2. 982 M. RAMACHANDRAN, D. M. EASTWOOD
THE JOURNAL OF BONE AND JOINT SURGERY
Saitou et al.11
A single innervation band is the pattern most
commonly found in limb muscles, speciﬁcally those with a
unipennate structure. A more complex conﬁguration of the
end-plate zone is found in multipennate muscles such as
gastrocnemius or deltoid. Scattered innervation bands are
found in sartorius and gracilis.
To maximise the clinical effectiveness of BTX-A, several
conditions must be met. The toxin must be injected inside
the fascial compartment of the muscle, in a dose sufﬁcient
to neutralise neuromuscular junction activity and in an
appropriate volume so that diffusion to these junctions in
the end-plate zone occurs while unwanted spread is mini-
Techniques for administration
BTX-A is available as two commercial preparations, Botox
(100 International Units (IU) per vial; Allergan Inc, Irvine,
California) and Dysport (500 IU per vial; Ipsen Ltd, Slough,
United Kingdom). One unit is equivalent to the amount of
toxin which is lethal to 50% of Swiss-Webster mice after
but the companies use different
biological mouse assays which means that the published
data on the relative potencies of the two products vary con-
siderably. Thus, a ﬁxed-dose ratio cannot be used when
comparing trials of clinical efﬁcacy or adverse events of the
toxins. The most effective dose per muscle is unknown,
although recommendations have been given.14
It is likely
that the dose required for effective muscle weakening varies
with the density of neuromuscular junctions in any given
muscles and perhaps with the pathology being treated as
well as its chronicity.14
There is a total-body dose which
must not be exceeded if toxicity is to be avoided. The rec-
ommendations for a safe total-body dose are 12 units/kg
and 30 units/kg for Dysport,16
clinicians have stated that they regularly exceed those doses
under certain circumstances.
Children receive a lower dose than adults although in an
animal model, Ma et al17
noted that while the neuromuscu-
lar junctions are smaller in juveniles their density within
muscle is higher than that in the adult. If this is representa-
tive of age-dependent differences, then relatively higher
doses in children may be appropriate, similar to the pattern
of use with anaesthetic neuromuscular blocking agents.
In over 50% of studies in the current literature, BTX
injections have been administered under local or general
anaesthesia, or with conscious sedation depending on the
age of the patient, the number of sites to be injected and the
Discomfort often relates to the
Localisation of the individual target muscle is often done
by palpation and based on clinical experience and anatom-
ical knowledge. This may be accurate for certain indica-
tions for neuromuscular blockade, for example, in the cos-
metic industry, but recently, placement of the needle and
injection of toxin based on such simplistic means have had
some criticism in orthopaedic practice. In large muscle
Failure of muscle
Figure 1a – Soluble (N-ethylmaleimide-sensitive fusion) attachment protein receptor (SNARE) proteins (SNAP
25, synaptobrevin and syntaxin) are necessary for acetylcholine vesicle fusion and release, leading to muscle
contraction. Figure 1b – Failure of formation of a vesicle-synaptic complex prevents fusion and release of ace-
tylcholine, leading to flaccid paralysis.
3. BOTULINUM TOXIN AND ITS ORTHOPAEDIC APPLICATIONS 983
VOL. 88-B, No. 8, AUGUST 2006
groups in the lower limbs, manual placement of the needle
may be accurate between 46% and 78% of the time,19,20
but in smaller muscle groups, the accuracy decreases to
between 18% and 37%.13,20,21
The use of electrical stimu-
lation, e.g. a Stimuplex needle (B Braun Medical Ltd, Shef-
ﬁeld, United Kingdom) aids precise localisation, particu-
larly for the small muscles within the ﬂexor compartment
of the forearm or deep muscles in the lower limb such as
tibialis posterior or ﬂexor hallucis longus. Chin et al20
recommended the use of electrical stimulation or other
guided techniques for the accurate placement of the needle
in all muscles except gastrocsoleus, although whether this
leads to better functional outcomes is still unknown. Other
guiding techniques which are less commonly used include
ﬂuoroscopy, and CT.24
Once the method for localisation of the muscle has been
established there is then uncertainty as to where the injec-
tion should be sited within the muscle, whether a single or
multiple injection is most effective and whether it should be
of high or low volume.14,25
Since the toxin exerts its effect
at the neuromuscular junctions and as, in many muscles,
these lie in well-deﬁned zones, there is a view which sup-
ports targeting the injection at the end-plate zone.25
is, however, little clinical evidence to support this belief.
Needle electromyographic stimulation can be used to
search for the characteristic visual or audible ‘noise’ of the
motor end-plate, but this technique demands a relaxed
patient and muscle and is not applicable in certain muscles,
e.g. tibialis posterior, in which the end-plate zones do not
fall in characteristic bands.
Motor points, deﬁned as the area in a muscle where a
minimal-intensity, short-duration electrical stimulus causes
contraction, are used to localise phenol nerve blocks.
Anatomically, the motor point corresponds to the area in
the muscle where small motor nerves terminate, and effec-
tively correlates with a point distal to the entrance of the
nerve into the muscle. For many muscles, localisation of the
motor point is probably as logical, appropriate and easier
than that of the end-plate zone. More accurate identiﬁca-
tion of the point of entry of motor nerves into the muscle in
each muscle group may be helpful in increasing the accu-
racy and hence the clinical effectiveness of BTX injec-
It is possible that the exact technique used should depend
on the type of muscle which is being injected and, perhaps,
the pathology which is being treated.
Side-effects are uncommon if the protocols of dosing and
technique are followed closely,16
but may be classiﬁed as
localised to the site of injection, and focal but distant from
the site of injection. Generalised pain at the site of the injec-
tion is mild and is rarely a clinical problem. Weakness in
adjacent muscles caused by diffusion of BTX across muscle
boundaries is the most common adverse event occurring
focally. The effects are temporary and are dose- and site-
related, but may be clinically signiﬁcant. The diffusion
characteristics of BTX-A in human muscle have not been
described scientiﬁcally but animal work and clinical prac-
tice suggest that diffusion occurs preferentially along the
muscle within its muscle compartment and that fascial
planes limit diffusion of toxin by about 23%.28,29
Generalised side-effects are rare and include mild gener-
alised weakness, urinary incontinence, constipation and
dysphagia in vulnerable patients, particularly children.
Many of the indications for intervention are in children or
adults who, although they have tight spastic muscles, are
weak and alteration in their overall muscle balance can
lead to some unpredicted effects on motor function. The
most serious side-effect is aspiration pneumonia in
patients with cerebral palsy who have total-body involve-
ment and pre-existing pseudobulbar palsy. This can occur
even with the systemic spread of small amounts of BTX
and can further impair pharyngeal function.30
history of pseudobulbar palsy, gastro-oesophageal reﬂux,
and frequent chest infections are relative contraindications
to the use of BTX. In adults, the use of BTX is not recom-
mended in pregnant or lactating women. Other contrain-
dications include a history of disease affecting the
neuromuscular junction, such as myasthenia gravis, and
the use of aminoglycoside antibiotics and non-depolaris-
Table I. The indications for the use of botulinum toxin
Alter motor function by
improving the balance between
agonist and antagonist forces
Improve equinus gait in cerebral
Improve arm function following a
Bladder control in spinal injury
Prevention of deformity Acetabular dysplasia in cerebral palsy
Glenoid dysplasia in obstetric
brachial plexus palsy
Equinus contracture post-head injury
Decrease ‘spasticity’-related pain Post-operatively
Myofascial pain syndromes
Improve quality of life Of the patient
Of the carer
Enhance self-esteem Prevention of involuntary movements
Management of athetoid cerebral
Pre-surgical diagnostic tool Predicting the effect of release of
Improvement of hand function in
Protection of soft-tissue repair Flexor tendon repairs in children
4. 984 M. RAMACHANDRAN, D. M. EASTWOOD
THE JOURNAL OF BONE AND JOINT SURGERY
ing muscle relaxants, since these medications potentiate
the action of BTX.
Despite concerns regarding the development of toxin-
neutralising antibodies after repeated injections of BTX,31
there is no current evidence that this results in subsequent
Indications for use
In musculoskeletal practice, the use of BTX has gained pop-
ularity as a treatment for spastic or dystonic muscle, most
commonly due to damage to the central nervous system. Its
most frequent use is in children with cerebral palsy, but
many other potential uses have been identiﬁed. The indica-
tions for the use of BTX are listed in Table I. It is important
to remember that the licensed indications for the ortho-
paedic use of both preparations of botulinum toxin are few.
Most usage occurs ‘off-licence’ and the success or otherwise
of much of the treatment is dependent on the adjunctive use
of physiotherapy and/or splinting. Similarly, for those indi-
cations in which repeated treatments are necessary, little is
known about the long-term effects of regular muscle dener-
vation, particularly in conditions such as cerebral palsy in
which weakness may be as important a feature as spasticity.
In cerebral palsy in which there is a generalised abnormality
of muscle tone, BTX is used as focal treatment for a
dynamic muscle imbalance which is interfering with func-
tion, producing deformity, or causing pain, in the absence
of signiﬁcant ﬁxed deformity.32
The aim of injections of
BTX is to achieve muscle weakening in spastic muscles in
the belief that they will encourage muscle strength and
hence muscle growth while allowing the weak antagonists
to be strengthened, thereby preventing the development of
bony deformity secondary to abnormal muscle pull and
contracted tendons and joints. As younger children tend to
have more spasticity and less ﬁxed-deformity than older
children, they respond better to injections of BTX-A. Before
injection, clinical examination must be directed speciﬁcally
towards differentiating spasticity from ﬁxed contracture,
although minimal degrees of contracture may improve with
It is hoped, but not proven, that in
young children the instigation of all elements of non-opera-
tive management such as physiotherapy, casting, orthotics
and spasticity management including the use of regular
BTX injections may delay or decrease the need for surgical
reserving single-event multi-level surgery for
ﬁxed musculotendinous contractures and bony deformity
in the older child.35
In the lower limb, several randomised, double-blind,
placebo-controlled trials have proved the short-term efﬁ-
cacy and safety of BTX-A in the management of spasticity,
with improvements in deformity and gait.36-39
In the spastic
hemiplegic or diplegic child, a dynamic equinus gait or the
equinus component of more complex gait patterns can be
helped by injection of gastrocsoleus.38,40
If this fails to cor-
rect an equinovarus deformity fully, tibialis posterior can be
injected or, if more appropriate, tibialis anterior.
Similarly, overactivity of the hamstrings can be improved
by injection of BTX-A and the response to injection may
also help to predict the results of hamstring lengthening41
or adductor tenotomy. Injection of the hip ﬂexors is more
technically demanding and may require ultrasound guid-
ance for the accurate localisation of the muscle, and hence
Overall, it is disappointing when reports fail to
deﬁne which muscles within the adductor or hamstring
group have been injected and which technique has been
The complex gait patterns shown by children with cere-
bral palsy often require treatment at multiple levels in a
manner similar to the development of the single-event
multilevel surgery strategy. Each muscle must then receive a
dose adequate for a clinical response and yet care must be
taken not to exceed the recommended total-body dosage.
Alternative neuromuscular blocking agents, such as 50%
concentrated alcohol solution, can be used for any remain-
ing muscle injections. In clinical terms, the effect of such a
multilevel approach may be equivalent to a medical rhizot-
In children with total-body involvement, treatment of
adductor spasticity can lead to improvements in position-
ing, perineal hygiene, and orthotic tolerance.44
with progressive subluxation of the hip, symptoms of pain
and stiffness can be improved by the injection of the
involved adductors and iliopsoas, when combined with
bracing of the hip in abduction.45
A reduction in, or stabi-
lisation of the hip migration percentage may occur, espe-
cially in a child under the age of two years whose initial
subluxation shows a migration percentage > 30%.45
The concomitant use of a plaster cast with BTX injec-
tions is quite common, although its use as a method of
applying stretch at the time of the injection is illogical since
the reduction in stretch reﬂex and spasticity has not yet had
time to develop. One recent publication has shown that the
equinus associated with considerable soft-tissue contrac-
tures is worsened when BTX-A is added to a serial casting
If BTX-A injection alone is used in patients with
ﬁxed contractures, severe spasticity or mixed hypertonia,
who cannot tolerate serial casting well, it is unlikely that
signiﬁcant improvement in movement will occur.
There are few randomised trials in the current literature
which have examined the efﬁcacy of BTX-A in the upper
limb, but Corry et al47
and Fehlings et al48
ments in spasticity and the range of movement in joints in
the upper limb with BTX-A, although the numbers of
patients were small. The results of BTX-A injection on
spasticity of the upper limb are less consistent and may be
related to inaccuracy of the placement of the needle in the
smaller muscles of the forearm and hand, and weakening of
neighbouring muscles by diffusion of toxin.49
Cochrane collaborative review concluded that there was
insufﬁcient current evidence to support the efﬁcacy of BTX-
5. BOTULINUM TOXIN AND ITS ORTHOPAEDIC APPLICATIONS 985
VOL. 88-B, No. 8, AUGUST 2006
A as an adjunct in the treatment of the upper limb in chil-
dren with cerebral palsy and called for further research.50
Other indications for BTX-A in cerebral palsy include
post-operative or post-treatment control of pain.51
medium- and long-term effects of the use of BTX in cere-
bral palsy are as yet unknown. Concerns include atrophy of
muscle ﬁbres and potentiation of muscle weakness, partic-
ularly in children with pre-existing weakness masked by
Other conditions of the central nervous system
Multiple sclerosis. Nearly all patients with multiple sclero-
sis develop spasticity at some stage and the use of BTX has
been recommended for relief from pain, improvement in
the range of movement, speciﬁcally related to perineal
hygiene, and for management of dys-synergia of the blad-
Stroke. The management of the hemiplegic limb secondary
to a stroke is similar, in some respects, to that of a child
with cerebral palsy and improvements in the pain associ-
ated with spasticity, the range of movement in the joints
and function of the upper limb have been noted after BTX
Head injury. In both adults and children, BTX injections
have been used to try and alter the natural history of the
condition. In a randomised, clinical trial examining the pre-
vention of equinus deformity in the acute phase after a head
injury, the use of BTX injections did not add to the beneﬁt
seen with early, active intervention with physiotherapy and
However, once an equinus posture had devel-
oped, BTX injections improved gait58
and the range of
Spinal injury. In this group of patients, BTX injections are
used most frequently to aid the control of bladder function.
Injections have also been used for relief from pain and the
avoidance of joint contracture and muscle shortening.60,61
Other paediatric orthopaedic conditions
Congenital talipes equinovarus. The rationale for the use of
BTX in congenital talipes equinovarus assumes that a
reduction of tone in the most contracted muscles may facil-
itate their lengthening by manipulative stretching. Initial
reports using injections into tibialis posterior, the gastroc-
soleus complex and other muscles in both infant feet and
post-surgical relapses were encouraging.62,63
Alvarez et al64
treated the gastrocsoleus muscle complex of
51 patients with 73 idiopathic club feet with BTX-A as an
alternative to tenotomy of tendo Achillis after a course of
manipulation and Ponseti casting. One foot ‘failed’, requir-
ing a tenotomy, and 12% of the feet relapsed as a result of
non-compliance with bracing. It was suggested that the use
of BTX-A produced satisfactory results with less skin scar-
ring and deep tissue ﬁbrosis than a percutaneous tenotomy
of tendo Achillis. By contrast, a recent prospective, ran-
domised, double-blind study of 20 newborn infants with
congenital talipes equinovarus,65
found no signiﬁcant dif-
ference between BTX-A and placebo in conjunction with
serial manipulation and casting with respect to the speed of
correction, the need for percutaneous tenotomy and the
risk of relapse. Further studies are therefore required to
resolve this conﬂicting evidence.
Idiopathic toe walking. BTX-A injection into gastrocsoleus,
in conjunction with immediate casting in 10˚ of dorsiﬂexion
for one week, has been used effectively in the treatment of
idiopathic toe walking.66
In this study, toe walking had
resolved in all ten treated patients at three months after
injection. Eight of the ten patients maintained normal walk-
ing for up to 18 months. In a more recent study,67
dren who were idiopathic toe-walkers and had been treated
with gastrocsoleus BTX-A injections, achieved a normal
gait pattern both clinically and on electromyography, with
the improvement persisting when reviewed after 12
Congenital muscular torticollis. This common form of torti-
collis in children presents as an idiopathic tightness of the
sternocleidomastoid muscle without a palpable sterno-
When conservative treatment is ineffec-
tive, surgery is considered,68
but BTX-A may be an
additional option. Joyce and de Chalain69
spectively 15 children with idiopathic tightness who had
been treated with BTX-A injection and subsequent addi-
tional physiotherapy after a poor response to conventional
physiotherapy and stretching exercises. Good improvement
in the range of movement of the neck and in position of the
head, thus avoiding the need for surgical release was
achieved in 14 children. In another retrospective series,
Oleszek et al70
reviewed 72 children with idiopathic sterno-
mastoid tightness treated with BTX-A injections into the
sternomastoid and/or the upper trapezius muscles, observ-
ing improvement in cervical rotation or head tilt in 20. Two
had transient side-effects, speciﬁcally mild dysphagia and
weakness of the neck.
Acquired muscular torticollis. In adults, acquired muscular
torticollis is often secondary to dystonia or one of the myo-
fascial pain syndromes. Both can be treated reliably, if tem-
porarily, with injections of BTX.
Neonatal injury to the brachial plexus. Unwanted muscular
co-contraction or inappropriate activation of antagonist
muscles can hamper co-ordinated movement, such as hand-
to-mouth movements, in children with severe neonatal
brachial plexopathy. BTX-A injections have been used suc-
cessfully to inhibit such co-contractions in biceps and tri-
and activation of antagonist muscles such as the
adductors and internal rotators of the shoulder72
rehabilitation of such patients. Recently, BTX-A injections
into the internal rotators of the shoulder, namely pectoralis
major and/or latissimus dorsi, have been shown to be a use-
ful adjunct to the primary and secondary surgical treatment
of brachial plexus birth injuries, with signiﬁcantly higher
grades of shoulder function in the 74 patients treated with
BTX-A in comparison with the 74 without BTX-A at a
minimum follow-up of two years.73
It is hoped that the
6. 986 M. RAMACHANDRAN, D. M. EASTWOOD
THE JOURNAL OF BONE AND JOINT SURGERY
early treatment of certain infants with obstetric brachial
plexus palsies with BTX injections may result in stronger,
normal muscles and may prevent the development of
glenoid dysplasia, secondary to an unbalanced muscle pull
on immature bones.
Pain syndrome. The study by Barwood et al51
a signiﬁcant reduction in post-operative pain in children
with cerebral palsy secondary to a reduction in muscle
spasm, has implications for the management of pain sec-
ondary to muscle spasm in other circumstances. After the
use of BTX injections, the relief from pain is usually due to
its effect on muscle tone rather than to any theoretical
direct effect on the pain ﬁbres. There is also some evidence
to support the use of BTX in certain patients with whip-
lash-associated disorders and low back pain.
Lateral epicondylitis. Morre, Keizer and van Os74
reported the use of BTX-A in the management of lateral
epicondylitis in 14 patients with chronic symptoms resis-
tant to non-operative treatment. The common extensor ori-
gin was injected and relief from pain in more than 50% on
a self-assessment scale was achieved for three to four
months in nine patients, with pain disappearing completely
in four. This prompted a randomised, controlled trial by the
same group, comparing injection of BTX-A and surgical
release with 20 patients in each group.75
were found between surgery and injection with respect to
subjective (e.g. visual analogue scores of pain) and objective
(e.g. grip-strength testing) outcomes for up to two years
after treatment, suggesting that BTX-A was equally as
effective as surgery, but less invasive.
Two more recent investigations have cast doubt on the
validity of these results. Hayton et al76
in a double-blind,
randomised, controlled trial involving 20 patients in each
group comparing BTX-A injections with injections of nor-
mal saline at the site of maximum tenderness, found no sig-
niﬁcant difference with regard to grip strength, pain, or
quality of life at three months. In a larger, double-blind,
randomised, controlled trial Wong et al77
and placebo injections and found lower pain scores in the
BTX-A group at three months, but no change in objective
measures such as grip strength. Signiﬁcantly, four patients
experienced weakness of ﬁnger extension at four weeks in
the BTX-A group, whereas no cases of paresis were
observed in the placebo group.
At present, there is insufﬁcient long-term evidence to
support the use of BTX-A in the management of lateral epi-
Tendon repair. A recent report described the use of BTX
injections to ‘protect’ ﬂexor tendon repairs in zone II and to
aid post-operative rehabilitation in a group of seven young
The authors believe that BTX injections could
serve as an alternative or adjunct to current regimes of
rehabilitation in children or other patients in whom compli-
ance with conventional management may be difﬁcult.
Botulinum toxin is undoubtedly a powerful neurotoxin
which, potentially, has many uses within the ﬁeld of
musculoskeletal medicine, but much remains to be learnt
with respect to the most appropriate method of delivery of
the toxin to the neuromuscular junction. Similarly,
although its chemodenervation effects are well recognised,
the most appropriate indications for its use still require fur-
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