Punit Agrawal, DO
DESCRIPTION 
Involuntary sustained or repetitive posturing/twisting movements in the face, neck, trunk, or limbs caused by abnormal activity in both agonistic and antagonistic muscles.
EPIDEMIOLOGY
Incidence and prevalence has been estimated for primary dystonia.
Incidence
2 per million for generalized dystonia and 24 per million for focal dystonia (1).
Prevalence
3.4 per 100,000 for generalized dystonia and 30 per 100,000 for focal dystonia.
RISK FACTORS
- Family history
- Central or peripheral nervous system injury
- Dopamine-blocking agents
- Recreational drugs
- Neurodegenerative condition
- Disease of eye
Genetics
Several genes have been identified classified to primary dystonia, dystonia plus syndromes, and paroxysmal disorders. Some of the better recognized ones are discussed here.
- Primary dystonia
- DYT1 is the most common primary genetic dystonia with onset in childhood or adolescence with autosomal dominant inheritance. Accounts for half of early onset primary dystonia. Causes focal, segmental, or generalized forms. Due to torsion A gene.
- Others: DYT4, DYT6, DYT7, and DYT13 are autosomal dominant. DYT2 is autosomal recessive.
- Dystonia plus syndromes
- Dopa-responsive dystonia or Segawa's disease (DYT5). Early childhood onset (1–12 years old) in the foot/leg with trouble walking plus hyperreflexia and slow generalization. Marked improvement and sustained response to levodopa. Two genetic deficits described:
- Guanosine triphosphate cyclohydrolase 1: Autosomal dominant
- Tyrosine hydroxylase: Autosomal recessive
- Myoclonus dystonia (DYT11): Autosomal dominant. Defect in epsilon-sarcoglycan. Childhood or adolescence onset of dystonia and myoclonus in the limbs, trunk, or face.
- Dystonia-parkinsonism syndromes
- DYT12: Autosomal dominant. Rapid onset dystonia and parkinsonism during adolescence that tends to level off with time without progression. Little or no response to dopaminergic agents.
- DYT3: X-linked dystonia-parkinsonism syndrome of Lubag of the Philippines.
- Paroxysmal dystonias are rare and include autosomal dominant DYT8–10. Characterized by brief episodes of abnormal movements with normal periods between attacks.
- Paroxysmal kinesigenic dyskinesia (DYT10). Triggered by sudden movement. Childhood onset.
- Paroxysmal non-kinesigenic dystonia (DYT8). Triggered by alcohol, caffeine, chocolate, or fatigue. Usual childhood onset, but possible adult onset. Also DYT9 familial variant with childhood onset associated spasticity and triggered by stress, exercise, caffeine, or chocolate (2).
PATHOPHYSIOLOGY
Exact pathophysiology is not known. Dysfunction in the sensory–motor portion of the basal ganglia or thalamus may lead to impaired inhibition of thalamic–cortical activity, which results in increased unwanted movements (2). This has been demonstrated with dystonia arising after structural lesions in these brain areas. Drugs and toxins that disrupt proper function of the basal ganglia can predispose to dystonia. Dopamine is implicated in some forms of dystonia supported by therapeutic effects in dopa-responsive dystonia, and also tardive dystonia seen with use of dopamine-blocking agents.
ETIOLOGY
Divided into 3 categories, but in many cases the cause may be difficult to determine.
- Primary dystonia includes both idiopathic and genetic causes and occurs in the absence of other abnormal neurological symptoms. It implies the absence of trauma, birth defect, nervous system lesion, or neurodegenerative condition.
- Dystonia plus syndromes are caused by specific genetic mutations with features of dystonia and other specific abnormalities (see “Genetics” section).
- Secondary dystonia is due to neurodegenerative disease, drugs, insult to the nervous system, or other exogenous cause.
COMMONLY ASSOCIATED CONDITIONS
- Primary and inherited
- Secondary dystonia
- Drugs include dopamine-blocking agents (antipsychotics, anti-emetics, metoclopramide), anticonvulsants, dopaminergic agents, antidepressants, cocaine, amphetamines, and stimulants.
- Toxins include manganese, thallium, methanol, carbon monoxide, carbon disulfide, and cyanide.
- CNS lesions such as infection, trauma, cerebrovascular accident, tumor (brain or spine), hypoxia, cerebral palsy, perinatal insult, multiple sclerosis, or CNS inflammatory/autoimmune disorder.
- Neurodegenerative conditions
- Inborn errors of metabolism (2)
[Outline]
HISTORY
- Age of onset with a wide range, but with bimodal peak at 9 and 45 years of age. Insidious onset usually with focal dystonia. May start as a slow repetitive uncontrolled movement associated with brief posturing. Generalized dystonia of early onset common to start in a limb and then spreads to contiguous areas (2,3)[C]. Dystonia with onset after age of 25 years tends to start in the cervical–cranial area (2,3)[C]. Features helpful in guiding assessment and treatment include age of onset, any preceding illness or injury, concomitant drugs/medications, aggravating or attenuating factors, and family history of dystonia (2,3)[C].
- Possible features:
- Diurnal variation in some inherited forms
- Sensory trick or geste antagoniste (i.e., simple placement of the hand on the involved part of the body reduces the dystonia)
- Occurring with action or at rest
- Present only with certain task performance (task-specific dystonia)
Classification
- Primary or secondary
- Age of onset: Before or after 25 years
- Distribution/extent of the involved areas
- Focal – involves a single body area (neck, face, voice, arm, leg, or trunk)
- Segmental – 2 contiguous areas
- Multifocal – 2 or more noncontiguous areas
- Hemidystonia – unilateral upper and lower limb (likely due to structural lesion)
- Generalized – involving the whole body
PHYSICAL EXAM
- Neurological exam to evaluate for the presence of other abnormalities to suggest secondary dystonia (2,3)[C].
- Evaluate abnormal movements with regard to characteristic appearance of posturing. Identify involved agonistic and antagonistic muscles.
- May have associated dystonic tremor with repeated directional component, but irregular rhythm due to variable amplitude and frequency.
- Task-specific dystonia will require evaluation while performing the specific task such as writing.
- Forms of dystonia include:
- Cervical dystonia
- Hemifacial spasm
- Blepharospasm
- Craniocervical dystonia (Meige's syndrome)
- Oromandibular dystonia
- Focal limb dystonia
- Task-specific dystonia (i.e., writer's cramp)
- Segmental dystonia
- Hemidystonia
- Generalized dystonia
- Suggestible or distractibility may suggest psychogenic etiology.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- If secondary dystonia suspected (2,3)[C]:
- CBC with smear for acanthocytes with a presence suggesting neuroacanthocytosis.
- Serum ceruloplasmin and/or 24-hour urine copper collection with abnormality suggesting Wilson's disease.
- Hepatic profile to evaluate for liver disease, and possible elevated bilirubin in kernicterus.
- Inflammatory markers if concerns for autoimmune disease or paraneoplastic panel if suspected underlying malignancy.
- Other testing may be warranted if other metabolic disorders, specific toxic, or other medical conditions are suspected.
Follow-Up & Special Considerations
If dystonia occurs in absence of other abnormal symptoms with onset before the age of 26 years, then consider commercially available DYT1 genetic testing, especially if positive family history of dystonia (2)[C].
Imaging
MRI/CT if hemidystonia or secondary dystonia to assess for CNS structural lesions (3)[C].
Diagnostic Procedures/Other
- EEG if present focal twitching and if history suspicious for seizures.
- 3-week trial of levodopa if suspect dopamine-responsive dystonia, especially in children (2,3)[C].
- Slit light exam if suspect Wilson's disease.
DIFFERENTIAL DIAGNOSIS
- Chorea
- Tic disorder
- Myoclonus
- Partial epilepsy
- Psychogenic
- Spasticity
- Contracture or joint deformity
[Outline]
MEDICATION
First Line
- Botulinum toxin therapy by an experienced practitioner (3,4)[A,B]. The dose varies on the type of botulinum toxin used, muscles involved, and severity of dystonia. Potential side effects include irritation/pain at the injection site and unexpected weakness of muscle of surrounding area if excessive spread. Rare formation of neutralizing antibodies.
- Trihexyphenidyl titrated to 2–15 mg divided (possible higher tolerability up to 80 mg in children) (2,3,5)[B]. Common side effects include confusion, psychosis, dry eyes, blurred vision, dry mouth, constipation, urinary retention, lightheadedness, and GI upset.
- Baclofen titrate to 15–80 mg divided (2,5)[C]. Common side effects include sedation, nausea, confusion, dizziness, and polyuria.
- Clonazepam titrated to 1–12 mg divided (2)[C]. More concerning side effects include potential for dependency. Other common side effects include sedation, cognitive trouble, and incoordination.
- Tardive dystonia and other drug-induced causes require weaning the offending agent.
Second Line
- Carbidopa/levodopa titrated to 25/100–50/200 mg 3 times a day for dopa-responsive dystonia (2,3,5)[C]. Common side effects include GI upset, flushing, lightheadedness, confusion, or psychosis.
- Tetrabenazine titrated to 37.5 mg divided (2,3,5)[C]. Common side effects include sedation, depression, fatigue, akathisia, anxiety, and nausea.
ADDITIONAL TREATMENT
Issues for Referral
- Expert evaluation may improve accuracy of diagnosis (3)[C]. This may include neurology, subspecialty movement disorder specialist, physical medicine, ophthalmology, or otolaryngology.
- Genetic counseling
Additional Therapies
Physical, occupational, or speech therapy
COMPLEMENTARY AND ALTERNATIVE THERAPIES
Surgical considerations for medication and botulinum toxin therapy refractory dystonia:
- Intrathecal baclofen (2,3,5)
- Deep brain stimulation therapy (2,3,5)
- Stereotactic pallidotomy or thalamotomy
- Rhizotomy/myomectomy
[Outline]
FOLLOW-UP RECOMMENDATIONS
Botulinum toxin therapy requires repeat treatment, but no sooner than 3 months apart. Also may require more frequent visits to observe for effects.
PATIENT EDUCATION
- Treatment goal is to lessen disability caused by dystonia.
- Review potential side effects of treatment.
- Genetic testing is not typically indicated, and genetic counseling advised if done.
- Other patient resources
PROGNOSIS
Chronic disorder that often requires ongoing symptomatic treatment. Focal dystonia may be self-limiting with plateau in progression. Generalized dystonia may spread and eventually cause severe disability.
COMPLICATIONS
Contractures may develop with sustained postures. Generalized dystonia may affect swallowing and breathing as well.
[Outline]
