Overview
Introduction
Dystonia is a disorder characterized by involuntary sustained muscle contractions resulting in twisting and repetitive movements or abnormal postures. Classification of dystonia is based on age of onset, body distribution, temporal pattern, and presence or absence of associated symptoms. Several types of dystonia based on bodily distribution have been described, including focal, segmental, hemidystonia, multifocal, and generalized dystonia. [1] Despite an incomplete understanding of the neurological mechanisms underlying dystonia, botulinum toxin (BTX) has proven to provide relief of dystonic posturing associated with pain and discomfort. Since the introduction of BTX therapy in the late 1980s, it has become the standard therapy for focal dystonia. Efficacy is determined by muscle selection and adequate dosing. BTX has been proven as an effective and safe long-term treatment option for dystonia. [2]
BTX is one of the most potent biologic substances known. The seven distinct serotypes, A, B, C, D, E, F, and G, are of similar sizes and structures. However, the serotypes differ in their potency, duration of action, and cellular target sites. Types A and B have proven safe and effective in double-blind clinical trials for dystonia treatment. One formulation of BTX-A is marketed worldwide under the name BOTOX® (Allergan Inc.) and another in Europe as Dysport (Speywood, UK). BOTOX® was approved in December 1989 by the US Food and Drug Administration (FDA) for "the treatment of strabismus, blepharospasm, and focal spasms including hemifacial spasm" and more recently for the treatment of cervical dystonia. Since then it has been widely used in neurology, urology, gastroenterology, and neuro-rehabiliation in pain management.
A formulation of BTX-B was approved in December 2000 by the FDA for the treatment of cervical dystonia. It is marketed under the name Myobloc in the United States and Neurobloc in Europe (Elan Pharmaceuticals). Based on 2016 AAN guidelines, there is Level A (effective) evidence for the use of specific serotypes of BTX in cervical dystonia, upper and lower limb spasticity, and chronic migraines, and Level B evidence in blepharospasm.
In addition to this, a new mosaic-type toxin known as BoNT/HA (also termed BoNT FA or H) was reported. BoNT/HA has 84% identical receptor binding domain (Hc) of BoNT/A but responds differently to some potent BoNT/A neutralizing antibodies. [3, 4]
The clinician must recognize that the various commercial formulations of BTX differ in the dosages used clinically owing to differences in potency and diffusion (see next 2 sections).
The various botulinum toxins possess individual potencies, and care is required to ensure proper use and avoid medication errors. Recent changes to the established drug names were intended to reinforce these differences and prevent medication errors. The products and their approved indications include the following:
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OnabotulinumtoxinA (Botox, Botox Cosmetic)
Botox - Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm, upper and lower limb spasticity (adults), upper limb spasticity (children 2 y or older), overactive bladder, urinary incontinence, migraine headache
Botox Cosmetic - Moderate-to-severe glabellar lines, lateral canthal lines
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AbobotulinumtoxinA (Dysport) - Upper and lower limb spasticity (adults), lower limb spasticity (children 2 y or older), cervical dystonia, and moderate-to-severe glabellar lines in adults; it is also indicated for lower limb spasticity in children aged 2 years or older
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IncobotulinumtoxinA (Xeomin) - Cervical dystonia, blepharospasm, upper limb spasticity (adults), glabellar lines
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RimabotulinumtoxinB (Myobloc) - Cervical dystonia
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DaxibotulinumtoxinA (Daxxify) - Cervical dystonia
Botulinum toxin type A
BTX proteins have been studied since the early 1900s, initially to gain an understanding of botulism, a form of food poisoning. Later, they were studied because of the unique and specific muscle paralysis induced by minute amounts of the toxins. During the past 30 years of work on the use of the toxin for human treatment, selective procedures for the production, purification, and dispensing of the toxin have been developed to make it suitable for injection. Today BTX-A is employed and considered safe and effective for the treatment of movement disorders and spasticity. One of the more common movement disorders treated with BTX-A is focal dystonia. The most common types are cervical dystonia, blepharospasm, hand dystonia, oromandibular dystonia, occupational dystonia, and laryngeal dystonia.
The administration of BTX therapy for focal dystonia requires a thorough understanding of the toxin itself and practical knowledge of typical dosages and anatomy, along with basic electromyographic skills. The optimal dose of BTX is the least amount needed to achieve a predetermined outcome (decreased muscle tone, improved range of motion, improvement of certain active function, improved hygiene) without causing an adverse effect such as weakness. [5]
BTX type A inhibits release of acetylcholinesterase (ACh) at the neuromuscular junction. Following local injection into muscles, the toxin enters the nerve terminal via endocytosis, interacts with intracellular proteins (soluble N -ethyl-maleimide sensitive factor attachment protein receptor [SNARE] proteins), and inhibits the vesicular release of the Ach neurotransmitter at the neuromuscular junction. [6, 7] This chemical denervation results in paralysis of the striated muscles, which usually peaks 2 weeks after the injection. Some nerve terminals are not affected by the toxin, allowing the injected dystonic muscle to contract. Because of the molecular turnover within the neuromuscular junction and neuronal sprouting, neuronal activity begins to return in an average of 3 months, with restoration of complete function at approximately 6 months. [8]
Many factors affect the dose of BTX including severity and chronicity of the disease, number of muscles involved, previous response to BTX, concurrent other medical therapy used, and the experience of the person performing the injection. Smaller doses are used in children, proportionate to the body mass.
Structure
BTX is synthesized as a single-chain peptide with a molecular mass of 150 kilodaltons. This form has relatively little potency as a neuromuscular blocking agent, and activation requires a 2-step modification in the protein's tertiary structure. This process converts the single-chain neurotoxin to a di-chain neurotoxin comprising a 100,000-dalton heavy chain (HC) linked by a disulfide bond to a 50,000-dalton light chain (LC). BTX acts at the neuromuscular junction where it exerts its effect by inhibiting ACh release from the presynaptic nerve terminal.
ACh is contained in vesicles, and several proteins (VAMP, SNAP-25, and syntaxin) are required to mediate fusion of these vesicles with the axon terminal membrane. BTX binds to the presynaptic terminal via the HC. The toxin is then internalized and the HC and LC are separated. The LC from BTX-A cleaves SNAP-25, the LCs from serotypes B and F cleave VAMP, and that from serotype C cleaves syntaxin. This disrupts ACh release and subsequent neuromuscular transmission, resulting in weakness of the injected muscle.
Other medications used to treat focal dystonia
See the list below:
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Botulinum toxin injections
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Benzodiazepines
Clonazepam
Lorazepam
Diazepam
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Baclofen
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Anticholinergics
Trihexyphenidyl
Benztropine
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Dopamine-depleting agents
Tetrabenazine
Clozapine
Optimum goals of treatment with botulinum toxin
The goal of BTX treatment is to achieve a balance between weakness sufficient to reduce spasm but insufficient to interfere with function. The best combination of reduction in dystonia and pain with optimization of function should be sought.
Botulinum toxin type B for dystonia
Myobloc (Elan Pharmaceuticals) was approved by the FDA in December 2000 for treatment of patients with cervical dystonia to reduce the severity of associated abnormal head position and neck pain. BTX-B also has received marketing authorization from the European Union's Committee for Proprietary Medicinal Products and will be marketed as Neurobloc (Elan Pharmaceuticals).
Reported clinical studies have shown Myobloc/Neurobloc to be a safe and effective treatment for cervical dystonia in patients who have responded to BTX-A and in those who developed resistance to BTX-A. As with all the botulinum toxins, BTX-B acts at the neuromuscular junction inhibiting the release of ACh at the presynaptic membrane; however, the primary mechanism of action of BTX-B differs from that of BTX-A, as BTX-B inactivates a different protein involved in the release of ACh.
In a multicenter study of 100 patients with cervical dystonia, Jankovic et al examined the immunogenicity of botulinum toxin type B (BTX-B). They correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit, suggesting that the high antigenicity of BTX-B limits its long-term efficacy. [9]
Relevant Anatomy
Most of the skeletal muscular system is arranged into groups of agonists and antagonist muscles that work in concert to provide efficient and controlled motion. This is achieved through the complex interaction of the musculoskeletal system with the pyramidal, extrapyramidal, and sensory components of the nervous system.
In gross anatomy, the nerves to skeletal muscles are branches of mixed peripheral nerves. The branches enter the muscles about one third of the way along their length, at motor points. Motor points have been identified for all major muscle groups for the purpose of functional electrical stimulation by physical therapists, in order to increase muscle power. Only 60% of the axons in the nerve to a given muscle are motor to the muscle fibers that make up the bulk of the muscle. The rest are sensory in nature, although the largest sensory receptors, the neuromuscular spindles, have a motor supply of their own.
A motor unit comprises a motor neuron in the spinal cord or brainstem together with the squad of muscle fibers it innervates. In large muscles (eg, the flexors of the hip or knee), each motor unit contains 1200 or more muscle fibers. In small muscles (eg, the intrinsic muscles of the hand), each unit contains 12 or fewer muscle fibers. Small units contribute to the finely graded contractions used for delicate manipulations.
For more information about the relevant anatomy, see Muscular System Anatomy.
Indications
Applications of botulinum toxin injections
See the list below:
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Focal dystonia
Focal limb dystonia
Blepharospasm
Cervical dystonia (torticollis)
Oromandibular-facial-lingual dystonia
Hemifacial spasm
Myoclonus
Dystonic tics
Tremors
Bruxism
Spasticity, upper and lower limb spasticity
Migraine headache
Overactive bladder, urinary incontinence
Treatment of focal dystonia with BTX is designed to improve the patient's posture and function and to relieve associated pain.
In a study of 123 subjects with a history of 2–8 moderate-to-severe migraine attacks per month with or without aura, Silberstein et al found that BTX-A was found to be safe and significantly reduced migraine frequency, migraine severity, acute medication usage, and occurrence of migraine-associated symptoms. [10, 11]
Moffat et al studied BTX treatment for axillary hyperhidrosis and found that axillary botulinum toxin treatment is durable. Patients experience gradual return of symptoms between 6 and 24 months. A minority of cases do not require retreatment at this time. [12]
Lin et al report that corticosteroid is superior to BTX-A in relieving pain in tennis elbow at 4 weeks after injection. Because BTX injection did not reduce pain significantly but is associated with weakness, the muscle weakness caused by BTX is unlikely to be the sole mechanism of the pain relief observed in previous studies. [13]
Toffola et al found that BTX-A injection treatment effectively reduced facial synkinesis, thus improving facial expression symmetry both at rest and in voluntary movements. [14]
Contraindications
Contraindications
No absolute contraindications to the use of BTX-A are known. Relative contraindications include myasthenia gravis or motor neuron disease. In a pregnant woman this molecule is not expected to enter systemic circulation following adequate intramuscular or intradermal injection. Additionally, BTX-A, having high molecular weight, does not appear to cross the placenta, although active transport cannot be excluded. Therefore, based on its local action and on the existing data, administering BTX-A to a pregnant woman is not expected to cause any fetal harm. However, until more data are available, benefits and potential risks to both the mother and the infant should be considered when recommending BTX-A injection to a pregnant patient. Patients who are pregnant or lactating may not be appropriate candidates for BTX therapy. [15] Long-term followup of the resulting child is usually lacking. So far there is no evidence of harm, but absence of evidence is not evidence of absence.
Relative contraindications for clinical application of botulinum toxin
See the list below:
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Pregnancy and lactation
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Neuromuscular disease (eg, myasthenia gravis, Eaton-Lambert syndrome)
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Motor neuron disease
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Concurrent use of aminoglycosides
Equipment
Preparation of botulinum toxin for injection
The toxin is produced by the gram-negative anaerobic bacterium Clostridium botulinum. It is harvested from a culture medium after fermentation of a toxin-producing strain of C botulinum, which lyses and liberates the toxin into the culture. The toxin is then extracted, precipitated, purified, and finally crystallized with ammonium sulfate. BTX-A should be diluted with preservative-free saline and the preparation used within 4 hours of reconstitution. Conditions for the stability of the toxin in solution include pH 4.2–6.8 and temperature less than 20 degrees Celsius. Crystallized toxin is inactivated quickly in solution by shaking.
Biological activity of the BTX-A distributed by Allergan Inc. onabotulinumtoxin A (BOTOX®) is different from that of the BTX-A produced by Speywood Pharmaceuticals in England abobotulinumtoxinA (Dysport) or Japan. The potency of BTX is expressed as mouse units, with 1 mouse unit equivalent to the median lethal dose (LD 50) for mice. BOTOX® is dispensed in small vials containing 100 units (U), while a vial of Dysport contains 500 U. The relative potency of BOTOX® units to Dysport units is approximately 1:3. [16] BOTOX® units are used throughout this article. Most physicians dilute the vial of BOTOX® with 1-4 mL of saline, for a concentration of 2.5-10 U/0.1 mL.
Electromyographic (EMG) guidance of injections is generally advised except for injections of muscles around the eye and some facial muscles. The dose of BOTOX® injected intramuscularly depends on the muscle size. Small muscles such as the vocal cords receive 0.75 U, whereas larger neck muscles may require 100-150 U and lower limb muscles may require 200-300 U to exert a desirable effect. After injection, BTX starts to weaken the muscle within 24-72 hours, and maximal effect occurs after about 14 days; benefit can last for 3-6 months.
Incobotulinumtoxin A (Xeomin), the most recently approved BTX-A product, is a lyophilized powder for injection that must be diluted for IM administration. Total dose is 120 units per treatment session. Higher doses did not provide additional efficacy and were associated with increased adverse effects. It is usually injected IM into sternocleidomastoid, splenius capitis, levator scapulae, scalenus, and/or trapezius muscle(s). [17, 18, 19]
Technique
BTX should be administered only by trained specialists utilizing correct equipment, which includes EMG monitoring to identify appropriate muscles for injection. Before treatment with BTX, patients should undergo neurologic evaluation and examination. Secondary causes of dystonia such as drugs or Wilson disease should be ruled out. Physicians administering BTX must have a good understanding of both the anatomy of affected muscles and the resultant movement disorder. Patient education and counseling are essential components of a comprehensive therapeutic approach to all patients with dystonia. BTX can be used as sole therapy or as an adjunct to oral medications. Physical therapy may play a role as a supplement to BTX depending on the case.
The injection techniques for individual clinical applications of botulinum toxin are described below.
Blepharospasm
See the list below:
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Blepharospasm is characterized by involuntary, intermittent, forced eyelid closure. BTX is considered the treatment of choice for blepharospasm and has been used for this disorder since 1983. It has been used effectively in the treatment of blepharospasm induced by drugs such as L-dopa or neuroleptics, dystonic eyelid and facial tics in patients with Tourette syndrome, and "apraxia of eyelid opening."
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Onset of improvement is seen in 4-7 days and benefit can last for up to 4 months. Studies evaluating the long-term use of BTX as a treatment for blepharospasm showed that benefits persist for several decades of treatment. A study of 128 patients who were receiving abobotulinumtoxin A or onabotulinumtoxin A maintained benefit at 15years. [23, 24]
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Injection technique
Treatment may be started with 10 U of BOTOX® per eyelid, injecting a total of 20 U per patient. The most common effective dose is 25 U per eye. Diluting the BOTOX® with 4 mL of isotonic saline is recommended.
As the orbicularis oculi muscle lies superficially, intradermal injection with a 27- to 30-gauge needle is recommended.
Typically, 3-5 points around each eye are injected. The principle is to avoid the mid portion of the upper eyelid to avoid inadvertent diffusion into the levator palpebrae superioris, which would lead to undesirable ptosis. Injection into the medial lower lid also is avoided.
Apraxia of eyelid opening
See the list below:
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Apraxia of eyelid opening is the inability to open the eyelid in the absence of paralysis, sensory loss, or other disorders that affect language or alertness. It is often seen co-existing with blepharospasm, Parkinson’s disease, and atypical parkinsonian syndromes, mainly progressive supranuclear palsy (PSP).
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Treatment may lead to improved lid opening post BTX injection and reduction in functional impairment based on a pilot study in 10 patients with apraxia of eyelid opening associated with blepharospam. [25]
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Injection technique
4–5 units of BOTOX® in the orbicularis oculi with 3 injections in the pretarsal portion (medial and lateral upper eyelid and lateral lower eyelid) and 4th injection in the external canthus. [26]
BTX yielded more benefit with injection into the pretarsal portion of orbicularis oculi compared to preseptal and orbital portions. [27]
Focal hand dystonia
See the list below:
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This condition typically presents with loss of speed and fluency of movement during a specific task. Neurologic evaluation is required to rule out radiculopathy or peripheral nerve entrapment for which specific treatment might be available. Nerve conduction studies may be required to exclude ulnar neuropathy or median entrapment neuropathy at the wrist. Examination of the forearm muscles should be performed during the specific task to determine which muscles are involved in the dystonia. Observations should be made at rest and during the provoking activity. The patient should be instructed to avoid compensating for the dystonia. The selection of muscles for injection depends on clinical examination, patient report of local pain or tightness, and/or EMG evidence of excessive activity.
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Treatment may lead to an improvement in abnormal posture and pain and/or restoration of normal function. Benefit has been reported in as many as 80-90% patients and is usually apparent 5-7 days after injection. Symptomatic relief peaks about 2 weeks after treatment and may last for 3-4 months.
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Injection technique
BTX is injected into the muscle belly; localizing muscles for injection in the forearm may be difficult, as many of the muscles are deep and overlapping.
EMG is recommended to help identify the target dystonic muscle. Once proper needle location is confirmed, BTX can be injected.
Common initial doses of BOTOX® for writer's cramp are 5 U for small muscles and 10-20 U for muscles in the forearm. Large doses into a single muscle are best given in multiple sites to aid diffusion of the toxin to a greater number of end plates. The dose of BTX is titrated over several injection sessions to the dose that maximizes relief from dystonia while minimizing muscle weakness.
Subsequent injections should be given at 2- to 4-month intervals. At each subsequent session, the patient should be examined for weakness that might indicate postponing treatment or reducing the dose. As the pattern of muscle contraction can change, the dystonia should be reevaluated at each session.
Cervical dystonia
See the list below:
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Cervical dystonia (CD) is the most common form of focal dystonia and is characterized by sustained postures or contractions of the neck muscles. Deviation of the head can occur in multiple directions; turning of head (torticollis) is the most common subtype of cervical dystonia. Laterocollis (tilting) bends the head laterally, moving the ear toward the ipsilateral shoulder; anterocollis (forward flexion) deviates the chin downward toward the chest; and retrocollis (extension) produces upward extension of the chin. Cervical dystonia can involve any combination of these deviations.
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Ninety percent of patients report some improvement in the postural deviation. In published reports 76-93% of patients experienced pain relief following treatment with BTX. In some studies, subjective pain relief is frequently more impressive than objective improvement in head posture. Latency between injections and onset of clinical benefit is around 7 days. Duration of effect is 3-4 months.
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According to the 2016 AAN Practice Guideline update, there is level A evidence for abobotulinumtoxin A and rimabotulinumtoxin B in patients with cervical dystonia and level B evidence (probably effective) in the use of onabotulinumtoxin A and incobotulinumtoxin B in cervical dystonia. All formulations are approved for use in United States. [20]
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Examination of the patient
CD is usually idiopathic but in some cases it follows trauma. A study including 300 patients at Baylor College of Medicine revealed that as many as 11% of patients had significant neck injury less than one year prior to the onset of CD. Exposure to neuroleptic drugs accounted for 6% of the cases of CD in the Baylor series. Neurologic examination is essential to rule out radicular processes or ophthalmologic disorders, which can present with abnormal posture of the head.
The anatomy of the neck is complex; a basic familiarity with anatomic landmarks, muscle origins and insertions, and vital structures in that region is necessary to use BTX injections effectively to treat these patients. The abnormal postures of CD usually result from abnormal activity of multiple muscles. Postures are complex, with combinations of turning, tilting, head flexion or extension, and shoulder elevation.
Proper selection of the involved muscles is critical in determining response to BTX treatment. Thus, careful examination of the patient in different positions is indicated; instruct the patient to position the head in a comfortable upright posture. Passively adjust the head and observe for additional extension, flexion, and rotation that may be compensated for by the patient and note any contractures. Palpate for contracting muscles and hypertrophy and any point tenderness. The patient should then be asked to walk and the head position observed and recorded. The most abnormal head position is used to select the muscles for injection. EMG is recommended to localize involved muscles.
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Injection techniques
The most commonly injected muscles include sternocleidomastoid, trapezius, splenius capitis, levator scapulae, and scalene complex. Muscles involved in the abnormal posturing are isolated using standard anatomic landmarks.
EMG guidance is recommended for injection purposes. Once the EMG electrode is inserted, the patient is instructed to activate the muscle evoking a full recruitment pattern. The needle is held in position and the patient resumes a relaxed position.
The syringe is aspirated to ensure that the tip is not within a blood vessel. The appropriate amount of BTX is then injected directly through the electrode into the muscle.
BOTOX® treatment doses range from 10-600 U, with 200–300 U most commonly used.
Usually, 2–6 muscles are injected at multiple sites; the BTX should be injected along the belly of the muscle to allow for adequate diffusion.
Patients with anterocollis also benefit from the infection of BTX into anterior scalene muscles, sternocleidomastoid muscles, and submental complex.
Camptocormia
See the list below:
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Camptocormia is characterized by abnormal forward flexion in the thoracolumbar region, of more than 45 degrees, apparent while standing or walking, but resolves in a supine position.
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In a case series of 16 patients, injection of BOTOX® 300 and 600 units into the rectus abdominus muscle of 9 patients showed improvement in 4 patients. [30]
Pisa syndrome
See the list below:
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Pisa syndrome is characterized by marked lateral flexion of the trunk of more than 10 degrees, which improves with lying down and with passive manipulation.
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In a randomized placebo-controlled trial of 26 patients, injection of 50 and 200 units of incobotulinumtoxin A using EMG guidance inot iliopsoas, rectus abdominus, thoracic, or lumbar paravertebral muscles showed significant improvement not only in trunk posture but also in pain and range of motion. [31]
Oromandibular dystonia
See the list below:
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Oromandibular dystonia (OMD) is characterized by abnormal involuntary movements or spasms of lower face, jaw, and tongue muscles. Patients present with spasms of these muscles and jaw deviation.
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Seventy to eighty percent of patients with OMD benefit from local injections of BTX into the inappropriately contracting muscles. Improvement is observed within the first week after BTX and the benefit can last for 3-4 months.
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Injection technique
Treatment of this condition with BTX requires a detailed knowledge of the local anatomy.
Evaluation by both a neurologist and otolaryngologist is recommended.
OMD can involve different combinations of muscles including the masseter, lateral and medial pterygoids, and temporalis.
The recommended dose of BTX is 20 U in each muscle.
Laryngeal dystonia
See the list below:
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Laryngeal dystonia, also called spasmodic dysphonia, is characterized by abnormal involuntary spasms of vocal muscles resulting in an abnormal voice pattern. This consists of 3 types: adductor spasmodic dysphonia (strain-strangled voice), abductor spasmodic dysphonia (whispering voice), and adductor breathing dystonia (paradoxical vocal fold motion). It is a chronic neurologic disorder of central motor processing characterized by action-induced spasms of the vocal folds, typically resulting in dysphonia during speaking. It is often made worse by emotional stress and patients often use sensory tricks (eg, yawning or laughing when beginning to speak) to overcome their symptoms.
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Seventy-five percent of patients note improvement in voice symptoms. Relief after BTX injection begins within 24–72 hours and lasts for an average of 4 months.
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Injection technique
Before a patient can be considered as a potential candidate for BTX injections, the diagnosis of laryngeal dysphonia must be confirmed by neurologic, otolaryngologic, and voice assessment. Clinical findings should be documented by video and voice recording with fiberoptic laryngoscopy.
The thyroarytenoid muscles are located with EMG guidance, and percutaneous injections of BTX are administered through the cricothyroid membrane.
BTX dose ranges from 1.5–3 U.
Currently, a bilateral injection approach is the most frequently used technique.
Hemifacial spasm
See the list below:
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Hemifacial spasm (HFS) is one of the more common craniofacial movement disorders. It is characterized by unilateral muscle contractions of the face. HFS may involve any combination of orbicularis oculi, frontalis, risorius, zygomaticus major, and platysmas muscles. This is not a form of focal dystonia but rather is caused most probably by irritation of cranial nerve VII by an artery compressing the nerve as it exits the brain stem.
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Allam et al concluded that the clinical improvement induced by BTX in patients with hemifacial spasm is largely symptomatic and does not seem to involve excitability changes of cortical motor areas from reorganization of inhibitory intracortical circuits. [32]
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Injection technique: Injections of BTX are tailored to the facial muscles in spasm; the muscles affected differ from patient to patient.
Complications
During injection, patients may report a stinging sensation, especially with treatment around the eyelids and face. Bruising at the site of injection may occur. In general, adverse effects usually are localized to the injection site and are related to excess weakness of injected muscles, which is transient and well tolerated. Systemic adverse effects, though rare, consist of a flu-like syndrome that is transient and may last as long as a few weeks. Serious adverse effects are dysphagia and respiratory compromise, which may occur with injections into the neck, mouth region, and vocal cords. Intravascular injection is to be avoided, as this may cause generalized weakness. Pneumothorax is a rare, potentially serious complication, from pleural penetration when performing injections into the lower neck or back.
Most frequently reported adverse reactions in the treatment of cervical dystonia were dysphagia (19%), upper respiratory infections (12%), neck pains (11%), and headaches (11%). In patients treated with blepharospasm, the common adverse events included ptosis (20.8%), superficial keratitis (6.3%), and eye dryness (6.3%).
A number of cases of systemic botulism-like reaction to BTX-A injections have been reported recently. Generalized weakness including bulbar weakness developed in 2 cases and resolved over several weeks. One of these patients had been treated for torticollis for many years and the other had only one series of injections for spasticity.
The lethal dose of BOTOX® in humans is not known; however, it has been estimated to be about 3000 U. The usual maximum recommended dose at an injection session is about 600–800 U.
Development of antibodies
Botulinum neurotoxins may be immunogenic. Antibodies may develop, bind to the BTX, and inactivate it. The incidence of antibody-mediated resistance to BOTOX®, as determined by the mouse lethality assay, is reported between 3% and 10% and is generally accepted to be about 5%. The only apparent symptom of the development of antibodies is lack of response to further injections. The use of other serotypes (F or B) may benefit those who have developed antibody resistance. In a patient who no longer responds to BTX-A (secondary nonresponder) and in whom immunogenicity is suspected, the recommended approach is to inject 20 U BOTOX® into hypothenar or forehead muscles. If the patient is still responsive, transient weakness will develop in the muscle 1-2 weeks after injection. An alternative or adjunct is to take blood for antibody assay, but this usually is not covered by insurance.
Risk factors for developing antibodies include higher doses, shorter intervals between injections, booster doses, and young age. Recommendations to help prevent development of antibodies include (1) use of smallest possible dose to achieve relief, (2) interval between injections of at least 1 month (preferred interval is 3 months), and (3) avoid "booster injection."
A patient who does not respond to the first injection of BTX-A is referred to as a "primary nonresponder." Still, reasons for nonresponse can include inappropriate site of injection and too low a dose. A person should not be considered a primary nonresponder until they have been injected by an expert using increasing doses or a lack of response has been demonstrated using one of the clinical tests discussed above.
Complications with particular clinical applications
See the list below:
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Blepharospasm
Ten percent of patients develop ptosis, which improves spontaneously in less than 2 weeks.
Other complications include blurring of vision, tearing, and local hemorrhage.
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Cervical dystonia
The most common adverse effects include neck weakness (20-30%), dysphagia (10-20%), and local pain. The occurrence of dysphagia appears to be related to the dose and the muscles injected.
Adverse effects are transient and usually resolve spontaneously within 2-3 weeks.
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Oromandibular dystonia
Adverse effects are uncommon and include dysphagia and pain at the injection site.
Allam et al support the view that executive dysfunction in primary cranial dystonia (PCD) is secondary to the disrupting effects of the symptoms. Treatment with BTX alleviates the symptoms and, consequently, improves sustained attention. [33]
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Laryngeal dystonia
Swallowing difficulties, which can last for 3-7 days, occur in 60% of patients.
Transient hypophonia and stridor also have been reported.
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Hemifacial spasm
Adverse effects depend on location of injection.
Lower face injections may result in facial weakness and asymmetry, face and mouth droop, drooling, and loss of facial expression. Forehead injections can result in brow ptosis or loss of eyebrow elevation.
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Thyroarytenoid injection for adductor spasmodic dysphonia. Needle is advanced through the cricothyroid membrane.
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Posterior cricoarytenoid (PCA) injection for abductor spasmodic dysphonia. Needle is advanced through the inferior constrictor muscle to the PCA muscle.
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Tourette syndrome and other tic disorders. Schematic of the hypothetical reorganization of the basal ganglia output in tic disorders, with excitatory projections (open arrows) and inhibitory projections (solid arrows). Line thickness represents the relative magnitude of activity. When a discrete set of striatal neurons becomes active inappropriately (right), aberrant inhibition of a discrete set of internal segment of globus pallidus (GPi) neurons occurs. The abnormally inhibited GPi neurons disinhibit thalamocortical mechanisms involved in a specific unwanted competing motor pattern, resulting in a stereotyped involuntary movement.
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Tourette syndrome and other tic disorders. Segregated anatomy of the frontal-subcortical circuits: dorsolateral (blue), lateral orbitofrontal (green), and anterior cingulate (red) circuits in the striatum (top), pallidum (center), and mediodorsal thalamus (bottom).
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Tourette syndrome and other tic disorders. Graphic shows the relative likelihood of lifetime sensory tics in a given region, as based on self-report of patients with Tourette syndrome. Overt tics are distributed similarly.
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Tourette syndrome and other tic disorders. Immunologic response found in patients with Sydenham chorea is also found in patients with Tourette syndrome and obsessive-compulsive disorder. Points on the graph represent percent expression of D8/17 antigen on circulating B lymphocytes.
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Tourette syndrome and other tic disorders. In a randomized controlled trial of habit reversal therapy (HRT), results differed significantly from those of a control therapy (massed practice; P< .001, analysis of variance). The HRT group had a 97% reduction in tics at 18-month follow-up, with 80% of patients tic-free.
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Tardive dyskinesia. Venn diagram of the classification of movement disorders.
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Botulinum toxin structure (schematic diagram).
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Proteolytic activity is located at the N-terminal end of the light chain of botulinum toxin type A.
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The 4-step process by which botulinum toxin reduces neuromuscular activity: (a) Normally functioning neuromuscular junction; (b) Binding step: The binding of botulinum dichain as the 100-kDa heavy chain binds to the cholinergic site on the cell membrane of the presynaptic cholinergic motor nerve terminal at a neuromuscular junction; (c) Internalization: The invagination of the cell membrane around the toxin molecule produces small endocytic vesicles within the cytoplasm of a motor nerve terminal; (d) Translocation step: Penetration and translocation of the neurotoxin 30-kDa light chain domain across the endosomal membrane of the endocytic vesicle into the cytosol of the motor nerve terminal; Blocking step: The neurotoxin 50-kDa light chain domain impedes the fusion of the acetylcholine vesicles on the inner side of the nerve terminal plasma membrane and the exocytosis of acetylcholine and its release into the synaptic cleft, preventing muscle contraction (Bendetto AV, 1999).
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The development of extrajunctional acetylcholine receptors and expansion of the motor endplate occur after an injection of BOTOX®. (a) An axon terminal proliferating external collateral sprouts. (b) A single nerve sprout reestablishing a new neuromuscular junction results in the return of muscle activity (Bendetto AV, 1999).
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This is a photomicrograph of Clostridium botulinum stained with Gentian violet. The bacterium, C botulinum, produces a neurotoxin which causes the rare, but serious, paralytic illness, botulism.
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A man with apraxia of lid opening is unable to open his lids at will. Eye movements were full. Attempted eye opening resulted in frontalis muscle contraction, backward thrusting of the head, and pretarsal orbicularis oculi activity. Spontaneous reflex blinking was normal. The lids remained open following manual elevation.
