w w w . r b o . o r g . b r
Original
Article
Focal
treatment
of
spasticity
using
botulinum
toxin
A
in
cerebral
palsy
cases
of
GMFCS
level
V:
evaluation
of
adverse
effects
夽
,
夽夽
Ana
Paula
Tedesco
∗,
Juliana
Saccol
Martins,
Renata
D’Agostini
Nicolini-Panisson
InstitutodeNeuro-Ortopedia,CaxiasdoSul,RS,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received7February2013
Accepted1August2013
Availableonline10May2014
Keywords:
Cerebralpalsy
Musclespasticity
Botulinumtoxin
a
b
s
t
r
a
c
t
Objective:ToreportontheexperienceofinjectionsofbotulinumtoxinA(BTA)inaseriesof
patientswithcerebralpalsyofGrossMotorFunctionClassificationSystem(GMFCS)levelV.
Methods:Thiswasaretrospectivecaseseriesstudyon33patientswithcerebralpalsyof
GMFCSlevelVwhoreceived89sessionsofBTAapplication(ofwhich84wereBotox®and
fivewereotherpresentations),inwhichthebasicaimwastolookforadverseeffects.
Results:Themeannumberofapplicationsessionsperpatientwasthree,andthemeanage
atthetimeofeachinjectionwas4+6years(range:1.6–13years).Themusclesthatmost
frequentlyreceivedinjectionswerethegastrocnemius,hamstrings,hipadductors,biceps
brachiiandfingerflexors.Themeantotaldosewas193Uandthemeandoseperweight
was12.5U/kg.Onlyonepatientreceivedanesthesiafortheinjectionsandnosedationwas
usedinanycase.Nolocalorsystemicadverseeffectswereobservedwithintheminimum
follow-upofonemonth.
Conclusion: Theabsenceofadverseeffectsinourserieswasprobablyrelatedtotheuseoflow
dosesandabsenceofsedationoranesthesia.Accordingtoourdata,BTAcanbesafelyused
forpatientswithcerebralpalsyofGMFCSlevelV,usinglowdosesandpreferablywithout
sedationoranesthesia.
©2014SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora
Ltda.Allrightsreserved.
Tratamento
focal
da
espasticidade
com
toxina
botulínica
A
na
paralisia
cerebral
GMFCS
nível
V
–
Avaliac¸ão
de
efeitos
adversos
Palavras-chave:
Paralisiacerebral
Espasticidademuscular
Toxinasbotulínicas
r
e
s
u
m
o
Objetivo:relataraexperiênciadaaplicac¸ãodetoxinabotulínicaA(TBA)emumasériede
pacientescomparalisiacerebral(PC)GMFCSnívelV.
Métodos:estudoretrospectivodesériedecasos,33pacientescomPCGMFCSnívelVque
receberam89sessõesparaaplicac¸ãodeTBA(84Botox®ecincooutrasapresentac¸ões),em
buscabasicamentedeefeitosadversos.
夽
Pleasecitethisarticleas:TedescoAP,MartinsJS,Nicolini-PanissonRD.TratamentofocaldaespasticidadecomtoxinabotulínicaAna
paralisiacerebralGMFCSnívelV–Avaliac¸ãodeefeitosadversos.RevBrasOrtop.2014;49:359–363.
夽夽
WorkperformedintheNeuro-OrthopedicsInstitute,CaxiasdoSul,RS,Brazil.
∗ Correspondingauthor.
E-mail:contato@anapaulatedesco.med.br(A.P.Tedesco).
Resultados: onúmeromédiodesessõesparaaplicac¸ãoporpacientefoitrêseaidademédia
em cadainjec¸ãofoi 4+6anos(1,6–13 anos).Os músculosmaisfrequentemente
injeta-dosforamgastrocnêmios,isquiotibiais,adutoresdoquadril,bícepsbraquialeflexoresdos
dedos.Adosemédiatotalfoi193Ueadosemédiaporpesofoi12,5U/k.Somenteumpaciente
recebeuanestesiaparaasinjec¸õesesedac¸ãonãofoiusadaemqualquercaso.Nãoforam
observadosefeitosadversoslocaisousistêmicosdentrodeseguimentomínimodeummês.
Conclusão: aausênciadeefeitosadversosemnossasérieestáprovavelmenterelacionada
aousodedosesbaixaseaonãoempregodesedac¸ãoouanestesia.Deacordocomnossos
dados,aTBApodeserusadadeformaseguraempacientescomPCGMFCSnívelV,emdoses
baixasepreferencialmentesemsedac¸ãoouanestesia.
©2014SociedadeBrasileiradeOrtopediaeTraumatologia.PublicadoporElsevier
EditoraLtda.Todososdireitosreservados.
Introduction
Botulinum toxin type A (BTA) has been used for more
than two decades for treating spasticity in cerebral palsy
cases, especiallyin the age groupfrom twoto eightyears
and in cases offocal dynamic deformities, with the main
aimof postponing surgical procedures through controlling
the deformity. Many studies have shown that if the total
dose, dose per unit weight and application technique are
respected,BTAissafetouseandadverseeffectsarepractically
absent.1
However,somerarecasesofseriousadverseeffectshave
been reported over the last few years,relating topatients
withGrossMotorFunctionClassificationSystem(GMFCS)level
V. These are patients with severe impairmentwho cannot
walk,presentlittleornocontrolovertheirheadpositionand
oftenhaverespiratorydysfunctionsofvariousdegrees.The
reportshaveconcludedthatthereisarelationshipwiththe
preexistingrespiratory dysfunctions, such aspseudobulbar
palsy,whichsuggeststhatothertypesoftherapyshouldbe
usedfortreating thesepatients.2–6 Despite the generalized
patternofspasticity,BTAmaybeindicatedforpatientswith
GMFCSlevelVinanattempt toimprove postureand
posi-tioning,alleviatediscomfortandfacilitatecareandorthosis
use.6
In our experience, BTA has been shown to be
com-pletely safe, independent of the GMFCS level. The aim of
thisstudywastoreportonourexperienceofapplyingBTA
to a series of patients with cerebral palsy of GMFCSlevel
V.
Materials
and
methods
Between 2000 and 2010, 188 patients with cerebral palsy
underwent 412 sessions of BTA application, performed by
the firstauthor. Ofthese, 33 patientswere atGMFCSlevel
V.They receivedBTAin89sessions andwere thetarget of
theanalysisinthisstudy.Afreeandinformedconsent
state-mentwasobtainedfromall thepatients,forapplicationof
themedicationandforuseofthedatarelatingtothe
treat-ment,whilemaintainingconfidentialityofidentity.Thestudy
wasapprovedbytheCircleResearchEthicsCommittee(Serra
GaúchaFoundation).
Results
Among thepatients, 25 were male and eight were female.
Theirmeanageatthetimeoftheapplicationswasfouryears
andsixmonths(minimumageofoneyearandsixmonths
andmaximumof13years).Around50%ofthepatients
pre-sentedaclinicalreportofdifficultiesinswallowingandthree
wereusinggastrostomyasthesolemeansoffeeding.Several
patientshadhistoriesofpulmonarycomplicationsand12had
alreadyneededhospitaltreatment.Atthetimeofthe
injec-tions,allthepatientswereinagoodstateofhealth,without
usingantibiotics.Theapplicationsessionstookplacewithout
sedationoranesthesia,exceptinonecaseinwhichanesthesia
wasadministeredbymeansofamask.
Thepatientscameforthesessionsafterorthopedic
assess-ment,inwhichplanning forwhichmusclesthe BTAwould
beappliedtowasconducted,along withcalculationofthe
totaldosageandthedosageperapplicationpoint.Thetotal
doseanddoseperunitweight,themusclesinjectedandthe
doseperapplicationpointwererecorded.Theresultsandany
occurrencesofadverseeffectswerenotedduringthe
follow-up.
Botox®wasthepresentationofBTAusedin84injections,
andotherpresentationswereusedinfivecases:two
applica-tionsofDysport®andthreeofProsigne®.Themeantotaldose
ofBotox®was193U,rangingfrom100to300U.Thetotaldose
ofDysport®was500Uinthetwoapplications,withamean
doseof45U/kginoneapplicationand50U/kgintheother.
ThetotaldoseofProsigne® was200Uinthethree
applica-tionsandthedosesperunitweightwere14,12.5and16U/kg.
In62injections,themeandosewas12.5U/kgfortheBotox®
presentation,witharangefrom6to22U/kg;in27injections,
thedoseperunitweightwasnotidentifiedinreviewingthe
medicalfile.
Themeannumberofsessionsperpatientwas2.7;13(40%)
hadonlyonesessionandeight(24%)hadtwo.Twopatients
(6%)hadninesessions.Theminimumintervalbetweenthe
applicationswassixmonths.
Themuscles mostfrequentlyinjectedwere the
gastroc-nemius (61 injections),hamstrings (54), hip adductors(30),
biceps brachii (28)and long flexorsofthe fingers (26).The
othermusclesinjectedwerethewristflexors,thumb
adduc-torandpronatorteres.Themeannumberofmusclegroups
injected per session was three. Three muscle groups were
musclegroupin11.Inalmostallthesessions,theapplication
wasbilateral.
Discussion
BTA makes an unquestionable contribution toward
man-agement ofspasticity. Thegreatmajority ofstudies inthe
literature have demonstrated low rates of complications
andadverseeffects.Areviewin2009onstudiesconducted
between1990and2008(20studiesinthemeta-analysis,with
882 participants) showed that there were only 35 adverse
events,whichwereallmild,includingrespiratoryinfections,
bronchitis, pharyngitis, asthma, muscle weakness, urinary
incontinence,falls,convulsionsandnonspecificpain.It
con-cluded that BTA was safe to use in cerebral palsy cases.1
Cotéetal.7reviewedthereportsystemoftheFoodandDrug
Administration(FDA),intheUnitedStates,coveringtheyears
1989–2003, searchingforadverse effectsfrom BTA (Botox®)
forestheticorcosmeticuse. Theyidentified1437reportsof
adverseeffects:1031fromcosmeticuseand 406from
ther-apeuticuse.Inbothtypesofindication,themajorityofthe
patientswhohadadverseeffectswerewomenwithamean
ageof50years.Amongthe406casesofadverseeventsfrom
therapeuticuse,217wereclassifiedasserious,including28
deaths(duetorespiratoryarrest,myocardialinfarction,stroke,
pulmonaryembolism and pneumonia,including aspiration
pneumonia),and 26 ofthemhad underlying diseases.The
meanage amongthe patientswho diedwas 44years.Itis
importanttoemphasizethatthisstudydidnotcitethe
diag-nosesofthepatientstreatedwithBTAanddidnotmakeany
agedistinctionforpatientsundertheageof20years.
There-fore,noparallelwithourdatacanbetracedout.7
PatientswithGMFCSlevelVpresentspasticitywith
defor-mitiesatmultiplelevelsthatoftenrequireabroaderapproach,
withuseoforalorintrathecalmedications.However,thereare
indicationsforfocalmanagementofspasticity,withaviewto
improvementofthepositioningandfacilitationoftheuseof
orthosesanddailycare.
Recently,reportsofcasesinwhichseverecomplications,
including death, occurring through administration of BTA
in cerebral palsy cases were published, with linkage to
greater severity offunctional impairment (GMFCS level V).
The adverse effects most frequently reported have been
respiratorydifficultiesandurinaryincontinence,whichcan
almostalwaysbeexplainedbylocaland/orhematogenic
dis-seminationofthedrugandautonomicdenervationthrough
retrogrademigration.Adverseeffectsofgeneralizedweakness
fromBTAintreatmentsforspasticityanddystoniahavealso
beendescribedandlikewiseexplainedintermsofsystemic
dissemination with pre-synaptic inhibition. One study in
whichamuscle biopsywas performedinamuscle distant
fromthe applicationsitedemonstrated denervation.
Retro-gradeaxonaltransportthereforecannotberuledout.2,3,8–10
Clinical conditions of botulism have been described after
administrationofBTA,almostalwaysrelatedtoexcessively
highdoses,suchas40U/kg.Otherauthorsreportedasimilar
case,inapatientwithGMFCSlevel,fromthedescription,who
wasusinggastrostomy.Nouseofanesthesiaorsedationwas
cited.Thepatient’sconditionofsevererespiratorydifficulty,
ptosis, fecal impaction, urinary retention and fever was
interpretedasiatrogenicbotulism.11,12
Intheliterature,thereseemstobearelationshipbetween
hightotaldosesandoccurrencesofadverseeffects,not
nec-essarilyincaseswithGMFCSlevelV.In2001,Bakheitetal.13
examinedthedatafrom758patients(94%withspastic
cere-bral palsy and 29% quadriplegic) who had received 1594
treatmentswithBTA(Dysport®).Sedationoranesthesiawas
usedin31%ofthecases.Thepatientswerenotclassifiedusing
the GMFCS,andit wasonlystated that13% ofthem could
onlywalkathome,whiletheotherswereabletowalkinthe
community.Themeandoseusedwas22.9U/kgandthe
max-imumtotaldose was2360U.Adverseeffectswerefoundin
7%,amongwhichthemostfrequentwere localizedmuscle
weakness(whichwasexplainedasresultingfromlocal
dis-seminationofthedrug)andurinaryincontinence(explained
asautonomicdysfunction).Theseweremainlycorrelatedwith
hightotaldoses(greaterthan1000U),buttherewasno
corre-lationwiththefunctionallevelorthedosageperunitweight.
Weaknessindistantmusclesoccurredinasmallpercentage
ofcasesand,accordingtotheseauthors,mayhavebeendueto
chemicaldenervation.TheyconcludedthatBTAwassafefor
treatingspasticityinchildrenwhenusedatdosesoflessthan
1000U(forDysport®),andthatlowerdosescouldbeused
with-outimpairingattainmentofthedesiredresults.13Itneedsto
betakenintoconsiderationthatthereisnoprecisecorrelation
betweenthedosesofBotox®andDysport®.
TherelationshipbetweencomplicationsandGMFCSlevel
VwasdemonstratedbyHowelletal.in2007.5Theypublished
acasereportonanadversereactiontoapplicationof400Uof
BTA(Botox®),i.e.20–25U/kg,inanine-year-oldpatientwho
presentedquadriplegicspasticcerebralpalsyofGMFCSlevel
Vandwastreatedundergeneralanesthetic.Thispatientwas
using gastrostomy.Hedevelopedrespiratorydifficulty after
thefirstinjection,whichwasrepeatedafterthesecond,third
andfourthinjections,andonthelastthreeoccasionshadto
beadmittedtohospital.Theauthorsexplainedtherespiratory
complicationsonthebasisofthepresenceofpseudobulbar
palsy,whichalterslaryngealandpharyngealfunction.These
areunderneuralcontrol,mediatedbycholinergicterminals,
and arethereforesubjecttoblockagethroughtheactionof
BTA.Theauthors statedthatBTAmightspreadbeyondthe
musclemotorpointsincertaincircumstancesandspeculated
thatitwouldnotbepossibletoruleoutallergicreactionsas
acauseoftheadverseeffectsthatoccurred.Theyconcluded
thatpatientswithGMFCSlevelV,whooftenpresentrisk
fac-torssuchaspseudobulbarpalsy,respiratorydifficultiesand
swallowing problems, should receive much lower doses of
BTA,i.e.between4and6U/kg.5
In2010,Naiduetal.14publishedtheresultsfrom1980BTA
in lower limbs, under anesthesia applied through a mask,
among 250 patients of GMFCS level V.14 There was a low
complication rate in the general sample(1% with
inconti-nence and 1.3%with respiratory abnormalities), and these
complicationswerecorrelatedwithuseofhighdosesofBTA.
Themean doseused was252Uintotal (13.4U/kg)and the
meannumberofmusclegroupswasthree.Amongthese,the
gastrocnemiusand hamstringswerethe musclesmost
fre-quentlyinjected.Therewasonedeath,whichwasrelatedto
respiratorycomplicationswascorrelatedwithGMFCSlevelV
andtothepresenceofpseudobulbarpalsy,historiesof
respi-ratorydiseasesanduseofinhaledanesthesia.Amongthe71
patientsinthegeneralsamplewhoshowedadverseeffects,24
receivedaseconddoseofBTAandtwodevelopednewadverse
effects.TheauthorsrecommendedthatpatientswithGMFCS
levelVshouldnotbetreatedwithBTA,whilethosewithlevel
IVshouldreceiveamaximumdoseof18U/kg.Inourstudy,
reapplicationsweremade,withoutanyappearanceofadverse
effects,eveninthepatientswhopresentedsomedegreeof
respiratorydysfunctionorswallowingdifficultyand
gastros-tomy.Itshouldbenotedthatinoursample,noanesthesiaor
sedationwasusedandthedosesusedweresmaller.
Aconsensuspublishedin2010advisedthatthetotaldose
andthedoseperunitweightshouldbecalculatedmore
care-fullyinpatientswithGMFCSlevelVandinthosepresenting
respiratorydysfunctionsand/ordysphagia,andthatan
inter-val of not less than six months should be given between
applications.6
Ontheotherhand,evenwithhigherdoses,in2010Unlu
et al.10 published the results from administration of BTA
undersedation(midazolam)among71patients,ofwhom33%
presentedGMFCSlevelV.Therewasnomentionofany
compli-cationsoradverseeffects,withdosesof15–20U/kgofBotox®
or30U/kgofDysport®,andthemaximumdoseswere
respec-tively300Uand500U.Theabsenceofcomplicationsmayhave
beenrelatedtononuseofanesthesia.
However,thisrelationshipwithnonuseofanesthesiacould
not be proven in another study, in which adverse effects
wereobserved in76 patientswithGMFCSlevel Vwho had
receivedBTAundersedationoranesthesiathroughamask.
Amongthesepatients,72%presentedhistoriesofdysphagia
andalmosthalfwereusinggastrostomy.Theauthors
mon-itoredthe appearance of sentinel events,i.e. worsening of
dysphagia,generalizedweaknessandinfectiouseventsofthe
lowerairways.Adverseeventsoccurredinmorethan20%of
thetotalnumberofcases.AmonglevelVpatients,three
pre-sented worsening ofdysphagiaand four had aninfectious
eventofthelowerairways;allofthemhadhistoriesof
dyspha-gia.Therewerenodeaths.Noneofthepatientswhoshowed
sentineleventshadreceivedBTAundergeneralanesthesia.9
MostreportsthathavedescribedadverseeventsfromBTA
haveindicatedthatdisseminationtolocationsfarfromthe
applicationsites,suchastheswallowingand/orrespiratory
muscles, as possible causes of complications. However, it
is unclear in the literature whether serious complications
suchasrespiratorydysfunctionanddeathmightberelated
tounderlyingconditionsthatwerenowinathresholdstate,
giventhatthesepatientsgenerallypresentedadverseeffects
thatweredirectlyrelatedtoBTA.Thispopulationofpatientsis
frequentlydependentongastrostomyforfeeding,sincethey
presentaspirationoffoodstotheairways,whichhasoften
beendocumented.Thus,thesearesituationsinwhichdeep
sedationoranesthesiacouldbeincriminatedasthecauseof
significantlackofprotectionoftheairways,therebyfavoring
aspiration and retention of secretions. Such conditions in
thesepatientscouldbelethal.14Olneyetal.15used
electroneu-romyographictoinvestigatedistantneuromusculareffects(in
thebicepsbrachii)afterapplicationof280UofBTAintheneck
muscles.Theydidnotfindanyelectrophysiologicalsignalsof
pre-synapticblockageandconcludedthathigherdosecould
beusedif necessary.Thus, itcould bepresumedthatonly
incontinencecouldbeattributedsolelytouseofBTA,given
that respiratory complications are very common in these
patients, even without any intervention, and it could also
beaskedwhetherthesedationand/oranesthesiaprocedure
alone might beincriminated. They suggested that options
otherthananesthesiausingamaskandadaptationofdoses
wouldbedesirableamongpatientswithGMFCSlevelsIVand
V.Occurrencesofurinaryand/orfecalincontinenceareoften
difficulttoregisteramongpatientswithGMFCSlevelV,who
generallydonothavesphinctercontrol.
Inourstudy,wedidnothaveanyadverseeffects,possibly
becausethedosesusedwerelow:ameanof193U(12.5U/kg).
In only15 applicationsdid the patientsreceive more than
15U/kg,andinonlytwocases,morethan20U/kg;andno
seda-tionoranesthesiawasused.Thismeandosewaslowerthan
themeandosesusedinstudiesinwhichcomplicationswere
shown.5,13,14Itseemsthatitwasimpossibletomakeany
corre-lationwithpreexistingrespiratorypathologicalconditionsin
oursample,giventhatwedidnothaveanycomplications.This
occurredeventhougharound50%ofthepatientshadclinical
reportsofdifficultieswithswallowingandaspiration(three
patientswereusinggastrostomyasthesolerouteforfeeding),
severalpatientshadhistoriesofpulmonarycomplicationsand
12requiredhospitaltreatment.
TheliteratureshowsthatadverseeffectsfromusingBTA
fortreatingspasticityincerebralpalsycasesare rare.Such
effectsincludegeneralizedmuscleweakness,urinary
incon-tinence, botulism and respiratory complications, and they
correlatemainlywiththerespiratorycomplicationsatGMFCS
level V. It is important to emphasize that the respiratory
adverseeffectsoccurredinpatientswhoreceivedhighdoses,
alreadyhadunderlyingrespiratorydysfunctionsand
under-wentsedationoranesthesiafortheapplications.Theadverse
effectsmightberelatedtosystemicdisseminationor
auto-nomicdysfunctionduetoretrogradepre-synapticinhibition.
Studies have recommendedthat thesepatients, who often
presentriskfactorssuchasunderlyingrespiratoryand
swal-lowing difficulties and have not received BTA, should be
treatedwithlowdoseswithoutsedationoranesthesia,since
thereisalikelycorrelationbetweenthesefactorsandthe
com-plications.Inourstudy,inwhichthepatients weretreated
with intermediate doses, without sedation or anesthesia,
therewerenocomplications.
Conclusion
Fromourfindings,BTAcanbeusedforfocaltreatmentof
spas-ticityinpatientswithcerebralpalsyofGMFCSlevelV,provided
thatlowdosesareused,withoutusingsedationoranesthesia.
Conflicts
of
interest
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1. Albavera-HernandezC,RodriguezJM,IdrovoAJ.Safetyof botulinumtoxintypeAamongchildrenwithspasticity secondarytocerebralpalsy:asystematicreviewof randomizedclinicaltrials.ClinRehabil.2009;23(5):394–407.
2. ApkonSD,CassidyD.Safetyconsiderationsintheuseof botulinumtoxinsinchildrenwithcerebralpalsy.PMR. 2010;2(4):282–4.
3. DavyM,RobinsonK,TaylorE.BotulinumtoxintypeA(Botox) anddistaltoxinspread.CanAdvReactNews.2008;18(1).
4. EarlyCommunicationaboutanOngoingSafetyReviewof
BotoxandBotoxCosmetic(BotulinumtoxinTypeA)and
Myobloc(BotulinumtoxinTypeB).Availablefrom:http://
www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm070366. htm
5. HowellK,SelberP,GrahamHK,ReddihoughD.Botulinum neurotoxinA:anunusualsystemiceffect.JPaediatrChild Health.2007;43(6):499–501.
6. LoveSC,NovakI,KentishM,DesloovereK,HeinenF, MolenaersG,etal.Botulinumtoxinassessment,intervention andafter-careforlowerlimbspasticityinchildrenwith cerebralpalsy:internationalconsensusstatement.EurJ Neurol.2010;17Suppl.2:9–37.
7. CoteTR,MohanAK,PolderJA,WaltonMK,BraunMM. BotulinumtoxintypeAinjections:adverseeventsreportedto theUSFoodandDrugAdministrationintherapeuticand cosmeticcases.JAmAcadDermatol.2005;53(3):407–15.
8.BhatiaKP,MunchauA,ThompsonPD,HouserM,ChauhanVS, HutchinsonM,etal.Generalisedmuscularweaknessafter botulinumtoxininjectionsfordystonia:areportofthree cases.JNeurolNeurosurgPsychiatry.1999;67(1):90–3.
9.O’FlahertySJ,JanakanV,MorrowAM,ScheinbergAM,Waugh MC.Adverseeventsandhealthstatusfollowingbotulinum toxintypeAinjectionsinchildrenwithcerebralpalsy.Dev MedChildNeurol.2011;53(2):125–30.
10.UnluE,CevıkolA,BalB,GonenE,CelıkO,KoseG.Multilevel botulinumtoxintypeAasatreatmentforspasticityin childrenwithcerebralpalsy:aretrospectivestudy.Clinics. 2010;65(6):613–9.
11.Beseler-SotoB,Sanchez-PalomaresM,Santos-SerranoL, Landa-RiveraL,Sanantonio-ValdearcosF,Paricio-TalayeroJM. Iatrogenicbotulism:acomplicationtobetakenintoaccount inthetreatmentofchildspasticity.RevNeurol.
2003;37(5):444–6.
12.CrownerBE,BrunstromJE,RacetteBA.Iatrogenicbotulism duetotherapeuticbotulinumtoxinainjectioninapediatric patient.ClinNeuropharmacol.2007;30(5):310–3.
13.BakheitAM,SeveraS,CosgroveA,MortonR,RoussounisSH, DoderleinL,etal.Safetyprofileandefficacyofbotulinum toxinA(Dysport)inchildrenwithmusclespasticity.DevMed ChildNeurol.2001;43(4):234–8.
14.NaiduK,SmithK,SheedyM,AdairB,YuX,GrahamHK. SystemicadverseeventsfollowingbotulinumtoxinAtherapy inchildrenwithcerebralpalsy.DevMedChildNeurol. 2010;52(2):139–44.
15.OlneyRK,AminoffMJ,GelbDJ,LowensteinDH.
