Dystonia is a movement disorder characterized by involuntary, sustained, patterned, and repetitive muscle contractions leading to twisting movements or abnormal postures. Dystonic movements may be classified by their anatomical distribution or by their clinical characteristics, and can be further categorized as primary (idiopathic) or secondary (symptomatic) in regard to etiology. Primary dystonia, by definition, is unaccompanied by other neurological deficits, and may be associated with several known genetic mutations. Secondary dystonia should be suspected when dystonia occurs in association with the following:
Other neurological abnormalities, other movement disorders, or other abnormalities on general medical examination
Presentation in a location or pattern atypical for demographics
Medical history that includes a known medical condition or treatment associated with dystonia
In all instances, dystonia is thought to involve the neuroanatomic circuitry that includes the basal ganglia nuclei, sensorimotor system, brainstem, and cerebellum. Secondary dystonia is associated with a very wide range of etiologies, each of which has a different prognosis and some of which are treatable; therefore, every effort should be made to identify secondary causes by obtaining a careful medical history.
A large number of heredodegenerative diseases can cause secondary dystonia, often in the setting of other multisystemic abnormalities and other movement disorders. Most of these disorders are rare and inherited as autosomal-recessive diseases; present at a younger age; are associated with abnormal neuroimaging; and may have other features more prominent than the dystonia, such as mental retardation, seizures, peripheral neuropathy, and ophthalmological abnormalities. However, some disorders are autosomal-dominant, X-linked, or mitochondrially inherited, and they may present in adolescence or adulthood. A specific diagnosis should be sought because some conditions have therapeutic interventions. Clues to diagnosis can include concomitant involvement of other organ systems. Table 1 summarizes those disorders that may present in adulthood. Some of the diseases seen in the table are discussed in the text that follows.
Aceruloplasminemia. Aceruloplasminemia is an autosomal-recessive disorder of iron metabolism caused by mutations in the CP gene, which encodes ceruloplasmin. This mutation results in iron accumulation in the brain and viscera and may be associated with anemia, diabetes mellitus, and retinal degeneration. Neurological symptoms may start in the fifth decade and include dystonia (60%, particularly craniocervical), parkinsonism (41%), ataxia, dysarthria, and progressive dementia. Brain MRI may be abnormal, with low intensities on T1- and T2-weighted images of the striatum, thalamus, and dentate nuclei representative of iron deposition.
Neuroacanthocytosis. Neuroacanthocytosis is a heterogeneous group of disorders in which abnormally spiculated red blood cells are found in association with a neurological syndrome. Chorea-acanthocytosis is an autosomal-recessive disorder caused by a mutation in the VPS13A gene, which encodes the protein chorein. Patients most characteristically present with involuntary movements of the face, mouth, and tongue, which may have a choreic or dystonic component, most dramatically with a tongue protrusion dystonia that interferes with eating. Dystonia occurs in 50% of patients and parkinsonism in one third. Dystonia and chorea may also be prominent features in McLeod's syndrome, an X-linked mutation of the XK gene.
Niemann-Pick Disease. Niemann-Pick Type C is an autosomal-recessive lipid storage disease caused by a mutation in the NPC1 or NPC2 gene. Patients can present over a wide age range, with the classic presentation in middle-to-late childhood with dementia, vertical supranuclear gaze palsy, and ataxia. Dystonia is common and can start in one limb, gradually involving all limbs as well as axial muscles; patients may also have myoclonus, chorea, or parkinsonism. Speech is affected with findings of dysphonia, dysarthria, and eventual dysphagia. Clues to Niemann-Pick C include hepatosplenomegaly, particularly in early childhood. Bone marrow, spleen, and liver contain characteristic foamy cells.
Homocystinuria. Homocystinuria is an autosomal-recessive inherited disease caused by cystathionine-ß-synthase deficiency, with multiple systemic, ophthalmological, and neuropsychiatric manifestations. Dystonia, chorea, tremor, and (rarely) parkinsonism have been reported in association with the disorder.
Disorders of Metabolism
Mitochondrial Disease. Mitochondrial/respiratory chain disorders may cause dystonia, typically presenting in childhood and associated with bilateral basal ganglia lesions on brain imaging. Dystonia may occur with Leigh syndrome, a heterogeneous disorder associated with multiple respiratory chain defects and pyruvate dehydrogenase deficiency. Dystonia is also reported in association with Leber hereditary optic neuropathy; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); and Kearns-Sayre syndrome.
Hypoxia. Hypoxic brain injury, particularly in the perinatal period, may cause any pattern of dystonia, typically more generalized, in ~1% of survivors of perinatal asphyxia, starting even up to 32 years after the initial insult. In a review of 12 patients recovering from hypoxic injury due to various causes, dystonia developed between 1 week and 36 months after the injury, was gradually progressive, and was most often associated with evidence of putamenal damage on neuroimaging. An older age at time of insult and lesions involving the globus pallidum predicted the development of an akinetic-rigid motor syndrome, which frequently later developed dystonic features.
Calcium Metabolism. Hypocalcemia from idiopathic hypoparathyroidism may cause paroxysmal dystonia and choreoathetosis, which, rarely, may be kinesigenic. It is associated with basal ganglia calcification on neuroimaging.
Thyroid Disease. Hyperthyroidism has been associated with the onset of segmental and task-specific dystonia that improved after treatment with antithyroid medications, with postulated alteration of the dopaminergic system by elevated thyroid hormone. Pseudohypoparathyroidism was discovered in one case of an 11-year-old girl presenting with paroxysmal, exercise-induced facial and upper extremity dystonic movements in association with hypocalcemia, which ceased with normalization of calcium levels.
Infectious agents associated with dystonia are numerous. Dystonia as a prominent symptom has been reported with viral encephalitis (Japanese encephalitis, influenza A, cytomegalovirus), tuberculous meningitis, cerebral malaria, and M. pneumoniae infection. Although reported less frequently in HIV infection, dystonia can occur in patients with HAD treated with dopamine receptor antagonists, who may have increased susceptibility due to underlying basal ganglia dysfunction. Dystonia may also occur in association with opportunistic infections related to HIV (particularly toxoplasmosis).
The relationship of dystonia to autoimmune disease has been demonstrated in a small number of case reports and case series. In a series of 100 patients with blepharospasm and orofacial-cervical dystonia (Meige syndrome), a high antinuclear antibody (ANA) titer (> 1:80) was found in 26%, and specific autoimmune disease was diagnosed in 7%. Antibasal ganglia antibodies were found in 63% of a series of 46 patients with atypical dystonia (adult onset generalized dystonia or fixed limb dystonia), suggesting an underlying autoimmune pathophysiology. A group of patients with dystonia and antibasal ganglia antibodies responded favorably to immunomodulatory therapy.
Systemic Lupus Erythematosus. Individual cases of blepharospasm and torticollis have been reported in the setting of systemic lupus erythematosus or myasthenia gravis. The dystonic movements in these cases responded to immunomodulatory therapies and, in the case of systemic lupus erythematosus, correlated in severity with autoimmune titers.
Neuro-Behçet's Disease. One case of Neuro-Behçet's disease presented as a jaw-opening dystonia in association with chorea as part of generalized cerebral, meningeal, and brainstem involvement, with good response to immunomodulatory treatment.
Celiac Disease. Celiac disease, a gluten-sensitive enteropathy associated with malabsorption and development of autoantibodies, may be associated with neurological syndromes, including ataxia, myoclonus, and dementia. Unilateral dystonic limb posturing, in association with cortical tremor, has been reported as the presenting neurological sign in a case of untreated celiac disease.
Case reports of paraneoplastic dystonia are rare, with dystonia occurring mostly in association with other movement disorders, as referenced in the section on parkinsonism. Two additional cases with dystonia predominance were reported in association with non-Hodgkin's lymphoma -- one case of camptocormia that began 3 years before the development of the malignancy, and another case associated with the CRMP-5 antibody manifesting as cervical dystonia, blepharospasm, dysphonia, bradykinesia, and choreodystonic limb movements. Anti-Ri (ANNA-2) antibodies were identified in four patients with laryngospasm and four patients with jaw opening dystonia (two of the latter with additional cervical dystonia and one with parkinsonism) in association with breast, cervix, and lung malignancies.
Many of the same toxins predisposing to parkinsonism may cause dystonia due to injury to the basal ganglia. Methanol, cyanide, carbon monoxide, manganese, mercury, carbon disulfide, and mycotoxin are examples. As discussed earlier, treatment involves removal of the offending agent in addition to the use of dopaminergic drugs or anticholinergic agents in cases of residual dystonia.
Drug-induced dystonia may appear otherwise similar to primary dystonia because it most commonly manifests only as dystonic movements. Therefore, careful questioning for the typically implicated medications during the medical history is crucial. Many of the drugs previously mentioned as causing drug-induced parkinsonism are also implicated in drug-induced dystonia, but, unlike parkinsonism, dystonia usually occurs either acutely or late in treatment.
Drugs can be grouped by their tendency to cause acute or late (tardive) dystonic syndromes, although many cause both. Classes of drugs that may cause acute dystonia include dopaminergic agents, antidepressants, neuroleptics, anxiolytics, antiepileptic drugs, and antihistamines. Acute dystonic reactions usually occur in axial, cranial, cervical, or pharyngeal muscles, but can be variable in location. Effective treatment of acute dystonic reactions includes discontinuation of the causative agent and intravenous diphenhydramine or anticholinergic medications. Tardive dystonia is most often associated with dopamine receptor-blocking antipsychotic drugs such as neuroleptics, antiemetics, and prokinetic gastrointestinal agents.  Next to haloperidol, metoclopramide is the second most common drug reported to cause tardive dystonia and tardive dyskinesia. Patients with HIV-associated dementia are particularly sensitive to dopamine receptor-blocking medications.
Some medical conditions can themselves mimic dystonia, and may be termed "pseudodystonia." Examples include tetany-related carpopedal spasm due to alkalosis, hypocalcemia, or hypermagnesemia; abnormal postures secondary to bone, joint, or ligamental pathology from orthopedic or rheumatologic conditions; torticollis associated with retropharyngeal abscess; or the head tilt associated with hiatal hernia and gastroesophageal reflux with Sandifer's syndrome.
Semin Neurol. 2009;29(2):97-110. © 2009 Thieme Medical Publishers
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