Dystonia

Etiology

Dystonia is a heterogeneous entity with diverse etiology and clinical presentation. One of the most useful classifications of dystonia is by etiology: primary and secondary dystonia.[5][6][7]

In primary dystonia (familial or sporadic, also called idiopathic torsion dystonia), dystonia is the sole neurologic sign (with exception of the tremor) and other causes of dystonia such as acquired or neurodegenerative processes have been ruled out.

Primary dystonia is further classified into early-onset and adult-onset forms.

Primary dystonia is thought to have a greater genetic contribution, even in the absence of a family history of dystonia. The precise cause of primary dystonia is unknown. There is some genetic susceptibility in conjunction with environmental factors.

Early-onset primary dystonia typically initially affects an extremity and then spreads, in many occurrences becoming generalized. DYT 1 and DYT 6 are the two genes that are responsible for early onset of primary dystonia.

As far as adult-onset dystonia usually involves either cervical, cranial, or brachial muscles, or remains focal or segmental. Worth mentioning that cervical dystonia is the most common form and at the same time is more common than early-onset primary dystonia.

Secondary dystonias are caused by the environmental insult and are brought in by some identified causes, such as head injury, drug side effects (e.g., tardive dyskinesia) or neurological disease (e.g., Wilson disease).

An intermediary category is termed ‘dystonia plus syndromes,’ and consists of disorders in which there is no acquired etiology or neurodegeneration, but in which there are neurologic symptoms other than dystonia. This category includes dopa-responsive dystonia (DRD/DYT5), myoclonus dystonia (MD/DYT11) and rapid-onset dystonia-parkinsonism (RDP/DYT12).

Medications associated with dystonia:

• Antipsychotics
• Metoclopramide
• Antiepileptics
• Dopamine agonists
• MAO inhibitors
• Amphetamines, cocaine
• Caffeine
• Antihistamines
• Beta-adrenergic agents
• Lithium
• Oral contraceptives
• Cimetidine

Epidemiology

Dystonia is the third most prevalent movement disorder, affecting approximately 500,000 adults and children in North America.

After Parkinson, dystonia is the most common movement disorder encountered in movement disorder clinics.

Pathophysiology

The principal cause of dystonia has been thought to be dysfunction of the basal ganglia, which emerged from the concept of the basal ganglia as the brain region responsible for integrating motor control. Also, secondary dystonia is often due to lesions of the basal ganglia, specifically the putamen or globus pallidus.

However, the absence of neurodegeneration in primary dystonia, as well as observations that lesions of brain regions other than the basal ganglia can cause secondary dystonia, has guided to the idea that dystonia is a neuro-functional disorder, i.e. a disorder characterized by abnormal connectivity that may occur in a structurally normal-appearing brain.

Dystonia is considered to be a motor system disorder rather than a disease of a particular motor structure. Studies have provided evidence of dysfunction in almost every region of the central nervous system involved in motor control and sensorimotor integration, including cortex, brainstem, cerebellum, and spinal cord.

Although standard MRIs have not revealed structural pathology, diffusion tensor imaging (DTI) has shown subtle abnormalities in the sensorimotor circuitry of dystonia patients. In DYT 1 mutation carriers there is reduced functional anisotropy (FA) in a sub-gyral white matter of the primary sensorimotor cortex, pons and left superior cerebellar peduncle. Abnormal functional anisotropy has also been observed in the lentiform nucleus and the white matter adjacent to the nucleus in patients with focal dystonia.

Neurophysiological studies demonstrate a variety of changes consistent with abnormalities in inhibitory control, sensorimotor integration, and brain plasticity. The EMG in the dystonia show co-contraction of agonist and antagonist muscles with prolonged bursts and overflow to the muscles.

Dystonia is worsened by stress, fatigue, anxiety, or lack of sleep.

History and Physical

It is important to distinguish between idiopathic and symptomatic dystonia (due to another disease process).

Idiopathic dystonia may be inherited, often has an insidious onset, and may come into sight initially during the execution of a specific, repetitive, well-learned action. In contrast, symptomatic (secondary) dystonia occurs after a stroke, tumor, infection, hypoxia-ischemia, encephalitis, neurodegenerative disease (e.g., hepato-lenticular degeneration or Wilson's disease), and toxins.

The clinical examination in dystonia may exhibit involuntary writhing/twisting movements precipitated by specific voluntary movements, such as walking or writing. Focal task-specific limb dystonia can begin as painful hand cramping or involuntary wrist/finger spasms when writing, while torticollis presents as an uncontrollable head-turning when driving or watching television.

• Oro-mandibular dystonia can manifest as night-time bruxism (jaw spasms producing forceful jaw closure) and may follow dental procedures, oro-mandibular-facial trauma, or temporomandibular joint dysfunction.
• Spasmodic dysphonia can commence as a strained voice. Despite the name dystonia, the tone of affected extremities at rest is often normal at the onset. Deep tendon reflexes may also be normal.
• A tremor in a patient with dystonia (dystonic tremor) is sometimes distinguished from other tremor types by the presence of a null point (e.g., a neutral position at which tremor attenuates).
• In cervical dystonia, head tremor sometimes decreases with the head held in a specific position, and displacement from that position, such as turning the head to one side, may worsen it.
• Dystonic tremor may be nonuniform in amplitude and frequency, can be linked with myoclonus (jerk-like movements), and disappears in sleep. Dystonia may cause hypertrophy and pain in affected muscles such as the sternocleidomastoid in spasmodic torticollis.

In its early stages, it may be viewed as an annoying mannerism or hysteria, and only later due to unremitted postural abnormality, lack of the typical psychological characteristics of hysteria, and becoming an apparent feature of the illness, the correct diagnosis is made.

Dystonic movements tend to be exacerbated by fatigue, stress, and emotional states; they tend to be suppressed with relaxation, hypnosis, and sleep.

A characteristic and almost unique feature of dystonic movements is that they can abate by tactile or proprioceptive sensory tricks (geste antagoniste). For example, patients with cervical dystonia (torticollis) often place a hand on the chin or side of the face to diminish nuchal contractions, and oro-lingual dystonia is often relieved by touching the lips or placing an object in the mouth. Lying down may reduce truncal dystonia; walking backward or running may reduce leg dystonia.

Some dystonic movements last several seconds/minutes but others can last for weeks/months. This can lead to permanent bone deformity, contractures and impairment in function.

Evaluation

Evaluation and work up are based on the type of dystonia where clinical presentation remains the cornerstone of evaluation.[8][9][10]

In primary dystonia, clinical evaluation and genetic testing (DYT1 and DYT6) can guide to the correct diagnosis. The gene at the DYT1 locus has been determined to serve as a cause of the dystonia described by Oppenheim. In a vast majority of patients with DYT1 dystonia, symptoms begin in childhood or adolescence, and the mean age of onset is 13 years. Oppenheim dystonia affects most ethnic groups but is considerably wide spread in the Ashkenazi Jewish population.

Dystonia plus syndrome encompasses nondegenerative disorders in which parkinsonism dopa-responsive dystonia (DRD) and rapid-onset dystonia-parkinsonism (RDP) or Myoclonus-Dystonia (M-D) co-occur with dystonia. Dopa responsive dystonia predominantly starts between ages six and 16 but can arise at any age. When it begins in infants has the appearance of cerebral palsy. When it occurs in adults, it often manifests as pure parkinsonism, responding to levodopa with a benign course. Dopa responsive dystonia affects girls more often than boys, has a worldwide distribution and is not known to have a higher specific prevalence in any particular ethnic group. Mutations in the gene for GTP cyclohydrolase 1(GCH1) located at 14q22.1 are accountable for the greater number of dopa-responsive dystonia. Dopa responsive dystonia can be suspected if a young patient with dystonia responds greatly to a low dose of anticholinergics. On the other hand, the most effective agent is levodopa.

Clues suggestive of secondary dystonia emerge from the definition of the disorder that develops as a result of environmental factors that affect the brain, especially the basal ganglia. Spinal cord injury and peripheral injury can serve as a cause of dystonia as well. So the history of possible head trauma, encephalitis, toxin and drug exposure, perinatal anoxia, also the presence of neurologic abnormality independently from dystonia, for example, Parkinsonism, dementia, seizures, ocular symptoms, ataxia, neuropathy, spasticity with abnormal brain imaging will guide to the diagnosis of secondary dystonia.

Because many of the neurodegenerations are a result of genetic abnormalities, the term Heredodegenerative dystonia is applied to this category. Dystonia in Neurodegeneration is a prominent feature. MRI of the brain, ceruloplasmin level, slit-lamp exam, lysosomal screen, peripheral blood smear, nerve conduction studies, creatine kinase (CK) level, vitamin E are a few worth mentioning investigations.

Imaging studies may identify central lesions, hemorrhage or hypoxic damage.

Treatment / Management

The medications that are most potent in the treatment of dystonia include anticholinergics (trihexyphenidyl), GABA agonists (baclofen and benzodiazepines), and dopaminergic agents. The mechanism of action of these drugs is due to modifications in dopaminergic and cholinergic neurotransmission and reduced GABA-mediated inhibition in the dystonic central nervous system (CNS).

Trihexyphenidyl is the first-line medication for management of childhood-onset primary generalized or segmental dystonia.

Focal dystonia can be effectively treated with botulinum toxin injections. The toxin blocks the vesicular release of acetylcholine into the neuromuscular junction, generating temporary local chemo-denervation and muscle weakness, lessening the excessive activity of the affected dystonic muscles.

Botulinum toxin is the first-line treatment for cervical dystonia and blepharospasm and is also habitually used to treat laryngeal dystonia (spasmodic dysphonia), and focal limb dystonia. Apart from its direct peripheral effect of weakening affected muscles, botulinum toxin injections may also reduce afferent feedback from affected muscles, possibly normalizing the abnormal plastic changes in the CNS.

The drug-induced tardive dyskinesia requires specialized treatment.

Historically, dystonia patients were treated surgically with pallidotomy or thalamotomy. These lesional surgeries provided significant benefit to dystonia symptoms in some cases, but also frequently caused permanent, debilitating side effects, particularly dysarthria. Lesional surgeries have now been succeeded by deep brain stimulation (DBS), which resembles a lesional effect but is reversible and adjustable. In the past two decades, DBS has come to the leading edge as an important treatment option for patients with severe medically refractory primary dystonia. The currently established target in DBS for dystonia is the globus pallidus (GPI). DBS is thought to produce its clinical effect by inducing functional changes within the abnormal motor networks in dystonia and ultimately normalizing pathologically overactive motor activation responses. In opposition to the rapid effect of DBS that occurs in Parkinson disease or essential tremor, the effect of DBS is typically delayed in dystonia, often taking weeks to months, confirming  with the concept of dystonia as a disorder of sensorimotor connectivity that compels time to restyle and adapt to changes along the entire motor circuit after DBS.

There is a distinct variability in response to DBS among dystonia patients, with some patients showing dramatic improvement whereas others benefit only modestly or not at all, and no single factor, including DYT1 gene status, has been found to be undeniably predictive of response. The question which patient with primary dystonia will have the best response to DBS remains open and requires further investigation.

Whether DBS should be considered as a treatment option for secondary dystonia is not entirely understood.

Physical therapy may help individuals with focal or segmental dystonic movements. Speech therapists can offer communication aids and provide techniques to relax the jaw.

Differential Diagnosis

• Cerebral palsy

• Lysosomal storage disease

• Neuronal ceroid lipofuscinoses

• Neuro acanthocytosis

• Parkinson-plus syndrome

• Parkinson disease in young adults

• Post-stroke spasticity

• Psychogenic dystonia

• Spinocerebellar ataxia

• Systemic lupus erythematosus (SLE)

Staging

Classification based on anatomy

• Focal dystonia involves a single body part
• Segmental dystonia affects 2 or more contiguous body parts. The classic example is head and neck dystonia
• Multifocal dystonia involves noncontiguous body parts
• Generalized dystonia may involve the trunk and the limbs
• Hemidystonia is typically associated with deficits in the contralateral basal ganglia and also called unilateral dystonia.