This is the current release of the guideline.

Essential tremor (ET)

Assessment of Therapeutic Effectiveness
Management
Treatment

Family Practice
Internal Medicine
Neurological Surgery
Neurology

Health Plans
Hospitals
Managed Care Organizations
Physicians

• To answer the following questions with regard to the pharmacologic treatment for essential tremor (ET):
  • What are the safety, tolerability, and efficacy of pharmacologic agents in treating ET?
  • Which drug should be used for initial treatment of ET?
  • Is combined treatment with primidone and propranolol better than monotherapy?
  • Is there evidence for sustained benefit of pharmacologic treatment of ET?
  • Do patients with ET benefit from chemodenervation with botulinum toxin type A or B?
• To answer the following questions with regard to the surgical treatment for ET:
  • What is the efficacy of thalamotomy in treating contralateral limb tremor in patients with ET?
  • What is the efficacy of deep brain stimulation (DBS) of the thalamus in treating tremor in patients with refractory ET?
  • Should thalamotomy or deep brain stimulation of the thalamus be the procedure of choice in patients with medically refractory ET?
  • What are the indications for bilateral versus unilateral surgical procedures in ET?

Patients with essential tremor (ET)

Pharmacologic Treatment

1. Propranolol (Inderal)
2. Propranolol LA (Inderal LA)
3. Primidone (Mysoline)
4. Alprazolam (Xanax)
5. Atenolol (Tenormin)
6. Gabapentin (Neurontin) as monotherapy
7. Sotalol (Sotacor)
8. Topiramate (Topamax)
9. Clonazepam (Klonopin)
10. Clozapine (Clozaril)
11. Nadolol (Corgard)
12. Nimodipine (Nimotop)
13. Botulinum toxin A
14. Considered, but not recommended:
    • Trazodone (Desyrel)
    • Acetazolamide (Diamox)
    • Isoniazid (Laniazid, Nydrazid)
    • Pindolol (Visken)
    • Methazolamide (Neptazane)
    • Mirtazapine (Remeron)
    • Nifedipine (Adalat, Procardia)
    • Verapamil (Calan)
    • Amantadine (Symmetrel)
    • Clonidine (Catapres)
    • Gabapentin as adjunct therapy
    • Glutethimide (Doriden)
    • L-tryptophan/pyridoxine
    • Metoprolol (Lopressor, Toprol)
    • Nicardipine (Cardene)
    • Olanzapine (Zyprexa)
    • Phenobarbital (Luminal)
    • Quetiapine (Seroquel)
    • Theophylline (Theo-dur)

Nonpharmacologic (Surgical) Therapy

1. Chronic thalamic deep brain stimulation (DBS) (recommended for limb tremor, but not recommended for head or voice tremor)
2. Thalamotomy
   • Unilateral
   • Bilateral (considered, but not recommended)
3. Gamma knife thalamotomy (considered, but not recommended)

• Tremor suppression (magnitude of effect, duration of effect)
• Adverse events severity

Searches of Electronic Databases

Panel Selection and Literature Review Process

Neurologists with expertise in essential tremor (ET) were invited by the Quality Standards Subcommittee (QSS) to perform the review. Computer-assisted literature searches were conducted for relevant English language articles pertinent to ET and for medications that are available in the United States. Databases searched include MEDLINE, EMBASE, Science Citation Index, and CINAHL between 1966 and 2004. A total of 502 articles pertaining to treatment and management of ET were published between 1966 and August 2004, and all search titles and abstracts were analyzed for content and relevance by individual committee members. Articles were accepted for further review if they consisted of double-blind controlled trials, open-label studies, case series, and case reports. There were 211 articles that were accepted for further review.

The following key words and phrases were used in the initial search and were paired with the term "essential tremor." Both brand and generic names were used in the searches (generic names are listed here only): acetazolamide, alprazolam, amantadine, aminophylline, antiepileptics, arotinolol, atenolol, atypical neuroleptics, beta-adrenergic blockers, benzodiazepines, botulinum toxin A, botulinum toxin B, calcium channel blockers, carbonic anhydrase inhibitors, chemodenervation, clinical trials, clonazepam, clonidine, clozapine, deep brain stimulation (DBS), gabapentin, gamma knife surgery, glutethimide, hypnotics, isoniazid, management, methazolamide, metoprolol, mirtazapine, nadolol, nicardipine, nifedipine, nimodipine, olanzapine, phenobarbital, pindolol, primidone, propranolol, propranolol long-acting, quetiapine, research design, sotalol, stereotactic surgery, thalamotomy, theophylline, therapy, topiramate, trazodone, verapamil, ventral intermediate (VIM) thalamic stimulation. Articles dedicated to dystonia, dystonic tremor, myoclonus, cerebellar tremor, "atypical tremor," Parkinson disease (PD), parkinsonism, orthostatic tremor, palatal tremor, primary writing tremor, animal models of ET, pathophysiology, genetics, epidemiology, cognitive dysfunction, quality of life, social phobia, and neuropsychiatric testing in ET were excluded from the review.

211 articles were accepted for further review.

Weighting According to a Rating Scheme (Scheme Given)

Classification of Evidence

Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required:

1. Primary outcome(s) clearly defined
2. Exclusion/inclusion criteria clearly defined
3. Adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias
4. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d

Class III: All other controlled trials including well-defined natural history controls or patients serving as own controls in a representative population, where outcome is independently assessed or independently derived by objective outcome measurement*

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion

*Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Systematic Review with Evidence Tables

Each of the articles accepted for review was classified by two panel members using a four-tiered classification scheme that was developed and approved by the Quality Standards Subcommittee (QSS) (see "Rating Scheme for the Strength of the Evidence" field above). Analysis of evidence is summarized in Tables 1 and 2 of the original guideline document.

Other

When formulating the recommendations the guideline developers considered the magnitude of the effect (benefit or harm of therapy, accuracy of tests, yield of studies) and the relative value of various outcomes. Under most circumstances, there is a direct link between the level of evidence used to formulate conclusions and the strength of the recommendation. Thus, an "established as" (two class I) conclusion supports a "should be done" (level A) recommendation; a "probably effective" (two class II) conclusion supports a "should be considered" (level B) recommendation; a "possibly effective" (two class III) conclusion supports a "may be considered" recommendation. In those circumstances where the evidence indicates that the intervention is not effective or useful, wording was modified. For example, if multiple adequately powered class I studies demonstrated that an intervention is not effective, the recommendation read, "should not be done."

There are important exceptions to the rule of having a direct linkage between the level of evidence and the strength of recommendations. Some situations where it may be necessary to break this linkage are listed below:

• A statistically significant but marginally important benefit of the intervention is observed
• The intervention is exorbitantly costly
• Superior and established alternative interventions are available
• There are competing outcomes (both beneficial and harmful) that cannot be reconciled

Under such circumstances the guideline developers may have downgraded the level of the recommendation.

Edlund W, Gronseth G, So Y, Franklin G. Clinical practice guideline process manual. St. Paul (MN): American Academy of Neurology (AAN); 2004. 49 p.

Classification of Recommendations

A = Established as effective, ineffective, or harmful for the given condition in the specified population (Level A rating requires at least two consistent Class I studies.)

B = Probably effective, ineffective, or harmful for the given condition in the specified population (Level B rating 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 (Level C rating requires at least one Class II study or two consistent Class III studies.)

U = Data inadequate or conflicting given current knowledge, treatment is unproven.

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Guidelines were approved by the Quality Standards Subcommittee (QSS) on July 24, 2004, by the Practice Committee on January 29, 2005, and by the American Academy of Neurology (AAN) Board of Directors on February 26, 2005.

Definitions of the strength of the recommendations (A, B, C, and U) and classification of the evidence (Class I-IV) are provided at the end of the "Major Recommendations" field.

Pharmacologic Treatment of Essential Tremor (ET)

1. Propranolol, propranolol LA, or primidone should be offered to patients who desire treatment for limb tremor in essential tremor (ET), depending on concurrent medical conditions and potential side effects (Level A).
2. Either primidone or propranolol may be used as initial therapy to treat limb tremor in ET (Level B).
3. Atenolol, gabapentin (monotherapy), sotalol, and topiramate should be considered as treatment of limb tremor associated with ET (Level B). Alprazolam is recommended with caution due to its abuse potential (Level B). Propranolol should be considered as treatment of head tremor in patients with ET (Level B).
4. Nadolol and nimodipine may be considered when treating limb tremor in patients with ET (Level C). Clonazepam should be used with caution due to its abuse potential and possible withdrawal symptoms (Level C). Clozapine is recommended only for refractory cases of limb tremor in ET due to the risk of agranulocytosis (Level C).
5. Trazodone is not recommended for treatment of limb tremor in ET (Level A).
6. Acetazolamide, isoniazid, and pindolol are not recommended for treatment of limb tremor in ET (Level B).
7. Methazolamide, mirtazapine, nifedipine, and verapamil are not recommended for treatment of limb tremor in ET (Level C).
8. There is insufficient evidence to make recommendations regarding the use of amantadine, clonidine, gabapentin (adjunct therapy), glutethimide, L-tryptophan/pyridoxine, metoprolol, nicardipine, olanzapine, phenobarbital, quetiapine, and theophylline in the treatment of limb tremor in ET (Level U).
9. Primidone and propranolol may be used in combination to treat limb tremor when monotherapy does not sufficiently reduce tremor (Level B).
10. The dosages of propranolol and primidone may need to be increased by 12 months of therapy when treating limb tremor in ET (Level C).
11. Botulinum toxin (BTX) A injections for limb, head, and voice tremor associated with ET may be considered in medically refractory cases (Level C for limb, head, and voice tremor).

Surgical Treatment of ET

1. Unilateral thalamotomy may be used to treat limb tremor in ET that is refractory to medical management (Level C), but bilateral thalamotomy is not recommended due to adverse side effects (Level C).
2. Deep brain stimulation (DBS) of the ventral intermediate (VIM) thalamic nucleus may be used to treat medically refractory limb tremor in ET (Level C).
3. There is insufficient evidence to make recommendations regarding the use of thalamic DBS for head or voice tremor (Level U).
4. DBS has fewer adverse events than thalamotomy (Level B). However, the decision to use either procedure depends on each patient's circumstances and risk for intraoperative complications compared to feasibility of stimulator monitoring and adjustments.
5. Bilateral DBS is necessary to suppress tremor in both upper limbs, but there are insufficient data regarding the risk:benefit ratio of bilateral vs unilateral DBS in the treatment of limb tremor (Level U). Similarly, there are insufficient data to recommend bilateral or unilateral DBS for head and voice tremors. Side effects are more frequent with bilateral DBS, and bilateral thalamotomy is not recommended.
6. There is insufficient evidence to make recommendations regarding the use of gamma knife thalamotomy in the treatment of ET (Level U).

Definitions:

Classification of Recommendations

A = Established as effective, ineffective, or harmful for the given condition in the specified population (Level A rating requires at least two consistent Class I studies.)

B = Probably effective, ineffective, or harmful for the given condition in the specified population (Level B rating 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 (Level C rating requires at least one Class II study or two consistent Class III studies.)

U = Data inadequate or conflicting given current knowledge, treatment is unproven

Classification of Evidence

Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required:

1. Primary outcome(s) clearly defined
2. Exclusion/inclusion criteria clearly defined
3. Adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias
4. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d

Class III: All other controlled trials including well-defined natural history controls or patients serving as own controls in a representative population, where outcome is independently assessed or independently derived by objective outcome measurement*

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion

*Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations" field).

Appropriate management of essential tremor

Adverse events of medications and procedures. Refer to Tables 1 and 2 of the original guideline document for adverse effects of specific medications and procedures.

Contrary to earlier recommendations, propranolol may be used in patients with stable heart failure due to left ventricular systolic dysfunction, unless there are clear contraindications to its use, such as unstable heart failure. It is recommended that physicians who are considering treating cardiac patients with propranolol follow the recommendations of the American Journal of Cardiology consensus statement (or the equivalent) for the complete indications and contraindications of its use, or consult with a cardiologist.

This statement is provided as an educational service of the American Academy of Neurology (AAN). It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.

An implementation strategy was not provided.

Living with Illness

Effectiveness

Not applicable: The guideline was not adapted from another source.

2005 Jun

American Academy of Neurology - Medical Specialty Society

American Academy of Neurology (AAN)

Quality Standards Subcommittee

Subcommittee Members: Gary Franklin, MD, MPH (Co- Chair); Gary Gronseth, MD (Co-Chair); Charles E. Argoff, MD; Stephen Ashwal, MD (ex-officio); Christopher Bever, Jr., MD; Jody Corey-Bloom, MD, PhD; John D. England, MD; Jacqueline French, MD (ex-officio); Gary H. Friday, MD; Michael Glantz, MD; Deborah Hirtz, MD; Donald J. Iverson, MD; David J. Thurman, MD; Samuel Wiebe, MD; William J. Weiner, MD; and Catherine Zahn, MD (ex-officio)

Not stated

This is the current release of the guideline.

This NGC summary was completed by ECRI on July 26, 2005. The information was verified by the guideline developer on August 19, 2005. This summary was updated by ECRI on January 18, 2006, following the U.S. Food and Drug Administration advisory on Clozaril (clozapine). This summary was updated by ECRI on February 16, 2006, following the FDA advisory on Nimotop (nimodipine).

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.