Primary Dystonia

Pathogenesis and Pathophysiology. Dystonia consists of sustained, repetitive, patterned contractions of the muscles producing twisting (e.g., torticollis) or squeezing (e.g., blepharospasm) movements or abnormal postures that may be present at rest, when changing position, or when performing a specific motor activity.y The most frequently encountered form of generalized dystonia is primary dystonia, formerly referred to as dystonia musculorum deformans or idiopathic torsion dystonia. It is an autosomal dominant disorder in which the genetic defect, consists of a three base pair deletion in a gene on chromosome 9q32-34 (DYT1), coding for an ATP-domain protein. Rarer forms of pure dystonia unrelated to this defect or due to enzyme deficiencies have been described ( i.Tab,le..,„34.z5. ) but are not well delineated.

Although autopsy studies have produced no reproducible histological or biochemical abnormalities in patients with primary dystonia, the disorder is thought to be due to altered physiological control of descending pathways from the basal ganglia and brain stem. Subtle changes on MRI have been reported in patients with primary dystonia, but in most patients no discernible abnormalities can be identified on imaging tests. PET studies have also failed to reveal consistent abnormalities. Studies using blink, acoustic, and vestibulo-ocular reflex testing, however, have revealed abnormalities suggesting that the brain stem reflexes have enhanced excitability. y Changes in norepinephrine, serotonin, and dopamine levels have been found in some patients.

Epidemiology and Risk Factors. Limited information is available about the epidemiology of primary dystonia,


I. Idiopathic (primary) dystonia

D. Due to a known specific cause

A. Sporadic (idiopathic torsion dystonia, ITD)

Perinatal cerebral injury and kernicterus: athetoid cerebral palsy, delayed onset dystonia

B. Inherited (hereditary torsion dystonia)

1. Classic autosomal dominant ITD (DYTl gene, 9q34)

2. Nonclassic autosomal dominant ITD (not DYTl gene)

Infection: Viral encephalitis, encephalitis lethargica, Reye's syndrome; subacute sclerosing panencephalitis; Creutzfeldt-Jakob disease acquired immune deficiency syndrome

3. Autosomal recessive tyrosine hydroxylase deficiency

II. Secondary dystonia

Other: tuberculosis, syphilis, acute infectious torticollis

A. Dystonia-plus syndromes

Paraneoplastic brain stem encephalitis

1. Myoclonic dystonia (not DYT1 gene)

Cerebral vascular and ischemic injury

2. Dopa-responsive dystonia (DRD, GTP cyclohydrolase I 14q22.1-q22.2 gene defect)

Brain tumor

Arteriovenous malformation

3. Rapid-onset dystonia-parkinsonism (RDP)

Head trauma and brain surgery

4. Early-onset parkinsonism with dystonia (EPD)

Peripheral trauma

5. Paroxysmal dystonia-choreoathetosis

Toxins: MN, CO<CS2 , methanol, disulfiram, wasp sting

B. Associated with neurodegenerative disorders 1. Sporadic

Drugs: levodopa, bromocriptine, antipsychotes, metoclopramide, fenfluramine, flecainide, ergot, anticonvulsants, certain calcium channel blockers

Parkinson's disease

Progressive supranuclear palsy

III. Other hyperkinetic syndromes associated with dystonia

Multiple system atrophy

A. Tie disorders with dystonic tics

Corticobasal ganglionic degeneration

B. Paroxysmal dyskinesias

Multiple sclerosis

1. Paroxysmal kinesigenic choreoathetosis

Central pontine myelinolysis

2. Paroxysmal dystonic choreoathetosis

2. Inherited

3. Intermediate paroxysmal dyskinesia

Wilson's disease

4. Benign infantile paroxysmal dyskinesia

Huntington's disease

IV. Psychogenic

Juvenile parkinsonism-dystonia

V Pseudodystonia

Progressive pallidal degeneration

Atlantoaxial subluxation

Hallervorden-Spatz disease


Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome)

Arnold-Chiari malformation Trochlear nerve palsy

Joseph's disease

Vestibular torticollis

Ataxia telangiectasia

Posterior fossa mass


Soft tissue neck mass

Rett's syndrome (?)

Congenital postural torticollis

Intraneuronal inclusion disease

Congenital Klippel-Feil syndrome

Infantile bilateral striatal necrosis

Isaac's syndrome

Familial basal ganglia calcifications

Sandiffer's syndrome

Spinocerebellar degeneration

Satoyoshi syndrome

Olivopontocerebellar atrophy

Stiff-person syndrome

Hereditary spastic paraplegia with dystonia

X-linked dystonia-parkinsonism or Lubag (pericentromeric)

Deletion of 18q

C. Associated with metabolic disorders

1. Amino acid disorders

Glutaric acidemia

Methylmalonic acidemia


Hartnup's disease


2. Lipid disorders

Metachromatic leukodystrophy

Ceroid lipofuscinosis

Dystonic lipidosis ("sea blue" histiocytosis)

Gangliosidoses GM! , GM2 variants

Hexosaminidase A and B deficiencies

3. Miscellaneous metabolic disorders

Wilson's disease

Mitochondrial encephalopathies:

Leigh's disease, Leber's disease

Lesch-Nyhan syndrome

Triosephosphate isomerase deficiency

Vitamin E deficiency

Biopterin deficiency

Modifed from Jankovic J, Fahn S: In Tolosa E (eds): Parkinson's Disease and Movement Disorders, 3rd ed. Baltimore, Williams & Wilkins, 1998, in press.

but data from Rochester, Minnesota reveal a prevalence of 34 per million population; specific cultural groups are more likely to develop primary dystonia than others, however, and among Jews of eastern European ancestry the prevalence is at least double that seen in other groups.

Clinical Features and Associated Disorders. Primary dystonia may involve the entire body (generalized dystonia) or may be confined to one body part (focal dystonia), for example, the head (cranial dystonia) or neck (cervical dystonia); alternatively, it may involve contiguous body

parts (segmental dystonia), for example, the neck, shoulder, and arm. The most common form of limb dystonia is dystonic writer's cramp. Although primary dystonia is a highly variable condition, there are a number of important clinical patterns. First, primary dystonia, regardless of its eventual outcome (focal, segmental, or generalized), usually begins as a focal condition, and in children the legs and feet are the areas most commonly affected. Second, environmental conditions affect dystonia, and, importantly, in the early stages of primary dystonia, dystonia is usually seen only during activity, for example, when walking or running (action dystonia). In addition, and related to exacerbation of disease with action, dystonic signs usually become prominent in the middle and later part of the day. This feature is most pronounced in a particular form of dystonia, termed dopa-responsive dystonia (see subsequent discussion), in which diurnal fluctuation in the gait disturbance may be so marked that the patient is almost normal in the early morning but becomes virtually crippled by late afternoon or evening. Third, the younger the age at onset, the more likely the dystonia is to become severe and spread to many body regions. Likewise, adult-onset primary dystonia is almost always focal or segmental and does not become generalized. Fourth, patients with primary dystonia often report that certain postures or sensory "tricks" or "gestes antagonistes" improve their dystonia. For example, gentle counterpressure by a hand against the chin in a patient with torticollis may enable the patient to maintain the primary or normal position of the head. Finally, one of the features in many patients with dystonia is an associated tremor in addition to the contorted posture. This tremor, termed dystonic tremor, involves the patient's attempt, conscious or not, to overcome the dystonia. It is most pronounced when the patient works maximally to resist the pull of the dystonic muscles and is least apparent when the patient permits the involved body part to drift with the dystonic spasm.

Differential Diagnosis. In addition to primary dystonia, the differential diagnosis of the dystonic patient (see IabJ,e.3.4.:5 ) must include, first, dystonia-plus syndromes, (see later discussion), a conglomerate term that includes other forms of primary dystonia associated with additional neurological deficits, and second, secondary forms of dystonia, in which the dystonia is related to underlying damage from a known pathological cause. In the latter category, causes of dystonia are numerous and include exposure to DA receptor-blocking drugs ("tardive dystonia"), hypoxic encephalopathy, head trauma, encephalitis, human immunodeficiency virus (HIV) and other infections, peripheral or segmental nerve injury, inherited disorders (e.g., Wilson's disease), metabolic disorders and other inborn errors of metabolism, mitochondrial disorders, and chromosomal abnormalities. y Unilateral dystonia (hemidystonia) is usually not part of the clinical picture of primary dystonia but is associated with a structural lesion in the contralateral striatum, particularly the putamen.

Evaluation. The diagnosis of primary dystonia should be considered in any patient with an abnormal posture and a family history of variable problems with cramps, spasms, tremors, and crippling conditions. In the initial evaluation the clinician should gather information about age at onset, initial and subsequent areas of involvement, course and progression of disease, tremor or other movement disorders, possible birth injury, developmental milestones, and exposure to neuroleptic medications, as well as a family history of dystonia, parkinsonism, or other movement disorders. Consanguinity or Jewish ancestry should be noted as well. Since the clinical expression of primary dystonia is highly variable even within families, the history and family tree may be extremely difficult to establish with confidence. Some family members may have severe problems and require extensive assistance with activities of daily living, while others may show only mild symptoms (e.g., writer's cramp).[57] Evidence of other conditions known to produce dystonia but associated with other neurological dysfunctions (e.g., cognitive, pyramidal, sensory, or cerebellar deficits) should be evaluated along with secondary causes of dystonia. The ceruloplasmin level should be obtained in all patients in whom onset of dystonia occurs before the age of 50, since Wilson's disease is highly treatable. Other blood tests, including genetic tests, depend on the clinical setting, and the various storage and metabolic disorders should be evaluated individually. An MR scan is important in the evaluation of structural abnormalities, and skull, neck, and spine evaluations may be needed if there is evidence of a secondary myelopathy or scoliosis due to axial dystonia.

Management. In treating primary dystonia, high-dose anticholinergic therapy (e.g., trihexyphenidyl in doses of up to 70 mg/day) may be effective in ameliorating dystonia, particularly in younger patients. However, many patients are unable to tolerate such high doses because loss of memory, hallucinations, blurring of vision, and other anticholinergic side effects may occur. In addition, all patients with childhood-onset dystonia deserve a trial of levodopa, using Sinemet in doses of up to 100/1000 mg/day.y Other agents such as oral baclofen, carbamazepine, and tetrabenazine have been reported to be beneficial in some dystonic patients. Recent interest has focused on the use of intrathecal baclofen in patients with generalized and axial dystonia, but controlled trials of this usage have not been published.

Intramuscular injections of botulinum toxin type A are the most effective treatment for focal dystonia and may be used in a limited form in patients with segmental or generalized dystonia. y Because it acts at the presynaptic membrane, this potent neurotoxin prevents release of acetylcholine at the nerve terminal, causing muscle weakness. Injection into dystonic muscles requires knowledge of the muscle anatomy and the site of muscle innervation, and some clinicians perform this procedure with the aid of EMG guidance. Treatment is necessary every 3 to 5 months in most patients, and this therapy has been used safely in some patients for more than 15 years. However, some patients develop resistance to the clinical response, and antibodies to the A toxin may develop. If the dose is limited to less than 300 units per procedure and the treatment is given no more frequently than every 3 months, the risk of immunoresistance is minimized. Other types of botulinum toxins, namely B and F, are currently being investigated for the treatment of focal dystonia.

Thalamotomy is occasionally performed in patients with otherwise medically intractable disease. It is more effective for distal than for proximal dystonia. y Unfortunately, when these procedures are bilateral, patients may be left with

severe dysarthria, dysphagia, and memory deficit. In this regard, pallidotomy may have some advantages. Cervical cord stimulation, peripheral nerve section, rhizotomy, and myotomy are occasionally effective.

Prognosis and Future Perspectives. Prognosis in primary dystonia is highly dependent on age of onset; the younger the age at onset, the higher the likelihood of spread and progression to generalized disabling dystonia. The biological markers and pathophysiological mechanisms of dystonia remain to be elucidated. It is likely that the gene or genes for primary dystonia will be identified, and the study of the gene product may provide clues to the pathogenesis of primary dystonia.

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