WASHINGTON — The diagnosis of drug-induced parkinsonism often gets missed, even by neurologists, according to an informal study of patients at one movement disorder clinic presented at the World Parkinson Congress.
Of all new patients with parkinsonian symptoms seen in the movement-disorders program at Emory University, Atlanta, between January 2004 and January 2006, 8% (23 of 304 patients) were diagnosed with drug-induced parkinsonism (DIP), said Dr. Stewart A. Factor, director of the program. The age range at diagnosis was 49–97 years; the age at onset ranged between 48 and 96 years. Most patients were female (73%). Records were available for 22 patients with DIP.
“Seventeen of the 22 patients had been seen previously by neurologists, and yet only 2 of them were diagnosed with drug-induced parkinsonism,” Dr. Factor said. Of these, 10 were misdiagnosed with Parkinson's disease (PD) and were treated with antiparkinsonian drugs. Seven patients had no clear diagnosis.
The older, conventional antipsychotic drugs have been most commonly associated with DIP. It has been assumed that the risk of DIP was reduced with the introduction of atypical antipsychotic drugs. However, Dr. Factor's experience has been just the opposite.
Only three patients in his clinic developed DIP in response to typical antipsychotics (haloperidol, trifluoperazine, and amoxapine). In contrast, 12 cases were caused by atypical antipsychotics (3 from risperidone, 6 from olanzapine, 1 from ziprasidone, and 2 from aripiprazole). Five cases were caused by metoclopramide and two were caused by drug combinations (metoclopramide/reserpine, metoclopramide/ziprasidone).
In terms of clinical features, 11 patients had tardive dyskinesia (including 5 with respiratory dyskinesia), 2 had akathisia, 19 had tremor (17 with resting tremor and 6 with asymmetric tremor, alone or in combination), and 3 had akinetic rigidity. Clinically, 11 patients had psychiatric diagnoses—primarily mood disorders (9 patients)—and 6 patients had neurologic diagnoses (dementia, Huntington's chorea, hydrocephalus). Of the 13 patients who stopped the drug and returned for follow-up, 12 had an improvement in symptoms within about 6 months.
DIP has a subacute onset and all of the cardinal features of Parkinson's disease—tremor, rigidity, bradykinesia, and abnormalities of posture, gait, and balance—can be seen. Akinetic rigidity (without tremor) is seen in most patients with DIP.
Drug-use history and tardive dyskinesia appear to be key to the differential diagnosis. Other factors that can help differentiate DIP from PD include subacute onset, bilateral features, more postural tremor than resting tremor, and the presence of other extrapyramidal signs.
Among psychiatric patients, 90% of DIP cases start in the first 3 months of drug use or within 3 months of a dosage increase. The condition may reverse spontaneously, but this is rare. The condition also may be chronic and progressive. Withdrawal of the drug does not lead to immediate improvement of symptoms, which typically take up to 6 months to resolve.
Metoclopramide, an antiemetic drug used mainly for gastrointestinal disorders, has been implicated in DIP. The drug is intended for short-term use (2–8 weeks), but many patients are treated long term with this drug. “With chronic use, they develop drug-induced parkinsonism or tardive dyskinesia,” he said.
Up to 25% of psychiatric patients on metoclopramide may have DIP. Women tend to be affected more often than men, particularly older women. Among patients with metoclopramide-induced parkinsonism, up to 70% have tremor, 70% have postural instability, and 40% have tardive dyskinesia. Once the drug is stopped, improvement typically takes 4 months.
The list of other drugs that have been reported as being associated with DIP includes SSRIs, dopamine depleters, bupropion, phenelzine, lithium, valproate, some cardiac drugs (amiodarone, captopril, verapamil, diltiazem, amlodipine, manidipine, methyldopa), and estrogens.
As to risk factors for DIP, women appear to be twice as likely as men to develop the disorder. Age older than 65 is associated with a five times greater risk. Greater drug potency or dose also plays a role. Less frequently described risk factors include prior brain injury, dementia, HIV infection, certain psychiatric disorders (mood disorders in particular), the presence of tardive dyskinesia, and a family history of PD.
“Recognition is the key to proper management because if you recognize that the drug causes it, you stop the drug if you can and the symptoms will reverse in most patients,” Dr. Factor said.
Amantadine and anticholinergics are often used to treat symptoms. Other potential treatments include levodopa, electroconvulsive therapy, propranolol, and clozapine.