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REVIEW
PUBLICATION DATA
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 nonambulant 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) participants 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 journals.
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 American 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 indications 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.
The Authors. Developmental Medicine & Child Neurology 2012 Mac Keith Press
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 peerreviewed 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
of this review with information provided in the studies. Relevant data from studies with participants of mixed GMFCS levels 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 neurological 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 available in each database to June 2012 across the following databases: 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 suitability. 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 systematic 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 However, 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 participants (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.20,21,2339
Of the 19 studies, 18 were classified as providing level IV or V
evidence: 15 non-controlled cohort studies,20,21,23,25,26,2932,3439
Figure 1: Inclusion and exclusion of studies found in literature searches. GMFCS, Gross Motor Function Classification System.
306 Developmental Medicine & Child Neurology 2013, 55: 304313
Review
307
Koman
et al.21
Linder
et al.30
V multiple single-participant AB
design
IV non-controlled cohort
study, before and after design
IV cross-sectional study,
before and after design
Jung et al.29
Gooch and
Sandell28
Fragala
et al.27
Coutinho
dos
Santos
et al.25
FattalValeviski
et al.26
I double-blinded RCT
IV non-controlled cohort
study, before and after design
Arens
et al.23
Barwood
et al.24
Cosgrove
et al.20
Aim
Study
Level of evidence
research designa
Population
Hemiplegia (n=3),
diplegia (n=4)
CP type
25 0
27 0
27 0
30
70
26 0
57 0
Range 316y;
mean 7y 14M, 13F
17 1b
26 0
Age range
Mean (SD) sex
15 0
Total
n
drop-outs
IV non-controlled cohort
study, before and after design
IV non-controlled cohort
study, before and after design
IV non-controlled cohort
study, before and after design
IV non-controlled cohort
study, before and after
design
IV non-controlled cohort
study, before and after
design
IV non-controlled cohort
study, before and after
design
IV non-controlled cohort
study, before and after
design
Aim
Effect of BoNT-A on
attainment of treatment goals
Study
Lundy
et al.31
Mall
et al.33
Mall
et al.32
Manzano
et al.34
Meholjic
and
Madjar35
Papavasiliou
et al.36
Vles
et al.37
Weigl
et al.38
Wong39
Population
Quadriplegia (n=26)
CP type
40 0
55 0
17 0
Age range
Mean (SD) sex
57 0
20 0
60
18 0
30
26 0
Total
n
drop-outs
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.
Level of evidence
research designa
Table I: Continued.
a
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;
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
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
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,
level V evidence with weak research rigor.
Fattal-Valevski et al.26
(IV-M) (n=5): NA
Arens et al.23 (IV-W)
(n=1): NA
Fragala et al.27
(V-M) (n=1): NA
Goal attainment
Improved motor function
Ease of care
Improved GMFM or GMFCS levels
Ease of positioning
Hip integrity
Functional changes
Ease of positioning and care, improvements in the GMFCS
level or Gross Motor Function Measure (GMFM) scores, and
various motor functions were arbitrarily grouped under functional changes (Table II). Three studies21,27,28 reported positive results of BoNT-A treatment in increasing ease of
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
statistically significant increase in ease of care in two studies34,37 (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
V showed an improvement in the GMFCS level (n=30 54 in
total) although statistical analysis was either not performed or
performed on a mixed population in these studies (Table SII).
For the GMFM score, statistically significant improvement
was noted in two studies30,32 (n=22 in total) (Tables II and
SII). Participants of six studies20,23,27,33,37,39 showed improvement 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
Pain reduction
Functional changes
Pain reduction
Of the six studies21,28,33,37 investigating the effects of BoNT-A
on pain reduction (Tables II and SII), two24,31 found a statistically significant improvement in the study participants (n=34
in total). Three studies21,28,33 reported positive changes in the
absence of statistical analysis (n=5 in total), and one study37
found a non-significant difference (n=2).
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
Review
309
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 IIII)
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 nonambulant 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 quality, 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 outcomes 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 outcomes (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 postorthopaedic 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 questionnaires 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 measures 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: 304313
preting the results in this review. Future research on the standards 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.
311
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
causal inferences from the study results. Positive changes following BoNT-A intervention were demonstrated in the
majority of participants in terms of pain reduction, maintaining hip integrity, achieving functional changes, and attaining
preset goals. Only one level I RCT showed statistically significant reduction in the postoperative pain for children who had
received BoNT-A injections, which provided moderate evidence 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 indications 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 supplied by the authors. Such materials are peer reviewed and may be re-organized 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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