Clinical manifestations

Presentation and course

Tardive dystonia consists of involuntary, persistent, and sustained muscle contractions that cause twisting and repetitive movements or abnormal postures, usually occurring after months or years of neuroleptic exposure. Tardive dystonia tends to arise insidiously, progress gradually over months to years, and then stabilize. Onset usually occurs in a single body location, typically the face or neck. The arms, trunk, and legs follow in descending order of frequency (06; 69; 19). Tardive dystonia may progress from focal involvement to encompass two or more contiguous or noncontiguous body parts, or it may generalize. Unlike classical tardive dyskinesia, which may be well tolerated or even unnoticed by patients, tardive dystonia is often distressing and disabling (77). The relationship between the age of onset and the distribution of tardive dystonia parallels that of the idiopathic variety: younger subjects, particularly younger male patients, tend to develop generalized dystonia with a more rapid spread and shorter duration of exposure to dopamine receptor blocking agents at onset of dystonia, whereas it more often remains focal or segmental in older patients (06; 42). Cervical dystonia, retrocollis, anterocollis, and torticollis to the right were found to be more common in tardive dystonia than in primary cervical dystonia (42). Late or cranial-onset symptoms, features rarely observed in DYT1 dystonic patients, may distinguish tardive dystonia from primary dystonia (05).

Tardive dystonic movements are clinically identical to those seen in idiopathic dystonia. Tardive dystonia can persist, even after discontinuation of the antipsychotic drug.

Trunk involvement in tardive dystonia is best described as arching backwards and differs from idiopathic dystonia where laterocollis and lateral trunk torsion are present (19). The posturing of the arms in internal rotation with flexion of the elbows and wrists is also characteristic of tardive dystonia. Another feature that differentiates between tardive and idiopathic dystonia is the improvement of the dystonic movements with voluntary action in the former. Most patients report some response to sensory "tricks" or task-specific worsening or improvement.

Retrocollis is a characteristic component occurring in almost half of all patients (36). Less common manifestations include respiratory muscle involvement, oculogyric crises, bruxism, and lingual protrusion dystonia (54; 68; 69). Other movement disorders may coexist, including the orofacial dyskinesias characteristic of tardive dyskinesia, parkinsonism, akathisia, chorea, tremor, and myoclonus (29).

As prevention is the key to minimize or ameliorate tardive dystonia, identifying patients who may be at higher risk of developing a tardive syndrome is of absolute importance. Several risk factors for the development of tardive dyskinesia have been described (32; 65). Nonmodifiable risk factors for increased risk of tardive dyskinesia include older patients, female gender, white and African descent, longer psychiatric illness duration, prior brain injury, dementia, and gene polymorphisms involving antipsychotic medication metabolism and dopamine functioning. These risk factors may be applied to all patients with potential to develop a tardive syndrome, including tardive dystonia, to improve on early recognition. However, and in contrast to tardive dyskinesia, tardive dystonia tends to affect younger men. Clinicians are advised to identify and address modifiable risk factors such as the presence of alcohol and substance abuse, presence of early parkinsonism, and early use of anticholinergic medications, and clinicians are advised to monitor cumulative antipsychotic dosage when determining the current doses of antipsychotic medications.

Table 1. Tardive Dystonia

Dystonic storm, or status dystonicus, is characterized by dystonia refractory to standard drug therapy. This entity is infrequent amongst patients with primary dystonia, and even rarer in those with tardive dystonia.

Prognosis and complications

Remissions are much rarer than in classical tardive dyskinesia. Remissions hardly ever occur even when the drug is discontinued and may take 1 year to 5 years for remission to become complete. In one study, 12% to 33% of patients experience remission after discontinuation of the offending drug, whereas spontaneous remission without discontinuation of offending agent was described as 2.5% per year (32). A fourfold chance of remission is possible when the dopamine receptor blocking drug is discontinued, yet tardive dystonia is probably irreversible in patients who have been on neuroleptics for more than 10 years (42). Patients who had a remission after cessation of the causative agent have developed permanent tardive dystonia when antidopaminergic drugs were resumed (06).

Unlike classical tardive dyskinesia, the movements of tardive dystonia are often disabling. The following list includes some described complications: death from myoglobinuric renal failure; fracture of the odontoid process in a patient with tardive retrocollis, rheumatoid arthritis, osteoporosis; bilateral rib fractures in a patient with severe axial and limb dystonia with opisthotonos; camptocormia; and Pisa syndrome (49; 42; 44; 27; 08).

Clinical vignette

A 48-year-old man had a history of a single manic episode 10 years earlier. He was treated with lithium for one year and then took no medication for eight years until he developed a “manic” episode. He received haloperidol for four days and became stiff for a week. Sixteen months later he was “acting bizarre.” He was initially treated with haloperidol and lithium; the former was then changed to thiothixene because of persistent symptoms. He discontinued thiothixene after 21 days because of visual difficulties. A week later, he started moving his head, neck, and jaw, smacking his lips, and blinking uncontrollably. Movements increased on a daily basis. He became unable to walk due to eye closure sustained for 5 to 10 seconds. He had to give up driving and fell into a pit at work because of impaired vision. He also bit his tongue and cheek frequently because of involuntary clenching of his teeth. He felt his head turning toward the right.

On examination 17 months after onset, there was intermittent tonic and clonic blepharospasm, grimacing, mouth opening with deviation of the lower jaw to the right, jaw clenching with bruxism, and grunting. There was also intermittent flexion and rotation of the head to the right. All movements diminished markedly when he spoke.

There was also intermittent flexion and rotation of the head to the right. All movements diminished markedly when he spoke.

Trials of anticholinergics, baclofen, reserpine, botulinum toxin injections, and valproate yielded no benefit. Recurrent psychosis necessitated prolonged neuroleptic therapy, and the use of clozapine was not associated with a change in his dystonia.

Biological basis

Etiology and pathogenesis

Tardive dystonia is a complication of long-term exposure to antidopaminergic drugs; however, the duration of exposure required may be shorter than that necessary for classical tardive dyskinesia. In one series, 21% of patients had been taking their medication for one year or less (36). Although tardive dystonia tends to appear after long-term treatment, there is no minimum period of neuroleptic treatment that may be considered safe. Cases of chronic dystonia after single exposures to antiemetics (eg, metoclopramide) have been reported (74).

All classes of dopamine receptor blockers are potential etiologic agents. A lower incidence of tardive complications from atypical, also known as second generation antipsychotics, compared with traditional antipsychotics (first generation), has not yet been established through long-term studies (70). A point-prevalence study of tardive dyskinesia in a cohort of more than 20,000 patients with dementia a year after starting treatment found no difference between those treated with typical versus those treated with atypical antipsychotics (50). In Martino and Karnik’s 2018 review of 316 randomized controlled trials, prevalence estimates for tardive dystonia ranged from 1.4% (quetiapine, a second-generation antipsychotic) to 15.3% (L-sulpiride, first generation) for dystonia (53). Nevertheless, the “atypicality” of most second-generation antipsychotics appears to be a relative property that is lost at higher doses (18). Clozapine and quetiapine appear to have little or no propensity to cause tardive dystonia. Other medications linked to tardive syndromes, including tardive dystonia, include aripiprazole, duloxetine and citalopram (serotonin reuptake or serotonin norepinephrine reuptake inhibitors), chronic lithium, flunarizine and cinnarizine, pimozide, tricyclic antidepressant amoxapine, and ziprasidone (11; 58; 32; 41).

Because only a minority of patients with long-term neuroleptic exposure develop tardive dystonia, genetic predisposition is suspected. A genetic association with dopamine D3 alleles has been advanced as a possible explanation for the development of tardive dystonia with atypical antipsychotics (10). Yet, no polymorphisms of the dopamine D2 or D3 receptors were significantly associated with the disorder in another study (55).

The hypothesis of dopamine receptor hypersensitivity due to chronic dopamine blockade used to explain the development of tardive dyskinesia may be applied to tardive dystonia (43; 41). With D2 blockade, antipsychotics inhibition or antagonism of dopaminergic output from globus pallidus and substantia nigra is lifted, thus leading to hyperkinetic movements. However, tardive dystonia has a somewhat different pharmacology from classical tardive dyskinesia. One theory proposes oxidative stress with increased dopamine turnover and high levels of free radicals leading to striatal degeneration as an explanation to persistence of tardive dystonia even after discontinuation of antipsychotics (41). Another hypothesis to explain the development of tardive dystonia is that of GABA insufficiency due to decreased glutamic acid decarboxylase in the substantia nigra, medial globus pallidus, and the subthalamic nucleus (09). Anticholinergic drugs, for example, are often beneficial in tardive dystonia but tend to aggravate the movements of tardive dyskinesia, suggesting that the pathophysiology of tardive dystonia differs in some key respects from that of tardive dyskinesia. There are reports of tardive dystonia-like syndromes occurring with selective serotonin reuptake inhibitors and with selective serotonin norepinephrine reuptake inhibitors; however, the mechanism is not known.

Epidemiology

There are few articles specifically reviewing epidemiology or natural history of tardive dystonia. Larger and more recent series include tardive dystonia in the tardive syndrome. Both psychiatric and nonpsychiatric patients treated with dopamine receptor blocking drugs are at risk. Although tardive dystonia, unlike tardive dyskinesia, shows no age or sex predilection, there is minimal male predominance with men presenting tardive dystonia at a younger age at first exposure (36; 42).

Tardive dystonia is greatly underreported. Many observers use the term “tardive dyskinesia” generically for all tardive movement disorders, just as many use the term “extrapyramidal syndromes” to refer collectively to drug-induced acute dystonia, akathisia, parkinsonism, and tardive syndromes (15). The reported prevalence of tardive dystonia ranges between 0.4% to 5% and can be as high as 21% if more inclusive criteria is utilized. In the psychiatric patient population, the prevalence of tardive dystonia has been estimated to be between 1% and 2% for both outpatients and chronic inpatients (78; 23; 60). However, a systematic search for evidence of dystonia in veterans with long-term exposure to antipsychotic drugs found a prevalence rate of more than 20%, most with focal dystonia (63).

These results correlate with a survey of tardive movement disorders (66) that found tardive dystonia to be the second most common type of dopamine receptor blocking drug-related movement disorder, almost as common as classical orofacial tardive dyskinesia, with 56 prevalence surveys and 34,555 subjects yielding an average prevalence of 20% of tardive dyskinesia in patients treated chronically with dopamine receptor blocking drugs (35). In Ferraz and Andrade’s study of 122 patients with a dystonic syndrome, tardive dystonia was the most common cause of secondary dystonia, accounting for 13% of all dystonic patients encountered (20).

Martino and colleagues found the prevalence of new onset tardive syndromes does not appear to be affected by treatment duration or the use of flexible versus fixed dosing of antipsychotic medications (53). Prevalence of tardive syndrome varies with reported lower rates with exposure to second generation antipsychotics compared to first generation antipsychotics (20.7% vs. 30.0%, p=0.002). The incidence of tardive syndrome is estimated to increase by 5% annually during the first 5 years of treatment, with incidence of 49% after 10 years of treatment, and 68% after 25 years of treatment (24; 14; 62).

Prevention

The keys to producing the lowest possible incidence of all tardive movement disorders are (1) to reserve the use of dopamine receptor blocking drugs only for those situations where they are absolutely necessary, (2) consider the factors (age, gender, prior brain injury, alcohol or drug use, etc.) individual to the patient that may increase risk of tardive syndrome when dosing DRBA, (3) to keep the dose at the lowest level needed to achieve the desired effect, and (4) to withdraw drug at the earliest opportunity. When the use of a dopamine receptor blocking drug is unavoidable, clinical monitoring specifically aimed at the detection of early signs of dystonia, as well as of other tardive syndromes, must be done on a regular basis. These strategies are most critical for avoiding tardive dystonia, where there is no "safe" period of exposure and remissions are rare.

Differential diagnosis

On a phenomenological basis, tardive dystonia is difficult to distinguish from any other etiology of dystonia. In comparison to idiopathic cervical dystonia patients, those with tardive cervical dystonia have been said to have a higher frequency of involvement of other body parts and more clonic head movements, to be less responsive to sensory tricks, and not to have a head tremor or family history of dystonia (56). Tardive patients often exhibit classic orofaciolingual, limb, and respiratory dyskinesias of tardive dyskinesia (69). Tan and Jankovic also found that tardive oromandibular dystonia (OMD) patients tended to manifest dystonia restricted to the oromandibular area in comparison to idiopathic OMD, where patients frequently had neck involvement.

Confusing conditions

The diagnosis of tardive dystonia can be established only by the history of exposure to an appropriate drug and exclusion of other causes of dystonia. Patients with idiopathic dystonia who are coincidentally being treated with antidopaminergic drugs may be misdiagnosed as having tardive dystonia. Nevertheless, and despite the lack of proper epidemiologic study, it is widely believed that the proportion of patients taking these drugs who develop dystonia greatly exceeds the expected frequency of idiopathic dystonia in the same population.

Wilson disease and dopamine-responsive dystonia may be considered in those patients developing dystonia at an early age. The presence of neurologic signs other than dystonia, or a positive family history of dystonia, should prompt additional studies to exclude other causes of dystonia.

Head injury, strokes, intracerebral hemorrhages, tumors, or psychogenic etiology causing dystonia can often be excluded as causes of tardive dystonia through careful history and through neuroimaging as indicated.

The presence of paroxysmal opisthotonus and retrocollis as features of tardive dystonia may be confused with seizures. Dystonia may be differentiated from seizures based on patient history, including antipsychotic medication use and clinical examination to assess the movement disorder phenomenology and detect other neurologic deficits.

Diagnostic workup

No laboratory studies, including brain imaging, EEG, and CSF analysis, support the diagnosis of tardive dystonia; however, they can be useful to exclude other causes of dystonia. Due to the young population often affected, serum and urine copper studies and slit-lamp examination are indicated in many patients to look for evidence of Wilson disease, and if the history and clinical exam are suggestive of dopamine-responsive dystonia, DYT-1 testing may be requested. Further laboratory evaluation for other causes of dystonia is only suggested for neurologic signs other than dystonia, if they are present.

Management

The best treatment for tardive dystonia is prevention. Tardive dystonia may be refractory to treatment, and there is no permanent cure. Early detection is key. The main hope for remission lies in the discontinuation of antidopaminergic drugs. Therefore, development of tardive dystonia should prompt a critical reevaluation of the indications for dopamine receptor blocker therapy. For a nonpsychotic illness, one should search diligently for substitute treatment. Gradual withdrawal with tapering of the dopamine blocking agent decreases the risk of exacerbation of tardive dystonia (64; 33). No evidence has been found to support switching from a typical antipsychotic to an atypical antipsychotic to reduce tardive symptomatology (03).

Even if the cause is removed, resolution of the involuntary movements is rare. For those in whom the offending drug cannot be discontinued and for that majority whose dystonia will persist despite cessation of the drug, symptomatic therapy is instituted with the goal of decreasing pain and dystonic spasms. The FDA has approved two vesicular monoamine transporter 2 inhibitors (VMAT2 inhibitors) for use in the management of tardive dyskinesia: deutetrabenazine and valbenazine (33; 57). The recommended initial dose of deutetrabenazine is 6 mg daily. Deutetrabenazine is contraindicated in patients with depression and suicidality, neuroleptic malignant syndrome, parkinsonism, prolonged QT, hepatic impairment, or on MAO-I. Valbenazine may be started at daily dose of 40 mg. Common side effects include somnolence, fatigue, and sedation. Valbenazine is contraindicated in patients with arrhythmias associated with QT prolongation or with drugs that can prolong QT interval (03). Tetrabenazine is also a presynaptic dopamine depleter used in the management of tardive syndrome (34; 30; 30; 39; 31; 32; 33; 57).

Slightly less effective are anticholinergic drugs such as trihexyphenidyl and benztropine. Guidelines by the AAN describe clonazepam and gingko biloba (level B evidence), and amantadine and tetrabenazine (level C evidence) as probably effective in improving tardive syndromes (02). Occasionally, patients may benefit from clonazepam, baclofen, botulinum toxin, or a variety of other drugs (77; 32; 03). Botulinum toxin appears to be most effective in focal or segmental dystonias involving the cranial, cervical, or truncal regions (04; 13; 37; 03). The degree of improvement in many patients is modest. Olanzapine has been effective for up to 12 weeks in this role but is known to cause tardive dystonia de novo (26; 51; 12). Quetiapine has produced considerable symptomatic improvement in several cases, but long-term effects were not reported (61; 25). Dopamine receptor antagonists will suppress the involuntary movements but probably at the expense of contributing to the eventual worsening of the disorder. Nevertheless, these agents may be useful temporarily if immediate control of the situation is necessary.

For those patients who must continue to receive antidopaminergic treatment, clozapine appears to be a neuroleptic drug that improves rather than exacerbates tardive dystonia (17).

Individual cases have responded to vitamin E, intrathecal baclofen, bilateral pallidotomy, and thalamotomy (16; 28; 03). Although several agents, including acetazolamide, thiamine, vitamins, melatonin, baclofen, calcium channel blockers, levetiracetam, and buspirone have been noted to have beneficial effect on tardive syndromes; there are not sufficient data to support or refute the use of these drugs (02; 03). Mechanical devices that take advantage of the phenomenon of sensory tricks may help (46).

Deep brain stimulation of the globus pallidus internus (GPi) has been shown to be a promising treatment option for patients with tardive dystonia refractory to medical therapy (48; 67; 21; 15; 72). In a metaanalysis of 35 studies with a total of 117 cases, the improvement was noted to be immediate in some cases, but more often occurred gradually over time (52). The optimal response to deep brain stimulation for tardive dystonia is delayed by several weeks (71). Deep brain stimulation of the GPi has been shown to be effective in controlling tardive dystonia, and it provides improvement in the quality of life with changes in cognition (07; 76; 72; 59; 52). The overall improvement was noted to persist even at the last follow up, averaging 25 months from surgery (52). In other studies, long-term improvement was described in ranges of 63 to 171 months following surgery (45; 47). Side effects of deep brain stimulation include transient worsening of psychiatric disease; surgical or device related complications such as pain due to traction of cable connection, infection, and infarction during lead placement; and stimulation-related events (dysarthria, gait and balance impairment, visual scotomas, phosphenes, mania, etc.) (52; 45).

Table 2. Treatment of Tardive Syndromes

Outcomes

The mainstay of treatment is removing the offending agent and concomitantly providing symptomatic treatment. Once tardive dystonia has developed, the dystonia is usually persistent. Epidemiologic studies and those reviewing outcomes describe 7.5% to 14% remission rate over periods ranging from 2.6 years to 8.5 years after discontinuation of dopamine blocking agent (06; 36; 42). These studies found remittance was more likely in younger patients, those with shorter duration of exposure to neuroleptics, and patients with less continual exposure to dopamine receptor agonists after onset of tardive dystonia. Patients on neuroleptics for more than 10 years were more likely to have permanent dystonia.

Special considerations

Pregnancy

No literature was found addressing tardive dystonia in pregnancy. It is unclear if pregnancy exacerbates or ameliorates dystonia. Clinicians are advised to discuss risks, benefits, and pregnancy category recommendations of medications used in treatment of tardive dystonia, as well as birth control in fertile female patients.

Anesthesia

Although several case reports describe acute dystonic reactions following general anesthesia, tardive dystonia has not been associated to the use of anesthetic agents.

COVID-19

No literature was found addressing tardive dystonia in COVID-19.