142 KEY POINTS: A A A Drug-induced parkinsonism is clinically indistinguishable from idiopathic Parkinson s disease and may occur as a symmetric or asymmetric phenomenon. The most effective treatment for drug-induced parkinsonism is elimination of the offending medication. If symptoms persist, the patient most likely has subclinical parkinsonism that was unmasked. Tardive dyskinesia is associated with chronic use, greater than 3 months, of dopaminergic blocking medications including typical and atypical neuroleptic medications, except quetiapine and clozapine and the antiemetic agents of prochlorperazine and metoclopramide. DRUG-INDUCED MOVEMENT DISORDERS Stacy Horn ABSTRACT Drug-induced movement disorders are varied and can be caused by a number of medications that alter central nervous system neurochemistry. Drug-induced movement disorders include parkinsonism, tardive phenomena, chorea, dystonia, tremor, akathisia, myoclonus, tics, and neuroleptic malignant syndrome. The movements can be acute or chronic phenomena and may be focal, hemi-, or generalized in nature. The drug-induced movement disorders, with the exception of the tardive phenomenon, can usually be treated by elimination of the offending medication. INTRODUCTION Drug-induced movement disorders are commonly seen in neurologic practice and may be caused by medications that alter neurotransmitter levels. The majority of drug-induced movement disorders can be improved with the elimination of the offending medication, and this remains the preferred method of treatment. Drug-induced movement disorders can be acute, subacute, or chronic phenomena and may occur with prescription or illicit drug use. Each drug-induced movement disorder will be discussed in the following sections. DRUG-INDUCED PARKINSONISM Drug-induced parkinsonism is a hypokinetic movement disorder that includes tremor, rigidity, bradykinesia, and less commonly postural instability. It is clinically indistinguishable from idiopathic Parkinson s disease and may occur as a symmetric or asymmetric phenomenon. Drug-induced parkinsonism is due to medications that affect presynaptic, synaptic, or postsynaptic dopamine levels. It can be either a subacute or chronic condition that can occur with both prescription and illicit drug use. Medications that deplete presynaptic dopamine in the central nervous system include tetrabenazine and reserpine. Methyldopa causes drug-induced parkinsonism by acting as a false neurotransmitter. The most common mechanism of drug-induced parkinsonism is through in the nigrostriatal system. This has been associated with the use of both typical and atypical neuroleptic agents or with antiemetic agents such as metoclopramide and prochlorperazine (Adler, 1999; Armon et al, 1996; Indo and Ando, 1982). Reports of drug-induced parkinsonism from dopamine blocking agents vary widely from 5% to 90% of patients treated depending upon the agent used and the population studied. Older adult patients and females are at higher risk of developing this syndrome. In patients at risk, 50% to 70% will develop symptoms within 1 month of starting therapy and 90% within 3 months (Ayd, 1961). Other medications less commonly associated with drug-induced parkinsonism include some of the calcium channel blockers, especially flunarizine and cinnarizine. These medications are thought to cause drug-induced parkinsonism by causing and mitochondrial chain dysfunction. Table 8-1
lists medications and drugs associated with drug-induced parkinsonism and their primary mechanism of action (Diederich and Goetz, 1998). A recent study in Olmstead County, Minnesota, to determine the incidence of parkinsonism found that 20% of patients were drug induced (Rocca et al, 2001). The most effective treatment for drug-induced parkinsonism is elimination of the offending medication. If symptoms persist, the patient most likely has subclinical parkinsonism that was unmasked. Neuroimaging with [18F] fluorodopa positron emission tomography suggests that patients with pure druginduced parkinsonism will have normalization of their radioactive dopa uptake in the basal ganglia after elimination of precipitating drugs while patients with unmasking of an underlying parkinsonism will have persistent diminished uptake after elimination of the precipitating medication (Burn and Brook, 1993) (Case 8-1). TARDIVE DYSKINESIA Tardive dyskinesia is a hyperkinetic movement disorder that causes choreic movements. Chorea is characterized by involuntary, rapid, nonrepetitive, random, small-amplitude movements that may be symmetric or asymmetric. Tardive dyskinesia is associated with chronic use, greater than 3 months, of dopaminergic blocking medications including typical and atypical neuroleptic medications except quetiapine and clozapine and the antiemetic agents of prochlorperazine and metoclopramide. Table 8-2 lists medications associated with tardive dyskinesia. The typical location is orobuccolingual, but chorea may be generalized. The exact pathophysiology for the development of the involuntary movements has not been completely elucidated, but one leading hypothesis is that chronic blockade of dopamine receptors may lead to supersensitivity of the receptors. This receptor supersensitivity causes normal amounts of available dopamine to create involuntary movements (Klawans, 1973). This syndrome is most prevalent in older females, and TABLE 8-1 Medication Chlorpromazine Fluphenazine Haloperidol Loxapine Thioridazine Molindone Pimozide Perphenazine Mesoridazine Trifluoperazine Risperidone Olanzapine Prochlorperazine Metoclopramide Methyldopa Reserpine Tetrabenazine Valproic acid Lithium Substances Associated With Drug-Induced Parkinsonism 1-Methyl-4-phenyl-1,2,3, 6-tetrahydropyridine Flunarizine Cinnarizine Verapamil Mechanism False neurotransmitter Presynaptic dopamine depletion Presynaptic dopamine depletion Mitochondrial respiratory chain dysfunction Unclear Selective dopamine cell death Mitochondrial respiratory chain dysfunction Mitochondrial respiratory chain dysfunction Mitochondrial respiratory chain dysfunction Reprinted with permission from Diederich NJ, Goetz CG. Drug-induced movement disorders. Neurol Clin 1998;16:125 139. Copyright # 1998, Elsevier. 143
"DRUG-INDUCED MOVEMENT DISORDERS Case 8-1 A 42-year-old male presents with the complaint of hand shaking for the past 6 months, which is causing him some social disability. He denies any interference with eating or activities of daily living. He has a past history significant for bipolar disorder with psychotic features. He has been treated for years with carbemazepine for mood stabilization and within the past year was started on risperidone for psychotic features. On neurologic examination, the patient has a resting tremor of both upper extremities, bradykinesia of rapid alternating movements in the upper and lower extremities, and cogwheel rigidity of all extremities. With gait testing, he has a diminished arm swing and mild retropulsion with the pull test. He is diagnosed with drug-induced parkinsonism, and risperidone is eliminated by his psychiatrist. Two months later the patient no longer has any tremor, bradykinesia, rigidity, or gait abnormalities. He currently has some paranoid ideations that will require treatment. Comment. This case illustrates parkinsonism in the clinical setting of a medication that blocks dopamine D2 receptor activity. The first treatment approach is to attempt to eliminate the risperidone, which was successful in this patient and eliminated his drug-induced syndrome; however, his psychiatric disease was exacerbated by the elimination of the precipitating medication. This patient may need long-term neuroleptic medications to control his psychosis. Two choices for therapy to control his psychosis without causing a drug-induced parkinsonism are quetiapine or clozapine. 144 prevalence increases with time treated. A meta-analysis calculated an incidence of 20% in patients treated with dopamine blocking agents (Kane and Smith, 1982) (Case 8-2). Choreic movements do not always extinguish with elimination of the offending medication. In fact, reports indicate that only 2% of patients have complete and persistent resolution of their involuntary movements (Glazer et al, 1990). Because these movements are often both socially and functionally disabling, pharmacologic treatment is often necessary if the choreic movements do not improve after the elimination of the offending agent. Pharmacologic treatments include dopamine-depleting agents such as reserpine or tetrabenazine, dopamine blocking agents such as quetiapine or clozapine, benzodiazepines, beta-blockers, and clonidine (Diederich and Goetz, 1998; Ondo et al, 1999). An alternative therapy includes vitamin E, which was shown to be effective in a small open-label study at a dose of 1600 mg a day (Sajjad 1998). Lastly, a controversial treatment that may be effective in selected patients includes TABLE 8-2 " Chlorpromazine " Fluphenazine " Haloperidol " Loxapine " Thioridazine " Molindone " Pimozide " Perphenazine " Mesoridazine " Trifluoperazine " Risperidone " Olanzapine " Prochlorperazine " Ziprasidone " Aripiprazole " Metoclopramide Medications Associated With Tardive Dyskinesia Adapted from Klawans HL Jr. The pharmacology of tardivedyskinesias.amjpsychiatry1973;130:82 86.
Case 8-2 A 70-year-old woman presents with a 3-month history of involuntary movements of her mouth and tongue. The patient has also noticed some gasping sounds. She states that these movements interfere with eating because they push food out of her mouth, and she has experienced a 10-pound weight loss. The patient also describes significant social disability due to the mouth movements. She has been taking olanzepine for the past year for insomnia and depression. On neurologic examination, the patient has respiratory dyskinesias and choreic movements of the tongue and lower face with tongue hypertrophy. The patient was felt to have tardive dyskinesia due to chronic dopaminergic blocking agents. Olanzapine was discontinued, and on follow-up at 3 months, the patient had a significant reduction in the involuntary movements with no current functional or social impairment. Comment. This case illustrates the patient population at risk for developing tardive dyskinesia and highlights some of the more serious complications, including respiratory dyskinesias, weight loss, and social disability. This patient s symptoms resolved with elimination of the offending medication. Had they persisted, she would have required symptomatic therapy guided by coexistent medical problems and concurrent medications. KEY POINT: A Tardive dyskinesia is most prevalent in older females, and prevalence increases with time treated. A meta-analysis calculated an incidence of 20% in patients treated with dopamine blocking agents. botulinum toxin type A injections into the affected musculature. This treatment has only been reported in case studies and should be used with caution in the anterior cervical musculature and oral regions because of the risk of weakness and dysphagia. Table 8-3 lists medications used in the treatment of tardive dyskinesia. TABLE 8-3 Medications Used in Treatment of Tardive Dyskinesia " Reserpine " Tetrabenazine " Clozapine " Quetiapine " Amantadine " Vitamin E " Botulinum toxin type A " Clonazepam DRUG-INDUCED CHOREA Drug-induced chorea is a hyperkinetic movement disorder that occurs as an acute or subacute phenomenon. The movements are again random, rapid, and of low amplitude. They are typically generalized or hemichoreic and can interfere with voluntary movement and gait. Patients with drug-induced chorea can be divided into two groups: parkinsonian patients and others. Acute and subacute drug-induced chorea are often associated with dopaminergic agents such as levodopa and, less commonly, dopamine agonists in parkinsonian patients. Dopaminergic-induced dyskinesias in parkinsonism are predominantly choreic in nature, but may also be dystonic. These movements typically occur with peak serum levels of levodopa and may be asymmetric. In the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, 9% of patients taking levodopa developed dyskinesias after 6 months of therapy, 17% after 12 months of therapy, and 145
"DRUG-INDUCED MOVEMENT DISORDERS 146 KEY POINTS: A Acute dystonic reaction is typically caused by medications that block dopamine D2 receptors in the central nervous system. A It is estimated that 2% to 3% of patients exposed to dopamine blocking medications develop an acute dystonic reaction. The movements are typically abrupt in onset and are more frequently seen in a younger population, with 90% of patients developing the abnormal movements in the first 5 days of treatment. 26% after 18 months of therapy. (Fahn, 2000) Drug-induced chorea can also be seen with other medications including stimulants such as amphetamines, oral contraceptives, antiepileptics, and some antidepressants. Illicit drugs, particularly cocaine, may also cause chorea. Patients with a prior history of basal ganglia dysfunction from such entities as Sydenham s chorea or cyanotic heart disease are at increased risk of developing drug-induced chorea. The exact incidence of drug-induced chorea in the general population is not clear. However, large numbers of patients are treated each year with the offending medications without problems. The proposed pathophysiology of drug-induced chorea is through dopaminergic augmentation, but this is incompletely understood. In parkinsonian patients with druginduced chorea, treatment strategies can include decreasing dopaminergic medications, increasing dosage frequency, and adding amantadine. If these fail, surgical therapies such as pallidotomy or deep brain stimulation of the globus pallidus interna or subthalamic nucleus may be helpful. The best treatment option in the general population is elimination of the underlying medication. With discontinuation of the offending agent, the abnormal movements should resolve over time. ACUTE DYSTONIC REACTION Dystonia is a central nervous system disorder that results in repetitive movements of agonist and antagonist musculature. Acute dystonic reaction is typically caused by medications that block dopamine D2 receptors in the central nervous system. Table 8-4 lists medications associated with acute dystonic reactions. The movements predominantly affect the cranial and cervical musculature and can be associated with oculogyric crisis. It is estimated that 2% to 3% of patients TABLE 8-4 " Metoclopramide " Prochlorperazine " Olanzapine " Risperidone " Trifluoperazine " Mesoridazine " Perphenazine " Pimozide " Molindone " Thioridazine " Loxapine " Haloperidol " Fluphenazine " Chlorpromazine " Cocaine Medications Commonly Associated With Acute Dystonic Reaction exposed to dopamine blocking medications develop an acute dystonic reaction (Ayd, 1961). The movements are typically abrupt in onset and are more frequently seen in a younger population, with 90% of patients developing the abnormal movements in the first 5 days of treatment. The acute dystonic reaction can be treated effectively with either intravenous anticholinergic medications or benzodiazepines. Patients may require a few additional days of oral therapy with the effective medication (Diederich and Goetz, 1998). TARDIVE DYSTONIA These movements are involuntary, repetitive, and twisting. They may be intermittent or sustained and are often painful. The dystonic movements are described by location as focal, segmental, hemi-, or generalized.
Tardive dystonia is a syndrome that occurs after prolonged use (ie, greater than 3 months) of dopamine blocking agents including typical and atypical neuroleptic medications and antiemetic medications. These medications are the same medications implicated in tardive dyskinesia. The typical types of tardive dystonia include cranial and cervical disorders such as blepharospasm, opisthotonos, retrocollis, and torticollis, but the dystonia may affect any body part or be generalized in nature. The incidence of tardive dystonia appears to be 1.5% to 2% of patients treated with central nervous system dopaminergic blocking agents (Friedman et al, 1987; Yassa et al, 1986). Spontaneous remissions are rare, and this disorder can often be disabling and painful, requiring treatment (Wojcik et al, 1991). Treatment options include elimination of the offending agent and monitoring for remission over several months. If this is ineffective and patients continue to have disability or pain, then other pharmacologic agents can be useful. For generalized forms of dystonia, a trial of oral medication such as anticholinergics, baclofen, benzodiazepines, tetrabenazine, quetiapine, or, in medically refractory cases, clozapine. In each case, the medications should be started at low dosage and titrated slowly to efficacy or side effects. For focal forms of tardive dystonia, botulinum toxin injections into the affected musculature may be useful for alleviating the spasms and pain. Table 8-5 contains a list of medications that may be effective in treating tardive dystonia. DRUG-INDUCED TREMOR Tremor is a rhythmic, involuntary, oscillatory movement of any body part and is named for the position of greatest prominence. Drug-induced tremor disorders typically begin shortly after institution of the offending medication. Drug-induced tremors may be postural, rest, or intention. The most common form is the enhanced physiologic tremor (Deuschl et al, 1998). Drug-induced tremors are associated with multiple medications, including stimulants, antidepressants, theophylline, lithium, valproic acid, amiodarone, cyclosporine, neuroleptics, and immunomodulators. Table 8-6 contains a more complete list of medications associated with drug-induced tremor (Deuschl et al, 1998). Elimination of the offending medication often ameliorates drug-induced tremor. If the offending agent cannot be discontinued, then medications commonly used to treat tremor can be effective, including beta-blockers such as propanolol up to 240 mg a day and primidone up to KEY POINT: A The incidence of tardive dystonia appears to be 1.5% to 2% of patients treated with central nervous system dopaminergic blocking agents. 147 TABLE 8-5 Pharmacological Therapy of Dystonia Medication Trihexyphenidyl Baclofen Clonazepam Tetrabenazine Clozapine Botulinum toxin type A Typical Therapeutic Dosage Up to 120 mg/d 25 mg/d to 80 mg/d 1.5 mg/d to 12 mg/d 12.5 mg/d to 400 mg/d Up to 400 mg/d Multiple dosages depending upon injection location
"DRUG-INDUCED MOVEMENT DISORDERS 148 KEY POINT: A Akathisia is a hyperkinetic movement disorder characterized by restlessness and the irresistible urge to move. Akathisia may be an acute, subacute, or tardive phenomenon. TABLE 8-6 Substances Associated With Drug-Induced Tremor " Nicotine " Atypical neuroleptics Risperidone Olanzapine " Typical neuroleptics Chlorpromazine Fluphenazine Haloperidol Loxapine Thioridazine Molindone Thiothixene Pimozide Perphenazine Mesoridazine Trifluoperazine " Antiemetics Metoclopramide Prochlorperazine Reserpine Tetra " Reserpine " Tetrabenazine " Antidepressants Tricyclic antidepressants Selective serotonin reuptake inhibitors Other depressants such as trazodone and mirtazapine TABLE 8-6 " Caffeine " Dopamine " Steroids Continued Progesterone Tamoxifen Adrenocorticosteroids " Valproic acid " Antiarrhythmics Amiodarone Mexiletine Procainamide " Calcitonin " Levothyroxine " Chemotherapeutics Vincristine Adriablastine Cytosinarabinoside Ifosfamide " Immunosuppressants Cyclosporin Mycophenolate mofetil Muromonab Basiliximab Daclizumab " Amphetamine From Deuschl G, Bain P, Brin. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13(suppl 3):2 23. Copyright # 1998, Movement Disorder Society. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. " Lithium " Cocaine " Alcohol " Beta-agonists " Theophylline 250 mg a day, and benzodiazepines such as clonazepam. AKATHISIA Akathisia is a hyperkinetic movement disorder characterized by restlessness
and the irresistible urge to move. Akathisia may be an acute, subacute, or tardive phenomenon. Akathisia occurs with medications that alter central nervous system dopamine levels, including typical and atypical neuroleptic medications, antiemetic agents, reserpine, and tetrabenazine. Akathisia is estimated to occur in 20% to 30% of patients exposed to these medications (Sachdev, 1995) (Case 8-3). The exact pathophysiologic basis for the development of akathisia is unknown. It can be improved by diminishing the dosage of the precipitating agent or eliminating this agent. If the akathisia persists or is a tardive phenomenon, then medical therapy may be necessary to help control symptoms. The most consistently effective treatment is propanolol. If propanolol is ineffective or cannot be tolerated, other agents that have been used, including benzodiazepines, amantadine, or clonidine, can be tried (Miller and Fleischhacker, 2000). DRUG-INDUCED MYOCLONUS Myoclonus is an involuntary hyperkinetic movement disorder that is classified as either positive or negative. Positive myoclonus features sudden brief muscular contractions, while negative myoclonus involves pauses in muscular activity (Fahn et al, 1986). Medication-induced myoclonus is typically generalized in nature and can be very debilitating. The underlying pathophysiologic mechanism of myoclonus appears to be mediated through enhancement of serotonin and g-aminobutyric acid (Marsden et al, 1982; Matsumoto et al, 2000). Multiple medications and illicit substances have been implicated in the etiology of drug-induced myoclonus. These medications are listed in Table 8-7 (Blindauer, 2001). The best therapy for drug-induced myoclonus is identification and elimination of the offending agent. DRUG-INDUCED TICS Tics are a hyperkinetic movement disorder consisting of repetitive, stereotyped motor or vocal movements that may be simple or complex in nature. Often patients can describe an urge to perform the movement, relief after performing the movement, and some ability to suppress the movement for Case 8-3 A 33-year-old pregnant woman presents with generalized involuntary movements. She has been taking metoclopramide 10 mg 4 times a day for the past month because of intractable nausea and vomiting. The patient describes the inability to sit still for long periods of time. She feels good when active. Her inability to sit still has been interfering with many daily activities. On examination, the patient is constantly moving. When asked to sit still, she can do this for several minutes but then becomes uncomfortable and begins to pace. The patient is diagnosed with akathisia due to dopamine blocking medications. The patient is asked to limit the amount of metoclopramide and to take this medication on an as-needed basis instead of around the clock. Two weeks later her symptoms have moderately improved. Comment. This case illustrates typical drug-induced akathisia. Abnormal movements, primarily chorea, can be seen in pregnancy. Akathisia may occur with the institution of any medication that blocks D2 receptors. Clinical improvement may be seen with reduction or elimination of the precipitating medication. 149
"DRUG-INDUCED MOVEMENT DISORDERS 150 KEY POINT: A Neuroleptic malignant syndrome is a syndrome of hyperthermia and autonomic dysfunction, altered mental status, and muscular rigidity. TABLE 8-7 Substances Associated With Myoclonus " Morphine " Meperidine " Hydromorphone " Fentanyl " Sufentanil " Diamorphine " Diltiazem " Nifedipine " Verapamil " Tricyclic antidepressants " Selective serotonin reuptake inhibitors " Monoamine oxidase inhibitors " Lithium " Buspirone " Neuroleptic medications " Phenytoin " Valproic acid " Carbamazepine " Gabapentin " Lamotrigine " Vigabatrin " Chlorambucil " Flecainide " Propafenone " Carvedilol " Levodopa " Bromocriptine " Metoclopramide " Pseudoephedrine " Tryptophan " Albuterol " Physostigmine " Alcohol Reprinted with permission from Blindauer K. Myoclonus and its disorders. Neurol Clin 2001; 19:723 734. Copyright # 2001, Elsevier. short amounts of time. Tics have a predilection for cranial and cervical musculature but may occur in any body location. They are caused by enhanced dopamine levels and have been associated with multiple substances, including stimulants such as methylphenidate, dextroamphetamine, pemoline, cocaine, and, lastly, lamotrigine (Kumar and Lang, 1997). A recent double-blind randomized study performed with methylphenidate to determine if stimulants exacerbate tics in Tourette s syndrome found no significant change in tic severity between the active drugs and the placebo groups (Tourette s Syndrome Study Group, 2002). This recent study suggests that stimulants may not exacerbate tics, although multiple case reports exist in the literature describing this phenomenon. The best therapy is again to eliminate any medication that may have been associated with the onset or worsening of tics. NEUROLEPTIC MALIGNANT SYNDROME Neuroleptic malignant syndrome (NMS) is a serious complication of medications that block D2 receptors. NMS is a syndrome of hyperthermia and autonomic dysfunction, altered mental status, and muscular rigidity. Diagnostic criteria for NMS, according to the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) include increased temperature and muscle rigidity accompanied by two or more of the following: diaphoresis, tremor, dysphagia, altered mental status, tachycardia, incontinence, dysregulation of blood pressure, leukocytosis, and elevated creatine kinase. Patients may develop the syndrome at any time during treatment with medications that block D2 receptors; it is seen most commonly with typical or atypical neuroleptic medications. Risk may be
slightly increased with depot forms of neuroleptic medications. NMS may occur at any time during therapy but is most commonly seen within the first 3 to 9 days of therapy. The incidence of NMS is between 0.5% and 2.4% of patients exposed to these medications, and mortality rates have been reported as low as 4% and as high as 20% (Bertorini, 1997). NMS has also been described with lithium and the rapid elimination of dopaminergic medications in idiopathic Parkinson s disease. The pathophysiologic basis is felt to be through dopaminergic dysregulation and blockade of dopamine in the basal ganglia and hypothalamus (Henderson and Wooten, 1981). Abnormal laboratory findings include leukocytosis and increased creatine kinase levels. The most important therapy is identification and elimination of the offending medication. Treatment includes supportive care such as aggressive intravenous fluid replacement and diuresis, blood pressure support, and temperature control. Medications that have been used to treat NMS include bromocriptine 5 mg 4 times a day and dantrolene 3mg/kg to 5 mg/kg intravenously in divideddoses3timesor4timesaday. Other modalities that have been described to be effective in the treatment of NMS include benzodiazepines, amantadine, and electroconvulsive therapy (Carbone, 2000). CONCLUSION Drug-induced movement disorders can be commonly seen in outpatient and inpatient clinical practice. When evaluating a patient with a movement disorder, it is important to take a thorough past and present medication history, including any recently added medications or changes in dosages. The best therapy for treating a drug-induced movement disorder is elimination of the offending agent. If elimination is not possible due to underlying illness, then attempting to decrease the dosage or change to a less-offensive agent would be the next line of therapy. If all of the above measures are impossible or a tardive syndrome exists, then medical therapy can be considered to help decrease disability. The choice of therapeutic agent is guided by the type of movement disorder and coexistent medical problems and medications. REFERENCES " Adler CH. Differential diagnosis of Parkinson s disease. Med Clin North Am 1999;83:349 367. Review article with an excellent differential diagnosis of parkinsonism. 151 " Armon C, Shin C, Miller P, et al. Reversible parkinsonism and cognitive impairment with chronic valproate use. Neurology 1996;47:626 635. Early description of valproate-induced parkinsonism. " Ayd FJ Jr. A survey of drug-induced extrapyramidal reactions. JAMA 1961; 175:1054 1060. One of the earliest articles describing drug-induced movement disorders. " Bertorini TE. Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurol Clin 1997;15:649 671. Review article describing the above phenomenon and how to differentiate among the disorders.
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