Essential tremor: Choosing the right management plan for your patient
ABSTRACTEssential tremor is a common neurologic problem seen widely at all levels of patient care. It should be differentiated from secondary causes of tremor and Parkinson disease. It can be managed with commonly used drugs. However, severe, resistant, or atypical cases should be referred to a specialist for evaluation and the possible use of botulinum toxin or deep brain stimulation.
KEY POINTS
- In addition to motor dysfunction, the tremor can also have a significant psychological impact on the patient, especially since it usually gets worse in social situations.
- Essential tremor is a clinical diagnosis. After a thorough review of the medical history and medication exposures, laboratory and imaging tests may be ordered to rule out a secondary cause.
- The two first-line agents in drug therapy for essential tremor are the nonselective beta-blocker propranolol (Inderal) and the antiepileptic primidone (Mysoline). They can be used alone or in combination.
- Botulinum toxin injection and deep brain stimulation are reserved for resistant tremor or for patients who do not tolerate drug therapy.
Primidone
Primidone (Mysoline) is an antiepileptic drug structurally similar to barbiturates. Its antitremor effect is equal to that of propranolol, though some studies suggest it is slightly more efficacious.30,31
It should be started at a low dose, ie, 25 mg once daily at bedtime. The dose should then be increased gradually until satisfactory and tolerable tremor control is achieved. Most patients respond to doses of around 250 mg per day.1,22,24–25 The dose can be increased if needed and tolerated.
Primidone reduces tremor by about 50% to 60%.1,22,24–25 Side effects include sedation, dizziness, fatigue, nausea, and depression, as well as ataxia and confusion in severe cases.
A good candidate for primidone in essential tremor is:
- A patient with no known contraindication to primidone
- A patient with contraindications to propranolol
- A younger patient
- A patient with epilepsy.
Absolute contraindications to primidone include:
- Confusion or dementia
- Oral anticoagulant therapy with difficulty controlling the International Normalized Ratio (primidone is a potent enzyme inducer).
Relative contraindications to primidone in essential tremor are:
- Depression
- Alcohol abuse
- Ongoing therapy with sedating drugs
- Ataxia or vertigo.
SECOND-LINE AGENTS
Other antiepileptics
Topiramate (Topamax) is a broad-spectrum antiepileptic shown to be significantly effective against essential tremor.32 It is usually started at a single daily dose of 25 mg and increased gradually to the most effective dose, usually around 300 mg.
Side effects include reduced appetite, weight loss, cognitive dysfunction, and paresthesia.
Favorable candidates include patients who are epileptic or overweight. Contraindications include cognitive impairment and low body weight. It is also not recommended in children so as to avoid any possible negative effect on cognitive development. In rare cases, topiramate has been reported to cause significant visual disturbances.
Gabapentin (Neurontin) is an antiepileptic that is now more often used as a symptomatic treatment for neuropathic pain. Studies have suggested a beneficial effect on essential tremor,33,34 but some investigators have questioned its efficacy.35
Like other antitremor agents, it should be started at a low dose, ie, around 300 mg, and escalated gradually until the tremor is controlled. The usual effective dose is 1,200 mg.
Gabapentin is generally well tolerated, and side effects such as dizziness, drowsiness, sedation, and unsteadiness are rare and usually mild.
The favorable candidate is a patient with associated neuropathy or multiple comorbidities. Gabapentin has also been reported to alleviate neuropathic tremor.
Contraindications are minimal and include intolerability or hypersensitivity to the drug. It also should be avoided in patients at a high risk of falling.
Levetiracetam (Keppra) is a novel antiepileptic effective against partial seizures. Studies have shown contradictory results regarding its antitremor effect. One double-blind, placebo-controlled study demonstrated significant reduction in essential tremor with 1,000 mg of levetiracetam.36 However, its effect on tremor is believed to be short-lived, and some studies argue against its efficacy.37 It has a favorable side-effect profile and is generally very well tolerated. It can be used as an adjunct to other antitremor agents and is preferred for patients with coexisting partial seizures or myoclonus.
Benzodiazepines. Minor tranquilizers are often used to control tremor, especially in coexisting anxiety or insomnia. Alprazolam (Xanax) is the one most widely used for this indication.38 It can be started in a dose of 0.25 mg once at bedtime and increased gradually up to 0.75 to 2 mg. Clonazepam (Klonopin) is particularly useful for orthostatic tremor, a variant of essential tremor characterized by tremor of the legs and trunk upon standing.39
Common side effects of benzodiazepines include sedation, cognitive dysfunction, hypotension, respiratory inhibition, and addiction after prolonged use. In the elderly, they can lead to confusion and disinhibition and can increase the risk of falling. They should be avoided in the elderly and in alcoholic patients and those with a high risk of substance abuse.
Stopping benzodiazepines should be done gradually to avoid withdrawal symptoms, including aggravation of tremor.
THIRD-LINE AGENTS
Clozapine
Clozapine (Clozaril) is a novel antipsychotic drug with no extrapyramidal side effects. It has been reported effective in essential tremor and drug-induced tremor,40,41 but the results of these early studies have not been confirmed.
Clozapine is started as a single daily dose of 12.5 mg and is increased up to 75 mg or 100 mg. It is an attractive option for patients with coexisting psychosis, bipolar disorder, or chorea. Its main side effects are sedation, salivation, weight gain, hypertension, diabetes, and seizures.
One especially serious side effect is agranulocytosis. This potentially fatal effect is rare, occurring in about 1.3% of patients receiving this drug. Weekly monitoring of the white blood cell count is mandated during treatment with clozapine, and this has made clozapine a less attractive option for the routine treatment of essential tremor.
Mirtazapine
Mirtazapine (Remeron) is a novel antidepressant widely used in Parkinson disease as both an antidepressant and a sleeping aid. Case studies have reported efficacy in both essential tremor and parkinsonian tremor,42 but controlled studies have not confirmed this.43 Mirtazapine is a reasonable option in patients with coexisting depression or insomnia. It is usually given as a single bedtime dose of 15 to 30 mg.
Other drugs
Studies of other agents for the treatment of essential tremor—eg, carbonic anhydrase enzyme inhibitors, calcium channel blockers, isoniazid (Tubizid), clonidine (Catapres), phenobarbital, and theophylline—have yielded highly contradictory results. Thus, they are not recommended as first- or second-line agents for essential tremor.
