Transcript Slide 1

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
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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© 2011 AMERICAN ACADEMY OF NEUROLOGY
Endorsed by the International Essential
Tremor Foundation
© 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 ET4 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
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 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
Inclusion criteria:
589 abstracts
- Articles dealing with ET
- Controlled trials,
observational studies,
cohort studies, open-label
studies, case series
Exclusion criteria:
- Case reports, review
papers
252 articles
© 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, Ltryptophan/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.
2.
3.
4.
5.
6.
Koller WC, Biary N, Cone S. Disability in essential tremor: effect of treatment.
Neurology 1986;36:1001–1004.
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.
Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and
primidone in essential tremor. Neurology 1989;39:1587–1588.
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;64:2008–2020.
Fernandez HH, Trieschmann ME, Friedman JH. Treatment of psychosis in
Parkinson’s disease: safety considerations. Drug Saf 2003;26:643–659.
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 www.aan.com/guidelines
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Questions/Comments
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Thank you for your participation!
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