Dystonia

Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia may be inherited, acquired, or idiopathic. The diagnosis is made clinically, and genetic testing is recommended in individuals with a family history of dystonia. Management is with botulinum toxin or other drugs that target the various neurotransmitters involved in the pathogenesis of dystonia.

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Overview

Definition

Dystonia is a group of movement disorders characterized by involuntary muscle contractions that cause abnormal control of movement and posture. Dystonia is a focal or generalized hyperkinetic disorder that presents with an excessive muscle-contraction response.

Epidemiology

  • High prevalence among movement disorders
  • An estimated 500,000 adults and children are affected in North America.
  • Heterogeneous disorder with variable prevalence:
    • Focal dystonia is more prevalent than generalized dystonia.
    • Cervical dystonia is the most common form of focal dystonia.
  • Prevalence of primary dystonia: approximately 16 in 100,000 cases
  • Prevalence of gene carriers: approximately 20 in 100,000 cases with variable penetrance

Etiology

  • Primary (isolated) dystonia:
    • Related to known genetic mutations:
      • DYT-TOR1A is the most common and most studied gene mutation.
      • Other causative DYT variants have been identified.
    • Must not have other known causes (aside from known genetic mutations)
    • Presents without other neurologic findings, except for tremors or myoclonus
  • Secondary (acquired) dystonia:
    • Caused by foreign insult or trauma:
      • Perinatal brain injury
      • Traumatic brain injury
      • Hypoxic brain injury
      • Antidopaminergic drugs
      • Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis
    • Encompasses diverse causes including drug-induced, degenerative, and metabolic disorders
  • Idiopathic dystonias:
    • No identifiable genetic or acquired etiology
    • The majority of adults with focal or segmental dystonia have an idiopathic etiology.
  • Dystonia-plus syndromes:
    • No identifiable genetic or acquired etiology
    • Presents with dystonia AND other neurologic symptoms

Pathophysiology

  • No consistent findings on pathological examination in primary dystonia
  • No evidence of cellular degeneration on pathological examination
  • No consistent neurotransmitter defects in primary dystonia
  • Functional imaging findings are variable among individuals affected with dystonia. Involved regions include:
    • Motor cortex
    • Basal ganglia
    • Brainstem
    • Cerebellum
  • Mechanisms likely to be involved include:
    • Changes in neural circuitry:
      • Disturbance in neurotransmitter communication of striatal dopaminergic and cholinergic systems
      • Loss of GABA-mediated inhibition
    • Based on animal and imaging models
  • Neurotransmitters likely to be involved:
    • Dopamine
    • Acetylcholine
    • GABA
    • Glutamate
  • Primary dystonias:
    • Appear to be neurofunctional disorders without neuron loss
    • Strong hereditary component
    • Varying age range in terms of onset
  • Secondary dystonias:
    • Symptoms thought to result from damage to the brain, specifically to the basal ganglia
    • Sensorimotor circuitry can be disrupted further by toxic compounds and physiological stress, among other causes.
    • Secondary stressors combine to shift selected brain regions into dystonia.

Classification

Body distribution

  • Focal: affects 1 body region:
    • Periocular muscles → blepharospasm
    • Jaw and tongue → oromandibular dystonia
    • Laryngeal dystonia → dysphagia
    • Brachial dystonia → “writer’s cramp”
    • Cervical dystonia → spasmodic torticollis
  • Segmental: affects 2 adjacent body regions:
    • Periocular + oromandibular
    • Cervical + brachial
  • Generalized: affects the trunk and ≥ 2 other sites:
    • Trunk involvement → abnormal posture
    • Limb involvement is variable.
  • Multifocal:
    • Affects ≥ 2 nonadjacent body regions
    • Does not meet the criteria for generalized dystonia
    • Most commonly observed in early-onset dystonia
  • Hemidystonia:
    • Affects multiple body regions on the same side of the body
    • Most commonly a manifestation of contralateral insult (acquired dystonia) to the basal ganglia
Neck dystonia

Cervical dystonia presentations

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Selected types of common dystonias

Table: Selected types of common dystonias
NameTypeOnsetCharacteristics
Early-onset dystoniaPrimary (inherited in an AD pattern) generalizedChildhood
  • Progressive, severe movement abnormalities
  • Most commonly begins in the leg(s)
  • May have an associated tremor
  • Absence of other neurologic or cognitive impairments
DYT-TOR1A dystoniaPrimary (inherited in an AD pattern) generalizedChildhood
  • Most common of the early-onset dystonias
  • Most commonly begins in the limb(s)
  • Commonly, but does not always progress to generalized dystonia
  • Absence of cognitive impairment
DYT-THAP1 dystoniaPrimary (inherited in an AD pattern) generalizedAdolescence
  • Early onset, most commonly with cranial-cervical dystonia
  • Laryngeal dystonia is common → progressive dysphagia
  • Moves from cranial to caudal to become more generalized
DYT-KMT2B dystoniaPrimary (usually de novo mutations)Childhood
  • Presents similar to DYT-TOR1A dystonia, but is associated with intellectual disabilities, developmental delays, facial and body dysmorphisms, and endocrine abnormalities
  • Also distinguished by a high incidence of oromandibular, laryngeal, and cervical involvement
Cervical dystonia (spasmodic torticollis)
  • Primary
  • Focal
Age: 30–50 years
  • Most common among the focal dystonias
  • Presents with abnormal neck movements and posture
  • Frequently associated with pain
Limb dystonia
  • Primary
  • Focal
Adulthood
  • Action dystonias that impact certain movements
  • Cause involuntary twisting flexion/extension posture of the arms, legs, or digits
  • In arms, typically occurs after repetitive manual activities
  • Includes “writer’s cramp” and dystonia of the foot
Laryngeal dystonia (isolated)
  • Primary
  • Focal
Adulthood
  • Intermittent involuntary muscle contractions of the laryngeal muscles
  • Interferes with physiologic function
Blepharospasm (isolated)
  • Primary
  • Focal
Adulthood
  • Intermittent involuntary muscle contractions of the eyelid(s)
  • Interferes with physiologic function
Primary generalized torsion dystonia
  • Primary
  • Generalized
Childhood
  • AD pattern linked to several genetic loci
  • Begins as focal dystonia and often progress to multifocal or generalized distribution
  • Causes severe disability due to gait and posture impairments
Meige syndromePrimary segmentalUsually adulthood
  • Presents with blepharospasm and oromandibular dystonia
  • Usually starts with unilateral blepharospasm, which spreads to the other side
  • Progressive muscle dysfunction
Drug-induced dystoniaSecondaryAfter exposure to offending drugs
  • Offending drugs include antipsychotics, anticonvulsants, levodopa, and dopamine agonists.
  • May be focal or generalized
Heredodegenerative disordersSecondaryVaries
  • Presents with dystonia as well as other distinctive neuropathologic findings
  • Encompasses a group of degenerative and metabolic disorders having a genetic etiology
  • Includes Wilson disease, Parkinson disease, and Huntington disease among many others
Dystonia-plus syndromesSecondaryUsually in childhood
  • Associated with dystonia and other focal neurologic deficits
  • Dystonia-plus syndromes are not associated with known neuropathologic findings.
AD: autosomal dominant

Clinical Presentation

Excessive and frequent muscle contractions leading to abnormal postures and/or repetitive movements are the hallmark of dystonia.

Examples of movement abnormalities

  • Abnormal postures:
    • May be sustained
    • May be intermittent
  • Repetitive movements
  • Patterned movements
  • Twisting movements
  • Tremors

Features of movement abnormalities

Can affect any part of the body:

  • Focal: affects 1 body region
  • Segmental: affects ≥ 2 adjacent body regions
  • Generalized: affects the trunk and ≥ 2 other sites
  • Multifocal: affects ≥ 2 nonadjacent body regions
  • Hemidystonia: affects multiple body regions unilaterally

Worsened by voluntary action:

  • Attempts to maintain normal posture
  • Purposeful coordinated movements (e.g., writing → “writer’s cramp”)

Most often occurs in anatomically distinct sites:

  • Neck
  • Limbs
  • Face
  • Trunk

May present early in life (early-onset dystonia):

  • May begin in:
    • Infancy (0–2 years)
    • Childhood (3–12 years)
    • Adolescence (13–20 years)
  • Most commonly begins as a focal lower limb dystonia
  • More likely to progress to generalized dystonia
  • Most often genetic or idiopathic etiologies

May present later in life (late-onset dystonia):

  • May begin in:
    • Early adulthood (21–40 years)
    • Late adulthood (> 40 years)
  • Most commonly begins as a focal or segmental upper body dystonia (e.g., cervical, facial, arm(s)):
    • Isolated generalized dystonia is rare in adults.
    • When present, exposure to antidopaminergics is the most common cause.
  • Some initial focal sites of onset are more likely to spread than others.

May have temporal dominance:

  • Fluctuations in frequency or intensity with circadian variation
  • Worsens as the wakeful period progresses
  • Improvement is observed after a period of rest.

May have dynamic features:

  • Dystonia only manifests with task specificity (i.e., “writers cramp”).
  • Overflow phenomenon:
    • May manifest with involuntary dystonic movement of an affected limb that “mirrors” voluntary movement of the contralateral limb
    • May manifest with involuntary dystonic movement of a nonadjacent or distant body region with voluntary movement of a limb or body region
  • Sensory trick:
    • Sensory stimulation of a dystonic body part abates dystonic movements.
    • Observed in approximately 60% of individuals affected with dystonia
    • May be useful in the management of dystonia:
      • Affected individuals may be trained to self-administer sensory tricks.
      • Affected individuals may even be trained to “imagine” the sensory trick to stop dystonic movements.

May present with comorbid movement disorders:

  • Examples:
    • Parkinsonism + dystonia
    • Myoclonus + parkinsonism
  • Other neurologic findings may be present:
    • Ataxia
    • Weakness
    • Cognitive impairment
    • Seizures
    • Ocular palsies

Diagnosis

Dystonia is diagnosed clinically based on a thorough history and physical examination, with a particular focus on musculoskeletal and nervous system examination findings.

History and physical

  • Thorough history taking should distinguish primary versus secondary dystonia:
    • Age of onset
    • Anatomic distribution
    • Other neurologic symptoms
  • History should rule out:
    • Trauma (especially head trauma)
    • Medication exposure:
      • Antidopaminergic drugs (dopamine receptor-blocking agents)
      • Metoclopramide
      • 1st-generation antipsychotics
      • 2nd-generation antipsychotics
    • Toxic exposure
  • Family history of dystonia, especially, is an important factor.
  • Detailed physical exam is key to diagnosing specific types of dystonia.
    • Presence of the following observable or palpable findings:
      • Muscle contractions
      • Abnormal movements
      • Abnormal posture
      • Tremors
      • Other neurologic findings
    • Note the anatomic distribution and laterality of findings.
  • Absence of neurologic findings, besides dystonia and tremor, should separate primary from secondary dystonias.
  • AIMS score:
    • Acronym for Abnormal Involuntary Movement Scale
    • Used to determine baseline score before commencing dopamine-blocking agents, such as antipsychotics

Levodopa trial

  • Recommended for individuals with early-onset dystonia of unknown etiology
  • Should also be considered in adults presenting with dystonia of unknown etiology
  • Helps identify affected individuals who may benefit from dopamine-agonist therapy

Laboratory evaluation

  • No specific routine laboratory markers are available that are diagnostic of dystonia.
  • Laboratory analysis helps exclude other etiologies that may present similarly, and in identifying comorbid and contributing conditions.
  • Workup includes:
    • CBC
    • Electrolytes
    • Renal and liver function tests
    • Antinuclear antibodies
    • Serum ceruloplasmin
    • Copper levels
    • 24-hour urinary copper
    • Lysosomal screen
    • Erythrocyte sedimentation rate
    • Rapid plasma reagin

Neuroimaging

  • Brain CT and/or MRI
  • Evaluate for lesions of the basal ganglia.

Genetic testing

  • Indicated in primary dystonia, especially in individuals with a strong family history or in cases with onset < 26 years of age
  • Mutations at the DYT1 locus is often associated with hereditary dystonia:
    • Specific panels are available to test for DYT variants.
    • Genetic counseling for affected individuals and their families is recommended.

Management

Treatment is largely symptomatic as there is no cure for dystonia.

Pharmacotherapy

  • Aim to address impairments in the dopaminergic and cholinergic neurotransmitter circuitry and/or GABA-mediated inhibition.
  • Drug classes include:
    • Anticholinergics (trihexyphenidyl)
    • Dopaminergic agents (carbidopa/levodopa)
    • GABA agonists (high-dose baclofen)
    • Vesicular monoamine transporter type 2 (VMAT2) inhibitors (tetrabenazine):
      • Combination of anticholinergic and antidopaminergic properties
      • Limited use due to side effects

Botulinum toxin

  • Treatment of choice for isolated cervical dystonia
  • Blocks acetylcholine release from motor neurons
  • Administered as IM injections to the affected areas
  • Aimed at reducing dystonic symptoms via neuromuscular blockade only to the affected area
  • Widespread use is not feasible due to the potential for systemic toxicity (iatrogenic botulism).
  • Some recipients lose responsiveness to botulinum toxin over time:
    • May need dose adjustments
    • May need more anatomically precise injections
    • May need adjunctive PT
  • Some recipients develop autoantibodies against botulinum toxin, leading to its inefficacy.

Surgery

  • Deep brain stimulation:
    • Targets the globus pallidus
    • Mixed evidence for efficacy and uncertain for use in secondary dystonia
  • Lesional surgeries were used in the past but discontinued due to severe side effects.

Rehabilitative therapy

  • PT for individuals whose gait or writing, among other actions, are affected
  • Speech therapy for individuals in whom dystonia has affected speech or swallowing

Differential Diagnosis

  • Parkinson disease: a chronic, progressive, neurodegenerative disorder. Affected individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson disease is diagnosed clinically based on its characteristic signs and symptoms. Treatment includes supportive physical and emotional care plus medications such as levodopa/carbidopa, monoamine oxidase type B inhibitors, and dopamine agonists.
  • Cerebral palsy: a group of conditions that limits physical activity and results in motor impairment, affecting tone and posture. Cerebral palsy is caused by a nonprogressive CNS injury to the fetal or infant brain. Cerebral palsy is classified according to muscle tone, its distribution, and the presumed time of injury. Diagnosis is based on a detailed history, physical exam, and MRI to confirm the CNS insult. Interventions are multidisciplinary and the prognosis depends on the degree of disability.
  • Tourette syndrome: a severe form of neurobehavioral disorder of childhood characterized by sudden, repeated, nonrhythmic, stereotyped muscle movements sometimes accompanied by sounds or vocalizations. Tourette syndrome is clinically diagnosed, and the treatment involves behavioral therapy, antipsychotics, and addressing comorbid conditions. A majority of children outgrow their symptoms in adulthood, although a minority of adults will continue to demonstrate severe tics.
  • Huntington disease: a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. The most common clinical presentation in adulthood is a movement disorder known as chorea, which is characterized by abrupt, involuntary movements of the face, trunk, and limbs. Psychiatric and cognitive features are also common. The diagnosis is primarily clinical, often with a positive family history followed by genetic confirmation. Management is supportive and involves an interdisciplinary team working toward the goal of maintaining the quality of life.
  • Wilson disease: an autosomal recessive disorder characterized by abnormal copper metabolism resulting from mutations in the ATP7B gene. Copper accumulates in the liver and CNS leading to progressive organ dysfunction. Neurologic symptoms are almost always limited to the motor system and include dystonia, tremor, ataxia, and loss of motor control. The diagnosis is based on laboratory findings, including reduced serum ceruloplasmin and elevated copper levels. Treatment consists of a diet low in copper and the use of copper-chelating agents.
  • Tardive dyskinesia: an extrapyramidal syndrome secondary to the long-term use of drugs, such as neuroleptics, which block dopamine-receptor activity. Tardive dyskinesia presents with focal dystonia, especially torticollis or blepharospasm. The onset is latent and occurs anywhere from days to years following the use of dopamine-blocking agents. Management involves early detection and discontinuation/change of the offending drug. Newer drugs such as VMAT2 inhibitors show promise.

References

  1. Tarsy, D. (2006). Dystonia. The New England Journal of Medicine, 355, 818–829. Retrieved September 28, 2021, from https://doi.org/10.1056/NEJMra055549
  2. Jankovic, J. (2006). Treatment of dystonia. The Lancet. Neurology, 5, 864–872. Retrieved September 28, 2021, from https://doi.org/10.1016/S1474-4422(06)70574-9
  3. Breakefield, X. (2008). The pathophysiological basis of dystonias. Nature Reviews, Neuroscience, 9, 222–234. Retrieved September 28, 2021, from https://doi.org/10.1038/nrn2337
  4. Pana, A., Saggu, B.M. (2020). Dystonia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Retrieved September 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448144/ 
  5. Diek, A. (2021). Etiology, clinical features, and diagnostic evaluation of dystonia. Retrieved September 28, 2021, from https://www.uptodate.com/contents/etiology-clinical-features-and-diagnostic-evaluation-of-dystonia
  6. Diek, A. (2021). Treatment of dystonia in children and adults. Retrieved September 28, 2021, from https://www.uptodate.com/contents/treatment-of-dystonia-in-children-and-adults

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