Botulinum Neurotoxin as a Therapeutic Modality in Orthopaedic

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Botulinum Neurotoxin as a Therapeutic Modality in Orthopaedic
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Botulinum Neurotoxin as a Therapeutic Modality in Orthopaedic
Surgery: More Than Twenty Years of Experience
Thorsten M. Seyler, Beth P. Smith, David R. Marker, Jianjun Ma, Jian Shen, Tom L. Smith, Michael A. Mont, Kat
Kolaski and L. Andrew Koman
J Bone Joint Surg Am. 2008;90:133-145. doi:10.2106/JBJS.H.00901
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BY
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BONE
AND JOINT
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Botulinum Neurotoxin as a Therapeutic
Modality in Orthopaedic Surgery:
More Than Twenty Years of Experience
By Thorsten M. Seyler, MD, Beth P. Smith, PhD, David R. Marker, BS, Jianjun Ma, MD, PhD, Jian Shen, MD, PhD,
Tom L. Smith, PhD, Michael A. Mont, MD, Kat Kolaski, MD, and L. Andrew Koman, MD
Introduction
otulinum neurotoxins are among the most potent toxins found in nature, and are produced by Clostridium
botulinum, an anaerobic, gram-positive, spore-forming rod-shaped bacterium1. There are seven known serotypes
of botulinum neurotoxins (termed A, B, C1, D, E, F, G) that
cleave soluble N-ethyl-maleimide-sensitive factor attachment
receptor (SNARE) proteins, preventing effective release of
neurotransmitters across specialized synaptic junctions.
Blocking SNARE protein function within neuromuscular
junctions produces flaccid paralysis, results in anhidrosis
within sweat glands, and increases nutritional blood flow in
vascular beds. On the basis of these findings, it was hypothesized that controlled injections of botulinum neurotoxins
could be used to treat neuromuscular disorders. The benefits
of botulinum neurotoxin injections in the treatment of various neurological disorders have captured the attention of
physicians from multiple specialties and have contributed to
the widespread use of botulinum neurotoxins in modern
medicine2.
Currently, only botulinum neurotoxin type-A (BoNTA) and B (BoNT-B) serotypes are approved by the U.S. Food
and Drug Administration. The mandated labeling includes
the following therapeutic and anesthetic indications: (1) treatment of cervical dystonia in adults; (2) treatment of strabismus and blepharospasm associated with dystonia, including
benign essential blepharospasm or seventh cranial nerve disorders in patients who are twelve years of age or older; (3)
treatment of severe primary axillary hyperhidrosis; and (4)
treatment of severe glabellar lines associated with corrugator
and/or procerus muscle activity in patients who are sixty-five
years of age or younger.
This article outlines the role of botulinum toxins, particularly type A, as a therapeutic modality in musculoskeletal
conditions on the basis of the peer-reviewed literature and the
B
personal experience of the authors. Some of the information
presented in this article describes off-label indications for
drugs as defined by the Food and Drug Administration. The
doses, side effects, techniques, and information reflect the
opinions of the authors and the cited literature.
Mechanism of Action
Regulated exocytosis of neurotransmitters, in which synaptic
or secretory vesicles fuse with the plasma membrane to release
their contents in response to a Ca2+ trigger, underlies neurotransmission and hormone secretion. Considerable advances
have resulted in the identification of SNARE proteins (synaptobrevin, syntaxin, and synaptosomal-associated protein-25
[SNAP-25]), which are essential for synaptic or secretory vesicle fusion to the plasma membrane and neurotransmitter exocytosis (Figs. 1-A and 1-B). Much of our understanding of the
critical role of these proteins is related to the finding that the
application of clostridial neurotoxins (botulinum toxins A
through G and tetanus toxin) blocks Ca2+-triggered neurotransmitter release by cleavage of these proteins3.
Research has shown that when botulinum neurotoxins find their primary targets, i.e., neuromuscular junctions,
they interfere with the acetylcholine release process, but not
with acetylcholine storage or Ca2+ influx, leading to a blockade of neurotransmitter release and muscular paralysis. All
botulinum neurotoxins employ a similar mechanism of action, which may be divided into three main steps: binding,
internalization, and intracellular action. Prior to binding,
botulinum neurotoxins are synthesized as single polypeptide
chains of approximately 150 kDa. This single chain is posttranslationally cleaved into a 50-kDa light chain and a 100kDa heavy chain. On cleavage, the light chain and heavy
chain of botulinum neurotoxins remain covalently and reversibly linked by a disulfide bond. The heavy chain of botulinum neurotoxins acts as the binding and translocation
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or
grants in excess of $10,000 from Allergan, Inc. Neither they nor a member of their immediate families received payments or other benefits or a
commitment or agreement to provide such benefits from a commercial entity. A commercial entity (Allergan, Inc.) paid or directed in any one year, or
agreed to pay or direct, benefits in excess of $10,000 to a research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which one or more of the authors, or a member of his or her immediate family, is affiliated or associated.
J Bone Joint Surg Am. 2008;90 Suppl 4:133-45 • doi:10.2106/JBJS.H.00901
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Fig. 1-A
Under normal physiological conditions, SNAP-25, a soluble N-ethyl maleimide-sensitive factor (NSF) attachment protein receptor (SNARE), is required for the release of neurotransmitters, such as acetylcholine, from the axon endings. (Reprinted, with permission, from: Koman LA. Wake Forest University Orthopaedics Handbook. Winston-Salem, North Carolina: Wake Forest University Orthopaedic Press; 2004. p 2.)
Fig. 1-B
The heavy chain of the BoNT-A targets the toxin to specific types of axon terminals due to their high affinity for external ectoreceptors. After the
heavy chain attaches to proteins on the surface of axon terminals, the toxin is taken into neurons by endocytosis. The light chain leaves the
endocytotic vesicles and reaches the cytoplasm. The light chain of the toxin has protease activity and prevents the formation of the SNARE
complex. (Reprinted, with permission, from: Koman LA. Wake Forest University Orthopaedics Handbook. Winston-Salem, North Carolina: Wake Forest University Orthopaedic Press; 2004. p 2.)
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TABLE I Rationale and Indications for the Use of BoNT-A in Orthopaedics
Rationale
Indications
Selective weakening of target muscles to restore muscle
balance
Shoulder dislocation; improve gross motor function in
patients with cerebral palsy; hip dislocation in hip dysplasia,
Legg-Calvé-Perthes disease; limb-lengthening; multiple sclerosis; torticollis
Combined with physical therapy as an alternative to
manipulation under anesthesia and arthroscopic release
Adhesive capsulitis, contractures following total knee arthroplasty, lateral epicondylitis, adductor tightness after total hip
arthroplasty
Combined with surgical releases
Talipes equinovarus, idiopathic toe-walking
Post-surgery and/or post-injury modulation
Tendon repair and/or transfer, fracture repair, muscle repair
Pain management
Intra-articular pain, postoperative pain related to muscle
spasms, pain secondary to nerve-root irritation associated
with degenerative disc disease, plantar fasciitis, pain after
amputation
Prevention of deformity
Stroke and traumatic brain injury, neonatal brachial plexus
injury, knee contracture in Duchenne muscular dystrophy, acetabular dysplasia in cerebral palsy
Improve health-related quality of life
Cerebral palsy, multiple sclerosis, torticollis, lateral epicondylitis, ease of caregiving
Enhance self-esteem
Prevention of involuntary movements in cerebral palsy patients
domain, facilitating endocytosis into cholinergic nerve terminals. Within the nerve terminal, the light chain of botulinum neurotoxin, a zinc-dependent endopeptidase, is
activated by the acidic environment and acts as the catalytic
domain, cleaving SNARE proteins. This proteolytic attack
prevents formation and fusion of the synaptic fusion complex necessary for release of intracellular neurotransmitters,
such as acetylcholine. SNARE proteins are involved in the
release of various neurotransmitters other than acetylcholine, which explains in part the diverse effects of botulinum
neurotoxins. These autonomic and noncholinergic effects
of botulinum neurotoxin introduced into noncholinergic
nerve terminals formed the rationale for the clinical
application of botulinum neurotoxin in hypersecretory
and pain conditions. For example, exocytosis is necessary
for SNARE-protein mediated release of pain mediators such
as substance P, calcitonin-gene-related peptide, and/or glutamate. Thus, blockade of the exocytosis of these substances
decreases painful stimuli.
Rationale for the Use of Botulinum Toxins
in Musculoskeletal Conditions
For patients with musculoskeletal disorders, botulinum neurotoxin injections produce safe, predictable, and reversible
motor weakness as demonstrated in both clinical and basic research. The use of botulinum neurotoxins, namely BoNT-A,
to modulate musculoskeletal disorders has evolved as a result
of the initial experiences with spasticity associated with cerebral palsy, stroke, head injury, spinal cord injury, and multiple
sclerosis. To date, many other potential indications have been
identified (Table I). However, it is important to remember
that the Food and Drug Administration-approved indications
for orthopaedic applications are limited and that most of the
usage is considered to be off-label.
Botulinum Toxin Preparations and Potency
Although there are seven known serotypes of botulinum neurotoxins, only BoNT-A and BoNT-B preparations are commercially available4. There are three preparations of BoNT-A:
Botox (Allergan, Irvine, California), Dysport (Ipsen, Slough
Berkshire, United Kingdom), and Xeomin (Merz, Frankfurt,
Germany). There is only one form of BoNT-B, and that is Myobloc (Elan Pharmaceuticals, South San Francisco, California). In Europe, Myobloc is distributed under a different trade
name, Neurobloc. As of May 2008, only Botox and Myobloc
were approved by the Food and Drug Administration for clinical use in the United States.
The formulations of the three available BoNT-A preparations are different. Botox is supplied in vials containing
100 units (U) of BoNT-A, 0.5 mg of human albumin, and 0.9
mg of sodium chloride. Similar to Botox, Xeomin is available
in 100-U vials also containing human albumin, and 20% sucrose. Dysport is available in vials containing 500 U of
BoNT-A, 125 μg of human albumin, and 2.5 mg of lactose.
All three preparations contain BoNT-A in a lyophilized form
requiring reconstitution with normal saline solution. Botulinum neurotoxin-B differs from BoNT-A not only by serotype but also by method of production and toxin activity.
Unlike BoNT-A preparations, Myobloc (BoNT-B) is supplied as a solution in vials containing 5000 U/mL of BoNTB, 0.05% albumin (human), 0.01 M sodium succinate, and
0.1 M sodium chloride buffer at a pH of 5.6.
Within BoNT-A formulations, there are differences in
potency among Botox, Xeomin, and Dysport and caution is
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Fig. 2
Some muscles, such as the latissimus dorsi and pectoralis major, require multiple injection sites due to the diffuse localization of neuromuscular
junctions. The injection sites for the latissimus dorsi and pectoralis major can be localized readily by palpation while the muscle is on stretch. (Reprinted, with permission, from: Koman LA. Wake Forest University Orthopaedics Handbook. Winston-Salem, North Carolina: Wake Forest University
Orthopaedic Press; 2006. p 4.)
required when extrapolating dosage from one product to
another. The standard unit used to measure botulinum neurotoxin potency is derived from the mouse lethality assay, in
which one mouse unit is defined as the amount of botulinum neurotoxin injected intraperitoneally that kills 50% of
female Swiss-Webster mice that weigh 18 to 22 g each (i.e.,
Lethal Dose-50). However, the assay methodology varies
among manufacturers, making dose comparisons difficult.
Dosing and Injection Technique
Historically, the reported dosage of BoNT-A used in studies
has varied (see Appendix). While some studies used dosages
of 100 or 200 U regardless of patient weight, many early reports were consistent with recommendations that determined
the units of toxin per kilogram of body weight, with the maximum total dose being based on body weight5,6. Although these
early recommendations proved to be safe, they did not address differences in the mass of the specific muscles being injected. A more specific approach has been developed on the
basis of the number of neuromuscular junctions and associated SNARE-containing organelles that need to be blocked.
This recommended approach is based on three primary concepts: (1) the optimal dosage for a 110-g lateral gastrocnemius muscle is 100 U, (2) higher dose volumes are more
effective, but volume should not exceed 30% of the mass of
muscle to be injected, and (3) blockade of each neuromus-
cular junction requires the same amount of toxin. After adjusting the ideal gastrocnemius muscle dose for the muscle
weight (e.g., a 55-g muscle would require only 50 U), the required dose for a specific muscle is determined by multiplying
the calculated gastrocnemius muscle dose by a predetermined
factor (see Appendix).
The decision about which muscles to inject with
BoNT-A is based on localization of the tightness and severity
of spasm in each individual patient. Additionally, a clinical
examination is required to determine the localization of
the muscle tightness as well as patient history and range-ofmotion measurements. The clinical examination consists
of standard range-of-motion assessments for the involved
joint(s) as well as palpation of the associated muscle(s) under stretch. While palpation and the use of osseous landmarks can be used to determine optimal injection sites for
large, superficial muscles7 (Fig. 2), electromyographic control and/or ultrasound guidance is recommended for technically demanding muscles that require precise needle
placement to optimize results (Fig. 3) (see Appendix)8,9. Our
injection algorithm is based on two fundamental concepts:
(1) the ideal injection site(s) is determined by the spatial distribution of the neuromuscular junctions, and (2) the number of injection sites reflects the anatomy of the target
muscle and assumes a toxin diffusion of 25 to 35 mm. On the
basis of this estimated diffusion radius, there needs to be ap-
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proximately one injection for every 50 to 70 mm of measured muscle-belly length.
After identifying the appropriate injection sites, a needle
size (ranging between 23 and 27 gauge) should be selected on
the basis of muscle depth, the amount of difficulty encountered in palpating the muscle, and whether electromyograms
will be utilized. If a long needle is required or the muscle is
difficult to palpate under stretch, a larger-bore needle should
be selected. The larger bore helps facilitate the sense of fascial
penetration on the part of the practitioner and provides an
appreciation of the relative resistance of a muscle belly compared with that of fat. Injections that require the use of electromyography should be performed with a needle that
permits the simultaneous injection of BoNT-A.
In general, BoNT-A injections may be safely performed
without sedation. Over the past fifteen years, more than 95%
of our patients (more than 20,000 injections) have tolerated
injections either with no anesthesia or with analgesia with
topical spray techniques (e.g., dichlorodifluoromethane 15%,
trichloromonofluoromethane 85% spray; Fluori-Methane
Spray and Stretch; Gebauer, Cleveland, Ohio). Recently, it has
been reported that cooling by spray solutions or ice can be
used to reduce anxiety and pain during injection10. Although
general anesthesia is typically not required, it can be used for
patients who experience severe apprehension or who require
B O T U L I N U M N E U RO T OX I N A S A T H E R A P E U T I C M O D A L I T Y :
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multiple injections, iliopsoas injections, and/or injection in
muscles that are difficult to localize (Fig. 4).
Orthopaedic Indications for the
Use of Botulinum Neurotoxin-A
Cerebral Palsy
erebral palsy is a nonprogressive group of syndromes of
posture and motor impairment that affects >500,000 individuals in the United States. These syndromes are characterized by fixed contractures, torsional deformities of long bones,
and joint instability resulting from muscle hypertonia during
growth and development (Fig. 5). Patients commonly present
with muscle spasticity as well as weakness, pain, joint deformity, osseous deformity, and/or rigidity. Traditional treatment
has been physical therapy and bracing. Unfortunately, some
problems are recalcitrant to these conventional interventions.
Although physical therapy combined with appropriate splinting has been shown to improve health-related quality of life
and to decrease disability, the lack of supporting randomized
prospective studies makes the long-term efficacy of these interventions unclear. A recent randomized controlled study
reported that physical therapy, five times per week, provided
improved motor function in the short term; however, the
results were not sustained11. Similarly, another randomized
controlled trial indicated that there was no evidence that addi-
C
Fig. 3
The iliacus and psoas major muscles may be injected through an anterior approach with the aid of either ultrasound or electromyographic guidance
or through a posterior approach with the aid of computed tomographic guidance. (Reprinted, with permission, from: Koman LA. Wake Forest University Orthopaedics Handbook. Winston-Salem, North Carolina: Wake Forest University Orthopaedic Press; 2000. p 4.)
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TABLE II Preliminary Outcomes of Cerebral Palsy Cohort
Group
Number of
Patients
Outcome
Paraspinal muscle spasticity
3
Caregivers reported that spasticity was reduced in all patients.
Nonambulatory−lower extremity
8
All patients exhibited reduced spasticity and improved positioning.
Ambulatory with foot deformities
16
tional physical therapy for one hour per week for six months
helps the motor or general development of young children
with spastic cerebral palsy12. Surgery is considered when other
treatments have failed. In an effort to discover less-invasive or
noninvasive treatments, options such as oral pharmacological
agents, injected alcohol or phenol, intrathecal medications,
and BoNT-A have been evaluated.
On the basis of the reported efficacy of the use of
BoNT-A for other spastic disorders, such as torticollis13, the
senior author (L.A.K.) recognized the potential benefit of
BoNT-A injections for the management of spasticity in patients with cerebral palsy and, in January 1987, initiated the
first clinical trial in the United States for the purpose of
studying this modality. That study assessed twenty-seven pediatric patients who had dynamic deformities that were unresponsive to other nonoperative treatment modalities and
for whom surgery was the only other realistic alternative5.
Following BoNT-A injections, all patients showed improvement in clinical assessment (Table II). There were no major
adverse outcomes in this initial cohort. The only side effects
reported were soreness at the injection site, generalized fatigue, and weakness of the injected muscle. These symptoms were transient, with complete resolution at the time of
the final follow-up visit. In addition, a placebo-controlled,
randomized double-blind study assessing BoNT-A in the
management of patients with cerebral palsy was also undertaken to evaluate the efficacy of toxin injections in the management of dynamic equinus deformities6. Five of six patients
receiving BoNT-A showed improvement as compared with
two of six patients in the placebo cohort.
On the basis of the success of these initial trials, a larger,
prospective, double-blind randomized clinical trial involving
114 children with cerebral palsy and dynamic equinus foot deformities was initiated to evaluate the safety and short-term
efficacy of BoNT-A14. Patients were seen at five scheduled
follow-up visits. The Physician Rating Scale5 composite score
responder rate was significantly greater in the BoNT-A group
compared with the placebo group at all follow-up visits. By
week eight, thirty-one (61%) of fifty-one patients in the
BoNT-A group responded as compared with only fourteen
(25%) of fifty-five in the placebo group. Similar to previous
study cohorts, there were no serious adverse events reported
in the BoNT-A group.
The most recent assessment at Wake Forest University
School of Medicine included 172 children who received injections of BoNT-A for the treatment of spastic-type cerebral
palsy15. A mixed modeling procedure was used to identify
Physician Rating Scale increased by a mean of 5.0 points.
changes both in physical functioning outcomes (Functional
Independence Measure for Children16) as well as in quality of
life of the parent caregiver (Stein and Riessman Impact on the
Family Scale17). It was reported that, in comparison with baseline, the administration of each additional BoNT-A injection
was associated with a 2.3% improvement in the functional
outcomes and a 2.5% improvement in the parent’s overall perception of the severity of the child’s condition.
Following the release of the initial report in 19935, other
research centers also began to assess the possible benefit of
BoNT-A in the treatment of cerebral palsy patients. The interest in this treatment option is reflected in the more than
doubling of publications concerning “cerebral palsy and botulinum” in the most recent five-year publication period (2003
to 2007, n = 250) as compared with the preceding five-year
period (1998 to 2002, n = 123). The recent studies (2003 to
2007) represent nearly 62% of the published cerebral palsyrelated botulinum reports to date; during the first five-year
period, relatively few studies (n = 32) were published. This interest served as one of the justifications for this current study,
in which we attempted to understand how the treatment of cerebral palsy has progressed over the last fifteen years.
In order to assess the reported efficacy of BoNT-A in the
treatment of cerebral palsy at other institutions, a systematic
review was conducted of the literature found on the MEDLINE and EMBASE bibliographic databases. The initial search
parameters used to identify potentially relevant articles were
cerebral palsy and botulinum. Bibliographies of review articles
were then searched for any additional relevant studies. Two of
the authors (D.R.M. and T.M.S.) screened all articles according to a previously defined protocol18. The review was limited
to Level-I or Level-II studies that reported clinical outcomes
following BoNT-A injections in patients with cerebral palsy.
There were thirty-three studies that were reviewed, with a total of 1267 patients treated in these studies. Twenty-six of the
studies assessed lower-extremity treatments. Overall, the conclusions from these studies were: (1) BoNT-A improved clinical outcomes as compared with the outcomes in placebo
cohorts, (2) BoNT-A combined with casting and/or therapy is
more effective than BoNT-A alone (maintenance and increases in muscle-fiber length are enhanced by active and passive range-of-motion exercises, splinting, and strengthening
programs), and (3) relatively few adverse events have been reported at the dosages used (see Appendix). We found only
seven randomized prospective studies that assessed the use of
BoNT-A for the treatment of upper-extremity spasticity in patients with cerebral palsy, which implies that the absolute ben-
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lateral epicondylitis (reported in one study to be 1.3% of the
population between the ages of thirty and sixty-four years21)
and its impact on health-related quality of life, early initiation
of nonoperative treatment modalities is indicated. On the basis of our experience, BoNT-A injection appears to be a viable
option for the treatment of lateral epicondylitis when initial
nonoperative treatment (rest, anti-inflammatory medications,
physical therapy, counterforce bracing, and corticosteroid in-
Fig. 4
Needle placement may be confirmed by passive range of motion; however, this technique requires anesthesia, except with very cooperative
patients. (Reprinted, with permission, from: Koman LA. Wake Forest
University Orthopaedics Handbook. Winston-Salem, North Carolina:
Wake Forest University Orthopaedic Press; 2000. p 5.)
efit for these patients is not clear cut (see Appendix).
The outcomes seen by us and the outcomes reported in
other studies suggest that the efficacy of the botulinum toxin
is variable. The outcome may be affected by the dosage and
toxin formulation, the location of the injection site within the
muscle, the type of muscle motor units that are injected, the
variability of the distribution of neuromuscular junctions
among muscle groups, and the variability in patient responses
to the injections. Additional research will be required to evaluate these variables.
Lateral Epicondylitis
Lateral epicondylitis affects 1% to 2% of the general population each year19. Men and women are affected equally, with
symptoms more commonly seen in the dominant arm. Although the term lateral epicondylitis suggests an inflammatory process, it is often a self-limiting disease; approximately
80% of newly diagnosed patients report symptomatic improvement at one year19,20. The majority of cases are idiopathic
and are often related to repetitive activity, such as playing tennis. The origin of the extensor carpi radialis brevis muscle is
thought to play a major role in the etiology because of its
unfavorable anatomic situation. Scars within any of the wrist
extensor origins, as well as irritation of the posterior interosseous nerve and intra-articular involvement of the elbow,
may also contribute to the disease. The resulting pain and
wrist extensor dysfunction can be extremely debilitating, leading to an interference with work and a negative impact on
health-related quality of life20. Given the high prevalence of
Fig. 5
The most common patterns of spasticity observed in pediatric patients
with cerebral palsy include both the upper extremity (internal rotation of
the shoulder, elbow flexion, forearm pronation, wrist and finger flexion,
and thumb-in-palm) and lower extremity (hip flexion and adduction,
knee flexion, ankle plantar flexion, hindfoot valgus, and forefoot pronation). (Reprinted, with permission, from: Koman LA. Wake Forest University Orthopaedics Handbook. Winston-Salem, North Carolina: Wake
Forest University Orthopaedic Press; 2006. p 6.)
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Fig. 6
With regard to muscle force generation, intramuscular BoNT-A
injections resulted in a 75% decrease in the force of twitch
contractions compared with the values on the contralateral control side
at one week and a >50% decrease at one month after tendon repair
and injection. Asterisks indicate a p value of <0.007. (Reprinted, with
permission, from: Koman LA. Wake Forest University Orthopaedics
Handbook. Winston-Salem, North Carolina: Wake Forest University Orthopaedic Press; 2007. p 4.)
jections) has failed. Recent evidence from the results of studies
evaluating the role of BoNT-A in the treatment of lateral epicondylitis is promising (see Appendix).
Tendon Repair
Research on tendon repair techniques has been directed primarily at increasing the strength of the repair site in order to
prevent tendon gapping and/or rupture during rehabilitation.
Rupture of the tendon repair site is a devastating complication
frequently caused by the excessive force generated by active
muscle contraction, co-contraction of antagonist muscles, and
friction between the tendon and the surrounding tissues. Following tendon repair, motion at the repair site is essential to
minimize adhesion formation and facilitate healing. However, disproportionate contraction of muscles may result in
forces strong enough to cause the repair to rupture. Therefore,
pharmacologically mediated aid (bioprotection) with the use
of BoNT-A may represent an important role in securing the
tendon repair site while achieving effective active mobilization. Due to the reversible nature of the toxin-caused muscle
weakness, the effects of the toxin are gone by the time that the
repaired tendon has healed.
The Orthopaedic Research Laboratory at the Wake Forest University School of Medicine developed an animal model
to evaluate the temporary and controlled reduction of muscle
force as a result of injection with BoNT-A, especially with regard to protecting the integrity of the tendon repair site, permitting safe postoperative active and passive range of motion,
and reducing the prevalence of postoperative complications.
The protective effects of BoNT-A injections on the tendon repair site were evaluated by measuring gap size, rupture rate,
B O T U L I N U M N E U RO T OX I N A S A T H E R A P E U T I C M O D A L I T Y :
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electrophysiology (twitch, tetanus), and mechanical strength
and through histologic examination of the repaired tendon.
Botulinum neurotoxin-A treatment prevented gap formation
and rupture when compared with saline-solution injections.
Moreover, the mechanical force that was required to mechanically rupture the tendon was significantly higher in the BoNTA group than in the saline-solution group at early time points
(less than four weeks) following tendon repair (p < 0.007 and
p = 0.0285). With regard to muscle force generation, intramuscular BoNT-A injections resulted in a significant decrease
(p < 0.007) in the force of twitch contractions (Fig. 6) and tetanic contractions (Fig. 7). At all time points prior to eight
weeks, twitch and tetanic contractions were significantly decreased in the BoNT-A injected group as compared with the
saline-solution-injected group (p < 0.007).
Tüzüner et al. reported on the results of BoNT-A injections as adjunctive therapy in zone-II flexor tendon repair in
seven children who were younger than six years22. Sufficient
relaxation of muscle tone was noted forty-eight to seventytwo hours after BoNT-A injection, and it continued for about
six weeks (range, three to ten weeks). Surgically, there were
two good and five excellent results according to the Strickland
criteria. Botulinum neurotoxin-A injections appeared to be
well-tolerated, safe, and effective at the injected dose (2.5 to 7
U/kg of body weight).
Contractures Following Total Joint Arthroplasty
Flexion and extension contractures may develop following total knee arthroplasty and total hip arthroplasty despite the use
of aggressive rehabilitation protocols. Because of its ability to
Fig. 7
Similar to the findings for twitch contractions, tetanic contractions in
the BoNT-A group decreased to 25% of the values on the control side at
one week after injection and remained <40% of the values on the control side during the first month. In the BoNT-A group, tetanus returned
to 76% of the baseline level at twelve weeks after injection and
returned to the normal level by twenty-four weeks. Asterisks indicate a
p value of <0.007. (Reprinted, with permission, from: Koman LA. Wake
Forest University Orthopaedics Handbook. Winston-Salem, North Carolina: Wake Forest University Orthopaedic Press; 2007. p 4.)
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TABLE III Percent Correction of Contractures for Total Joint Arthroplasty Patients Following BoNT-A Injections
Maximum
Mean
Minimum
Knee
Flexion (%)
Knee
Extension (%)
Hip
Adductor (%)
Hip
Abductor (%)
100
100
100
100
90
78
74
84
65
72
–67
–10
50
0
43
provide temporary muscle paralysis and reduce musculoskeletal pain by inhibiting release of pain mediators and decreasing
muscle spasm, we evaluated BoNT-A as a potential treatment
for flexion contractures that occurred after total joint arthroplasty and were recalcitrant to standard nonoperative treatment methods. Our initial case series consisted of ten patients
(eleven knees; nine primary total knee arthroplasties, two revision total knee arthroplasties) with a flexion contracture following total knee arthroplasty23. The preoperative mean range
of motion, extension lag, and flexion contracture were 75°
(range, 40° to 120°), 13° (range, 0° to 30°), and 6° (range, 0° to
20°), respectively. The mean time from the index surgery to
treatment with BoNT-A injections was twenty-eight months
(range, three to eighty-one months). The medial hamstring
muscles were injected in nine patients, and both the medial
and lateral hamstring muscles were injected in one patient.
Two patients also received injections to both heads of the gastrocnemius muscle in addition to the medial hamstring. All
patients were followed for a minimum of two years after the
BoNT-A injection. Clinical improvement was seen in all nine
primary total knee arthroplasties. The injections were less effective in the two patients who had flexion contractures following revision knee arthroplasty. In summary, BoNT-A
injections used following primary total knee arthroplasty resulted in sustained improvement and desirable outcomes at
the time of the two-year follow-up. These results suggest that
BoNT-A therapy is an appropriate treatment modality for patients who have a flexion contracture following primary total
knee arthroplasty. The outcomes suggest that patients with
any history of infection or component revision may not be appropriate candidates.
Following the encouraging results of our total knee arthroplasty cohort, additional patients were treated for flexion
contracture of the knee (n = 20), extension contracture of the
knee (n = 7), adductor contracture of the hip (n = 5), abductor contracture of the hip (n = 7), and flexion contracture of
the hip (n = 4). These patients are part of an ongoing study.
Longer-term follow-up will be conducted, but the preliminary
results have shown excellent clinical outcomes in the majority
of patients. Overall, including the initial cohort of total knee
arthroplasty patients, twenty-six or 87% of knees achieved extension to within 10° of a neutral position and had improvement in gait parameters and Knee Society scores24 following
BoNT-A treatment. Similar results were seen in the patients
with extension contractures of the knee, with six or 86% of
knees showing no residual limit in flexion. All five patients
who underwent BoNT-A injection for the treatment of adduc-
Hip
Flexion (%)
tor contractures following total hip arthroplasty had excellent
clinical outcomes on the basis of a final Harris hip score of
≥80. Table III depicts the percent correction following BoNTA injections.
To the best of our knowledge, there are only two other
case reports in the literature that investigate the effect of
BoNT-A treatment following total joint arthroplasty. Shah et
al. reported on the use of BoNT-A treatment for flexion contracture after total knee arthroplasty in a patient with Parkinson disease25. At one month postoperatively, their patient
showed little improvement and had a range of motion from
30° to 100° of flexion. The patient was injected with 200 U of
BoNT-A into the long head of the biceps femoris and the
semitendinosus muscles at six weeks after surgery and also received an injection in the gastrocnemius muscle at four
months after surgery. At the time of final follow-up of 6.5
months, the patient demonstrated improvement, with a
range of motion from 8° to 125° of flexion. Fish and Chang
reported on the use of BoNT-A for the treatment of tendinitis
of the iliopsoas after a left total hip arthroplasty26. A seventyone-year-old woman reported pain that worsened over four
months and interfered with daily activities such as walking
and climbing stairs. She showed no signs of periprosthetic infection or malpositioning of the prosthesis. Following injection of 100 U of BoNT-A, she experienced an improvement in
function and a decrease in pain. In addition, the Oswestry
Disability Index functional score27 improved from 26% to
18% and the pain intensity numerical rating decreased from
7 to 1 on a 10-point scale (for which 10 indicated the worst
pain imaginable).
Talipes Equinovarus (Clubfoot)
Idiopathic talipes equinovarus has a prevalence of approximately one in 1000 live births in the United States28. In children with this disorder, the pathology includes contracture
of muscle-tendon units in addition to abnormalities of the
tarsal bones and joint capsules. Correction of this deformity
requires stretching of the musculotendinous structures, including the Achilles, the flexor digitorum communis, the
posterior tibial, and the flexor hallucis longus tendons.
Lengthening of the Achilles tendon is critical for the success
of the various surgical techniques as well as nonoperative
interventions, such as weekly manipulations and casting.
Botulinum neurotoxin-A has been utilized to facilitate nonoperative techniques (stretching and application of a cast),
to augment surgical release, and to serve as an alternative to
Achilles tendon-lengthening (see Appendix). The Wake For-
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est University School of Medicine experience with use of
BoNT-A injections and casting parallels the report of Alvarez
et al.29, who evaluated the effectiveness of BoNT-A in attenuating the function of the triceps surae muscle complex as an
alternative to Achilles tenotomy. There were fifty-one patients (seventy-three idiopathic clubfeet) who were divided
into two age groups (less than thirty days old and greater
than thirty days old). They reported that, following BoNT-A
injections, ankle dorsiflexion with the knee flexed and with it
extended remained above 20° and 15°, respectively. Other
studies have reported on the treatment of patients with injections during percutaneous tenotomy, during extensive
posterior medial release, and as an alternative to surgery for
recurrence after surgery. There have been no complications
observed to date, and BoNT-A appears to be a safe and effective alternative to selected surgical interventions in the treatment of idiopathic talipes equinovarus.
Idiopathic Toe-Walking
It is not unusual for children to display intermittent tip-toe
gait when they first begin to walk; however, a more mature
heel-to-toe gait pattern should become consistent during
independent (unsupported) walking30. Older children with
persistent tip-toe gait are often referred to as idiopathic toewalkers. In 1967, Hall et al. first described this entity as “congenital short tendo calcaneus.”31 Although the majority of
cases occur in normal children, toe-walking has been associated with neurological disorders, including autism and
cerebral palsy. Treatment recommendations for idiopathic
toe-walking range from conservative modalities, such as
stretching, behavior modification, night-splinting, and serial
casting, to surgical release and Achilles tendon-lengthening.
The management of this entity and its associated impairments
(the development of progressive Achilles tendon contractures)
may be frustrating for parents and health-care providers. The
use of BoNT-A has markedly changed the management of idiopathic toe-walking. In our experience, 100 U of BoNT-A,
per extremity, diluted in 2 to 6 mL of saline solution can be
used alone for patients with mild cases of tip-toe gait or in
conjunction with night bracing for patients with moderate
cases of tip-toe gait. In a recent review of this experience, we
reported on the injection of ten idiopathic toe-walking patients who were between the ages of two and seventeen years32.
In all patients, previous treatment, including physical therapy,
bracing, and/or casting, had failed. Following BoNT-A injections, one to three weeks of subsequent bracing and physical
therapy was provided. Nine out of the ten patients had resolution of toe-walking by three months. One patient required repeat injections at three months and another patient at one
year. Later follow-up (not previously reported) documented
the need for surgery in one patient. Similarly, Brunt et al. assessed the effects of BoNT-A on ankle muscles in children who
were idiopathic toe-walkers33. In their study of five children
(mean age of four years), each child was injected with BoNT-A
in the gastrocnemius and soleus muscles. By twenty days following injection, the authors concluded that, following treat-
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ment with BoNT-A, the patterns of foot contact normalize,
permitting better ground contact, improved foot-loading responses, a better ankle electromyographic pattern during gait,
and more normal foot-strike patterns.
Plantar Fasciitis
Heel pain secondary to plantar fasciitis affects at least 1 million Americans and is a frequent cause for visits to foot and
ankle surgeons and podiatric practitioners. Pathologic findings include: (1) contracture of the plantar fascia, (2) attritional fibrosis and/or periostitis of the plantar fascial origin
from the calcaneus, (3) shortening of the quadratus plantae
muscle and short toe flexors, and (4) contracture or shortening of the Achilles tendon. No evidence strongly supports the
effectiveness of any treatment modality for plantar fasciitis,
and most patients improve either without specific therapy or
after nonoperative treatment. Shoe inserts, custom orthoses,
and stretching exercises may be beneficial and should be the
first step in treatment. Although no data support the use of
nonsteroidal anti-inflammatory drugs, the effectiveness of
such drugs in managing other musculoskeletal conditions
makes them reasonable choices for adjunctive therapy. For patients who do not improve after initial nonoperative treatment, BoNT-A injections represent a viable alternative to
corticosteroid injections.
Botulinum neurotoxin-A treatment of plantar fasciitis is
directed at reducing painful forces on the plantar fascia, facilitating lengthening of the contracted structures, and decreasing nociceptive signals. Injections are performed in the painful
fascia and periosteum (25 U in 0.5 mL of saline solution) and
in the quadratus plantae and short toe flexors (75 U in 1.5 mL
of saline solution). The injections are accompanied by a home
stretching program and night-splinting. A recent prospective
randomized study demonstrated that injections of BoNT-A
into the plantar region significantly decreased the pain associated with recalcitrant plantar fasciitis (p < 0.0005) (see
Appendix).
Safety Issues
otulinum neurotoxin-A has a long-established safety profile and has been approved by the Food and Drug Administration for more than seventeen years to treat a variety of
medical conditions. In 2002, approval was granted for its aesthetic use for glabellar lines. There are more than 3000 publications on BoNT-A in scientific and medical journals, and the
results of dozens of clinical trials involving more than 10,000
patients have been used to establish its safety profile. Recently,
however, the Food and Drug Administration announced in an
“Early Communication” that it was reviewing certain serious
adverse events following the use of botulinum toxins for spasticity management in patients with juvenile cerebral palsy34.
This posting is a routine step that is typically used to provide
early information regarding safety or other related reviews, often before any conclusions are, or can be, made. The posting
of this information does not mean that there is a causal relationship between the products and the adverse events. Al-
B
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though overdosage of BoNT-A can lead to hypersensitivity
reactions, respiratory arrest, cardiovascular events, and even
death, the results of our literature review as well as the outcomes of patients treated at our institution suggest that the
dosage used for musculoskeletal applications does not put patients at risk for any of these serious complications. In our
more than twenty years of experience with BoNT-A treatment
of musculoskeletal disorders, we have not seen any cases of
systemic toxicity, permanent weakness, or death. Adverse
events observed included pain at the injection site, cramping,
and transient weakness. Key points for a safe and successful
application of BoNT-A are knowledge of indications, contraindications, labeling warnings, adverse events, and dosage
recommendations.
Conclusions
fter its introduction as a therapeutic agent in the early
1980s, BoNT-A has gained popularity in multiple fields of
medicine. More recently, studies at our institutions as well as
other studies reported in the literature have shown the applicability of this treatment modality for patients with cerebral
palsy, multiple sclerosis, flexion and extension contractures of
the knee and hip, and idiopathic clubfoot. Looking ahead, a
variety of “off-label” uses of the toxin are being evaluated.
These uses are based on the theoretical considerations related
to the effects of the toxin on muscle units and to the potential
for tendon protection and its positive impact on fixed muscle
A
B O T U L I N U M N E U RO T OX I N A S A T H E R A P E U T I C M O D A L I T Y :
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contractures when injections are coupled with bracing, therapy, or surgery.
Appendix
Tables listing pertinent references and a table listing dosage recommendations of muscles commonly injected
with BoNT-A are available with the electronic versions of this
article, on our web site at jbjs.org (go to the article citation
and click on “Supplementary Material”) and on our quarterly
CD/DVD (call our subscription department, at 781-449-9780,
to order the CD or DVD). „
Thorsten M. Seyler, MD
Beth P. Smith, PhD
Jianjun Ma, MD, PhD
Jian Shen, MD, PhD
Tom L. Smith, PhD
Kat Kolaski, MD
L. Andrew Koman, MD
Department of Orthopaedic Surgery, Wake Forest University School of
Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1070.
E-mail address for B.P. Smith: [email protected]
David R. Marker, BS
Michael A. Mont, MD
Rubin Institute for Advanced Orthopedics, Center for Joint Preservation
and Reconstruction, Sinai Hospital of Baltimore, 2401West Belvedere Avenue, Baltimore, MD 21215
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