Practice Guidelines

AAN Releases Recommendations for Managing Essential Tremor



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Am Fam Physician. 2005 Nov 1;72(9):1908-1913.

The Quality Standards Subcommittee of the American Academy of Neurology (AAN) has released evidence-based recommendations for the initiation of pharmacologic and surgical therapies for patients with essential tremor. The recommendations are based on a systematic literature review and were rated for strength of evidence. The full report was published in the June 28, 2005, issue of Neurology and can be found online at http://www.neurology.org/cgi/content/full/64/12/2008.

Essential tremor is defined as the presence of postural and kinetic tremor. Classic essential tremor most commonly affects the upper limbs, but it also can affect a patient’s head, lower limbs, voice, tongue, face, and trunk. Although essential tremor does not reduce life expectancy, and symptoms are limited to tremors, the condition may cause substantial physical and psychosocial disability (e.g., difficulty with writing, drinking, eating, dressing, speaking, and other fine motor skills). Propranolol (Inderal) is the only drug approved by the U.S. Food and Drug Administration for the management of essential tremor. However, an estimated 30 percent of patients will not respond to this medication. Other drugs may be used, and surgical intervention is an invasive alternative to pharmacologic therapy.

Recommendations

PHARMACOLOGIC THERAPY

Table 1 summarizes the evidence for the pharmacologic management of essential tremor.

Level A

Propranolol was effective in managing limb tremor related to essential tremor. The results of treatment with once-daily, long-acting propranolol (Inderal LA) were similar to those of standard propranolol in managing limb tremors. Physicians might consider the use of propranolol, long-acting propranolol, or primidone (Mysoline) to manage limb tremor in patients with essential tremor, depending on concurrent medical conditions and potential side effects. Primidone and propranolol were equally effective for initial treatment of patients with limb tremor.

Trazodone (Desyrel) did not significantly affect postural or kinetic tremor and is not recommended for managing limb tremor.

Level B

Alprazolam (Xanax), atenolol (Tenormin), gabapentin (Neurontin) monotherapy, sotalol (Betapace), and topiramate (Topamax) may reduce limb tremor associated with essential tremor. Atenolol, gabapentin monotherapy, sotalol, and topiramate may be used for limb tremor, although data are limited. Alprazolam should be used with caution because of the potential for abuse. Propranolol should be considered for the management of head tremor.

Acetazolamide (Diamox), isoniazid (INH), and pindolol (Visken) probably do not reduce limb tremor and are not recommended for managing essential tremor.

Level C

Nadolol (Corgard) and nimodipine (Nimotop) may be considered to manage limb tremor associated with essential tremor, but clonazepam (Klonopin) should be used with caution because of its potential for abuse and withdrawal symptoms. Clozapine (Clozaril) is recommended only for refractory cases of essential tremor because of the risk of agranulocytosis.

Methazolamide (Neptazane), mirtazapine (Remeron), nifedipine (Procardia), and verapamil (Calan) probably do not reduce limb tremor and are not recommended for managing essential tremor.

SURGICAL THERAPY

Table 2 summarizes the evidence for the surgical management of essential tremor. Surgical intervention should be considered only for patients who do not respond to pharmacologic therapy.

TABLE 1

Pharmacologic Agents in the Treatment of Essential Tremor

InterventionLevel of evidence*Number of studiesTotal number of patients studiedDosageAdverse events severityMagnitude of effect

Primidone (Mysoline)

A

12

218

Up to 750 mg per day

Mild to moderate (sedation, drowsiness, fatigue, nausea, giddiness, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, acute toxic reaction)

50 percent mean improvement by CRS and accelerometry

Propranolol (Inderal)

A

32

533

60 to 800 mg per day

Mild to moderate (reduced arterial pressure, reduced pulse rate, tachycardia, bradycardia, impotence, drowsiness, exertional dyspnea, confusion, headache, dizziness)

50 percent mean improvement by CRS and accelerometry

Propranolol LA (Inderal LA)

A

2

33

80 to 320 mg per day

Mild (skin eruption, transient dizziness)

30 to 38 percent improvement by accelerometry

Alprazolam (Xanax)

B

2

46

0.125 to 3 mg per day

Mild (fatigue, sedation; potential for abuse)

25 to 34 percent mean improvement in CRS compared with baseline

Atenolol (Tenormin)

B

5

79

50 to 150 mg per day

Mild to moderate (lightheadedness, nausea, cough, dry mouth, sleepiness)

25 percent mean improvement by CRS and 37 percent mean improvement by accelerometry compared with baseline

Gabapentin (Neurontin) monotherapy

B

3

61

1,200 to 1,800 mg per day

Mild (lethargy, fatigue, decreased libido, dizziness, nervousness, shortness of breath)

77 percent improvement by accelerometry and 33 percent improvement by CRS compared with baseline

Sotalol (Betapace)

B

3

50

75 to 200 mg per day

Mild (decreased alertness)

28 percent mean improvement by CRS compared with baseline

Topiramate (Topamax)

B

5

335

Up to 400 mg per day

Mild (appetite suppression, weight loss, paresthesias, anorexia, concentration difficulties)

22 to 37 percent mean improvement in CRS compared with baseline

Clonazepam (Klonopin)

C

3

44

0.5 to 6 mg per day

Mild to moderate (drowsiness)

71 percent mean improvement by accelerometry and 26 to 57 percent improvement in CRS compared with baseline

Clozapine (Clozaril)

C

2

27

6 to 75 mg per day

Mild (sedation); severe (potential agranulocytosis)

45 percent mean improvement by accelerometry

Nadolol (Corgard)

C

1

10

120 to 240 mg per day

None

60 to 70 percent improvement by accelerometry in patients who had previously responded to propranolol

Nimodipine (Nimotop)

C

1

16

120 mg per day

Mild (headache, heartburn)

53 percent improvement by accelerometry and 45 percent improvement in CRS compared with baseline

Botulinum toxin type A (Botox; for hand tremor)

C

6

206

50 to 100 U per arm

Moderate (hand and finger weakness, reduced grip strength, pain at injection site, stiffness, cramping, hematoma, paresthesias)

20 percent improvement in CRS for low- and high-dose botulinum toxin type A for postural tremor at six, 12, and 16 weeks, and 27 percent improvement in kinetic tremor at six weeks (only significant scores listed)

Botulinum toxin type A (for head tremor)

C

3

53

40 to 400 U

Mild to moderate (neck weakness, postinjection pain)

67 percent improvement by accelerometry, moderate to marked improvement by CRS but did not differ from placebo

Botulinum toxin type A (for voice tremor)

C

3

25

0.6 to 15 U

Mild to moderate (breathiness, weak voice, difficulty swallowing)

22 percent improvement with unilateral injection, 30 percent with bilateral injection, 67 percent improvement in self-report


CRS = clinical rating scale; LA = long acting.

*—A = established as effective, ineffective, or harmful for the given condition in the specified population (requires at least two consistent Class I studies); B = probably effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or at least two consistent Class II studies); C = possibly effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or two consistent Class III studies); U = inadequate or conflicting data. Class I = well-designed, randomized, controlled trial; Class II = other randomized controlled trial or well-designed cohort study; Class III = other controlled trial.

†—Mild = somewhat bothersome; moderate = very bothersome; severe = potentially harmful to patients.

Reprinted with permission from Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey RB Jr, et al. Practice parameter: therapies for essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64:2010.

TABLE 1   Pharmacologic Agents in the Treatment of Essential Tremor

View Table

TABLE 1

Pharmacologic Agents in the Treatment of Essential Tremor

InterventionLevel of evidence*Number of studiesTotal number of patients studiedDosageAdverse events severityMagnitude of effect

Primidone (Mysoline)

A

12

218

Up to 750 mg per day

Mild to moderate (sedation, drowsiness, fatigue, nausea, giddiness, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, acute toxic reaction)

50 percent mean improvement by CRS and accelerometry

Propranolol (Inderal)

A

32

533

60 to 800 mg per day

Mild to moderate (reduced arterial pressure, reduced pulse rate, tachycardia, bradycardia, impotence, drowsiness, exertional dyspnea, confusion, headache, dizziness)

50 percent mean improvement by CRS and accelerometry

Propranolol LA (Inderal LA)

A

2

33

80 to 320 mg per day

Mild (skin eruption, transient dizziness)

30 to 38 percent improvement by accelerometry

Alprazolam (Xanax)

B

2

46

0.125 to 3 mg per day

Mild (fatigue, sedation; potential for abuse)

25 to 34 percent mean improvement in CRS compared with baseline

Atenolol (Tenormin)

B

5

79

50 to 150 mg per day

Mild to moderate (lightheadedness, nausea, cough, dry mouth, sleepiness)

25 percent mean improvement by CRS and 37 percent mean improvement by accelerometry compared with baseline

Gabapentin (Neurontin) monotherapy

B

3

61

1,200 to 1,800 mg per day

Mild (lethargy, fatigue, decreased libido, dizziness, nervousness, shortness of breath)

77 percent improvement by accelerometry and 33 percent improvement by CRS compared with baseline

Sotalol (Betapace)

B

3

50

75 to 200 mg per day

Mild (decreased alertness)

28 percent mean improvement by CRS compared with baseline

Topiramate (Topamax)

B

5

335

Up to 400 mg per day

Mild (appetite suppression, weight loss, paresthesias, anorexia, concentration difficulties)

22 to 37 percent mean improvement in CRS compared with baseline

Clonazepam (Klonopin)

C

3

44

0.5 to 6 mg per day

Mild to moderate (drowsiness)

71 percent mean improvement by accelerometry and 26 to 57 percent improvement in CRS compared with baseline

Clozapine (Clozaril)

C

2

27

6 to 75 mg per day

Mild (sedation); severe (potential agranulocytosis)

45 percent mean improvement by accelerometry

Nadolol (Corgard)

C

1

10

120 to 240 mg per day

None

60 to 70 percent improvement by accelerometry in patients who had previously responded to propranolol

Nimodipine (Nimotop)

C

1

16

120 mg per day

Mild (headache, heartburn)

53 percent improvement by accelerometry and 45 percent improvement in CRS compared with baseline

Botulinum toxin type A (Botox; for hand tremor)

C

6

206

50 to 100 U per arm

Moderate (hand and finger weakness, reduced grip strength, pain at injection site, stiffness, cramping, hematoma, paresthesias)

20 percent improvement in CRS for low- and high-dose botulinum toxin type A for postural tremor at six, 12, and 16 weeks, and 27 percent improvement in kinetic tremor at six weeks (only significant scores listed)

Botulinum toxin type A (for head tremor)

C

3

53

40 to 400 U

Mild to moderate (neck weakness, postinjection pain)

67 percent improvement by accelerometry, moderate to marked improvement by CRS but did not differ from placebo

Botulinum toxin type A (for voice tremor)

C

3

25

0.6 to 15 U

Mild to moderate (breathiness, weak voice, difficulty swallowing)

22 percent improvement with unilateral injection, 30 percent with bilateral injection, 67 percent improvement in self-report


CRS = clinical rating scale; LA = long acting.

*—A = established as effective, ineffective, or harmful for the given condition in the specified population (requires at least two consistent Class I studies); B = probably effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or at least two consistent Class II studies); C = possibly effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or two consistent Class III studies); U = inadequate or conflicting data. Class I = well-designed, randomized, controlled trial; Class II = other randomized controlled trial or well-designed cohort study; Class III = other controlled trial.

†—Mild = somewhat bothersome; moderate = very bothersome; severe = potentially harmful to patients.

Reprinted with permission from Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey RB Jr, et al. Practice parameter: therapies for essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64:2010.

TABLE 2

Nonpharmacologic Agents in the Treatment of Essential Tremor

TreatmentLevel of evidence*Number of studiesTotal number of patients studiedAdverse events severityMagnitude of effect

Chronic thalamic DBS (hand)

C

24

398

Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, lead dislodgement, ischemic changes, generalized motor seizures, decreased verbal fluency)

60 to 90 percent improvement in CRS

Thalamotomy

C

8

181

Mild to severe (hemiparesis, transient problems with speech and motor function, dysarthria, verbal or cognitive deficit, weakness, confusion, somnolence, facial paresis)

55 to 90 percent improvement in tremor by CRS

Gamma knife surgery

U

2

61

Mild to severe (transient arm weakness, numbness in the contralateral arm, dysarthria, increased action tremor, dystonia of the contralateral upper and lower limbs, choreoathetosis); case report documented delayed side effects

70 to 85 percent improvement in CRS

Chronic thalamic DBS (head)

U

3

72

Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, microthalamotomy effect, lead dislodgement, ischemic changes, generalized motor seizures, decreased verbal fluency)

N/A

Chronic thalamic DBS (voice)

U

1

7

Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, microthalamotomy effect, lead dislodgement, ischemic changes, generalized motor seizures, decreased verbal fluency)

N/A

Unilateral versus bilateral DBS (hand)

U

1

13

More frequent side effects with bilateral surgery

N/A


DBS = deep brain stimulation; CRS = clinical rating scale.

*—A = established as effective, ineffective, or harmful for the given condition in the specified population (requires at least two consistent Class I studies); B = probably effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or at least two consistent Class II studies); C = possibly effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or two consistent Class III studies); U = data inadequate or conflicting given current knowledge; treatment is unproven.

† —Mild =somewhat bothersome; moderate = very bothersome; severe = potentially harmful to patients.

Reprinted with permission from Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey RB Jr, et al. Practice parameter: therapies for essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64:2011.

TABLE 2   Nonpharmacologic Agents in the Treatment of Essential Tremor

View Table

TABLE 2

Nonpharmacologic Agents in the Treatment of Essential Tremor

TreatmentLevel of evidence*Number of studiesTotal number of patients studiedAdverse events severityMagnitude of effect

Chronic thalamic DBS (hand)

C

24

398

Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, lead dislodgement, ischemic changes, generalized motor seizures, decreased verbal fluency)

60 to 90 percent improvement in CRS

Thalamotomy

C

8

181

Mild to severe (hemiparesis, transient problems with speech and motor function, dysarthria, verbal or cognitive deficit, weakness, confusion, somnolence, facial paresis)

55 to 90 percent improvement in tremor by CRS

Gamma knife surgery

U

2

61

Mild to severe (transient arm weakness, numbness in the contralateral arm, dysarthria, increased action tremor, dystonia of the contralateral upper and lower limbs, choreoathetosis); case report documented delayed side effects

70 to 85 percent improvement in CRS

Chronic thalamic DBS (head)

U

3

72

Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, microthalamotomy effect, lead dislodgement, ischemic changes, generalized motor seizures, decreased verbal fluency)

N/A

Chronic thalamic DBS (voice)

U

1

7

Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, microthalamotomy effect, lead dislodgement, ischemic changes, generalized motor seizures, decreased verbal fluency)

N/A

Unilateral versus bilateral DBS (hand)

U

1

13

More frequent side effects with bilateral surgery

N/A


DBS = deep brain stimulation; CRS = clinical rating scale.

*—A = established as effective, ineffective, or harmful for the given condition in the specified population (requires at least two consistent Class I studies); B = probably effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or at least two consistent Class II studies); C = possibly effective, ineffective, or harmful for the given condition in the specified population (requires at least one Class I study or two consistent Class III studies); U = data inadequate or conflicting given current knowledge; treatment is unproven.

† —Mild =somewhat bothersome; moderate = very bothersome; severe = potentially harmful to patients.

Reprinted with permission from Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey RB Jr, et al. Practice parameter: therapies for essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64:2011.

Level C

Sufficient evidence was available only on the effectiveness of chronic thalamic deep brain stimulation (DBS) and thalamotomy for managing essential tremor. Unilateral thalamotomy may be used to manage limb tremor, but bilateral thalamotomy is not recommended because of adverse effects. Thalamic DBS may be used to treat patients with limb tremor, but insufficient evidence exists to make a recommendation regarding its effectiveness in managing head and voice tremor. Although DBS has fewer adverse effects, physicians should choose between DBS and thalamotomy based on the patient’s circumstances and the risk for intraoperative complications compared with the practicality of the procedures.

Level U

Gamma knife surgery, chronic thalamic DBS (head), chronic thalamic DBS (voice), and unilateral versus bilateral DBS (hand) should be considered unproven therapies at this time.

Conclusion

The committee concludes that research on the management of essential tremor is limited, and additional prospective, double-blind, placebo-controlled trials are needed to better determine the effectiveness and side effects of pharmacologic and surgical therapy for essential tremor.



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