WORKUP	Section 5 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

Lab Studies:

• No biological markers exist for ET.

• If the family history and examination findings are indicative of ET, no laboratory or imaging studies are required.

• If the family history and examination findings are not indicative of ET, laboratory and imaging studies should be considered.

• Laboratory investigations include standard electrolyte panel, thyroid function tests, BUN, creatinine, liver function tests, and serum ceruloplasmin (for Wilson disease).

Imaging Studies:

• Findings on CT scanning and MRI of the head are normal in ET. MRI helps exclude structural and inflammatory lesions (including multiple sclerosis) and Wilson disease. MRI should be performed if the tremor has acute onset or stepwise progression.

Procedures:

• Electromyography or accelerometry can be used to assess tremor frequency, rhythmicity, and amplitude but are not part of the routine evaluation.

	TREATMENT	Section 6 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

Medical Care: Primidone and propranolol are the cornerstones of maintenance medical therapy for ET. These medications provide good benefit in reducing tremor amplitude in approximately 75% of patients.

For patients who require symptomatic therapy, one or the other of these medications is introduced at a low dose and increased slowly until sufficient benefit is achieved or the usual maximum dosage is reached (see Medication for dosing suggestions). If no benefit is derived, the medication is weaned and discontinued. If a partial benefit occurs, the other medication is added and slowly increased until sufficient benefit is achieved or the usual maximum dosage is reached. If no additional benefit occurs, this medication is then weaned and discontinued. 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 half hour prior to the event. Alcohol consumption is not an appropriate maintenance therapy for patients who seek tremor reduction throughout the day.

• 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 effect of ethanol is mediated centrally.

• Propranolol
  • Winkler first noted remarkable tremor reduction in a patient treated with propranolol for paroxysmal atrial tachycardia.

  • In a double-blind crossover study, propranolol at doses from 60-240 mg/d reduced tremor in 75% of patients with ET. In a dose-response study, 240-320 mg/d was found to be the optimal dose range with no additional benefits above 320 mg/d.

  • Average tremor reduction is 50-60%, but some patients experience marked tremor reduction and others no benefit.

  • The mechanism of action probably is related to peripheral beta2-receptor antagonism.

  • The long-acting formulation of propranolol has an efficacy similar to 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 antagonists. Metoprolol, a relatively selective beta1 antagonist, may be useful in patients with asthma and other pulmonary conditions.

• Primidone
  • O'Brien initially observed that primidone, when administered to a patient with epilepsy and ET, 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/d did not provide additional benefit.

  • The 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 low dose and slowly increasing the dose. A suspension is available that allows even more gradual introduction. However, some patients are unable to tolerate primidone even at very low doses.

• Topiramate
  • Topiramate is an anticonvulsant medication that enhances gamma-aminobutyric acid 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.

  • Multiple studies indicate that tremor is reduced by an average of approximately 20% when compared to placebo.

  • Clinical trials indicate a fairly substantial dropout rate of 40% because of adverse effects such as cognitive difficulty or somnolence.

• Many other medications have been reported to be of benefit in the treatment of ET. Most of these have been case reports or small open-label studies.

• Clozapine
  • A single dose of 12.5 mg of clozapine and placebo were compared in a randomized, double-blind crossover study in patients with drug-resistant ET. Tremor was reduced significantly by clozapine in 13 of 15 patients (P <0.01).

  • A significant reduction of tremor was reported with long-term (open-label) clozapine therapy (39.9 mg/d).

  • No tolerance was observed over 15 months.

• Mirtazapine
  • In a small, open-label case series, mirtazapine was reported to reduce tremor in patients with ET and PD.

  • Currently the authors often try mirtazapine as a second-line agent.

• Gabapentin: A double-blind crossover trial comparing gabapentin (400 mg tid) to propranolol (40 mg tid) found that both drugs demonstrated significant and comparable reductions in tremor compared to baseline. However, a double-blind, placebo-controlled crossover study identified no difference between gabapentin and placebo.

• Benzodiazepines: Benzodiazepines, particularly clonazepam and alprazolam, are used commonly in the treatment of ET, but their effectiveness is limited. They probably work to reduce the anxiety that can amplify tremor amplitude.

• Botulinum toxin: Botulinum toxin has been evaluated for the treatment of ET. 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.

• Practical management of pharmacologic therapy
  • For patients who require daily maintenance treatment for ET, a decision is made whether to start with primidone or propranolol. Usually, propranolol is started first in younger individuals and primidone is started first in older individuals. Generally, propranolol has increased risk of serious adverse effects in older patients than in younger patients. 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 do.

  • If the patient has a relative contraindication to propranolol, such as pulmonary disease or heart block, starting with primidone is preferable; a beta1 antagonist can be tried if necessary.

  • If the patient receives no benefit from the first medication, it is weaned and discontinued before starting the other. If the benefit is partial but insufficient, the initial medication is maintained and the other medication is added.

  • Once an effective maintenance dose of propranolol is achieved, switching to the long-acting preparation is considered. An alternative is to use the long-acting formulation from the beginning, but this requires multiple prescriptions and is more cumbersome.

  • If sufficient benefit is not achieved with primidone or propranolol, other medications are considered based on the severity of the residual tremor.
    • The authors often try mirtazapine as a second-line agent.

    • If the tremor is mild and more of a nuisance than disabling, a benzodiazepine is considered, usually clonazepam.

    • If the tremor is severe or causing disability, clozapine is introduced next. Blood monitoring is required with this drug, and patients sign informed consent because of the rare risk of agranulocytosis.

    • For patients with head tremor, cervical injections of botulinum toxin may be given.

Surgical Care: For patients with medically refractory disabling upper extremity tremor, surgery is considered. Stereotactic thalamotomy and thalamic ventralis intermedius nucleus deep brain stimulation (DBS) are the procedures of choice.

Both procedures offer high rates of tremor reduction in the contralateral arm. Recent information suggests that they are also useful in reducing head and voice tremor. 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 rate of 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 already had a unilateral thalamotomy in an effort to avoid the potentially serious complications of bilateral thalamotomy. Thalamic stimulation now is considered an alternative to thalamotomy as the initial procedure of choice. Long-term efficacy and adverse events are still being defined.

• Thalamotomy

• In 1997, a retrospective study by Jankovic et al evaluated 60 patients who underwent thalamotomy for medically intractable tremor. Forty-two had PD, 6 had ET, 6 had cerebellar tremor, and 6 had posttraumatic tremor. Patients were observed for a mean 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 PD, 83% of patients with ET, 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, dysarthria in 6, contralateral ataxia in 1, blepharospasm in 1, and pulmonary embolus resulting in death in 1.

• A study of thalamotomy in 8 patients with ET by Goldman demonstrated a reduction in tremor from moderate-to-severe to mild or no tremor in all 8 patients. Mild persistent dysarthria was seen in 2, and a "mild verbal cognitive defect" was seen in 1.

• Stereotactic thalamotomy is less expensive than DBS, 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.

• Thalamic deep brain stimulation

• In a multicenter study, high-frequency unilateral thalamic stimulation was assessed in 29 patients with ET and 24 with PD. A blinded evaluation at 3 months with patients randomized to stimulation on or stimulation off demonstrated a significant reduction in both ET and PD contralateral tremor with stimulation on. Measures of function were improved significantly in patients with ET. Stimulation was associated commonly with transient paresthesias. Other adverse events were mild and well tolerated.

• In 1998, Ondo et al reported an average 83% reduction in contralateral arm tremor in a study of 14 patients with ET.

• In 1999, Pahwa et al reported good results with bilateral thalamic DBS in 9 patients with ET. 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), postoperative seizures (1), hematoma over the implanted pulse generator (1), lead repositioning (1), and IPG malfunction (1). Adverse effects related to stimulation were mild and resolved with adjustment of stimulation parameters.

• In a 1999 report, Taha et al evaluated thalamic DBS contralateral to thalamotomy in 23 patients (6 with PD, 15 with ET, and 2 with multiple sclerosis); of 20 patients with bilateral limb tremor, 85% improved to having no tremor or only stress-induced tremor. The main advantage of thalamic DBS is that it is adjustable; adverse effects from stimulation can be controlled by reducing stimulation. Disadvantages of DBS include expense, foreign body implant, need to optimize parameters, and hardware maintenance including battery replacement after several years.

• Thalamotomy versus thalamic deep brain stimulation
  • In 1998, a retrospective comparison by Tasker of DBS and thalamotomy in ET and PD 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 DBS group, and recurrence in 15% of the DBS group and 5% of the thalamotomy group. Fifteen percent of thalamotomies and none of the DBS implants had to be repeated. Side effects, including ataxia, dysarthria, and gait disturbance, were more common with thalamotomy (42%) than DBS (26%); side effects were persistent in 31% of people undergoing thalamotomy; and those occurring after DBS were almost always controlled by adjusting stimulation parameters. Paresthesias were persistent in 19% of patients undergoing thalamotomy and were avoidable in DBS by parameter modification.

  • In a prospective study in 2000, Schuurman et al compared thalamic stimulation and thalamotomy in a prospective randomized study of 68 patients with PD, ET, or multiple sclerosis. 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 to 27 of 34 patients in the thalamotomy group. One patient in the stimulation group died perioperatively after an intracerebral hemorrhage. These investigators 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 a recently reported, 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.

	MEDICATION	Section 7 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

Beta-adrenergic blockers (principally propranolol) and primidone are the first-line treatment for ET. 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 more prominent later in treatment with propranolol. Starting with propranolol is preferable in younger individuals, and primidone is started first in older individuals.

Patients are usually started on one of these medications. The drug is introduced at a low dose that is increased slowly until complete response, tolerance, or usual maximum dose is attained. If some benefit is achieved but is incomplete, the other medication may be introduced and 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 rather than frequency 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 the antidepressant mirtazapine. Clozapine, an atypical neuroleptic, has been shown to be effective in a randomized, double-blind crossover study of patients who had definite or probable ET and poor response to propranolol or primidone. Thirteen of 15 patients demonstrated greater than 50% improvement of upper extremity tremor with 12.5 mg of clozapine.

Drug Category: Beta-adrenergic blockers -- The mechanism of action in the reduction of ET 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.

Drug Name	Propranolol hydrochloride (Inderal, Betachron ER) -- One of 2 medications of choice for ET, shown to be effective in double-blind, placebo-controlled trials. Nonselective beta-adrenergic blocker with negative inotropic, chronotropic, and dromotropic properties. Lipophilic with CNS effects. Mechanism of action probably related to peripheral beta2 antagonism. Long-acting formulation has efficacy similar to that of standard formulation and may allow fewer daily doses. In general, beta1 antagonists are more effective than placebo but are not as effective as beta2 antagonists. Metoprolol, a relatively selective beta1 antagonist, may be useful in patients with asthma and other pulmonary conditions.
Adult Dose	20 mg PO qam initially; increase by 20 mg/d qwk to 20 mg tid; continue increase by 20 mg/d qwk until tremor is adequately controlled, adverse effects become intolerable, or usual maximum of 240-320 mg/d is reached Effective dose range is 40-320 mg/d in divided doses; typical dose range is 120 mg (40 mg tid) to 240 mg/d
Pediatric Dose	Not established; dosing for other indications ranges from 1-4 mg/kg/d in divided doses
Contraindications	Documented hypersensitivity; sinus bradycardia; second- or third-degree heart block; congestive heart failure; cardiogenic shock; allergic bronchospastic disease; Raynaud disease; malignant hypertension
Interactions	Catecholamine-depleting drugs may produce excessive reduction in resting sympathetic nervous activity, resulting in hypotension, marked bradycardia, vertigo, syncopal attack, or orthostatic hypotension; calcium channel blockers, particularly verapamil, may decrease cardiac contractility or AV conduction; anti-arrhythmic drugs may increase cardiac effects; phenothiazines may have additive hypotensive activity; chlorpromazine may reduce clearance; high doses may potentiate effects of neuromuscular blocking agents; cimetidine can reduce clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in diabetes mellitus, myasthenia, nonallergic bronchospastic disease, and impaired hepatic or renal function; potential adverse effects include bradycardia, hypotension, heart failure, fatigue, depression, weight gain, male impotence, nausea, diarrhea, and rash; lethargy, fatigue, and depression may emerge over time; relative contraindications include heart failure, second- or third-degree AV block, asthma, chronic obstructive pulmonary disease, and insulin-dependent diabetes mellitus; may mask symptoms of thyrotoxicosis or hypoglycemia or interfere with glaucoma screening tests; abrupt withdrawal may precipitate unstable angina or myocardial infarction in patients with angina or coronary artery disease

Drug Category: Anticonvulsant agents -- Both primidone and, to a lesser extent, phenobarbital have demonstrated tremor-suppressing effects. Mechanism of action is unknown, but it presumably involves the CNS.

Drug Name	Primidone (Mysoline) -- Metabolized to phenobarbital and PEMA. 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 independent mechanism for its effect on tremor. Strongly recommended that treatment be initiated with low doses because adverse effects at initiation of treatment are common. Start with one quarter or one half of 50-mg tablet at bedtime and increase dose slowly every week. Alternatively, introduce primidone using 250 mg/5 mL suspension. Start with 1 drop at bedtime and increase dose by 1 drop each night for 20 nights. Then convert to 50-mg tab and increase slowly every week. For patients who initially respond but develop tolerance later, increasing dose to as high as 1000 mg/d in effort to regain benefit is advisable.
Adult Dose	25 mg/d (half of 50-mg tab) PO qhs, then increase by 25 mg/d qwk to dose of 100 mg/d When further increase is required, split dose one third in morning and two thirds at bedtime, up to usual maximum daily dose of 300 mg/d Usual dose range is 12.5-250 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; porphyria
Interactions	Alcohol, phenobarbital, heparin, isoniazid, and phenytoin increase blood levels; phenobarbital, a metabolite of primidone, is both competitive inhibitor and inducer of hepatic enzymes; enhances hepatic clearance of oral contraceptives, steroids, calcium channel blockers, theophylline, digitoxin, acetaminophen, cimetidine, cyclosporin, lamotrigine, felbamate, topiramate, and tiagabine; has variable interactions with phenytoin
Pregnancy	D - Unsafe in pregnancy
Precautions	Potential adverse effects include sedation, ataxia, vertigo, dizziness, nausea, vomiting, diplopia, and nystagmus; these effects usually occur, if at all, early in course of treatment and may occur with first dose; other adverse effects include maculopapular and morbilliform rash, leukopenia, thrombocytopenia, SLE, and lymphadenopathy; ataxia and vertigo very common and tend to resolve with repeated use; overdose produces symptoms similar to barbiturate overdose, including profound CNS depression, shock, and respiratory depression; caution in patients with renal or hepatic impairment; abrupt discontinuation of medication may precipitate status epilepticus; caution in pulmonary insufficiency; may have paradoxical effects in children, including irritability, hyperactivity, and disturbed sleep

Drug Name	Topiramate (Topamax) -- Mechanism of action unknown but blockage of voltage-dependent sodium channels and augmentation of GABA thought to play a role. Not extensively metabolized and excreted unchanged in the urine.
Adult Dose	25 mg/d PO and increase 25 mg/wk in divided doses to maximum dose of 400 mg/d (200 mg bid)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Phenytoin, carbamazepine, and valproic acid can significantly decrease topiramate levels; topiramate reduces digoxin and norethindrone levels when administered concomitantly; concomitant use with carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; use topiramate with extreme caution when administering concurrently with CNS depressants because may have an additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Risk of developing a kidney stone is increased 2-4 times over that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; patients taking topiramate should seek immediate medical attention if they experience blurred vision or periorbital pain; continued usage after symptoms develop can lead to glaucoma; primary treatment is discontinuation of topiramate; if left untreated, serious sequelae, including permanent vision loss, may occur; oligohidrosis and hyperthermia has been reported predominantly in children during vigorous exercise or exposure to warm environmental temperatures (ensure proper hydration prior and during activity and warm temperatures); may cause hyperchloremic nonanion gap metabolic acidosis, acute or chronic metabolic acidosis resulting in hyperventilation, and nonspecific symptoms, such as fatigue and anorexia; more severe adverse effects include cardiac arrhythmias or stupor; chronic untreated metabolic acidosis may increase nephrolithiasis or nephrocalcinosis risk, osteomalacia (ie, rickets in pediatric patients), or osteoporosis with an increased risk for bone fractures; chronic metabolic acidosis in pediatric patients may also reduce growth rates; measure baseline and periodic serum bicarbonate

Drug Category: Atypical neuroleptics -- In a randomized, double-blind crossover study of 15 patients who had definite or probable ET and poor response to propranolol or primidone, 13 showed greater than 50% improvement of upper extremity tremor with 12.5 mg of clozapine.

Drug Name	Clozapine (Clozaril) -- Mechanism of effect in ET unknown. Long-term effects in ET have not been studied. May be tried before resorting to surgery when other methods have failed. Weakly antidopaminergic, antiadrenergic (alpha1 and alpha2 receptors), anticholinergic, antihistaminergic (H1, H3), and antiserotonergic (5-HT1c, 5-HT2, 5-HT3).
Adult Dose	Start at dose of 12.5 mg/d PO or less; introduce using a chip (~1/8) of a 25-mg tab and increase slowly Usual dose 12.5-50 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; myeloproliferative disorders; uncontrolled epilepsy; severe CNS depression or comatose state; history of agranulocytosis or severe granulocytopenia induced by clozapine
Interactions	Should not be used with drugs known to cause agranulocytosis or otherwise suppress bone marrow function; increases anticholinergic effect of anticholinergics; because of CNS depressive effects, should not be used with alcohol; respiratory and cardiac functions should be monitored when used with other psychotropic drugs, particularly benzodiazepines; because protein bound, may cause elevations in plasma concentrations of other protein-bound drugs, such as warfarin or digitoxin; cimetidine, erythromycin, and SSRIs may increase plasma levels; phenytoin or carbamazepine may decrease plasma levels; drugs that are metabolized by cytochrome P450 2D6 may affect levels of either clozapine or other drug
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Frequent blood monitoring required because of risk of agranulocytosis, recommended baseline WBC count and differential prior to treatment and WBC count qwk for 6 mo; if WBC maintained at >3000/mm3 and ANC maintained at >1500/mm3, then testing may be carried out on alternate wk until 4 wk after drug discontinued Other potential adverse effects include seizures, sedation, dizziness/vertigo, delirium, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects; sedation commonly resolves after several wk

Drug Category: Antidepressant agents -- In a recent case series report, 4 patients (3 with PD and 1 with ET) who had responded initially to propranolol had improvement of tremor with mirtazapine.

Drug Name	Mirtazapine (Remeron) -- Potent 5-HT2, 5-HT3, and H1 antagonist; moderate peripheral alpha1-adrenergic antagonist and moderate antagonist of muscarinic receptors. Half-life is 20-40 h.
Adult Dose	15 mg/d PO qam initially (limited data available); increase to 15 mg PO bid if necessary Usual dose 15-45 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; MAOI use within last 14 d; caution in patients with mania or hypomania
Interactions	If used with MAOIs may have serious and sometimes fatal interactions
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with bipolar disorder or hypomania, may precipitate mania; potential adverse effects include somnolence, dizziness, increased appetite, and increased transaminases; rare cases of symptomatic agranulocytosis (2 of 2796) and 1 case of severe neutropenia reported—all recovered with discontinuation of medication; can cause orthostatic hypotension; use with care in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension or in patients predisposed to hypotension; discontinue drug in patients with signs or symptoms of neutropenia or agranulocytosis; clearance decreased in liver or kidney disease and in elderly people, particularly elderly men (as much as 40%)

	FOLLOW-UP	Section 8 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

Further Outpatient Care:

• ET is slowly progressive; therefore, medication doses may need to be adjusted. 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. Frequency of follow-up must be individualized.

• ET is often familial; follow-up with family members may be appropriate. Concerns about disability arising in family members may need to be addressed.

Patient Education:

• For excellent patient education articles, see eMedicine's Brain and Nervous System Center.

	BIBLIOGRAPHY	Section 9 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

• Agundez JA, Jimenez-Jimenez FJ, Tejeda R, et al: CYP2D6 polymorphism is not associated with essential tremor. Eur Neurol 1997; 38(2): 99-104[Medline].
• Bain PG, Findley LJ, Thompson PD, et al: A study of hereditary essential tremor. Brain 1994 Aug; 117 ( Pt 4): 805-24[Medline].
• Benabid AL, Pollak P, Gao D, et al: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996 Feb; 84(2): 203-14[Medline].
• Boecker H, Wills AJ, Ceballos-Baumann A, et al: The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study. Ann Neurol 1996 May; 39(5): 650-8[Medline].
• Brin MF, Koller W: Epidemiology and genetics of essential tremor. Mov Disord 1998; 13 Suppl 3: 55-63[Medline].
• Bucher SF, Seelos KC, Dodel RC, et al: Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol 1997 Jan; 41(1): 32-40[Medline].
• Busenbark K, Barnes P, Lyons K, et al: Accuracy of reported family histories of essential tremor. Neurology 1996 Jul; 47(1): 264-5[Medline].
• Chouinard S, Louis ED, Fahn S: Agreement among movement disorder specialists on the clinical diagnosis of essential tremor. Mov Disord 1997 Nov; 12(6): 973-6[Medline].
• Cleeves L, Findley LJ: Beta-adrenoreceptor mechanisms in essential tremor: a comparative single dose study of the effect of a non-selective and a beta-2 selective adrenoreceptor antagonist. J Neurol Neurosurg Psychiatry 1984 Sep; 47(9): 976-82[Medline].
• Critchley M: Observations on Essential (Heredofamilial) Tremor. Brain 1949; 72: 113-139.
• Deuschl G, Bain P, Brin M: Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998; 13 Suppl 3: 2-23[Medline].
• Factor SA, Friedman JH: The emerging role of clozapine in the treatment of movement disorders. Mov Disord 1997 Jul; 12(4): 483-96[Medline].
• Gironell A, Kulisevsky J, Barbanoj M, et al: A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol 1999 Apr; 56(4): 475-80[Medline].
• Gorman WP, Cooper R, Pocock P, Campbell MJ: A comparison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry 1986 Jan; 49(1): 64-8[Medline].
• Gulcher JR, Jonsson P, Kong A, et al: Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997 Sep; 17(1): 84-7[Medline].
• Hallett M: Overview of human tremor physiology. Mov Disord 1998; 13 Suppl 3: 43-8[Medline].
• Higgins JJ, Loveless JM, Jankovic J, Patel PI: Evidence that a gene for essential tremor maps to chromosome 2p in four families. Mov Disord 1998 Nov; 13(6): 972-7[Medline].
• Higgins JJ, Pho LT, Nee LE: A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord 1997 Nov; 12(6): 859-64[Medline].
• Hua SE, Lenz FA, Zirh TA, et al: Thalamic neuronal activity correlated with essential tremor. J Neurol Neurosurg Psychiatry 1998 Feb; 64(2): 273-6[Medline].
• Hubble JP, Busenbark KL, Pahwa R, et al: Clinical expression of essential tremor: effects of gender and age. Mov Disord 1997 Nov; 12(6): 969-72[Medline].
• Hulihan J, Connor GS, Shu-Chen W, et al: Topiramate in essential tremor: pooled data from a double-blind, placebo-controlled, crossover trial. American Academy of Neurology 2003 Abstracts: P04.068. Class II. Neurology 2003.
• Jankovic J, Schwartz K, Clemence W, et al: A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord 1996 May; 11(3): 250-6[Medline].
• Jankovic J, Beach J, Pandolfo M, Patel PI: Familial essential tremor in 4 kindreds. Prospects for genetic mapping. Arch Neurol 1997 Mar; 54(3): 289-94[Medline].
• Koller W, Pahwa R, Busenbark K, et al: High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997 Sep; 42(3): 292-9[Medline].
• Koller WC: Dose-response relationship of propranolol in the treatment of essential tremor. Arch Neurol 1986 Jan; 43(1): 42-3[Medline].
• Koller WC, Royse VL: Efficacy of primidone in essential tremor. Neurology 1986 Jan; 36(1): 121-4[Medline].
• Koller WC, Royse VL: Time course of a single oral dose of propranolol in essential tremor. Neurology 1985 Oct; 35(10): 1494-8[Medline].
• Koller WC: Long-acting propranolol in essential tremor. Neurology 1985 Jan; 35(1): 108-10[Medline].
• Koller WC, Vetere-Overfield B: Acute and chronic effects of propranolol and primidone in essential tremor. Neurology 1989 Dec; 39(12): 1587-8[Medline].
• Louis ED, Ford B, Lee H, et al: Diagnostic criteria for essential tremor: a population perspective. Arch Neurol 1998 Jun; 55(6): 823-8[Medline].
• Louis ED, Wendt KJ, Pullman SL, Ford B: Is essential tremor symmetric? Observational data from a community-based study of essential tremor. Arch Neurol 1998 Dec; 55(12): 1553-9[Medline].
• Louis ED, Ford B, Pullman SL: Prevalence of asymptomatic tremor in relatives of patients with essential tremor. Arch Neurol 1997 Feb; 54(2): 197-200[Medline].
• Louis ED, Ford B, Bismuth B: Reliability between two observers using a protocol for diagnosing essential tremor. Mov Disord 1998 Mar; 13(2): 287-93[Medline].
• Louis ED, Ottman R, Hauser WA: How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998 Jan; 13(1): 5-10[Medline].
• Louis ED, Ottman R: How familial is familial tremor? The genetic epidemiology of essential tremor. Neurology 1996 May; 46(5): 1200-5[Medline].
• Ogawa N, Takayama H, Yamamoto M: Comparative studies on the effects of beta-adrenergic blockers in essential tremor. J Neurol 1987 Oct; 235(1): 31-3[Medline].
• Ondo W, Jankovic J, Schwartz K, et al: Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor. Neurology 1998 Oct; 51(4): 1063-9[Medline].
• Ondo WG, Jankovic J, Stacy MA, et al: Topiramate for essential tremor. BS.004. Class II. Neurology 2004; 62.
• Pact V, Giduz T: Mirtazapine treats resting tremor, essential tremor, and levodopa-induced dyskinesias. Neurology 1999 Sep 22; 53(5): 1154[Medline].
• Pahwa R, Lyons KL, Wilkinson SB, et al: Bilateral thalamic stimulation for the treatment of essential tremor. Neurology 1999 Oct 22; 53(7): 1447-50[Medline].
• Schrag A, Muenchau A, Bhatia KP, et al: Overdiagnosis of essential tremor [letter]. Lancet 1999 May 1; 353(9163): 1498-9[Medline].
• Schuurman PR, Bosch DA, Bossuyt PM, et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000 Feb 17; 342(7): 461-8[Medline].
• Taha JM, Janszen MA, Favre J: Thalamic deep brain stimulation for the treatment of head, voice, and bilateral limb tremor. J Neurosurg 1999 Jul; 91(1): 68-72[Medline].
• Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998 Feb; 49(2): 145-53; discussion 153-4[Medline].
• Wasielewski PG, Burns JM, Koller WC: Pharmacologic treatment of tremor. Mov Disord 1998; 13 Suppl 3: 90-100[Medline].
• Zirh A, Reich SG, Dougherty PM, Lenz FA: Stereotactic thalamotomy in the treatment of essential tremor of the upper extremity: reassessment including a blinded measure of outcome. J Neurol Neurosurg Psychiatry 1999 Jun; 66(6): 772-5[Medline].

Essential Tremor excerpt