Essential Tremor

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 tremor in head but absence of abnormal posturing
• At least 3-year history of tremor

Exclusion criteria are as follows:

• 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 (functional) 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.)[11]

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.

The etiology and pathophysiology of essential tremor is not well understood. 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
• Cerebellar-brainstem-thalamic-cortical circuits are likely involved
• The pathophysiology of essential tremor is heterogeneous ^{[12, 13]}

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.[14] 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,[13] including Lewy bodies in the locus ceruleus, loss of Purkinje cells, and abnormalities of the dentate nucleus[15, 16] ; reduction in cerebellar cortical N-acetylaspartate/total creatine (NAA/tCR)[14] ; white matter changes on diffusion tensor imaging;[17] and clinical studies demonstrating an association with cognitive[18, 19] and gait changes.

Conflicting data argues against essential tremor being a neurodegenerative disease. This data includes improvement of gait abnormalities with ethanol administration,[20] lack of gray matter volume loss on voxel-based morphometry,[21] failure to confirm prominent presence of Lewy bodies in the locus ceruleus,[13] and other pathologic findings.[22]

Genetics

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

Essential tremor is familial in 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.[23]

Variations in methodology (ie, assessment procedures and diagnostic criteria) account for 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 ^[24]
• 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 ^[25]
• 6p23 - Identified in 2 families ^[26]

An association with a polymorphism in the HS1-BP3 gene has been reported, but this has not been confirmed.[23, 27]

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.[28, 29, 30]

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 has been reported to differ considerably in individuals living in various regions of the United States (New York, Mississippi, and Arizona), with estimates for ages > 60 years ranging widely, from 1.3% to 20.5%.[31]

International occurrence

In 2020, the global prevalence of essential tremor in the general population was estimated to be 0.32%, ranging from 0.04% in people younger than 20 years to 2.87% in those aged 80 years and older. The total number of people suffering from essential tremor worldwide was 24.91 million in 2020.[32]

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.[33]

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.[34]

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 the center, with the population-based study revealing a significant peak only in older adults. This suggests that the bimodal peak may be attributable to preferential referral of young-onset essential tremor patients to tertiary centers.[35]

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.

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.[36]

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.[37] Further studies are needed.

Disability from essential tremor is common.[38] 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.

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

• A family history of essential tremor is noted in 50–70% 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 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, hyperthytoidism, fever, and anxiety, and should be excluded.

Essential tremor 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 these could be clues to an alternative diagnosis.

The tremor is characteristically postural (occurring with voluntary maintenance of a position against gravity) and/or 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 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,[39] mood,[40] hearing,[41, 42] and motor symptoms associated with cerebellar outflow.[43]

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.[44, 45]

Laboratory investigations may 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.

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 essential tremor, Parkinson’s disease often does cause postural and action tremors in addition to resting tremors and may be difficult to distinguish from essential tremor if other signs are absent or minimal. Single-photon emission CT (SPECT) scanning using ioflupain 123 I (DaTSCAN) is a US Food and Drug Administration (FDA)–approved procedure that can help determine whether there is loss of dopamine neurons as occurs in Parkinsons disease and related disorders (and not in essential tremor), thus helping to distinguish these conditions.[5, 6, 7, 46]

Midbrain ultrasonography has been suggested as a tool to differentiate essential tremor from Parkinson’s disease as a result of a study finding that high substantia nigra hyperechogenicity has a high positive predictive value for Parkinson disease. Another study found a significant increase in substantia nigra hyperechogenicity in patients with essential tremor compared with controls.[47, 48, 49, 50]

In 2017, researchers described an electrophysiological 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.[51]

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.[52, 53, 54]

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 to one half hour prior to the event. Alcohol consumption is not an appropriate maintenance therapy for patients who seek tremor reduction throughout the day.[9]

Surgery

For patients with disabling, medically refractory upper extremity tremor, surgery is considered. MRI-guided focused ultrasound 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.[55]

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 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.[56] Thalamic stimulation now is considered a procedure of choice.

Focused ultrasound thalamotomy is an alternative to thalamic stimulation. According to one randomized trial, patients who underwent MRI-guided focused ultrasound thalamotomy for essential tremor 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%.[10]

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.

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 and/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.[53]

Propranolol was studied in 13 Level-I (randomized, controlled ) studies in a total of 255 patients with essential tremor and classified as efficacious and clinically useful.[8]

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 is probably 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.

Common adverse effects include fatigue, hypotension, and bradycardia

American Academy of Neurology (AAN) Practice Parameters are as follows:[57]

• 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.[58]

Primidone was studied in 8 Level-I studies that included a total of 274 patients with essential tremor, comparing primidone with placebo classified as efficacious and clinically useful.[8]

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.

Common adverse effects include sedation, dizziness, and ataxia at higher doses.

AAN Practice Parameter is as follows:[57]

• 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.

Topiramate was studied in 4 placebo-controlled Level-I studies in a total of 322 patients with essential tremor, as monotherapy or add-on treatmentand classified as efficacious and clinically useful in dose more then 200 mg a day.[8]

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:[57]

• 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.

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.

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.

Adverse effects include sedation, dizziness, edema, weight gain.

AAN Practice Parameter is as follows:[57]

• 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 may reduce the anxiety that can amplify tremor amplitude.

Adverse effects include sedation, ataxia, habit formation, risk of withdrawal symptoms with abrupt discontinuation

AAN Practice Parameters are as follows:[57]

• 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.

By MDS evidence-based review of treatments, botulinum toxin type A was considered likely efficacious for upper limb tremor. Botulinum toxin type A was studied in 3 placebo-controlled, Level-I studies that included a total of 168 patients with essential tremor refractory to oral drugs.[8]

AAN Practice Parameter is as follows:[57]

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

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:[57]

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

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.

Adverse effects include bradycardia and seizures with higher dose. There is potential for severe neutropenia, thus clozapine is only used in refractory cases and under close monitoring.

AAN Practice Parameter is as follows:[57]

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

Pipeline treatment of essential tremor

T-type calcium channel blocking agents are in trials for essential tremor management. T-type calcium channels are mostly neuronal and have significantly less cardiovascular effect. T-type calcium channels are present in the thalamus, cerebellum, and cortex, and thought to play a role in rhythmic neuronal firing. Several agents are currently in phase I–II clinical trials with promising results.

Modulators of GABA-A receptors have been evaluated for essential tremor. These drugs potentiate both synaptic and extrasynaptic receptors. Physiologically, this class reduces occipital beta activity, a possibly biomarker for tremor.[59]

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.

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.[42]

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.[60]

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.[55]

During MRI-guided focused ultrasound thalamotomy procedure patients are placed in a stereotactic head frame that is coupled to an MRI-compatible ultrasound transducer. After stereotactic targeting with the use of MRI, acoustic energy is sequentially titrated to temperatures sufficient for tissue ablation. 

Elias et al conducted a randomized parallel study of unilateral MRI-guided focused ultrasound thalamotomy versus sham procedure in 81 patients with medically refractory moderate-severe upper limb tremor attributed to essential tremor.[10]  

Seventy-six patients were included in the analysis. Outcomes were based on the tremor score (on a scale ranging from 0 to 32, with higher scores indicating more severe tremor) was derived from the Clinical Rating Scale of Tremor( CRST) , Part A (three items: resting, postural, and action or intention components of hand tremor), and the CRST, Part B (five tasks involving handwriting, drawing, and pouring) 

Hand-tremor scores improved more after focused ultrasound thalamotomy (from18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points). The improvement in the thalamotomy group was maintained at 12 months. 

Adverse events associated with focused ultrasound thalamotomy included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.[10]

A significant advantage of focused US over stereotactic radiofrequency surgery is that it allows intraoperative clinical assessment and graded lesioning procedure.[61]

For upper limb tremor, unilateral MRI-guided focused ultrasound thalamotomy was considered likely efficacious with an acceptable risk with specialized monitoring.[8]

The FDA approved the use of Cala system (Cala Health, Burlingame, CA, USA) for patients with essential tremor. The Cala system is a device worn around the wrist that stimulates the peripheral sensory nerves and should be worn on the more affected side of the body. Cala Trio needs to be calibrated to individual tremor frequency and provides temporary benefit for tremor.[62]

The open-label PROSPECT trial recruited 265 patients from 26 centers across North America and assessed the longitudinal and long-term applicability of in-home use of the Cala Two device. Participants in the trial used the Cala device twice daily for three months. After three months of use, 22% improvement in the TETRAS and 28% improvement in the Bain and Findley ADL scores were observed. The physiological data correlated significantly with the clinical ratings and there was a 50% reduction in tremor amplitude in nearly 54% of patients.[62]

The Cala system is not recommended in patients with implanted devices such as a pacemaker, defibrillator, or deep brain stimulator and can’t be used in active seizure disorder, pregnancy, skin eruptions, open wounds, lesions, or infected skin areas.[62]

Adaptive aids, such as Gyenno Spoon, can also be helpful for patients who have not experienced adequate benefit with other treatments.

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.

Beta-adrenergic blockers (principally propranolol) and primidone are the first-line treatments 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 commonly started first in older patients.

Patients who require medication treatment are usually started on one of these medications. The drug is introduced at a low dose and is increased slowly until complete response, intolerability, or usual maximum dose is attained. If some benefit is achieved but is incomplete, the other medication may be added, and slowly 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 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. Gabapentin and clonazepam may also be tried. 

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. May be used as monotherapy or in combination with primidone.

Class Summary

Some agents in this class 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, Qudexy XR, Topamax Sprinkle, Trokendi XR)

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.

Clonazepam (Klonopin)

Benzodiazepines, particularly clonazepam, are commonly used in treating essential tremors, but their effectiveness is limited. Clonazepam may probably work to reduce anxiety, which can amplify tremor amplitude. May also enhance GABA activity. 

Gabapentin (Gralise, Neurontin)

Gabapentin, a membrane stabilizer, is a structural analog of the inhibitory neurotransmitter GABA, although it is thought not to exert an effect on GABA receptors. Appears to exert its action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gated calcium channels. May also modulate excitatory neurotransmitter release.