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Japanese Journal of Comprehensive Rehabilitation Science (2020)

Original Article

Effect of two doses of botulinum toxin type A on maximum plantar
contact area in hemiplegic stroke patients with pes equinovarus
Yoshitaka Wada, MD,1,2,3 Naruhito Otsuka, MD, PhD,1 Nobuyuki Kawate, MD, PhD,2,3
Hiroshi Moriyama, DDS, PhD,1 Hiromitsu Ezure, DDS, DDSc, PhD,1 Yuriko Inoue, PhD1
Department of Anatomy, School of Medicine, Showa University, Tokyo, Japan
Department of Rehabilitation Medicine, School of Medicine, Showa University, Tokyo, Japan
3
Showa University Fujigaoka Rehabilitation Hospital, Kanagawa, Japan1
2

ABSTRACT
Wada Y, Otsuka N, Kawate N, Moriyama H, Ezure H,
Inoue Y. Effect of two doses of botulinum toxin type A
on maximum plantar contact area in hemiplegic stroke
patients with pes equinovarus. Jpn J Compr Rehabil
Sci 2020; 11: 85-90.
Objectives: To quantitatively demonstrate thetherapeutic effects of two doses of botulinum toxin
type A (BoNT-A) on pes equinovarus in hemiplegicstroke patients.
Methods: The subjects of this study included eightchronic stroke patients who received two BoNT-A
doses (mean dose interval: 136.0 (10.5) days) from
April 2011 to March 2013 and underwent a sheet-type
weight-bearing lower limb test. The maximum plantar
contact area on the paralyzed side, ratio of maximum
plantar contact areas on the paralyzed and nonparalyzed sides, and Modified Ashworth Scale (MAS)were measured before BoNT-A administration and 4
weeks after both the first and second doses.
Results: A significant increase in the maximum
plantar contact area was observed after administrationof the second dose compared to that of the first dose on
the paralyzed side. Additionally, a significant increase
was observed in the ratio of paralyzed/non-paralyzed
maximum plantar contact areas after the administrationof both the first and second doses compared to that
before BoNT-A administration. MAS was observed to
decline significantly after the administration of boththe first and second doses compared to that prior to
BoNT-A administration.
Conclusions: We suggest that comparison of the plantar
Correspondence: Yoshitaka Wada, MD
Showa University Fujigaoka Rehabilitation Hospital, 2-1-1
Fujigaoka, Aoba-ku, Yokohama, Kanagawa 213-0004, Japan.
Email: yoshi1201@med.showa-u.ac.jp
Accepted; April 26, 2020.
Declaration of interest statement: No potential conflict ofinterest were reported by the authors.
©Kaifukuki Rehabilitation Ward Association 2020
doi.org/10.11336/jjcrs.11.85

contact area is useful for assessing the therapeutic effectsof BoNT-A doses on pes equinovarus in hemiplegicstroke patients.
Key words: spasticity, botulinum therapy, equinovarus,
stroke, plantar contact area
Introduction
Spasticity is a symptom of upper motor neuron
damage, defined as “a velocity-dependent increase intonic stretch reflexes (muscle tone) with exaggerated
tendon jerks, resulting from hyperexcitability of thestretch reflex” [1]. It is notable that spasticity wasobserved in 19% of patients at 3 months after a strokeand 38% of patients at 12 months after a stroke [2, 3].
In Japan, botulinum toxin type A (BoNT-A) is often
used to treat spasticity. BoNT-A acts on theneuromuscular junctions of the skeletal muscles tosuppress the release of acetylcholine at nerve endings
and reduces spasticity by inhibiting muscle
contractions [4]. It takes 2 to 3 days for BoNT-A to
exhibit an effect, which is maintained for about 3
months and then attenuates [5]. The Japaneseguidelines for stroke therapy from 2015 [6] state that,“Botulinum therapy is strongly recommended forspasticity of the upper and lower limbs (grade A),” and“botulinum therapy and 5% phenol are recommended(grade A) as an intramuscular nerve block of the tibial
nerve or lower leg muscles when pes equinovarus due
to spasticity inhibits walking or other everyday
activities.” Severe lower limb spasticity can exhibit anextension synergy pattern accompanied by pes
equinovarus that affects walking functions [7, 8].
Botulinum therapy is expected to reduce lower limb
spasticity, improve pes equinovarus, and improve thegait and walking ability [9, 10].
In clinical practice, botulinum therapy is often
performed multiple times and not just as a single dose.
Although the effectiveness of multiple doses of
BoNT-A has been demonstrated [11], there are only a
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Wada Y et al.: Effect of two doses of botulinum toxin type A in hemiplegic stroke patients with pes equinovarus

few reports on repeated doses in the lower limbs
compared to the upper limbs [12-14]. In addition, theeffects of multiple BoNT-A doses on pes equinovarus
in hemiplegic stroke patients have not been
demonstrated. Generally, the Modified Ashworth
Scale (MAS) [15] is used to evaluate spasticity.
Nevertheless, MAS assesses the resting muscle tone
and is not suitable for evaluating the muscle tone
during movement. Assessing the muscle tone while
standing and walking as well as at rest would help tocreate more appropriate treatment plans and improve
the assessments of efficacy. The therapeutic effects on
pes equinovarus can be judged by the increase in thearea of plantar contact with the first metatarsal bones
and heel of the foot [16]. We believe that by assessing
the effects of BoNT-A using MAS and the plantar
contact area during movement, we can comprehensively
examine the usefulness of repeated BoNT-A doses on
pes equinovarus.
Therefore, the objective of this study was toquantitatively examine the therapeutic effects ofrepeated BoNT-A doses on hemiplegic stroke patients
presenting with lower limb spasticity by comparing
the changes in the maximum plantar contact area, theratio of paralyzed/non-paralyzed maximum plantar
contact areas, and MAS before the first dose, 4 weeks
after the first dose, and 4 weeks after the second dose.
Subjects and methods
1. Subjects
This study was a retrospective observational study.
Patients with hemiplegia who received botulinum
therapy at the Showa University Hospital from April
2011 to March 2013 and who underwent a sheet-type
weight-bearing lower limb test before and after thedoses were eligible for the study. The criteria forinclusion were patients who did not have subarachnoid
hemorrhage, did not have recurrences, did not consume
oral antispasmodics, and could walk independently intheir daily life. Consequently, eight chronic stroke
patients who fulfilled these criteria were included as
subjects. We obtained approval from the Showa
University ethics committee for research on humansubjects (approval No. 2974) for this series of studies;notably, informed consent was waived.
2. BoNT-A administration
BoNT-A was dissolved in physiological saline foradministration. The site of administration was decided
by the physician in charge and was selected fromamong the gastrocnemius, soleus, tibialis posterior,and flexor digitorum longus muscles. The
gastrocnemius and soleus were identified by palpation,
while the tibialis posterior and flexor digitorum longus
were identified by electrical stimulation. The paralyzed
leg was evaluated 4 weeks after BoNT-A (BOTOX®,
GlaxoSmithKline) administration and the physician in
Jpn J Compr Rehabil Sci Vol 11, 2020

charge evaluated it again at least 12 weeks afteradministration of the BoNT-A dose. If the physician incharge decided that another BoNT-A dose was required
after the examination, a second dose was administeredafter obtaining consent from the patient.
3. Assessments
The weight-bearing lower limb test was performed
using a sheet-type foot pressure sensor (Anima, WalkWay
MW-1000). Each measurement was performed on asheet-type sensor of length 4.8 m without shoes, cane orfoot orthosis. The maximum plantar contact area wascalculated as the mean of the maximum plantar contact
areas for all the steps on the sheet. The ratio of theparalyzed/non-paralyzed maximum plantar contact areas
was calculated using the maximum plantar contact areasof the paralyzed and non-paralyzed sides. At the sametime, the physician in charge used MAS to evaluate theparalyzed ankle joint. The measurements and assessments
were performed three times: before BoNT-A
administration, 4 weeks after the first dose, and 4 weeks
after the second dose.
4. Statistical processing
It is notable that MAS 1+ was treated as 1.5. The
Shapiro-Wilk normality test was used to confirm
normal distributions. The Friedman test was used as
an analysis of variance of repeated measurements tocompare the maximum plantar contact areas on theparalyzed and non-paralyzed sides, the ratio ofparalyzed/non-paralyzed maximum plantar contact
areas, and MAS. Multiple comparisons between
groups were performed using the Wilcoxon signedrank test with Bonferroni correction. Two-sided
p-values <0.05 were considered statisticallysignificant. JMP® 14 (SAS Institute Inc., Cary, NC,
USA) was used as the statistical software.
Results
Table 1 shows the subjects’ characteristics. Table 2
shows the sites of administration and doses. The meaninterval between the first and second BoNT-A doses(mean (SD)) was 136.0 (10.5) days. The total dose wasaltered in two cases between the first and second
doses. Additionally, there were changes in the site ofadministration and dosage with respect to the second
dose in five cases.
1. Paralyzed side maximum plantar contact area
The maximum plantar contact area on the paralyzed
side (mean (SD)) was 128.1 (29.8) cm2 before the first
dose, 137 (27.8) cm2 4 weeks after the first dose, and146.9 (21.8) cm2 4 weeks after the second dose (p =0.044 using the Friedman test). The maximum plantar
contact area on the paralyzed side increased
significantly after the first and second doses (p < 0.05)(Figure 1).

Wada Y et al.: Effect of two doses of botulinum toxin type A in hemiplegic stroke patients with pes equinovarus
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Table 1. Subject characteristics.
Sex
Age at injection, years
Cerebral hemorrhage/Cerebral infarction, nSide of hemiparesis, nBrunnstrom Recovery Stage (lower limb), nTime between onset and treatment, years

Male 6/Female 2
57.8 (10.3)
5/3
Right 2/Left 6
III 5/IV 2/V 1
9.0 (7.2)

Data are mean (SD) or number.
Table 2. BoNT-A doses and administration site.
MusclePatients

Injected dosage of
botulinum toxin type A

The first dose

Gastrocnemius
SoleusTibialis posterior
Flexor digitorum longus
Total

7
6
8
5
8

150
58.3(11.8)
62.5(12.5)
40 (12.2)
262.5(69.6)

The second dose

Gastrocnemius
SoleusTibialis posterior
Flexor digitorum longus
Total

8
7
8
3
8

131.3(24.2)
60.7(12.2)
59.4(12.4)
50 (10.8)
262.5(72.8)

Data are mean (SD) or number.

Figure 1. Changes in maximum plantar contact area on the paralyzed
side before BoNT-A administration, 4 weeks after the first dose, and 4
weeks after the second dose.
2. Non-paralyzed side maximum plantar contact area
The maximum plantar contact area on the nonparalyzed side (mean (SD)) was 165.4 (23.3) cm2
before the first dose, 167.8 (20.9) cm2 4 weeks after
the first dose, and 164.1 (19.9) cm2 4 weeks after thesecond dose. No significant differences were observed
from the Friedman test (p = 0.65).


3. Ratio of paralyzed/non-paralyzed maximum plantar
contact areas
The ratio of the maximum planted ground contact
area between the paralyzed and non-paralyzed sides(mean (SD)) was 0.78 (0.14) before the first dose, 0.80
(0.14) weeks after the first dose, and 0.89 (0.05) 4
weeks after the second dose (p = 0.00037 using the
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Wada Y et al.: Effect of two doses of botulinum toxin type A in hemiplegic stroke patients with pes equinovarus

Friedman test). Significant increases were observed 4
weeks after the first dose compared to before, and 4
weeks after the second dose compared to before (p <0.05) (Figure 2).
4. MAS
The median MAS was observed to be 4 before thefirst dose, 1.75 at 4 weeks after the first dose, and 1 at
4 weeks after the second dose (p = 0.00014 using theFriedman test). Significant decreases were observed
after the first dose compared to before, and after thesecond dose compared to before (p < 0.05).
Discussion
The results of this study suggest that comparison of
the plantar contact area is useful for assessing thetherapeutic effects of repeated administration of
BoNT-A for pes equinovarus in hemiplegic stroke
patients. Significant improvements were observed in
the MAS and the ratio of paralyzed/non-paralyzed
maximum plantar contact areas at 4 weeks after the
first dose and 4 weeks after the second dose comparedwith the values prior to the first BoNT-A dose.
Significant increases in the maximum plantar contact
area on the paralyzed side were observed 4 weeks after
the first dose and 4 weeks after the second dose. The
methods of quantitatively assessing pes equinovarus
after botulinum therapy include using a plantarpressure distribution sensor to perform measurementsin the standing position [17], measuring the ratio of
maximum plantar contact areas during walking using
a sheet-type plantar pressure sensor [18], and using a
3-dimensional motion analyzer [19]. However,previous studies analyzed the comparisons before andafter a single dose. To our knowledge, our study is thefirst to use a sheet-type plantar pressure sensor toevaluate the effects of repeated BoNT-A doses onhemiplegic stroke patients with a focus on pes
equinovarus.
Pes equinovarus is mainly caused by spasticity,
contracture, weakness of the ankle dorsiflexors, andinstability of the tibial and peroneal muscles [20, 21].
The effects of contracture are particularly evident in
the chronic phase and the evaluation of spasticity withMAS alone is insufficient [22]. Hypertonia is divided
into reflexive elements based on stretch reflexes andnon-reflexive elements based on the viscoelasticity ofthe tissues that make up a joint [23]. Bakheit et al. [22]and Takeuchi et al. [24] suggested that MAS measures
the non-reflexive elements of hypertonic states. In thesubjects of the present study, a mean of 9.0 (7.2) years
had elapsed from the onset to the administration of
BoNT-A, indicating that the effects of the non-reflexive
elements cannot be ignored. Tanikawa et al. [19]evaluated the effect of botulinum therapy on ankle
varus during walking using a 3D motion analyzer.
They reported that while MAS had returned to the predose levels 12 weeks after BoNT-A administration, themaximum foot varus angle during the swing phase had
improved significantly, indicating that the spasticity at
rest and improvements in movement are not always
consistent. While the effects of BoNT-A on spasticity
attenuate over time, promoting continuous weightbearing on the paralyzed side throughout its durationof effectiveness is thought to improve the factors
besides spasticity. We believe that in addition to using
MAS, the therapeutic effects on pes equinovarus canbe examined in more detail if quantitative assessments
during movements are also performed using a sheet-

Figure 2. Changes in the ratio of paralyzed/non-paralyzed maximum
plantar contact areas before BoNT-A administration, 4 weeks after the
first dose, and 4 weeks after the second dose.
Jpn J Compr Rehabil Sci Vol 11, 2020

Wada Y et al.: Effect of two doses of botulinum toxin type A in hemiplegic stroke patients with pes equinovarus
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type weight-bearing lower limb test.
Previous studies have demonstrated the usefulnessof repeated administration of BoNT-A to the lower
limbs. In a study of repeated BoNT-A doses performed
in Japan, the mean interval between the doses was
133.2 days, with the dose interval in the upper limbs
not markedly different from that in the lower limbs[25]. The dose and administration interval in thepresent study were similar to those in previous
research. Takekawa et al. showed that with multiple
BoNT-A doses, spasticity gradually lessened witheach one to create a greater therapeutic effect. They
reported that even if the effect of a single dose isinsufficient, repeated doses should be given [26]. Haraet al. reported that the combination of four BoNT-A
doses and intensive inpatient rehabilitation
significantly improved the ankle MAS, ankle
dorsiflexion angle, 10-Meter Walk Test, Functional
Reach Test, and the Timed Up and Go Test after the
fourth dose [12]. We believe that the treatment should
be judged not merely by the effects of a single dose,but should be examined continuously by assessing theeffects of multiple BoNT-A doses. The results of thepresent study support findings that repeated BoNT-A
doses lead to a continuous improvement of pes
equinovarus. To assess the plantar contact area, we
could quantitatively assess the improvement of
spasticity and the non-reflexive elements of hypertonic
states after repeated BoNT-A doses. In our study,
while the effect of the second BoNT-A dose was
equivalent to that of the first dose, a continuous
improvement in factors other than spasticity wasobserved. However, the improvement was not
sufficient to produce a significant difference comparedto the improvement after the first dose. For analyzing
treatment plans and improving the assessments ofefficacy, the assessment of the plantar contact area isbetter than MAS which is an ordinal scale. Adding
rehabilitation to botulinum therapy has been shown tobe effective. Additionally, while the subjects of thisstudy received outpatient stretching guidance andother forms of rehabilitation, the amount of stretching
they actually performed during the study remains
unclear. In our future study, we plan to research thechanges in pes equinovarus by adding constant
exercise therapy after BoNT-A dose using a sheet-type
foot pressure sensor.
The limitations of this study include the following.
First, the sample size was small. Second, the amount​of rehabilitation performed during the study was​not standardized. Third, there was no comparison of
the changes in walking abilities such as speed andmaximum distance. Fourth, it was a retrospective
observational study using medical records without acontrol group. Furthermore, although an increased
maximum plantar contact area indicates an improvementin pes equinovarus, it is unclear how much thisimprovement was reflected in improved abilities, which

is a topic for future research. In the future, we would
like to examine the mid- to long-term effects of BoNT-A
on spasticity, walking ability, and range of activity whenrehabilitation is included in the study period.
Conclusion
Our study suggested that comparison of the
maximum plantar contact area is useful for judging theeffect of the BoNT-A doses on pes equinovarus. This
study was the first to use a sheet-type plantar pressure
sensor to evaluate the effects of repeated BoNT-A
doses on hemiplegic stroke patients with pes
equinovarus. We believe that in addition to MAS, thetherapeutic effects on pes equinovarus can be examinedin more detail if quantitative assessments are also
performed using a sheet-type foot contact sensor.
Acknowledgement
We would like to thank Editage (www.editage.com)
for English language editing.

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