Annotation
Botulinum toxin in
the management of
cerebral palsy
Rosalind J Jefferson MB BS BSc PhD DIC MRCP MRCPCH,
Consultant Paediatrician, Dingley Child Development
Centre, Battle Hospital, Reading, UK.
Correspondence to author at Dingley Child Development
Centre, Battle Hospital, Oxford Road, Reading RG30 1AG, UK.
E-mail: Rosalind.Jefferson@rbbh-tr.nhs.uk
Botulinum toxin has rapidly gained wide acceptance as a treat-
ment for focal spasticity, and is becoming more readily avail-
able. Early studies established its effectiveness, but many issues
are still open for discussion. After a brief review of the historical
and scientific development of botulinum toxin as a clinical tool
and an outline of previous work in the field, some important
questions are discussed in the light of more recent trials.
History
The clinical effects of botulinum toxin were first recognized at
the end of the nineteenth century when van Ermingen related
botulism to a toxin produced by Clostridium botulinum, a
Gram-negative anaerobic bacterium.1 Subsequently, the toxin
has become recognized as one of the most potent bacterial
toxins known to man and has been used as a chemical weapon
and as a therapeutic tool.
The clinical use of botulinum toxin began in the 1970s
with the treatment of strabismus in nonhuman primates.2
Eight years later the first report of its use as an alternative to
strabismus surgery in humans was published.3 Success was
such that its applications rapidly extended to diverse condi-
tions whose clinical features arise from inappropriate mus-
cle activity, including blepharospasm, hemifacial spasm,
various dystonias, stuttering, tremors, tics, and occupational
hand cramps.4,5 Further extensions included tension headaches
and migraine as well as the treatment of autonomic dysfunc-
tion: sphincter-related problems, achalasia, and hyperhydro-
sis.5,6 More recently its cosmetic benefit has been exploited
in the treatment of facial wrinkles.5
Mode of action
Seven immunologically divergent serotypes of botulinum
toxin have been recognized and labelled A to G. Of these, the
most potent, botulinum toxin type A (BTX-A), is the serotype
available for clinical use. The clinical efficacy of other serotypes
(namely types B and F) is under investigation, and a form of
botulinum toxin type B is soon to be marketed in the US7 with
possible use in patients who have developed resistance to
BTX-A. Each of the serotypes has a similar macrostructure and
mechanism of action. The toxins are synthesized as single-
chain polypeptides with a molecular mass of about 150kDa,8
consisting of a heavy chain (about 100kDa) tethered by a
Developmental Medicine & Child Neurology 2004, 46: 491–499 491
disulphide bond to a light chain (about 50kDa). They bind with
high affinity and specificity to receptors on the cell surface of
the presynaptic membranes of cholinergic motor neurons.9
Internalization occurs via receptor-mediated endocytosis and
is followed by the cleavage of light and heavy chains. The
heavy chain then forms a channel to allow passage of the
enzymically poisonous light chain into the cytoplasm, where
the latter prevents acetylcholine release from the synaptic
vesicles by enzymic cleavage of essential polypeptides. BTX-A
cleaves SNAP 25 (SyNaptosomal Associated Protein 25), a
component of the neuraxonal membrane essential for the
exocytosis of acetylcholine.8 Chemodenervation results in a
reversible partial flaccid paralysis, usually lasting 12 to 16
weeks, followed by longitudinal muscle growth and a func-
tional carry-over that can continue for up to 6 months or
longer in a small percentage of cases.9,10 Recovery of the neu-
romuscular junction occurs by means of compensatory proxi-
mal axonal sprouting and takes place over 6 to 8 weeks in the
experimental animal. A biphasic repair process is described.11
In the early phase, nerve stimulation leads to muscle contrac-
tion, but involves only the new sprouts; in the later phase
true regeneration occurs with vesicle turnover returning to
the original terminal and atrophy of the by then superfluous
sprouts. Because of the rapid and high-affinity binding of
BTX-A to the neuromuscular junction, only a small amount
of toxin reaches the systemic circulation.12
Cerebral palsy
Muscle in cerebral palsy (CP) is characterized by increased
resting tone resulting from the primary brain lesion. Stretch,
an important stimulus to normal muscle growth, is vigorous-
ly opposed by an exaggerated stretch reflex response, and
both spasm and spasticity tend to maintain the muscle in a
shortened position.13 Inherent changes in the spastic muscle
itself lead to a loss of sarcomeres and are paralleled by a
chain of clinical events progressing through reduced muscle
excursion, increased muscle stiffness, and fixed musculo-
tendinous contracture to bony torsional abnormalities and
joint instability.14
During recent years several medical and surgical treatments
have become available for the treatment of muscle spasticity
in CP. Oral medications, such as baclofen, dantrolene, and
diazepam, are limited by systemic side effects such as drowsi-
ness and generalized muscle weakness. Selective chemical
neurectomy with alcohol or phenol is associated with sensory
denervation, irreversible nerve injury, and permanent mus-
cle damage and fibrosis.15 Other invasive forms of manage-
ment include intrathecal baclofen (of very limited availability
in the UK and not without significant complications16) and
selective dorsal rhizotomy, which has never gained wide
acceptance in the UK although it retains a degree of popularity
in the US.17 In children, physiotherapy, augmented by serial
casting and orthoses, has been the mainstay of treatment to
reduce tone,18 prevent secondary deformities, and improve
function, although justification of these interventions by rig-
orous assessment is sadly lacking.19 Conservative management
is favoured in younger children to avoid potential risks such
as overlengthening, infection, scarring, and anaesthetic prob-
lems, whereas in older children orthopaedic surgery has a
significant role.
The use of botulinum toxin for the treatment of spasticity
was a logical extension from its established use in dystonias.
Its clinical usefulness as an anti-spasticity treatment was
based on animal studies in the hereditary spastic mouse.20
Compared with untreated mice, a single BTX-A injection into
the calf muscle during the 3-month growth period of the ani-
mal allowed normal longitudinal growth, preventing both
muscle shortening and tendon overgrowth. The natural
extension was to consider children with CP, in whom the pre-
vention of long-term fixed muscle contractures and the
improvement of function are the expected goals of treatment.
Early studies of BTX-A in CP
Koman et al.21 first described the use of BTX-A in children
with CP in an open-label study of 27 children with dynamic
deformities. Clinically useful reductions in spasticity were
observed lasting for 3 to 6 months without major adverse
effects, and it was postulated that adjuvant therapy with BTX-
A might delay orthopaedic surgery. This generated a small
number of related reports from various groups around the
world. Most early studies concentrated on the effectiveness
of the toxin in the treatment of dynamic equinus (gastrocne-
mius muscle), highlighting the importance of treating chil-
dren at as early an age as possible, before fixed contractures
develop. A few important studies extended the use of BTX-A
outside its licence to include other lower-limb muscle
groups, such as tibialis posterior, hamstrings (crouch gait),
and adductors (scissoring),22–24 while an even smaller num-
ber looked at the upper limb.25,26 These early trials, together
with more recent studies, are summarized in Appendix I. A
significant proportion are open-label studies involving only
small numbers of patients receiving varying doses of BTX-A,
and employing a variety of outcome measures. Therefore,
any comparison between studies is difficult.
The early studies of botulinum toxin were evaluated criti-
cally by Forssberg and Tedroff.12 They highlighted the lack of
controlled studies with appropriate functional outcome mea-
sures and adequate power supporting the use of BTX-A in
childhood CP and called for a further strict evaluation of its
impact before release for wider clinical use. This call was
echoed in a position paper from the UK Botulinum Toxin
and Cerebral Palsy Working Party.27
A Cochrane systematic review of BTX-A in the treatment of
lower-limb spasticity in CP28 found only three fully random-
492 Developmental Medicine & Child Neurology 2004, 46: 491–499
ized controlled trials meeting their inclusion criteria.15,29,30
Unfortunately, meta-analysis was not possible because of
incompatible presentation of results and, disappointingly,
the reviewers had to conclude that there was a lack of strong
controlled evidence to support or refute the use of BTX-A for
the treatment of lower-limb spasticity in CP. The need for
both short-term and longer-term randomized studies was
highlighted, as well as for outcome measures relevant to
function and disability.
Because early work has already been so ably evaluated, it
is not discussed in detail in this review. Instead we turn our
attention to more recent studies. How well have they addressed
the earlier criticisms and sought to answer the important
questions, both established and more recently emerging, in
relation to botulinum toxin and its use in CP?
What are the indications for BTX-A use?
The main use of botulinum toxin A is as an adjuvant therapy
in the management of dynamic contractures or spasticity.
Very early mixed contractures where there is spasticity with
some early fixed shortening, may be managed with BTX-A
combined with an alternative measure such as serial casting.
Major fixed contractures and bony torsional abnormalities
are more effectively managed by a combination of soft tissue
and bony surgery.
Two BTX-A preparations are available in the UK, both with
a limited licence for approved use, namely ‘dynamic equinus
foot deformity in ambulant patients with CP, 2 years of age or
older, only in hospital specialist centres with appropriately
trained personnel’. One preparation, Dysport, is licensed for
use in both gastrocnemius and tibialis posterior muscles,
whereas the other, Botox, is licensed for the gastrocnemius
muscle only. However, off-licence uses abound, whether in
the treatment of dynamic deformity in different muscle groups
or of spasticity of different aetiology, for example, traumatic
brain injury, hereditary spastic paraplegia, and spina bifida.
A recent consensus statement19 was an attempt by a group
of 15 clinicians and scientists from a variety of disciplines to
arrive at an agreement and produce a framework of guidelines
for the safe and efficacious use of BTX-A in terms of appropri-
ate patient selection and assessment, dosage, injection tech-
nique, and outcome measurement. Favourable factors for
patient selection included focal goals with specific anticipated
functional benefits and increased dynamic muscle stiffness;
negative factors were the presence of fixed contractures, bony
deformity or unstable joints, or too many target muscles. Early
treatment is preferable to give maximum response, although
later treatment can still be valuable, bringing gains such as
pain relief, ease of care, and improved seating.
Current suggested indications for the use of BTX-A14,19,27
are the following. (1) Calf injection for dynamic equinus,
persistent throughout gait cycle. (2) Hamstring injection for
dynamic knee flexion angle greater than 20˚ during the gait
cycle or interfering with gait (crouch gait). (3) Injection of
the hip adductors (scissoring) and hamstrings in severely
involved children to improve seating. (4) Diagnostic mea-
sure before surgery, for example, injection of the tibialis poste-
rior. (5) Management of focal limb dystonia. (6) Analgesic
agent to reduce pain and spasm in the peri-operative period.
(7) In the upper limb: persistent thumb-in-palm/thumb adduc-
tion, wrist posture preventing effective hand use, or tight
elbow flexion.
What is the recommended dose of BTX-A?
Only BTX-A is available therapeutically in the UK in two
injectable formulations, Botox (Allergan) and Dysport (Ipsen),
produced by different assay processes and with differing
bioavailabilities. This means that the recommended doses
are not equivalent, and there is no agreed mathematical con-
version between the two. Clinical data in adults with dysto-
nia suggested a Botox : Dysport ratio of 1 : 2.5 – 5 units.19,27
Intramuscular injection of BTX-A leads to a reduction in
spasticity within 12 to 72 hours, with clinical effects lasting at
least 3 to 6 months.14 Injections can be repeated about every
16 weeks, but no more frequently than every 8 weeks. The
usual treatment frequency is once per 6 to 12 months.19
Initial studies of the dose-response of BTX-A on spastic
muscle indicated a bell-shaped curve with response increas-
ing to a plateau then declining at high dosages, possibly owing
to excessive weakness or the diffusion of excess drug to muscle
antagonists. Morton et al.7 noted that the magnitude of the
peak response and the overall duration were directly propor-
tional. The escape of toxin from the muscle through venous
and lymphatic drainage, and by reverse axonal spread to the
central nervous system, limits the total dose administered
safely to 30 units of Dysport per kg body weight, or equiva-
lently 10 units of Botox per kg of body weight.7 The maximum
recommended dose is 900 units of Dysport or 300 units of
Botox in the older child.27 One group with wide experience
of BTX-A injections routinely uses around 25 units of Dysport
per kg per session in the lower limbs.27
Until recently there has been no move to arrive at a con-
sensus on the ‘correct’ dose of BTX-A for the treatment of
spasticity, neither in adult nor paediatric practice.19 The dose
has been determined empirically by the size of the muscle to
be injected, seeking to achieve a clinical response without
excessive weakness or systemic side effects.27 One compara-
tive study of ‘high’ and ‘low’ doses of BTX-A (200 units vs 100
units of Botox per leg)31 demonstrated a dose-dependent
functional improvement of dynamic deformity and gait,
especially evident in younger children. In contrast, Eames
and co-workers,32 using ankle-joint excursion based on
three-dimensional gait analysis, found that the magnitude of
the dynamic lengthening of the gastrocnemius muscle after
BTX-A injection was independent of the dose used. Two
recent studies are of particular relevance: Baker et al.33 and
Polak et al.34 The latter, a double-blind comparison study of
low (8 units/kg) and high (24 units/kg) doses of Dysport sug-
gested a nonlinear dose–response relationship with the
higher dose treatment being slightly more effective and longer
lasting than lower doses. There was a peak response in the
absolute dose range of 200 to 500 units of Dysport. Saturation
of motor endplates and regional spread of the toxin might
have contributed to the lack of statistically significant results,
together with possible individual variability in sensitivity
according to age and type of CP.27 The former was a robustly
designed study33 which demonstrated that whereas doses in
the range 10 to 30 units of Dysport per kg were safe and effec-
tive in the treatment of dynamic equinus spasticity in chil-
dren with CP, the best and longest lasting results were achieved
with a dose of 20 units/kg. Local spread of the toxin, especial-
ly to the soleus, might have accounted for the superior
results compared with higher doses of BTX-A. It was conse-
quently recommended that 20 units of Dysport per kg be
used as an optimal starting dose.
Bakheit et al.35 applied a risk/benefit assessment to try to
rationalize dosage guidelines. Their multicentre, retrospec-
tive study of case records comprised an impressive 758 chil-
dren (94% with spastic CP, 6% with spasticity from other
central pathology) undergoing a total of 1594 treatments
using the Dysport preparation. The overall incidence of
adverse effects was low, but these occurred most frequently in
patients receiving higher doses of BTX-A per treatment ses-
sion and were related to total dose received rather than dose
calculated per kg body weight (suggesting that the number of
neuromuscular junctions is more important than muscle
weight for response to treatment, and supporting the prac-
tice of injecting BTX-A into the target muscle around the site
of nerve penetration and arborization, where the concentra-
tion of neuromuscular junctions is highest). More patients in
the highest dose group reported subsequent functional
deterioration; multilevel injections of smaller doses into a
single muscle resulted in a better response than a single-level
high-dose treatment. They concluded that a dose of more
than 1000 units did not improve the therapeutic response
and possibly increased the risk of adverse events.
What are the adverse effects associated with BTX-A?
Adverse effects of BTX-A can occur locally as a result of exces-
sive doses in a single muscle producing significant transient
focal weakness, or systemically because of an excessive total
body dose to several muscles. With regard to the latter,
although single-fibre electromyography reveals the distant
spread of toxin, few or no generalized effects have been
detected clinically. With local injection, a small amount of
toxin diffuses across fascial planes to neighbouring muscle
groups; this can be reduced, and the positive effects of BTX-A
enhanced, by administering multiple injections into a target
muscle.35 This effect has been explained by the concept of ‘sat-
uration’ of injection sites: once a site is saturated, spread can
occur to neighbouring structures, whereas a larger dose split
between several injection sites is quickly bound locally with no
effects on neighbouring tissues or more centrally.19
Adverse effects are reported to occur infrequently and are
generally mild in nature. Most commonly reported are pain
around the injection site, frequent falls from balance prob-
lems, and generalized fatigue.21,30,32,35–38 Boyd et al.39 propose
that excessive weakening might be under-reported because of
its perception as a positive effect by the physician. In their study
(along with those of Koman et al.37 and Bakheit et al.35) there
was a disquieting report of a small number of children who
experienced transient urinary and faecal incontinence in the
early period after injection, despite the administration of only a
low dose of toxin. They postulated that acetylcholine-mediated
sphincter function might be sensitive to small systemic doses of
botulinum toxin without overt signs of botulism (no study
reported any incidence of the latter); in this light, they advocat-
ed caution in treating children with oropharyngeal impair-
ment and dysphagia, or in injecting the sternocleidomastoid
muscle. The issue of possible systemic spread in children with
pseudo-bulbar palsy is particularly important, because further
impairment of pharyngeal function risks aspiration with poten-
tially fatal consequences. Graham et al.19 called for meticulous
reporting of these potentially serious side effects.
Considerable discussion has centred on the phenome-
non of secondary unresponsiveness, that is, a decreased
response to BTX-A on subsequent administration, after an
Annotation 493
earlier successful treatment. This has been attributed to
the development of neutralizing antibodies against BTX-A.
Although such antibodies are reported to develop in 3 to 10%
of adult patients (especially those requiring frequent injec-
tions, high doses, or booster injections8) their incidence has
not so far been established in children.27,38 Graham19 is hesi-
tant to accept that the low concentrations of neutralizing anti-
bodies found in human patients would block high-affinity
binding to cholinergic nerve terminals within the intramus-
cular compartment. Graham prefers the explanation that
late commencement of treatment allows the natural history
of muscle contracture in CP to unfold, whereby an early
dynamic contracture slowly becomes fixed with passage of
time. An additional consideration is that children undergoing
repeat treatments have rarely returned to their original base-
line parameters, so that later improvements never seem as
marked as those after the initial treatment. Research contin-
ues in this area.
How do changes induced by botulinum toxin influence daily
life and functional disability?
This is one of the most fundamental and important questions
to answer about BTX-A.
After interventions to reduce spasticity, functional gains are
more difficult both to achieve and to measure than objective
parameters, such as reductions in muscle tone and increased
joint range of motion. To be realistic, these goals are often indi-
vidual to the patient, further complicating their measurement
in a formal trial. The measurement tools themselves are limit-
ed, few are validated, and most are, of necessity, influenced by
subjective assessment, whether of the parent/child or the pro-
fessional. The continuing maturation of the central nervous
system and the growth of the child also influence outcome
measures and need to be taken into account. Forssberg and
Tedroff12 highlighted the lack of controlled studies with appro-
priate functional outcome measures and adequate power sup-
porting the use of BTX-A in children, whereas a systematic
review28 found no consistent evidence of any beneficial effect
of BTX-A on function. We need both the validated functional
tools and well-designed trials to detect significant change due
to treatment in children with CP.19
The most widely accepted validated outcome measure is
the Gross Motor Function Measure (GMFM),40 although it may
only be well suited to moderately affected children – children
with severe disability are not good candidates for GMFM assess-
ment and, at the other end of the spectrum, functional changes
in mildly affected children might be missed because of inade-
quate sensitivity. Standardized questionnaires such as the
Pediatric Evaluation of Disability Inventory (PEDI)41 and the
Functional Independence Measure for Children (WeeFIM)42
also measure changes in functional independence and/or
impact on lifestyle, and can be performed relatively easily in
the home or school environment by a trained therapist.
However, their major disadvantage is a lack of specificity
because they fail to differentiate between improved function
from compensatory mechanisms and improvement directly
due to the intervention under assessment.43
In ambulant patients one important measurable functional
outcome for both parents and professionals is improved gait.
A wide range of gait assessment tools has been developed
during recent years, from the simple subjective videotape to
the highly sophisticated combined kinematic/kinetic gait analy-
494 Developmental Medicine & Child Neurology 2004, 46: 491–499
sis. These have been exploited to varying degrees in studies
of the effects of botulinum toxin. In non-ambulant patients,
as well as in the upper limb, measures are less standard-
ized, although factors such as comfort, ease of care, and
cosmesis, all influenced by the level of muscle tone, are
highly significant.
Early studies demonstrated improvements in walking
after injection of BTX-A, with the use of a variety of outcome
measures. The most frequently favoured is observational assess-
ment of gait from videotape by using the Physician Rating
Scale,21 which is particularly useful when children are too
small or insufficiently cooperative for instrumented gait analy-
sis. A few studies36,44,45 included three-dimensional gait analy-
sis and demonstrated post-injection improvements in both
kinematics (dynamic range of ankle joint motion) and kinet-
ics (ankle joint moments and power generation). Koman et
al.37 reported the first large well-controlled randomized study
to document improvement in gait pattern and active ankle
range of movement after BTX-A injections, with documented
improvements lasting a minimum of 8 weeks.
Ubhi et al.38 also confirmed improvements in walking pat-
tern after reduction in lower-limb spasticity with BTX-A, but
they did not relate this to changes in general gait parameters
(stride length, cadence, velocity), which are sensitive indica-
tors of how well a patient walks. Changes in energy expendi-
ture/walking efficiency, measured by the Physiological Cost
Index, were not statistically different before and after treat-
ment. (Physiological Cost Index = (Hw – Hr)/S, where Hw is the
average heart rate throughout a standard walk in beats/min,
Hr is the resting heart rate, and S is the average speed of walk-
ing in metres/s.) However, functional outcomes assessed by
the GMFM showed a statistically significant improvement in
favour of BTX-A.
Energy expenditure, and hence walking efficiency, was
also measured by Corry et al.22 in their study of BTX-A injec-
tions into the hamstring muscles of children with CP and
crouch gait. A significant improvement in knee joint kinemat-
ics was associated with a significant decrease in energy con-
sumption, as measured by the Cosmed K2 system. Massin and
Allington46 showed an improvement in oxygen uptake dur-
ing a standardized exercise protocol, which was maintained
in some patients at 6 months’ follow-up.
Boyd et al.36 used three-dimensional gait analysis, and in
particular ankle joint kinematics and kinetics, in a prospec-
tive study of the effects of BTX-A on the gastrosoleus muscle
complex in ambulant children with CP. They confirmed pre-
vious reports of improved sagittal plane kinematics, and
showed a tendency towards normalization of ankle joint
kinetics after injection. Of particular note was the restoration
of the characteristic burst of ankle power associated with
push-off in terminal stance in children responsive to BTX-A.
Reddihough et al.47 performed a cross-over study of botu-
linum toxin plus physiotherapy and physiotherapy alone in
49 children with spastic diplegia or mild to moderate quadri-
plegia. Gross motor functional outcome was assessed by the
GMFM,48 performed at 3 and 6 months in the BTX-A period
and at 6 months in the control period. The expected benefits
of regular physiotherapy were once again demonstrated, with
both groups showing sustained improvement of gross motor
function. However, parents consistently reported more func-
tional benefits from the BTX-A, with ‘best results’ occurring
about 6 to 12 weeks after injection, that is, before the first
formal assessment, which might therefore have missed the
peak response.
In the treatment of hip adductor spasticity with BTX-A, the
aim is twofold, depending on the level of motor involvement
of the child. In mildly and moderately affected patients,
improvement of gross motor function and walking is the goal,
whereas pain relief or the facilitation of hygienic care are
important in more severely affected patients. Open-label trials
from Germany have demonstrated functional benefits after
BTX-A treatment of adductor spasticity, but there remains a
need for placebo-controlled trials to provide further, more
concrete, evidence. Heinen et al.23 reported a prospective
study of 26 children in whom functional benefit was assessed
with the GMFM as well as by parental evaluation of treatment
with the use of a standardized questionnaire. Reported ben-
efits included facilitation of daily care, ease of positioning,
and reduction of pain. For children with milder forms of the
disability, functional benefits were improved comfort in sit-
ting, standing for longer periods, and/or walking for longer
distances.
Functional outcome is particularly difficult to measure in
the upper limb, with fewer validated tools and more reliance
on subjective measurements. Corry et al.25 found that although
BTX-A significantly reduced tone at wrist and elbow, with
improvements in active elbow and thumb extension, func-
tional results measured in terms of grasp were equivocal,
with some patients even reporting temporary deterioration.
Fehlings et al.26 demonstrated improvements in both the
quality of functional movement in the upper extremity and
functional capability in children with hemiplegic CP with the
use of the QUEST (Quality of Upper Extremity Skills Test), a
standardized measure of quality of function in the upper
extremity. Parents reported improved self-care skills. The sin-
gle most reported benefit25 had little to do with function but
everything to do with cosmesis; namely, a reduction in elbow
flexion posturing during fast walking. The importance of the
cosmetic factor should not be forgotten in evaluating the
benefits in children who do not wish to be perceived as differ-
ent from their peers.
The serendipitous observation by Graham and colleagues14
that children with spastic CP who received BTX-A to ham-
strings and calf muscles during hip surgery experienced less
post-operative pain opened up a further application for BTX-
A. Barwood et al.49 conducted a randomized controlled trial
of 16 such patients undergoing adductor release surgery, and
found that not only did children receiving BTX-A have reduced
mean pain scores and analgesic medication requirements,
but their mean hospital stay was also reduced, making BTX-A
a cost-effective option. The analgesic effect of BTX-A in acute
pain, caused at least partly by muscle spasm, has a potentially
wider application to other clinical situations.
What are the long-term effects of BTX-A on muscle
contracture?
Short-term effects of BTX-A have been well established since
the days of early clinical trials. Eames et al.32 reported a tem-
porary muscle lengthening effect in the gastrosoleus muscle
complex during gait, with a linear response between this
dynamic lengthening and the response to BTX-A injection.
However, by 1 year after treatment there was no measurable
response in the vast majority of children and, unlike the orig-
inal hereditary spastic mouse model, the short-term increase
was not translated into long-term benefit. In contrast, uncon-
trolled studies with repeated injections over at least a year21,30
showed continuing improvements in gait persisting in some
patients after 46 months of therapy.
Boyd et al.39 attempted to address this question in their
analysis of the medium-term response to BTX-A. Their open-
label study included 197 children followed up for a period of
21⁄2 years, all of whom received the Botox preparation of BTX-A
at multiple sites. Four subgroups of responders were identi-
fied. By far the largest comprised the ‘clinical responders’
(75% of the total) who experienced functional gain for 6 to
12 months. A further 15% were classified as minimal respon-
ders on the basis of reduced muscle tone but no functional
gain, and only 5% failed to respond at all. The remaining 5%
constituted an interesting subgroup, the so-called ‘golden
responders’, in whom functional benefits persisted well
beyond the expected duration of the pharmacological effects
of BTX-A. This ‘golden response’, occurring in younger chil-
dren with focal dynamic problems only, has been attributed
to a change in clinical progression due to medication.32 Of
the total of 197 children, just less than half were still receiv-
ing BTX-A injections at approximately 12-monthly intervals
at the time of the latest follow-up, whereas 17% had required
isolated soft tissue release, and 38% had progressed to sin-
gle-event multilevel surgery. BTX-A apparently slowed the
progression to surgery, allowing more appropriate timing in
terms of linear growth.
Only recently have the early cohorts of BTX-A patients
started to progress to surgical management, meaning we can
begin to assess the effects of the treatment on the natural his-
tory of the deformity. Increasing years of clinical experience
and more widespread use of BTX-A will lead to the accumula-
tion of the necessary long-term data on safety and outcomes.
Such long-term follow-up trials will require a consensus
opinion on objective outcome measures and clinical rating
scores by all involved with these children through the transi-
tion to adult care.
Will BTX-A treatment delay the development of fixed
deformity and defer the need for orthopaedic surgery?
This is a corollary from the question relating to the long-term
effects of BTX-A on muscle contracture, and the long-term
follow-up data needed to answer it are likewise still being accu-
mulated. Evidence is mounting to support the theory that
different muscles follow different ‘biological clocks’ in the
transition from reversible/dynamic posturing to fixed/mus-
culotendinous contracture – for example, the dynamic phase
of spasticity has been noted to persist longer in the upper
limb than in the lower.19 Biomechanical data suggest that bio-
mechanical alignment and gait patterns (factors shown to be
influenced by BTX-A treatment) are also important in the
development of fixed deformity.14
To delay surgery for as long as possible has benefits in
terms of subsequent mobility and independence. At an older
age the risk of recurrence of deformity or operative compli-
cations is reduced,21 and what has been termed by Mercer
Rang as the ‘birthday syndrome’ (an operation for each birth-
day, followed by physiotherapy to relearn a walking tech-
nique, followed by further surgery to release the consequently
contracted muscles)48 is replaced by a single definitive proce-
dure. Firm evidence is currently scanty. Koman et al.50 studied
the effect of BTX-A on the natural history of equinus foot
Annotation 495
deformity in CP. They followed their patients for a maximum
of 61⁄2 years after injection and demonstrated that tendo-
achilles lengthening was delayed by a mean of 3.8 years. In a
series of 12 patients in whom tendo-achilles surgery was rec-
ommended before BTX-A therapy, BTX-A delayed surgery by
an average of 21 months, and three patients avoided surgery
for more than 60 months.37
Is it possible to influence gross motor learning during early
childhood by repeated injections?
The rationale behind this hypothesis is that a reduction in
muscle tone might allow a child to develop normal motor
coordination that is otherwise prevented by spasticity and
secondary musculoskeletal malformations, and thus alters
the natural history of the deformity. Although muscle tone is
reduced within 72 hours of BTX-A injection, acquisition of
functional skills does not always take place immediately in
children with CP, as motor learning to utilize the new biome-
chanical conditions might be delayed.
Eames32 noted that the effects of BTX-A persisted beyond
1 year after injection in a minority of their study group, and
postulated that altered muscle balance around a joint might
impose a different biomechanical environment on the muscle,
thus influencing long-term outcome. Koman et al.37 hypothe-
sized that BTX-A might improve a patient’s ability to strength-
en weaker antagonist muscles, and the chemically-induced
improvement in muscle balance might then seem to enhance
the effects of physiotherapy and orthotics. Graham19 noted that
treatment during the dynamic phase of motor development
maximized the chance of permanent modification of the dis-
ease and possibly allowed postponement, simplification, or
even avoidance of surgery. The problem is to identify the crit-
ical injection period early in the history of the deformity, dur-
ing which these favourable effects can be achieved.
Is BTX-A treatment cost effective?
The cost of any disease can be considered as a combination
of four components: medical resources used to treat the ill-
ness, associated non-medical resources, the lost productivity,
and the intangible cost of pain. Although improvement in qual-
ity of life from treatment is central, its financial cost is difficult
to calculate. At present, the data that specifically quantify the
health economic benefits of BTX-A treatment is limited.
Corry et al.29 performed a preliminary calculation of the cost
of BTX-A compared with serial casting. Although the cost of
the two treatments was of a similar order of magnitude at the
time of the study, they postulated that the costs of BTX-A
would decrease as it was used more widely. Flett et al.15
found that, for a single leg, cost analysis was in favour of cast-
ing, but when both legs were treated in the same individual
the costs were more comparable.
Boyd et al.51 reported an analysis of cost effectiveness of
BTX-A with or without casting versus casting alone in the
management of spastic equinus, with outcome defined by
progression to surgery. Their modelled economic evaluation
synthesized data from published randomized controlled tri-
als15,29 and a prospective cohort study. Costs were estimated
in terms of resource utilization. Both treatment groups deliv-
ered equal efficacy in terms of magnitude of response, but
BTX-A provided a superior duration of response.29 Although
there were additional costs per child per year associated with
BTX-A with or without casting versus casting alone, these
496 Developmental Medicine & Child Neurology 2004, 46: 491–499
were offset against a delayed need for surgery and a superior
long-term outcome. They concluded that BTX-A was both
valuable and cost effective in the treatment of CP.
Conclusion
Botulinum toxin is a treatment with great potential, but it
needs to be given in the right dose, to the right child, at the
right time and frequency, with outcome measured in the
right way. However, with no standardized established proto-
cols, there is no precise definition of what we mean by ‘right’.
Further studies are continuing, and as more information
becomes available, especially with respect to the longer-term
outcome, the answers will become clearer. It is important that
such studies be allowed to continue unimpeded by popular
opinion based on sensational media publicity, if we are to
give children with CP and their families the care they truly
deserve in the future.
DOI: 10.1017/S0012162204000817
Accepted for publication 10th February 2004.
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Annotation 497
Appendix I: Summary of botulinum toxin A trials

Reference Design Participants Outcome measures Results Implication

21 Preliminary 27 patients, dynamic deformities Physician Rating Scale, Reductions in spasticity BTX-A may delay
open-label 16 ambulatory, 11 more severe subjective assessment lasting 3–6mo without orthopaedic surgery
study 1–2U/kg Botox/muscle group by carers major side effects
18 Open-label study 26 patients, BTX-A to Sagittal-plane Reduced tone; improved Fixed contractures
gastrosoleus complex/tibialis/ kinematics ankle kinematics with develop gradually
posterior/hamstrings. electrogoniometry gains in dorsiflexion with age
Dynamic contractures inversely proportional to
5–28U/kg body weight Dysport the age of participant
30 Randomized Small trial: 6 children BTX-A, Physician Rating Scale 83% BTX-A group versus BTX-A an effective
double-blind 6 placebo for gait, muscle 33% placebo group treatment for
placebo-controlled 1 U/kg Botox/leg strength, physiotherapy, showed improved gait dynamic deformity;
trial carer questionnaire effects last 3–6mo
29 Randomized 20 children with dynamic Physician Rating Scale, Improved gait in both BTX-A at least as
clinical trial, BTX-A calf equinus 3D kinematics, groups. BTX-A effective as serial
vs serial casting 6 U Botox/kg/muscle or muscle tone significantly improved casting, but longer
15 U Dysport/kg/muscle dynamic range of lasting
ankle joint motion
15 Randomized 20 children, 10 BTX-A, 10 Muscle tone, GMFM Improved gait, muscle BTX-A and casting
controlled trial, placebo with dynamic (REF), ankle joint tone, passive ankle have similar effects
BTX-A vs serial calf tightness range of movement, dorsiflexion in both and costs. Parents
casting 4–8U/kg Botox gait – Physician Rating groups at 6mo favoured BTX-A
Scale, parent satisfaction
questionnaire
45 Double-blind 20 children, gastrosoleus Gait studies with 3D Improvements in Short-term efficacy
placebo-controlled complex injected. kinematics/kinetics, maximum dorsiflexion of BTX-A to improve
trial 2–4U Botox/kg body weight EMG in both stance and gait
swing phases
32 Open-label 39 children, gastrocnemius 3D kinematics as Short-term muscle Need for orthopaedic
prospective study injected. 8–10U/kg Botox or measure of changes in lengthening. Diplegia surgery, delayed
20–25U/kg Dysport gastrocnemius length better response than
hemiplegia
50 Open-label study 48 patients Response to BTX-A: Improved gait and BTX-A delayed
4–7U Botox/kg body weight Physician Rating Scale, function, sustained need for surgery
progression to surgery long term
46 Open-label 15 children, Energy cost of walking: Reduced energy cost and –
prospective study 6U/kg Botox oxygen uptake in improved endurance
response to exercise
31 Randomized 33 children Muscle tone, range of High dose better Dose-dependent
double-blind, High dose: 40–80U Botox/muscle movement (knee and response than low. functional
high dose vs Low dose: 20–40U Botox/muscle ankle), general gait Greater functional benefit improvement
low dose parameters in younger children
39 Open-label 197 children Response to BTX-A 55% later surgery BTX-A safe and
cohort study 2–4U Botox/kg/muscle Time to next intervention 45% repeated BTX-A effective
Adverse effects 80% clinical responders
with improved function
36 Open-label 25 children, 15 diplegia, Muscle tone, ankle Improved patterns of Change in
prospective 10 hemiplegia range of movement. ankle joint moment functioning of
study 4–9U Botox/kg/muscle 3D kinetics: ankle joint and power generation muscle post BTX-A
moment and power
37 Randomized 114 children with CP Physician Rating Scale, Improved gait, partial BTX-A may delay
double-blind, and dynamic foot deformity ankle range of motion, denervation of injected orthopaedic surgery
placebo-controlled 4U Botox/kg EMG: quantification muscle
trial of muscle denervation

3D, three-dimensional; BTX-A, botulinum toxin type A; EMG, electromyogram; GMFM, Gross Motor Function Measure; QUEST, Quality of
Upper Extremity Skills Test.

continued...

498 Developmental Medicine & Child Neurology 2004, 46: 491–499

Appendix I: continued

Reference Design Participants Outcome measures Results Implication

38 Randomized 40 children: 22 BTX-A, 18 placebo; Video gait analysis, Improved gait and Effective adjunctive
double-blind, gastrosoleus injected GMFM, ankle function in BTX-A treatment to
placebo-controlled 25U/kg Dysport in diplegia, dorsiflexion range, group improve spasticity and
trial 15U/kg in hemiplegia Physiological Cost Index functional mobility
35 Multicentre 758 patients undergoing Adverse events from Increased adverse effects Recommended
retrospective 1594 treatments BTX-A with higher doses. maximum total
study Dysport Multilevel treatments dose = 1000U
give better response Dysport
than single level

33 Multicentre, 125 children with diplegic Change in dynamic Dynamic component Recommended
randomized cerebral palsy and dynamic component of of spasticity most optimal starting
double-blind equinus spasticity during walking gastrocnemius improved in 20U/kg dose 20U/kg
placebo-controlled Patients randomized to receive shortening at 4wks group
study 10, 20 or 30U/kg Dysport after injection
34 Double-blind 48 children with spastic Instrumented gait Optimal dose range –
comparison study hemiplegic CP. analysis, maximum between 200 and 500U
High dose (24 U/kg) versus ankle angle in stance with higher dose/kg
low dose (8U/kg) Dysport and swing phases; more effective and
gastrocnemius longer lasting
muscle length
47 Cross-over study 49 children with spastic GMFM, fine motor Unsustained Timing of formal
diplegia/quadriplegia assessment, modified improvements in gross assessments missed
BTX-A plus physiotherapy Ashworth scale, motor function in peak gross motor
versus physiotherapy alone parental perception both groups, small function response
ratings increase in fine motor
ratings in BTX-A group.
Parental ratings
favoured BTX-A
24 Open-label 10 children with crouch gait Hamstring length and Increased muscle length, Short hamstrings
study, hamstring 5–8U Botox/kg/muscle excursion from with improved knee over-diagnosed
spasticity 35U/kg Dysport computer model extension. Increased in crouch gait
walking speed, pelvic tilt,
and hip flexion
22 Open-label 10 children, dynamic Muscle tone, range Improved knee extension Longitudinal
study, hamstring hamstring spasticity of movement, in stance; mean pelvic muscle growth
spasticity 5–8U botox/kg 3D kinematics tilt increased. Energy cost occurs after
6U/kg Dysport Oxygen uptake of walking unchanged BTX-A injection
23 Open-label 2 children with adductor Tone, joint mobility, Improved function, Beneficial effects
prospective study spasticity GMFM, parent positioning, gait and of BTX-A on daily
No dose of BTX-A stated questionnaire posture, facilitation of care activities
25 Double-blind, 14 children Range of movement, Maximum elbow and Improved cosmesis
randomized, 4–7U Botox/kg muscle tone, functional thumb extension subjectively. Need
placebo-controlled or 8–9U Dysport/kg hand tests increased; reduced tone good motor control
trial Injections to upper limb wrist and elbow; fine motor to benefit
function unchanged functionally
26 Randomized 30 children, hemiplegia Functional assessment Functional improvement BTX-A effective to
controlled 2–6U Botox/kg into at least 1 of 3 (QUEST), goniometry, on QUEST; improvement improve upper limb
single-blind trial upper limb muscle groups grip strength, muscle tone in self care skills function in hemiplegia
49 Double-blind, 16 patients undergoing Pain scores, analgesia Reductions in all 3 Significant proportion
randomized hip adductor release surgery. requirements, length outcome measures of post-op pain from
controlled trial 8U Botox/kg body weight of hospital stay with BTX-A muscle spasm,
relieved by BTX-A

Annotation 499