Botulinum Toxin in The Management of Children With Cerebral Palsy

Pediatric Drugs (2019) 21:261–281
https://doi.org/10.1007/s40272-019-00344-8
REVIEW ARTICLE
Botulinum Toxin in the Management of Children with Cerebral Palsy

Iqbal Multani1,2 · Jamil Manji1,2 · Tandy Hastings‑Ison1,3 · Abhay Khot1,2,3 · Kerr Graham1,2,3,4
Published online: 1 July 2019

© The Author(s) 2019
Abstract
During the past 25 years, botulinum toxin type A (BoNT-A) has become the most widely used medical intervention in
children with cerebral palsy. In this review we consider the gaps in our knowledge in the use of BoNT-A and reasons why
muscle morphology and function in children with cerebral palsy are impaired. We review limitations in our knowledge
regarding the mechanisms underlying the development of contractures and the difficulty in preventing them. It is clear from
this review that injection of BoNT-A in the large muscles of both the upper and lower limbs of children with cerebral palsy
will result in a predictable decrease in muscle activity, which is usually reported as a reduction in spasticity, for between 3
and 6 months. These changes are noted by the use of clinical tools such as the Modified Ashworth Scale and the Modified
Tardieu Scale. Decreased muscle over-activity usually results in improved range of motion in distal joints. Injection of the
gastrocnemius muscle for toe-walking in a child with hemiplegia or diplegia usually has the effect of increasing the passive
range of dorsiflexion at the ankle. In our review, we found that this may result in a measurable improvement in gait by the
use of observational gait scales or gait analysis, in some children. However, improvements in gait function are not always
achieved and are small in magnitude and short lived. We found that some of the differences in outcomes in clinical trials may
relate to the use of adjunctive interventions such as serial casting, orthoses, night splints and intensive therapy. We note that
the majority of clinical trials of the use of BoNT-A in children with cerebral palsy have focussed on a single injection cycle
and this is insufficient to understand the balance between benefit and harm. Most outcomes were reported in terms of changes
in muscle tone and there were fewer studies with robust methodology that reported improvements in function. Changes in
the domains of activities and participation have rarely been reported in studies to date. There were no clinical reviews to
date that consider the findings of studies in human volunteers and in experimental animals and their relevance to clinical
protocols. In this review we found that studies in human volunteers and in experimental animals show muscle atrophy after
an injection of BoNT-A for at least 12 months. Muscle atrophy was accompanied by loss of contractile elements in muscle
and replacement with fat and connective tissue. It is not currently known if these changes, mediated at a molecular level, are
reversible. We conclude that there is a need to revise clinical protocols by using BoNT-A more thoughtfully, less frequently
and with greatly enhanced monitoring of the effects on injected muscle for both short-term and long-term benefits and harms.
1 Introduction
In this review, we are aware of the complexity of cerebral

palsy, our lack of knowledge about pathophysiology and
the mechanisms that lead from hypertonia to contractures
* Kerr Graham and how little is known about the long-term effects of one
[email protected] of the most frequently used interventions, botulinum toxin
1
Royal Children’s Hospital, 50 Flemington Road, Parkville,
type A (BoNT-A). The quotation attributed to Voltaire may
VIC 3052, Australia be appropriate:
2
Orthopaedic Department, Royal Children’s Hospital, 50 “Doctors prescribe medicines of which they know lit-
Flemington Road, Parkville, VIC 3052, Australia tle, to cure diseases of which they know less in human
3
Hugh Williamson Gait Laboratory, Royal Children’s beings of whom they know nothing.”
Hospital, 50 Flemington Road, Parkville, VIC 3052,
Australia The first publications reporting the use of BoNT-A in
4
University of Melbourne, Parkville, Australia children with cerebral palsy (CP) were by Koman et al. in
Vol.:(0123456789)
262 I. Multani et al.
also merits discussion, given the heterogeneous indications

Key Points and the risk of systemic adverse events [11, 12]. Injections
of BoNT-A may also be used as an analgesic agent, particu-
Injection of botulinum toxin type A (BoNT-A) is effec- larly when pain is related to muscle spasm [3].
tive for reducing over-activity in muscles in children In recent years, there has been a proliferation of basic sci-
with cerebral palsy. This results in a reduction in muscle ence animal studies reporting the effects of BoNT-A using
strength and muscle tone with small, short-lived gains invasive techniques that would not be possible in children
in aspects of gait and function, in some children with [7]. These studies may be relevant to BoNT-A protocols and
cerebral palsy. will also be discussed.
This is achieved at the cost of muscle atrophy, which
may not be completely reversible. The harmful effects 1.1 Muscle Imaging
of muscle atrophy may be related to the function of the
target muscle. The use of ultrasound in BoNT-A management is important
for two reasons. Firstly, 2-Dimensional Ultrasound (2DUS)
Injections of BoNT-A are generally safe for the child has emerged as the preferred technique for imaging muscles
but there are local risks to the injected muscle in the during the injection procedure [13]. Secondly, 3-Dimen-
ambulant child and there are increased risks of systemic sional Ultrasound (3DUS) has yielded substantial new infor-
adverse events in non-ambulant children. mation regarding the natural history of muscle development
There are grounds for modification of existing injection in children with CP, as well as changes following injection
protocols and further research is required to evaluate of BoNT-A [14, 15].
the long-term effects and risk versus benefit of BoNT-A
injections in skeletal muscle, in children with cerebral 1.2 Botulinum Toxin Preparations and Warning/
palsy. Disclaimer
The timing of progression from BoNT-A therapy to New preparations of botulinum neurotoxins are being devel-
definitive muscle–tendon lengthening should be care- oped and released on the market on a regular basis. Exten-
fully considered by the multidisciplinary team. sive clinical data exists for only two type A preparations,
onabotulinum toxin A ( Botox®, Allergan) and abobotulinum
toxin A (Dysport®, Ipsen, UK), for children with CP [1–6,
the United States in 1993 and by Graham et al. in the United
9, 11, 12, 16, 17]. Information is growing with respect to
Kingdom in 1994 [1, 2]. Since then, the use of BoNT-A has
the use of Xeomin®, from Merz Pharmaceuticals, Germany
become a ‘standard of care’ for children with CP in many
and for several preparations from Korea and China (Table 1)
countries, leading to widespread clinical use and the pub-
[18]. The new preparations that are being developed are type
lication and dissemination of consensus statements [3–6].
A toxins with different formulations in terms of additional
There is a need for a review of the recent literature with a
proteins and other excipients [18]. The clinical effects may
view to modifying existing BoNT-A protocols, in the light of
be similar to existing formulations but there will almost cer-
recent animal and clinical studies that have raised concerns
tainly be differences that will require further research and
regarding harm to the injected muscle [7]. Gough et al. were
clinical trials. There is limited clinical information relating
the first to raise concerns regarding the use of BoNT-A in
to the use of the more recently released toxins and the fol-
children with CP [8]. They questioned the use of an agent
lowing warning/disclaimer is relevant.
whose mechanism of action is to cause weakness, in order
Botulinum neurotoxins are the most potent biological
to manage a condition characterised by weakness. They also
toxins known in the natural world. Deaths from ingested
raised the issue of the potential for long-term effects before
botulinum toxin, in the form of food poisoning, still occur
much of the recent experimental work in animal models [7,
as well as deaths from botulinum toxin injected for medical
8].
and therapeutic purposes. The licencing and registration of
The most frequent indication for BoNT-A therapy in CP is
preparations of botulinum toxins, vary from country to coun-
to treat focal muscle over-activity to improve gait and func-
try and labelling may be specific for indications within each
tion in children who can walk [1, 2]. Injection of the upper
jurisdiction [18, 19]. Within countries where the prepara-
limb to improve posture and function is the second most fre-
tions have been approved, many current clinical indications
quent indication for BoNT-A therapy in children with CP [9,
are ‘off-label’ [18–20].
10]. The use of BoNT-A in non-ambulant children with CP
Botulinum Neurotoxin and Cerebral Palsy 263
Table 1 Botulinum neurotoxin preparations

Generic name Onabotulinum Toxin A Abobotulinum Toxin A Incobotulinum Toxin A Rimabotulinum Toxin B
® ® ®
Brand name Botox Dysport Xeomin Myobloc/Neurobloc®
Manufacturer Allergan Inc. (USA) Ipsen (UK) Merz Pharmaceuticals (Ger- Solstice Neurosciences (USA)
many)
Units/vial 100 500 100 2500, 5000 or 10,000
Constituents Haemaglutinin, human Haemaglutinin, human Human albumin, saccharose Haemaglutinin, human albumin
and excipi- albumin, saccharose, sodium albumin, 20% solution solution, 0.05% sodium chlo-
ents chloride lactose ride, sodium succinate
pH 7.4 7.4 7.4 5.6
Preparation Vacuum dried Lyophilised Lyophilised Solution
2 Definition of Cerebral Palsy (CP) 3 Classification of CP
The internationally agreed definition of CP, devised in 2005, 3.1 Topographical Distribution

is as follows:
The most common types of CP are hemiplegia (one side of
“A group of permanent disorders of development of
the body is affected), diplegia (both lower limbs are affected
movement and posture, causing activity limitation,
with fine motor problems restricted to the upper limbs) and
that are attributed to non-progressive disturbances
quadriplegia, in which all four limbs are affected [19]. Top-
that occurred in the developing foetal or infant brain.
ographical classification is useful because it identifies the
The motor disorders of CP are often accompanied by
limb segments in which there may be hypertonia requiring
disturbances of sensation, perception, cognition, com-
intervention. It is not very reliable and precise classification
munication, and behaviour, by epilepsy and by second-
is not always possible. This has led colleagues in Europe to
ary musculoskeletal problems” [21].
simplify the topographical distribution into ‘unilateral’ and
CP is an umbrella term covering a wide range of cerebral ‘bilateral’ [27].
disorders, with the common finding of a motor disorder,
originating from early childhood [22] (Fig. 1). Although the 3.2 Gross Motor Function
brain insult is static, the effects of the neurological involve-
ment are dynamic and change with time and growth of the The Gross Motor Function Classification System (GMFCS)
child [22, 23] (Fig. 2). CP can be defined as a “static enceph- is a five-level ordinal grading system based on the assess-
alopathy, with progressive musculoskeletal pathology” [23, ment of self-initiated movement with emphasis on func-
24]. The progression of dynamic contracture to fixed con- tion during sitting, standing and walking [28]. It has been
tracture is a fundamental issue underpinning effective use of shown to be valid, reliable, stable and a clinically relevant
BoNT-A [22, 23] (Figs. 1 and 2). The mechanisms by which method for the classification and prediction of motor func-
the CNS lesions are expressed as a movement disorder are tion in children with CP, between the ages of 2 and 18 years.
complex, as are the mechanisms underlying progression to GMFCS is important when using BoNT-A therapy because
fixed musculoskeletal deformity [19, 25]. The majority of the indications and adverse event profile are different accord-
muscles in children with CP have a combination of muscle ing to GMFCS level [19].
overactivity (dynamic contracture) with some element of
fixed shortening. Muscle deformity may be related more to 3.3 Movement Disorder
impaired muscle growth and altered adaptation than to spas-
ticity [25]. However, at this time we have interventions that Much work has been done in recent years to standardise the
address muscle over-activity (BoNT-A) and interventions for definitions of movement disorders and the reader is referred
fixed contracture, which include muscle–tendon lengthen- to these monographs for further information [29, 30]. The
ing, hence the simplified scheme illustrated in Fig. 2. For majority of children with CP develop hypertonia, as one
a fuller discussion please see the hypotheses discussed by feature of spasticity [19, 30]. Spastic CP is the most com-
Gough and Shortland and the review of muscle morphology mon type of movement disorder, accounting for approxi-
in CP by Barrett and Lichtwark [25, 26]. mately 60–85% of all CP in developed countries [27, 31]. A
widely used definition of spasticity is “a velocity-dependent
resistance to passive movement of a joint and its associated
Fig. 1 Schematic of the interac-

tion between the positive and
negative features of the upper
motor neuron (UMN) syn-
drome, leading to spasticity
with dynamic contractures and
fixed muscle–tendon contrac-
tures. Dynamic or flexible
contractures are often treated
by injection of botulinum toxin
type A (BoNT-A). Fixed con-
tractures are usually treated by
orthopaedic surgery. LMN lower
motor neuron
musculature”. Historically, the term encompassed many of 3.4 International Classification of Functioning

the components of the whole upper motor neuron (UMN)
syndrome [29, 30, 32]. Spasticity, along with other fea- The World Health Organisation’s (WHO) International Clas-
tures of the UMN syndrome, leads to a loss of the ability sification of Functioning (ICF) describes health conditions
of a muscle to stretch in a relaxed state, which may in turn in several domains, including body structure and function,
impair longitudinal growth of the muscle [33]. Dyskinetic activity and participation, modified by both environmental
CP affects between 10 and 25% of children and is charac- and personal factors as noted in Fig. 3 [34]. A number of
terised by involuntary movements, fluctuating muscle tone tools exist to measure parameters in children with CP within
and inability to execute and co-ordinate simple tasks with ICF domains and new measurement tools are under devel-
accuracy. Dyskinetic movement disorders may be athetoid, opment. Many of the traditional measures of body structure
dystonic or choreiform [30]. Ataxic CP is relatively uncom- and function predate the development of ICF and clinicians
mon, accounting for < 5% of children with CP [19, 31]. and researchers are not always in agreement as to which
measure belongs to which domain. Recent tools for measur-
ing activities and participation have been designed for task
appropriateness [22, 34].
Fig. 2 Staging the musculoskeletal pathology in children with cer- A (BoNT-A) or neurosurgical procedures such as selective dorsal rhi-
ebral palsy. Younger children have spasticity which is dynamic and zotomy (SDR) may be helpful. At Stage 2 and 3, the musculoskeletal
which reduces at rest and disappears under the relaxation of a general pathology is fixed and correction requires orthopaedic surgery
anaesthetic. This is the stage when injections of botulinum toxin type
3.5 Progressive Musculoskeletal Pathology contracture is more complicated than the presence of spastic-
ity [25, 26]. Frequent stretching of relaxed skeletal muscle
Children with CP do not have contractures, hip disloca- is a prerequisite for normal muscle growth [23]. In chil-
tion or spinal deformity at birth [22]. Fixed musculoskel- dren with CP, skeletal muscles are often hypertonic and do
etal pathology usually develops during childhood [19, 23, not readily relax. They are less frequently stretched due to
24]. There are many statements in the literature linking reduced physical activity and because of antagonist co-con-
contractures to spasticity, but the pathogenesis of muscle traction [19, 26]. The limb pathology can be considered in
Fig. 3 Schematic of the World

Health Organisation’s (WHO)
International Classification of
Functioning (ICF) and potential
outcome measures. AM activity
monitor, CHQ Child Health
Questionnaire, FMS Functional
Mobility Scale, GMFM66
Gross Motor Function Meas-
ure, GOAL® Gait Outcomes
Assessment List, MAS Modified
Ashworth Scale, MTS Modified
Tardieu Scale, ROM range of
motion (goniometry), 3DGA
3-dimensional gait analysis
three stages for simplicity but, in reality, these stages overlap 4.2 Passive Range of Motion by Goniometry
and are a complex continuum (Fig. 2).
Measurement of joint ROM is a widely used proxy measure
for muscle tendon length. Joint ROM using a goniometer
4 Measurement Scales and Outcome is used in clinical practice and outcomes research in the
Measures use of BoNT-A [42]. Accuracy and reliability are improved
by training and by two clinicians working together, one to
4.1 Measurement of Spasticity: Modified Ashworth stabilise the joint and the second to apply the goniometer
and Modified Tardieu Scales to recognised anatomical landmarks and read the appropri-
ate angle. Reliability of goniometric measurements can be
The Modified Ashworth Scale (MAS) is the most widely improved by standardising the applied force and by using
used scale to measure spasticity in the child with CP, despite digital photography of anatomic landmarks as described by
problems with validity and reliability [35, 36]. It is neces- Hastings-Ison et al. [43].
sary to consider both its utility and limitations in the clinic
and in the understanding of outcome studies [19, 35, 36]. 4.3 Canadian Occupational Performance Measure
The Modified Tardieu Scale (MTS) grades the quality of and Goal Attainment Scales
muscle reaction to passive stretch and measures the dynamic
component of muscle spasticity. To measure the dynamic Injections of BoNT-A are used to achieve functional goals
component, the joint is moved as fast as possible through that are meaningful to children with CP and their parents.
its full range of movement. The angle when the muscles For these reasons various forms of Goal Attainment Scal-
first ‘catch’, that is, when the stretch reflex is activated, is ing (GAS) as well as the Canadian Occupational Perfor-
measured as R1. The angle of full passive range of motion mance Measure (COPM) have been used in an effort to
(ROM) is R2. The difference between these angles (R2–R1) add a patient-reported outcome measure (PROM) to MAS
reflects the potential ROM available to the child if spasticity and MTS [44]. The COPM is an individualised measure
could be eliminated (dynamic component). designed to detect change in occupational performance over
The MTS is considered to be a substantial improvement time [44]. GAS is also used as an individualised outcome
and of greater utility than the MAS [37, 38]. Nevertheless, measure, especially for attributes where no standardised
both MAS and MTS have limitations, in the domains of measure exists [45]. Ideally, the COPM is used first to iden-
both validity and reliability [35–38]. For this reason, several tify functional goals for the GAS. Between three and five
research groups have pursued efforts to measure spasticity goals for intervention are selected and scaled by applying a
and joint ROM objectively, using biomechanical approaches numerical score. Both COPM and GAS are subjective, but
[39, 40]. they give a voice to the child and parent or carer. However,
Ordinal scales such as MAS are prone to bias. In our first given the subjective nature of these scales, they should be
double-blind, randomised, placebo-controlled trial (RCT) of combined with objective outcome measures. Without the
the use of BoNT-A in the upper limb of children with hemi- combination of subjective and objective outcome measures,
plegia, we included a question to physiotherapists and the interpretation of change is more difficult.
parents of children enrolled in the trial. We asked, “Do you
think your child was injected with Botox or placebo?” [9]. 4.4 Gait Assessment for Ambulant Children
The majority of therapists and parents correctly identified
whether their child had been injected with active drug or pla- The most common indication for the use of BoNT-A therapy
cebo, despite careful measures to ensure that injections were for children with cerebral palsy is to improve walking [1–6].
administered in a double-blind fashion. This experience was In younger children, the most common gait abnormalities
repeated in a second RCT investigating the potential role of are toe-walking, secondary to spastic equinus [19]. In older
BoNT-A injection as an analgesic agent, with the same result children, flexed knee gait (crouch) and stiffness around the
[41]. Therefore, although many clinical trials are described knee are the most commonly reported gait problems [46,
as single-blind or double-blind, both clinicians and parents 47]. The gold standard assessment is 3-Dimensional Gait
(who frequently complete questionnaires) are able to deter- Analysis (3DGA), which provides accurate, valid and reli-
mine from examination and observation of their child as to able information regarding a child’s gait pattern [19]. It is
whether the child has been injected with the active drug or capable of identifying both gait deviations and the response
placebo. This renders blinding ineffective and also means to BoNT-A therapy [19, 48]. However, 3DGA has limited
that the risk of bias and a placebo effect, when using MAS, availability and is not easy to use in children under the age of
pain scales or quality-of-life (QoL) measures, is high [11, 3–4 years or below one meter in height. Given that BoNT-A
41].
therapy is frequently used in children from age 2–4 years, 4.6 Outcome Measures for Non‑Ambulant Children
alternatives to 3-DGA are needed [1, 2].
A number of scales to rate gait in children with CP have BoNT-A therapy in non-ambulant children with CP has
been devised, commencing with the Physician Rating Scale been less well studied and BoNT-A is less suitable in non-
(PRS) by Koman et al. in 1994 [49]. However, we found ambulant children than in ambulant children. Children at
the PRS to have poor reliability, necessitating modifications GMFCS Level IV and V generally have a mixed move-
in clinical trials [50]. Since then, the Observational Gait ment disorder with generalised hypertonia, which is often
Scale (OGS) and the Edinburgh Visual Gait Scale (EVGS) severe and affects all four limbs as well as the trunk [19, 22].
have been widely use and reported in the literature [51–53]. MAS, MTS, goniometry and radiology can be combined to
Observational scales are best conducted using good quality assess issues related to hypertonia in the ICF domains of
2-dimensional video recording with the option for archiving body structure [22, 34]. Many non-ambulant children have
data and video replay with slow-motion capability [51–53]. complex medical comorbidities [19, 22]. Injecting multi-
The EVGS is currently the best available observational tool ple muscle groups on a recurrent basis poses a risk of seri-
for gait assessment when 3-dimensional gait analysis is not ous adverse events including severe respiratory events and
available [53]. All observational gait scales are limited in mortality [61]. For the majority of non-ambulant children,
sensitivity to detect small changes following injection of generalised tone management may require oral medications
BoNT-A and have limitations in both reliability and validity. or a neurosurgical procedure such as insertion of an intrath-
Recent studies were able to detect change in EVGS follow- ecal baclofen pump (ITB) [62]. In children at GMFCS IV
ing BoNT-A therapy but failed to confirm clinically signifi- and V, the musculoskeletal pathology becomes fixed with a
cant improvements [52]. very high prevalence of muscle tendon contractures, joint
Three-dimensional gait analysis provides objective, valid contractures, hip dislocation and spinal deformity [19, 24].
and reliable documentation of gait in children with CP [19, BoNT-A is not ideal as standard therapy for hypertonia in
45]. Earlier studies utilised isolated kinematic measures at the non-ambulant child because only a few of the many
the ankle and knee and were able to detect improvements hypertonic muscles can be treated due to limitations in total
following injection of BoNT-A [54]. More recently, dynamic BoNT-A dose [1–6]. The most useful outcome measures at
electromyography, kinetics and summary statistics of gait GMFCS IV and V may not be measures of body structure
such as the Gait Profile Score (GPS) have also been reported and function, in isolation. Health status, health-related qual-
[55, 56]. A combination of kinematic parameters and a sum- ity of life (HRQoL) and caregiver burden can be reliably
mary statistic of overall gait pattern (GPS) are recommended ascertained using the CPCHILD© questionnaire [63].
as the highest level for objective documentation of changes
in gait in children with CP [55, 56]. 4.7 Outcome Measures for the Upper Limb
4.5 Gross Motor Function Upper-limb function is more complex than gait function and
is impacted to a greater degree by impairments of sensation,
The gold standard for the measurement of Gross Motor proprioception and selective motor control [22]. The equiva-
Function is the Gross Motor Function Measure (GMFM), lent classification system to the GMFCS for classification of
which has been shown to be valid, reliable and responsive gross motor function in the upper limb is the Manual Ability
to clinically meaningful change [57]. The GMFM requires Classification System (MACS) [64]. More complex classi-
approximately 1 h to perform and is conducted by experi- fication systems that can also be used as outcome measures
enced, trained physiotherapists. In children who can walk, include the House classification [65]. Generic measures of
dimensions D and E are most relevant. When GMFM is hypertonia and spasticity such as the MAS and MTS are
used as the primary outcome measure in trials of BoNT-A widely used in the upper limb in children with CP [35–37].
therapy, the outcomes have been mixed [58, 59]. The COPM and GAS are also applicable as they can be indi-
GMFCS is valid (based on GMFM), reliable and stable vidualised to the child and family goals and are not specific
in children with cerebral palsy [60]. It is the definitive tool to lower-limb function [44, 48]. Specific outcome measures
to classify a child’s current function and to predict future with good to excellent psychometric properties for the upper
function [60]. It was not intended to be used as an outcome limb in children with CP include the ABILHANDS-Kids,
measure and it does not have the psychometric properties to the Assisting Hand Assessment (AHA), the Melbourne
be used as such [19]. Assessment of Unilateral Upper Limb Function (MUUL)
and the Shriners Hospitals for Children Upper Extremity
Evaluation (SHUEE). Upper-limb outcome measures have
been reviewed in detail elsewhere [66, 67].
5 Interventions for Spasticity and Dystonia variations continue to be identified using immunological
techniques [18].
The choice of interventions for the management of the BoNT primarily acts to inhibit the release of acetylcho-
movement disorders associated with CP in children is exten- line from the presynaptic terminal. The regulation of fusion
sive [19]. It can be difficult at first sight to determine on of the synaptic vesicle with the plasma membrane involves
what criteria the choice should be made between the many a complex of proteins collectively referred to as SNAREs
options. Some have observed that the choice is determined (Soluble-N Ethylmaleimide, Sensitive Factor Attachment
“more by luck than judgement” [68]. Oral medications are Protein Receptor) or SNAP receptors. The principle SNARE
increasingly used as first-line management for spasticity and proteins include VAMP/synaptobrevin, the pre-synaptic
dystonia in children with CP. Medications include baclofen, plasma membrane protein, syntaxin, and the synaptosomal
diazepam, tizanidine and less commonly dantrolene [69, 70]. protein, SNAP25. BoNT interferes with normal vesicle-
Artane and l-dopa are being trialled in dystonia [70]. Most membrane fusion by a multi-step process, illustrated in
oral medications are limited by a combination of limited Fig. 4. The overall effect can be described as a neuro-paral-
benefit and a high prevalence of side effects [19, 69, 71]. ysis or chemical denervation of muscle [80–82]. BoNT does
Medications for both spasticity and dystonia management not cross the blood–brain barrier and although retrograde
have been reviewed extensively elsewhere and will not be transfer to the CNS from peripheral injection sites occurs
considered further here [69–72]. Some studies have exam- to a limited degree, there is little evidence for direct central
ined the benefits of using a background of oral spasticity effects. The explanation for central effects is that peripheral
management using either tizanidine or baclofen, combined chemo-denervation may lead to central reorganisation as a
with focal neurolytic injections of hypertonic muscles with result of neuroplasticity [18].
BoNT-A [73, 74]. Others have investigated combining injec-
tions of BoNT-A and phenol [75].
Neurosurgical procedures for hypertonia include selec- 7 BoNT in CP
tive dorsal rhizotomy (SDR) for spasticity, the insertion of
an ITB or insertion of electrodes for deep brain stimulation Of the seven major BoNT serotypes, only types A and B
(DBS) for various forms of hypertonia [19, 76, 77]. have been used in children with CP. BoNT type B (BoNT-
Chemo-denervation by the injection of neurolytic agents B) has a shorter duration of action than BoNT-A and a less
has a long history in the management of focal and regional satisfactory adverse event profile in children with CP [82].
spasticity. Neurolysis by injection of phenol and alcohol was The only indication for BoNT-B is resistance to BoNT-
widely used before the introduction of BoNT-A [75, 78, 79]. A caused by the presence of neutralising antibodies. The
vast majority of clinical studies in children with CP have
been with the various preparations of BoNT-A, princi-
6 Pharmacology and Mechanism of Action pally onabotulinum toxin A (Botox®) and abobotulinum
of Botulinum Neurotoxins (BoNT) toxin A (Dysport®) [1–5]. Injection of BoNT-A produces a
dose-dependent, partially reversible chemo-denervation of
Botulinum neurotoxins (BoNT) are large proteins of approx- injected muscle by blocking pre-synaptic release of acetyl-
imately 150 kilodaltons (kDa) that are produced by bacteria choline at the neuromuscular junction [18, 80, 81]. Because
from the Clostridia Botulinum family. The effects of BoNT of rapid and high-affinity binding to receptors at the neuro-
at the molecular level are so precise that BoNT has been muscular junction of the target muscle, little systemic spread
described as a “marvel of protein design” and a “molecular of toxin occurs. However, it is important to note that some
nano-machine” [80]. BoNT consists of an N-terminal light systemic spread occurs following every injection and this
chain (LC, 50 kDa), which is a metalloprotease, connected can be detected at remote sites by specialised techniques
to a C-terminal heavy chain (HC, 100 kDa) [18]. The heavy [18]. The diffusion of BoNT-A may be altered by alterations
chain consists of two principal domains, the N terminal por- in muscle morphology such as reduced muscle volume and
tion, which is the translocation domain that is involved in increased connective tissue [7, 25, 26].
the release of the light chain into the cytosol of the motor Neurotransmission is restored initially by the sprouting
neuron, and the C-terminal part that is the receptor binding of new nerve endings, but these are eliminated after about
domain, critical for the binding and endocytosis of BoNT-A 3 months when the original nerve endings regain their abil-
into the presynaptic neuron [18]. ity to release acetylcholine [83]. Muscle strength is reduced
Although there are seven major serotypes of BoNT because of acute muscle atrophy with the secondary effect of
(BoNT-A to BoNT-G), there are more than 40 BoNT sub- a reduction in muscle spasticity [7]. The clinical effects last
types including several hybrid or mosaic types, and new from 3 to 6 months. Some biomechanical and imaging stud-
ies have shown effects lasting for > 12 months after a single
Fig. 4 Botulinum toxin type A (BoNT-A) mechanism of action. The cular vesicle in the nerve terminal. The effects of chemodenervation
BoNT-A heavy chain is shown in green and the light chain in yellow, by injection of BoNT-A are summarised at macroscopic, microscopic
linked by a disulphide bond. Acetylcholine (Ach), the neurotransmit- and molecular levels. SNAP 25 soluble N-ethylmaleimide fusion pro-
ter which is blocked by BoNT-A, is shown as red dots within a cir- tein, attachment protein, VAMP vesicle associated membrane protein
injection of BoNT-A [84, 85]. The duration of action there- such as muscle atrophy last longer than the clinical effects,
fore should be considered not just in clinical terms but also such as muscular relaxation [7, 84].
in terms of muscle biomechanics and the effects on skeletal The predictable movement patterns and postures that are
muscle at the macroscopic, microscopic and molecular lev- characteristic of spasticity enable a systematic rationale to be
els [7]. It is particularly concerning that the adverse effects developed to identify the role of BoNT-A to manage muscle
overactivity [1–6]. The management of dystonia with BoNT- reported had a single injection cycle and the mean follow-up
A is more complex and spasticity and dystonia frequently was usually about 6 months.
occur in combination as in mixed movement disorders [19, In terms of outcome tools, the most frequent were MAS
22, 30]. Although the principle of BoNT-A therapy in chil- and MTS, which were used in about three quarters of stud-
dren with CP is remarkably simple, the application is chal- ies, followed by ankle ROM in about half of the studies.
lenging in the presence of complex changing movement dis- Observational gait scales (PRS, OGS, EVGS) were used
orders and the insidious development of fixed contractures with or without video in about a third of studies and some
[22] (Fig. 5). form of instrumented gait analysis was used in almost half of
the studies, but the equipment used and the reliability were
7.1 BoNT in the Ambulant Child with Equinus poorly described.
When MAS or MTS was the primary outcome measure,
The most common dynamic deformity in children with CP the majority reported a statistically significant improvement,
is equinus, which affects between 60 and 80% of children in that is, a reduction in spasticity. The majority of studies uti-
early childhood [1, 2, 19]. Injection of the gastrocnemius or lising observational gait scales reported an improvement,
the gastrosoleus is the most common indication for BoNT- as did those utilising instrumented gait analysis [6, 82]. The
A therapy in children with CP [1–6]. This is for two main majority of studies that reported GMFM reported improved
reasons. Injection of the gastrosoleus is moderately effective gross motor function, but the majority of these studies were
in the younger child with dynamic equinus and the alterna- uncontrolled, making gains in GMFM as the result of natu-
tive, muscle–tendon lengthening surgery, is unpredictable ral history difficult to disentangle from gains as a result of
and frequently harmful [86]. However, the reverse is true as injection of BoNT-A [22]. There was a trend for better study
the child becomes older. The response to BoNT-A is barely designs to report smaller or no improvements in GMFM
detectable and surgical lengthening of the gastrocsoleus is [58]. Of concern was the observation that change in GMFCS
effective and reliable [87, 88]. was reported as an outcome measure in a number of studies.
To assess the evidence for the use of BoNT-A in equi- Study designs were variable, the numbers of participants
nus, we reviewed numerous publications, which were mainly were generally small and mean follow up was short. Out-
cohort studies, in combination with the higher quality stud- come measures were often poorly described and reliability
ies previously reviewed in systematic reviews and evidence was not reported. Some measures were used incorrectly (e.g.
statements [6, 82]. The majority of studies were cohort GMFCS). The majority of studies reported outcomes in the
studies, and more were described as prospective then retro- ICF domain of body structure, fewer reported valid measures
spective. However, the majority were uncontrolled, which of function and very few reported outcomes in the domains
has little impact on the evidence for change in scales in the of activities and participation [34].
domain of body structure such as MAS or MTS. The lack It was concluded that there is strong evidence for a reduc-
of controls undermine many claims for improvements or tion in spasticity in the plantar flexors of the ankle after
changes in gross motor function. The majority of studies injection of BoNT-A; there was moderate evidence for small
improvements in gait with the caveat that observational gait
Fig. 5 Algorithm as to the

timing of the use of botuli-
num toxin type A (BoNT-A)
and orthopaedic surgery for
ambulant children with cerebral
palsy (CP). The peak age for
the use of BoNT-A is between
2 and 6 years. The peak age for
the use of orthopaedic surgery
is between 6 and 12 years. It is
desirable to have a ‘washout’
period with no injections when
the response of the target mus-
cle is limited
scales have limitations [51, 52, 89]. There was weak evi- which clearly shows a dose response curve [90]. There are
dence for improvements in gross motor function, related to two RCTs that investigated and reported frequency of injec-
lack of controls and incorrect use of GMFCS [6, 82]. tion for spastic equinus. Both studies compare an injection
schedule of three times per year (every 4 months) to once per
7.1.1 Systematic Reviews and Evidence Summaries year. Both studies reported that the once-per-year injection
schedule was as effective with fewer adverse events than
There are several good quality RCTs investigating the out- three times per year [91, 92]. Despite this Level I evidence,
come of injection of BoNT-A for equinus with positive many clinicians inject at more frequent intervals. The once-
results utilising objective outcome measures such as 3-DGA per-year schedule is also aligned to experimental work in
as well lower quality outcome measures such as PRS, OGS, small mammal models, in which more frequent injections
EVGS, MTS and MAS. These studies have been reviewed were reported to cause cumulative harm in terms of mus-
and graded by Simpson et al. and more recently, by Love cle atrophy, weakness and loss of contractile elements and
et al. [6, 82]. fibrosis [7, 93, 94].
It is important to note that the higher the quality of the
study design and the more objective the outcome measure 7.1.3 Muscle Targeting
in terms of validity and reliability, the smaller and less pre-
dictable the response to BoNT-A therapy is reported. Even Identification of the target muscle has traditionally been
with 3-DGA, earlier studies focused on outcome measures based on anatomical landmarks and palpation [1, 2]. The
of interest such as the range of equinus in stance and swing accuracy of injection based on palpation is poor except for
phases of gait [50, 54]. When newer, more global measures the gastrocsoleus [95]. Electromyography, electrical stimu-
of gait function such as the GPS have been utilised, improve- lation and real-time ultrasound have improved the accuracy
ments in overall gait function have been noted to be much of injection of target muscles in children with CP [13, 95].
smaller, or absent [56]. It has been more difficult to determine if improved accuracy
One of the reasons for the paradox is that injection of of injection has improved clinical outcomes. Extensive lit-
BoNT-A to the gastrosoleus in children with spastic diple- erature and atlases now exist to enhance the understanding
gia (bilateral CP) is in the context of generalised spasticity of 3-dimensional topographical anatomy based on real-time,
affecting proximal muscle groups including the hamstrings high-quality ultrasound. The use of ultrasound is strongly
and iliopsoas [19]. Improvements in ankle dorsiflexion may recommended and requires specific training and equipment
be offset by deterioration in knee extension or hip extension, [13].
resulting in the paradox of improvement at the ankle level
with deterioration at proximal levels [56]. Most clinicians 7.1.4 Conclusions
are aware that in the long term, crouch gait (increased hip
and knee flexion) is a more insidious and intractable gait In younger children with no fixed contracture, injection of
disorder than equinus, which is easy to correct surgically, BoNT-A for equinus increases the dynamic length of the
when a child is older, as a definitive procedure with a low gastrocsoleus and results in improvements in selected gait
rate of recurrence [87]. parameters [96]. There is also evidence that appropriate use
Most studies have shown that the improvements following of BoNT-A in younger children may delay the onset of fixed
BoNT-A therapy in children for spastic equinus are small equinus to a small but important degree, permitting later
and short-lived. In addition, children become unresponsive utilisation of orthopaedic surgery at optimum age [19, 56].
to injection of BoNT-A at a younger age than previously In general, this means a more predictable outcome for sur-
thought [52, 56]. Most clinically significant improvements gical treatment for equinus and less need for repeat surgery
are seen under the age of 4 years for equinus in spastic hemi- [87, 88]. However, almost 100% of children who need injec-
plegia [6]. The response reduces between the ages of 4 and tions of BoNT-A for spastic equinus will also need surgical
6 years, and after the age of 6 years recent studies includ- lengthening of the gastrocsoleus.
ing both EVGS and 3DGA confirm little or no benefit from The optimism regarding prevention of contractures gener-
continued use of BoNT-A therapy [52, 56]. ated by the spastic mouse study has never been translated
to the clinical situation [33]. In fact, there is mounting evi-
7.1.2 Dose and Frequency of Administration dence that injection of BoNT-A might cause loss of con-
tractile elements and increased fibrosis, which might lead
Doses and dilutions of BoNT-A for the management of to increases in contracture [7, 93, 94]; hence the need for
equinus depend on the preparation used and have been pub- constant dialogue between clinicians in the multidiscipli-
lished and discussed extensively elsewhere [1–6]. There is nary team who practice both non-operative and operative
one comprehensive dose ranging study for spastic equinus management for children with CP [6]. Short-term gains in
achieving ‘foot-flat’ might be offset by longer-term harm to child consisting of targeted injections to the spastic muscles,
a muscle complex, which is a key to long-term gait function serial casting, orthoses for daytime use, night splinting and
and independence [7, 17, 22–24]. Hence the urgent need for intensive post-injection physiotherapy.
long-term studies, over multiple injection cycles (Fig. 6). The Leuven Group has reported improvements in gait and
function in several studies, of a degree and level that have
7.2 Injection of Proximal Muscles in the Lower Limb rarely been matched in other centres [45, 56, 99]. Perhaps
the integration of all of the components of their approach is
The indications, techniques and outcomes for injecting the required for optimum outcome [45]. However, the combina-
hamstrings and adductor muscles were first described by tion of so many medical, physical and therapy components
Cosgrove et al., Corry et al. and subsequently by others [97, to the programme makes it very difficult to isolate the con-
98]. Muscle hyper-activity in the hamstring and adductor tribution of each of the components to the overall outcome
muscles is more prevalent in the more severely involved [45].
child with bilateral involvement. This may result in scis- In contrast to the Leuven philosophy, Bakheit argues that
soring postures and flexed, stiff-knee gait. Injection of the BoNT-A injections can be effective as a stand-alone inter-
hamstrings can be combined with injection of the gastroc- vention when ancillary management is not available [100].
nemius in high-functioning children with diplegia [96, 97]. The evidence base for or against ancillary interventions is
Most experienced clinicians consider that injection of up to weak because it is very difficult to isolate component parts
four large muscle groups at a single session may be appropri- of the multimodal intervention strategy and subject them to
ate and is generally safe, if dose limitations and appropriate adequately powered RCTs.
techniques are used [3–6]. Injection of more than four large
muscle groups increases the risk of systemic spread, and 7.4 BoNT in the Non‑Ambulant Child
local and systemic adverse events [19, 61].
Hip displacement may affect up to 90% of children at
7.3 Multi‑Level Lower‑Limb Injections GMFCS Level V [19]. In the past, spastic adduction was
considered to be the primary cause of hip displacement
Molenaers et al. in Leuven, Belgium have pioneered inte- and the management of adductor spasticity and contracture
grated, multilevel BoNT-A spasticity management in the received much attention [19]. It is now known that hip dis-
child with CP similar to the concept of single-event multi- placement in the non-ambulant child is much more related
level surgery [45, 99]. Gait deviations are identified using to limited function in hip abductors than spasticity in the
3DGA, muscle overactivity is identified using a combination hip adductors.
of 3DGA, electromyography and instrumented measures for Graham et al. conducted a 3-year RCT investigating the
spasticity. A tailored programme is then developed for each outcomes of 6-monthly BoNT-A injections of the adductors
Fig. 6 Risk versus benefit for

injection of botulinum toxin
type A (BoNT-A) in the ambu-
lant child with cerebral palsy
(CP). The benefits (decreased
spasticity, increased range of
motion and improvements in
gait may outweigh the harms
(weakness, muscle atrophy and
fibrosis). The understanding of
risk to benefit may change with
further studies, both clinical and
in animal models. The endpoint
is orthopaedic surgery for gait
improvement. GMFCS Gross
Motor Function Classification
System
and hamstrings in children with CP, combined with a hip termination strategy for the use of BoNT-A. In the ambu-
abduction brace. The outcomes of this study were nega- lant child, the logical endpoint of BoNT-A therapy, for the
tive. Gross motor function as determined by GMFM did not majority of children, is orthopaedic surgery for fixed con-
improve in the treatment group compared with the control tracture [87, 88]. In the non-ambulant child, the endpoint
group [101]. Hip displacement was not prevented and chil- is not clear and each injection cycle exposes the child to a
dren in both groups required the same number of orthopae- greater risk of serious adverse events than is the case in the
dic operations for hip displacement with the same outcomes ambulant child [19, 104, 105] (Fig. 7). Hip adductor spastic-
in terms of hip morphology and pain at 10-year follow-up ity is more effectively treated by phenolisation of the obtu-
[102, 103]. rator nerve than by injection of BoNT-A, especially when
Although smaller studies with short-term follow-up have combined with adductor release surgery [78].
suggested more optimistic outcomes, the weight of evidence There is a small role for focal management of spastic-
suggests that gross motor function is not improved, and hip dystonia in the non-ambulant child for specific functional
displacement and the need for orthopaedic surgery is not goals [11, 22]. In the upper limb, these include improvement
avoided by injection of the hip adductors in non-ambulant of reach and grasp to facilitate control of a powered wheel-
children with CP [101–103]. chair. In the lower limb, a very useful indication is pallia-
Copeland et al. reported the outcomes of an RCT of the tion of painful hip dislocation in a child who is too fragile
use of BoNT-A in 41 non-ambulant children with CP for a to consider orthopaedic surgery [106]. However, prevention
range of heterogeneous indications, described as “care and of hip displacement by hip surveillance and early surgery is
comfort” [11]. They described the use of sham injections as clearly a better option.
controls and reported significant benefits in the COPM as
the primary outcome measure. This trial was methodologi- 7.4.1 Risks of BoNT in the Non‑Ambulant Child
cally weak because blinding was not maintained with 77%
of parents correctly identifying group allocation at 4 weeks In non-ambulant children, global spasticity management
after injection [11]. The combination of imperfect blinding using oral medications and when appropriate an intrathecal
and subjective outcome measures undermines the validity baclofen pump are both more effective and safer than inject-
of the conclusions. Although there was no increase in seri- ing multiple muscles on a recurring basis with large doses
ous adverse events in the treatment group compared with of BoNT-A [76]. It is in the group of non-ambulant children
the control group, this may not be the case when BoNT-A with medical comorbidities that most of the fatalities have
is used in non-ambulant children in non-RCT conditions, occurred after injection of BoNT-A leading the FDA in the
when serious adverse events and deaths have been reported United States to insist on a ‘black box warning’ for all botu-
[61, 104]. In addition, those who advocate injections of linum toxin products [18]. Despite the limited benefits and
BoNT-A in non-ambulant children rarely discuss an exit or poor evidence base, BoNT-A therapy continues to be widely
Fig. 7 Risk versus benefit for

injection of botulinum toxin
type A (BoNT-A) in the non-
ambulant child with cerebral
palsy (CP). The harms are the
risk of serious/fatal adverse
events and the benefits are mod-
est. There may not be a defined
endpoint and intermittent, life-
long injections are not an ideal
proposition. GMFCS Gross
Motor Function Classification
System
used in non-ambulant children. In Australia, there have been power wheelchair [111]. In the upper limb, it is even more
four deaths in recent years attributed to the use of BoNT-A important that BoNT-A therapy be goal-directed in the con-
therapy in non-ambulant children with CP and the risk-to- text of a multidisciplinary programme including splinting
benefit profile is poor [102, 107]. One exception may be the and occupational therapy [22, 110].
use of BoNT-A for pain relief, which is so prevalent in this Additional problems in the upper limb will relate to a
population [106, 108]. higher prevalence of dystonia, weakness, sensory impair-
ment and impairment of selective motor control [19, 22].
7.5 Upper‑Limb Injections: Impairments These negative features may overshadow any benefit gained
and Interventions from BoNT-A injection and lead to more limited results of
shorter duration [9]. The suitable candidate for BoNT-A
Upper-limb dysfunction is a common functional and cos- therapy in the upper limb should be able to initiate active
metic consequence of CP, particularly in children with hemi- finger movements and activate and strengthen antagonist
plegia [22]. A wide variety of management strategies have muscles to take advantage of temporary BoNT-A paresis of
been adopted and the evidence base has been reviewed by the agonists [10]. Children should have good grip strength
Boyd et al. and more recently by Sakzewski et al. [109, 110]. because good grip strength may be reduced by BoNT-A
Conventional therapeutic management of upper-limb injection [9, 10, 111]. Family-identified limitations, prob-
hyperactivity in children with CP has involved the use of lems and goals should be analysed in great detail [112, 113].
splinting and casting, and passive stretching, the facilita- In typical hemiplegic posturing, the most common target
tion of posture and movement, medication and sometimes muscles are the biceps, brachialis, pronator teres, flexor carpi
orthopaedic or plastic surgery [109]. In a recent high-quality ulnaris, flexor carpi radialis and the adductor pollicis [22,
meta-analysis, Sakzewski et al. reported moderate to strong 111]. Injection of the long finger flexors should be mini-
effects for BoNT-A and occupational therapy to improve mised to avoid weakening of grip strength [9, 10]. However,
outcomes compared with occupational therapy alone. Con- in non-ambulant children with severe spastic dystonia, and in
straint-induced movement therapy achieved modest to strong some children with hemiplegia, if the aim is to improve pal-
treatment effects on improving movement quality and effi- mar hygiene, injection of the long finger flexors is required
ciency of the impaired upper limb compared with usual care in combination with serial casting [111]. The larger muscles
[110]. are injected in one or two sites with the smaller muscles
Impairment of upper-limb function can impact on self- injected in a single site. Small-volume, high-concentration
care abilities, activities of daily living, education, leisure injections are advised, using ultrasound control, to avoid
activities and vocational outcomes (participation) [22]. Chil- injection of unwanted muscles and diffusion into other mus-
dren may not be able to reach for objects, manipulate toys, cle groups [112, 114].
feed themselves efficiently or use assistive communication
devices [22, 109, 110]. A modest improvement in reaching 7.5.2 BoNT‑A in the Upper Limb: Evidence
function can be beneficial. Different muscles develop fixed
contracture at different speeds. The pronator teres is invari- Corry et al. conducted the first double-blind, placebo-con-
ably the first muscle in the hemiplegic upper limb to develop trolled study involving multiple injections in the spastic
a contracture [22]. upper extremity in children with CP [9]. As with many stud-
ies, a reduction in measures of spasticity were demonstrated
7.5.1 BoNT‑A in the Upper Limb: Overview but improvements in function were much more difficult to
achieve [9]. Fehlings et al. conducted a single-blind, ran-
The use of BoNT-A in the lower limb of children with CP is domised study in 30 children with hemiplegia [10]. There
well established and RCTs have also been conducted in the were significant improvements in function in the BoNT-A
upper limb, soon after the introduction of BoNT-A to clini- group as measured by the Quality of Upper Extremities
cal practice [9, 10]. The principal goal of treatment using Skills Test (QUEST) at 1 month but the gains were not sig-
BoNT-A in the upper limb of children with CP is to enhance nificant at longer term follow up.
function by allowing children to employ their treated arm Wallen et al. demonstrated that the dynamic joint ranges
and conduct daily activities more efficiently and effectively in the upper limb respond to BoNT-A injection and that
[9, 10, 22]. Additional aims are to decrease tone and increase there was a significant improvement in activities and partici-
ROM to prevent contracture and delay the need for surgery pation at 3 and 6 months following injection [112]. Olesch
[9, 10, 22, 110, 111]. It is invariably the non-dominant arm et al. demonstrated the safety of repeated injections to the
that requires treatment, except in children with quadriplegia, upper limb [113].
when the dominant arm may benefit from intervention to In 2005, Speth et al. reported a high-quality RCT investi-
improve grasp and release in activities such as steering a gating the addition of injections of BoNT-A, with intensive
therapy, to intensive therapy alone [114]. As in the first events including pain at the site of injection, weakness in
upper-limb RCT by Corry et al. in 1997, Speth et al. found a the injected muscle or nearby muscles, falling, tripping, flu-
reduction in muscle overactivity, with some gains in ROM like illness and short-term functional deterioration have all
but very limited evidence for changes in function or partici- been reported, in studies ranging from small cohort studies
pation [9, 114]. and RCTs to evidence-based reviews [1–6, 9, 16, 82].
Objective evaluation of upper-limb function using a Systemic adverse events occur in ambulant children at a
standardised, validated instrument is strongly recommended rate of between 1 and 5% [1–6]. Such events include tran-
to document baseline function and also to assess changes fol- sient incontinence of bowel, bladder or both [3, 6]. This is
lowing treatment. There are a variety of established instru- because cholinergic sphincter function is mediated by acetyl-
ments that can be used as outcome measures for upper-limb choline and therefore can be affected by systemic spread of
assessments, including QUEST, Melbourne Assessment of BoNT-A [3]. The laryngeal and lower oesophageal sphincter
Unilateral Upper Limb Function (Melbourne Assessment) are also controlled by smooth muscle with cholinergic inner-
and the Assisting Hand Assessment (AHA). In studies utilis- vation. The most serious adverse event, resulting in mor-
ing these valid, reliable and objective measures, sustained tality, is paralysis of the pharyngeal or lower oesophageal
improvements in function have been difficult to identify sphincter, allowing aspiration of gastric contents into the
[115]. As in the lower limb, the use of adjunctive interven- respiratory tract with hypoxia, pneumonia, and in extreme
tions makes interpretation of treatment effects problem- cases, cardiac arrest and death [3].
atic [115]. As in the lower limb, children with upper-limb Paradoxically, RCTs may not be the optimum source for
involvement should be considered for definitive orthopaedic determining the true prevalence of adverse events, especially
surgery, when the response to injections of BoNT-A plateau, serious adverse events. RCTs are conducted by experienced
especially when fixed contractures progress and impair func- clinicians, with the dose, dilution and muscle targeting
tion [110]. In the first RCT in which injections of BoNT-A, carefully prescribed and approved by an ethics committee.
tendon transfer surgery and usual therapy were compared, Patients enrolled in RCTs and prospective cohort studies are
the surgical group had superior outcomes [116]. monitored closely and have frequent contact with clinicians
[9, 16, 45, 96–98].
7.6 BoNT‑A as an Analgesic Agent Adverse events in general clinical practice reflect the
wider variety of techniques, dosing, dilution, targeting
The analgesic role of BoNT-A is complex and under contin- techniques and experience of clinicians in a wide range of
ued evaluation both in animal models and in clinical trials practice settings [105, 120–122]. Naidu et al. conducted a
[41, 117]. One of the most recent evidence-based reviews retrospective study of a large number of injection episodes in
concluded that there was Level B evidence to support the children with CP, GMFCS I–V. They reported a strong asso-
use of BoNT-A in various neuralgias [117]. Musculoskel- ciation between serious adverse events requiring hospitalisa-
etal pain is a major clinical problem for many children with tion and GMFCS level [104]. They made a recommendation
CP and appears to increase in the second decade and is not to offer injections to non-ambulant children at GMFCS
very common in young adults [118]. Hypertonia amplifies levels IV and V [104]. In a study with more robust meth-
pain and there is frequently a ‘vicious cycle’ of pain and odology, using a prospective injection database, O’Flaherty
spasm, in which pain provokes muscle spasm, which further et al. reported a similar prevalence of adverse events in non-
increases pain [41]. The pain–spasm cycle may sometimes ambulant children with CP in the month before injection
be broken by injection of BoNT-A. as the month after injection [122]. In the O’Flaherty study,
In one small RCT, injection of BoNT-A reduced the there were a limited number of experienced injectors, with
requirements for opiates and resulted in a shorter hospital high levels of training and experience [122].
stay in children having adductor releases than in a control
group [41]. However, in a recent, larger and higher quality 7.7.1 Clinical Adverse Events and Pharmacovigilance
trial, these findings were not replicated in children having Studies
bony reconstructive hip surgery [119]. This suggests that
BoNT-A is more effective for painful spasms than for mus- Given the importance of experience and oversight, pharma-
culoskeletal pain [41, 119]. covigilance studies may be an important source of informa-
tion on the prevalence of serious adverse events in com-
7.7 Adverse Events of BoNT‑A munity settings [105]. In 2016, a study was published from
data using the WHO Global Individual Case Safety Report
Injection of BoNT-A in ambulant children with cer- (ICSR) database, V igiBase®. Between 1995 and 2015, 162
ebral palsy, who are physically well and have few medi- ICSR were registered in VigiBase®. The most frequent
cal comorbidities, is generally safe [1–6]. Minor adverse adverse event was dysphagia, (n = 27, 17%) followed by
weakness (n = 25, 16%). There were 19 deaths recorded Injection of BoNT-A causes a chemo-denervation of skel-
following injection of BoNT-A and mortality was more etal muscle and denervation is followed by acute muscle
common in children than in adults [105]. Death and seri- atrophy [7, 84, 85, 106, 123]. The reduction in spasticity
ous adverse events have rarely been reported in RCTs and is not a primary effect but secondary to muscle atrophy [7]
indicate the need for ongoing recording and monitoring of (Fig. 9). During the period of muscle atrophy, contractile
serious adverse events in community settings [102, 105]. muscle elements are partially replaced by fat and con-
We consider that the risk-to-benefit ratio for the use of nective tissue [7, 85, 123]. When the effects of injection
BoNT-A injections in large muscle groups, in non-ambulant wear off, there is a partial recovery of muscle morphology
children with CP, may not be acceptable (Fig. 7). There have and function, but the evidence in human volunteers and in
been at least four deaths in Australia in non-ambulant chil- experimental animals suggests that recovery is incomplete
dren with cerebral palsy following injection of BoNT-A, at 12 months after injection [7, 85, 123]. To date, there are
with other events going unreported or underreported [102, no studies that extend for more than 12 months [7, 84, 85].
105, 107]. At this time, the degree of muscle recovery is not known
nor is it known if skeletal muscle ever recovers fully after a
7.7.2 Adverse Events of BoNT‑A in the Injected Muscle single injection of BoNT-A. If there is even a small deficit at
6–12 months after the first injection, it is possible the deficits
The literature addressing the safety of BoNT-A has rightly in skeletal muscle morphology and function may accumulate
focussed on the safety of the child with CP and the preva- over time, with each injection cycle [94]. The implications
lence of adverse events [61, 121, 122]. However, during the will vary according to the muscle injected and its function.
past 15 years there has been a growing body of literature Muscle fibrosis is unlikely to help muscle function in any
describing harmful effects of injection of BoNT-A at the area of the body but might have more serious implications
level of the injected muscle [7, 93, 94]. These bodies of liter- in antigravity, lower-limb muscles in ambulant children than
ature rarely intersect and the majority of reviews of BoNT-A in upper-limb muscles or perhaps in the muscles on non-
make no mention of the risks of muscle atrophy and fibro- ambulant children. These ideas all remain to be investigated
sis [3, 7, 81]. In earlier literature, injection of BoNT-A was and tested.
thought to be completely reversible and if the injection failed The Leuven and Perth groups have led the way in measur-
to improve gait and function, at least it would do no harm ing changes in muscle volumes and morphology after injec-
(Fig. 8) [83]. tion of BoNT-A, using serial MRI or 3DUS [124, 125]. They
have reported smaller reductions in muscle volumes than
Fig. 8 Historical view of

changes in the gastrocnemius
muscle after injection of botu-
linum toxin type A (BoNT-A)
for equinus gait. The spastic
gastrocsoleus muscle is shown
as a tightly coiled spring, caus-
ing the child to walk on their
toes. After injection the spring
(spasticity) is relaxed and the
child achieves foot-flat. After
3–6 months, the effects of injec-
tion wear off and the equinus
returns
Fig. 9 Contemporary view of

changes in the gastrocnemius
muscle after injection of botuli-
num toxin type A (BoNT-A) for
equinus gait. The gastrocnemius
is small before injection with
dynamic shortening and equinus
at the ankle. After injection of
BoNT-A there is acute atrophy,
a decrease in spasticity and foot-
flat. After 6–12 months there is
partial recovery of the muscle
and the equinus returns
reported in animal studies, which is encouraging [124, 125]. We suggest that objective evaluation of each injection
Changes in muscle volume may be related to the status of cycle be performed in the knowledge that there is a “law of
the muscle prior to injection. Muscle atrophy and recovery diminishing returns” for repeat injections, especially in the
would be expected to differ in children with CP, typically gastrocsoleus (Fig. 5). It is not only acceptable but good
developing volunteers and experimental animals. Changes medicine to stop injecting when muscle stops responding,
in echo intensity in the muscles of children with CP at even if the child and family are not ready for definitive sur-
baseline and after injection of BoNT-A have recently been gery (Fig. 5). Knowing when to stop depends critically on
reported [25, 26, 124, 126]. The quality of the muscle as recognition of the progression from dynamic to fixed con-
well as the volume needs to be considered, specifically the tracture (Fig. 3). Better communication between BoNT-A
effects of BoNT-A injections on both contractile elements injectors and surgeons would facilitate this process.
and non-contractile elements of the skeletal muscle [93, There is much more work to be done to improve the
94]. Decreases in muscle volume combined with increases safety of BoNT-A injection by altering injection protocols
in echo intensity might signal the double insult of muscle and by using ancillary measures such as muscle strengthen-
atrophy and muscle fibrosis [126]. There is pressing need for ing to mitigate the effects of BoNT-A-induced atrophy [22,
non-invasive monitoring of muscle structure and function 124–126].
throughout treatment with BoNT-A.
Compliance with Ethical Standards
8 Conclusions Funding Kerr Graham received non-financial support from the

National Health and Medical Research Council of Australia (NHMRC)
Centre of Research Excellence in Cerebral Palsy (CRE-CP). None of
Given that two RCTs suggest that injection once every the authors received financial support for the publication of this review.
12 months is as effective as injection every 4 months, we
suggest decreasing the frequency of injection of BoNT-A Conflict of interest Iqbal Multani declares no conflict of interest. Jamil
to match this evidence. This would also align with evidence Manji declares no conflict of interest. Tandy Hastings-Ison declares no
from studies in animal models [91–94]. We propose that conflict of interest. Abhay Khot declares no conflict of interest. Kerr
Graham declares no conflict of interest.
measurement of muscle volume be performed before injec-
tion of BoNT-A and at regular intervals during the treat- Open Access This article is distributed under the terms of the Crea-
ment phase to reduce as much as possible iatrogenic muscle tive Commons Attribution-NonCommercial 4.0 International License
atrophy and fibrosis. (http://creativecommons.org/licenses/by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any medium, for paediatric upper limb hypertonicity: international consensus
provided you give appropriate credit to the original author(s) and the statement. Eur J Neurol. 2010;17(Suppl. 2):38–56.
source, provide a link to the Creative Commons license, and indicate 17. Nahm NJ, Graham HK, Gormley ME Jr, Georgiadis AG. Man-
if changes were made. agement of hypertonia in cerebral palsy. Curr Opin Pediatr.
2018;30(1):57–64.
18. Jankovic J. Botulinum toxin: state of the art. Mov Disord.
2017;32(8):1131–8.
References 19. Graham HK, Rosenbaum P, Paneth N, Dan B, Lin JP, Damiano
DL, et al. Cerebral palsy. Nat Rev Dis Primers. 2016;2:15082.
1. Koman LA, Mooney JF 3rd, Smith B, Goodman A, Mulvaney T. 20. Albanese A. Terminology for preparations of botuli-
Management of cerebral palsy with botulinum-A toxin: prelimi- num neurotoxins: what a difference a name makes. JAMA.
nary investigation. J Pediatr Orthop. 1993;13(4):489–95. 2011;305(1):89–90.
2. Cosgrove AP, Corry IS, Graham HK. Botulinum toxin in the 21. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Dami-
management of the lower limb in cerebral palsy. Dev Med Child ano D, et al. A report: the definition and classification of cerebral
Neurol. 1994;36(5):386–96. palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8–14.
3. Graham HK, Aoki KR, Autti-Ramo I, Boyd RN, Delgado MR, 22. Leonard J, Graham H. Treatment of motor disorders in cerebral
Gaebler-Spira DJ, et al. Recommendations for the use of botu- palsy with botulinum neurotoxin. In: Jankovic J, Albanese A,
linum toxin type A in the management of cerebral palsy. Gait Atassi MZ, Dolly JO, Hallett M, Mayer NH, editors. Botulinum
Posture. 2000;11(1):67–79. toxin: therapeutic clinical practice and science. Philadelphia:
4. Heinen F, Molenaers G, Fairhurst C, Carr LJ, Desloovere K, Saunders Elsevier; 2009. p. 172–91.
Chaleat Valayer E, et al. European consensus table 2006 on 23. Graham HK, Selber P. Musculoskeletal aspects of cerebral palsy.
botulinum toxin for children with cerebral palsy. Eur J Paediatr J Bone Jt Surg Br. 2003;85(2):157–66.
Neurol. 2006;10(5–6):215–25. 24. Graham HK, Thomason PNTF. Cerebral palsy. In: Weinstein
5. Heinen F, Desloovere K, Schroeder AS, Berweck S, Borggraefe SL, Ponseti IVJM, editors. Lovell and Winter’s pediatric ortho-
I, van Campenhout A, et al. The updated European Consensus paedics. 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott
2009 on the use of botulinum toxin for children with cerebral Williams & Wilkins; 2014. p. 484–554.
palsy. Eur J Paediatr Neurol. 2010;14(1):45–66. 25. Gough M, Shortland AP. Could muscle deformity in children
6. Love SC, Novak I, Kentish M, Desloovere K, Heinen F, Molen- with spastic cerebral palsy be related to an impairment of mus-
aers G, et al. Botulinum toxin assessment, intervention and after- cle growth and altered adaptation? Dev Med Child Neurol.
care for lower limb spasticity in children with cerebral palsy: 2012;54(6):495–9.
international consensus statement. Eur J Neurol. 2010;17(Suppl. 26. Barrett RS, Lichtwark GA. Gross muscle morphology and struc-
2):9–37. ture in spastic cerebral palsy: a systematic review. Dev Med
7. Multani I, Manji J, Tang MJ, Howard J, Graham HK. Sarcopenia, Child Neurol. 2010;52(9):794–804.
botulinum toxin A and cerebral palsy. J Bone Jt Surg Am. 2019. 27. Cans C. Surveillance of cerebral palsy in Europe: a collaboration
(in press). of cerebral palsy surveys and registers. Dev Med Child Neurol.
8. Gough M, Fairhurst C, Shortland AP. Botulinum toxin and 2000;42(12):816–24.
cerebral palsy: time for reflection? Dev Med Child Neurol. 28. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi
2005;47(10):709–12. B. Development and reliability of a system to classify gross
9. Corry IS, Cosgrove AP, Walsh EG, McClean D, Graham HK. motor function in children with cerebral palsy. Dev Med Child
Botulinum toxin A in the hemiplegic upper limb: a double-blind Neurol. 1997;39(4):214–23.
trial. Dev Med Child Neurol. 1997;39(3):185–93. 29. Lin JP. The contribution of spasticity to the movement disorder
10. Fehlings D, Rang M, Glazier J, Steele C. An evaluation of of cerebral palsy using pathway analysis: does spasticity matter?
botulinum-A toxin injections to improve upper extremity Dev Med Child Neurol. 2011;53(1):7–9.
function in children with hemiplegic cerebral palsy. J Pediatr. 30. Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, Mink JW,
2000;137(3):331–7. et al. Definition and classification of hyperkinetic movements in
11. Copeland L, Edwards P, Thorley M, Donaghey S, Gascoigne- childhood. Mov Disord. 2010;25(11):1538–49.
Pees L, Kentish M, et al. Botulinum toxin A for nonambulatory 31. Howard J, Soo B, Graham HK, Boyd RN, Reid S, Lani-
children with cerebral palsy: a double blind randomized con- gan A, et al. Cerebral palsy in Victoria: motor types, topog-
trolled trial. J Pediatr. 2014;165(1):140–46.e4. raphy and gross motor function. J Paediatr Child Health.
12. Pin TW, Elmasry J, Lewis J. Efficacy of botulinum toxin A in 2005;41(9–10):479–83.
children with cerebral palsy in gross motor function classifica- 32. Pandyan AD, Gregoric M, Barnes MP, Wood D, Van Wijck F,
tion system levels IV and V: a systematic review. Dev Med Child Burridge J, et al. Spasticity: clinical perceptions, neurologi-
Neurol. 2013;55(4):304–13. cal realities and meaningful measurement. Disabil Rehabil.
13. Berweck S, Schroeder AS, Fietzek UM, Heinen F. Sonography- 2005;27(1–2):2–6.
guided injection of botulinum toxin in children with cerebral 33. Cosgrove AP, Graham HK. Botulinum toxin A prevents the
palsy. Lancet. 2004;363(9404):249–50. development of contractures in the hereditary spastic mouse.
14. Barber L, Hastings-Ison T, Baker R, Barrett R, Lichtwark G. Dev Med Child Neurol. 1994;36(5):379–85.
Medial gastrocnemius muscle volume and fascicle length in 34. Schiariti V, Selb M, Cieza A, O’Donnell M. International classifi-
children aged 2 to 5 years with cerebral palsy. Dev Med Child cation of functioning, disability and Health core sets for children
Neurol. 2011;53(6):543–8. and youth with cerebral palsy: a consensus meeting. Dev Med
15. Fry NR, Gough M, Shortland AP. Three-dimensional realisation Child Neurol. 2015;57(2):149–58.
of muscle morphology and architecture using ultrasound. Gait 35. Mutlu A, Livanelioglu A, Gunel MK. Reliability of Ashworth
Posture. 2004;20(2):177–82. and Modified Ashworth scales in children with spastic cerebral
16. Fehlings D, Novak I, Berweck S, Hoare B, Stott NS, Russo RN, palsy. BMC Musculoskelet Disord. 2008;9:44.
et al. Botulinum toxin assessment, intervention and follow-up
36. Yam WK, Leung MS. Interrater reliability of Modified Ashworth 53. Read HS, Hazlewood ME, Hillman SJ, Prescott RJ, Robb JE.
Scale and Modified Tardieu Scale in children with spastic cer- Edinburgh visual gait score for use in cerebral palsy. J Pediatr
ebral palsy. J Child Neurol. 2006;21(12):1031–5. Orthop. 2003;23(3):296–301.
37. Gracies JM, Burke K, Clegg NJ, Browne R, Rushing C, Fehlings 54. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG,
D, et al. Reliability of the Tardieu Scale for assessing spastic- Mubarak SJ. Double-blind study of botulinum A toxin injec-
ity in children with cerebral palsy. Arch Phys Med Rehabil. tions into the gastrocnemius muscle in patients with cerebral
2010;91(3):421–8. palsy. Gait Posture. 1999;10(1):1–9.
38. Haugh AB, Pandyan AD, Johnson GR. A systematic review 55. Baker R, McGinley JL, Schwartz MH, Beynon S, Rozumalski A,
of the Tardieu Scale for the measurement of spasticity. Disabil Graham HK, et al. The gait profile score and movement analysis
Rehabil. 2006;28(15):899–907. profile. Gait Posture. 2009;30(3):265–9.
39. Bar-On L, Aertbelien E, Molenaers G, Dan B, Desloovere K. 56. Hastings-Ison T, Sangeux M, Thomason P, Rawicki B, Fahey M,
Manually controlled instrumented spasticity assessments: a Graham HK. Onabotulinum toxin-A (Botox) for spastic equinus
systematic review of psychometric properties. Dev Med Child in cerebral palsy: a prospective kinematic study. J Child Orthop.
Neurol. 2014;56(10):932–50. 2018;12(4):390–7.
40. Wood DE, Burridge JH, van Wijck FM, McFadden C, Hitch- 57. Russell DJ, Rosenbaum PL, Wright M, Avery LM. Gross motor
cock RA, Pandyan AD, et al. Biomechanical approaches applied function measure (GMFM-66 & GMFM-88) user’s manual. 3rd
to the lower and upper limb for the measurement of spastic- ed. London: Mac Keith Press; 2002.
ity: a systematic review of the literature. Disabil Rehabil. 58. Reddihough DS, King JA, Coleman GJ, Fosang A, McCoy AT,
2005;27(1–2):19–32. Thomason P, et al. Functional outcome of botulinum toxin A
41. Barwood S, Baillieu C, Boyd R, Brereton K, Low J, Nattrass injections to the lower limbs in cerebral palsy. Dev Med Child
G, et al. Analgesic effects of botulinum toxin A: a randomized, Neurol. 2002;44(12):820–7.
placebo-controlled clinical trial. Dev Med Child Neurol. 59. Scholtes VA, Dallmeijer AJ, Knol DL, Speth LA, Maathuis CG,
2000;42(2):116–21. Jongerius PH. The combined effect of lower-limb multilevel
42. Thomason P, Willoughby K, Graham HK. Orthopaedic assess- Botulinum Toxin A and comprehensive rehabiliation on mobil-
ment. In: Dan B, Paneth N, Rosenbloom L, editors. Cerebral ity in children with cerebral palsy: a randomised clinical trial.
palsy: science and clinical practice. London: Mac Keith Press; Arch Phys Med Rehabil. 2006;87(12):1551–8.
2014. p. 287–312. 60. Palisano RJ, Cameron D, Rosenbaum PL, Walter SD, Russell D.
43. Hastings-Ison T, Blackburn C, Opie NL, Graham HK, Rawicki Stability of the gross motor function classification system. Dev
B, Wolfe R, et al. Reproducibility of an instrumented meas- Med Child Neurol. 2006;48(6):424–8.
ure for passive ankle dorsiflexion in conscious and anaesthe- 61. Howell K, Selber P, Graham HK, Reddihough D. Botulinum neu-
tized children with cerebral palsy. Dev Med Child Neurol. rotoxin A: an unusual systemic effect. J Paediatr Child Health.
2014;56(4):378–85. 2007;43(6):499–501.
44. Law M, Cooper B, Strong S, Stewart D, Rigby P, Letts L. The 62. Albright AL, Cervi A, Singletary J. Intrathecal baclofen for spas-
person-environment-occupation model: a transactive approach to ticity in cerebral palsy. JAMA. 1991;265(11):1418–22.
occupational performance. Can J Occup Ther. 1996;63(1):9–23. 63. Narayanan UG, Fehlings D, Weir S, Knights S, Kiran S, Camp-
45. Molenaers G, Desloovere K, Eyssen M, Decat J, Jonkers I, De bell K. Initial development and validation of the Caregiver Priori-
Cock P. Botulinum toxin type A treatment of cerebral palsy: an ties and Child Health Index of Life with Disabilities (CPCHILD).
integrated approach. Eur J Neurol. 1999;6(Suppl 4):51-S7. Dev Med Child Neurol. 2006;48(10):804–12.
46. Rethlefsen SA, Blumstein G, Kay RM, Dorey F, Wren TA. Prev- 64. Eliasson AC, Krumlinde-Sundholm L, Rosblad B, Beckung E,
alence of specific gait abnormalities in children with cerebral Arner M, Ohrvall AM, et al. The Manual Ability Classification
palsy revisited: influence of age, prior surgery, and Gross Motor System (MACS) for children with cerebral palsy: scale develop-
Function Classification System level. Dev Med Child Neurol. ment and evidence of validity and reliability. Dev Med Child
2017;59(1):79–88. Neurol. 2006;48(7):549–54.
47. Wren TA, Rethlefsen S, Kay RM. Prevalence of specific gait 65. House JH, Gwathmey FW, Fidler MO. A dynamic approach to
abnormalities in children with cerebral palsy: influence of cer- the thumb-in palm deformity in cerebral palsy. J Bone Jt Surg
ebral palsy subtype, age, and previous surgery. J Pediatr Orthop. Am. 1981;63(2):216–25.
2005;25(1):79–83. 66. Klingels K, De Cock P, Molenaers G, Desloovere K, Huenaerts
48. Molenaers G, Fagard K, Van Campenhout A, Desloovere K. C, Jaspers E, et al. Upper limb motor and sensory impairments
Botulinum toxin A treatment of the lower extremities in children in children with hemiplegic cerebral palsy. Can they be measured
with cerebral palsy. J Child Orthop. 2013;7(5):383–7. reliably? Disabil Rehabil. 2010;32(5):409–16.
49. Koman LA, Mooney JF 3rd, Smith BP, Goodman A, Mulvaney 67. Wagner LV, Davids JR. Assessment tools and classification sys-
T. Management of spasticity in cerebral palsy with botulinum-A tems used for the upper extremity in children with cerebral palsy.
toxin: report of a preliminary, randomized, double-blind trial. J Clin Orthop Relat Res. 2012;470(5):1257–71.
Pediatr Orthop. 1994;14(3):299–303. 68. Patrick JH, Roberts AP, Cole GF. Therapeutic choices in the
50. Corry IS, Cosgrove AP, Duffy CM, McNeill S, Taylor TC, Gra- locomotor management of the child with cerebral palsy—more
ham HK. Botulinum toxin A compared with stretching casts in luck than judgement? Arch Dis Child. 2001;85(4):275–9.
the treatment of spastic equinus: a randomised prospective trial. 69. Delgado MR, Hirtz D, Aisen M, Ashwal S, Fehlings DL,
J Pediatr Orthop. 1998;18(3):304–11. McLaughlin J, et al. Practice parameter: pharmacologic treat-
51. Mackey AH, Lobb GL, Walt SE, Stott NS. Reliability and valid- ment of spasticity in children and adolescents with cerebral palsy
ity of the Observational Gait Scale in children with spastic diple- (an evidence-based review): report of the Quality Standards
gia. Dev Med Child Neurol. 2003;45(1):4–11. Subcommittee of the American Academy of Neurology and the
52. Read FA, Boyd RN, Barber LA. Longitudinal assessment of Practice Committee of the Child Neurology Society. Neurology.
gait quality in children with bilateral cerebral palsy following 2010;74(4):336–43.
repeated lower limb intramuscular botulinum toxin-A injections. 70. Verrotti A, Greco R, Spalice A, Chiarelli F, Iannetti P. Pharma-
Res Dev Disabil. 2017;68:35–41. cotherapy of spasticity in children with cerebral palsy. Pediatr
Neurol. 2006;34(1):1–6.
71. Masson R, Pagliano E, Baranello G. Efficacy of oral pharma- diplegia: a pilot randomized controlled trial. J Bone Jt Surg Am.
cological treatments in dyskinetic cerebral palsy: a systematic 2011;93(5):451–60.
review. Dev Med Child Neurol. 2017;59(12):1237–48. 89. Boyd RN, Graham HK. Objective measurement of clinical find-
72. Albright AL. Spasticity and movement disorders in cerebral ings in the use of botulinum toxin type A for the management
palsy. J Child Neurol. 1996;11(Suppl. 1):1–4. of children with cerebral palsy. Eur J Neurol. 1999;6(Suppl.
73. Dai AI, Aksoy SN, Demiryurek AT. Comparison of efficacy 4):23–35.
and side effects of oral baclofen versus tizanidine therapy 90. Baker R, Jasinski M, Maciag-Tymecka I, Michalowska-Mrozek
with adjuvant botulinum toxin type A in children with cer- J, Bonikowski M, Carr L, et al. Botulinum toxin treatment of
ebral palsy and spastic equinus foot deformity. J Child Neurol. spasticity in diplegic cerebral palsy: a randomized, double-blind,
2016;31(2):184–9. placebo-controlled, dose-ranging study. Dev Med Child Neurol.
74. Dai AI, Wasay M, Awan S. Botulinum toxin type A with oral 2002;44(10):666–75.
baclofen versus oral tizanidine: a nonrandomized pilot com- 91. Kanovsky P, Bares M, Severa S, Richardson A, Dysport Paediat-
parison in patients with cerebral palsy and spastic equinus foot ric Limb Spasticity Study G. Long-term efficacy and tolerability
deformity. J Child Neurol. 2008;23(12):1464–6. of 4-monthly versus yearly botulinum toxin type A treatment for
75. Gooch JL, Patton CP. Combining botulinum toxin and phe- lower-limb spasticity in children with cerebral palsy. Dev Med
nol to manage spasticity in children. Arch Phys Med Rehabil. Child Neurol. 2009;51(6):436–45.
2004;85(7):1121–4. 92. Hastings-Ison T, Blackburn C, Rawicki B, Fahey M, Simpson P,
76. Buizer AI, Martens BHM, van Ravenhorst GC, Schoonmade Baker R, et al. Injection frequency of botulinum toxin A for spas-
LJ, Becher JG, Vermeulen RJ. Effect of continuous intrathecal tic equinus: a randomized clinical trial. Dev Med Child Neurol.
baclofen therapy in children: a systematic review. Dev Med Child 2016;58(7):750–7.
Neurol. 2019;61(2):128–34. 93. Fortuna R, Vaz MA, Youssef AR, Longino D, Herzog W.
77. Vidailhet M, Yelnik J, Lagrange C, Fraix V, Grabli D, Thobois S, Changes in contractile properties of muscles receiving
et al. Bilateral pallidal deep brain stimulation for the treatment of repeat injections of botulinum toxin (Botox). J Biomech.
patients with dystonia-choreoathetosis cerebral palsy: a prospec- 2011;44(1):39–44.
tive pilot study. Lancet Neurol. 2009;8(8):709–17. 94. Minamoto VB, Suzuki KP, Bremner SN, Lieber RL, Ward
78. Khot A, Sloan S, Desai S, Harvey A, Wolfe R, Graham HK. SR. Dramatic changes in muscle contractile and structural
Adductor release and chemodenervation in children with properties after 2 botulinum toxin injections. Muscle Nerve.
cerebral palsy: a pilot study in 16 children. J Child Orthop. 2015;52(4):649–57.
2008;2(4):293–9. 95. Chin TY, Nattrass GR, Selber P, Graham HK. Accuracy of
79. Koman LA, Mooney JF 3rd, Smith BP. Neuromuscular block- intramuscular injection of botulinum toxin A in juvenile cer-
ade in the management of cerebral palsy. J Child Neurol. ebral palsy: a comparison between manual needle placement and
1996;11(Suppl. 1):23–8. placement guided by electrical stimulation. J Pediatr Orthop.
80. Montal M. Botulinum neurotoxin: a marvel of protein design. 2005;25(3):286–91.
Annu Rev Biochem. 2010;79:591–617. 96. Eames NW, Baker R, Hill N, Graham K, Taylor T, Cosgrove
81. Cocco A, Albanese A. Recent developments in clinical trials of A. The effect of botulinum toxin A on gastrocnemius length:
botulinum neurotoxins. Toxicon. 2018;147:77–83. magnitude and duration of response. Dev Med Child Neurol.
82. Simpson DM, Gracies JM, Graham HK, Miyasaki JM, Nau- 1999;41(4):226–32.
mann M, Russman B, et al. Assessment: botulinum neurotoxin 97. Corry IS, Cosgrove AP, Duffy CM, Taylor TC, Graham HK.
for the treatment of spasticity (an evidence-based review): Botulinum toxin A in hamstring spasticity. Gait Posture.
report of the Therapeutics and Technology Assessment Sub- 1999;10(3):206–10.
committee of the American Academy of Neurology. Neurology. 98. Thompson NS, Baker RJ, Cosgrove AP, Corry IS, Graham HK.
2008;70(19):1691–8. Musculoskeletal modelling in determining the effect of botuli-
83. de Paiva A, Meunier FA, Molgo J, Aoki KR, Dolly JO. Func- num toxin on the hamstrings of patients with crouch gait. Dev
tional repair of motor endplates after botulinum neurotoxin type Med Child Neurol. 1998;40(9):622–5.
A poisoning: biphasic switch of synaptic activity between nerve 99. Desloovere K, Molenaers G, Jonkers I, De Cat J, De Borre L,
sprouts and their parent terminals. Proc Natl Acad Sci USA. Nijs J, et al. A randomized study of combined botulinum toxin
1999;96(6):3200–5. type A and casting in the ambulant child with cerebral palsy
84. Koerte IK, Schroeder AS, Fietzek UM, Borggraefe I, Kerscher using objective outcome measures. Eur J Neurol. 2001;8(Suppl.
M, Berweck S, et al. Muscle atrophy beyond the clinical effect 5):75–87.
after a single dose of OnabotulinumtoxinA injected in the pro- 100. Bakheit AMO. Botulinum toxin as a stand-alone treatment for
cerus muscle: a study with magnetic resonance imaging. Derma- muscle spasticity: review of the evidence. J Neurol Disord.
tol Surg. 2013;39(5):761–5. 2013;1(1):109.
85. Schroeder AS, Ertl-Wagner B, Britsch S, Schroder JM, Nikolin S, 101. Boyd RN, Dobson F, Parrott J, Love S, Oates J, Larson A, et al.
Weis J, et al. Muscle biopsy substantiates long-term MRI altera- The effect of botulinum toxin type A and a variable hip abduction
tions one year after a single dose of botulinum toxin injected orthosis on gross motor function: a randomized controlled trial.
into the lateral gastrocnemius muscle of healthy volunteers. Mov Eur J Neurol. 2001;8(Suppl. 5):109–19.
Disord. 2009;24(10):1494–503. 102. Graham HK, Boyd R, Carlin JB, Dobson F, Lowe K, Nattrass
86. Borton DC, Walker K, Pirpiris M, Nattrass GR, Graham HK. G, et al. Does botulinum toxin a combined with bracing pre-
Isolated calf lengthening in cerebral palsy. Outcome analysis of vent hip displacement in children with cerebral palsy and “hips
risk factors. J Bone Jt Surg Br. 2001;83(3):364–70. at risk”? A randomized, controlled trial. J Bone Jt Surg Am.
87. Firth GB, Passmore E, Sangeux M, Thomason P, Rodda J, Don- 2008;90(1):23–33.
ath S, et al. Multilevel surgery for equinus gait in children with 103. Willoughby K, Ang SG, Thomason P, Graham HK. The impact
spastic diplegic cerebral palsy: medium-term follow-up with gait of botulinum toxin A and abduction bracing on long-term hip
analysis. J Bone Jt Surg Am. 2013;95(10):931–8. development in children with cerebral palsy. Dev Med Child
88. Thomason P, Baker R, Dodd K, Taylor N, Selber P, Wolfe R, Neurol. 2012;54(8):743–7.
et al. Single-event multilevel surgery in children with spastic
104. Naidu K, Smith K, Sheedy M, Adair B, Yu X, Graham HK. 116. Van Heest AE, Bagley A, Molitor F, James MA. Tendon transfer
Systemic adverse events following botulinum toxin A ther- surgery in upper-extremity cerebral palsy is more effective than
apy in children with cerebral palsy. Dev Med Child Neurol. botulinum toxin injections or regular, ongoing therapy. J Bone
2010;52(2):139–44. Jt Surg Am. 2015;97(7):529–36.
105. Montastruc J, Marque P, Moulis F, Bourg V, Lambert V, Durrieu 117. Safarpour Y, Jabbari B. Botulinum toxin treatment of pain syn-
G, et al. Adverse drug reactions of botulinum neurotoxin type dromes—an evidence based review. Toxicon. 2018;147:120–8.
A in children with cerebral palsy: a pharmaco-epidemiological 118. Parkinson KN, Gibson L, Dickinson HO, Colver AF. Pain in chil-
study in VigiBase. Dev Med Child Neurol. 2017;59(3):329–34. dren with cerebral palsy: a cross-sectional multicentre European
106. Lundy CT, Doherty GM, Fairhurst CB. Botulinum toxin type study. Acta Paediatr. 2010;99(3):446–51.
A injections can be an effective treatment for pain in children 119. Will E, Magill N, Arnold R, Davies M, Doherty G, Fairhurst
with hip spasms and cerebral palsy. Dev Med Child Neurol. C, et al. Preoperative botulinum neurotoxin A for children with
2009;51(9):705–10. bilateral cerebral palsy undergoing major hip surgery: a rand-
107. Graham HK. Unpublished data. 2019. omized double-blind placebo-controlled trial. Dev Med Child
108. Ostojic K, Paget SP, Morrow AM. Management of pain in chil- Neurol. 2019;. https://doi.org/10.1111/dmcn.14145.
dren and adolescents with cerebral palsy: a systematic review. 120. Crowner BE, Brunstrom JE, Racette BA. Iatrogenic botulism due
Dev Med Child Neurol. 2019;61(3):315–21. to therapeutic botulinum toxin a injection in a pediatric patient.
109. Boyd RN, Morris ME, Graham HK. Management of upper limb Clin Neuropharmacol. 2007;30(5):310–3.
dysfunction in children with cerebral palsy: a systematic review. 121. Roche N, Schnitzler A, Genet FF, Durand MC, Bensmail D.
Eur J Neurol. 2001;8(Suppl. 5):150–66. Undesirable distant effects following botulinum toxin type a
110. Sakzewski L, Ziviani J, Boyd RN. Efficacy of upper limb thera- injection. Clin Neuropharmacol. 2008;31(5):272–80.
pies for unilateral cerebral palsy: a meta-analysis. Pediatrics. 122. O’Flaherty SJ, Janakan V, Morrow AM, Scheinberg AM, Waugh
2014;133(1):e175–204. MC. Adverse events and health status following botulinum toxin
111. Chin TY, Duncan JA, Johnstone BR, Graham HK. Manage- type A injections in children with cerebral palsy. Dev Med Child
ment of the upper limb in cerebral palsy. J Pediatr Orthop B. Neurol. 2011;53(2):125–30.
2005;14(6):389–404. 123. Fortuna R, Horisberger M, Vaz MA, Herzog W. Do skeletal mus-
112. Wallen M, O’Flaherty SJ, Waugh MC. Functional outcomes of cle properties recover following repeat onabotulinum toxin A
intramuscular botulinum toxin type a and occupational therapy injections? J Biomech. 2013;46(14):2426–33.
in the upper limbs of children with cerebral palsy: a randomized 124. Alexander C, Elliott C, Valentine J, Stannage K, Bear N, Don-
controlled trial. Arch Phys Med Rehabil. 2007;88(1):1–10. nelly CJ, et al. Muscle volume alterations after first botuli-
113. Olesch CA, Greaves S, Imms C, Reid SM, Graham HK. Repeat num neurotoxin A treatment in children with cerebral palsy:
botulinum toxin-A injections in the upper limb of children with a 6-month prospective cohort study. Dev Med Child Neurol.
hemiplegia: a randomized controlled trial. Dev Med Child Neu- 2018;60(11):1165–71.
rol. 2010;52(1):79–86. 125. Williams SA, Reid S, Elliott C, Shipman P, Valentine J. Muscle
114. Speth LA, Leffers P, Janssen-Potten YJ, Vles JS. Botulinum toxin volume alterations in spastic muscles immediately following
A and upper limb functional skills in hemiparetic cerebral palsy: botulinum toxin type-A treatment in children with cerebral palsy.
a randomized trial in children receiving intensive therapy. Dev Dev Med Child Neurol. 2013;55(9):813–20.
Med Child Neurol. 2005;47(7):468–73. 126. Schless SH, Cenni F, Bar-On L, Hanssen B, Kalkman B, O’Brien
115. Hoare BJ, Imms C. Upper-limb injections of botulinum toxin-A T, et al. Medial gastrocnemius volume and echo-intensity after
in children with cerebral palsy: a critical review of the literature botulinum neurotoxin A interventions in children with spastic
and clinical implications for occupational therapists. Am J Occup cerebral palsy. Dev Med Child Neurol. 2019;61(7):783–90. https
Ther. 2004;58(4):389–97. ://doi.org/10.1111/dmcn.14056.

Botulinum Toxin in The Management of Children With Cerebral Palsy

Uploaded by

Copyright:

Available Formats

Botulinum Toxin in The Management of Children With Cerebral Palsy

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Botulinum Toxin in The Management of Children With Cerebral Palsy

Uploaded by

Copyright:

Available Formats

Pediatric Drugs (2019) 21:261–281