Botulinum toxin is a potent neurotoxin that attacks peripheral neuromuscular and autonomic synapses in humans. It is produced by the gram-positive, spore-forming anaerobic bacteria Clostridium botulinum. The organism responsible for food-borne botulism acts by blocking acetylcholine release at the neuromuscular junction.[1,2]
In 1989, the U.S. Food and Drug Administration approved the use of botulinum toxin A, a toxin serotype, in the treatment of strabismus, blepharospasm and seventh-nerve disorders in patients 12 years of age or older. The American Academy of Neurology, the American Academy of Ophthalmology,[3,4] the American Academy of Otolaryngology and the National Institutes of Health have released consensus statements supporting the therapeutic use of botulinum toxin A, outlining clinical guidelines for its use and confirming its efficacy. Clinical investigation and the response of health insurance carriers support treatment with botulinum toxin in many cases of focal dystonic and nondystonic disorders of muscle spasm (Table 1) that have yet to receive FDA endorsement.
Therapeutic Uses for Botulinum Toxin Focal dystonias -- sustained muscular activity producing abnormal posture and functional disability
Blepharospasm (eyelid closure)
Cervical (torticollis, anterocollis, laterocollis)
Laryngeal (spasmodic dysphonia -- abductor or adductor spasms of
the vocal cords)
Oromandibular (opening or closing of the mouth or jaw)
Orolingual (tongue involvement)
Limb dystonia (occupational or task-driven, parkinsonism)
Axial or truncal Nondystonic disorders of involuntary movement
Tremor (e.g., essential, parkinsonism)
Myokymia and synkinesis
Myoclonus (e.g., middle ear, palatal) Disorders of conjugate eye movement (e.g., strabismus, nystagmus) Spasticity
Traumatic brain injury
Cerebral palsy Disorders of localized muscle spasm
Sphincter spasm (detrusor-sphincter dyssynergia)
Skeletal muscle spasm (e.g., myofascial dysfunction, hyperkinetic
Temporomandibular joint-associated bruxism
Following initial diagnostic evaluation and management, appropriate subspecialty consultation for therapeutic injection of botulinum toxin A may be indicated. Some injections require electromyography, ultrasonography or radiology for guidance of needle placement into target muscles. In addition to problems potentially posed by needle placement, botulinum toxin injection may include or induce excessive or adjacent muscle weakness. Discretion must be applied when using botulinum toxin in patients with potential or preexisting disorders of the neuromuscular junction, such as myasthenia gravis, Eaton-Lambert syndrome and motor neuron disease (amyotrophic lateral sclerosis).[2,7]
Botulinum toxin A should not be given to patients during pregnancy or lactation, or to patients taking aminoglycosides or other drugs that interfere with neuromuscular transmission. The therapeutic benefit of botulinum toxin A in humans generally lasts for three to four months.[1,2,6] Reversibility of the neuromuscular blockade is the result of neuromuscular sprouting and reinnervation of the affected muscle.[1,2,6]
Botulinum Toxin in Specific Clinical Disorders
Focal dystonia results from sustained or spasmodic muscle contractions that produce abnormal trunk or limb movements and postures through the combination of involved muscles (i.e., torsion of the neck, flexion of the fingers or inversion and plantar flexion of the foot). Some forms of dystonia may affect the body, diffusely and are usually more amenable to oral pharmacotherapy, although focal injections may relieve painful and disabling postures or prevent contractures and skin breakdown.
Blepharospasm is a condition of excessive involuntary eyelid closure, generally the result of spasms of the orbicularis oculi muscle. This condition may occur in isolation (benign essential blepharospasm) or in combination with other involuntary muscle contractions, such as spasms of the muscles of the lower face, mouth and tongue that occur in Meige's syndrome.[6,9]
Blepharospasm, as well as other focal dystonias, may occur secondary to disorders such as parkinsonism or side effects from drugs such as neuroleptics or levodopa. Evaluation should include a search for ophthalmologic causes, including inflammation or drying of the tissues of the lid or eye. Treatment of underlying conditions may reduce secondary eyelid spasm, thus avoiding the need for other therapies. Botulinum toxin is the first choice of therapy for primary blepharospasm, with a success rate of approximately 90 percent. Side effects are usually transient and mild, including tearing, blurry vision, diplopia, ptosis and dry eyes.[1-4,10]
Other craniocervical dystonias may produce involuntary dystonic movements of the forehead, facial, masticatory, lingual and oral muscles. Oromandibular dystonia involves muscles of the jaw, tongue and lower face. Involuntary sustained jaw-closure or jaw-opening spasms may threaten fluid and food intake, and interfere with speech. Treatment of jaw-closing dystonia by injection into the masseter and temporalis muscles is relatively straightforward, benefiting about 70 percent of patients. However, injections into the submental and pterygoid muscles for jaw-opening dystonia are beneficial in only 50 percent of patients. When used to treat lingual (tongue) dystonia, botulinum toxin carries a greater risk for adverse side effects, primarily dysphagia (up to 50 percent for dysphagia), and aspiration pneumonia has occurred.
Laryngeal dystonia or spastic dysphonia caused by adductor or abductor spasm of the vocal cords can also be treated with botulinum toxin. Sustained hyperadduction of the vocal cords causes speech to sound strained and strangled, with frequent interruptions of output. Abductor dystonia of the larynx results in a whispery or breathy voice of weak volume. Botulinum toxin injection into the laryngeal region should be performed by experts with intimate knowledge of the anatomy, using electromyographic guidance. Furthermore, the treating physician should be capable of managing potential complications, which include dysphagia, aspiration, laryngeal stridor or spasm, and respiratory insufficiency.[1,2,7]
Cervical dystonia or spasmodic torticollis results from involuntary sustained tonic or clonic contractions of neck muscles, which produce abnormal postures of the head and neck, such as twisting (torticollis), side bending (laterocollis), flexion (anterocollis), extension (retrocollis) or various combinations of these patterns. Dystonic postures may be accompanied by phasic jerking or tremor from antagonist muscles opposing dystonic muscle contraction. An abbreviated differential diagnosis of cervical dystonia is outlined in Table 2.
Differential Diagnosis of Cervical Dystonia
Neurologic disorders Primary idiopathic Secondary causes
Cerebrovascular (stroke, hemorrhage)
Encephalitis or postinfectious
Drugs (dopamine blockers, levodopa,
ergotamine derivatives, anticonvulsants)
Toxic (e.g., carbon monoxide, methanol)
Structural abnormality of the posterior fossa
or cerebellum, including neoplasm Neuro-ophthalmology (e.g., disorders of
conjugate gaze) Focal seizures Spinal cord tumor or syrinx Orthopedic or musculoskeletal (e.g., cervical or craniocervical junction)
Post-traumatic fracture or dislocation
Acute disc herniation
Osteomyelitis, metabolic bone disorder or
other type of bone softening
Soft tissue disorder (e.g., postradiation
Congenital anomaly (e.g., Klippel-Feil
syndrome or muscle agenesis) Infections (e.g., pharyngitis or painful lymphadenopathy) Psychiatric disorders (conversion)
Occupational and other task-induced dystonias are triggered by performance of specific complex motor tasks and may result in disability.[10,11] Botulinum toxin infection often requires electromyographic guidance to aid needle placement into small muscles of the hand or forearm. Infection for dystonias that interfere with complex dexterous hand activities such as writing or playing a musical instrument may be complicated by weakness, not only of the injected muscles, but also of nearby muscles, into which the toxin may diffuse.[10,11]
Pharmacologic management of dystonia usually includes a trial of anticholinergic medication such as trihexyphenidyl (Artane, Trihexy), which is started at 2 mg two or three times daily (going as high as 70 mg daily in some cases) and titrated to produce the best clinical response with tolerable side effects.[11,12]
Other reasonable medication trials include benztropine (Cogentin), levodopa-carbidopa (Sinemet), clonazepam (Klonopin) and other benzodiazepines, baclofen (Lioresal), carbamazepine (Tegretol), and some antidopaminergic agents, such as haloperidol (Haldol).[11,12]
Dopamine depleters, such as reserpine and tetrabenezine (available in Europe), have also been beneficial in some cases.
Since these medications often cause uncomfortable side effects, patient tolerance of oral therapy may affect the decision to consider botulinum toxin therapy.
Procedures that surgically denervate the affected muscles, although advocated in the past, are less often prescribed since the introduction of botulinum toxin. Transcutaneous electrical nerve stimulation (TENS), relaxation techniques, biofeedback and other nonpharmaceutical therapies may also be helpful.
NONDYSTONIC DISORDERS OF ABNORMAL MUSCLE CONTRACTION
Hemifacial spasm is characterized by recurrent involuntary clonic or tonic contractions of muscles innervated by a compressed or irritated facial nerve (cranial nerve VII). Causative brain-stem pathology includes aberrant or tortuous vasculature, tumors and demyelinating plaques. Oral medication management with anticonvulsants such as phenytoin (Dilantin), carbamazepine and clonazepam is frequently beneficial but may be limited by sedative effects. Microvascular decompression of the facial nerve is often effective but is a risky neurosurgical procedure. Botulinum toxin almost always provides improvement, with an average duration of five months. Complications, if they occur, are minimal and transient.
Tremor is a rhythmic oscillation of body parts produced by reciprocal or simultaneous contraction of agonist and antagonist muscles across a joint. Botulinum toxin has been reported to be beneficial in some cases of disabling head, neck and hand tremor that have been poorly responsive to oral pharmacotherapy.[1,11]
Botulinum toxin therapy was developed as an alternative to incisional surgery for the treatment of strabismus. Electromyo-graphically guided injections are placed into extraocular muscles which, when weakened, allow alignment of the visual axis. In addition, botulinum toxin is effective in other disorders, such as lateral rectus palsy, dysthyroid myopathy and nystagmus.[1,4] Side effects may include excessive weakness, unwanted ocular deviations or eyelid ptosis.[1,4]
Other disorders of localized involuntary muscle contraction or spasm that cause pain or impairment can also be improved with administration of botulinum toxin. Botulinum toxin may be tried empirically in some conditions that have defied more invasive -- or merely unsatisfactory -- methods of treatment. Such conditions include esophageal achalasia, detrusor-sphincter dyssynergia, temporomandibular joint-associated bruxism and myofascial pain syndrome. Although botulinum toxin therapy in patients with these disorders is considered investigational, it is worth considering in difficult circumstances, because it is reversible and less expensive than surgical intervention.
Spasticity is an upper motor neuron disorder characterized by a velocity-dependent increase in muscle tone with increased tendon reflexes secondary to hyperex-citability of the tonic stretch reflex. Spasticity can occur as the result of a variety of etiologies, including stroke, cerebral palsy, traumatic brain injury and multiple sclerosis. Disability resulting from spasticity includes pain, muscle spasm, reduced range of motion and impaired functional abilities. Oral medications for spasticity, such as baclofen, dantrolene (Dantrium) and benzodiazepines, are sometimes effective, but their use may be limited by adverse side effects.
Surgical treatments, including tenotomy, myotomy and selective rhizotomy, have variable success. Intrathecal baclofen infusion, although often effective, requires careful medical supervision. In contrast, botulinum toxin has been shown to alleviate pain and functional disability caused by spasticity in selective muscles. Disadvantages include increased weakness of involved muscles and the inability of botulinum toxin to alleviate other neurologic impairments that may coexist in these conditions, such as limb ataxia.
Investigation into the use of botulinum toxin has revealed promising opportunities to reduce disability and pain in a myriad of disorders associated with pathologic muscle contraction. Depending on the amount of toxin used and whether radiologic or electromyographic guidance is necessary, the cost of botulinum toxin injections usually varies between $500 and $2,500. Many of these disorders are among the most miserable of maladies, long defiant of effective treatment. The FDA has approved several clinical applications of botulinum toxin therapy. Ongoing investigation and experience, along with development of alternate serotypes for therapeutic use, may reveal other important applications.
[1.] Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186-94.
[2.] Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1990;40:1332-6.
[3.] Botulinum-A toxin for ocular muscle disorders [Editorial]. Lancet 1986;1(8472):76-7.
[4.] Botulinum toxin therapy of eye muscle disorders. Safety and effectiveness. American Academy of Ophthalmology. Ophthalmology 1989;Pt 2:37-41.
[5.] Botox for spasmodic dysphonia. American Academy of Otolaryngology-Head and Neck Surgery Policy Statement. Am Acad Otolaryngol Head Neck Surg Bull 1990;9(12):8.
[6.] Clinical use of botulinum toxin. National Institutes of Health Consensus Development Conference Statement, November 12-14, 1990. Arch Neurol 1991;48:1294-8.
[7.] Training guidelines for the use of botulinum toxin for the treatment of neurologic disorders. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1994;44:2401-3.
[8.] Hallett M, Daroff RB. Blepharospasm: report of a workshop. Neurology 1996;46:1213-8.
[9.] Holds JB, White GL Jr, Thiese SM, Anderson RL. Facial dystonia, essential blepharospasm, and hemifacial spasm. Am Fam Physician 1991;43:2113-20.
[10.] Jankovic J, Schwartz K, Donovan DT. Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:633-9.
[11.] Jankovic J, Brin M. Diagnosis and management of dystonia. American Academy of Neurology, 46th annual meeting program, May 1-7, 1994, Washington D.C.
[12.] Carlos S, Weiner WJ, Griffin JW, eds. Torticollis. In: Johnson RT, ed. Current therapy in neurologic disease. 4th ed. St. Louis: Decker, 1990:261-5.
[13.] Koman LA, Mooney JF III, Smith BP, Goodman A, Mulvaney T. Management of spasticity in cerebral palsy with botulinum-A toxin: report of a preliminary, randomized, double-blind trial. J Pediatr Orthop 1994;14:299-303.
Botulinum Toxin Injections: A Treatment for Muscle Spasms
What is botulinum toxin?
Botulinum toxin is a protein. It can stop some of the chemical messages that are sent from nerves. These messages cause muscles to contract in spasms (to tighten up). Botulinum toxin is used to stop muscle spasms because it blocks these messages.
Botulinum toxin is made by the same bacteria that causes food poisoning. A high dose of botulinum toxin could be fatal, just as food poisoning can be fatal. The dose people get in injections is very small, however. This dose is so small that it's unlikely you'll have any harmful effects from the toxin.
Botulinum toxin has been used safely in thousands of people. It has been used for more than 10 years.
Why do I need botulinum toxin injections?
Your doctor may be considering botulinum injections to treat certain muscle spasms on your face or eyelids. It can also be used for some disorders of eye movement, such as lazy eye. Botulinum toxin is a standard treatment for spasmodic torticollis, a muscle spasm that causes the head and neck to pull in one direction.
How are botulinum toxin injections given?
Botulinum toxin is mixed with salt water and injected into a muscle with a very small needle.
You may receive five to 10 injections.
You might have some soreness at the injection sites. If your injection sites get sore, you can take acetaminophen (brand name: Tylenol) or ibuprofen (brand names: Advil, Motrin, Nuprin). You can also put an ice pack on the painful area.
Will I have any side effects?
You might have weakness in that muscle, muscle soreness that may affect your whole body, difficulty swallowing and a red rash that lasts for several days after the injections. Some people have severe weakness in the muscles that were injected. All side effects go away quickly.
ANTHONY H. WHEELER, m.d. is a neurologist in private practice with Pain and Orthopedic Neurology at the Charlotte (N.C.) Spine Center. Dr. Wheeler graduated from the University of North Carolina at Chapel Hill School of Medicine and completed an internship and a residency at the Baylor College of Medicine in Houston.
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