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Functional Outcomes of Intramuscular Botulinum Toxin
Type A in the Upper Limbs of Children With Cerebral Palsy:
A Phase II Trial
Margaret A. Wallen, MA, BAppScOT, Stephen J. O’Flaherty, FRACP, FAFRM, MB ChB, MD,
Mary-Clare A. Waugh, FRACP, MBBS, FAFRM
ABSTRACT. Wallen MA, O’Flaherty SJ, Waugh M-CA.
Functional outcomes of intramuscular botulinum toxin type A
in the upper limbs of children with cerebral palsy: a phase II
trial. Arch Phys Med Rehabil 2004;85:192-200.
Objective: To describe the functional and family-centered
assessment protocol and outcomes of a phase II trial evaluating
upper-limb function after botulinum toxin injections in children
with cerebral palsy (CP).
Design: Intervention study, case series, phase II trial, fol-
low-up at 2 weeks and 3 and 6 months.
Setting: Specialist outpatient physical disabilities clinic
within a public pediatric teaching hospital.
Participants: Convenience sample of 16 children with CP
(age range, 2–12y).
Interventions: Botulinum toxin type A (Botox) injections
after electrical stimulation localization of appropriate muscle.
Main Outcome Measures: The Canadian Occupational Per-
formance Measure (COPM), Goal Attainment Scale (GAS),
Melbourne Assessment of Unilateral Upper Limb Function,
Child Health Questionnaire (CHQ), parent questionnaire, Mod-
ified Ashworth Scale (MAS), Tardieu scale, and active
(AROM) and passive (PROM) range of motion.
Results: On the COPM, there was significant improvement
at 3 months and 6 months. On the GAS, the T-scores were 42
and 47 at 3 and 6 months, respectively. On the Melbourne
Assessment and CHQ, there was no significant change. The
parent questionnaire indicated acceptability of injections and
positive outcomes. On the MAS, there was a significant reduc-
tion in tone at 2 weeks, with a return to baseline by 6 months.
On the Tardieu scale, there was a significant increase in angle
of first catch at 2 weeks, but only the elbow maintained a
significant difference at 3 and 6 months. No significant change
was found for AROM or PROM.
Conclusions: Sustained functional outcomes occurred after
botulinum toxin injections despite increasing muscle tone after
an initial reduction in tone. Randomized controlled trials are
required.
Key Words: Arm; Botulinum toxin type A; Cerebral palsy;
Clinical trials, phase II; Outcome assessment (health care);
Rehabilitation.
©2004 by the American Congress of Rehabilitation Medi-
cine and the American Academy of Physical Medicine and
Rehabilitation
INTRAMUSCULAR BOTULINUM TOXIN type A (BTX)
injections are an option available for the management of
spasticity in children with cerebral palsy (CP). The injections
are widely used and accepted practice in managing lower-limb
spasticity but are a more recent addition to the management of
the upper limb. In preparation for a randomized controlled trial
(RCT), we completed this phase II trial to test our methodol-
ogy, injection procedures, and outcome measures and to gather
preliminary data on the efficacy of BTX injections to the upper
limbs of children with CP.
Botulinum toxins are protein products of Clostridium botu-
linum,
1-3
which is a potent neuromuscular paralyzing agent.
When injected in minute doses into muscle, BTX blocks the
release of acetylcholine, functionally denervating parts of the
muscle and resulting in a localized, dose-related weakness of
the muscle.
1,4
Because of the toxin’s rapid and high-affinity
binding to receptors at the neuromuscular junctions of the
target muscle, little or no systemic absorption of toxin occurs.
5
The nerves resume function after several weeks when they
generate new neuromuscular junctions by terminal axonal
sprouting.
3,5
Research in mice has found that these new termi-
nal sprouts ultimately recede when function returns to the
original terminals.
5
In theory, the weakness and resultant reduction in muscle
tone caused by BTX injections provides a window of oppor-
tunity for therapeutic intervention.
3
It is postulated that the
decreased muscle tone will enable increased range of motion
(ROM), the potential to strengthen the antagonist muscles, and,
therefore, the opportunity to develop better motor control.
6
This period of reduced muscle tone may allow recipients of
BTX to learn new patterns of movement on which to build
functional abilities.
The evidence for the use of BTX in upper-limb spasticity is
emerging. Two RCTs
6,7
have investigated the effects of BTX
injections in the upper limb in children with spastic CP. A
double-blind trial by Corry et al
7
compared BTX injections
with a saline placebo in 14 children (age range, 4–19y) with
CP. Coexisting interventions were not mentioned. Some dif-
ferences in muscle tone, active ROM (AROM), and a single
grasp and release score were noted. Corry reported that there
were no systemic complications and that 2 of the 7 children had
excessive but temporary weakness interfering with hand func-
tion.
The second RCT by Fehlings et al
6
was a single-blinded
(data collector) study of 30 children (age range, 2–10y) with
From the Departments of Occupational Therapy (Wallen) and Rehabilitation
(O’Flaherty, Waugh), The Children’s Hospital, Westmead, NSW, Australia.
Presented in part at the OT Australia 21st National Conference, April 1–4, 2001,
Brisbane, Australia; the 8th Annual Scientific Meeting of the Australasian Faculty of
Rehabilitation Medicine, August 15–19, 2000, Melbourne, Australia; satellite meeting
of the 8th Annual Meeting of the Australasian Faculty of Rehabilitation Medicine,
August 19, 2000, Melbourne, Australia; and the European Academy of Childhood
Disability, 2000, Tubingen, Germany.
Supported by the Small Grants Scheme of The Children’s Hospital at Westmead.
Botox was donated by Allergan Australia P/L.
No commercial party having a direct financial interest in the results of the research
supporting this article has or will confer a benefit upon the author(s) or upon any
organization with which the author(s) is/are associated.
Reprint requests to Margaret Wallen, MA, Occupational Therapy Department, The
Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Austra-
lia, e-mail: margarew@chw.edu.au.
0003-9993/04/8502-8098$30.00/0
doi:10.1016/j.apmr.2003.05.008
192
Arch Phys Med Rehabil Vol 85, February 2004
spastic CP randomized into either BTX or no BTX groups.
Both groups continued with their usual occupational (OT) and
physical therapy (PT) at a frequency of approximately 1 ses-
sion per fortnight. This RCT found no significant differences
between groups on muscle tone, passive ROM (PROM), or grip
strength. Significant improvement in quality of upper-limb
function (Quality of Upper Extremity Skills Test [QUEST])
was noted in the BTX group at 1 month (but not 3 or 6mo) and
on the functional skills self-care domain raw score of the
Pediatric Evaluation of Disability Inventory (PEDI; 2-way
analysis of variance). On post hoc analysis, the differences
approached, but did not reach, significance at 1 and 6 months
and were not reported at 3 months. The only side effect
reported was decreased grip strength in 1 child, which lasted 2
weeks.
In addition to these RCTs, there have been a small number
of pre-post studies have evaluated the effects of BTX in chil-
dren with spastic CP, for example, Wall,
8
Friedman,
9
and
Autti-Ramo
10
and colleagues. The results from 2 small RCTs
and the nonrandomized studies are not sufficient evidence to
justify the use of BTX injections as standard clinical manage-
ment of spasticity in the upper limbs of children with CP.
11
The
RCTs
6,7
reported conflicting results for tone and ROM, al-
though Friedman’s study
9
provided some evidence for im-
proved muscle tone. Three studies
6-8
reported some other pos-
itive findings (hand function, appearance, caregiver ratings),
but the evidence is inconclusive. This appraisal of the literature
generated a number of research questions including (1) What
are the functional outcomes of BTX injections (upper-limb
function, daily living skills, achievement of goals)? (2) Is BTX
effective in reducing muscle tone and increasing ROM? (3)
What is the influence of changing muscle tone and ROM on
functional outcomes? and (4) Does OT after BTX injections
enhance the outcomes of the injections? Children receiving
BTX injections should experience meaningful improvements in
their abilities to use their upper limbs to participate in activities
of daily living (ADLs). Further research using objective out-
come measures of hand and upper-limb function and ADLs is
required.
We completed this phase II trial in preparation for an RCT
to explore some of these research questions. The aims of our
project were to pretest our methodology, the procedures, and,
in particular, the outcome measures and to consolidate exper-
tise in selecting children for BTX treatment and in using
electrical stimulation for localization of muscles. We also
aimed to collect preliminary data on functional outcomes,
muscle tone, and ROM.
The 2 objectives of our report were to present our functional,
objective, and family-centered assessment protocol and to re-
port the outcomes of the project.
METHODS
Participants
Sixteen children who had spastic CP and were between the
ages of 1 and 14 years were selected from a convenience
sample of children presenting to the Physical Disabilities Clinic
at The Children’s Hospital at Westmead, Australia. One study
arm from each child was selected for injection. Eligibility
criteria included (1) presence of spasticity with a rating of 2 or
3 on the Modified Ashworth Scale
12
(MAS) in at least 1
upper-limb muscle group and (2) a family goal relevant to 1
study upper limb (eg, improve function, hygiene, splint toler-
ance, limb positioning). Participants were eligible provided that
they maintained their existing spasticity management program
(eg, splints, medications) for at least 6 weeks before trial
commencement. Exclusion criteria included fixed contracture,
lack of motor control, and fluctuating muscle tone in the study
arm. No new management strategies were introduced during
the 6-month follow-up period.
Procedure
The study was approved by the Ethics Committee of The
Children’s Hospital. Written, informed consent was obtained
before participation. Each child received 1 set of injections
after baseline assessment and was reevaluated 2 weeks, 3
months, and 6 months later. Experienced pediatric occupational
therapists collected the data. Participants completed the video-
taped Melbourne Assessment of Unilateral Upper Limb Func-
tion
13
(Melbourne Assessment), and their families completed
the Child Health Questionnaire
14
(CHQ) and a questionnaire to
determine parents’perceptions of change. Families were as-
sisted in completing the Canadian Occupational Performance
Measure
15
(COPM) and the Goal Attainment Scale
16
(GAS).
The parent, caregiver, and child were invited to participate in
these assessments; together they made the decision whether
there was a primary or joint respondent. A neurodisability
pediatrician and research nurse assessed each participant’s
study arm using the MAS, the Tardieu scale, and goniometric
measurements of AROM and PROM. See table 1 for the
complete assessment schedule. Another independent occupa-
tional therapist, blinded to the temporal ordering of the assess-
ments, scored the videorecorded Melbourne Assessment. Fam-
ilies and therapists were asked to maintain existing levels of
therapy through the 6-month study period.
Outcome Measures
Outcome measures were selected to assess impairment, ac-
tivity, and participation according to the World Health Orga-
nization’sInternational Classification of Functioning, Disabil-
ity and Health.
17
Canadian Occupational Performance Measure. The
COPM
15,18
is a family-centered tool that guides participants to
identify difficulties in their self-care abilities, productivity (in
the case of children, usually school or preschool), and leisure
activities. Five of the most important areas are selected and
then rated by participants on 2 scales: perception of current
performance and satisfaction with current performance. The
rating scales are 10-point scales where scores closer to 10
indicate perceived better performance and increased satisfac-
tion. These ratings were repeated at 3 and 6 months to deter-
mine change in the participants’perceptions. The COPM,
which has been used previously in research with children with
CP,
19
has adequate validity, excellent test-retest reliability, and
responsiveness.
18-22
Table 1: Assessment Schedule
Baseline 2 Weeks 3 Months 6 Months
Melbourne
Assessment
✓✓✓✓
COPM ✓✓✓
GAS Goals
established
✓✓
CHQ ✓✓✓
Parent
questionnaire
✓✓✓✓
MAS, Tardieu
scale, ROM
✓✓✓✓
193UPPER-LIMB OUTCOMES OF BOTULINUM TOXIN IN CEREBRAL PALSY, Wallen
Arch Phys Med Rehabil Vol 85, February 2004
Goal Attainment Scale. The GAS is widely used as an
individualized outcome measure of attributes where no stan-
dardized measure exists.
16,23,24
Responses to the COPM guided
participants to identify up to 5 functional goals that were used
for the GAS. Each goal was scaled from –2 (current level of
performance) through 0 (desired outcome) to ⫹2 (much greater
than expected outcome). At 3 and 6 months, the scores from the
level of goals achieved were summed and converted to a
T-score. A T-score of 50 indicates that goals are, on average,
achieved. Experienced pediatric occupational therapists were
trained in and completed the GAS collaboratively with the
families, thus enhancing the reliability of the GAS.
24
Melbourne Assessment. The Melbourne Assessment
13
was
developed to quantify quality of upper-limb function in chil-
dren aged 5 to 15 years old with neurologic impairment. The 16
items examine reach, grasp, release, or manipulation. Items are
scored from a videotape according to ROM, accuracy of move-
ment, fluency of movement, dexterity, speed, and/or sustained
grasp.
Construct and content validity of the Melbourne Assessment
are established,
25
and support for concurrent-criterion validity
exists.
13,25
Internal consistency and interrater and intrarater
reliabilities for the total score are better than adequate.
13,26,27
Test-retest reliability is high.
27
There is preliminary support for
the sensitivity of the Melbourne Assessment in children with
acquired cerebral insult.
13
Australian authorised adaptation of the CHQ. This 50-
item parent/proxy report form of the CHQ (PF50) has adequate
reliability and validity
14,28
and is a measure of functional health
and well-being in children aged 5 years and older.
14
The utility
of the American version
29
for measuring the health and well-
being of a North American cohort of children with CP has
already been established.
29
The 50 items are spread over 13
health-related scales including physical functioning, bodily
pain, general health, self-esteem, social/physical roles, and
family cohesion.
Parent questionnaire. The parent questionnaire designed
for this study gathered information on parents’perceptions of
change. Parents rated muscle tone, ROM, smoothness of move-
ment, and use of the study upper limb in daily activities on a
10-point ordinal scale where 1 represented least impairment
(ie, normal muscle tone, greatest ROM, smooth movement,
good use) and 10, greatest impairment. (The questionnaire is
available on request from the corresponding author).
Modified Ashworth Scale. The MAS is a 6-point, criteri-
on-referenced ordinal scale of muscle tone measuring resis-
tance during passive muscle stretching. Scores range from 0
(no increase in muscle tone) to 4 (rigid) (includes a rating of
1⫹).
12
Muscle tone in the elbow flexors, wrist flexors, and
pronators were measured using the MAS.
12
Face validity
12
and
good interrater reliability have been reported for the elbow
flexors of adults with spasticity.
12,30,31
Tardieu scale. The Tardieu scale
32-34
grades the quality of
the reaction of the muscle to passive stretch and measures the
dynamic component of muscle spasticity. The dynamic com-
ponent, measured first, is determined by moving a joint as fast
as possible through its full range of movement and measuring
the angle when the muscles first catch, that is, when the stretch
reflex is elicited. The difference between the catch angle and
full PROM of the joint reflects the potential ROM available to
the child if spasticity could be eliminated. The quality of the
muscle reaction is rated from 0 (no resistance through the
course of the passive movement) to 5 (joint immovable). The
Tardieu scale has adequate sensitivity when measuring spas-
ticity in the lower limb, that is, it discriminates between chil-
dren with CP who did and did not receive BTX injections to the
leg.
33
Range of motion. Active and passive shoulder flexion and
abduction, elbow extension, forearm supination, and wrist and
finger extension were measured using standard goniometric
procedures.
35
Intrarater and interrater reliability for passive
elbow flexion and extension is high.
36
Test-retest reliability for
elbow extension, supination, and wrist extension in a group of
children with CP is good.
37
Muscle Selection and Injections
Muscle groups that provided moderate to significant resis-
tance to PROM—contributing to abnormal limb positioning or
movement and inhibiting functional goal achievement—were
identified and injected (table 2). All muscles in a group were
injected—for example, in children whose elbow flexors were
identified for intervention, all elbow flexor muscles were in-
jected (brachialis, brachioradialis, biceps). Injection sites were
identified using surface anatomy and an electromyography
guide
38
to be as close as possible to motor endplates. Electrical
stimulation then confirmed needle placement. A lignocaine-
based topical anesthetic cream (EMLA) was applied to the
injection site at least 60 minutes before injections. Children
inhaled nitrous oxide to assist with sedation and periprocedure
amnesia.
39
The injections were completed in an outpatient
clinic, and children were able to go home immediately after the
injections. One child with a significant intellectual disability
and a behavior disorder required a light general anesthetic and
was discharged the same day. Botulinum toxin type A (Botox),
reconstituted with normal saline to a concentration of 100U in
1mL, was used for all injections. The Teflon-coated Botox
injection needle (37mm, 27 gauge) was used, allowing electri-
cal stimulation to confirm needle placement, particularly for
the smaller and deeper muscles of the forearm. Doses of Botox
were administered according to the recommendations by Russ-
man et al
40
: 0.5 to 2U of Botox per kilogram of bodyweight per
muscle, a total dose not exceeding 12U/kg (or 400U) per visit,
and a maximum of 50U (volume, 0.5mL) per injection site.
Once the intended muscle was located with electrical stimula-
tion, the needle was aspirated to ensure that the dose of Botox
was not injected into the vascular compartment.
Data Analysis
Data were managed and analyzed using Microsoft Access
a
database and SPSS.
b
Nonparametric tests were used where
appropriate, given the unlikelihood of achieving normality of
Table 2: Muscle Groups Injected and Dose of Botox
Muscle Groups Injected No. of Participants
Dose of Botox (U/kg)
(mean ⫾SD)
Pronators (pronator
quadratus and teres)
16 2.03⫾.32
Elbow flexors
(brachioradialis,
biceps, brachialis)
10 4.6⫾.36
Wrist flexors (FCR, FCU) 5 2.31⫾.73
Finger flexors (FDP, FDS
⫾lumbricales)
5 3.13⫾1.2
Thumb (FPL, adductor
pollicis, opponens)
6 2.5
Abbreviations: FCR, flexor carpi radialis; FCU, flexor carpi ulnaris;
FDP, flexor digitorum profundus; FDS, flexor digitorum superficialis;
FPL, flexor pollicis longus; SD, standard deviation.
194 UPPER-LIMB OUTCOMES OF BOTULINUM TOXIN IN CEREBRAL PALSY, Wallen
Arch Phys Med Rehabil Vol 85, February 2004
data in a sample of 16 subjects. Statistical significance was set
at the 2% level to account for the use of multiple comparisons.
The 1⫹grade, which is part of the scoring for the MAS, was
recoded to 1.5 for data analysis. Data for the MAS, Tardieu
scale, and ROM are presented for the whole sample and for
those participants who had the respective muscle groups in-
jected. For example, elbow data are presented for all 16 par-
ticipants as well as only for those 10 children who received
injections to the elbow flexors. This procedure was undertaken
to explore whether the influence of the Botox injections was
restricted only to the muscles injected.
RESULTS
The families of 16 children (resulting in 16 injected arms)
provided written informed consent to participate. There were
11 boys and 5 girls, with a mean age ⫾standard deviation of
6.38⫾3.24 years (range, 2–12y). Eight participants had quad-
riplegic spastic CP, 7 had hemiparetic spastic CP, and 1 had
triplegic spastic CP. Fourteen participants had their nondomi-
nant arms injected. Each participant had between 1 and 4
muscle groups injected (mean, 2.6). See table 2 for a summary
of muscles and doses injected. The mean total dose of Botox
was 158.44⫾80.22U, and mean dose per kilogram was
7.16⫾3.26U. All children attended the baseline, 2-week, and
3-month follow-up appointments. Two children did not attend
the 6-month follow-up, despite encouraging changes at 3
months and reminders by telephone and letter to attend the
6-month clinics.
Canadian Occupational Performance Measure
The COPM score used for data analysis was the average
rating (ie, for performance, the ratings on each area identified
were totalled and divided by the number of areas). The median
COPM scores (25th–75th percentile) for the performance rat-
ings were 3.20 (2.52–4.50), 5.65 (4.85–6.36), and 6.10 (5.46–
7.05) for the baseline, 3-month, and 6-month ratings, respec-
tively, and the change differed significantly from baseline at 3
months (P⫽.004) and at 6 months (P⫽.002). The median
scores (25th–75th percentile) for the satisfaction ratings were
3.60 (2.45–5.55), 6.64 (5.60–7.24), and 6.20 (5.65–8.28), and
the changes from baseline to 3 months (P⫽.012) and 6 months
(P⫽.003) were significant.
Goal Attainment Scale
The mean T-scores for the GAS were 42.31⫾13.99 (range,
21–80) at 3 months and 47.36⫾47.36 (range, 21–74) at 6
months. Three participants achieved a T-score of 50 or above
at 3 months, and 8 participants achieved at least 50 by 6
months. Notably, scores indicate achievement of additional
goals from 3 months to 6 months. The most frequent categories
of goals selected (total, 74) were dressing (28%; eg, pushing
arm through sleeve, pulling up pants), leisure (22%; eg, catch-
ing a ball), and eating (20%; eg, holding a cup, stabilizing a
bowl/plate). Other categories of goals were school/preschool
abilities (14%; eg, stabilizing paper to write or cut), postural
and weight bearing (11%; eg, cosmetic appearance of arm
when walking), and other self-care activities (5%; eg, hair
care).
Melbourne Assessment
Ten of the sample were 5 years or older and thus completed
the Melbourne Assessment. The score used for analysis was the
percentage score, calculated by dividing the total raw score by
the total score possible. The total score possible accounted for
missed items or items that could not be scored from video. The
median score (25th–75th percentile) at baseline was 62.06
(52.29–66.39); at 2 weeks, 65.58 (52.81–75.00); at 3 months,
61.48 (56.28–68.85); and at 6 months, 63.11 (54.10–67.21).
No significant differences existed between baseline scores and
the follow-up scores (2wk, P⫽.59; 3mo, P⫽.53; 6mo, P⫽.96).
Authorised Australian Adaptation of the CHQ
No significant difference existed between baseline and 3
months or 6 months on any of the 13 scales or on the physical
and psychosocial scale summaries, which are calculated from
related scales. A positive trend, however, was noted in the
physical functioning scale.
Parent Questionnaires
Overall, the majority of participants reported that the in-
jected arm was “a bit better”or “much better”after injections
at the 2-week (n⫽13/15), 3-month (n⫽10/14), and 6-month
(n⫽10/14) assessments. The remainder of the participants re-
ported that their arm was “much the same.”Most participants
(n⫽9/14) reported that they would “probably”or “definitely”
consider having their child injected again, 4 of 14 would think
about it, and only 1 of 14 would “probably”or “definitely not.”
Parents’ratings of muscle tone, smoothness of movement,
and use in daily activities indicated less impairment at 2 weeks
followed by a gradual increase in impairment by 6 months.
Figure 1 provides graphic presentation of the medians for the 4
Fig 1. Parents’ ratings of child’s muscle tone, use, and smoothness
of movement (1ⴝleast impaired, 10ⴝmost impaired).
Fig 2. Parents’ ratings of ROM at the elbow, wrist, fingers, and
thumb for all participants (1ⴝleast impaired, 10ⴝmost impaired).
195UPPER-LIMB OUTCOMES OF BOTULINUM TOXIN IN CEREBRAL PALSY, Wallen
Arch Phys Med Rehabil Vol 85, February 2004
assessment points. Parents reported that muscle tone decreased
significantly between baseline (median, 7.5; 25th–75th percen-
tile, 5.5–8.75) and 2 weeks (3.5; 3–4; P⫽.001), and 3 months
(4; 2.75–6.25; P⫽.002) but not 6 months (6.5; 4.75–7;
P⫽.035). Smoothness of movement (baseline median, 7; range,
5–8; 2-wk median, 4; range, 4–5; P⫽.008) and arm use in
daily activities (baseline median, 7; range, 5.5–8; 2-wk me-
dian, 5; range, 4–7; P⫽.017) were significantly improved only
at 2 weeks.
Parents’ratings of ROM are presented in figure 2 and table
3. The trends in the data indicate that ROM improved at 2
weeks. The improvement was at least maintained at 3 months,
with a trend toward baseline at 6 months. ROM increased
significantly at 2 weeks and 3 months for the elbow and wrist.
Modified Ashworth Scale
Data are presented for the whole sample as well as for those
participants who had the relevant muscles injected (see table 4;
figs 3A, B). Generally, the muscle tone of the elbow flexors,
pronators, and wrist flexors improved significantly at 2 weeks
and then gradually returned to or neared baseline at 6 months.
The wrist at 3 months for the whole sample continued to differ
significantly from baseline.
Tardieu Scale
Data are presented for the whole sample and for those
participants who had the respective muscle groups injected. For
both these sets of data, the angle of first catch increased
significantly at 2 weeks for the pronators and elbow, indicating
that the stretch reflex was elicited later in the ROM. The
Table 3: Parents’Ratings of ROM
Whole Sample* Injected Muscles Only*
ROM: elbow n⫽16 n⫽10
Baseline 4 5.5
2.25–7.75 1.00–8.00
2wk 3 2.5
1.25–41–4
.012
†
.026
3mo 2.5 1
1–3.25 1.00–4.75
.007
†
.027
6mo 3 1
1–71–5.5
.233 .066
ROM: wrist n⫽16 n⫽5
Baseline 6 8
2.25–7.75 2.00–9.5
2wk 2.5 2
1–41–6
.004
†
.066
3mo 1.5 1.5
1–4 1.00–2.75
.006
†
.109
6mo 3 1
1–4.25 1.00–2.5
.065 .180
ROM: thumb n⫽16 n⫽6
Baseline 4 3.5
1–6.75 1.75–7.5
2wk 1.5 4
1–4.75 1–5
.024 .279
3mo 2 3
1–51–5
.210 .581
6mo 2 2
1–5.5 1–5.5
.348 .655
ROM: fingers n⫽16 n⫽5
Baseline 2 3
1–5.25 1–6.5
2wk 1 1
1–1.75 1–1
.042 .109
3mo 1 1.5
1–3.25 1–2
.260 .276
6mo 1.5 1
1–41–1
.832 .317
NOTE. Values are median, 25th–75th percentile, and *Pvalues for
difference from baseline.
†
Indicates significant difference.
Table 4: MAS
Whole Sample* Injected Muscles Only*
Pronators n⫽16
Baseline 2
2–2
2wk 1 All participants had
pronators injected1–1
.000
†
3mo 2
2–2
.194
6mo 2
2–2.25
.216
Elbow n⫽16 n⫽10
Baseline 2 2
1.5–22–2
2wk 1 1
.25–10–1
.001
†
.004
†
3mo 2 1.5
1–21–2
.135 .039
6mo 1.75 2
1–21–2
.357 .059
Wrist n⫽16 n⫽5
Baseline 1.25 2
1–22–2
2wk 0 0
00–0.5
.001
†
.034
3mo 1 1
0–21–2
.017
†
.083
6mo 1 1.75
0–2 1.125–2
.079 .180
NOTE. Values are median, 25th–75th percentile and *Pvalues for
difference from baseline.
†
Indicates significant difference.
196 UPPER-LIMB OUTCOMES OF BOTULINUM TOXIN IN CEREBRAL PALSY, Wallen
Arch Phys Med Rehabil Vol 85, February 2004
difference remained significant at 3 and 6 months for the
elbow. The quality of muscle tone improved significantly at 2
weeks and 3 months for the whole sample for the elbow only
(see figs 4A and B for angle of catch; table 5 for data).
Range of Motion
There was no change over time in PROM or AROM of
shoulder flexion or abduction, elbow extension, wrist exten-
sion, supination, or finger extension. The exception was that
median passive shoulder abduction increased from 127.5°at
baseline to 142.5°at 2 weeks (P⫽.018). The median baseline
PROM measurements were full, consistent with the selection
criteria of no contracture, so a change was not expected; that is,
median baseline elbow extension was 180°, supination was
180°, and wrist extension was 180°. There were no differences
over time when data were examined for muscle groups that
were injected.
Adverse Events
Excessive and prolonged weakness of long finger flexors
interfered with grasp in 2 participants. The weakness resolved
in both cases by 3 months. The long finger flexors were not
injected in 1 of these participants, possibly indicating the
spread of BTX from the injection site of flexor pollicis longus.
There were no other adverse events.
DISCUSSION
Our study describes an assessment procedure that is com-
prehensive, objective, functional, and family-centered. An im-
portant part of this research was to investigate whether BTX
injections, which are invasive and costly, result in meaningful
change for the child and family.
There were positive results in support of BTX injections
effecting meaningful changes in children’s abilities to partici-
pate in life tasks. The majority of participants made meaningful
gains according to parent report and on the functional outcome
measures. In particular, 9 of 14 respondents would probably or
definitely consider having injections again, a positive indicator
for the efficacy and acceptability of BTX injections. The pri-
mary functional outcome measures were the COPM and GAS.
For the COPM, parents rated performance and satisfaction with
performance on important self-care, productivity, and leisure
difficulties. Overall, the improvement on the performance and
satisfaction scales were both clinically important (ⱖ2 points on
Fig 4. Tardieu score on angle of first catch for (A) the whole sample
and (B) the injected muscles.
Fig 3. MAS scores for elbow, wrist, and supination (0ⴝnormal,
4ⴝrigid) for (A) the injected-muscle groups and (B) the whole sam-
ple.
197UPPER-LIMB OUTCOMES OF BOTULINUM TOXIN IN CEREBRAL PALSY, Wallen
Arch Phys Med Rehabil Vol 85, February 2004
the rating scale)
15
and statistically significant at 3 months. This
improvement was maintained at 6 months. Although mean
T-scores of 50, indicating average achievement of goals, were
not achieved on the GAS, all children made progress on some
goals on the GAS. As expected, many of the goals selected for
intervention related to dressing and eating abilities. Of note is
the frequency with which leisure activities were the focus of
goals, reinforcing the importance of considering leisure when
working with children with CP.
Only 1 other study
6
has evaluated function after upper-limb
BTX injections. That study’s results on the self-care domain of
the PEDI were ambiguous, because there was significant
change on the raw score at 1 of the follow-up points but not on
the scaled score. Our study showed more positive results on the
functional outcomes than this previous study. This difference is
probably a consequence of using the COPM, which focuses on
issues that are identified by and are, therefore, important to the
family.
The improvement measured by means of the COPM and
GAS was maintained after 3 months, when it is expected that
the pharmacologic effects of the BTX are no longer present.
This expectation was verified by results on both the MAS and
Tardieu scale. That is, muscle tone improved significantly at 2
weeks, with significant improvement being maintained in only
some muscle groups at 3 months. By 6 months, however, these
measures did not differ significantly from baseline except for
the angle of first catch at the elbow.
The observed pattern of early improvement in tone with
return toward baseline is expected, considering that the effects
of BTX are temporary. Corry et al
7
found a similar pattern of
response for muscle tone, but Fehlings et al
6
found no changes
in muscle tone during their study. The relation between
changes in muscle tone and functional outcomes requires fur-
ther investigation. Our results, however, suggest that functional
outcomes are maintained beyond both the pharmacologic ef-
fects of the BTX and the return of increased muscle tone.
Children’s OT and PT were not manipulated in this study,
but several children did receive their regular therapy after
injections. Therapy and input by families may have inadver-
tently increased in response to the opportunity posed by having
injections and by the changed presentation of an injected limb.
Therapy may have facilitated the lasting functional gains ob-
Table 5: Tardieu Scale Angle of Catch and Quality of Tone
Whole Sample
Angle of Catch*
Injected Muscles Only
Angle of Catch*
Whole Sample
Quality of Catch*
Injected Muscles Only
Quality of Catch*
Pronators n⫽16 n⫽16
Baseline 107.5 2
95–135 2–2
2wk 140 2
123.75–172.5 1–2
.008
†
.180
3mo 120 2
106.25–138.75 2–2
.801 1.0
6mo 120 2
103.75–122.5 2–2
.637 .317
Elbow n⫽16 n⫽10 n⫽16 n⫽10
Baseline 105 102.5 2 2
92.5–128.75 87.5–121.25 2–22–2
2wk 180 180 1 0.5
141.25–180 143.75–180 0–20–1
.001
†
.005
†
.008
†
.015
†
3mo 155 147.5 1 0.5
125–180 118.75–180 0–20–2
.001
†
.005
†
.010
†
.034
6mo 142.5 150 2 2
110–180 110–170 0.5–2 0.5–2
.026 .021 .098 .102
Wrist n⫽16 n⫽5n⫽16 n⫽5
Baseline 137.5 110 1 2
106.25–177.5 97.5–132.5 1–22–2
2wk 160 150 1 2
146.25–180 140–180 0–2 0.5–2
.044 .043 .160 .18
3mo 165 140 1 2
136.25–180 127.5–160 0–21–2
.072 .074 .234 .317
6mo 145 130 2 2
123.75–162.5 91.25–146.25 1–2 1.25–2
.461 .357 1.0 .317
NOTE. Values are median, 25th–75th percentile, and *Pvalues for difference from baseline.
†
Indicates significant difference.
198 UPPER-LIMB OUTCOMES OF BOTULINUM TOXIN IN CEREBRAL PALSY, Wallen
Arch Phys Med Rehabil Vol 85, February 2004
served in this phase II trial. Further research should incorporate
OT or PT after injections into the design to determine whether
the functional outcomes might be enhanced by the addition of
therapy.
The quality of upper-limb function of participants did not
change when measured by the Melbourne Assessment (10
participants; ages, ⱖ5y). Possible explanations are that the
quality of upper-limb function is not responsive to BTX or that
the Melbourne Assessment was not sufficiently sensitive to
change in our sample of children with CP. Previous work on
the sensitivity of the Melbourne Assessment has only been
published on children with acquired cerebral insult who were
expected to improve rapidly
13
and where a significant change
in physical status was expected.
40
Significant changes were found in muscle tone and on the
COPM, although the Melbourne Assessment results did not
change over time. It may be that the changes in muscle tone
measured by the MAS and Tardieu scale do not translate into
more “normal”movement patterns, which is what the Mel-
bourne Assessment seeks to measure. Further, the children may
be completing the functional activities (evaluated positively in
the COPM and GAS) without using more normal movement
patterns. The study by Fehlings et al
6
did report some changes
on a quality of upper-limb function measure (QUEST) but only
at 1 month. The relation between the QUEST and the Mel-
bourne Assessment warrants further study.
Like Fehlings,
6
we found no change in PROM. This reflects
both studies’selection criteria, which precluded participants
with significant underlying contractures. We also recorded no
change in AROM, unlike Corry et al,
7
who reported some
increase in elbow extension (median, 5°) and thumb extension
at 2 weeks. Our study clearly indicates important improve-
ments on functional outcome measures, despite no change in
AROM. Goniometric measurement of AROM may not reflect
the ROM required for functional activities (usually midrange).
Further, therapy may be required to improve the activity of the
antagonist muscles during the period of denervation to effect
change in ROM and augment functional change.
Experience with this phase II trial has provided us with
invaluable preparation for an RCT, which is currently under-
way. Consistent with the aims of this phase II trial, we con-
firmed that electrical stimulation is integral to successful mus-
cle localization. We gained experience in subject and muscle
selection and about appropriate dose adjustments. Further, we
recognized the need to broaden our functional assessment
battery to include both the QUEST (to ensure data on quality of
upper-limb movement in younger children) and the PEDI (to
further evaluate self-care outcomes). Limitations of the study
included the small sample size and the heterogenous nature of
the sample in relation to diagnosis and age.
CONCLUSIONS
This phase II trial provided support for the use of BTX
injections to the upper limb to effect functional gains in chil-
dren with CP. More RCTs are required to investigate further
the efficacy of BTX. Other variables that may impact the
outcome of BTX—such as impaired sensation, age, severity of
motor impairment, and intellectual ability—should be ex-
plored. Further, studying the effects of repeated injections and
the influence of postinjection OT on outcomes will contribute
to the evidence-based clinical management of children with
CP.
Acknowledgments: We gratefully acknowledge the invaluable
assistance of Rachel Rolinson, senior occupational therapist, Suzanne
Mackay, occupational therapist, and Lynn McCartney, clinical nurse
consultant.
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Suppliers
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Arch Phys Med Rehabil Vol 85, February 2004
