6Journal ofNeurology, Neurosurgery, and Psychiatry 1993;56:526-530

The use of botulinum toxin in the treatment ofadductor spasmodic dysphonia

R Whurr, M Lorch, H Fontana, G Brookes, A Lees, C D Marsden

AbstractBotulinum toxin injections have beenused to treat 31 patients with adductorspasmodic dysphonia. Injections of300-3 75 units of botulinum toxin wereperformed bilaterally into the thyroary-tenoid muscle. This treatment signifi-cantly decreased the standard deviationof the fundamental frequency of thespeech sample, indicating a reduction inthe variability of pitch amongst patients.A total of 96% of patients' subjectivediary reports showed an improvementwith a median of 7 days to peak effectand a 5 week duration ofpeak effect.

(7 Neurol Neurosurg Psychiatry 1993;56:526-530)

The National Hospitalfor Neurology andNeurosurgery, LondonR WhurrM LorchH FontanaG BrookesA LeesC D MarsdenThe Institute ofNeurologyThe NationalHospital, LondonM LorchCD MarsdenBirckbeck Coilege,University ofLondon,UKM LorchCorrespondence to:Dr Whurr, Speech andLanguage TherapyDepartment, The NationalHospital, Queen Square,London WC1N 3BG, UKReceived 7 February 1992and in final revised form12 August 1992.Accepted 26 August 1992

Adductor spasmodic dysphonia (SD) is a

chronic voice disorder of adult onset andunknown aetiology. SD is not a "spastic" dis-ease, but is a focal laryngeal dystonia whichshould be differentiated from vocal tremorand myoclonus.'-3 Although it is often erro-

neously labelled "spastic" dysphonia, no signsof spasticity have been found in the vocalfolds of patients with spasmodic dysphonia.This voice disorder is characterised by regularfrequent breaks in phonation, staccato-likecatches, pitch breaks and variations in pitch.Attempts to speak are usually accompaniedby effortful, jerky, groaning, and strainedphonation.

Spasmodic dysphonia was first describedby Traube,4 who suggested that SD was an

hysterical illness. A psychiatric aetiology was

supported by Beck,5 Berendes,6 and Kiml,7and this concept led to a variety of treat-ments, including psychotherapy, acupunc-ture, hypnosis, biofeedback, faradism anddrug therapy, all of which had little benefit. Aphysical cause of SD was first proposed in1874 by Schnitzlere who described twopatients with "cramping of the vocal cordsand forced voice". He called this entity "spas-tic aphonia". In 1939, Critchley9 describedtwo patients with a vocal disorder who hadassociated neurological signs and concludedthat the site of the pathological process was

likely to be the cerebellum or the basalganglia.More recent studies have linked SD with

dystonia. The association of SD with Meige'ssyndrome led to the disorder being redefinedas a focal form of dystonia, one of a group ofmovement disorders which are characterisedby prolonged muscle contractions with twist-

ing spasms, which may have additionalmyoclonic or tremulous components.' 10 1

Fibreoptic observations in patients withSD have shown rapid twitch-like movementsand forceful spasm-like jerking of the vocalfolds, and oscillations of the arytenoids.Forceful, rapid, jerking spasms are noted inthe velum as well as in the superior pharynxand tongue. Such abnormal movements ofthe vocal folds may even be evident duringquite respiration. These are exacerbated dur-ing phonation."2The growing acceptance of the neurologi-

cal aetiology of SD led to a change inapproach to the treatment of the disorder.Dedo13 practised surgical resection of therecurrent laryngeal nerve. It was thought thatunilateral vocal fold paralysis would result incompensation due to the strong adductiveforces in the unparalysed contralateral side.Laryngeal nerve resection provided initialrelief, but relapses were common. Long termresults were disappointing, with reports insome cases of symptoms being made worse.'4The cause for the relapse was thought to bedue to the hyperadduction of the non-dener-vated cord with exaggeration of the dystonicspasms, or reinnervation on the surgicalside.'6 Other forms of surgery have includedarytenoid replacement, laser therapy, spinalcord stimulation, and even thalamotomy, allwith no benefit or transient effects.Pharmacological intervention has includedthe use of anticholinergics, benzodiazepines,baclofen and carbamazepine.16 Only mildbenefit from clonazepam and anticholinergicshas been reported.

Recently, injections of botulinum toxininto targeted muscular sites have proved to bebeneficial in the treatment of certain focaldystonias."7 19 Botulinum toxin acts pre-synaptically to block the calcium dependentrelease of acetylcholine. When injected in lowdoses the toxin causes local weakness in themuscle into which it is injected. This elimi-nates the abnormal muscle contractions whilepreserving functional ability. The effect of thetoxin is temporary due to the re-sprouting ofaxons which form new neuro-muscular junc-tions.The use of botulinum toxin treatment

in spasmodic dysphonia of the adductortype is currently being tested in severalcentres. 6192>24 Table 1 summarises the vari-ous methods of botulinum toxin treatmentcurrently being pursued. The potency oftoxin being used in the UK (Dysport) differsfrom that being used in the USA (Oculinum)

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The use of botulinum toxin in the treatment of adductor spasmodic dysphonia

Table 1 Summary of studies of the use of botulinum toxin in the treatment ofSD

Number of Dosel Re-Study Patients Anaesthetic Toxin Needle Site Side volume Ratings injection

Blitzer et al 3 NS NS NS NS1986 NS Bilateral NS Video and audio NSUSA-New York recordingsMiller et al23 2 Lidocaine Botox A 27 gauge Thyro- Left Ptl: 30/37U Intra-thoracic Yes1987 Hydrochloride Oculinum teflon arytenoid Pt2: 20U pressure, ValsalvaUSA-Houston coated EMG manoeuvre, subjective

needle speech ratings, videoBlitzer et al19 5 NS Botox A 25 gauge and audio recordingsFebruary 1988 Lyophilised monopolar Vocalis Left or 2 5-7-5U Fibre-optic laryngoscopy, Yes

Oculinum teflon thyro- Right varied Video recordingsBlitzer et a! 34 NS coated arytenoid Unilateral concentration EMG, brain stem evokedJune 1988 EMG needle complex also potentials, MRI scansUSA-New York BilateralLudlow et al 22 16 Xylocaine Botox A 27 gauge Thyro- Left 2 5U in 6 Fibre-optic video Yes1988 Oculinum teflon coated arytenoid Multiple sites = 20-25U laryngoscopy, speechUSA-Bethseda EMG needle sites (6) therapist ratings, acousticBrin et al 16 42 NS Botox A Hollow analysis, spectrography1989 mono-polar Vocalis Bilateral 2-5-3 75U Fibre-optic laryngoscopy, YesUSA-New York teflon coated thyro- audio and video recordings,

EMG needle arytenoid subjective ratings,Jankovic et al2' 24 NS Botox A 0 5" 30 gauge complex patient self ratings1990 Oculinum hollow teflon Vocalis Left 30U Fibre-optic video YesUSA-Houston coated EMG thyro- laryngoscopy, rating scale,

needle arytenoid "peak effect" ratingZwirner et a! 24 19 NS Botox A Teflon coated complex1991 Oculinum hollow needle Thyro- Left 15-30U Laryngologist, speech YesUSA-San Diego arytenoid therapist ratings, acoustic

analysis

There are differences in the techniquesreported for dose, site, and number of injec-tions of botulinum toxin. In spite of these dif-ferences, all centres utilising botulinum toxinin the treatment of adductor SD claimedgood results for improving the voice.Symptoms generally return after the restora-tion of vocal cord movement over a period ofabout 12 weeks. There have been no reportsof patients becoming refractory to therapy.Brin et al 16 found that there was a trend for aprogressively longer period of benefit betweeninjections.The methods of evaluation of the results of

botulinum toxin injections on vocal qualityalso have varied. Methods of assessment haveincluded neurological, speech therapy/pathol-ogy, fibre-optic laryngoscopy, EMG, audioand video recording. Evaluation of results hascommonly included subjective speech/videorecordings, though Ludlow22 and Zwirner24included objective acoustic analysis of speech.Other methods have been patient diaries26and measures of interthoracic pressure andValsalva manoeuvres.23

This paper describes the procedure used toassess, treat and evaluate treatment ofpatients with spasmodic dysphonia usingbotulinum toxin.

MethodSubjectsBetween December 1988 and April 1991, 49patients with suspected spasmodic dysphoniaof the adductor type were referred to thespasmodic dysphonia (SD) clinic. Eighteenpatients were removed from the trial: 12 werefound on assessment not to have SD, 3patients were treated elsewhere (1 found thetravel too far, 1 was too unwell and 1 patientdied). Thirty one patients entered the trial,11 male, 20 female with a mean age at thetime of initial assessment of 57 years (range

31-82). The mean age of the male subjectswas 46 years (range 31-65); that of femaleswas 63 years (range 43-82). Mean durationof symptoms was 5 years 2 months (range 11months-1 8 years). There was no difference inmean duration of symptoms for males andfemales.

Fourteen of the 31 subjects (45%) hadassociated neurological signs: 10 female(50%), 4 male (36%). These signs were: a)tremor (n = 5, female patients) of varioustypes-2 had hand tremor, 2 had head tremor(including voice tremor), 1 head, voice andhand tremor; b) dystonias (n = 8, 3 male and5 female) of various types-2 torticollis, 1multifocal dystonia, 1 torticollis and writerscramp, 2 blepharospasm, 2 Cranial dystonia;c) Parkinsonism (n = 1, male) (see table 2).Twenty two patients (71%) had had previ-

ous treatments including: recurrent laryngealnerve crush, drugs, faradism, hypnotherapy/hypnosis, acupuncture, reflexology, chiro-practice, herbalism, psychotherapy, speechtherapy. All found the treatments to have hadno lasting effect on the voice. Four patientswere receiving drug treatment at the time oftheir initial injection of botulinum toxin, theyreported that the drugs were having no effecton their voice.No control subjects were studied, because

of the remarkable efficacy of this treatment,shown not only by this study but also byother studies (see table 1). A placebo con-trolled trial would probably not be ethicallyjustified.

Assessment ProceduresEach patient had initial assessment by a teamof a neurologist, a neuro-otolaryngologist anda speech-language therapist. The laryngologi-cal assessment was performed using either aflexible fibreoptic or rigid endoscope connect-ed to a video camera. The speech-languagetherapist assessed each patient on a voice pro-

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Whurr, Lorch, Fontana, Brookes, Lees, Marsden

Table 2 Patient characteristics

Duration ofvoice symptoms Associated

Sex Age range (range) neurological signs

Male 31-65 years 1-18 years n = 4n 11 1 cranial dystonia,

1 torticollis, 1 torticollis andwriters cramp, 1 Parkinsonism.

Female 43-82 years 11 months-15 years n = 10n = 20 2 head and voice tremor, 2 hand

tremor, 1 head hand and voicetremor, 2 blepharospasm,1 torticollis, 1 multifocaldystonia, 1 cranial dystonia.

tocol which was audio and video recorded.This vocal protocol included the reading of a

passage (The North Wind and the Sun) whichwould be used for later analysis. The audiorecording was made using a UHER CR 160AV stereo cassette recorder in conjunctionwith a UHER M534/A cardiod directionalmicrophone. Filters were used to extractextraneous ambient background noise. Allrecordings were carried out in a video record-ing studio. Each patient was reassessed by theteam at each follow up visit.

Botulinum toxin treatment procedureThe toxin Clostridium Botulinum toxin Type A(Dysport) is obtained from Porton ProductsLtd as a freeze dried toxin-haemagglutoninpreparation. Fifty nanograms is equivalent to2000 mouse-units. To begin with we dilutedin normal saline to a concentration of 25units per ml. Now we use a concentration of40 units per ml.The injection procedure used followed that

of Brin et al.'6 A small dose of botulinumtoxin was injected into both thyroarytenoidmuscles (that is, left and right). Before theinjection 2% lignocaine was injected downthrough the cricothyroid membrane to pro-vide local anaesthesia. EMG recordings were

employed to localise the thyroarytenoid mus-

cle. A 26 gauge hollow monopolar tefloncoated needle was used with a skin reference(clavicle) and a ground in position. The

needle was advanced through the cricothyroidmembrane in a superior and lateral directionuntil a crisp motor unit interference patternwas heard. When the monopolar teflon coat-ed laryngeal EMG needle was in the correctposition, the toxin was administered throughthe same needle which was then withdrawn.The original injection dose was 3*75 units

in 0 15 mls. Recently the dose was alteredslightly to 3 units in 0-075mls. The first 22patients in the series received the originallarger dose; 9 subsequent patients receivedthe new smaller dose.The procedure was tolerated well by the

majority of patients, although at times cough-ing and gagging occurred. The use ofMerocaine lozenges (benzocaine cetylo-pyridium chloride) sucked 30 minutes beforethe injection has proved useful to suppressthe tendency to cough during the injection.

Follow upAfter the injections the patients were request-ed to keep voice diaries recording the occur-

rence, quality, and duration of any negativeside effects and of positive improvement intheir voices after treatment. Speech sampleswere collected when patients returned to theSD clinic for follow up.

Patients were usually seen for a follow upassessment 2-3 months after their injectionand, if appropriate, they were re-injected withthe same dose bilaterally. Patients were againassessed by the speech-language therapistwho recorded the vocal protocol. The intervalbetween the recordings was not the same forevery subject (mean interval = 10 weeks,range 2-30 weeks). As the SD clinic drawspatients from great distances, many couldonly attend the clinic for follow up visitswhen their voices were beginning to deterio-rate. Typically patients were found to requirere-injection at this time. The post-injectionrecordings were most commonly made atthe point when the voice was beginning todeteriorate and had passed the peak period ofmaximum benefit.

Speech analysisThe effect of botulinum toxin injections onthe patients' vocal quality was investigatedwith two different measures: 1) objectiveacoustic speech analysis and 2) patients' sub-jective diary reports.

Acoustic analysisThe audio taped recordings of the patients'reading of The North Wind and the Sun wereanalysed using the Visispeech speech analysispackage (RNID) on a BBC Master computer.The Visispeech speech analysis programmemeasures the fundamental frequency of thevoice over the duration of the entire speechsample. The data are scaled into 85 "bins" orcompartments, and measures of central ten-dency, variance and standard deviation arecalculated.The measures of standard deviation of the

distribution of frequency in the entire speechsamples were compared pre- and post-injec-tion. This measure can be taken as an indica-tion of regularity of pitch of voice. Thus avoice with many pitch breaks and variationsin pitch has a high standard deviation value.The standard deviation values pre-injectionand post-injection were compared using aWilcoxon Signed-Ranked Test.

Patient diariesThe analysis of the patients' diary records wascarried out to determine: 1) the length ofdelay before the benefits of the injectionswere noted; 2) the duration of peak effect,that is, the length of time the voice was at itsmaximum improvement before any deteriora-tion was noted, and 3) the duration ofresponse, the length of time the patientreceived any benefit from the injection.

ResultsAcoustic analysisOf the 31 patients' audio recordings both pre-and post-injection only 22 were technically

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The use of botulinum toxin in the treatment of adductor spasmodic dysphonia

30-O

I-re injec-cion-Post injection

20

.)

0--

0 L-

acceptable for acoustic analysis. These 22speech samples were analysed for the stan-dard deviation of long term fundamental fre-quency. The measures of standard deviationof the speech samples recorded post-injectionwere found to be significantly lower than thepre-injection values (p < 0 005) using theWilcoxon signed ranks test (see figure).

Beneficial effectsAt the follow up visit the vast majority ofpatients (96%) in our study reportedimprovement in their voice, some reporting it"back to normal", and many gave veryfavourable reactions speaking of theirincreased confidence at work and sociallysince the change in their voices. Only a pro-portion of the 31 patients successfully keptvoice diaries. The data available was analysedon diaries from 24 patients. The median timefor onset of effects post-injection was 7 days(n = 23, range 1-18 days). The median dura-tion of peak effects was 5 weeks (n = 24,range 1-12 weeks). The vast majority of our

patients, at the time of their second injection,reported that their voice quality, thoughdeteriorated from a peak level, was still an

improvement on their pre-injection voicequality.

Beneficial vocal effects after injectionreported by the patients included: reducednumber of pitch and voice breaks, increasedvolume and increased overall ease of produc-tion (that is, reduced effortfulness).

Adverse effectsTemporary side effects were reported by 8out of 22 patients (25%). These negative sideeffects included: some dysphagia for fluids(without aspiration) (n = 5), weak cough(n = 2) and slight pain at the site of injection(n =2).

DiscussionThis study shows that bilateral botulinumtoxin injections into the thyroarytenoid pro-vide an effective treatment for spasmodic dys-phonia of the adductor type. This furtherconfirms evidence of previous studies thathave indicated the beneficial effects of botu-linum toxin on this voice disorder.3 l12426

At the time we started this study, thelargest experience of botulinum toxin injec-tions for adductor spasmodic dysphonia hadused bilateral injections.16 Others, however,have employed unilateral injections. The rela-tive merits of these two approaches have notbeen assessed formally. In theory, a unilateralinjection might be safer, but bilateral injec-tions might produce the same physiologicalresult with smaller doses.The analysis of standard deviation of fun-

damental frequency of a speech sample pro-vided a useful objective assessment of theeffects of treatment on the regularity of pitch,an important indicator of vocal quality. Thefinding of decreased standard deviation of fre-quency distributions after injection indicatedan increase in regularity of the voice and a

decrease in pitch breaks and variations inpitch. This objective acoustic measure con-

firmed the subjective assessment of thespeech-language therapist and the patients'own reports. These findings on long term fre-quency measures substantiate those reportedby Zwirner et al24 comparing the standarddeviation of fundamental frequency for a sus-

tained vowel segment pre- and post-injectionwith botulinum toxin. They also found thatstandard deviation values were lower afterinjection.As the post-injection assessments and

recordings were not necessarily obtained dur-ing the peak period of maximum benefit, butat a time when the positive effects of thetreatment were presumably already on thewane, this analysis can be taken conservative-ly. This evidence suggests that even when thepeak period is over there is still a marked andlasting improvement in the voice comparedwith the voice pre-injection. This supportsthe findings reported by Brin et al 16 that vocalsymptoms do not recur after injection to thesame level of strength and intensity as beforebotulinum toxin treatment.

Patients reports of vocal effects after injec-tion indicated that onset of beneficial effectsoccurred at day 7 on average. The duration ofpeak voice benefit was typically 5 weeks. Only25% of patients reported any negative sideeffects which were transitory in nature.Jankovic and Brin 5 state that a higher inci-dence of side effects have been reported whenusing the British toxin, Dysport, comparedwith the American toxin, Oculinum. Theysuggest that this might be accounted for bythe higher potency of Dysport compared withOculinum (1 nanogram of Dysport contains40 units whereas 1 nanogram of Oculinumcontains 2-5 units, where a "unit" is a stan-dard measure of potency of commerciallyavailable toxin). However, when the inci-dence of side effects in the study by Blitzer26which utilised low dose bilateral injections(range of doses 1 v25-375units) was com-

pared with the results obtained during thisstudy it was seen that the incidence was verysimilar. Blitzer and Brin26 reported 45% ofpatients with a short period of breathy dys-phonia and 22% with mild dysphagia forfluids. For low dose bilateral injections for

Figure Values forstandard deviation offundamentalfrequency preand post botulinum toxininjection for adductorspasmodic dysphonia. -l

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50Whurr, Lorch, Fontana, Brookes, Lees, Marsden

adductor SD the results reported here concur

with those obtained by Blitzer et al and thereis no evidence for a higher incidence of sideeffects using the British toxin.

Only one of the 31 patients in the studyfailed to gain an improvement in his voice fol-lowing the initial injection. Acoustic analysisrevealed very minimal change in standarddeviation of the speech sample pre- and post-injection. This patient had previously under-gone recurrent laryngeal nerve crush afterwhich the voice symptoms gradually recurred.He has since been reinjected with a slightlylarger dose (5 units/cord) and has obtainedan excellent result. Others16 have reportedpositive results in treating patients with recur-

rent nerve crushes.Three patients had voice tremor in addi-

tion to SD. The injections of botulinum toxinalleviated the symptoms of SD but the voicetremor remained. Though the tremor did notmarkedly impede the speaker's intelligibility itwas perceived by them as socially disabling.

In the present report, only data pertainingto the effects of the first injection have beenanalysed. All patients have, however, receivedfollow up injections, and data from these sug-

gests that the injection continues to have a

beneficial effect. All 31 patients have con-

tinued with injections every 2-4 months, as

appropriate, for periods of up to 3 years, withcontinued benefit.The majority of treated patients derive the

most dramatic improvement after the firstinjection of botulinum toxin. Most patientsrequire subsequent multiple injections atvarying intervals to maintain spasm-free vocalperformance. Graded responses of muscleweakness can be obtained by using low dosesof botulinum toxin. Once the patient's sensi-tivity to treatment is determined, an individu-alised protocol can be used for futureinjections, with small dose "top-ups" injectedinto one or both vocal cords. Low dose bilat-eral injections into the thyroarytenoid is sug-

gested as the preferred method of treatmentfor SD of the adductor type.

Occasionally, patients report that they didnot have any (positive or negative) effects fol-lowing an injection, when previously (andsubsequently) they have had a good response.At the outset it appeared that the botulinumtoxin had not taken effect in these cases.

However, these rare instances of failure of theinjection to produce an effect may be linkedto difficulties in the injection procedure itself,particularly if there have been problemsobtaining a satisfactory EMG signal. Ourexperience therefore indicates the importanceof using EMG to locate the thyroarytenoidmuscle. Not every "failed" injection can

probably be attributed to this factor, and fur-ther investigation of this problem is needed.

In conclusion, the use of botulinum toxin

in SD is an efficient method of treatment forthis chronic voice disorder. It enables patientsto use their voice effortlessly and to com-municate easily-in some instances for thefirst time for many years, with very few andtemporary side effects.

This project was supported by a grant from the JointResearch Advisory Committee, National Hospital forNeurology and Neurosurgery, and Institute of Neurology,University of London.

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