Movement Disorders Caused by Medical Disease

Brandon Barton; S. Elizabeth Zauber; Christopher G. Goetz

Disclosures

Semin Neurol. 2009;29(2):97-110. 

In This Article

Nonparkinsonian Tremor

As opposed to parkinsonian tremor, which most often occurs at rest, tremor induced by drugs and metabolic disorders typically causes postural and/or action tremor. Most postural tremor is due to enhanced physiological tremor.

Disorders of Metabolism

Conditions associated with increased catecholamine levels are common causes of enhanced physiological tremor, such as pheochromocytoma, stress, anxiety, fever, and amphetamine use. Metabolic derangements such as hypoglycemia, hyperthyroidism, and renal and hepatic dysfunction also cause tremor.

Of special note, Wilson's disease is an autosomal-recessive disorder caused by a mutation in the ATP7B gene, which encodes a copper transport protein. Although the gene is known and genetic testing can be used to identify affected family members, gene testing is not useful as a screening test for the disease because the gene is large and there are many different disease-causing mutations. Expression of the defective ATP7B protein results in the failure of the biliary excretion of excess copper, leading to progressive accumulation of copper in liver hepatocytes and other organs and tissues. Symptoms usually appear in the second or third decade of life and may include hepatic, neurological, and psychiatric symptoms. Patients who present with neurological symptoms tend to be older than those presenting with hepatic symptoms.[46]

Neurological features can be the presenting signs of Wilson's disease in 40 to 60% of patients, with tremor being the most frequent initial finding; the proximal "wing-beating" tremor is common, but other types of tremor may also occur, including rest, posture, and action tremor.[47] A wide variety of other neurological symptoms may occur, including dystonia, gait abnormalities, dysarthria, ataxia, and parkinsonism as well as cognitive or behavioral changes such as depression, anxiety, and psychosis. Dystonia can occur in ~40% of cases and can be generalized, segmental, or multifocal, but the "sardonic smile" is most characteristic of the disorder.[48] Other systemic findings include renal dysfunction, cardiac involvement, pancreatic disease, hemolytic anemia, hypoparathyroidism, osteoporosis, and skin abnormalities.

Workup for Wilson's disease should be considered in any patient with a new-onset movement disorder and liver abnormalities of uncertain cause. Patients with Wilson's disease have low serum ceruloplasmin, although this finding is not sensitive or specific enough to be used alone as a screening tool. Additional workup should include measurement of 24-hour urine copper, which is increased (> 100 µg) in Wilson's disease, and slit-lamp examination to look for Kaiser-Fleischer rings because these are present in the majority of patients with neurological symptoms. Liver biopsy is usually not required but can be diagnostic. Brain MRI shows increased T2 and decreased T1 signal in the basal ganglia. Treatment consists of either copper chelation to promote copper excretion or treatment with zinc to reduce copper absorption. Trientine is recommended as first-line treatment because of its effectiveness and fewer side effects than penicillamine.[46]

Drugs

Drugs are a common cause of acquired tremor. In general, patients with advanced age, impaired renal and hepatic function, or underlying medical or neurological disease are more susceptible to drug-induced tremor.

Amiodarone causes tremor in one third of exposed patients. The tremor is usually postural and increases with intention, closely resembling essential tremor. Dose reduction usually leads to improvement in 2 weeks. Cyclosporin frequently causes a postural tremor with rates as high as 40% reported, but the tremor is usually mild and does not require dose reduction.[49] Tacrolimus causes a more disabling tremor: most frequent reports are in liver transplant patients, although it has also been described in patients with rheumatoid arthritis.[50]

Antidepressants are a common cause of tremor, which occurs in ~20% of patients treated with selective serotonin reuptake inhibitors (SSRIs), and even more frequently in patients treated with tricyclic antidepressants. Tremor usually develops 1 to 2 months after starting therapy and resolves 1 month after discontinuation. Lithium causes tremor frequently: at least 30% of patients develop tremor at therapeutic levels, and at toxic levels nearly all patients have tremor. Concomitant treatment with SSRIs increases the likelihood of developing tremor with lithium use. Valproic acid is the most common antiepileptic drug to cause tremor: tremor occurs in ~25% of patients, usually after 3 months of treatment. Tremor severity does not necessarily correlate with serum level, although dose reduction and long-acting preparations may reduce the tremor.[50]

Other types of drugs used to treat medical diseases that can cause tremor are antiviral agents (acyclovir, vidarabine) and chemotherapy drugs (thalidomide, cytarabine).

In general, the approach to treating drug-induced tremor is to taper the drug or substitute another drug with a lower risk of tremor. Propranolol can be added if tapering or changing the medicine is not feasible.

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