Medication-Induced Movement Disorders

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41 Medication-Induced Movement Disorders

Diana Apetauerova

Clinical Vignette

A 57-year-old woman with history of chronic nausea and concomitant use of antiemetic medications presented for evaluation of slowness and tremor. She had been followed by a gastroenterologist for the past 3 years for her nausea. No specific mechanism was identified to explain her symptoms; treatment was initiated with various antinausea medications. Approximately 1.5 years ago, metoclopramide was initiated; it was continued daily. This led to significant improvement of her nausea. Her past medical history was not otherwise of note.

One year ago, she began to note that both hands were shaking and her dexterity diminished, particularly with her handwriting becoming smaller and progressively telescoping. Her family also noticed that she had developed facial masking, a shuffling gait, and a hunched posture. On occasion, her speech had an indistinct and low volume. There was no family history of Parkinson disease or other neurologic conditions. She denied any prior toxic exposure.

Neurologic examination revealed facial masking; hypophonic speech; mild perioral tremor; symmetric generalized bradykinesia and rigidity; a bilateral 5-Hz frequency postural as well as action hand tremor; and a slow, shuffling parkinsonian gait. The diagnosis of drug-induced parkinsonism was suspected. Metoclopramide was discontinued. She had complete resolution of her symptoms and was normal when seen 6 months later.

There are a large number of pharmaceutical agents with the potential to cause a movement disorder (Table 41-1). These medications primarily interfere with dopaminergic transmission within the basal ganglia (levodopa, dopamine agonists, dopamine receptor–blocking agents [DRBs]). Other classes of these movement disorder–inducing agents do not have as precisely defined biochemical mechanisms. These medications include central nervous system (CNS) stimulants, anticonvulsants, tricyclic antidepressants, and estrogens. From a clinical perspective, the medications most commonly responsible for iatrogenic movement disorders are the various neuroleptics and pharmacologic agents that block or stimulate dopamine receptors.

Table 41-1 Types of Drug-Induced Movement Disorders and Responsible Medications

Syndrome	Responsible Medication
Postural tremor	Sympathomimetics Levodopa Amphetamines Bronchodilators Tricyclic antidepressants Lithium carbonate Caffeine Thyroid hormone Sodium valproate Antipsychotics Hypoglycemic agents Adrenocorticosteroids Alcohol withdrawal Amiodarone Cyclosporin A Others
Acute dystonic reactions	Antipsychotics Metoclopramide Antimalarial agents Tetrabenazine Diphenhydramine Mefenamic acid Oxatomide Flunarizine and cinnarizine
Akathisia	Antipsychotics Metoclopramide Reserpine Tetrabenazine Levodopa and dopamine agonists Flunarizine and cinnarizine Ethosuximide Methysergide
Parkinsonism	Antipsychotics Metoclopramide Reserpine Tetrabenazine Methyldopa Flunarizine and cinnarizine Lithium Phenytoin Captopril Alcohol withdrawal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Other toxins (manganese, carbon disulfide, cyanide) Cytosine arabinoside
Chorea, including tardive and orofacial dyskinesia	Antipsychotics Metoclopramide Levodopa Direct dopamine agonists Indirect dopamine agonists and other catecholaminergic drugs Anticholinergics Antihistaminics Oral contraceptives Phenytoin Carbamazepine Ethosuximide Phenobarbital Lithium carbonate Methadone Benzodiazepines Monoamine oxidase inhibitors Tricyclic antidepressants Methyldopa Digoxin Alcohol withdrawal Toluene sniffing Flunarizine and cinnarizine
Dystonia, including tardive dystonia (excluding acute dystonic reactions)	Antipsychotics Metoclopramide Levodopa Direct dopamine agonists Phenytoin Carbamazepine Flunarizine and cinnarizine
Neuroleptic malignant syndrome	Antipsychotics Tetrabenazine with α-methyl-para-tyrosine Antiparkinsonian drugs withdrawal
Tics	Levodopa Direct dopamine agonists Antipsychotics Carbamazepine
Myoclonus	Levodopa Anticonvulsants Tricyclic antidepressants Antipsychotics
Asterixis	Anticonvulsants Levodopa Hepatotoxins Respiratory depressants

The clinical temporal profile of drug-induced movement disorders can be acute, subacute, or chronic. Acute syndromes include dystonia, choreoathetosis, akathisia, and tics. Subacute syndromes include drug-induced parkinsonism and tremor. Chronic syndromes include levodopa-induced dyskinesias in Parkinson disease and tardive dyskinesia (TD). There is no direct evidence of precise CNS pathology predisposing to the development of drug-induced movement disorders. Because no precise pathoanatomic correlation or model is known, a primary biochemical mechanism is therefore the likely responsible pathophysiologic mechanism here.

Clinical Syndromes

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a very unusual complication and is one of the most severe reactions to neuroleptic therapy. It has a relatively high incidence (0.5–1%) considering the very large numbers of patients taking neuroleptic medication. Symptoms typically occur shortly after institution of neuroleptic therapy or at time of initiating increased dosage. Young men are at higher risk than the general population. Pathogenesis is thought to involve both central and peripheral effects of dopamine receptor blockade.

Typically, NMS patients present with an acute onset of a severe movement disorder characterized by rigidity, tremor, and dystonia. There are often manifestations of very significant dysautonomic disturbances, including fever, diaphoresis, and cardiovascular/pulmonary dysfunction. Often the patients are stuporous, and a very intense concomitant myonecrosis usually accompanies the NMS; this leads to significant elevation of serum creatine kinase with its own innate risk of significant renal compromise. There is an associated leukocytosis. The fatality rate in NMS may reach as much as 20% because of the various associated complications, including dehydration, cardiac arrhythmias, pulmonary embolism, and renal failure. As soon as this clinical setting of NMS is recognized, it is very important to begin treatment. Medications that are frequently useful include levodopa, dopamine agonists, and the antispastic agent dantrolene.

Acute Dystonic Reactions

These very dramatic movement disorder syndromes usually develop within 5 days after initiation of various neuroleptic medications. This clinical picture typically presents very rapidly after initiation of the responsible therapeutic agent. The craniocervical region is the most commonly affected site. These patients are sometimes thought to have tetanus what with the facial spasms mimicking the classic trismus with risus sardonicus (Fig. 41-1).

Figure 41-1 Acute Dystonic Reaction.

Pathophysiologically, these disorders are related to a sudden imbalance between the striatal dopamine and cholinergic systems. Typically these disorders are diagnosed by their relatively acute resolution either spontaneously subsequent to drug withdrawal or more immediately by parenteral administration of an antihistamine, such as diphenhydramine, or sometimes anticholinergics.

Medication-Induced Parkinsonism

Various medications have the potential to interfere with the synthesis, storage, and release of dopamine, as well as the varied dopamine-blocking agents, and may precipitate an akinetic-rigid syndrome that is nearly indistinguishable from idiopathic Parkinson disease (Fig. 41-2). Substituted benzamides, particularly metoclopramide, used to treat gastrointestinal disorders, and calcium channel blockers particularly have the potential to produce a medication-induced parkinsonism. The basic pathophysiologic mechanism here is related to a predominant presynaptic effect on dopamine and serotonin neurons.

Figure 41-2 Medication-Induced Parkinsonism.

In contrast to Parkinson disease where the presentation often has a focal distribution, therapeutic medication-induced parkinsonism is often characterized by a symmetric bilateral presentation. Bradykinesia predominates over typical rigidity and resting tremor. When a tremor is present, it is usually postural instead of resting. Although drug-induced parkinsonism may persist long after withdrawal of the offending drug, eventually most patients improve without further therapeutic interventions if use of the offending drug can be stopped.

Akathisia

This unusual disorder is typified by an inability to keep still; subjectively, it is often accompanied by feelings of restlessness, primarily resulting from the initiation of neuroleptic therapy. Akathisia is the most poorly understood, acute drug-induced syndrome; no neuroanatomic correlates explain it. Dose reduction or withdrawal of the offending drug is the most effective treatment. At times, introduction of other medications, such as propranolol and clonidine, can provide reasonable treatment. The pathophysiologic mechanisms are not well defined. It is known that these neuroleptics have little or no direct effect on β-adrenergic receptors.

Tardive Dyskinesia Syndromes

The prevalence of TD varies between 0.5% and 65%, making it the most feared complication of long-term neuroleptic therapy. These syndromes present after a latency period following initiation of these various inciting medications. They usually do not present until at least 3 months after—or, more commonly, 1 to 2 years after—the patient begins taking the responsible medication. The timing of presentation for these disorders can be varied during treatment per se, after dose reduction, or subsequent to medication withdrawal. Unfortunately, some of these syndromes are irreversible. Neuroleptics are the most common offending drugs, particularly because of dopamine receptor blocking (DRB).

Most commonly, TD clinically affects the orofacial region, in particular, various chewing movements, tongue protrusion, vermicular tongue motion, lip smacking, puckering, and pursing (Fig. 41-3A). TD patients also have hyperkinesias, including chorea (Fig. 41-3B), athetosis, dystonia, and tics affecting the limb and truncal regions, or paroxysms of rapid eye blinking. Various risk factors are thought to be operative, including female sex, older age, and duration and dosage of therapy. It may take months for TD to resolve if they are going to do so, and sadly this is not predictable.