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Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions of antagonist muscles causing abnormal often repetitive movements and postures. Dystonic movements are typically patterned and twisting and may be associated with a “dystonic tremor”. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia can range from focal minor contractions affecting only an individual muscle group to severe and disabling involvement of multiple muscle groups. The frequency is estimated to be 16 per 100,000 (~50,000 cases in the United States) but is likely to be much higher because many cases are not recognized. Dystonia is often brought out by voluntary movements (action dystonia) and can extend to involve other muscle groups and body regions not required for a given action (overflow). It can be aggravated by stress and fatigue and attenuated by relaxation and sensory tricks such as touching the affected body part (geste antagoniste).
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Historically, dystonia has been described as primary or secondary. However, because of a confusing and not always congruent combination of phenotypic and etiologic features, the older terms are no longer recommended. A Movement Disorder Society Task Force charged with redefining dystonia recommends classifying dystonia along two main axes: clinical and etiologic. On clinical grounds, dystonia can be categorized by age of onset (infancy, childhood, adolescence, early and late adulthood), body distribution (focal, segmental, multifocal, and generalized), temporal pattern (static or progressive, action-specific [diurnal and paroxysmal]), and association with additional features. Clinical description along these lines enables formulating specific dystonia syndromes (e.g., early-onset generalized isolated dystonia).
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Etiology of dystonia primarily reflects genetic abnormalities, although occasionally there may be other causes such as trauma and stroke. Genetic features used for classification include mode of inheritance or identification of a specific genetic defect. In the past three decades, more than 200 genes have been linked to different, mainly childhood-onset and generalized forms of dystonia. These include forms in which dystonia is the only disease manifestation with the exception of tremor (“isolated dystonia”), forms in which dystonia co-occurs with another movement disorder such as parkinsonism or myoclonus (“combined dystonia”) and disorders in which dystonia is only one of several clinical manifestations and may be a less prominent or even inconsistent feature (“complex dystonia”). Most of the genetic forms belong to the latter phenotypic group, which also represents the most heterogeneous class in terms of clinical expression.
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Focal (Multifocal, Segmental) Dystonia
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Adult-onset, focal dystonia is by far the most frequent form of isolated dystonia, with women being affected about twice as often as men. Focal dystonia typically presents in the fourth to sixth decade and can be focal, multifocal, or segmental. The major clinical phenotypes are as follows: (1) Cervical dystonia—dystonic contractions of neck muscles causing the head to deviate to one side (laterocollis), twist (torticollis), move in a forward direction (anterocollis), or move in a backward direction (retrocollis). Muscle contractions can be painful and occasionally can be complicated with a secondary cervical radiculopathy. (2) Blepharospasm—dystonic contractions of the eyelids with increased blinking that can interfere with reading, watching television, working on a computer, and driving. This can sometimes be so severe as to cause functional blindness. (3) Oromandibular dystonia (OMD)—contractions of muscles of the lower face, lips, tongue, and jaw (opening or closing). Meige’s syndrome is a combination of OMD and blepharospasm that predominantly affects women aged >60 years. (4) Spasmodic dysphonia—dystonic contractions of the vocal cords during phonation, causing impaired speech. Most cases affect the adductor muscles and cause speech to have a choking or strained quality. Less commonly, the abductors are affected, leading to speech with a breathy or whispering quality. (5) Limb dystonias—these can be present in either arms or legs and are often brought out by task-specific activities such as handwriting (writer’s cramp), playing a musical instrument (musician’s cramp), or putting in golf (the yips). The vast majority of patients have dystonia of the neck (cervical dystonia; ~50%) or the eye lid (blepharospasm; ~20%). Focal hand or leg dystonia (~5%), spasmodic dysphonia (~2%), musician’s dystonia (~3%), or OMD (~1%) are much less common. Focal dystonias can extend to involve other body regions (about 30% of cases) and are frequently misdiagnosed as psychiatric or orthopedic in origin. Their cause is usually not known, but genetic factors, autoimmunity, and trauma have been suggested. Focal dystonias are often associated with a high-frequency tremor that can resemble ET. Dystonic tremor can usually be distinguished from ET because it tends to occur in conjunction with the dystonic contraction and disappears when the dystonia is relieved (e.g., turning the head in the opposite direction of the dystonia).
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Generalized dystonia is often hereditary in nature and, unlike focal dystonia, generally has an age of onset in childhood or adolescence. There are currently at least four well established genes for isolated dystonia; TOR1A, THAP1, ANO3, and GNAL. According to the recommendations of the International Parkinson’s Disease and Movement Disorder Society, confirmed monogenic forms are classified according to absence or presence of accompanying clinical features and preceded by a “DYT” prefix, e.g., DYT-TOR1A. These genetic forms are all inherited in an autosomal dominant fashion and found in <5% of dystonia patients. Not all mutation carriers develop generalized dystonia; about 35% remain unaffected despite harboring a pathogenic mutation (reduced penetrance), and rarely they present with dystonia that remains focal or segmental in nature.
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Mutations in the TOR1A gene (torsin family 1 member A—formerly known as the DYT1 gene) are the most common cause of early-onset generalized dystonia. The first, and currently the only clearly established mutation, is a 3-base pair deletion in the TOR1A gene. The mutation is frequently found among Ashkenazi Jewish patients due to a founder effect. Mutation carriers usually present with dystonia in an extremity in childhood that later progress to other body parts, but typically spare the face and neck.
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THAP1 gene (THAP domain containing, apoptosis associated protein 1) mutations have been linked to adolescent-onset dystonia with mixed phenotype. About 100 different mutations have been reported in THAP1. Mutations typically manifest with dysphonia or writer’s cramp beginning in late childhood or adolescence. Over the course of the disease, dystonia spreads to other body parts with prominent craniocervical involvement.
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Mutations in the ANO3 gene (anoctamin 3) were first reported in patients with predominantly craniocervical dystonia with a broad range of ages of onset. While a large number of missense variants can be found in healthy individuals, a pathogenic role of ANO3 mutations has recently been supported by the description of additional families with dystonia and myoclonic jerks.
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Mutations in the GNAL gene (guanine nucleotide-binding protein subunit alpha L) are a rare cause of cervical or cranial dystonia with a mean age of onset in the thirties. About 30 different GNAL mutations have been reported in dystonia patients.
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In addition to the above, missense mutations in KMT2B (lysine methyltransferase 2B) have recently been identified, and confirmed to be a cause of an early-onset generalized dystonia which may be accompanied by other syndromic features including intellectual disability, microcephaly, psychiatric features, dysmorphia, or skin lesions. The majority of the mutations occurred de novo. KMT2B mutations may account for up to 10% of early-onset generalized dystonia but further validation is warranted and placement into the group of isolated vs complex dystonias is currently under debate.
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A number of other well-established genes have been described for combined forms of dystonia in which dystonia occurs in conjunction with a different movement disorder, such as parkinsonism or myoclonus.
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Dopa-responsive dystonia (DRD; also known as Segawa syndrome) is caused by mutations in the GCH1 gene (GTP cyclohydrolase-1) that encodes for the rate-limiting enzyme in the biosynthesis of dopamine via the biopterin pathway. It is manifest as a childhood-onset form of dystonia with diurnal fluctuations and is important to recognize as the condition dramatically responds to low doses of levodopa. Parkinsonism can be a major, or even the only finding, and there may be a presynaptic dopaminergic deficit as evidenced by SPECT. To date, more than 100 different mutations have been reported with a penetrance of around 50% which is considerably higher in women compared to men. Recessively inherited (biallelic) mutations in GCH1 result in a much more severe clinical phenotype with developmental delay and infantile onset. Due to the enzymatic defect in the levodopa biosynthesis, there is a lifelong and dramatic response to levodopa therapy. Indeed, all young onset forms of dystonia should be tested with levodopa to exclude the possibility of DRD.
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X-linked dystonia-parkinsonism (Lubag) is a combined form of dystonia and parkinsonism that is found exclusively in patients of Filipino origin due to a founder effect and seems to be fully penetrant. Patients usually develop focal (cranial) dystonia first that rapidly generalizes and, after 5–10 years, is gradually replaced by a form of L-dopa-unresponsive parkinsonism. The exact mutation causing X-linked dystonia-parkinsonism (Lubag) is not yet known but several variants in a disease haplotype segregate with the disease and a retrotransposon insertion in the TAF1 (TATA-Box Binding Protein Associated Factor 1) gene has been suggested as the most likely disease cause.
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Biallelic mutations in the PRKRA (protein activator of interferon-induced protein kinase EIF2AK2) gene are linked to a dystonia-parkinsonism syndrome and mostly due to the same missense mutation that seems to result from a shared founder. The phenotype includes early-onset generalized dystonia, often with laryngeal dystonia, tongue protrusion, prominent oromandibular involvement, dysphagia, and retrocollis. Parkinsonian features are mild (or even absent) and do not respond to levodopa therapy.
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Mutations in the ATP1A3 (ATPase Na+/K+ transporting subunit alpha 3) gene present with a characteristic, sudden onset usually in adolescence or young adulthood, often triggered by high fever, physical exertion, or emotional stress. Dystonic symptoms frequently show a rostrocaudal gradient with a strong involvement of the bulbar region and are often accompanied by bradykinesia as a parkinsonian feature. In addition, mutations in ATP1A3 have also been linked to a variety of clinical syndromes (pleiotropy) including epileptic or hemiplegic attacks, ataxia, cognitive decline, and other neurological disorders, often with a more severe course and an earlier age at onset.
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Myoclonic-dystonia is characterized by action-induced, alcohol-responsive myoclonic jerks predominantly involving the upper body half. Onset is usually in childhood or adolescence. Additionally, many individuals develop psychiatric features such as depression, anxiety-related disorders, and alcohol dependence. The disorder is primarily related to mutations in the SGCE gene (sarcoglycan epsilon) which codes for the ε member of the sarcoglycan family. About 80 different mutations have been reported in SGCE including deletions of the entire gene. The latter type of mutation often also involves loss of adjacent genes leading to additional clinical features such as joint problems. SGCE mutations are incompletely penetrant and only manifest when inherited from the father due to the epigenetic effect of maternal imprinting of SGCE.
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A number of additional monogenic causes have been suggested for isolated and combined forms of dystonia but still await independent confirmation. Table 428-2 provides a list of the confirmed Monogenic Forms of Isolated and Combined Dystonias.
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In the complex dystonias, dystonia is one part of a syndrome with multiple different disease manifestations. Most frequently, they are hereditary such as Wilson’s disease (WD), Huntington’s disease (HD), Lesh Nyhan syndrome, corticobasal ganglionic disorders, and a variety of other neurologic, neurometabolic, and mitochondrial disorders. Complex dystonias may also develop as a consequence of drugs or toxins (previously referred to as secondary dystonias). Drug-induced dystonia may be acute or chronic, and is most commonly seen with neuroleptic drugs or after chronic levodopa treatment in PD patients. Dystonia can also be observed following discrete lesions in the striatum, and occasionally in the pallidum, thalamus, cortex, and brainstem due to infarction, hemorrhage anoxia, trauma, tumor, infection, or toxins such as manganese or carbon monoxide. In these cases, dystonia often assumes a segmental distribution, but may be generalized when lesions are bilateral or widespread. More rarely, dystonia can develop following peripheral nerve injury and be associated with features of complex regional pain syndrome (Chap. 432). A psychogenic origin is responsible for some cases of dystonia; these typically present with fixed, immobile dystonic postures (see below).
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PATHOPHYSIOLOGY OF DYSTONIA
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The pathophysiologic basis of dystonia is not completely known. The phenomenon is characterized by co-contracting synchronous bursts of agonist and antagonist muscle groups with recruitment of muscle groups that are not required for a given movement (overflow). Dystonia is characterized by derangement of the basic physiological principle of action-selection, leading to abnormal recruitment of inappropriate muscles for a given action with inadequate inhibition of this undesired motor activity. Physiologically, loss of surround inhibition is observed at multiple levels of the motor system (e.g., cortex, brainstem, spinal cord) accompanied by increased cortical excitability and reorganization. Attention has focused on the basal ganglia as the site of origin of at least some types of dystonia because there are alterations in blood flow and metabolism in these structures. Further, lesions of the basal ganglia (particularly the putamen) can induce dystonia, and surgical ablation or deep brain stimulation (DBS) of specific regions of the globus pallidus may ameliorate dystonia. The dopamine system has also been implicated, because dopaminergic therapies can both induce and treat some forms of dystonia in different circumstances. Interestingly, no specific pathology has been consistently identified in dystonia.
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TREATMENT Dystonia
Treatment of dystonia is for the most part symptomatic except in rare cases where correction of a primary underlying condition is possible. Wilson’s disease should be ruled out in young patients with dystonia. Levodopa should be tried in all cases of childhood-onset dystonia to test for DRD. High-dose anticholinergics (e.g., trihexyphenidyl 20–120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of side effects related to cognitive impairment and hallucinations. Oral baclofen (20–120 mg) may also be helpful, but benefits, if present, are usually modest, and side effects of sedation, weakness, and memory loss can be problematic. Intrathecal infusion of baclofen is more likely to be useful, particularly for leg and trunk dystonia, but benefits are frequently not sustained, and complications can be serious and include infection, seizures, and coma. Tetrabenazine is another consideration (the usual starting dose is 12.5 mg/d and the average treating dose is 25–75 mg/d), but its use may be limited by sedation and the development of parkinsonism. Neuroleptics can improve as well as induce dystonia, but they are typically not recommended because of their potential to induce parkinsonism and other movement disorders, including tardive dystonia. Clonazepam and diazepam are rarely effective.
Botulinum toxin has become the preferred treatment for patients with focal dystonia, particularly where involvement is limited to small muscle groups such as in blepharospasm, torticollis, and spasmodic dysphonia. Botulinum toxin acts by blocking the release of acetylcholine at the neuromuscular junction, leading to reduced dystonic muscle contractions. However, treatment with botulinum toxin can be complicated by excessive weakness that can be troublesome, particularly if it involves neck and swallowing muscles. Two serotypes of botulinum toxin are currently available (A and B). Both are effective, and it is not clear that there are advantages of one over the other. No systemic side effects are encountered with the doses typically used, but benefits are transient, and repeat injections are required at 2–5 month intervals. Some patients fail to respond after having experienced an initial benefit. This has been attributed to antibody formation, but improper muscle selection, injection technique, and inadequate dose should be excluded.
Surgical therapy is an alternative for patients with severe dystonia who are not responsive to other treatments. Peripheral procedures such as rhizotomy and myotomy were used in the past to treat cervical dystonia, but are now rarely employed. DBS of the pallidum can provide dramatic benefits for some patients with various forms of hereditary and nonhereditary generalized dystonia. This represents a major therapeutic advance because previously there was no consistently effective therapy, especially for patients with severe disability. Benefits tend to be obtained with a lower frequency of stimulation and often occur after a relatively longer latency (weeks to months) than in PD. Better results are typically obtained in younger patients with shorter disease duration. Recent studies suggest that DBS may also be valuable for patients with focal and secondary dystonias, although results are less consistent. Supportive treatments such as physical therapy and education should be a part of the treatment regimen.
Physicians should be aware of dystonic storm, a rare but potentially fatal condition that can occur in response to a stress situation such as surgery or a systemic infection in patients with preexisting dystonia. It consists of the acute onset of generalized and persistent dystonic contractions that can involve the vocal cords or laryngeal muscles, leading to airway obstruction. Patients may experience rhabdomyolysis with renal failure and should be managed in an intensive care unit with airway protection if required. Treatment can be instituted with one or a combination of anticholinergics, diphenhydramine, baclofen, benzodiazepines, and dopaminergic agents. Spasms may be difficult to control, and anesthesia with muscle paralysis may be required.