DYSTONIA

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CHAPTER 35 DYSTONIA

The dystonias are an unusual group of movement disorders whose main feature is involuntary muscle contraction or spasm. The term dystonia was originally introduced by Hermann Oppenheim in 1911 to describe alterations in muscle tone and postural abnormalities that are seen in this condition. The concept of dystonia can be confusing because the term has been used to describe a symptom (e.g., a dystonic arm posture), a disease (primary torsion dystonia), or a syndrome. The dystonias constitute a relatively common group of movement disorders that encompass a wide range of conditions from those in which the only manifestation is dystonic muscle spasms to those in which dystonia is one part of a more severe neurological condition.

DEFINITION AND CLASSIFICATION

Dystonia is characterized by involuntary sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures.¹ The movements range from slower twisting athetosis to rapid, shocklike jerky movements. They are repetitive and sometimes rhythmic and can be accompanied by tremor. Dystonic movements can be aggravated by movement (action dystonia) that can be nonspecific or task-specific (e.g., writing). Over time the dystonia can occur with less specific movements and eventually can be present at rest, leading to sustained abnormal postures.

Three basic approaches are used to classify dystonia: age at onset, distribution of affected body parts, and etiology. The categories of age at onset and affected body distribution (Table 35-1) are important in describing clinical signs and have clinical implications for prognosis and treatment.

TABLE 35-1 Classification of Dystonia

Age at Onset

Early: <26 years

Late: >26 years

Distribution:

Focal: Single body part affected

Neck: cervical dystonia (spasmodic torticollis)

Eyelids: blepharospasm

Mouth: oromandibular dystonia

Larynx: laryngeal dystonia

Hand or arm: writer’s cramp and other limb dystonias

Segmental: two or more contiguous body parts

Cranial: head and/or neck

Axial: neck and trunk

Brachial: one arm and axial; both arms ± neck ± trunk

Crural: one leg and trunk, both legs ± trunk

Generalized: segmental crural and any other segment

Multifocal: two or more noncontiguous parts

Hemidystonia: ipsilateral arm and leg

Etiology

Primary

Dystonia is only sign, plus tremor; no acquired or degenerative cause

Secondary

Inherited

Dystonia-plus syndromes

Heredodegenerative disorders

Acquired

Structural lesions, drugs, toxins, etc.

Complex/unknown

Dystonia associated with parkinsonism

±, with or without.

Age at Onset

Dystonia can develop at any age, although those with earlier age at onset are more likely to have a more severe course affecting more of the body. The ages at onset were initially divided into childhood (0 to 13 years), adolescence (13 to 21 years) and adulthood (>21 years), but a more pragmatic division into early (<26 years) and late (>26 years) onset is now used.

Distribution

The distribution distinguishes patients on the basis of whether dystonia is localized to a single body region (focal), whether it has spread to contiguous (segmental) or noncontiguous (multifocal) regions, or whether the legs are affected along with other body regions (generalized). The age at onset and the body distribution are related: The earlier the age at onset, the more likely dystonia is to be severe, spreading to a generalized distribution. In addition, the body region first affected is also important: Onset in the legs is most frequent during childhood, and with increasing age, the site of onset ascends to the arms/hands, neck, and then cranial muscles. Thus, childhood limb onset dystonia usually generalizes; writer’s cramp occurs with a mean onset in the 30s and can spread to become segmental dystonia; cervical dystonia has a mean onset in the 40s, and blepharospasm usually starts in the sixth decade, and both usually remain focal.

Etiology

The third approach to classification is by etiology. Dystonia can be divided into primary and secondary or symptomatic dystonia. Primary torsion dystonia (PTD) comprises a group of dystonias with predominantly genetic causes. Phenotypically, in PTD, dystonia must be the only clinical feature (except for tremor of the arms or head and neck), and there must be no evidence of neuronal degeneration or acquired cause. Secondary dystonias make up all other causes and are divided into inherited, complex, and acquired causes. Among the inherited causes are the dystonia-plus syndromes, which are characterized by the presence of dystonia plus other neurological features and have a genetic basis without evidence of neurodegeneration. Dystonia can also be part of a more widespread neurological disorder in which there is underlying neurodegeneration (such as Wilson’s disease), and these are referred to as heredodegenerative causes.

EPIDEMIOLOGY

The true population incidence and prevalence of dystonia are unknown. The prevalence data available are usually based on studies of diagnosed cases only and therefore are underestimates of the real numbers. This is particularly the case with dystonia, which can manifest in a variety of ways, and a significant number of cases of focal dystonia are undiagnosed or even misdiagnosed. In an early study in the United States that was based on case note review, the prevalence for PTD was estimated to be 329 per million population. In more recent studies of diagnosed cases in Japan and Europe, the prevalence was estimated to be between 101 and 150 per million. The most reliable estimate is from an ongoing study in the northeast of England, where ascertainment was more complete, and some previously undiagnosed cases were identified. This finding has implied a prevalence rate of 485 per million. The prevalence of secondary dystonia is unknown, although it is estimated from case series that it may be less than 20% to 25% the rate for PTD.

The most prevalent form of PTD is focal dystonia, of which cervical dystonia is the commonest, with prevalence rates reported between 57 and 290 per million population. Rates for blepharospasm are 17 to 80 per million, and for writer’s cramp, 14 to 61 per million.

In a study in South Tyrol in Austria, a random sample of the population older than 50 years was examined.² Primary dystonia was diagnosed in 6 of the 707 individuals studied, implying a prevalence of 7320 per million in this age-selected population, although 95% confidence intervals were very wide, at 3190 to 15,640, because of the small sample. However, this indicates that in the aging population, dystonia is a relatively common neurological disorder.

CLINICAL FEATURES

The diagnosis of dystonia is based on clinical findings. Primary dystonia has no other neurological features apart from dystonia and tremor.³ Features suggestive of a secondary cause of dystonia are listed in Table 35-2. Investigations are usually performed to help rule out a secondary cause of dystonia.

TABLE 35-2 Clinical Features Suggestive of Secondary Dystonia

Primary Dystonia

Early-Onset Primary Torsion Dystonia (Dystonia Musculorum Deformans, Oppenheim’s Dystonia)

The commonest cause of early onset PTD is mutation in the DYT1 gene on chromosome 9q34, which is inherited as an autosomal dominant trait with reduced penetrance (30% to 40%). The disorder typically manifests in childhood or adolescence (mean age at onset, 12 years) with dystonia causing posturing of a foot, leg, or arm. Dystonia is usually first apparent with specific actions (e.g., writing or walking) but becomes evident with less specific actions over time and spreads to other body regions. No other neurological abnormalities are present apart from postural arm tremor. Disease severity varies considerably even within the same family, and isolated writer’s cramp may be the only sign. However, approximately 60% to 70% of individuals have progression to generalized or multifocal dystonia involving at least a leg and an arm, and often axial muscles. In 10% of cases, segmental dystonia develops, and only 25% remain focal. The cranial muscles are involved in about 10% of affected patients.

Key investigations are to exclude treatable differential diagnoses, such as Wilson’s disease and dopa-responsive dystonia (DRD). DYT1 dystonia is diagnosed through molecular genetic testing of the TOR1A gene, which reveals a three-base pair deletion in all affected individuals. There is a higher prevalence of DYT1 PTD in the Ashkenazi Jewish population, which is the result of a founder mutation that appeared about 250 years ago.

Most forms of early-onset PTD are genetic in origin, and Table 35-3 lists the genetic forms that have been identified to date. Most are autosomal dominant, some reported only in single families. The existence of autosomal recessive forms (DYT2) is controversial.

TABLE 35-3 Genetic Forms of Primary Dystonia

Secondary/Symptomatic Dystonias

Dystonia-Plus Syndromes

Dystonia-plus syndromes describe a group of conditions that can be distinguished from PTD on the basis of clinical characteristics found in addition to dystonia, or specific pharmacological responses. They usually have a genetic etiology but do not have underlying neurodegeneration. The group comprises three distinct conditions: DRD, myoclonus dystonia syndrome, and rapid-onset dystonia parkinsonism (RDP).

Dopa-responsive dystonia

DRD was first described in Japan in 1977 by Masaya Segawa. Patients typically present in childhood with gait disturbance caused by foot dystonia. The dystonia frequently worsens as the day goes on (diurnal variation) and is relieved by rest or sleep. Progression is variable; some patients develop severe generalized dystonia, whereas others develop features suggestive of lower limb spasticity. Parkinsonian features such as bradykinesia and rigidity can develop in later life in some affected individuals but can also be the presenting features in adult life in a minority of cases. On occasion, DRD can manifest with adult-onset limb dystonia (e.g., writer’s cramp), with cranial or cervical dystonia, or with signs resembling spastic paraplegia. In most cases, DRD is inherited as an autosomal dominant trait with reduced penetrance.

The key feature in DRD is a dramatic and sustained response to small doses of levodopa (L-dopa), often as low as 50 to 200 mg. Benefit is usually apparent within days to weeks, and the motor complications of L-dopa treatment seen with Parkinson’s disease rarely develop, even with long-term treatment. Anticholinergic drugs also can be beneficial.

The principal considerations in the differential diagnosis for childhood DRD are early-onset PTD, spastic paraplegia and cerebral palsy, and early-onset parkinsonism, especially when it is caused by mutations in the parkin gene. The patients thought to have early-onset parkinsonism often present with dystonia and show good initial response to L-dopa. However, clues to the diagnosis come from the inheritance pattern (usually autosomal recessive for the parkin gene) and the occurrence of motor fluctuations and dyskinesias with L-dopa treatment. Positron emission tomography (PET) with markers for presynaptic dopaminergic terminals (¹⁸F-dopa) or single photon emission computed tomography can also differentiate between the two conditions.

The gene for dominant DRD has been mapped to chromosome 14 (DYT5) and mutations within the gene for guanosine triphosphate (GTP) cyclohydrolase 1 have been identified. Numerous mutations have been identified in all five exons, which makes genetic testing laborious. Other extremely rare forms of DRD have been reported, including a recessive form with genetic deficiency of tyrosine hydroxylase and defects in other enzymes involved in pterin synthesis. The diagnosis can usually be confirmed by an excellent response to L-dopa treatment in dosages slowly increasing up to 400 mg a day. Alternatively detecting reduced levels of pterins in the cerebrospinal fluid or an abnormal oral phenylalanine loading test can substantiate the diagnosis.

Myoclonus-dystonia syndrome

Myoclonus-dystonia syndrome (MDS) is characterized by the presence of dystonia in combination with brief lightning-like myoclonic jerks. It is frequently inherited as an autosomal dominant trait, caused by mutations in the gene for ε-sarcoglycan (DYT11), although sporadic cases also occur. A further autosomal dominant locus (DYT14) has been mapped to chromosome 18.

MDS usually has onset in childhood or early adolescence, with myoclonic jerks affecting the upper limbs and axial muscles (trunk and neck). The myoclonus can occur on rest and also be precipitated by action. Dystonia occurs in approximately two thirds of patients; cervical dystonia and writer’s cramp are the most common forms. On occasion, dystonia affects the legs. Several reports have identified psychiatric features associated with MDS, including obsessive-compulsive disorder, panic attacks, and anxiety. Most affected patients note significant relief of symptoms with alcohol or benzodiazepines and can have marked rebound of symptoms after administration of these drugs. This can often lead to abuse of these substances.

Rapid-onset dystonia parkinsonism

Rapid-onset dystonia parkinsonism (RDP) is a rare autosomal dominant movement disorder with reduced penetrance. It is characterized by abrupt or subacute onset of both dystonia and parkinsonism with prominent bulbar involvement. Symptoms, including dystonic posturing of the limbs, bradykinesia, dysarthria, and dysphagia, and postural instability, develop over hours to days, followed by little or no progression. Onset is usually in adolescence or young adulthood, and the subacute extrapyramidal storm can be preceded by stable mild limb dystonia for a number of years. Potential triggers in some families include emotional trauma, extreme heat, or physical exertion.

Investigation with magnetic resonance imaging (MRI), computed tomography, and PET of the presynaptic dopamine uptake sites has yielded normal results. In some patients, reduced levels of cerebrospinal fluid dopamine metabolites have been detected. The current assumption is that RDP is caused by neuronal dysfunction rather than neurodegeneration.

The condition is rare, and only a small number of families with evidence of autosomal dominant inheritance with reduced penetrance have been described. The gene was mapped to chromosome 19q13.2 (DYT12), and mutations in the gene for the Na⁺/K⁺-adenosine triphosphatase α₃ subunit (ATP1A3) have been identified in seven unrelated kindreds with RDP. This finding implicates the Na⁺/K⁺ pump, which is crucial for maintaining the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

Secondary Dystonia

The term secondary implies that an identifiable cause for the dystonia can be found. Many of these directly involve the basal ganglia and lead to contralateral hemidystonia. Table 35-4 summarizes the most common causes of secondary dystonia. Strokes, tumors, vascular malformations, and traumatic injuries to the basal ganglia are well-described causes of dystonia, but dystonia also, more rarely, occurs after injury to cortical or brainstem structures, the spinal cord, and even peripheral nerves. Perinatal injury may cause dystonia at the time of brain injury (dystonic or choreoathetoid cerebral palsy) or can lead to delayed-onset dystonia, which can begin years after the injury and progress. Infectious, postinfectious, and inflammatory syndromes associated with dystonia usually manifest in combination with other movement disorders, such as parkinsonism, chorea, athetosis, and tics. Drugs may also cause transient or chronic (tardive) dystonia. Acute dystonic reactions occur shortly after the introduction of a drug and have been described for a number of drugs, including dopamine receptor-blocking (DRB) agents, antidepressants (selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), calcium antagonists, general anesthetic agents, anticonvulsants (carbamazepine, phenytoin), L-dopa, ranitidine, 3,4-methylenedioxymethamphetamine (“ecstasy”), and cocaine. Tardive dystonia is usually seen with use of dopamine receptor-blocking drugs and is defined as dystonia present for at least 1 month and occurring either during or within 3 months of discontinuation of a dopamine receptor-blocking drug. It most commonly affects the face and neck but can spread and even generalize in some cases.

TABLE 35-4 Secondary Causes of Dystonia

Cause	Examples
CNS lesion	Brain tumor, stroke, hypoxia, intracranial hemorrhage, CNS trauma, congenital malformations, cervical cord lesions
Perinatal cerebral injury	Cerebral palsy, delayed-onset dystonia, perinatal hypoxia, kernicterus
Infectious, postinfectious, and inflammatory	Subacute sclerosing panencephalopathy, Reye’s syndrome, viral encephalitis, Creutzfeld-Jakob disease, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren’s syndrome
Peripheral nerve injury
Drug-induced	Dopaminergic agents (L-dopa, dopamine agonists), dopamine receptor–blocking drugs (neuroleptics, prochlorperazine, metoclopramide), selective serotonin reuptake inhibitors, MAO inhibitors, antiepileptic drugs, ergots, flecainide, cocaine, ranitidine, calcium antagonists, anesthetic agents
Toxin-induced	Manganese, carbon monoxide, carbon disulfide, cyanide, methanol, disulfiram, wasp sting venom
Metabolic	Hypoparathyroidism

CNS, central nervous system; L-dopa, levodopa; MAO, monoamine oxidase.

Toxins such as manganese and carbon monoxide that can directly affect the basal ganglia also result in secondary dystonia.

Heredodegenerative Disorders

Dystonia also occurs in a wide range of heredodegenerative disorders in which there is progressive neuronal loss with a mixture of neurological symptoms and signs, sometimes with systemic involvement. Table 35-5 lists the various heredodegenerative disorders that can be divided into those with disorders of metabolism, mitochondrial disease, trinucleotide repeat diseases, parkinsonian disorders, and other degenerative processes without defined causes.

TABLE 35-5 Heredodegenerative Disorders That Can Cause Dystonia

Metabolic Disorders
Metal and mineral metabolism	Wilson’s disease, neurodegeneration with brain iron accumulation type I, neuroferritinopathy, idiopathic basal ganglia calcification (Fahr’s disease)
Lysosomal storage disorders	Niemann-Pick disease type C, GM₁ and GM₂ gangliosidoses, metachromatic leukodystrophy, Krabbe’s disease, Pelizaeus-Merzbacher disease, fucosidosis
Inborn errors of metabolism	Lesch-Nyhan syndrome, triosephosphate isomerase deficiency, glucose transport defects
Amino and organic acidurias	Glutaric aciduria type I, homocystinuria, propionic acidemia, methylmalonic aciduria, 4-hydroxybutyric aciduria, 3-methylglutaconic aciduria, 2-oxoglutaric aciduria, Hartnup’s disease
Mitochondrial Disorders
Leigh’s disease
Leber’s hereditary optic neuropathy
Mohr-Tranebjaerg syndrome (dystonia/deafness)
Trinucleotide Repeat Disorders
Huntington’s disease
Spinocerebellar ataxias
Parkinsonian Disorders
Parkinson’s disease (especially familial young-onset forms)
Progressive supranuclear palsy
Multiple-system atrophy
Corticobasal ganglionic degeneration
X-linked dystonia–parkinsonism (“Lubag”)
Others
Ataxia-telangiectasia
Chorea-acanthocytosis
Rett’s syndrome
Infantile bilateral striatal necrosis
Ataxia with vitamin E deficiency
Progressive pallidal degeneration
Sjögren-Larsson syndrome
Ataxia–amyotrophy–mental retardation–dystonia syndrome

Psychogenic Dystonia

The concept of psychogenic dystonia is difficult because in the first half of the 20th century many cases of organic dystonia were thought to be psychiatric in origin as a result of the unusual and variable nature of the symptoms. Psychogenic dystonia does exist, often resulting in profound disability, but is a rare form of dystonia. As with organic dystonias, it is difficult to diagnose with certainty, and the assessment should be undertaken only by a neurologist with considerable experience with organic dystonias. One reason for this is the absence of a specific diagnostic test for dystonia. The diagnosis is based on the presence of clinical inconsistencies and incongruities with organic dystonia. The pathophysiology is poorly understood. Prompt diagnosis and treatment are necessary, in view of the poor prognosis of conversion disorders when there has been considerable delay between symptom onset and diagnosis, and treatment often involves a combination of psychotherapy, physical therapy, and psychopharmacologic therapy.

INVESTIGATIONS

Table 35-6 list potential investigations. However, the clinical presentation determines which of these are appropriate. For instance, a woman aged 60 presenting with blepharospasm alone may need no investigation, whereas a child with dystonia and other neurological features would need extensive tests to identify a potential secondary cause. A history of birth injury, a family history of other neurological disorders, and exposure to dystonia-inducing drugs are important.

TABLE 35-6 Investigation of Dystonia

Dystonia Phenotype	Investigation
Primary torsion dystonia
Early onset (<28 years)	Copper studies, slit-lamp examination
	Brain MRI
	DYT1 gene analysis
	Trial of L-dopa
Late onset (>28 years)	Copper studies, slit-lamp examination if younger than 50 years
	Brain MRI
	Spine MRI if dystonia fixed or painful
	EMG if painful axial muscle spasm
Secondary dystonia	Brain/spine MRI
	Nerve conduction studies
	Copper studies, slit-lamp examination, liver biopsy
	Genetic test for neurodegenerative disorders (e.g., Huntington’s disease)
	White blood cell enzymes
	α-Fetoprotein, immunoglobulins
	Lactate, pyruvate, mtDNA analysis; muscle biopsy
	Blood film for acanthocytes
	Urine amino acid, organic acid, oligosaccharide measurements
	Bone marrow biopsy
	Phenylalanine loading test, CSF pterin measurement
	ERG, retinal examination

CSF, cerebrospinal fluid; EMG, electromyography; ERG, electroretinogram; MRI, magnetic resonance imaging; mtDNA, mitochondrial deoxyribonucleic acid.

Hemidystonia is highly suggestive of a contralateral lesion of the basal ganglia, and cranial imaging with MRI is mandatory. For young-onset generalized dystonia, imaging may also aid in diagnosis, such as revealing the “eye of the tiger” sign in brain iron accumulation type 1 (Fig. 35-1), typical changes in the midbrain of a patient with Wilson’s disease, or basal ganglia calcification in Fahr’s disease. If MRI appearance is normal, further tests should be performed to exclude Wilson’s disease as it is potentially treatable. Slit-lamp examination for Kayser-Fleischer rings (Fig. 35-2), serum ceruloplasmin measurement, and 24-hour urinary copper excretion measurement are required.

Figure 35-1 Cranial magnetic resonance image from a patient with brain iron accumulation type 1, showing the “eye of the tiger” sign.

Figure 35-2 Typical Kayser-Fleischer ring (arrow) in a patient with Wilson’s disease.

For cases of possible secondary dystonics, futher investigations for metabolic and heredodegenerative disorders are required, with testing for serum amino and organic acids and investigation for specific enzymatic disorders in white blood cell or fibroblast cultures.

PATHOPHYSIOLOGY OF DYSTONIA

Neurophysiological Studies

The hallmark of dystonia is involuntary sustained muscle contractions, which are characterized by an abnormal pattern of EMG activity: excessive co-contraction of antagonist muscles during an action and overflow into extraneous muscles. Other findings include prolongation of EMG bursts. These findings have been described in patients with primary focal hand dystonia, and it was also noted that there was loss of selectivity to perform independent finger movements, occasional failure of willed activity, and tremor. These features emphasize that in dystonia, there is excessiveness of movements and lack of fine control.

The problem of excessive co-contraction of agonist and antagonist muscles appears to be caused in part by loss of reciprocal inhibition, a mechanism present at many levels in the central nervous system that has been shown to be impaired in generalized dystonia, writer’s cramp, cervical dystonia, and blepharospasm. Studies of other spinal and brainstem inhibitory reflexes have also confirmed that a common theme in various forms of primary dystonia is the reduction in inhibitory processes within the motor system.

However, it has become clear that dystonia is not a pure motor disorder and that individuals with dystonia have sensory abnormalities that play an important role in causing motor dysfunction. Studies have demonstrated evidence of abnormalities in both somatosensory spatial discrimination and temporal discrimination (the shortest time two successive stimuli are perceived as separate). The importance of the sensory system in dystonia is also evident from study of the sensory tricks (geste antagoniste), which are various maneuvers used by patients with focal dystonia to temporarily relieve the dystonic spasms; for example, a finger placed on the face of an individual with cervical dystonia can eliminate neck muscle spasm. There is also evidence to suggest that abnormal sensory input can trigger dystonia, such as trauma to a body part before the dystonia. Another line of evidence comes from study of processing of muscle spindle input. In patients with hand cramps, vibration can induce the patient’s dystonia, and cutaneous input similar to that which produces the sensory trick can reverse this vibration-induced dystonia.

Studies of intracortical inhibition with transcranial magnetic stimulation paradigms have shown that there is motor cortex hyperexcitability in dystonia. This has been shown to result from deficient intracortical inhibition in the cortical hand muscle representation, not only in focal hand dystonia but also in blepharospasm, in which hand muscles are clinically normal. This defect in inhibition appears to occur specifically during dystonic muscle contraction and not during more normal movements, which implies that the contraction is dystonic because of the deficient inhibition. These findings of reduced intracortical inhibition, shorter silent period, and abnormal spinal reciprocal inhibition have also been demonstrated in patients with DYT1 generalized dystonia.

It is therefore believed that the excessive muscle contractions that occur in dystonia are generated by loss of inhibition, particularly loss of “surround inhibition”: the suppression of unwanted movements when a specific motor task is performed. Surround inhibition is believed to be essential for the production of precise, functional movement, just as surround inhibition in the visual system leads to more precise perceptions. Studies with transcranial magnetic stimulation and PET/functional MRI have supported the view that deficient intracortical inhibition leads to hyperexcitability of the motor cortex, which in turn could lead to the excessive movement seen in dystonia.

Most of the clinical evidence points to the basal ganglia as the site of the pathology in dystonia. There is experimental evidence that the basal ganglia output can influence cortical inhibition and also that the basal ganglia are anatomically organized to work in a center-surround mechanism, which would allow surround inhibition.

Molecular Genetic Studies

Dopa-responsive dystonia is the best characterized genetic form of dystonia. Mutations within the GTP cyclohydrolase 1 gene lead to marked reduction in the activity of the enzyme it encodes. GTP cyclohydrolase 1 is the rate-determining enzyme in the synthesis of tetrahydrobiopterin, a key cofactor in the monoamine synthesis pathway. Reduced levels of tetrahydrobiopterin lead to reduced dopamine synthesis, which appears to play a key role in the production of dystonia in this condition. The central role of abnormal dopaminergic neurotransmission in dystonia is supported by the finding that dopamine-blocking drugs can produce both acute and tardive dystonia. In DYT1 dystonia, the protein product torsin A, which normally resides in the endoplasmic reticulum, becomes mislocated to the nuclear envelope and abnormal inclusions that also contain proteins involved in dopaminergic transport. Whether mutant torsin A affects neurotransmission, however, is unclear.

Summary

Evidence therefore suggests that dystonia is characterized pathophysiologically by abnormal sensory processing and deficient cortical inhibition.⁴ The current model implicates abnormal surround inhibition as the substrate that leads to generation of uncontrolled dystonic movements. Dystonia could result from lesions in the basal ganglia, which disrupt intricate pathways and push normal movements to abnormal. Genetic defects (such as those found in DYT1 dystonia) may also affect these pathways, possibly through abnormal dopaminergic neurotransmission. Repetitive movements or use of a body part may also lead to dystonia. Thus, a combination of factors may lead to the cortical abnormality that results in the production of dystonic movements.

TREATMENT OF DYSTONIA

Treatment options for dystonia have increased dramatically since the mid-1980s. This has been the result of the use of botulinum toxin and a renewed interest in functional neurosurgery for dystonia. Drug treatment has some use, particularly for DRD and MDS and the more severe childhood-onset primary dystonias. Table 35-7 lists the treatment options for various forms of dystonia.

TABLE 35-7 Treatment Options for Dystonia

Therapy	Agent/Procedure	Uses
Drugs	Dopaminergic agents	DRD, sometimes primary and secondary dystonia
	Anticholinergics	Primary and secondary dystonia and DRD
	Baclofen (oral or intrathecal)	Childhood primary dystonia
	Benzodiazepines	Primary and secondary dystonia, MDS
	Antidopaminergic agents	Occasional primary/secondary dystonia
Botulinum toxin	Type A and B	Main treatment of focal and segmental dystonia
Destructive neurosurgery	Selective peripheral denervation	Cervical dystonia
	Myectomy/myotomy	Cervical dystonia/blepharospasm
	Intradural rhizotomy/nerve sectioning	Cervical dystonia (rarely used)
Functional stereotactic neurosurgery	Pallidotomy, thalamotomy	Primary and secondary generalized or hemidystonia
Functional stereotactic neurosurgery	Deep brain stimulation	Primary generalized and segmental dystonia

DRD, dopa-responsive dystonia; MDS, myoclonus-dystonia syndrome.

Drug Therapy

Drug treatment of dystonia has changed little since the mid-1980s. Although many forms of dystonia are relatively unresponsive to drugs, there is still an important role for drug therapy for primary generalized dystonia, dystonia-plus conditions, and some forms of secondary dystonia.

Dopaminergic Agents

Patients with DRD show dramatic response to low doses of L-dopa (with decarboxylase inhibitor) and all patients with young-onset dystonia should undergo an L-dopa trial. The mean daily dose effective in DRD is 250 mg, although higher doses are sometimes required. Symptoms of DRD may also respond to dopamine agonists and anticholinergic drugs.

The role of dopaminergic agents in the treatment of primary dystonia is less clear. Reviews of small treatment trials suggest that improvement with these drugs was rarely dramatic. Twenty percent of patients believed that they actually deteriorated, but on occasion there was benefit.

Anticholinergic Drugs

Trihexyphenidyl can be useful for childhood-onset primary dystonia. One prospective placebo-controlled trial revealed that 67% of treated patients showed improvement and 68% continued to benefit after 2.4 years at a mean daily dose of 40 mg. It appears to be less useful for adult-onset primary focal dystonia. In both children and adults, the dose of anticholinergic must be titrated up gradually to minimize side effects, particularly of dry mouth, gastrointestinal upset, and confusion.

Baclofen

Baclofen is a derivative of γ-amino butyric acid that reduces spinal cord interneuron and motor neuron excitability. A retrospective study showed it to have useful benefit, especially in childhood-onset primary dystonia, but only in a minority of adult cases. It appeared to be better tolerated by the younger patients, but significant side effects of lethargy, dizziness, and confusion have been reported.

Intrathecal baclofen has also been used with benefit, particularly for secondary generalized dystonia and in patients with dystonia and spasticity. Intrathecal baclofen is administered through an implanted infusion pump connected to an intrathecal catheter, which is inserted at approximately the L2-L3 level and advanced to C7-T1.

Benzodiazepines

Benzodiazepines have been frequently used, although there are no data from controlled trials. They appear to be effective, although use is limited by sedation, ataxia, and habituation. Diazepam and clonazepam are the benzodiazepines most frequently used.

Other Drugs

Numerous other drugs have been used to treat various forms of dystonia. Paradoxically, some patients with dystonia appear to improve with use of antidopaminergic drugs, such as tetrabenazine and haloperidol. The concern with dopamine-blocking drugs is the development of tardive dystonia and dyskinesia. Other drugs that have been used to treat dystonia in single cases include carbamazepine, propranolol, phenytoin, clonidine, tizanidine, lithium, and cannabidiol.

Botulinum Toxin

Botulinum toxin injections are the first line of treatment for focal and segmental dystonias.⁵ Botulinum toxin consists of a number of serotypes of a potent neurotoxin that acts by inhibiting neurotransmitter release at the neuromuscular junction, which leads to temporary weakness of the muscle. Botulinum toxin types A and B are most commonly used in clinical practice. Its principal mode of action in dystonia is to cause denervation of motor end plates, although there is evidence that its effect on sensory symptoms may also be important, possibly by modulating muscle spindle input to the central nervous system. Local injection of botulinum toxin type A into overactive dystonic muscles can provide very effective relief of symptoms. Double-blind placebo-controlled trials have shown botulinum toxin type A to be efficacious in treating cervical dystonia and blepharospasm (60% to 70% patients showed improvement), and retrospective and open-label studies have also demonstrated its efficacy for laryngeal dystonia, writer’s cramp, and limb dystonias and for selected cases of oromandibular dystonia. Botulinum toxin has a temporary effect; patients require repeat injections at intervals, usually every 12 to 16 weeks. For uncomplicated cases of blepharospasm and cervical dystonia, muscles to receive injection are usually selected clinically. For more complex cases and other types of dystonia, EMG guidance is often required.

The most common side effects are of unwanted weakness, which is related to the dose used and local spread of toxin. Thus, for cervical dystonia, transient dysphagia can occur, especially when the sternocleidomastoid muscles have received injections. Ptosis is a common complication of injections for blepharospasm. Another problem is the development of resistance to botulinum toxin as a result of the formation of neutralizing antibodies, which occurs in up to 10% of patients. The development of neutralizing antibodies is a serious problem because it essentially prevents further response to that type of toxin, although the patient may respond to a different serotype of botulinum toxin.