© 2011 AMERICAN ACADEMY OF NEUROLOGY Update: Treatment of Essential Tremor Report of the Quality Standards Subcommittee of the American Academy of Neurology Theresa A. Zesiewicz, MD, FAAN; Rodger J. Elble, MD, PhD, FAAN; Elan D. Louis, MD, MS, FAAN; Gary S. Gronseth, MD, FAAN; William G. Ondo, MD; Richard B. Dewey, Jr., MD, FAAN; Michael S. Okun, MD; Kelly L. Sullivan, MSPH; William J. Weiner, MD, FAAN

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© 2011 AMERICAN ACADEMY OF NEUROLOGY Presentation Objectives To present analysis of the efficacy of pharmacologic and nonpharmacologic treatments to reduce tremor in patients with essential tremor (ET) To present evidence-based recommendations

© 2011 AMERICAN ACADEMY OF NEUROLOGY Overview Background Gaps in care American Academy of Neurology (AAN) guideline process Analysis of evidence, conclusions, recommendations Recommendations for future research

© 2011 AMERICAN ACADEMY OF NEUROLOGY Background ET is the most common tremor disorder and often affects activities of daily living, including writing and eating. 1 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. o Propranolol is the only medication approved by the US Food and Drug Administration to treat ET. o Unfortunately, 30% to 50% of patients will not respond to either primidone or propranolol. 3 This evidence-based guideline is an update of the AAN 2005 practice parameter regarding treatment of ET 4 and includes relevant research published since the 2005 publication.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Gaps in Care General practitioners often mistakenly believe that ET is not treatable. Some health care providers, including some experts, confuse ET with Parkinson disease (PD) or with other forms of tremor.

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Guideline Process Clinical Question Evidence Conclusions Recommendations

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Questions: Pharmacologic Treatments What are the safety, tolerability, and efficacy of pharmacologic agents in treating ET? Which drug should be used for initial treatment of ET? In patients with ET, is combined treatment with primidone and propranolol superior to monotherapy? In patients with ET, is there evidence for sustained benefit of pharmacologic treatment? Do patients with ET benefit from chemodenervation with botulinum toxin (BTX) type A or B?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Questions: Nonpharmacologic Treatments 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 DBS of the thalamus be the procedure of choice in patients with medically refractory ET? What are the indications for bilateral vs. unilateral surgical procedures in ET? Does gamma knife thalamotomy effectively reduce ET?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Literature Search/Review Relevant Complete Search Review abstracts Review full text Select articles Rigorous, Comprehensive, Transparent

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence All studies rated Class I, II, III, or IV Five different classification systems: o Therapeutic −Randomization, control, blinding o Diagnostic −Comparison to gold standard o Prognostic o Screening o Causation

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Level of Recommendations A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. Note that recommendations can be positive or negative.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Translating Class to Recommendations A = Requires at least two consistent Class I studies.* B = Requires at least one Class I study or two consistent Class II studies. C = Requires at least one Class II study or two consistent Class III studies. U = Studies not meeting criteria for Class I through Class III.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Translating Class to Recommendations, cont. *In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Applying This Process to the Issue We will now turn our attention to the guidelines.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Methods MEDLINE, EMBASE, Science Citation Index, and CINAHL o 2004 to April 2010 o Relevant, fully published, peer-reviewed articles o See published guideline for search terms

© 2011 AMERICAN ACADEMY OF NEUROLOGY Methods, cont. At least two authors reviewed each article for inclusion. Risk of bias was determined using the classification of evidence for each study (Classes I–IV). Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed. Panel members who were authors of reviewed studies did not grade their own research.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Literature Review 252 articles 589 abstracts Inclusion criteria: - Articles dealing with ET - Controlled trials, observational studies, cohort studies, open-label studies, case series Exclusion criteria: - Case reports, review papers

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for Therapeutic Intervention Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: o Concealed allocation o Primary outcome(s) clearly defined o Exclusion/inclusion criteria clearly defined

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for Therapeutic Intervention, cont. o Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias. o For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: –The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority. –The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). –The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. –The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for Therapeutic Intervention, cont. Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a  e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b  e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

© 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for Therapeutic Intervention, cont. 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: Studies not meeting Class I, II or III criteria including consensus or expert opinion. *Note that numbers 1  3 in Class I, item 5 are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. **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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Original vs. Updated Recommendations Recommendations that are new or changed from the 2005 recommendations are indicated as such.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 1 Question 1: What are the safety, tolerability, and efficacy of pharmacologic agents in treating ET?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Treatments with Positive Recommendations Conclusions: Prospective, randomized clinical trials indicate that propranolol, propranolol long-acting (LA), and primidone reduce limb tremor in ET. Magnitudes of effect of primidone and propranolol were approximately similar. Limited data indicate that propranolol LA is as effective as standard propranolol for reducing tremor. Recommendation: Propranolol, propranolol LA, or primidone should be offered to patients who desire treatment for limb tremor in ET, depending on concurrent medical conditions and potential side effects (Level A).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Treatments with Positive Recommendations, cont. Conclusions: Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate probably reduce limb tremor associated with ET. Propranolol probably reduces head tremor in ET, but data are limited. Recommendations: 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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Treatments with Positive Recommendations, cont. Conclusion: Clonazepam, nadolol, and nimodipine possibly reduce limb tremor associated with ET. Recommendations: 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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Treatments with Negative Recommendations Conclusions: Trazodone is ineffective in reducing limb tremor associated with ET. Acetazolamide, isoniazid, and pindolol probably do not reduce limb tremor associated with ET. Methazolamide, mirtazapine, nifedipine, and verapamil probably do not reduce limb tremor in ET. Recommendation: Trazodone is not recommended for treatment of limb tremor in ET (Level A). Acetazolamide, isoniazid, and pindolol are not recommended for treatment of limb tremor in ET (Level B). Methazolamide, mirtazapine, nifedipine, and verapamil are not recommended for treatment of limb tremor in ET (Level C).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Treatments with No Recommendation Conclusion: There are insufficient or conflicting data regarding the use of amantadine, clonidine, gabapentin (adjunct therapy), glutethimide, L-tryptophan/pyridoxine, metoprolol, nicardipine, olanzapine, phenobarbital, quetiapine, and theophylline to treat limb tremor associated with ET. Recommendation: 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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Recommendations New/Changed since 2005 Conclusions: Levetiracetam probably does not reduce limb tremor in ET (2 Class II studies). 3,4-diaminopyridine probably does not reduce limb tremor in ET (1 Class I study). Flunarizine possibly has no effect in reducing limb tremor in ET (2 Class III studies). 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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 1a Question 1a: Which drug should be used for initial treatment of ET ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Recommendation Regarding Initial Treatments Conclusion: Primidone and propranolol have similar efficacy when used as initial therapy to treat limb tremor in ET. Recommendation : Either primidone or propranolol may be used as initial therapy to treat limb tremor in ET (Level B).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 2 Question 2: In patients with ET, is combined treatment with primidone and propranolol superior to monotherapy ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Recommendation Regarding Combined Treatments Conclusion: The combined use of primidone and propranolol possibly reduces limb tremor in ET more than either drug alone. There was no worsening of adverse events when primidone and propranolol were used in combination. Recommendation : Primidone and propranolol may be used in combination to treat limb tremor when monotherapy does not sufficiently reduce tremor (Level B).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 3 Question 3: In patients with ET, is there evidence for sustained benefit of pharmacologic treatment ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Recommendation Regarding Sustained Treatment Benefit Conclusion: Primidone and propranolol maintain anti-tremor efficacy in the majority of patents for at least 1 year. Recommendation : The dosages of propranolol and primidone may need to be increased by 12 months of therapy when treating limb tremor in ET (Level C).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 4 Question 4: Do patients with ET benefit from chemodenervation with botulinum toxin type (BTX) A or B ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Pharmacologic Recommendation Regarding BTX Conclusions: The effect of BTX A on limb tremor in ET is modest and is associated with dose dependent hand weakness. BTX A may reduce head tremor and voice tremor associated with ET, but data are limited. When used to treat voice tremor, BTX A may cause breathiness, hoarseness, and swallowing difficulties. Recommendation : 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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 5 Question 5: What is the efficacy of thalamotomy in treating contralateral limb tremor in patients with ET ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Nonpharmacologic Recommendations: Thalamotomy in Contralateral Limb Tremor Conclusions: Unilateral thalamotomy effectively treats contralateral limb tremor in ET. Bilateral thalamotomy is associated with more frequent and often severe side effects. Recommendations : 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).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 6 Question 6: What is the efficacy of DBS of the thalamus in treating tremor in patients with refractory ET ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Nonpharmacologic Recommendations: DBS of Thalamus in Refractory ET Conclusions: DBS of the ventral intermediate (VIM) thalamic nucleus effectively reduces contralateral limb tremor in medically refractory ET. There are conflicting data regarding the use of DBS for head and voice tremor in ET. Recommendations : DBS of the VIM thalamic nucleus may be used to treat medically refractory limb tremor in ET (Level C). There is insufficient evidence to make recommendations regarding the use of thalamic DBS for head or voice tremor (Level U).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 7 Question 7: Should thalamotomy or DBS of the thalamus be the procedure of choice in patients with medically refractory ET ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Nonpharmacologic Recommendation: Preferred Treatment in Refractory ET Conclusion: Both DBS and thalamotomy effectively suppress tremor in ET. Recommendation : 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.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 8 Question 8: What are the indications for bilateral vs unilateral surgical procedures in ET ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Nonpharmacologic Recommendations: Bilateral vs. Unilateral Surgery in ET Conclusions: Thalamic DBS suppresses contralateral limb tremor, so bilateral DBS is necessary to suppress tremor in both upper limbs. However, there is no evidence of a synergistic effect on limb tremor with bilateral DBS, and there are insufficient data regarding the risk-benefit ratios of unilateral vs. bilateral DBS. Similarly, there are insufficient data regarding the use of bilateral DBS for head and voice tremors. Recommendations : 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.

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Question 9 Question 9: Does gamma knife thalamotomy effectively reduce ET ?

© 2011 AMERICAN ACADEMY OF NEUROLOGY Nonpharmacologic Recommendation: Gamma Knife Thalamotomy in ET Conclusion: Several studies have found favorable results with gamma knife thalamotomy, but delayed complications have been reported, and clinical improvement may take weeks to months to occur. Recommendation : There is insufficient evidence to make recommendations regarding the use of gamma knife thalamotomy in the treatment of ET (Level U).

© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Context: Surgical Treatments No high-quality, long-term studies exist regarding the efficacy and safety of these interventions for ET.

© 2011 AMERICAN ACADEMY OF NEUROLOGY 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%). 5 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. 6 Thus, these first-line medications for ET clearly fail to meet the needs of many patients.

© 2011 AMERICAN ACADEMY OF NEUROLOGY 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.

© 2011 AMERICAN ACADEMY OF NEUROLOGY References 1.Koller WC, Biary N, Cone S. Disability in essential tremor: effect of treatment. Neurology 1986;36:1001– 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. 3.Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in essential tremor. Neurology 1989;39:1587– Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64:2008– Fernandez HH, Trieschmann ME, Friedman JH. Treatment of psychosis in Parkinson’s disease: safety considerations. Drug Saf 2003;26:643– Diaz NL, Louis ED. Survey of medication usage patterns among essential tremor patients: movement disorder specialists vs. general neurologists. Parkinsonism Relat Disord 2010;16:604–607.

© 2011 AMERICAN ACADEMY OF NEUROLOGY References, cont. For a complete list of references, please access the full guideline at

© 2011 AMERICAN ACADEMY OF NEUROLOGY Questions/Comments

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