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Acute and subacute drug-induced movement disorders
Parkinsonism and Related Disorders 20S1 (2014) S108–S112
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Acute and subacute drug-induced movement disorders Pierre R. Burkhard * Movement Disorders Unit, Department of Neurology, Geneva University Hospitals, Switzerland
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Keywords: Drug-induced movement disorders Parkinsonism Dyskinesia Tremor Acute dystonic reaction Akathisia Neuroleptic malignant syndrome Serotonin syndrome
Many pharmacological agents may induce a variety of movement disorders, including dystonia, tremor, parkinsonism, myoclonus and dyskinesia, with an acute, subacute or more chronic time course. Motor symptoms may be isolated or part of a more extensive cerebral or systemic condition, such as the neuroleptic malignant syndrome or the serotonin syndrome. Drug-induced movement disorders share a number of features that should make them easy to identify, including a clear temporal relationship between medication initiation and symptom onset, a dose-effect, and, with the exception of tardive syndromes, complete resolution after discontinuation of the offending agent. Diagnosis relies on a thorough medication history. Medications commonly involved include dopamine receptor blockers, antidepressants and anti-epileptics, among many others. Mechanisms underlying drug-induced movement disorders involve blockade, facilitation or imbalance of dopamine, serotonin, noradrenaline and cholinergic neurotransmission in the basal ganglia. The present review focuses on drug-induced movement disorders that typically develop as an acute (hours to days) or subacute (days to weeks) event, including acute dystonic reactions, akathisia, drug-induced parkinsonism, neuroleptic malignant syndrome, serotonin syndrome, parkinsonism-hyperpyrexia syndrome, drug-induced tremor, drug-induced hyperkinesias and movement disorders associated with the use of recreational drugs. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Shortly after the large-scale use of the first conventional neuroleptic chlorpromazine in schizophrenia by Delay, Deniker and Harl in 1952, a rapidly growing list of “drug-induced extrapyramidal reactions” was reported [1]. Since many other drugs were later associated with various movement disorders, the concept of drug-induced movement disorders (DIMDs) emerged in the early 1970s as a distinct clinical entity [2] and remains a major contributor to adult and pediatric movement disorders worldwide [3–5]. DIMDs can be classified according to (1) their temporal profile (acute and occurring within hours to days after exposure; subacute and building up more slowly after days to weeks of exposure; and chronic following long-term therapy with the offending medication) [6], (2) their phenomenology (dystonia, dyskinesia, tremor, parkinsonism, myoclonus, akathisia, tic, chorea) [5], and (3) the pharmacological agent likely involved (typical and atypical neuroleptics and other dopamine receptor blockers (DRBs), antidepressants, anti-epileptics, and many others, including recreational drugs and toxic agents). In general, DIMDs are treatable and tend to respond to the discontinuation of the offending agent. * Correspondence: Prof. Pierre Burkhard, Department of Neurology, Geneva University Hospitals, 4, rue Gabrielle-Perret-Gentil, 1211 Geneve ` 14, Switzerland. Tel.: +41 22 372 83 09; fax: +41 22 372 83 32. E-mail address: [email protected] (P.R. Burkhard). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
In this paper, the focus is on acute and subacute DIMDs, excluding tardive syndromes (TDs) which are discussed in another review in this supplement [Aquino and Lang, p. S113]. This group of conditions is relatively common yet likely underdiagnosed, since they are usually seen in the emergency room [7–9], and may appear atypical to non-neurologists. Diagnosis and treatment may therefore be delayed and the condition may worsen, whereas early recognition and adequate management leads to usually complete recovery. It is worthwhile to remember that, when facing an acute or subacute movement disorder, DIMD should be high on the list of differential diagnoses, and an extensive medication history is mandatory. 2. Acute dystonic reactions The prevalence of acute dystonic reactions (ADRs) has been variably estimated to range from 2.3% to 60% of patients treated with conventional neuroleptics [10] and 2% to 3% with atypical ones [11]. Mostly seen after exposure to DRBs, including antiemetics and gastrointestinal promotility agents, ADRs have also been reported after as diverse medications as SSRIs, opioids, methylphenidate, rivastigmine, albendazole, gabapentine, cetirizine, foscarnet, quininine, and during or shortly after general anesthesia using propofol, fentanyl [12], sevoflurane and morphine. Typically, ADRs occur in young males (including adolescents and children), who have a recent history of psychosis for which a high dose DRB has been initiated.
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ADRs characteristically start within hours to a few days after a neuroleptic has been introduced, with 50% of cases occurring during the first 24 hours and 90% within the first five days. Clinical manifestations are usually restricted to the head and neck, but, particularly when the medication is maintained, may extend toward upper and lower limbs as well as the trunk. Motor symptoms may be preceded by generalised discomfort, anxiety and restlessness. One of the most common manifestations is acute oro-mandibular dystonia affecting tongue and mouth, impairing speech and sometimes swallowing, potentially leading to temporo-mandibular joint subluxation, and sometimes evolving into overt trismus. Other modes of presentation include oculogyric crises, blepharospasm, complex cervical dystonia with a mixture of retrocollis, laterocollis and antecollis, focal limb dystonia, usually more distal than proximal, Pisa syndrome, and back arching potentially evolving into opisthotonos. A particularly spectacular and life-threatening form of ADR is acute laryngeal dystonia, affecting the vocal cords and laryngeal muscles and leading to upper airway partial or complete obstruction. This condition manifests as stridor, respiratory distress and sudden death. Known since the early use of DRBs [13], electromyography studies have demonstrated overactivity in vocal cord adductors, amenable to botulinum toxin injections in thyroarytenoid muscles with an excellent response [14]. This approach is probably life-saving in some cases. ADRs respond dramatically, usually within minutes, to intravenous or intramuscular injections of anticholinergic drugs. Depending on the availability of specific medications in individual countries, the following agents may be used: biperiden (2.5–5 mg), procyclidine (5–10 mg), benztropine (1–2 mg), trihexyphenidyl (2.5–5 mg) or diphenhydramine (25–50 mg). Benzodiazepines may also be helpful but are not as effective as anticholinergics. Because of their short half-life, recurrence of the ADR hours after the first anticholinergic injection may necessitate repeated injections and a limited oral course of anticholinergics is usually recommended for a few days. Medications implicated in ADRs, notably DRBs, should be discontinued, although this may not be possible because of an ongoing psychiatric condition. In this case, it has to be kept in mind that patients who have experienced a single episode of ADR are at higher risk for future dystonic reactions when exposed to other DRBs and it is worth discussing a prophylactic approach using low-dose oral anticholinergics in addition to DRB. Interestingly, a few patients have been reported to exhibit druginduced oculogyric crises that recurred spontaneously months to years after discontinuation of the offending DRB [15], the reason for which remains unclear. Pathogenic mechanisms of ADRs are uncertain but may involve dopamine receptor blockade being associated with enhanced dopamine turnover and subsequent dopamine receptor supersensitivity. It may also be that the hypodopaminergic state results in relative cholinergic overactivity and muscarinic receptor supersensitivity. An inhibitory effect of M4 muscarinic receptors on striatal D1 dopamine receptor has also been proposed [15]. The propensity for DRBs to bind sigma opiate receptors has been considered as an alternative mechanism. Finally, there may be some genetic background as the basis of the sensitivity of some patients toward these side effects [3]. 3. Akathisia Akathisia has been variably defined and may develop as an acute or chronic movement disorder, or even a tardive syndrome [16]. It is considered the more frequent extrapyramidal manifestation related to the use of DRBs, and has an incidence ranging from 21% to 75%. Acute akathisia typically develops soon (within a
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few days), after DRB initiation, during dose escalation, or when switching to a more potent DRB [10]. It has a subjective component, including inner tension, anxiety, irritability, the urge to move and a feeling of jitteriness [1]. There is an objective component, with patients exhibiting global restlessness and increased, semipurposeful motor activity, including the incapacity to stay still, crossing and uncrossing their legs while sitting, and repetitive, stereotypic movements of the trunk, hands or legs. Importantly, in the setting of psychiatric conditions akathisia may be overlooked and misinterpreted as psychotic agitation, euphoria, anxiety, insomnia, delirium, restless legs syndrome or drug withdrawal. Akathisia is not a benign condition as it is considered by patients as highly unpleasant, interfering negatively with quality of life and potentially leading to violent behaviour and to suicide in severe forms. Acute akathisia tends to persist with DRB maintenance and abates soon after dose reduction or, more frequently, after DRB discontinuation. Atypical neuroleptics are less prone to induce akathisia and may be considered useful alternatives. However, even in this class of agents, the incidence of akathisia and of extrapyramidal side effects varies considerably from one study to another and it is unclear which of clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone or paliperidone is superior with respect to risks of developing akathisia [16]. Anticholinergics, beta-blockers, benzodiazepines, amantadine, mirtazapine, and clonidine as add-on medications have all proven useful to reduce akathisia when conventional or atypical neuroleptics have to be maintained, yet the level of evidence, in the absence of randomized controlled trials for most, is generally low. Acute akathisia is not limited to the use of DRBs and has also been reported with SSRIs, antiepileptics, and cocaine recreational use. In these conditions, therapeutic strategies are similar. 4. Drug-induced parkinsonism A parkinsonian syndrome developing over a short period of time (days or weeks to months) is highly suggestive of secondary parkinsonism, notably exposure to medications or toxins, and a neurodegenerative origin is rarely part of the differential diagnosis, perhaps with the exception of rapid-onset dystoniaparkinsonism related to mutations in the ATP1A3 gene. Subacute parkinsonism was recognized early on after the initial use of neuroleptics as one of the most frequent extrapyramidal side effects, with an incidence reaching over 15% of patients using conventional neuroleptics [1]. Nowadays, other medications, in particular calcium-channel blockers, seem to be equally frequent offending agents and, in general, it has been proposed that, despite considerable variations in incidence estimates, ranging from 20% to more than 50%, drug-induced parkinsonism (DIP) is the second most common form of parkinsonism in the elderly after Parkinson’s disease (PD). Typically, and at variance with ADR, DIP is more frequent in elderly female patients, overlapping partly with the age, but not gender, distribution of PD, but otherwise differs from PD in many aspects. DIP manifests as an akinetic-rigid, rather symmetrical parkinsonian syndrome that develops over a period of less than three months in 90% of cases and that responds poorly or not at all to levodopa [17]. Tremor and gait impairment is less common than in PD. In pure DIP, DaTSCAN is normal and parkinsonism resolves completely within months after discontinuation of the offending drug, but it may take up to a year in some cases. However, it is not uncommon to see patients whose DIP exhibits an asymmetrical distribution and who demonstrate reduced tracer binding on DaTSCAN images. This pattern is suggestive of preclinical PD or other forms of degenerative parkinsonism, which might have
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been unmasked by exposure to parkinsonism-prone medications, despite complete resolution of symptoms after drug withdrawal. For example, dementia with Lewy bodies, even in the early stages, may be extremely sensitive to DRB-induced adverse events. Long-term evolution of these cases is variable. Treatment of DIP is difficult, as it is resistant to all antiparkinsonian medications, including levodopa, dopamine agonists or anticholinergics. Reducing dosage might be of some help, but discontinuation of the causative agent is usually the only alternative. In this case, a global strategy is to try substituting the offending agent with a related compound that has a better side-effect profile. Switching from a typical to an atypical neuroleptic is usually a viable option, yet DIP has also been reported in association with the latter. For nausea, metoclopramide and other DRBs may be replaced by domperidone. At-risk patients and those who have already presented with a previous episode of DIP should be followed up carefully when exposed to other drugs that are associated with the condition. Neuroleptics, either conventional or atypical, antiemetics and gastrointestinal promotility agents, and calcium-channel blockers are not the only classes of pharmaceutical agents to be responsible for DIP, and less commonly reported medications should be considered when DIP is suspected. For example, antiepileptics, like phenytoin, valproate and levetiracetam, and antidepressants, including lithium, MAOIs and SSRIs, may rarely be associated with the rapid occurrence of a symmetrical akinetic-rigid syndrome similar to that seen after DRB therapy. Furthermore, in the setting of cancer, acute parkinsonism has been reported after bone marrow transplantation or chemotherapy containing, alone or in variable association, cystosine arabinoside, cyclophosphamide, vincristine, adriamycin, doxorubicin, etoposide, paclitaxel, or prednisone. Immunosuppressants like cyclosporine and tacrolimus have also been implicated. Besides medications, a number of toxic agents can produce acute parkinsonism, sometimes in isolation, like in accidental exposure to MPTP and organophosphate pesticides, sometimes in the context of a more complex encephalopathy, including agents such as manganese, methanol, cyanide, carbon monoxide or carbon disulfide poisoning. Interestingly, parkinsonism induced by organophosphate pesticides, like parathion and malathion, may be reversible and levodopa-responsive in some cases. 5. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a severe, potentially lethal, idiosyncratic reaction that occurs in an estimated 0.07% to 3.23% of patients treated with both conventional and atypical neuroleptics. The incidence of NMS is lower in the latter class, as are NMS severity and mortality (3% versus 16% for conventional neuroleptics [18]). NMS has been also reported with other DRBs and drugs interfering with dopaminergic tone, including metoclopramine, tetrabenazine and lithium. Typically, NMS presents with an acute onset of fever, autonomic instability, altered mental state and rigidity and other movement disorders including tremor, dystonia and myoclonus. This classical combination may be accompanied by increased serum creatine kinase, altered liver function tests, leukocytosis, electrolyte disturbance, renal impairment, altered coagulation tests, and ECG abnormalities. However, NMS induced by atypical neuroleptics tends to present in an atypical, usually less severe form, lacking rigidity, fever or with normal laboratory tests. While developing acutely within hours to 2–3 days, NMS tends to plateau for days and, in favourable cases, recovery usually takes 2 to 3 weeks. While several diagnostic criteria have been published over the years, an international panel of experts recently developed
new diagnostic criteria using a Delphi consensus procedure [19]. A consensus was reached on the following criteria: (1) recent dopamine antagonist exposure, or dopamine agonist withdrawal, within past 72 hours; (2) hyperthermia, >100.4°F or >38.0°C on at least 2 occasions; (3) rigidity; (4) mental status alteration; (5) creatine kinase (CK) elevation, at least 4 times the upper limit of normal; (6) sympathetic nervous system lability manifesting as at least two of the following: blood pressure elevation of ≥25% above baseline for systolic or diastolic; blood pressure fluctuation by ≥20 mmHg (diastolic) or ≥25 mmHg (systolic) within 24 hours; diaphoresis; urinary incontinence; (7) hypermetabolism defined as tachycardia ≥25% above baseline and tachypnea ≥50% above baseline; and (8) negative workup for other causes. These criteria, which have been validated recently [20], may have an advantage over pre-existing criteria in their ranking of the value of individual criteria compared to others, and also in that they provide critical values. Therapeutic approaches rely on immediate discontinuation of the causative medication, introduction of dopaminergic agents and, in severe forms, supportive care usually in the intensive care unit. For historical reasons, bromocriptine is considered a firstline treatment but it is likely, in the absence of randomized controlled trials, that any dopaminergic medication is equally effective including pramipexole, ropinirole or even levodopa [21]. We have found it particularly helpful to use repeated subcutaneous injections of apomorphine in the acute phase of NMS, which, in our experience, has a rapid effect on rigidity and fever. Dantrolene and benzodiazepines may also improve rigidity and reduce rhabdomyolysis. Importantly, treatment should be maintained for one to a few weeks and not discontinued too early in view of the risk of early relapse. Electroconvulsive therapy has been advocated by some. The occurrence of NMS increases the risk of a new episode when patients are re-challenged with the same or other DRBs. In this case, if a neuroleptic is absolutely necessary, preference would be for atypical agents, and the dose would have to be increased slowly, and patients monitored very carefully using temperature and CK dosage as early markers of NMS relapse. 6. Serotonin syndrome Serotonin syndrome (SS) is another acute iatrogenic condition, which resembles NMS but results from exposure to drugs increasing serotonin activity, including SSRIs, SNRIs, tricyclics, MAOIs, lithium, opiates and antiepileptics, among others [22]. Incidence of SS has not been well characterized but is considered rare or, alternatively, underdiagnosed. SS develops as an acute condition within 24 hours after drug initiation, sometimes only a few hours, 60% of cases within the first 6 hours. It encompasses a complex clinical picture whose severity varies from subtle and nonspecific symptoms to lethal multiorgan failure. Typical manifestations include an altered mental state characterized by agitation, anxiety, confusion or euphoria, dysautonomia with fever, tachycardia, high blood pressure, tachypnea, diaphoresis and diarrhea, and various movements disorders such as tremor, akathisia and, more notably, myoclonus. Additional neurological abnormalities can be found including mydriasis, rigidity, hyperreflexia, clonus and altered coordination, usually more marked in the lower limbs. Various diagnostic criteria have been proposed but comparisons between these separate sets of criteria have not been performed yet. As manifestations of SS are poorly specific when taken individually, the differential diagnosis is broad, including infectious diseases, metabolic abnormalities and encephalitis. It is difficult to differentiate SS from NMS, but exposure to serotoninergic drugs, a hyperacute state that resolves quickly,
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absence of severe rigidity, and the presence of mydriasis, clonus and myoclonus are in favor of SS rather than NMS [21]. Treatment of SS relies on immediate discontinuation of the offending agent which may be sufficient to achieve complete recovery within 24 hours. Besides supportive care, sometimes in the intensive care unit when required by severity of symptoms, the use of benzodiazepines or of 5-HT2A receptor antagonists, such as cryptoheptadine, chlorpromazine or olanzapine, may be useful. It must be stressed that none of these approaches have been validated in randomized controlled trials. 7. Parkinsonism-hyperpyrexia syndrome In PD and other degenerative parkinsonisms, a variant of NMS has been observed after drug holidays that were sometimes performed in the past. Variably referred to as akinetic crisis, acute akinesia, NMS-like syndrome, malignant syndrome or, more recently, parkinsonism-hyperpyrexia (PH) syndrome, it covers rare yet severe and abrupt conditions characterized by massive worsening of parkinsonism with nearly complete akinesia, altered mental state and drowsiness, fever, dysautonomia and increased creatine kinase enzymes [23]. While also described in the setting of a concomitant infectious disease, trauma or surgery, PH occurs most frequently as a consequence of inappropriate or involuntary antiparkinsonian drug changes, including rapid reduction or withdrawal of levodopa, dopamine agonists or even amantadine. Interestingly, it has also been reported after inadvertently turning off subthalamic nucleus deep brain stimulation systems [24]. Recovery may take a few hours to several weeks after previous treatment has been restored, yet it may be incomplete in some cases and multiple relapses may occur. Fatalities have been reported. Subcutaneous apomorphine by pump infusion or by repeated injections or intravenous amantadine sulfate, if available, may be rapidly efficacious. Sometimes, acute episodes of nearly complete akinesia with or without other features of NMS may occur in PD in the absence of any known drug modification. Whether this is a distinct subtype of PH is unclear [25]. Because akinesia may mimic other conditions like brainstem stroke, metabolic disturbances, infectious diseases or drug overdose, and in view of its duration (sometimes for days to weeks) and severity, the diagnosis may be missed and inappropriate treatment undertaken, the more so as precipitating factors may be present, such as a recent onset of influenza, bronchopneumonia, trauma and fracture, or acute gastrointestinal conditions. In this case, a striking aspect is that this syndrome is resistant to any drugmediated dopaminergic stimulation by usual medications even when given through nasogastric tubes. 8. Drug-induced tremor Many neurological conditions may be associated with a postural, resting or intentional tremor, and drug-induced tremor (DIT), which may appear as an acute event, has been associated with a variety of medications, notably SSRIs, lithium and tricyclics, antiepileptics, notably valproic acid, bronchodilators, amiodarone and immunosuppressants among many others [26]. As for other DIMDs, some suggestive features may help orientate the diagnosis toward DIT, including a clear temporal relationship between tremor onset and severity and drug initiation and dose, respectively, exclusion of common medical or neurological causes of tremor (hyperthyroidism, essential tremor, for example) and, as opposed to most neurodegenerative diseases, an absence of tremor progression over time and a relative symmetry of tremor distribution. Therapeutic approaches are, here also, based on dose reduction and switching to a less tremor-inducing agent, whenever possible. This is particularly true for valproate-induced tremor which can
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be switched for other antiepileptic drugs, the more so as some of them have proven efficacy in essential tremor, such as gabapentine, topiramate or even primidone. On the other hand, it must be kept in mind that a minimal, non-disabling tremor due to a drug essential for the underlying primary condition may not be reduced nor changed, and, in general, a side-effect to benefit ratio should be assessed in each case. Medications used for essential tremor may sometimes help, in particular propranolol. 9. Drug-induced hyperkinesias Besides dystonia, akathisia, parkinsonism and tremor, a variety of medications may induce, in a more or less acute scenario, chorea, myoclonus and tics, although this mode of presentation of DIMDs is much rarer [27]. The typical example is levodopa-induced dyskinesia. In fact, most pharmacological agents reported above may be associated with various movement disorders, sometimes apparently very distinct. The best illustration is DRBs, a class of drugs that may produce either hypokinetic or hyperkinetic movements, sometimes in the same individual. Acute drug-induced chorea, myoclonus or even tics have all been reported with the use of DRBs, amphetamines, antiepileptics, tricyclics, calciumchannel blockers, buspirone, steroids, oral contraceptives, lithium and digoxine. Importantly, these conditions are to be distinguished from tardive syndromes in view of their complete and immediate or rapid disappearance after discontinuation of the offending agent. Indeed, acute DIMDs usually cease spontaneously after withdrawal of the suspected drug and require no further treatment. 10. Movement disorders associated with the use of recreational drugs The extensive use of recreational drugs provides a variety of associated movement disorders that typically evolve as an acute and self-limited condition in young and otherwise healthy subjects [28]. When drug abuse takes place in patients with neurological conditions, in particular with psychostimulants, they may profoundly exacerbate the underlying movement disorder [29]. Cocaine is a potent psychostimulant which binds to the presynaptic dopamine transporter protein and blocks dopamine reuptake, leading to prolonged dopaminergic transmission in the basal ganglia, including the nucleus accumbens. In addition, cocaine enhances noradrenergic and serotonergic neurotransmission. Mostly inhaled or smoked (crack), cocaine has a potent yet transient effect which lasts no longer than an hour. Besides euphoria and agitation, cocaine may produce an array of acute movement disorders, including chorea (crack dancing), dystonia, stereotypies, tremor and myoclonus, that may start minutes after intake and last for a few days. Sometimes, abnormal movements begin during periods of withdrawal and may last for months. Amphetamines, like methamphetamine and dextroamphetamine, facilitate dopamine, noradrenaline and serotonine release at synaptic terminals. Besides euphoria, mood swings, hallucinations and paranoia, amphetamine abusers typically exhibit punding characterized by repetitive, complex and purposeless motor behavior. In addition, tremor, dystonia, choreoathetosis and orolingual movements such as tongue protrusion and bruxism have been described. Chronic use of amphetamines leads to dopamine depletion, yet parkinsonism is not a feature of amphetamine users. This is at variance with long-term effects of using khat, which contains amphetamine-like compounds like cathinone or methcathinone, or ecstasy (3,4-methylenedioxymethamphetamine (MDMA), where rare cases of levodopa-unresponsive parkinsonism have been reported. Importantly, ecstasy may cause hyperthermia, seizures and conditions resembling SS and NMS.
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Opioids are commonly given to treat pain and may be occasionally associated with myoclonus and persistent hiccup. This is particularly true for meperidine and analogues which, in addition to myoclonus, may induce tremor, seizures and delirium, in particular when taken with MAOIs, and SS when taken in association with serotonergic agents. On the other hand, abusers of the meperidine analogue MPTP developed a severe form of levodopa-responsive parkinsonism that appeared as an outbreak in 1982 in California but has almost never recurred. Heroin abusers do not usually show abnormal movements with the exception of some cases of chorea, yet they may develop a range of brain lesions that in turn may be responsible for movement disorders. This may be the case after heroin overdose that may be complicated by basal ganglia anoxia and spongiform leucoencephalopathy after “chasing the dragon” [30]. Conflict of interests The author has no conflict of interest to declare. References [1] Ayd FJ Jr. A survey of drug-induced extrapyramidal reactions. JAMA 1961;175: 1054–60. [2] North RR. Drug-induced movement disorders. Postgrad Med 1971;50:180–5. [3] Gilbert DL. Drug-induced movement disorders in children. Ann N Y Acad Sci 2008;1142:72–84. [4] Robottom BJ, Shulman LM, Weiner WJ. Drug-induced movement disorders: emergencies and management. Neurol Clin 2012;30:309–20. [5] Rodnitzky RL. Drug-induced movement disorders. Clin Neuropharmacol 2002; 25:142–52. [6] Dressler D, Benecke R. Diagnosis and management of acute movement disorders. J Neurol 2005;252:1299–306. [7] Kirkham FJ, Haywood P, Kashyape P, Borbone J, Lording A, Pryde K, et al. Movement disorder emergencies in childhood. Eur J Paediatr Neurol 2011;15:390–404. [8] Robottom BJ, Factor SA, Weiner WJ. Movement disorders emergencies. Part 2: hyperkinetic disorders. Arch Neurol 2011;68:719–24. [9] Robottom BJ, Weiner WJ, Factor SA. Movement disorders emergencies. Part 1: hypokinetic disorders. Arch Neurol 2011;68:567–72. [10] Cunningham Owens DG. A guide to the extrapyramidal side-effects of antipsychotic drugs. Cambridge: Cambridge University Press; 1999, 351pp. [11] Pierre JM. Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management. Drug Saf 2005;28:191–208.
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Acute and subacute drug-induced movement disorders Pierre R. Burkhard * Movement Disorders Unit, Department of Neurology, Geneva University Hospitals, Switzerland
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Keywords: Drug-induced movement disorders Parkinsonism Dyskinesia Tremor Acute dystonic reaction Akathisia Neuroleptic malignant syndrome Serotonin syndrome
Many pharmacological agents may induce a variety of movement disorders, including dystonia, tremor, parkinsonism, myoclonus and dyskinesia, with an acute, subacute or more chronic time course. Motor symptoms may be isolated or part of a more extensive cerebral or systemic condition, such as the neuroleptic malignant syndrome or the serotonin syndrome. Drug-induced movement disorders share a number of features that should make them easy to identify, including a clear temporal relationship between medication initiation and symptom onset, a dose-effect, and, with the exception of tardive syndromes, complete resolution after discontinuation of the offending agent. Diagnosis relies on a thorough medication history. Medications commonly involved include dopamine receptor blockers, antidepressants and anti-epileptics, among many others. Mechanisms underlying drug-induced movement disorders involve blockade, facilitation or imbalance of dopamine, serotonin, noradrenaline and cholinergic neurotransmission in the basal ganglia. The present review focuses on drug-induced movement disorders that typically develop as an acute (hours to days) or subacute (days to weeks) event, including acute dystonic reactions, akathisia, drug-induced parkinsonism, neuroleptic malignant syndrome, serotonin syndrome, parkinsonism-hyperpyrexia syndrome, drug-induced tremor, drug-induced hyperkinesias and movement disorders associated with the use of recreational drugs. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Shortly after the large-scale use of the first conventional neuroleptic chlorpromazine in schizophrenia by Delay, Deniker and Harl in 1952, a rapidly growing list of “drug-induced extrapyramidal reactions” was reported [1]. Since many other drugs were later associated with various movement disorders, the concept of drug-induced movement disorders (DIMDs) emerged in the early 1970s as a distinct clinical entity [2] and remains a major contributor to adult and pediatric movement disorders worldwide [3–5]. DIMDs can be classified according to (1) their temporal profile (acute and occurring within hours to days after exposure; subacute and building up more slowly after days to weeks of exposure; and chronic following long-term therapy with the offending medication) [6], (2) their phenomenology (dystonia, dyskinesia, tremor, parkinsonism, myoclonus, akathisia, tic, chorea) [5], and (3) the pharmacological agent likely involved (typical and atypical neuroleptics and other dopamine receptor blockers (DRBs), antidepressants, anti-epileptics, and many others, including recreational drugs and toxic agents). In general, DIMDs are treatable and tend to respond to the discontinuation of the offending agent. * Correspondence: Prof. Pierre Burkhard, Department of Neurology, Geneva University Hospitals, 4, rue Gabrielle-Perret-Gentil, 1211 Geneve ` 14, Switzerland. Tel.: +41 22 372 83 09; fax: +41 22 372 83 32. E-mail address: [email protected] (P.R. Burkhard). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
In this paper, the focus is on acute and subacute DIMDs, excluding tardive syndromes (TDs) which are discussed in another review in this supplement [Aquino and Lang, p. S113]. This group of conditions is relatively common yet likely underdiagnosed, since they are usually seen in the emergency room [7–9], and may appear atypical to non-neurologists. Diagnosis and treatment may therefore be delayed and the condition may worsen, whereas early recognition and adequate management leads to usually complete recovery. It is worthwhile to remember that, when facing an acute or subacute movement disorder, DIMD should be high on the list of differential diagnoses, and an extensive medication history is mandatory. 2. Acute dystonic reactions The prevalence of acute dystonic reactions (ADRs) has been variably estimated to range from 2.3% to 60% of patients treated with conventional neuroleptics [10] and 2% to 3% with atypical ones [11]. Mostly seen after exposure to DRBs, including antiemetics and gastrointestinal promotility agents, ADRs have also been reported after as diverse medications as SSRIs, opioids, methylphenidate, rivastigmine, albendazole, gabapentine, cetirizine, foscarnet, quininine, and during or shortly after general anesthesia using propofol, fentanyl [12], sevoflurane and morphine. Typically, ADRs occur in young males (including adolescents and children), who have a recent history of psychosis for which a high dose DRB has been initiated.
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ADRs characteristically start within hours to a few days after a neuroleptic has been introduced, with 50% of cases occurring during the first 24 hours and 90% within the first five days. Clinical manifestations are usually restricted to the head and neck, but, particularly when the medication is maintained, may extend toward upper and lower limbs as well as the trunk. Motor symptoms may be preceded by generalised discomfort, anxiety and restlessness. One of the most common manifestations is acute oro-mandibular dystonia affecting tongue and mouth, impairing speech and sometimes swallowing, potentially leading to temporo-mandibular joint subluxation, and sometimes evolving into overt trismus. Other modes of presentation include oculogyric crises, blepharospasm, complex cervical dystonia with a mixture of retrocollis, laterocollis and antecollis, focal limb dystonia, usually more distal than proximal, Pisa syndrome, and back arching potentially evolving into opisthotonos. A particularly spectacular and life-threatening form of ADR is acute laryngeal dystonia, affecting the vocal cords and laryngeal muscles and leading to upper airway partial or complete obstruction. This condition manifests as stridor, respiratory distress and sudden death. Known since the early use of DRBs [13], electromyography studies have demonstrated overactivity in vocal cord adductors, amenable to botulinum toxin injections in thyroarytenoid muscles with an excellent response [14]. This approach is probably life-saving in some cases. ADRs respond dramatically, usually within minutes, to intravenous or intramuscular injections of anticholinergic drugs. Depending on the availability of specific medications in individual countries, the following agents may be used: biperiden (2.5–5 mg), procyclidine (5–10 mg), benztropine (1–2 mg), trihexyphenidyl (2.5–5 mg) or diphenhydramine (25–50 mg). Benzodiazepines may also be helpful but are not as effective as anticholinergics. Because of their short half-life, recurrence of the ADR hours after the first anticholinergic injection may necessitate repeated injections and a limited oral course of anticholinergics is usually recommended for a few days. Medications implicated in ADRs, notably DRBs, should be discontinued, although this may not be possible because of an ongoing psychiatric condition. In this case, it has to be kept in mind that patients who have experienced a single episode of ADR are at higher risk for future dystonic reactions when exposed to other DRBs and it is worth discussing a prophylactic approach using low-dose oral anticholinergics in addition to DRB. Interestingly, a few patients have been reported to exhibit druginduced oculogyric crises that recurred spontaneously months to years after discontinuation of the offending DRB [15], the reason for which remains unclear. Pathogenic mechanisms of ADRs are uncertain but may involve dopamine receptor blockade being associated with enhanced dopamine turnover and subsequent dopamine receptor supersensitivity. It may also be that the hypodopaminergic state results in relative cholinergic overactivity and muscarinic receptor supersensitivity. An inhibitory effect of M4 muscarinic receptors on striatal D1 dopamine receptor has also been proposed [15]. The propensity for DRBs to bind sigma opiate receptors has been considered as an alternative mechanism. Finally, there may be some genetic background as the basis of the sensitivity of some patients toward these side effects [3]. 3. Akathisia Akathisia has been variably defined and may develop as an acute or chronic movement disorder, or even a tardive syndrome [16]. It is considered the more frequent extrapyramidal manifestation related to the use of DRBs, and has an incidence ranging from 21% to 75%. Acute akathisia typically develops soon (within a
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few days), after DRB initiation, during dose escalation, or when switching to a more potent DRB [10]. It has a subjective component, including inner tension, anxiety, irritability, the urge to move and a feeling of jitteriness [1]. There is an objective component, with patients exhibiting global restlessness and increased, semipurposeful motor activity, including the incapacity to stay still, crossing and uncrossing their legs while sitting, and repetitive, stereotypic movements of the trunk, hands or legs. Importantly, in the setting of psychiatric conditions akathisia may be overlooked and misinterpreted as psychotic agitation, euphoria, anxiety, insomnia, delirium, restless legs syndrome or drug withdrawal. Akathisia is not a benign condition as it is considered by patients as highly unpleasant, interfering negatively with quality of life and potentially leading to violent behaviour and to suicide in severe forms. Acute akathisia tends to persist with DRB maintenance and abates soon after dose reduction or, more frequently, after DRB discontinuation. Atypical neuroleptics are less prone to induce akathisia and may be considered useful alternatives. However, even in this class of agents, the incidence of akathisia and of extrapyramidal side effects varies considerably from one study to another and it is unclear which of clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone or paliperidone is superior with respect to risks of developing akathisia [16]. Anticholinergics, beta-blockers, benzodiazepines, amantadine, mirtazapine, and clonidine as add-on medications have all proven useful to reduce akathisia when conventional or atypical neuroleptics have to be maintained, yet the level of evidence, in the absence of randomized controlled trials for most, is generally low. Acute akathisia is not limited to the use of DRBs and has also been reported with SSRIs, antiepileptics, and cocaine recreational use. In these conditions, therapeutic strategies are similar. 4. Drug-induced parkinsonism A parkinsonian syndrome developing over a short period of time (days or weeks to months) is highly suggestive of secondary parkinsonism, notably exposure to medications or toxins, and a neurodegenerative origin is rarely part of the differential diagnosis, perhaps with the exception of rapid-onset dystoniaparkinsonism related to mutations in the ATP1A3 gene. Subacute parkinsonism was recognized early on after the initial use of neuroleptics as one of the most frequent extrapyramidal side effects, with an incidence reaching over 15% of patients using conventional neuroleptics [1]. Nowadays, other medications, in particular calcium-channel blockers, seem to be equally frequent offending agents and, in general, it has been proposed that, despite considerable variations in incidence estimates, ranging from 20% to more than 50%, drug-induced parkinsonism (DIP) is the second most common form of parkinsonism in the elderly after Parkinson’s disease (PD). Typically, and at variance with ADR, DIP is more frequent in elderly female patients, overlapping partly with the age, but not gender, distribution of PD, but otherwise differs from PD in many aspects. DIP manifests as an akinetic-rigid, rather symmetrical parkinsonian syndrome that develops over a period of less than three months in 90% of cases and that responds poorly or not at all to levodopa [17]. Tremor and gait impairment is less common than in PD. In pure DIP, DaTSCAN is normal and parkinsonism resolves completely within months after discontinuation of the offending drug, but it may take up to a year in some cases. However, it is not uncommon to see patients whose DIP exhibits an asymmetrical distribution and who demonstrate reduced tracer binding on DaTSCAN images. This pattern is suggestive of preclinical PD or other forms of degenerative parkinsonism, which might have
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been unmasked by exposure to parkinsonism-prone medications, despite complete resolution of symptoms after drug withdrawal. For example, dementia with Lewy bodies, even in the early stages, may be extremely sensitive to DRB-induced adverse events. Long-term evolution of these cases is variable. Treatment of DIP is difficult, as it is resistant to all antiparkinsonian medications, including levodopa, dopamine agonists or anticholinergics. Reducing dosage might be of some help, but discontinuation of the causative agent is usually the only alternative. In this case, a global strategy is to try substituting the offending agent with a related compound that has a better side-effect profile. Switching from a typical to an atypical neuroleptic is usually a viable option, yet DIP has also been reported in association with the latter. For nausea, metoclopramide and other DRBs may be replaced by domperidone. At-risk patients and those who have already presented with a previous episode of DIP should be followed up carefully when exposed to other drugs that are associated with the condition. Neuroleptics, either conventional or atypical, antiemetics and gastrointestinal promotility agents, and calcium-channel blockers are not the only classes of pharmaceutical agents to be responsible for DIP, and less commonly reported medications should be considered when DIP is suspected. For example, antiepileptics, like phenytoin, valproate and levetiracetam, and antidepressants, including lithium, MAOIs and SSRIs, may rarely be associated with the rapid occurrence of a symmetrical akinetic-rigid syndrome similar to that seen after DRB therapy. Furthermore, in the setting of cancer, acute parkinsonism has been reported after bone marrow transplantation or chemotherapy containing, alone or in variable association, cystosine arabinoside, cyclophosphamide, vincristine, adriamycin, doxorubicin, etoposide, paclitaxel, or prednisone. Immunosuppressants like cyclosporine and tacrolimus have also been implicated. Besides medications, a number of toxic agents can produce acute parkinsonism, sometimes in isolation, like in accidental exposure to MPTP and organophosphate pesticides, sometimes in the context of a more complex encephalopathy, including agents such as manganese, methanol, cyanide, carbon monoxide or carbon disulfide poisoning. Interestingly, parkinsonism induced by organophosphate pesticides, like parathion and malathion, may be reversible and levodopa-responsive in some cases. 5. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a severe, potentially lethal, idiosyncratic reaction that occurs in an estimated 0.07% to 3.23% of patients treated with both conventional and atypical neuroleptics. The incidence of NMS is lower in the latter class, as are NMS severity and mortality (3% versus 16% for conventional neuroleptics [18]). NMS has been also reported with other DRBs and drugs interfering with dopaminergic tone, including metoclopramine, tetrabenazine and lithium. Typically, NMS presents with an acute onset of fever, autonomic instability, altered mental state and rigidity and other movement disorders including tremor, dystonia and myoclonus. This classical combination may be accompanied by increased serum creatine kinase, altered liver function tests, leukocytosis, electrolyte disturbance, renal impairment, altered coagulation tests, and ECG abnormalities. However, NMS induced by atypical neuroleptics tends to present in an atypical, usually less severe form, lacking rigidity, fever or with normal laboratory tests. While developing acutely within hours to 2–3 days, NMS tends to plateau for days and, in favourable cases, recovery usually takes 2 to 3 weeks. While several diagnostic criteria have been published over the years, an international panel of experts recently developed
new diagnostic criteria using a Delphi consensus procedure [19]. A consensus was reached on the following criteria: (1) recent dopamine antagonist exposure, or dopamine agonist withdrawal, within past 72 hours; (2) hyperthermia, >100.4°F or >38.0°C on at least 2 occasions; (3) rigidity; (4) mental status alteration; (5) creatine kinase (CK) elevation, at least 4 times the upper limit of normal; (6) sympathetic nervous system lability manifesting as at least two of the following: blood pressure elevation of ≥25% above baseline for systolic or diastolic; blood pressure fluctuation by ≥20 mmHg (diastolic) or ≥25 mmHg (systolic) within 24 hours; diaphoresis; urinary incontinence; (7) hypermetabolism defined as tachycardia ≥25% above baseline and tachypnea ≥50% above baseline; and (8) negative workup for other causes. These criteria, which have been validated recently [20], may have an advantage over pre-existing criteria in their ranking of the value of individual criteria compared to others, and also in that they provide critical values. Therapeutic approaches rely on immediate discontinuation of the causative medication, introduction of dopaminergic agents and, in severe forms, supportive care usually in the intensive care unit. For historical reasons, bromocriptine is considered a firstline treatment but it is likely, in the absence of randomized controlled trials, that any dopaminergic medication is equally effective including pramipexole, ropinirole or even levodopa [21]. We have found it particularly helpful to use repeated subcutaneous injections of apomorphine in the acute phase of NMS, which, in our experience, has a rapid effect on rigidity and fever. Dantrolene and benzodiazepines may also improve rigidity and reduce rhabdomyolysis. Importantly, treatment should be maintained for one to a few weeks and not discontinued too early in view of the risk of early relapse. Electroconvulsive therapy has been advocated by some. The occurrence of NMS increases the risk of a new episode when patients are re-challenged with the same or other DRBs. In this case, if a neuroleptic is absolutely necessary, preference would be for atypical agents, and the dose would have to be increased slowly, and patients monitored very carefully using temperature and CK dosage as early markers of NMS relapse. 6. Serotonin syndrome Serotonin syndrome (SS) is another acute iatrogenic condition, which resembles NMS but results from exposure to drugs increasing serotonin activity, including SSRIs, SNRIs, tricyclics, MAOIs, lithium, opiates and antiepileptics, among others [22]. Incidence of SS has not been well characterized but is considered rare or, alternatively, underdiagnosed. SS develops as an acute condition within 24 hours after drug initiation, sometimes only a few hours, 60% of cases within the first 6 hours. It encompasses a complex clinical picture whose severity varies from subtle and nonspecific symptoms to lethal multiorgan failure. Typical manifestations include an altered mental state characterized by agitation, anxiety, confusion or euphoria, dysautonomia with fever, tachycardia, high blood pressure, tachypnea, diaphoresis and diarrhea, and various movements disorders such as tremor, akathisia and, more notably, myoclonus. Additional neurological abnormalities can be found including mydriasis, rigidity, hyperreflexia, clonus and altered coordination, usually more marked in the lower limbs. Various diagnostic criteria have been proposed but comparisons between these separate sets of criteria have not been performed yet. As manifestations of SS are poorly specific when taken individually, the differential diagnosis is broad, including infectious diseases, metabolic abnormalities and encephalitis. It is difficult to differentiate SS from NMS, but exposure to serotoninergic drugs, a hyperacute state that resolves quickly,
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absence of severe rigidity, and the presence of mydriasis, clonus and myoclonus are in favor of SS rather than NMS [21]. Treatment of SS relies on immediate discontinuation of the offending agent which may be sufficient to achieve complete recovery within 24 hours. Besides supportive care, sometimes in the intensive care unit when required by severity of symptoms, the use of benzodiazepines or of 5-HT2A receptor antagonists, such as cryptoheptadine, chlorpromazine or olanzapine, may be useful. It must be stressed that none of these approaches have been validated in randomized controlled trials. 7. Parkinsonism-hyperpyrexia syndrome In PD and other degenerative parkinsonisms, a variant of NMS has been observed after drug holidays that were sometimes performed in the past. Variably referred to as akinetic crisis, acute akinesia, NMS-like syndrome, malignant syndrome or, more recently, parkinsonism-hyperpyrexia (PH) syndrome, it covers rare yet severe and abrupt conditions characterized by massive worsening of parkinsonism with nearly complete akinesia, altered mental state and drowsiness, fever, dysautonomia and increased creatine kinase enzymes [23]. While also described in the setting of a concomitant infectious disease, trauma or surgery, PH occurs most frequently as a consequence of inappropriate or involuntary antiparkinsonian drug changes, including rapid reduction or withdrawal of levodopa, dopamine agonists or even amantadine. Interestingly, it has also been reported after inadvertently turning off subthalamic nucleus deep brain stimulation systems [24]. Recovery may take a few hours to several weeks after previous treatment has been restored, yet it may be incomplete in some cases and multiple relapses may occur. Fatalities have been reported. Subcutaneous apomorphine by pump infusion or by repeated injections or intravenous amantadine sulfate, if available, may be rapidly efficacious. Sometimes, acute episodes of nearly complete akinesia with or without other features of NMS may occur in PD in the absence of any known drug modification. Whether this is a distinct subtype of PH is unclear [25]. Because akinesia may mimic other conditions like brainstem stroke, metabolic disturbances, infectious diseases or drug overdose, and in view of its duration (sometimes for days to weeks) and severity, the diagnosis may be missed and inappropriate treatment undertaken, the more so as precipitating factors may be present, such as a recent onset of influenza, bronchopneumonia, trauma and fracture, or acute gastrointestinal conditions. In this case, a striking aspect is that this syndrome is resistant to any drugmediated dopaminergic stimulation by usual medications even when given through nasogastric tubes. 8. Drug-induced tremor Many neurological conditions may be associated with a postural, resting or intentional tremor, and drug-induced tremor (DIT), which may appear as an acute event, has been associated with a variety of medications, notably SSRIs, lithium and tricyclics, antiepileptics, notably valproic acid, bronchodilators, amiodarone and immunosuppressants among many others [26]. As for other DIMDs, some suggestive features may help orientate the diagnosis toward DIT, including a clear temporal relationship between tremor onset and severity and drug initiation and dose, respectively, exclusion of common medical or neurological causes of tremor (hyperthyroidism, essential tremor, for example) and, as opposed to most neurodegenerative diseases, an absence of tremor progression over time and a relative symmetry of tremor distribution. Therapeutic approaches are, here also, based on dose reduction and switching to a less tremor-inducing agent, whenever possible. This is particularly true for valproate-induced tremor which can
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be switched for other antiepileptic drugs, the more so as some of them have proven efficacy in essential tremor, such as gabapentine, topiramate or even primidone. On the other hand, it must be kept in mind that a minimal, non-disabling tremor due to a drug essential for the underlying primary condition may not be reduced nor changed, and, in general, a side-effect to benefit ratio should be assessed in each case. Medications used for essential tremor may sometimes help, in particular propranolol. 9. Drug-induced hyperkinesias Besides dystonia, akathisia, parkinsonism and tremor, a variety of medications may induce, in a more or less acute scenario, chorea, myoclonus and tics, although this mode of presentation of DIMDs is much rarer [27]. The typical example is levodopa-induced dyskinesia. In fact, most pharmacological agents reported above may be associated with various movement disorders, sometimes apparently very distinct. The best illustration is DRBs, a class of drugs that may produce either hypokinetic or hyperkinetic movements, sometimes in the same individual. Acute drug-induced chorea, myoclonus or even tics have all been reported with the use of DRBs, amphetamines, antiepileptics, tricyclics, calciumchannel blockers, buspirone, steroids, oral contraceptives, lithium and digoxine. Importantly, these conditions are to be distinguished from tardive syndromes in view of their complete and immediate or rapid disappearance after discontinuation of the offending agent. Indeed, acute DIMDs usually cease spontaneously after withdrawal of the suspected drug and require no further treatment. 10. Movement disorders associated with the use of recreational drugs The extensive use of recreational drugs provides a variety of associated movement disorders that typically evolve as an acute and self-limited condition in young and otherwise healthy subjects [28]. When drug abuse takes place in patients with neurological conditions, in particular with psychostimulants, they may profoundly exacerbate the underlying movement disorder [29]. Cocaine is a potent psychostimulant which binds to the presynaptic dopamine transporter protein and blocks dopamine reuptake, leading to prolonged dopaminergic transmission in the basal ganglia, including the nucleus accumbens. In addition, cocaine enhances noradrenergic and serotonergic neurotransmission. Mostly inhaled or smoked (crack), cocaine has a potent yet transient effect which lasts no longer than an hour. Besides euphoria and agitation, cocaine may produce an array of acute movement disorders, including chorea (crack dancing), dystonia, stereotypies, tremor and myoclonus, that may start minutes after intake and last for a few days. Sometimes, abnormal movements begin during periods of withdrawal and may last for months. Amphetamines, like methamphetamine and dextroamphetamine, facilitate dopamine, noradrenaline and serotonine release at synaptic terminals. Besides euphoria, mood swings, hallucinations and paranoia, amphetamine abusers typically exhibit punding characterized by repetitive, complex and purposeless motor behavior. In addition, tremor, dystonia, choreoathetosis and orolingual movements such as tongue protrusion and bruxism have been described. Chronic use of amphetamines leads to dopamine depletion, yet parkinsonism is not a feature of amphetamine users. This is at variance with long-term effects of using khat, which contains amphetamine-like compounds like cathinone or methcathinone, or ecstasy (3,4-methylenedioxymethamphetamine (MDMA), where rare cases of levodopa-unresponsive parkinsonism have been reported. Importantly, ecstasy may cause hyperthermia, seizures and conditions resembling SS and NMS.
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Opioids are commonly given to treat pain and may be occasionally associated with myoclonus and persistent hiccup. This is particularly true for meperidine and analogues which, in addition to myoclonus, may induce tremor, seizures and delirium, in particular when taken with MAOIs, and SS when taken in association with serotonergic agents. On the other hand, abusers of the meperidine analogue MPTP developed a severe form of levodopa-responsive parkinsonism that appeared as an outbreak in 1982 in California but has almost never recurred. Heroin abusers do not usually show abnormal movements with the exception of some cases of chorea, yet they may develop a range of brain lesions that in turn may be responsible for movement disorders. This may be the case after heroin overdose that may be complicated by basal ganglia anoxia and spongiform leucoencephalopathy after “chasing the dragon” [30]. Conflict of interests The author has no conflict of interest to declare. References [1] Ayd FJ Jr. A survey of drug-induced extrapyramidal reactions. JAMA 1961;175: 1054–60. [2] North RR. Drug-induced movement disorders. Postgrad Med 1971;50:180–5. [3] Gilbert DL. Drug-induced movement disorders in children. Ann N Y Acad Sci 2008;1142:72–84. [4] Robottom BJ, Shulman LM, Weiner WJ. Drug-induced movement disorders: emergencies and management. Neurol Clin 2012;30:309–20. [5] Rodnitzky RL. Drug-induced movement disorders. Clin Neuropharmacol 2002; 25:142–52. [6] Dressler D, Benecke R. Diagnosis and management of acute movement disorders. J Neurol 2005;252:1299–306. [7] Kirkham FJ, Haywood P, Kashyape P, Borbone J, Lording A, Pryde K, et al. Movement disorder emergencies in childhood. Eur J Paediatr Neurol 2011;15:390–404. [8] Robottom BJ, Factor SA, Weiner WJ. Movement disorders emergencies. Part 2: hyperkinetic disorders. Arch Neurol 2011;68:719–24. [9] Robottom BJ, Weiner WJ, Factor SA. Movement disorders emergencies. Part 1: hypokinetic disorders. Arch Neurol 2011;68:567–72. [10] Cunningham Owens DG. A guide to the extrapyramidal side-effects of antipsychotic drugs. Cambridge: Cambridge University Press; 1999, 351pp. [11] Pierre JM. Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management. Drug Saf 2005;28:191–208.
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