Neurologic uses of botulinum neurotoxin type A
Neuropsychiatric Disease and Treatment
Neurologic uses of botulinum neurotoxin type A
John P Ney Kevin R Joseph 0
0 Madigan Army Medical Center, Neurology Service , Tacoma, WA , USA
This article reviews the current and most neurologic uses of botulinum neurotoxin type A (BoNT-A), beginning with relevant historical data, neurochemical mechanism at the neuromuscular junction. Current commercial preparations of BoNT-A are reviewed, as are immunologic issues relating to secondary failure of BoNT-A therapy. Clinical uses are summarized with an emphasis on controlled clinical trials (as appropriate), including facial movement disorders, focal neck and limb dystonias, spasticity, hypersecretory syndromes, and pain.
History and background
Botulism was first described in the early 19th century following an outbreak of poisonings
from the ingestion of blood sausages. The term “botulism” owes its origins to this
association, as botulus is latin for “sausage”
. By the end of the 1800s,
the organism Clostridium botulinum was isolated after a case of fatal food poisonings,
and a neurotoxic mechanism was postulated. Victims were described as suffering
from a rapidly progressive paralysis with intact cognition, ultimately causing fatal
(van Ermengem 1979)
. The canning of food for long-term
preservation led to a number of botulism outbreaks in the early 20th century in the
United States. The industry reacted with better canning techniques
doctors attempted to counter the toxin effects. The development of antisera capable
of neutralizing the toxin effect in one outbreak with lack of efficacy in another led
to discovery of differing immunologic serotypes
. Botulinum toxin
type A was purified and crystallized in the post-World-War II search for biological
weaponry measures and countermeasures by United States Army researchers
and Johnson 1997)
Botulism remains a deadly illness that can result from ingestion, enteric bacterial
overgrowth, or wound infection. Food-borne botulism causes regular outbreaks with
symptoms ranging from mild diplopia to muscle weakness and respiratory compromise
. Infantile botulism results from ingestion of Clostridium spores, is
associated with honey intake, and is a cause of acquired hypotonia
(Shapiro et al 1998)
Clostridium spores are present in soil, but may also contaminate illicit intravenous
drugs, with the typical syndrome of descending weakness
resulting from intramuscular injections (wound botulism)
(Cooper et al 2005)
Despite the dangers of botulism, therapeutic use of
BoNT-A was begun in the late 1960s, when an
ophthalmologist, Dr. Alan B. Scott, successfully injected rhesus
monkey extraocular muscles to correct strabismus. His
results were later replicated in humans
(Scott et al 1973)
Studies showed efficacy in the treatment of muscle control
syndromes such as blepharospasm and cervical dystonias.
Further purification of BoNT-A led to the US Food and
Drug Administration (FDA) approval for treatment of
blepharospasm, strabismus, and facial nerve dysfunction
in 1989. Commercially available BoNT-A was marketed
by Allergan, Inc. (Irvine, CA) as BOTOX®, and by Ipsen,
Ltd. (Slough, UK) as Dysport®. Xeomin®, a protein-free
BoNT-A manufactured by Merz Pharmaceuticals GmbH
(Frankfurt-am-Main, Germany), and Prosigne® (Lanzhou
Biologic Products Institute, China), a Chinese formulation
of BoNT-A, are approved for usage in Germany (Xeomin®)
and parts of Asia and South America (Prosigne®). In 2000,
cervical dystonia became an FDA-approved indication for
both serotypes A and B of botulinum neurotoxin. Current
FDA-approved uses of BoNT-A also include the reduction
of glabellar lines and the treatment of axillary hyperhidrosis
(Cheng et al 2006)
. Off-label in the United States include
the treatment of sialorrhea, muscle control disorders (limb
dystonias and spacticity), and painful disorders (low back
The anaerobic bacillus Clostridium botulinum secretes
seven known serotypes of botulinum toxin, typed
alphabetically A-G. The toxins are 150 kd single chain polypeptides
which undergo protease-mediated nicking to form heavy
and light chains
(Montecucco et al 1996)
. Heavy chains
irreversibly bind to the SV2 receptor on the presynaptic
(Dong et al 2006)
, allowing for entry of the
toxin into the axon terminal
. Once inside
the axon, the light chains act to impede exocytosis of
acetylcholine. Specifically, the toxins are zinc-dependent
metalloproteases that interfere with portions of the SNARE
(soluble N-ethylmaleimide-sensitive factor attachment
protein receptor) protein complex
. The SNARE
complex allows for fusion of neurotransmitter-containing
intra-axonal vesicles with the presynaptic membrane,
resulting in extrusion of acetylcholine into the synaptic
cleft. Botulinum toxin type A is responsible for cleavage
of the SNARE component SNAP-25 (25 kilodalton
synaptosomal- associated protein) molecule
(Blasi et al
, whereas botulinum toxin type B cleaves SNARE
component synaptobrevin (vesicle-associated membrane
protein or VAMP). Only types A and B have been utilized
for commercial applications.
Botulinum neurotoxins reduce presynaptic outflow of
acetylcholine at the neuromuscular junction, with a
consequent diminution in muscle contraction. A basal rate of
acetylcholine secretion across the synaptic cleft occurs
continuously, with each packet of acetylcholine
depolarizing the post-synaptic membrane to create miniature end
plate potentials (MEPPs). MEPPs summate to maintain the
motor end-plate potential (EPP). Botulinum neurotoxins
prevent acetyclcholine secretion, reducing the frequency and
quantity, but not amplitude of MEPPs.
(Maselli et al 1992)
BoNT-A effects a reduction in MEPP frequency twice that of
The motor EPP is reduced below
the muscle membrane threshold and the ability to generate
muscle fiber action potentials and subsequent contraction is
diminished. The muscle fibers supplied by the nerve terminal
affected by botulinum toxins are effectively denervated (with
dose and diffusion-gradient -related reduction in the size of
(Borodic et al 1994)
), although the gross
histologic appearance of the neuromuscular junction remains
normal (Duchen and Strich 1968).
Once acetylcholine release is effectively impaired from
the axon terminal, or terminal bouton, the process of recovery
begins. New nerve sprouts emerge from the nodes of Ranvier
in the region preceding the presynaptic membrane. These
may begin in as little as one week after botulinum neurotoxin
administration in the case of slow-twitch muscle fibers, or up to
6 weeks for fast-twitch muscles
. Sprouts form
new neuromuscular junctions and new endplates with adjacent
muscle. Acetylcholine is released from new nerve terminals,
and as new endplates mature, functional recovery begins.
Muscle fiber atrophy may occur prior to full maturation of the
motor end plates. Eventually, the SNARE protein complex is
regenerated, acetylcholine release resumes from the original
nerve terminal, and axon sprouts retract
(de Paiva 1999)
functional paralysis usually lasts for 3–4 months.
Formulations, safety, and adverse effects
The commercial formulation of BoNT-A as BOTOX® is
packaged as a vacuum-dried powder, 100 units per vial.
Specific activity of BOTOX® is rated at 20U/ng. The 150 kDa
botulinum neurotoxin molecule is complexed with 600kDa
hemagglutinizing and non-hemagglutinizing non-toxic proteins
(Dressler and Hallett 2006)
for a total concentration of 5 ng per
100 units in its current formulation. 0.5 mg of human albumin
is present in each vial as an excipient. Storage at 2 ºC–8 ºC
is recommended. The shelf life is 2 years. To administer the
medication, the vial is reconstituted with 1–4 ml of normal
saline (0.9% NaCl), and given intramuscularly within 4 hours
(BOTOX® package insert 2004)
. Retail cost
is approximately $600 US per vial.
Dysport® is distributed in 500U vials as a freeze-dried
powder with 0.125 mg albumin and 2.5 mg lactose as
excipients. Specific activity of Dysport® is rated at 40U/ng.
Protein content is 12.5 ng/vial. Storage and reconstitution are
similar to BOTOX®
(Dysport® package insert 2005)
Xeomin® is packaged in 100U vials as a freeze-dried
powder with handling and administration similar to
(Jost et al 2007
). Prosigne® formulation, handling and
administration requirements were not available as of this
writing. Table 1 compares the commercial BoNT-As based
on available data.
Dosing conversions between various preparations of
BoNT-A is not necessarily intuitive. Studies of Xeomin® and
Prosigne® use unit dosing comparable (1:1) with
(Rieder et al 2007
; Wohlfarth et al 2007). BOTOX® to
Dysport® dosing has been suggested to be anywhere from 1:2 to
(Rosales et al 2006)
. Dosing of Dysport® should be based
on trials conducted with that formulation of BoNT-A rather
than an absolute conversion ratio from BOTOX®.
Athough botulinum toxin is one of the most deadly
(Osbourne et al 2007)
, the therapeutic
administration of BoNT-A is quite safe. Studies of
intramuscular administration of BoNT-A in laboratory-based
non-human primates showed an LD50 of 38U/kg in a
study of eight rhesus monkeys (Scott and Suzuki 1988),
and a minimal lethal dose of 24U/kg in adult cynomolgus
monkeys (BOTOX® package insert). For a 75 kg man, this
works out to be 1800U. The LD50 in conventional
laboratory mouse assay units has not been consistently established
Both serious and more benign side effects have been
reported with BoNT-A administration. Injections are
local, intramuscular, and systemic complications are rare
(BOTOX® package insert 2004)
. More concerning events
include ptosis and diplopia for strabismus, and dysphagia
from injection for cervical dystonia (reported in up to 24% of
patients in one trial (Commella and Thompsen 2006)). This
latter event is most disturbing for relatively high frequency
and for increased risk of aspiration pneumonia. Other adverse
events include cough, fever, upper respiratory infection,
flulike malaise, headache, and very commonly, injection site
reactions (erythema, swelling) and bruising.
Hypersensitivity reactions such as edema and dyspnea have been noted.
Anaphylaxis has been reported in one patient who received
BOTOX® mixed with lidocaine. Spontaneous death after
botulinum toxin A administration has been reported, but a
causal link has not been established. A meta-analysis of
controlled trials for BOTOX® efficacy in a variety of conditions
concluded that focal weakness local to the area of injection
were the only consistent events not reflected in controls
(Naumann and Jankovic 2004)
. Generally, these events were
mild to moderate in severity, temporary, and related to the
medication’s mechanism of action. Strategies for avoiding
focal weakness include minimal dilution of the BoNT-A
(eg, 100U/1cc for BOTOX®), this prevents diffusion of the
neurotoxin outside the target location. Division of doses
with to multiple sites allows for less neurotoxin in a single
depot in muscle, with less focal functional denervation, and
a presumed reduction in focal weakness.
Tolerance and immunogenicity
An antibody-mediated tolerance has been invoked as a
rationale for secondary failure of BoNT-A after initial good
response to treatment. BoNT-A and the proteins complexed
with the neurotoxins provide sites of antigenic stimulation
and ultimately antibody formation, as has been demonstrated
experimentally with Western Blot (Hanna and Jancovic
2000) or ELISA. The commercially available assessment
of antibodies is done using a mouse lethality assay (MLA),
Lanzhou Biological Products Institute
Based on BOTOX Product Insert 2004; Dysport® product insert 2005;
Jost et al 2007
Tang and Wan 2000
or the more sensitive mouse hemidiaphragmatic paralysis
model (also known as a mouse protection assay or MPA)
. In the MLA, the patient’s serum is
incubated with a lethal dose of botulinum toxin, then injected
into the peritoneal cavities of mice. Laboratory mouse death
ensues unless presumed blocking antibodies prevent
botulinum neurotoxin function. The MPA uses the same method of
serum incubation with botulinum toxin, which is injected in
a bath of excised mouse phrenic nerve and hemidiaphragm
where amplitude of contraction to electrical stimulation is
measured. Failure to produce a 50% or greater decrement
in contraction amplitude is evidence of antibodies to the
(Dressler et al 2000)
Antibodies to BoNT-A have been noted in 36%–60%
of patients with secondary failure of BOTOX® for cervical
(Anderson et al 1992; Jancovic and Schwartz 1995)
and in up to 100% for focal dystonias (Jancovic and Schwartz
1995). These figures are from relatively small series of
patients. Subsequent analysis suggested that short intervals
between repeated injections and dosage of BOTOX®
correlated with antibody development
(Dressler and Dimberg
. All of these studies were of the BOTOX® formulation
prior to 1998.
In 1998, the amount of neurotoxin complex protein in
BOTOX® was reduced from 25 ng/100U to 5 ng/100U, with
a presumed reduction in antigenic potential.
Jankovic et al
), prospectively tested 119 patients with minimal or no
response to the current formulation of BoNT-A treatment for
cervical dystonia on two consecutive visits for antibodies
using the mouse lethality assay. None of the patients had
antibodies noted by a positive MLA. In contrast, 4 of 42
patients treated with the original (FDA-approved 1989–98)
formulation of botulinum toxin meeting the same criteria for
treatment failure had antibodies present. Although the risk of
antibody formation does appear to be significantly decreased
with the present formulation of BOTOX®, several cases of
antibody-associated treatment failure have been reported
(Dressler 2004; Dressler and Saberi 2007)
Botulinum toxin A in clinical neurology
BoNT-A, by acting at the neuromuscular junction to
reversibly alter muscle tone and selectively functionally
denervate muscle, is used extensively in disorders of muscle
overactivity, such as facial movement disorders, limb and
neck dystonias, and spasticity. Botulinum neurotoxins are
also effective at inhibiting acetylcholine release at sites other
than neuromuscular junction
, leading to
effective treatments for hypersecretory syndromes, especially
sialorrhea and hyperhidrosis. Lastly, painful syndromes such
as headache and low back pain have been treated with some
success by BoNT-A injections.
Facial movement disorders
With early research for botulinum toxin focusing on selective
denervation for dysconjugate gaze, overactivity of muscles
involving eye and mouth closure were targeted next.
Blepahrospasm is a focal dystonia of eyelid closure, which
can be quite disabling and, in more extreme cases, render the
sufferer functionally blind
(Ben Simon and McCann 2005)
Patients may have a noticeable increased frequency in blink
rate, endure spasms of eyelid closure, or have continuous lid
closure with significantly impaired voluntary eyelid opening.
Oromandibular dystonias involve the muscles of mastication,
particularly masseter, temporalis, and pterygoid muscles,
and can result in disabling jaw deviation, jaw clenching or
(Bhidayasiri et al 2006)
. Tongue and pharyngeal
muscles may also be involved, and the affected patient
may be unable to speak, chew, or swallow effectively.
Meige syndrome describes oromandbular dystonia and
blepharospasm in combination
spasms are non-dystonic paroxysms of muscle twitching on
one side of the face, often due to vascular compression of the
7th cranial nerve, variably including upper and lower facial
Effective management of blepharospasm with BoNT-A
was established largely via small, uncontrolled, open-label
(Scott et al 1985; Kennedy et al 1989; Borodic and
prior to United States FDA approval of BOTOX®.
A recent Cochrane Review and metanalysis of BoNT-A
(Costa et al 2005)
found a paucity of
blinded, controlled trials consisting of small numbers only.
Review of pooled case-controlled data of over 2500 patients
demonstrated a 90% efficacy rate of BoNT-A injections in
(Jost and Kohl 2001)
. Most published clinical
research was conducted with BOTOX®, but Dysport® has
also proven efficacy in placebo-controlled and head-to-head
settings comparable to BOTOX®
a trial of equal units of Xeomin® (NT 201) vs
(Wohlfarth et al 2007
) yielded comparable success for
The large volume and duration of practitioner experience
has distilled into recommended injection strategies for
blepharospasm. Up to 20U per eye of BOTOX® are injected
into the orbicularis oculi at 2.5–5.0U per site through a 27–30
gauge needle. Two injections are made at the upper lid near
the canthus medially and laterally to avoid the bulk of the
levator palpebrae muscle and consequent ptosis
et al 2006)
. Two lower lid injections are conducted one in the
middle portion, and one at the lower lateral canthus.
Avoidance of the medial canthus spares the nasolacrimal
(Bhidayasiri et al 2006)
. Dysport® dosing ranges from
40–120U per eye in clinical trials
effects of periocular BoNT-A injection include ptosis, dry
eyes, and diplopia. Avoidance of the medial aspect of the
lower lid, and injection into the pre-tarsal region rather than
the preseptal orbicularis oculi may increase efficacy and
(Cakmur et al 2002)
Oromandibular dystonias have responded poorly to
systemic medications (clonazepam, anticholinergics, and
(Greene et al 1988)
, but mostly small
openlabel trials of BoNT-A indicate significant improvement
with neurotoxin injection. Most studies have been done
using BOTOX®, but similar effects have been obtained in
small series with Dysport®
(Van der Bergh et al 1995)
. In a
prospective uncontrolled study of 162 patients followed an
average of 4.4 years, Tan and Jankovic
(Tan and Jancovic
noted a mean duration of effect of 16.4 weeks and global
improvement effect rated as a 3.1/4. Greatest improvement
was seen in patients with primarily jaw-closure dystonias.
Jaw opening dystonias proved more difficult to treat and had
a 40% incidence of dysarthria and dysphagia (relative to only
19% with treated jaw closure dystonias.)
Injection strategies for BoNT-A in oromandibular dystonias
should be individualized to target the specific anatomy of the
dystonic movements. Jaw closure dystonia injections should
include the masseters, and temporalis muscles, at starting
doses of 40–50U BOTOX® or 100U Dysport® each; medial
pterygoids may also be targeted with 20U BOTOX® or 30U
(Bhidayasiri et al 2006)
. Jaw opening dystonias
should focus primarily on the lateral pterygoids, with
starting doses of 20U BOTOX®
(Blitzer et al 1989)
(Bhidayasiri et al 2006)
. The submentalis complex
(mylohyoid, geniohyoid, and anterior digastricus) has been
targeted as well, with a recommended starting dose of 20U
BOTOX® or 90U Dysport®
(Bhidayasiri et al 2006)
awareness of the anatomical relationships of these muscles is crucial
to avoid nearby secretory and vascular structures. The use of
electromyography has been suggested for muscles that are not
surface-palpable, but has not been validated.
Hemifacial spasm (HFS) has been treated with oral
anticholinergic, antispasmodic, and anticonvulsive medications
(Kemp and Reich 2004)
with small degrees of success.
Surgical microvascular decompression has been reported
to offer long-term relief in up to 95% of treated patients
(Chung et al 2001)
, but there may be significant morbidity
and mortality from invasive intracranial procedures. BoNT-A
offers the hope of symptom reduction or relief without the
adverse effects of surgery. Although BoNT-A is routinely
used as a treatment for HFS, a thorough scientific validation
of efficacy is lacking. A meta-analysis involving BoNT-A
(Costa et al 2005)
revealed only a single well-designed,
prospective, blinded, placebo-controlled trial of 11 patients
(treated with BOTOX®)
(Yoshimura et al 1992)
, in addition
to many larger open-label trials, concluding that the
medication is safe in HFS and supporting the conclusions of the
uncontrolled studies that efficacy ranges from 76%–100%.
Peak effect was reported at 2 weeks and effect duration was
nearly 3 months
(Yoshimura et al 1992)
. Other BoNT-A
preparations, Dysport® and Prosigne®, were evaluated to
have similar success rates as BOTOX® in small
randomized, uncontrolled trials but with increased side effects noted
(Sampaio et al 1997; Rieder et al 2007)
Therapeutic administration of BoNT-A for HFS is similar
to strategies described for blepharospasm, with the addition
of targeting very small doses to lower facial muscles as well.
In addition to the 4 orbicularis oculi injections suggested
for blepharospasm treatment, zygomaticus major,
buccinator, and depressor anularis oris have been targeted by some
authors, at 1–2U BOTOX® or 3–6U Dysport® per muscle
(Frei et al 2006)
. Adverse effects include dry eyes, ptosis, and
facial or mouth drooping. Other experts suggest staging upper
facial (periorbital) injections first, with lower facial injections
only on 2-week follow-up after careful discussion with the
patient about likelihood of significant lower facial drooping,
including lip biting and asymmetric smile
Precautions for injection include those recommended for
BoNT-A injections for blepharospasm, but also to take care
to avoid injections into elevators or the lips or mouth such as
levator labii superioris, levator angularis oris, and orbicularis
(Comella and Pullman 2004)
Focal neck and limb dystonias
Botulinum neurotoxins have been applied with particular
success to the treatment of focal neck and appendicular dystonias
(Ward et al 2006)
. Cervical dystonias are involuntary
movements or postures of the head, neck, and shoulders. There
may be head rotation (torticollis), neck flexion (anterocollis)
or extension (retrocollis), or lateral deviation (laterocollis).
Movements may be spasmodic, rhythmic (tremoring), or
fixed. Pain accompanies cervical dystonia in the
majority of patients (Lew 2002). Focal dystonias can produce
undesirable torsional, flexion or extension movements of
the limbs or digits, limiting manual dexterity in the upper
extremities, and impairing walking in the lowers
. The most reported, and often most disabling,
are the occupational dystonias, particularly writer’s cramp
and musicians’ dystonia. Unwanted hand postures occur in
relation to particular tasks, often writing or playing musical
Treatment of cervical dystonia (CD) has been the most
studied of all the potential applications of BoNT-A. Early
studies showed safety and efficacy in small cohorts
(Tsui et al
1985; Tsui et al 1986)
with a minority of patients reporting
transient neck weakness or dysphagia. A meta-analysis of
cervical dystonia treatment trials evaluating BoNT-A from
(Costa et al 2005)
revealed 13 controlled studies,
eight done using BOTOX®, and five with Dysport®. Pre-and
post-treatment ratings were performed with one of three
validated scales: the Toronto Western Spasmodic Torticollis
(Consky and Lang 1994)
, the Tsui scale
(Tsui et al 1996), and the Cervical Dystonia Severity Scale
(Brashear et al 1998)
. TWSTRS is rated in increasing
severity from 0–87, summed from three subsets for pain
(0–20), disability (0–23), and severity (0–25). The Tsui scale
measures severity based on presence of head tremor, degree
of postural impairment, and spasmodic or continuous quality
of the dystonia from 0 (no impaiment) to 25 (severe
impairment). The CDSS charts the progression of dystonia in three
planes based on angle of deviation from the normal. Studies
variably utilized electromyographic (EMG) guidance to help
target muscles. A variety of dosing schemes and injection
strategies were used.
(Costa et al 2005)
pooled data from the
relevant trials to find a mean two to three point
improvement on the Tsui scale at peak effect, with odds ratio (OR)
vs placebo at 95% confidence interval favoring BoNT-A of
8.16 for a one point improvement of Tsui scale, OR 4.25
for a three point improvement of Tsui scale, and OR 5.47
for any improvement on either the Tsui scale or TWSTRS.
Adverse events were reported as mild to moderate,
transient or intermittent, with an overall OR of 2.1 vs placebo.
The highest likelihood events were again neck weakness
(OR 4.9) and dysphagia (OR 3.9). Subgroup analysis of
BOTOX® vs placebo and Dysport® vs placebo showed no
statistically significant differences between the two BoNT-A
formulations in efficacy or side effects. Trends for dosing
were analyzed, and trials involving larger doses of either
formulation (BOTOX®: > 200U, Dysport®>960U) suggested
increased efficacy but a larger incidence of adverse effects,
particularly for Dysport®.
Although BoNT-A has statistically proven clinical
improvement for treatment of neck dystonia, the disorder is
quite heterogeneous in both presentation and therapy
solutions and several questions remain unresolved. Like other
dystonias, dosing strategies should be modified based on
severity and muscle involvement. Experienced clinicians
note a mean total of 200U of BOTOX® or 500U Dysport®
as effective in cervical dystonias
, but this
reflects stable doses rather than starting dosing, and varies
significantly per patient. Careful examination and
observation of the abnormal movements and postures are essential
for developing a successful treatment algorithm
. The WEMOVE® website (http://www.wemove.org
or http://www.mdvu.org) is an excellent tool replete with
anatomical diagrams and dosing recommendations for CD
and other dystonias. Nevertheless, a standardized dosing
regimen of 500U Dysport in moderate to severe CD has
demonstrated safety and efficacy over a ten week period
(Wissel et al 2001)
Primary non-response, duration of effect, and long-term
results of BoNT-A treatment of CD have been studied.
Although the majority of patients respond to their first dose
of BoNT-A, approximately 15% fail to derive significant
improvement of their cervical dystonia. Non-response is
reported by patients as the primary reason for discontinuation
of BoNT-A treatment
(Brashear, Bergan et al 2000)
non-responders with longstanding dystonia may have fibrous
contractures of neck muscles with rheological changes of
soft tissue and muscle, creating fixed postures not amenable
to neuromuscular blockade. Anterocollis with inaccessible
prevertebral muscle involvement responds poorly to treatment
(Comella and Thompson 2006). Inaccurate muscle targeting
and insufficient dosing have also been cited as reasons for
Length of effect has
been assessed with retrospective chart review of 60 patients
treated for twelve or more months showed a single injection
benefit duration of 12.2–24.3 (mean 15.4) weeks
Watts et al 2000)
. Comparison of Dysport® and BOTOX®
showed average duration of improvement, as measured by
Tsui scores as 83.9 days (Dysport®) and 80.7 days (BOTOX®)
(Odergren et al 1998)
. Repeated BoNT-A injections for CD
indicate continued good response in 63% of patients treated
over ten years
(Hsuing et al 2002)
; secondary non-response
was seen in only 7.5%.
EMG guidance of BoNT-A injections for CD is contested.
Many of the potentially involved musces of the neck,
particularly the scalenes, levator scapulae, and the splenius and
semispinalis muscles are quite deep with accuracy impaired
using only surface landmarks for localization. A study of
needle placement without EMG guidance showed inaccurate
placement in the sternocleidomastoid and the levator scapulae
in 17% and 57% of all attempts, respectively
. A randomized study of 52 CD patients receiving
BoNT-A injections with and without EMG-guidance showed
a statistically greater degree of benefit and number of patients
benefiting from EMG-guided injections
(Comella et al 1992)
Jancovic contends that the degree of benefit is likely minimal
relative to a general BoNT-A response rate of 85%, and may
not justify the added expense and patient discomfort of EMG
Focal dystonias of the upper and lower extremities are
particularly well-suited to treatment with localized injections
of BoNT-A. Systemic medications carry unwanted central
nervous system side effects and are generally ineffective.
BoNT-A has the advantage of being a targeted, minimally
invasive, reversible therapy, acting at the site of muscle
dysfunction with few side effects.
Clinical trials of BoNT-A have focused largely on
occupational dystonias, especially writer’s cramp (WC). Most
studies were open-label, case-controlled, or reports of clinical
experience with a number of patients. In one double-blinded,
(Tsui et al 1993)
, 12/20 WC sufferers
experienced improved pen control after BoNT-A injections, but
only 4/20 noted improved writing ability. A prospective study
of 47 patients assessed after BoNT-A injection
(Djebbari et al
concluded that patients with forearm pronation and
flexion dystonias had the most improvement of their WC. Clinical
experience suggests that most patients (75%–80%) have onset
of benefit one week following BoNT-A injection, peaking at
two weeks, and lasting 3 months
(Das et al 2006)
. The majority
return and continue to have benefit with repeated injections over
(Hsuing et al 2002)
. Indeed, physiologic studies suggest
that successive BoNT-A injections for WC may effect
reorganization in the premotor cortex
(Byrnes et al 1998)
Leg and foot dystonias are far less common and less
well-studied. Case series of primary foot dystonia patients
showed improvement to repeated BoNT-A injections in
(Schneider et al 2006)
. Four patients with primary foot
dystonias received significantly greater benefit from
BoNTA injections than oral pharmacotherapies in a retrospective
review (Singer and Papapetropoulos 2006).
The administration of BoNT-A therapy for limb
dystonias, like other focal dystonias, should tailor localization and
dose to the individual movements through careful
observation and examination. EMG is an invaluable adjunct for
muscle localization, as more than half of non-EMG guided
BoNT-A injections for limb dystonias may be inaccurately
(Molloy et al 2002)
. EMG recording during the
task associated with dystonia may be helpful to pinpoint
muscle activation patterns
. Injections for WC
are usually focused on finger flexors and extensors in the
forearm, but wrist pronators and flexors are often involved
(Das et al 2006)
. Dosing ranges from 10–50U BOTOX®
and 30–120U Dysport®
(Das et al 2006)
per muscle. Hand
intrinsic muscles may require smaller doses. Lower limb
dystonias often present with foot inversion, toe dorsiflexion,
and/or ankle plantar flexion. Injected muscles may include
tibialis posterior, extensor hallucis longus, gastrocnemius,
and long toe flexors.
Central nervous system disorders with upper motor neuron
dysfunction often produce spasticity, hypertonia of the limb
that is distinguished from rigidity by being both
and dependent on range of motion.
The muscles most prominently affected are those
innervated by the pyramidal tracts. In the upper extremities, the
shoulder adductors, elbow flexors, wrist pronators, finger
and thumb flexors are most involved
(Mayer et al 1997)
In the lower extremities, hip adductors (often resulting in
hygiene issues), knee extensors, and ankle plantar flexors
and inverters may have increased spastic tone
(Pathak et al
. The most common causes of spasticity in adults
are trauma, stroke, and multiple sclerosis, while in
children, cerebral palsy (CP) is the primary culprit
. Treatment is aimed at prevention of contractures
and improved functional outcome
(Brin et al 1997)
to dystonias, oral medications may have some benefit, but
produce sedation or other cognitive side effects in patients
who may have
(Dones et al 2006)
. Intrathecal baclofen has
advantages in reduced dosing and likely fewer cognitive
effects, but requires surgery for initial placement and is
reserved for those with more generalized severe spasticity
(Albright et al 2003)
BoNT-A has been studied as a spasticity treatment in adults.
Most studies assessed pre- and post-treatment muscle tone
via Ashworth scores. Many were performed in conjunction
with electrical stimulation, and physical or occupational
therapies. Upper limb tone has been shown in blinded,
placebo-controlled studies to improve with 200–300U
(Brashear et al 2002; Simpson et al 1996)
to 1000U Dysport®
(Hesse et al 1998)
; the effect is likely
(Childers et al 2004)
. Lower extremity tone
improved in spastic patients after BoNT-A injection,
especially hip adductors
(Hyman et al 2000)
and calf spasticity
(Mancini et al 2005)
. Higher doses ( 1000U Dysport® or
500U BOTOX®) had significantly increased likelihood of
adverse events. Functional improvement in spastic, paretic
limbs evaluating dexterity and gait after BoNT-A treatment
has been limited, at best (Sheehan 2001). The
clinicianinjector is directed to the Neurotoxin Institute website (www.
neurotoxininstitute.org) which is an excellent clinical tool
with dosing schemes, muscle localization charts, and
education materials for limb spasticity.
BoNT-A as a treatment for the spasticity associated with
cerebral palsy has also been studied. Rigorous reviews identified
2 randomized, blinded, placebo-controlled trials for upper
(Wasiak et al 2004)
and 3 trials for lower limb
(Ade-Hall et al 2001)
. One upper limb trial
et al 1997)
showed statistically significant improvement at
two weeks and three months in active range of motion and
Ashworth score in a cohort of 14 hemiplegic CP children
randomized to normal saline or BoNT-A (BOTOX® at
4–7U/kg or Dysport® at 8–9U/kg). Twenty-nine children
with hemiplegic CP randomized to occupational therapy
with or without BOTOX® (total dose 2–6U/kg)
et al 2000)
, trended toward favoring BoNT-A treatment, but
did not show significance in relevant outcome measures. No
statistically significant difference in outcomes was found in a
study of twelve CP children randomized to calf injections of
BOTOX® (3–8U/kg) in follow-up
(Koman et al 1994)
trials of casting vs calf injection with BoNT-A
(Corry et al
1998; Flett et al 1999)
in twenty ambulant CP children each
showed largely non-significant trends favoring BoNT-A. All
of the above trials suffered from small numbers, and
nonstandardized outcome measures, decreasing the likelihood of
significance. A larger and more recent trial of 125 children
randomized to three doses of Dysport® (10, 20, 30U/kg)
and placebo injections to the calves showed significant
improvement in gastrocnemius shortening at 4 and 16 weeks
(Baker et al 2002)
. Several very recent trials have focused on
the combination of BoNT-A with concurrent occupational
therapy (OT). In one study, eighty children with CP involving
the upper limb were randomized to single dose BoNT-A
and placebo, with further randomization for 12 weeks of
OT in each group. While the functional outcomes were
achieved more quickly in the BoNT-A treated groups, there
was no difference in final outcome among groups
et al 2007)
. In another study, children with hemiplegic CP
received 4 sessions of OT and were randomized to receive
upper limb BoNT-A. Outcome measures were assessed and
grouped based on activity participation, body structure,
and self-perception. All three grouped measures improved
significantly in the BoNT-A treated group over controls
(Russo et al 2007)
. Despite the preponderance of results
failing to show treatment effect, open label trials suggest
et al 2003)
and many clinicians feel
(Verotti et al 2006)
BoNT-A is a useful adjunct to conventional measures for
treatment of CP and helps to reduce the need for surgical
interventions such as heel-cord lengthening.
Sialorrhea and hyperhidrosis are socially and physically
awkward conditions involving secretion of fluids mediated
by cholinergic synapses. Primary sialorrhea may result
from overproduction of saliva, but more often drooling
is the sequelae of neurologic disorders with poor oral or
(Potulsha and Friedman 2005)
, such as
(Lagalla et al 2006)
, stroke, or cerebral palsy
(Lal and Hotaling 2006). The condition may lead to increased
perioral skin irritation, infections, unpleasant odors, social
embarrassment and withdrawal. Hyperhidrosis is excessive
sweating, often in the palms and soles of the feet, but also
in the axillary region and the face. Complications include
skin breakdown and dehydration, with possible secondary
infections, in addition to social and psychological difficulties.
Available treatments for both conditions include oral
anticholinergic medications, often with associated unwanted CNS
side effects, and surgeries for gland or ductal resection or
(Hockstein et al 2004)
, or surgical denervation.
Parasympathetic cholinergic nerve terminals at the
neurosecretory junction are dependent on the SNARE complex
for exocytosis of acetylcholine, which is vulnerable to the
action of botulinum toxins
(Dolly and Aoki 2006)
Injection of BoNT-A into parotid and/or submandibular glands
has been studied in controlled and open-labeled settings for
management of sialorrhea. Controlled studies of adults with
(Mancini et al 2003)
or other neurologic
(Lipp et al 2003)
found that the drooling was
significantly reduced at follow-up of 1 week to 3 months with
clinical measures (number of dental rolls, drooling severity
and frequency scores). No adverse effects were reported.
A study of 45 children with CP comparing BOTOX® at
15–25U/gland with scopolamine
(Jongerius et al 2004)
showed similar efficacy among the two groups with fewer
side effects from BOTOX®. Consensus for optimal
dosing remains elusive, with wide ranges for both parotid
(5–75U BOTOX®, 10–145U Dysport®) and submandibular
(5–30U BOTOX®, 70–80U Dysport®) injection
Although some studies were done using ultrasound-guided
techniques, ultrasound guidance may not be necessary
for the large and superficial parotids, and may contribute
extra cost to an already expensive procedure
Sympathetic cholinergic nerve terminals in the eccrine
and apocrine sweat glands are also amenable to botulinum
(Bhidayasiri and Truong 2005)
(Lowe et al 2007)
and palmar hyperhidrosis
(Naumann and Jost 2004)
treatment with BoNT-A has been
studied in randomized clinical trials with objective and
subjective measures confirming safety and efficacy. The effect
of BoNT-A for palmar or axillary hyperhidrosis lasts for a
mean of 7 months
(Eisenach et al 2005)
. A trial comparing
50U BOTOX® and 150U
Dysport® (Talarico-Filho et al 2007
found no difference in efficacy or duration of treatment effect
for axillary hyperhydrosis. Palmar hyperhidrosis requires
higher doses (120U–220U BOTOX®) due to larger surface
area, and a greater number of injections
. Adverse effects can include considerable pain
necessitating local anesthesia
(Campanati et al 2004)
and intrinsic hand muscle
weakness. Topical use of botulinum toxin has been suggested
for hyperhidrosis as well
(Lim et al 2006)
. A pilot study using
topical BOTOX® (mixed with a proprietary transport peptide)
at 200U per axilla reduced absolute sweat amount by 40%
relative to placebo at 4 weeks
trials of injected subcutaneous BoNT-A indicate single dose
efficacy in Frey’s syndrome (gustatory sweating due to
aberrant facial nerve reinnervation
(Reich and Grill 2005)
an average of one year with optimum dosing of BOTOX® at
3U/cm2 affected skin
(Nolte et al 2004)
Chronic headache and low back pain are two commonly
seen complaints in the neurologist’s office. Both involve at
least subjective muscular overactivity, particularly the
bandlike bitemporal tightening of tension headache, and lumbar
Treatment of these conditions has been difficult, requiring
multiple approaches with both acute and chronic
pharmacotherapies and adjunctive measures
(Jabbari and Ney 2004;
Garza and Swanson 2006)
Botulinum toxin and pain
BoNT-A as a mediator of pain relief is a subject of
considerable speculation, but both central and peripheral nervous
system actions have been hypothesized
(Lang 2003; Borodic
et al 2001)
. The known effect of BoNT-A at the
neuromuscular junction has considerable implications in treating pain of
muscular origin. The activation of poorly myelinated group III
and unmyelinated group IV afferents (a large fraction of which
(Borodic et al 2001)
) with overactivation of
alpha motor neurons produces abnormal patterns of muscle
contraction, resulting in spasm and cramping
et al 1999)
. In diminishing synaptic acetylcholine, the
corelease of local factors for nociceptive transmission, such as
calcitonin-gene-related protein (CGRP), glutamate, substance
P and bradykinin
, is reduced as well.
Altered function of wide dynamic range (WDR) neurons in
the central nervous system may also play a role in pain
(Graven-Nielsen and Mense 2001)
. Chronic pathologic
conditions can create a failure of stimulus discrimination in
WDR neurons. Non-painful stimuli may be perceived as
causing pain. As a wider range of peripheral inputs are perceived as
painful, nociception becomes exaggerated (Craig 2003). BoNT-A
diminishes non-nociceptive stimuli (such as muscle spindle
) to WDR neurons, attenuating pain
perception. Additionally, BoNT-A may alter post-ganglionic
cholinergic fibers within blood vessels following
neuromuscular injection. This may reduce ischemia and prevent
sensitization of muscle nociception by local factors. BoNT-A reduction
in peripheral glutamatergic pain modulation may also play a
(Cui et al 2004)
. Neuroplastic mechanisms within the CNS
respond to the alteration of stimuli through these mechanisms
and the chronic pain state may be ameliorated
(Filippi et al
1993; Mannion and Woolf 2000)
Anecdotal evidence of botulinum toxin efficacy in headache
has been present since early uses in ocular disorders
and Fowler 2007)
. A number of blinded, placebo-controlled
studies have looked at the use of BoNT-A in headache
disorders, particularly migraine and chronic tension-type headache
(CTTH). Evers and Oelsen
(Evers and Oelsen 2006)
reviewed the results of these studies and concluded that
although two of nine studies showed some positive results
(Barrientos and Chana 2003; Silberstein et al 2000)
statistical review of the majority of trials failed to show a significant
treatment effect. Unfortunately, uniform dosing protocols and
injection sites have not been developed, so dismissal of BoNT-A
as a prophylactic treatment for headache may be premature
. Ultimately, clinical experience suggests that
patient selection is important, and a greater focus on the subset
characteristics of patients who respond to BoNT-A therapy
may provide insight for future trials
Low back pain
Low back pain is exceedingly common and debilitating,
and has been demonstrated in limited studies to respond to
(Difazio and Jabbari 2002)
. Foster et al (2001)
conducted a randomized, placebo-controlled,
doubleblinded study of Botulinum toxin A versus saline injection
in 31 patients with unilateral or predominantly unilateral
low back pain. Patients were evaluated by quantitative and
qualitative pain measures at baseline, three weeks and two
months. After injection into paravertebral muscles 73% of
enrollees at 3 weeks and 60% of enrollees at two months
had a significant response. Limitations of this study were
the small size of cohort (15 patients received 200 units
of BOTOX®) and the short duration of observation. The
authors reported no significant side effects. Ney and
Jabbari demonstrated efficacy in an open-labeled with repeated
injections of BoNT-A in patients with initial good-response
over a six and fourteen-month time frame
(Jabbari et al
2006; Ney et al 2006; Rotenberg et al 2006)
While these studies are encouraging, larger
placebocontrolled trials are needed, especially in light of the greater
quantity and thus higher cost of neurotoxin that is required
for these lower spinal muscles. Clinically,
Jabbari and Ney
suggest trigger point-injections of the low back,
using 40–50U BOTOX® per injection in four to five sites on
each side of the spine. They report a beneficial effect within
7–10 days, lasting 3–4 months.
Other uses of botulinum toxin A
BoNT-A is becoming the tool of a wide range of
medical specialties, often as a part of a multidisciplinary effort
involving neurologists and other sub-specialists. Movement
and behavioral disorders such as essential tremor
(Brin et al
, tic disorder
(Porta et al 2004)
, and bruxism (Van
Zandijcke and Marchau 1990) have all been the subject of
BoNT-A treatment trials. Otolaryngologists and neurologists
have long used BoNT-A for the treatment of spasmodic
, but hypersecretion due to excessive
(Unal et al 2003; Keegan et al 2002)
has also been addressed anecdotally and in treatment trials.
Neuro-urologic/procotologic uses in anal fissure
and Chodorowski 2006)
and bladder emptying disorders
(Patel and Chappel 2006)
are established. The role of BoNT-A
for facial cosmesis is well-known and well-publicized with
reduction in glabellar lines and facial rhytides (Flynn 2006)
The uses of BoNT-A discussed in this review is by no means
exhaustive, and research into new mechanisms of action
as well as new clinical applications is only growing.
Success with conditions of muscle overactivity due to central
nervous system dysfunction lends BoNT-A to conditions
with a possible psychological component such as
temporalmandibular joint dysfunction
(Schwartz and Freund 2002)
(Ghazizadeh and Nikzad 2004)
, and anismus
(Ron et al 2001)
. Experimental reduction in pain-related
behavior in rodents pre-treated with BoNT-A has suggested
mechanisms of analgesia in inflammatory and neuropathic
pain in sensory neurons independent of action at the
(Cui et al 2004; Aoki 2005; Luvisetto
et al 2007)
, discussed above. BoNT-A for perioperative pain
(Davies et al 2003)
, treatment for amputation stump-related
and phantom-limb pain
(Kern et al 2003)
, plantar fasciitis
(Babcock et al 2005)
, carpal tunnel related-pain
(Tsai et al
, and even refractory restless-legs syndrome
et al 2006)
have been reported. Botulinum toxins may have
a role in electrodiagnosis, using BoNT-A pretreatment to
reduce electromyographic frontotemporal artifact in
electroencephalographic localization of aberrant cerebral discharges
(Grant and Hermanowicz 2007)
. Lastly, direct infusion of
botulinum toxin A has been shown in vivo to inhibit enzymes
responsible for hippocampal cell death following induced
seizures in rats
(Manno et al 2007)
. Hence, in addition to
its role at the neuromuscular junction and peripheral nerve,
BoNT-A may be a neuroprotective agent for the central
nervous system. With the all of the current interest and
speculation in botulinum neurotoxins, one can only assume
that a myriad exciting new therapeutic applications will come
to light in the decades.
Neurotoxin Institute http://www.neurotoxininstitute.org University of South Florida Yes
Xeomin® http://www.xeomin.com Merz Pharmaceuticals
Dysport® http://www.dysport.co.nz/index.php Ipsen, LTD
BOTOX® Portal http://www.botoxmedical.com Allergan, Inc.
The views expressed in the article are those of the authors
and do not reflect the official policy of the Department of the
Army, the Department of Defense or the U.S. Government.
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