Primary Torsion Dystonia

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Background

Dystonia is a syndrome of sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures.[1]

In 1908, Schwalbe first described primary, or idiopathic, torsion dystonia in a Jewish family, and in 1911, Oppenheim termed this dystonia musculorum deformans (DMD).[2] Initially believed to be a manifestation of hysteria, idiopathic torsion dystonia gradually became established as a neurologic entity with a genetic basis. DMD and Oppenheim disease are terms now used for childhood- and adolescent-onset dystonia due to the DYT1 gene.

Advances in the area of dystonia genetics have identified new genetic loci and increased understanding of phenotypic spectrum. Dystonia can be either primary or secondary. Primary torsion dystonia (PTD), historically called DMD, is dystonia in isolation without brain degeneration and without an acquired cause. Secondary dystonia includes a heterogenous group of etiologies including inherited (without and with brain degeneration) and acquired neurologic disorders. The phenotypic spectrum associated with PTD is broad ranging, from early onset generalized to adult-onset focal dystonia.[3, 4]

Primary torsion dystonia may be focal, segmental, multifocal, or generalized, depending on which anatomic sites are involved (see Table 1).

Table 1. Anatomic Distribution of Primary Torsion Dystonia



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Pathophysiology

Although secondary forms of dystonia are frequently associated with structural lesions of the basal ganglia and thalamus, no consistent histologic or biochemical findings are noted in primary torsion dystonia. However, perinuclear inclusion bodies have been described in the midbrain reticular formation and in the periaqueductal gray matter in 4 patients in whom DYT1 was clinically documented and genetically confirmed.[5]

No discernible abnormalities are seen on current structural neuroimaging studies. Abnormal brain networks have been described in different functional imaging studies; substantial evidence implicates dysfunction in dopaminergic pathways in the pathophysiology of primary torsion dystonia.[6, 7]

Besides motor control difficulties, defective sensory processing and sensory abnormalities are described.[8, 9]

Current models of basal ganglia circuitry have been adapted and suggest dysfunction at the basal ganglia level.[10] These aberrations involve the direct and indirect pathways and result in impaired inhibition at the cortical level with consequent loss of normal inhibitory reflexes at the level of the brainstem and spinal levels.

See the image below for a diagram of the basal ganglia circuitry dysfunction in dystonia.



View Image

Idiopathic torsion dystonia. Major nuclear complex of the basal ganglia is the striatum, which is composed of the caudate and putamen. The striatum re....

Epidemiology

Frequency

United States

The relative frequencies of primary and secondary forms of dystonia are not known.

The prevalence of primary torsion dystonia is difficult to estimate because of the variation in its expression and the tendency for mild cases to go undiagnosed. In Rochester, Minnesota, the prevalence was calculated to be approximately 34 per million persons for generalized dystonia and 295 per million persons for all focal dystonia from a study conducted in 1980s.[11] Late-onset focal primary dystonia was 10 times more common than early-onset generalized primary torsion dystonia.[11]

Several large studies have shown that early-onset primary torsion dystonia is 5-10 times more common in Ashkenazi Jews than in people who were not Jewish or in Jewish individuals not of Ashkenazi heritage. Subsequent studies have found a wide range in the prevalence of dystonia from 6-7,320 persons per million population.[12, 13]

International

In a European collaborative study (the Epidemiological Study of Dystonia in Europe [ESDE]), investigators found a crude annual prevalence of 15.2 cases per 100,000 individuals, the majority of whom had focal dystonia at a rate of 11.7 cases per 100,000 individuals.[14]

Race

Childhood- and adolescent-onset primary dystonia is more common in Jews of Eastern European or Ashkenazi ancestry than in other groups.

Sex

In a large study of 957 cases of primary dystonia from Europe, segmental and focal dystonias had notable female predilections. This finding suggested that patients with focal dystonia should not be treated as a homogeneous group and that sex-linked factors may play a role.[14]

History

The following history should be elicited:

Physical

It is important to note the distribution of body parts affected. Although classification of the distribution is arbitrary, it may serve as a useful guide in clinical practice and may help in grouping families and patients for clinical trials and genetic studies.

Causes

Dystonia has historically been classified into 2 main etiologic groups: primary (idiopathic) and secondary (symptomatic).[1] Idiopathic dystonia was distinguished from the symptomatic dystonias both by its lack of known cause and the absence of consistent brain pathology. However, it has become clearer that idiopathic dystonia consists of a group of clinical syndromes that are likely to have a genetic basis. Primary dystonia is a genetically heterogeneous disease.[17, 18] . Currently, 20 DYT loci are recognized and dystonia forms are labeled DYT in the order they were discovered; 12 are inherited as autosomal dominant, 4 are inherited as autosomal recessive, and 1 (dystonia parkinsonism) is an X-linked recessive trait.[19]

Table 2 below lists the genetic loci for dystonia.

Table 2. Genetic Loci for Dystonia



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See the list below:

Laboratory Studies

See the list below:

Other Tests

A routine neurophysiological is not recommended as part of work-up towards the diagnosis and classification of dystonia. To differentiate patients with dopa-responsive dystonia from juvenile Parkinson disease presenting with dystonia, one can consider presynaptic dopaminergic scan (DAT) or fluorodopa (F-DOPA) scanning.[27]

Medical Care

Therapy for most people with dystonia is symptomatic, directed at controlling the intensity of the dystonic contractions.

Surgical Care

Surgical care is reserved for patients with severe symptoms in whom drug therapy fails. In general, it should be considered in patients with generalized dystonia because these patients are severely affected, because their condition is most likely to be refractory to therapy, or because they have unfavorable responses to medical therapy primarily due to adverse effects related to their need for increasing doses or to drug interactions from polypharmacy. Careful patient selection is one of the most important aspects of ensuring a successful surgical outcome.

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.

Trihexyphenidyl (Artane, Benzhexol hydrochloride)

Clinical Context:  Benefits often delayed by several wk; patients must take for several wk before full benefits appear. Trial may take as long as 3 mo.

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

Baclofen (Lioresal)

Clinical Context:  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.

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.

Clonazepam (Klonopin)

Clinical Context:  Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.

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.

Carbidopa/levodopa (Sinemet)

Clinical Context:  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.

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.

Tetrabenazine

Clinical Context:  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.

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.

Botulinum toxin A (Botox)

Clinical Context:  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)

Clinical Context:  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).

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]

Further Outpatient Care

See the list below:

Patient Education

For excellent patient education resources, see eMedicineHealth's patient education article BOTOX® Injections.

Author

Vijaya K Patil, MD, Assistant Professor, Department of Neurology, Edward Hines Jr Veterans Affairs Medical Center, Loyola University, Chicago Stritch School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jasvinder Chawla, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nestor Galvez-Jimenez, MD, MSc, MHA, The Pauline M Braathen Endowed Chair in Neurology, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai, Greenwich, Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova, Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.

Additional Contributors

Stephen T Gancher, MD, Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University

Disclosure: Nothing to disclose.

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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.

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.

Focal Body Site
Segmentaltwo or more contiguous body regions
Multifocaltwo or more noncontiguous body regions
Generalizedinvolving atleast one leg, the trunk and another body region
Hemidystoniainvolving one side of the body
Gene Inheritance Locus Features
DYT1* Autosomal dominant9q34Early onset generalized PTD; GAG deletion in DYT1 coding for torsin A
DYT2 Autosomal recessiveNoneAutosomal recessive in Gypsy populations; early onset
DYT3 X-linked recessiveXq13.1X-linked (ie, Lubag) dystonia parkinsonism; almost all due to a founder Filipino mutation; young adult-onset, cranial (including larynx and/or stridor) and limb dystonia, parkinsonism develops (or is present at onset) with shuffling, drooling
DYT4 Autosomal dominantNoneWhispering dysphonia in Australian family (autosomal dominant)
DYT5 Autosomal dominant14q22.1Childhood-onset dopa-responsive dystonia (DRD) and parkinsonism; autosomal dominant, sex influenced, reduced penetrance (higher in girls than in boys); gene encodes guanosine triphosphate cyclohydrolase I, with many different mutations
DYT6* Autosomal dominant8pAdolescent onset, mixed phenotype with limb, cervical, and cranial onset (limited and generalized spread); originally found in Amish-Mennonite families, but numerous variants have subsequently been found in families of European descent[14]
DYT7* Autosomal dominant18pLate-onset primary cervical dystonia in North German families
DYT8 Autosomal dominant2q33-35Paroxysmal nonkinesiogenic dyskinesia or chorea
DYT9 Autosomal dominant1p21Episodic choreoathetosis/spasticity (CSE), episodic choreoathetosis with spasticity
DYT10 Autosomal dominant16p11.2-q12.1Paroxysmal kinesiogenic dyskinesia/choreoathetosis
DYT11 Autosomal dominant7q21Myoclonus-dystonia, childhood-onset dystonia (especially limbs and neck) and myoclonus (especially neck, shoulders, face); often improves with alcohol
DYT12 Autosomal dominant19q13Rapid-onset dystonia parkinsonism
DYT13* Autosomal dominant1p36.13-35.32Prominent craniocervical and upper-limb involvement and mild severity in a large Italian family
DYT14 Autosomal dominant Redefined as DYT5[20]
DYT15 Autosomal dominant18p11Myoclonus dystonia[21]
DYT16 Autosomal recessive2q31Progressive, generalized, early onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia, and sometimes parkinsonian features, unresponsive to levodopa therapy[22]
DYT17 Autosomal recessive20p11.22-q13.12Primary focal torsion dystonia in a large Lebanese family[23]
DYT18 Autosomal dominant1p35-p31.3Paroxysmal exertion-induced dystonia with hemolytic anemia; autosomal dominant
DYT19† Autosomal dominant1p35-p31.3Episodic kinesigenic dyskinesia 2
DYT20† Autosomal dominant1p35-p31.3Paroxysmal nonkinesigenic dyskinesia 2
Note: Although the etiologies for these dystonic syndromes are attributed mainly to genetic causes and to no other secondary causes, only some of these conditions have dystonia as the sole clinical finding to fulfill the criteria for a diagnosis of primary torsion dystonia.



*Adapted from Bressman et al.[24]



†Adapted from Barrett and Bressman.[25]