Farmacologia e paralisia cerebral

Simone Amorim Neurologista infantil

Ambulatório de bloqueio neuromuscular com toxina botulínica do Hospital das Clínicas da Universidade de São Paulo - USP

Farmacologia e PC*

•  Distúrbios do humor

•  Distúrbios do sono

•  Epilepsia

•  Dor…

•  Hipertonia

•  Sialorréia

*Paralisiacerebral

Sanger et al., 2003;

Síndrome do moto neurônio superior

Hipertonia

Espasticidade Distonia Rigidez

Presença de resistência muscular, velocidade

dependente e pode variar com a direção do

movimento articular

Contrações musculares involuntárias e

intermitentes, levando a movimentos e posturas

anormais ou ambos

Independente de velocidade e postura.

Pode haver co contração

Neural Não-neural

Receptores aferentes

O

O

SMNS

X

Aumento na hiperexcitabilidade do reflexo de estiramento / tonus muscular.

Reflexo de estiramento

Espasticidade na paralisia cerebral

Transtorno primário (1-3 anos): desequilíbrio de forças, diminuição do movimento articular e muscular.

Transtorno secundário (3-12 anos): Encurtamento de tendões e músculos. Surgem contraturas e deformidades osteoarticulares.

Transtorno terciário (a partir dos 12 anos): Compensações do desequilibrio de forças com posturas e movimentos anormais

Intervenção precoce!

50 2,5 3,5 4,5 12 0

100

Paralisia cerebral é a maior causa de espasticidade na criança, cerca de 80% das crianças com PC são afetadas por espasticidade.

Delgado, M et al., 2010

Paralisia cerebral (PC) descreve um grupo de distúrbios do movimento e postura, causando limitação da atividade, os quais são atribuídos a injúrias que ocorreram no desenvolvimento do cérebro no período pré, peri ou pós nata l . No entanto , as desordens motoras são frequentemente acompanhadas por distúrbios da sensibilidade, cognição, comunicação, percepção, comportamento e/ou epilepsia.

Bax et al., 2005

Paralisia cerebral – Conceitos

A prevalência da paralisia cerebral tem se mantido c o n s t a n t e n o s ú l t i m o s a n o s , principalmente em virtude da melhora na sobrevida dos RN pré termos

OSKOUI et al., 2013

2.11 por 1000 nascidos vivos

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW

An update on the prevalence of cerebral palsy: a systematicreview and meta-analysis

MARYAM OSKOUI1 | FRANZINA COUTINHO2 | JONATHAN DYKEMAN3 | NATHALIE JETT!E3 |TAMARA PRINGSHEIM4

1 Departments of Pediatrics and Neurology, McGill University, Montreal, Quebec; 2 School of Physical and Occupational Therapy, McGill University, Montreal, Quebec;3 Department of Clinical Neurosciences and Hotchkiss Brain Institute, Department of Community Health Sciences and Institute of Public Health, University of Calgary,Calgary, Alberta; 4 Departments of Clinical Neurosciences and Pediatrics, University of Calgary, Calgary, Alberta, Canada.

Correspondence to Dr Maryam Oskoui, Departments of Pediatrics and Neurology, McGill University, Montreal Children’s Hospital, 2300 Tupper Street, A-512, Montreal, Quebec,

Canada H3H 1P3. E-mail: maryam.oskoui@mcgill.ca

PUBLICATION DATA

Accepted for publication 22nd October 2012.

Published online 24th January 2013.

AIMS The aim of this study was to provide a comprehensive update on (1) the overall

prevalence of cerebral palsy (CP); (2) the prevalence of CP in relation to birthweight; and (3)

the prevalence of CP in relation to gestational age.

METHOD A systematic review and meta-analysis was conducted and reported, based on the

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement.

Population-based studies on the prevalence of CP in children born in 1985 or after were

selected. Statistical analysis was carried out using computer package R, version 2.14.

RESULTS A total of 49 studies were selected for this review. The pooled overall prevalence of

CP was 2.11 per 1000 live births (95% confidence interval [CI] 1.98–2.25). The prevalence of

CP stratified by gestational age group showed the highest pooled prevalence to be in

children weighing 1000 to 1499g at birth (59.18 per 1000 live births; 95% CI 53.06–66.01),although there was no significant difference on pairwise meta-regression with children

weighing less than 1000g. The prevalence of CP expressed by gestational age was highest in

children born before 28 weeks’ gestation (111.80 per 1000 live births; 95% CI 69.53–179.78;p<0.0327).INTERPRETATION The overall prevalence of CP has remained constant in recent years despite

increased survival of at-risk preterm infants.

Cerebral palsy (CP) encompasses a heterogeneous group ofearly-onset, non-progressive, neuromotor disorders thataffect the developing fetal or infant brain.1 CP is one of themost common causes of childhood physical disability, withan estimated lifetime cost, for persons born in the UnitedStates in 2000, of 11.5 billion dollars.2 Accurate prevalenceestimates are needed to guide operational health policiesand to aid with appropriate resource allocation.

In the past decade, two limited reviews on theprevalence of CP have been published.3,4 The first, pub-lished in 2007, looked at both the overall prevalence of CPand the prevalence reported by birthweight in preterminfants. The overall median prevalence estimate reportedwas 2.4 per 1000 live births.3 For preterm infants, a med-ian prevalence of 11.2 per 1000 live births was reportedamong children weighing between 1500g and 2499g atbirth, and 63.5 per 1000 live births among children weigh-ing less than 1500g. This review did not follow the PRIS-MA (Preferred Reporting Items for Systematic Reviewsand Meta-analyses) statement and had several methodolog-ical limitations. Only English-language articles were

included, published between 1 January 1990 and 31 Janu-ary 2005, searching a single bibliographic database (Pub-Med). A meta-analysis was not performed; rather, theoverall prevalence estimates of selected studies were com-bined equally to provide a median estimate. Studies report-ing prevalence estimates with different denominators (livebirths, neonatal survivors, children at a certain age) werecombined, and studies including participants born before1985 were included.

A second systematic review, published in 2008, examinedthe prevalence of CP only in relation to gestational age anddemonstrated a significant decrease in the prevalence of CPwith increasing gestational age.4 The prevalence rangedfrom 146 (95% confidence interval [CI] 125–170) per 1000children born at 22 to 27 weeks of gestation, steadily declin-ing thereafter to an estimated 62 (95% CI 49–78) per 1000children born at 28 to 31 weeks, 7 (95% CI 6–9) per 1000 at32 to 36 weeks’ gestation, and 1.13 (95% CI 0.93–0.14) per1000 in term-born infants. This systematic review used rig-orous methodology, searching four bibliographic databases(MEDLINE, CINAHL, Cochrane library, and Science

© The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press DOI: 10.1111/dmcn.12080 509

Paralisia cerebral – Prevalência

Palisano et al, 1997;

GMFCS E & R between 6th and 12th birthday:Descriptors and illustrations

GMFCS Level VChildren are transported in a manual wheelchair in all settings. Children are limited in their ability to maintain antigravity head and trunk postures and control leg and arm movements.

GMFCS Level IVChildren use methods of mobility that require physical assistance or powered mobility in most settings. They may walk for short distances at home with physical assistance or use powered mobility or a body support walker when positioned. At school, outdoors and in the community children are transported in a manual wheelchair or use powered mobility.

GMFCS Level IIIChildren walk using a hand-held mobility device in most indoor settings. They may climb stairs holding onto a railing with supervision or assistance. Children use wheeled mobility when traveling long distances and may self-propel for shorter distances.

GMFCS Level IIChildren walk in most settings and climb stairs KROGLQJ�RQWR�D�UDLOLQJ��7KH\�PD\�H[SHULHQFH�GLIÀFXOW\�walking long distances and balancing on uneven WHUUDLQ��LQFOLQHV��LQ�FURZGHG�DUHDV�RU�FRQÀQHG�VSDFHV�� Children may walk with physical assistance, a hand-held mobility device or used wheeled mobility over long distances. Children have only minimal ability to perform gross motor skills such as running and jumping.

GMFCS Level IChildren walk at home, school, outdoors and in the community. They can climb stairs without the use of a railing. Children perform gross motor skills such as running and jumping, but speed, balance and coordination are limited.

GMFCS descriptors: Palisano et al. (1997) Dev Med Child Neurol 39:214–23 CanChild: www.canchild.ca

Illustrations Version 2 © Bill Reid, Kate Willoughby, Adrienne Harvey and Kerr Graham, The Royal Children’s Hospital Melbourne ERC151050

Gross Motor Function Classification System – GMFCS

GMFCS I: 35,5% ˜ 60% GMFCS II: 24,5%

GMFCS III: 13,7 ˜10%

GMFCS IV: 12,2% ˜30% GMFCS V: 14,1%

Novak, 2014

I-II-III:Melhorarmarchaefunção

III-IV:Principalmentemelhorarpostura

IV-V:Alíviodedoremelhoranoscuidadospessoais

IV-V:Éogrupomaisvulnerávelacomplicaçoes

Love et al., 2010

Palisano et al, 1997; Novak, 2014

GMFCS E & R between 6th and 12th birthday:Descriptors and illustrations

GMFCS Level VChildren are transported in a manual wheelchair in all settings. Children are limited in their ability to maintain antigravity head and trunk postures and control leg and arm movements.

GMFCS Level IVChildren use methods of mobility that require physical assistance or powered mobility in most settings. They may walk for short distances at home with physical assistance or use powered mobility or a body support walker when positioned. At school, outdoors and in the community children are transported in a manual wheelchair or use powered mobility.

GMFCS Level IIIChildren walk using a hand-held mobility device in most indoor settings. They may climb stairs holding onto a railing with supervision or assistance. Children use wheeled mobility when traveling long distances and may self-propel for shorter distances.

GMFCS Level IIChildren walk in most settings and climb stairs KROGLQJ�RQWR�D�UDLOLQJ��7KH\�PD\�H[SHULHQFH�GLIÀFXOW\�walking long distances and balancing on uneven WHUUDLQ��LQFOLQHV��LQ�FURZGHG�DUHDV�RU�FRQÀQHG�VSDFHV�� Children may walk with physical assistance, a hand-held mobility device or used wheeled mobility over long distances. Children have only minimal ability to perform gross motor skills such as running and jumping.

GMFCS Level IChildren walk at home, school, outdoors and in the community. They can climb stairs without the use of a railing. Children perform gross motor skills such as running and jumping, but speed, balance and coordination are limited.

GMFCS descriptors: Palisano et al. (1997) Dev Med Child Neurol 39:214–23 CanChild: www.canchild.ca

Illustrations Version 2 © Bill Reid, Kate Willoughby, Adrienne Harvey and Kerr Graham, The Royal Children’s Hospital Melbourne ERC151050

Gross Motor Function Classification System – GMFCS

disabling as the physical disability. A meta-analysis of cer-ebral palsy register data has summarized the comorbiditiesrates and translated these rates into parent-friendly

prognostic messages for communicating to parents36 (Figure3). Figure 3 also outlines evidence-based management stra-tegies for each comorbidity.

Infant Diagnostic Case Study:

Medical History: Twins born at 26 weeks. At 5 weeks corrected; the twins are discharged home, with twin 2, the male twin, on nasogastric feeding.Prior to discharge from the Neonatal Intensive Care, the Occupational Therapists assesses twin 2 to have abnormal General Movements (ie,poor quality of spontaneous movement), with a profile predictive of cerebral palsy. This is despite having a normal head ultrasound, mildlyabnormal neurologic exam and no hypertonia present. At 12 weeks corrected, the General Movements assessment is repeated (since that is themost accurately predictive time window) and twin 2 is found to have persistent abnormal General Movements, with a profile 98% predictive ofcerebral palsy. The parents are informed that twin 2 is at high risk of cerebral palsy and early intervention was recommended. The neurologisthowever, reassures the mother that twin 2, had a normal head ultrasound, is growing normally, feeding well and is smiling and therefore mightnot have cerebral palsy and to ‘‘wait and see.’’ The mother embraces the ‘‘good news’’ and declines early intervention. At age 2, twin 2 isdiagnosed with diplegic cerebral palsy following failed motor milestones and a magnetic resonance imaging (MRI) confirming white matter injury.A subsequent hip radiograph reveals twin 2’s hips are both subluxing, secondary to the untreated bilateral spastic cerebral palsy.

The factsSubstantial risks for cerebral palsy existed in the medical history: multiple birth, extreme prematurity, male gender, feeding issues, and prolonged

hospitalization14

The General Movements assessment has the best sensitivity of all tools for detecting cerebral palsy early (98% sensitivity and 91% specificity at10-20 weeks post term age; versus gold standard MRI with 80%-87% sensitivity; versus neurologic examination with 57%-86% sensitivity inpreterms and 68%-96% sensitivity post-term age).17,18

12%-20% of children with cerebral palsy will have normal neuroimaging and neuroimaging should not be used in isolation.17 Moreover, MRI isdiagnostically superior to ultrasound.

Spasticity and dyskinesia may not be observable until 1-2 years of age.23

The combined sensitivity of abnormal General Movements plus abnormal MRI showing white matter injury, in preterms, is 100%.24

Waiting and watching until children fail motor milestones conflicts with neuroscience evidence about the benefits of early enrichment topromote neuroplasticity.6

Diagnosis-specific evidence-based early intervention was not provided to this child (eg, hip surveillance to prevent hip dislocation) directly as aresult of late diagnosis. Late diagnosis in this case was harmful, as hip dislocation is preventable in this population.25 Unmanaged hip dislocationcauses pain and hinders ambulation, markedly affecting outcomes and quality of life.

Early diagnosis is evidence-based and contributes to better child outcomes. Involvement of therapists in conducting motor assessments can helpaccelerate data gathering to make a diagnosis early.

Figure 2. Proportion of cerebral palsy by topography and severity.28,30

Novak 1145

by guest on July 21, 2014jcn.sagepub.comDownloaded from

Espasticidade Função

e cuidados

Tilton., 2009

Espasticidade pediátrica – Manejo

ü  Tratamento individualizado e precoce

ü  Comorbidades

ü  Terapias físicas ü  Tratamento

farmacológico

ü  Rizotomia dorsal seletiva / Cirurgia ortopédica

1)  Anti espasmódicos orais ü  Diazepan (nível B) ü  Dantrolene (nível U) ü  Baclofen (nível U) ü  Tizanidine (nível C)

2)  Denervaçao química ü  Toxina botulínica tipo A (nível A) ü  Toxina botulínica tipo B (nível U) ü  Álcool e fenol (nível U)

3)  Bomba de baclofeno intratecal ü  Bomba de baclofeno intratecal (nível U)

Practice Parameter: Pharmacologic treatment ofspasticity in children and adolescents withcerebral palsy (an evidence-based review)Report of the Quality Standards Subcommittee of the American Academy ofNeurology and the Practice Committee of the Child Neurology Society

M.R. Delgado, MD,FRCPC, FAAN

D. Hirtz, MD, FAANM. Aisen, MD, FAANS. Ashwal, MD, FAAND.L. Fehlings, MD,

MSc, FRCPCJ. McLaughlin, MDL.A. Morrison, MDM.W. Shrader, MDA. Tilton, MD, FAANJ. Vargus-Adams, MD,

MS

ABSTRACT

Objective: To evaluate published evidence of efficacy and safety of pharmacologic treatments forchildhood spasticity due to cerebral palsy.

Methods: A multidisciplinary panel systematically reviewed relevant literature from 1966 to July2008.

Results: For localized/segmental spasticity, botulinum toxin type A is established as an effectivetreatment to reduce spasticity in the upper and lower extremities. There is conflicting evidenceregarding functional improvement. Botulinum toxin type A was found to be generally safe in chil-dren with cerebral palsy; however, the Food and Drug Administration is presently investigatingisolated cases of generalized weakness resulting in poor outcomes. No studies that met criteriaare available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalizedspasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data onits effect on motor function and its side-effect profile. Tizanidine is possibly effective, but thereare insufficient data on its effect on function and its side-effect profile. There were insufficientdata on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequentlyreported.

Recommendations: For localized/segmental spasticity that warrants treatment, botulinum toxintype A should be offered as an effective and generally safe treatment (Level A). There are insuffi-cient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). Forgeneralized spasticity that warrants treatment, diazepam should be considered for short-termtreatment (Level B), and tizanidine may be considered (Level C). There are insufficient data tosupport or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).Neurology® 2010;74:336 –343

GLOSSARYAAN ! American Academy of Neurology; AE ! adverse event; AS ! Ashworth scale; BoNT-A ! botulinum toxin type A;BoNT-B ! botulinum toxin type B; CP ! cerebral palsy; FDA ! Food and Drug Administration; GAS ! Goal Attainment Scale;GMFM ! Gross Motor Function Measure; ITB ! intrathecal baclofen; MAS ! Modified Ashworth scale; OT ! occupationaltherapy; PT ! physiotherapy; QUEST ! Quality of Upper Extremity Skills Test; TS ! Tardieu scale.

The prevalence of cerebral palsy (CP) was recentlyreported to be 3.6 cases per 1,000 in 8-year-old chil-dren,1 with very little variation among Western na-tions.2 More than 10,000 babies born in the UnitedStates each year will be affected by CP.3 CP is themost common cause of spasticity in children, and themajority of children with CP are affected by spasticity.4

The Taskforce on Childhood Motor Disorders definesspasticity as “hypertonia in which one or both of thefollowing signs are present: 1) resistance to externallyimposed movement increases with increasing speed ofstretch and varies with the direction of joint movement;2) resistance to externally imposed movement rises rap-idly above a threshold speed of joint angle.”5

Supplemental data atwww.neurology.org

Address correspondence andreprint requests to AmericanAcademy of Neurology, 1080Montreal Avenue, St. Paul, MN55116guidelines@aan.com

From the University of Texas Southwestern Medical Center (M.R.D.), Dallas; National Institute of Neurological Disorders and Stroke (D.H.),Bethesda, MD; United Cerebral Palsy Research Foundation (M.A.); Loma Linda University (S.A.), Loma Linda, CA; Bloorview Kids Rehab (D.L.F.),Toronto, Canada; University of Washington (J.M.), Seattle; University of New Mexico (L.A.M.), Albuquerque; The Core Institute (M.W.S.), SunCity West, AZ; Louisiana State University (A.T.), New Orleans; and Cincinnati Children’s Hospital (J.V.-A.), Cincinnati, OH.

Appendices e-1 through e-4, tables e-1 through e-3, and references e1 through e19 are available on the Neurology® Web site at www.neurology.org.

Approved by the Quality Standards Subcommittee on February 7, 2009; by the AAN Practice Committee on April 10, 2009; by the CNS PracticeCommittee on December 7, 2009; by the AAN Board of Directors on October 19, 2009; and by the CNS Board of Directors on December 11, 2009.

Disclosure: Author disclosures are provided at the end of the article.

SPECIAL ARTICLE

336 Copyright © 2010 by AAN Enterprises, Inc.

Focal

Generalizada

Generalizada

A- Melhores evidências para indicar o tratamento. Benefício > dano B- Razoáveis evidências. Parece benéfico, mas existem poucos dados que sustentem a indicação C- Mínimas evidências. Sem dados que indiquem ou contra indiquem o tratamento U- Pobres evidências. Trabalhos inconclusivos para indicar o tratamento

Níveis de evidências

ü  Reduz espasticidade, hiperrreflexia e espasmos musculares.

ü  Auxilia no sono, reduz a ansiedade e auxilia no controle das crises convulsivas.

ü  Efeitos colaterais mais comuns: sedação, alteração de memória, retenção urinária, toxicidadde hepática e dependência química.

ü  Retirada abrupta pode causar agitação, tremor, hiperrreflexia e crises convulsivas.

ü  Deve ser iniciado em doses baixas, noturnas. Absorçao oral é rápida, concentraçao plasmática entre 30-90 min, metabolizaçao hepática (citocromo P450)

ü  Dose: 6 meses ou mais – Dose inicial 1 a 2,5mg, 3 a 4x/dia (0,12 a 0,8mg/kg). O aumento será diante da necessidade e tolerabilidade.

Anti espasmódicos orais

Diazepam

Farmacocinética do diazepam

17

Os desvios de uma relação dose-resposta linear que ocorrem nas benzodiazepinas,

exigem incrementos proporcionalmente maiores da dose para obter-se uma depressão do

Sistema Nervoso Central (SNC) mais profunda do que a hipnose, resultando assim,

numa superior margem de segurança que, por conseguinte, fornece uma importante

razão para o seu uso clínico extenso no tratamento dos estados de ansiedade e distúrbios

do sono (Katzung et al, 2009).

As benzodiazepinas afiguram-se, portanto, como fármacos muito eficazes, que têm uma

menor probabilidade de interagir com outros medicamentos, de provocar overdose e

menor potencial de provocar dependência quando comparados com os barbitúricos

(Clayton e Stock, 2002).

I.2. Classificação química

O diazepam representado na Figura 2 (C16H13ClN2O ou 7-cloro-1,3-dihidro-1-metil-5-

fenil-2H-1,4-benzodiazepina-2-ona) existe nas condições ambientais sob a forma um pó

cristalino branco ou quase branco, muito pouco solúvel na água e solúvel em etanol.

Apresenta um pKa de 3,4 (Farmacopeia Portuguesa VIII, 2005; Kaplan et al., 1973;

Korolkovas e Burckhalter, 1988).

Figura 2. Fórmula estrutural do diazepam.

A sua estrutura consiste num núcleo 1,4-benzodiazepínico, que possui um grupo

carboxamida no anel heterocíclico com sete membros. É necessário um átomo de cloro

na posição 7 para conferir atividade sedativo-hipnótica. (Gilman e Goodman, 2001;

Katzung et al, 2009).

Tilton, 2009

Anti espasmódicos orais

Dantrolene (nível U)

ü  Dantrolene inibe a liberação de cálcio do retículo sarcoplasmático

durante a contração muscular. Levando a uma redução do tônus e

espasmos musculares.

ü  Os efeitos colaterais mais comuns são: sedação (< que diazepan

ou baclofeno), mal estar, náusea, vômito, diarréia, parestesias.

ü  Metabolizaçao hepática, o que pode causar hepatotoxicidade e

não é dose dependente. Pico de ação de 4 a 8h.

ü  Crianças com 5 ou mais anos: a dose inicial é de 0,5mg /kg/dia

por 7 dias. Aumento gradual e lento. A dose máxima é de

100mg 4X/dia (12mg/kg/dia)

Tratamento da hipertermia maligna ou retirada abrupta de baclofeno

Anti espasmódicos orais Baclofeno (nível U)

Baclofeno é um agonista do

receptor GABA B, age nas sinapses

pré e pós sinápticas a nível medular

e supra medular, resultando em

diminuiçao dos espasmos, clônus,

dor e espasticidade.

Day I, et al; 2014; Goyal, et al;2016

Ação pré sináptica: ü  Reduz l iberaçao do

cá lc io , reduz indo a l i b e r a ç a o d e a m i n o á c i d o s e x c i t a t ó r i o s , c o m o glutamato e aspartato.

Ação pós sináptica: ü  Estimula a abertura de

canais de potássio, levando a hiperpolarização neuronal.

ü  Inibe a liberação de substância P.

ReceptorGABAB

Anti espasmódicos orais

Baclofeno

ü  Efeitos colaterais mais comuns: sedação, reduz o limiar

convulsivo, hipotonia, fadiga,retençao urinária, constipação,

náuseas e vertigens.

ü Retirada abrupta pode levar a espasticidade rebote,

hipertensão, halucinações, cr ises convulsivas e

hiperrreflexia

ü Menor efeito sedativo que o diazepan.

ü Não atravessa a barreira hemato encefálica – 90% corrente

sanguínea

ü Metabolização hepática e excreção renal - monitorização

Tilton, 2009, Day I, et al; 2014; Goyal, et al;2016

Anti espasmódicos orais

Baclofeno

ü Crianças > 12 anos: iniciar com 2,5mg/dia e aumentar para 5mg de 8/8hs por 3 dias, (S/N aumentar 5mg / dose a cada 3 dias) até o máximo de 20-60mg/dia.

ü  A dose usual é de 40-80mg/dia, mas a dose efetiva pode exceder a dose máxima diária de 80mg/dia (20mg 4X/dia).

ü  Efeito dose dependente

ü Doses excessivas podem levar a diminuição dos ganhos funcionais.

Spósito M, 2010

Anti espasmódicos orais

Tizanidina (Nível C)

Tizanidina é um derivado imidazólico, agonista do receptor alfa2 adrenérgico. ü  Age predominantemente a nível pré sináptico, reduzindo a

liberação de aminoácidos excitatórios, glutamato e aspartato do terminal pré sináptico dos interneurônios

ü  Reduz a liberaçao de substância P ü  Reduz tônus, frequência de espasmos e hiperrreflexia. ü  Devido a ação adrenérgica pode causar hipotensão

arterial e hipotensão ortostática.

É uma potente neurotoxina, composta de um complexo proteico produzido pela bactéria anaeróbia, Clostridium botulinum

Denervação química Toxina botulínica (Nível A)

Toxina botulínica Clostridium botulinun produz 7 sorotipos: A, B, C, D, E, F e G Na prática clínica são utilizados os sorotipos A e B No Brasil utilizamos apenas o sorotipo A

Mecanismo de ação: ü  A toxina botulínica inibe a liberação das vesículas de acetilcolina na

fenda pré sináptica dos terminais nervosos motores, levando a uma diminuição da contração muscular.

ü  Atua também em receptores sensitivos, reduzindo liberação de neurotransmissores de dor.

Toxina botulínica

There are no dose-ranging studies that address theoptimum dose of BOTOX!. Recommendations inprevious studies, consensus statements and this docu-ment are !expert opinion"; that is to say, no RCTs havebeen published. Given recent concerns about adverseevents, the authors have chosen total doses in units perKg body weight for BOTOX!, which are intermediatebetween the figures proposed in two previous consensusstatements, and which err on the side of caution(Table 3). It is the responsibility of the treating physi-cian to carefully choose the dose they consider appro-priate for the individual case concerned.

In addition to the RCTs reviewed in detail by theauthors, review of non-RCT literature confirms markedescalation in recommended doses of BOTOX!, both inrelation to specific indications such as spastic equinus aswell as in multilevel protocols. For example, in 2000,Graham [78] made the following recommendations:maximum dose at any one site 50 Units, maximum dosein any one injection session 300 Units or 12 Units per

Kg. In 2006, Heinen [79] in a European consensusstatement reported a published total dose range up to20–24 Units per Kg for this preparation (Table 3). Itshould be noted that both of these suggested upper doselimits were determined by expert opinion, not sup-ported by clinical trial.

One Class I study exists for the use of Dysport!, andthis is only for the indication of spastic equinus [52].(Table 3).

Although the incidence of adverse events followinginjection of BoNT-A in the RCTs reviewed in thispaper and in other literature remains relatively low,systemic adverse events can include generalized weak-ness, diplopia, dysphagia, aspiration, pneumonia anddeath. This serves as a warning that systemic spread ofBoNT-A may occur in children with CP and muchfurther work is required before high-dose protocols canbe accepted as safe. Given that the major risks ofserious systemic adverse events reside in the child, itseems prudent to make recommendations based on

Table 3 Products and doses

Product

Dose U/kg body weight

Maximum Total DoseRange in literature Recommendation

BOTOX! 6–24 U/Kg

(up to 30 U/Kg used

in occasional multilevel

injections)

GMFCS I–IV without risk factors: 16–20 U/Kg

GMFCS V with risk factors: 12–16 U/Kg*

<300 U [53,57]

<400–600 U [79]

Dysport! 10–30 U/Kg 20 U/Kg [52]

(level B recommendation)

200–500 U [54] (level U

Recommendation)

<900 U [79]

Risk factors include symptoms and signs of pseudobulbar palsy, swallowing difficulties, history of aspiration and respiratory disease. When risk

factors are present, evaluate the level of risk and either further reduce the total dose or avoid using BoNT-A.

*Expert opinion.

Table 4 Favourable Response to BoNT-A and physiotherapy

Aim Expected Outcome Indication

Grade of

Recommendation

Reduction in body

structures impairment

Reduction in spasticity

and improved dynamic

ROM

Decreased involuntary over-activity of injected muscles. Observed

by a reduction in !R1 R2" difference, measured on the ASAS [36]

and MTS [18].

A

Improved selective motor

control

Improved ability to isolate and selectively control ankle

movements. Selective motor control is measured via Selective

Motor Control Scale [18].

U

Improved strength Greater strength in agonist and antagonist muscle groups,

measured via a dynamometer or the Medical Research Council

scale (graded 1–5).

U

Improved passive ROM BoNT-A in combination with casting is used to reduce contracture.

Improved passive ROM is measured via goniometry.

B

Improved functional

activity performance

Improved function and

task performance

Improvements in individualized goal performance of functional

tasks (e.g. walking, running, kicking a ball). Observed by an

increase in GMFM scores [99] and /or measured by an increase in

GAS [45].

B

Improved quality of life

and personal factors

Reduction in pain Decreased pain and spasm, measured on a Visual Analogue Scale

(VAS), COPM [100], GAS [45] WeeFIM! [43] or PEDI [44].

U

18 S. C. Love et al.

" 2010 The Author(s)Journal compilation " 2010 EFNS European Journal of Neurology 17 (Suppl. 2), 9–37

ü  Avaliação clínica ü  Exame físico/neurológico ü  Escalas de avaliação ü  Intervenções anteriores? ü  Alinhar as expectativas do paciente/família com os objetivos

realísticos ü  Eleição de músculos ou grupos musculares a serem tratados. ü  Gerenciamento de doses x limite de peso corporal

Love S, et al; 2010

Toxina botulínica

ü  As injeções podem ser feitas a nível ambulatorial ou hospitalar (com ou sem sedação). Anestésico tópico.

ü  Intervalo mínimo entre as aplicações: 4 meses

ü  Métodos de localização: o  Palpação anatômica

ü  Métodos de localização guiados o  Eletroestimulador o  Ultrasson o  Eletroneuromiografia

Denervação química

Fenol (nível U) ü  É um ácido, também chamado de benzenol, ácido carbólico,

ácido fénico.

ü  Injetado diretamente no nervo, causa uma proteólise devido a sua intensa atividade inflamatória. Sua ação neurolítica é local e temporária.

ü Não seletivo quanto a fibra sensitivas ou motoras - disestesias.

ü  Preferencialmente sob sedação, pois trata-se de procedimento doloroso

ü Necessita de método guiado, como eletroestimulador. Estímulo justa neural

ü Complicaçoes mais comuns: excessivo déficit de força, alteraçoes vaculares.

Gracies JM, et al, 1997; Sposito M, 2010.

Denervação química Fenol

FENOL X TBA

+ :Início de ação mais rápido, baixo custo, perda de antigenicidade, maior flexibilidade tempo entre injeções. - :Não é seletivo, lesa o nervo, dor durante injeção, disestesias, reação inflamatória em mm e vasos.

FENOL + TBA

50 2,5 3,5 4,5 12 0

100

Bomba de baclofeno intratecal (Nível U)

Riscos: Infecção, mal funcionamento do cateter, lesão na pele, meningite, subdose ou superdosagem. Efeitos colaterais dose dependente: retenção urinária, constipação, sialorréia, fraqueza, insuficiência respiratória e perda do controle do tronco

ü  Efetivo no tratamento da espasticidade medular e central ü  Poucos estudos randomizados que possam conferir alto nível de evidência ü  Três décadas de uso e aprovado em 1996 foi aprovado pelo FDA para

tratamento da espasticidade quando não houver resposta à outras terapias.

Boster A, et al, 2016; Saulino M, et al, 2016

50 2,5 3,5 4,5 12 0

100

Dose teste: 25 microgramas/bolus

Sistema da bomba de baclofeno intratecal

Quando considerar bomba de baclofeno intratecal: ü  Objetivos realistas para reduçao do tonus, dos espasmos e melhora

funcional ü  Pacientes, familiares, cuidadores devem entender todas as etapas do

processo: teste de triagem, implantação, pós implantação, reabilitação . ü  Seguimento de longo prazo: reposiçao da bomba, reposição de bateria,

troca de cateter intratecal devido ao crescimento da criança.

Boster A, et al, 2016; Saulino M, et al, 2016

Sialorréia

h8p://www.aacpdm.org/resources/care-pathways

Salivaçao anterior – extravasamento pela boca Salivação posterior – retenção na oro e hipofaringe

Glândulas salivares

M e n o r e s : v e s t i b u l a r e s , palatinas, labiais, linguais. São ímpares e se ab rem na cavidade bucal M a i o r e s : P a r ó t i d a s , submandibulares e sublinguais.

Glândulas submandibulares - 60 % da produção de saliva

Glândulas parótidas - 20% a 30% da produção de saliva

Glândulas sublinguais - 10% da produção de saliva

Sialorréia

Tratamento farmacológico

1) Drogas anticolinérgicas

Sialorréia Tratamento farmacológico

1) Toxina botulínica

Doses recomendadas Onabotulinun Abobotulinun Sítio de injeção U U __________________________________________________ Glândula submandibular 10-50 15-75 Glândula parótida 10-50 15-75

U=Unidade Ef. adverso:

Disfagia

Reddihoughetal,2010

Review

Evidence-based review and assessment of botulinum neurotoxin for thetreatment of secretory disorders

Markus Naumann a,*, Dirk Dressler b, Mark Hallett c, Joseph Jankovic d, Giampietro Schiavo e,Karen R. Segal f, Daniel Truong g

aDepartment of Neurology and Clinical Neurophysiology, Academic Hospital of the Ludwigs-Maximilians-University Munich, Klinikum Augsburg, GermanybDepartment of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germanyc The George Washington University School of Medicine and Health Sciences, Ross Hall, 2300 Eye Street NW, Suite 713W, Washington, DC 20037, USAd Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, The Smith Tower, Suite 1801, 6550 Fannin,Houston, TX 77030, USAeMolecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, Lincoln’s Inn Fields Laboratories, 44 Lincoln’s Inn Fields,London WC2A 3LY, United Kingdomf 10 West 66 Street, New York, NY 10023, USAg The Parkinson and Movement Disorder Institute, 9940 Talbert Ave., Suite 204, Fountain Valley, CA 92708, USA

a r t i c l e i n f o

Article history:Received 18 June 2012Accepted 31 October 2012Available online xxxx

Keywords:Botulinum toxinSecretory disordersAxillary hyperhidrosisPalmar hyperhidrosisGustatory sweatingAllergic rhinitis

a b s t r a c t

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a largerange of clinical conditions. To assess the efficacy and safety of BoNT injections for thetreatment of certain hypersecretory disorders, including hyperhidrosis, sialorrhea, andchronic rhinorrhea, an expert panel reviewed evidence from the published literature.Data sources included English-language studies identified via MEDLINE, EMBASE,CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials.Evidence tables generated in the 2008 Report of the Therapeutics and TechnologyAssessment Subcommittee of the American Academy of Neurology (AAN) review of theuse of BoNT for autonomic disorders were also reviewed and updated. The panel eval-uated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A andBoNT-B, as well as the four individual commercially available formulations: abobotuli-numtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), andrimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations for eachtherapeutic indication, based upon the strength of clinical evidence and following theAAN classification scale. For the treatment of axillary hyperhidrosis in a total of 923patients, the evidence supported a Level A recommendation for BoNT-A, with a Level Brecommendation for A/Abo and A/Ona and a Level U recommendation (insufficient data)for A/Inco and B/Rima. Five trials in 82 patients supported the use of BoNT in palmarhyperhidrosis, with a Level B recommendation for BoNT-A and a Level C recommendationfor BoNT-B; individual formulations received a Level U rating due to insufficient data.BoNT (and all individual formulations) received a Level U recommendation for thetreatment of gustatory sweating. Support for use of BoNT in sialorrhea was derived fromeight trials in a total of 222 adults and children. Evidence supported a Level B recom-mendation for A/Abo, A/Ona, and B/Rima and a Level U recommendation for A/Inco.Evidence supported a Level B recommendation for A/Ona for the treatment of allergicrhinitis, based on two Class II studies in 73 patients. A lack of published studies for A/Abo,

* Corresponding author.E-mail address: markus.naumann@klinikum-augsburg.de (M. Naumann).

Contents lists available at SciVerse ScienceDirect

Toxicon

journal homepage: www.elsevier .com/locate/ toxicon

0041-0101/$ – see front matter ! 2012 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.toxicon.2012.10.020

Toxicon xxx (2012) 1–12

Please cite this article in press as: Naumann, M., et al., Evidence-based review and assessment of botulinum neurotoxin for thetreatment of secretory disorders, Toxicon (2012), http://dx.doi.org/10.1016/j.toxicon.2012.10.020

ü  Nível B de recomendação para Abobotulinun e Onabotulinun toxin

ü  Nível U de recomendação para Incobotulinun

ü  São necessários mais estudos na populaçao pediátrica sobre doses precisas, quais glandulas devam ser aplicadas para a otimizaçao do tratamento e sobre o uso guiado de US

Obrigada!

simone.amorim@vitaclinica.com.br