AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Background

Dystonia is a syndrome of sustained muscle contractions that produce twisting and repetitive movements or abnormal postures. The extent and severity of muscle involvement are remarkably variable, ranging from intermittent contraction limited to a single body region to generalized dystonia involving the limbs and axial muscles. According to the body regions affected, dystonia is focal if a single area is involved, such as (1) the face, (2) oromandibular area, (3) arm, or (4) neck. It is segmental if 2 or more contiguous areas are affected, such as (1) cranial and cervical areas or (2) the face, jaw, and tongue. It is multifocal if 2 or more noncontiguous body regions are involved, such as (1) an arm and a leg with cranial muscle involvement or (2) blepharospasm and leg dystonia. Finally, it is generalized if both legs and 1 other body region are involved.

Many dystonic movements are action-specific. Some individuals develop involuntary movements only during writing (eg, writer's cramp), while others may have dystonic movements in the arm and trunk when walking but not when dancing. Many patients with dystonia can partially control their arms using small tactile maneuvers, such as touching the chin in the case of cervical dystonia or touching the brow in the case of blepharospasm (geste antagonistique). These tactile maneuvers may mislead physicians to the erroneous diagnosis of malingering or hysteria.

In 1911, Oppenheim introduced the term dystonia to describe the variable tone present in patients with abnormal muscle spasms. Persistent dystonia was introduced by the French to describe the late complications of chlorpromazine therapy. In 1973, Keegan and Rajput introduced the term dystonia tarda to describe drug-induced sustained muscle spasm causing repetitive movements or abnormal postures in patients who were treated with levodopa.¹

In 1982, Burke et al coined the term tardive dystonia; tardive derives from the Latin word meaning late onset.² They proposed the following 4 criteria for diagnosis:

1. The presence of chronic dystonia


3. A history of antipsychotic drug treatment preceding or concurrent with the onset of dystonia


5. The exclusion of known causes of secondary dystonia by appropriate clinical and laboratory evaluation


7. A negative family history of dystonia

A fifth criterion was also proposed but appeared to gain little acceptance from other researchers—"If other involuntary movements (such as dyskinesia, akathisia) are additionally present, the dystonia is the most prominent."

Traditionally, tardive dystonia is considered an extremely disabling subtype of a broader syndrome known as tardive dyskinesia. The original descriptions of tardive dyskinesia referred to stereotyped orolingual and masticatory movement of a choreic nature, taking the form of lip smacking and pursing, tongue protrusion, and licking and chewing movements. This term should only be used for those movement disorders developing after long-term exposure to dopamine receptor–blocking agents (by definition, at least within 3 mo of total cumulative drug exposure, which can be continuous or discontinuous) and lasting more than 3 months.

However, this traditional view has come under attack in recent years, as some argue these should be characterized as 2 separate disorders. In 1982, Burke et al suggested that tardive dystonia is distinguished from the classic oral-buccal-lingual choreic form of tardive dyskinesia not only by the dystonic nature of the involuntary movements but also by the frequency with which it causes significant neurologic disability. Burke et al noted that symptoms can begin after only a few weeks or a few days of exposure and the degree of improvement was much more limited compared with tardive dyskinesia.² Other writers have followed the lead of Burke and his colleagues, publishing reviews that point to the differences in clinical manifestations, prevalence, prognosis, and treatments between tardive dystonia and dyskinesia.^{3, 4}

Pathophysiology

The pathophysiology of tardive dystonia and dystonias in general is not well understood, partly because it describes a symptom that may arise from a variety of cerebral structures, such as the basal ganglia, cerebellum, thalamus, or brainstem or cortex, or may be caused by genetic alterations.

The basal ganglia (ie, striatum and globus pallidus) and functionally related structures (eg, subthalamic nucleus, substantia nigra, motor thalamus, cerebellum, amygdala) modulate motor function using several neurotransmitters via segregated parallel efferent pathways. These neurotransmitters, including glutamate, gamma-aminobutyric acid (GABA), endorphins, enkephalins, dopamine, acetylcholine, and substance P, are intrinsically involved in the modulation of movement via these functionally segregated motor, oculomotor, and behavioral circuits (ie, dorsolateral prefrontal, mesolimbic).

By pharmacologic (ie, dopamine receptor–blocking agents, CNS stimulants) or toxic (ie, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine [MPTP]) manipulation, many disease states can be induced, such as drug-induced parkinsonism (by blockade of D1 plus D2 receptors), hyperkinetic movement disorders (ie, tardive dyskinesia, by blocking D2 receptors), and drug-induced dyskinesias observed in late-stage Parkinson disease (by excessive dopaminergic stimulation).

Due to limited understanding of the pathophysiology of tardive dystonia, it is helpful to first review what is known about the pathophysiology of the related disorders of tardive dyskinesia and the nontardive dystonias to put this information in context.

Tardive dyskinesia

The current model used to explain the mechanism underlying tardive dyskinesia is the supersensitivity of the postsynaptic dopamine striatal receptors resulting from the long-term administration of dopamine receptor–blocking agents. According to this theory, long-term blockade of postsynaptic dopamine receptors results in denervation supersensitivity with up-regulation and increased numbers of receptors. This condition leads to an increase in postsynaptic dopamine receptors available to interact with endogenous dopamine. If these receptors are blocked, the abnormal involuntary movements decrease. If these receptors are freed, more receptors are available for stimulation, leading to an increase in the severity of these movements. These conditions explain the clinical observation that characterizes tardive dyskinesia.

If the dose of neuroleptic medication is decreased or discontinued, the severity of the abnormal movements increases. If the dose of dopamine receptor–blocking agents increases, these movements ameliorate or disappear completely. This also explains the improvements observed with dopamine-depleting agents for the treatment of tardive dyskinesia. Drugs such as alpha-methyl paratyrosine, tetrabenazine, or reserpine deplete dopamine and are extremely helpful in the management of these excessive movements. At times, treatment of tardive dyskinesia may require a combination of both dopamine-depleting agents and dopamine-blocking drugs. In some cases, botulinum toxin may be used as an add-on treatment for some disabling dystonic movements.

Dystonia of basal ganglia origin

Dystonia of basal ganglia origin may develop after focal striatal lesions, occurring weeks or months after the inciting basal ganglia lesion and suggesting that the condition may result from secondary changes, rather than from the primary lesion. Therefore, compensatory changes in the affinity or number of dopamine receptors in the remainder of the striatum or a reorganization of striatal topography may lead to changes in the activity of the other basal ganglia structures.

Dystonic postures

Dystonic postures are caused by inappropriate tonic contraction of antagonistic muscles or muscle groups; these signs have been confirmed with electromyographic studies.

Multichannel surface electromyography shows phasic bursts predominating in one antagonist muscle corresponding to dystonic movements. Tremulous movements are accompanied by irregular, grouped contraction. Voluntary efforts do not influence the involuntary activity of affected muscles, but they do precipitate contraction of muscles from neighboring segments of the body. The Westphal phenomenon, or paradoxical activation of passively shortened muscles, can be elicited easily.

Electrophysiologic studies combining the H reflex of peripheral nerves and cortical stimulation suggest an abnormality of activation of 1a inhibitory interneurons in the spinal cord, permitting the abnormal simultaneous contraction of antagonistic muscles.

Some reports suggest hyperactivity of brainstem interneurons in patients with blepharospasm. The R2 response of the blink reflex has been found to recover much faster after a conditioning stimulus in patients with cranial dystonia (even those without blepharospasm) than in normal controls. Evidence exists for altered vagal reflexes in patients with spasmodic dysphonia and a failure of exteroceptive suppression of neck motor neuron activity in patients with spasmodic torticollis. These electrophysiologic results suggest a defect in the functions of brainstem and spinal cord interneurons normally concerned with reciprocal and other inhibitions of unwanted motor activity. The role of disturbances of descending basal ganglia influences on these interneurons remains to be defined.

Idiopathic dystonia

Disturbances of sensory input and processing in dystonia have also been emphasized in recent studies. Electrophysiologic and positron emission tomography (PET) studies demonstrate variable evidence of motor cortical hyperexcitability. Based on evidence for dissociation between lentiform (increased) and thalamic (decreased) metabolism, Eidelberg et al suggest that the indirect striatopallidal pathway may be overactive in persons with idiopathic dystonia.

Pharmacologic agents with variable therapeutic actions produce dystonia as an immediate adverse effect of the pharmacologic treatment or as a persistent and often permanent complication. Many of these compounds modify the metabolism of brain monoamines, namely dopamine, norepinephrine, and serotonin. Most frequently, dopamine stimulant agents, such as L-dopa and dopamine agonists, induce acute dystonia, especially in patients with akinetic-rigid syndromes.

Reports show that persistent and, occasionally, paroxysmal dystonia may occur after the administration of amphetamines and related compounds. Dopamine receptor blockers produce acute and persistent dystonia, especially in patients with akinetic-rigid syndromes. Recently, some cases were reported of occasional tardive dystonia after intake of amphetamines and related compounds.

Pathophysiologic basis of tardive dystonia

The pathophysiologic basis of tardive dystonia remains obscure. Not all cases of tardive dystonia have been related to neuroleptic exposure. Why exposure to neuroleptics produces dystonia in some patients, choreas in some, and both in others is not clear.

Sachdev has raised the question if tardive dystonia develops in individuals who are already vulnerable to dystonia, with the antipsychotic drugs activating a latent predisposition.⁵

Although acute dystonias and tardive dystonias have many similarities, they also have differences and some have been hesitant to conclude that these exist on a continuum with each other. In terms of genetic studies, the evidence for similar genetic mechanisms has been lacking. For example, in many families affected by idiopathic torsion dystonia, a mutation of the DYT1 gene on band 9q34 has been identified, but currently, no evidence exists that similar genetic factors cause the predisposition to tardive dystonia.

Further, the genetic evidence has been lacking that factors that predict tardive dyskinesia also predict tardive dystonia. For instance, the Ser9Gly polymorphism in the D3 receptor has been associated with vulnerability to tardive dyskinesia, but a study by Mihara et al looking at that gene and 2 other mutations known to cause decreased metabolism of neuroleptics through changes in cytochrome P4502D6 and a decreased baseline density number of D2 receptors, respectively, found no overrepresentation with any of these mutations and their sample of 9 patients with tardive dystonia.⁶ To date, no genetic markers have been identified that predict the development of tardive dystonia.

The neuropharmacology changes underlying tardive dystonia also remain poorly understood. A possible role for serotoninergic and noradrenergic modulation of cholinergic pathways was suggested in tardive dystonia.

The striatum (caudate and putamen) receives excitatory glutamatergic impulses from most regions of the cortical mantle. The striatum funnels these impulses to the pallidum, which is its main efferent zone. From the striatum, 2 distinct, functional, direct, and indirect output pathways act as efferent pathways transmitting impulses to other basal ganglia structures. A direct and indirect connection occurs in the motor loop. Both pathways have different subtypes of dopamine receptors. The direct striatopallidal pathway has D1 subtype dopamine receptors acting directly into the motor thalamus.

The D1 receptor is an excitatory pathway, and the D2 receptor is an inhibitory pathway. During normal basal ganglia function, both pathways work in concert to maintain equilibrium of both direct and indirect pathways. The direct pathway connects the striatum to the medial globus pallidus or globus pallidus interna and substantia nigra reticulata with the motor ventrolateral and ventral anterior nucleus of the thalamus. The direct pathway drives the motor cortex (ie, primary motor cortex, supplementary motor cortex) via the motor thalamus to allow cortically mediated impulses.

One of the more popular theories has been proposed by Trugman, who maintained that repetitive stimulation of the D1 receptor by endogenous dopamine, resulting in sensitization of the D1-mediated striatal output in the presence of D2 receptor blockade, is a fundamental mechanism mediating tardive dyskinesia and tardive dystonia (Trugman, 1994). This hypothesis is based on a relative segregation of outputs; the D1-mediated striatal output is directed preferentially to the globus pallidus, internal segment and substantia nigra, and pars reticulata, and the D2-mediated output is directed preferentially to the globus pallidus and external segment.

By selectively blocking D2 receptors, long-term treatment with a conventional neuroleptic disrupts the normal, coordinated balance of D1- and D2-mediated striatal outputs. With long-term neuroleptic administration, endogenous dopamine is able to stimulate D1 receptors, whereas D2 receptors are occupied by neuroleptics.

The hypothesis that sensitization of the D1-mediated striatal output is involved in the pathogenesis is consistent with both the delayed onset of dystonia after neuroleptic initiation and the persistence of symptoms after neuroleptic withdrawal; therefore, this model predicts that the D1 antagonist will be beneficial in the treatment of tardive dystonia.

The major limitation to this theory is that it tries to conceptualize tardive dystonia and dyskinesia with a single pathway, yet the 2 disorders have differences that are difficult to explain if this were in fact the case. The most striking is the differences in natural course and treatment. Tardive dystonia tends to be much more resistant to treatment then tardive dyskinesia, yet medications, such as anticholinergics, that occasionally treat the dystonic symptoms have been much less effective in tardive dyskinesia.

Frequency

International

The prevalence of tardive dystonia is 0.5-21.6% of patients who are treated with neuroleptics, with most on the lower end of that range. This condition undoubtedly is less common than oral-buccal-lingual tardive dyskinesia. In a survey of 555 psychiatric patients, Yassa et al found a prevalence rate of 34% for oral tardive dyskinesia and only 1.4% for tardive dystonia.⁷ Similarly, Friedman and coworkers found a prevalence rate of only 1.5% among 352 hospitalized psychiatric patients.⁸ One recent study by Sethi et al indicated a prevalence rate of 21% for tardive dystonia among veterans institutionalized long-term. However, most of these cases were mild; only 20% were symptomatic.⁹

Mortality/Morbidity

Tardive dystonia causes pain and physical and emotional disability. Disability is moderate to severe in 70% of patients with tardive dystonia.

• Disabilities involve the activities of daily living and are socially embarrassing.


• Impairment of speech, vision, eating, sitting, and gait has been reported. Pain is also often an accompanying symptom. Any truncal or lower-limb dystonia causes a gait abnormality, leading to a bedridden state only in severe cases.


• The social embarrassment and distress over the movements are the issues that often concern the patients most. Limitations (real or perceived) in keeping gainful employment and making new friends and romantic partners can be devastating.

Race

Tardive dystonia appears to occur in all ethnic and racial groups in which it has been studied. However, no large-scale prevalence studies have been done to determine its specific prevalence in each group.

Sex

The literature shows a higher prevalence in men than in women.

• In 1982, Burke et al reported a 1.6:1 male-to-female preponderance ratio. In a follow-up of 107 patients, 16 of which had been previously followed by Burke, the ratio was 1.14:1.²


• Friedman et al⁸ and Yassa et al⁷ conducted studies of 2 unselected psychiatric populations, the results of which supported a male-to-female predominance ratio of 4:1 and 3:1, respectively.

Age

Although no large unselected population study exists, tardive dystonia appears to have an earlier mean age of onset than other related dystonic conditions.

• In the study by Yassa et al, tardive dystonia had a mean age of onset of 40.5 years.⁷ In a study by Kiriakakis et al of 107 patients with tardive dystonia, the mean age of onset was 38.3 +/- 13.7 years, with males having a younger age of onset then females (but also starting neuroleptics earlier).¹⁰ It was also noted that the younger a patient's neuroleptic exposure, the shorter the interval before developing tardive dystonia.


• In 1982, Burke et al found an average age of onset of tardive dystonia of 34 years for men and 44 years for women.²


• In 1985, Gimenez-Roldan et al found the age at onset to be 36 years for tardive dystonia and 61.8 years for tardive dyskinesia.¹¹


• Davis and Cummings observed that segmental tardive dystonia has an earlier age of onset than cranial tardive dystonia.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

History

Tardive dystonia starts insidiously and progresses over months or years, until it becomes static.

• Young male psychiatric patients commonly develop tardive dystonia after variable periods (weeks or years) of exposure to dopamine antagonists.


• In most patients, tardive dystonia begins in the face or neck; less commonly, the dystonia may begin in one of the arms and, rarely, as a focal foot dystonia.


• In 1992, Burke et al conducted a study of patients at the time of maximum severity of their illness.¹² Most patients had involvement of cranial nerves. The neck was involved in almost 80% of the cases; retrocollis was characteristic, occurring in 50% of those with neck involvement. The trunk was affected in 35% of the patients, and most of them had back-arching movements. The arms were affected in 42% of the patients, often in the form of sustained extension to the elbow, especially when walking. The legs were affected in a minority of patients. According to Burke et al, the diagnosis of tardive dystonia requires the following 4 criteria:
• • The patient must have dystonic movements defined as sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures.
  
  
  • The dystonia must develop either during or within 3 months of a course of neuroleptic treatment. The 3-month cutoff recognizes the fact that neuroleptics may suppress tardive dyskinesia, which often does not become apparent until some time after drugs are stopped.
  
  
  • No other neurologic signs should be present to suggest one of the many known causes of secondary dystonia, such as Wilson disease.
  
  
  • The patient must have a negative family history for dystonia. In the presence of a positive family history, knowing whether the affected individual has neuroleptic-induced dystonia or simply expresses an inherited form that is coincident with neuroleptic use is not possible.


• A history of recent trauma in the same body region as the focal dystonia or head trauma suggests a posttraumatic dystonia. Hemidystonia is almost always related to a brain lesion on the contralateral side of the abnormal movements.

Physical

The movements evident in patients with tardive dystonia are not dissimilar to those observed in patients with primary torsion dystonia. Dystonic movements can be focal, segmental, generalized, multifocal, or hemidystonic.

• Focal dystonia indicates that only a single area of the body is affected. Commonly occurring types of focal dystonia have specific labels such as the following:
• • Blepharospasm is dystonic movements of the eyelid.

  • Torticollis is dystonic movements of the neck.

  • Writer's cramp is dystonic movements of the arm.

  • Oromandibular dystonia is dystonic movements of the mouth.

  • Dystonic adductor dysphonia is dystonia that causes larynx spasm.

• Segmental dystonia can be subdivided into cranial, axial, brachial, and crural.
• • Cranial dystonia refers to involvement of any combination of musculature in the head and neck region.

  • Segmental axial dystonia represents involvement when both neck and trunk are affected, without involvement elsewhere.

  • Segmental brachial dystonia refers to dystonia affecting both arms only, one arm plus a contiguous axial structure (eg, neck, trunk, or both), or both arms plus the contiguous axial region (eg, neck, trunk, or both).

  • Segmental crural dystonia indicates that dystonia is present in both legs (with or without the trunk also being affected) or one leg plus the trunk.

• Generalized dystonia represents a combination of segmental crural dystonia plus involvement of any other area of the body.
• The term multifocal dystonia applies to the involvement of 2 or more noncontiguous parts of the body; examples include one leg and the opposite arm, one leg and the neck, or one arm and the jaw.
• Hemidystonia affects one half of the body; dystonia is almost always symptomatic rather than idiopathic.
• The classic oral-lingual-buccal tardive dyskinesia with repetitive stereotypic movements may precede the onset of dystonic movements and, in some patients, may occur after the onset of dystonic movements. Retrocollis and trunk-arching backward seem to occur more frequently in patients with tardive dystonia rather than in those with idiopathic dystonia.
• The clinical diagnosis of tardive dystonia is often aided by the coexistence of other tardive involuntary movement.
• • Classic oral-buccal-lingual tardive dyskinesia occurs sometime during the course among 55% of patients with tardive dystonia.

  • Tardive akathisia, characterized by subjective and motor restlessness, is present in 31% of patients with tardive dystonia.

• Videotape recordings of patients with tardive dystonia have several practical advantages. Close and prolonged observations are less intrusive with videotape recordings than with one or more clinical observers and are less revealing of the true purpose of assessment. If the patients are aware that their movements are the focus of attention, they might deliberately or involuntarily suppress or control their movements. Videotaped recordings may be useful in increasing diagnostic sensitivity for tardive dystonia, particularly with regard to the detection of early signs of the condition.

• Most of the clinical investigations in a patient with tardive dystonia are directed toward uncovering a possible cause for the disorder. Toxins, such as manganese and methanol, can cause similar symptoms, usually after an initial neurologic insult. In some patients, symptomatic dystonia may appear month to years after the initial cerebral insult.

• Delayed-onset dystonias can occur in adolescence and relate to birth asphyxia; however, this phenomenon can also be observed with central pontine myelinosis and cyanide intoxication.

• Details of the onset, distribution, and clinical characteristics of the dystonic spasms are often helpful in the diagnosis of a patient with symptomatic dystonia. A focal dystonia of abrupt onset suggests a structural nervous system lesion or a psychogenic etiology. Idiopathic dystonias are typically action-induced at onset, followed by overflow dystonia, and, eventually, are present at rest.

• Dystonia at rest, even from the beginning, strongly suggests a secondary dystonia.

• Once a diagnosis of dystonia is made, considerations must be given to the possible causes. Evaluating patients for Wilson disease by obtaining a serum ceruloplasmin value and a slit-lamp examination by an ophthalmologist is recommended. Patients with Wilson disease can present with dystonia or other abnormal movement disorders.

• Differentiating tardive dystonia from other causes of dystonia is important. Other causes include the following:
• • Familial

  • Sporadic

  • Perinatal injury

  • Encephalitis

  • Head injury

  • Stroke

  • Tumor

  • Huntington disease

  • Hallervorden-Spatz syndrome

  • Friedreich ataxia

  • Olivopontocerebellar atrophy

  • Ceroid lipofuscinosis

  • Juvenile dystonic lipidosis

  • GM1 and GM2 gangliosidoses

  • Ataxia telangiectasia

  • Lesch-Nyhan syndrome

  • Leigh syndrome

  • Metachromatic leukodystrophy

  • Glutaric acidemia

  • Degenerative disease (eg, Parkinson disease, progressive supranuclear palsy)

• If neurologic signs other than dystonia are progressive, then tardive dystonia may be associated with other pathologic conditions because neuroleptics do not induce progressive changes in intellect, such as sensory function, pyramidal motor systems, and cerebellar function.

Causes

Young age, male sex, mental retardation, and convulsive therapy have been identified as specific risk factors. Neuroleptic exposure is the most significant etiologic factor. Other medications associated with tardive dystonia include antiemetics (eg, prochlorperazine, promethazine, metoclopramide) and antidepressants (eg, amoxapine). Also, a benzamide derivative, veralipride, has been reported to cause tardive dystonia.

• Neuroleptics
• • The main cause of tardive dystonia is neuroleptic exposure. Tardive dystonia develops in a shorter period and with significantly less total neuroleptic exposure than severe tardive dyskinesia. Also, patients with tardive dystonia seem to receive fewer doses of neuroleptic agents than persons who develop tardive dyskinesia.
  
  
  • Virtually all dopamine receptor antagonists that reportedly cause oral tardive dyskinesia also reportedly cause tardive dystonia. These agents include the following:
    
    
    • Aliphatic, piperazine, and piperidine classes of phenothiazines
    
    
    • Butyrophenones (eg, haloperidol)
    
    
    • Thioxanthenes
    
    
    • Dibenzepin agents
    
    
    • Diphenylbutylpiperidines
    
    
    • Indalone (molindone)


• Antidepressants
• • Amoxapine, an antidepressant with dopamine receptor–blocking properties, has been implicated in cases of tardive dystonia.
  
  
  • In 1997, Vandel et al reviewed the literature and found that tricyclic antidepressants induced extrapyramidal symptoms, including tardive dyskinesia, tardive dystonia, myoclonus, and akathisia.¹³


• Antiemetics
• • Several antiemetics with dopamine receptor–blocking properties have also been associated with tardive dystonia.
  
  
  • These include prochlorperazine, promethazine, and metoclopramide.


• Benzamide derivatives: In 1992, Gabellini et al reported one case of tardive dystonia caused by a benzamide derivative, veralipride.¹⁴


• Antipsychotics
• • Some recent reports correlate the use of atypical antipsychotics, including clozapine, olanzapine, and risperidone, with tardive dystonia and tardive dyskinesia.
  
  
  • No adequate epidemiologic data exist regarding whether any particular psychiatric diagnosis constitutes a risk factor for the development of tardive dystonia.
  
  
  • The duration of exposure to antipsychotics required to cause tardive dystonia ranges from months to years. Exposure to antipsychotics need not be long, and a minimum safe period is not apparent. This duration of neuroleptic exposure seems to be shorter for women. A longer duration of exposure to neuroleptics does not correlate with the severity of dystonia; however, patients with generalized dystonia have shorter neuroleptic exposure than patients with focal dystonia.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Other Problems to be Considered

Hallervorden-Spatz syndrome
Friedreich ataxia
Olivopontocerebellar atrophy
Lesch-Nyhan syndrome
Metachromatic leukodystrophy
Perinatal injury

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Lab Studies

• To differentiate tardive dystonia from all causes of dystonia, base the workup on the history findings and clinical presentation of the dystonic movements. Diagnostic studies used to differentiate among these numerous causes may need to be extensive in some cases.
• Any CNS disorder affecting the basal ganglia can produce dyskinetic movements, which can be misleading to the diagnosis of tardive dystonia. A routine evaluation may include the following:
• • Electrolyte levels

  • CBC count with peripheral smear

  • Thyroid hormone indices

  • Calcium level

  • Magnesium level

  • Liver enzyme values

  • Erythrocyte sedimentation rate

  • Antinuclear antibody level

  • VDRL test

  • HIV antibody titer

  • Serum, copper, and ceruloplasmin values

  • Electroencephalogram, CT scan, or MRI of the brain

  • Additional tests - May be warranted in specific cases

• These tests are expensive; therefore, consider the cost-to-benefit ratio to avoid unnecessary tests.

Imaging Studies

• Most neuroimaging studies used for dystonia have been performed on patients with idiopathic torsion dystonia. A problem with several of the PET studies on dystonia is the heterogeneity of the patient group recruited. Familial, sporadic, and acquired dystonia have been considered together, and patients with focal or hemidystonia have been favored to provide a side-to-side comparison of basal ganglia function.


• Increased resting lentiform nucleus metabolism has been described in patients with dystonia.


• In 1988, Chase et al published a study of 6 patients with sporadic idiopathic dystonia with fluorodeoxyglucose, all of whom had normal findings from CT scan or MRI studies.¹⁵ Three patients had increased lenticular glucose use contralateral to the more affected limbs.


• PET activation findings in patients with idiopathic and acquired dystonia are compatible with inappropriate overactivity of the basal ganglia and their frontal projections on limb movements underlying this condition. Whether the frontal association area overactivity is simply secondary to primary basal ganglia overactivity or represents an adaptive phenomenon in a conscious attempt to suppress the syndrome is unclear.

Other Tests

• Tardive dystonia is not associated with a characteristic pathological finding. In some reports, the brain is normal, whereas other reports show inferior olive damage, substantia nigra, or nigrostriatal degeneration or swelling of the large neurons of the caudate.


• Postmortem neurochemical studies found alterations in dopamine concentrations and receptor binding in the brains of persons with schizophrenia, but no specific change correlated with tardive dystonia. In 1987, Arai et al examined the brains of patients with drug-treated schizophrenia who had orofacial dyskinesia and found markedly inflated neurons in the cerebellar dentate nucleus without accompanying neuronal loss or gliosis.¹⁶

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Medical Care

The treatment of patients with tardive dystonia is difficult. Refractoriness to treatment is a substantial clinical concern. Several pharmacologic and other somatic interventions have been tried with variable results. The treatment of this condition is probably more difficult and frustrating than for any other movement disorder.

• The clinical pharmacology of tardive dystonia differs from that of classic tardive dyskinesia. Both respond to dopamine-depleting drugs and dopamine antagonists, but tardive dyskinesia does not respond to anticholinergics and may worsen with therapy with these agents.
• The first therapeutic step after the diagnosis of tardive dystonia induced by neuroleptics or other drugs is to taper and then discontinue the causative drugs. Many times, a severe psychiatric illness makes this impossible, but carefully reconsidering the indications for dopamine antagonists in a given patient and considering alternate therapy are imperative. No study mentioned declares how quickly the neuroleptic must be withdrawn, but the recommendation is to attempt a progressive dose reduction.
• A comprehensive approach to patients with tardive dystonia includes patient education and supportive care. Physical therapy and well-fitted braces are designed primarily to improve posture and to prevent contractures. Although braces are tolerated poorly, particularly by children, they may be used in some cases as a substitute for sensory input. For example, in some patients with cervical dystonia, neck and head braces seem to provide sensory input by touching certain portions of the head or neck in a fashion similar to the patient's own sensory trick, thus enabling the patient to maintain a desirable head position.
• In an attempt to help patients with writer's cramp, various hand devices have been developed to enable them to use their hands more effectively and comfortably. Some patients find various muscle relaxation techniques and sensory feedback therapy useful adjuncts to medical or surgical management.

Surgical Care

• The surgical approach for patients with tardive dystonia is indicated in those who do not respond to medical treatment and continue having severe disabling dystonic forms. The most successful surgeries are stereotactic thalamotomy and selective denervation for cervical dystonia.
• • Thalamotomy helps most for upper limb dystonia, offers (at most) a mild benefit for dystonia of the lower extremities, and has virtually no effect on cervical or truncal dystonia. Thalamotomy should be considered in patients with hemidystonia or generalized dystonia who, at least, are moderately disabled and in whom medical therapies have failed.
  
  
  • Selective denervation for cervical dystonia is both safe and effective in carefully selected patients. Good results are obtained in patients with a stereotyped pattern of head deviation, such as pure rotation, lateral tilt, or retrocollis, who have a limited number of involved muscles and significant improvement with botulinum toxin therapy.


• The role of pallidotomy and deep brain stimulation in the treatment of the dystonic abnormal movements is currently under investigation. Recent small studies by Trottenberg et al and Zhang et al have reported some success in deep brain stimulation of the globus pallidus interna and bilateral subthalamic nuclei.^{17, 18}

Activity

Physical activity depends on the grade of disability caused by the dystonic movements. In most patients, physical and occupational therapy encourage activity and help make life more comfortable and actions more effective.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

Tardive dystonia may improve or, rarely, may resolve, after discontinuation of neuroleptics; however, the condition is often permanent. Treatment with medications includes antidopaminergics, anticholinergics, atypical antipsychotics, benzodiazepines, baclofen, anticonvulsants, or local botulinum toxin injections.

Drug Category: Acetylcholine receptor inhibitors

The most promising development for treating tardive dystonia and all other forms of dystonia has been botulinum toxin type A (BTTA). BTTA produces neuromuscular blockade by inhibiting the calcium ion–mediated release of acetylcholine at the motor nerve terminals. This results in diminished endplate potential and subsequent flaccid paralysis of the affected muscles. The paralysis persists until new nerve terminals form, usually within 2-3 months.

BTTA is effective in treating focal dystonias, including blepharospasm, oromandibular dystonia, spasmodic torticollis, spasmodic dysphonia (especially the adductor form), and some cases of focal limb dystonia. Injections are well tolerated. Systemic complications are not evident, although single-fiber electromyelogram studies show mild distant effects. Following administration, the onset of effect is apparent within a few days. Peak effects are evident within the first few weeks and wear off over 2-4 months.

Typical adverse effects are excessive weakness with inadvertent IM injection (eg, ptosis with eyelid injection, dysphagia in spasmodic torticollis). Treatment with large or frequent doses may prompt the development of antibodies to the toxin and may correlate with loss of the original benefit. Development of less antigenic forms of type A toxin or use of other botulinum toxin strains (ie, strains B or F) may overcome this problem. Patients should be advised that botulinum toxin is not curative but offers nonimmediate temporary improvement.

Drug Category: Anticholinergic agents

Anticholinergic therapy (eg, trihexyphenidyl, ethopropazine) has been used. Kang et al reported a 38% response to trihexyphenidyl alone and 44% when combined with other medications.³ Effective doses were 10-32 mg/d. Severe adverse effects (eg, drowsiness, confusion, hallucinosis, memory difficulties) occurred at 60-100 mg/d. Ethopropazine showed 27% improvement when administered alone and 42% as adjuvant therapy. Doses were 100-450 mg/d. Adverse effects included confusion, forgetfulness, GI problems, dizziness, blurry vision, dry mouth, urinary retention, lethargy, palpitations, and sleep disturbances. Diphenhydramine, an anticholinergic with H1 antagonist properties, also has antidystonic effects.

Drug Category: Dopamine-depleting agents

The most effective medications are those that deplete catecholamines (eg, reserpine, tetrabenazine). A study by Kang et al in 1988 showed a 63% response to at least one of these drugs.³ Effective doses of reserpine were 2-9 mg/d. Significant adverse effects were parkinsonism, dizziness, lethargy, depression, headache, GI upset, and hallucination. Effective doses of tetrabenazine were 12.5-250 mg/d. Most patients required >100 mg/d. Adverse effects included parkinsonism, depression, lethargy, euphoria, hallucinations, confusion, dizziness, vomiting, and unilateral leg tremor. Tetrabenazine (not available in United States) has minimal risk of tardive dyskinesia, which is an advantage compared to other antidopaminergic drugs.

Drug Category: Benzodiazepines

Bind to a specific benzodiazepine receptor on GABA receptor complex, thereby increasing GABA affinity for its receptor. Also increases the frequency of chlorine channel opening in response to GABA binding. GABA receptors are chlorine channels that mediate postsynaptic inhibition, resulting in postsynaptic neuron hyperpolarization. Final result is a sedative-hypnotic effect. Benzodiazepines may provide additional benefit. Clonazepam is effective for blepharospasm and myoclonic dystonia.

Drug Category: Gamma-aminobutyric acid inhibitors

Structural analog of GABA that inhibits both monosynaptic and polysynaptic reflexes at the spinal level. Decreases excitatory neurotransmitter release from primary afferent terminals. Several studies have shown reduction in spasticity and sudden painful spasms. Anxiolytic effect may contribute to antispasticity action. Used IT for severe spasticity.

Drug Category: Atypical antipsychotics (serotonin dopamine receptor antagonists)

Atypical antipsychotics (eg, clozapine, risperidone, olanzapine) bind to dopamine D2 receptors and may improve tardive dystonia when lower doses are used. Recent trials have shown that they not only may cause or aggravate tardive dystonia but ultimately may prove to be highly useful therapeutic agents to treat dystonias. Long-term safety is not fully established for this indication.

Drug Category: Anticonvulsants

Used to manage severe muscle spasms and to provide sedation in patients with dystonia. Kinesigenic paroxysmal dystonia may be controlled with anticonvulsants (eg, carbamazepine, phenytoin). The nonkinesigenic forms of paroxysmal dystonia are less responsive to pharmacologic therapy, although clonazepam and acetazolamide may be beneficial.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

In/Out Patient Meds

According to conventional wisdom, the new atypical antipsychotic medications, which appear to have less adverse extrapyramidal and tardive dystonic effects, have decreased the incidence of this syndrome. To this point, no rigorous studies support this belief.

BTTA injections appear to be a good development in the treatment of tardive dyskinesia, especially the tardive cranial and cervical forms.

Deterrence/Prevention

Unless necessary, avoid use of all drugs that may be offending agents. Before beginning treatment, consider carefully the risks and benefits of using medications such as neuroleptics for nonindicated uses (eg, sedation) or at doses higher then clinically necessary.

Prognosis

The prognosis of patients with tardive dystonia is very poor. Unfortunately, once developed, this condition is usually persistent.

• The discontinuation of all dopamine receptor antagonists appears to be the most important factor related to remission; patients who permanently discontinue these agents increase their chance of remission 4-fold compared with those patients who do not.
  

• Another factor related to remission is the total duration of dopamine receptor antagonist therapy; patients taking dopamine receptor antagonists for less than 10 years have a 5-times higher chance of remission than those with more than 10 years of exposure.
  

• Tardive dystonia is most likely permanent in patients who continue using neuroleptic drugs for more than 10 years.
  

• The indication for long-term use of neuroleptic agents must be well established. Patients must be evaluated repeatedly in hopes of early detection of tardive dystonia; once tardive dystonia is present, the causative drug should be withdrawn if possible. If the patient is not disabled by dyskinesia, observing and hoping for a spontaneous recovery, rather than treating, is best.

Patient Education

For excellent patient education resources, visit eMedicine's Back, Ribs, Neck, and Head Center. Also, see eMedicine's patient education article Torticollis.

Organizations such as WE MOVE and the Dystonia Foundation provide excellent resources for patients and families. Both sites provide education about dystonia and resources for support and advocacy around the world.

ACKNOWLEDGMENTS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Nestor Galvez-Jimenez, MD and Perla Periut, MD, to the development and writing of this article.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• References

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