Essential Tremor Treatment & Management

Primidone and propranolol are the cornerstones of maintenance medical therapy for essential tremor. These medications provide good benefit, reducing tremor amplitude in approximately 50–70% of patients. ^{[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.