Essential Tremor 

Updated: Oct 22, 2018
Author: Deborah A Burke, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Practice Essentials

Essential tremor, the most common movement disorder, is a syndrome of unknown etiology characterized by a slowly progressive postural and/or kinetic tremor, usually affecting both upper extremities. Fundamental debate exists as to whether essential tremor is a neurodegenerative disease.

Signs and symptoms

In general, essential tremor is considered to be monosymptomatic (tremor only). Although some patients have abnormalities in gait and balance, most do not; therefore, carefully consider alternative diagnoses in the presence of gait abnormalities.

Patients with essential tremor may exhibit the following signs and symptoms:

  • Tremor begins in one upper extremity and then affects the other upper extremity; tremor rarely extends from an upper extremity to the ipsilateral lower extremity

  • Tremor may initially be intermittent, occurring during periods of emotional activation, and then becomes persistent over time

  • A mild degree of tremor asymmetry is not unusual

  • Tremor may also affect the head, voice, jaw, lips, and face

  • The tremor frequency is fixed at any point in time

  • The tremor amplitude is highly variable, worsened by emotion, hunger, fatigue, temperature extremes; the baseline amplitude gradually increases over several years; ethanol intake temporarily reduces tremor amplitude in about 50-70% of cases

  • Typically, there is a degree of voluntary control; tremor may be suppressed by performing skilled manual tasks

  • Tremor resolves when the body part relaxes as well as during sleep

  • Muscle tone and reflexes are normal; there is no bradykinesia or rigidity

See Clinical Presentation for more detail.

Diagnosis

Essential tremor is usually diagnosed based on family history and examination findings; thus, laboratory and imaging studies are usually not required. No biologic markers exist for essential tremor. Electromyography or accelerometry can be used to assess tremor frequency, rhythmicity, and amplitude but is not part of the routine evaluation.

Laboratory testing

If the patient’s family history and examination findings are not indicative of essential tremor, consider the following laboratory studies:

  • Standard electrolyte panel

  • Thyroid function tests

  • Blood urea nitrogen and creatinine levels

  • Liver function tests

  • Serum ceruloplasmin (for Wilson disease)

Imaging studies

Head computed tomography (CT) scanning and magnetic resonance imaging (MRI) findings are normal in essential tremor.

Perform MRI if the tremor has an acute onset or stepwise progression. MRI also helps to exclude structural and inflammatory lesions (including multiple sclerosis) and Wilson disease.

Single-photon emission CT (SPECT) scanning using 123I-ioflupain (DaTSCAN) may be used to support a diagnosis of parkinsonism, thereby reducing misdiagnosis of essential tremor as Parkinson disease.[1, 2, 3]

See Workup for more detail.

Management

Primidone and propranolol are the cornerstones of maintenance medical therapy for essential tremor. These medications provide good benefit, reducing tremor amplitude in approximately 50-70% of patients.[4, 5, 6]

Some patients require only intermittent tremor reduction (eg, to attend a meeting or engage in a social activity). For these patients, a cocktail or beer prior to the activity may be sufficient, or they may take propranolol (10-40 mg) approximately one half hour prior to the event.

Alcohol consumption is not an appropriate maintenance therapy for patients who seek tremor reduction throughout the day.[7]

Pharmacotherapy

The following medications are used in the management of essential tremor:

  • Nonselective beta-blockers (eg, propranolol hydrochloride)

  • Anticonvulsants (eg, primidone, topiramate)

  • Second-generation antipsychotics (eg, clozapine)

  • Antidepressants (eg, mirtazapine)

Surgery

Consider surgical intervention in patients with disabling, medically refractory upper extremity tremor. The procedures of choice are stereotactic thalamotomy and thalamic ventralis intermedius nucleus deep brain stimulation.

See Treatment and Medication for more detail.

Background

Essential tremor is the most common movement disorder. It is a syndrome characterized by a slowly progressive postural and/or kinetic tremor, usually affecting both upper extremities. The etiology of essential tremor is not known, and fundamental debate exists as to whether essential tremor is a neurodegenerative disease. (See Etiology and Presentation.)

Inclusion and exclusion criteria

The Movement Disorders Society has proposed the following diagnostic criteria for classic essential tremor. Inclusion criteria are as follows (see Presentation and Workup):

  • Bilateral, largely symmetrical, postural (occurring with voluntary maintenance of a position against gravity) or kinetic (occurring during voluntary movement) tremor involving hands and forearms that is visible and persistent

  • Possible additional or isolated tremor in head but absence of abnormal posturing

Exclusion criteria are as follows:

  • Other abnormal neurologic signs, especially dystonia

  • The presence of known causes of enhanced physiologic tremor, including current or recent exposure to drugs that are known to cause tremor or a drug-withdrawal state

  • Historic or clinical evidence of psychogenic tremor

  • Convincing evidence of sudden onset or evidence of stepwise deterioration

  • Primary orthostatic tremor

  • Isolated voice tremor

  • Isolated position- or task-specific tremors, including occupational tremors and primary writing tremor

  • Isolated tongue or chin tremor

  • Isolated leg tremor

Association with other diseases

Essential tremor has been hypothesized to be a risk factor for the development of Parkinson disease. Some patients with Parkinson disease report a long-standing history of bilateral upper extremity postural tremor. Moreover, in a large cohort study by the Mayo Clinic, the risk of essential tremor was significantly increased in relatives of patients with Parkinson disease with younger onset and in relatives of patients with tremor-predominant Parkinson disease. (See Etiology and Presentation.)[8]

Without biologic markers for these diseases, however, determining whether long-standing postural tremor is part of a Parkinson disease syndrome or reflects the presence of both essential tremor and Parkinson disease is not possible. (See Workup.)

An association between essential tremor and dystonia has also been suggested. Some patients with focal dystonia, such as torticollis, have mild, bilateral upper extremity postural tremors. Again, however, without biologic markers for these diseases, determining whether postural tremor is part of a focal dystonia syndrome or reflects the presence of both dystonia and essential tremor is not possible.

Etiology

The etiology of essential tremor is not known. No pathologic findings are known to be consistently associated with essential tremor. However, the following has been hypothesized:

  • Essential tremor is the result of an abnormally functioning central oscillator, which is located in the Guillain Mollaret triangle near the brainstem and involves the inferior olivary nucleus

  • The cerebellar-brainstem-thalamic-cortical circuits probably are involved

  • The pathophysiology of essential tremor is heterogeneous[9, 10]

Harmane, a heterocyclic amine (HCA), is a potent tremor-producing neurotoxin. It is often found in the human diet. Blood concentrations have been found to be elevated in patients with essential tremor as compared with controls.[11] The most likely etiology appears to be alterations in metabolism rather than increased dietary intake.

In patients with essential tremor, [18 F]fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan studies identified increased glucose consumption in the medulla. In addition, [15 O]H2 O PET scan studies demonstrated an increase in medullary regional cerebral blood flow in subjects with essential tremor (only after the administration of ethanol), and bilateral overactivity of cerebellar circuitry.

Fundamental debate exists as to whether essential tremor is a neurodegenerative disease. Data suggesting that it is neurodegenerative includes postmortem findings of pathologic abnormalities in the brainstem and cerebellum,[10] including Lewy bodies in the locus ceruleus, loss of Purkinje cells, and abnormalities of the dentate nucleus[12, 13] ; reduction in cerebellar cortical N-acetylaspartate/total creatine (NAA/tCR)[11] ; white matter changes on diffusion tensor imaging;[14] and clinical studies demonstrating an association with cognitive[15, 16] and gait changes.

Conflicting data argues against essential tremor being a neurodegenerative disease. This data includes improvement of gait abnormalities with ethanol administration,[17] lack of gray matter volume loss on voxel-based morphometry,[18] failure to confirm prominent presence of Lewy bodies in the locus ceruleus,[10] and other pathologic findings.[19]

Genetics

Essential tremor probably represents a syndrome, and multiple etiologies will likely be identified. Most or all of these causes are probably genetic.

Essential tremor is familial in at least 50-70% of cases. Transmission is autosomal dominant, with incomplete penetrance. Some cases are sporadic with unknown etiology. Twin studies suggest that genetic and environmental factors contribute to the pathogenesis. Non-Mendelian transmission in kindreds with an apparent autosomal dominant inheritance of essential tremor was demonstrated in one study.[20]

Variations in methodology (ie, assessment procedures and diagnostic criteria) account for the wide variation in findings; reported studies have found that 17% to almost 100% of cases are familial.

One study demonstrated that the frequency of having an affected relative increased from 67.7% to 96% after repeated and varied questioning followed by direct interviews of family members.

The following 3 susceptibility loci have been found:

  • 3q13 (EMT1) - Identified in 75 members of 16 Icelandic families; a Ser9Gly variant on the DRD3 gene has been associated with EMT1[21]

  • 2p25-22 (EMT2) - Identified in 15 members of 4 generations of Americans; abnormalities found in 3 additional American families have been reported to map to this locus[22]

  • 6p23 - Identified in 2 families[23]

An association with a polymorphism in the HS1-BP3 gene has been reported, but this has not been confirmed.[20, 24]

In one family with levodopa-responsive, autosomal dominant, Lewy-body parkinsonism, a chromosome arm 4p haplotype that segregates with the disease was identified. This haplotype also occurred in individuals in the family who did not have parkinsonism but rather a postural tremor consistent with essential tremor. This suggests that in some cases, postural tremor can be an alternative phenotype of the same mutation.

LINGO1 (leucine-rich repeat and Ig-containing domain 1) variant rs9652490 has been identified as a risk factor for familial essential tremor.[25, 26, 27]

Epidemiology

Occurrence in the United States

Assessments of the prevalence and incidence of essential tremor vary widely depending on ascertainment methodology and diagnostic criteria employed in detecting the condition. The prevalence of essential tremor is estimated to be 0.3-5.6% in the general population. A 45-year study of essential tremor in Rochester, Minn, reported an age- and sex-adjusted prevalence of 305.6 cases per 100,000 and an annual incidence of 23.7 cases per 100,000. An estimated 0.5-11.1% of affected individuals seek medical attention.

International occurrence

Using a “door-to-door” method in Mersin Province, Turkey, 2253 individuals older than 40 years were examined by neurologists; 89 essential tremor cases were identified.[28]

Race-related demographics

Race has not been extensively studied in essential tremor. One evaluation of a multiethnic group (white, African American, Hispanic) found differences in the presence or absence of head tremor and a variable tremor score among the subgroups. White subjects had a tremor score that was 5.3 points lower than that for nonwhites. Head tremors were present in 25% of whites and 29% of Hispanics and were absent in African Americans.[29]

Sex-related demographics

Essential tremor affects both sexes with equal frequency. However, head tremor may be more frequent in women, and postural hand tremor may be more severe in men. Childhood essential tremor may be more frequent in boys than in girls.[30]

Age-related demographics

The prevalence of essential tremor increases with age. Data has suggested bimodal peaks in age of onset—one in late adolescence to early adulthood and a second in older adulthood. The mean age at presentation is 35-45 years. One comparison of a population-based cohort with patients at a tertiary care center found a significant bimodal presentation only at center, with the population-based study revealing a significant peak only in older adults. This suggested that the bimodal peak may be attributable to preferential referral of young-onset essential tremor to tertiary centers.[31]

Essential tremor usually manifests by age 65 years and virtually always by age 70 years. Tremor amplitude slowly increases over time, but tremor frequency decreases with increasing age. An 8-12 Hz tremor is seen in young adults, and a 6-8 Hz tremor is seen in elderly individuals. Although essential tremor is progressive, no association has been found between age of onset and severity or disability.

Rare cases of essential tremor have been reported in newborns and infants. A strong correlation between age of onset before 20 years and family history of essential tremor was found in an environmental epidemiologic study of 195 essential tremor cases.[32]

Prognosis

Mortality rates have been thought to be the same between patients with essential tremor and the general population. However, in a longitudinal, prospective study of patients aged 65 and older from 3 communities in central Spain, the risk of mortality in persons with essential tremor was found to be increased.[33] Further studies are needed to assess mortality rates in essential tremor.

Disability from essential tremor is common.[34] Of individuals with essential tremor, 85% report significant changes in their livelihood and socializing, and 15% report being seriously disabled by the condition.

Decreased quality of life results from loss of function and from embarrassment. In a study of hereditary essential tremor, 60% of affected individuals did not seek employment; 25% changed jobs or took early retirement; 65% did not dine out; 30% did not attend parties, shop alone, partake of a favorite hobby or sport, or use public transportation; and 20% stopped driving.

 

Presentation

History

The following characteristics can be noted in patients with essential tremor:

  • A family history of essential tremor is noted in 50-60% of cases

  • Tremor usually begins in one upper extremity and soon affects the other; essential tremor rarely extends from the upper extremity to the ipsilateral leg

  • A mild degree of asymmetry is not unusual

  • In about 30% of cases, tremor involves the cranial musculature; the head is involved most frequently, followed by voice, jaw, and face

  • Tremor may be intermittent initially, emerging only during periods of emotional activation

  • Over time the tremor becomes persistent

  • At any point in time, the frequency of the tremor is relatively fixed

  • The amplitude of the tremor is highly variable, depending on the state of emotional activation; tremor amplitude is worsened by emotion, hunger, fatigue, and temperature extremes

  • The baseline tremor amplitude slowly increases over several years

  • A degree of voluntary control is typical, and the tremor may be suppressed by skilled manual tasks

  • The tremor resolves during sleep

  • Ethanol intake temporarily reduces tremor amplitude in an estimated 50-70% of cases

Visible tremor is generally pathologic, but distinguishing between essential tremor and enhanced physiologic tremor can be difficult. Causes of enhanced physiologic tremor, including medications, stimulants such as caffeine, hyperthyroidism, fever, and anxiety, should be excluded.

Like a previous population-based study from Spain, a community-based cohort study from New York by Thawani et al found an association between essential tremor and dementia. In cross-sectional analyses, dementia was present in 31 of 124 subjects with essential tremor versus 198 of 2,161 controls (25% vs 9.2%). In prospective analyses, dementia developed in 17 of 93 subjects with essential tremor versus 171 of 1,963 controls (18.3% vs 8.7%).[35]

Physical Examination

Essential tremor generally is considered to be monosymptomatic (tremor only), although some patients have abnormalities in gait and balance. If patients have such abnormalities, the diagnosis should be carefully considered, because most patients with essential tremor do not have gait abnormalities.

The tremor is characteristically postural (occurring with voluntary maintenance of a position against gravity) and kinetic (occurring during voluntary movement). It usually resolves when the body part relaxes. Other characteristics of essential tremor include the following:

  • Both upper extremities are typically affected

  • Mild asymmetry is not uncommon

  • Tremor also may affect the head, voice, and lips

  • Tone and reflexes are normal

  • Parkinsonian features such as bradykinesia and rigidity are absent

There are data calling into question the tenet that essential tremor is truly monosymptomatic. Findings associated with essential tremor include changes in cognition, personality,[36] mood,[37] hearing,[38, 39] and motor symptoms associated with cerebellar outflow.[40]

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of essential tremor include the following:

  • Cerebellar tremor

  • Dystonia and dystonic tremors

  • Enhanced physiologic tremor

  • Isolated chin tremor

  • Isolated voice tremor

  • Movement disorders

  • Orthostatic tremor

  • Palatal tremor

  • Rubral tremor

  • Writer's tremor and other task-specific tremors

  • Psychogenic tremor

Drug-induced tremors can result from the following:

  • Antidepressants, especially tricyclics

  • Beta agonists

  • Depakote

  • Dopamine

  • Lithium

  • Metoclopramide

  • Neuroleptics

  • Theophylline

  • Thyroid hormones

  • Withdrawal of drugs

Metabolism-related tremors can result from the following disorders:

  • B-12 deficiency

  • Hyperthyroidism

  • Hyperparathyroidism

  • Hypocalcemia

  • Hyponatremia

  • Kidney disease

  • Liver disease

Toxin-related tremors can result from the following :

  • Alcohol

  • Arsenic

  • Caffeine

  • Dichlorodiphenyltrichloroethane (DDT)

  • Lead

  • Nicotine

  • Toluene

  • Withdrawal of alcohol, cocaine

Differential Diagnoses

 

Workup

Approach Considerations

No biologic markers exist for essential tremor. If the family history and examination findings are indicative of essential tremor, no laboratory or imaging studies are required. However, if the family history and examination findings are not indicative of essential tremor, laboratory and imaging studies should be considered.[41, 42]

Laboratory investigations include the following:

  • Standard electrolyte panel

  • Thyroid function tests

  • Blood urea nitrogen (BUN)

  • Creatinine

  • Liver function tests

  • Serum ceruloplasmin (for Wilson disease)

Procedures

Electromyography or accelerometry can be used to assess tremor frequency, rhythmicity, and amplitude but is not part of the routine evaluation.

Imaging Studies

Findings on computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the head are normal in essential tremor. MRI helps to exclude structural and inflammatory lesions (including multiple sclerosis) and Wilson disease. MRI should be performed if the tremor has acute onset or stepwise progression.

Although the classic resting tremor of Parkinson disease is different in many aspects from that of essential tremor, it is often difficult to distinguish variants. Single-photon emission CT (SPECT) scanning using ioflupain 123 I (DaTSCAN) is now a US Food and Drug Administration (FDA)–approved procedure that can support a diagnosis of parkinsonism, hence decreasing the misdiagnosis of essential tremor as Parkinson disease.[1, 2, 3]

Midbrain ultrasonography has been suggested as a tool to differentiate essential tremor from Parkinson disease as a result of a study finding that high substantia nigra hyperechogenicity has a high positive predictive value for Parkinson disease. However, another study found a significant increase in substantia nigra hyperechogenicity in patients with essential tremor compared with controls.[43, 44, 45, 46]

Other Tests

In 2017, researchers presented a new neuropsychological measure that can discriminate Parkinson's disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index, derived from kinematic measurements of tremulous activity, was tested in a cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson's disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 55 tremulous Parkinson's disease and essential tremor recordings. The index's maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively.[47]

 

Treatment

Approach Considerations

Primidone and propranolol are the cornerstones of maintenance medical therapy for essential tremor. These medications provide good benefit, reducing tremor amplitude in approximately 50-70% of patients.[4, 5, 6]

Some patients require only intermittent tremor reduction, such as when attending a meeting or engaging in a social activity. For these patients, a cocktail or beer prior to the activity may be sufficient. An alternative is propranolol (10-40 mg) approximately one half hour prior to the event. Alcohol consumption is not an appropriate maintenance therapy for patients who seek tremor reduction throughout the day.[7]

Surgery

For patients with disabling, medically refractory upper extremity tremor, surgery is considered. Stereotactic thalamotomy and thalamic ventralis intermedius nucleus deep brain stimulation are the procedures of choice. Both procedures offer high rates of tremor reduction in the contralateral arm. Information suggests that they are also useful in reducing head and voice tremor.[48]

Bilateral thalamotomy is associated with a relatively high risk of dysarthria, occurring in as many as 29% of patients, and a risk of cerebral hemorrhage. The potential advantage of thalamic stimulation is that it is adjustable. If the stimulation causes an adverse effect, the rate of stimulation can be modified or discontinued.

In 1996, Benabid et al initially proposed that thalamic stimulation might be a useful procedure on the opposite side in patients who have already had a unilateral thalamotomy, in an effort to avoid the potentially serious complications of bilateral thalamotomy.[49] Thalamic stimulation now is considered the procedure of choice.

According to one randomized trial, patients that underwent MRI-guided focused ultrasound thalamotomy for ET experienced a 47% improvement in composite hand tremor scores 3 months later. Patients who underwent a sham procedure experienced a 0.1% improvement. After 1 year, improvement was still significant, decreasing only to 40%.[50]

Practical Management of Pharmacologic Therapy

For patients who require daily maintenance treatment for essential tremor, a decision is made whether to start with primidone or propranolol. Usually, propranolol is started first in younger patients and primidone is started first in older individuals. Generally, propranolol carries more risk of serious adverse effects in older patients than in younger ones. Additionally, younger patients, particularly those who are in school or working, find the sedating and cognitive side effects of primidone more troublesome than older patients do.

If the patient has a relative contraindication to propranolol, such as pulmonary disease or heart block, starting with primidone is preferable.

The chosen medication, primidone or propranolol, is introduced at a low dose and increased slowly until sufficient benefit is achieved or the usual maximum dosage is reached. If no benefit is derived, the patient is completely weaned off the drug before the alternative medication is started. If a partial benefit from the first drug occurs, the second medication is added and slowly increased until sufficient benefit is achieved or the usual maximum dosage is reached. If no additional benefit occurs, the patient is weaned off the second medication.

If sufficient benefit is not achieved with primidone or propranolol, other medications are considered based on the severity of the residual tremor. A beta1-receptor antagonist can be tried if necessary; in general, however, beta1-receptor antagonists are more effective than placebo but are not as effective as beta2-receptor antagonists. (Metoprolol, a relatively selective beta1-receptor antagonist, may be useful in patients with asthma or other pulmonary conditions.)

If the tremor is mild and more of a nuisance than it is disabling, a benzodiazepine (usually clonazepam) is considered. For patients with head tremor, cervical injections of botulinum toxin may be given.

Propranolol

Winkler and Young first noted remarkable tremor reduction in a patient treated with propranolol for paroxysmal atrial tachycardia.[5]

In a double-blind, crossover study, propranolol at doses from 60-240 mg/day reduced tremor in 75% of patients with essential tremor. In a dose-response study, 240-320 mg/day was found to be the optimal dose range, with no additional benefits above 320 mg/day.

Average tremor reduction is 50-70%, but while some patients experience marked tremor reduction, others derive no benefit from the drug. The mechanism of action probably is related to peripheral beta2-receptor antagonism.

Once an effective maintenance dose of propranolol is achieved, switching to the long-acting preparation is considered. The long-acting formulation of propranolol has an efficacy similar to that of the standard formulation and may allow the patient to take fewer daily doses. An alternative is to use the long-acting formulation from the beginning, but this requires multiple prescriptions and is more cumbersome.

American Academy of Neurology (AAN) Practice Parameters are as follows[51] :

  • Level A (established as effective)

  • Level B (possibly effective) for head tremor

Primidone

O'Brien et al initially observed that primidone, when administered to a patient with epilepsy and essential tremor, reduced tremor. In a placebo-controlled study, primidone significantly reduced tremor in otherwise untreated patients and patients treated with propranolol. Doses greater than 250 mg/day did not provide additional benefit.[52]

Primidone’s mechanism of action is unknown. Active metabolites are phenylethylmalonamide (PEMA) and phenobarbital. PEMA has no effect on tremor, and phenobarbital has only modest effect on tremor. Tremor reduction is not correlated with serum levels of primidone or phenobarbital.

Adverse effects, if any, usually occur early in the course of treatment, possibly with the first dose. Acute adverse effects are minimized by starting at a very low dose and then slowly increasing the dose. However, some patients are unable to tolerate primidone even at very low doses.

AAN Practice Parameter is as follows[51] :

  • Level A (established as effective)

Topiramate

Topiramate is an anticonvulsant medication that enhances gamma-aminobutyric acid (GABA) activity, carbonic anhydrase inhibition, antagonism of alpha-amino-3-hydroxy-5-methylisoxazole-4 propionic acid/kainite receptors, and blockage of voltage-dependent calcium and sodium channels.

Multiple studies indicate that tremor is reduced by an average of approximately 20% in comparison with placebo. However, clinical trials indicate a fairly substantial dropout rate of 40% because of adverse effects such as cognitive difficulty and somnolence.

AAN Practice Parameter is as follows[51] :

  • Level B (probably effective)

Alcohol

The mechanism of tremor reduction by alcohol is unknown. In a double-blind study, the 6-carbon alcohol methylpentynol did not have any effect on tremor. This suggests that the alcohol group of ethanol is not the element that provides antitremor activity and that the antitremor effect of ethanol is not due to sedation.

Restricted intra-arterial ethanol administration does not reduce tremor in the perfused limb. This suggests that ethanol’s effect is mediated centrally.

Additional Medications

Many other medications have been reported to be of benefit in the treatment of essential tremor. Most of the evidence, however, has come from case reports and small, open-label studies.

Clozapine

In a randomized, double-blind, crossover study, tremor was reduced significantly by clozapine in 13 of 15 patients with drug-resistant essential tremor. The investigators compared a single 12.5 mg dose of clozapine with placebo.

A significant reduction of tremor was reported with long-term (open-label) clozapine therapy (39.9 mg/day). No tolerance was observed over 15 months.

AAN Practice Parameter is as follows[51] :

  • Level C (possibly effective) “only for refractory cases of limb tremor in ET due to the risk of agranulocytosis”

Mirtazapine

In a small, open-label case series, mirtazapine was reported to reduce tremor in patients with essential tremor and Parkinson disease.

AAN Practice Parameter is as follows[51] :

  • Level C (possibly ineffective); weak evidence suggests this treatment is ineffective

Gabapentin

A double-blind, crossover trial comparing gabapentin (400 mg tid) with propranolol (40 mg tid) found that both drugs demonstrated significant and comparable reductions in tremor compared with baseline. However, a double-blind, placebo-controlled, crossover study identified no difference between gabapentin and placebo.

AAN Practice Parameter is as follows[51] :

  • Level B (probably effective)

Benzodiazepines

Benzodiazepines, particularly clonazepam and alprazolam, are used commonly in the treatment of essential tremor, but their effectiveness is limited. They probably work to reduce the anxiety that can amplify tremor amplitude.

AAN Practice Parameters are as follows[51] :

  • Alprazolam - Level B (probably effective); "recommended with caution due to abuse potential"

  • Clonazepam - Level C (possibly effective) but "should be used with caution due to abuse potential and possible withdrawal symptoms"

Botulinum toxin

Botulinum toxin has been evaluated for the treatment of essential tremor. Its use in the treatment of tremor of the upper extremities is limited because it commonly causes weakness. It is more useful in the treatment of head tremor because it often provides benefit without unwanted, troublesome weakness.

AAN Practice Parameter is as follows[51] :

  • Level C (possibly effective) for “limb tremor in medically refractory cases”

Thalamotomy

A retrospective study by Jankovic et al evaluated 60 patients who underwent thalamotomy for medically intractable tremor and found that, of those patients with essential tremor, most showed improvement in tremor and in function. In the study, 42 patients had Parkinson disease, 6 had essential tremor, 6 had cerebellar tremor, and 6 had posttraumatic tremor. Patients were observed for a mean period of 53.4 months and for as long as 13 years.

Cessation or moderate to marked improvement in contralateral tremor with improvement in function occurred in 86% of patients with Parkinson disease, 83% of patients with essential tremor, 67% of patients with cerebellar tremor, and 50% of patients with posttraumatic tremor. Fourteen of the 60 patients had a total of 18 persistent complications, including weakness in 9 patients, dysarthria in 6, contralateral ataxia in 1, blepharospasm in 1, and pulmonary embolus resulting in death in 1.

In a study by Goldman et al of thalamotomy in 8 patients with moderate to severe essential tremor, the condition in all of the patients was reduced to a mild tremor or disappeared completely. Mild persistent dysarthria was seen in 2, and a "mild verbal cognitive defect" was seen in 1.

Stereotactic thalamotomy is less expensive than deep brain stimulation, no hardware remains, and it has been demonstrated to provide long-term efficacy. Potential adverse effects include intracerebral hemorrhage, motor weakness, dystonia, speech disturbance, and memory loss.

Thalamic Deep Brain Stimulation

In a multicenter study, measures of function improved significantly in patients with essential tremor, following the administration of high-frequency, unilateral thalamic stimulation. In the study, the results of such stimulation were assessed in 29 patients with essential tremor and 24 individuals with Parkinson disease. A blinded evaluation at 3 months with patients randomized to stimulation on or stimulation off demonstrated a significant reduction in essential tremor and Parkinson disease contralateral tremor with stimulation on. However, stimulation was commonly associated with transient paresthesias. Other adverse events were mild and well tolerated.

In a study of 14 patients with essential tremor, Ondo et al reported an average 83% reduction in contralateral arm tremor following unilateral thalamic deep brain stimulation.[39]

Pahwa et al reported good results with bilateral thalamic deep brain stimulation in 9 patients with essential tremor. Patients experienced 68% improvement in hand tremor following the first surgery and 75% improvement in the opposite hand following the second surgery. Complications were noted in 5 patients and included asymptomatic intracranial hematoma (1 patient), postoperative seizures (1 patient), hematoma over the implanted pulse generator (1 patient), lead repositioning (1 patient), and implantable pulse generator (IPG) malfunction (1 patient). Adverse effects related to stimulation were mild and resolved with the adjustment of stimulation parameters.

Two deep brain stimulation devices are approved by the FDA to reduce the symptoms of Parkinson disease and essential tremor. The first was approved in 1997 and the second in 2015.[53]

Thalamotomy Versus Deep Brain Stimulation

In a retrospective comparison study of deep brain stimulation and thalamotomy in essential tremor and Parkinson disease, Tasker demonstrated complete contralateral tremor abolition in 42% of patients treated with either procedure, near abolition in 69% of the thalamotomy group and 79% of the deep brain stimulation group, and recurrence in 15% of the deep brain stimulation group and 5% of the thalamotomy group. None of the deep brain stimulation implants and 15% of the thalamotomies had to be repeated.

In the study, adverse effects, including ataxia, dysarthria, and gait disturbance, were more common with thalamotomy (42%) than with deep brain stimulation (26%); adverse effects were persistent in 31% of people undergoing thalamotomy; and those occurring after deep brain stimulation were almost always controlled by adjusting stimulation parameters. Paresthesias were persistent in 19% of patients undergoing thalamotomy and were avoidable in deep brain stimulation by stimulation modification.

Taha et al evaluated thalamic deep brain stimulation contralateral to thalamotomy in 23 patients (6 with Parkinson disease, 15 with essential tremor, and 2 with multiple sclerosis); of 20 patients with bilateral limb tremor, 85% improved to having no tremor or only stress-induced tremor.

In a prospective study, Schuurman et al concluded that, although thalamotomy and thalamic stimulation are equally effective for tremor suppression, stimulation results in greater functional improvement and has fewer adverse effects. In the study, the investigators compared thalamic stimulation and thalamotomy in a prospective, randomized study of 68 patients with Parkinson disease, essential tremor, or multiple sclerosis.

The investigators found that functional status improved more in the thalamic stimulation group. Tremor was suppressed completely or almost completely in 30 of 33 patients who underwent thalamic stimulation, compared with 27 of 34 patients in the thalamotomy group. One patient in the stimulation group died perioperatively after an intracerebral hemorrhage.

In a long-term study of a series of patients who underwent thalamic stimulation, the rates of stimulator reoperations, explants, and device failures were relatively high, suggesting that long-term evaluations may be necessary to assess definitively the relative benefits and complications of these procedures.

Another study found gamma knife thalamotomy to be safe and effective in patients who were not eligible for open surgical techniques and had medically refractory tremor.

The main advantage of thalamic deep brain stimulation is that it is adjustable; adverse effects from stimulation can be controlled by reducing stimulation. Disadvantages of deep brain stimulation include expense, the use of a foreign body implant, the need to optimize parameters, and hardware maintenance, including battery replacement after several years.[48]

Follow-Up

Essential tremor is slowly progressive; therefore, medication doses may need to be adjusted over time. Additionally, loss of medication benefit and long-term adverse effects are not uncommon. Adverse effects, including depression and male impotence, should be monitored in patients on propranolol.

Ongoing attention to activities of daily living, as well as to social and psychological adaptation, is warranted. The frequency of follow-up must be individualized.

Essential tremor is often familial; follow-up with family members may be appropriate. Concerns about disability arising in family members may need to be addressed.

 

Medication

Medication Summary

Beta-adrenergic blockers (principally propranolol) and primidone are the first-line treatment for essential tremor. Each provides good benefit in 50-70% of cases and neither has been demonstrated to be unequivocally superior to the other. Adverse effects are more prominent early in treatment with primidone but are more prominent later in treatment with propranolol. Starting with propranolol is preferable in younger individuals, and primidone is started first in older patients.

Patients are usually started on one of these medications. The drug is introduced at a low dose that is increased slowly until complete response, tolerance, or usual maximum dose is attained. If some benefit is achieved but is incomplete, the other medication may be introduced and increased in an effort to achieve maximum benefit. Treatment with both drugs has been shown to be effective in patients who have had an insufficient response to one. Patients should not expect complete resolution of symptoms.

More evidence exists to support effectiveness in upper extremity tremor than in head or lower extremity tremor. A decrease in tremor amplitude rather than in frequency is the usual response, although some evidence indicates that primidone may decrease tremor frequency as well.

For patients who do not achieve an adequate response with primidone and propranolol, the authors try topiramate. Clozapine, an atypical neuroleptic, has been shown to be effective in a randomized, double-blind, crossover study of patients who had definite or probable essential tremor and poor response to propranolol or primidone. Thirteen of 15 patients demonstrated greater than 50% improvement of upper extremity tremor with 12.5 mg of clozapine.

Beta-Blockers, Nonselective

Class Summary

The mechanism of action in the reduction of essential tremor is not known. The action is hypothesized to be mediated primarily by peripheral beta2 adrenoreceptors, but some evidence indicates that beta1-receptor antagonists such as metoprolol also have some efficacy. Peripheral beta2 adrenoreceptors are located in the extrafusal muscle fibers and on the intrafusal fibers of the muscle spindles.

Propranolol hydrochloride (Inderal, InnoPran XL)

Propranolol, 1 of 2 medications of choice for essential tremor, has been shown to be effective in double-blind, placebo-controlled trials. It is a nonselective beta-adrenergic blocker with negative inotropic, chronotropic, and dromotropic properties. Propranolol is lipophilic with central nervous system (CNS) effects. Its mechanism of action is probably related to peripheral beta2 antagonism. The drug's long-acting formulation has efficacy similar to that of the standard formulation and may allow fewer daily doses.

In general, beta1-receptor antagonists are more effective than placebo but are not as effective as beta2-receptor antagonists. Metoprolol, a relatively selective beta1-receptor antagonist, may be useful in patients with asthma and other pulmonary conditions.

Anticonvulsants, Other

Class Summary

Primidone and, to a lesser extent, phenobarbital have demonstrated tremor-suppressing effects. Their mechanism of action is unknown, but it presumably involves the CNS.

Primidone (Mysoline)

Primidone is metabolized to phenobarbital and PEMA. It has tremor-suppressing activity independent of plasma concentrations of phenobarbital and is thought to be superior to phenobarbital. PEMA is not tremorolytic. Primidone is believed to have an independent mechanism for its effect on tremor.

It is strongly recommended that treatment with primidone be initiated with low doses because adverse effects at initiation of treatment are common. Start with one quarter or one half of a 50-mg tablet at bedtime and increase the dose slowly every week. Alternatively, introduce primidone using a 250 mg/5 mL suspension. Start with 1 drop at bedtime and increase the dose by 1 drop each night for 20 nights. Then convert the patient to a 50-mg tablet and increase the dose slowly every week.

For patients who initially respond to primidone but later develop a tolerance to it, increasing the dose to as high as 1000 mg/day in an effort to regain benefit is advisable.

Topiramate (Topamax)

Topiramate's mechanism of action is unknown, but the blockage of voltage-dependent sodium channels and the augmentation of GABA are thought to play a role. Topiramate is not extensively metabolized and is excreted unchanged in the urine.

Antipsychotics, 2nd Generation

Class Summary

In a randomized, double-blind, crossover study of 15 patients who had definite or probable essential tremor and poor response to propranolol or primidone, 13 showed greater than 50% improvement of upper extremity tremor with 12.5 mg of clozapine.

Clozapine (Clozaril, FazaClo)

Clozapine's mechanism of effect in essential tremor is unknown. The long-term effects of clozapine in essential tremor have not been studied. The drug may be tried before resorting to surgery when other methods have failed. Clozapine is weakly antidopaminergic, antiadrenergic (alpha1 and alpha2 receptors), anticholinergic, antihistaminergic (H1, H3), and antiserotonergic (5-HT1c, 5-HT2, 5-HT3).

Antidepressants, Other

Class Summary

In a case series report, 4 patients (3 with Parkinson disease and 1 with essential tremor) who responded initially to propranolol had improvement of tremor with mirtazapine.

Mirtazapine (Remeron, Remeron SolTab)

Mirtazapine is a potent 5-HT2, 5-HT3, and H1 antagonist. It is a moderate peripheral alpha1-adrenergic antagonist and a moderate antagonist of muscarinic receptors. The drug's half-life is 20-40 hours.

 

Questions & Answers

Overview

When are lab studies indicated for the diagnosis of essential tremor?

What is essential tremor?

How is essential tremor differentiated from other disorders?

What are the signs and symptoms of essential tremor?

How is essential tremor diagnosed?

What is the role of imaging in the diagnosis of essential tremor?

What is the role of MRI in the diagnosis of essential tremor?

What is the role of single-photon emission CT (SPECT) using 123I-ioflupain (DaTSCAN) in the diagnosis of essential tremor?

Which medications are used as maintenance therapy for the essential tremor?

What are the treatment options for essential tremor only requiring intermittent tremor reduction?

What is the role of alcohol in the treatment of essential tremor?

Which medications are used in the management of essential tremor?

What is the role of surgery in the treatment of essential tremor?

What is essential tremor?

What are the Movement Disorders Society inclusion criteria for diagnosis of essential tremor?

What are the Movement Disorders Society exclusion criteria for diagnosis of essential tremor?

What is the relationship between essential tremor and Parkinson disease?

What is the association between essential tremor and dystonia?

What is the role of glucose in the etiology of essential tremor?

What is the pathophysiology of essential tremor?

What is the role of harmane, a heterocyclic amine (HCA), in the etiology of essential tremor?

What is the evidence for and against categorizing essential tremor as a neurodegenerative disease?

What is the role of genetics in the etiology of essential tremor?

What are the susceptibility loci associated with the etiology of essential tremor?

What is the evidence that essential tremor is an alternative phenotype of a mutation causing parkinsonism?

What is the incidence of essential tremor in the US?

What is the global prevalence of essential tremor?

What are the racial predilections for essential tremor?

How does the incidence of essential tremor vary by sex?

How does the prevalence of essential tremor vary by age?

What are the mortality rates for essential tremor?

What is the likelihood of disability from essential tremor?

What are the causes of decreased quality of life in patients with essential tremor?

Presentation

Which history is characteristic of essential tremor?

How are essential tremor and enhanced physiologic tremor distinguished?

What is the relationship between dementia and essential tremor?

How is essential tremor described?

How is essential tremor characterized?

What are the physical findings characteristic of essential tremor?

DDX

Which conditions should be included in the differential diagnoses of essential tremor?

Which drugs can induce tremors and should be considered in the differential diagnoses for essential tremor?

Which metabolism-related tremors should be included in the differential diagnoses for essential tremor?

Which toxins can induce tremors and should be considered in the differential diagnoses for essential tremor?

What are the differential diagnoses for Essential Tremor?

Workup

What are the biologic markers for essential tremor?

Which lab tests are performed in the evaluation of essential tremor?

What is the role of electromyography and accelerometry in the evaluation of essential tremor?

What is the role of imaging in the diagnosis of essential tremor?

What is the role of single-photon emission CT (SPECT) using ioflupain 123 I (DaTSCAN) in the diagnosis of essential tremor?

What is the role of midbrain ultrasonography in the diagnosis of essential tremor?

What is the role of the tremor stability index in the diagnosis of essential tremor?

Treatment

What is the role of primidone and propranolol in the treatment of essential tremor?

What is the treatment for intermittent tremor reduction in essential tremor?

When is surgery indicated in the treatment of essential tremor?

What is the role of bilateral thalamotomy in the treatment of essential tremor?

What is the role of thalamic stimulation in the treatment of essential tremor?

What is the efficacy of primidone for the treatment of essential tremor?

What is primidone's mechanism of action in the treatment of essential tremor?

How is treatment selected for daily maintenance of essential tremor?

What is the alternative treatment for essential tremor when propranolol is contraindicated?

How is primidone or propranolol administered in the treatment of essential tremor?

What are the treatment options for mild essential tremor?

What is the efficacy of propranolol in the treatment of essential tremor?

What are the adverse effects of primidone in the treatment of essential tremor?

What is the AAN recommendation for use of primidone in essential tremor?

What is the AAN recommendation for use of topiramate in essential tremor?

What is the effectiveness of topiramate in the treatment of essential tremor?

What is alcohol's mechanism of action in the treatment of essential tremor?

What is the evidence base supporting use of less common medications for the treatment of essential tremor?

What is the effectiveness of clozapine in the treatment of essential tremor?

What is the AAN recommendation for use of clozapine in the treatment of essential tremor?

What is the AAN recommendation for use of mirtazapine in the treatment of essential tremor?

What is the AAN recommendation for use of gabapentin in the treatment of essential tremor?

What is the AAN recommendation for use of botulinum toxin in the treatment of essential tremor?

What is the effectiveness of mirtazapine in the treatment of essential tremor?

What is the effectiveness of gabapentin in the treatment of essential tremor?

What is the effectiveness of benzodiazepines in the treatment of essential tremor?

What are the AAN recommendations for use of benzodiazepines in the treatment of essential tremor?

What is the effectiveness of botulinum toxin in the treatment of essential tremor?

What is the effectiveness of thalamotomy in the treatment of essential tremor?

What are the potential adverse effects of thalamotomy in the treatment of essential tremor?

What is the effectiveness of unilateral thalamic stimulation in the treatment of essential tremor?

What is the effectiveness of bilateral thalamic stimulation in the treatment of essential tremor?

How do the outcomes of thalamotomy compare with that of thalamic stimulation in the treatment of essential tremor?

What are the adverse effects of thalamotomy in the treatment of essential tremor?

What are the benefits of thalamic stimulation in the treatment of essential tremor?

How does the functional status of patients with essential tremor compare following thalamotomy or thalamic stimulation?

What are the rates of stimulator reoperations following thalamic stimulation for essential tremor?

How does the efficacy of gamma knife thalamotomy compare with open surgical techniques for the treatment of essential tremor?

What are the advantages and disadvantages of thalamic stimulation for the treatment of essential tremor?

What is included in the follow-up of essential tremor?

Medications

What are the first-line medical treatments for essential tremor?

What are the second-line medical treatments for essential tremor?

Which medications in the drug class Antidepressants, Other are used in the treatment of Essential Tremor?

Which medications in the drug class Antipsychotics, 2nd Generation are used in the treatment of Essential Tremor?

Which medications in the drug class Anticonvulsants, Other are used in the treatment of Essential Tremor?

Which medications in the drug class Beta-Blockers, Nonselective are used in the treatment of Essential Tremor?