DYSTONIA

Dystonia consists of repetitive, patterned, twisting, and sustained movements that may be either slow or rapid. Dystonic states are classified as primary, secondary, or psychogenic depending upon the cause. By definition, primary dystonia (formerly known as dystonia musculorum deformans or idiopathic torsion dystonia) is associated with no other neurologic impairment, such as intellectual, pyramidal, cerebellar, or sensory deficits. However, tremor that appears identical to essential tremor occurs in approximately 20 percent of patients with this condition. In some families, dystonia and essential tremor coexist. Cerebral palsy probably is the most common cause of secondary dystonia seen in children.

Clinical features — The onset of involuntary movements occurs before age 20 in approximately 30 percent of patients with dystonia. The distribution of the affected muscle groups appears to depend upon age. The disorder typically begins distally in children, whereas a cranial-cervical distribution is more common in adults. Childhood dystonia usually progresses to a generalized disorder, whereas adult dystonia usually remains focal or segmental.

The range of severity of dystonia is variable and may depend upon the situation. As an example, some patients have task-specific dystonias that occur only when they participate in certain activities, such as writing, typing, or playing the piano ("musician's hands"). As the dystonia worsens, it typically extends to adjacent muscles and eventually occurs even at rest. In rare cases, the spasms become severe and may cause cervical disc, nerve, or root problems. Muscle breakdown with myoglobinuria ("dystonic storm") also can occur.

No specific morphologic changes have been noted in neuropathologic examinations of patients with primary dystonia. In the brains of a few patients, the norepinephrine concentration was markedly reduced in the posterior and lateral hypothalamus and increased in the red nucleus, suggesting a neurotransmitter abnormality. However, further studies are needed to confirm these findings. The fluorodopa positron emission tomography (PET) scan usually is normal, although (18F) fluorodeoxyglucose shows an abnormal pattern of metabolic activity when data are averaged from a large group of dystonic patients.

Genetics — Primary dystonia may be sporadic or inherited. Cases with onset in childhood usually are inherited in an autosomal dominant pattern. Many hereditary cases are caused by a defect in torsinA, a protein with uncertain function that is expressed in the brain. A rare cause of hereditary dystonia is dopa-responsive dystonia.

TorsinA mutation — Many patients with hereditary dystonia have a mutation in the TOR1A (DYT1) gene that encodes the protein torsinA, a novel ATP-binding protein in the 9q34 locus. TorsinA is expressed widely in the brain, particularly in the hippocampus, substantia nigra pars compacta, and cerebellum. Almost all patients have a three base pair deletion that results in loss of a glutamic acid residue in the C-terminal region of the torsinA protein.

The role of torsinA in the pathogenesis of primary dystonia is unknown. In cultured mouse cells, distribution of the mutant and normal protein differed; the mutant protein accumulated in multiple large inclusions in the cytoplasm around the nucleus rather than distributing throughout the cytoplasm. DNA testing for the abnormal TOR1A gene can be performed on individuals with dystonia.

Dopa-responsive dystonia — Dopa-responsive dystonia (DRD) is an unusual form of hereditary progressive dystonia that begins during the first decade after birth. The dystonia usually starts in the legs and becomes generalized. Some patients may also have hyperreflexia, rigidity, tremor, and other parkinsonian features, and less commonly, cerebellar signs. The severity of the disorder has a diurnal variation in many patients who may be asymptomatic in the morning or after a nap, but become increasingly fatigued with dystonic movements during the day. The characteristic feature of DRD is the marked improvement after treatment with levodopa or dopamine agonists. Affected patients also respond to anticholinergic therapy.

DRD is inherited in an autosomal dominant pattern, although it has a 3:1 female preponderance. Several mutations in the GTP-cyclohydrolase I (GCHI) gene on chromosome 14 have been identified in patients with DRD. GTP-cyclohydrolase I catalyzes the first step in the synthesis of tetrahydrobiopterin (BH4), the natural cofactor for tyrosine hydroxylase. This gene defect results in impaired synthesis of dopamine by nigral neurons without neuronal degeneration.

Paroxysmal dystonia — Two forms of paroxysmal dyskinesias occur: paroxysmal kinesigenic and nonkinesigenic dystonia. The kinesigenic form is precipitated by a sudden movement, such as rising rapidly from a chair or turning suddenly. This disorder predominantly affects boys and presents at 5 to 15 years of age. The dystonia often is asymmetric and associated with choreoathetosis and epilepsy. The attacks typically last a few seconds and recur as often as 100 times a day. Most patients with kinesigenic dystonia improve with anticonvulsant therapy, including phenytoin, carbamazepine, and barbiturates.

In the nonkinesigenic disorder, which may begin in infancy, dystonia occurs spontaneously. Episodes last minutes to hours and recur two or three times a month. Alcohol, coffee, fatigue, stress, exercise, or excitement may be precipitating factors. Many affected patients also have choreoathetosis and ataxia, especially during the attacks. Nonkinesigenic dystonia is resistant to pharmacologic therapy, although some patients improve with clonazepam, oxazepam, acetazolamide, valproate, carbamazepine, and haloperidol.

Hemidystonia — Hemidystonia (also known as unilateral dystonia) involves one-half of the body and occurs frequently in children and young adults. Approximately 75 percent of patients with hemidystonia have a structural lesion in the contralateral basal ganglia, often the putamen, that resulted from an insult to the brain. Causes associated with these lesions are infarction or hemorrhage (30 percent) and perinatal trauma (20 percent). Hemidystonia often presented several years after the precipitating factor; this delay occurred more often in children.

Drug reaction — An acute dystonic reaction that usually is transient is a recognized complication of the dopamine receptor-blocking drugs, such as the antipsychotics (eg, haloperidol, chlorpromazine) and antiemetics (eg, phenothiazines, metoclopramide), and also can occur with levodopa, anticonvulsants, and ergots. The offending drug should be discontinued. Patients treated with dopamine receptor-blocking agents occasionally develop persistent tardive dystonia after the offending drug is stopped. If no spontaneous improvement occurs, they may respond to trials of muscle relaxants, anticholinergic drugs, and tetrabenazine.

Other causes — Other causes of paroxysmal or fluctuating dystonia in children include gastroesophageal reflux (Sandifer syndrome), multiple sclerosis, thyrotoxicosis, metabolic disorders (eg, Hartnup disease), paroxysmal dystonia in sleep (hypnogenic dystonia), and "infectious torticollis." Dystonia may be erroneously attributed to a postural deformity that results from common musculoskeletal or orthopedic problems such as congenital torticollis or scoliosis. The number of cases of these disorders that actually represent dystonia is not known.

Treatment — Appropriate treatment of dystonia depends upon an accurate diagnosis. Patients with atypical features, such as impaired intellect, seizures, neuro-ophthalmologic abnormalities, ataxia, corticospinal tract signs, sensory deficits, severe speech disturbance, and unilateral distribution of the dystonia, are more likely to have an underlying disorder that can be treated, such as Wilson disease.

All patients with childhood-onset dystonia, especially those with parkinsonian features, should be treated with levodopa because they may have DRD. Anticholinergic therapy in high doses (eg, 30 to 60 mg/day of trihexyphenidyl) is effective in approximately two-thirds of children with primary dystonia. Trihexyphenidyl is introduced in small doses (1 mg bid) and gradually increased by 2 to 4 mg per week over several weeks or months until symptoms improve or side effects (eg, mental dullness, blurred vision, or other anticholinergic reactions) prevent further increases.

Tetrabenazine, a monoamine-depleting agent, is effective in some patients with dystonia (including 63 percent of those with primary dystonia); sometimes it is combined with pimozide, a postsynaptic dopamine receptor-blocking drug, and the anticholinergics. Other drugs that sometimes are effective include oral and intrathecal baclofen, carbamazepine, valproate, primidone, and lithium.

Botulinum toxin injections are given when pharmacologic therapy fails, and may be most helpful in patients with focal dystonia.

 Surgery — Deep brain stimulation (DBS) of the internal globus pallidus (GPi) has emerged as the surgical treatment of choice for patients with disabling dystonia who do not respond to pharmacologic therapy or chemodenervation with botulinum toxin. In a randomized controlled trial that evaluated 40 patients with primary segmental or generalized dystonia, bilateral DBS of the GPi was significantly more effective than sham stimulation at three months for improvement in the severity of dystonia, reduction in disability, and improvement in the physical aspects of quality of life.

Since the advent of DBS, stereotactic thalamotomy, pallidotomy, and cervical rhizotomy are rarely used to treat refractory dystonia.