3'ournal ofNeurology, Neurosurgery, and Psychiatry 1995;59:601-607

Botulinum toxin F in the treatment of torticollisclinically resistant to botulinum toxin A

Geoffrey L Sheean, Andrew J Lees

AbstractTwo reports have shown a Japanesepreparation of botulinum toxin type F(BTX-F) to be an effective alternativefor patients with torticollis who developclinical resistance to botulinum toxintype A (BTX-A). A group of patients withtorticollis, comprising five secondarynon-responders and one primary non-responder, were treated with a prepara-tion of BTX-F produced in the UK(Speywood Pharmaceuticals). A low doseofBTX-F (220 mouse units (MU) in total)was given into clinically affected neckmuscles, followed six weeks later by aninjection of a total of 520 MU. Antibodiesto BTX-A (mouse protection assay) werepresent in all secondary non-respondersbut not in the primary non-responder. Nopatients developed atrophy after injectionof Dysport BTX-A (40 MU) into the leftextensor digitorum brevis musclewhereas pronounced atrophy occurred inall patients after injection of 40 MU ofBTX-F into the right extensor digitorumbrevis muscle. Three patients improvedsubjectively after treatment with 220 MUBTX-F and five (all secondary non-responders) after the subsequent dose of520 MU (two considerably), with reducedTsui scores, but group scores were onlysignificantly changed after the higherdose. The primary non-responderremained unchanged after both doses ofBTX-F. One patient reported mild dys-phagia with 520 MU BTX-F. Mean dura-tion of improvement with 520 MU BTX-Fwas five (range 4-6)weeks. Thus BTX-Fprovides benefit for BTX-A non-respon-ders with few side effects but for a shorterperiod than BTX-A, possibly due to rela-tive underdosing. As with BTX-A, biolog-ical sensitivity to BTX-F does notnecessarily predict a clinical response.

The National Hospitalfor Neurology andNeurosurgery, QueenSquare, London,WC1N 3BG, UKG L SheeanA J LeesCorrespondence to:Dr Andrew Lees, TheNational Hospital forNeurology andNeurosurgery, QueenSquare, London,WC1N 3BG, UK.

Received 12 May 1995and in final revised form9 August 1995Accepted 11 August 1995

(3 Neurol Neurosurg Psychiatry 1995;59:601-607)

Keywords: torticollis; clinical resistance; botulinumtoxin F; antibodies

Botulinum toxin (BTX) is a well established,effective treatment for torticollis,1-7 ble-pharospasm,8 9 and laryngeal dystonia. 101I Newindications for BTX treatment also being eval-uated include focal hand dystonias,'2-"7tremor,'8 and spasticity.'9 20 Of the seven

immunologically distinct types of botulinumneurotoxins, labelled A to G,21 the only type in

routine clinical use at present is botulinumtoxin type A (BTX-A).

Although most patients with torticollis bene-fit from BTX, about 10% never respond totreatment (primary non-responders)22-24 andup to 10% of patients may become resistant totreatment after initially responding (secondarynon-responders).25 Technical factors such asincorrect storage or reconstitution of the toxinmay be responsible for isolated secondarytreatment failures. Explanations for sustainedlate failure of response include underdosing,injection of inappropriate muscles, a worsen-ing or change in the pattern of dystonia, possi-bly with involvement of deep, inaccessiblemuscles, development of contractures, alteredperception of response, and the developmentof immunity.2325 Immunity is particularly sus-pected when injected muscles fail to becomeatrophic; antibodies to botulinum toxin areoften present in such patients.2526 Risk factorsfor the development of antibodies seem to behigher frequency of injections, the use of"booster" injections and higher doses of BTXper treatment,25 and possibly cumulative doseand small body size.2327 Antibodies have beendetected after treatment with each type ofBTX-A in use (Botox and Dysport). 23-26 28-30

Secondary non-responders who have devel-oped immunity to BTX-A should be theoreti-cally ideal candidates for treatment with typesofBTX that are immunologically distinct fromtype A. It has already been established thattheir dystonia responds to weakening of theaffected muscles with BTX but assumes thatthe resistance (immunity) is specific to BTX-Aand that this is the only reason for failure oftreatment. Two groups have reported success-ful treatment of patients who have developedantibodies and clinical resistance to the Botoxform of BTX-A using a Japanese preparationof botulinum toxin type F (BTX-F).263132We report the first results of open labelled

treatment of patients with torticollis clinicallyresistant to Dysport BTX-A with anotherpreparation of BTX-F.

Patients and methodsSix patients clinically resistant to BTX-A wereselected from a large torticollis clinic. Five hadinitially obtained a definite benefit (secondarynon-responders) and one had never respondedto treatment (primary non-responder). All hadultimately failed to develop atrophy in injectedmuscles. The study had the approval of thehospital ethics committee and all patients gaveinformed consent. The BTX-A (Dysport) and

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BTX-F used in this study were produced andsupplied by Speywood Pharmaceuticals.

INJECTION PROTOCOLOn entry into the study, the patients receivedone further treatment with BTX-A and werereviewed two weeks later. This was to confirmthat they were still clinically resistant to BTX-Abecause of the sometimes long interval sincethe cessation of regular BTX-A injections dueto treatment failure. The target muscles in theneck and the doses given to each were chosenand injected (without EMG guidance) by aphysician (AJL) with considerable experiencein the treatment of this condition. The dosesof BTX-A (400-500 mouse units; MU) werebased on this experience. Based on the LD5,data for BTX-F, using the same method asthat used to evaluate potency of their BTX-Aproduct, the suppliers suggested an initial totaldose of 260 MU of BTX-F, to be dividedamong the affected muscles. This dose wasdeliberately low for safety reasons as thispreparation of BTX-F had not been tried onhumans before. Provided that there were noadverse events with the lower dose, a subse-quent total dose of 520 MU was suggested,this being comparable with the average dose ofBTX-A used, again to be divided among theaffected muscles. Vials of BTX-A contained500 MU each and were diluted with 2-5 ml ofsterile normal saline to a concentration of 200MU/ml. Vials of BTX-F contained 260 MUeach and were diluted with 2-5 ml of normalsaline to a concentration of 100 MU/ml. Thecommonest muscles injected were the ster-nomastoid and splenius and less often thesemispinalis and trapezius.

At least six weeks after the BTX-A injec-tion, ensuring that there was no clinical effect ofthis injection, the patients received an injec-tion of a total dose of 220 MU of BTX-F andwere reviewed after two and six weeks. At thesix week review, a second injection of a total of520 MU BTX-F was given if there was noresidual response to the first injection ofBTX-F, and the patients were reviewed again twoand six weeks later.

CLINICAL EVALUATIONClinical assessment was performed at baselineand at each clinical review by one of us (AJL)using the Tsui scale.' Video recordings werealso made at these times. These were shuffledand arranged in random order by an audiovi-sual technician and later reviewed by both ofus, who were blind to their chronologicalorder; only the recording made on entry intothe study was identified, to serve as a baseline.The severity of the torticollis in all subsequentvideo recordings was compared with thatmade at entry and rated using a seven pointscale. The baseline state was assigned a scoreof 0 and no change from baseline was scoredas 0, and mild, moderate, or considerableimprovement or deterioration were scored as+ or - 1, 2, or 3 respectively. The patientswere asked to report any changes after eachinjection of BTX-A or BTX-F using the sameseven point scale.

ELECTROPHYSIOLOGICAL TESTINGBaseline electrophysiological testing was per-formed on the same day as the patientsreceived the BTX-A injections to the neck.Compound muscle action potential (CMAP)was recorded from the extensor digitorum bre-vis muscle bilaterally in response to supramax-imal stimulation of the deep peroneal nerve atthe ankle. Routine EMG of this muscle wasthen performed with a concentric needle elec-trode followed by quantitative EMG (NicoletViking II). The peak to peak amplitude, meanvoltage, root mean square voltage, and turns/swere recorded during a two second maximalvoluntary contraction of the muscle from threeseparate sites within the muscle. To test forbiological sensitivity, 40 MU of BTX-A wasthen injected with EMG guidance into the leftextensor digitorum brevis muscle through amonopolar, teflon coated 25 gauge needle.Electrophysiological testing of extensor digito-rum brevis muscle was repeated at two andfour weeks afterwards, when the muscle wasalso examined for strength and bulk. The con-tralateral extensor digitorum brevis musclewas tested serially as a control.

Immediately after the injection of 220 MUof BTX-F to the neck, the electrophysiologicaltests were performed (as before), followedby an injection of 40 MU of BTX-F (theremainder of the vial of 260 MU) into the rightextensor digitorum brevis muscle, the sideopposite that which received BTX-A.Electrophysiological testing was repeated attwo and four weeks as before.

SEROLOGICAL TESTINGBlood was taken on entry into the study, onthe same day and just before receiving theBTX-A neck injection, to test for antibodies toBTX-A. The details of the mouse protectionassay are similar to those previously reported.29

STATISTICAL ANALYSISThe Tsui scores, video ratings, and the elec-trophysiological data before and after theinjections were compared with the Wilcoxonrank sum test. P values < 0 05 were consid-ered significant.

ResultsTable 1 gives the clinical details of thepatients. There were five women and oneman, ranging in age from 27 to 63 (mean47'8) years. One patient was a primary non-responder and the remaining five were sec-ondary non-responders. The patients weredeclared clinically resistant to BTX-A injec-tions after seven to 18 treatments (mean 13,median 13-5) given over a period of 18 to 83months (mean 43-8, median 43-5 months).The total dose of BTX-A received by thepatients, before treatment was abandoned dueto resistance, ranged from 4000 to 12 300 MU(mean 8383 MU, median 8850 MU).

RESPONSE TO BTX INJECTIONSAfter injection of BTX-A, there was no signifi-cant change in the Tsui scores of the group at

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Botulinum toxin F in the treatment of torticollis clinically resistant to botulinum toxin A

Table 1 Clinical characteristics and antibody status ofpatients

Agel Clinical Disease Treatment Total dose4 AntibodyPatients sex typet duration (y) duration (months) (treatments) status51* 47,F Rot 4 18 4000 (7) None2 27,F Rot, lat, ret 10 83 6200 (10) Int-high3 51,M Rot 19 52 12300 (18) Int-high4 51,F Rot 7 51 8500 (13) Int-high5 48,F Rot 5 23 9200 (16) Int-high6 63,F Rot, ret 18 36 10100 (14) Int-high

*Primary non-responder; all others were secondary non-responders.tRot = rotation; lat = lateral flexion; ret = retrocollis.tCumulative dose, in mouse units, of Dysport BTX-A received before declared resistant. Treatments = number of treatmentsessions.SInt-high = antibodies to botulinum toxin A detected in intermediate to high levels.

two weeks and all patients felt unchanged,confirming their clinical resistance. Table 2shows the clinical response to the injections ofBTX-F given to the neck. Three patients(patients 2, 3, and 5) reported improvementafter the low dose of BTX-F (220 MU). Fortwo of these (patients 3 and 5), the onset ofthe response was before the two week review.The third patient (patient 2) noticed a moder-ate response beginning just after her two weekassessment; her Tsui score thus showed nochange at this time. Tsui scores were reducedat two weeks in the other two patients(patients 3 and 5) who reported improvementand in another (patient 4) who was unaware ofany improvement. The duration of response tothis dose ranged from two to four weeks.

All patients had returned to baseline (orbelow) by six weeks after the low dose ofBTX-F, subjectively and according to Tsuiscores. None had experienced any adverseeffects with the lower dose of BTX-F andtherefore all received the higher dose of 520MU at that time. After this, five patients (allsecondary non-responders) reported improve-ment (ranging from mild to considerable)accompanied by a significant reduction inTsui scores (P < 0O05) at two weeks. The pri-mary non-responder did not change clinicallyafter either dose of BTX-F, subjectively orobjectively; her Tsui score reduced after 520MU BTX-F by one point only.

Assessment of video recordings made twoweeks after each dose of BTX-F agreed, formost patients, with the subjective reports fromthe patients and the Tsui scores in terms of thedirection of change (improvement or deterio-ration) and often the degree of change (table3). A statistically significant change in the

averaged video scores of the two reviewers forthe group after 520 MU BTX-F could not,however, be demonstrated. There were toofew numbers to allow separate statisticalanalysis of the secondary non-respondersalone or of the individual reviewer's scores.Similarly for the results after 220 MU BTX-F.The duration of response in the three

patients who reported subjective improvementafter the lower dose of BTX-F (220 MU)ranged from two to four weeks. The meanduration of response after 520 MU BTX-Fwas five (range 4-6) weeks and all respondersstated that the duration of benefit was muchshorter than that previously experienced withBTX-A (usually 10 to 12 weeks). Two of thethree patients responding to the lower dosereported a benefit of increased magnitude andlonger duration after the higher dose; the thirdpatient reported considerable improvementafter both doses but a longer duration ofresponse with the higher dose. The onset ofbenefit began within two weeks, except for onepatient in whom the response was delayedwith the low dose of BTX-F to just beyondtwo weeks; with the higher dose, the onset waswithin two weeks.

Side effects were reported in only twopatients and only after the higher dose ofBTX-F. One (patient 3) experienced a drymouth and mild dysphagia for a few days; thisdose had produced a moderate subjectiveimprovement. The other patient (patient 2)reported a dry mouth for a few days, but no

dysphagia, accompanied by a pronouncedbenefit. All patients received injections ofBTX-F into the sternomastoid and developedsome degree of atrophy subsequently,although this was substantial in only two.

Table 2 Clinical response to BTX-F: Tsui scores, subjective ratings, and response duration

Response ResponseSubjective duration Subjective duration

BTX-F 220MU Response (weeks) BTX-F 520 MU response (weeks)

Tsui scorest Tsui Scores

Patient Baseline 2 weeks 6 weeks* 2 weeks 6 weeks

1 10 11 1 1 - 0 10 10 - 02 11 11 13 ++ 2 7 7 +++ 63 13 11 11 + 4 9 13 + + 54 9 7 9 - 0 7 13 ++ 45 13 7 13 + + + 3 8 11 + + + 66 15 15 18 - 0 13 15 + 4

*BTX-F dose 520 MU given 6 weeks after BTX-F dose 220 MU; therefore, Tsui scores here represent baseline for BTX-F 520 MU.Subjective clinical response: - = no change; + = mild; + + = moderate; + + + = pronounced improvement.tTsui scores are calculated from severity scores (incorporating degree and duration) of the elements of head rotation, lateral tilt, and shoulder elevation, along withtremor or jerk. Scores range from 0 (normal) to 25 (very severe torticollis). For details see Tsui et al.'*Response began after the 2 week assessment.

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Table 3 Video scores of torticollis severity* at two weeks after each dose ofBTX-F

BTX-F (220 MU) BTX-F (520 MU)

Patient Reviewer 1 Reviewer 2 Average Reviewer 1 Reviewer 2 Average

1 0 -1 -05 1 0 052 0 0 0 2 1 1-53 1 1 1 0 -1 -054 2 1 1-5 2 2 25 2 2 2 2 1 1-56 1 0 05 1 1 1.0* Baseline clinical state was assigned a score of 0. Thus 0 = no change, 1 = mild,2 = moderate, 3 = pronounced change from baseline.Negative scores indicate deterioration.

SEROLOGICAL RESULTSTable 1 gives the results of the antibody tests.The delay between the cessation of regularBTX treatment and the testing of antibodiesranged from two to 28 months (mean 12'3,median 10). Intermediate to high levels ofantibodies to BTX-A were present in all fivesecondary non-responders but were notdetected in the primary non-responder.

ELECTROPHYSIOLOGICAL RESULTSTable 4 gives the electrophysiological data.After injection of BTX-A into the left extensordigitorum brevis muscle, there was no signifi-cant change in the CMAP amplitude of eitherthe left or right extensor digitorum brevis mus-cle at two and four weeks (data for right exten-sor digitorum brevis muscle not shown).Similarly, there was no evidence of denerva-tion or any motor unit changes with routineneedle EMG and no significant change in thequantified EMG variables measured (notshown). No patient developed wasting orweakness of the left extensor digitorum brevismuscle. The primary non-responder (withoutdetectable antibodies) showed a change in theleft extensor digitorum brevis muscle CMAPamplitude ratio (compared with baseline) attwo weeks which was similar to that of themean of the secondary non-responders. Bycontrast, by two weeks after injection of BTX-F into the right extensor digitorum brevismuscle there was a dramatic reduction inCMAP amplitudes in all patients, wherebyresponses became nearly unrecordable. Thiswas accompanied by near total wasting andsevere weakness of that muscle. This changewas so pronounced and so dramatically differ-ent from the response from injection of the leftextensor digitorum brevis muscle with BTX-Athat statistical analysis was hardly necessarybut none the less confirmed the result to besignificant.

DiscussionIn this study, all secondary non-responders(previously responsive to BTX-A) had anti-bodies to BTX-A and all showed subjectiveand objective improvement with the higherdose of BTX-F. The primary non-responder,who did not have antibodies to BTX-A, alsofailed to respond to BTX-F. Biological resis-tance to BTX-A and sensitivity to BTX-Fwere established in all patients in the study bythe responses (clinical and electrophysiologi-cal) of the extensor digitorum brevis musclemuscle to injections of each type of BTX. Theinability to show a significant change in thevideo scores despite close agreement with thesubjective reports and the Tsui scores mayreflect the difficulties inherent in this methodof evaluation and possibly the lack of valida-tion of the method. Furthermore, one of theclinical raters performing the Tsui scores alsoscored the videos so that, although blind to thechronological order of the recordings, thisevaluation was not wholly independent.Our results are similar to those previously

reported. Greene et al'6 treated 15 antibodypositive patients with torticollis with BTX-F.All patients had initially developed atrophywith BTX-A, but later failed to do so indicatingsecondary biological resistance. Antibodies toBTX-A were present in all patients and allultimately failed to develop atrophy in injectedneck muscles. Ten patients responded toBTX-F, including nine of the 12 secondarynon-responders and one who had been a pri-mary non-responder to BTX-A. Five patientsdid not respond to BTX-F, of whom two hadalso not responded to BTX-A; of the remain-ing three, two had either absent or short livedatrophy with BTX-F. Two patients developedpronounced atrophy to BTX-F but were stillclinically unresponsive; one had initiallyresponded to BTX-A.

Another group have also reported theirexperience with BTX-F in 10 patients, sevenof whom had torticollis. 32 All patients wereclinically resistant to BTX-A and had antibod-ies detected with a bioassay; all improved aftertreatment with BTX-F for a period of six to 10weeks. Side effects were reported to be similarin frequency and severity to those with BTX-Atreatment.

These studies of BTX-F, including ourown, have been uncontrolled and haveinvolved few patients. Despite this, it seems

that most secondary BTX-A non-responderswill benefit from BTX-F. Biological sensitivity

Table 4 Electrophysiological responses to injections ofBTX-A and BTX-F

Left EDB BTX-A Right EDB BTX-FCMAP (mI'9 (40MU) CMAP (mV) (40MU)

Patient Baseline 2 weekst 4 weekst Wasting Baseline 2 weekst 4 weeks* Wasting1 49 32 3-6 - 5-6 02 0 5 +++2 79 58 57 - 7-3 01 14 +++3 6-2 6-6 5-3 - 4-3 0.1 03 +++4 6-1 4-4 5 0 - 6-3 0 9 0 3 +++5 2-7 2-0 1 9 - 3-0 0-2 0 3 +++6 40 49 4-4 - 3-3 0.1 03 +++

EDB = extensor digitorum brevis; MU = mouse units; CMAP = compound muscle action potential amplitude.*Wasting: - = no wasting, +++ = severe wasting of EDB; t no significant change from baseline; t significant change from base-line (P < 0 05, Wilcoxon rank sum test).

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to BTX-F, however, as determined by thedevelopment of muscle atrophy, does notguarantee a clinical response, even if thepatient was previously responsive to BTX-A.It is well known from biologically sensitiveprimary and secondary non-responders thatfactors other than immunity must be involvedin a lack of clinical response. These include achange in the pattern of affected muscles,possibly involvement of deep, inaccessiblemuscles, insufficient doses, injection ofinappropriate muscles, failure to place thetoxin accurately within the muscle, or thedevelopment of contractures.2'24 Such factorsmay have contributed to the late failure ofBTX-A, in addition to immunity, or mayhave intervened in the meantime to renderthe patients unresponsive to BTX-F. Althoughthe numbers are small, primary non-responders seem less likely to respond toBTX-F (one of four patients in this studyand those from Greene et a126) suggestingthat factors independent of the type of toxinused are chiefly responsible for the lack ofresponse.Our primary non-responder (patient 1) was

resistant both biologically and clinically toBTX-A. She had been managed aggressivelywith escalating doses and injections of differ-ent muscles, including treatment sessionsinvolving injections of up to four muscles at atime with a total dose of 1100 MU of BTX-A.Despite biological resistance, antibodies toBTX-A were not detectable. The frequency ofantibodies detected by bioassay in cases ofclinical resistance to BTX-A ranges from 11 to60%.232527 This may be an underestimate asnot all patients with clinical resistance aretested. Furthermore, it is not always clearfrom these reports whether the patients arealso biologically resistant (lack of atrophy).Thus factors other than this may beresponsible for the clinical resistance andmay partly explain the low incidence of anti-bodies in cases of secondary resistance. On theother hand, only three out of eight patients(38%) who were both clinically and bio-logically resistant had antibodies in onestudy.25 Therefore, even when biologicallyresistant, antibodies may not be detectable.Such seronegative cases, including ourprimary non-responder, may reflect the tech-nical difficulty and insensitivity of the mousebioassay. Alternatively, some other non-humoral factor may underlie the resistancein antibody negative patients. Animals inocu-lated with botulinum toxoid may beprotected from its neurotoxic effects despitethe absence of antibodies with the mousebioassay."The frequency of antibodies on mouse

bioassay in patients continuing to respond toBTX-A is also difficult to estimate giventhat such testing is usually only performedwhen there is a diminished clinical response.Whereas there are occasional reports of sero-positivity among continuing responders,2427screens of such patients generally yield nega-tive results.23 24 29 These findings should be dis-tinguished from those of studies employing an

in vitro assay, such as enzyme linkedimmunosorbent assay (ELISA) or spherelinked immunodiagnostic assay (SLIDA),28'0in which a high incidence of antibodies in con-tinuing responders has been found, probablybecause the antibodies detected do not neces-sarily neutralise the biological activity of thetoxin. Thus there is a better correlationbetween antibodies detected by a bioassay andclinical response. A more reliable indicator,however, might be a quantifiable response tothe injection of BTX into a muscle, such asthe extensor digitorum brevis muscle injectionused in this study. This would at least deter-mine biological sensitivity irrespective of anti-body status.A mean duration of response to BTX-F of

five weeks in this study is similar to thatreported by Greene et al 26 and is much shorterthan our experience with BTX-A, which isaround 12 weeks.7 The mean duration of ben-efit in the four patients treated with BTX-F byLudlow et al"l was longer at 7-5 weeks (range6-10 weeks in their later expanded report),'2although in three patients the response wasshorter than that previously experienced withBTX-A. The reason for this difference in theduration of benefit using BTX-F from thesame source (Japanese) is not clear but mayinvolve the different injection techniques andthe different assay estimates of toxin potencyobtained by each institution. It had been sug-gested that the duration of response may bedifferent in facial or laryngeal muscles,26 but astudy of blepharospasm seems to confirm ashorter duration of action for BTX-F, regard-less of muscle size.'4We have the advantage that the potencies of

BTX-F and BTX-A used in this study weredetermined by the same method. According tothe manufacturer's current information, thespecific activities (units of biological activityper unit amount of toxin) of the two types ofBTX are virtually identical. Thus equalamounts of each type of toxin should have thesame biological activity, or at least the samelethal activity in mice. This may not mean thatthey have equal muscle weakening effects.Animal studies suggest that BTX-F producesless potent neuromuscular junction blockadeand has a shorter duration of action thanBTX-A.'5 The initial dose of BTX-F used inthe present study was low for safety reasonswhereas the higher dose of 520 MU is similar(in MU) to the doses of BTX-A used in theroutine clinic. It is still possible, however, thatthe short duration of response we noted wasdue to relative underdosing. The threepatients responding to the lower dose (220MU) of BTX-F obtained benefit from thehigher dose (520 MU) ofBTX-F which was oflonger duration, or greater magnitude,or both,suggesting that the degree and duration ofresponse may be dose related, similar to BTX-A. Furthermore, atrophy of the stemomastoidwas often not prominent and only one patientexperienced side effects due to regional weak-ness (mild dysphagia) with the higher dose ofBTX-F; dysphagia was reported after 44% oftreatments with BTX-A in a review of the

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results from this institution.24 Therefore, evenhigher doses of BTX-F may have provided agreater response of longer duration. Althoughthe dilutions of the two types of toxin used (Aand F) were different, this could only beexpected to affect the degree of benefit and notthe duration. All of our patients developednear total atrophy of the extensor digitorumbrevis muscle after injection of 40 MU ofBTX-F but we have no experience ofinjections of this muscle with BTX-A for com-parison. Although we did not follow thetime course of the physiological responses ofthe BTX-F injections into the extensor digito-rum brevis muscle, it is the duration of clinicalresponse which is more important. Cross reac-tivity between the anti-BTX-A antibodies andBTX-F has also been suggested to explain theshorter duration of BTX-F,2632 even thoughthis does not occur experimentally.36

If lower potency and a shorter duration ofclinical action ofBTX-F is confirmed, this willnecessitate the use of higher doses more often,variables which have been identified as riskfactors for antibody development to BTX-A.25This could limit the value of BTX-F in longterm treatment and it may not prove to be apractical solution for patients with torticollisclinically resistant to BTX-A. A preliminaryreport37 on the use of BTX-B as primary treat-ment in torticollis looks promising but as yetthere are no data concerning its use in patientsclinically resistant to BTX-A. Treatment withBTX-F might also be of value in the rare situa-tion where treatment with BTX-A has becomecontraindicated because of complicationswhich are possibly immune mediated.40A2

Greene et al 26 suggested several situations inwhich use could be made of the shorter dura-tion of action of BTX-F. Another may betreatment of writer's cramp and other taskspecific dystonias in which a stepwiseapproach with very fine adjustments of BTXdoses and muscles injected is sometimesneeded and where excessive weakness ispoorly tolerated and may last for three monthsor more. It may be possible to optimise thetreatment (muscles injected and degree ofweakness) with BTX-F first and then continuewith BTX-A.

In summary, BT`X-F is a potentially usefulalternative for those who have failed torespond to BTX-A, particularly secondarynon-responders. As with BTX-A, biologicalsensitivity to BTX-F does not guarantee aclinical response and other causes of clinicalresistance should be considered. Althoughthere are still some questions about thedose-response relation, the duration ofbenefit seems to be shorter than with BTX-A.The need for higher doses more frequentlycould limit the clinical value of BTX-F andpossibly make it more immunogenic. Furtherdose ranging and long term studies areneeded.

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2 Jankovic J, Orman J. Botulinum A toxin for cranial-cervicaldystonia: a double-blind, placebo-controlled study.Neurology 1987;37:616-23.

3 Gelb D, Lowenstein D, Aminoff M. Controlled trial of bot-ulinum toxin injections in the treatment of spasmodictorticollis. Neurology 1989;39:80-4.

4 Greene P, Kang U, Fahn S, Brin M, Moskowitz C, FlasterE. Double-blind, placebo controlled trial of botulinumtoxin injections for the treatment of spasmodic torticollis.Neurology 1990;40:1213-8.

5 Lorentz I, Subramaniam SS, Yiannikas C. Treatment ofidiopathic spasmodic torticollis with botulinum toxin A:a double-blind study on twenty-three patients. MovDisord 1991;6: 145-50.

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8 Jankovic J. Botulinum toxin A in the treatment of ble-pharospasm. Adv Neurol 1988;49:467-72.

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NEUROLOGICAL STAMP

Mentha piperita (peppermint)

The mints (Mentha species) are among the oldest ofEuropean herbs and are widely cultivated in temperatezones. Medicinal mints date from the 1st century AD. InElizabethan times more than 40 ailments were reportedlyremedied by mints. Menthol, a derivative of peppermint,has been used in upper respiratory ailments and as a

soothing rub for sore muscles. Mints are also used in bothhome remedies and pharmaceutical preparations torelieve the stomach of intestinal gas that is often causedby certain foods. The many varieties of after dinner mintsreflect its use in this role.Mentha pulegium (European pennyroyal) taken in large

doses has produced convulsions and coma.

Peppermint (Mentha pipeita) is shown as part of a setof stamps issued by East Germany in 1960 illustratingmedicinal plants (Stanley Gibbons E 490, Scott 496).

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