Botulinum Toxin Therapy in Children

Clinical Article

Botulinum Toxin Therapy in Children

Abe M. Chutorian, MD

Abstract
Botulism toxin (BTX) is effective and safe for the treatment of spasticity, dystonia, and selected smooth muscle and exocrin disorders.
This article will emphasize the use of BTX in children with cerebral
palsy due to the relative infrequency of multiple sclerosis, stroke,
and pediatric focal dystonia. Int Pediatr. 2001;16(1).
Key words: Botulism toxin (BTX)

Introduction
The first therapeutic use of botulism toxin (BTX) was for
strabismus, which required only minute doses to weaken the
selected extraocular muscle for improved binocular alignment.1
Treatment since the earliest demonstration of efficacy in
the 1980s has been expanded to include the treatment of
dystonia,1-6 tremor, and spasticity.7-16 In the latter domain, the
principal disorder in children is cerebral palsy, though efficacy has been demonstrated as well in stroke,17 multiple sclerosis18 and post-traumatic brain and spinal cord spasticity.
More recently, efficacy has been demonstrated in other
than pyramidal and extrapyramidal disorders, for example in
cholinergic blockade of smooth muscle, e.g., bladder detrusor hypertonus. Striking benefit, with abolition of urinary
incontinence in patients with bladder hypertonus due to spinal cord pathology, with continence achieved in the majority of patients, resulted from treatment of the bladder detrusor muscle with multiple injections of BTX.20 Disorders of
exocrin function such as hyper-hydrosis, have been effectively treated by the use of BTX for blockade of the cholinergic sympathetic function in this regard. The various disorders amenable to treatment with botulinum toxin are classified in Tables 1, 2, and 3.
The relative infrequency of dystonia and of multiple sclerosis in children suggests the advisability of emphasizing the
pediatric therapeutic use of botulinum toxin for cerebral
palsy. Spasticity resulting from stroke in children requires
treatment not dissimilar to that which is appropriate for cerebral palsy, particularly for the hemiplegic upper extremity.15

Table 1. - Botulinum Toxin for Spasticity

Disorders
Cerebral Palsy
Stroke
Multiple Sclerosis
Spinal Cord + Cerebral Trauma
Aim
Increase Function
- Spastic Gait
- Hemiplegic Extremity
- Spastic Bladder Incontinence
Reduce Pain
Enhance Physical Therapy
Enhance Hygienic Care

Table 2. - Botulinum Toxin in Focal Dystonia

Blepharospasm
Facial Hemispasm
Oromandibular Dystonia
Spasmodic Dysphonia
Cervical Dystonia
Extensor Truncal Dystonia
Focal Limb Dystonia

Table 3. - Botulinum Toxin for Disorders

Ocular Striated Muscle
- Strabismus
Cholinergic Parasympathetic
- Bladder Detrusor Hypertonus
Cholinergic Sympathetic
- Hyperhydrosis

Alternative or additional therapeutic modalities for cerebral palsy are listed in Table 4. Without detailed comment
on each of these modalities, it may be stated in summary that
BTX enhances physical therapy by reduction in dynamic
contractures owing to spasticity, that phenol or alcohol are
painful injections requiring anesthesia in children (in contrast BTX is associated only with the transient pain of injection itself), oral pharmacotherapy is relatively ineffective,
and surgical procedures can, by the judicious use of BTX, be
deferred, or less often avoided.
Pharmacologic Effects

Address reprint requests to the corresponding author, (Dr

Chutorian).

Clostridium botulinum is cultured in a fermenter and harvested by centrifugation following acidification. The pre-

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Botulinum Toxin Therapy in Children

Table 4. - Reduction of Spasticity in Therapeutic Modalities

Physical Therapy
Neuropharmacologic Therapy
Neurosurgery
A) Neurectomy
B) Selective Posterior Rhizotomy
Orthotics
Orthopedic Surgery
Local Injection Alcohol or Phenol
Intrathecal Baclofen
Botulinum Toxin

cipitated toxin is purified, made soluble, and tested for contamination and potency. The final form is diluted in human
serum albumen and is freeze-dried and sealed in storage vials.
Sample vials are periodically tested for sterility and potency.19-21
While multiple separable toxins are produced by
clostridium botulinum, which are antigenically distinct,
they are biochemically similar and capable of paralyzing
neuromuscular transmission.22,23 The mechanism of paralysis
is by inhibition of release, rather than synthesis or storage of
acetylcholine.24 Transmitter release is quantitatively related
to intracellular calcium influx, which is interfered with by
BTX.
Although animal studies have shown that BTX can reach
the central nervous system following muscle inoculation,25
clinically such spread virtually never occurs. In the rare patient who suffers transient global weakness, other mechanisms may be operative. Long-term effects include non-collateral nerve sprouting, which cannot be correlated with
clinical consequences
The highest concentration of motor end plates most
closely approximates the mid belly of a muscle, and the size
of the field of denervation is affected by dose and volume of
BTX. While multiple injections along affected muscle may
be optimal (diffusion is 4.5 cm from the injection site), in
practice it has been demonstrated that a single injection of
the calculated therapeutic dose into the promontory of the
mid-muscle belly produces the best result.
There is correlation over time between the development
of antibodies to BTX and reduced intensity and duration of
therapeutic effect.26 Rarely does this occur in serial injections during a period less than two years. In any event, the
incidence appears to be less than five percent, and has yet to
surface as a problem in the treatment of cerebral palsy in
children.
Clinical Considerations
Spasticity is defined as a velocity-dependent increase in
reflex tone triggered by spindle stretch, the hypertonus resulting from the loss of upper motor neuron inhibition of the
spinal reflex arc. The aim of treatment with BTX is to reduce

International Pediatrics/Vol. 16/No. 1/2001

contractural deformity, relieve pain, and improve function

or care.
At the Hospital for Special Surgery the author participated in a national study involving multiple treatment centers, the results of which were published in 1995.27,28 The
study involved 114 ambulatory children with equinus gait
due to cerebral palsy, treated in a double blinded, cross-over
fashion with BTX and placebo. Injection was into the medial and lateral heads of the gastrocnemius muscles, with
subsequent assessment of the effect on ankle range of motion
and gait.
Preliminary results of that study showed improvement of
statistical significance in children receiving BTX which persisted for between two and three months and subsequently
data from multiple centers nationally and internationally
documented statistically signifiant benefit.27 The assessment
of efficacy was based on objective measurements of the range
of motion in the direction of dorsiflexion before and after
injection in both arms of the cross-over study, employing
rating scales described below. This study may serve as a
model for the measurement of efficacy of BTX employed to
treat dynamic spastic contracture at any other site in the
body.
The children in the national study underwent initial histories and physical examinations, and were entered into the
closed label study if they had spastic paraparesis without
fixed contractures, and were ambulatory. They received
blinded injections of BTX of placebo, total dosage of BTX 4
mg/kg of body weight, diluted to 8 ccs, and divided into four
injections of 2 cc each into the medial and lateral heads of
the gastrocnemius muscle of each leg, at the site of presumed
optimal arborization of innervation, avoiding the midline
parent neural and vascular trees.
The children were permitted their usual non-invasive
therapeutic interventions over the course of the study, including physical therapy, orthotics, and where appropriate,
medication. Injections were given at least twice during the
study interval, the repeat injection given if no therapeutic
benefit was evident after a latency of thirty days (for crossover).
Physical therapy and physician rating scales (Tables 5)
were completed for each patient initially, and at interval
evaluations before and after calf injections. Video recording
for gait analysis was recorded at intervals.
Significant reduction of equinus gait was achieved without the production of crouch, or of knee extension, to a
statistically significant degree of probability, (P < .02), as
based upon the mean change from baseline in hindfoot posture, at the end of the study period (12 weeks). An improvement of two grades or more on the physician rating scale was
statistically significant to the same degree.
This randomized, multi-center, double blind, placebocontrolled trial of botulinum toxin type A in the treatment
of lower limb spasticity for pediatric cerebral palsy, involved

Botulinum Toxin Therapy in Children

Table 5. Physician Rating Scale

Gait Pattern

Toe/Toe
0

Occasional Heel Toe

1

Heel/Toe
2

Hindfoot (Ankle)Position
(Stance-Floor Contact)

Equinous*
0

Calcanous
1

Neutral
2

Hindfoot Position
(Foot Strike)

Valgus
0

Varus
1

Occasional Neutral
2

Knee Position
(Degree of Recurvation)

Severe
0

Moderate
1

Mild
2

Neutral/Flexed
3

Crouch

Severe
0

Mild
2

None
3

Speed of Gait

Slow
0

Moderate
1

Neutral
3

Variable
1

Best Score Possible = 14

*Equinous hindfoot ankle position required for entry.

investigators from nine institutions in Europe, Canada and

the US. One-hundred-fourteen children were entered into
the study, fifty-six of whom received BTX, and fifty-eight
placebo. Demographics were strikingly similar for both the
BTX and placebo groups, who were allowed the continued
use of both orthotics and of physical therapy during the study
period.
The study concluded that BTX injections were well tolerated, had a duration of action of at least eight weeks,
yielded no serious treatment-related adverse events, and provided no evidence during this period of antibody formation.
Electromyography provided additional objective evidence
of efficacy at a significantly statistical level.
A number of previous studies have demonstrated efficacy
of BOTOX for the treatment of spasticity. These include the
treatment of stroke-related hemiplegia by Das and Park,17 the
treatment of children with cerebral palsy by Koman and colleagues in 1990,8 an enlarged and amplified study by Koman
and colleagues in 1993,9 the treatment of spasticity of leg
adductors by Snow and colleagues,7 and the treatment of
ambulatory children with cerebral palsy by Cosgrove and
Graham in 1992.10
It is of interest that in recent studies employing higher
dosage than those of the previous studies described, significant improvement has been achieved at a level of even
greater statistical significance (P < 0.001), on the Ashworth
Scale (Table 6), and P < 0.01 on range of motion scales.
Similar results were obtained on the analysis of gait velocity.
The study of Wissel, Heinen, Schenkel, and colleagues in
Austria,12 demonstrated dose-dependent functional improvement of dynamic deformities and spastic gait pattern in
children and young adults with cerebral palsy treated with
local injections of botulinum toxin. They found that a dose

of 200 units of BTX per leg distributed to four or five muscle

bellies per leg was superior in comparison to 100 units of
BTX per leg without significantly affecting the risk of side
effects.
The simplest and yet most useful scales employed for the
study of spasticity in both children and adults owing to multiple etiologies, including cerebral palsy, multiple sclerosis,
stroke, and traumatic brain and spinal cord injury, include
the spasm frequency score (Table 7), the modified Ashworth
Scale (Table 6), and a subjective pain rating scale (Table 8).
The spasm frequency score varies from 0 (no spasms) to 4
(ten or more spasms), the Ashworth Scale extends from 0 (no
increase in muscle tone) to 4 (affected muscle group rigid in
flexion or extension), and the subjective score varies from 0
(no pain) to 100 (maximal pain). Also studied are range of
motion, active and passive, hygiene scores, and functional
independence measures.
All of these methods have been employed for the objective verification of the usefulness of BTX in the treatment of
spasticity owing to multiple etiologies. These include the
treatment and study of children with spastic gait due to cerebral palsy, the treatment of the hemiplegic upper limb, the
treatment of spasticity owing to head and spinal cord injury,
multiple sclerosis and stroke.
Multiple studies have demonstrated the efficacy of botulinum toxin in the treatment of cervical dystonia, extensor
truncal dystonia, blepharospasm, facial hemi-spasm, oromandibular dystonia, and laryngeal dystonia (spasmodic
dysphonia).
A more novel use for botulinum toxin is described by
Racette, Lauryssen and Perlmutter, who used botulinum
toxin to facilitate cervical fusion in dystonic cerebral palsy
pre-operatively.5

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Botulinum Toxin Therapy in Children

Table 6. - Spasticity M odified Ashworth Scale

0 = No Increase in M uscle Tone
1 = Slight Increase in M uscle Tone, Manifested by a Catch and
Release or by M inim al Resistance at the End Range
of M otion w hen the Affected Part is M oved in
Flexion or Extension
1+ = Slight Increase in M uscle Tone, M anifested by a Catch,
follow ed by Minimal Resistance Throughout the
Rem ainder (Less than Half) of the Range of M otion
2 = M ore M arked in Increase in M uscle Tone Through M ost of
the Range of M otion, but the Affected Part is Easily
M oved
3 = Considerable Increase in M uscle Tone, Passive M ovem ent
is Difficult
4 = Affected Part is Rigid in Flexion or Extension

Table 7. - Spasticity Spasm Frequency Score

How m any spasm s have you had in the (involved part) in the
last 24 hours
0
1
2
3
4

=
=
=
=
=

No Spasm s
One or Few er Spasm s
2 to 5 Spasm s
6 to 9 Spasm s
10 or M ore Spasm s, or Continuous Spasm s

Table 8. - Spasticity Pain Score

"Rate the total am ount of pain you have had in the (affected
body part) in the last 24 hours from 0 m eaning no pain to
100 m eaning m aximal pain.

Table 9. - Paraphernalia for Treatment with Botulinium Toxin

Toxin
Alcohol Sw abs
Gauze
Tuberculin Syringe
Standard Syringe
(for Dilution of Toxin)
23-Guage 1-Inch Needle
Standard Freezer

An interesting study was reported by Flett, Stern, Waddy,

and colleagues reporting from North Adelaide, Australia, in
1999, on the similar efficacy of botulinum toxin A to serial
fixed plaster casting,14 in improving dynamic calf tightness in
ambulant or partially ambulant children with cerebral palsy.
The safety and efficacy of a variety of types of botulinum
toxin other than type A have been demonstrated in a number
of studies. Equivalent efficacy has been reported for the use
of botulinum toxin type B,29,30 for cervical dystonia, for botulinum toxin type F,31 for botulinum toxin C,32 for the treatment of a variety of dystonic manifestations, in patients both
tolerant of and resistant to botulinum toxin type A.
Of interest is the report of Odergrin, Haaltason, Kaakkola
and colleagues in 19983 on the dose equivalence of Dysport

International Pediatrics/Vol. 16/No. 1/2001

and BOTOX in the treatment of cervical dystonia. These

workers found that patients with cervical dystonia treated
with the clinically indicated dose of BOTOX or three times
that does in Dysport units showed similar improvements, and
similar safety profiles.
Bhatia, Munchau, Thompson and colleagues reported
three patients with generalized muscular weakness following
botulinum toxin injections for dystonia.33 The authors felt
that clinical and electrophysiological findings were in keeping with mild botulism. All the patients had received previous botulinum toxin injections without side effects and one
patient continued injections without recurrence of generalized weakness.
The authors concluded that most likely pre-synaptic inhibition occurred due to systemic spread of the toxin. Patients with symptomatic dystonia were felt to be more likely
to have this side effect. The author is unaware of this occurrence in any child treated with BOTOX to date. The reactions in the three reported cases were all transient, and caused
no lasting harm.
Dosage and Toxicity of BTX
Children with equino varus or equino valgus have
achieved improved gait and lower extremity posture from
the injection of four units of BOTOX (botulinum toxin A
produced by Allergan) per kilogram of body weight injected
into the affected gastrocnemii. The injection is made into
the medial and lateral heads of each gastrocnemius muscle,
in each affected leg (i.e. four injections in one treatment in
diplegic children, two injections in hemi- or mono-plegic
children). Each injection volume was 2 ccs, i.e. the total
dose of BTX of 4 mg/kg of body weight was diluted to 8 ccs.
Injections were made well off the midline of the calf to avoid
the main neurovascular bundle.
Clinical benefit was evident within several days, and
lasted an average of three months (2 to 4 months).
Side effects were rare, and mild. Excessive weakness of
the target muscle was transient. An uncommon influenzalike syndrome lasted only a few days.
A note of caution is required in regard to BTX of foreign
manufacture. The British product Dysport and the US
BOTOX, are not of equivalent dosage. Users of Dysport are
advised to follow British dosage guidelines. Clinical
equivalence has been tested in the treatment of cervical dystonia.3
The potency of commercial toxin is measured by a mouse
assay in which one unit of BTX is equivalent to the LD-50
(lethal dose for 50 percent of a group of Swiss-Webster
mice).34,35 The monkey LD-50 for BTX is approximately 39
units/kg of body weight.36 Since toxicity in the monkey
begins at 33 units/kg, the margin of safety in the monkey is

Botulinum Toxin Therapy in Children

quite narrow. In mice the LD-50 is more than twice the

minimum toxic dose.
The lethal dose in humans is estimated from published
data on accidental poisoning. It is estimated that approximately 105 x the parenteral therapeutic dose is required for
the lethal effect in humans, i.e. several thousand times the
lethal dose in mice.37 If the human lethal dose were similar to
that of the monkey, the LD-50 would be about 3000 units.
Thus the dose-toxicity ratio, or safety factor, in humans is
about 10 (4 units/kg to 40 units/kg). More important is the
fact that clinical experience with these guidelines has
proven to be safe. Contra-indications to BTX are few, and
are due to co-existent myo-neural junction disorders such as
myasthenia or treatment with amnioglycocides.
Other Treatment Issues Site of Injection
The site of injection for equino varus or equino valgus
gait has been described, and the rationale for choice of midbelly muscle mass has been outlined. The number of sites
chosen for injection depends upon the size and distribution
of muscle mass. Injection for spasticity of the adductors of
the thighs, for example, requires several injections along the
distribution of the adductus longus, brevis, and magnus.
Standard anatomical guidelines have been established
for locating the approximate location of the motor end plate
for each muscle. While precise and elegant, the use of electromyography for location of the motor end plate is not necessary. Children tolerate EMG less well than the actual injection of BTX. Moreover, results do not appear to be enhanced
by the use of EMG.
The paraphernalia required for the preparation and injection of BTX are listed in Table 9.
Latency of response to BTX varies according to the disorder. A latency of two to six weeks is described for dystonia,37
but a two to six day latency is the rule for cerebral palsy.
Since serologic blocking antibodies occur with prolonged duration of use of BTX, strategies to reduce this problem include the choice of the minimum effective dose, and
the lowest frequency of administration. Change of toxin
type is still uncommon, but increasing in usage (botulinum
type B, C, F, etc.).29-32
It should be emphasized that the detection of fixed contracture at any joint, either before initiating treatment or
during ongoing treatment, is cause for discontinuation of
treatment with BTX, as improved range of motion cannot be
reasonably expected under those circumstances. Also requiring emphasis is the detection of compensatory abnormalities of posture or gait prior to or during treatment. For
example, the reduction of equinus gait by the occurrence of
crouch, or of knee hyperextension (recurvatum). Such compensatory postures are at times voluntary, and at times reflex.

They interfere with the assessment of response, and may even

influence future orthopedic function.
Summary
BTX is effective and safe for the treatment of spasticity,
dystonia, and selected smooth muscle and exocrin disorders.
This review has emphasized the use of BTX in children with
cerebral palsy due to the relative infrequency of multiple
sclerosis, stroke, and pediatric focal dystonia. The principles
of muscle selection and injection, however, apply alike to all
of these disorders, in which specific muscle relaxation is
sought.
It is only two to three years since BTX for spasticity was
considered experimental, but is now widely used for this
purpose by neurologists, physiatrists, and orthopedic physicians and surgeons.
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