DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

Long-term effects of repeated botulinum neurotoxin A, bimanual

training, and splinting in young children with cerebral palsy
GIT R M LIDMAN 1,2 | ANN K NACHEMSON 3 | MARIE B PENY-DAHLSTRAND 1,2 |
KATE M E HIMMELMANN 2,4

1 Institute of Neuroscience and Physiology at the Sahlgrenska Academy, University of Gothenburg, Gothenburg; 2 Regional Rehabilitation Centre for Children and
Adolescents, Queen Silvia’s Children’s Hospital, Sahlgrenska University Hospital, Gothenburg; 3 Department of Hand Surgery, Sahlgrenska University Hospital,
Gothenburg; 4 Department of Paediatrics, Institute of Clinical Sciences at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Correspondence to Git Lidman, Institute of Neuroscience and Physiology, University of Gothenburg, Regional Rehabilitation Centre for Children and Adolescents, Box 455, SE-405 30
G€oteborg, Sweden. E-mail: git.lidman@vgregion.se

PUBLICATION DATA AIM To investigate long-term development of hand function after repeated botulinum
Accepted for publication 8th May 2019. neurotoxin A (BoNT-A) and occupational therapy at a young age.
Published online METHOD Twenty children with unilateral spastic cerebral palsy (CP) (14 males, six females;
median inclusion age 3y 1mo, range 1y 11mo–4y 3mo) participated in this longitudinal study.
ABBREVIATIONS Ten children received occupational therapy after a randomized controlled trial and 10
AHA Assisting Hand Assessment repeated BoNT-A plus occupational therapy during 1-year. The Assisting Hand Assessment
ICF-CY International Classification of (AHA) and active supination, assessed the following 3 years. The assessments were
Functioning, Disability and compared with data from a reference group to investigate development over time.
Health: Children and Youth RESULTS The improvement in AHA (7.5 AHA units) after BoNT-A plus occupational therapy
version was maintained at final follow-up. The occupational therapy group, unchanged after 1-year,
improved by 5 AHA units (96% confidence interval [CI] 2–10), thus there was no difference
between the groups. Median active supination increased in comparison with the reference
group. In the BoNT-A/occupational therapy group, 9 out of 10 (97.85% CI 45 115) children
improved in active supination. In the occupational therapy group, 7 out of 10 (97.85% CI –2
to 68) children improved in active supination. No correlation between active supination and
AHA was found.
INTERPRETATION Bimanual performance achieved after BoNT-A plus occupational therapy
was maintained, while it increased by follow-up in the occupational therapy group,
suggesting that combined intervention gave earlier access to bimanual skills. Active
supination was unrelated to AHA.

The long-term goal of interventions in young children
with unilateral spastic cerebral palsy (CP) is to facilitate
the development of skills that are needed to become an
independent individual. Children with unilateral spastic CP
have one well-functioning hand and one less efficient hand,
often with spasticity, reduced speed, and muscle weak-
ness.1,2 They often experience disturbances of sensation,
perception, and cognition.2 This may cause difficulties in
learning and performing activities requiring bimanual abil-
ity1 and participation may be affected,3 which is further
described in the International Classification of Function-
ing, Disability and Health: Children and Youth version
(ICF-CY).4
Botulinum neurotoxin A (BoNT-A) is used to reduce
spasticity in children with unilateral spastic CP.5 Bimanual
performance has been shown to improve in the short-term
after intervention with occupational therapy combined with
BoNT-A.5 Long-term studies investigating the efficacy of
repeated upper limb BoNT-A treatment are needed, but
scarce.6,7 Long-term follow-up is difficult to conduct
because of several uncontrollable factors affecting perfor-
mance, making it difficult to distinguish the effects of the
intervention being evaluated.8 Such factors are growth and
development with age, accompanying impairments, and
different interventions.6 Still, long-term studies are impor-
tant, if the purpose of interventions for young children is
to create improvement that is maintained over time with
an ultimate impact on future ability to perform daily activi-
ties.
For this reason, a 4-year study was conducted in chil-
dren with unilateral spastic CP and upper limb spasticity.9
Two groups were compared during a first year of interven-
tion: one received BoNT-A combined with an occupational
therapy programme, and one received occupational therapy
alone. The occupational therapy programme included
bimanual training, manual stretching, goal-directed activi-
ties, and a static circular night splint, holding the forearm
in a supine position and the thumb in abduction (Fig. 1).

© 2019 Mac Keith Press DOI: 10.1111/dmcn.14298 1

The interventions were repeated in two blocks over the
course of 1-year. Superior outcomes were found for
bimanual performance in the BoNT-A/occupational ther-
apy group compared with occupational therapy alone.
Active supination improved in both groups.10
This report presents the concluding results from this 4-
year study. The first aim was a long-term follow-up of the
effectiveness of repeated BoNT-A combined with occupa-
tional therapy compared with occupational therapy alone
at a young age. The second aim was to compare the devel-
opment of the children’s hand function and bimanual per-
formance over time with a reference group from a Swedish
national quality register.11
What this paper adds
• Children whose bimanual performance improved after botulinum neurotoxin
A and/or occupational therapy, maintained skills or progressed during
follow-up.
• Bimanual performance increased with age, similar to a quality-register refer-
ence group.
• Increased active supination after intervention improved at follow-up but was
not related to bimanual performance.
the latter group underwent hand surgery. The Reference
group consisted of 69 children with unilateral spastic CP
(32 females, 37 males; range 2y 5mo–7y 4mo) from a
national quality register, the CP follow-up programme,11

METHOD
In the first year of this long-term, population-based study,
referred to as the intervention year, two intervention pro-
grammes (repeated BoNT-A combined with occupational
therapy vs occupational therapy alone) were compared in
a randomized controlled design.10 The outcome measures
were bimanual performance and active supination of the
forearm. In the concluding 3 years, the study had a
prospective longitudinal design. The long-term effects
were compared between the original two groups. The
assessments were also compared with data from a refer-
ence group to investigate the development over time
(Fig. 2). Data were collected from October 2004 to
August 2015.
The study was approved by the Regional Ethical Review
€
Board at the University of Gothenburg (O177-00, T1038-
15) and was registered with Current Controlled Trials
(ISRCTN84681422). Informed consent was given by the
parents.

Participants
Children who completed the intervention year, carefully
selected because of spasticity distributed in the pronator
and thumb muscles interfering with bimanual activity, con-
tinued to participate in the follow-up. A reference group
was added (Table I).
The BoNT-A/occupational therapy group (n=10, three
females, seven males, median inclusion age 2y 11mo, range
2y 4mo–4y 3mo) received BoNT-A combined with an
occupational therapy programme including a splint during
the intervention year. The occupational therapy group
(n=10, three females, seven males, median inclusion age 3y
1mo, range 1y 11mo–3y 9mo) received an occupational
therapy programme including a splint during the interven-
tion year. The Total group (n=20, six females, 14 males,
median inclusion age 3y 1mo) comprised the children in
the BoNT-A/occupational therapy and the occupational
therapy group and was considered to be a group of chil-
dren who had received intervention at a young age
(Fig. 2). The reason for this group formation was that five Figure 1: A static circular splint for night-time use, which is holding the
children in the occupational therapy group and four chil- forearm in supine position, with extended wrist and the thumb in abduc-
dren in the BoNT-A/occupational therapy group received tion. This splint is made of a low-temperature thermoplastic with flexible
BoNT-A during the follow-up period. Three children in and dynamic properties.

2 Developmental Medicine & Child Neurology 2019

 AHA and active supination

Intervention year
BoNT-A/OT group compared to OT group

BoNT-A/OT group OT group

n=10 (AHA) n=9 n=10
(active supination)

Follow-up from baseline to year 4

BoNT-A/OT group compared to OT group and Total group compared to
Reference group

OT group
BoNT-A/OT group
Year 1–2 n=10
n=10
Year 3–4 n=9

Total group
Reference group
Year 1–2 n=20
n=69
Year 3–4 n=19

Figure 2: Flow chart of the study design including the intervention year and the long-term follow-up period of the botulinum neurotoxin A (BoNT-A) and
occupational therapy (OT) group, the OT group, and the Total group. Assessments of the Assisting Hand Assessment (AHA) and range of motion of
active supination of the forearm.

where all children with CP in Sweden are regularly
assessed to detect early signs of deterioration. All children
with unilateral spastic CP of comparable age with available
data in both Assisting Hand Assessment (AHA) scores and
range of motion active supination were included. This
group consisted of children not selected for the BoNT-A/
occupational therapy group or occupational therapy group
because of the presence or localization of spasticity.
During follow-up, the children from all groups includ-
ing the Reference group received standard therapy con-
sidered appropriate for their individual needs. Therefore,
some of the children were subject to interventions and
some did not receive any interventions (Table I). In
seven out of 69 children in the Reference group, one
BoNT-A upper limb treatment had taken place before
the age of 3 years 5 months, an age corresponding to
the inclusion age of the Total group. Three of seven
received a second injection within 6 months, similar to
the children in the BoNT-A/occupational therapy group.
One of these three participants used a night splint with
the forearm in a supine position, but did not receive
bimanual training. Therefore, treatment in the Reference
group was not considered to be similar to the interven-
tion in this study (Table I).
Data collection and assessments
The assessments of the BoNT-A/occupational therapy and
occupational therapy groups were conducted at the Regio-
nal Rehabilitation Centre, Gothenburg, Sweden.
The baseline assessments from the Total group (median
inclusion age 3y 1mo) were compared with the children
aged 2 years 5 months to 3 years 4 months from the Ref-
erence group. Similarly, all the annual assessments during
the follow-up were compared with the age ranges 3 years
5 months to 4 years 4 months, 4 years 5 months to 5 years
4 months, and onward (Fig. 2).
Primary outcome measure – ICF-CY activity/participation
The AHA (version 4.1) is a standardized and crite-
rion-referenced test for children aged 18 months to
12 years assessing how effectively children with a uni-
lateral motor disability use their less efficient hand in
bimanual activities. A play session was videotaped and
the performance was rated on a four-point rating
scale of 22 items.12,13 The AHA sessions were con-
ducted by the first author and scored by another cer-
tified AHA assessor, blinded to previous scores and
order of assessments.
Secondary outcome measures – ICF-CY body function/
structure
Range of motion of active supination was measured with a
standardized medical goniometer following standard proce-
dures.14 To encourage the children to supinate optimally,
they were asked to look at a sticker attached to their palm.
The procedure was performed by two occupational thera-
pists aware of the child’s intervention but blinded to previ-
ous results.
Statistical analysis
The AHA scores, transformed into AHA units,15 and the
score for range of motion active supination were compared

BoNT-A and Occupational Therapy in CP Git R M Lidman et al. 3

Table I: Demographic data of the participants in the botulinum neurotoxin Primary outcome – ICF-CY activity/participation
A plus occupational therapy (BoNT-A/OT) group, OT group, the Total gro- The improvement (7.5 AHA units [98% CI 2–16]) in the
up, and the Reference group BoNT-A/occupational therapy group achieved after
12 months was maintained after 4 years.
BoNT-A/OT OT Total Reference
group group group group In the occupational therapy group, where the AHA score
Characteristics (n=10) (n=10) (n=20) (n=69) was unchanged during the intervention year (median of 0
AHA units), there was a successive improvement by a med-
Females/males, n 3/7 3/7 6/14 32/37
Median inclusion 35 37 37 40 ian of 5 AHA units from baseline to 4 years (96% CI 2–
age, mo 10), mainly achieved during the follow-up period.
Affected side 4/6 3/7 7/13 39/30
Improvement was found in eight out of 10 participants
right/left, n
MACS levela by five or more AHA units in the BoNT-A/occupational
I 2 2 4 9 therapy group and in five out of nine in the occupational
II 6 8 14 38
therapy group after 4 years, with a non-significant differ-
III 2 0 2 20
IV 0 0 0 1 ence (95% CI –0.2 to 0.6) between the groups. All planned
V 0 0 0 0 AHA assessments were performed except for two assess-
Interventions during the follow-up period
ments for one child in the occupational therapy group.
BoNT-A 4 5 9 12
Hand surgery 3 0 3 2 In the Reference group, two or three AHA assessments
Night splintb 7 5 12 6 per individual were available, without significant difference
Constraint induced 0 0 0 10
in AHA units to the Total group at baseline. Both groups
movement therapy
Bimanual trainingc 0 0 0 4 increased in AHA with age, without difference in the mean
a
AHA scores during the follow-up period (Table I; Tables
Manual Ability Classification System (MACS) classification27 was
carried out after the child’s fourth birthday. Data of the child’s SI and SII, online supporting information).
MACS level was missing for one of the children in the Reference
group. bStretching the forearm pronator muscles. cSeparate from Secondary outcome – ICF-CY body function/structure
other interventions.
Improved active supination by age was found in the
BoNT-A/occupational therapy group and the occupational
between the BoNT-A/occupational therapy group and the therapy group. At final assessment, nine out of 10 partici-
occupational therapy group. Tests of differences between pants in the BoNT-A/occupational therapy group (97.85%
proportions were performed using Fisher’s exact test CI 45–115) had improved by more than 10° and with a
because of few observations. Exact confidence intervals median improvement of 43°. In the occupational therapy
(CIs) for differences between proportions were calculated group, seven out of 10 improved (97.85% CI –2 to 68),
using the Chan and Zheng method.16 and with a median improvement of 47° (Table II). Three
Changes between baseline and year 4 for each of the assessments from one child were missing in the BoNT-A/
groups were tested using Wilcoxon’s signed rank test. occupational therapy group during the intervention year
Exact CIs, based on the Wilcoxon test, for the median and two assessments from one child in the occupational
change were calculated. The calculations were performed therapy group during follow-up.
by the frequency and univariate procedures in the Statisti- The median at baseline was 10° in the Total group and
cal Analysis System version 9.4 (SAS Institute, Cary, NC, 45° in the Reference group. At 4-year follow-up, both
USA). groups had a median of 70° (Table II), while mean change
The data from the Total group were compared with the differed both at baseline and at 4-year follow-up (Tables
Reference group and analysed with mixed models for SI and SII). The two intervention groups BoNT-A/occu-
repeated measures with unstructured covariance structure. pational therapy and occupational therapy showed similar
No functional relation between time and means in the patterns (Table II).
groups was assumed. The SAS procedure mixed with least No correlation between AHA and active supination was
squares means and estimate options was used and missing found in any of the groups at final assessment.
values were handled with population marginal means
adjusted in SAS. DISCUSSION
Spearman rank correlation statistics were used for AHA This study reports the long-term development of hand
and active supination data (SPSS IBM Statistics version 21, function in children with unilateral spastic CP receiving
IBM Corp., Armonk, NY, USA). The level of statistical occupational therapy with or without repeated BoNT-A at
significance was set at p<0.05. young age, additionally compared with children in a refer-
ence group, derived from a national quality register.11
RESULTS The improved bimanual performance after the interven-
The data from the assessments in the BoNT-A/occupa- tion year was maintained and increased at follow-up in the
tional therapy group and the occupational therapy group BoNT-A/occupational therapy group. While no improve-
were analysed over time, and the Total group was com- ment in AHA was found in the occupational therapy group
pared with the Reference group. after the intervention year, the bimanual performance

4 Developmental Medicine & Child Neurology 2019

increased by follow-up. It can be speculated that the com-
bined intervention received in the BoNT-A/occupational
therapy group provided conditions for the children to
reach their ability of bimanual performance earlier in life
despite their initial difficulties.17 This supports the value of
intervention at a young age and demonstrates maintained
effects in the long-term, which may serve as guidance for
long-term interventions.5,18 Supported by findings from
recent studies, the timing of interventions may be impor-
tant as there is a limited window for bimanual performance
development.17,19 The lack of difference between the Total
group and the Reference group regarding bimanual perfor-
mance may be due to the various interventions occurring
during follow-up in both groups, in addition to the chil-
dren’s individual development.19
One significant finding was that the median active
supination after the intervention year increased further by
follow-up, also in comparison to the Reference group.
More than half in the Total group continued using their
night splints. In the Reference group, 2 per cent used a
splint stretching the pronator muscles, which may have
affected the outcome.
No relationship between the AHA and active supination
was found, as suggested by the findings from the interven-
tion year, where the group receiving BoNT-A increased in
both measurements.10 This is in contrast to earlier find-
ings, showing the range of active supination to be predic-
tive of upper limb activity.20,21 Studies using 3D
kinematics have concluded that active supination is impor-
tant in daily life activities.22,23 Ponten et al.24 emphasized
that when one hand holds an object in pronated position,
it will impede visual control and thus subsequently the
bimanual activity, as supported by clinical experience.
Explanations for the lack of relationship between the AHA
and active supination may be that some bimanual activities
do not require the full range of supination, or that the per-
formance is made possible through compensatory move-
ments. James et al.21 found a positive correlation between
the AHA and active supination in children with unilateral
spastic CP awaiting surgery; however, the active supination
in that group was poorer. Ponten et al.24 demonstrated
improved bimanual performance after surgery, including
pronator muscle release. That group was older, starting at
a lower AHA level compared with the BoNT-A/occupa-
tional therapy group in our study. There may be a point
where increased supination will not lead to further
improvement of bimanual performance, or the AHA may
not be sensitive to all changes in activities that benefit
from increased supination. Elvrum et al.25 discussed the
lack of transfer of improved use of the less efficient hand
despite increased active supination after treatment with
BoNT-A and resistance training. Furthermore, the ability
to supinate must be considered in relation to the need to
pronate the forearm in bimanual activities. Increased
supination at the cost of decreased pronation may not be
desired. The entire range of movement is of interest in
future studies.
Long-term studies are important for the evaluation of
interventions aimed at promoting the development of chil-
dren with unilateral spastic CP. Future studies should

Table II: Medians and means from all assessments in the botulinum neurotoxin A plus occupational therapy (BoNT-A/OT) group (n=10), the occupa-
tional therapy group (OT) group (n=10), the Total group (n=20), and the Reference group (n=69), with data from active supination and the Assisting Hand
Assessment (AHA)
Active Active
AHA score AHA score Standard Supination supination Standard
(mean) (median) error (median) (mean) error

BoNT-A/OT group
Baseline 55 51 6.03 10 18 35.53
Year 1 61 61 5.10 25 31 35.53
Year 2 60 57 4.60 10 33 35.47
Year 3 63 59 4.03 40 38 35.47
Year 4 63 61 4.68 33 68 35.47
OT group
Baseline 56 55 4.09 25 15 19.63
Year 1 57 56 3.21 48 38 13.44
Year 2 58 55 4.23 65 50 15.87
Year 3 60 60 3.61 73 51 14.88
Year 4 59 57 3.85 72 50 17.75
Total group
Baseline 56 53 4.10 10 0 10.11
Year 1 59 57 3.56 45 35 8.83
Year 2 59 55 3.18 58 39 9.26
Year 3 62 62 2.93 61 45 9.03
Year 4 62 60 3.33 70 60 8.44
Reference group
Baseline 49 49 2.47 45 44 6.53
Year 1 56 59 2.21 50 39 7.09
Year 2 58 60 2.05 50 41 7.68
Year 3 59 56 2.20 70 56 6.13
Year 4 59 51 2.47 70 52 8.55

BoNT-A and Occupational Therapy in CP Git R M Lidman et al. 5

evaluate combined interventions at all ICF levels, address-
ing problems with structure and function in combination
with occupation-based treatment, including interventions
with problem-solving approaches.26 Aiming at future inde-
pendence, emphasis should be put on the timing of inter-
ventions and the involvement of the children’s own specific
goals in different life situations.
Methodological considerations and limitations
A strength of this study was the homogeneous nature of
the study groups with localized spasticity and the fact that
the same team of professionals assessed the children. How-
ever, this long-term study was influenced by several factors.
Albeit population-based, the sample is small and the study
design includes partially blinded assessors of the secondary
outcome. For ethical reasons, the children not receiving
BoNT-A during the intervention year were given the
opportunity to be treated during follow-up, if considered
clinically appropriate. This confounded the data. The two
intervention groups were thus merged. In the CP follow-
up programme register, from which the Reference group
was derived, the AHA is not a mandatory assessment. This
limited the size of the Reference group. Still, this study
shows the possible use of quality registers and illustrates
that it was possible to follow the effects during an inter-
vention year, but it also highlights the obstacles of long-
term studies, suggesting that conclusions become more
uncertain the longer the study.
CONCLUSION
In this small study, bimanual performance was maintained
in the BoNT-A/occupational therapy group and increased
with age, similar to a quality-register reference group. The
occupational therapy group instead improved during fol-
low-up, in which half the children received BoNT-A injec-
tions. The increased median active supination for children
with unilateral spastic CP achieved after intervention at a
young age improved more than the Reference group.
However, no relation between active supination and the
AHA was found. This raises the question whether there is
a limit to the degree of supination needed to affect biman-
ual ability as measured by the AHA. Bimanual performance
is complex and dependent on many factors, creating many
challenges in life for children with unilateral spastic CP.
A CK N O W L E D G M E N T S
We would like to express our sincere gratitude to all children and
their families. We sincerely thank occupational therapists Kristina
Olsson and Karin Lindh at the Regional Rehabilitation Centre for
Children and Adolescents. We also thank the national quality reg-
ister CP follow-up programme for providing reference data and
Kjell Pettersson PhD who assisted with statistical calculations. This
study was funded by the Queen Silvia Jubilee Foundations, the
Promobilia Foundations, the Foundation Samariten, the Nor-
rbacka-Eugenia Foundations, the Folke Bernadotte Memorial
Foundations, the Petter Silfverski€old Memorial Foundations, the
RBU Research Foundation, the Sahlgrenska University Founda-
tions, and the Local Research and Development Board for Gothen-
burg and S€ odra Bohusl€an. The authors have stated that they had
no interests that might be perceived as posing a conflict or bias.
SUPPORTING INFORMATION
The following additional material may be found online:
Table SI: Comparison of the Assisting Hand Assessment test
and active supination of the botulinum neurotoxin A plus occupa-
tional therapy, occupational therapy, and Total groups with the
Reference group at each time interval.
Table SII: Comparison of the Assisting Hand Assessment test
and active supination of the botulinum neurotoxin A plus occupa-
tional therapy, occupational therapy, and Total with the Refer-
ence group at baseline and each year separately compared for
each group.

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