Click here for a list of Drugs and the Movement Disorders they cause
Acute Dystonic reaction
An acute dystonic reaction consists of sustained, often painful muscular spasms, producing twisting abnormal postures. 50% occur within 48 hours of initiation of the neuroleptic drug. 90% occur within 5 days. These reactions are more common with intramuscular than with oral medications. They’re more common in younger patients, and more common in males than females in the young age group.
Approximately 3 to 10% of patients exposed to neuroleptics will experience an acute dystonic reaction. Haldol (haloperidol) and the long acting injected fluphenazine have the highest incidence of these reactions. The risk is higher in patients with a prior history of a similar reaction or a family history of dystonia. The order of the most frequent types include cervical (neck) dystonia 30%, tongue dystonia 17%, jaw dystonia 15%, oculorgyric crisis (eyes rolling back, and neck arching) 6%, and opisthotonus (body arching) 3.5%. The movements then may fluctuate over hours and temporarily abate in response to reassurance. This can cause an inappropriate diagnosis of hysteria. They typically last minutes to hours without treatment. Occasionally the movements are more choreiform. They are more typically generalized in young patients and more focal in the older patients.
The pathophysiology of an acute dystonic reaction secondary to neuroleptics remains unknown. The movements typically occur at a time when the blood level of medication is dropping. Patients with liver dysfunction are more prone to these reactions. There is a higher incidence in patients with a prior history of a similar reaction or family history of dystonia.
The treatment is to discontinue the offending agent. Intramuscular anticholinergics (e.g. benztropine 2 mg IV) should be used and should be continued orally for 24 – 48 hours depending on the half-life of the neuroleptic used. If the neuroleptic treatment is to be continued, usually the anticholinergic can be safely tapered over 2 – 3 weeks. Some evidence suggests that long-term concomitant anticholinergics may predispose to tardive dyskinesia.
Amantadine is a preferred treatment option by some due to a better side effect profile. Routine prophylaxis with these medications would be appropriate in patients with a previous proven risk for dystonic reactions.
Akathisia (the inability to sit still) is a term introduced to describe restlessness. It is now used to describe the restlessness observed in patients secondary to neuroleptics, typically manifested by excessive voluntary movement. The movements are typically stereotyped motor patterns such as pacing, body rocking, or foot tapping. Occasionally akathisia can result in repetitive vocalizations.
Occasionally the inner subjective feeling of restlessness is absent. The term “pseudoakathisia” has been used in this situation.
Akathisia is likely the most common neuroleptic induced movement disorder. The symptoms typically start within days of neuroleptic exposure but may be delayed as long as several weeks. Up to 90 percent of patients exposed to neuroleptics will experience some degree of akathisia within the first three to four months. There is no age or sex predisposition.
Akathisia may slowly subside with continued therapy but often persists, resulting in poor medication compliance. This condition is often misdiagnosed as increased agitation, resulting in higher doses of neuroleptics, which further aggravates the situation.
The key is prevention and failing that, early recognition.
Decreasing the dose of the offending medication would be the treatment of choice. When this is not possible, switching to a neuroleptic of lower side effect potency would be the next best option. If this fails, treatment with other medications including anticholinergics, amantadine, and beta-blockers (e.g. propranolol) can be useful. The most effective treatments appear to be lipophilic beta-blockers, especially propranolol and metoprolol, Anticholinergic use to prevent acute dystonias, especially in high-risk patients, is controversial as some feel long-term prophylaxis increases the risk of tardive movement disorders. Propranolol should be the drug of first choice. The dose required is usually low. Treatment should result in improvement within three to five days. Other drugs occasionally reported to be effective include clonidine, clonazepam, amitriptyline, and opioids (an option which should only be used as a last resort).
Although, typically a chronic problem, Parkinsonism occurs early in the course of neuroleptic treatment and therefore can be included in the acute neuroleptic induced movement disorders. This is probably the most easily understood side effect of dopamine blocking agents, and has a reported prevalence of 15 – 60% of patients on neuroleptics. In one study of patients presenting to general neurology, > 50% of 300 cases of Parkinsonism were induced or aggravated by medication. These cases often fail to respond to dopaminergic drugs. The symptoms occur within one month of starting neuroleptics in 50% of cases and within three months in 90%. It is not infrequent to see Drug-induced Parkinsonism, Akathisia, and other Dyskinesias simultaneously. Mild extrapyramidal features on exam can be identified as early as the fourth day of treatment in elderly patients.
Clinical phenomenology is indistinguishable from Parkinson’s disease, though Drug-induced Parkinsonism is more likely to be symmetric and less likely to be associated with tremor. However, a clear asymmetric pattern (30%) and tremor dominant cases have been described. Up to 25% of cases are unable to walk at initial presentation (only 10 percent of patients with Parkinson’s disease could not walk when first examined). The earliest feature is akinesia with loss of arm swing. The rigidity tends to lack the cog-wheel phenomenon. Tremor, when it does occur, tends to be of slower frequency then Parkinson’s disease and is more likely to be seen with posture and action as opposed to just at rest.
There is a higher prevalence of this complication in elderly patients. It is twice as common in females than males. Other risk factors include hypothyroidism, concomitant fluoxetine therapy, a positive history of Parkinson’s disease, and a family history of affective disorder.
Metoclopramide tends to induce a Parkinsonism frequently affecting females over the age of 60, particularly with the renal failure. These cases have a bilateral onset and a prominent tremor with coexistent oral facial dyskinesias. The risk relates to the duration of use of metoclopramide. 60% of patients will recover within 2 months but some may take two years for their Parkinsonian signs to resolve. One study reported that 16% of cases went on to be confirmed to have Parkinson’s disease – the drug itself was not thought to have caused Parkinson’s disease, but rather “unmasked” the disease by bring the patient to medical attention sooner.
Neuroleptic Parkinsonism is caused by under-activity of the dopamine pathways in the brain. Although the antipsychotic action of the neuroleptics relates to the dopaminergic mesolimbic receptor blockade, inadvertent nigro-striatal receptor antagonism accounts for the Parkinsonism. One explanation for the higher incidence of Parkinsonism in elderly patients likely relates to the age-dependent loss of dopaminergic cells.
If at all possible the neuroleptic should be reduced, discontinued, or switched to a less potent drug. If this is impossible, then one can use anticholinergics or amantadine. As above amantadine again tends to have fewer side effects than the anticholinergics – Cogentin (Benztropine) can also be used, but tends to have more severe side effects. There’s some evidence to suggest amantadine may prevent the development of tardive stereotypies. Treatment should be reassessed every 4 – 5 months to clarify the persistence of the original problem.
Approximately 10% of patients with Drug-induced Parkinsonism will respond to Levodopa/carbidopa (Sinemet).
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is the rarest of the neuroleptic induced movement disorders. It is the most serious and represents a neurologic emergency in most cases. It has now been reported to occur with all drugs that effect the central dopaminergic system (including dopamine agonists and levodopa). There’s an isolated report of neuroleptic malignant syndrome in a patient on a trycyclic medication. It is likely an idiosyncratic reaction and patients can, if needed, be given the same agent again without recurrence.
It is estimated that 0.5 to 1% of patients exposed to neuroleptics will develop this syndrome. Most patients will develop it shortly after initial exposure and 90% within two weeks of starting the neuroleptic. It can occur with all the neuroleptics but Haldol (haloperidol) and trifluperazine are the most common. It has also been seen with clozapine and metoclopramide.
The classic triad of presenting features involves the autonomic nervous system (fever in 100%), the extrapyramidal system (rigidity), and cognitive changes. The two characteristic laboratory findings reported in 75% of cases are a high CK and leukocytosis (elevated white blood cells). 95% of patients are iron deficient. The CSF is usually normal. An electroencephalogram (EEG) can show diffuse slowing. Other features include tachypnea (fast breathing – 78%), diaphoresis (profuse sweating – 60%), and labile blood pressure (54%). The temperature does not usually exceed 41°C and often peaks before the motor systems become prominent. The most frequent extrapyramidal findings include rigidity (90%) and tremor (56%). Dystonia and chorea have also been reported. Mental status changes occur in 75% of patients. This starts as drowsiness and confusion but can progress to stupor and coma. Other symptoms can include seizures, pyramidal tract findings (weakness and spasticity), ocular flutter, and cardiac arrhythmias.
Physical exhaustion, dehydration, hyponatremia, young male gender, affective disorders, thyrotoxicosis, or prior brain pathology all increase the rate of this syndrome developing. An increased risk occurs in patients combining Haldol with lithium.
Once symptoms develop, progression is quite rapid and reaches peak intensity in about 72 hours – though this can vary from 45 minutes to as long as 65 days. Some cases remain mild and clear up without intervention. The duration of the symptoms can last from 8 hours to 40 days (longer with parental medication). With early recognition and aggressive treatment there is only a 5% mortality rate (much improved in the last 20 years). Most patients who survive make a full recovery. Some are left with permanent Parkinsonism, ataxia, and dementia. Re-occurrences have been described following exposure to the same neuroleptic but this is not common.
The pathophysiology is not completely understood but is thought to involve abnormalities in 3 systems:
- Central dopamine system
- Muscle membrane dysfunction
- Sympathetic nervous system.
Evidence for the central dopamine mechanism comes from the fact that a similar syndrome is seen in Parkinson’s disease with abrupt withdrawal of levodopa or anticholinergics. Additionally, 95% of patients with this syndrome develop Parkinsonian symptoms. Muscle abnormalities have been invoked because of the clinical similarity to malignant hyperthermia. Abnormalities in the sympathetic system are supported by changes in urine and plasma catecholamine levels.
Early recognition is extremely important to reduce mortality. Without therapy this syndrome will resolve on its own over several weeks but with active treatment improvement will occur within 48-72 hours.
The first phase of treatment is supportive therapy with adequate hydration and metabolite (electrolyte) stabilization with cooling blankets to reduce hyperthermia. Ventilatory assistance may be required and occasionally dialysis is necessary for renal dysfunction.
Drug therapy starts with discontinuing the neuroleptic. There are a variety of other effective medications that can be used but the two most frequent ones include Dantrolene sodium and Bromocriptine (individually or combined). These drugs reduce the mortality and shorten the course of the syndrome. Dantrolene can be given intravenously or orally starting with 2-3 mg per kg doses divided TID up to a total of 10 mg/kg/day. Bromocriptine can be given orally or by NG tube starting with 2.5 mg TID and increasing every 24 hours by 2.5 mg TID until a response is seen or until a maximum dose of 60 mg is achieved.
It is reasonable to start both drugs at the same time with intravenous Dantrolene and oral Bromocriptine. Once symptoms start to resolve the Dantrolene can be discontinued and the Bromocriptine can be maintained. The duration of treatment should be at least for ten days for oral neuroleptics, and two to three weeks for parental drugs. Other treatments that can be used include levodopa, pergolide, benzodiazepines, and rarely electro-convulsive therapy (ECT).
If this syndrome occurs in the setting of Parkinson’s disease, the treatment is basically the same except the patient’s Parkinsonian medications should be re-instituted as quickly as possible. Because of the risk of this syndrome, drug holidays are no longer routinely recommended for Parkinson’s disease.
If the neuroleptic is to be reintroduced, a waiting period of two weeks should be used for oral medication, and at least six weeks for parental medication. However, it would be prudent to use a different neuroleptic than the one that originally caused the syndrome.
Withdrawal emergent dyskinesia
It has been recognized that reduction or discontinuation of neuroleptics can produce new movement disorders or exacerbate pre-existing ones. The incidence is likely between 10 to 20%. These disorders are described as “withdrawal dyskinesia” or “withdrawal emergent dyskinesia”. Others describe these phenomenon has a “reversible tardive dyskinesia”. Although a continuum from withdrawal dyskinesia to tardive dyskinesia may be present this has so far not been proven.
Withdrawal dyskinesias may take the form of generalized chorea, athetosis, tongue protrusion, chewing movements, facial grimacing, finger, toe, and ankle movements, ballistic movements, vocalizations, and spasmodic torticollis. The movements worsen with increasing level of arousal or anxiety.
The minimal length of time or dosage of neuroleptics required to produce dyskinesia is not known. The rate is higher in relation to the duration of treatment or dose used. Long acting inter-muscular preparations are less likely to show emergent dyskinesia. The dyskinesia typically occurs within a few days after dosage reduction or discontinuation. This is then followed by rapid improvement over several weeks or rarely 2 to 3 months.
The pathophysiology of withdrawal dyskinesia is unknown. The most widely accepted theory is that of dopaminergic hypersensitivity. Human evidence of this is indirect and inconclusive. Due to the heterogeneity of the condition, multiple neurochemical factors are likely involved.
The most important factor in the management of withdrawal dyskinesia is to explain the situation to the patient. Often the patients have not noticed the problem or don’t seem to care. The patient can at least be partially reassured that withdrawal dyskinesia usually disappears within a few weeks.
If the patient’s movements become so severe that they impair day-to-day activity treatment would be indicated. The clinician may decide to reintroduce the neuroleptic at a lower dose and taper more slowly. Another option particularly when anxiety is prominent could be to prescribe benzodiazepines. Some evidence suggests that clonidine might also be effective.
If the psychosis for which the neuroleptic was originally used becomes problematic in patients who’ve already demonstrated withdrawal dyskinesia significant discussion with the patient and/or family would be required to clearly outline the risks. Frequently, the risk of harm from the continued psychosis outweighs the risk of tardive dyskinesia. The need to reinstate neuroleptics becomes a concerning issue when patients have already shown evidence of dyskinesia. To date, there is no definite proof that patients who have demonstrated withdrawal dyskinesia are at a higher risk of going on to develop tardive dyskinesia.
Tardive stereotypies and Dyskinesia
Stereotypies can be defined as an “involuntary, coordinated, patterned, repetitive, rhythmic, purposeless, but seemingly purposeful or ritualistic movement or utterance”. The diagnosis of stereotypies is based on the recognition of the typical type of movement. Stereotypies can be seen in a variety of childhood-onset conditions including autism, mental retardation, and Rett’s syndrome.
It is important to realize that up to 14% of non-medicated schizophrenic patients have involuntary movements. 1-8% of the elderly develop spontaneous oral facial dyskinesias. This is higher in the edentulous population. The overall prevalence of tardive dyskinesia among patients chronically treated with neuroleptics is about 25%. The incidence in young adults is about 5% per year. Aging, female gender, a positive family history, mood disorders, “organic” brain dysfunction, as well as early extrapyramidal side effects all increase the risk of developing these movements. The risk directly correlates with the duration of the neuroleptic exposure. The longer the tardive movements are present the less likelihood they will resolve.
The most common and typical tardive movements are tardive dyskinesias – the repetitive oral facial and lingual movements that resemble chewing, lip smacking, tongue protrusion (” fly-catching”) or lateral tongue movements in the floor of the mouth (“Bon-Bon sign”). Often the patient is unaware of these early movements which are often predictive of future dyskinesias. Other examples of tardive stereotypies include repetitive and patterned hand waving, toe waving, body rocking, and head bobbing. More complex movements consist of repetitive leg crossing, standing and sitting, picking at clothes, rubbing the face and head, shifting weight, as well as marching. Abdominal and pelvic muscle involvement can produce pelvic rocking (“copulatory stereotypy”). In younger patients the limbs are more frequently involved. Vocal stereotypies include humming, moaning, and altered breathing patterns (“respiratory stereotypies”).
Unlike typical idiopathic dystonia, tardive dystonia improves with action, and is usually not helped by “sensory tricks”. Facial stereotypies improve when protruding the tongue and tend not to involve the upper face distinguishing these movements from those seen in Huntington’s Disease. Tardive stereotypies are accentuated by distraction such as writing or performing rapid alternating movements, and like tics, they are suppressible, but to a much lesser degree.
The pathophysiology of tardive stereotypy / dyskinesia is not understood but striatal dopamine (D2) receptor super-sensitivity has been the traditional explanation. Although there are several dopamine containing systems in the CNS, it is believed that the nigro-striatal system is the most important in tardive stereotypy / dyskinesia. There is significant evidence revealing up-regulation of striatal dopamine receptors in patients and animals in Dopamine receptor ligand-binding studies. Rodent models treated with neuroleptics for two weeks show an increased activity and number of Dopamine D2 receptors. More recent human studies, including PET scanning data, have not confirmed this. There is PET scan data showing that the metabolic rates are increased in the motor cortex and the globus pallidus suggesting over activity of these regions.
There are several problems with an isolated Dopamine hypothesis:
- The late appearance of the abnormal involuntary movements (AIMS), yet receptor super sensitivity is seen very early.
- Dopamine receptor supersensitivity is likely present in all patients, but only 25 % get tardive AIMS.
- Tardive movements persist after drug withdrawal even though there is a resolution of supersensitivity.
- Tardive stereotypy is not seen with dopamine depleting agents that can also induce dopaminergic receptor supersensitivity. Other transmitter systems are likely involved including GABA and noradrenaline. A GABA-hypothesis has been suggested whereby neuroleptics induce the destruction of a sub-population of the GABA neurons in the striatum. Supporting this is the finding of decreased levels of glutamate decarboxylase activity in the basal ganglia of patients with tardive stereotypy.
A third hypothesis is related to an excess of free radicals producing cytotoxic damage. It is possible the neuroleptics may interact with transitional metals in the basal ganglia and this may produce neural oxidative damage through the production of free radicals. There are some studies suggesting free radical scavengers including vitamin E may be helpful in management. A recent meta-analysis combining studies published since 1987 demonstrated that a significant subgroup (28.3%) show a modest improvement in tardive dyskinetic movements with vitamin E. This isn’t considered generally accepted as proven. Recently, abnormalities in mitochondrial complex I enzymes have been found in rat brain and human platelets with chronic neuroleptic exposure, lending further support for the free radical theory.
Some investigators hypothesize that neuroleptics enhance striatal glutamatergic neurotransmission by blocking presynaptic dopamine receptors, which causes neuronal damage as a consequence of oxidative stress. Cerebral spinal fluid (CSF) studied in patients with schizophrenia and tardive dyskinesia had significantly higher concentrations of N-acetylaspartate, N-acetylaspartylglutamate, and aspartate in their CSF than patients without tardive dyskinesia. These findings suggest that there are elevated levels of oxidative stress and glutamatergic neurotransmission in tardive dyskinesia, both of which may be relevant to the pathophysiology of tardive dyskinesia.
Research has also demonstrated abnormalities in a variety of other peptide systems including cholecystokinin, neurotensin, and opiates. Further work is needed to delineate the significance of these neurochemical findings in human tardive dyskinetic patients.
Metabolism of most drugs influences their pharmacological and toxicological effects. Scattered information about genetic vulnerability leading to an increased risk of tardive AIMS has been emerging over the years. It seems that human polymorphic variation of drug metabolism leading to adverse reactions is an unavoidable phenomenon (e.g. Tolcapone). Evidence for a familial co-occurrence of medication induced movement disorders has been increasing. Familial cases of drug-induced Parkinsonism, akathisia, tardive dyskinesia, neuroleptic malignant syndrome, and dystonia-parkinsonism have been described. Varying phenotypes of movement disorders have been identified among members of the same family. Genetic predisposition may relate to a defect in drug metabolism via an enzymatic defect, or to a familial co-factor or heavy metal deficiency.
Iron deficiency has been associated with both restless leg syndrome and the akathisia, while ferritin levels have shown a correlation with the risk of tardive dyskinesia. In one study, diabetes doubled the risk of tardive dyskinesia.
The strongest evidence for correlation of genetic factors and drug induced movement disorders occurs in patients with already known genetic predisposition for movement disorders. For example, neuroleptic malignant syndrome has been shown to be more frequent in association with Wilson’s disease, Huntington’s chorea, and variety of other familial neurodegenerative diseases. It is quite likely that there is a pathophysiological link between the major psychiatric disorders and the neuro-motor dysfunction that occurs following exposure to some medications.
Recent genetic studies have also identified a higher frequency of tardive dyskinesia associated with homozygosity for the Ser9Gly variant of the gene for the D3 receptor subtype of the dopamine receptors.
As this condition can be refractory to all treatments the emphasis needs to be placed on prevention rather than treatment. Patients on chronic therapy need to be advised of the risks and reviewed periodically to screen for early manifestations of these movements.
In general, neuroleptics should be used only when a psychosis is present and should not be used for anxiety, depression, or insomnia. Chronic use of drugs such as metoclopramide (Maxeran) or Stemetil should be avoided. There are alternative medications with a far lower risk of tardive movement disorders. If neuroleptics are to be used chronically, the lowest effective dose should be used and the need for these medications should be a reassessed every four to six months. Drug holidays from neuroleptics are now believed to increase the risk of persistent tardive movements and are not recommended. Chronic concomitant use of anticholinergics also appears to increase the risk of tardive stereotypy.
The first step in medical treatment of tardive stereotypy is to attempt to withdraw the neuroleptic, if possible. This can be expected to increase the severity of the dyskinesia transiently. If discontinuation of the neuroleptic is not possible, switching to a less potent neuroleptic would be the next best option. The risk of AIMS with the novel antipsychotics is less than with the older conventional drugs, as agents that produce a lower likelihood of acute extrapyramidal syndromes produce less tardive dyskinesia.
If tardive stereotypy persists despite the above interventions, there are a variety of other medications that have been used to try to control these movements. The previous first drug of choice, clonazepam is reported to help approximately 40% of the time (probably through GABA mechanisms). The newer drug of choice would be tetrabenazine, which is effective in suppressing these movements in up to 50% of cases. This drug comes in 25 mg tabs and is used in a tid regime up to 150 mgs /day. Side effects of concern include hypotension, depression, and parkinsonism. Propranolol more recently seems to have a high potential for success.
Other medications with some potential include baclofen, valproic acid, cholinergic agonists, clonidine, and buspironel. Bromocriptine and diltiazem have also been useful in severe tardive stereotypy.
Alpha-tocopherol (Vitamin E), as mentioned above, may have potential therapeutic effect in a subgroup of patients.
Combinations of the above drugs may be required. For example, the combination of clozapine and clonazepam is reported to be an effective treatment for tardive stereotypy.
ECT (electroconvulsive therapy) may be considered for patients with severe disabling tardive stereotypy who have failed to respond to medications.
Thankfully initial advances in atypical neuroleptics (clozapine and risperidone) are now being superseded by newer options such as olanzapine and seroquel. These new agents may prove it is possible to have effective antipsychotic agents with a low risk of tardive dyskinesia. They do need to be used carefully and AIMS should be watched for.
An Oculogyric crisis (OGC) usually occurs as a side effect of neuroleptic drug treatment. It is one of the acute dystonic reactions. It is the most common of the ocular dystonic reactions (which include blepharospasm, periorbital twitches, and protracted staring episodes). Of those patients with dystonic reactions, OGC makes up 6%. The clinical spectrum though is poorly understood, leading to the frequent mislabel of a functional disorder.
Alcohol, emotional stress, fatigue, as well as suggestion have all been identified as being able to precipitate OGC attacks in susceptible individuals. The onset of a crisis may be paroxysmal or stuttering over several hours.
Initial symptoms include restlessness, agitation, malaise, or a fixed stare followed by the more characteristically described maximal upward deviation of the eyes in a sustained fashion. The eyes may also converge, deviate upward and laterally, or deviate downward. The most frequently reported associated findings are backwards and lateral flexion of the neck, widely opened mouth, tongue protrusion, and ocular pain. A wave of exhaustion follows some episodes. The abrupt termination of the psychiatric symptoms at the conclusion of the crisis is most striking.
Other features that are noted during attacks include mutism, palilalia, eye blinking, lacrimation, pupil dilation, drooling, respiratory dyskinesia, increased blood pressure and heart rate, facial flushing, headache, vertigo, anxiety, agitation, compulsive thinking, paranoia, depression, recurrent fixed ideas, depersonalization, violence, and obscene language.
Causes or triggering factors in OGC include: neuroleptics, amantadine, benzodiazepines, carbamazepine, chloroquine, cisplatin, diazoxide, influenza vaccine, levodopa, lithium, metoclopramide, nifedipine, pemoline, phencyclidine, reserpine, tricyclics, postencephalitic Parkinson’s, Tourette’s syndrome, Multiple Sclerosis, Neurosyphilis, head trauma, bilateral thalamic infarction, lesions of the fourth ventricle, cystic glioma of the 3rd ventricle, Herpes encephalitis, and Juvenile Parkinson’s.
It is often not realized that in addition to the acute presentation, OGC can develop as a recurrent syndrome, triggered by stress, and exposure to the above drugs.
Treatment in the acute phase involves reassurance and treatment with Cogentin (IV or IM) and/or Benadryl (diphenhydramine) and/or diazepam or lorazepam. Maintenance therapy with oral forms of the above medications or amantadine are indicated in more chronic recurrent cases.
Other tardive movement disorders
This is indistinguishable clinically from idiopathic torsion dystonia, except that it has a higher incidence of retrocollis and opisthotonic posturing. Tardive dystonia is often disabling and unfortunately has a lower rate of remission than tardive stereotypy. It is always important to remember Wilson’s disease can initially present as a psychiatric disorder, requiring neuroleptics, that later becomes associated with dystonia.
Tardive dystonia differs from tardive stereotypy in that it affects the young and old in an equal distribution and there’s no increased ratio of female to male. In the younger age group, males do appear to be affected more often than females. The onset of tardive dystonia can occur as early as 3 weeks and 20% of patients are affected within the first year of exposure to the neuroleptic. Prevalence rates run from 2-20% of those chronically exposed to neuroleptics.
The overall remission rate is in the range of 10-20%, which is much lower than tardive stereotypy. Remission can occur as late as five years after stopping the neuroleptic. Most patients progress for the first few months to a year and then stabilize.
The pharmacological substrates for tardive dystonia are different than that of tardive stereotypy, as anticholinergics often benefit these patients (45%). When tardive stereotypy is associated with tardive dystonia the use of anticholinergics can exacerbate the stereotypies. Often it does not. The physician has to make a decision as to which of the movement disorders is more disabling and treat accordingly.
As with tardive stereotypy, prevention has to be stressed. The first approach in treatment is to remove the offending neuroleptic, if possible, or choose a lower potency neuroleptic. If troublesome dystonia persists, then the most effective treatments are the dopamine depleters (Reserpine and Tetrabenazine) which have been reported to improve over 60% of patients. Anticholinergics improve the dystonia in 45% of patients. Some use anticholinergics in the young and dopamine depleters in older patients because of age related side effects. Other drugs that have had some success include clonazepam and baclofen. For focal dystonias, botulinum toxin is an excellent option. If all treatments fail, then one has no choice but to resume the dopamine antagonist in increasing doses. In this situation you’re committing the patient to lifelong neuroleptic therapy.
Focal botulinum toxin injection can provide useful symptomatic treatment for patients with relatively localized tardive dystonia unresponsive to other treatment.
True tardive chorea is extremely rare and most cases of “Rhythmic Chorea” would now be classified as stereotypy. These chorea-like movements are more patterned, rhythmical, and coordinated than typical chorea and the location is often different.
Tardive Tics or Tardive Tourettism
The occurrence of tardive tics is rare but there are reports of neuroleptic-induced motor and vocal tics as well as other behavioural symptoms. Often patients with this presentation have had preexisting brain damage. As this syndrome is rare, consensus on treatment is unavailable. The guidelines as above, stopping the neuroleptic and considering dopamine depleters would likely be the main steps in management.
Tardive myoclonus has been rarely described and typically is a postural myoclonus when it occurs. Clonazepam is an effective treatment.
Tardive tremor has recently been described. This is typically a postural tremor but occasionally a rest tremor co-exists. Tetrabenazine is an effective treatment.
This is a late and persistent complication of neuroleptic treatment and is similar to acute akathisia. The motor phenomenon resembles and can be termed tardive stereotypy. The pharmacology of tardive versus acute akathisia is clearly different, with tardive akathisia often behaving like tardive stereotypy. In one study it was found 34% of tardive akathisia occurred within one year and two-thirds of these patients had persistent tardive dyskinesia at a mean follow-up of 4.2 years. A female to male ratio of 2:1 has been reported. Leg, and or trunk movements are the most common.
The easiest and most effective treatment is to increase the neuroleptic, but it seems judicious to try to discontinue the neuroleptic, if at all possible, as a first line of treatment. The next choice would be a dopamine-depleting agent such as tetrabenazine. A trial of clonazepam, or an anticholinergic may be helpful. Unlike acute akathisia, opiates or beta-blockers are ineffective.