Dystonia

Francesca Morgante, MD, PhD; Christine Klein, MD Movement Disorders p. 1225-1241 October 2013, Vol.19, No.5 doi: 10.1212/01.CON.0000436154.08791.67
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KEY POINTS

Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal (often repetitive) movements, postures, or both.

Dystonic movements are typically patterned and twisting and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

The two main axes of classification of dystonia are clinical and etiologic.

The clinical categorization of the dystonias is based on age at onset, site of onset, distribution of symptoms, disease progression and temporal pattern, and presence or absence of triggers or additional clinical features, as well as response to substances or treatment.

A revised classification of the dystonias distinguishes “isolated” (isolated dystonia or dystonic tremor) versus “combined” (dystonia with another movement disorder, such as parkinsonism or myoclonus). The latter category is further subdivided into “persistent” and “paroxysmal.”

Dystonic syndromes involving additional signs beyond movement disorders are referred to as complex dystonia.

Causes of dystonia range from environmental factors to pathogenic mutations in genes causing monogenic dystonia.

Currently, genes have been reported for 14 types of monogenic isolated and combined dystonia.

Isolated dystonia can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25); combined persistent dystonia by mutations in GCHI (DYT5), SGCE (DYT11), ATP1A3 (DYT12), PRKRA (DYT16), and most likely TAF1 (DYT3); and paroxysmal dystonia by mutations in PNKD (DYT8), PRRT2 (DYT10), and SLC2A1 (DYT18).

Early-onset generalized dystonia starting in a lower limb is most commonly associated with mutations in the TOR1A gene (DYT1) or in the GCHI gene (DYT5).

Spasmodic dysphonia and prominent craniocervical involvement are the clinical hallmarks of DYT6 dystonia.

Dystonia is considered a circuit disorder, characterized by abnormal functioning within the basal ganglia–sensorimotor network and the cerebellothalamocortical pathway.

Functional abnormalities in cortical areas involved in the execution and preparation of movement have been described in isolated dystonia by functional and structural imaging.

The main electrophysiologic anomalies described in dystonia are impaired inhibition at different levels of the CNS, impairment of somatosensory processing and sensorimotor integration, and maladaptive plasticity of sensorimotor circuits.

The core feature of maladaptive plasticity is the lack of spatial specificity, which is a specific feature of idiopathic dystonia.

Current treatment of dystonia is based on three main strategies: medical treatment with oral medications, chemodenervation with botulinum toxin, and surgical treatment with deep brain stimulation.

Focal and segmental dystonia can usually be treated with botulinum toxin injections, whereas generalized forms of the disease may be managed with deep brain stimulation and oral medications with or without additional botulinum toxin.

Three preparations of botulinum toxin type A and one of botulinum toxin type B are currently available, which differ in manufacturing processes, potency, and dosing.

Botulinum toxin chemodenervation is the first-line treatment for most types of focal dystonia, including blepharospasm, cervical dystonia, writer’s cramp, and adductor-type laryngeal dystonia.

EMG or ultrasound guidance may improve outcome of chemodenervation and reduce the frequency of side effects.

Four classes of oral drugs are employed in the treatment of dystonia: dopaminergic, anticholinergic, dopamine-depleting, and muscle relaxants.

Deep brain stimulation of the globus pallidus pars interna has been established as an effective treatment for dystonia refractory to medical treatment, particularly in patients with isolated generalized or segmental dystonia and those with tardive dystonia.

Nonpharmacologic interventions for dystonia include physical therapy as an add-on to botulinum toxin for cervical dystonia, sensorimotor training and transcutaneous electrical nerve stimulation in writer’s cramp, and speech therapy as an add-on to botulinum toxin for laryngeal dystonia.

Purpose of Review The purpose of this review is to provide an update on the classification, phenomenology, pathophysiology, and treatment of dystonia.

Recent Findings A revised definition based on the main phenomenologic features of dystonia has recently been developed in an expert consensus approach. Classification is based on two main axes: clinical features and etiology. Currently, genes have been reported for 14 types of monogenic isolated and combined dystonia. Isolated dystonia (with dystonic tremor) can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), PRKRA (DYT16), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25). Combined dystonias (with parkinsonism or myoclonus) are further subdivided into persistent (GCHI [DYT5], SGCE [DYT11], and ATP1A3 [DYT12], with TAF1 most likely but not yet proven to be linked to DYT3) and paroxysmal (PNKD [DYT8], PRRT2 [DYT10], and SLC2A1 [DYT18]). Recent insights from neurophysiologic studies identified functional abnormalities in two networks in dystonia: the basal ganglia–sensorimotor network and, more recently, the cerebellothalamocortical pathway. Besides the well-known lack of inhibition at different CNS levels, dystonia is specifically characterized by maladaptive plasticity in the sensorimotor cortex and loss of cortical surround inhibition. The exact role (modulatory or compensatory) of the cerebellar-cortical pathways still has to be further elucidated. In addition to botulinum toxin for focal forms, deep brain stimulation of the globus pallidus internus is increasingly recognized as an effective treatment for generalized and segmental dystonia.

Summary The revised classification and identification of new genes for different forms of dystonia, including adult-onset segmental dystonia, enable an improved diagnostic approach. Recent pathophysiologic insights have fundamentally contributed to a better understanding of the disease mechanisms and impact on treatment, such as functional neurosurgery and nonpharmacologic treatment options.

Address correspondence to Prof Christine Klein, Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Strasse 1, 23562 Lübeck, Germany, [email protected].

Relationship Disclosure: Dr Morgante serves on the scientific advisory board of Allergan and serves as a speaker for Chiesi, Lundbeck, Medtronic, Novartis, and UCB. Dr Morgante serves on the editorial advisory board of Frontiers in Movement Disorders. Dr Klein serves as a consultant for Centogene and as a speaker for Boehringer Ingelheim and Orion Corporation. Dr Klein serves on the editorial board of Neurology and as a course faculty member for the American Academy of Neurology. Dr Klein is the recipient of a career development award from the Hermann and Lilly Schilling Foundation; receives support from Deutsche Forschungsgemeinschaft, Possehl Foundation, and Volkswagen Foundation; and has received institutional support from the University of Lübeck for genetics research.

Unlabeled Use of Products/Investigational Use Disclosure: Drs Morgante and Klein report no disclosures.

Supplemental digital content: Videos accompanying this article are cited in the text as Supplemental Digital Content. Videos may be accessed by clicking on links provided in the HTML, PDF, and iPad versions of this article; the URLs are provided in the print version. Video legends begin on page 1238.

DEFINITION AND CLASSIFICATION

Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal (often repetitive) movements, postures, or both. Dystonic movements are typically patterned and twisting and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

Isolated dystonia is often referred to as primary dystonia; conversely, secondary dystonia commonly occurs as one of several disease manifestations within a syndrome. Previously, the term “secondary dystonia” was also used to indicate a known cause of the dystonia. However, as a number of etiologies have been identified for both isolated dystonia and dystonia as part of a clinical syndrome (complex dystonia), use of the terms “primary” and “secondary” with dystonia has led to some confusion and is no longer suggested.

Several classification schemes have been employed to categorize the various forms of dystonia. There are two main axes of classification: clinical and etiologic. The traditional clinical categorization of the dystonias is based on age at onset, site of onset, distribution of symptoms, disease progression and temporal pattern, and presence or absence of triggers or additional clinical features, as well as response to substances or treatment. Dystonias may be focal (Supplemental Digital Content 3-1, links.lww.com/CONT/A59), segmental (Supplemental Digital Content 3-2,links.lww.com/CONT/A60), multifocal, generalized (Supplemental Digital Content 3-3,links.lww.com/CONT/A61), or restricted to one side of the body (hemidystonia) (Supplemental Digital Content 3-4,links.lww.com/CONT/A62). Dystonia can occur with and without neurodegeneration. While most forms of dystonia initially tend to worsen and some focal dystonias may spread and eventually generalize, types of dystonia without neurodegeneration usually reach a plateau without further clinical decline, whereas those associated with neuronal loss show a (gradually) progressive disease course. Some forms of dystonia exquisitely respond to certain substances and treatments, such as alcohol or levodopa. Treatment response may also be used for classification purposes, for example, in dopa-responsive forms of dystonia. Dystonia is often present at rest but may be elicited or worsened by action (and ameliorated by gestes antagonistes or sensory tricks-Figure 3-1). In contrast, paroxysmal dystonias and dyskinesias show characteristic temporal patterns and are elucidated by differenttriggers. Dystonia can be associated not only with other movement disorders, such as parkinsonism or myoclonus (previously referred to as the dystonia-plus category), but also with a wide variety of other neurologicand non-neurologic features. Takingan expert consensus approach, a revised classification of the dystonias has recently been proposed that differentiates isolated versus combined (with parkinsonism or myoclonus). The latter category is further subdivided into persistent and paroxysmal (Figure 3-2). In the present review, wewill use the terms “isolated” and “combined” dystonia as defined above; dystonic syndromes involving additional signs beyond movement disorders will be referred to as complex dystonia.

Etiology is the second axis when attempting to classify dystonia. Causes of dystonia range from environmental factors (such as trauma or drugs, as in Case 3-1), to other hereditary or sporadic neurodysfunctional or neurodegenerative diseases (Supplemental Digital Content 3-6,links.lww.com/CONT/A64), to pathogenic mutations in genes causing monogenic dystonia (Case 3-2). Genetic features used for classification include mode of inheritance and molecular genetic data, such as linkage to a known gene locus or identification of a specific genetic defect (Table 3-1). In the past 20 years, monogenic defects have been found to underlie many forms of dystonia. Monogenic forms of isolated dystonia are referred to as DYTs. Despite marked pathophysiologic heterogeneity, some convergent disease mechanisms are beginning to emerge. Based on the proteins involved and known disease mechanisms, some forms of dystonia are grouped with other diseases sharing similar pathways. For example, DYT1 dystonia is considered a member of the family of nuclear envelope diseases.

Case 3-1

A 72-year-old woman had major depression for 23 years and was on treatment with tricyclic and selective serotonin reuptake inhibitor antidepressants as well as typical (haloperidol) and atypical antipsychotics (risperidone, olanzapine). She had a 15-year history of mild retrocollis. She presented with an exacerbation of cervical dystonia (Supplemental Digital Content 3-5, links.lww.com/CONT/A63), which had begun 1 year before; at that time, olanzapine had been increased to 5 mg/d. Neurologic examination showed severe isolated cervical dystonia characterized by repetitive retroflexion. There were no additional signs. She was treated with abobotulinumtoxinA injections (300 units in each splenius capitis muscle, 500 units into each upper trapezius muscle); tetrabenazine was given and titrated to 56.25 mg/d and olanzapine was slowly reduced to 2.5 mg/d. After 6 months and two cycles of chemodenervation with abobotulinumtoxinA, her dystonia substantially improved.

Comment. The common phenomenology of dystonia induced by drugs blocking dopamine receptors (tardive dystonia) includes retrocollis, often paroxysmal or intermittent, and truncal dystonia. Both typical and atypical antipsychotic drugs (such as risperidone and olanzapine) can produce tardive dystonia. The main risk factors are advanced age and intermittent or long duration of exposure to dopamine receptor-blocking agents.

Case 3–2

A 22-year-old woman had developed writer’s cramp in her right hand when she entered primary school at 6 years of age. After she switched to using her left hand for writing, dystonia spread to involve the left arm, as well. In the following years, the dystonia also became present with other tasks, such as holding a cup, and was accompanied by dystonic tremor (Supplemental Digital Content 3-7, links.lww.com/CONT/A65). However, it remained bibrachial with no spread to any other body region and no further worsening. The patient reported a positive family history suggestive of dominant inheritance: Her father had mild writer’s cramp and her brother was affected with severe generalized dystonia. Genetic testing revealed the GAG deletion in the TOR1A gene as cause of the dystonia in all three family members.

Comment. Onset of dystonia in a limb below the age of 26 years, sparing of the craniocervical region, and a dominant inheritance pattern are typical of DYT1 dystonia. The phenotypic spectrum of the disease can be broad (even within the same family), ranging from mild writer’s cramp to severe generalized dystonia. Importantly, no prediction as to the phenotypic expression can be made in an individual mutation carrier.

DYTs have been traditionally classified according to the gene or locus involved. However, this list of DYTs cannot be considered a classification in the true sense of the word. Rather, it represents an assortment of clinically and genetically heterogeneous disorders and includes erroneously assigned loci, duplicated loci, and missing and unconfirmed loci in a consecutively numbered system. Currently, 23 types of dystonia are considered DYTs and designated DYT1 through DYT25. DYT9 and DYT14 have been removed from this list, as they turned out to be identical with DYT18 and DYT5, respectively. Genes have been unambiguously identified for 11 of these monogenic dystonias and dyskinesias: DYT1, DYT4, DYT5, DYT6, DYT8, DYT10, DYT11, DYT12, DYT16, DYT18, and DYT25. Two additional putative dystonia genes have been recently identified (DYT23 and DYT24) and await independent confirmation; the exact genetic cause underlying DYT3 (X-linked dystonia-parkinsonism) remains a matter of debate, with TAF1 considered most likely but not yet proven. The list of DYT types will continue to lengthen as additional genes are implicated in various forms of hereditary dystonia. Given the advent of new molecular technologies (ie, next-generation sequencing), novel gene identification occurs at an even more rapid pace, as demonstrated by the identification of four new genes by next-generation sequencing in the past year.

PHENOMENOLOGY

Despite the large phenotypic and etiologic heterogeneity, all forms of dystonia share the above-mentioned clinical characteristics of involuntary movements and postures. However, diagnosis is complicated by two important issues: first, phenotypic heterogeneity may lead to clinical misclassification. For example, carriers of the same GAG deletion in the TOR1A (DYT1) gene may be unaffected (reduced penetrance) or may present with mild writer’s cramp, severe generalized dystonia, or even a jerky type of dystonic tremor reminiscent of myoclonus-dystonia. More recently, broader variations of the phenotype have been observed for two forms of dystonia/dyskinesia, which extend well beyond the clinical spectrum of the dystonias: mutations in the PRRT2 gene (DYT10) cause both paroxysmal kinesigenic dyskinesia and benign febrile infantile seizures, and mutations in ATP1A2 (DYT12) are the underlying cause of rapid-onset dystonia-parkinsonism and alternating hemiplegia of childhood. Also, the clinical presentation may vary over time, which is particularly common in conditions in which dystonia is part of a syndrome (ie, complex dystonia). For example, four members of a family with genetically proven SCA17 presented first with a purely dystonic syndrome, which was later followed by ataxia and other signs consistent with spinocerebellar ataxia. Similarly, patients with early-onset Parkinson disease frequently manifest initially with dystonia. The second important issue with respect to clinically diagnosing a specific form of dystonia is related to the fact that genetic heterogeneity exists in cases with virtually identical forms of dystonia. For instance, isolated dystonia (with dystonic tremor) can be caused by mutations in TOR1A (DYT1), THAP1 (DYT6), PRKRA (DYT16), ANO3 (DYT24), and GNAL (DYT25).

While identifying a specific form of dystonia solely on clinical grounds in a cross-sectional setting is often difficult if not impossible, careful observation of the phenotypic expression of the dystonia itself, of any associated features and “red flags,” and of the disease course may provide helpful hints with respect to the correct classification of the dystonia, which is the first and critical step toward establishing its etiology. A detailed discussion of the clinical features of the different forms of dystonia is beyond the scope of this article; however, some general considerations are listed below for isolated, combined, and complex dystonia. The majority of the isolated dystonias with or without dystonic tremor present in adulthood and remain focal or segmental. Although a high heritability of these forms has long been described, the genes that cause a small fraction of this form of dystonia have only been identified very recently. Interestingly, even in the absence of a known genetic defect, positive family history has been shown to influence the manifestation of the dystonia, resulting in a significantly earlier age of onset in familial versus sporadic cases. Early-onset generalized dystonia starting in a lower limb is most commonly associated with mutations in the TOR1A gene (DYT1) or in the GCHI gene (DYT5). Although mutations in the latter gene cause dopa-responsive dystonia with its characteristic response to treatment, these two conditions can be look-alikes in a young patient. Early onset in an upper limb also points to TOR1A (DYT1) mutations (especially when the cranial musculature is spared) but may also be a sign of THAP1 mutations (DYT6), the second known form of early-onset dystonia with a tendency to generalize. However, unlike in DYT1 dystonia, spasmodic dysphonia and prominent craniocervical involvement are the clinical hallmarks of DYT6 dystonia.

Revisiting dystonic syndromes with involvement of dopamine synthesis, several forms of combined or even complex dystonia exist, for example, due to mutations in the tyrosine hydroxylase (TH) or sepiapterin reductase genes. However, these forms of dystonia tend to present with a much more severe clinical picture than dopa-responsive dystonia due to heterozygous GCHI mutations and resemble the phenotype observed in the rare carriers of homozygous GCHI mutations. Most dopa-responsive dystonias manifest parkinsonian features, as also seen in dystonia due to PRKRA mutations (DYT16) and X-linked dystonia-parkinsonism (DYT3). Dystonia combined with myoclonus is the characteristic clinical presentation of myoclonus-dystonia, commonly caused by SGCE mutations (DYT11). Of further note, several patients have been described to carry large deletions of the SGCE chromosomal region, also involving neighboring genes. This results in contiguous gene syndromes with complex phenotypic features, such as skeletal involvement, that are seemingly unrelated to the dystonia but explained by the same underlying genetic defect. Dystonias and dyskinesias occurring in a paroxysmal fashion can be further subdivided by (the) specific trigger(s) involved: sudden movement elicits paroxysmal kinesigenic dyskinesia due to PRRT2 mutations (DYT10); alcohol, caffeine, and fatigue trigger paroxysmal nonkinesigenic dyskinesias (DYT8) with mutations in the PNKD (also known as MR-1) gene; and prolonged exercise precedes paroxysmal exertion-induced dyskinesia (DYT18) with SLC2A1 mutations.

PATHOPHYSIOLOGY

In the past 20 years, molecular studies have improved our knowledge on the pathogenesis of dystonia and suggested numerous potential disease pathways, including dopamine signaling, intracellular transport, cytoskeletal dynamics, transcriptional regulation, cell cycle control, ion channel function, energy metabolism, signal transduction, and detoxification mechanisms. For example, dopaminergic transmission is affected at the level of levodopa biosynthesis (GTP cyclohydrolase 1, tyrosine hydroxylase, sepiapterin reductase) in DYT5 dystonia. Dopamine signaling is involved in DYT25, since the encoded stimulatory alpha-subunit Gαolf of a G protein couples dopamine type 1 receptors. Electrophysiologic studies in mouse models of DYT1 dystonia suggest that the site of dysfunctional dopaminergic transmission is the striatum and that dystonia may result from altered dopaminergic control of cholinergic function and intrinsic cholinergic defects.

In patients with isolated dystonia, electrophysiologic and neuroimaging studies explored the neural basis of dystonia and identified functional abnormalities in two networks: the basal ganglia–sensorimotor network and, more recently, the cerebellothalamocortical pathway (Figure 3-3).

Basal ganglia involvement is strongly supported by findings from neuropathologic studies and clinical evidence that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is beneficial in dystonia.

Functional abnormalities in cortical areas involved in execution and preparation of movement in patients with isolated dystonia have been identified by functional MRI (fMRI) and positron emission tomography (PET), as well as by structural imaging of the gray (voxel-based morphometry) and white matter (diffusion tensor imaging). PET and fMRI studies have identified a wide spectrum of functional anomalies within the basal ganglia and sensorimotor areas. These abnormalities include altered excitability of the primary motor area, the supplementary motor area, and the dorsal premotor cortex. Structural imaging has demonstrated changes in gray matter volume in the sensorimotor area and globus pallidus in focal hand dystonia and increased volume in the putamen in blepharospasm, focal hand dystonia, and cranial dystonia, as well as in first-degree relatives of dystonic patients manifesting abnormal somatosensory processing.

In keeping with functional neuroimaging results, electrophysiologic studies have revealed three types of neurophysiologic alterations in the basal ganglia–sensorimotor network and their interconnected pathways (Figure 3-3): (1) impaired inhibition at the spinal, brainstem, and cortical level; (2) impairment of somatosensory processing and sensorimotor integration; and (3) abnormal plasticity of sensorimotor circuits.

Impairment of inhibitory mechanisms at various levels of the CNS might explain some clinical features of dystonia, such as muscular cocontraction and overflow. At the cortical level, transcranial magnetic stimulation (TMS) studies have demonstrated reduced inhibition and abnormal spread of facilitation. Furthermore, impaired surround inhibition during movement initiation and altered premotor-motor interactions have been highlighted. At the spinal and brainstem level, reflex studies measuring inhibition have demonstrated an impaired blink-reflex recovery cycle and reciprocal inhibition regardless of the topographical distribution of dystonia or whether it is expressed as dystonic tremor.

In addition to motor abnormalities, a consistent body of literature has shown sensory abnormalities in dystonia, including impaired cortical representation of the individual digits in the somatosensory cortex, as well as abnormalities of sensorimotor integration and of sensory processing. Specifically, the tactile temporal discrimination threshold is increased in different types of isolated dystonia, in nonmanifesting DYT1-mutation carriers, and in unaffected relatives of both familial and sporadic adult-onset dystonia patients.

Importantly, the above-mentioned electrophysiologic alterations in the motor and sensory system are not an exclusive feature of isolated dystonia, as they have also been described in Parkinson disease, other movement disorders, and even in psychogenic dystonia. It may be hypothesized that these electrophysiologic alterations are partly caused by the dystonic movement itself or that they co-occur to maintain dystonia once it has manifested.

An experimental paradigm involving repetitive sensorimotor stimulation demonstrated abnormal plasticity in sensorimotor circuits. The core feature of maladaptive plasticity in dystonia is the lack of spatial specificity. This abnormality distinguishes isolated dystonia from Parkinson disease, in which sensorimotor plasticity is deficient without dopaminergic stimulation, and from psychogenic dystonia, in which it is normal. Of note, a recent TMS study demonstrated that abnormal plasticity normalizes following GPi DBS; however, lack of spatial specificity persists, regardless of the beneficial clinical effects of DBS and modulation of cortical excitability.

In addition to dysfunction in the basal ganglia–sensorimotor network, a growing body of evidence suggests a contribution of the cerebellum to the pathophysiology of dystonia, possibly through its interconnections with the basal ganglia. Accordingly, PET and diffusion tensor imaging studies have demonstrated reduced integrity of cerebellothalamic fiber tracts in carriers of DYT1 and DYT6 mutations. Moreover, gray matter decrease by voxel-based morphometry was demonstrated in the left primary sensorimotor cortex (hand area), bilateral thalamus, and cerebellum of patients with focal hand dystonia. Finally, reduced cerebellar inhibition and impaired performance in an eye-blinking conditioning paradigm was reported in focal hand and cervical dystonia. These findings have strengthened the concept of dystonia as a circuit disorder characterized by an abnormal functioning of a network of cortical and subcortical areas. However, the exact role of the cerebellar-cortical pathways in modulating the basal ganglia–cortical network still has to be further elucidated.

TREATMENT

Current treatment of dystonia is symptomatic and based on three main strategies, according to the distribution and severity of the dystonia: medical treatment with oral medications, chemodenervation with botulinum toxin (BoNT), and surgical treatment with DBS. Several nonpharmacologic interventions, such as physical therapy and sensory training, have been also suggested in addition to the three main lines of treatment, although evidence for their efficacy is needed in larger samples.

Factors influencing choice of treatment are age, severity and clinical presentation of dystonia, body distribution, and co-occurrence of tremor. Focal and segmental dystonia can usually be managed with BoNT, whereas DBS and oral medications are reserved for the generalized form of the disease with or without additional BoNT.

Botulinum Toxin

Three preparations of BoNT type A (BoNT-A) and one of BoNT type B (BoNT-B) are currently available, which differ with respect to manufacturing, potency, and dosing: onabotulinumtoxinA (ona-B), abobotulinumtoxinA (abo-B), and incobotulinumtoxinA (inco-B) are forms of BoNT-A; rimabotulinumtoxinB (rima-B) is the only commercially available BoNT-B. Both the American Academy of Neurology evidence-based review on BoNT and the European Federation of Neurological Sciences guidelines on dystonia recommended chemodenervation with BoNT as first-line treatment for most types of focal dystonia, including blepharospasm, cervical dystonia, focal hand dystonia, and adductor-type laryngeal dystonia. Class I and long-term observational studies have demonstrated safety of BoNT for blepharospasm and cervical dystonia without decay of efficacy over time. Efficacy of BoNT for task-specific focal hand dystonia was shown at short follow-up by one class I and three class II studies. Pronation/flexion pattern of task-specific focal hand dystonia was associated with the best outcome.

Improvement of dystonia after BoNT-A starts about 1 to 7 days after the injection, depending on the size of the injected muscle, with a peak of the effect in 6 to 8 weeks and an overall duration of benefit of about 12 weeks. Injections are usually repeated every 3 months. Detailed clinical examination to determine the affected muscles is crucial, especially for cervical and focal hand dystonia, in which response to BoNT treatment is highly dependent on recognizing the muscles involved and identifying compensatory from dystonic postures. EMG or ultrasound guidance may improve outcome of chemodenervation and limit side effects by allowing less diffusion on to nontargeted muscles, especially in focal hand dystonia. Adverse effects of BoNT treatment tend to be focal and transient, mainly consisting of ptosis, dry eyes, tearing, diplopia (in blepharospasm), dysphagia, neck weakness (in cervical dystonia), and hand weakness (in focal hand dystonia). Higher cumulative doses of BoNT-A and shorter between-treatment intervals may increase the risk of formation of neutralizing antibodies. However, presence of such antibodies does not alwayspredict nonresponsiveness to treatment. Secondary nonresponsiveness due to the development of neutralizing antibodies rarely affects clinical outcome.

Table 3-2 and Table 3-3 show muscles targeted in blepharospasm, cervical dystonia, focal hand dystonia, and spasmodic dysphonia and average BoNT dosage for each muscle according to the distribution and pattern of dystonic contractions.

Oral Medication

Oral medications represent the main pharmacologic approach in generalized and segmental dystonia. Four classes of drugs can be used: dopaminergic, anticholinergic, dopamine-depleting, and muscle relaxants. Levodopa is the criterion standard in dopa-responsive dystonia and should be given as a trial for 1 month in childhood-onset dystonias, given the potential for substantial improvement and even complete resolution. Small doses (10 mg/kg body weight/d) are usually effective, although rarely higher doses are required. Among anticholinergic drugs, two small class III crossover studies have shown short-term benefit of trihexyphenidyl (starting dose 1 mg/d; effective dose: 6 to 30 mg/d) for childhood-onset primary or secondary dystonias; however, no improvement has been reported for adult-onset cranial dystonia in a class III crossover study and in a retrospective analysis of a cohort with adult-onset dystonia. Because the benefit of anticholinergic drugs is limited by side effects (memory impairment, confusion, dry mouth, dizziness), slow titration is recommended. Dopamine-depleting drugs such as tetrabenazine (starting adult dose 12.5 mg/d; therapeutic dose: 50 to 75 mg/d) have shown efficacy, especially in patients with tardive dystonia. Slow increase in dosage and monitoring of motor function is recommended because of the potential development of depression, parkinsonism, drowsiness, and insomnia. Finally, several muscle relaxants such as baclofen (adult dose 25 to 120 mg/d) and clonazepam (adult dose 1 to 6 mg/d) may be helpful if spasticity or tremor are associated with dystonia.

Surgery

Functional neurosurgery has been employed for a long time for the treatment of dystonia, but a major role of surgical techniques dates back only to the last decade with the consolidation of GPi DBS and replacement of surgical denervation.

Deep brain stimulation of the GPi has been proven to be an effective treatment for various types of dystonia. The largest magnitude of benefit is in primary generalized or segmental dystonia refractory to medical treatment. Among secondary dystonias, only tardive dystonia appears to benefit from GPi DBS. Selected patients with complex forms of dystonia, such as cerebral palsy and pantothenate kinase–associated neurodegeneration, may also lessen their disability after GPi DBS, albeit to a lesser extent. Efficacy of GPi DBS is supported by one randomized, sham-controlled, crossover 3-month study in patients with isolated generalized and segmental dystonia, regardless of DYT1-mutation status. Long-term efficacy was shown with 5 years of follow-up for generalized, segmental, and cervical dystonia. Shorter disease duration and younger age at time of surgery predicted better outcome. The phasic component of dystonia tends to improve over weeks after DBS, whereas the improvement of tonic postures takes months. The most frequent side effects are related to the device (infection, lead breakage, or dislodgement) or stimulation (dysarthria and transient worsening of dystonia). A rare but important side effect is depression with suicidal ideation.

Other Treatment Options

Several options currently with lower-level evidence for the treatment of dystonia have been proposed: physical therapy as an add-on to BoNT for cervical dystonia; sensorimotor training and transcutaneous electrical nerve stimulation in writer’s cramp; and speech therapy in addition to BoNT for laryngeal dystonia.

Based on PET and fMRI findings of hypoactivity and hyperactivity in areas involved in movement execution and preparation, noninvasive brain stimulation by repetitive TMS has been proposed as a potential treatment for dystonia. Most of these studies were conducted in patients with focal hand dystonia, demonstrating short-term efficacy of multiple sessions of repetitive TMS delivered over the premotor cortex. More recently, a randomized, single-session, sham-controlled, observer-blinded study proved that repetitive TMS over the anterior cingulate cortex might be helpful in primary blepharospasm.

CONCLUSIONS

Dystonia is an etiologically heterogeneous hyperkinetic movement disorder. The revised classification and identification of new genes for different forms of dystonia, including adult-onset segmental dystonia, enable an improved diagnostic approach. Recent findings from neurophysiologic studies have provided a better understanding of the underlying disease mechanisms and impact on surgical and nonpharmacologic treatment.

VIDEO LEGENDS

Supplemental Digital Content 3-1

Focal dystonia. The first video segment shows a 36-year-old woman with torticollis. The second video segment shows a 72-year-old man with a 30-year history of task-specific focal hand dystonia. Motor overflow is evident when the patient writes. The third segment shows lower limb dystonia in a patient with advanced Parkinson disease in the off-medication phase. Dystonia in Parkinson disease can be very painful and typically affects the lower limbs, causing inward rotation of the foot and flexion of the toes.

links.lww.com/CONT/A59

© 2013 American Academy of Neurology.

Supplemental Digital Content 3-2

Segmental dystonia. Video shows a 78-year-old woman with a 25-year history of craniocervical dystonia. Blepharospasm occurred when the patient was 53 years old, and dystonia spread to her oromandibular (at 55 years old) and cervical areas (at 60 years old).

links.lww.com/CONT/A60

© 2013 American Academy of Neurology.

Supplemental Digital Content 3-3

Generalized dystonia. Video shows a 5-year-old child with generalized dystonia caused by perinatal brain injury. The first symptoms appeared in the patient’s lower limbs, affecting gait, and subsequently spread to the trunk and upper limbs.

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Supplemental Digital Content 3-4

Hemidystonia. Video shows a 56-year-old woman with hemidystonia occurring as part of multiple system atrophy. Dystonic movements affecting the right side of her body presented 1 hour after taking 150 mg of levodopa/carbidopa.

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Supplemental Digital Content 3-5

Tardive dystonia. Video shows cervical dystonia in the patient described in Case 3-1 who was chronically exposed to antipsychotic drugs and experienced major depression for 23 years and mild retrocollis for 15 years.

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Supplemental Digital Content 3-6

Multiple system atrophy. Video shows a 66-year-old woman with the parkinsonian variant of multiple system atrophy. She presented with a 2-year history of gait and balance problems, parkinsonism, dysarthria, and cranial dystonia affecting the upper and lower face. Levodopa was poorly effective, induced severe orthostatic hypotension, and worsened her cranial dystonia.

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Supplemental Digital Content 3-7

DYT1 dystonia. Video shows writer’s cramp in the patient described in Case 3-2. At 6 years of age, the patient developed writer’s cramp in her right hand; after she switched to using her left hand for writing, dystonia spread to the left arm. Over several years, the dystonia became present with other tasks and was accompanied by dystonic tremor; however, it remained bibrachial with no spread to any other body region and no further worsening.

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KEY POINTS

  • Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal (often repetitive) movements, postures, or both.
  • Dystonic movements are typically patterned and twisting and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.
  • The two main axes of classification of dystonia are clinical and etiologic.
  • The clinical categorization of the dystonias is based on age at onset, site of onset, distribution of symptoms, disease progression and temporal pattern, and presence or absence of triggers or additional clinical features, as well as response to substances or treatment.
  • A revised classification of the dystonias distinguishes “isolated” (isolated dystonia or dystonic tremor) versus “combined” (dystonia with another movement disorder, such as parkinsonism or myoclonus). The latter category is further subdivided into “persistent” and “paroxysmal.”
  • Dystonic syndromes involving additional signs beyond movement disorders are referred to as complex dystonia.
  • Causes of dystonia range from environmental factors to pathogenic mutations in genes causing monogenic dystonia.
  • Currently, genes have been reported for 14 types of monogenic isolated and combined dystonia.
  • Isolated dystonia can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25); combined persistent dystonia by mutations in GCHI (DYT5), SGCE (DYT11), ATP1A3 (DYT12), PRKRA (DYT16), and most likely TAF1 (DYT3); and paroxysmal dystonia by mutations in PNKD (DYT8), PRRT2 (DYT10), and SLC2A1 (DYT18).
  • Early-onset generalized dystonia starting in a lower limb is most commonly associated with mutations in the TOR1A gene (DYT1) or in the GCHI gene (DYT5).
  • Spasmodic dysphonia and prominent craniocervical involvement are the clinical hallmarks of DYT6 dystonia.
  • Dystonia is considered a circuit disorder, characterized by abnormal functioning within the basal ganglia–sensorimotor network and the cerebellothalamocortical pathway.
  • Functional abnormalities in cortical areas involved in the execution and preparation of movement have been described in isolated dystonia by functional and structural imaging.
  • The main electrophysiologic anomalies described in dystonia are impaired inhibition at different levels of the CNS, impairment of somatosensory processing and sensorimotor integration, and maladaptive plasticity of sensorimotor circuits.
  • The core feature of maladaptive plasticity is the lack of spatial specificity, which is a specific feature of idiopathic dystonia.
  • Current treatment of dystonia is based on three main strategies: medical treatment with oral medications, chemodenervation with botulinum toxin, and surgical treatment with deep brain stimulation.
  • Focal and segmental dystonia can usually be treated with botulinum toxin injections, whereas generalized forms of the disease may be managed with deep brain stimulation and oral medications with or without additional botulinum toxin.
  • Three preparations of botulinum toxin type A and one of botulinum toxin type B are currently available, which differ in manufacturing processes, potency, and dosing.
  • Botulinum toxin chemodenervation is the first-line treatment for most types of focal dystonia, including blepharospasm, cervical dystonia, writer’s cramp, and adductor-type laryngeal dystonia.
  • EMG or ultrasound guidance may improve outcome of chemodenervation and reduce the frequency of side effects.
  • Four classes of oral drugs are employed in the treatment of dystonia: dopaminergic, anticholinergic, dopamine-depleting, and muscle relaxants.
  • Deep brain stimulation of the globus pallidus pars interna has been established as an effective treatment for dystonia refractory to medical treatment, particularly in patients with isolated generalized or segmental dystonia and those with tardive dystonia.
  • Nonpharmacologic interventions for dystonia include physical therapy as an add-on to botulinum toxin for cervical dystonia, sensorimotor training and transcutaneous electrical nerve stimulation in writer’s cramp, and speech therapy as an add-on to botulinum toxin for laryngeal dystonia.

ACKNOWLEDGMENTS

Dr Morgante thanks Annibale Arena for editing Figure 3-3.

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