US Pharm. 2008;33(1):50-52.

Dystonia is a term used to describe a neurologic movement disorder characterized by prolonged involuntary muscle contractions resulting in repetitive twisting motions and abnormal postures of the neck or torso.1,2 Contractions may affect a single group of muscles in the neck or torso, but adjacent muscle groups may also be affected.3 Dystonia is often difficult to diagnosis because it can be confused with spasticity or rigidity, leading to misdiagnoses such as cervical muscle strain in adults and cerebral palsy in children.3 The exact cause of dystonia is unknown,Ü but experts believe that those suffering from dystonia lack the ability to properly process neurotransmitters in the brain. Some of the neurotransmitters involved in muscle contractions are gamma-aminobutyric acid (GABA), dopamine, acetylcholine, norepinephrine, and serotonin.2 It is also thought that dystonia may be caused by environmental factors or result from an injury to the basal ganglia of the brain. The symptoms of dystonia initially are often mild, but as time progresses they become more noticeable. Symptoms have been documented with heavy-metal poisonings, trauma, and adverse reactions to medications.2

Dystonia is classified according to the area of the body that is affected. Generalized dystonia affects most parts of the body; focal dystonia affects one specific area of the body; multifocal dystonia affects more than one unrelated area of the body; segmental dystonia affects more than one adjacent part of the body; and hemidystonia involves the limbs of one side of the body.2,4 The most common type of dystonia is focal dystonia, with cervical dystonia (CD) or spasmodic torticollis being the most prevalent.5

Etiology
Cervical dystonia is the third most common movement disorder after Parkinson's disease and tremor.6 Approximately 90,000 people in the United States are living with CD.3 The most common form of CD is torticollis, which is the rotation of the neck to one side.5 Cervical dystonia is characterized by a syndrome of sustained or intermittent involuntary contractions of the neck muscles and abnormal head postures, and it is frequently associated with pain.5 The exact etiology of CD is unknown; it may result from stroke, cervical cord injuries, trauma to the head or neck, or genetic predisposition, or it may be induced by certain medications such as levodopa or neuroleptics.6,7 The predominant risk factors include female gender (twice as likely to occur in women as men), age (most likely to occur between the ages of 30 and 70), and a history of head or neck injury (5%ñ16% occurrence).6 Symptoms include the involuntary turning, tilting, or extension of the neck muscles, as well as tremor, pain, and stiffness or tightness of the neck.6 This condition may lead to physical disabilities and adversely affect the patient's quality of life. There is no cure for CD; it is primarily managed through pharmacotherapy and, in rare instances, surgical denervation.6

Treatment
Pharmacotherapy for cervical dystonia has historically included anticholinergics, skeletal muscle relaxants, benzodiazepines, and tricyclic antidepressants.8,9 Unfortunately, use of these agents has been limited due to their undesirable adverse effects. Anticholinergic medications such as trihexyphenidyl and benztropine have shown some success in CD, usually at higher doses. Their pharmacologic effects are achieved by blocking acetylcholine. This same mechanism is responsible for the following adverse effects that make these medications difficult to tolerate: confusion, drowsiness, amnesia, constipation, xerostomia, and urinary retention.10-12 Skeletal muscle relaxants such as baclofen were often used in treating CD due to their ability to calm muscle spasticity.9,10 Baclofen is a derivative of GABA and is thought to act at the level of the spinal cord to cause muscle relaxation.11,13 Drowsiness is the most common adverse effect,Ü while confusion, dizziness, and nausea may also occur. Benzodiazepines such as clonazepam, lorazepam, and diazepam augment the inhibitory effects of GABA, which leads to their skeletal muscleñrelaxant properties and utility in CD. 9,10 It is possible for patients to tolerate high doses of benzodiazepines, but common and often dose-limiting adverse effects include sedation, confusion, dizziness, ataxia, and headache.11 Tricyclic antidepressants as well as carbamazepine (structurally related to the tricyclic antidepressants) have been used for CD in the past.9 The ability of these agents to block acetylcholine is the most likely explanation for their function in CD as well as for their limited use in this condition. Common adverse reactions include sedation, confusion, dizziness, and constipation.11,13

In 1989, the FDA approved the use of botulinum toxin type A (BoNTA) for the treatment of blepharospasm, a focal dystonia affecting the eye.10 In 2000, the FDA approved the use of BoNTA (Botox) and botulinum toxin type B (BoNTB as Myobloc) for the treatment of CD.10 Chemodenervation with botulinum toxin is the most effective treatment for CD, with more than 80% of those afflicted achieving relief of symptoms.8 BoNTA is considered the first-line therapy for CD, and BoNTB is considered an alternative for those nonresponsive to type A.10,14,15

Botulinum toxin is the most neurotoxic substance known to man.16 It is produced by the bacterium Clostridium botulinum and has seven different serotypes (A, B, C, D, E, F, and G).10,14 Each serotype has distinctively different properties and actions with an affinity to different proteins. BoNTA cleaves the synaptosomal-associated protein of 25 kd or SNAP-25, and BoNTB cleaves synaptobrevin.8,14 All botulinum serotypes work at the presynaptic nerve terminals, preventing the release of acetylcholine. The lack of acetylcholine results in the denervation of the muscle, producing paralysis. 14 Doses for BoNTA and BoNTB are not equivalent. Botulinum toxin type A is commercially available in 100-unit vials and botulinum toxin type B is commercially available in 2,500-, 5,000-, and 10,000-unit vials.5,8,14-16 The use of botulinum toxin is generally well tolerated. The most common adverse effects are dysphagia (approximately 20% of patients), upper respiratory infection, dry mouth, dyspepsia, and injection site pain. 5,15-17

Treating CD with botulinum may require a trial phase to determine the exact dose needed and the specific injection sites to alleviate symptoms.10 Botulinum toxin injections should only be injected into the muscles responsible for the abnormal posture. High doses (e.g., greater than 400 units of type A) or frequent injections (less than three months apart) should be avoided.17,18 BoNTA is the most studied serotype for the treatment of CD. According to a Cochrane review, eight studies have compared BoNTA to placebo, proving it is a safe and effective drug for the treatment of CD.18 However, concerns about long-term treatments and the development of immunoresistance may limit its usefulness in those who become unresponsive to BoNTA.17,18 Three studies have compared BoNTB to placebo to test its safety and efficacy in the treatment of CD.19 Both reviews concluded that both BoNTA and BoNTB are safe and effective treatments. Only two studies have directly compared BoNTA and BoNTB to each other. Comella et al compared the clinical efficacy of BoNTA versus BoNTB in CD, and Tintner et al directly compared the autonomic effects of both serotypes.8,20 These studies concluded that BoNTA had a longer duration of action than BoNTB, but patients experienced more constipation and less saliva production with BoNTA than with BoNTB. Other autonomic symptoms were similar between the serotypes.17,20 BoNTB is a viable option for those patients who have developed resistance to BoNTA. According to the American Academy of Neurology, physicians need to be specially trained in the pharmacology and proper clinical use of botulinum toxin; those untrained should not administer it.17 Injections are individualized, and modifications to a treatment regimen must be based on prior responses.17 It is recommended that physicians attend at least one course to acquire the necessary skills and gain experience to be competent in the administration of botulinum toxin injections for CD.17 Botulinum toxin injections can be administered on an outpatient basis with the use of electromyography (EMG).17 EMG produces a sound that can identify the electrical activity of the muscle while at rest and when it contracts. This tool is useful to ascertain which muscles require injections when they are not easily identified through physical examination.17 The Dystonia Medical Research Foundation and other support agencies are available to find physicians adequately trained in movement disorders and in the administration of botulinum toxin injections (TABLE 1).







Nonpharmacologic or complementary treatments have been used in conjunction with pharmacologic therapies to maximize results. Complementary treatments included physical therapy to stretch and strengthen muscles, relaxation techniques or stress-reduction activities, yoga, and acupuncture.3,10

Surgery

Surgical removal of the nerves responsible for the overactive muscles have been performed with focal dystonias such as CD, but these surgeries have had inconsistent results with short-term relief of symptoms.2,3 Deep brain stimulation of the globus pallidus is reserved for those patients refractory to current pharmacologic treatments.3,10 Electrodes are implanted in targeted areas of the brain and a battery-operated pulse generator is implanted under the patient's skin in the intraclavicular area. The electrodes and the generator are connected by a thin wire extending from a small opening in the skull to the generator under the collarbone.3,10,17 Implantation of the generator is performed under anesthesia, but the patient is awake during implantation of the electrodes to aid the surgeon in monitoring the patient's brain function.10 The batteries in the generator are activated and electrical currents are sent to the brain. Voltage settings are individualized and may take months to adjust to the correct voltage. This surgery does not eliminate the possible need for further pharmacologic treatments such as botulinum toxin injections.10 As with any surgery, risks include hemorrhage (rare), infection, and hardware malfunctions.10

Summary and Conclusion
Cervical dystonia is the third most common movement disorder. Currently, there is no cure for CD, but treatment options have improved over the years to enhance the quality of life for those suffering from this condition. Botulinum toxins type A and type B have been available for patients with CD since 2000. This therapy is more advantageous than past pharmacotherapeutic options for CD, which were limited in use due to significant adverse reactions. Botulinum toxins have resulted in modest effects by providing symptomatic relief and improving overall quality of life. The National Institute of Neurological Disorders and Stroke is currently conducting research to possibly find a cure and better treat those who are afflicted with dystonia.

References

1. Fahn S, Marsden CD, Calne DB. Classification and investigation of dystonia. In: Marsden CD, Fahn S, eds. Movement Disorders 2. London, England: Butterworths; 1987:332-358.

2. Dystonias Fact Sheet. National Institute of Neurological Disorders and Stroke. Available at: http://ninds.nih.gov/disorders/dystonias/details_dystonias.htm. Accessed October 15, 2007.

3. Tarsy D, Simon D. Dystonia. N Engl J Med. 2006;355:818-29.

4. Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol. 1998;78:1-10.

5. Botulinum toxin for cervical dystonia. Med Lett Drugs Ther. 2001;43:63-64.

6. Jankovic J, Leder S, Warner D, Schwartz K. Cervical dystonia: clinical findings and associated movement disorders. Neurology. 1991;41:1088-1091.

7. Frei K, Pathak M, Jenkins S, Truong D. Natural history of posttraumatic cervical dystonia. Move Disord . 2004;12:1492-1498.

8. Comella C, Jankovic J, Shannon K, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology. 2005;65:1423-1429.

9. Greene P, Shale H, Fahn S. Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Mov Disord. 1988;3:46-60.

10. Dystonia Medical Research Foundation. Available at: www.dystonia-foundation.org. Accessed October 5, 2007.

11. Clinical Pharmacology Web site. Available at: http://cp3.clinicalpharmacology-ip.com. ezproxy. mcphs.edu. Accessed October 30, 2007.

12. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology. 1986;36:160-164.

13. Micromedex Healthcare Series Web site. Available at: www.thomsonhc.com/ezproxy.mcphs.edu/home/dispatch. Accessed October 30, 2007.

14. Berman B, Seeberger L, Kumar R. Long-term safety, efficacy, dosing and development of resistance with botulinum toxin type B in cervical dystonia. Move Disord. 2005; 20:233-237.

15. Botox [package insert]. Irvine, CA: Allergan, Inc.

16. Myobloc [package insert]. Malvern, PA: Solstice Neuroscience, Inc.

17. Comella C, Janovic J, Mitchell B. Use of botulinum toxin type A in the treatment of cervical dystonia. Neurology. 2000;55(suppl 5):S15-S21.

18. Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database of Systematic Reviews. 2. 2006.

19. Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type B for cervical dystonia. Cochrane Database of Systematic Reviews. 1. 2006.

20. Tintner R, Gross R, Winzer U, et al. Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial. Neurology. 2005;65:765-767.

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