NEUROTOXIN INJECTION FOR MOVEMENT DISORDERS

NEUROTOXIN INJECTION
FOR MOVEMENT
DISORDERS
David Charles, Chandler E. Gill
ABSTRACT
The therapeutic use of botulinum neurotoxin has exploded since the first US Food
and Drug Administration indication was obtained in 1989, and today it represents
the first-line therapy for several hyperkinetic movement disorders. Of the seven
serotypes (A to G), types A and B have been approved for use in the United States.
Two type A toxins, onabotulinumtoxinA (Botox) and abobotulinumtoxinA (Dysport),
are available, and one type B toxin, rimabotulinumtoxinB (Myobloc) is available. The
commercially available toxins differ by protein target, duration of action, and
adverse event profile; no formula exists for interconversion. The clinical develop-
ment of the toxin is outlined and methods for muscle targeting are compared.
Treatment regimens should be designed to achieve a specific care or functional goal
by interdisciplinary teams consisting of physicians, patients, caregivers, and
therapists, when appropriate. We discuss dosing considerations and safety profiles
in the context of hyperkinetic movement disorders commonly encountered by
neurologists, including cervical dystonia, spasticity, pediatric spasticity, blepharo-
spasm, focal limb dystonias, and essential tremor. Finally, the multiple illustrative
cases sprinkled throughout the chapter demonstrate the highly individualized, goal-
focused nature of treatment with neurotoxins.
Continuum Lifelong Learning Neurol 2010;16(1):131–157.
INTRODUCTION cause death in exposed humans or

Clostridium botulinum bacterium is a animals. The human illness botulism
naturally occurring gram-positive rod can be caused by types A, B, and E
that forms spores commonly found in and most commonly occurs through
soil and water. Under anaerobic con- ingestion of contaminated foods. Re-
131
ditions, the bacterium thrives and pro- sulting weakness, paralysis, dysarthria,
duces botulinum neurotoxin (BoNT), dysphagia, constipation, and urinary
the most potent neurotoxin known retention may persist over a course
to mankind. No other neurotoxin pro- of weeks to months. Death due to dif-
duced by bacteria, plants, reptiles, in- fuse muscular paralysis can occur af-
sects, arachnoids, or aquatic species ter exposure to just one microgram of
has as potent toxicity by weight to the toxin.
Relationship Disclosure: Dr Charles has received personal compensation for speaking or consulting activities
with Allergan, Inc., and Medtronic, Inc. Vanderbilt University receives income in the form of grants or
contracts from Allergan, Inc., and Medtronic, Inc., for research led by Dr Charles. Ms Gill has nothing to
disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Charles discusses the unlabeled use of neuro-
toxin treatments for spasticity, essential tremor, and focal dystonia. Ms Gill discusses the unlabeled use of
neurotoxin treatments for spasticity, essential tremor, and focal dystonia.
Copyright # 2010, American Academy of Neurology. All rights reserved.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

" NEUROTOXIN INJECTION
KEY POINTS
The bacterium was isolated and char- the neurotransmitter’s release into the
A More than 20
acterized through the 19th and early synaptic cleft.
years have
passed since the 20th centuries. Attempts to weaponize Commercially available BoNTs have
first FDA the toxin likely occurred during the a manufacturing process that creates a
approval of Second World War, but the toxin’s ther- neurotoxin-protein complex. Entirely dif-
botulinum apeutic potential was not recognized ferent than typical small-molecule phar-
neurotoxin until the 1970s. At that time Dr Alan maceutical agents, BoNTs are large,
(BoNT), and it is Scott of the Smith-Kettlewell Eye Re- complex protein structures compris-
now considered search Institute began animal and then ing heavy and light chains linked to-
a first-line human trials with the goal of treating gether by a disulfide bond that, when
therapy for strabismus, characterized by a lack of injected into muscle, bind to the ace-
some movement
coordination between the extraocular tylcholine nerve terminal and are trans-
disorders.
muscles, preventing the patient from ported across the membrane. When the
A BoNT is a focusing the eyes at one point and im- toxin enters the nerve terminal, the light
biological drug pairing binocular vision. One of the first chain (active portion) cleaves presynap-
that causes neurologic symptoms observed with tic SNARE proteins, thereby preventing
chemodenervation botulinum poisoning is prolonged pa- the fusion of vesicle and release of ace-
by interfering
ralysis of ocular muscles, and Dr Scott tylcholine. Once exposed to toxin, the
with the
hypothesized the toxin could be ideally nerve terminal is disabled from releas-
release of
suited for the treatment of strabismus ing acetylcholine for a prolonged dura-
neurotransmitters.
because it would allow for the strength- tion but is not destroyed and continues
ening of antagonist muscles. The re- to manufacture acetylcholine. During
sults of the first trials were positive, and this time, the nerve sprouts new termi-
botulinum toxin type A was approved nals with intact ability to release acetyl-
by the US Food and Drug Administra- choline, thereby returning functional
tion (FDA) in 1989 for the treatment of interface between nerve and muscle.
strabismus and blepharospasm (Scott, With no further exposure to toxin, the
2004). Blepharospasm, a movement dis- original nerve terminals eventually re-
order with few satisfactory treatment cover their functional status and the
options, also responded well, and neu- new nerve terminal sprouts regress.
rologists quickly adopted BoNT for that This mechanism of action translates
and other movement disorders. It is into a lengthy therapeutic effect. After
now considered the treatment of choice injection, the clinical effect begins in
for blepharospasm and focal dystonias 3 to 10 days and lasts 3 to 4 months,
including cervical dystonia. peaking at 2 weeks.
132
MECHANISM OF ACTION TOXIN DIFFERENTIATION
Normally functioning motor neurons Seven immunologically distinct BoNT
manufacture acetylcholine, package it serotypes (A to G) have been identified
into vesicles that migrate to the nerve and are further divided into subtypes,
terminal, and release acetylcholine onto although only three formulations are
the postsynaptic muscle membrane, commercially available in the United
causing muscular contraction. When States. Types A, B, and E commonly
movement is initiated, vesicles of acetyl- cause human botulism, while avian and
choline are bound to the nerve terminal animal botulism are caused by types C
membrane by soluble N-ethylmaleimide- and D. The various types have similar
sensitive factor attachment protein re- mechanisms of action; all cleave SNARE
ceptor (SNARE) proteins. These pro- proteins but BoNTs A, C, and E cleave
teins draw the vesicles of acetylcholine SNAP-25, and BoNTs B, D, F, and G
into the membrane, thereby allowing cleave synaptobrevin. They also differ in
Continuum Lifelong Learning Neurol 2010;16(1)

KEY POINTS
neurotoxin complex protein size, dura- secondary nonresponse to BoNT-A. The
A New and detailed
tion of action, and potency (Smith et al, two toxins are equivalent in magnitude
safety
2007), and there is currently no consen- of peak response (Comella et al, 2005), information is
sus on dosing conversion rates between but widespread clinical use of BoNT-B now included in
the available formulations. Therefore, is currently limited by the shorter du- the labeling of
BoNTs are not therapeutically inter- ration of therapeutic effect as well as all available
changeable. This point is so important variation in safety profiles; neutraliz- BoNTs.
for patient safety that the FDA has in- ing antibody formation and autonomic
A Three BoNTs
cluded language in the labeling of all complications are more common with are currently
available toxins making clear that the po- BoNT-B therapy (Chapman et al, 2007; available in the
tency units of one toxin are not inter- Comella et al, 2005; Jankovic et al, United States.
changeable with another toxin and the 2006; Yablon et al, 2007). These dif- They are not
units of biological activity cannot be com- ferences are partially explained by dif- interchangeable,
pared or converted to any other toxin. fusion rates and cell membrane af- and their dosing
Three neurotoxin products are cur- finity differences between serotypes. units cannot be
rently approved in the United States Also, BoNT-A has been available in the compared or
for medicinal use. The first approved United States for a longer time than converted
between toxins.
is now known as onabotulinumtoxinA BoNT-B, so the fact that older physi-
(Botox) and is indicated for the treat- cians are more experienced and com-
ment of blepharospasm, severe primary fortable with the use of this serotype
axillary hyperhidrosis, cervical dystonia, may explain its more widespread use.
and strabismus. The two other available BoNT-D is newly available in the United
neurotoxins are approved by the FDA States, and its utilization compared with
only for the treatment of cervical dys- BoNT-A and BoNT-B remains to be
tonia; rimabotulinumtoxinB (Myobloc) determined.
and abobotulinumtoxinA (Dysport). BoNT-B is supplied in a liquid
A third formulation of type A (Xeomin) ready-to-use form, and BoNT-A and
is approved in Europe and is currently BoNT-D must be reconstituted with
being investigated in clinical trials in preservative-free normal saline. The
the United States. Types C and F have most common dilution for BoNT-A is
been investigated in Italy and Japan, 1 mL per 100 units of toxin and for
although neither is available commer- BoNT-D is 1 mL per 500 units of toxin.
cially (Scott, 2004). In this chapter, we Other dilutions are often used, but in-
will limit our discussion to the brands creasing the dilution (for example, to
currently available in the United States. 2 mL to 3 mL per 100 units) does in-
Because the subtypes differ in dosing crease toxin diffusion once injected. 133
and duration of action, suggested doses For the cases presented in this chap-
and side effects are different among ter, whole dilutions of BoNT-A are 1 mL
brands, and from this point on BoNT-A of preservative-free normal saline per
will refer to onabotulinumtoxinA, brand 100 units of toxin.
name Botox, BoNT-B to rimabotuli-
numtoxinB, brand name Myobloc, and TREATMENT CONSIDERATIONS
BoNT-D to abobotulinumtoxinA, brand The most important factors in ensuring
name Dysport. The term BoNT will re- treatment efficacy are selection of ap-
fer collectively to the commercially avail- propriate dose and muscles, and place-
able BoNTs. ment of the toxin. Toxin doses are
In the United States, BoNT-A is typi- specific to the treated disorder and the
cally preferred over BoNT-B, which is toxin used and are therefore discussed
considered by some clinicians to be an in the clinical applications sections later
option only in the case of primary or in this chapter.

KEY POINTS
Because BoNT works directly at the placement attempts accurately targeted
A Successful use of
neuromuscular junction, accurate place- the muscle when EMG was not used,
BoNT depends
on correct ment into the region (located at the and the use of EMG significantly im-
muscle selection midpoint of the muscle fiber) is vital and proved the likelihood of clinical benefit
and accurate has been shown to increase clinical re- (Molloy et al, 2002). Since the increased
dosing. sponse by 50% (Shaari and Sanders, precision rendered by EMG requires
1993). Dose per muscle is usually di- less toxin to produce the same benefit,
A Some
vided into several injection sites, and use it also may decrease the frequency of
neurologists
prefer using of up to eight injection sites per mus- neutralizing antibody formation. While
EMG guidance cle has been reported. Two commonly the general consensus is that EMG
for injections in used methods of muscle localization are guidance is not necessary for a positive
the neck and palpation and EMG guidance. Palpation response, it is often helpful, and these
limbs although involves recognition of bony landmarks authors use EMG guidance for all injec-
it is not and manual palpation of the muscle tions. Other methods for muscle belly
necessary for belly. The needle is then inserted at the localization include CT guidance, so-
accurate muscle bulkiest part of the muscle. Detailed nography, and electrical stimulation,
targeting. knowledge of muscle anatomy is im- but these methods are not as com-
portant for correct injection using this monly utilized.
method, and precision can be reduced if
the target muscle is very small or deep. SAFETY PROFILE AND
EMG is a guidance technique in PRECAUTIONS
which a hollow Teflon-coated needle Side effects are primarily related to un-
with a monopolar recording surface on wanted diffusion from the target mus-
the tip is attached to the toxin syringe cles, and the FDA has recently placed a
and a surface reference electrode and a boxed warning in the labeling of each
ground electrode are attached to the of the available neurotoxins.
skin. The needle records biphasic and In addition to the boxed warning,
triphasic motor unit action potentials of the FDA requires all manufacturers to
muscle fascicles (O’Brien, 1997, Preston implement a risk evaluation and miti-
and Shapiro, 2002), and produces a re- gation strategy, including enhanced
petitive crackling sound, which, when education of patients and physicians
present without voluntary contraction, about the newly labeled risks.
indicates proximity to a potentially spas- Contraindications to treatment with
tic muscle belly (O’Brien, 1997, Preston BoNT include pregnancy, the presence
and Shapiro, 2002). The usefulness of of preexisting pareses, impaired neu-
134 EMG has been debated, and some claim romuscular transmission, and myop-
it should only be used when the in- athies; however, in cases of extreme
volved muscles are difficult to palpate or medical necessity, certain movement
the injection sites are difficult to find disorders may be safely treated with
(Comella et al, 1992). Critics cite several low doses of BoNT (Fasano et al, 2005;
disadvantages of the technique, includ- Newman et al, 2004; Singer et al, 2007).
ing increased materials, cost, and time Aminoglycoside antibiotic use may am-
and the inability to differentiate be- plify paresis. Adverse effects of neuro-
tween antagonistic and agonist muscle toxin injection are mainly injection site
contractions (Jankovic, 2004). Propo- dependent and dose dependent. Site-
nents suggest EMG should be used for specific adverse events are broken
most BoNT injections because muscle down by treated disorder in the sec-
palpation alone may not successfully lo- tions that follow. Systemic effects are
cate dystonic muscles (Barbano, 2001); rare and occur after administration of
in fact, in one study only 37% of needle 10 times the doses typically used in

KEY POINT
practice. It is also possible for neu- mon movements. The most difficult to
A The frontalis test is
tralizing antibodies to form; a recent treat with BoNT, and fortunately the a straightforward
pooled analysis reported this event in least common, is anterocollis (a chin- way to assess
0.5% of patients treated with BoNT-A down, head-tilting forward position); immunity to BoNT.
(Yablon et al, 2007), but in other studies toxin doses high enough to dampen
the occurrence has been reported in up this movement tend to result in dys-
to 5% of patients treated with BoNT-D phagia. The goal of treatment can be to
(Naumann et al, 2006) and 34.4% of pa- target any combination of these move-
tients treated with BoNT-B (Jankovic ments, or another goal, such as al-
et al, 2006). Because it causes therapeu- leviation of muscle discomfort or pain
tic failure, clinicians should take mea- (Case 6-1).
sures to prevent this occurrence by using The development and widespread
the minimum effective dose at injection use of neurotoxin injection have not
cycles of no more often than 12 weeks. If changed the natural history of the dis-
a treating physician suspects that a pa- ease, which involves gradual onset and
tient has become resistant to a particular progression characterized by increas-
formulation, antibody testing is avail- ingly abnormal postures, pain, and hy-
able. It is of only marginal clinical use, pertrophy of affected muscles. A small
however, because of a significant rate of minority of patients can have a some-
false-positives. More useful is the fron- what dramatic onset; in these cases,
talis test, which is simply the injection of spasmodic hyperkinetic movements
a small dose of toxin unilaterally into are often present. In the early stages,
the frontalis muscle. Re-examination in the head and neck position may be
2 weeks can elucidate whether the fron- only mildly abnormal and pain is the
talis has been weakened, indicating the most common troubling symptom.
patient remains responsive to therapy. Symptoms initially progress, with a
plateau typically achieved after sev-
CLINICAL APPLICATIONS eral years. Very few patients experi-
ence spontaneous remission, but this
Cervical Dystonia is usually temporary, and the likeli-
Cervical dystonia, historically referred hood of such an event has not in-
to as spasmodic torticollis, is the most creased following the availability of the
common form of focal dystonia, occur- BoNTs. Before beginning treatment,
ring in 0.28% of the general population the patient should be counseled to un-
(Jankovic et al, 2007) and causing signif- derstand that the goal of BoNT ther-
icantly decreased quality of life. Most pa- apy is to manage the condition and that 135
tients do not actually have spasmodic the injection cannot effect a cure or per-
features but instead more sustained con- manent improvement of symptoms.
traction of the neck musculature that Pharmacologic agents such as anti-
make the condition uniquely suited for cholinergics and skeletal muscle relax-
toxin administration. Complicating fo- ants are often unsatisfactory because
cal treatment, however, is the fact that of side effect profiles at the doses re-
head and neck movements are often quired to improve symptoms. The chap-
multidirectional in nature. Torticollis ter ‘‘Overview of Common Movement
(head turning) is the most common Disorders’’ provides an overview of cer-
type of movement and occurs in 82% vical dystonia and its treatment with
of patients ( Jankovic et al, 1991). Late- these agents. BoNT injection is now
rocollis (lateral head tilt, with ear to- widely accepted as the first-line therapy,
ward the shoulder) and retrocollis with high-quality clinical trials in BoNT-
(head tilted backward) are other com- A, BoNT-B, and BoNT-D demonstrating

KEY POINT
A BoNT injection is Case 6-1
the first-line A 48-year-old right-handed computer technician noticed aching in her left
therapy for the hand, causing difficulty completing her work. She specialized in the repair
treatment of of microprocessor components, requiring her to use magnifying lenses, a
cervical head-mounted lamp, and very small repair instruments. During the most
dystonia. tedious portions of the repair procedure, she noted that her headlamp
would be illuminating an area to the right of where she was working and
that her left hand would become somewhat stiff and achy when trying
to hold parts in place for repair with the right hand. She learned that if she
disengaged from the work and stretched her hands and neck, she then
could resume her work for a short period of time. Within a few minutes of
continued activity, however, the headlamp’s field of illumination would
again diverge from her field of work. Over time, this progressed and
involved pain, particularly in the muscles in the posterior aspect of the
right neck. On examination in the seated position with eyes closed, she had
right head turn with tilt to the left and right shoulder elevation. She
had normal range of motion in all directions but did note more difficulty
turning her head to the left than the right. Review of candid family
photographs and her driver’s license revealed the abnormal head position
had been mildly present for at least 3 years. There was no history of
trauma. Brain and cervical spine imaging were normal, and laboratory
studies were negative for secondary causes of cervical dystonia. After
informed consent was given, the first injection procedure was conducted
via EMG guidance and involved doses of 100 units of BoNT-A into the right
splenius capitis and 100 units into the left sternocleidomastoid. Within
1 month, the patient reported significant pain reduction and a modest
improvement in head position. Injections were repeated every 90 days, and
the injection dose was gradually increased to include 50 units in the left
scalene, 100 units in the right trapezius, and 50 units in the right rhomboid
for a total of 400 units. She received regular injections on a 90-day cycle
for 12 years and continued to report significant benefit.
Comment. The onset of cervical dystonia is usually slow and insidious,
but a small minority of patients can present with much more acute
onset of symptoms. This case represents a classic form, and while repeat
injections continue to provide benefit, complete resolution of symptoms is
usually never achieved.
136
benefit in 70% to 94% of patients treated. because of symptom progression or in-
This effect remains robust and the treat- adequate response.
ment is safe for many years (Brin et al, Accurate dose and muscle selection
2008; Skogseid and Kerty, 2005). Pa- are two of the most important determi-
tients with cervical dystonia are typi- nants of response to neurotoxin inject-
cally treated with dose ranges of 200 ion. The anatomy of the head and neck
to 600 total units of BoNT-A per injec- musculature is complex, however, and
tion cycle (average 250 to 300 units), the prospect of neurotoxin injection in
7500 to 30,000 units of BoNT-B (aver- this area can be intimidating to the no-
age 10,000 to 22,000 units), or 100 to vice. Courses that describe in detail the
1000 units of BoNT-D (average 250 musculature and appropriate doses to
to 500 units). Injections are repeated be injected are offered by professional
at 12- to 16-week intervals, and slight societies, continuing medical education
increases in dose may be warranted providers, and toxin manufacturers;

however, certain generalizations are ap- ever successful, as diffusion of the toxin
propriate. Table 6-1 describes doses from the targeted muscles into the mus-
commonly injected grouped by affected cles that mediate swallowing causes
muscles, and Figures 6-1 and 6-2 dem- dysphagia.
onstrate the wide range of possible When treating cervical dystonia, ad-
injection sites. For torticollis, the most verse events vary by formulation used.
commonly injected muscles are the ipsi- In a pooled analysis including 1825
lateral splenius capitis and contralateral treatments with BoNT-A, 5781 treat-
sternocleidomastoid. For laterocollis, ments with BoNT-D, and 875 treat-
the ipsilateral scalene complex is the ments with BoNT-B, dysphagia was the
most commonly injected. Additionally, most commonly reported side effect
the sternocleidomastoid, splenius cap- (8.9% BoNT-A, 26.8% BoNT-D, 19.0%
itis, and levator may be injected. Re- BoNT-B), which was dose dependent
trocollis is best treated by injecting the for BoNT-D but not for the other two
bilateral splenius capitis, longissimus, (Chapman et al, 2007). While dyspha-
or deep paraspinal muscles. Antero- gia almost always resolves without se-
collis is the most difficult to treat. quelae, it can rarely require temporary
The bilateral sternocleidomastoid and feeding per tube. Dry mouth is much
scalene group are involved, but in- more commonly seen after injection
jection into these muscles is rarely if with BoNT-B than BoNT-A, with one
TABLE 6-1 Reported Dose Distributions for Cervical Dystonia
Muscle BoNT-A (Units) BoNT-B (Units) BoNT-D (Units)
Levator scapulae 20–100 1000–4000 20–200

Longissimus capitis 30–100 1000–5000 100–200
Scalene group 15–50 1000–5000 50–300
Semispinalis 30–100 1000–5000 50–250
Splenius capitis 15–100 1000–5000 20–700
Splenius cervicis 20–60 Not reported Not reported
Sternocleidomastoid 15–100 1000–3000 10–350
Trapezius 20–100 1000–5000 20–300 137
BoNT-A = onabotulinumtoxinA; BoNT-B = rimabotulinumtoxinB; BoNT-D = abobotulinumtoxinA.
Brashear A. Treatment of cervical dystonia with botulinum toxin. Operative Techniques Otolaryngol Head Neck Surg
2004;15(2):122–127.
Buchman AS, Comella CL, Stebbins GT, Weinstein SL. Determining a dose-effect curve for botulinum toxin in the
sternocleidomastoid muscle in cervical dystonia. Clin Neuropharmacol 1994;17(2):188–195.
Dowson AJ, Kilminster SG, Salt R. Clinical profile of botulinum toxin A in patients with chronic headaches and cervical
dystonia: a prospective, open-label, longitudinal study conducted in a naturalistic clinical practice setting. Drugs R D
2008;9(3):147–158.
Dubinsky RM, Gray CS, Vetere-Overfield B, Koller WC. Electromyographic guidance of botulinum toxin treatment in
cervical dystonia. Clin Neuropharmacol 1991;14(3):262–267.
Dysport1 full prescribing information and medication guide. www.dysport.com/index.html. Accessed September 20,
2009.
Mohammadi B, Buhr N, Bigalke H, et al. A long-term follow-up of botulinum toxin A in cervical dystonia. Neurol Res
2009;31(5):463–466.
Poewe W, Deuschl G, Nebe A, et al; German Dystonia Study Group. What is the optimal dose of botulinum toxin A in
the treatment of cervical dystonia? Results of a double-blind, placebo-controlled, dose-ranging study using Dysport. J
Neurol Neurosurg Psychiatry 1998;64(1):13–17.
Tsui JK, Eisen A, Stoessl AJ, et al. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;
2(8501):245–247.

FIGURE 6-1 Possible neurotoxin injection sites for cervical dystonia (posterior view).
study reporting dry mouth in up to weeks after injection (Comella et al,

80% of patients treated with BoNT-B 4 2005). Reactions such as urticaria, edema,
138
FIGURE 6-2 Possible neurotoxin injection sites for cervical dystonia (lateral view).

KEY POINT
shortness of breath, and anaphylaxis ated with unacceptable side effects such
A Spasticity can
are very rare; however, the FDA has re- as sedation, which may be especially
result from
cently issued a boxed warning for all pronounced in adults with chronic ill- injury or illness
available neurotoxins concerning these nesses, who often take multiple medi- to the CNS, and
potential adverse events. cations (Case 6-2). BoNT injection offers BoNT therapy
the distinct advantage of being a focal for spasticity
Spasticity in Adults intervention that is not associated with has been widely
Spasticity is characterized by increased sedation or addictive properties. studied in both
muscle tone and hyperactive reflexes The decision of whether or not to children and
and can follow many types of injury or treat, and how to treat, a spastic limb adults.
illness to the brain or spinal cord. An using BoNT therapy should always be
overview of the condition is provided based on the individual patient’s symp-
in the chapter ‘‘Overview of Common tom presentation. Treatment plans are
Movement Disorders.’’ When it is pres- designed to achieve a specific goal,
ent, decreased mobility of affected limbs such as improving a self-performed or
can impair activities of daily living and caregiver-assisted activity of daily liv-
hygiene. Patients may experience pres- ing (Cases 6-3 to 6-5). This may in-
sure ulcers, urinary tract infections, skin clude transfers, shirt change, perineal
breakdown, and contractures, and all of hygiene, incontinence care, and ambu-
these can combine with overall disa- lation. Cosmesis and comfort level are
bility to negatively affect self-esteem and also commonly targeted. Interestingly,
quality of life. Oral medications typically the presence of spasticity may not be a
used to treat spasticity are often associ- hindrance but may even improve some
Case 6-2
A 41-year-old man had profound intellectual disability secondary to
cerebral palsy. He resided in a state-operated developmental center and
required total care for all activities of daily living. His caregivers and
physical therapist noted that it was very difficult to separate his legs for
undergarment change, hygiene, and dressing. This problem had been
present for many years, and he routinely required two staff members
for every undergarment change and bathing procedure. During
undergarment change, one staff member was needed solely for the purpose
of forcibly separating the knees so that the second staff member could
clean and perform the change. On examination, there was increased muscle
tone throughout the hips and legs causing hip adduction, knee flexion,
139
and plantar flexion at the ankles. Deep tendon reflexes were hyperactive, toes
were upgoing, and a spastic catch was present when attempting to
extend the knees. After obtaining informed consent from the patient’s
conservator, 200 units of BoNT-A was injected into the right hip adductors
and 200 units into the left hip adductors. All injections were done via EMG
guidance. Two weeks later, the physical therapist reported that the range
of motion for hip adduction had improved by 19 degrees. Furthermore,
the center staff noted that it was much easier to separate the legs for
undergarment change, hygiene, and dressing, and that the patient seemed
to be more comfortable during these procedures.
Comment. In patients who are nonambulatory, there is less concern for
excessive weakness in the hip adductors. Diffuse injection of moderate
doses without concern for worsening ambulation may result in better
hygiene, dressing, and undergarment change.

KEY POINT
A Treatment for Case 6-3
spasticity with A 51-year-old woman resided at a facility for people with intellectual
BoNT has been disabilities. A diagnosis of cerebral palsy had been made, and she had
approved for spasticity that caused disfiguring postures since early childhood. The staff
years by many of the facility was concerned about bilateral hand closure, which had
European become so severe that the nails were beginning to erode into the skin of
countries. The the palms. The palms were always moist and malodorous due to the
FDA is actively inability of staff to sufficiently open the hands for hygiene. The staff had
considering an great difficulty applying bilateral hand splints fashioned by the patient’s
indication for occupational therapist. On examination, there was spasticity involving
BoNT-A for the multiple limbs, but the involuntary muscle contraction causing bilateral
treatment of hand closure was clearly the most problematic. At the time of examination,
spasticity. the staff was only able to place a rolled washcloth in the palm in an
attempt to absorb excess moisture and keep the nails from eroding the
skin. Two hundred units of BoNT-A was injected diffusely into the bilateral
finger flexors. Injection cycles were repeated every 90 days, and passive
hand opening was markedly improved. Appropriate nail care was much
easier, skin breakdown resolved, and application of splints could be done
with ease. The patient continued to benefit from neurotoxin injection
every 4 to 5 months.
Comment. The spastic hand with a closed fist posture can be particularly
problematic. If the goal of voluntary movement is simply not practical,
diffuse injection of neurotoxin across a broad range of muscles may greatly
improve passive hand opening, and thus hygiene and nail care.
activities of daily living, such as trans- quality, double-blind, placebo-controlled

fers. Alternatively, a patient with diffuse clinical trials have investigated the
spasticity throughout the body may be treatment of spasticity with BoNT, and
bothered by the increased tone in the it has been reported to reduce tone,
hip adductors causing difficulty with increase range of motion, and improve
hygiene and dressing, but may use the passive functional goals such as caregiver-
increased tone in the upper limb to assisted hygiene and dressing. Objec-
grip a walker. In this case, the patient tively assessing improvement in active
and physician would develop a treat- function in the setting of a clinical trial
ment plan to address spasticity in the is more difficult because of the goal-
140 lower limbs while leaving the upper centric nature of focal spasticity care
limbs untreated. and high variability in goals between in-
While neurotoxin injection is cur- dividuals. The largest trial was a double-
rently off-label for the treatment of blind, placebo-controlled, multicenter
spasticity in the United States, it is study of BoNT-A that included 126 pa-
approved in the European Union. The tients with upper limb spasticity re-
body of clinical evidence is overwhelm- sulting from stroke. Figure 6-3 dem-
ingly positive, and the American Acad- onstrates the range of injection sites
emy of Neurology has issued practice commonly used to treat upper limb
guidelines (Appendix B). BoNT injec- spasticity. Functional assessments were
tion for spasticity is commonly covered made across a range of activities, in-
by Medicare and Medicaid, and the FDA cluding hygiene, dressing, pain and limb
is currently considering an indication position, with dressing and limb po-
for BoNT-A for upper limb spasticity sition representing two-thirds of the
resulting from stroke. Over 10 high- therapeutic targets. The primary end

point, wrist flexor tone, was signifi- siderations. For instance, a physician
cantly reduced at all measurement treating a patient with good voluntary
points. Secondary end points, includ- control, mild spasticity, low weight and
ing the physician’s global assessment muscle bulk, or practicing a career or
and achievement of the therapeutic hobby requiring extreme precision, may
goal (dressing, hygiene, etc) were also elect to reduce the toxin dose. Con-
significant. Most studies have focused versely, a large patient with inadequate
on upper limb spasticity, but one response to the previous treatment, very
study of spasticity in the lower limbs severe spasticity, or poor voluntary mus-
found that a set dose of 400 units of cle control may require an increased
BoNT-A divided into the bilateral hip dose at the next injection cycle. While
adductors resulted in better comfort total doses of up to 850 units of BoNT-A
when positioned in the wheelchair and have been reported for extensive spas-
improved nursing care. ticity, these authors implement a maxi-
Dosing ranges are based on age, mus- mum total dose of 600 units to reduce
cle size, and the number of muscles the likelihood of neutralizing antibody
injected; Table 6-2 contains doses re- formation and excessive side effects.
ported by physicians in the literature.
There are accepted guidelines for initial
dose per muscle, after which treatment Pediatric Spasticity
optimization is largely dependent on Spasticity can occur at any age as a
physician experience and assessment result of CNS injury but in children
of treatment effect as well as other con- most commonly occurs in the setting
Case 6-4
A 19-year-old man 2 years prior to initial consultation had suffered a
catastrophic brain injury from a gunshot wound, resulting in devastating
cognitive impairment and spasticity involving all four limbs. He resided in a
long-term skilled nursing facility and required total assistance for all activities
of daily living. At initial consultation, staff members were concerned with
very prominent posturing of the upper limbs causing elbow flexion. They
reported skin breakdown in the antecubital fossa and great difficulty with
dressing. On examination the patient was noncommunicative and could not
follow commands. A tracheostomy and gastrointestinal feeding tube were
in place. There was diffuse spasticity and hyperreflexia involving all four limbs.
In the upper limbs, there was a prominent involuntary muscle contraction
141
causing bilateral elbow flexion, more prominent on the left when compared
with the right. Examination of the antecubital fossa showed both to be
moist; on the left, the skin was red and there was concern for imminent skin
breakdown. One hundred and fifty units of BoNT-A was injected into the
left biceps and 50 units into the left brachioradialis. The same doses were
administered to the biceps and brachioradialis on the right. Two weeks
after the first injection, elbow extension was sufficiently improved to ease
dressing. On follow-up examination the antecubital fossa were clean and dry
bilaterally with normal skin integrity.
Comment. In extreme cases, skin breakdown and subsequent infection
result from untreated spasticity. When the severity of CNS disease
prohibits the goal of voluntary movement in the affected limbs,
neurotoxin injection can be used to achieve enough range of motion
to prevent catastrophic consequences of spasticity.

KEY POINT
A Children with Case 6-5
cerebral palsy A 35-year-old woman had a history of cerebral palsy causing profound
often suffer intellectual disabilities and involuntary muscle spasm and spasticity
from spasticity affecting all four limbs and the trunk. She had resided in an institutional
that interferes setting since early childhood, was fed by tube, and required total care
with care and for all activities of daily living. Spasticity affecting the bilateral elbow
function. flexors had been present long-standing and interfered with dressing and
hygiene in the antecubital fosses. She experienced episodes of skin
breakdown, which presented a continual challenge to caregivers. Also, her
abnormal postures interfered with caregivers’ ability to appropriately
position their bodies to perform transfers. BoNT-A had been successfully
used in the past to improve elbow extension and thus hygiene in the
antecubital fosses. After several years of use, however, the injections
no longer provided benefit. A frontalis test was undertaken with the
injection of 20 units of BoNT-A into the left frontalis muscle. Examination
2 weeks after the injection revealed no difference in movement when
comparing the left and right frontalis. Surmising the patient had possibly
become resistant to BoNT-A, injection with BoNT-B was undertaken.
Four thousand units of BoNT-B was injected into the left and right biceps,
and 1000 units was injected into the left and right brachial radialis.
The total dose injected was 10,000 units, and all injections were done via
EMG guidance. Two weeks after injection, examination revealed a very
good response with a range of motion similar to that achieved at the
initiation of injection with BoNT-A. Range of motion for elbow extension
was adequate to allow for hygiene in the antecubital fossa and improve
dressing. Repeat injections with BoNT-B continued to be successful over
1
the next 2 /2 years.
Comment. Antibody formation to BoNTs is possible, and loss of
previously achieved benefits may indicate resistance. Serum antibody tests
may not be as helpful as the frontalis test because of false-positive and
false-negative responses. Physicians and patients benefit from the
availability of differing botulinum toxin types.
of cerebral palsy. Just as for adults, the lower limbs, spasticity causing knee ex-
goal of treatment can be any of the tension and hip adduction, as well as
care-focused or function-focused goals. an equinus or equinovarus ankle pos-
142 Additional goals in growing children are ture, contributes to delays in inde-
to prevent torsional deformities in long pendent standing and ambulation. Hip
bones or to correct joint instability, po- adduction, in particular, can impede un-
tentially delaying or avoiding the need dergarment change, hygiene, and dress-
for later orthopedic or neurosurgical ing and lead to scissoring of the legs
intervention. when attempting to walk (Case 6-6).
BoNT injection has been used to Equinus posture at the ankle leads to
treat spasticity in children for many the absence of a heel strike, and toe
years. While it has rarely been used in walking can be further complicated
infants, it is more commonly first ap- by incomplete extension of the knees
plied around the age of 2. At this age, and adduction of the hips. The lower
children with cerebral palsy may begin limbs can be affected symmetrically or
to exhibit spasticity that interferes with asymmetrically.
care and delays the achievement of ma- Approaches to injection for pediat-
jor developmental milestones. In the ric spasticity are generally similar to

FIGURE 6-3 Possible neurotoxin injection sites for upper limb spasticity.
adults, but in some cases, different ther- fortable. For the child with a clenched
apeutic goals and expectations may ne- fist that is nonfunctional, injection of
cessitate unique treatment considera- a moderate dose of BoNT diffusely
tions. The injections can be painful and into the finger and wrist flexors can
anxiety producing for young patients be of significant benefit (Case 6-7). In
in particular, and low-dose topical an- wrist and elbow flexors and shoulder
esthetic or even sedation can be pre- adductors, treatment with BoNT often
scribed. Pediatric dosing is reported in improves hygiene and dressing and as-
the range of 1 to 6 units of BoNT-A per sists in reaching rehabilitation goals.
kilogram of body weight, translating As in adults, coordinating ongoing treat-
into total doses of 25 to 100 units. The ments with a physical therapist im-
maximum dose that should be used in proves appropriate muscle selection
children is 400 units, with no more than and attainment of rehabilitation goals.
50 units given in any one injection site. Parents considering BoNT for the 143
Injection into the lower extremities has treatment of their child’s spasticity are
been shown in different studies to be often appropriately concerned and have
effective at decreasing tone and length- many questions. During initial consul-
ening the hamstring, widening the dis- tation, providing education on the risks,
tance between the knees, improving benefits, and alternatives to neurotoxin
gait kinematics, and reducing pain. In injection is essential. Parents are often
particular, low doses of BoNT into the reassured when they learn that bot-
plantar flexors can be helpful in let- ulinum toxins have been used ther-
ting the heels down so that the child apeutically for many years, including in
achieves a heel strike, or at least a flat- children. That injections must be re-
footed posture when attempting to peated every 3 to 4 months is often
stand or walk. Additionally, relaxation relieving to parents, as they begin to
of these muscle groups can make wear- understand that the effects of an in-
ing an ankle/foot orthotic more com- dividual injection are not permanent.

TABLE 6-2 Reported Dose Distributions for Spasticity
Hip Adductors
Adductor longus 20–400 Not reported 63–188
Adductor magnus 75–300 125–375
Adductor brevis 75–400 63–188
Hip Flexors
Iliopsoas 40–70 5000–10,000 Not reported
Iliacus 50–150 Not reported
Psoas 50–200 Not reported
Rectus femoris 75–200 500–2500
Knee Flexors
Medial hamstrings 50–150 2500–7500 Not reported
Semitendinosus 100–400 Not reported 100–600
Semimembranosus 400 Not reported 100–600
Lateral hamstrings 100–200 2500–7500 Not reported
Knee Extensors
Quadriceps 50–200 5000–7500 Not reported
Ankle Flexors
Gastrocnemius 50–250 3000–7500 89–600
Soleus 50–200 2500–5000 100–600
Posterior tibialis 40–320 3000–7500 100–600
Anterior tibialis 50–150 2500–5000 Not reported
Foot Flexors
Extensor hallucis longus 25–100 1500–3500 Not reported
144 Flexor hallucis longus 25–75 1500–3500 Not reported

Toe Flexors
Flexor digitorum longus 25–125 2500–5000 Not reported
Flexor digitorum brevis 20–70 2500–5000 Not reported
Flexor hallucis longus 25–75 1500–3500 Not reported
Flexor hallucis brevis 15–25 Not reported Not reported
Shoulder
Infraspinatus 100 Not reported Not reported
Pectoralis complex 75–150 2500–5000 500
Latissimus dorsi 50–150 2500–5000 400
continued on next page

TABLE 6-2 Continued
Teres major 25–100 1000–3000 400

Subscapularis 25–100 1000–3000 100–400
Triceps 50–200 2500–5000 Not reported
Biceps 50–200 2500–5000 Not reported
Forearm
Pronator quadrates 10–50 1000–2500 Not reported
Pronator teres 25–75 1000–2500 Not reported
Elbow Flexors
Biceps brachii 25–100 1000–3000 150–400
Brachioradialis 15–100 3750 100–300
Brachialis 25–100 Not reported 250
Wrist Flexors
Flexor carpi radialis 15–100 1000–3000 50–225
Flexor carpi ulnaris 10–70 1000–3000 50–225
Finger Flexors
Flexor digitorum 20–100 1000–3000 50–225
profundus
Flexor digitorum 20–75 1000–3000 50–225
superficialis
Thumb
Adductor pollicis 5–25 Not reported Not reported
Flexor pollicis longus 5–30 1000–2500 Not reported
Opponens pollicis 5–25 500–1500 Not reported
Adductor pollicis 5–25 Not reported Not reported
Lumbricals 10–50 per hand 1500–4500 per hand Not reported 145
Dorsal interossei 10–50 Not reported
Anwar K, Barnes MP. Botulinum toxin injections for spasticity. Operative Techniques Neurosurg 2004;7(3):128–135.
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concurrent therapy interventions: a preliminary analysis of goals and outcomes. Disabil Rehabil 2009;31(3):220–226.
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randomized, double-blind, placebo-controlled, dose-ranging study. Dev Med Child Neurol 2002;44(10):666–675.
Bakheit AM, Fedorova NV, Skoromets AA, et al. The beneficial antispasticity effect of botulinum toxin type A is
maintained after repeated treatment cycles. J Neurol Neurosurg Psychiatry 2004;75(11):1558–1561.
Bakheit AM, Thilmann AF, Ward AB, et al. A randomized, double-blind, placebo-controlled, dose-ranging study to
compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity
after stroke. Stroke 2000;31(10):2402–2406.
Bhakta BB, Cozens JA, Bamford JM, Chamberlain MA. Use of botulinum toxin in stroke patients with severe upper
limb spasticity. J Neurol Neurosurg Psychiatry 1996;61(1):30–35.
Borg-Stein J, Pine ZM, Miller JR, Brin MF. Botulinum toxin for the treatment of spasticity in multiple sclerosis: new
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TABLE 6-2 Continued
Brin MF; Spasticity Study Group. Dosing, administration, and a treatment algorithm for use of botulinum toxin A
for adult-onset spasticity. Muscle Nerve Suppl 1997;6:S208–S220.
Burbaud P, Wiart L, Dubos JL, et al. A randomised, double blind, placebo controlled trial of botulinum toxin in the
treatment of spastic foot in hemiparetic patients. J Neurol Neurosurg Psychiatry 1996;61(3):265–269.
Caty GD, Detrembleur C, Bleyenheuft C, et al. Effect of simultaneous botulinum toxin injections into several
muscles on impairment, activity, participation, and quality of life among stroke patients presenting with a stiff
knee gait. Stroke 2008;39(10):2803–2808.
Cheng CM, Chen JS, Patel RP. Unlabeled uses of botulinum toxins: a review, part 1. Am J Health Syst Pharm
2006;63(2):145–152.
Dunne JW, Heye N, Dunne SL. Treatment of chronic limb spasticity with botulinum toxin A. J Neurol Neurosurg
Psychiatry 1995;58(2):232–235.
Girlanda P, Quartarone A, Sinicropi S, et al. Botulinum toxin in upper limb spasticity: study of reciprocal inhibition
between forearm muscles. Neuroreport 1997;8(14):3039–3044.
Guo Y, Shin K. Unique use of botulinum toxin to decrease adductor tone and allow surgical excision of vulvar
carcinoma. Int J Gynecol Cancer 2004;14(1):100–103.
Hesse S, Reiter F, Konrad M, Jahnke MT. Botulinum toxin type A and short-term electrical stimulation in the
treatment of upper limb flexor spasticity after stroke: a randomized, double-blind, placebo-controlled trial. Clin
Rehabil 1998;12(5):381–388.
Hyman N, Barnes M, Bhakta B, et al. Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple
sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study. J Neurol Neurosurg
Psychiatry 2000;68(6):707–712.
Jankovic JJ, Tolosa E, editors. The Parkinson’s disease and movement disorders. 5th ed. Philadelphia: Lippincott
Williams & Wilkins, 2006.
Lim JY, Koh JH, Paik NJ. Intramuscular botulinum toxin-A reduces hemiplegic shoulder pain: a randomized,
double-blind, comparative study versus intraarticular triamcinolone acetonide. Stroke 2008;39(1):126–131.
Marco E, Duarte E, Vila J, et al. Is botulinum toxin type A effective in the treatment of spastic shoulder pain in
patients after stroke? A double-blind randomized clinical trial. J Rehabil Med 2007;39(6):440–447.
Mohammadi B, Balouch SA, Dengler R, Kollewe K. Long-term treatment of spasticity with botulinum toxin type A:
an analysis of 1221 treatments in 137 patients. Neurol Research 2009 Sep 1 [Epub ahead of print].
Reiter F, Danni M, Lagalla G, et al. Low-dose botulinum toxin with ankle taping for the treatment of spastic
equinovarus foot after stroke. Arch Phys Med Rehabil 1998;79(5):532–535.
Simpson DM, Alexander DN, O’Brien CF, et al. Botulinum toxin type A in the treatment of upper extremity
spasticity: a randomized, double-blind, placebo-controlled trial. Neurology 1996;46(5):1306–1310.
Simpson DM, Gracies JM, Yablon SA, et al. Botulinum neurotoxin versus tizanidine in upper limb spasticity: a
placebo-controlled study. J Neurol Neurosurg Psychiatry 2009;80(4):380–385.
Suputtitada A, Suwanwela NC. The lowest effective dose of botulinum A toxin in adult patients with upper limb
spasticity. Disabil Rehabil 2005;27(4):176–184.
A common strategy is to begin with low tomed to the benefits, side effects, and
to moderate doses in a few selected effect duration, muscle groups can be
muscles with very specific goals. As both expanded and the dose cautiously in-
the parent and child become accus- creased as appropriate. Finally, parents
146 Case 6-6

A 4-year-old child with cerebral palsy causing significant cognitive
impairment and developmental delay of motor milestones was
experiencing diffuse spasticity throughout the hips, pelvis, and legs.
The most problematic feature, however, was spasticity affecting the hip
adductors. This caused the knees and legs to be held tightly together,
interfering with undergarment change, hygiene, and dressing. Injection of
75 units of BoNT-A diffusely into the bilateral hip adductors for a total
dose of 150 units provided significant relaxation. Approximately 2 weeks
after injection, caregivers and the therapist noted a significant reduction
in involuntary muscle spasm and spasticity causing hip adduction,
providing improved access to the perineum and improved ease with
hygiene, undergarment change, and dressing.
Comment. Caution must be used when treating children with spasticity.
Careful attention to muscle selection and dosing is essential but should not
prevent practitioners from appropriately treating spasticity.

KEY POINTS
Case 6-7 A New FDA

A 10-year-old boy with cerebral palsy causing delay in language milestones warnings for all
and a right hemiparesis was referred by his occupational therapist because BoNTs should
of spasticity with involuntary muscle spasm causing a clenched fist and be carefully
flexed elbow. The clenched fist caused difficulties with nail care and hygiene reviewed prior
in the palm, and the flexed elbow made dressing difficult, particularly to treating
for putting on coats and sweaters in the winter months. The therapist spasticity,
noted both of these were worse with ambulation and activity. Fifty units particularly in
of BoNT-A injected diffusely into the finger flexors, as well as 25 units into children.
the brachioradialis and 50 units into the biceps, produced a very good A BoNT-A injection
relaxation of the treated muscle groups. Nail care and palm hygiene were is considered to
greatly improved, and the reduction of elbow flexion produced a more be the first-line
natural posture in the limb and resolved the difficulty in dressing. Treatment therapy for
was ongoing for 6 years with injections separated by 4 months and doses blepharospasm.
cautiously increased as appropriate for age and growth.
Comment. When treating children, continual reevaluation of muscle
selection and dosing is essential because of the ongoing growth and
development of the neuromuscular system. Close partnership with physical
and occupational therapists may improve overall outcomes.
may be reassured that BoNT therapy can within the orbicularis oculi (Figure 6-4).
be applied long-term without a decrease With adjustments made over succes-
in the quality of response with successive sive treatments for response and pro-
treatments, an important consideration gression, the total dose may increase
for a young child diagnosed with a life- to 50 units or more per side (Table 6-3).
long condition. In fact, in a recent study This amount can be twice as high in
involving 172 children with spastic cere- patients profoundly affected; however,
bral palsy, functional status actually incre- doses of greater than 50 units per eye
mentally improved with each successive are generally reserved for patients
injection (Balkrishnan et al, 2004). who have extensive involvement of fa-
cial muscles other than the orbicularis
Blepharospasm oculi (Kenney and Jankovic 2008).
Blepharospasm is a focal dystonia af- Adverse events after BoNT injection
fecting the periocular muscles that in the eye muscles include diplopia,
mediate eye closure. The natural his- ptosis, dry eyes, bruising, edema, ex- 147
tory involves slow progression over time posure keratitis, blurred vision, lacri-
with an eventual plateau, although in mation, and formation of neutralizing
about 12% of patients this plateau is se- antibodies. In spite of the fact that ble-
vere enough to cause functional blind- pharospasm was the first focal dys-
ness, as the eyelids have to be physi- tonia to receive an FDA indication for
cally held open. Injection of low-dose BoNT-A, relatively few high-quality, double-
BoNT-A into the periocular muscles blind, placebo-controlled clinical tri-
provides significant benefit for the over- als have been done and no published
whelming majority of patients. Initial reports of clinical trials investigating
dosing ranges reported by physicians BoNT-B are available. A retrospective
in the literature are from 12.5 to 20.0 review of all available clinical data (a
units per side. An initial injection pat- combined total of 2500 patients) for
tern that these authors commonly use BoNTs A and D showed a success rate
is 20 units divided into four locations of 90%, and the toxin continues to be

KEY POINTS
A Blepharospasm
can be very
disabling, even
causing
functional
blindness.
A Focal limb
dystonias,
particularly
those that are
task specific,
cause disability
and pose
significant
treatment
challenges.
FIGURE 6-4 Possible neurotoxin injection sites for blepharospasm and oromandibular
dystonia.
considered the first-line treatment for tions of a small number of muscles that
blepharospasm (Case 6-8). occur only during a specific, highly re-
Another example of a facial focal dys- petitive activity. Writer’s cramp and mu-
tonia is oromandibular dystonia. Dysto- sician’s dystonia are two common ex-
nia affecting the oromandibular region amples that involve contraction of wrist
can cause a host of differing movements and finger muscles when attempting
in the tongue and jaw area. Meige syn- to perform the affected task. Symp-
drome is defined as oral facial dystonia, toms become evident almost immedi-
and treatment is focused on the affected ately upon using the writing or musical
148 musculature (Case 6-9; Figure 6-4). instrument and are conspicuously ab-
sent when performing other activities
Focal Limb Dystonias with the affected muscles.
Focal limb dystonias, while more com- BoNT injection is an off-label treat-
plicated and less well characterized ment for focal limb dystonias, and a
than other movement disorders, can few high-quality clinical trials docu-
also be treated with neurotoxin injec- ment positive results. In theory, task-
tion. The chapter ‘‘Overview of Com- specific dystonias are ideally suited for
mon Movement Disorders’’ describes treatment with BoNT because only
in detail the etiology, presentation, and one or two muscles are typically af-
pharmacologic treatment of focal dys- fected. Anecdotal evidence suggests
tonias. Briefly, ‘‘task-specific’’ or ‘‘occu- that these dystonias can be success-
pational’’ dystonias comprise most focal fully treated with BoNT, and type A
limb dystonias. They are characterized has most commonly been used. For
by tonic or spasmodic muscle contrac- writer’s cramp, small doses of 10 to 50

TABLE 6-3 Typical Dose Ranges for Blepharospasm
Orbicularis Oculi
Lateral upper eyelid 1.25–5.0 250–750 7.5–20.0
Medial upper eyelid 1.25–5.0 250–750 7.5–20.0
Lateral lower eyelid 1.25–5.0 250–750 7.5–20.0
Medial lower eyelid 1.25–5.0 250–750 7.5–20.0
Corrugator 2.5–5.0 500–1000 Not reported
Procerus 2.5–5.0 500–750 Not reported
Barnes MP, Best D, Kidd L, et al. The use of botulinum toxin type-B in the treatment of patients who have become
unresponsive to botulinum toxin type-A: initial experiences. Eur J Neurol 2005;12(12):947–955.
Benign Essential Blepharospasm Research Foundation. Botulinum toxin for treatment of blepharospasm. www.
blepharospasm.org/botulinum.html. Accessed September 20, 2009.
Bhidayasiri R, Cardoso F, Truong DD. Botulinum toxin in blepharospasm and oromandibular dystonia: comparing
different botulinum toxin preparations. Eur J Neurol 2006;13(suppl 1):21–29.
Botulinum Toxin Type A. www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/3730AF/DuplicationsHieldsync/
5ED38E/ND_PG/PRIH/ND_B/HCS/SBK/2/ND_P/Main/PFACTIONID/hcscommonretrievedocumentcommon/Docid/1022/
cpmtemtSsetld/31/searchterm/botulinum+ hcin+ /searchoption/beginwith.
Botulinum Toxin Type B. www.thomsonhc.com/hcs/librarian/PFActionId/hcs.external.RetrieveDocument/eid/28810001/
DocId/2031/ContentSetCode/DRUGDEX-EVALS#adultDosageSection.
Colosimo C, Chianese M, Giovannelli M, et al. Botulinum toxin type B in blepharospasm and hemifacial spasm. J Neurol
Neurosurg Psychiatry 2003;74(5):687.
Dutton JJ, White JJ, Richard MJ. Myobloc for the treatment of benign essential blepharospasm in patients refractory to
Botox. Ophthal Plast Reconstr Surg 2006;22(3):173–177.
Faucett DC. Essential blepharospasm. In: Yanoff M, Duker JS, editors. Ophthalmology. 3rd ed. Philadelphia: Mosby,
2008.
Mohammadi B, Kollewe K, Wegener M, et al. Experience with long-term treatment with albumin-supplemented
botulinum toxin type A. J Neural Transm 2009;116(4):437–441.
units are often sufficient to improve Better outcomes are achieved when weak-
symptoms and make writing more com- ening of the muscles is effected in con-
fortable. Musicians, however, present a junction with retraining the surrounding
much greater challenge. Three primary muscles to adapt to the problem, and
symptom patterns have been described: so it is often helpful to combine BoNT
in pianists, flexion of the fourth and fifth with occupational therapy. 149
fingers; in guitarists, flexion of the third The treatment goal for neurotoxin
finger; and in clarinet players, extension injection for focal limb dystonias is
of the third finger. A reduction in tone simply to weaken (without paralyzing)
may be elicited by injection of very small the overactive muscles, and, therefore,
doses into these muscles, but adminis- the primary adverse events are ex-
tration of doses high enough to cause cessive weakness in the injected mus-
therapeutic benefit can cause excessive cles and disability for activities that
weakness for patients who make their utilize those muscles, as illustrated in
living skillfully performing one precise Cases 6-10 and 6-11.
repetitive movement. Unfortunately, pro-
fessional musicians often report that af- Essential Tremor
ter neurotoxin injection, their abilities BoNTs A and D have been used for the
never reach the level at which they per- treatment of essential tremor with vary-
formed prior to the onset of dystonia. ing benefit, depending on the type of

Case 6-8
A 62-year-old woman reported that her family had noticed the onset of frequent and forceful
blinking approximately 8 years prior to her presentation. This movement became progressively
worse over the years and was exacerbated by reading and bright light, particularly outdoors.
After the symptoms were sufficiently developed, the patient became concerned that the
condition was a consequence of anxiety and situational depression, leading to a protracted course
of counseling visits with her physician and a psychologist. At the time of the first neurologic
examination, the patient had great difficulty opening her eyes and at times would have to
forcibly hold her eyes open with her fingers. On neurologic examination, a very prominent
involuntary muscle contraction of the bilateral periocular muscles was present, causing eye
closure. The remainder of the examination was normal. Workup for secondary causes of dystonia
and blepharospasm was negative, including brain imaging and laboratory studies. Twenty units
of BoNT-A was injected into the bilateral periocular muscles in a pattern shown in Figure 6-4.
The total dose injected was 40 units, with each site receiving 5 units. In follow-up examination,
the patient reported receiving benefit beginning on the third day postinjection. This peaked
at 2 weeks and lasted approximately 11 weeks. She had been treated repeatedly over the past
8 years and required a very slow dose escalation as the natural history of blepharospasm is to
slowly worsen over time.
Comment. Blepharospasm can progress to the point of causing functional blindness when,
despite no abnormality in the eye or visual system, the patient may have to hold the eyelid open
with the fingers in order to see. While most patients respond to low-dose injection, some require
higher doses. The approach should involve a slow escalation of dose with injection cycles
separated by at least 90 days until a sufficient dose is identified.
tremor. No blinded randomized trials in- Head tremor. Essential tremor af-
vestigating the effect of BoNT-B in es- fecting the head, causing a lateral ‘‘no-
sential tremor have been reported. no’’ type movement can be improved
Case 6-9
A 66-year-old right-handed newspaper publisher presented with involuntary chewing movements
and protrusion of his tongue. His medications included metoclopramide 10 mg 4 times daily, which
had been prescribed 18 months earlier after a coronary artery bypass procedure. The medication
was prescribed in the perioperative period and also at discharge and continued uninterrupted
until the time of his first neurology consultation. Aside from hypertension and coronary artery
150 disease, the patient had no other significant medical illness and no family history of neurologic
disease or dystonia. On examination, there were very prominent chewing movements of the mouth
and tongue protrusion when attempting to talk or eat. Movements were temporarily suppressible
but were otherwise prominent and very distracting to the patient and others. The involuntary
movement was felt to be secondary to the use of metoclopramide, and the medication was
discontinued. The movements persisted after discontinuation of the medication, however, and
neurotoxin injection was suggested to reduce the tongue protrusion movements. A total of 20 units
of BoNT-A was injected into the genioglossus, divided into four sites as depicted in Figure 6-4. This
reduced his involuntary movements and he did not experience adverse events, which could include
swallowing difficulty, choking, and speech changes. Injections were repeated every 90 days, and once
he had been off the metoclopramide for approximately 2 years the involuntary movements subsided.
Comment. A host of medications has been implicated in the possible association with tardive or
late-onset drug-induced movement disorders. These movements are a known risk of many
medications, but quite often the benefit of the medication far outweighs the risk of potentially
developing a late-onset movement disorder.

KEY POINT
Case 6-10 A Lateral head

A 47-year-old police officer reported difficulty gripping the writing tremor
instrument and controlling it during writing. He saw multiple physicians for (‘‘no-no’’)
this problem because it impaired his ability to complete the large number typically
of forms and paperwork necessary for his vocation. A detailed history responds better
revealed no difficulty using either hand for any other activity. He was able to to BoNT than
use eating utensils normally and qualify with his service revolver without vertical tremor
difficulty using the same hand affected by his writing problems. The (‘‘yes-yes’’).
neurologic examination was entirely normal except for the handwriting
sample. During the act of writing, he had involuntary contraction of the index
and middle finger flexors, causing them to excessively push the writing
instrument into the page. This occurred almost as soon as writing was
initiated. At times, an irregular tremor-type movement of the hand was
present, but this was not a prominent feature or concern. A total of 25 units of
BoNT-A was injected via EMG guidance into the flexor muscles of the index
and middle fingers. Two weeks after the injection, the patient noted that his
writing was much improved, but he could no longer qualify with his service
revolver because of weakness in his index finger. His finger strength slowly
improved, and he requalified with his weapon 4 weeks postinjection. He
1
was treated approximately every 3 months over the next 2 /2 years. He
attempted to requalify with his weapon 2 weeks postinjection and, if he was
unable to qualify, his employer reassigned him to duties not requiring him
to be armed. Fortunately, the ability to complete forms and paperwork was
predominant in the daily activities of officers of this particular police force.
Comment. Focal dystonias that are task specific can be particularly
challenging. In this case, however, the vocational functions and potential
disabilities from excessive weakness could be adequately managed.
Unfortunately, this is not always the situation, as demonstrated in Case 6-11.
with low-dose injection into the bilat- an unsteady feeling, and the head can
eral splenius capitis (50 units) and, if unexpectedly tip forward, especially
needed, sternocleidomastoid (25 units). when bending or leaning forward.
Potential side effects include weakness Limb tremor. Postural tremor re-
of the neck extensors causing head sponds more adequately to BoNT injec-
droop, headache, dysphagia, and injection than does either kinetic or action
tion site pain (Lyons et al, 2003). Typi- tremor. Common injection patterns are 151
cally, however, low-dose injection in this 50 to 100 units total of BoNT-A or 25 to
manner is well tolerated and can be 175 units of BoNT-D, divided into the
mildly to moderately effective. Essen- flexor carpi radialis, flexor carpi ulnaris,
tial tremor causing a vertical ‘‘yes-yes’’ extensor carpi radialis, extensor carpi
type movement is more difficult to ulnaris, biceps, and triceps (Brin et al,
treat. The anterior neck muscles in- 2001; Pacchetti et al, 2000).
volved in this movement are in close Attempts to utilize BoNT for the treat-
proximity to the muscles that mediate ment of limb tremor have been of mod-
swallowing, and spread of the toxin can erate success. Several randomized, fixed-
be associated with dysphagia. The pos- dose, blinded studies showed a mild to
terior neck extensors involved in this moderate improvement in tremor am-
movement also support the head for plitude when measured by tremor rat-
upright posture, so excessive weakness ing scales, accelerometry, or functional
in these muscles can be associated with ability; however, in these trials a high

Case 6-11
A 20-year-old right-handed graduate student studying violin came for
consultation. She began playing the instrument at age 4 and was
very active in ensembles and her school orchestra, in addition to her
formal graduate studies of her instrument. During the 14 months prior
to presentation, she noticed that the fingers of her left hand felt as if
they were lifting off the strings when attempting to play. She was
both embarrassed and perplexed by this sensation, and she noted that
it began as soon as she placed her chin at the base of the instrument
and assumed the posture to play. Specifically, she noted that the
sensation was present prior to playing the first note and that it
increased with playing, causing missed notes and excessive fatigue in
the forearm muscles on the left. At the time of presentation, she was
both perplexed and distraught over the development and progression of
this problem. A detailed history revealed that she had no difficulty
using the hands for any other activity, even activities that required
precise movements of the fingers such as typing or playing other
musical instruments. The neurologic examination was otherwise normal.
BoNT-A was injected in 5-unit doses into four sites of involved finger
extensors. She subsequently noted improvement in her ability to
sustain performance with her instrument; however, she felt that the
level of her playing ability never reached its previous maximum during
any period of her treatment course. Repeat injections were done
approximately every 90 days.
Comment. Task-specific dystonias for activities that require an
exceptionally high level of performance are particularly challenging for
the practitioner. Sufficient control of symptoms may not be achievable
when performance of the task at the very highest levels is required.
Professional musicians, surgeons, archers, and golfers often note
improvement but can remain very discouraged when they are unable to
achieve previous levels of performance.
incidence of dose-dependent adverse activities of daily living that are most

events occurred, including finger weak- troublesome for the patient (Pacchetti
ness, injection-site pain, hematoma, and et al, 2000). These studies also differed
152 paresthesias (Brin et al, 2001; Lyons from the larger ones in that they ex-
et al, 2003). In fact, the remarkably high cluded injection into the extensor car-
incidence of excessive weakness (self- pi muscles unless they were the only
reported by 70% of patients from the muscles causing disability. This injec-
high-dose group in one study (Brin et al, tion protocol resulted in a lower in-
2001) and by all patients in another cidence of finger weakness accompa-
(Jankovic et al, 1996) may effectively un- nied by significant improvements in
blind participants and investigators to tremor amplitude and function for the
treatment status, and so even trials with participants’ most affected activities, in-
positive results must be interpreted with cluding writing, using a spoon, holding
some caution. a cup, and pouring milk.
In contrast to studies of high fixed In summary, neurotoxin injection rep-
doses, several open-label studies have resents a viable second-line treatment
instead utilized individualized injec- for essential tremor. Because modest re-
tion patterns that focus on the specific duction in tremor amplitude is usually

outweighed by a high occurrence of dis- selecting an injection pattern specifi-
abling adverse events, it is typically used cally designed to reduce disability. A
only in patients who fail to respond to careful trial of neurotoxin injection
pharmacologic treatments (about 50% is certainly warranted before patients
of cases). It should be stressed that choose to undergo more drastic mea-
experienced clinicians may successfully sures such as thalamotomy or deep
treat tremor using BoNT, especially when brain stimulation.
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NEUROTOXIN INJECTION

INTRODUCTION cause death in exposed humans or

Copyright # 2010, American Academy of Neurology. All rights reserved.

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Continuum Lifelong Learning Neurol 2010;16(1)

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Continuum Lifelong Learning Neurol 2010;16(1)

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Continuum Lifelong Learning Neurol 2010;16(1)

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Continuum Lifelong Learning Neurol 2010;16(1)

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TABLE 6-1 Reported Dose Distributions for Cervical Dystonia

Muscle BoNT-A (Units) BoNT-B (Units) BoNT-D (Units)

Levator scapulae 20–100 1000–4000 20–200

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study reporting dry mouth in up to weeks after injection (Comella et al,

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activities of daily living, such as trans- quality, double-blind, placebo-controlled

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TABLE 6-2 Reported Dose Distributions for Spasticity

Muscle BoNT-A (Units) BoNT-B (Units) BoNT-D (Units)

144 Flexor hallucis longus 25–75 1500–3500 Not reported

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Muscle BoNT-A (Units) BoNT-B (Units) BoNT-D (Units)

Teres major 25–100 1000–3000 400

continued on next page

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TABLE 6-2 Continued

146 Case 6-6

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Case 6-7 A New FDA

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Muscle BoNT-A (Units) BoNT-B (Units) BoNT-D (Units)

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Case 6-10 A Lateral head

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incidence of dose-dependent adverse activities of daily living that are most

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Ashford S, Turner-Stokes L. Management of shoulder and proximal upper limb spasticity