AAN Evidence-Based Guideline: Treatment of Essential Tremor (2011, Reaffirmed 2025)
This is a condensed summary of the American Academy of Neurology (AAN) evidence-based guideline update on the treatment of essential tremor (Zesiewicz et al., 2011), which updated the 2005 AAN practice parameter. The guideline was developed by the Quality Standards Subcommittee based on a literature review through April 2010 using MEDLINE, EMBASE, Science Citation Index, and CINAHL databases. Recommendations are classified using the AAN evidence classification system (Level A = established as effective, Level B = probably effective, Level C = possibly effective, Level U = insufficient evidence). The guideline was reaffirmed in 2025 without changes.
Bottom Line: Key Recommendations
- Level A (established as effective): Propranolol and primidone for limb tremor
- Level B (probably effective): Alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate for limb tremor
- Level B (probably NOT effective): Levetiracetam and 3,4-diaminopyridine should not be considered (new in this update)
- Level C (possibly effective): Nadolol, nimodipine, clonazepam, botulinum toxin A, DBS, thalamotomy
- Level C (possibly no effect): Flunarizine (new in this update)
- Level U (insufficient evidence): Gamma knife thalamotomy, pregabalin, zonisamide, clozapine
- Clinical context: 30–50% of patients do not respond to propranolol or primidone; 56% of patients in a survey discontinued one or both first-line medications
Pharmacological Interventions
Level A: Established as Effective
| Agent | Evidence Level | Indication | Notes |
|---|---|---|---|
| Propranolol | Level A | Limb tremor | Only FDA-approved medication for ET; most commonly used first-line agent |
| Primidone | Level A | Limb tremor | Equal efficacy to propranolol; initial titration important to minimize acute "toxic" reaction |
Level B: Probably Effective
| Agent | Evidence Level | Indication | Notes |
|---|---|---|---|
| Alprazolam | Level B | Limb tremor | Second-line; risk of sedation and dependence |
| Atenolol | Level B | Limb tremor | Alternative beta-blocker |
| Gabapentin (monotherapy) | Level B | Limb tremor | As monotherapy only; as adjunct to other agents evidence is insufficient |
| Sotalol | Level B | Limb tremor | Beta-blocker with additional Class III antiarrhythmic properties |
| Topiramate | Level B | Limb tremor | Confirmed by 2 additional Class II studies since 2005; cognitive side effects may limit use |
Level C: Possibly Effective
- Nadolol — alternative beta-blocker
- Nimodipine — calcium channel blocker
- Clonazepam — benzodiazepine; sedation risk
- Botulinum toxin A — for limb tremor; dose-dependent hand weakness is the main limitation
- Propranolol — Level C specifically for head tremor (weaker evidence than limb tremor)
Agents That Should NOT Be Considered
- Levetiracetam: Probably does NOT reduce limb tremor in ET (Level B against, based on 2 Class II studies). 1 Class I study showed only transient improvement in line drawing at single dose; 2 Class II crossover studies showed no benefit. Should not be considered.
- 3,4-Diaminopyridine: Probably does NOT reduce limb tremor in ET (Level B against, based on 1 adequately powered Class I study). Should not be considered.
- Flunarizine: Possibly has no effect in reducing limb tremor (Level C against, based on 2 Class III studies). Additionally, may cause parkinsonism, akathisia, dyskinesia, and dystonia. May not be considered.
Insufficient Evidence (Level U)
- Pregabalin: Conflicting Class II studies (1 positive, 1 negative with worsening QoL scores) — cannot recommend
- Zonisamide: Conflicting Class III studies — cannot recommend
- Clozapine: Downgraded from Level C in 2005 to Level U due to uncertain long-term benefit (only acute effects studied in controlled setting)
- Olanzapine: Single Class III study vs propranolol; cannot rule out placebo effect; risk of parkinsonism (44% worsening in PD studies)
Surgical Interventions
No new trials rated better than Class IV were available since the 2005 parameter. Previous conclusions remained unchanged.
| Procedure | Evidence Level | Notes |
|---|---|---|
| Deep brain stimulation (Vim thalamus) | Level C (possibly effective) | For medically refractory contralateral limb tremor |
| Thalamotomy | Level C (possibly effective) | For contralateral limb tremor; DBS preferred given adjustability and reversibility |
| Gamma knife thalamotomy | Level U (insufficient evidence) | No controlled trials available at time of review |
No additional trials rated greater than Class IV assessed relative efficacy of thalamotomy vs thalamic DBS, bilateral vs unilateral procedures, or subthalamic vs zona incerta stimulation.
Practical Treatment Algorithm (AAN 2011)
- First-line: Propranolol or primidone (Level A) — propranolol is the only FDA-approved medication for ET
- Second-line if first-line fails or is not tolerated: Alprazolam, atenolol, gabapentin monotherapy, sotalol, or topiramate (Level B)
- Third-line options: Nadolol, nimodipine, clonazepam, or botulinum toxin A (Level C)
- Medically refractory: DBS or thalamotomy (Level C)
- Avoid: Levetiracetam, 3,4-diaminopyridine, flunarizine (evidence against benefit)
- 30–50% of patients do not respond to first-line medications; a survey showed 56% of patients discontinued propranolol and/or primidone
- No high-quality long-term studies exist for any ET intervention
Key Changes from 2005 Practice Parameter
- New Level B against: Levetiracetam and 3,4-diaminopyridine should not be considered (previously not reviewed)
- New Level C against: Flunarizine may not be considered (risk of parkinsonism)
- Downgraded: Clozapine changed from Level C to Level U due to insufficient evidence for chronic use
- Unchanged: All other recommendations from 2005 remain in effect
Comparison: AAN vs MDS Classification Systems
The AAN and MDS evidence classification systems use different methodologies, which can lead to different conclusions from the same data:
| Agent | AAN 2011 | MDS 2019 |
|---|---|---|
| Propranolol | Level A (established effective) | Efficacious (clinically useful) |
| Primidone | Level A (established effective) | Efficacious (clinically useful) |
| Topiramate | Level B (probably effective) | Efficacious >200 mg (clinically useful) |
| Alprazolam | Level B (probably effective) | Likely efficacious (possibly useful) |
| Gabapentin | Level B (probably effective) | Insufficient evidence |
| Atenolol/sotalol | Level B (probably effective) | Insufficient evidence |
| Botulinum toxin A | Level C (possibly effective) | Likely efficacious (possibly useful) |
| DBS | Level C (possibly effective) | Likely efficacious (possibly useful) |
Differences reflect methodological approaches: the AAN uses Class I–IV evidence levels, while the MDS uses quality scores and specific criteria for each efficacy designation. The MDS review (2019) also includes additional studies published after the AAN guideline.
Reference
Zesiewicz TA, Elble RJ, Louis ED, et al. Evidence-based guideline update: Treatment of essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2011;77(19):1752-1755. doi: 10.1212/WNL.0b013e318236f0fd. Reaffirmed 2025.