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eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Essential Tremor

Deborah A Burke, MD, Consulting Staff, Sub-investigator, Clinician, Movement Disorder/Parkinson's Disease Center, University of South Florida; Investigator, Physician, Roskamp Institute Memory Clinic
Robert A Hauser, MD, MBA, Professor of Neurology, Molecular Pharmacology and Physiology, Director, Parkinson's Disease and Movement Disorders Center, University of South Florida; Clinical Chair, Signature Interdisciplinary Program in Neuroscience; Theresa McClain, MSN, ARNP, Parkinson's Disease and Movement Disorders Center, University of South Florida

Updated: Oct 26, 2009

Introduction

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.

Pathophysiology

The pathophysiology of essential tremor is not known. No pathological 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 brain stem and involves the inferior olivary nucleus.
  • The cerebellar-brainstem-thalamic-cortical circuits probably are involved.
  • The pathophysiology of essential tremor is heterogeneous.1,2

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.3 The most likely etiology appears to be alterations in metabolism rather than increased dietary intake.

In patients with essential tremor, [18 F]fluorodeoxyglucose PET studies identified increased glucose consumption in the medulla. [15 O]H2 O PET 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 pathological abnormalities in the brainstem and cerebellum2 , including Lewy bodies in the locus ceruleus, loss of Purkinje cells, and abnormalities of the dentate nucleus4,5 ; reduction in cerebellar cortical NAA/tCR3 ; white matter changes on diffusion tensor imaging6 ; and clinical studies demonstrating an association with cognitive7,8 and gait changes. Conflicting data argues against essential tremor being a neurodegenerative disease. This data includes improvement of gait abnormalities with ethanol administration9 , lack of grey matter volume loss on voxel-based morphometry10 , failure to confirm prominent presence of Lewy bodies in the locus ceruleus2 , and other pathological findings11 .

Frequency

United States

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

International

Using a “door-to-door” method in Mersin Province, Turkey, 2253 individuals older than age 40 years were examined by neurologists; 89 essential tremor cases were identified.12

Mortality/Morbidity

Mortality rates have been thought to be the same between patients with essential tremor and the general population. However, in a recent, longitudinal prospective study of patients age 65 and older from 3 communities in central Spain, the risk of mortality was found to be increased.13  Further studies are needed to assess mortality rates in essential tremor.

Disability from essential tremor is common.

  • Of individuals with essential tremor, 85% report significant changes in their livelihood and socializing and15% report being seriously disabled by essential tremor.
  • Decreased quality of life results from both loss of function and 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.

Race

Race has not been extensively studied in essential tremor. One evaluation of a multiethnic group (White, African American, and Hispanic) found differences in presence or absence of head tremor and variable tremor score among the subgroups. White subjects had a tremor score that was 5.3 points lower than nonwhites. Head tremors were present in 25% of Whites, 29% of Hispanics, and absent in African Americans.14

Sex

Essential tremor affects both sexes with equal frequency.

  • Head tremor may be more frequent in women.
  • Postural hand tremor may be more severe in men.
  • Childhood essential tremor may be more frequent in boys than in girls.15

Age

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 the latter, suggesting preferential referral of young-onset essential tremor to tertiary centers.16
  • Essential tremor usually manifests by age 65 years and virtually always by 70 years. Tremor amplitude slowly increases over time. Tremor frequency decreases with increasing age. An 8- to 12-Hz tremor is seen in young adults and a 6- to 8-Hz tremor is seen in elderly individuals.
  • Rare cases of essential tremor have been reported in newborns and infants. Although essential tremor is progressive, no association has been found between age of onset and severity or disability
  • A strong correlation between age of onset before 20 years and family history of essential tremor was found in a environmental epidemiological study of 195 essential tremor cases.17

Clinical

History

  • 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 of time the frequency of tremor is relatively fixed, but amplitude 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.
  • A family history of essential tremor is noted in 50-60% 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%; unadjusted odds ratio [OR] 3.31, 95% confidence interval [CI] 2.15-5.09, p < 0.001; adjusted OR 1.84, 95% CI 1.13-2.98, p = 0.01). In prospective analyses, dementia developed in 17 of 93 subjects with essential tremor versus 171 of 1,963 controls (18.3% vs 8.7%; unadjusted hazard ratio [HR] 2.78, 95% CI 1.69-4.57, p < 0.001; adjusted HR 1.64, 95% CI 0.99-2.72, p = 0.055).18

Physical

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.

  • 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 (see above), personality, 19 mood, 20 hearing, 21, 22 and motor symptoms associated with cerebellar outflow. 23

Causes

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.24
    • 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 directly interviewing family members.
  • Three susceptibility loci have been found.
    • A locus at 3q13 (EMT1) was identified in 75 members of 16 Icelandic families. A Ser9Gly variant on the DRD3 gene has been associated with EMT1.25
    • Another locus, 2p25-22 (EMT2), was identified in 15 members of 4 generations of Americans. Abnormalities found in 3 additional American families have been reported to map to this locus.
    • A locus on 6p23 was identified in 2 families.26
    • An association with a polymorphism in the HS1-BP3 gene has been reported but this has not been confirmed.27,24
    • 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.
  • Associations between essential tremor and Parkinson disease  and essential tremor and dystonia have been suggested.
    • 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. Without biological markers for these diseases, 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.
    • Some patients with focal dystonia, such as torticollis, have mild bilateral upper extremity postural tremors. Without biological 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.
    • 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.28
  • The Movement Disorders Society has proposed the following diagnostic criteria for classic essential tremor:
    • Inclusion criteria are as follows:
      • Bilateral, largely symmetric postural or kinetic 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

Differential Diagnoses

Arsenic
Parkinson-Plus Syndromes
Multiple System Atrophy
Thyroid Disease
Neurologic Effects of Caffeine
Torticollis
Parkinson Disease
Wilson Disease

Other Problems to Be Considered

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
Antidepressants, especially tricyclics
Beta-agonists
Depakote
Dopamine
Lithium
Metoclopramide
Neuroleptics
Theophylline
Thyroid hormones
Withdrawal of drugs

Metabolism-related tremors
B-12 deficiency
Hyperthyroidism
Hyperparathyroidism
Hypocalcemia
Hyponatremia
Kidney disease
Liver disease

Toxin-related tremors
Alcohol
Arsenic
Caffeine
DDT
Lead
Nicotine
Toluene
Withdrawal of alcohol, cocaine

Workup

Laboratory Studies

  • No biological markers exist for essential tremor.
  • If the family history and examination findings are indicative of essential tremor, no laboratory or imaging studies are required.
  • If the family history and examination findings are not indicative of essential tremor, laboratory and imaging studies should be considered.
  • Laboratory investigations include standard electrolyte panel, thyroid function tests, BUN, creatinine, liver function tests, and serum ceruloplasmin (for Wilson disease).

Imaging Studies

  • Findings on CT scanning and MRI of the head are normal in essential tremor. MRI helps exclude structural and inflammatory lesions (including multiple sclerosis) and Wilson disease. MRI should be performed if the tremor has acute onset or stepwise progression.
  • Midbrain sonography has been suggested as a tool to differentiate essential tremor from Parkinson disease in 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.29,30

Procedures

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

Treatment

Medical Care

Primidone and propranolol are the cornerstones of maintenance medical therapy for essential tremor. These medications provide good benefit in reducing tremor amplitude in approximately 75% of patients.

For patients who require symptomatic therapy, one or the other of these medications is introduced at a low dose and increased slowly until sufficient benefit is achieved or the usual maximum dosage is reached (see Medication for dosing suggestions). If no benefit is derived, the medication is weaned and discontinued. If a partial benefit occurs, the other medication is added and slowly increased until sufficient benefit is achieved or the usual maximum dosage is reached. If no additional benefit occurs, this medication is then weaned and discontinued. 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.

  • 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 effect of ethanol is mediated centrally.
  • Propranolol
    • Winkler first noted remarkable tremor reduction in a patient treated with propranolol for paroxysmal atrial tachycardia.
    • In a double-blind crossover study, propranolol at doses from 60-240 mg/d reduced tremor in 75% of patients with essential tremor. In a dose-response study, 240-320 mg/d was found to be the optimal dose range with no additional benefits above 320 mg/d.
    • Average tremor reduction is 50-60%, but some patients experience marked tremor reduction and others no benefit.
    • The mechanism of action probably is related to peripheral beta2-receptor antagonism.
    • The long-acting formulation of propranolol has an efficacy similar to 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 antagonists. Metoprolol, a relatively selective beta1 antagonist, may be useful in patients with asthma or other pulmonary conditions.
  • Primidone
    • O'Brien 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/d did not provide additional benefit.
    • The 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.
  • Topiramate
    • Topiramate is an anticonvulsant medication that enhances gamma-aminobutyric acid 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% when compared to placebo.
    • Clinical trials indicate a fairly substantial dropout rate of 40% because of adverse effects such as cognitive difficulty or somnolence.
  • Many other medications have been reported to be of benefit in the treatment of essential tremor. Most of these have been case reports or small open-label studies. 
    • Clozapine
      • A single dose of 12.5 mg of clozapine and placebo were compared in a randomized, double-blind crossover study in patients with drug-resistant essential tremor. Tremor was reduced significantly by clozapine in 13 of 15 patients (P <0.01).
      • A significant reduction of tremor was reported with long-term (open-label) clozapine therapy (39.9 mg/d).
      • No tolerance was observed over 15 months.
    • Mirtazapine: In a small, open-label case series, mirtazapine was reported to reduce tremor in patients with essential tremor and Parkinson disease.
    • Gabapentin: A double-blind crossover trial comparing gabapentin (400 mg tid) to propranolol (40 mg tid) found that both drugs demonstrated significant and comparable reductions in tremor compared to baseline. However, a double-blind, placebo-controlled crossover study identified no difference between gabapentin and placebo.
    • 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.
    • 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.
  • 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 individuals and primidone is started first in older individuals. Generally, propranolol carries more risk of serious adverse effects in older patients than in younger patients. 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; a beta1 antagonist can be tried if necessary.
    • If the patient receives no benefit from the first medication, it is weaned and discontinued before starting the other. If the benefit is partial but insufficient, the initial medication is maintained and the other medication is added.
    • Once an effective maintenance dose of propranolol is achieved, switching to the long-acting preparation is considered. An alternative is to use the long-acting formulation from the beginning, but this requires multiple prescriptions and is more cumbersome.
    • If sufficient benefit is not achieved with primidone or propranolol, other medications are considered based on the severity of the residual tremor.
    • If the tremor is mild and more of a nuisance than disabling, a benzodiazepine is considered, usually clonazepam.
    • For patients with head tremor, cervical injections of botulinum toxin may be given.

Surgical Care

For patients with medically refractory disabling upper extremity tremor, surgery is considered. Stereotactic thalamotomy and thalamic ventralis intermedius nucleus deep brain stimulation (DBS) are the procedures of choice.

Both procedures offer high rates of tremor reduction in the contralateral arm. Recent information suggests that they are also useful in reducing head and voice tremor. 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 already had a unilateral thalamotomy in an effort to avoid the potentially serious complications of bilateral thalamotomy.31 Thalamic stimulation now is considered the procedure of choice.

  • Thalamotomy
    • In 1997, a retrospective study by Jankovic et al evaluated 60 patients who underwent thalamotomy for medically intractable tremor. Forty-two had Parkinson disease, 6 had essential tremor, 6 had cerebellar tremor, and 6 had posttraumatic tremor. Patients were observed for a mean 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, dysarthria in 6, contralateral ataxia in 1, blepharospasm in 1, and pulmonary embolus resulting in death in 1.
    • A study of thalamotomy in 8 patients with essential tremor by Goldman demonstrated a reduction in tremor from moderate-to-severe to mild or no tremor in all 8 patients. Mild persistent dysarthria was seen in 2, and a "mild verbal cognitive defect" was seen in 1.32
    • 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, high-frequency unilateral thalamic stimulation was assessed in 29 patients with essential tremor and 24 with Parkinson disease. A blinded evaluation at 3 months with patients randomized to stimulation on or stimulation off demonstrated a significant reduction in both essential tremor and Parkinson disease contralateral tremor with stimulation on. Measures of function were improved significantly in patients with essential tremor. Stimulation was associated commonly with transient paresthesias. Other adverse events were mild and well tolerated.
    • In 1998, Ondo et al reported an average 83% reduction in contralateral arm tremor in a study of 14 patients with essential tremor.22
    • In 1999, 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), postoperative seizures (1), hematoma over the implanted pulse generator (1), lead repositioning (1), and IPG malfunction (1). Adverse effects related to stimulation were mild and resolved with adjustment of stimulation parameters.33
  • Thalamotomy versus thalamic deep brain stimulation
    • In 1998, a retrospective comparison study by Tasker of deep brain stimulation and thalamotomy in essential tremor and Parkinson disease 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. Side effects, including ataxia, dysarthria, and gait disturbance, were more common with thalamotomy (42%) than deep brain stimulation (26%); side 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.34
    • In a 1999 report, 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. 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, foreign body implant, need to optimize parameters, and hardware maintenance including battery replacement after several years.35
    • In a prospective study in 2000, Schuurman et al compared thalamic stimulation and thalamotomy in a prospective randomized study of 68 patients with Parkinson disease, essential tremor, or multiple sclerosis. 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. These investigators concluded that, although thalamotomy and thalamic stimulation are equally effective for tremor suppression, stimulation results in greater functional improvement and has fewer adverse effects.36
    • 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. 
    • Gamma knife thalamotomy was studied in patients who were not eligible for open surgical techniques and had medically refractory tremor. Findings indicated that gamma knife thalamotomy was safe and effective.37

Medication

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 more prominent later in treatment with propranolol. Starting with propranolol is preferable in younger individuals, and primidone is started first in older individuals.

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 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-adrenergic blockers

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, Betachron ER)

One of 2 medications of choice for essential tremor, shown to be effective in double-blind, placebo-controlled trials. Nonselective beta-adrenergic blocker with negative inotropic, chronotropic, and dromotropic properties. Lipophilic with CNS effects. Mechanism of action probably related to peripheral beta2 antagonism. Long-acting formulation has efficacy similar to that of standard formulation and may allow fewer daily doses.
In general, beta1 antagonists are more effective than placebo but are not as effective as beta2 antagonists. Metoprolol, a relatively selective beta1 antagonist, may be useful in patients with asthma and other pulmonary conditions.

Dosing

Adult

20 mg PO qam initially; increase by 20 mg/d qwk to 20 mg tid; continue increase by 20 mg/d qwk until tremor is adequately controlled, adverse effects become intolerable, or usual maximum of 240-320 mg/d is reached
Effective dose range is 40-320 mg/d in divided doses; typical dose range is 120 mg (40 mg tid) to 240 mg/d

Pediatric

Not established; dosing for other indications ranges from 1-4 mg/kg/d in divided doses

Interactions

Catecholamine-depleting drugs may produce excessive reduction in resting sympathetic nervous activity, resulting in hypotension, marked bradycardia, vertigo, syncopal attack, or orthostatic hypotension; calcium channel blockers, particularly verapamil, may decrease cardiac contractility or AV conduction; anti-arrhythmic drugs may increase cardiac effects; phenothiazines may have additive hypotensive activity; chlorpromazine may reduce clearance; high doses may potentiate effects of neuromuscular blocking agents; cimetidine can reduce clearance

Contraindications

Documented hypersensitivity; sinus bradycardia; second- or third-degree heart block; congestive heart failure; cardiogenic shock; allergic bronchospastic disease; Raynaud disease; malignant hypertension

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in diabetes mellitus, myasthenia, nonallergic bronchospastic disease, and impaired hepatic or renal function; potential adverse effects include bradycardia, hypotension, heart failure, fatigue, depression, weight gain, male impotence, nausea, diarrhea, and rash; lethargy, fatigue, and depression may emerge over time; relative contraindications include heart failure, second- or third-degree AV block, asthma, chronic obstructive pulmonary disease, and insulin-dependent diabetes mellitus; may mask symptoms of thyrotoxicosis or hypoglycemia or interfere with glaucoma screening tests; abrupt withdrawal may precipitate unstable angina or myocardial infarction in patients with angina or coronary artery disease

Anticonvulsant agents

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


Primidone (Mysoline)

Metabolized to phenobarbital and PEMA. 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 independent mechanism for its effect on tremor.
Strongly recommended that treatment be initiated with low doses because adverse effects at initiation of treatment are common. Start with one quarter or one half of 50-mg tablet at bedtime and increase dose slowly every week. Alternatively, introduce primidone using 250 mg/5 mL suspension. Start with 1 drop at bedtime and increase dose by 1 drop each night for 20 nights. Then convert to 50-mg tab and increase slowly every week.
For patients who initially respond but develop tolerance later, increasing dose to as high as 1000 mg/d in effort to regain benefit is advisable.

Dosing

Adult

25 mg/d (half of 50-mg tab) PO qhs, then increase by 25 mg/d qwk to dose of 100 mg/d
When further increase is required, split dose one third in morning and two thirds at bedtime, up to usual maximum daily dose of 300 mg/d
Usual dose range is 12.5-250 mg/d PO

Pediatric

Not established

Interactions

Alcohol, phenobarbital, heparin, isoniazid, and phenytoin increase blood levels; phenobarbital, a metabolite of primidone, is both competitive inhibitor and inducer of hepatic enzymes; enhances hepatic clearance of oral contraceptives, steroids, calcium channel blockers, theophylline, digitoxin, acetaminophen, cimetidine, cyclosporin, lamotrigine, felbamate, topiramate, and tiagabine; has variable interactions with phenytoin

Contraindications

Documented hypersensitivity; porphyria

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Potential adverse effects include sedation, ataxia, vertigo, dizziness, nausea, vomiting, diplopia, and nystagmus; these effects usually occur, if at all, early in course of treatment and may occur with first dose; other adverse effects include maculopapular and morbilliform rash, leukopenia, thrombocytopenia, SLE, and lymphadenopathy; ataxia and vertigo very common and tend to resolve with repeated use; overdose produces symptoms similar to barbiturate overdose, including profound CNS depression, shock, and respiratory depression; caution in patients with renal or hepatic impairment; abrupt discontinuation of medication may precipitate status epilepticus; caution in pulmonary insufficiency; may have paradoxical effects in children, including irritability, hyperactivity, and disturbed sleep


Topiramate (Topamax)

Mechanism of action unknown but blockage of voltage-dependent sodium channels and augmentation of GABA thought to play a role. Not extensively metabolized and excreted unchanged in the urine.

Dosing

Adult

25 mg/d PO and increase 25 mg/wk in divided doses to maximum dose of 400 mg/d (200 mg bid)

Pediatric

Not established

Interactions

Phenytoin, carbamazepine, and valproic acid can significantly decrease topiramate levels; topiramate reduces digoxin and norethindrone levels when administered concomitantly; concomitant use with carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; use topiramate with extreme caution when administering concurrently with CNS depressants because may have an additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of developing a kidney stone is increased 2-4 times over that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; patients taking topiramate should seek immediate medical attention if they experience blurred vision or periorbital pain; continued usage after symptoms develop can lead to glaucoma; primary treatment is discontinuation of topiramate; if left untreated, serious sequelae, including permanent vision loss, may occur; oligohidrosis and hyperthermia has been reported predominantly in children during vigorous exercise or exposure to warm environmental temperatures (ensure proper hydration prior and during activity and warm temperatures)
May cause hyperchloremic nonanion gap metabolic acidosis, acute or chronic metabolic acidosis resulting in hyperventilation, and nonspecific symptoms, such as fatigue and anorexia; more severe adverse effects include cardiac arrhythmias or stupor; chronic untreated metabolic acidosis may increase nephrolithiasis or nephrocalcinosis risk, osteomalacia (ie, rickets in pediatric patients), or osteoporosis with an increased risk for bone fractures; chronic metabolic acidosis in pediatric patients may also reduce growth rates; measure baseline and periodic serum bicarbonate

Atypical neuroleptics

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)

Mechanism of effect in essential tremor unknown. Long-term effects in essential tremor have not been studied. May be tried before resorting to surgery when other methods have failed. Weakly antidopaminergic, antiadrenergic (alpha1 and alpha2 receptors), anticholinergic, antihistaminergic (H1, H3), and antiserotonergic (5-HT1c, 5-HT2, 5-HT3).

Dosing

Adult

Start at dose of 12.5 mg/d PO or less; introduce using a chip (~1/8) of a 25-mg tab and increase slowly
Usual dose 12.5-50 mg/d

Pediatric

Not established

Interactions

Should not be used with drugs known to cause agranulocytosis or otherwise suppress bone marrow function; increases anticholinergic effect of anticholinergics; because of CNS depressive effects, should not be used with alcohol; respiratory and cardiac functions should be monitored when used with other psychotropic drugs, particularly benzodiazepines; because protein bound, may cause elevations in plasma concentrations of other protein-bound drugs, such as warfarin or digitoxin; cimetidine, erythromycin, and SSRIs may increase plasma levels; phenytoin or carbamazepine may decrease plasma levels; drugs that are metabolized by cytochrome P450 2D6 may affect levels of either clozapine or other drug

Contraindications

Documented hypersensitivity; myeloproliferative disorders; uncontrolled epilepsy; severe CNS depression or comatose state; history of agranulocytosis or severe granulocytopenia induced by clozapine

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Frequent blood monitoring required because of risk of agranulocytosis, recommended baseline WBC count and differential prior to treatment and WBC count qwk for 6 mo; if WBC maintained at >3000/mm3 and ANC maintained at >1500/mm3, then testing may be carried out on alternate wk until 4 wk after drug discontinued
Other potential adverse effects include seizures, sedation, dizziness/vertigo, delirium, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects; sedation commonly resolves after several wk

Antidepressant agents

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


Mirtazapine (Remeron)

Potent 5-HT2, 5-HT3, and H1 antagonist; moderate peripheral alpha1-adrenergic antagonist and moderate antagonist of muscarinic receptors. Half-life is 20-40 h.

Dosing

Adult

15 mg/d PO qam initially (limited data available); increase to 15 mg PO bid if necessary
Usual dose 15-45 mg/d

Pediatric

Not established

Interactions

If used with MAOIs may have serious and sometimes fatal interactions

Contraindications

Documented hypersensitivity; MAOI use within last 14 d; caution in patients with mania or hypomania

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with bipolar disorder or hypomania, may precipitate mania; potential adverse effects include somnolence, dizziness, increased appetite, and increased transaminases; rare cases of symptomatic agranulocytosis (2 of 2796) and 1 case of severe neutropenia reported—all recovered with discontinuation of medication; can cause orthostatic hypotension; use with care in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension or in patients predisposed to hypotension; discontinue drug in patients with signs or symptoms of neutropenia or agranulocytosis; clearance decreased in liver or kidney disease and in elderly people, particularly elderly men (as much as 40%)

Follow-up

Further Outpatient Care

  • 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. 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.

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Keywords

essential tremor, essential tremor treatment, movement disorder, benign essential tremor, familial tremor, senile tremor

Contributor Information and Disclosures

Author

Deborah A Burke, MD, Consulting Staff, Sub-investigator, Clinician, Movement Disorder/Parkinson's Disease Center, University of South Florida; Investigator, Physician, Roskamp Institute Memory Clinic
Deborah A Burke, MD is a member of the following medical societies: American Academy of Neurology and Movement Disorders Society
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Hauser, MD, MBA, Professor of Neurology, Molecular Pharmacology and Physiology, Director, Parkinson's Disease and Movement Disorders Center, University of South Florida; Clinical Chair, Signature Interdisciplinary Program in Neuroscience
Robert A Hauser, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Neuroimaging, and Movement Disorders Society
Disclosure: Allergan Sales, LLC Honoraria Speaking and teaching; Boehringer Ingelheim  Honoraria Consulting; Genzyme Corporation Honoraria Consulting; GlaxoSmithKline Honoraria Consulting; IMPAX Laboratories, Inc. Honoraria Consulting; Novartis Pharmaceuticals Corp. Honoraria Consulting; Schering Plough  Consulting; Solvay Pharmeceuticals Honoraria Consulting; Teva Neuroscience Honoraria Speaking and teaching

Theresa McClain, MSN, ARNP, Parkinson's Disease and Movement Disorders Center, University of South Florida
Theresa McClain, MSN, ARNP is a member of the following medical societies: Sigma Theta Tau International
Disclosure: Teva Consulting fee Consulting; GSK Consulting fee Consulting; Valeant Pharm Consulting fee Consulting; Solvay Consulting fee Consulting; Shering Plough Consulting fee Consulting

Medical Editor

Daniel H Jacobs, MD, Associate Professor of Neurology, University of Central Florida College of Medicine
Daniel H Jacobs, MD is a member of the following medical societies: American Academy of Neurology, American Society of Neurorehabilitation, and Society for Neuroscience
Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex Grant/research funds Independent contractor; Serono EMD Royalty Speaking and teaching; Pfizer Royalty Speaking and teaching; Berlex Royalty Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Nestor Galvez-Jimenez, MD, MSc, MHA, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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