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(European) Consensus on the use Botulinum Toxin in Children with CP

A. Sebastian Schroeder, Florian Heinen, Steffen Berweck

Hauner Children‘s Hospital, Ludwig-Maximilians-University Munich, GermanySpecialist Centre of Paediatric Neurology and Rehabilitation

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Consensus framework for BoNT treatment in CP

1. The updated European Consensus 2009 on the use of Botulinum toxin for children with cerebral palsy. Heinen F, et al. Eur J Paediatr Neurol. 2010 Jan;14(1):45-66.

2. Botulinum toxin assessment, intervention and after-care for lower limb spasticity in children with cerebral palsy: international consensus statementLove et al. Eur. J. Neurol. 2010, 17 Suppl.

3. Botulinum toxin assessment, intervention and follow-up for pediatric upper limbhypertonicity: international consensus statementFehling et al. Eur. J. Neurol. 2010, 17 Suppl. 2

Botulinum toxin assessment, intervention and after-care for lowerlimb spasticity in children with cerebral palsy: internationalconsensus statement

S. C. Lovea, I. Novakb, M. Kentishc, K. Desloovered, F. Heinene, G. Molenaersf, S. O!Flahertyg

and H. K. Grahamh

aCentre for Musculoskeletal Studies, University of Western Australia, Princess Margaret Hospital, Western Australia; bCerebral Palsy

Institute, School of Medicine, University of Notre Dame Australia, Darlinghurst, Sydney, NSW; cQueensland Cerebral Palsy Health Service,

Department of Paediatric Rehabilitation, Royal Children!s Hospital, Brisbane, QLD, Australia; dDepartment of Rehabilitation Sciences,

KUL, Leuven, Belgium; ePaediatric Neurology & Developmental Medicine, Children!s Hospital University of Munich, Munich, Germany;fDepartment of Musculoskeletal Sciences, KUL, Leuven, Belgium; gRehabilitation Dept, Children!s Hospital at Westmead, Westmead, NSW,

Australia; and hUniversity of Melbourne, Department of Orthopaedics and Murdoch Children!s Research Institute, The Royal Children!s

Hospital, Parkville, Vic., Australia

Keywords:

botulinum neurotoxin A,cerebral palsy, equinus,gait, goal attainment,gross motor function,spasticity

Received 9 July 2009

Accepted 14 May 2010

Botulinum neurotoxin type-A (BoNT-A) has been used in association with otherinterventions in the management of spasticity in children with cerebral palsy (CP) foralmost two decades. This consensus statement is based on an extensive review of theliterature by an invited international committee. The use of BoNT-A in the lowerlimbs of children with spasticity caused by CP is reported using the AmericanAcademy of Neurology Classification of Evidence for therapeutic intervention. Ran-domized clinical trials have been grouped into five areas of management, and theoutcomes are presented as treatment recommendations. The assessment of childrenwith CP and evaluation of outcomes following injection of BoNT-A are complex, andtherefore, a range of measures and the involvement of a multidisciplinary team isrecommended. The committee concludes that injection of BoNT-A in children withCP is generally safe although systemic adverse events may occur, especially in childrenwith more physical limitations (GMFCS V). The recommended dose levels areintermediate between previous consensus statements. The committee further concludesthat injection of BoNT-A is e!ective in the management of lower limb spasticity inchildren with CP, and when combined with physiotherapy and the use of orthoses,these interventions may improve gait and goal attainment.

Introduction & objectives

Botulinum neurotoxin type-A (BoNT-A) has been usedin the management of spasticity in the lower limbs ofchildren with CP for more than 15 years, with the firstreports by Koman et al. from the United States in 1993[1] and Graham et al. in the United Kingdom in 1994[2]. The original indication, which remains the mostcommon today, was injection of the gastrocsoleus forthe correction of spastic equinus or improvement of

equinus gait (toe-walking). Since the first reports,indications have been extended to almost every majormuscle in the lower limb, with varying degrees of suc-cess and variable levels of evidence.

This international consensus statement reviews theevidence for the use of BoNT-A therapy in the lowerlimbs of children with spasticity caused by CP, formu-lates them into appropriate treatment recommendationsand identifies areas for future research based on gaps inthe literature. In addition, areas of clinical relevancewithout high levels of evidence have been reviewedincluding assessments, outcome measures, adjunctivetherapies, recommended doses, dilution, muscle locali-zation techniques and screening for adverse events. Asuggested management algorithm is also provided.

Correspondence: S. C. Love, Associate Professor, Manager Outpatient

Physiotherapy Services, Princess Margaret Hospital, GPO Box D184

Perth 6840, WA, Australia (tel.: +61 8 9340 8503; fax:

+61 8 93408597; e-mail: [email protected]).

! 2010 The Author(s)Journal compilation ! 2010 EFNS 9

European Journal of Neurology 2010, 17 (Suppl. 2): 9–37 doi:10.1111/j.1468-1331.2010.03126.x

Botulinum toxin assessment, intervention and follow-up forpaediatric upper limb hypertonicity: international consensusstatement

D. Fehlingsa, I. Novakb, S. Berweckc, B. Hoared, N. S. Stotte and R. N. RussofaBloorview Research Institute, Bloorview Kids Rehab, Department of Paediatrics, University of Toronto, Toronto, ON, Canada; bCerebral

Palsy Institute, School of Medicine, University of Notre Dame Australia, Darlinghurst, Sydney, New South Wales, Australia; cTreatment

Centre Vogtareuth, Specialist Centre for Paediatric Neurology, Paediatric Rehabilitation and Epilepsy for Children & Adolescents,

Vogtareuth, Germany; dVictorian Paediatric Rehabilitation Service, Monash Children!s, Southern Health, Clayton, Victoria, Australia;eDepartment of Surgery, The University of Auckland, Auckland, New Zealand; and fFlinders University School of Medicine, Flinders

University South Australia and Paediatric Rehabilitation Department, Women!s and Children!s Hospital, South Australia, Australia

Keywords:

assessment, botulinumtoxin A, children,hypertonicity,occupational therapy,spasticity, systematicreview, upper limb/extremity

Received 9 July 2009

Accepted 14 May 2010

The primary objective of this paper was to evaluate the published evidence of e!cacyand safety of botulinum neurotoxin (BoNT) injections in paediatric upper limbhypertonia (PULH). Secondary objectives included the provision of clinical context,based on evidence and expert opinion, in the areas of assessment, child and muscleselection, dosing, and adjunctive treatment. A multidisciplinary panel of authorssystematically reviewed, abstracted, and classified relevant literature. Recommenda-tions were based on the American Academy of Neurology (AAN) evidence classifi-cation. Following a literature search, 186 potential articles were screened for inclusion,and 15 of these met the criteria and were reviewed. Grade A evidence was found tosupport the use of BoNT to reach individualized therapeutic goals for PULH. There isgrade B evidence (probably e"ective) for tone reduction following BoNT injectionsand grade U evidence (inconclusive) for improvement in upper limb (UL) activity andfunction. BoNT injections were generally found to be safe and well tolerated with themost common side e"ect identified as a transient decrease in grip strength.

Introduction and objective

Botulinum neurotoxin (BoNT) has been used for over15 years to manage paediatric upper limb hypertonia(PULH). The goals include improvement in function,or the reduction in hypertonia facilitating ease of careand passive positioning of the arm. This paper sys-tematically reviews the evidence for BoNT use inPULH and outlines "best practice! in assessment, dos-ing, injection techniques and adjunctive interventions,based on evidence, where available, and the expertopinion of the authors to provide assistance to clini-cians managing children with PULH, as well as iden-tifying areas for future research based on gaps in theliterature.

Literature was searched and appraised using aconventional evidence hierarchy. The highest levels ofevidence available were used to develop recommenda-

tions, with randomized controlled trials (RCTs) andsystematic reviews preferentially sought. Expert opin-ions, where included, have been clearly labelled andshould be interpreted with judicious caution. Recom-mendations for research were made based on the gapsindentified in the literature. All recommendations weregraded based on the American Academy of Neurology(AAN) [1] evidence classification. The expert interna-tional team included a developmental paediatrician,occupational therapists, an orthopaedic surgeon, apaediatric neurologist and a paediatric rehabilitationspecialist.

Definition

Hypertonia is defined as "abnormally increased resis-tance to externally imposed movement about a joint![2]. In the paediatric upper limb (UL), hypertonia ismost frequently associated with spasticity, dystonia,or a combination of both hypertonia sub-types.Cerebral palsy (CP) and acquired brain injury are thetwo most common diagnoses associated with PULH[2]. In addition to hypertonia, other UL impairments

Correspondence: D. Fehlings, MD, MSc, FRCPC, Bloorview

Research Institute, Bloorview Kids Rehab, University of Toronto,

Toronto, ON, Canada (tel.: +416 425 6220, x3586;

fax: +416 424 3837 ; e-mail: [email protected]).

38! 2010 The Author(s)

Journal compilation ! 2010 EFNS

European Journal of Neurology 2010, 17 (Suppl. 2): 38–56 doi:10.1111/j.1468-1331.2010.03127.x


European Consensus - Update 2009

Part I | tabulated evidence report

(1) cerebral palsy (2) integrated therapy(3) medico-legal and medico-economical aspects of BoNT(4) common indications(5) dosage and dose modifiers(6) safety(7) therapy and procedures(8) assessment and evaluation(9) therapy adherence(10) research challenge

Part 2 | CPGraph Treatment Modalities Gross Motor Function


2: Integrated therapy - evidence based

1. Range of conservative and surgical strategies considering all dimensions of ICF(PT, OT, Speech, Robotics, CIMT, HABIT, orthosis, casting, splints, baclofen, other pharmacotherapy, surgery, etc….Botulinum toxin)

2. Insufficient evidence to either support or refute the use of these interventions before or after BoNT injections (Lowe K, DMCN 2006, Hagglund G, JPO (B) 2005, Molenaers G, 2006 JBJSA, Lannin DMCN 2006)

3. Robotic assisted therapy can serve as an intervention model where activity parameters can be measured during therapy intervention (Meyer-Heim, Arch Dis Child 2009, Borggraefe MovDisord 2008, Fasoli AJPMR 2008, Borggraefe, EJPRM 2010)


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Botulinum neurotoxin (BoNT)

1. Anaerob gram + bacteria

2. 7 Serotypes (A-‐G)

3. Light chain / heavy chain

4. InjecCon into the targeted Cssue

5. Does not cross blood-‐brain-‐barrier

6. Not cytotoxic

7. New Terminology

- Botox: onabotulinumtoxinA

- Xeomin: incobotulinumtoxinA

- Dysport: abobotulinumtoxinA

- Neurobloc: rimabotulinumtoxinB


BoNT - Mechanism of action

1. Local / Focal inhibition - Neuro-muscular junction- Muscle spindle - down regulation of spinal circuit- Neuro-glandular junction

2. Heavy chain: binding & internalisation

3. Light chain: inhibition of cholinergic transmission

4. Cleavage of membrane-fusion proteines

5. dose-dependent effect


3: Medico-legal & Medico-economical aspects

1. Licenses for BoNT treatment show a great variety between countries, and are restricted to specific preparations => be familiar

2. Licensing does not reflect the clinical needs, especially for children with CP (multi-centre studies of different preparations on theway) => documentation

3. Strong level of pharmaco-vigilance is required:=> severely affected children with bilateral CP, GMFCS Levels (III–) IV-V suffering from multiple additional impairments=> careful decision-making on dosage, dilution, procedure and injection => control rests in the hands of the treating physician and has to be adapted


4: Common indications

1. Spastic movement > dystonic movement disorders=> therapy goal defined according ICF dimensions

2. Increasing number of ‘‘focal’’ indications > multi-muscle, multi-level treatment approach (Molenaers G, Eur J Neurol 1999, Heinen MovDisord 2006) => reversibility of BoNT during motor development

3. Development of distinctive motor patterns (Rodda & Graham, Winters, Gage & Hicks) => adaptive approach to changing clinical patterns


5: Dosage and dose modifiers

1. Different preparations => different biological activity=> dose conversion factors are NOT applicable

2. Individual dosages must be calculated independently „check & balance“- units per muscle, per injection site, per kg body weight per muscle (U/kg/muscle)- total units per kg body weight per session,- total units per treatment session

3. Dose modifiers- severity of CP- accompanying diagnoses- predominance of movement disorder (spasticity, dystonia)- activity and size of the injected muscle- dynamic versus fibrotic muscle- distribution of motor endplates- experience from previous BoNT injections


1. ona: Powder 50 & 100 Units / Vial

2. abo: Powder 500 Units / Vial

3. inco: Powder 50 & 100 Units / Vial

4. rima: Solution 0,5 & 1 ml / Vial = 2500 & 5000 Units / Vial

=> Dilute in 1 / 2 / 4 / 5 ml / Vial = different concentrations

=> small muscles 1-2 ml / Vial=> large muscles 2-5 ml / Vial

Dosage & Dilution


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

World consensus 2010 (EJN)


allow for adaptation to reduced tone and to avoidexcessive weakness through repeated injections.

Recommendation 4

Authors suggest the following:

• Not to use conversion factors between different preparations even

amongst the same serotype [44,60]

• Consideration of the severity of the motor disorder, goal of

treatment, size of the targeted muscle and body region, neuro-

muscular junction distribution in the muscle, and previous BoNT

experience when determining dose [expert opinion, supported by

15,46,54,57]

• BoNT doses should be calculated cautiously in patients with

dysphagia and breathing problems [60]

• If the treatment is to improve function, the calculated dosage should

be distributed in a small amount of normal saline in themuscle at 1–2

injection sites depending on age/size of the child [15,18,46]

• Intervals between BoNT injections should exceed 3 months and be

extended as far as clinically justifiable whilst treating the child with

functional therapy and orthotic devices [expert opinion supported

by 61–64]

Recommendations for treatment: injectiontechnique

Proper localization of the toxin injection in the desiredmuscle is crucial for maximizing the clinical e!ects of thetoxin [42,46,65]. From animal data, we can expect dif-fusion of the toxin up to 4 cm along the longitudinal axisof the muscle from the point of injection, although nosimilar data exist for humans [54]. Di!usion crossesanatomic barriers such as fascias, as described in animals

as well as in humans [55,56]; therefore, injection tech-nique, concentration, volume per injection site [57,66]and dosage potentially have an impact on treatmentoutcome. As the injection is aimed to reach the motorend-plates, their location should be kept in mind [67].

Techniques to localize the muscle [68]

PalpationAlthough used in six studies [6,7,9,10,13,17], it has beendemonstrated in adults as well as in children that pal-pation is inadequate for muscle identification, especiallyin the forearm [69,70].

EMGElectromyography was used to control injections in theUL in children with CP in two studies. There are factorsthat might reduce accuracy and practicability of theprocedure: children with CP have a limited ability toco-operate and perform selective movements [11,71],the acoustic signal is reduced in sedated children andthe procedure is painful and can require severalattempts until correct positioning of the needle isachieved. Diagnostically, EMG (multi-channel surfacerecording) can be useful in children with dystonia toidentify muscles that are responsible for the dystonicposture or movement.

Electrical stimulationElectrical stimulation is independent of selectivevoluntary motor function, and the patient!s ability to

Table 2 Dose recommendations for muscles of the shoulder and upper extremity [48,49]

Muscle

Dose range

(U/kg BOTOX!)

Max. Dose per

muscle (U BOTOX!)

Dose range

(U/kg Dysport!)

Max. Dose per muscle

(U Dysport!)

Pectoralis major 2 50 5–10 150

Teres major 2 50 5–10 150

Triceps brachii 2–4 100 10–15 250

Biceps brachii 2–3 50 5–10 150

Brachialis 2–3 50 5–10 150

Brachioradialis 0.5–2 50 5–10 150

Flexor carpi radialis 0.5–2 50 5–10 150

Flexor carpi ulnaris 0.5–2 50 5–10 150

Pronator teres 1–2 50 5–10 150

Pronator quadratus 0.5–1 25 5 150

Flexor digitorum profundus 0.5–2 50 5–10 150

Flexor digitorum superficialis 0.5–2 50 5–10 150

Extensor digitorum communis 0.5–2 25 5 100

Flexor pollicis longus 1 25 5 100

Flexor pollicis brevis/Opponens pollicis* 0.5–1 25 5 75

Adductor pollicis 0.5–1 25 5 75

Lumbricales 0.5–1 25 5 75

Total dose per treatment session 16 U/kg 400 30 U/kg 1000

Please be aware that the recommendations for BOTOX! and Dysport! are not based on a fixed conversion ratio between the two preparations

(please refer to "Preparations, conversion factors! within the text). *Due to the proximity of the two muscles they are not listed separately.

48 D. Fehlings et al.


World consensus 2010 (EJN)

„BOTOX doses used in controlled trials have a range of 1–9 U/kg body weight per treatment session and 0.3–2 (forearm) up to 4 (upper arm) U/kg body weight per muscle.Neurobloc is not included in the table, as there is limited experience with BoNT-‐B in children with PULH.“


European Consensus: Heinen et al. 2010

Dose / kg bodyweight up to 24 kg - then adult dosages

Dose ranges [U!Units; kg bw! kilogram body weight]a

BoNT Serotype A- Preparation BOTOX!

range [U/kg bw] 1–20 (–25)max total dose [U] 400 (–600)range max dose/site [U] 10–50

- Preparation Dysport!

range [U/kg bw] 1–20 (–25)max total dose [U] 500–1000range max dose/site [U] 50–250

- Preparation Xeomin! (adult studies suggest dosage equivalence withBotox!,160, 161 but for children this needs to be confirmed)

range [U/kg bw] not established yetmax total dose [U] not established yetmax dose/site [U] not established yet

BoNT Serotype B- Preparation Neurobloc! (mainly used as second line preparation in adultneurology in case of secondary non-response to BoNT/A)

range [U/kg bw] not establishedmax total dose [U] not establishedmax dose/site [U] not established

= ona

= abo

= inco

= rima

large muscles

small muscles

onA /incoA

3-6 U/kgBW

0.5-2 U/kgBW

aboA 10-20 U/kgBW

5-10 U/kgBW


BoNT - Cerebral Palsy:how to decide if BoNT could work

no BoNT,

but ac-vity training

&motor control training

elevated muscle tone?

+ -‐

spas-city? (MTS, MAS)

Define personal, ADL-‐relevant goals

does spas-city interfer with these goals?

(mul--‐) fokal spas-city?

good range of mo-on?Structure: BoNT & cas-ng

or hygiene, pain, posi-oningversussurgeryTherapy goal BoNT:

Func-on & Ac-vity & Par-cipa-on (Locomo-on) Injec-onprotocol

Love et al. 2010 EJ of Neurology Vol. 17, Supplement 2

+ -‐

+ -‐

+ -‐

oralmedica-on


clincial examinationREPEAT THE LOOP UNTIL EVERY STEP IS WITHIN THE ACCEPTED DOSE RANGE,

THEN PROCEED TO THE INJECTION PROCEDURE

DOSING-LOOP BOTULINUM TOXIN

CLINICAL EXAMINATIONWHICH MUSCLES SHOULD BE TREATED?

INJECTION PROTOCOLDOSE MUSCLE

UNITS KG BW MUSCLE

TOTAL DOSE SESSIONTOTAL DOSE KG BW* SESSION MAXIMUM UNITS MUSCLE

MAXIMUM UNITS SITE

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Reduce number of muscles if neccessary


Example injection documentation

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13.06.12 25 4 Botox 2x50 2x50 3x25 3x25 ... 350 14

_____________________________________ 1


6: Safety

1.! Used for over 20 years

2.! AE: focal (local, distant), generalized and procedural

3.! Safety discussion (Germany, USA, etc.)=> Germany 06/2007 – 09/2008: No evidence showing a causal

connection between the fatal outcome of five reported patients and their prior treatment with BoNT.

=> USA, FDA 01/2008 – 08/2009: boxed warnings on their labels: spread from the area of injection to other areas of the body with potentially life-threatening swallowing and breathing difficulties and even death.

4.! Cave: more severe GMFCS and /or accompanied impairments


Abb 4: Prädiktives Risiko (incl. random intercept)

Safety 180 Patients - 616 sessions - 54 AE - 8.8 %

Predictive Risk of occurence of AE in correlation to dose / kg bodyweight

Retrospectiv versus prospective assessment of AE differs

AE rating: light: 5,0 %, moderate: 3,1 %, severe: 0,2%


7: Therapy and procedures

1.! Repeated multiple, painful, but elective procedure

2.! The right for a pain free therapy (ethical necessity)

3.! Optimal regimen will vary between individuals & institutions:- influenced by the age of the child- the GMFCS- the number of muscles to be treated

4.! Accurate localization technique


8: Assessment and evaluation

1. Purpose-built classification tools and standardized clinical assessments => same language => using consistent and valid instruments, matched to the dimensions of the ICF

2. SCPE, GMFCS, MACS, HIP-SURVEILLANCE

3. Clinical Examination: - Modified Ashworth Scale (MAS) - Modified Tardieu Scale (MTS)- Active / passive Range of Motion- (3-D / observational) Gait analysis (PRS)- Goal Attainment Scaling (GAS)

Evaluation vor

Injektion

Ultraschall-gesteuerte

Botulinumtoxin

Evaluation 4-6

Wochen nach BoNT

V1 V2 V3

t

Spasticity versus Contracture


World consensus 2010: Assessment

Table 2 Recommended assessments

Tool

ICF domain Domain of measurement Properties Purpose

Body

Structures Activities Participation Spasticity Function Valid Reliable Responsive

Clinical

Practice Research

Australian Spasticity

Assessment Scale

(ASAS) [36]

• Quantifies the amount of muscle

spasticity present via measurement

of the !spastic catch" on an ordinal

scale

• • ? • •

Modified Tardieu Scale

(MTS) [18]

• Quantifies the degree of muscle

spasticity present via measurement

of the !spastic catch" to determine

muscles for injection (continuous

scale in degrees)

? ? ? • •

Muscle length as

measured by range of

joint motion (ROM)

• Measure the muscle length to

understand the degree of

contracture present (represented in

degrees of joint movement)

• • • • •

Goal Attainment Scaling

(GAS) [45]

• • • Measures intervention outcomes

based on individualised goals

• • • • •

Video Gait Analysis

(VGA or 2DGA)

• Records sagittal and frontal gait

parameters

? • • • •

3DGA • • Primarily EMG Kinetic and kinematic data • • • •Physician Rating Scale

(PRS) [38]

• Ordinal criteria descriptors of gait

quality

? • • •

Functional Independence

Measure for Children

(WeeFIM!) [43]

• Evaluation, self-care independence of

children

• • ? •

Pediatric Evaluation of

Disability

Inventory(PEDI) [41]

• Evaluation, self care, mobility and

social function of children with

physical disability

• • • •

Gross Motor Function

Measure (GMFM-66)

[44]

• Evaluation, determination of gross

motor capacity

• • • •

• Addresses this domain/possesses this property/fulfills this purpose; ?: may possess this property.

12S.C.Love

etal.

"2010TheAuthor(s)

Journalcompilatio

n"

2010EFNSEuropeanJo

urnalofNeurology17(Suppl.2),9–3

7

Love et al. 2010 EJ of Neurology Vol. 17, Supplement 2Freitag, 23. November 2012

Example patients - select assessment tools

1. BSCPGMFCS Level 2,4 years of age

- mod. Tardieu Scale- a/p ROM- Video Gait doc.- GAS- X-Ray hip

2. Dyskinetic CPGMFCS Level 516 years of age

- Positioning- Pain- CPCHILD- X-Ray hip & spine- autonomic function- GAS

3. USCP right sideGMFCS Level 16 years of age

- MACS level- AHA-Test- a/p ROM- mod. Tardieu Scale (large joints)- GAS


World consensus: BoNT/A evaluation of effectiveness

adductors and hamstrings combined with use of thestanding, walking and sitting hip (SWASH) bracecompared with !standard" management (Appendix 1).Whilst children in the treatment group progressed tosurgery at a significantly lower rate than those in thecontrol group (possibly influenced by the rate ofprogression of contractures), the authors concludedthis was not an e!ective way to manage hip displace-ment in the long term. Moreover, a significant numberof adverse events were reported in the BoNT-A group,and, in a previous subgroup analysis, no significantimprovement in GMFM was found.

In summary, taking into consideration the class ofthe study and the direction of the change in outcomemeasure, there is a Grade A recommendation thatBoNT-A injections to the adductors and hamstrings isnot effective to improve gross motor function in chil-dren with CP, as determined by GMFM. There is aGrade A recommendation that BoNT-A injections areeffective in delaying the need for surgery in the man-agement of hip displacement in children with CP, butonly in the short term. There is a level C recommen-dation that BoNT-A injections are possibly e!ective inchildren achieving intervention goals as determined bythe GAS.

Group 5 RCTs: multilevel BoNT-A injections to

improve gait and functioning. N = 6

The RCTs in this group were even more heterogeneousin terms of study populations, quality of RCT, injectionprotocols and outcome measures than the previouslyreported groups [72–77].

Of the six RCTs identified, the authors graded fouras Class II and two as Class III, with no studiesreaching a Class I grading (Appendix 1). The studiesreported widely di!erent outcome measures, with thestudy by Scholtes et al., although included twice,presumably reports the same patient cohort. The 2006study by Scholtes [74] reports gross motor outcomes,and the 2007 study [75] reports spasticity, musclelength and gait outcomes. In this group, only onestudy reports the following outcomes: Vulpe Assess-ment Battery (VAB) [72], GAS [4], 3DGA [75] andPEDI [77]. In contrast, four studies reported outcomesin terms of gross motor function, principally using theGMFM [72,74,76,77]. However, the changes in grossmotor function were contradictory, with two studies[72,77] finding no significant improvement in grossmotor function and two studies [74,76] reporting asmall improvement. Therefore, the classification ofrecommendation for multilevel injections is graded aslevel U. That is to say, current data are inadequate orconflicting.

Comparisons of the studies reporting variable chan-ges in gross motor function in children with CP showconsiderable variation in age and GMFCS levels.Studies reporting younger children at GMFCS levels Iand II have found more consistent improvements ingross motor function. In those studies investigatingchanges in gross motor function in older children and atGMFCS levels III and IV, either less improvement orno improvement in gross motor function is generallyreported. In older children with more physical limita-tions, there may be less potential to show improvementin gross motor function, and the presence of occultcontractures may also be an important factor indecreasing the benefits of BoNT-A injection.

Recommendation 3

• BoNT-A is established as effective in the management of spastic

equinus to improve gait. (level A)

• BoNT-A is probably effective to improve goal attainment and

function in the management of spastic equinus (level B)

• BoNT-A is similar to serial casting in the management of spastic

equinus with current data being inadequate or conflicting (level U)

• BoNT-A injections to the adductor muscles is probably effective in

some specific areas of goal attainment (level B)

• BoNT-A injections to the adductor muscles do not improve gross

motor function (level A)

• BoNT-Ainjections to theadductor (andhamstring)musclesmaydelay

hip displacement, but does not affect long-term outcome (level A)

• BoNT-A injections to multiple lower limb muscles have inadequate

and conflicting data in respect of gait, goal attainment and function

(level U)

Injection protocols, dose, dilution andinjection sites

Given the widespread use of BoNT-A therapy in chil-dren with CP, the multiple indications and heteroge-neous groupings of target muscles, it is unsurprisingthat the evidence base for promoting safety and e"cacyremains very limited, and much of the current clinicaluse of BoNT-A in children with CP remains !o! label".

Two commercially available BoNT-A preparationsare regularly used in children with CP: BOTOX!

(Allergan Pty Ltd) and Dysport! (Ipsen). There is verylittle published information on the use the Xeomin!

(Merz Pharmaceuticals) BoNT-A product, which waslaunched in 2005. Each preparation has a unique bio-logical potency, and there are no firmly establishedconversion factors. It is important for clinicians to beaware that the doses for these products are not inter-changeable. We strongly advise against the use ofconversion factors between di!erent preparations onBoNT-A.

BoNT-A consensus statement: PLL 17


Love et al. 2010 EJ of Neurology Vol. 17, Supplement 2Freitag, 23. November 2012

Conclusion Consensus

European Journal of Neurology (2010) Vol. 17, Supplement 2

• It is recommended that BoNT treatment for spastic-ity is used as part of an integrated multidisciplinaryrehabilitation programme to optimise the likelihoodof treatment goals being achieved.

• BoNT should be used to address clearly identifiedproblems resulting from muscle over-activity con-fined to one or a group of muscles that contribute toa specific functional deficit.

• BoNT will not necessarily recover lost function, butmay improve functional outcomes by allowing rangeof motion to be regained, reducing pain and restoringmore balanced muscle function, leading to improve-ment in movement control.

• BoNT treats muscle over-activity, while targetedtherapy treats muscle under-activity; consequently,BoNT treatment is usually an adjunct to therapyrather than the other way round.

What is the effectiveness of BoNT treatmentfor children and adults with neurologicalimpairments?

A summary of the scientific evidence for the e!ective-ness of BoNT treatment in children and adults withneurological impairments is provided (Table 2).Detailed appraisal of this evidence is contained withinthe seven specialty International Consensus Statementsin this supplement.

Conclusion

BoNT is now an established safe and e!ective treatmentfor many indications in children and adults with neu-rological impairments. There is good quality scientificevidence to support the e"cacy of BoNT to reducemuscle over-activity in the limbs secondary to centralnervous system disorders in adults and children, toaddress primary or secondary cervical dystonia, toreduce saliva flow and to treat some pain syndromes.There is emergent evidence for the e"cacy of BoNT toreduce other types of pain, including neuropathic pain,to ameliorate focal tremor and also to improve func-tion, following treatment of focal muscle over-activity.

Acknowledgements

The Cerebral Palsy Institute would like to sincerelythank the Principal Authors involved in the develop-ment and leadership of these International ConsensusStatements, including: Professor H. Kerr Graham;Professor John Olver; Associate Professor Victor S.C.Fung; Associate Professor Barry Rawicki; Dr BarbaraJ. Singer and Dr Iona Novak. Sincere thanks are alsoextended to the Sub-Committee Chairs: AssociateProfessor Darcy Fehlings; Associate Professor Sarah C.Love; Professor Geo! Sheean and Associate ProfessorDinah Reddihough.

Table 2 Effectiveness of BoNT for children and adults with neurological impairments

Treatment outcomes from

intra-muscular injections

Adults Children

Lower limb

hypertonicity

Upper limb

hypertonicity

Neck region

hypertonicity

Lower limb

hypertonicity

Upper limb

hypertonicity

Neck region

hypertonicity

Reduced spastic

muscle over-activity

A

Established

effective

A

Established

effective

U

Inconclusive

A

Established

effective

B

Probably effective

U

Inconclusive

Reduced dystonic

muscle over-activity

Ua

Inconclusive

Ua

Inconclusive

A

Established

effective

Not reviewed Ba

Probably effective

Ua

Inconclusive

Increased range

of motion

U

Inconclusive

U

Inconclusive

B

Probably effective

B

Probably effective

U

Inconclusive

U

Inconclusive

Increased gross

motor function

U

Inconclusive

d d B

Probably effective

d d

Increased goal

achievement

B

Probably effective

U

Inconclusive

B

Probably effective

B

Probably effective

A

Established effective

U

Inconclusive

Reduced pain U

Inconclusive

U

Inconclusive

B

Probably effective

U

Inconclusive

U

Inconclusive

U

Inconclusive

Treatment outcomes from intra-glandular injections Adults Children

Reduced saliva secretion A


A


aLack of sensitive outcome measures & difficulty in assembling homogenous groups for clinical trials affect this finding.

A, established effective; B, probably effective; U, inconclusive; d, not appropriate

6 A. Esquenazi et al.

! 2010 The Author(s)Journal compilation ! 2010 EFNS European Journal of Neurology 17 (Suppl. 2), 1–8


This systematic review found high level evidence supporting the use of BoNT-A as an adjunct to managing the upper limb in children with spastic CP.

BoNT-A should not be used in isolation but should be accompanied by planned occupational therapy.

Further research is essential to identify children most likely to respond to BoNT-A injections, monitor longitudinal outcomes, determine timing and effect of repeated injections and the most effective dosage, dilution and volume schedules.

The most effective adjunct therapies including frequency and intensity of delivery also requires investigation.

[Intervention Review]

Botulinum toxin A as an adjunct to treatment in themanagement of the upper limb in children with spasticcerebral palsy (UPDATE)

Brian J Hoare1, Margaret A Wallen2, Christine Imms3, Elmer Villanueva4, Hyam Barry Rawicki5, Leeanne Carey6

1School of Occupational Therapy, La Trobe University, Victorian Paediatric Rehabilitation Service, Monash Medical Centre, Clayton,Australia. 2Occupational Therapy, The Children’s Hospital at Westmead, Westmead, Australia. 3School of Occupational Therapy,LaTrobe University, Murdoch Children’s Research Institute, Royal Children’s Hosptial, Melbourne, Australia. 4Gippsland MedicalSchool, Monash University, Churchill, Australia. 5Victorian Paediatric Rehabilitation Service, Monash Medical Centre, Clayton,Australia. 6Division of Neurorehabilitation and Recovery, National Stroke Research Institute, Florey Neuroscience Institutes and,School of Occupational Therapy, LaTrobe University, Melbourne, Australia

Contact address: Brian J Hoare, School of Occupational Therapy, La Trobe University, Victorian Paediatric Rehabilita-tion Service, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3086, Australia. [email protected]@southernhealth.org.au.

Editorial group: Cochrane Movement Disorders Group.Publication status and date: New search for studies and content updated (conclusions changed), comment added to review, publishedin Issue 1, 2010.Review content assessed as up-to-date: 17 August 2008.

Citation: Hoare BJ, Wallen MA, Imms C, Villanueva E, Rawicki HB, Carey L. Botulinum toxin A as an adjunct to treatment in themanagement of the upper limb in children with spastic cerebral palsy (UPDATE). Cochrane Database of Systematic Reviews 2010, Issue1. Art. No.: CD003469. DOI: 10.1002/14651858.CD003469.pub4.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T

Background

Cerebral palsy (CP) is “a group of permanent disorders of the development of movement and posture causing activity limitation(s) thatare attributed to non-progressive disturbance that occurred in the developing fetal or infant brain” (Rosenbaum 2007, p.9). The spasticmotor type is the most common form of CP. Therapeutic management may include splinting/casting, passive stretching, facilitationof posture/movement, spasticity-reducing medication and surgery. Botulinum toxin-A (BoNT-A) is now used as an adjunct to thesetechniques in an attempt to reduce spasticity, improve range of movement and function.

Objectives

To assess the effectiveness of injections of BoNT-A or BoNT-A and occupational therapy in the treatment of the upper limb in childrenwith CP.

Search methods

We searched the Cochrane Controlled Trials Register/CENTRAL (The Cochrane Library, Issue 3, 2008), MEDLINE (1966 to AugustWeek 1 2008), EMBASE (1980 to 2008 Week 28) and CINAHL (1982 to August Week 1 2008).

Selection criteria

All randomised controlled trials (RCTs) comparing BoNT-A injection or BoNT-A injection and occupational therapy in the upperlimb(s) with other types of treatment (including no treatment or placebo) in children with CP.

1Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE)

(Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


Thank you very much

Paediatric NeurologyHauner Children‘s Hospital, Munich, Germany:

Helene AuffermannIngo BorggraefeRosemarie GeenenMaesa Al-‐HallakFlorian HeinenMaria HomburgKrisCna HußAnita Laage GauppAlexandra SitzbergerKatharina VillBirgit WarkenMaren Jawad

Integrated Center for Research and Treatment of Ver-go, Balance and Ocular Motor Disorders, IFBLMU,: Munich, Germany:Verena BruemmerKlaus JahnThyra LanghagenThomas Stephan

Dep. of Clincial Radiology, Munich, Germany:Birgit Ertl-‐WagnerInga KoerteDenise Steffinger

Paediatric NeurologyRehabilita-ons Centre, Vogtareuth:

Steffen BerweckChrisCne Janssen

Clinic of Physical Medicine and Rehabilita-on, Munich, Germany:

Josef IlmbergerCornelia Schlick

Bregenz, Austria:Kurt Schlachter

Trondheim, Oslo, Norway:Guro AndersenAreej ElkamilTorstein Vic

Perth, Australia:Catherine ElliotSiobhan ReidJane ValenCne

NIH, Washington, USA:Katharine Alter Siddhartha Sikdar


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