Lukban Rosales Effectiveness in CP 2009

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BASIC NEUROSCIENCES, GENETICS AND IMMUNOLOGY - REVIEW ARTICLE
Effectiveness of botulinum toxin A for upper and lower limb
spasticity in children with cerebral palsy: a summary of evidence
Marissa Barlaan Lukban Æ Raymond L. Rosales Æ
Dirk Dressler
Received: 14 September 2008 / Accepted: 11 December 2008
� Springer-Verlag 2009
Abstract Botulinum toxin type A (BoNT-A) therapy has
gained wide acceptance in the management of spasticity in
cerebral palsy (CP). Clinical experience from numerous case
reports and series, retrospective and prospective open label
cohort studies, and randomized controlled trials (RCT) has
grown over the past 10 years. Several independent system-
atic reviews on the role of BoNT-A for upper and lower limb
spasticity have been written by various authors. The objec-
tive of this paper is to summarize past systematic reviews and
recent RCT not yet included in the systematic reviews that
assess the effectiveness of BoNT-A in upper and lower limb
spasticity in children with CP. We reviewed four Class II
RCT discussed in five independent systematic reviews and
two new Class II trials on the use of BoNT-A alone or with
occupational therapy compared to placebo or occupational
therapy alone in children with upper limb spasticity. There
were 229 children recruited in these six trials and of those,
115 children receivedBoNT-A in the upper limbs. Five of six
RCT showed a time limited decrease in muscle tone most
especially at the wrist. Four of six trials showed improve-
ment of hand function on a few specific functional tests. Four
systematic reviews concluded that there is insufficient and
inconsistent evidence to support or refute the effectiveness of
BoNT-A in upper limb spasticity but one recent review
recommended that BoNT-A should be considered as a
treatment option in upper limb spasticity. For lower limb
spasticity, we reviewed 13 RCT discussed in six systematic
reviews and two new trials comparing BoNT-Awith placebo
or other rehabilitation modalities such as physiotherapy,
occupational therapy, casting or electrical stimulation. In
these studies, 617 children were recruited and of those, 360
children receivedBoNT-A in the lower limbs. Therewere six
Class I and nine Class II trials. Three Class I trials docu-
mented significant improvement in gait pattern in children
with gastrocnemius spasticity and one Class I study showed
significant reduction in tone in the hip adductors. The most
recent review establishes BoNT-A as an effective treatment
for equinovarus deformity. Adverse events in these trials
were mild and self-limited. The most common complaints
were pain in the injection sites and transient weakness.
BoNT-A is considered safe for use in children. In conclusion,
there is now growing convincing evidence for the time
limited beneficial effect of BoNT-A in decreasing muscle
tone in children with upper and lower limbs spasticity
associated with CP. Decrease muscle tone in the lower limbs
translates to improved gait in CP children with spastic
equinovarus however more systematic studies are necessary
to show sufficient evidence for improved hand function from
BoNT-A injection in the upper limbs.
Keywords Botulinum toxin � Spasticity � Cerebral palsy �
Review
Introduction
Cerebral palsy (CP) is a static encephalopathy character-
ized by aberrant control of movement or posture
M. B. Lukban (&)
Departments of Pediatrics and Neurosciences,
University of the Philippines College of Medicine,
Manila, Philippines
e-mail: mblukban@yahoo.com
R. L. Rosales
Department of Neurology and Psychiatry,
Santo Tomas University Hospital, Manila, Philippines
D. Dressler
Department of Neurology, Hannover Medical School,
Hannover, Germany
123
J Neural Transm
DOI 10.1007/s00702-008-0175-8
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013144
appearing early in life secondary to a central nervous
system lesion, damage or dysfunction and not as a result
of a progressive or degenerative brain disease (Russman
et al. 1997). CP is due to a variety of conditions that may
occur during the prenatal, perinatal and postnatal life of
the newborn infant. The hallmarks of the damage to the
developing brain’s motor system include increased or
decreased muscle tone, spasticity, muscle weakness,
involuntary movements and loss of control of muscle
coordination (Goldstein 2004). Impairment in movement
and tone and other associated central nervous system
dysfunction may lead to motor, verbal, visual, hearing and
learning disabilities.
The management of CP, therefore, involves two issues:
the treatment of injured brain areas that control muscle
coordination and movement and the management of
impaired muscle coordination and its resulting disabilities
(Goldstein 2004). Depending on the injury mechanism, the
manifestations may vary, with spasticity as the most
common symptom. Pharmacologic treatment with antisp-
asmodics and nonpharmacologic modalities such as
physiotherapy (PT) and occupational therapy (OT) have
been mainstays in spasticity management. In 1988, the first
clinical trials using botulinum neurotoxin (BoNT) for
spasticity in children with CP were started by Andrew
Koman and co-workers. Results of these trials were first
reported in 1993 (Koman et al. 1993).
BoNT is a potent neurotoxin produced by the anaerobic
bacterium Clostridium botulinum with serotypes A (BoNT-A)
and B (BoNT-B) used for therapeutic purposes. BoNT
causes chemodenervation and muscle relaxation by dis-
rupting acetylcholine release into the synaptic cleft thus
blocking the neuromuscular junction (Pidcock 2004). The
different formulations available in the market, BoNT-A as
Botox� (100 units/vial, Allergan), Dysport� (500 units/
vial, Ipsen), or Xeomin� (100 units, free of complexing
proteins/vial, Merz) and BoNT-B as Myobloc� or Neu-
robloc� (5,000 and 10,000 units/vial, Solstice) are not
generically bioequivalent and have different recommended
dosing, efficacy and side effects profile.
After its first application in strabismus, BoNT-A was
introduced for the treatment of blepharospasm and cervical
dystonia. Currently, its use has been extended for other
neurologic conditions such as post-stroke spasticity, hem-
ifacial spasms, strabismus and eye movement disorders,
urinary bladder dysfunction, exocrine gland hyperactivity,
hyperkinetic movement disorders and pain syndromes
(Panicker and Muthane 2003). It has gained acceptance as
an adjunct therapy for spasticity for children with CP. For
the past 10 years, clinical experience from numerous case
reports, retrospective and prospective open label cohort
studies and randomized controlled trials (RCT) have
described the potency of BoNT-A to treat upper and lower
limb spasticity in children with CP. Additionally, several
independent systematic reviews, meta analysis and con-
sensus statements from various groups have been
published. We are unaware of published trials in CP, using
Xeomin� for spasticity. The clinical trials with BoNT-B
for CP are limited, mostly open label pilot studies and
include patients who were secondary non-responders to
BoNT-A therapy (Schwerin et al. 2004; Sanger et al. 2007).
The regional and systemic anticholinergic adverse side
effects of BoNT-B limit its clinical use.
The objective of this review is to summarize the inde-
pendent systematic reviews and recent (RCT) which are
not yet included in the past systematic reviews. We hope to
present the evidence on the effectiveness of BoNT-A for
reducing upper and lower limb spasticity in children with
CP and to show whether these studiesreduce muscle tone
and translate into an improved functional outcome.
Methods
A literature search using the electronic databases MED-
LINE, PUBMED, DARE, BMJ updates, and TRIP
database for published articles in English from 1990 to
May 2008 was conducted using botulinum toxin, CP,
spasticity and treatment as search terms. Systematic
reviews and recent RCT that were not included in previous
systematic reviews are included in this review. Studies
must compare BoNT-A with placebo, other pharmaco-
therapies, or a combination of BoNT-A with non
pharmacological therapies. Only studies in children with
CP were included. Only class I and class II studies were
retrieved, reviewed and tabulated. Clinical trials on the arm
and the legs were separately reviewed. The RCT were
graded according to the American Academy of Neurology
Classification of Evidence for Therapeutic Articles (Edlund
et al. 2004).
In 2005, the Philippine Society of Neurorehabilitation
(PSNR) formed a technical review panel composed of
pediatric neurologists and rehabilitation specialists whose
aim was to appraise all available studies on BoNT-A from
1994 to 2004 to make consensus statements for Filipino
practitioners on the use of BoNT-A for children with CP.
The members of the technical review panel which was
headed by the primary author (M. L.) independently
reviewed and graded the class I and class II RCT, which
are included in this review. Each trial was appraised
independently by two reviewers. Any disagreements were
settled by the whole group (Lukban et al. 2006). Recent
RCT from 2005 to 2008 and the newly published system-
atic reviews were appraised and summarized by the
primary author, then concurred with the coauthors
(R. R. and D. D.).
M. B. Lukban et al.
123
Results
Upper limbs spasticity
There are only six RCT on BoNT-A involving 229 children
with upper limb spasticity due to CP (Corry et al. 1997;
Fehlings et al. 2000; Speth et al. 2005; Lowe et al. 2006;
Wallen et al. 2007; Russo et al. 2007) and all are class II
studies (Table 1). BoNT-A injections were administered to
115 children. Five independent systematic reviews pub-
lished from 2004 to 2008 evaluated these studies (Table 2)
(Wasiak et al. 2004; Garces et al. 2005; Reeuwijk et al.
2006; Park and Rha 2006; Simpson et al. 2008). The recent
trials by Wallen et al. (2007) and Russo et al. (2007) have
not been reviewed.
Two groups independently produced systematic
reviews on BoNT-A for upper limb spasticity in CP and
both appraised the two RCT available at that time.
Wasiak et al. (2004) with the Cochrane Movement Dis-
orders Group from Australia (Wasiak et al. 2004) and
Garces et al. (2005)with the Canadian Coordinating Office
for Health Technology Assessment (Garces et al. 2005)
both selected and appraised the studies of Corry et al.
(1997) and Fehlings et al. (2000). Corry et al. (1997)
performed a randomized double-blind, placebo-controlled
trial comparing Botox� (Allergan) and Dysport� (Ipsen)
to placebo in 14 children with CP. The trial lasted for
12 weeks and evaluated muscle tone by the Ashworth
scale (Ashworth 1964), active range of motion (AROM),
patients’ and parents’ assessment of disability and func-
tion by a five scale questionnaire as well as occurrence of
adverse events (AE) (Corry et al. 1997). The study by
Fehlings et al. (2000) was a randomized, single-blind
study comparing Botox� with OT to OT alone. The trial
involved 29 patients, lasted for 24 weeks and assessed
muscle tone using the modified Ashworth scale (MAS)
(Bohannon and Smith 1987), functional outcome using
Quality of Upper Extremity Skills Test (QUEST)
(DeMatteo et al. 1992) and Pediatric Evaluation Disability
Inventory (PEDI) (Haley et al. 1992) as well as AE
(Fehlings et al. 2000).
Corry et al. (1997) reported a significant improvement in
elbow muscle tone at 2 weeks but not at 12 weeks after
BoNT injection and significant improvement of wrist
muscle tone 2 and 12 weeks after BoNT injections. Thumb
muscle tone was not improved by BoNT. There was also a
significantly greater median change in the AROM of the
elbow and thumb extension 2 weeks, but not 12 weeks
after BoNT injections. Wrist extension, thumb abduction or
metacarpophalangeal extension was not improved. How-
ever, in a five category scale questionnaire, the patients and
their parents reported improvement in function at 2 and
12 weeks after BoNT injection.
Fehlings et al. (2000) showed a decline in spasticity in
both the children treated with BoNT-A plus OT and those
managed with OT alone. Although the BoNT-A group
showed greater reduction in muscle tone (MAS), the
overall differences between BoNT-A and the control group
were not statistically significant. Despite the lack of sig-
nificant difference in MAS between the two groups, in the
QUEST and PEDI assessments for functional outcomes,
those who received BoNT-A significantly performed better
compared to occupational therapy alone.
Both studies reported transient excessive weakness but
no other AE. Because of the small sample size in these
studies and their conflicting results, the use of BoNT-A for
upper limb spasticity was initially not recommended as
standard care.
More recently, two additional single-blind RCT were
published by Speth et al. (2005) and Lowe et al. (2006).
Speth et al. (2005) enrolled 20 children with spastic
hemiplegia aged 4–16 years. Half of the children were
randomly assigned to receive BoNT-A injections after
6 months of PT and OT. Increase in active dorsal flexion
and reduced tone in the wrist was observed in the BoNT-A
group compared to the control group. However, functional
outcomes as measured by the Melbourne assessment of
unilateral upper limb function (Johnson et al. 1994; Randall
et al. 1999), PEDI, and nine hole peg test (Mathrowitz et al.
1985) were not significantly different between the BoNT-A
and control group.
Lowe et al. (2006) enrolled 42 children aged 2–8 years
who previously received OT and the intervention group
were randomly assigned to receive BoNT-A. Muscle
tone was described by the Ashworth scale, functional
improvement by QUEST, Canadian Outcome Performance
Measure (COPM) (Law et al. 1998), parent and therapist
Goal Attainment Scaling (GAS) (Kiresuk et al. 1994) and
PEDI. Differences in mean QUEST total scores between
treatment and control groups were significant at 1 and
3 months (p\ 0.001) but not at 6 months (p = 0.318).
A significantly larger proportion of children in the BT
group showed a greater than 20% change above baseline
QUEST scores at 1 and 3 months. Although both treatment
and control groups showed improvement in functional
skills and attainment of treatment goals from baseline
scores as measured by COPM, GAS and PEDI, there was
greater improvement seen in the BoNT-A group which was
statistically significant.
The RCT studies of Corry et al., Fehlings et al. and
Speth et al. (class II) and nine other uncontrolled trials
(class IV) were reviewed by Reeuwijk et al. (2006). They
analyzed the overall effect of BoNT-A on short (less than
12 weeks) and long-term (more than 12 weeks) change in
tone, active and passive range of motion (PROM) and
upper limb function based on the level of activity. Only the
Effectiveness of botulinum toxin A for upper and lower limb spasticity in children with CP
123
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M. B. Lukban et al.
123
small RCT study of Corry and four of seven uncontrolled
studies showed short-term significant difference in tone in
the BoNT-A group. For long-term reduction of spasticity,
none of the RCT and only one out of five uncontrolled
studies reported significant difference in measurements of
tone compared with the baseline values. Short-term
increase in AROM was observed by both Corry and Speth
but none in five uncontrolled trials. The improvement in
AROM extended until 9 months in the trial by Speth. No
trial showed significant change in short-term PROM. No
trial consistently showed improvement in most functional
measures. They concluded that for the time being, the
evidence is still neither sufficient nor consistent to support
or refute the clinical use of BoNT-A in upper limb spas-
ticity in children with CP.
Park and Rha (2006) reviewed the three previous RCT
of Corry, Fehlings and Speth and added the RCT of Lowe
(class II), eight uncontrolled case series and four case
reports (class III, IV). Different assessment tools were used
in the four RCT trials thus a pooled risk difference between
groups was not possible. This group also arrived at the
same conclusion: that the use of BoNT-A for upper limb
spasticity is still inconclusive.
Recently, Wallen et al. (2007) extended his case series
and prospectively and randomly assigned 80 children with
spastic quadriplegia, triplegia and hemiplegia into four
groups: BoNT-A plus OT, BoNT-A alone, OT alone and no
treatment (class II). The objective was to assess whether
BoNT-A with OT improves spasticity and function com-
pared to BoNT-A alone, OT alone or neither treatment. By
concealed allocation, each group randomly enrolled 17–20
patients in each group. In those children treated with
BoNT-A plus OT, muscle tone (MAS) was significantly
reduced 2 weeks after BoNT-A injection compared to the
three other groups. Six months after BoNT-A injection, the
tone had returned to baseline evaluation. However, despite
the time limited improvement in muscle tone, primary
functional outcomes measured by COPM and GAS showed
that with the combination of BoNT-A and OT the children
reached their functional goals earlier. Secondary outcome
assessment tools such as the Melbourne Assessment of
Unilateral Upper Limb Function, QUEST, PEDI, and Child
Health Questionnaire (Waters et al. 1999) did not show
differences between both groups. The active and PROM
was not different as well (Wallen et al. 2007).
To further emphasize functional measurements and
quality of life, Russo et al. (2007) in a single-blind RCT,
studied 43 hemiplegic children aged 3–16 years comparing
BoNT-A plus OT with OT alone. Outcome measures
included domains on body structure by the MAS and
Table 2 Systematic reviews on botulinum toxin use alone or in combination with other modalities for upper limb spasticity in cerebral palsy
Author (year) Study design Included trials AAN class
of evidence
Conclusion AAN level of
recommendation
Wasiak et al. (2004) Systematic review 2 RCT
(Corry et al. 1997;
Fehlings et al. 2000)
Class II Data inadequate treatment
unproven (U)
Garces et al. (2005) Systematic review 2 RCT
(Corry et al. 1997;
Fehlings et al. 2000)
Class II Data inadequate treatment
unproven (U)
Reeuwijk et al.
(2006)
Systematic review 3 RCT
(Corry et al. 1997;
Fehlings et al. 2000;
Speth et al. 2005)
9 uncontrolled studies
Class II
Class III
Class IV
Data inadequate
Insufficient evidence for short or
long-term effects in decreasing
tone, range of motion and
improved function (U)
Park and Rha (2006) Systematic review 4 RCT
(Corry et al. 1997;
Fehlings et al. 2000;
Speth et al. 2005;
Lowe et al. 2006)
8 case series
4 case reports
Class II
Class III
Class IV
Data inadequate treatment possibly
effective in improving muscle
tone, but unproven in improving
function (U)
Simpson et al.
(2008)
Systematic review 3 RCT
(Corry et al. 1997;
Fehlings et al. 2000;
Speth et al. 2005)
Class II BoNT-A should be considered as a
treatment option (B)
RCT randomized controlled trials, BoNT-A botulinum toxin type A, AAN American Academy of Neurology, U unproven, B treatment probably
useful/effective
Effectiveness of botulinum toxin A for upper and lower limb spasticity in children with CP
123
Tardieu Scale (Tardieu et al. 1954) and activities partici-
pation domains using the Assessment of Motor and Process
Skills (Fisher 2003), GAS, PEDI, and Pediatric Quality of
Life Inventory (Varni et al. 2001). Self-perception was also
measured 3 months after BT injections. Childrenwho
received BoNT-A and OT performed significantly better in
terms of body structure and activities participation com-
pared to the children who received OT alone. The authors
reported improvements in self-perception for the global
self-worth domain. Six months after BoNT-A injection the
differences between the intervention and the control groups
persisted for the measures of body structure, but not for
activities participation or self-perception (Russo et al.
2007).
Only the studies of Corry, Fehlings and Speth were
included in the review by Simpson et al. (2008)with the
Therapeutics and Technology Assessment Subcommittee
of the American Academy of Neurology. Based on these
three class II studies, they recommended that BoNT-A
injection should be considered as a treatment option in
children with upper limb spasticity in children with CP.
Thus, based on the systematic reviews of earlier studies
and the two recent single-blind RCT studies of Russo et al.
(2007) and Wallen et al. (2007) five of six class II RCT
show that there is a greater decrease in tone among children
who received BoNT-A therapy compared to placebo or OT
alone. In addition, in four of six RCT, a reduction in
spasticity led to a time limited improvement in hand
function.
Lower limbs spasticity
There are 15 RCT on BoNT-A involving 617 children with
lower limb spasticity due to CP (Koman et al. 1994; Corry
et al. 1998; Flett et al. 1999; Sutherland et al. 1999; Ubhi
et al. 2000; Koman et al. 2000; Baker et al. 2002; Love
et al. 2001; Boyd et al. 2001; Bjornson et al. 2007; Scholtes
et al. 2007; Detrembleur et al. 2002; Bottos et al. 2003;
Ackman et al. 2005; Mall et al. 2006), eight of which are
class I trials (Table 3). Two of these studies are recent and
have not been reviewed. Six independent systematic
reviews were published from 2000 to 2008 to evaluate
these studies (Garces et al. 2005; Simpson et al. 2008;
Ade-Hall and Moore 2000; Boyd and Hays 2001)
(Table 4). BoNT-A was administered to 360 children.
Ade-Hall and Moore (2000) were the first to summarize
RCT on BoNT-A for lower limb spasticity in a systematic
review. They combined three RCT from the groups of
Koman et al. (1994), Corry et al. (1998) and Flett et al.
(1999). Koman et al. (1994) compared BoNT-A with
injection of a placebo in 12 ambulatory children with
spastic diplegia and found statistically non-significant
improvements in gait in the BoNT-A group. Corry et al.
(1998) and Flett et al. (1999) compared BoNT-A with the
use of casts. Each included 20 children and found that
compared to baseline scores, there were improvements in
gait, range of ankle movement and muscle tone in both the
BoNT-A and the cast groups. However, there were no
statistically significant differences between the two groups
in either trial.
Flett et al. (1999) also assessed motor function using the
gross motor function measure (GMFM) (Russell et al.
1989) and found statistically significant improvements in
each group compared to baseline but no statistically sig-
nificant differences between the groups. Corry et al. (1998)
performed 3D gait analysis on those children able to
co-operate. Maximal plantar flexion and maximal dorsi-
flexion during walking were both found to be significantly
greater in the BoNT-A group compared to the cast group.
In all other dimensions there were no statistically signifi-
cant differences between both groups.
Increased availability of published studies allowed Boyd
et al. (2001) to include 10 RCT with a total of 407 patients
and seven prospective non-randomized studies with a total
of 193 patients in her systematic review. The RCT trials
were considered of moderate to high methodological
quality. Nine of 10 trials had concealed allocation. Because
the selected studies were designed differently and had
varying outcome measures, the investigators were unable
to pool the results of all or most of the studies together.
Nevertheless, four trials comparing BoNT-A with placebo
showed a pooled risk difference of 0.25 (95% CI 0.13,
0.37) using the Physicians Rating Scale (PRS) (Maathuis
et al. 2005). Two trials (Corry et al. 1998; Flett et al. 1999)
comparing BoNT-A with casting yielded a pooled risk
difference of 0.23 (95% CI 0.06, 0.53) in the PRS. Thus
these early studies concluded that moderate dose-depen-
dent treatment effects of botulinum toxin in the lower
extremities can be assumed (Boyd and Hays 2001).
The Canadian group led by (Garces et al. 2005) also
evaluated BoNT-A for lower limb spasticity in CP children
and included 13 RCT in their review. We did not retrieve
and review two clinical abstracts, one crossover trial and
one trial on hip adductor spasticity which was designed to
study the effect of BoNT-A on pain. These studies were
assessed as poor quality studies with unclear concealments.
Of the remaining studies reviewed, five trials were ran-
domized, double-blind and placebo controlled (Koman
et al. 1994; Sutherland et al. 1999; Ubhi et al. 2000; Koman
et al. 2000; Baker et al. 2002). Two trials compared BoNT-
A with serial casting (Corry et al. 1998; Flett et al. 1999)
and two trials compared BoNT-A with physiotherapy
(Love et al. 2001; Boyd et al. 2001). Outcome measures
were not similar in all studies: two reported on muscle
tone, six assessed PROM, three reported on AROM, five
studied motion and gait analysis, seven used caregivers’
M. B. Lukban et al.
123
T
a
b
le
3
R
an
d
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m
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ed
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(1
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)
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v
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p
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y
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P
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if
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if
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in
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if
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in
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p
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4
5
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n
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d
if
fe
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in
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in
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(2
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in
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(2
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I
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inP
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at
4
w
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II
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II
M
A
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in
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fu
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ct
io
n
Effectiveness of botulinum toxin A for upper and lower limb spasticity in children with CP
123
T
a
b
le
3
co
n
ti
n
u
ed
A
u
th
o
r
(y
ea
r)
S
tu
d
y
d
es
ig
n
In
te
rv
en
ti
o
n
st
u
d
ie
d
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m
b
er
o
f
p
at
ie
n
ts
T
x
:C
o
n
tr
o
l
(a
g
e)
A
A
N
le
v
el
o
f
ev
id
en
ce
O
u
tc
o
m
e
m
ea
su
re
s
R
es
u
lt
B
jo
rn
so
n
et
al
.
(2
0
0
7
)
R
C
T
D
B
P
C
B
o
N
T
-A
v
s.
p
la
ce
b
o
3
3
1
7
:1
6
(3
–
1
2
y
ea
rs
)
I
G
M
F
M
A
sh
w
o
rt
h
E
M
G
C
O
P
M
G
A
S
S
ig
n
ifi
ca
n
t
im
p
ro
v
em
en
t
in
to
n
e,
ra
n
g
e
o
f
m
o
ti
o
n
an
d
g
ro
ss
m
o
to
r
fu
n
ct
io
n
fa
v
o
ri
n
g
B
o
N
T
-A
S
ch
o
lt
es
et
al
.
(2
0
0
7
)
R
C
T
S
in
g
le
b
li
n
d
B
o
N
T
-A
w
it
h
co
m
p
re
h
en
si
v
e
re
h
ab
(P
T
,
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rt
h
o
se
s,
ca
st
in
g
)
v
s.
u
su
al
ca
re
4
7
2
3
:2
4
(4
–
1
1
y
ea
rs
)
II
G
o
n
io
m
et
ry
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M. B. Lukban et al.
123
and physicians’ assessment of function and disability, two
reported on pain and five noted AE.
BoNT-A treatment resulted in decreased muscle tone
across most trials. Compared to baseline values, increased
range of motion and improved gait are shown in many
studies but statistical significant difference between the
treatment and control group is not always reached (Garces
et al. 2005). Parents and caregivers however rate greater
satisfaction in those treated with BoNT-A. Pain in the
injection site and transient weakness were the AE most
commonly reported. However, none of the AE led to the
withdrawal of patients from the study. Pooled data on three
trials on AE showed a risk difference of 0.16 (95% CI 0.07,
0.25) suggesting a significant difference in the treatment
group (Ubhi et al. 2000; Koman et al. 2000; Baker et al.
2002).
Cardoso et al. (2006) limited his review to class I studies
that evaluate functional outcome using PRS and video gait
analysis for children with equinovarus. His meta-analysis
of double-blind RCT with placebo control included six
studies with a total of 335 patients (Koman et al. 1994;
Sutherland et al. 1999; Ubhi et al. 2000; Koman et al. 2000;
Baker et al. 2002; Love et al. 2001). Four studies with a
total of 183 patients were pooled together to assess gait
improvement using the Physician Rating Scale and video
gait analysis (Koman et al. 1994; Sutherland et al. 1999;
Ubhi et al. 2000; Koman et al. 2000). His analyses showed
statistically significant gait improvement in CP children
with spastic equinus foot (Peto odds ratio 3.49, 95% CI
2.20–7.22) (Cardoso et al. 2006). In subjective assessment
of disability and function using questionnaires adminis-
tered to 136 parents or guardians, two studies reported
significant improvement in the BoNT-A group (Peto odds
ratio 3.99, 95% CI 1.50–8.12) (Koman et al. 1994; Baker
et al. 2002) AE were reported in four studies with a total of
332 patients. AE which were mild and self-limited were
significantly higher with BoNT-A (Peto odds ratio 2.62,
95% CI 1.47–4.67) (Koman et al. 1994; Sutherland et al.
1999; Ubhi et al. 2000; Koman et al. 2000; Baker et al.
2002).
In the American Academy of Neurology (AAN),
Simpson et al. (2008) reviewed four class I double-blind,
placebo-controlled RCT which were also reviewed by
Cardoso et al., but the group excluded the small trial of 12
children by Koman et al. (2000) and the trial of Love et al.
which had unclear concealment (Sutherland et al. 1999;
Ubhi et al. 2000; Baker et al. 2002). The video gait anal-
ysis, which is a clinically relevant outcome measure was
reported in two studies and showed statistically significant
difference between the treatment and placebo group (Ubhi
et al. 2000; Koman et al. 2000) In summary, these two
Class I studies establishes that BoNT-A is an effective
treatment in the management of spastic equinus in children
with CP.
The most recent studies which were not yet reviewed in
the systematic reviews from Bjornson (Bjornson et al.
2007) and Scholtes (Scholtes et al. 2007). Bjornson et al.
(2007) attempted to evaluate the effect of BoNT-A injec-
tions in 33 children in five domains of medical
rehabilitation: pathophysiology, impairment, functional
Table 4 Systematic reviews on botulinum toxin use alone or in combination with other treatment modalities for lower limb spasticity in cerebral
palsy
Author (year) Study design Included trials AAN level
of evidence
Conclusion AAN level of
recommendation
Ade-Hall and Moore (2000) Systematic review 3 RCT II Weak evidence favoring treatment
however, statistically
insignificant (B)
Boyd and Hays (2001) Systematic review
Meta-analysis
10 RCT
7 prospective cohort
I, II, III Significant improvement favoring
BoNT-A (B)
Garces et al. (2005) Systematic review 13 RCT I, II, III Significant improvement favoring
BoNT-A (B)
Cardoso et al. (2006) Systematic review
Meta-analysis
6 Class I RCT I, II Significant improvement favoring
BoNT-A (A)
Lannin et al. (2006) Systematic review
(comparesaddition
of other therapies post
BT-A)
9 RCT II, III Inconsistent benefit of
combination therapies vs.
BoNT-A alone (U)
Simpson et al. (2008) Systematic review 14 RCT (4 Class I for
gastrocnemius spasticity)
(2 class I for adductor spasticity
and pain)
I, II BoNT-A is an effective treatment
for equivarus deformity (A),
BoNT-A should be considered
for adductor spasticity (B)
RCT randomized controlled trials, BT-A botulinum toxin A, AAN American Academy of Neurology, U unproven, B treatment probably useful/
effective, A treatment effective
Effectiveness of botulinum toxin A for upper and lower limb spasticity in children with CP
123
limitation, disability and societal or contextual factors. The
study is a randomized, double-blind, placebo-controlled
trial comparing BoNT-A with saline injections into the
gastrocnemius of children with spastic diplegia. They
showed a significant improvement in tone, range of motion
and some functional outcome measures (GMFM) but no
significant difference between the two groups in satisfac-
tion with performance goals (COPM, GAS), energy
expenditure, Ashworth and AE.
The study by Scholtes et al. (2007) is a randomized
single-blind trial on the effect of BoNT-A and compre-
hensive rehabilitation vs. usual care in 46 children with
spastic CP who walk on flexed knees. Multilevel injections
and comprehensive rehabilitation (intensive physiotherapy,
orthoses and/or serial casting) which were given to the
treatment group demonstrated significant improvements in
knee extension during gait, increased muscle length and
decreased spasticity compared to control.
The American Academy for Cerebral Palsy and Devel-
opmental Medicine (AACPDM) systematic reviews
provide biomedical researchers and clinical practitioners
with current analyses of various interventions for the
management of developmental disabilities. In 2006, Lannin
et al. (2006) specifically reviewed published articles on
children and adolescents with CP who had received BoNT-
A injections in either upper or lower limbs in combination
with other therapies such as physiotherapy, electrical
stimulation and serial casting. Aside from the effect of
BoNT-A, they wanted to study the additional benefits of
other non medical interventions on the outcome of children
who had prior BoNT-A therapy. Eight trials on lower limb
spasticity were identified. One was a retrospective chart
review and four were case series. Two class III cohort
studies with a concurrent control group studied the effect of
serial casting after BoNT-A. One small RCT studied the
effect of electrical stimulation post BONT-A. This single
RCT by (Detrembleur et al. 2002) enrolled 12 CP children
and showed that electrical stimulation for 30 min, six times
a day for 3 days after lower limb BoNT-A had no signifi-
cant effect on gait parameters.
The before and after BoNT-A study of Boyd et al.
(2000) compared the 3D gait analysis of 15 diplegic and
10 hemiplegic children. Subanalysis of the cohort of 10
children who underwent post BoNT-A casting 3 weeks
after injection revealed that all children were reported to
show improvement in ankle kinematics from baseline to
12 and 24 weeks, irregardless of whether they received
post BoNT-A casting or not. There was an additional
improvement of PROM in the subgroup of children who
received casting post BoNT-A. The cohort study of
Desloovere et al. (2001) randomly assigned children to
be put on serial stretching casts either before or imme-
diately after BoNT-A. None of the studies showed a
significant benefit to the addition of casting post BoNT
injection.
The recent small RCT by Bottos et al. (2003) and
Ackman et al. (2005) have not been included in the sys-
tematic review by Lannin et al. Ten children who were
injected with BoNT-A were randomly assigned by Bottos
and coworkers to either the treatment group who immedi-
ately were placed on a 3-week period of casting or the
control group who were fitted with ankle-foot orthosis and
physiotherapy after the injections. Both groups showed
reduction of spasticity on Ashworth scale, improved gross
motor activities on GMFM and increased walking speed
from baseline values. In addition, there was statistically
significant difference in the outcome measures between the
two groups, with greater improvement seen in those who
had post BoNT casting which was maximally observed at
4 months post injections (Bottos et al. 2003).
Ackman et al. (2005) randomly assigned children into
three groups: BoNT-A alone, placebo and casting, or
BoNT-A plus casting. Outcome measures include gait
analysis, change in tone using Ashworth and Tardieu scales
and ranges of motion. Contrary to previous studies, he did
not show any improvement in any of the outcome measures
among those treated with BoNT-A alone. There were
improvements in the outcome measures among those who
received casting and placebo but the greatest improvement
was seen in those who received both BoNT-A and casting.
Based on these single blinded studies, Simpson et al.
(2008) concluded that there is still insufficient and con-
sistent evidence to support or refute the benefit of
additional casting to BoNT injection.
Lastly, there is a recent single class I study by Mall et al.
(2006) that evaluated the effect of BoNT-A injection into
the adductors and medial hamstrings which showed sig-
nificant improvement in knee-to-knee distance of about
9 cm (p\ 0.002) and decrease in adductor spasticity on
MAS (p\ 0.001). This was included in the review by
Simpson and they concluded that based on this single class
I study, botulinum toxin injection is probably effective in
improving adductor spasticity and range of motion
(Simpson et al. 2008).
AE in the upper and lower limb studies
Parallel to that of upper and lower limb post-stroke spas-
ticity (Rosales 2008), most of the trials considered BoNT-
A to be safe for use in children. The AE reported were mild
to moderate, self-limited, and were not sufficient to cause
withdrawals from the studies. The most common com-
plaints were pain in the injection sites as well as transient
local weakness.
In the upper limb trials, Corry et al. (1997) and Fehlings
et al. (2000) reported upper limb weakness resulting in
M. B. Lukban et al.
123
temporary decrease in grip strength and worsening in
performance of certain functional tests. Wallen and
co-workers (2007) report transient soreness at the wrist,
nausea and vomiting, flu-like symptoms, and fever. No
child or family reported excessive weakness, however;
Lowe et al. (2006) showed no significant difference in the
AE between groups. The most severe AE was reported by
Russo in two patients with previous history of epileptic
attacks who had prolonged seizures, one coming from the
intervention group and the other patient from the control
group. Five children in his intervention group also had
excessive weakness (Russo et al. 2007).
In the lower limb trials, other AE include increased
frequency of falls, dysphagia, and incontinence (Sutherland
et al. 1999; Ubhi et al. 2000; Koman et al. 2000; Baker
et al. 2002). One child in the study by Sholtes et al. (2007)
had increased micturition and fecal soiling for 1 month.
The meta-analysis of Cardoso et al. 2006) which pooled the
AE of four trials reported 69 AE in the BoNT group
compared to 17 AE in the placebo group giving a Peto odds
ratio of 2.63 (Koman et al. 1994; Ubhi et al. 2000; Koman
et al. 2000; Baker et al. 2002.
Discussion
Although the United States Food and Drug Administration
have approved BoNT-A in the management of strabismus,
blepharospasm, hemifacial spasms and cervical dystonia,
its use for spasticity in children with CP remains off label.
However, since botulinum toxin therapy for CP children
was introduced in 1999 there is growing evidence that for a
limited period of time, it can decrease muscle tone and
improve range in joints served by injected muscles.Vari-
ous independent systematic reviews further supported these
findings thus reinforcing the conclusions of different
groups and strengthening recommendations to consider
botulinum toxin therapy as one of the most important
therapeutic options to treat CP children with spasticity,
both in the upper and lower limbs.
The clamor to establish that a decreased muscle tone and
an improved joint range of motion leads to improvements
of function, patient satisfaction and quality of life has been
emphasized in all the systematic reviews that has been
done so far. The recent RCT completed last year for both
upper and lower limb spasticity addressed this issue. There
is now clinical evidence establishing the role of botulinum
toxin to improve function in the upper and lower limb.
Further trials will most likely address functionality in more
detail with the establishment of a combination of validated
instruments with respect to the dimensions of the interna-
tional classification of functioning, disability and health
(Rosenbaum and Stewart 2004). This is echoed by the 2006
European consensus table panelists who outlined in detail
the best practice and current understanding regarding
botulinum toxin treatment options in children with CP
(Heinen et al. 2006).
Most of the previous trials cover short observation
periods ranging from 6 to 24 weeks only. They are,
therefore, insufficient to capture long-term effects of
repeated botulinum toxin injection such as the prevention
of contractures and secondary pain. Attempts to document
the ability of early intervention with botulinum toxin to
decrease or delay the need for orthopedic surgery have
been started thru the retrospective evaluation of the expe-
rience with BoNT-A for the past 10 years (Hagglund et al.
2005; Ruiz et al. 2004). Early interventions may be espe-
cially important in a growing organism. This trend of early
intervention with BoNT-A in the management of spasticity
has also been alluded to in post-stroke intervention
(Rosales 2008). What may spell the difference between
spasticity states would be the growing nature of the mus-
cles in a child and the unitary concept of separating
chronicity (and hence even contracture) from those, where
so much of neuroplasticity factors (and hence disease
modification) may still play roles at early stages.
Since botulinum toxin injection has been part of stan-
dard treatment on some medical units, a prospective study
will later best answer how BoNT-A will affect the future
need for surgery and its associated outcomes including the
cost effectiveness of botulinum toxin injection in the
comprehensive management of CP (Ruiz et al. 2004).
Future consensus statements on botulinum toxin and CP
should include injection schemes, i.e., target muscle
selection for best responders, BoNT-A dosages, use of
anesthesia during injections and use of electromyography/
ultrasound for injection guidance. Target muscle selection
and dosaging may be influenced by numerous consider-
ations including (1) the specific aim of the injection (e.g.,
complementary to rehabilitation care and orthopedic care,
hygienic considerations, prevention of fixed contracture,
cosmesis, etc.); (2) the degree of muscle hyperactivity and
(3) maturity of muscle fascial planes influencing diffusion
(Rosales and Dressler 2006). The factors of muscle
hyperactivity and diffusion along fascial planes may
impact on certain AE that occur following BoNT-A
injection in CP. Thus, one should exercise extreme caution
in injecting BoNT-A in the very young and sick children
who are malnourished with atrophic muscles.
Conclusion and recommendation
This review which summarized the class I and class II trials
involving 115 children with upper limb spasticity and 360
children with lower limb spasticity shows the growing
Effectiveness of botulinum toxin A for upper and lower limb spasticity in children with CP
123
evidence that BoNT-A is effective in reducing spasticity
and provides a time limited improvement in function in the
upper and lower limbs for children with CP. The man-
agement of CP is multidisciplinary as the central nervous
system dysfunction in CP leads to various disabilities.
BoNT-A is a major breakthrough in the treatment of
spasticity. Combined with surgical and nonpharmacologi-
cal interventions by an interdisciplinary team is the best
treatment approach for children with CP. The goals of
BoNT-A therapy in CP spasticity go beyond decrease in
muscle tone leading towards pain relief, prevention of
contractures, psychosocial integration and—finally—func-
tional improvement. Future discussion should focus on
optimized injection schemes. Pharmacoeconomic issues
will eventually also have to be addressed.
Acknowledgments We thank the members of the technical panel of
the Philippine Society of Neurorehabilitation who appraised the early
studies on BoNT-A: Dr. Myrna S. Fojas, Dr. Ermenilda L. Avendano,
Dr. Fe A. de los Reyes and Dr. Sharon D. Ignacio.
Conflict of interest statement None.
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 /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. Stvoreni PDF dokumenti mogu se otvoriti Acrobat i Adobe Reader 5.0 i kasnijim verzijama.)
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