100 years have passed since Oppenheim first used the term dystonia to describe the altering muscle tone and postural abnormalities in a family with an autosomal dominant movement disorder.1
The dystonias are now recognised as a group of hyperkinetic movement disorders whose main feature is involuntary sustained muscle contraction. This contraction results in twisting and repetitive movements or abnormal postures.2
In addition to the abnormal postures and movements, other characteristic features include gestes antagonistes, mirror movements, and overflow dystonia.3
Prevalence estimates of dystonia range from 15 to 30 per 100 000 population.4
In a study of a random sample of the population over 50 years of age, prevalence of primary dystonia was estimated to be 732 per 100 000, which suggests that, in the ageing population, dystonia is a common neurological disorder.6
In this Review, we describe the primary forms of dystonia (which are the most common forms) and the more complex forms (dystonia-plus syndromes) that are caused by neuronal dysfunction but not neuronal death. We focus on the clinical phenomenology and diagnosis of dystonia and on current understanding of the pathogenesis of dystonia from genetic, cell biological, imaging, and neurophysiological studies.
Classification of dystonia
The classification of dystonia is controversial and has been through numerous revisions over time, influenced by a better understanding of clinical phenotype, genetics, and pathophysiology. However, this increased understanding of the complexity of dystonia has also led to increasingly confused classification schemes. Classification of dystonia is not helped by use of the term dystonia to describe a symptom, sign, syndrome, or specific diagnosis.
Three basic parallel approaches are used to classify dystonia: age of onset, distribution of affected body parts, and cause.2
The categories of age at onset and affected body distribution have clinical implications for prognosis and treatment and are mainly relevant for primary or idiopathic dystonia. The classification by cause attempts to describe all forms of dystonia and is the most contentious.
Dystonia can develop at any age, although those with earlier onset are more likely to have a severe course.2
Division into early (<26 years) and late (>26 years) onset is now used, on the basis of the age by which almost all carriers of the mutant DYT1
gene (see later) will have developed dystonia.8
Distribution of affected body parts describes whether dystonia is localised to a single body region (focal) or has spread to contiguous (segmental) or non-contiguous (multifocal) regions. In generalised dystonia there is involvement of the legs, trunk, and another body part, whereas hemidystonia just affects the body and limbs on one side. Age at onset and distribution of affected body parts are linked: onset in the legs is most frequent during childhood, and with increasing age the site of onset ascends to the arms and hands, neck, and then cranial muscles.
The third approach to classification is by cause. This approach has been revised several times over the years and, confusingly, involves use of both clinical and pathological features as well as reference to the presence or absence of genetic factors. Here, we outline the difficulties of current terminology but also refer to an alternative, descriptive, classification.
At present, primary torsion dystonia (PTD) is perhaps the least contentious term and is commonly defined as a syndrome in which dystonia is the only clinical feature (except for tremor of the arms or head and neck) without evidence of neurodegeneration. However, some groups have used the term primary-plus dystonia to refer to conditions such as dopa-responsive dystonia (DRD) in which there can be additional features such as parkinsonism, whereas others keep them as a separate category, traditionally known as dystonia-plus syndromes. The same disparity in classification applies to the unusual paroxysmal dyskinesias: certain forms are characterised by almost pure dystonia, whereas others display a combination of dystonia, chorea, and athetosis, which might or might not be due to a single gene disorder.
A category of secondary dystonia has also been used to describe cases in which dystonia is symptomatic of an identifiable acquired cause (eg, exposure to specific drugs, damage to the basal ganglia). However, by definition, this category should include all so-called non-primary dystonias, including heredodegenerative disorders in which dystonia is part of a more complex phenotype caused by underlying neurodegeneration. Other groups have defined heredodegenerative dystonia as a separate category that defines cause.
There is no easy solution to this historic, and sometimes geographic, debate, but we show one strategy recently put forward to encompass the various forms of dystonia syndrome (table 1
This strategy would best be called a descriptive classification of dystonia, rather a than causative classification.
A descriptive classification of dystonia
Diagnosis of dystonia
The diagnosis of dystonia is clinical; the key characteristics are abnormal postures (with or without tremor) and presence of specific features. The absence of specific diagnostic tests means that expert clinical examination is recommended for diagnosis. A dystonic posture flexes, extends, or twists a body part often along its longitudinal axis. Dystonic movements are usually irregular and sustained at their peak, although they can include regular, tremor-like movements. Movements are repetitive and predictable (affecting the same body part), sometimes rhythmic, and are aggravated by task-specific (eg, writing) or non-specific movement (action dystonia). Over time, the dystonia can occur with less specific movements and can lead to sustained abnormal postures that are present at rest. Gestes antagonistes are sensory tricks, typically described in cervical dystonia, whereby light touch to the face or chin can alleviate the neck muscle spasm. The mechanism of gestes is uncertain but they can affect most body parts and help to relieve both dystonic postures and movements. Overflow and mirroring are also useful diagnostic clinical features. Overflow describes the spread of involuntary muscle contraction from the primary site of dystonia to an unaffected, usually contiguous, body part. Mirror dystonia occurs on the affected side of the body when a specific task is done by the opposite unaffected body part—eg, in patients with writer's cramp, mirror dystonia of the dominant hand is seen while writing with the opposite unaffected hand.
Although in most cases the recognition of dystonia is based on clinical features, electromyogram (EMG) mapping can be useful for detection of coactivation of agonist and antagonist muscles, the presence of phasic and tonic components of the movements, and the effect of gestes. EMG mapping is also helpful for differentiating dystonic tremor from other tremors.9
Clinical features of PTD
PTD accounts for around 75% of cases of dystonia and has a broad clinical spectrum, from childhood-onset generalised dystonias to adult-onset focal PTD.3
Early-onset PTD is a progressive, disabling disorder that often begins in a limb with subsequent involvement of the other limbs and trunk. Most cases are genetic in origin.
Focal PTD is about ten times as common as generalised forms, has onset in adulthood, and usually involves craniocervical muscles or arms. Generalisation is unusual, although dystonia can become segmental in less than 30% of cases, depending on the site of onset.10
Focal dystonia affecting the craniocervical region is more common in women than in men, and the converse is true for focal limb dystonia.11
Cervical dystonia is the most common form of focal dystonia, usually with onset in the fifth decade.4
Variable involvement of sternocleidomastoid, trapezius, and posterior cervical muscles results in abnormal head, neck, and shoulder positions, most frequently involving horizontal turning (torticollis) and head tremor.12
Initial symptoms include pulling, pain, or stiffness of the neck. Muscle tone and bulk are increased in the dystonic muscles. Cervical dystonia often progresses within the first 5 years before stabilising. Spontaneous symptom remission occurs in less than 20% of patients and most of those who do have remission subsequently relapse. Cervical dystonia adversely affects quality of life.13
Blepharospasm is caused by dystonic contractions of the orbicularis oculi.14
Onset is usually insidious in the sixth decade, with eye irritation or dryness followed by excessive blinking, especially in bright light. Symptoms worsen over years, leading to sustained eye closure, and severe symptoms can lead to functional blindness. The spasms are sometimes accompanied by perioral muscle involvement. Prolonged remission is rare.
Oromandibular dystonia affects the jaw muscles, with prominent jaw opening or closing.3
There is often additional involvement of the tongue, facial, and pharyngeal muscles. Oromandibular dystonia worsens on eating or talking, with dysarthria and dysphagia. It is a visible, distressing, and painful condition that can result in temporomandibular joint impairment.
Laryngeal dystonia is a rare task-specific dystonia that affects speech and occurs in late adult life.15
Adductor laryngeal dystonia results in strained or strangled voice quality caused by hyperadduction of the vocal cords. Abductor spasmodic dysphonia presents with breathy breaks in speech, especially with consonants. Voice tremor can occur with both types of laryngeal dystonia.
Writer's cramp is the commonest form of task-specific dystonia, with onset between the ages of 30 and 50 years. Patients describe tension and aching in the fingers and forearm progressing to persistent cramp on writing, with abnormally forceful grip.16
Excessive flexion of the thumb and index finger, with pronation of the hand and ulnar deviation of the wrist, often occurs, with arm tremor in less than 50% of patients. Other task-specific dystonias include musician's dystonia and dystonia in those performing highly learned motor skills, such as professional craftsmen and sportsmen (eg, tennis, snooker, golf) whose work involves frequent, repetitive and precise movements of particular muscle groups.17
Late-onset PTD: genetic and environmental factors
The genetics of late-onset focal PTDs are complex and most cases seem to be sporadic. Families with autosomal dominant inheritance and low penetrance have been described.48—50
In a large German family with late-onset cervical and laryngeal dystonia, the DYT7
locus was mapped to chromosome 18p.51
Allelic association to polymorphisms in this region was reported in patients with sporadic adult-onset focal dystonia from north-western Germany, suggesting the existence of a founder mutation.52
However, other studies could not replicate these findings and their relevance remains uncertain.53
Support for a monogenic cause of late-onset focal PTD came from a recent study that used the neurophysiological temporal discrimination test (TDT) as a marker for the dystonia endophenotype.54
22 of 24 families of index cases who had focal PTD had at least one relative with an abnormal TDT result, implying that dystonia was caused by an autosomal dominant gene with low penetrance. More work is needed to confirm these findings and verify the suitability of the TDT as a marker for dystonia.
Adult-onset focal PTD is probably multifactorial, with several genes, along with environmental factors, combining to reach the threshold for dystonia. There might be particular genes that are common to various clinical types, which, when combined with other specific genes or environmental factors, contribute to the variability of clinical expression.55
An association between common DYT1
haplotypes (including the D216H single nucleotide polymorphism) and adult focal PTD has been reported56
but not replicated elsewhere.58
The same is true for the association with a multiallelic polymorphism of the dopamine D5 receptor gene in cervical dystonia and blepharospasm.59
Genome-wide association studies should help resolve these inconsistencies and enable identification of other potential loci.
There have been limited case-control studies that have suggested that environmental factors might play a part in the development of focal PTD. These factors include disease of the anterior segment of the eye for blepharospasm, neck trauma and scoliosis for cervical dystonia, and repetitive motor tasks for upper limb dystonia.61
Differences in prevalence, age of onset, and sex distribution in the focal dystonias are likely to be a result of age-related and sex-related exposure to environmental factors against a background of genetic susceptibility.55
Conclusions and future directions
Dystonia syndromes are common disorders of CNS inhibition that have considerable clinical and genetic heterogeneity. In recent years, improvements in genetic, imaging, and neurophysiological technology has led to significant advances in our understanding of the nosology and pathogenesis of the primary dystonias. The existence of a disease spectrum is clear, starting with more severe early-onset dystonias, which are often monogenic, through to adult-onset focal PTD, which might develop as a result of a greater interaction between genetic and environmental factors (figure
Pathogenetic mechanisms in primary dystonia
GTPCH1=GTP cyclohydrolase 1. SMA=supplementary motor area.
However, the net result of the underlying pathogenic changes in PTD is a defect in neural networks involving the basal ganglia, sensorimotor cortex, and cerebellum, which contribute to motor control. The abnormalities lead to reduced inhibition at cortical, brainstem, and spinal levels and result in abnormal sensorimotor cortical plasticity. The cumulative effect of these changes leads to the generation of excessive uncontrolled muscle spasms that are the hallmark of dystonia, which seem to be associated with enduring functional changes in neural networks and subtle structural changes.
The sensorimotor circuits seem to be impaired in dystonia and can be disrupted by many causes at numerous levels, resulting in a susceptibility state that might allow secondary insults (eg, physiological stress, environmental insults, increased sensory input, and repetitive activity) to push these pathways into a dystonic state. A situation is then created in which this imbalance in circuitry becomes perpetuated by feedback reinforcement. Therefore, in some ways, the dystonia could be described as abnormally learned.
The vast increase in our understanding of the abnormal cellular, circuitry, and neural networks in dystonia might lead to new therapeutic targets. If dystonia is caused by abnormal motor learning, can it be unlearned? This unlearning might be the process that is seen in those patients with generalised dystonia in whom globus pallidus internus deep brain stimulation is successful, or in patients with focal task-specific hand dystonia who benefit from constraint-induced therapy, whereby non-dystonic digits are immobilised and the dystonic digits are retrained.118
Fundamentally, understanding of the genetic and cellular pathogenesis of dystonia might lead to specific therapies at a protein or enzymatic level. Gene therapy might also have a role to switch off abnormal genes or introduce wild-type versions in cases such as DRD with GCH1
mutations, in which the mutation leads to reduced concentrations or function of the protein. Thus, just as there might be multiple ways in which the sensorimotor control of voluntary movements can be altered in dystonia, there might also be many ways that these pathways can be specifically targeted by therapy.
JP and TW coordinated the Review, did the literature search, and prepared the first draft. All authors revised and modified this and subsequent drafts.
We declare that we have no conflicts of interest.