Medication Summary
The goals of pharmacotherapy are to reduce morbidity and prevent complications. The following drug categories are commonly used medications in the treatment of dystonia.
Anticholinergics
Class Summary
In general, these are the most successful medications for oral therapy for most forms of dystonia. This family of drugs includes trihexyphenidyl (Artane), benztropine (Cogentin), procyclidine (Kemadrin), diphenhydramine (Benadryl), and ethopropazine (Parsidol). Approximately 40% of patients improve, though adverse effects often limit the benefits. Slow uptitration helps to reduce the occurrence of early adverse effects.
High doses of up to 120 mg/day have been used to achieve maximal benefit. [42, 43] In general, the dose is increased slowly in 3 or 4 divided doses until adverse effects limit further increases
Trihexyphenidyl (Artane, Benzhexol hydrochloride)
Benefits often delayed by several wk; patients must take for several wk before full benefits appear. Trial may take as long as 3 mo.
Muscle relaxants
Class Summary
The most commonly used muscle relaxant in dystonia is baclofen, but other muscle relaxants include tizanidine (Zanaflex) and cyclobenzaprine (Flexeril), with limited benefits reported in some patients. Adverse effects are common and include sedation and dysphoria.
Baclofen (Lioresal)
Derivative of gamma-aminobutyric acid (GABA) that reduces spinal-cord interneuron and motor neuron excitability, possibly by activating presynaptic GABA-B receptor by L-isomer. Effective in about 20% of patients. Appears to offer dramatic benefit in as many as 30% of children with dystonia, though not always sustained. Adults less likely than children to benefit.
Intrathecal baclofen infusion given with implanted refillable pump of some benefit in secondary dystonia, especially with spasticity (Ford, 1996). Patients with primary dystonia also may benefit. Before implantation, trial of intrathecal series of bolus infusions during lumbar puncture (LP) usually performed.
Benzodiazepines
Class Summary
Lorazepam and clonazepam (Klonopin) may be used. They should be uptitrated slowly and decreased gradually, as abrupt cessation may lead to withdrawal symptoms.
Clonazepam (Klonopin)
Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.
Dopaminergic medications
Class Summary
Levodopa is the first drug that many specialists in dystonia prescribe. The dopa-responsive form of dystonia shows a dramatic response to levodopa. Levodopa has minimal adverse effects (eg, nausea) and can be administered for an indefinite time. Rapid discontinuation is possible. Other dopamine agonists, such as pramipexole (Mirapex) may also be tried.
Carbidopa/levodopa is a valuable diagnostic and therapeutic tool for DRD; when administered in gradually increasing doses, it is well tolerated in children.
Carbidopa/levodopa (Sinemet)
Large neutral amino acid absorbed in proximal small intestine by saturable carrier-mediated transport system. Meals that include other large neutral amino acids decrease absorption. Only patients with meaningful motor fluctuations need consider low-protein or protein-redistributed diet. Increased consistency of absorption achieved when levodopa taken 1 h after meals. Nausea often reduced if levodopa taken immediately after meals; some patients with nausea benefit from additional carbidopa in doses up to 200 mg/d.
Half-life of levodopa/carbidopa approximately 2 h.
Provide at least 70-100 mg/d of carbidopa. When more carbidopa required, substitute 1 25-mg/100-mg tab for each 10-mg/100-mg tab. When more levodopa required, substitute 25-mg/250-mg tab for 25-mg/100-mg or 10-mg/100-mg tab.
Slow-release (SR) formulation absorbed more slowly and provides more sustained levodopa levels than immediate-release (IR) form. SR form as effective as IR form when levodopa initially required and may be more convenient when fewer intakes desired.
Antidopaminergic medications
Class Summary
The usefulness of these agents in primary dystonia is controversial. Some small controlled studies have shown a benefit, whereas others have not. Percentages of patients who benefitted in large, open-label studies were 11-30%.
The risk of developing permanent involuntary movements (ie, tardive syndromes) superimposed on preexisting dystonia limits the long-term use of most dopamine receptor blockers. Because of the risk of permanent tardive syndromes, typical neuroleptics should not be used to treat dystonia except in extremely severe cases.
Dopamine depleters, such as reserpine and tetrabenazine, are especially useful in the treatment of tardive dystonia. Neither tetrabenazine nor reserpine is convincingly implicated as the cause of tardive dyskinesia but they can cause transient acute dystonic reaction, parkinsonism, and depression. Atypical neuroleptics, such as clozapine, have been used to treat tardive dystonia. Initial data on the use of these agents in treating primary dystonia are not promising.
For severe dystonia in children, a combination of an anticholinergic, a dopamine depleter, and a dopamine receptor blocker called the Marsden cocktail, is reported to be of benefit. However, treatment with dopamine receptor blocker may cause involuntary movements (eg, dyskinesia, akathisia, dystonia) that may persist after the agent is stopped and may be permanent.
Tetrabenazine
Dopamine depleter/receptor blocker not available in United States but preferred over reserpine because, unlike reserpine, adverse effects and maximal benefits usually seen in < 2 wk.
Toxoids
Class Summary
Botulinum toxins are the most effective way to treat focal dystonia. The benefit from botulinum toxin A was proven in controlled trials for several focal dystonias: blepharospasm, torticollis, spasmodic dysphonia, and brachial dystonia.
Botulinum toxin B (Myobloc) is a sterile liquid formulation of purified neurotoxin that acts at neuromuscular junctions to produce flaccid paralysis by inhibiting acetylcholine release. It specifically cleaves synaptic vesicle-associated membrane protein (VAMP, also known as synaptobrevin), a component of the protein complex responsible for docking and fusion of synaptic vesicles to presynaptic membranes, a necessary step for neurotransmitter release. The most commonly reported adverse events are dry mouth, dysphagia, dyspepsia, and pain at the injection site.
In 2009, the FDA required a boxed warning for all botulinum toxin products (both type A and B) because of reports that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing effects similar to those of botulism. These effects have included life-threatening, and sometimes fatal, swallowing and breathing difficulties. Most of the reports involved children with cerebral palsy being treated for spasticity, which is not an approved use, but both approved and unapproved uses of these agents in adults have resulted in adverse effects. [44, 43]
Botulinum toxin A (Botox)
Potent neurotoxin that prevents release of acetylcholine at neuromuscular junction by specific action on proteins responsible for fusion of acetylcholine-containing vesicles with presynaptic membrane. Injected into affected muscle, producing temporary muscle weakness and atrophy. Seven serotypes; at present, only serotypes A and B are commercially available. Effect not permanent. Onset of benefit usually within 3-7 d. Duration of benefit may be 3-6 mo.
Botulinum Toxin Type B (Myobloc)
Paralyzes muscle by blocking neurotransmitter release. Cleaves synaptic vesicle association membrane protein (VAMP, synaptobrevin), component of protein complex responsible for docking and fusion of synaptic vesicle to presynaptic membrane (necessary step for neurotransmitter release).
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Idiopathic torsion dystonia. Major nuclear complex of the basal ganglia is the striatum, which is composed of the caudate and putamen. The striatum receives glutamatergic input from the cerebral cortex and dopaminergic input from the substantia nigra pars compacta (SNc). Two types of spiny projection neurons receive cortical and nigral inputs: those that project directly and those that project indirectly to the internal segment of the globus pallidus (GPI), which is the major output site of the basal ganglia. Complementary action of both of these pathways regulates the overall function of the GPI. The GPI, which, in turn, provides tonic inhibitory (ie, gamma-aminobutyric acid [GABA]–ergic) discharges downstream into the thalamic nuclei that project to the frontal cortical and other CNS areas. Direct pathway (D1) inhibits the substantia nigra pars reticulata (SNr) and the GPI, which are the major output sites, resulting in a net disinhibition and facilitation of thalamocortical circuits. Indirect pathway (D2), through serial connections with the globus pallidus pars externa (GPe) and the subthalamic nucleus (STN), is excitatory to the GPI, resulting in further inhibitory action on thalamocortical pathways. In this model, the mean discharge rate of the GPI is the key factor that determines a hypokinetic or hyperkinetic movement disorder. Increased inhibitory influences of the GPI on the thalamocortical circuitry result in hypokinetic disorders, such as Parkinson disease, whereas decreased GPI activity results in hyperkinetic disorders, such as hemiballismus. VL = ventrolateral thalamus.
Tables
Focal |
Body Site |
Segmental |
two or more contiguous body regions |
Multifocal |
two or more noncontiguous body regions |
Generalized |
involving atleast one leg, the trunk and another body region |
Hemidystonia |
involving one side of the body |
| Type | Designation | Mode of Inheritance | Gene | Gene Locus | OMIM# |
|---|---|---|---|---|---|
DYT1 |
Early-onset generalized | Autosomal dominant | TOR1A | 9q.34.11 | 128100 |
| DYT2 | Early-onset generalized | Autosomal recessive | Uknown | Uknown | 224500 |
| DYT3 | X-linked dystonia parkinsonism (Lubag syndrome) | X-chromosomal recessive | TAF1 | Xq13.1 | 314250 |
| DYT4 | Torsion dystonia (Whispering dysphonia) | Autosomal dominant | TUBB4A | 19p13.3 | 128101 |
| DYT5a | Dopa-responsive dystonia (Segawa disease) | Autosomal dominant | GCH1 | 14q22.1–22.2 | 128230 |
| DYT5b | Dopa-responsive dystonia | Autosomal recessive | TH | 11p15.5 | 605407 |
| DYT6 | Adolescent-onset mixed phenotype | Autosomal dominant | THAP1 | 8p11.21 | 602629 |
| DYT7 | Paroxysmal dystonic choreoathetosis | Autosomal dominant | Unknown | 18p | 602124 |
| DYT8 | Paroxysmal kinesigenic, nonkinesigenic dyskinesia | Autosomal dominant | MR-1 | 2q33–35 | 118800 |
| DYT9 | Paroxysmal choreoathetosis with spasticity | Autosomal dominant | CSE | 1p | 601042 |
| DYT10 | Paroxysmal kinesigenic dystonia | Autosomal dominant | PRRT2 | 16q11.2–12.1 | 128200 |
| DYT11 | Myoclonus dystonia | Autosomal dominant | SGCE | 7q21.3 | 159900 |
| DYT11 | Myoclonus dystonia | Autosomal dominant | DRD2 | 11q23.2 | 159900 |
| DYT12 | Rapid-onset dystonia parkinsonism (syndrome) | Autosomal dominant | ATP1A3 | 19q12–13.2 | 128235 |
| DYT13 | Early- and late-onset focal or craniocervical dystonia | Autosomal dominant | Unknown | 1p36.32-p36.13 | 607671 |
| DYT14 | Dopa-responsive generalized dystonia | ||||
| DYT15 | Myoclonus-dystonia | Autosomal dominant | Unknown | 18p11 | 607488 |
| DYT16 | Dystonia-parkinsonism syndrome | Autosomal recessive | PRKRA | 2q31.2 | 612067 |
| DYT17 | Adolescent onset | Autosomal recessive | Unknown | 20p11.2-q13.12 | 612406 |
| DYT18 | Paroxysmal exertion-induced dyskinesia | Autosomal dominant | SLC2A1 | 1p34.2 | 612126 |
| DYT19 | Paroxysmal kinesigenic dyskinesia 2 | Autosomal dominant | Unknown | 16q13-q22.1 | 611031 |
| DYT20 | Paroxysmal nonkinesigenic dyskinesia 2 | Autosomal dominant | Unknown | 2q31 | 611147 |
| DYT21 | Late-onset torsion dystonia | Autosomal dominant | Unknown | 2q14.3-q21.3 | 614588 |
| DYT22 | Unknown | Unknown | Not listed | ||
| DYT23 | Adult-onset cervical dystonia | Autosomal dominant | CIZ1 | 9q34 | 614860 |
| DYT24 | Focal dystonia | Autosomal dominant | ANO3 | 11p14.2 | 615034 |
| DYT25 | Adult-onset focal dystonia | Autosomal dominant | GNAL | 18p11.21 | 615073 |
