In order to receive a certificate for this activity


1. Read the CME information on this page.

2. Review information on the contributor biographies.

3. Go to the module and review the material.

4. Complete the CME Post-Test.

5. Complete the evaluation and registration forms.


A link to your certificate will be e-mailed to you within 24 hours of satisfactory completion of these documents.



CME Information for Muscle Overactivity in the Upper Motor Neuron Syndrome(UMNS)



Upper motor neuron syndrome (UMNS) is a collective term for positive signs (ie, different clinical forms of involuntary muscle overactivity) and negative signs (impaired voluntary movement and motor control) that occur in patients with lesions of the descending corticospinal system. Such lesions may occur in patients with cerebral palsy or multiple sclerosis and in those who have experienced stroke, traumatic brain injury, or spinal cord injury. Patients with UMNS may experience impaired voluntary and involuntary motor activity and interference with limb positioning, along with poor hygiene, pain, abnormal gait, and reduced activities of daily living. Effective treatment often requires integration of a variety of conservative, interventional, and surgical options that are targeted to a specific patient’s functional impairment. Botulinum neurotoxin (BoNT), a recent addition to the treatment armamentarium, has been shown to reduce upper and lower limb spasticity and other forms of muscle overactivity in the UMNS. In 2010, the indication for BOTOX® (onabotulinumtoxinA [BoNT-A]) was expanded by the US Food and Drug Administration (FDA) to include treatment of upper limb spasticity in adults .


Educational Objectives


Upon completion of this activity, participants should be able to:

  • Describe the different types of muscle overactivity associated with UMNS, in order to improve the differential diagnosis of spasticity due to upper motor neuron syndrome (UMNS)
  • Understand the differences between positive and negative signs associated with UMNS and the complications that may occur as a result of these symptoms, in order to facilitate better understanding of the consequences of UMNS among patients and their caregivers
  • Explain the differences in clinical efficacy and safety among the 3 FDA-approved botulinum toxin (BoNT) formulations, in order to support evidence-based treatment decisions by physicians that are considering BoNT treatment for patients with UMNS

  • Identify clinical scenarios that are amenable to treatment with BoNT and describe methods of administration that may enhance the clinical utility of BoNT injection, in order to provide individualized treatment and improve patient outcomes


Target Audience

Neurologists, physiatrists, primary care physicians, physical therapists, speech and language pathologists, and other healthcare professionals involved in the treatment of adult spasticity/upper motor neuron syndrome using neurotoxin therapy.


Method of Participation
To receive a maximum of 1.0 AMA PRA Category 1 Credit(s)™ you should:
• View the presentations in this CME activity and evaluate the content presented
• Complete and submit the post-test, CME registration, and activity evaluation forms


Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Beth Israel Medical Center and Scientiae, LLC. The provider is accredited by the ACCME to provide continuing medical education for physicians.


Credit Designation Statement
Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals designate this online educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Term of Approval

Febuary 2011 through Febuary 2013. Original Release Date: Febuary 2011.


Program Directors


Alberto Esquenazi, MD (bio)
Chair, Department of Physical Medicine and Rehabilitation
Director, Gait & Motion Analysis Laboratory
Albert Einstein Healthcare Network
Elkins Park, Pennsylvania


Nathaniel Mayer, MD
Emeritus Founder & Director
Drucker Brain Injury Center
Director, Motor Control Analysis Laboratory
Albert Einstein Healthcare Network
Emeritus Professor of Physical Medicine and Rehabilitation
Temple University Health Sciences Center
Elkins Park, Pennsylvania


CME Program Reviewer


Susan Bressman, MD
Chairman of the Department of Neurology
Beth Israel Medical Center
Professor of Neurology
Albert Einstein College of Medicine
New York, New York


Disclosure Statement

It is the policy of Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals that faculty and providers disclose real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals have established policies that will identify and resolve all conflicts of interest prior to this educational activity.

This CME activity discusses the off-label use of botulinum neurotoxin.


Alberto Esquenazi, MD

  • Research Grants: Allergan, Inc. 
  • Advisor: Ipsen

Nathaniel Mayer, MD

  • Advisor: Ipsen
  • Interviewer: Allergan, Inc.

Susan Bressman, MD

  • Dr. Bressman has indicated no conflict of interest


Acknowledgement of Support

This activity is jointly sponsored by Beth Israel Medical Center and Scientiae, LLC.



It is supported by an unrestricted educational grant from Allergan, Inc.



Upper motor neuron syndrome (UMNS) is a collective term for positive signs (ie, different clinical forms of involuntary muscle overactivity) and negative signs (impaired voluntary movement and motor control) that occur in patients with lesions of the descending corticospinal system. Such lesions may occur in patients with cerebral palsy or multiple sclerosis and in those who have experienced stroke, traumatic brain injury, or spinal cord injury. Patients with UMNS may experience impaired voluntary and involuntary motor activity and interference with limb positioning, along with poor hygiene, pain, abnormal gait, and reduced activities of daily living. Effective treatment often requires integration of a variety of conservative, interventional, and surgical options that are targeted to a specific patient’s functional impairment. Botulinum neurotoxin (BoNT), a recent addition to the treatment armamentarium, has been shown to reduce upper and lower limb spasticity and other forms of muscle overactivity in the UMNS. In 2010, the indication for BOTOX® (onabotulinumtoxinA [BoNT-A]) was expanded by the US Food and Drug Administration (FDA) to include treatment of upper limb spasticity in adults .


In the upper motor neuron syndrome (UMNS), the negative signs of paresis—impaired dexterity, loss of selective activation and control of limb segments, in part and as a whole—undermine voluntary goal-directed actions.1 Moreover, in many patients with partial neurological recovery, voluntary effort appears to generate obligatory motor behaviors or synergies (ie, relatively fixed movement patterns) that tend to overwhelm or impede the patient's volitional attempts at producing selective activation and functional control of movement (Table 1).2

Table 1. Positive and Negative Motor Signs in the Upper Motor Neuron Syndrome2

Negative signs

  • Weakness
  • Loss of finger dexterity
  • Loss of selective control of limb movement

Positive signs

  • Exaggerated tonic and phasic stretch reflexes
  • Flexor and extensor spasms
  • Co-contraction
  • Associated reactions (synkinesias)
  • Spastic dystonia
  • Increased muscle stiffness that may contribute to contracture formation


Positive signs of the UMNS, characterized by involuntary muscle overactivity, may also impair function and interfere with participation. Involuntary muscle overactivity may be broadly categorized into stretch-sensitive and non-stretch-sensitive clinical phenomena. Among the different types of muscle overactivity and allied phenomena found in UMNS are the following3-5:

Stretch-sensitive phenomena

  • Spasticity (stretch of inactive ‘resting’ muscle leads to exaggerated phasic and tonic stretch reflexes)
  • Spastic dystonia (muscle activity at ‘rest’ that is also sensitive to subsequent stretch)
  • Spastic co-contraction of antagonist muscles during volitional effort

Non-stretch-sensitive phenomena

  • Associated reactions (synkinesias)
  • Increased flexor reflex afferent activity (manifested by increased flexor and extensor spasms)
  • Rheologic tissue changes and contracture (a principal consequence of muscle overactivity and paresis with important clinical implications)

Efferent neural activity from the central nervous system to skeletal muscle produces torque, a force acting through a bony lever arm that generates rotation of a limb segment about its rotational joint axis. In everyday life, agonist and antagonist torques are bidirectional (ie, freely intermixed); as a result, fixed, unidirectional joint postures do not occur. In the UMNS, the combined effects of positive and negative signs lead to a net imbalance of torques about a given joint that is expressed as impediments to dynamic movement and also manifested as static, unidirectional postures. For example, a flexed elbow is a common ‘resting' posture in patients with hemiplegia due to an imbalance of torque favoring flexors over extensors.6

With respect to dynamic movement, efforts to extend an elbow volitionally may be impaired by paresis of the agonist triceps group combined with the restraining effect of involuntary muscle activity of antagonist flexors. Such restraint may derive from spasticity, spastic co-contraction, spastic dystonia, and/or rheologic changes in muscle reflecting increased physical stiffness of the flexors. By forcing joints into undesired static positions or into uncontrolled dynamic movements, the combined effects of positive and negative signs may lead to maladaptive soft tissue and musculoskeletal or movement consequences for the patient.6

Spasticity and other forms of involuntary muscle overactivity are associated with common neurological disorders, including stroke, cerebral palsy, traumatic and hypoxic brain injuries, multiple sclerosis, and spinal cord injury. Within these populations, spasticity, a major form of muscle overactivity, occurs at a variable frequency. While the incidence of spasticity is not known with certainty, the condition likely affects over half a million people in the United States and over 12 million people worldwide.7 The aging population and improvements in acute management of traumatic brain injury (TBI) and stroke will likely increase the prevalence of spasticity.

The National Multiple Sclerosis Society estimates that there are 400,000 cases presently in the United States.8 A review surveyed the best evidence available and estimated the worldwide incidence of multiple sclerosis to be 4.2 cases per 100,000, and the prevalence 0.9 per 1000. In North America, the numbers were somewhat higher, with an estimated incidence of 7. 4 cases per 100,000 and a prevalence of 2.0 per 1000. Both the incidence and prevalence of multiple sclerosis are higher in women than in men.9 An analysis of the North American Research Committee On Multiple Sclerosis (NARCOMS) registry—a cross-sectional database comprising 20,969 patients with multiple sclerosis—revealed the following: 15.7% had no spasticity, 50.3% had minimal to mild spasticity, 17.2% had moderate spasticity, and 16.8% had severe spasticity.10

The estimated annual incidence of first ischemic and hemorrhagic stroke is 183 per 100,000 in the United States, with a prevalence of 2% among those aged 25 to 74 years.9 Some studies have indicated that spasticity affects approximately 35% of stroke patients.11,12 In a 2010 study, 301 patients with clinical signs of paresis due to a first-ever ischemic stroke were examined in the acute stage, and 211 were reassessed after 6 months. Spasticity developed in 42.6% of these patients. More severe spasticity (Modified Ashworth Scale [MAS] ≥3) developed in 15.6% of patients.13

Each year, approximately 795,000 people in the United States experience a new (about 610,000) or recurrent (185,000) stroke.14 The National Center for Injury Prevention and Control (NCIPC) of the Centers for Disease Control and Prevention estimates that the annual incidence of spinal cord injury (SCI) in the US is approximately 11,000,15 and spasticity affects 40% of these patients.16 About 200,000 Americans currently live with a disability related to SCI. The NCIPC estimates that the annual US incidence of TBI is approximately 1.7 million. The majority of these cases are concussions or other forms of mild TBI (ie, a brief change in mental status or consciousness after head injury).15,17 In one inpatient rehabilitation unit, spasticity was found in an estimated 25% of patients with TBI (ie, an extended period of unconsciousness or amnesia after head injury).18


The UMNS results from damage to descending motor pathways at cortical, brainstem, or spinal cord levels.7 The clinical manifestations of UMNS are due to both underactivity (negative signs) and overactivity (positive signs) of the affected muscles.19

Stretch-Sensitive Phenomena
Spasticity refers to a velocity-dependent increase in excitability of phasic and tonic muscle stretch reflexes that is present in many patients with the UMNS. Clinically, the defining characteristic of spasticity is excessive resistance of muscle to passive stretch. In spasticity, normally latent stretch reflexes become obvious; tendon reflexes have a lowered threshold to tap, the response of tapped muscle is increased, and muscles besides the tapped one usually respond; tonic stretch reflexes are similarly affected.3

Hyperactivity of phasic stretch reflexes (exaggerated tendon jerks and clonus) is also considered a spastic phenomenon. Clonus is characterized by repetitive, rhythmic contractions observed in one or more muscles of a single limb segment or multiple limb segments.2

Spasticity depends on muscle stretch, its onset occurring after passive stretch has been initiated by the examiner (ie, after some degree of muscle lengthening has taken place). After an acute lesion, particularly after stroke, muscle tone is often flaccid, with hyporeflexia preceding the appearance of spasticity. The interval between acute lesion and the appearance of spasticity varies from days to months according to the level, severity, and cause of the lesion.7

Other stretch-sensitive phenomena associated with the UMNS hinder effectiveness of residual voluntary motor activity. Co-contraction, characterized by simultaneous activation of agonist and antagonist muscles during a voluntary movement, restrains movement generated by agonist muscles, contributing to a greater sense of effort and fatigability experienced by the patient during volitional movement. Spastic dystonia is characterized by tonic muscle contraction with electromyographic activity at rest in the absence of passive stretch or voluntary effort.2,4,5,20

Non-Stretch-Sensitive Phenomena

There are also non-stretch-sensitive phenomena characteristic of the UMNS. Associated reaction (synkinesis) refers to involuntary activity in one limb that is associated with a voluntary effort made in another limb. Standing up from a chair can elicit an associated reaction in the spastic limb producing, for example, undesired abduction of the shoulder and flexion of the elbow. Associated reactions can severely impact gait, transfers, and other routine activities.1

Flexor reflex afferents (FRAs) include cutaneous receptors (touch, temperature, pressure), nociceptors, group II afferents from muscle spindles, and free nerve endings that are scattered in and around muscles. After entering the spinal cord, FRA activity ascends and descends a number of cord levels so that motor neurons at different levels, controlling muscle groups across different joints, can be activated. In the UMNS, FRA activity is enhanced, resulting in flexor and extensor spasms. Spasms may be triggered by overt or covert stimuli, such as a distended bowel or bladder, an ingrown toenail, or unrelieved skin pressure resulting in unnoticed skin ischemia.6,19 Multijoint spasms triggered by ascending and descending FRA activity in the spinal cord can disturb sleep, wheelchair positioning, and transfers.19

Muscle shortening may occur early after an acute lesion due to a combination of muscle inactivity and improper positioning.4 In the chronic stage, stiffness and fixed limb position may also be due to the increased rheologic (resistive) properties of soft tissues that occur after prolonged involuntary muscle overactivity.3-5

The UMNS Impact on Quality of Life

Patients with upper limb spasticity can develop abnormal limb posturing, such as the classic adducted internally rotated shoulder, flexed elbow, flexed wrist, and clenched fist.3 These positions can make it difficult to wash the axilla, elbow crease, and hand, leading to hygiene problems that in turn can lead to skin maceration, breakdown, and infection. Dressing can also be a challenge because muscle stiffness makes limb manipulation more difficult. When a patient cannot voluntarily use a spastically affected limb, excessive (involuntary) stiffness of muscles—typically, shoulder adductors, elbow, flexors, wrist and finger flexors in the upper limb—often makes it difficult to carry out activities of daily living. For example, some tasks may require the patient to use the unaffected limb to pry open flexed fingers for washing, or to pull a sleeve up and around postured and contorted wrist, elbow and shoulder.6 In some cases, the patient may even need the assistance of another person.21 Impairments in gait and breakdown of tissues surrounding weight-bearing areas are commonly seen in the lower limbs of patients with the UMNS.22 Prolonged posturing can also lead to peripheral nerve injury, chronic pain, and osteoporosis, with the attendant risks of fracture during falls and patient transfers.6


The corticospinal or pyramidal tract is a collection of axons that travel between the cerebral cortex of the brain and the spinal cord. The motor neuron cell bodies in the motor cortex, together with their axons that descend through the brain stem and cord, are referred to as upper motor neurons. The corticospinal tract is concerned specifically with discrete voluntary skilled movements, especially of the distal parts of the limbs. In the spinal cord, the axons of the upper motor neuron connect with lower motor neurons in the ventral horn, most connecting by means of interneurons but some by direct synapse as well. The lower motor neuron axons leave the spinal cord by means of the anterior roots of spinal nerves, terminating at junctions between nerve and muscle tissue (motor endplates) that transmit the signals for motor innervation of voluntary muscles.23

An upper motor neuron lesion, such as occurs with cerebral palsy, stroke, TBI, or SCI, disrupts the corticospinal tract and interferes with the production of voluntary movement, resulting in paresis, the cardinal negative sign of the UMNS, along with impaired selective control of joint motion, especially of the fingers (finger fractionation). A corticospinal lesion may also result in a number of positive UMNS signs that are comprised of different forms of involuntary muscle activity. These signs may be categorized as stretch-sensitive and non-stretch-sensitive in character.19 The term spasticity is appropriately correlated with stretch-sensitive signs such as spastic co-contraction, spastic dystonia, and enhanced tonic and phasic stretch reflexes. Non-stretch-sensitive positive signs include associated reactions and increased FRA activity. One example of FRA activity is the best known neurological sign, pathognomonic of an upper motor neuron lesion, namely, the extensor Babinski response. By definition, non-stretch-sensitive signs are not manifestations of spasticity, though they are reflective of the UMNS.19

The pathophysiological bases of stretch-sensitive and non-stretch-sensitive phenomena are incompletely understood. After a variable period of time, spinal circuits undergo neurophysiological changes in the excitability of motor neurons, interneuronal connections, and local reflex pathways.7 Clinical expressions of muscle overactivity probably result from alterations in the balance of inputs from reticulospinal and other descending pathways to the motor and interneuronal circuits of the spinal cord, and from the absence of an intact corticospinal system.7

Involuntary muscle overactivity characteristic of spinal cord lesions is often marked by a slow increase in excitation and overactivity of both flexors and extensors with reactions spreading many segments away from a segmental stimulus.1,19 Cerebral lesions often cause rapid build-up of excitation with a bias toward involvement of antigravity muscles.3 The excitability of alpha motor neurons is increased, as is suggested by enhanced H-M ratios24 and F-wave amplitudes.25 Recordings from Ia spindle afferents suggest that muscle spindle sensitivity is not increased in human tonic stretch reflexes.26


Clinical description of a patient's physical condition, dysfunction, and status remains the mainstay of patient assessment. Diagnostic nerve blocks and dynamic electromyography (EMG) can be valuable tools to help 1) identify target muscles for treatment; 2) evaluate muscle activity not otherwise detected by clinical examination; and 3) assist in establishing whether clinical postures are attributable to involuntary muscle overactivity or to rheologic phenomena (muscle stiffness and, especially, contracture), or both.19


Identifying Deficits and Treatment Goals
Together, the positive and negative phenomena and rheologic (combined viscoelastic and plastic) properties of muscle and tissues affected by UMNS produce unbalanced forces that ultimately affect patient functionality.3 Understanding the patterns of the UMNS and identifying the contributing muscles can serve as a basis for selecting from among several available treatment strategies, including pharmacotherapy, chemodenervation, and neuro-orthopaedic surgery.1,5 The most common UMNS conditions and the underlying muscle involvement are shown in Table 2.2

Table 2. Upper Motor Neuron Syndrome—>Related Limb Postures and Potentially Involved Muscles2



 Potentially Involved Muscles

 Adducted, internally
 rotated shoulder

 Pectoralis major, teres major,latissimus dorsi,  subscapularis

 Flexed elbow

 Biceps, brachialis, brachioradialis,
 pronator teres

 Pronated forearm

 Pronator teres, pronator quadratus

 Flexed wrist

 Flexor carpi radialis, flexor carpi ulnaris,
 palmarislongus, flexor digitorum
 superficialis, flexor digitorum profundus

 Clenched fist

 Flexor digitorum superficialis,
  flexor digitorum profundus, lumbricals


 Flexor pollicis longus, flexor pollicis
 brevis, adductor pollicis

 Flexed hip

 Iliopsoas, rectus femoris, pectineus,
 adductor longus and brevis

 Adducted h

 Adductor longus, brevis, and magnus,
 gracilis, iliopsoas, pectineus, medial

Stiff (extended) knee

 Rectus femoris, vastus intermedius,
 vastus medialis and lateralis, gluteus

 Flexed knee

 Medial and lateral hamstrings,
 gastrocnemius, gracilis

 Equinovarus foot

 Tibialis anterior and posterior,
 flexor digitorum longus and flexor
 hallucis longus, medial and lateral
 gastrocnemius, soleus

 Striatal (hitchhiker) toe

 Extensor hallucis longus

 Flexed toes

 Flexor digitorum longus and brevis,
 flexor hallucis longus and brevis

 Combination Therapy for UMNS

 Table 3. Key Elements of Management of Muscular Overactivity2

  •  Reduction/elimination of noxious stimuli
  •  Multidisciplinary rehabilitation therapy
  •  Physical therapy
    •  Physiotherapy and exercise programs, promoting:
      •  Muscle stretching
      •  Strengthening
      •  Motor training
    •  Electrical stimulation
  •  Occupational therapy
  •  Promoting functional integration of the extremity
  •  Splinting
  •  Serial casting
  •  Adaptive and orthotic devices
  •  Surgical intervention
  •  Pharmacological therapy
    •  Chemodenervation
    •  Neurolysis
    •  Oral agents
    •  Intrathecal drugs

The most effective treatment strategies for UMNS usually involve a combination of procedures and pharmacological treatments tailored to the needs of the individual patient.2 Treatment options and goals in early and late recovery are listed in Table 3.2 Untreated UMNS may result in contractures, pain, and deformity.27 During the course of early neurological recovery, muscle overactivity rather than rheologic changes in soft tissue is likely to underlie clinical deformity.1 Chemodenervation combined with range-of-motion exercise may be effective for treating focal, deforming muscle overactivity, particularly during the early period of motor recovery.27  

Pharmacological Therapy
Pharmacological options for managing muscle overactivity can be broadly categorized as systemic, regional, or focal treatments. Systemic treatment (agents distributed throughout the central nervous system and body by the cardiovascular system) include oral medications, such as the muscle relaxants baclofen, tizanidine, dantrolene, and diazepam. Oral agents are widely used as first-line treatment of spasticity, with perceived benefits in convenience and cost. However, the potential benefit of systemic medications can be limited by sedation, weakness, and other systemic side effects, as well as falls and fractures.28-30

Regional treatment includes intrathecally delivered medications such as baclofen and morphine, leading to effects on regional structures (eg, lower trunk, lower limb, and bladder musculature). Multisegmental treatment with botulinum neurotoxin (BoNT) also can be included in this group

Focal treatment—ie, effects narrowed to muscles creating dynamic joint deformities—can be achieved by using neurolytic agents such as phenol and alcohol, and more recently with chemodenervation agents such BoNT.

To enhance clinical guidance of focal treatments, nerve and muscle localization can be achieved using EMG, electrical stimulation, or ultrasound techniques.31 Ultrasound has utility in localizing deep muscles and in identifying surrounding regions, such as lung tissue and vasculature, in high-risk locations.32

Chemodenervation with BoNT via intramuscular injection has been shown to be a safe and effective treatment for focal and multifocal muscle overactivity in patients of different etiologies with the UMNS.33,34 By reducing focal muscle activity, BoNT may provide a therapeutic window for clinicians to address a variety of passive and active function issues.32,35

Chemodenervation and phenol neurolysis that mitigate underlying muscle overactivity combined with serial casting or progressive splinting may be helpful in the chronic stage of the UMNS, when stiffness and fixed limb position have occurred after prolonged involuntary muscle overactivity. In well-advanced contracture, tonic and phasic reflex activity is often reduced. Postural deformity associated with severe muscle contractures and the now reduced underlying muscle activity does not respond well to pharmacotherapy or chemodenervation but may improve with surgery and other physical interventions.19

Phenol neurolysis is typically injected into motor nerves of large proximal muscles to avoid sensory dysesthesia. Phenol is inexpensive compared with BoNT and is highly specific in its effect on muscles innervated by the injected motor nerve. Moreover, large proximal muscles typically require large amounts of BoNT so that the upper limit of BoNT dosing may be reached before all treatment needs of a patient are met.36

It may be prudent to administer phenol to large proximal muscles when total BoNT dosing for many smaller distal muscles is likely to approach its upper limit. Phenol is technically more difficult to administer because the injector has to hone in skillfully on a motor nerve using iterative electrical stimulation.37 Such a technique works poorly in uncooperative patients or severely dystonic patients whose contractile tension obscures the effect of the injector’s twitch technique.

Phenol neurolysis has the potential for sensory disorders, although incidence appears to be <10% and effects do not last long with treatment. It is that it is chemically destructive of soft tissues, leading to inflammatory reaction and fibrosis. Partial long-term damage of nerve and muscle tissue can occur (an effect that may or may not be clinically useful) and successive phenol blocks may lead to fibrosis extensive enough to prevent use of surgical or other interventions.37 

Oral and intrathecal agents may be more effective than BoNT for mass flexor movements. Temporary block of peripheral nerves using local anesthetics such as lidocaine or bupivacaine can be used to facilitate serial casting or to evaluate the functional impact of relaxing an overactive muscle.19

Evaluating Outcomes
Clinical and physiological outcomes that reflect changes in muscle overactivity and spasticity have been categorized and discussed by Elovic et al.38 The development of outcome measures in UMNS has been hampered by difficulty in developing objective measures of activities of daily living and personal care that are sensitive to the effects of treatment for the positive signs of the UMNS. The Ashworth Scale and MAS, validated assessments of muscle resistance with good inter-rater reliability for the elbow flexors, have been commonly used in BoNT clinical trials.38 However, changes in resistance to passive movement of antagonist muscles do not consistently correlate with changes in active function of their companion agonist muscles that may be exhibiting the UMNS negative sign of weak volition.39
The impact of reductions in muscle tone can also vary widely among patients, yielding inconsistent benefit.40 A number of functional scales have been used in spasticity-treatment trials. Broad scales of global function may not be sensitive to small but meaningful changes that are important to the patient.40 The Disability Assessment Scale is an ordinal self-report instrument that measures change in target tasks chosen by the subject and the investigator from among the areas of hygiene, dressing, pain, and limb positioning.39 However, the Disability Assessment Scale was originally created for research purposes and has not been widely used in the clinical setting.

BoNT is used clinically to suppress muscle contraction associated with a number of conditions, including cervical dystonia and other movement disorders, the UMNS, and facial wrinkles (rhytids) known as glabellar lines.41 Seven serotypes of BoNT have been identified and are designated A–G. Only serotypes A and B are currently used clinically; other serotypes of BoNT are currently being evaluated in clinical trials.42

Table 4 lists the names and indications of the three FDA-approved BoNT-A formulations—onabotulinumtoxinA (BOTOX®), abobotulinumtoxinA (Dysport™), and incobotulinumtoxinA (Xeomin®)—as well as the one FDA-approved BoNT-B formulation, rimabotulinumtoxinB (Myobloc®). All four formulations are FDA approved for the treatment of cervical dystonia in adults. Only one formulation, onabotulinumtoxinA, is FDA approved for the treatment of spasticity; specifically, onabotulinumtoxinA is indicated for the treatment of upper limb spasticity in adults, to decrease the severity of increased muscle tone in elbow, wrist, and finger flexors.43

Different BoNT preparations vary in potency and duration. Existing data indicate that BoNT-A has a longer duration of effect than BoNT-B.44 Within BoNT-A brands, there are differences in potency among onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA that require differences in dosages.39,45 Given the variability in response, it is essential that dosing of BoNT preparations be individualized.39

Table 4. FDA-approved Botulinum Neurotoxins (BoNTs)



BoNT Product FDA-approved Indication(s)


Initial FDA approval: 1989



Initial FDA


  • Strabismus in patients ≥12 years of age*
  • Blepharospasm associated with dystonia in patients ≥12 years of age*
  • -------------------------------------------------------------------------

  • Cervical dystonia in adults, to reduce the severity of abnormal head position and neck pain 
  • Severe primary axillary hyperhidrosis (excessive sweating) that is inadequately managed by topicals in adults 
  • Upper limb spasticity in adults, to decrease the severity of increased muscle tone in elbow, wrist, and finger flexors 
  • Chronic migraine, for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer)

Initial FDA approval: 2002

Botox® Cosmetic
  • Temporary improvement in the appearance of moderate to severe glabellar lines in adult patients ≤65 years of age*

Initial FDA approval: 2009

  • Cervical dystonia in adults, to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients*
  • Temporary improvement in the appearance of moderate to severe glabellar lines in adult patients ‹65 years of age*

Initial FDA approval: 2010

  • Cervical dystoniain adults,to reduce the severity of abnormal head position and neck pain in both toxin-naïve and reviously treated patients*
  • Blepharospasm in adults previously treated with onabotulinumtoxinA*

Initial FDA approval: 2010

  • Cervical dystonia in adults, to reduce the severity of abnormal head position and neck pain*

* First FDA-approved indication

Note: Only BoNT serotypes A and B have been approved by the FDA for clinical use.

Appropriate Use of BoNT

BoNT has been widely used as a treatment for muscle overactivity, yielding some general guidance on which groups of muscles may benefit from treatment with BoNT injections.2

Figure 1. Common injection sites and potential target muscles in spasticity treatment.2


Both a 2008 consensus report by the American Academy of Neurology (AAN)39 and a 2010 international consensus statement35 reviewed BoNTs as a class for the treatment of spasticity. Among the conclusions was that the evidence supports BoNT as a treatment option to reduce muscle tone and improve passive function in adults with spasticity (level A), and it may also improve active function (level B).39* An analysis of data from subjects with poststroke spasticity found consistently favorable effects on upper extremity spasticity with BoNT-A but not BoNT-B.46 In patients with lower extremity spasticity, most studies have demonstrated efficacy of BoNT-A in reducing muscle tone.39 Studies thus far have failed to demonstrate efficacy in lower limb spasticity, particularly walking speed, with BoNT-A or BoNT-B.46-49

[FOOTNOTE] *According to the AAN classification of recommendations for clinical care, level A treatments should be offered and level B treatments should be considered.39

Patients must be aware of the nature and onset of BoNT-induced changes. In particular, they must understand that the effects of medication may not become apparent until 5 to 7 days after injection, with peak effect occurring after 2 to 6 weeks. The duration of effect depends on the type of toxin, dose, muscle, and severity of the spasticity but is typically 3 to 6 months.19 BoNT may be re-administered when the effect wears off and the original clinical problem redevelops. At the present time, clinical consensus is not to reinject BoNT before 90 days have elapsed from a previous injection.41 Clinical data have demonstrated that improvements in upper50-52 and lower53 limb spasticity are maintained with repeated injection.

Most clinical trials of BoNT in the treatment of upper-extremity spasticity in adults have emphasized changes in resistance to passive movement (muscle tone). In these trials, reduction in tone has been fairly consistent with BoNT; however, functional benefits have been more difficult to assess.29 Patient- and caregiver-assessed improvements in daily function have been shown following BoNT injection in the spastic upper limb.39 Some of these changes, such as easier nursing care and better comfort when sitting in a wheelchair, may be more subtle or difficult to define for measurement purposes, yet are certainly important to patients and caregivers.54

With respect to voluntary movement, it is well known that agonist muscle strength is variable, ie, some agonists are weak, generating little active movement, while others are stronger (but not normal), sometimes capable of generating active movement and sometimes restrained by overactive antagonists from generating active movement. Therefore, it has been difficult to prove that BoNT has a significant impact on voluntary functional movement, since good residual agonist strength combined with antagonist restraint of active movement are probably the necessary ingredients for the indirect effect of BoNT on voluntary movement after BoNT injection of antagonist muscles loosens their restraint of active movement.29 While active (ie, voluntary) functional improvement with BoNT is reported in case series and frequently observed in clinical practice, proper patient selection is of key importance for the issue of voluntary movement enhancement, and there is also no consensus on appropriate outcome measures for active function.39 The Physician Global Rating Scale together with the Disability Assessment Scale to assess the benefits of BoNT has been shown to reduce the spasticity of wrist and finger muscles and improve associated disability.55

BoNT Injection Technique
Muscle identification, dose, and dilution of BoNT, proper injection technique, and follow-up therapy are essential to maximize the effectiveness of BoNT injections. Electrical stimulation and EMG devices are useful for localizing the muscles and guiding needle positioning at the time of BoNT injection. Ultrasound or fluoroscopy can be used for localizing deeper muscles such as the psoas. A number of researchers recommend the use of electrical stimulation, EMG, or ultrasound as guidance techniques to identify muscles and guide BoNT injections. In some studies, EMG-guided injection has been associated with improved clinical results.56-58 The FDA recommends electromyographic guidance or nerve stimulation techniques to localize involved muscles when using Botox®.43

Patients with the UMNS often require injection into multiple target muscles. It is important, therefore, to stay within accepted limits for total-body BoNT dose.59,60 The lowest effective dose should be used to achieve the desired outcome and, except in select situations, an interval between injections of at least 90 days is recommended.  

Various dilutions of BoNT-A have been described in the literature (20-25 to 50-100 units/mL for onabotulinumtoxinA; 250 or 500 Units/mL for abobotulinumtoxinA, with preliminary evidence suggesting an enhanced effect with a more dilute preparation.)43,61,62 Smaller muscles can be injected in 1 or 2 sites, whereas multiple injection sites have been suggested for large muscles.63 A recent study supports a low-dose, high-dilution strategy as having a role in reducing drug cost and total body dose.59 Describing a study that used high-volume, low-dose injections for spasticity of elbow flexors, the investigators reported similar outcomes on three different measures of hypertonia (root mean square EMG, Ashworth scores, Tardieu catch angle) when using either a single motor point or a multisite distributed injection technique. Noting good effects on all three measures of hypertonia, the authors argued that “atypical” lower doses, higher volumes, and greater dilutions of onabotulinumtoxinA could provide clinicians with greater treatment flexibility when cost was an issue or when treatment of many muscles with “typical” doses could have reached maximum total-body dose above clinically recommended limits. Other factors to consider include the severity of muscle overactivity, the presence of contracture, age and body mass, and prior response to treatment, and other concurrent therapies (see Table 4).62

BoNT Outcome Data
Numerous publications have documented the utility of onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA in the management of spasticity; however, limited efficacy in spasticity has been shown with rimabotulinumtoxinB.32 Of the four BoNT preparations available in the United States, only onabotulinumtoxinA is approved by the FDA for the treatment of spasticity (see Table 4).

Note: Only BoNT serotypes A and B have been approved by the FDA for clinical use.

OnabotulinumtoxinA was approved in March 2010 for the treatment of upper limb spasticity in adult patients. Specifically, BOTOX® can be used to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis).43

In a 12-week, multicenter, double-blind, placebo-controlled study,55 onabotulinumtoxinA was evaluated in 126 stroke patients with increased flexor tone in the wrist and fingers who received either placebo or onabotulinumtoxinA (200 to 240 U) in four wrist and finger muscles (50 U per muscle) and, possibly, thumb muscles (20 U per muscle). At all follow-up visits (weeks 1, 4, 6, 8, and 12), patients receiving onabotulinumtoxinA had significantly greater improvements in flexor tone in treated muscles compared with patients given placebo. Patients treated with onabotulinumtoxinA also had significantly greater improvements in their principal therapeutic intervention targets (at weeks 4, 6, 8, and 12) and a significantly greater increase was observed in the proportion reporting an improvement of ≥ 1point in Disability Assessment Scale scores at week 6. No major adverse events were associated with treatment.55 In an open-label, follow-up study of this treatment cohort, repeated administration of onabotulinumtoxinA was associated with sustained improvements in wrist, finger, and thumb flexor tone, as well as patient function, particularly as it relates to Disability Assessment Scale scores for hygiene and limb position.51

A prospective, open-label study measured the effect of upper limb botulinumtoxinA injections on walking velocity in 15 patients with hemiparesis attributable to stroke or TBI. Walking data were obtained before and 2 to 12 weeks after injections (120 to 200 total units to the affected biceps, brachialis, and/or brachioradialis at the investigator’s discretion). The onabotulinumtoxinA group demonstrated a statistically significant increase in comfortable walking velocity, from 0.56 m/sec before treatment to 0.63 m/sec after treatment; no significant change was seen in an untreated control group. Mean elbow MAS was also significantly reduced.64

In 2009, Simpson, Gracies, et al reported a placebo-controlled trial comparing the effects of onabotulinumtoxinA versus tizanidine in adults with acquired upper limb spasticity. They reported significant improvements as reflected in MAS score in fingers and wrist flexors with onabotulinumtoxinA but not with oral tizanidine. Significantly greater improvements in cosmesis were also seen with onabotulinumtoxinA compared with tizanidine or placebo, whereas adverse events were significantly higher with tizanidine.28

AbobotulinumtoxinA (Dysport™) was granted approval by the FDA in April 2009 for the treatment of adults with cervical dystonia (see Table 4). Although abobotulinumtoxinA is not currently FDA approved for the treatment of spasticity, clinical trials continue, and positive clinical trial results have been reported.42

In a 16-week, randomized, multicenter, placebo-controlled trial, 59 patients with post-stroke spasticity of the elbow, wrist, and finger flexors received placebo or 1000 IU of abobotulinumtoxinA into five muscles of the affected arm: biceps brachii (300 to 400 IU), flexor digitorum superficialis (150 to 250 IU), and the flexor digitorum profundus/flexor carpi ulnaris/flexor carpi radialis (150 IU into each). Muscle tone was assessed using the MAS. Subjects treated with abobotulinumtoxinA demonstrated significant improvement versus placebo on the primary efficacy outcome, defined as the week 4 change in MAS in the target area (elbow, wrist, or finger joint) with the best response. Mean change in wrist and finger, but not elbow, MAS over weeks 0 to 16 was significantly greater in the abobotulinumtoxinA-treated group. Global improvement was reported by 92.3% and 50% of patients treated with abobotulinumtoxinA and placebo, respectively. No significant differences in active or passive range of motion, pain, or Barthel’s index score were seen at week 4 (the primary end point). No safety concerns were noted.65

BoNT Safety
OnabotulinumtoxinA has an acceptable safety profile for treatment of patients with focal spasticity following stroke, a population in which adverse events and comorbidities are common.66 In spasticity studies, the most common adverse events were pain in an extremity, bronchitis, fatigue, and nausea.67 The FDA had established the safety and effectiveness of onabotulinumtoxinA for the treatment of upper limb spasticity involving elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis).67 Safety and efficacy have not been established for the treatment of other upper limb  muscle groups, the treatment of lower limb spasticity, or the treatment of spasticity in pediatric patients under age 18 years. Patients with compromised respiratory function should be monitored closely when treated with onabotulinumtoxinA for spasticity, as a study showed increased event rate in change of forced vital capacity for such patients compared with patients treated with placebo, and bronchitis and upper respiratory tract infections were reported more frequently in patients with reduced lung function treated with onabotulinumtoxinA compared with placebo.67

A pooled analysis of data from nine studies (534 patients and 258 controls) of onabotulinumtoxinA for post-stroke spasticity showed that only nausea occurred significantly more often in the treatment group than in the placebo group.66

No other formulation of BoNT is FDA approved, although clinical studies have been reported with data on safety.

In one study of 51 spasticity patients receiving abobotulinumtoxinA, 24% of patients experienced adverse events related to BoNT; all were mild to moderate and none was life threatening. The most common adverse events were pain at the injection site, fatigue, and dysphagia.50

In a randomized, placebo-controlled trial of 73 patients receiving incobotulinumtoxinA for the treatment of post-stroke upper limb spasticity and 75 receiving placebo, there was no significant difference in the incidence of adverse events between the treatment and placebo groups. Tolerability was rated as “good” or “very good” in 96.7% of all patients, with no significant difference between the treatment and placebo groups. One adverse event of special interest, a case of nasopharyngitis, occurred in the treatment group. Follow-up was 12-20 weeks.68

In one study, 8 of 9 patients treated with rimabotulinumtoxinB for upper limb post-stoke spasticity experienced dry mouth. In an open-label follow-up, 10 of 13 patients experienced dry mouth; all cased resolved by 12 weeks. One death occurred that did not appear to be treatment related.69

In 2009, the FDA began requiring a boxed warning for all botulinum neurotoxin products because of postmarketing reports of distant spread of toxin effects. Symptoms may appear hours to weeks after injection, and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. Difficulty breathing and swallowing may be life threatening, and deaths have been reported. The risk is probably greatest in children treated for spasticity, but may also occur in adults.43,61,70-72

The FDA has also recommended that healthcare professionals understand that dosage strength expressed in ‘Units’ is different among the BoNT formulations, and that clinical doses are not interchangeable from one product to another.42 Units of biological activity of one BoNT formulation cannot be compared with or converted to units of another.43,61,70-72

OnabotulinumtoxinA and Physical and Occupational Therapy
Strengthening of the opposing muscles—coupled with aggressive stretching of the injected muscles and functional retraining with the aid of a therapist—is of great importance in ensuring that patients derive the most benefit from onabotulinumtoxinA treatment for muscle overactivity. An integrated treatment pathway that combines onabotulinumtoxinA with serial casting, splinting, taping, bracing, and other physical manipulation may provide significant benefits in spasticity, function, limb posture, pain, and attainment of treatment goals.67,73-76 Electrical stimulation of agonist and antagonist muscles may also enhance the effectiveness of onabotulinumtoxinA injections22,77 and, in particular, improve the benefit on walking speed after calf muscle injection.78


  1. 1. Mayer NH, Esquenazi A: Muscle overactivity and movement dysfunction in the upper motoneuron syndrome. Phys Med Rehabil Clin N Am 14:855-83, vii-viii, 2003<
  2. 2. Neurotoxin Institute: A Multispecialty Guide to the Use of Botulinum Neurotoxins, rev ed. New York, NY, Neurotoxin Institute, 2009
  3. 3. Mayer NH: Clinicophysiologic concepts of spasticity and motor dysfunction in adults with an upper motoneuron lesion. Muscle Nerve Suppl 6:S1-13, 1997
  4. 4. Gracies JM: Pathophysiology of impairment in patients with spasticity and use of stretch as a treatment of spastic hypertonia. Phys Med Rehabil Clin N Am 12:747-68, vi, 2001
  5. 5. Sheean G: Botulinum toxin treatment of adult spasticity. Expert Rev Neurother 3:773-85, 2003
  6. 6. Mayer N, Esquenazi A: Upper limb skin and musculoskeletal consequences of the UMNS, in Jankovic J, Hallett M, Alassi M, et al (eds): Botulinum Toxin, Therapeutic Clinical Practice & Science. New York, NY, Elsevier Health Sciences, 2009
  7. 7. Vanek Z, Menkes J: Spasticity. Medscape Web site. Accessed April 29, 2010.
  8. 8. National Multiple Sclerosis Society: Epidemiology of MS. Accessed November 20, 2010
  9. 9. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al: How common are the "common" neurologic disorders? Neurology 68:326-37, 2007
  10. 10. Rizzo MA, Hadjimichael OC, Preiningerova J, et al: Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler 10:589-95, 2004
  11. 11. Watkins CL, Leathley MJ, Gregson JM, et al: Prevalence of spasticity post stroke. Clin Rehabil 16:515-22, 2002
  12. 12. Welmer AK, von Arbin M, Widen Holmqvist L, et al: Spasticity and its association with functioning and health-related quality of life 18 months after stroke. Cerebrovasc Dis 21:247-53, 2006
  13. 13. Urban PP, Wolf T, Uebele M, et al: Occurence and clinical predictors of spasticity after ischemic stroke. Stroke 41:2016-20, 2010
  14. 14. Lloyd-Jones D, Adams R, Carnethon M, et al: Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119:480-6, 2009
  15. 15. Centers for Disease Control and Prevention: Spinal Cord Injury (SCI): Fact Sheet. Accessed August 23, 2010.
  16. 16.Noreau L, Proulx P, Gagnon L, et al: Secondary impairments after spinal cord injury: a population-based study. Am J Phys Med Rehabil 79:526-35, 2000
  17. 17. Department Visits, Hospitalizations and Deaths 2002–2006. Accessed August 23, 2010
  18. 18. Elovic E, Zafonte R: Spasticity management in traumatic brain injury. State Art Rev Rehabil 15:327-348, 2001
  19. 19. Mayer N, Esquenazi A: Muscle overactivity in the upper motor neuron syndrome. Asia Pacific Neurotoxin Institute Web site. Accessed June 5, 2010
  20. 20. Mayer NH, Herman RM: Phenomenology of muscle overactivity in the upper motor neuron syndrome. Eura Medicophys 40:85-110, 2004
  21. 21. Sheean GL: Botulinum treatment of spasticity: why is it so difficult to show a functional benefit? Curr Opin Neurol 14:771-6, 2001
  22. 22. Esquenazi A, Mayer N: Clinical experience and recent advances in the management of gait disorders with botulinum neurotoxin, in Jankovic J, Hallett M, Alassi M, et al (eds): Botulinum Toxin, Therapeutic Clinical Practice & Science. New York, NY, Elsevier Health Sciences, 2009
  23. 23. Berne R, Levy M: Principles of Physiology, 3rd ed. St. Louis, Mosby, Inc, 2000
  24. 24. Angel RW, Hofmann WW: The H reflex in normal, spastic, and rigid subjects. Arch Neurol 9:591-6, 1963
  25. 25. Eisen A, Odusote K: Amplitude of the F wave: a potential means of documenting spasticity. Neurology 29:1306-9, 1979
  26. 26. Hagbarth KE, Wallin G, Lofstedt L: Muscle spindle responses to stretch in normal and spastic subjects. Scand J Rehabil Med 5:156-9, 1973
  27. 27. Esquenazi A, Mayer NH, Elia AE, et al: Botulinum toxin for the management of adult patients with upper motor neuron syndrome. Toxicon 54:634-8, 2009
  28. 28. Simpson DM, Gracies JM, Yablon SA, et al: Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study. J Neurol Neurosurg Psychiatry 80:380-5, 2009
  29. 29. Gracies JM, Nance P, Elovic E, et al: Traditional pharmacological treatments for spasticity. Part II: General and regional treatments. Muscle Nerve Suppl 6:S92-120, 1997
  30. 30. Esquenazi A: Falls and fractures in older post-stroke patients with spasticity: consequences and drug treatment considerations. Clinical Geriatrics 12:27-35, 2004
  31. 31. Schroeder AS, Berweck S, Lee SH, et al: Botulinum toxin treatment of children with cerebral palsy — a short review of different injection techniques. Neurotox Res 9:189-96, 2006
  32. 32. Elovic EP, Esquenazi A, Alter KE, et al: Chemodenervation and nerve blocks in the diagnosis and management of spasticity and muscle overactivity. PM R 1:842-51, 2009
  33. 33. McGuire JR: Effective use of chemodenervation and chemical neurolysis in the management of poststroke spasticity. Top Stroke Rehabil 8:47-55, 2001
  34. 34. Khot A, Sloan S, Desai S, et al: Adductor release and chemodenervation in children with cerebral palsy: a pilot study in 16 children. J Child Orthop 2:293-9, 2008
  35. 35. Esquenazi A, Novak I, Sheean G, et al: International consensus statement for the use of botulinum toxin treatment in adults and children with neurological impairments—introduction. Eur J Neurol 17 Suppl 2:1-8, 2010
  36. 36. Gracies JM, Elovic E, McGuire J, et al: Traditional pharmacological treatments for spasticity. Part I: Local treatments. Muscle Nerve Suppl 6:S61-91, 1997
  37. 37. Horn L, Singh G, Dabrowski E: Chemoneurolysis with phenol and alcohol: A "dying art" that merits revival, in Brashear A, Elovic E (eds): Spasticity: Diagnosis and Management. New York, NY, demosMEDICAL, 2011
  38. 38. Elovic EP, Simone LK, Zafonte R: Outcome assessment for spasticity management in the patient with traumatic brain injury: the state of the art. J Head Trauma Rehabil 19:155-77, 2004
  39. 39. Simpson DM, Gracies JM, Graham HK, et al: Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70:1691-8, 2008
  40. 40. Brashear A, Lambeth K: Spasticity. Curr Treat Options Neurol 11:153-61, 2009
  41. 41. Esquenazi A: Botulinum toxin in the treatment of lower limb spasticity, in Brashear A, Elovic E (eds): Spasticity: Diagnosis and Management. New York, NY, demosMEDICAL, 2011
  42. 42. Brashear A: Botulinum toxin in the treatment of upper limb spasticity, in Brashear A, Elovic E (eds): Spasticity: Diagnosis and Management. New York, NY, demosMEDICAL, 2011
  43. 43. BOTOX (onabotulinumtoxinA) prescribing information. Irvine, CA: Allergan, Inc.,
  44. 44. Albanese A, Bentivoglio A: Botulinum toxin in movement disorders, in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders, ed 5. Philadelphia, PA, Lippincott Williams & Wilkins, 2007, pp 605-619
  45. 45. Hunt T, Clarke K: Potency evaluation of a formulated drug product containing 150-kd botulinum neurotoxin type A. Clin Neuropharmacol 32:28-31, 2009
  46. 46. Elia AE, Filippini G, Calandrella D, et al: Botulinum neurotoxins for post-stroke spasticity in adults: a systematic review. Mov Disord 24:801-12, 2009
  47. 47. 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 61:265-9, 1996
  48. 48. Richardson D, Sheean G, Werring D, et al: Evaluating the role of botulinum toxin in the management of focal hypertonia in adults. J Neurol Neurosurg Psychiatry 69:499-506, 2000
  49. 49. 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 39:2803-8, 2008
  50. 50. 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 75:1558-61, 2004
  51. 51. Gordon MF, Brashear A, Elovic E, et al: Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 63:1971-3, 2004
  52. 52. Elovic EP, Brashear A, Kaelin D, et al: Repeated treatments with botulinum toxin type a produce sustained decreases in the limitations associated with focal upper-limb poststroke spasticity for caregivers and patients. Arch Phys Med Rehabil 89:799-806, 2008
  53. 53. Catz A, Barkol H, Steinberg F, et al: Repeated botulinum toxin injections can improve mobility in patients with spinal cord lesions. Eura Medicophys 43:319-25, 2007
  54. 54. Snow BJ, Tsui JK, Bhatt MH, et al: Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol 28:512-5, 1990
  55. 55. Brashear A, Gordon MF, Elovic E, et al: Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 347:395-400, 2002
  56. 56. Chin TY, Nattrass GR, Selber P, et al: Accuracy of intramuscular injection of botulinum toxin A in juvenile cerebral palsy: a comparison between manual needle placement and placement guided by electrical stimulation. J Pediatr Orthop 25:286-91, 2005
  57. 57. Molloy FM, Shill HA, Kaelin-Lang A, et al: Accuracy of muscle localization without EMG: implications for treatment of limb dystonia. Neurology 58:805-7, 2002
  58. 58.Cordivari C, Misra VP, Vincent A, et al: Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test. Mov Disord 21:1737-41, 2006
  59. 59. Mayer NH, Whyte J, Wannstedt G, et al: Comparative impact of 2 botulinum toxin injection techniques for elbow flexor hypertonia. Arch Phys Med Rehabil 89:982-7, 2008
  60. 60. Gormley ME, Jr., O'Brien CF, Yablon SA: A clinical overview of treatment decisions in the management of spasticity. Muscle Nerve Suppl 6:S14-20, 1997
  61. 61. Dysport (abobotulinumtoxinA) prescribing information. Wrexham, UK: Ipsen Biopharm Ltd.
  62. 62. Francisco GE: Botulinum toxin for post-stroke spastic hypertonia: a review of its efficacy and application in clinical practice. Ann Acad Med Singapore 36:22-30, 2007
  63. 63. Brin MF: Dosing, administration, and a treatment algorithm for use of botulinum toxin A for adult-onset spasticity. Spasticity Study Group. Muscle Nerve Suppl 6:S208-20, 1997
  64. 64. Esquenazi A, Mayer N, Garreta R: Influence of botulinum toxin type A treatment of elbow flexor spasticity on hemiparetic gait. Am J Phys Med Rehabil 87:305-10; quiz 311, 329, 2008
  65. 65. Bakheit AM, Pittock S, Moore AP, et al: A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. Eur J Neurol 8:559-65, 2001
  66. 66. Turkel C, Bowen B, Liu J, et al: Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity. Arch Phys Med Rehabil 87:786-792, 2006
  67. 67. Ashford S, Turner-Stokes L: Management of shoulder and proximal upper limb spasticity using botulinum toxin and concurrent therapy interventions: a preliminary analysis of goals and outcomes. Disabil Rehabil 31:220-6, 2009
  68. 68. Kanovsky P, Slawek J, Denes Z, et al: Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity. Clin Neuropharmacol 32:259-65, 2009
  69. 69. Brashear A, McAfee AL, Kuhn ER, et al: Botulinum toxin type B in upper-limb poststroke spasticity: a double-blind, placebo-controlled trial. Arch Phys Med Rehabil 85:705-9, 2004
  70. 70. Myobloc (rimabotulinumtoxinB) prescribing information. South San Francisco, CA: Solstice Neurosciences, Inc.,
  71. 71. Xeomin (incobotulinumtoxinA) prescribing information. Greensboro, NC: Merz, LLC,
  72. 72. BOTOX Cosmetic (onabotulinumtoxinA) prescribing information. Irvine, CA: Allergan, Inc.
  73. 73.Baricich A, Carda S, Bertoni M, et al: A single-blinded, randomized pilot study of botulinum toxin type A combined with non-pharmacological treatment for spastic foot. J Rehabil Med 40:870-2, 2008
  74. 74. Farina S, Migliorini C, Gandolfi M, et al: Combined effects of botulinum toxin and casting treatments on lower limb spasticity after stroke. Funct Neurol 23:87-91, 2008
  75. 75. Lai JM, Francisco GE, Willis FB: Dynamic splinting after treatment with botulinum toxin type-A: a randomized controlled pilot study. Adv Ther 26:241-8, 2009
  76. 76. Sun SF, Hsu CW, Sun HP, et al: Combined botulinum toxin type A with modified constraint-induced movement therapy for chronic stroke patients with upper extremity spasticity: a randomized controlled study. Neurorehabil Neural Repair 24:34-41, 2010
  77. 77. Frasson E, Priori A, Ruzzante B, et al: Nerve stimulation boosts botulinum toxin action in spasticity. Mov Disord 20:624-9, 2005
  78. 78. Johnson CA, Burridge JH, Strike PW, et al: The effect of combined use of botulinum toxin type A and functional electric stimulation in the treatment of spastic drop foot after stroke: a preliminary investigation. Arch Phys Med Rehabil 85:902-9, 2004

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