Volume 345:887-891

September 20, 2001

Number 12

Essential Tremor

Elan D. Louis, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.

A 66-year-old woman presents with tremor of the hands. She first noticed a mild tremor six years earlier, but the tremor has been worsening for the past two years. It occurs when she is using her hands, interfering with some activities of daily living. For example, she can no longer eat soup without spilling, put in her contact lenses, or apply lipstick. A writer, she is no longer able to write in longhand or type her manuscripts and must dictate them. The tremor causes a great deal of embarrassment in social situations. How should this patient be evaluated and treated?

The Clinical Problem

The first step in evaluating any patient with tremor is to characterize the tremor. All humans have physiologic tremor, or rhythmic oscillatory movements, of their hands that is detectable with the use of electrophysiological techniques such as quantitative accelerometry. Stressful circumstances, such as those inducing fear, anger, or fatigue, may cause transient enhanced physiologic tremor, which may be visible to the naked eye.

In addition to these normal forms of tremor, there are several pathologic tremors. They may take several forms: resting tremor, action tremor (also referred to as akinetic or postural tremor), and intention tremor. Resting tremor occurs while the limb is relaxed and stationary — for example, in the hand while a person is standing or walking. Action tremor occurs during sustained extension of the arm or during voluntary motion such as writing or pouring. Intention tremor is a coarse terminal tremor that occurs as the limb approaches a target — for example, during the finger-to-nose maneuver. It is often accompanied by ataxic gait and other signs of cerebellar disease (e.g., nystagmus and slurred or scanning speech).

Action tremor is the most prevalent of these types of tremor and, because it is present when the hands are in active use, is disabling. The most common action tremor is essential tremor, a tremor of the hands of 4 to 12 Hz. It may also affect the head, voice, trunk, and legs. Estimates of the prevalence of essential tremor in the general population range from 0.4 to 6 percent¹ and are higher among persons over 65 years of age. Although essential tremor is often referred to as benign, this description is misleading. Between 15 and 25 percent of patients with essential tremor who are seen in clinical practice retire prematurely, and 60 percent choose not to apply for a job or promotion because of the uncontrollable shaking of their hands.²

Strategies and Evidence

Diagnosis

In addition to essential tremor, the differential diagnosis of an action tremor includes enhanced physiologic tremor that is sustained (as a result of either an identifiable cause, such as medication or hyperthyroidism, or a cause that is not readily identifiable), Parkinson's disease, adult-onset idiopathic dystonia, and Wilson's disease (Table 1). With the exception of essential tremor and enhanced physiologic tremor, these other disorders are rare (prevalence, <1 percent). The diagnostic approach includes obtaining a history, physical examination, and laboratory tests.

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Table 1. Prevalence, Features, and Differential Diagnosis of Action Tremor.

During the history-taking, the age at onset, type, and rate of progression of the tremor should be assessed, along with information about family history (Table 1). Caffeine, cigarettes, and medications such as lithium, prednisone, levothyroxine, beta-adrenergic bronchodilators, valproate, and selective serotonin-reuptake inhibitors commonly result in enhanced physiologic tremor; a complete inventory of all current medications, as well as caffeine intake and smoking habits, is important in order to exclude these as the cause of tremor. Patients with tremor due to other disorders usually have symptoms of these disorders at presentation; for example, diarrhea or weight loss in patients with hyperthyroidism, loss of normal facial expression or a change in normal arm swing in patients with Parkinson's disease, the sensation that muscles in the hand or neck are being pulled or twisted in patients with dystonia, and reports of depression, cognitive impairment, or other involuntary movements in patients with Wilson's disease.

During the physical examination, the clinician should carefully assess the characteristics of the tremor (Table 1). Although many patients with Parkinson's disease have a mild postural tremor,⁵ resting tremor is also present and affects approximately 85 percent of patients in studies of autopsy-proved Parkinson's disease.⁶ Approximately 20 to 30 percent of patients with dystonia have a postural tremor that superficially resembles essential tremor (Table 1). If symptoms or signs of hyperthyroidism are present, then thyroid-function tests should be performed.

In any patient with action tremor who is younger than 40 years of age, the possibility of Wilson's disease should be explored with a measurement of serum ceruloplasmin. The level is low (<20 mg per deciliter) in 95 percent of patients with this disorder.⁷ If other clinical features suggestive of Wilson's disease are present, such as dysarthria, dystonia, and parkinsonism, then a careful slit-lamp examination of the eye should be performed by an experienced ophthalmologist. Kayser–Fleischer rings on Descemet's membrane are detectable in 99.3 percent of patients with Wilson's disease who have neurologic abnormalities.³

Quantitative computerized analysis of tremor is available at some tertiary care centers and may guide the clinician in distinguishing essential tremor from other types of tremor, but its diagnostic validity, like that of positron-emission tomography, has not been established. At present, the diagnosis of essential tremor is based on clinical findings; there are no validated serologic, radiologic, or pathological markers (videotaped examples of clinical findings in patients with essential tremor are available as Supplementary Appendix 1). There is no gold standard for diagnosis, but the level of agreement is high between clinicians using the same clinical criteria (Table 2).^1,4

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Table 2. Reliable Clinical Criteria for Essential Tremor.

Treatment

Pharmacotherapy may be used to improve function or reduce the embarrassment associated with essential tremor. Medications are not indicated for mild cases that do not cause dysfunction or embarrassment. Surgery is indicated for severe cases that are refractory to medications. This discussion, with one exception,⁸ includes results only from double-blind, placebo-controlled trials, but these have generally been small.

Two issues deserve special emphasis. First, although a reduction in the amplitude of tremor, measured by clinical rating scales or accelerometric methods, may be important, the ultimate evidence of efficacy is a reduction in functional impairment. Second, although in groups of patients these medications reduce the severity of tremor, on an individual basis, a large proportion of patients (25 to 55 percent) have no response. A number of factors may be responsible for this high rate of nonresponse. There is evidence that essential tremor is not a homogeneous condition, and that different clinical subtypes (e.g., young-onset essential tremor or essential tremor with head tremor) may differ in pathogenesis and response to treatment.⁹ The value of most current medications was discovered as a result of serendipity rather than through an understanding of the mechanisms of the disease, which remains limited.

            First-Line Therapies

Propranolol and primidone are the first-line agents in the treatment of essential tremor (Table 3). Peripheral -adrenergic receptors probably mediate the effects of -adrenergic–blocking agents,¹¹ although central mechanisms may be involved as well. Several placebo-controlled studies have demonstrated that propranolol (at a dose of at least 120 mg per day) results in a significant reduction in the severity of tremor,¹² and subjectively, 45 to 75 percent of patients report that propranolol is more effective than placebo in reducing their tremor. Although propranolol is well tolerated, relative contraindications include asthma, congestive heart failure, diabetes mellitus, and atrioventricular block. Propranolol, a nonselective antagonist, is more effective than antagonists with relatively selective ₁ activity,¹¹ and trials of ₁-selective agents (such as atenolol and metoprolol) have had mixed results.^11,13 Long-acting propranolol is as effective as conventional propranolol, and compliance with the long-acting formulation is significantly better.¹⁴

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Table 3. Doses and Side Effects of Medications for Tremor.

Primidone, an anticonvulsant medication, is metabolized to phenylethylmalonamide and phenobarbitone. Although the barbiturate metabolite may contribute to the therapeutic effect, the parent compound is thought to mediate most of this effect.^15,16,17 Primidone is superior to phenobarbital in reducing the severity of tremor.¹⁸ Primidone in doses of up to 750 mg per day was significantly more effective than placebo in reducing tremor,^15,16,17 but tolerability is a common problem. Even at a low starting dose (62.5 mg per day), an acute toxic reaction consisting of nausea, vomiting, or ataxia has been reported in 23 percent¹⁵ to 73 percent¹⁶ of patients, requiring discontinuation of primidone in approximately 20 percent of patients in some studies.¹⁵

A 750-mg daily dose of primidone was compared with a 120-mg daily dose of propranolol, and although each was significantly better than placebo,¹⁷ neither was conclusively shown to be superior to the other in this small study. The mean reduction in the amplitude of tremor was 76 percent while patients were taking primidone, as compared with a reduction of 60 percent during treatment with propranolol, a nonsignificant difference. More patients indicated a preference for primidone than for propranolol.¹⁷ In another study, the amplitude of tremor was reduced by a mean of 60 percent in 9 patients who were taking primidone (250 mg per day), as compared with a mean reduction of 35 percent in 22 patients who were taking their maximally effective dose of propranolol (P value not reported).¹⁹

Although initial tolerability is a problem with primidone, there is some evidence that the long-term tolerability of primidone is superior to that of propranolol. In a study of 25 patients with essential tremor, acute adverse reactions occurred in 8 percent of the propranolol group and 32 percent of the primidone group; however, clinically significant long-term (one year) side effects occurred in none of the patients in the primidone group, as compared with 17 percent of those in the propranolol group.²⁰

            Second-Line Therapies

Gabapentin, an anticonvulsant medication, is structurally similar to the inhibitory neurotransmitter -aminobutyric acid (GABA). There is some evidence that the GABA-ergic system is disturbed in essential tremor.²¹ There have been three trials of gabapentin involving a total of 54 patients. In two of the three studies, gabapentin (1200 to 3600 mg per day) reduced tremor significantly more than did placebo, and in one of the two, its effect was similar to that of propranolol.²² Gabapentin is well tolerated.

Benzodiazepines potentiate the effect of GABA by binding to the GABAA receptor. Alprazolam is the only benzodiazepine shown to be effective in essential tremor in controlled trials. In one placebo-controlled trial, alprazolam (0.75 to 2.75 mg per day) resulted in a significant reduction in tremor, and 75 percent of the patients had at least some improvement; however, drowsiness or sedation occurred in 50 percent of the patients.²³ Clonazepam, another benzodiazepine, did not significantly reduce the severity of tremor in a placebo-controlled trial.²⁴ One concern with the use of benzodiazepines is the risk of dependence.

Calcium-channel blockers have had variable rates of success. Trials of flunarizine (10 mg per day), which is not available in the United States, have reported mixed results. In one placebo-controlled trial, flunarizine significantly reduced the severity of tremor, with 13 of 15 patients having an improvement. In a second trial, however, none of the patients had a decrease in the severity of tremor.²⁵ Differences in the severity of tremor and the use of concurrent medications may have accounted for some of this variation. In one placebo-controlled trial, nimodipine (30 mg per day) significantly reduced the severity of tremor, with 8 of 15 patients having an improvement.²⁶ Some calcium-channel blockers, such as nifedipine,²⁷ may worsen tremor.

Theophylline may enhance the sensitivity to GABA. Theophylline (150 mg per day) was compared with propranolol (80 mg per day) and placebo.¹⁰ Theophylline reduced tremor significantly more than did placebo, and its effect was similar to that of propranolol. However, the investigators acknowledged that although the trial was designed as a double-blind study, the side effects experienced by the patients meant that in practice the treatments could be distinguished.

            Other Therapies

Intramuscular injections of botulinum toxin A into the intrinsic muscles of the dominant hand may reduce tremor by weakening the muscles or by blocking gamma motor efferents and muscle spindle afferents.²⁸ Although there was a significant reduction in the amplitude of tremor among patients receiving one to two such injections, no significant improvement in function was observed.

Action tremor may be mediated by neuronal loops that pass from the cerebellum to the cortex by way of the ventral intermediate nucleus of the thalamus. Two surgical approaches to tremor reduction involve continuous deep-brain stimulation through an electrode implanted in the ventral intermediate nucleus of the thalamus and surgical lesioning of this nucleus (thalamotomy) contralateral to the more disabled arm. The two methods were compared in a prospective, randomized, single-blind study.⁸ Both procedures were equally effective in reducing tremor. Thalamic stimulation resulted in greater improvement in self-reported measures of function and fewer adverse events, including cognitive deterioration, dysarthria, and gait or balance disturbances.⁸ Thalamic stimulation is the surgery of choice, because there are fewer adverse events and the clinician can adjust the stimulator settings during follow-up care.

Areas of Uncertainty

The response to medications is variable, and factors that predict a positive response have not been identified. It is often necessary to try several agents sequentially. Some clinical trials have suggested that the efficacy of medications is lower in patients with tremor of the head than in those with tremor of the hands, although most have not enrolled adequate numbers of patients with head tremor, so have had limited power to detect changes in this subgroup.

Guidelines

There are no guidelines from the American Academy of Neurology or the Movement Disorder Society on the diagnostic workup or treatment of essential tremor.

Conclusions and Recommendations

Action tremor is commonly seen in clinical practice, and essential tremor is the most frequent cause. There is no diagnostic laboratory test for essential tremor; the diagnosis is based on the history and physical examination. In persons younger than 40 years of age, the possibility of Wilson's disease should be excluded. Treatment of essential tremor should be reserved for patients who have functional impairment or embarrassment, as is the case for the patient described in the vignette. Both primidone and propranolol are effective. There is some evidence that primidone may be more effective and better tolerated than propranolol, although this needs to be studied further. Therefore, I consider primidone to be a reasonable first choice, and if it cannot be tolerated, then propranolol is my second choice. Gabapentin and benzodiazepines are alternatives, although the latter may result in sedation at the doses required to treat tremor. There are too few data to support the use of nimodipine and theophylline. If the patient has no response to medications and is sufficiently disabled, then unilateral implantation of a deep-brain thalamic stimulator contralateral to the more disabled arm is another option in centers where this is available.

Supported by a grant from the National Institutes of Health (R01 NS39422) and by a Paul Beeson Physician Faculty Scholars in Aging Research Award.

Source Information

From the Gertrude H. Sergievsky Center and the Department of Neurology, Columbia University, New York.

Address reprint requests to Dr. Louis at Unit 198, Neurological Institute, 710 W. 168th St., New York, NY 10032, or at [log in to unmask].

References

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Edward E. Rylander, M.D.

Diplomat American Board of Family Practice.

Diplomat American Board of Palliative Medicine.