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DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW

Efficacy of botulinum toxin A in children with cerebral palsy in Gross

Motor Function Classification System levels IV and V: a systematic
review
TAMIS W PIN 1 , 2 | JESSICA ELMASRY 1 , 3 | JENNY LEWIS 1

1 Kids Rehab Department, The Children's Hospital at Westmead, Westmead, NSW; 2 School of Science and Health, The University of Western Sydney, Penrith, NSW;.
3 Faculty of Medicine, University of New South Wales, NSW, Australia.
Correspondence to Dr Tamis Pin, School of Science and Health, The University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia. E-mail: tamispin@hotmail.com

PUBLICATION DATA
Accepted for publication 12th July 2012.
Published online 24th October 2012.
AIM Previous studies have shown the efficacy of botulinum toxin type A (BoNT-A) in the manage-
ment of ambulant individuals with cerebral palsy (CP). There is little evidence on its use in non-
ambulant children with CP. This review aimed to investigate indications and efficacy for BoNT-A
use in managing pain, care, and comfort, and improving function in children with CP in Gross
Motor Function Classification System (GMFCS) levels IV and V.
METHOD Electronic databases were searched from the earliest available date to June 2012 using a
combination of subject headings and free text. Inclusion criteria consisted of studies with (1) par-
ticipants aged 18 or under, (2) participants with CP in GMFCS levels IV and V, (3) participants
receiving BoNT-A treatment, and (4) studies published in English-language peer-reviewed jour-
nals.
RESULTS The search resulted in a total of 814 studies, of which 19 met the inclusion criteria.
Eighteen studies provided level IV or V evidence and one level I evidence according to the Ameri-
can Academy for Cerebral Palsy and Developmental Medicine guidelines for the development of
systematic reviews. Most of the studies were of weak to moderate methodological quality.
INTERPRETATION The evidence that BoNT-A is effective in reducing postoperative pain in children
with CP in GMCFS levels IV and V is limited, with only one level I study identified. Remaining indi-
cations were general pain reduction, maintaining hip integrity, achieving functional changes, and
goal attainment. A high percentage of participants in the studies showed positive changes in these
areas. With the poor level of evidence of the included studies, no definite conclusion could be
drawn on the indications for BoNT-A use in children with CP in GMCFS levels IV and V. Further
investigation by rigorous studies is required.

Cerebral palsy (CP) refers to a group of non-progressive
movement and posture disorders resulting from injuries to the
developing fetal or infant brain.1 Owing to a diverse and multi-
factorial aetiology, CP is often accompanied by epilepsy, sec-
ondary musculoskeletal abnormalities, and deficits in
sensation, cognition, behaviour, and communication.1 The
worldwide incidence of CP is 2 to 3 per 1000 live births, mak-
ing it the most common cause of physical disability in child-
hood.2,3 Classifications of CP are usually based on
topographical distribution, functional motor abilities, and
types of muscle tone.4
Topographical classification describes the distribution of
affected body parts. These include hemiplegia (unilateral dis-
tribution), diplegia (bilateral involvement, usually the lower
limbs more affected than the upper limbs), and quadriplegia
(involvement of all four limbs, the head and trunk).5 This clas-
sification is commonly employed despite being of questionable
reliability and validity.1,6
The Gross Motor Function Classification System
(GMFCS) has been shown to be a reliable method of classify-
ing children with CP according to age-specific gross motor
function.7,8 It is an ordinal grading system of five levels (I–V),
in which self-initiated movements, such as sitting, standing, or
walking, are described in relation to different age groups. Dis-
tinctions between levels I to V are based on assessment of
functional abilities or limitations and reliance on assistive tech-
nology (walking aids or wheeled mobility). Children of levels I
and II can generally walk without aids while children of level
III can walk with aids for short distances but usually choose
wheeled mobility in community settings. Children at level IV
have limited motor ability in assisted standing, stepping, and
transfers. Children classified as level V are completely depen-
dent on others for transportation in a wheelchair and lack
antigravity postural control.7,8
Types of muscle tone are generally classified as spastic,
dystonic ⁄ dyskinetic, ataxic, or mixed.2 Spasticity is a

304 DOI: 10.1111/j.1469-8749.2012.04438.x ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press

velocity-dependent increase in resistance of a muscle when the
muscle is moved passively or stretched.9 It is the most common
motor type, accounting for 70% to 80% of individuals with
CP.10 Individuals with spastic CP experience stiffness in
affected limbs due to focal muscular hyperactivity, resulting in
limited or awkward movements. Dystonia ⁄ dyskinesia, affecting
10% to 20% of individuals with CP,10 is characterized by fluc-
tuating muscle tone, causing slow writhing and twisting move-
ments, repetitive movement, and ⁄ or abnormal postures.9 Ataxic
CP is the least common form of CP, in which individuals have
poor coordination and balance due to low muscle tone.2
Management of spasticity in CP involves multidisciplinary
intervention intended to increase functionality, sustain health,
and improve quality of life for individuals and their carers.11
This may include physiotherapy, occupational therapy, ortho-
ses, surgical interventions, and pharmacological agents such as
botulinum toxins.12 Botulinum toxin type A (BoNT-A) is a
serotype of botulinum toxin, produced by the Gram-positive
bacterium Clostridium botulinum.13 This potent neurotoxin
selectively inhibits the release of acetylcholine from peripheral
nerve terminals by binding to synaptic vesicles.12 Interruption
of neuromuscular conduction by BoNT-A induces a tempo-
rary weakness, which reduces focal spasticity. The effects of
BoNT-A last for approximately 3 months as the muscle will
recover via proximal axonal sprouting, the formation of new
neuromuscular junctions, and the regeneration of the original
neuromuscular junctions.14,15
The efficacy of BoNT-A in the management of individuals
with CP has been widely reported in the literature. Several
studies have proven its effectiveness in the treatment of spastic
equinus in ambulant children with CP (i.e. GMFCS levels
I–III) with the aim of improving gait pattern.16,17 Use of
BoNT-A to improve hand function has also been shown in
children with less impairment.18,19 On the other hand,
BoNT-A has been used in children with severe functional lim-
itations (i.e. GMFCS levels IV and V), aimed at reducing pain
and improving ease in care and positioning.20,21 In our clinical
experience, these are the main goals for the use of BoNT-A in
these more involved children. Nevertheless, the effectiveness
of BoNT-A intervention in this group of children has not
been thoroughly examined. The aim of this review was to
investigate whether BoNT-A has been used to treat children
with CP in GMCFS levels IV and V for pain, care and com-
fort, and motor function, and, if so, to report its efficacy.
METHOD
Inclusion and exclusion criteria
Studies were included in this review if they met the following
criteria: (1) participants were aged 18 years of age or less, (2)
participants were diagnosed with CP equivalent to GMFCS
levels of IV or V, (3) participants were receiving BoNT-A
treatment, (4) the research design was anything other than a
review or expert opinion that did not provide data for analysis,
and (5) studies were published in English-language peer-
reviewed journals. Studies were excluded if participants were
not classified according to their GMFCS level and if it was not
possible to classify the participants accurately by the authors
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What this paper adds
• The majority of studies on the use BoNT-A for children with severe CP in
GMFCS levels IV and V were of poor methodological quality.
• Moderate evidence was shown to support the use of BoNT-A in reducing pain
after hip adductor release surgery with one level I RCT.
• Clinical application of the evidence of benefits of BoNT-A is limited by the low
quality of the studies.
of this review with information provided in the studies. Rele-
vant data from studies with participants of mixed GMFCS lev-
els would be included in this review if the results for
participants in GMCFS levels IV and V could be separated.
The same principle was applied to studies containing a mixed
group of participants with a diagnosis of CP and other neuro-
logical disorders. All studies involving the use of BoNT-A to
treat drooling were excluded, as the main focus of this review
was on the impact of BoNT-A on reducing pain, improving
ease of care and positioning, and improving the motor
function of the individuals.
Search strategy
The literature search was begun from the earliest date avail-
able in each database to June 2012 across the following data-
bases: MEDLINE, EMBASE, CINAHL, and PsycINFO.
The terms ‘cerebral palsy’, ‘spasticity’, ‘dystonia’, ‘Botulinum
toxin A’, ‘Botox’, ‘BTX’, ‘BTA’, ‘BoNT’, ‘Dysport’, and
‘Myobloc’ were searched as subject headings and free text if
supported by the databases. Results were limited to studies
involving humans aged 18 years or less and published in the
English language. The reference lists of relevant studies and
reviews were also searched for citation tracking and by hand.
The titles and abstracts of articles identified in the initial
search were screened against inclusion and exclusion criteria
separately by the first two authors (TP and JE). When in
doubt, the full text of an article was read to determine its suit-
ability. Any disagreement between the two authors was
resolved by consensus. No authors of excluded studies were
approached to investigate if relevant data could be extracted.
Levels of evidence and quality assessment
The level of evidence of each included study was graded
according to the American Academy for Cerebral Palsy and
Developmental Medicine Treatment Outcome Committee
(AACPDM TOC) guidelines for the development of system-
atic reviews.22 In general, the higher the level of the study, the
more likely the intervention of interest was responsible for the
outcomes.
Studies were also given a quality assessment score based on
the scoring system of the AACPDM TOC guidelines.22 These
scores were used to grade each study as ‘strong’, ‘moderate’,
or ‘weak’ according to the methodological rigour of the study.
The AACPDM TOC does not recommend the use of this
quality assessment system for levels IV and V studies.22 How-
ever, preliminary screening of this review showed that the
majority of studies conducted under the topic of interest had
less rigorous research designs and hence, it was decided that
included studies were critically reviewed and scored as a means
of informing future studies.
Review 305

RESULTS
Of the 814 studies identified in our electronic database
search, 68 met the inclusion criteria (Fig. 1). Full-text analysis
of these 68 articles led to the exclusion of a further 49 articles
for the following reasons: (1) study population was non-CP
or mixed (CP and non-CP) and data for participants with CP
could not be separated; (2) results for participants in GMCFS
levels IV and V could not be isolated from a group analysis;
or (3) participants were not classified according to GMFCS
but according to topographical classification and there was
inadequate information for the authors to reclassify the par-
ticipants (Table SI, online supporting information). Hence,
19 studies investigating the use of BoNT-A in children with
CP in GMCFS levels IV and V were included in this
review.20,21,23–39
Of the 19 studies, 18 were classified as providing level IV or V
evidence: 15 non-controlled cohort studies,20,21,23,25,26,29–32,34–39
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two case studies,28,33 and one single-subject design study.27
Only one study, a double-blinded randomized controlled trial
(RCT), provided level I evidence.24 Quality assessment of the
level IV and V studies of showed weak to moderate methodo-
logical rigour, whereas the level I RCT was a rigorous study
(see Tables SII–SIV, online supporting information).
Table I summarizes the purpose, study design, and demo-
graphics of the 19 included studies. Study purposes were var-
ied, and included investigating the effects of BoNT-A on pain
reduction, maintaining hip integrity, functional changes to
attainment of preset goals. Two32,34 of the 19 studies recruited
participants over 18 years and their data were excluded in the
statistical analysis carried out for this review. Only two stud-
ies24,31 investigated the use of BoNT-A solely in children clas-
sified as GMFCS levels IV and V. Nine studies25,27,29,30,32,35–38
consisted of participants with mixed GMFCS levels and
the data for participants in levels IV and V were separated for

1799 records identified through

database searching

814 records after duplicates 746 records excluded

removed

68 full-text articles assessed for 49 full-text articles excluded,

eligibility reasons provided below

Non CP or could not separate

19 studies included in review CP from other disorders (5
studies)

Results for participants in

GMFCS levels IV and V could
not be isolated from a group
analysis (16 studies)

Participants were not classified

according to GMFCS (but by
topography) and there was
inadequate information for the
authors to classify the
participants (28 studies)

Figure 1: Inclusion and exclusion of studies found in literature searches. GMFCS, Gross Motor Function Classification System.

306 Developmental Medicine & Child Neurology 2013, 55: 304–313

 Table I: Purpose, design, and demographics of 19 included studies

Total
Level of evidence ⁄ n⁄ Age range
Study Aim research designa Population CP type drop-outs Mean (SD) ⁄ sex

Arens Effect of BoNT-A on dynamic IV ⁄ non-controlled cohort Group 1, spastic (n=5); group 2, Hemiplegia (n=5), diplegia (n=5), 15 ⁄ 0 Range 5–17y; mean 10y
et al.23 spasticity and dystonic study, before and after design dystonic (n=5), group 3, mixed quadriplegia (n=5) 10mo
posturing spastic and dystonic (n=5)
Barwood Effect of BoNT-A on post I ⁄ double-blinded RCT Severe spastic CP with ‘hips at Diplegia (n=3), quadriplegia 17 ⁄ 1b Range 2–10y; mean
et al.24 operative pain risk’; GMFCS IV (n=4) or V (n=12) (n=13) 4y 3mo (1y 3mo) ⁄ 6M, 10F
Cosgrove Indications, safety procedures, IV ⁄ non-controlled cohort study, Community ambulators (n=7), Hemiplegia (n=8), diplegia 26 ⁄ 0 Range 2–17y; mean
et al.20 and effects of BoNT-A before and after design i.e. GMFCS I ⁄ II;c functional (n=7), quadriplegia (n=11) 6y ⁄ 19M, 7F
ambulators (n=8), i.e. GMFCS
II ⁄ III;c non-functional ambulators
(n=8), i.e. GMFCS III or IV;c
non-ambulators (n=3), i.e.
GMFCS IV or Vc
Coutinho Effect of BoNT-A on quality of life IV ⁄ cross-sectional study, GMFCS I (n=7), II (n=18), III Spastic hemiplegia (n=21), 57 ⁄ 0 Mean 6y (2y 4mo) ⁄ 34M, 23F
dos before and after design (n=6), IV (n=13), V (n=13) spastic diplegia (n=14), spastic
Santos quadriplegia (n=10),
et al.25 others (n=12)
Fattal- Markers for a favourable IV ⁄ non-controlled cohort Independent walkers (n=12), i.e. Hemiplegia (n=7), spastic 26 ⁄ 0 Range 2–5y; mean 3y 7mo
Valeviski outcome with BoNT-A study, before and after design GMFCS I or II;c walkers with diplegia (n=19) (1y 2mo) ⁄ 16M, 10F
et al.26 aids (n= 9), i.e. GMFCS III;c
non-walkers (n=5),
i.e. GMFCS IV or Vc
Fragala Effect of BoNT-A on impairment, V ⁄ multiple single-participant AB CP with lower extremity Hemiplegia (n=3), 7⁄0 Range 3–11y ⁄ 6M, 1F
et al.27 disability, and parent design spasticity, GMFCS I (n=3), II diplegia (n=4)
satisfaction (n=2), III (n=1), IV (n=1)
Gooch and Effect of BoNT-A on spasticity V ⁄ case study, before and Severe athetoid, dependent in Quadriplegia (n=1), hemiplegia 3⁄0 Ages 17y, 11y, 3y ⁄ 2M, 1F
Sandell28 and athetosis after design all cares (n=1), i.e. GMFCS IV (n=1), athetosis (n=1)
or V;c spastic quadriplegia in
wheelchair (n=1), i.e. GMFCS IV
or V;c spastic hemiplegia
ambulant (n=1), i.e. GMFCS I–IIIc
Jung et al.29 Effect of BoNT-A on hip IV ⁄ non-controlled cohort study, Bilateral spastic CP with bilateral Bilateral spastic (n=26), 27 ⁄ 0 Range 2–10y; mean 5y 2mo
lateralization before and after design adductor spasticity, GMFCS I dyskinetic (n=1) (1y 11mo) ⁄ 18M, 9F
(n=1), II (n=3), III (n=3), IV
(n=12), V (n=8)
Koman Efficacy of BoNT-A on the IV ⁄ non-controlled cohort study, Group 1, non-ambulatory severe Hemiplegia (n=8), diplegia 27 ⁄ 0 Range 3–16y;
et al.21 management of muscle before and after design spastic and mixed quadriparesis (n=9), quadriplegia (n=8), mean 7y ⁄ 14M, 13F
imbalance in paediatric CP (n=3), i.e. GMFCS IV or V;c quadriplegia with
group 2, severe spasticity in athetosis (n=2)
lower limbs affecting
positioning and hygiene
(n=8), i.e. GMFCS IV or V;c
group 3, ambulatory (n=16),
i.e. GMFCS I–IIIc
Linder Medium-term (1y) efficacy of IV ⁄ non-controlled cohort study, Spastic CP, GMFCS I (n=5), Hemiplegia (n=4), diplegia 25 ⁄ 0 Range 1y 6m–15y 6m;
et al.30 BoNT-A on gross motor before and after design II (n=5), III (n=4), IV (n=7), V (n=12), quadriplegia (n=9) mean 6y 2mo; 15M, 10F
function (n=4)

Review
307
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 Table I: Continued.

Total
Level of evidence ⁄ n⁄ Age range
Study Aim research designa Population CP type drop-outs Mean (SD) ⁄ sex

Lundy Effect of BoNT-A on pain IV ⁄ non-controlled cohort study, CP with spasticity and pain at hip Quadriplegia (n=26) 26 ⁄ 0 Range 2–19y; mean 11y 6mo
et al.31 due to hip spasms before and after design level; GMFCS V (n=26) (4y 9mo); 12M, 14F
Mall Effect of BoNT-A on disability V ⁄ case study, before and Participant 1 – severe spastic Diplegia (n=1), tetraparesis 3⁄0 Participant 1 M, 13y; participant
et al.33 and QOL after design tetraparesis i.e. GMFCS IV or V;c (n=2) 2 F, 16y; participant 3 M, 15y
participant 2 – spastic tetraparesis
with hand contracture, unknown
GMFCS;d participant
3 – ambulant spastic diplegia i.e.
GMFCS II–IIIc

308 Developmental Medicine & Child Neurology 2013, 55: 304–313

Mall Effect of BoNT-A on gross IV ⁄ non-controlled cohort CP with adductor spasm, GMFCS II Diplegia (n=4), quadriplegia 18 ⁄ 0 Range 5y 6m–21y 1mo;e mean
et al.32 motor function study, before and after design (n=2), III (n=5), IV (n=7), V (n=4) (n=14) 10y 7mo (4y 1mo) ⁄ 2M, 16F
Manzano Safety and effect of BoNT-A on IV ⁄ non-controlled cohort CP with spasticity of masticatory Quadriplegia (n=6) 6⁄0 Range 5–20ye; mean 9y 9mo ⁄
et al.34 spastic masticatory musculature study, before and after design musculature, GMFCS IV ⁄ V (n=6)c 1M, 5F
Meholjic Effect of BoNT-A on spasticity IV ⁄ non-controlled cohort CP with spasticity in lower limbs, Diplegia (n=7), hemiplegia 20 ⁄ 0 Range 2–15y; mean 5y 9mo
and and functional progress study, before and after design GMFCS II (n=4), III (n=3), IV (n=2), quadriplegia (n=10), (3y 7mo) ⁄ 11M, 9F
Madjar35 (n=10), V (n=3) triplegia (n=1)
Papavasiliou Effect of BoNT-A on multimodal IV ⁄ non-controlled cohort Preterm born children with spastic Hemiplegia (n=4), diplegia 57 ⁄ 0 Range 2y 6m–13y 6mo; mean
et al.36 spasticity management study, before and after CP, GMFCS I (n=13), II (n=9), III (n=26), quadriplegia (n=27) 4y 4mo ⁄ 31M, 26F
design (n=16), IV (n=15), V (n=4)
Vles Effect of BoNT-A on visual IV ⁄ non-controlled cohort GMFCS I (n=16), II (n=9), III Unilateral (n=13), bilateral 55 ⁄ 0 Range 3–18y; mean 8y 3mo
et al.37 analogue scale score study, before and after (n=15), IV (n=7), V (n=8) (n=42) (3y 3mo) ⁄ 25M, 30F
design
Weigl Effect of BoNT-A on IV ⁄ non-controlled cohort Spastic CP, GMFCS I (n=13), II Diplegia (n=16), hemiplegia 40 ⁄ 0 Range 1y 6mo–16y; mean
et al.38 attainment of treatment goals study, before and after (n=11), III (n=3), IV (n=6), V (n=15), quadriplegia (n=9) 5y ⁄ 21M, 19F
design (n=7)
Wong39 Effect of BoNT-A on daily care IV ⁄ non-controlled cohort Spastic CP; community Diplegia (n=8), triplegia 17 ⁄ 0 Range 2–15y; mean 5y; 9M, 8F
and ⁄ or functional mobility study, before and after ambulators (n=1), i.e. GMFCS (n=1), quadriplegia (n=8)
design I ⁄ II;c functional ambulators
(n=4), i.e. GMFCS II ⁄ III;c
non-functional ambulators
(n=6), i.e. GMFCS III or IV;c
non-ambulators (n=6), i.e.
GMFCS IV or Vc

a
Grading of evidence according to levels of evidence proposed by the American Academy for Cerebral Palsy and Developmental Medicine methodology for developing systematic reviews of
treatment interventions (Revision 1.2), 2008.22 bEight participants in each intervention and control group. cGross Motor Function Classification System (GMFCS) level classified by the authors
according to the information provided in the paper. dInadequate information provided in the paper to allow classification according to GMFCS. eParticipants over 18 years of age were excluded from
analysis in this review. CP, cerebral palsy; BoNT, botulinum toxin; RCT, randomized controlled trial; M, male; F, female; y, years; mo, months.

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 14698749, 2013, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04438.x by Readcube-Labtiva, Wiley Online Library on [26/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
analysis in this review. In the remaining eight

participants who had a positive result as the nominator and total number of participants in that study as the denominator; SS, statistically significant difference; IV-M, level IV evidence with moderate
Fattal-Valevski et al.26

Fragala et al.27 (V-M)

Lundy et al.31 (IV-M)

Weigl et al.38 (IV-M)

studies,20,21,23,26,28,33,34,39 the study participants were classified

In this study, improvement in Visual Analogue Scale standing score for nine participants and in Visual Analogue Scale walking score for five participants. GMFM, Gross Motor Function Measure;
(IV-M) (n=5): NA

research rigor; NS, no statistically significant difference; V-M, level V evidence with moderate research rigor; NA, not statistically analysed; IV-W, level IV evidence with weak research rigor; V-W,
Goal attainment
according to the GMFCS using the information provided in
the papers.

(n=26): NA

(n=13): NS
(n=1): NA

GMFCS, Gross Motor Function Classification System; I-S, level I evidence with strong research rigor; n, the number of participants with a positive result. In case of a fraction, n, number of
Table SII shows the outcome measures and results of the
included studies. In five studies with participants of mixed
GMFCS levels,29,30,32,34,37 separate statistical analyses were
performed in this review for participants with levels IV and V

Improved motor function

only, using a paired t-test for continuous data and Wilcoxon

Cosgrove et al.20 (IV-M)

Fragala et al.27 (IV-M)

signed-rank test for nominal data (on those outcome measures

Arens et al.23 (IV-W)

Vles et al.37 (IV-W)

Mall et al.33 (V-W)
used before and after the BoNT-A intervention). In eight

Wong39 (IV-M)
studies, descriptive outcome measures were used and no statis-

(n=3 ⁄ 6): NA
(n=14):a SS
(n=1): NA

(n=3): NA

(n=1): NA

(n=1): NA
tical analysis was applied (Table SII). The main outcomes of
interest in these 19 studies could be grouped under pain
reduction, hip integrity, functional changes, and goal attain-
ment. Table II regroups, under these four main outcomes of

Table II: Summary of 19 included studies showing positive results under the four main outcomes of interest for participants with GMFCS levels IV and V only

Gooch and Sandell28

interest, participants in the included studies who were

Vles et al.37 (IV-W)

GMFCS levels IV and V and who showed a positive effect

(IV-W) (n=5): SS
(V-W) (n=2): NA

(V-W) (n=1): NA
(V-M) (n=1): NA

Manzano et al.34
Fragala et al.27
from the intervention. Reduction in muscle tone and improve-

Ease of care

Mall et al.33

(n=13):SS
ments in ranges of motion were also shown in several studies
(Table SII).20,25–28,30,32–34,36,39

Functional changes
Pain reduction
Of the six studies21,28,33,37 investigating the effects of BoNT-A

Improved GMFM or GMFCS levels

on pain reduction (Tables II and SII), two24,31 found a statisti-

Linder et al.30 (IV-W) (n=11): SS

Meholjic and Madjar35 (IV-W)

Mall et al.32 (IV-M) (n=11): SS
Coutinho dos Santos et al.25
cally significant improvement in the study participants (n=34

Papavasiliou et al.36 (IV-M)

in total). Three studies21,28,33 reported positive changes in the
(IV-W) (n=13 ⁄ 26): NA
absence of statistical analysis (n=5 in total), and one study37
found a non-significant difference (n=2). but SS as a group

(n=12 ⁄ 13): NA

(n=5 ⁄ 15): NA
Maintaining hip integrity
Only one study29 investigated the effect of BoNT-A on hip
integrity (Tables II and SII). The results showed a non-signifi-
cant difference in hip migration percentage over a 2-year per-
iod (n=27).
Koman et al.21 (IV-M)
Gooch and Sandell28
Fragala et al.27 (V-M)
Ease of positioning

(V-W) (n=1): NA

Functional changes
Ease of positioning and care, improvements in the GMFCS
(n=1): NA

(n=8): NA

level or Gross Motor Function Measure (GMFM) scores, and

various motor functions were arbitrarily grouped under func-
tional changes (Table II). Three studies21,27,28 reported posi-
tive results of BoNT-A treatment in increasing ease of
(IV-M) (n=27): NS

positioning but with no statistical analysis of the results (n=10

in total; Tables II and SII). BoNT-A was shown to result in a
Hip integrity

Jung et al.29

statistically significant increase in ease of care in two stud-

level V evidence with weak research rigor.

ies34,37 (n=18 in total) and also in another three studies27,28,33

without any statistical analysis (n=4 in total; Tables II and SII).
In three studies,25,35,36 participants in GMCFS levels IV and
Koman et al.21 (IV-M) (n=3): NA

Lundy et al.31 (IV-M) (n=26): SS

V showed an improvement in the GMFCS level (n=30 ⁄ 54 in

Vles et al.37 (IV-W) (n=2):NS
Mall et al.33 (V-W) (n=1):NA

total) although statistical analysis was either not performed or

performed on a mixed population in these studies (Table SII).
Gooch and Sandell28

For the GMFM score, statistically significant improvement

(V-W) (n=1): NA

was noted in two studies30,32 (n=22 in total) (Tables II and

Barwood et al.24
(I-S) (n=8): SS
Pain reduction

SII). Participants of six studies20,23,27,33,37,39 showed improve-

ment in various motor functions. The study by Vles et al.37
demonstrated statistically significant improvement in standing
and walking (n=14) and the other five studies showed positive
a

Review 309

improvements, including transfers and ambulation, without
conducting statistical analyses on the data20,23,27,33,39 (n=9 in
total; Tables II and SII).
Goal attainment
Four studies26,27,31,38 investigated the efficacy of BoNT-A on
the attainment of preset goals by the participants and ⁄ or their
carers (Tables II and SII). Three studies26,27,31 noted positive
results using descriptive measures (n=32 in total) and one
study38 showed non-statistically significant changes using a
modified goal attainment scale (n=13).
DISCUSSION
BoNT-A has been closely scrutinized for its effectiveness in
treating ambulant children with CP (i.e. GMFCS levels I–III)
with the aim of improving their gait pattern.16,17 Clinically,
this intervention has also been used for pain reduction and
improvement in positioning or ease of hygiene40 in non-
ambulant children with CP (i.e. GMFCS levels IV and V);
however, its effectiveness has not been thoroughly reviewed.
This review was carried out attempting to fill in the gap in
existing knowledge. We found 19 studies that examined the
use of BoNT-A in children with CP in GMFCS levels IV and
V for pain reduction, better positioning, ease of hygiene, and
better motor function. As almost all of these studies had low
levels of evidence and low to moderate methodological qual-
ity, except the RCT by Barwood et al.,24 caution is advised
when interpreting the results of this review. Over two-thirds
of the included studies demonstrated that the use of BoNT-A
reduced spasticity and increased range of movements in the
related joints at the impairment level with or without statistical
analyses (Table SII). These are believed to be known out-
comes based on the mechanism of BoNT-A at neuromuscular
junctions.12,14,15 Pain reduction and maintaining hip integrity
are less frequently reported outcomes at this level. At the level
of function and activity, it appears that after the BoNT-A
injections positive results were demonstrated in terms of
achieving functional changes and attaining goals. These out-
comes (i.e. pain reduction, maintaining hip integrity, achieving
functional changes, and attaining preset goals) are the main
focus of this review.
Several studies were found to investigate if BoNT-A was
effective in reducing general pain as well as specific post-
orthopaedic surgery pain in children classified as GMFCS
levels IV and V. Outcome measures used to assess pain varied
among the studies. Descriptive measures were used in three
studies,21,28,33 while Lundy et al.31 used both objective ques-
tionnaires and subjective parent description to assess the pain
reduction post intervention. In these studies, the majority of
participants demonstrated positive changes (Tables II and
SII). In their RCT, Barwood et al.24 used three outcome mea-
sures – amount of analgesia required, pain score, and hospital
admission time – and found a statistically significant reduction
in all these outcome measures in the treatment group
(Table SII). With its strong methodological quality, this study
provided good evidence to show that BoNT-A is effective in
reducing post-operative pain in children in GMCFS levels IV
310 Developmental Medicine & Child Neurology 2013, 55: 304–313
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and V, but the clinical application of this evidence may be
limited by the lack of further high-quality RCTs to support
this outcome. In the study by Vles et al.,37 pain, as assessed by
Visual Analogue Scale scores, was reduced non-significantly
after the BoNT-A injections (Tables II and SII). This result
may have been insignificant because of the very small number
of participants who were assessed (2 ⁄ 55 participants in the
study). This review has found moderate evidence to support
the use of BoNT-A for pain reduction in children undergoing
hip adductor release surgery and weak to moderate evidence
for its use in the reduction of spasticity-related pain.
Among children with severe CP, spastic hip disease is a com-
mon problem, putting their hips at ‘high risk’ of disloca-
tion.41,42 It has also been shown that hip lateralization occurs
in as many as 90% of children in GMFCS level V.43 Only one
study29 we found investigated the effects of BoNT-A on main-
tenance of hip integrity, using the migration percentage as an
outcome measure (Tables II and SII). The authors of this study
found that the mean changes in the migration percentage were
of no clinical significance (<10%) over a 2-y period, indicating
that the BoNT-A assisted in maintaining hip stability. Owing
to the low level of evidence, moderate methodological rigour,
and lack of a control group in this study (Table SII), it is not
possible to conclude that BoNT-A had real impact on hip
integrity for these participants. Indeed, another RCT with a
high level of evidence has shown that children with hip adduc-
tor spasticity would require surgery for hip integrity in the
long term.44 While it appears that hip integrity may be a possi-
ble indication for the use of BoNT-A in children in GMCFS
levels IV and V, existing evidence in this area is weak. Studies
with rigorous study designs are needed to verify this possible
indication for the use of BoNT-A in maintaining hip status for
children in GMCFS levels IV and V.
Fourteen studies found positive results of BoNT-A treat-
ment on ease of positioning and care, improvements in
GMFM scores or GMFCS levels, and motor function, such as
transfer and assisted ambulation (Tables II and SII). In all
studies in which statistical analyses were performed, statistical
significance was achieved,25,30,32,34,37 whereas those studies
using descriptive measures reported marked improvement in
gross motor function, standing, walking, ambulatory status,
transfer, positioning, and ease of care20,21,23,27,28,33,35,36,39
(Table SII). Three studies25,35,36 used the GMFCS level to
document changes in the gross motor function of the partici-
pants. Over half of the participants in these studies showed
improvement in the GMFCS level post BoNT-A injections
(Tables II and SII). GMFCS levels have been shown to be sta-
ble with time in older children and adolescents with CP, but
not in children under 6 years of age.45,46 The study partici-
pants in these three studies25,35,36 were relatively young (mean
age 6, 5.7, and 4.4y, respectively) (Table I), which might
explain the large improvement in their gross motor function
after BoNT-A intervention. In fact, the GMFCS is a classifica-
tion of motor abilities of individuals with CP, not a functional
assessment, and hence more robust outcome measures, such as
the GMFM or the Pediatric Evaluative of Disability Inven-
tory,47 should be used to document changes in motor function

after the use of BoNT-A. Despite positive results in this
domain after the BoNT-A intervention, all studies investigat-
ing functional mobility provided low levels of evidence and
were of weak to moderate methodological vigour. It remains
unclear whether targeting functional changes is an appropriate
indication for the use of BoNT-A in children in GMCFS
levels IV and V who have severe functional limitations.
Three of the four studies26,27,31 examining the use of
BoNT-A to attain present goals showed positive results in all
study participants using subjective assessments by the par-
ent ⁄ carer (Tables II and SII). The study by Weigl et al.38
found the changes in attaining present goals were not statisti-
cally significant (Tables II and SII). A possible explanation for
this negative outcome may be that a modified goal attainment
scale was used to measure how the goals were achieved post
BoNT-A injections, in which the grades of the modified scale
were not individualized to the study participants (Table SII).
This modification may have reduced the sensitivity of this out-
come measure. Positive results to achieve preset goals were
demonstrated by various studies of low levels of evidence and
moderate methodological quality. This highlights the need for
more rigorous studies to establish the efficacy of the use
of BoNT-A in achieving goals set by the individuals and their
carers.
Although the main goals of using BoNT-A in this popula-
tion group were to reduce pain and improve care and comfort,
only one study25 formally assessed the health-related quality of
life of the children and ⁄ or their carers, and another study31
reported positive comments from the parents’ questionnaires
when assessing functional gains of the children post interven-
tion (Table SII). Pain reduction and improvement in position-
ing and ease in caring activities do not necessarily lead to
improvement in the health-related quality of life of children
and ⁄ or their carers. This highlights another area of the use of
the BoNT-A in children in GMCFS levels IV and V requiring
further research.
The efficacy of the BoNT-A in children with CP is dose
dependent and varies with time intervals between injections.48
All except two included studies35,36 explicitly stated the injec-
tion dose and total dose used in the participants (Table SII).
Two studies did not state which preparation of BoNT-A was
used.21,27 The injection dose varied from 2 to 15U ⁄ kg using
Botox (Allergan, Irvine, CA, USA) or from 5 to 150U ⁄ kg
using Dysport (Ipsen, Basking Ridge, NJ, USA); the total dose
varied from 100 to 500U of Botox or 100 to 1500U of Dy-
sport (Table SII). The dose of BoNT-A used in all except two
studies32,37 was within the recommended limits suggested in
the recent international consensus statement.19 The two stud-
ies that used a high dose of BoNT-A were those by Mall
et al.32 and Vles et al.;37 interestingly, both studies yielded sta-
tistically significant results in participants post intervention
(Table SII). The follow-up periods varied from a few days to
12 months (Table SII). Moreover, the age of the study partici-
pants ranged from 2 to 17 years at the time of injections
(Table I). All these variations may have important implications
when assessing the effectiveness of BoNT-A. Readers are
urged to take these variations into consideration when inter-
14698749, 2013, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04438.x by Readcube-Labtiva, Wiley Online Library on [26/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
preting the results in this review. Future research on the stan-
dards of administration of BoNT-A, such as optimal dosage
and optimal injection intervals, and identification of which
subgroup of children in GMCFS levels IV and V would be
likely to benefit the most from BoNT-A, and in what way and
at what age, is needed.40
One may argue that studies on children in GMFCS level III
should be included in this review as these children are more
vulnerable to secondary musculoskeletal abnormalities and
pain because of their relatively more limited motor abilities
compared with children in GMCFS levels I and II. However,
the goal of the use of BoNT-A in children in GMFCS level
III is predominantly to improve ambulation,48 which is very
different from the goals of this intervention in non-ambulant
children in GMCFS levels IV and V. Hence, this review
focused on studies of children in the latter group.
It appears that, other than to reduce post-operative pain
due to hip adductor release surgery, the benefits of the use of
BoNT-A for this group of children remain uncertain. In our
recent retrospective file audit (unpublished material), about
25% of the total number of clients who received BoNT-A in
our clinic in 2010 were diagnosed with CP in GMCFS levels
IV and V. Over 80% of the parents or carers reported that this
intervention greatly reduced their burden of care in terms of
improving ease of personal hygiene, dressing, and positioning.
While rigorous research studies, as well as sensitive outcome
measures, are urged to investigate the indications for the use
of BoNT-A in this group of children, we believe that there is a
strong clinical role for this intervention in the management of
children in GMCFS levels IV and V.
Limitations of this review and future research
A large number of studies have investigated the effect of
BoNT-A on a population of children with CP of mixed levels
of severity. In the majority of these studies, we were unable to
separate data on children in GMCFS levels IV and V, or to
classify the study participants according to GMFCS level
(Fig. 1 and Table SI). Since relevant information about study
participants in GMCFS levels IV and V in these studies was
not included, this review may not show a complete picture of
clinical indications for the use of BoNT-A in this population
group, which may have imposed a selection bias in this review.
However, we are confident with what we believe to be a thor-
ough literature search and careful classification of study partic-
ipants according to the GMFCS levels with the information
provided in the papers, and that we have included the majority
of, if not all, relevant studies that examined the effect of
BoNT-A in this population group. Another limitation of this
review is that screening of studies in the initial literature search
and quality grading of studies were not performed indepen-
dently. We were unable to access one article49 found in the
initial literature search owing to the rarity of the publication.
However, from the information provided in the abstract of
that paper, it is believed that inclusion of this study would not
significantly modify the conclusions of this review.
There are several challenges in conducting high level of
evidence research studies on the use of BoNT-A in children
Review 311

in GMCFS levels IV and V. Maintaining blinding in the
intervention group is not possible as changes in spasticity are
often conspicuous. Nowadays, use of BoNT-A is almost part
of standardized intervention regime for children with
CP.8,19,50 It appears to be unethical to have a control group
without intervention because of the known benefits of BoNT-
A in treating muscle spasticity. It is also difficult to justify hav-
ing to subject children in the control group to an injection
procedure for a sham placebo. Moreover, finding a suitable
control group that is comparable in terms of co-interventions
and comorbidities is a challenge in a disorder as varied as CP,
especially in a population of children in GMCFS levels IV and
V who usually have complex medical needs. Hence, large and
expensive RCTs may not be appropriate when investigating
the indications for the use of BoNT-A in this population
group. Alternative research designs such as high-quality longi-
tudinal population-based studies or multiple single-participant
study designs with sensitive outcome measures may be more
viable options for future research studies in this area.
CONCLUSION
Nineteen studies were included in this review examining the
efficacy of BoNT-A in terms of ease of pain, care and comfort,
and improvement in motor abilities in children with CP in
GMFCS levels IV and V. Almost all of the included studies
provided level IV or V evidence and were of poor to moderate
methodological rigour. Caution is required when drawing
14698749, 2013, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04438.x by Readcube-Labtiva, Wiley Online Library on [26/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
causal inferences from the study results. Positive changes fol-
lowing BoNT-A intervention were demonstrated in the
majority of participants in terms of pain reduction, maintain-
ing hip integrity, achieving functional changes, and attaining
preset goals. Only one level I RCT showed statistically signifi-
cant reduction in the postoperative pain for children who had
received BoNT-A injections, which provided moderate evi-
dence for this intervention in reducing pain after orthopaedic
surgery. For the remaining outcomes of interest, the efficacy
of BoNT-A was inconclusive. Future studies of rigorous
methodological quality are required to investigate the indica-
tions for the use of BoNT-A in children in GMFCS levels IV
and V.
SUPPORTING INFORMATION
The following additional material may be found online.
Table SI: Excluded studies and reasons for exclusion.
Table SII: Summary of study methods, outcome measure,s and results of
19 included studies.
Table SIII: Quality conduct of the 18 group studies
Table SIV: Quality conduct of the single-participant design study.
Please note: This journal provides supporting online information sup-
plied by the authors. Such materials are peer reviewed and may be re-orga-
nized for online delivery, but may not be copy-edited or typeset.
Technical support issues or other queries (other than missing files) should
be addressed to the authors.

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