Treatment of essential tremor

Evidence-based guideline update:

Treatment of essential tremor

Report of the Quality Standards Subcommittee of the American

Academy of Neurology

T.A. Zesiewicz, MD,

FAAN

R.J. Elble, MD, PhD,

FAAN

E.D. Louis, MD, MS,

FAAN

G.S. Gronseth, MD,

FAAN

W.G. Ondo, MD

R.B. Dewey, Jr., MD,

FAAN

M.S. Okun, MD

K.L. Sullivan, MSPH

W.J. Weiner, MD,

FAAN

ABSTRACT

Background: This evidence-based guideline is an update of the 2005 American Academy of Neurology

practice parameter on the treatment of essential tremor (ET).

Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was

performed to identify clinical trials in patients with ET published between 2004 and April 2010.

Results and Recommendations: Conclusions and recommendations for the use of propranolol,

primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol,

topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A,

deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy

(Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions

and recommendations from the previous guideline include the following: 1) levetiracetam

and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered

(Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered

(Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin,

zonisamide, or clozapine as treatment for ET (Level U). Neurology® 2011;77:1752–1755

GLOSSARY

AAN American Academy of Neurology; DBS deep brain stimulation; ET essential tremor; FTM Fahn-Tolosa-Marin;

TRS Tremor Rating Scale.

Essential tremor (ET) is the most common tremor

disorder and often affects activities of daily living,

including writing and eating.1 The head and voice

are commonly affected. Diagnostic criteria for ET

may be found in the Consensus Statement of the

Movement Disorder Society on Tremor.2

Propranolol and primidone are the medications

used most frequently and successfully to treat ET,

and propranolol is the only medication approved by

the US Food and Drug Administration to treat ET.

Unfortunately, 30% to 50% of patients will not respond

to either primidone or propranolol.3 This

evidence-based guideline is an update of the American

Academy of Neurology (AAN) 2005 practice parameter

regarding treatment of ET4 and includes

relevant research published since the 2005 publication.

DESCRIPTION OF THE ANALYTIC PROCESS

The AAN invited neurologists with expertise in ET

to perform the review. Computer-assisted literature

searches were conducted for relevant Englishlanguage

articles pertinent to the treatment of ET.

The MEDLINE, EMBASE, Science Citation Index, and

CINAHL databases were searched from the years 2004 to

2010. Appendix e-1 on the Neurology® Web site at

www.neurology.org lists the key words and phrases used in

the search.

The search identified 589 articles pertaining to

the treatment of ET, the titles and abstracts of which

were each reviewed by at least 2 committee members.

Articles were accepted for further review if they consisted

of controlled trials, observational studies, cohort

studies, open-label studies, or case series. Of the

Supplemental data at

www.neurology.org

Address correspondence and

reprint requests to American

Academy of Neurology, 1080

Montreal Avenue, Saint Paul,

MN 55116

guidelines@aan.com

From the University of South Florida (T.A.Z., K.L.S.), Tampa; Department of Neurology (R.J.E.), Southern Illinois University School of Medicine,

Springfield; Neurological Institute (E.D.L.), Columbia University, New York, NY; University of Kansas (G.S.G.), Kansas City; Department of

Neurology (W.G.O.), Baylor College of Medicine, Houston, TX; University of Texas Southwestern Medical School (R.B.D.), Dallas; Departments of

Neurology and Neurosurgery (M.S.O.), Movement Disorders Center, University of Florida, Gainesville; and University of Maryland School of

Medicine (W.J.W.), Baltimore.

Study funding: This evidence-based guideline was funded by the American Academy of Neurology. No author received honoraria or financial support

to develop this document.

Approved by the Quality Standards Subcommittee on November 13, 2010; by the Practice Committee on May 23, 2011; and by the AAN Board of

Directors on August 13, 2011.

Disclosure: Author disclosures are provided at the end of the article.

SPECIAL ARTICLE

1752 Copyright © 2011 by AAN Enterprises, Inc.

Published Ahead of Print on October 19, 2011 as 10.1212/WNL.0b013e318236f0fd

Downloaded from www.neurology.org by guest on November 26, 2011

589 articles, 252 were reviewed in their entirety.

Panel members who were authors of reviewed studies

did not grade their own research.

ANALYSIS OF EVIDENCE Pharmacologic agents

without evidence to change the conclusions or recommendations.

There were no additional trials published

since the previous guideline and rated better

than Class IV that examined the efficacy and safety of

propranolol, primidone, alprazolam, atenolol, gabapentin

(monotherapy), sotalol, propranolol for head

tremor, clonazepam, nadolol, nimodipine, botulinum

toxin, clozapine, acetazolamide, isoniazid, pindolol,

trazodone, methazolamide, mirtazapine,

nifedipine, verapamil, sodium oxybate (in ethanolsensitive

ET), oxcarbazepine, tiagabine, amantadine,

clonidine, gabapentin (adjunct therapy), glutethimide,

l-tryptophan/pyridoxine, metoprolol, nicardipine,

phenobarbital, quetiapine, and theophylline.4

Several new Class II studies addressed the

efficacy of topiramate for ET.5,6 The results of

these studies confirmed those of previous studies

showing efficacy of topiramate for ET and do not

lead to a change in the previous guideline’s recommendation.

Table e-1 summarizes the previous

conclusions and recommendations regarding pharmacologic

interventions.

Olanzapine. Olanzapine, an atypical antipsychotic,

was compared with propranolol in one Class III study

of limb tremor.7 Thirty-eight patients were randomized

to receive olanzapine (20 mg/day) or propranolol (120

mg/day) in a crossover study and were evaluated at baseline

and after 1 month. Propranolol and olanzapine significantly

reduced scores on all evaluation measures,

although a placebo effect cannot be ruled out. The evidence

is insufficient to support or refute the efficacy of

olanzapine for ET (single Class III study).

Surgical interventions without evidence to change the

conclusions or recommendations. There were no additional

trials rated better than Class IV that examined

the efficacy and safety of thalamotomy for

contralateral limb tremor, gamma knife thalamotomy,

or deep brain stimulation (DBS) of the thalamus for the

treatment of ET. Moreover, no additional trials rated

greater than Class IV were available that assessed the

relative efficacy of thalamotomy vs thalamic DBS, bilateral

vs unilateral surgical procedures, or direct subthalamic

vs zona incerta/prelemniscal stimulation.4 Table

e-2 summarizes the previous conclusions and recommendations

pertaining to surgical interventions.

Clinical context. No high-quality, long-term studies

exist regarding the efficacy and safety of these interventions

for ET.

Pharmacologic agents with evidence supporting new

conclusions or recommendations. Levetiracetam. One

Class I study and 2 Class II studies investigated the

efficacy of levetiracetam in ET. The randomized,

crossover Class I study evaluated the acute effects of a

single dose of levetiracetam on limb tremor and

found some improvement in line drawing at 70 and

130 minutes (p 0.007), whereas other tests did not

show improvement (handwriting at 70 and 130 minutes

and spirals at 70 minutes).8 Because the clinical

relevance of the short-term outcome in this Class I

study is unclear, the study was not considered further.

Two Class II randomized, crossover studies

showed no benefit of levetiracetam for ET.9,10

Conclusion. Levetiracetam probably does not reduce

limb tremor in ET (2 Class II studies).

3,4-Diaminopyridine. One adequately powered

Class I study failed to find any improvement in ET

with 3,4-diaminopyridine.11

Conclusion. 3,4-Diaminopyridine probably does not

reduce limb tremor in ET (1 Class I study).

Flunarizine. Flunarizine is a selective calcium channel

blocker. Two Class III studies using blinded video analysis

found flunarizine to be ineffective in treating ET.12,13

Conclusion. Flunarizine possibly has no effect in reducing

limb tremor in ET (2 Class III studies).

Pregabalin. The effect of pregabalin on tremor was

evaluated in 2 Class II studies. One study was a randomized,

parallel-group, double-blind, placebocontrolled

trial of 22 patients with ET.14 Pregabalin

was initiated at 50 mg/day and escalated by 75 mg/

day every 4 days to a maximum dose of 600 mg/day.

Significant reduction in tremor amplitude in the pregabalin

group at a mean dose of 286 mg/day and

improvement in action tremor limb scores on the

Fahn-Tolosa-Marin (FTM) Tremor Rating Scale

(TRS) were observed. A second Class II randomized,

crossover study of pregabalin in 20 patients with ET

found no improvement in any of the TRS measures

and a significant worsening of Quality of Life in Essential

Tremor Questionnaire scores.15 Patients were

treated with pregabalin (150–600 mg/day) or placebo,

titrated over 6 weeks. Reported adverse events

in these studies included drowsiness and dizziness.

Conclusion. The evidence is insufficient to support

or refute the efficacy of pregabalin for ET (conflicting

Class II studies).

Zonisamide. The effect of zonisamide, an antiepileptic

medication, in ET was investigated in 2 Class III and

several open-label studies.16–18 One Class III doubleblind,

placebo-controlled, randomized trial evaluated

the efficacy and tolerability of zonisamide in treating

ET in 20 patients at a mean dose of 160 50 mg/

day.17 No significant improvements in the FTM total

score or its subsections were observed at the study end-

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point, although tremor amplitude as assessed by accelerometry

significantly improved in the zonisamide group

at endpoint relative to baseline. Another evaluatorblinded

Class III study found significant improvements

in FTM rating scores in patients treated with zonisamide

in both the blinded treatment phase and the

open-label extension phase, with mean doses of zonisamide

of 252 mg/day and 225 mg/day, respectively.16

Conclusion. The evidence is insufficient to support

or refute the efficacy of zonisamide for ET (conflicting

Class III studies).

Clozapine. Clozapine, an antipsychotic medication

that received a Level C recommendation in the 2005

practice parameter, has been downgraded to a Level U

recommendation because of a trial that evaluated the

acute effects of clozapine in a controlled setting, followed

by a chronic open-label phase of the study in

“responders”19 (Level U for chronic use).

Conclusion. The evidence is insufficient to support

or refute the efficacy of clozapine for chronic use in

the treatment of ET.

NEW RECOMMENDATIONS Levetiracetam and

3,4-diaminopyridine should not be considered for

treatment of limb tremor in ET (Level B).

Clinicians may choose not to consider flunarizine

for treatment of limb tremor in ET (Level C).

The evidence is insufficient to make recommendations

regarding the use of pregabalin, zonisamide,

or clozapine (Level U).

CLINICAL CONTEXT Flunarizine use may result in

development of movement disorders, including

akathisia, dyskinesia, dystonia, and parkinsonism.

As an atypical neuroleptic agent, olanzapine can

induce parkinsonism. A review of 11 published studies

of olanzapine use in patients with PD found reports

of worsening parkinsonism in 64 of 145

patients (44%).20 However, this side effect was not

observed in the study of patients with ET.

ET is a common movement disorder, and Class

I evidence supports the successful use of primidone

and propranolol in ET treatment. However,

not all patients improve on or tolerate these medications.

A survey of 223 patients in a clinical database

revealed that 70.9% had taken primidone or

propranolol, and 56.3% had discontinued one or

both medications.21 Thus, these first-line medications

for ET clearly fail to meet the needs of many

patients.

RECOMMENDATIONS FOR FUTURE RESEARCH

Controlled clinical trials of additional medications

are needed using standardized outcome measures of

tremor, including disability scales and cost-benefit

analyses.

The pursuit of better treatments for ET is hampered

by our limited understanding of the pathophysiology

of ET. Despite its high prevalence, few

postmortem studies had historically been conducted.

Recent postmortem evidence, however, indicates the

presence of a heterogeneous set of degenerative

changes in the brains of people with ET, indicating

that ET is likely to be a syndrome or family of diseases

rather than a single disease, which adds a layer

of complexity to matters. Furthermore, the sequence

of molecular events that underlie these degenerative

changes has yet to be elucidated, and until such a

time, it will be difficult to design specific targets for

pharmacotherapeutic intervention.

AUTHOR CONTRIBUTIONS

Dr. Zesiewicz: drafting/revising the manuscript, study concept or design,

analysis or interpretation of data, acquisition of data, study supervision.

Dr. Elble: drafting/revising the manuscript, study concept or design, analysis

or interpretation of data, acquisition of data. Dr. Louis: drafting/

revising the manuscript, analysis or interpretation of data, acquisition of

data. Dr. Gronseth: drafting/revising the manuscript, study concept or

design, analysis or interpretation of data, statistical analysis. Dr. Ondo:

drafting/revising the manuscript, acquisition of data. Dr. Dewey: drafting/

revising the manuscript. Dr. Okun: drafting/revising the manuscript,

analysis or interpretation of data, study supervision, critical revision.

K.L. Sullivan: drafting/revising the manuscript. Dr. Weiner: drafting/

revising the manuscript, study concept or design, analysis or interpretation

of data, acquisition of data, study supervision.

DISCLOSURE

Dr. Zesiewicz serves on the speakers’ bureau for and has received funding

for travel and speaker honoraria from Teva Pharmaceutical Industries

Ltd.; serves on the editorial board of Tremor and Other Hyperkinetic Movement

Disorders; serves/has served as a consultant for Boehringer Ingelheim,

Teva Pharmaceutical Industries Ltd., Allergan, Inc., UCB, and Novartis;

is listed as an inventor on a provisional patent on the use of nicotinic

modulators in treating ataxia and imbalance held by the University of

South Florida; and receives/has received research support from Pfizer Inc,

the National Ataxia Foundation, the Friedreich’s Ataxia Research Association,

and the Bobby Allison Ataxia Research Center. Dr. Elble serves on

the scientific advisory board for the International Essential Tremor Foundation;

has received funding for travel from the Movement Disorders

Society; receives research support from GlaxoSmithKline, Teva Pharmaceutical

Industries Ltd., Pfizer Inc, Phytopharm, Janssen (Ortho-

McNeil), the NIH/NINDS, and the Spastic Paralysis Research

Foundation of Kiwanis International; and has acted as an expert witness in

a medico-legal proceeding. Dr. Louis has received honoraria from the

American Academy of Neurology; receives research support from the

NIH/NINDS and the Parkinson’s Disease Foundation; and has served as

a legal consultant on epidemiologic issues. Dr. Gronseth serves on the

editorial advisory board of Neurology Now, serves on the speakers’ bureau

for Boehringer Ingelheim, and receives research support from the American

Academy of Neurology. Dr. Ondo has received speaker honoraria

from GlaxoSmithKline, Boehringer Ingelheim, Allergan, Inc., Teva Pharmaceutical

Industries Ltd., Novartis, Ipsen, Merz Pharmaceuticals, LLC,

and Lundbeck Inc.; serves on the editorial board of Tremor and Other

Hyperkinetic Movements; receives publishing royalties for Restless Legs Syndrome:

Diagnosis and Treatment (Informa, 2008) and Handbook of Movement

Disorders (Wiley-Blackwell, 1998); and has received research support

from Takeda Pharmaceutical Company Limited, ACADIA Pharmaceuticals,

Ipsen, IMPAX Laboratories, Inc., XenoPort, Inc., Bayer Schering

Pharma, and Allergan, Inc. Dr. Dewey serves on the speakers’ bureaus for

and has received funding for travel and speaker honoraria from Teva Pharmaceutical

Industries Ltd., GlaxoSmithKline, Ipsen, Boehringer Ingelheim,

and Allergan Inc.; serves as a consultant for Teva Pharmaceutical

1754 NeuroloDgoyw7n7loaNdoevde mfrboemr 8 w, 2w0w1.1neurology.org by guest on November 26, 2011

Industries Ltd.; receives research support from the NIH; and has served as

an expert witness in a medico-legal case. Dr. Okun serves on scientific

advisory boards for the Dystonia Medical Research Foundation and the

National Parkinson Foundation and the Medical Advisory Board for the

Tourette Syndrome Association; has received funding for travel and

speaker honoraria from Medtronic, Inc. prior to 2010; has served/serves

on the editorial boards of Neurology® and Parkinsonism and Related Disorders;

is a founder of the COMPRESS software used for deep brain stimulation

(DBS) screening and has filed patents regarding double lead DBS,

DBS targeting, and COMPRESS; receives royalties from the publication

of Ultimate Neurology Review (DEMOS, 2007), Parkinson’s Disease (Manson,

2009), and Deep Brain Stimulation for Neurological and Psychiatric

Diseases (Humana Press, 2009); serves as Medical Director of the National

Parkinson Foundation and as a member of the Ask the Expert Forum; and

has received research support from Medtronic, Inc. (devices and training

fellowship grants), the NIH, the University of Florida Foundation, the

Parkinson Alliance, the Michael J. Fox Foundation, and the National

Parkinson Foundation. K.L. Sullivan reports no disclosures. Dr. Weiner

has served on scientific advisory boards for Santhera Pharmaceuticals and

Rexahn Pharmaceuticals, Inc.; serves on the editorial boards of Parkinsonism

and Related Disorders and Neurological Reviews and as Editor of Treatment

Options in Neurology; receives royalties from the publication of

Neurology for the Non-Neurologist (6th edition, Wolters Kluwer/Lippincott,

2010), Parkinson’s Disease: A Complete Guide for Patients and Family

(2nd edition, Hopkins University Press, 2007), and Handbook of Clinical

Neurology Hyperkinetic Disorders (Elsevier, 2011); has received research

support from Novartis, Santhera Pharmaceuticals, and Boehringer Ingelheim;

and has provided expert testimony and served as a subject matter

expert in legal proceedings.

DISCLAIMER

This statement is provided as an educational service of the American

Academy of Neurology. 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. The clinical context section is made available in order to place

the evidence-based guideline(s) into perspective with current practice habits

and challenges. No formal practice recommendations should be inferred.

CONFLICT OF INTEREST

The American Academy of Neurology is committed to producing independent,

critical and truthful clinical practice guidelines (CPGs). Significant

efforts are made to minimize the potential for conflicts of interest to

influence the recommendations of this CPG. To the extent possible, the

AAN keeps separate those who have a financial stake in the success or

failure of the products appraised in the CPGs and the developers of the

guidelines. Conflict of interest forms were obtained from all authors and

reviewed by an oversight committee prior to project initiation. AAN limits

the participation of authors with substantial conflicts of interest. The

AAN forbids commercial participation in, or funding of, guideline projects.

Drafts of the guideline have been reviewed by at least three AAN

committees, a network of neurologists, Neurology peer reviewers and representatives

from related fields. The AAN Guideline Author Conflict of

Interest Policy can be viewed at www.aan.com.

Received May 25, 2011. Accepted in final form August 16, 2011.

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