Tardive dystonia is a form of tardive dyskinesia. It is a movement disorder characterized by involuntary muscle contractions caused primarily by taking dopamine receptor blockers like antipsychotic medications.
Tardive dystonia starts insidiously and progresses over months or years, until it becomes static. Dystonia typically presents in a twisting pattern with deviations on multiple anatomical planes. The movements typical of tardive dystonia are generally slower and more sustained than other dyskinesias.
Symptoms of dystonia can range from very mild to severe. Dystonia can affect different body parts, and often the symptoms of dystonia progress through stages. Some early symptoms include:
See Clinical Presentation for more detail.
There is no single test to confirm the diagnosis of dystonia. To differentiate tardive dystonia from all causes of dystonia, base the workup on the history findings and clinical presentation of the dystonic movements.
A routine evaluation may include the following:
See Workup for more detail.
The first 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. Switching these patients to antipsychotic medications, like clozapine, with less potent dopamine blockade may be considered.[1] Unfortunately, it is not uncommon for the symptoms to worsen for a time after the offending medication is discontinued or reduced.
A recently introduced treatment is botulinum toxin which is injected into the affected muscle. There it blocks the effect of the chemical acetylcholine that produces muscle contractions. Consider botulinum toxin therapy if the dystonia is focal and amenable to the treatment.
The primary pharmacological treatment for tardive dystonia is dopamine-depleting agents. Another option would be dopamine receptor blockers (ie, neuroleptics).[2, 3, 4] However, 2013 guidelines from the American Academy of Neurology do not recommend the use of risperidone because it appears to cause tardive symptoms.[5] Instead, amantadine and tetrabenazine are recommended. A common observation for all tardive syndromes is that the symptoms improve with an increase of dopamine blockade and worsen with a decrease. Thus, the goal is to add a medication that will provide dopamine blockade while minimizing the risk of worsening the tardive syndrome or creating new tardive syndromes.
Deep brain stimulation is probably the surgical treatment of choice at this time for those with severely disabling dystonia who have not responded to medical therapy.
See Treatment and Medication for more detail.
Dystonia is commonly defined as "a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures."[6] Historically, the first use of the term was by Oppenheim in 1911, but earlier descriptions of the syndrome have been widely acknowledged.[7, 8]
The phenomenology of dystonia is remarkably variable. Differences in the extent and severity of muscle and frequency of symptom involvement range from intermittent contraction limited to a single body region to generalized dystonia involving the limbs and axial muscles. Features such as age of onset and presumed etiology play a tremendous role in prognosis and treatment. As such, a complete diagnosis of dystonia typically includes its characterization along three axes: age of onset, distribution, and presumed etiology.[7, 8]
Age is generally divided into early onset (≤26 years) and late onset (>26 years), with a younger age of onset associated with a more generalized and severe course in primary dystonias.
Distribution is divided into focal (a single part of the body affected), segmental (contiguous parts of the body affected), and generalized (the entire body affected). Terms such as multifocal (multiple noncontiguous body parts affected) and hemidystonia (an entire side of the body affected) are also used.
An abbreviated list of body parts commonly affected can include all four limbs, the trunk (pisa syndrome for a lateral deviation, camptocormia for a severe anterior flexion), the neck (torticollis for lateral rotation, anterocollis for anterior flexion, and posterocollis for posterior flexion), the jaw (mandibular dystonia or oromandibular dystonia), the tongue (lingual dystonia), the vocal cords (spasmodic dystonia), the larynx (laryngeal dystonia) or the eyelids (blepharospasm). Symptoms can occur intermittently, only with specific tasks (such as writer's cramp, embouchur dystonia or golf yips), or more chronically. In general, the more of the body involved, the worse the prognosis.
The etiology of dystonias typically divide into 4 broad categories: primary, dystonia-plus, heterodegenerative diseases with dystonia, and secondary dystonia. Primary dystonia is used for familial and nonfamilial genetic syndromes where dystonia is the major feature. A dystonia-plus syndrome is also a genetic syndrome with dystonia as the primary symptom but with other neurologic symptoms prominent (such as the dystonia-Parkinsonism or dystonia-myoclonus syndromes). This is in contrast to heterodegenerative diseases with dystonia when dystonia is present but not the major symptom (such as Wilson's disease or PKAN). Secondary dystonia is a dystonia brought on by an inciting event, such as a stroke, trauma, or drugs.
Tardive dystonia is a form of drug-induced secondary dystonia. 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.[9]
Today, drug-induced dystonias are roughly divided into acute, chronic acute, and tardive. Acute dystonia is an immediate reaction to a drug treatment and chronic acute is the term used for continued symptoms with long-term treatment with an offending agent. In 1982, Burke et al coined the term tardive dystonia for dystonias that did not present as immediately after the introduction of the drug, but presented later and either continued or worsened after the drug's removal.[2] Tardive derives from the Latin word meaning late onset, and had already been used to describe abnormal orobuccal-lingual facial movements (ie, tardive dyskinesias) that also appeared as a late side effect to medications and tended to continue or worsen with the removal of the drugs.
In that paper, Burke and colleagues proposed the following four criteria for diagnosis:
The question of whether tardive dystonia should be considered a subset of tardive dyskinesia has been debated for a number of years. Grossly, there are many similarities. All tardive syndromes are caused by dopamine receptor blockers. They are all characterized by both their presentation days to months after the initial exposure and their continuation, or worsening, after the offending agent has been removed. However, in spite of these similarities, Burke et al suggested that tardive dystonia could be distinguished from the classic orobuccal-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.[10, 3]
The pathophysiology of tardive dystonia is not well understood. Due to this limited understanding, it is helpful to briefly review what is known about the pathophysiology of dystonias in general to put this information in context.
Dystonia is considered to be a sign of basal ganglia dysfunction. One line of evidence for this is from the stroke and traumatic brain injury literature. Dystonia never occurs with pure cortical lesions and only develops after striatal lesions, sometimes occurring weeks or months after the inciting basal ganglia lesion.
Electrophysiologically, dystonia is characterized by a sustained co-contraction of both agonist and antagonist muscles. Although most research has been done on primary focal dystonias, three areas of investigation have emerged in the literature. First, both EMG and imaging evidence shows a loss of reflex inhibition in spinal and brainstem reflexes and a loss of normal inhibitory patterns in the motor cortex. Second, there is evidence of abnormal cortical motor plasticity in patients with dystonia. Third, there is evidence of sensory processing abnormalities. Subtle impairment in spatial and temporal discrimination tasks as well as somatosensory evoked potentials are well documented.[7]
The pathophysiologic basis of tardive dystonia itself remains obscure. Why exposure to neuroleptics produces dystonia in some patients, chorea in some, and both in others is not clear.
Sachdev suggests that tardive dystonia may develop in individuals who are already vulnerable to dystonia, with the antipsychotic drugs activating a latent predisposition.[11]
However, although primary 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 two 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 nine patients with tardive dystonia.[12] 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. Dopamine receptor blocking agents can cause an acute dystonic reaction that appears superficially similar to tardive dystonia. Two basic theories have emerged to explain this reaction: hypoactivity of dopamine system leading to an overactivity of acetylcholine activity, and a paradoxical hyperactivity of dopamine due to preferential blocking presynaptic receptors. There are studies that support both of these hypotheses; however, it is unclear how well this can generalize to tardive dystonia. For instance, although clinically anticholinergics can be used to treat tardive dystonia, they are far less effective than they are in acute drug-induced dystonias.
One theory has been proposed by Trugman et al, 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.[13] 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 in epidemiology, natural course, and treatment.
Young age, male sex, mental retardation, and electroconvulsive therapy have been identified as specific risk factors. Exposure to dopamine receptor blocking agents (DRBAs) is essential for the diagnosis of this disorder. Antipsychotic medications are the most significant etiologic factor. Other medications associated with tardive dystonia include antiemetics (eg, prochlorperazine, promethazine, metoclopramide) and antidepressants (eg, amoxapine). Also, single case reports for veralipride, a benzamide derivative, and lithium causing dystonia have been reported.
The most common cause of tardive dystonia is exposure to antipsychotic medications (neuroleptics). 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.
All dopamine receptor antagonists that reportedly cause oral tardive dyskinesia also reportedly cause tardive dystonia. These include all first generation and second generation antipsychotic medications.
The duration of exposure to antipsychotic medications 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 minimum duration of antipsychotic exposure seems to be shorter for women. A longer duration of exposure to antipsychotic medication does not correlate with the severity of dystonia; however, patients with generalized dystonia have shorter neuroleptic exposure than patients with focal dystonia.
Other agents implicated in cases of tardive dystonia include amoxapine, an antidepressant with dopamine receptor–blocking properties, and antiemetics such as prochlorperazine, promethazine, and metoclopramide.[3]
The prevalence of tardive dystonia is 0.5-21.6% of patients who are treated with antipsychotic medications, 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.[14] Similarly, Friedman et al found a prevalence rate of only 1.5% among 352 hospitalized psychiatric patients.[15] One 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.[16]
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.
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 al[15] and Yassa et al[14] conducted studies of two unselected psychiatric populations, the results of which supported a male-to-female predominance ratio of 4:1 and 3:1, respectively.
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.[14] 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).[4] It was also noted that the younger a patient's neuroleptic exposure, the shorter the interval before developing tardive dystonia.
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.[4]
The indication for long-term use of dopamine receptor antagonists 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.
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.[3]
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.[17] 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:
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.
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 (as described in the Introduction).[18]
A detailed movement disorders examination should be performed. This should include an evaluation for dystonia and abnormal movement disorders such as dyskinesias, parkinsonism, and akathisia.
Dystonia typically presents in a twisting pattern with deviations on multiple anatomical planes. For instance, torticollis usually presents with both a deviation to one side as well as a head tilt. A hand dystonia often presents with an ulnar deviation as well as fingers in flexion or extension. This twisting pattern can be stable or more dynamic in an athetoid pattern.
Dystonia can present with a tremor. One helpful hint in identifying a tremor as dystonic is if it resolves when the patient is asked to allow their affected body part to go into the position that the dystonia is trying to make it go (ie, not fight the movement). Although it does not rule out a dystonic tremor if it does not go away with this maneuver, it is pathognomonic if it does resolve.
Dystonia frequently presents with a sensory trick or geste antagonist. This involves a point on the body where sensory stimulation can frequently overcome or reduce the dystonic symptoms. For instance, patients with torticollis (dystonic neck rotation) frequently find that pressure on their chin or sides of their face can cause the dystonic movements to subside. Patients with jaw or lingual dystonia may find that holding a straw or toothpick inside their mouth helps to reduce their symptoms. These tricks can be helpful diagnostically, but also can be used in developing treatment plans.
Dystonia can be surprisingly task specific. For instance, symptoms can occur with speech but resolve with silence or occur while walking but resolve with running or walking backwards. Again, this can be used to assist with diagnosis and occasionally in developing nonpharmacologic treatment strategies.
A routine physical and neurologic examination should also be included, with an ophthalmologic examination with a slit-lamp if indicated, to look for other symptoms. If general physical examination signs or neurologic signs other than dystonia are present, 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.
A mental status examination should be performed, but the results can be completely normal since tardive dystonia does not indicate a psychiatric disease. It is merely a secondary dystonia and any patient who takes a dopamine receptor blocker chronically for any reason (including patients taking antinausea medications) can develop this condition. Given that this is a neurologic and not a psychiatric condition, the mental status examination is not helpful for diagnostic purposes and is most useful in determining whether a patient needs to remain on dopamine blocking agents or can be weaned off.
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:
These tests are expensive; therefore, consider the cost-to-benefit ratio to avoid unnecessary tests.
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.[19] 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.
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.[20]
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 first step after the diagnosis of tardive dystonia induced by antipsychotic medications 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. Unfortunately, it is not uncommon for the symptoms to worsen for a time after the offending medication is discontinued or reduced.
If the dystonia is focal and amenable to botulinum toxin therapy, this should be considered.[21, 22]
The primary pharmacological treatment for tardive dystonia is dopamine-depleting agents. Another option would be dopamine receptor blockers (ie antipsychotic medications).[2, 3, 4] A common observation for all tardive syndromes is that the symptoms improve with an increase of dopamine blockade and worsen with a decrease. Thus, the goal is to add a medication that will provide dopamine blockade while minimizing the risk of worsening the tardive syndrome or creating new tardive syndromes. The treatments of choice are dopamine depleters such as tetrabenazine or reserpine, since these do not appear to cause tardive symptoms. However, their side effects can make these difficult to tolerate, and they are not as effective at treating psychiatric illness as dopamine receptor blockers.
Another strategy, particularly for those with severe psychiatric illnesses or who are intolerant to the side effects of dopamine depleters, is to start a neuroleptic such as clozapine, which has minimal risk for creating tardive syndromes. Clozapine is frequently chosen because it has the least number of credible reports of inducing tardive symptoms and the most data for alleviating those symptoms. Other neuroleptics could also be considered; however, given that there are case reports of all neuroleptics causing tardive dystonia, other choices should be made with caution.[1]
If starting a dopamine-depleting or a dopamine receptor blocking agent is only partially successful, treatment can be supplemented with alpha-methyl-para-tyrosine (AMPT) for additional dopamine blockade.
If dopamine blockade is not successful or only partially successful, anticholinergic medications such as artane can be tried.[2, 3, 4]
There are case reports of clonazepam being added to clozapine for additional benefit, and this could be considered if a single medication is only partially successful.[23, 24]
There is also limited evidence of the effectiveness of electroconvulsive therapy in this condition, and this may be considered if pharmacological treatments have failed and there is reason not to consider deep brain stimulation (DBS).[3]
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. Some patients find various muscle relaxation techniques and sensory feedback therapy useful adjuncts to medical or surgical management.
Deep brain stimulation is probably the surgical treatment of choice at this time for those with severely disabling dystonia who have not responded to medical therapy.
Small studies by Trottenberg et al and Zhang et al initially showed some success in deep brain stimulation of the globus pallidus interna and bilateral subthalamic nuclei.[25, 26]
Thobois et al were able to show improvement by 63% in 5 patients with bilateral GPi stimulation compared to 8 controls[27] . Gruber et al were able to show improvement in 9 patients by nearly 75% on the Burke-Fahn-Marsden Dystonia Rating Scale after 3-6 months.[28]
Gruber et al assessed the long-term effects, including motor function, quality of life, and mood, of bilateral globus pallidus internus DBS on patients with tardive dystonia and concluded it is a safe and effective long-term treatment. Patients were assessed 3 times using established movement disorder and neuropsychological scales. Results showed significant improvement in quality of life regarding physical components and affective state. They also noted that cognitive functions remained unchanged, and no permanent adverse effects occurred.[28]
Other treatments, such as thalamotomy and pallidotomy, have also been investigated, but as there is no evidence that these provide benefits beyond DBS (and certainly carry greater risk due to their irreversibility), these would be considered second-line.[3]
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.
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.
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.
Tardive dystonia may improve or, rarely, resolve, after discontinuation of neuroleptics; however, the condition is often permanent. Medications used for treatment include dopamine-depleting agents, dopamine receptor blocking agents, and anticholinergics. Local botulinum toxin injections have been useful for well-chosen focal dystonias.
Clinical Context: Tetrabenazine is a presynaptic dopamine antagonist with minimal risk of tardive dystonia. It is designated as an orphan drug in the United States.
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.[7] 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 include 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.
Clinical Context: Clozapine binds to dopamine D2 receptor with 20 times lower affinity than for serotonin-2 receptor.
Atypical (or second generation) antipsychotics (eg, clozapine, risperidone, olanzapine) bind to dopamine D2 receptors and may improve tardive dystonia when lower doses are used. 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.
Clinical Context: This agent is a central inhibitor of the parasympathetic nervous system, resulting in diminished muscle spasms. It is often the drug of choice for young persons with generalized, multifocal, or segmental dystonia, especially with lower extremities and trunk involvement.
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.[7] 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.
Clinical Context: Neurotoxins produced by Clostridium botulinum exert paralytic effects at the neuromuscular junction by inhibiting the release of acetylcholine, thus, inhibiting impulse transmission in neuromuscular tissue. It has become a mainstay of therapy for focal and segmental dystonia, including tardive dystonia.
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.
Clinical Context: Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia).
Benzodiazepines bind to a specific benzodiazepine receptor on GABA receptor complex, thereby increasing GABA affinity for its receptor. They also increase 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. The final result is a sedative-hypnotic effect. Benzodiazepines may provide additional benefit. Clonazepam is effective for blepharospasm and myoclonic dystonia.