Essential Tremor

Essential tremor (ET), the most common movement disorder, is an insidiously progressive often inheritable disorder usually beginning before the age of 50. It is characterized by involuntary rhythmical oscillations of a body part resulting from either alternating or synchronous contractions of opposing muscles. Tremor is essentially the only symptom present although subtle gait abnormalities may be present when the legs are affected. Weakness is not a primary symptom although tremor can in fact produce weakness by reducing the strength of contraction.

                The tremor is classically present in posture but may be exacerbated by action and may be present at rest. It most often occurs in the hands and arms but may also affect the head, voice, tongue and legs. Tremor frequency ranges from 4-12 Hz with a tendency towards the higher frequencies. The tremor is invariably worsened with stress, fatigue, and stimulant medications and is significantly improved by small amounts of alcohol. Although many features of  ET differ from those of Parkinson’s Disease, the two are often confused.

                Treatment for ET is individualized (figure1). Patients with significant functional impairment often opt for treatment. For some patients, the tremor may not be functionally disabling but instead may be a source of severe embarrassment causing social isolation, so that they also opt for treatment. The decision to treat pharmacologically is made when the degree of impairment or discomfort outweighs treatment side effects. 

Patient Education

Most patients being evaluated for ET are concerned that they have Parkinson's Disease and usually are greatly relieved to be told that they do not. They should be reassured that ET rarely leads to severe disability and that any progression of their symptoms will be very gradual. It should be made clear to them that any treatments offered will not result in a cure but will instead simply reduce their symptoms. They should be made aware that in at least 50% of the cases there is a family history of ET and that the disorder may be passed on to their children in an autosomal dominant fashion. Referral to support groups and to the International Tremor Foundation can help reduce some of the anxiety of being diagnosed with a chronic disease.

Nonmedical therapy           

                Although ET is thought to result from a central oscillator, perhaps in the inferior olive, a mechanical component of the tremor can be separated and dampened by weighting the limb (usually at the wrist). In a small proportion of patients, this can dampen the tremor effectively enough to improve functioning.

                Since anxiety/stress classically make the tremor worse, non-medical relaxation techniques and biofeedback can be effective in selected individuals. Likewise, medications known to exacerbate tremors should be eliminated or minimized. These include lithium, many antipsychotics, valproic acid, corticosteroids, tricyclic antidepressants and β- adrenergic agonists. Patients should be evaluated for hyperthyroidism since this state can induce tremors.

                Alcohol can be extremely effective in reducing tremor. Although there is a minor concern about alcohol addiction, small amounts of alcohol can be used prior to social events to reduce tremor. In fact, many patients have already discovered this on their own before coming to medical attention.           

Pharmacological therapy

Pharmacological therapies have largely been discovered by chance when patients with ET have been treated for other medical conditions. The mainstay medications include beta adrenergic blockers and primidone. Although propranolol has been used effectively to treat essential for several decades, it is not the medication of first choice. This is because chronic use of propranolol is often not well tolerated and there are several relative contraindications to its use.

Primidone

Primidone's efficacy in treating ET was first noted in a patient being treated for epilepsy. Its mechanism of action is not well understood but it may work directly on the neuronal oscillator or uncouple the oscillator from spinal pathways. Its efficacy does not appear to be mediated through phenobarbital, one of its metabolites. It has been shown to be effective in several controlled trials. Its use is often associated with transient, acute vertiginous reactions and feelings of unsteadiness and nausea when therapy is first initiated (the first dose phenomena). Sedation is also a common side effect. However, if patients are warned of the first dose phenomena and if treatment is initiated at small doses, most persons are able to tolerate it.. Long term studies indicate a lack of tolerance. The tremor amplitude but not frequency is reduced and it is most effective in the extremities compared to the head and voice. Granulocytopenia and red-cell hypoplasia have been rarely reported so that a complete blood count should be checked every 6-12 months. It is contraindicated in patients with porphyria.

Various schedules for gradually increasing the dose of primidone have been employed. Some of these involve beginning with a bedtime dose of 25-67.5 mg which is gradually increased over weeks to 250 mg, before increasing the total dose to 750-1000 mg in three divided doses. Others involve gradual increases beginning at 25 mg on a three times/day schedule (Figure 1). Patients are instructed to begin therapy on a night when they do not have work or social obligations the next day to minimize the inconvenience of the first dose phenomena. They are further instructed to continue at the dose in the schedule at which they are satisfied with the level of tremor control. Recent studies indicate little benefit above a dose of 250 mg. In various studies, 60-100% of patients demonstrate response to primidone.

Propranonol

Propranolol was also discovered by chance to be effective for ET.  β-adrenergic blocking agents are affective in 40-50% of patients. It appears that the effectiveness is mediated through peripheral b2 action, perhaps by reducing sensitivity of muscle spindles. Like primidone, the effects are less in reducing head and voice tremor. They should not be used in patients with bronchospastic disease because they may block bronchodilation. They should be used with caution in persons with diabetes on insulin because they may mask the tachycardia occurring during hypoglycemia. They are contraindicated in patients with congestive heart failure and heart block. They may reduce exercise tolerance, exacerbate depression, and cause impotence. Treatment may be begun with a single dose of  60 mg of the sustained-release preparation of propranolol.  This is gradually increased as needed and tolerated on a weekly basis to 240-300 mg/day. Patients should be cautioned about the possibility of hypotension and when appropriate, the blood pressure and pulse should be monitored during the titration period. In elderly patients, initiation with use of a smaller dose (10-20 mg) of the short-acting formulation may be better tolerated. Like primidone, tolerance to the drug is rare. Other beta-blockers such as atenolol, nadolol, metoprolol, and timolol may also be effective and with less side effects.

Combination therapy

If both primidone and propranolol are not effective alone, there may be a synergistic effect in combination and this should be tried unless there are contraindications. The dosing can proceed by adding the second drug according to the schedules stipulated above once primidone is at a dose of 750 mg/day, or propranolol at 300 mg/day.

Miscellaneous medications

Benzodiazepines, especially clonazepam, have long been used in the treatment of ET. There is little direct efficacy although relief of anxiety may indirectly lessen the tremor.  Because of the sedative effects, these should only be used rarely in individuals with a significant anxiety problem exacerbating the tremor.

Gabapentin, methazolamide, clonidine and calcium channel blockers have been suggested to be effective in treatment of ET but in placebo-controlled trials, they have not been shown to be efficacious. Clozapine was effective in an uncontrolled trial but requires frequent blood monitoring because of the risk of agranulocytosis. There is a recent report of efficacy of Remeron, but this has not yet been subjected to controlled trials.

Botulinum Toxin Injections

                Systemic medications are effective treatments for the tremor of the arms but not as much for voice and head tremor. Although head tremor rarely leads to impairment of functional abilities, the social embarrassment may be extreme causing social isolation. Several studies have shown that botulinum toxin  injections may significantly help the head tremor (as well as the voice tremor).  It is more common for patients to have lateral ("no-no") head tremors in which case doses of 50-150 units into each splenius capitus muscle and perhaps the sternocleidomastoid muscles is usually effective. If there is a dystonic component, a larger dose is given to the more affected side. If there is an anterior-posterior ("yes-yes") tremor, injections into the sternocleidomastoid muscle, and sometimes the scalene muscles, may be effective. Although the amplitude of hand tremors may be reduced with botulinum toxin, the injections are more difficult and there has not been shown to be clear functional improvement.

Surgical Treatments

                When patients do not achieve satisfactory control of their tremor with medical therapy, and there is significant functional impairment, surgical options should be considered. The ventralis intermedius (VIM) of the thalamus has been empirically shown to be the preferred site for either stereotactic lesions or deep brain stimulation. Thalamotomy has been employed for decades and between 80-100% of patients have sustained benefit. There are postoperative complications including numbness, dysarthria, gait problems and cognitive changes. However, less than 10% of patients have sustained morbidity. Bilateral thalamotomies result in significant dysarthria.

                Deep brain thalamic stimulation at high frequencies (above 100 Hz) is effective in most patients and appears to be a safer option. Advantages include that it creates a reversible lesion, the stimulus parameters can be changed in response to waning efficacy, and it can be used safely for bilateral treatment.

In summary, treatment of essential tremor can be quite satisfactory and a systematic approach should be taken (Figure 1). This should begin with conservative approaches, followed by systemic pharmacologic treatments, focal treatments with botulinum toxin, and if necessary, thalamotomy or deep brain stimulation of the VIM nucleus of the thalamus.

 

Suggested Reading

Deuschl G, Bain P, Brin M (1998) Consensus Statement of the Movement Disorder Society on Tremor. Movement Disorders, 13: 2-23

Koller WC (1986) Dose Response Relationship of Propranolol in Essential Tremor. Arch Neurology, 35:42-43

Koller WC, Royse VL (1986) Efficacy of Primidone in Essential Tremor. Neurology, 36:121-124.

Wasielewski PG, Burns JM, Koller WC,(1998) Pharmacologic Treatment of Tremor. Movement Disorders, 13:90-100

 

Patient Resource

International Tremor Foundation - 7046 West 105th Street, Overland Park, KS 66212-1803, Phone: 913-341-3880, Fax: 913-341-1206, email: IntTremorFnd@worldnet.att.com, Web site: www.essentialtremor.org.

Figure 2 Titration of Primidone in Treating Essential Tremor

 

Mysoline (Primidine) to treat Essential Tremor: Information, dosing and diary

 

Mysoline is effective treatment for essential tremor. It is a drug used in individuals with seizure disorders. The most common side effects are vertigo and unsteadiness which tend to disappear with continued therapy. There is occasional nausea, loss of appetite, vomiting, fatigue as well as other symptoms. In order to avoid these side effects, the dose is gradually increased using initially 50 mg tablets. Call if you have any side effect which you are concerned about. Follow the schedule below and make comments as required. Fill in the small squares after each day.

 

 

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Figure 1 Management of Essential Tremor

Combination Primidone and

Propranolol

 

Thalamotomy or

Deep Brain Stimulation of Thalamus

 
 

 

 

 

 

 


                                                                                                                                                               

 

Text Box: Yes Text Box: No
 

 

 

 

 

 

 

 

 

 

 

 


Text Box: Not improvedText Box:   Not improved

Consider botulinum toxin injections,

Alternate medications

 
Text Box:   Not improved