Tardive Dystonia 

Dystonia is commonly defined as "a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures."^[1] Historically, the first use of the term was by Oppenheim in 1911, but earlier descriptions of the syndrome have been widely acknowledged.^{[2, 3]}

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 3 axes: age of onset, distribution, and presumed etiology.^{[2, 3]}

Age is generally divided into early onset (≤ 26 y) and late onset (>26 y), 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 4 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 eye-lids (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.

Etiology is typically divided 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.

Of these descriptors, presumed etiology is the most relevant to our current discussion. 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.^[4]

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.^[5] 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 4 criteria for diagnosis:

1. The presence of chronic dystonia
2. A history of antipsychotic drug treatment preceding or concurrent with the onset of dystonia
3. The exclusion of known causes of secondary dystonia by appropriate clinical and laboratory evaluation
4. A negative family history of dystonia

To illustrate these ideas, it may be helpful to reproduce one of the cases described in the initial paper. The following is listed as Patient 1 in Burke et al's original paper:^[5]

This man developed persistent dystonia at age 19 years. The parents were non-Jewish, and there was no family history of dystonia. Birth was abnormal in being 2 weeks premature with a breech presentation. Developmental milestones were delayed; he did not walk until age 2 years. He was diagnosed to be mentally retarded at age 6 years. At age 17, he was placed in an institution because of aggressive behavior. During this time, he was treated with haloperidol 15 mg daily and chlorpromazine 450 mg daily, but it is not known for how long. He was again admitted at age 19 and treated with unknown doses of haloperidol, chlorpromazine, and thioridazine when he developed facial grimacing and abnormal trunk postures that persisted.

On our examination, at age 21 years, he was mentally retarded. There were no Kayser-Fleischer rings on slit-lamp examination. There was intermittent, sustained facial grimacing affecting predominantly the lower face, retrocollis, and opisthotonic trunk extension that was exacerbated by walking, and intermittent, sustained extension movements of the arms. The opisthotonus tended to force him off a chair and he could not sit. There was no oral chorea.

Withdrawal of antipsychotics did not diminish the movement disorder. Treatment with carbamazepine and valproate in succession was without benefit. Tetrabenazine caused sustained, forced jaw opening and oculogyric crisis, and so it was discontinued. Ethopropazine 25 mg four times daily improved the dystonic movements. At the most recent examination, age 22 years, he remained much improved on ethopropazine 150 mg each day.

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.^[5]

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.^{[6, 7]}

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, 3 area 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.^[2]

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.^[8]

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 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.^[9] 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.^[10] 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.

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.^[11] Similarly, Friedman and coworkers found a prevalence rate of only 1.5% among 352 hospitalized psychiatric patients.^[12] 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.^[13]

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.^[5]
• Friedman et al^[12] and Yassa et al^[11] 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.^[11] 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).^[14] 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.^[5]
• 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.^[15]
• Davis and Cummings observed that segmental tardive dystonia has an earlier age of onset than cranial tardive dystonia.