Essential tremor: Treatment and prognosis

INTRODUCTION — Essential tremor (ET) is the most common cause of action tremor in adults (table 1). It classically involves the hands and is brought out by arm movement and sustained antigravity postures, affecting common daily activities such as writing, drinking from a glass, and handling eating utensils.

ET is slowly progressive and can also involve the head, voice, and, uncommonly, the legs. Disability from the tremor can be significant, especially when the upper limbs are affected. A variety of symptomatic therapies are available.

In most cases, ET can be managed by primary care clinicians, beginning with exclusion of secondary causes and followed by initiation of therapy with propranolol or primidone if the tremor is causing disability. The decision to refer to a neurologist depends upon the clinician's confidence in the diagnosis, their comfort level with use of the drugs recommended for tremor suppression, and the patient's response to treatment.

This topic will review the treatment and prognosis of ET. Additional topics on tremor are available separately. (See "Overview of tremor" and "Essential tremor: Clinical features and diagnosis" and "Surgical treatment of essential tremor".)

GOALS AND EXPECTATIONS — Treatment of ET is symptomatic, and no disease-modifying therapies are available. The degree of tremor control provided by medications varies among patients and often depends on the dose of the agents used, tremor severity, and a patient's individual response to the chosen agent. Patients with mild tremor may experience complete tremor suppression with available therapies. However, the goal of therapy for most patients is to reduce tremor severity enough to prevent disability while minimizing medication side effects.

It is important to explain to patients that tremor will worsen over time, and that increased doses and second-line therapies will likely be required. Tremor progression is not indicative of an alternate diagnosis such as Parkinson disease as long as no additional signs or symptoms emerge (table 2). (See "Essential tremor: Clinical features and diagnosis", section on 'Parkinson disease'.)

TREATMENT APPROACH

Exacerbating and mitigating factors — When possible, medications or other substances (eg, caffeine) that could be exacerbating tremor should be discontinued (table 3); at times, doing this will suffice to control tremor, even if temporarily.

Alcohol is well-known to reduce tremor in many patients with ET and often has an effect in modest amounts (eg, a half to one glass of wine). Some patients find this effect useful in social situations. (See 'Others' below.)

Criteria for pharmacotherapy — Drug treatment should be offered to patients with ET who have intermittent or persistent disability caused by tremor (algorithm 1) [1]. When possible, medications or other substances (eg, caffeine) that could be exacerbating tremor should be discontinued (table 3); at times, doing this will suffice to control tremor, even if temporarily.

Individuals with mild ET and little or no tremor-related disability usually do not require treatment, although some patients are bothered by the cosmetic effect of even the smallest amount of shaking. Patients may not volunteer that they are bothered or embarrassed by the tremor, and it is important to assess both the physical and the psychosocial impact.

Patients with frequent/daily symptoms — Patients with persistent functional or psychological disability (including embarrassment or anxiety) due to ET generally require a daily medication (algorithm 1). Propranolol, a nonselective beta adrenergic blocker, and primidone, an antiseizure medication, are each considered first-line therapies for ET [2,3], and they have equivalent efficacy based on small comparative trials. The choice between these agents is based on side effect profiles, concomitant medications, and comorbidities. (See 'Choice of agent' below.)

For ET that does not respond adequately to monotherapy with either propranolol or primidone, the two drugs can be used together. Switching from one to the other is also a reasonable strategy if either agent is poorly tolerated. Several additional drugs or classes of drugs have more limited evidence of benefit for ET but can be tried as second-line agents, either alone or in combination with a first-line therapy. These include topiramate, benzodiazepines, and gabapentin. (See 'Second-line therapies' below.)

Additional options in patients with refractory ET include various adaptive devices, botulinum toxin (BoNT) injections, and surgical therapy. (See 'Refractory tremor' below.)

Patients with situational exacerbations — Some patients with ET develop exacerbations of tremor triggered by stressful social occasions or public performances. Intermittent drug treatment of ET in anticipation of these situations can be useful in such cases (algorithm 1) [1].

Use of medication in this setting is individualized and may require a trial-and-error approach, as side effects are variable and may have adverse effects on performance. For most patients with mild ET who have situational exacerbations of tremor that cause concern, we suggest treatment as needed with low-dose propranolol. (See 'Propranolol' below.)

Some experts report that primidone may also be effective when used intermittently for ET that is exacerbated by situational stress or anxiety, but its slow onset of action limits its utility in this setting. (See 'Primidone' below.)

Alternative options include judicious use of a low-dose short-acting benzodiazepine. In purely social settings, some patients find that a small amount of alcohol lessens tremor to an acceptable level. (See 'Benzodiazepines' below and 'Others' below.)

INITIAL PHARMACOTHERAPY

Choice of agent — Of the available medications for ET, evidence of efficacy is most robust for propranolol and primidone [1-3]. Although efficacy is similar and both are endorsed as clinically useful by expert guideline panels [2,3], we suggest propranolol as first-line therapy in most cases, based largely on side effect profile and drug interactions. Primidone is not commonly used as initial therapy except when there are contraindications to the use of propranolol.

Propranolol and primidone each may reduce tremor amplitude by approximately 50 percent [4], according to evidence from three small clinical trials that compared the two drugs [5-7]. In the first of these, both propranolol and primidone significantly and equally reduced limb tremor compared with placebo [5]. Equivalent tremor reduction was found in the second trial after one week of propranolol treatment and two weeks of primidone treatment [6]. In vitro, these medications have been shown to influence the expression of genes related to calcium signaling, endosomal sorting, axon guidance, and neuronal morphology [8].

Neither drug is effective for all patients with ET, however. In an open-label study that examined propranolol and primidone treatment for ET in 50 patients, propranolol had no therapeutic effect in 7 of 23 patients (30 percent) and primidone had no effect in 7 of 22 (32 percent) [7]. In addition, acute adverse reactions with primidone, especially drowsiness and ataxia, and chronic side effects of propranolol appear to be important limitations to the use of these drugs. However, some side effects of primidone can be self-limited (eg, "first-dose effect") and avoided by starting with a low dose and titrating as tolerated over several weeks.

Administration and efficacy

Propranolol — Propranolol is the best-studied beta blocker for ET. Several other nonselective beta blockers appear to have similar benefits but are not as well studied. If a beta-1 selective agent is desired due to comorbidities such as asthma/bronchospasm, atenolol is usually chosen but may not be as effective as propranolol. (See 'Other beta blockers' below.)

Beta blockers are thought to impact tremor severity through action on adrenoreceptors in a deep compartment within muscle spindles [9]. In mice, propranolol has been shown to modulate the spiking activity of Purkinje cells and cerebellar nuclei neurons [10].

●Dose and formulation – Either immediate-release or extended-release (once daily) propranolol can be used for ET, and they provide the same therapeutic response [4]. We prefer the extended-release formulation for daily use because it is more convenient [11].

The usual starting dose of propranolol for ET is 60 or 80 mg daily (divided two to four times per day for immediate-release). If a starting dose lower than 60 mg is desired due to comorbidities or advanced age, the immediate-release formulation can be used initially. The dose may be increased as needed at ≥1-week intervals up to a usual maximum of 360 mg daily [3]. The mean end-titration dose of propranolol for ET in nine trials was approximately 185 mg per day [2,4].

Single doses of immediate-release propranolol taken in anticipation of social situations that are likely to exacerbate tremor are useful in some patients. A single starting dose of 10 or 20 mg is suggested, which may be reasonably effective within an hour of taking the dose.

●Side effects – Side effects attributable to propranolol, including lightheadedness, fatigue, impotence, and bradycardia, occurred in 12 to 66 percent of patients in clinical trials [4]. As an example, one open-label study reported that such side effects led to discontinuation in 4 of 23 patients (17 percent) taking propranolol [7].

Propranolol is relatively contraindicated in the presence of heart block, unstable heart failure, asthma, and type 1 diabetes mellitus. (See "Major side effects of beta blockers", section on 'Heart failure' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

The American Academy of Neurology (AAN) guideline advises consultation with a cardiologist prior to starting propranolol in patients with cardiac disease [4].

●Efficacy – A 2019 systematic review by the International Parkinson and Movement Disorder Society (MDS) identified 13 randomized trials in a total of 225 patients with ET comparing propranolol with placebo (nine trials) or an active comparator (four trials) [3]. Daily doses of up to 360 mg were studied, and the median treatment duration was 3.5 weeks. Propranolol improved a range of outcome measures including tremor severity scores, task performance, activities of daily living, and objective accelerometer data. Overall, tremor magnitude was reduced by approximately 50 percent, and responder rates ranged from 50 to 70 percent [3,12,13]. Rates of functional improvement tended to be lower than responses measured by accelerometry.

Evidence to support the efficacy of propranolol for head and voice tremor is more limited and mixed [2-4]. The best-designed study, a randomized controlled trial involving 18 patients, found that propranolol reduced head tremor amplitude by approximately 50 percent, as measured by accelerometry [14]. However, propranolol was not effective for head tremor in two smaller studies [15,16]. It is important to remember that isolated head tremor suggests the presence of cervical dystonia, as opposed to essential tremor that is restricted to this area, and its management differs considerably. (See "Cervical dystonia: Treatment and prognosis".)

Primidone — Primidone is an antiseizure medication that is metabolized to phenobarbital and phenylethylmalonamide. The mechanism of action for ET is unknown, and neither metabolite appears to influence tremor when used alone [17,18]. Primidone is used less commonly than propranolol but has similar efficacy and is a reasonable alternative first-line agent for ET [3].

Primidone is a potent inducer of hepatic microsomal metabolizing enzymes. Thus, drug-drug interactions should be checked before primidone is added to existing medications. Specific interactions may be determined using the drug interactions program included within UpToDate.

●Dose – We suggest starting primidone at 25 mg (one-half of the available 50 mg tablet) once daily before sleep. The dose should be titrated up carefully over several weeks as tolerated and according to therapeutic response. One suggested regimen is to titrate in 25 mg increments every three to seven days to a maximum of 250 mg at night, according to response and side effects. Sedation is usually the limiting factor with rapid titration or higher doses. Titration can be even slower for older adults.

The medication should be withdrawn if there is no benefit using 250 mg each night. If there is a partial response at 250 mg nightly, the titration can continue up to 750 mg nightly as tolerated [3,19,20]. The mean end-titration dose of primidone for ET in three trials was approximately 480 mg/day [12,13].

●Side effects – Side effects from primidone are typically more severe at treatment initiation and may include sedation, drowsiness, fatigue, depression, nausea, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, and an uncommon acute toxic reaction [4]. In an open-label study, transient acute side effects occurred in 8 of 22 patients (36 percent) assigned to primidone [7]. Use of a very low dose of primidone (7.5 mg) for initiation and titration did not improve tolerability in one study [21].

Primidone may be better tolerated in patients with epilepsy in whom hepatic enzymes have been induced by the previous administration of phenobarbital or other antiseizure medications [22,23]. It is also possible that there are inherent characteristics of patients with ET that make them more prone to intolerance compared with epilepsy patients [23]. Nevertheless, stopping primidone because of adverse effects is not necessarily a contraindication to trying it again for ET; significant adverse effects may not recur if rechallenged with the medication, particularly if the rechallenge starting dose is low and the rate of increase is slow.

●Efficacy – Supportive evidence for primidone includes eight randomized trials in a total of 274 patients with ET comparing primidone with placebo (six trials) or an alternative formulation or dose of primidone (two trials) [3]. Doses studied ranged from 150 to 750 mg/day, and the average treatment duration was 10.1 weeks. Primidone improved tremor severity scores, task performance, and activities of daily living. A 12-month trial comparing two different doses of primidone (250 and 750 mg/day) found similar long-term efficacy and sustained benefit between the two doses. Primidone, up to 750 mg/day, is effective for the treatment of limb tremor associated with ET [2,4]. Similar to propranolol, tremor magnitude was reduced by approximately 50 percent, and clinical rating scales also improved by approximately 50 percent [3,12,13].

Supportive evidence for vocal tremor is insufficient to draw firm conclusions [3]. A retrospective series reported that primidone was associated with improvement in vocal symptoms in 14 of 26 patients (54 percent) [24]. Of note, this study used categorical, subjective vocal outcomes and did not have a control group.

Other beta blockers — Propranolol is the best-studied beta blocker for ET, but several other beta blockers, mainly nonselective agents, also have anti-tremor effects based on more limited evidence.

For nonselective agents like sotalol and nadolol, in most instances there is no advantage to using these drugs for ET, since the evidence is stronger for propranolol [3]. However, nadolol may still have a role, as it is a largely peripheral-acting beta blocker and may avoid adverse central effects that are sometimes induced by propranolol, such as depression [4,12,25-27].

Among beta-1 selective agents, atenolol is probably the best alternative to propranolol for patients with a relative contraindication to a nonselective beta blocker (eg, asthma or chronic obstructive lung disease). However, beta-1 selectivity is not absolute and may diminish at higher doses (eg, >100 mg daily) (see "Major side effects of beta blockers"). Metoprolol is of uncertain benefit for ET.

●Atenolol – Two small randomized trials in patients with ET found that atenolol improved symptoms [28] or accelerometer readings [29] compared with placebo. In the first study, which only included nine patients, atenolol was less effective than propranolol [28]; the second found that both atenolol and propranolol were similarly effective compared with placebo [29]. The dose range of atenolol studied for ET is 50 to 150 mg daily.

●Metoprolol – Data regarding its effectiveness are conflicting [4]. A randomized controlled trial found that a single dose of metoprolol 150 mg was effective for improving tremor [30]. However, a subsequent small, randomized, double-blind crossover study found that propranolol improved outcomes compared with placebo, but metoprolol did not [31].

It appears that patients who do not respond to adequate doses of one beta blocker for ET are unlikely to respond to another [25].

Duration of benefit — The symptomatic benefit of drugs used to treat ET declines over time, due either to disease progression or to the development of drug tolerance [1,12]. Propranolol and primidone remain effective for limb tremor reduction in most patients for at least one year, although increased doses of both drugs may be needed after 12 months of therapy [4].

SECOND-LINE THERAPIES — Medication options for ET that fails continuous treatment with first-line pharmacotherapy include using combination therapy with propranolol and primidone, switching to the other first-line agent, and adding or switching to a second-line agent such as topiramate, a benzodiazepine, or gabapentin. Success rates are generally lower for second-line agents, and side effects may be dose limiting, especially for combination therapy or in older adults.

When tolerated, we favor propranolol and primidone in combination before trying alternative second-line agents (see 'Propranolol plus primidone' below). For patients who fail first-line treatment due to side effects, we try the other first-line agent as monotherapy, when possible, before trying other second-line agents, which have less chance of benefit and/or more side effects.

For patients who fail or do not tolerate further pharmacologic treatment, options include use of adaptive devices, surgery with deep brain stimulation or thalamotomy to treat persistently disabling limb tremor, and botulinum toxin (BoNT) injections. (See 'Refractory tremor' below.)

Propranolol plus primidone — Propranolol plus primidone is our preferred second-line strategy for patients with inadequate benefit on first-line therapy, when possible, based on side effects and comorbidities. The combined use of these drugs is possibly more effective than either drug alone [4]. Supporting evidence includes two nonrandomized studies [17,32].

●One study found that propranolol monotherapy at the maximum effective dose (average 260 mg/day) reduced tremor amplitude by a mean of 35 percent; the addition of primidone, 50 to 1000 mg/day, decreased tremor amplitude by a mean of 60 to 70 percent [17]. Acute reactions to primidone, including ataxia and confusion, occurred in 12 percent, and primidone titration was limited in others because of sedation and vertigo.

●In a second study, the combined use of propranolol and primidone was more effective than either drug alone for the treatment of postural and kinetic tremor [32].

Topiramate — Topiramate, when used at doses >200 mg/day, is effective for reducing limb tremor associated with ET and improving functional disability, but its use is associated with a relatively high rate of adverse effects [33]. We avoid use in adults >70 years of age due to risk of cognitive side effects.

●Dose and side effects – The initial dose of topiramate is 25 mg once or twice a day, followed by weekly increases of 25 to 50 mg per day as tolerated up to a goal dose of at least 200 mg per day and a maximum total dose of 400 mg per day. The most common treatment-limiting adverse events in trials of topiramate for ET included paresthesias, reduced appetite, weight loss, somnolence, concentration/attention difficulty, and memory difficulty [33]. We avoid use of topiramate in patients over the age of 70 given the increased risk for cognitive side effects in this population.

●Efficacy – A 2019 systematic review identified four randomized controlled trials comparing topiramate with placebo as monotherapy or add-on therapy in a total of 322 patients with ET [3,33]. The mean effective dose of topiramate in three trials ranged from 215 to 333 mg/day; one trial assessing a 50 to 100 mg dose range did not show a benefit.

The largest controlled trial randomly assigned 223 patients with moderate to severe ET to 24 weeks of treatment with placebo or topiramate (target dose 400 mg daily) as either monotherapy or adjunct therapy [34]. Topiramate treatment at a mean final dose of 292 mg daily resulted in a significantly greater improvement in a tremor rating scale, the primary outcome measure, than placebo. The degree of clinical improvement with topiramate was considered moderate, whereas that seen with placebo was mild. However, the rate of treatment-limiting adverse events was higher with topiramate than placebo (31.9 versus 9.5 percent, respectively).

Benzodiazepines — Benzodiazepines are widely used because of the usually mistaken belief that tremor is due to anxiety. Be that as it may, in patients in whom tremor is aggravated by anxiety, an anxiolytic may partially reduce tremor.

Caution is urged with the use of benzodiazepines for ET because of the potential for abuse and dependence, as well as the potential for drug discontinuation to cause withdrawal symptoms (including seizures) and tremor rebound. These problems make benzodiazepines a second-line choice for the chronic treatment of ET. The two benzodiazepines that have been studied for ET are alprazolam and clonazepam.

●Alprazolam may be useful for the treatment of limb tremor associated with ET in select patients [2-4,12], although high-quality data are lacking [35]. Two small clinical trials found that alprazolam, 0.125 to 3 mg/day, was associated with an improvement in clinical rating scales of 25 to 34 percent compared with placebo [36,37]. Side effects included mild sedation and fatigue. A tremor reduction of 69 and 76 percent (according to electromyography [EMG] data recorded at 40 and 80 minutes, respectively, after a dose of alprazolam) was documented in a study involving eight patients [38].

●Clonazepam is occasionally used for the treatment of limb tremor associated with ET [2,4,12], although data are mixed. One clinical trial found that clonazepam 0.5 to 6 mg/day significantly reduced tremor [39], while another study found that clonazepam 0.4 to 4 mg/day was ineffective and resulted in a 40 percent study completion rate due to drowsiness [40].

Gabapentin — Gabapentin as monotherapy has antitremor effects in some patients with ET, but supporting data are very limited [4,12,41].

●Dose and side effects – If using gabapentin for ET, we suggest an initial dose of 100 to 300 mg three times daily, using the low end of the range for older adult patients. The dose can be titrated upwards as tolerated, typically by increasing the total daily dose by 300 mg every four to seven days. An effective range is not well established for ET, but 1200 mg daily was used in the only monotherapy trial [42]. Gabapentin may have fewer side effects than primidone but can cause sleepiness, dizziness, and gait unsteadiness, particularly in older adults.

●Efficacy – One small randomized controlled trial in six patients with new-onset ET and 10 patients previously treated with propranolol found that gabapentin 1200 mg/day reduced tremor compared with placebo [42]. Gabapentin as adjunct therapy has shown conflicting results for the treatment of ET [4,43,44].

Others — Antiseizure medications other than primidone, gabapentin, and topiramate have not shown consistent effects on ET, including levetiracetam [2,12,45-49], phenobarbital [2,4], zonisamide [50-54], and pregabalin [55-58]. The noncompetitive glutamate receptor antagonist perampanel was superior to placebo in reducing tremor severity in one small crossover trial; however, it was also much more likely to cause imbalance/falls, dizziness, and irritability [59].

Alcohol has long been known to ameliorate ET [60-62]. Although the exact mechanism is not fully understood, a controlled study of 20 subjects with ET undergoing electroencephalography (EEG), EMG, and structural magnetic resonance imaging (MRI) observed a robust relationship between contralateral cerebellar coherence and change in tremor amplitude following alcohol intake [63]. A peripheral mechanism for tremor control is also possible [61]. Patients will often describe that small amounts of alcohol taken before meals or social events provide temporary tremor control, although the tremor tends to worsen when the effect of alcohol wears off. Regular (daily) use of alcohol to manage tremor is strongly discouraged.

Whether other alcohols exist that might have the same benefits on tremor without intoxicating effects is not yet clear. Oral 1-octanol showed promise in preliminary studies as a treatment for ET [64-66]. However, a small trial of octanoic acid (a metabolite of 1-octanol) only demonstrated benefit at 180 minutes in one study [67], approximately 110 minutes past the drug's expected plasma peak. The authors believe this delayed effect was the result of a second compartment (the central nervous system). No intoxication was observed in these studies. In a subsequent crossover study in 14 volunteers with ET, a single dose of octanoic acid (4 mg/kg) reduced tremor power in both the central and the peripheral component, as demonstrated by accelerometry data [68].

REFRACTORY TREMOR

Adaptive devices — Several different devices are being developed to noninvasively modulate and/or compensate for tremor severity [69-71]. All patients with ET may find benefit from adaptive devices, but patients with disabling tremor who either are not candidates for other treatment modalities or have suboptimal tremor control with them may be the best candidates for these technologies. Examples include the following:

●Neuromodulation – In a randomized, sham-controlled pilot study involving 23 blinded subjects, noninvasive median and radial nerve stimulation resulted in an improvement in the Archimedes spiral drawing task [72]. Subsequent studies, including a larger sham-controlled trial in 77 patients and other open-label, lower quality studies, suggest that noninvasive neuromodulation therapy used repeatedly at home in 40-minute sessions is safe and improves patient-rated function and accelerometer-based tremor measurements during use of the device and for up to an hour afterwards [73-75].

●Biomechanical loading – Biomechanical loading refers to either the external application of force on a tremulous limb or the facilitation of antagonist muscle contraction within the limb to reduce tremor. At least two small research projects have explored different wearable robots to effectively suppress tremor [76]. One of the studies examined a robotic exoskeleton that applied forces to tremulous limbs, and the other was a neuroprosthesis capable of providing transcutaneous neurostimulation.

●Tremor cancellation devices – Commercially available tremor-canceling devices aim to facilitate activities such as eating in patients with hand tremor. In a double-blind study involving 15 study subjects, a noninvasive handheld device using Active Cancellation of Tremor (ACT) technology was shown to reduce tremor amplitude and severity for eating and transferring tasks [77]. The device used consists of a spoon or other utensil attachment, a motion-generating platform, a controller/sensor, and a power source.

●Local vibrational therapy – A small, uncontrolled study of a local hand-arm vibration device producing vibrations in the 8 to 18 Hz frequency range was found effective in some of the study subjects [78].

Botulinum toxin — Botulinum toxin (BoNT) injections have shown variable benefits in trials for hand, voice, and head tremor and are associated with dose-dependent risk of weakness in the injected muscles [2-4,12]. However, they are endorsed by an International Parkinson and Movement Disorder Society (MDS) evidence-based review as possibly useful in clinical practice with specialized monitoring [3]. We discuss the option of BoNT therapy in patients who cannot tolerate or are uninterested in trying oral medications for tremor.

Patient selection — The best candidates for upper limb injections are patients whose tremor amplitude is mild enough to respond to low doses of BoNT type A (BoNT-A) or patients with severe and disabling upper limb tremor who would prefer hand weakness over tremor. Although reversible once the effects of BoNT wear off, hand weakness can be disabling while present, particularly when the dominant hand is affected. Only experienced limb injectors should administer this procedure.

For head and vocal tremor, there are also trade-offs between benefits and side effects. BoNT-A for voice tremor is associated with side effects that include breathiness, hoarseness, and swallowing difficulty [2,4,79], and common side effects with head tremor injections include dysphagia and neck weakness, stiffness, and/or pain. BoNT for vocal tremor is best administered by an otolaryngology specialist with expertise in treating ET.

Administration and efficacy — In the United States, three different types of BoNT-A are marketed: abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), and onabotulinumtoxinA (Botox); the efficacy of BoNT type B for ET has not been evaluated [2,4].

●Limb tremor – When used for limb tremor, BoNT-A is injected into forearm muscles (flexor carpi radialis and ulnaris, and extensor carpi radialis and ulnaris muscles). In the largest trial, 133 patients with ET were randomly assigned to low-dose BoNT-A (50 units), high-dose BoNT-A (100 units), or placebo [80]. Short-term improvement in clinical rating scales was reported, but there was no consistent improvement in motor tasks or functional disability. Dose-dependent hand weakness was observed for the low- and high-dose BoNT-A groups (30 and 70 percent, respectively). Additional side effects of BoNT-A included injection site pain, stiffness, cramping, hematoma, and paresthesias [80]. These side effects are likely to have interfered with blinded treatment and evaluation [4].

In several studies, customized approaches to injection have improved the therapeutic ratio for hand tremor [81]. A blinded crossover trial in 33 patients with hand tremor investigated a customized approach to deliver 80 to 120 units of incobotulinumtoxinA into 8 to 14 hand and forearm muscles [82]. Compared with placebo, incobotulinumtoxinA injections led to improvements in tremor severity scores at four and eight weeks after injection. The incidence of hand weakness was very low (4 percent), in contrast to that observed in most previous studies (often >50 percent). The use of electromyography (EMG) [83] or of kinematic technology also seems to have a role in improving the efficacy of BoNT-A injections for hand tremor and minimizing toxin-derived weakness [84-86].

●Head tremor – When used for head tremor, BoNT-A is injected into sternocleidomastoid and splenius capitis muscles. In a randomized trial of 117 patients with essential or isolated head tremor, BoNT-A injections into each splenius capitus muscle improved patient-assessed head tremor severity compared with placebo injections, with expected waning of response by 12 weeks after each injection [87]. The proportion of patients with an improvement of at least two points on the clinical Global Impression of Change (CGI) scale at week 6 after the second injection was 31 percent in the BoNT-A group and 9 percent in the placebo group. Most secondary outcomes measuring function and objective tremor severity also favored BoNT-A. Adverse effects were more frequent with BoNT-A (47 versus 16 percent), most commonly headache or neck pain (34 percent), dysphagia (16 percent), posterior cervical weakness (15 percent), and cervical stiffness (10 percent). These results are consistent with earlier smaller studies [88,89].

●Voice tremor – For voice tremor, the injection target is one or both vocal folds. One study involving 15 patients found that self-reported benefit after BoNT-A occurred in 10 patients (67 percent) [90]. Side effects included voice weakness and breathiness lasting for one to two weeks after treatment in 12 patients (80 percent), and hoarseness and swallowing difficulty for four weeks in three patients (20 percent). Another study found that tremor severity was reduced after bilateral vocal cord injection in 3 of 10 patients (30 percent), and tremor was reduced after unilateral injection in two of nine patients (22 percent) [91]. Some patients undergoing injections may experience additive benefit from adjunctive oral medication [92].

Surgical therapies — Deep brain stimulation of the ventral intermediate nucleus of the thalamus, magnetic resonance imaging (MRI)-guided focused ultrasound, and stereotactic thalamotomy appear to be effective treatments for severely disabling, medication-resistant ET, as discussed in detail separately. (See "Surgical treatment of essential tremor".)

PROGNOSIS — Although prospective longitudinal data are limited, the usual course of ET is one of slow, gradual progression of tremor, which usually occurs over years [93,94]. Younger onset often correlates with a slower rate of progression, such that individuals with tremor since their teenage years may not require treatment until decades later.

Tremor often (but not always) starts in the hands and spreads to the neck and voice. Head tremor in patients with ET usually starts as an intermittent tremor in one direction (particularly "no-no") and eventually becomes more frequent and multiaxial [95]. ET may also remain stable in a minority of patients. However, a stable course should raise suspicion for an alternative diagnosis (eg, enhanced physiologic tremor or drug-induced tremor).

Although there are large variations in tremor amplitude and disability among patients with ET [1], it is a disabling condition for a substantial proportion of affected individuals [96,97]. Several reports suggest that functional disability in ET is associated with the amplitude of kinetic tremor in the upper limbs [32,98,99]. While prospective data are very limited, it has been suggested but not always agreed upon that ET may be associated with an increased risk for developing Parkinson disease [100]. Survival in ET does not differ from the general population [101].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Essential tremor".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Tremor (The Basics)")

●Beyond the Basics topics (see "Patient education: Tremor (Beyond the Basics)")

PATIENT PERSPECTIVE TOPICS — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Essential tremor with onset in childhood" and "Patient perspective: An artist with essential tremor".)

SUMMARY AND RECOMMENDATIONS

●Care setting – Essential tremor (ET) is the most common cause of action tremor in adults. In most cases, ET can be managed by primary care clinicians. Referral to a neurologist is appropriate when there is diagnostic uncertainty, poor response to standard pharmacotherapies, or disabling tremor. (See 'Introduction' above and 'Goals and expectations' above.)

●Criteria for treatment – Drug treatment should be offered to patients who have functional or psychological disability caused by tremor. Treatment of ET is symptomatic, and medications have variable benefits and side effects. (See 'Criteria for pharmacotherapy' above.)

●Initial pharmacotherapy – Of the available medications, evidence for efficacy is most robust for propranolol and primidone (algorithm 1). Efficacy is comparable between the two, and treatment selection and dosing are based on the nature of disability (frequent/daily or situational), side effects, drug interactions, and comorbidities.

•Frequent/daily symptoms – For most patients with frequent/daily functional or psychological disability due to ET, we suggest initial therapy with propranolol rather than primidone (Grade 2C). Primidone is a reasonable alternative to propranolol when there is a desire to avoid beta blockers, and slow titration can help with tolerability. (See 'Choice of agent' above.)

If a beta-1 selective beta blocker is preferred over propranolol due to comorbidities, atenolol is the best-studied alternative. (See 'Other beta blockers' above.)

•Situational exacerbations – For patients with mild ET who have situational exacerbations of tremor that cause disability, we suggest treatment as needed with low-dose, immediate-release propranolol (Grade 2C). Other intermittent options include judicious use of a low-dose short-acting benzodiazepine or primidone. (See 'Patients with situational exacerbations' above.)

●Second-line therapies – Success rates are generally lower for second-line agents, and side effects may be dose limiting, especially for combination therapy. When tolerated, we favor propranolol and primidone in combination before trying alternative second-line agents such as topiramate, benzodiazepines, and/or gabapentin. (See 'Second-line therapies' above.)

●Refractory tremor – For patients who fail pharmacologic treatment for ET, options include adaptive devices for limb tremor, surgery with deep brain stimulation or thalamotomy to treat persistently disabling limb tremor, and botulinum toxin (BoNT) injections to treat persistently disabling head or vocal cord tremor (algorithm 1). (See 'Refractory tremor' above.)

●Prognosis – The usual course of ET is one of slow, gradual progression. Younger onset often correlates with a slower rate of progression. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ludy Shih, MD, and Daniel Tarsy, MD, who contributed to earlier versions of this topic review.