Dystonia

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40 Dystonia

Julie Leegwater-Kim

Clinical Vignette

A 22-year-old previously healthy woman developed slurred speech, difficulty walking, and hand tremors over the course of 1 month after a severe psychological trauma. She had mild neck pain and took cyclobenzaprine without benefit. She denied history of fever, head trauma, or exposure to dopamine receptor–blocking agents. There was no family history of neurologic disease. Exam revealed lower facial dystonia, including risus sardonicus and tongue dystonia, dysarthria, bradykinesia, mild cogwheel rigidity, mild rest and kinetic tremor, dystonic gait, and loss of postural reflexes. After several weeks, her symptoms plateaued. Trial of carbidopa/levodopa was ineffective. She reported slight benefit on high doses of trihexyphenidyl.

Workup included blood glucose, creatinine, electrolytes, complete blood count, liver function tests, thyroid-stimulating hormone, erythrocyte sedimentation rate, antinuclear antibodies test, vitamin B₁₂, ceruloplasmin, and 24-hour urine copper, all of which were within normal limits. Slit-lamp exam was negative for Kayser–Fleischer rings. Spinocerebellar ataxia genetic testing was negative. Brain magnetic resonance imaging was unremarkable. Electroencephalography and electromyography were unremarkable. ATP1A3 genetic sequencing revealed a mutation.

Dystonia is a hyperkinetic movement disorder characterized by involuntary, sustained muscle contractions that frequently cause twisting and repetitive movements or abnormal postures. Dystonic movements are patterned, meaning they repeatedly involve the same group of muscles. There is simultaneous contraction of agonist and antagonist muscles. In general, the duration of dystonic muscle contractions is longer than other hyperkinesias (i.e., chorea), though sometimes the movements can be rapid enough to resemble repetitive myoclonic jerking. One of the characteristic features of dystonia is that it is often temporarily diminished by tactile sensory tricks (gestes antagonistes). For example, a patient with cervical dystonia may be able to reduce dystonic movements by placing a hand on the chin or the side of the face. Patients with orobuccolingual dystonia often experience improvement by touching the lips or placing an object, such as a toothpick, in the mouth. In some patients, simply thinking about performing the sensory trick diminishes dystonia. The efficacy of sensory tricks can be exploited in the development of therapies. For example, some patients with lower cranial dystonia may benefit from wearing a mouthguard.

The initial presentation of dystonia is usually focal (affecting one body part) and task-specific—the dystonia occurs with a particular action. For example, a subject with foot dystonia may initially note dystonia when walking forward, but not walking backward or running. In the majority of patients, the dystonia remains focal without spreading to other parts of the body. If dystonia spreads, it tends to involve contiguous body parts and becomes a segmental dystonia. In more severe cases, the dystonia can become generalized. As a rule, the younger the age at onset, the more likely the dystonia is to spread. Recent data have also suggested that in the primary dystonias there is a caudal-to-rostral anatomic gradient in the site of onset as a function of age.

As dystonia progresses, it emerges with other actions of the affected body part, therefore becoming less task-specific. For example, the patient with foot dystonia may experience it when walking forwards and backwards, running, or tapping the foot. Further progression can lead to “overflow dystonia,” in which movement of a distant body part elicits the dystonia. As dystonia worsens, it can occur at rest. In the most severe cases of dystonia, contractures may develop.

Dystonia is frequently worsened by fatigue and stress and diminished with relaxation and sleep. Pain is generally uncommon in dystonia except for cervical dystonia, in which ~75% of patients report pain.

Classification of Dystonia

There are several recognized classification schemes for dystonia: (1) age at onset, (2) anatomic distribution, and (3) etiology.

Age at Onset

Early-onset dystonia is defined as dystonia developing at or before the age of 26 years and late onset is defined as dystonia developing after age 26 years. Age at onset is an important factor determining prognosis in patients with dystonia, with earlier age at onset correlating with increased likelihood of spread of dystonia to other body parts. In general, young-onset dystonia tends to begin in a limb and become generalized whereas adult-onset dystonia tends to be craniocervical and remain focal or become segmental.

Anatomic Distribution

The topographic characteristics of dystonia are useful in defining the severity of the dystonia and guiding treatment. Focal dystonia affects a single body part. Virtually any part of the body can be involved in dystonia and many types of focal dystonia have specific names: blepharospasm (dystonic eye closure), spasmodic torticollis (rotational cervical dystonia), and writer’s cramp (focal hand dystonia). When dystonia involves two or more contiguous body parts/regions, it is referred to as segmental dystonia. Multifocal dystonia refers to the involvement of two or more noncontiguous body parts. Generalized dystonia represents a combination of crural dystonia (one or both legs plus trunk) and any other area of the body. In hemidystonia, as its name implies, dystonia affects one half of the body. Hemidystonia suggests a symptomatic (secondary), rather than primary, dystonia.

Etiology

The growth in our understanding of the genetics of dystonia has contributed significantly to the etiologic classification of dystonia. There are essentially two broad categories: primary and secondary.

Primary Dystonia

Primary dystonias are characterized by pure dystonia (with the exception that tremor can be present) and they may be sporadic or familial. Most primary dystonias are sporadic with onset in adulthood and a focal or segmental presentation. The most common focal dystonia presenting to movement disorders clinics is cervical dystonia (Fig. 40-1). After cervical dystonia, the most common focal dystonias are blepharospasm, spasmodic dysphonia, oromandibular dystonia, and hand dystonia.

Figure 40-1 Cervical Dystonia.

A minority of primary dystonias have an identified genetic etiology (Box 40-1). Perhaps the best studied of the primary dystonias is DYT1 dystonia, or Oppenheim’s dystonia, a generalized torsion dystonia that usually begins in childhood affecting the limbs first. DYT1 dystonia is caused by a deletion in the DYT1 gene, which encodes for the torsin A protein. The disease is inherited in an autosomal dominant fashion and has 30–40% penetrance. Phenotype can vary widely within an affected family. The DYT1 mutation is estimated to account for 90% of limb-onset dystonia cases in the Ashkenazi Jewish population and 50–70% of cases in the non-Jewish population. A number of other primary dystonias (DYT6, DYT7 and DYT13) have had their genetic loci mapped (Table 40-1).

Table 40-1 Genetic Dystonias

Secondary Dystonia

Secondary dystonia encompasses a broad clinical category that includes inherited degenerative disorders, degenerative disorders of unknown etiology, acquired dystonias (i.e., drug-induced, structural lesions, trauma), and psychogenic dystonia. Patients with secondary dystonia frequently display associated clinical abnormalities including other movement disorders besides tremor (i.e., parkinsonism), dementia, spasticity, ataxia, weakness, reflex changes, eye movement abnormalities, or seizures. Other historical and clinical features that suggest secondary dystonia include history of trauma, perinatal anoxia, toxin or drug exposure, onset of dystonia at rest, and hemidystonia.

A number of heredodegenerative disorders may present with dystonia. Autosomal dominant disorders (Huntington disease, spinocerebellar ataxia type 3, neuroferritonopathy), autosomal recessive disorders (Wilson disease, pantothenate-kinase associated degeneration), X-linked recessive disorders (DYT3 or Lubag), and mitochondrial disorders (Leigh disease) have been described and are listed in Box 40-2.

Dystonia can also be seen in various neurodegenerative parkinsonian syndromes, including Parkinson disease, as well as the atypical parkinsonian syndromes including progressive supranuclear palsy and corticobasal ganglionic degeneration (CBD). Adult-onset focal foot or leg dystonia can be the initial presentation of Parkinson disease (PD). Patients with PD may also develop dystonia as an off-symptom or as part of levodopa-induced dyskinesias. A dystonic, apraxic limb is a hallmark of CBD.

Dystonia-plus syndromes are a rare group of inherited nondegenerative diseases that include dopa-responsive dystonia (DRD), myoclonus–dystonia (MD), and rapid-onset dystonia–parkinsonism (RDP). These diseases are considered neurochemical disorders because they are due to biochemical defects that are not associated with neuronal loss. Dystonia is associated with parkinsonism in DRD and RDP and with myoclonus in MD.

1. Dopa-responsive dystonia (DRD), also called Segawa disease or DYT5, is characterized by the onset of progressive dystonia and parkinsonism in midchildhood. Patients exhibit a diurnal variation in symptoms and the feet and legs are predominantly involved. The disease is inherited in an autosomal dominant pattern and is caused by genetic mutations in the GTP-cyclohydrolase I (GCHI) gene. GCHI is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase. Patients respond dramatically to small doses of levodopa.

2. Rapid-onset dystonia–parkinsonism (RDP) is an autosomal dominant disorder characterized by young-onset dystonia and parkinsonism. The symptoms appear dramatically over days to weeks and can often emerge in the setting of a stressor. Bulbar symptoms are very common. Symptoms tend to plateau after weeks. Patients exhibit little if any response to levodopa. The gene for RDP has been identified as ATP1A3, which encodes an Na⁺/K⁺ ATPase.

Myoclonus-dystonia (MD) is an autosomal dominant disorder characterized by alcohol-responsive myoclonus and dystonia. Symptoms can emerge in childhood or in adulthood. Psychiatric disorders such as obsessive–compulsive disorder and alcohol abuse are frequently seen. This disorder has been associated with mutations in the epsilon sarcoglycan gene.

3. Iatrogenic dystonia can occur with exposure to dopamine receptor–blocking agents, levodopa, and selective serotonin reuptake inhibitors. Tardive dystonia may be focal, segmental, or generalized and often is characterized as retrocollis and opisthotonic posturing. Acute dystonia reactions may also develop in association with exposure to dopamine receptor–blocking agents.

A variety of lesions causing damage to the basal ganglia are associated with dystonia. These include perinatal hypoxia, stroke, head trauma, brain tumor, infection, and autoimmune disorders.

Psychogenic dystonia is perhaps the most diagnostically challenging type of secondary dystonia as illustrated by the record that many now-recognized organic dystonia patients were initially thought to have a primary psychiatric disorder. It is also important to recognize that a minority of patients with organic movement disorder may have a superimposed psychogenic movement disorder including dystonia. Features on history and exam that can suggest a psychogenic dystonia include abrupt onset, spontaneous remission, distractible or entrainable movements, variability and inconsistency of movements (i.e., nonpatterned dystonic movements), false weakness or sensory complaints, multiple somatizations, the presence of secondary gain, and concomitant psychiatric disease.

Pathophysiology

Although the genetics of a number of primary dystonias have been elucidated, the pathophysiology of dystonia remains unclear. Lesions in the basal ganglia, particularly the thalamus and putamen, point to these structures as having key roles in the development of dystonia. Models of basal ganglia circuitry suggest that there is an imbalance between direct and indirect pathways leading to reduced pallidal inhibition of the thalamus with subsequent overactivity of the premotor cortex. However, this hypothesis does not square with the finding that pallidotomy and deep brain stimulation of the globus pallidus internus can improve dystonia. A more complex pathophysiological model of dystonia is emerging that incorporates not only rate but pattern, synchronization, and somatosensory responsiveness of neuronal activity.

Treatment

Treatment of dystonia is determined by etiology and anatomic region(s) involved. All children and young adults presenting with dystonia should be given a trial of levodopa to rule out DRD.

The first-line treatment for cervical dystonia, blepharospasm, focal limb dystonia, and spasmodic dysphonia is botulinum toxin. Both serotypes A and B are available in the United States. Botulinum toxin and baclofen can be beneficial for oromandibular dystonia. In addition to medications, physical therapy is an important adjunct in the treatment of dystonia.

For patients with generalized dystonia, trihexyphenidyl at high doses (~90 mg per day) can provide some benefit. Baclofen may also be tried for generalized dystonia and can also be given at high doses. The benzodiazepines may provide adjunctive benefit. Variable results have been found for diphenhydramine, carbamazepine, dopamine agonists and dopamine antagonists. Tetrabenazine can be helpful, especially in tardive dystonia.

For medication-refractory dystonia, surgery can be considered. Peripheral denervation surgeries such as rhizotomy have produced variable results. More recently, deep brain stimulation (DBS) of the globus pallidus has been performed in patients with medication-refractory dystonia. In a recent prospective, double-blind, video-controlled study of patients with primary generalized dystonia (DYT1 and non-DYT1), DBS patients experienced ~50% improvement in motor and disability scores at 1 year. A follow-up study in this group of patients has shown a sustained improvement in both motor and quality of life at 3 years postsurgery. Case series have described benefit of DBS in the treatment of cervical dystonia. DBS also shows promise for treating tardive dystonia.

Additional Resources

Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol. 1998;78:1-10.

Fahn S, Jankovic J. Principles and practice of movement disorders. Churchill and Livingstone. 2007.

Tarsy D, Simon DK. Dystonia. N Engl J Med. 2006;355:818-829.

Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med. 2005;352:459-467.

Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol. 2007;6:223-229.

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