Torsion Dystonias 

Updated: Feb 15, 2016
Author: Priyantha Herath, MD, PhD; Chief Editor: Selim R Benbadis, MD 

Overview

Background

Dystonia is a syndrome of sustained muscle contractions of agonist and antagonist muscles, usually resulting in twisting, torsional, and repetitive movements or abnormal postures.[1]  It can either be primary or secondary. Primary torsion dystonia (PTD) is dystonia in isolation without brain degeneration and without an acquired cause. Secondary dystonia includes a heterogenous group of etiologies including inherited (with and without brain degeneration) and acquired neurologic disorders. The phenotypic spectrum associated with PTD is broad, from early-onset generalized to adult-onset focal dystonia.[3, 4]

The first description of what is now considered primary, or idiopathic, torsion dystonia was described by Schwalbe in 1908. In 1911, Oppenheim termed this same condition dystonia musculorum deformans (DMD) or dysbasia lordotica progressiva.[2] Initially believed to be a manifestation of hysteria, idiopathic torsion dystonia is now established as a specific neurologic entity with a well-established genetic basis. DMD and Oppenheim disease are terms now used for childhood- and adolescent-onset dystonia due to the DYT1 gene.

Classification of dystonia

At the present time there are 25 types of genetically determined dystonias. Several classification schemes have been used to categorize the various forms of dystonia. One common scheme is based on genetic features, including mode of inheritance and molecular genetic data. There is also a topographic classification where torsion dystonia may be described as focal, segmental, multifocal, or generalized, depending on which anatomic distribution of the symptoms (see Table 1).

Table 1. Anatomic Distribution of Primary Torsion Dystonia (Open Table in a new window)

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

In addition, depending on the clinical features, dystonias can be divided into two main groups: isolated dystonia or combined dystonia. Combined dystonia can be classified into three sub-types: those accompanied by parkinsonism, by myoclonus, or by a mixed pattern of various hyperkinetic movements.

Genetically defined isolated dystonias include TOR1A/DYT1, TUBB4/DYT4, THAP1/DYT6, PRKRA/DYT16, CIZ1/DYT23, ANO3/DYT24, and GNAL/DYT25. Combined dystonias, accompanied by parkinsonism with known genetic loci include TAF1/DYT3, GCH1/DYT5a, TH/DYT5b, and ATP1A3/DYT12. Genetically determined dystonias that are accompanied by myoclonus include SGCE/DYT11, whereas dystonias that accompany a mixed pattern of hyperkinetic disorders include MR-1/DYT8, PRRT2/DYT10, and SLC2A1/ DYT18.[51]  

Sometimes, combined dystonias are also classified depending on whether the symptoms are continually and continuously present or whether they are paroxysmal. Generic forms of common, persistent combined dystonias are GCH1/ DYT5a, TH/DYT5b, SGCE/DYT11, APT1A3/DYT12, and TAF1/ DYT3. Genetically defined paroxysmal combined dystonias include MR-1/DYT8, PRRT2/DYT10, and SLC2A1/DYT18.[51]  

DYT1 (early-onset generalized dystonia)

DYT1 are caused by a 3-base pair in-frame deletion within the coding region of the TOR1A (torsinA) gene located on chromosome 9q34. TorsinA is expressed at high levels in neuronal cytoplasm of specific neuronal populations in the adult human brain, including the SN, thalamus, cerebellum, hippocampus, and neostriatum.

DYT1 is the most common hereditary dystonia. Phenomenologically, it is an isolated dystonia. Some degree of genetic anticipation in regards to the age of onset and disease severity has been noted in DYT1. It is especially common among the Ashkenazi Jewish population.

In most instances, DYT1 symptoms often start with a focal dystonia as talipes equinovarus of one leg in early childhood, typically around 6 years of age. The dystonic posturing then gradually progresses with age to other extremities and trunk muscles by the early teens. There is obvious asymmetry to the dystonia, with involvement of the extremities on the dominant side along with the ipsilateral sternocleidomastoid muscle. In these patients, interlimb coordination and locomotive movements are not affected at all. Moreover, intellectual, mental, and psychological functions are completely intact in these patients.

Based on clinical characteristics, DYT1 can be classified into two types: the postural type with appendicular and truncal dystonias, or the action type, which is associated with violent dyskinetic movements in addition to dystonic posture.

DYT5 (dopa-responsive dystonia)

Hereditary progressive dystonia with marked diurnal fluctuation, or Segawa disease, is an autosomal dominantly inherited dopa-responsive dystonia (DRD) caused by heterozygous mutations of the GCH1 gene located on chromosome 14q22.1-q22.2. DYT5 shows a marked female predominance in the young. In contrast, adult-onset cases show a male predominance

Onset is around 6 years of age, mostly with rigid talipes equinovarus of one foot not dissimilar to DYT1. With age, it expands to other limbs and trunk muscles by the midteens with progressive rigidity. Starting around age 10 years, postural tremor of 8 to 10 Hz appears. These symptoms show marked diurnal fluctuations, worsening through the day and almost absent in the early morning. However, this fluctuation decreases with age in the late teens, and is no longer apparent in early adulthood, when symptoms become static. Clinically, DYT5 is also classified into two types: postural and action. Patients with the action type develop dystonic movements of one extremity or the neck (action retrocollis) in addition to dystonic, and show focal or segmental dystonia during the teenage years.

Pathophysiology

In DYT1 and the other genetic dystonias, no consistent histologic or biochemical abnormalities have been identified. 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]  This is in contrast, however, to the secondary forms of dystonia that are frequently associated with macroscopic structural lesions of the basal ganglia and thalamus.

As such, in primary torsion dystonias and other genetic dystonias no discernible abnormalities are seen on 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]  but these findings are inconsistent.

While the exact pathogenesis of dystonia is unknown, based on the current models of basal ganglia circuitry, some form of electro-biochemical dysfunction at the basal ganglia level has been proposed as the underlying unifying mechanism behind various forms of dystonia.[10]  Such dysfunctions may involve direct and indirect pathways and result in impaired center-surround inhibition at the cortical level. 

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

Idiopathic torsion dystonia. Major nuclear complex 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.

Epidemiology

Frequency

The exact relative frequencies of primary and secondary forms of dystonia remain unknown.

The prevalence of primary torsion dystonia is difficult to estimate because of the variation in its phenotypic 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]

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 and seemingly rare in Far Eastern populations.

  • Many cases of early primary torsion dystonia, especially those among non-Jewish populations, are not due to the TOR1A GAG deletion in DYT1. The DYT6 locus was identified by means of linkage analysis in 15 affected members from 2 Swiss Mennonite families.[15]

  • A genome-wide search for primary torsion dystonia in a large family from central Italy in whom 11 members were definitely affected revealed a novel locus, namely, DYT13.[16]

Gender

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]

 

Presentation

History

When evaluation a patient with what appears to be a dystonic syndrome, the following history should be documented:

  • Age of onset

  • Initial site of involvement and progression to other body sites and time course of progression

  • Occurrence of dystonia at rest, with any specific voluntary action, or posture maintenance

  • Presence or absence of tremor or other movement disorders

  • Presence or absence of a sensory trick, or geste antagoniste[52]

  • A family history of similar symptoms or other involuntary movements, the age of onset of similar symptoms, and body part predominantly affected

  • Previous therapeutic trial and response to low-dose levodopa, to exclude dopamine-responsive dystonia

  • Any secondary etiologies, such as trauma, infectious process, birth injury, or developmental delay

  • Exposure to any medications reported to cause dystonia, such as levodopa, dopamine agonists, antipsychotics, neuroleptics, dopamine-blocking agents, metoclopramide, fenfluramine, flecainide, ergot agents, anticonvulsive agents, and certain calcium channel blockers

  • Other complaints associated with the dystonic symptoms

  • Pain, which is not usually a prominent feature except in some cases of cervical dystonia and other forms of secondary dystonia (eg, reflex sympathetic dystrophy and foot dystonia occurring with Parkinson disease)

  • Aggravating or attenuating factors

  • Degree of functional impairment resulting from the dystonia

  • Additional questions about the following may help in determining if dystonia is affecting other body parts (such involvement might not be otherwise volunteered):

    • Increased blinking

    • Intermittent puckering of the mouth

    • Chewing movements

    • Tongue popping

    • Stuttering

    • Difficulty speaking

    • Becoming breathless when speaking with a soft voice

    • Turning, tilting, or shifting of the head in any direction

    • Jerking of the head

    • Twisting of the body

    • Tremors of the hands or feet, arms, or legs

    • Twisting or moving involuntarily when using hands or walking

    • Difficulty with writing

    • History of clumsiness

    • Cramps when using the hands or legs

    • Toes going up or down involuntarily or being pigeon toed

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.

Distributions are classified as follows:

  • Focal (single body region)

  • Segmental (2 or more contiguous regions)

  • Multifocal (2 or more noncontiguous regions)

  • Hemidystonia (involving one side of the body)

  • Generalized (leg, trunk, and one other region or both legs with or without trunk involvement plus 1 other region)

The central features that distinguish dystonia from other involuntary movement disorders are the posture-assuming features or directional quality and patterned predictable involvement of a specific set of muscles involved.

Although the pattern of muscle contractions in dystonia is consistent and predictable, involuntary movements vary with changing postures or tasks.

The site of involvement may remain focal or progress to involve other parts of the body over time.

The speed of dystonic contractions may be rapid or slow.

Various sensory tricks may be performed that diminish the dystonic movements, termed geste antagoniste.

Dystonic movements intensify with voluntary action. Movements of primary dystonia commonly occur with specific actions and are not present at rest. As the dystonic condition progresses, relatively nonspecific voluntary actions can bring out the dystonic movements. With still further worsening, the affected limb can develop dystonic movements while at rest, and the patient eventually develops sustained posturing.

Irregular, rhythmic contractions termed dystonia tremors may be observed. The tremor is irregular compared to the tremor seen in essential tremor.

Facial muscles are affected, as manifested by patterned and sustained contractions of the forehead, eyelids, and lower face. Limbs may be affected as well, and specific voluntary tasks may intensify such contractions. Examples are writing when the upper extremities are affected and walking forward but not backward when lower extremities are affected.

It is important to note other physical and abnormal neurologic findings in addition to the dystonia.

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, 25 DYT loci are recognized and dystonia forms are labeled DYT in the order they were discovered; 20 are inherited as autosomal dominant, 4 are inherited as autosomal recessive, and 1 (dystonia parkinsonism) is an X-linked recessive trait.[19, 51]

Table 2 below lists the genetic loci for dystonia.

Table. (Open Table in a new window)

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

Table. (Open Table in a new window)

Primary dystonia

  • Idiopathic or primary torsion dystonia: Despite a negative family history, a genetic basis for dystonia is not ruled out completely, as its mode of inheritance is usually autosomal dominant with incomplete penetrance.

  • Sporadic and familial torsion dystonia (various genetic forms; see Table 2)

  • Inherited (ie, hereditary) dystonia (various genetic forms; see Table 2)

Secondary dystonia

  • Vascular

    • Cerebrovascular, or ischemic injury

    • Arteriovenous malformation

    • Perinatal cerebral injury

  • Infectious
    • Viral encephalitis

    • Subacute sclerosing panencephalitis

    • AIDS

    • Creutzfeldt-Jakob disease

Trauma

  • Head trauma

  • Peripheral trauma

  • Space-occupying lesions in the brain

Drugs

  • Levodopa, dopamine agonists, antipsychotics, metoclopramide, fenfluramine, flecainide, ergot agents, anticonvulsant agents, certain calcium channel blockers

Toxins

  • Manganese, carbon monoxide, carbon disulfide, methanol, disulfiram, wasp sting

Metabolic conditions

  • Kernicterus

  • Wilson disease

  • Amino acid disorders

  • Glutaric acidemia

  • Methylmalonic acidemia

  • Homocystinuria

  • Hartnup disease

  • Tyrosinosis

  • Lipid disorders

  • Metachromatic leukodystrophy

  • Neuronal ceroid lipofuscinosis

  • Dystonic lipidoses - Niemann-Pick disease, type C (ie, sea blue histiocytosis)

  • Primary antiphospholipid antibody syndrome

  • Gangliosidoses (ie, GM1, GM2)

  • Mitochondrial encephalopathies (eg, Leigh disease, Leber disease)

  • Lesch-Nyhan syndrome

  • Triosephosphate isomerase deficiency[26]

  • Vitamin E deficiency

  • Biopterin deficiency

Genetic factors

  • Dystonia plus syndromes

  • Myoclonus dystonia

  • Dopa-responsive dystonia (DRD)

  • Rapid-onset dystonia parkinsonism

  • Lubag or X-linked dystonia parkinsonism

Neurodegenerative conditions

  • Progressive supranuclear palsy

  • Multiple systems atrophy

  • Corticobasal-ganglionic degeneration

  • Hallervorden-Spatz disease

  • Hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration (HARP) syndrome

  • Neuroacanthocytosis

  • Spinocerebellar ataxia (SCA), types 1, 2, or 3

  • Ataxia telangiectasia

  • Huntington disease

  • Dentatorubropalidoluysian atrophy

Demyelination

Other structural conditions

  • Atlantoaxial subluxation

  • Syringomyelia

  • Arnold-Chiari malformation

  • Congenital Klippel-Feil syndrome

 

DDx

Diagnostic Considerations

If dystonia clinically manifests with another syndrome complex, consider the following differential diagnoses:

  • Parkinsonism -Dopamine-responsive dystonia, juvenile Parkinson disease, Huntington disease, X-linked dystonia parkinsonism, rapid-onset dystonia parkinsonism, dystonic lipidoses, Hallervorden-Spatz disease, corticobasal ganglionic degeneration, basal ganglia calcification, progressive supranuclear palsy, Parkinson disease, Machado-Joseph disease (SCA, type 3), Wilson disease, gangliosidoses, neuroacanthocytosis

  • Neuropathy - Metachromatic leukodystrophy, acanthocytosis, SCA types 2 and 3, GM2 gangliosidosis

  • Ataxia - Ataxia-telangiectasia, neuronal ceroid lipofuscinosis, metachromatic leukodystrophy, Hartnup disease

  • Optic and/or retinal conditions - GM2 gangliosidosis, Hallervorden-Spatz disease, metachromatic leukodystrophy

  • Oculomotor findings - Dystonic lipidoses, SCA types 1-3, ataxia-telangiectasia, corticobasal ganglionic degeneration, progressive supranuclear palsy, Huntington disease

  • Tics -Neuroacanthocytosis

Differential Diagnoses

 

Workup

Approach Considerations

Routine laboratory and neurophysiological investigations are not recommended as part of workup to diagnosis and classify dystonia. Most often, the diagnosis is clinical. However, a useful investigative algorithm for dystonia workup is given here. 

Laboratory Studies

The following is recommended when age of onset is younger than 26 years (or the patient has a relative with early-onset dystonia):

  • DYT1 testing (with genetic counseling)

  • If negative for DYT1 testing, consider trial of levodopa

  • If no response to levodopa trial, perform MRI, ceruloplasmin test, and slitlamp examination

The following is recommended when age of onset is older than 26 years:

  • MRI

  • 24-hour copper urinary excretion

To differentiate patients with dopa-responsive dystonia from junvenile Parkinson disease presenting with dystonia, one can consider presynaptic dopaminergic scan (DAT) or fluorodopa (F-DOPA) scanning.[27]

The following is the proposed algorithm for dystonia workup when the history and physical findings show dystonia and other deficits:

  • Possibly tardive condition: Assess for a history of exposure to a dopamine- blocking agent

  • Possibly structural condition: Perform MRI and CT angiography

  • Possibly metabolic and/or neurodegenerative: Perform the following:

    • Trial of levodopa

    • Measurement of 24-hour serum copper excretion

    • Slitlamp examination

  • MRI of brain
  • Blood smear for acanthocytes
  • Antiphospholipid antibody testing
  • Genetic testing for Huntington disease, SCA, mitochondrial diseases
  • Lysosomal screening (GM1, GM2 gangliosidoses)
  • Test for serum and urine organic acids and amino acids
  • Chromosomal analysis
  • Alpha-fetoprotein test
  • Determination of lactate and pyruvate in serum and CSF with the lactate-pyruvate ratio
  • Skin, muscle, and nerve biopsy
  • CSF analysis
 

Treatment

Medical Care

Available therapies for dystonia include oral medications or subcutaneous botulinum toxin injections, surgical procedures, and physical and/or rehabilitation therapies.[28, 29] Therapy for most people with dystonia is symptomatic, directed at controlling the intensity of the dystonic contractions.

  • Although no curative treatment for dystonia is available, treatment of the underlying disorder may help reverse symptoms in patients with secondary forms of dystonia (eg, from Wilson disease or DRD).

  • Early diagnosis and start of treatment for dystonia, though not proven to alter its course or increase the likelihood for remission, may improve quality of life and alleviate the disability of patients with dystonia.

  • Overall, about 40% of patients improve with oral therapy. Adverse effects of the particular agents used can limit the benefits.

  • Overall, the goals of therapy should be directed at increasing movement, alleviating pain, preventing contractures, restoring functional abilities, and minimizing adverse effects from medical therapy.[30]

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.

  • Thalamotomy was originally the preferred surgery for dystonia.[31] However, GPI pallidal deep brain stimulation (DBS) has produced remarkable improvement in dystonic symptoms associated with Parkinson disease. In light of this, pallidotomy or thalamotomy is no longer considered appropriate.

  • With the development of high-frequency stimulation as an alternative to the creation of surgical lesions, surgical procedures have become safer and adverse effects are easier to control than before. As the disease progresses, stimulation may be varied.[32]

  • Over the past few years, DBS of the globus pallidus interna (GPI) has gained widespread acceptance as an effective treatment for primary generalized dystonia.[33, 34, 35] {ref36

  • GPI DBS is becoming popular in patients with primary dystonia because of its effectiveness and safety. It can be proposed at the initial phase of the disease to limit the functional consequences and to improve the prognosis for functional recovery. The consensus is that the secondary forms are less responsive than primary forms, yet responses in secondary forms do occur.[39]

  • Selective peripheral denervation with partial rhizotomy performed by an experienced surgeon may have a role in cervical dystonia that does not respond to other therapies.[41]

  • Myectomy may be beneficial for blepharospasm and minimally effective for cervical dystonia. Problems include weakness and disfigurement.

 

Medication

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).