MDS Evidence-Based Medicine Review: Essential Tremor Treatment (2019)
This is a condensed summary of the first MDS Evidence-Based Medicine Review dedicated to essential tremor (ET) (Ferreira et al., 2019). The task force reviewed 64 studies of pharmacological and surgical interventions published through December 2016. Interventions are classified by efficacy (efficacious, likely efficacious, unlikely efficacious, nonefficacious, insufficient evidence) and clinical practice implication (clinically useful, possibly useful, investigational, unlikely useful, not useful). All recommendations apply to upper limb tremor only — there was insufficient evidence for head and voice tremor.
Bottom Line: Key Conclusions
- Clinically useful (limb tremor): Propranolol, primidone, and topiramate (>200 mg/day) — these are the only three interventions with robust efficacy evidence
- Possibly useful (limb tremor): Alprazolam, botulinum toxin type A, unilateral Vim-DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy
- Not useful: Levetiracetam and pregabalin (both nonefficacious); trazodone (unlikely efficacious); isoniazid and acetazolamide (unlikely useful due to safety)
- Head and voice tremor: Insufficient evidence for any intervention
- Limitations: Most studies had small sample sizes, short follow-up, crossover designs, and used nonvalidated rating scales
Pharmacological Interventions
First-Line Agents (Clinically Useful)
| Agent | Evidence | Efficacy | Safety | Notes |
|---|---|---|---|---|
| Propranolol | 13 studies, 255 patients | Efficacious | Acceptable risk without monitoring | Doses up to 240–360 mg/day; 50–70% responder rate; <10% dropout from AEs; IR and LA formulations may be equivalent |
| Primidone | 8 studies, 274 patients | Efficacious | Acceptable risk with monitoring | 150–750 mg/day; no tolerance at 12 months; acute “toxic” reaction in up to 23% at initiation; dropout rate 7.5–42% |
| Topiramate (>200 mg/day) |
4 studies, 322 patients | Efficacious | Acceptable risk without monitoring | Mean effective dose 215–333 mg/day; 3/4 studies positive; negative study used only 50–100 mg; paresthesia, cognitive effects, weight loss; 30–54% dropout |
Choosing Initial Therapy
- Propranolol has the most evidence and fewest initial side effects — preferred for patients who tolerate beta-blockers
- Primidone may have higher patient preference (64% vs 36% in head-to-head comparison) but causes more bothersome initial side effects (malaise, dizziness, unsteadiness even at 62.5 mg)
- Combination therapy (primidone 250 mg QHS + propranolol 80 mg TID) showed greater benefit for postural tremor than either drug alone
- Topiramate requires doses >200 mg/day for efficacy; cognitive side effects and paresthesia limit use
- No head-to-head comparison establishes superiority of one first-line agent over another
Second-Line Agents (Possibly Useful)
- Alprazolam: Likely efficacious (2 studies, 46 patients; doses 0.75–1.5 mg/day; improved severity and task performance). Acceptable risk with specialized monitoring (somnolence up to 50%; dependence risk). Possibly useful
- Botulinum toxin type A: Likely efficacious for upper limb tremor (3 studies, 168 patients; conflicting results — improved tremor severity but not function). Acceptable risk with specialized monitoring — dose-dependent hand weakness in 30% (50 IU) to 69% (100 IU). Effect maintained ~16 weeks. Possibly useful
Agents with Insufficient Evidence
| Class | Agents | Conclusion |
|---|---|---|
| Beta-blockers | Propranolol LA, nadolol, metoprolol, atenolol, sotalol | Insufficient evidence — investigational |
| Anticonvulsants | Gabapentin, carisbamate, zonisamide | Insufficient evidence — investigational |
| Barbiturates | Phenobarbital, T2000 | Insufficient evidence — investigational |
| Calcium channel blockers | Flunarizine (risk of parkinsonism), nimodipine | Insufficient evidence — investigational |
| Carbonic anhydrase inhibitors | Methazolamide | Insufficient evidence — investigational |
| Other | Mirtazapine, olanzapine, theophylline, amantadine | Insufficient evidence — investigational |
Agents That Are Not Useful
- Levetiracetam: Nonefficacious — not useful
- Pregabalin: Nonefficacious — not useful
- Trazodone: Unlikely efficacious — unlikely useful
- Progabide: Unlikely efficacious — unlikely useful
- Isoniazid: Insufficient evidence for efficacy — unlikely useful (unacceptable risk: severe/fatal hepatitis)
- Acetazolamide: Insufficient evidence — unlikely useful (safety concerns)
Surgical Interventions
All surgical recommendations are for medically refractory upper limb tremor and require specialized monitoring.
| Procedure | Evidence | Conclusion | Key Findings |
|---|---|---|---|
| Unilateral Vim-DBS | 1 RCT + 6 case series (160 total patients) | Likely efficacious — possibly useful | Tremor absent/slight in all 7 RCT patients; Frenchay ADL improvement 6.4 points; paresthesia in ~61% (transient); some benefit reduction at 5–7 years |
| Bilateral Vim-DBS | 1 case series (13 patients) | Insufficient evidence — investigational | Greater arm/leg tremor improvement than unilateral but more AEs (76% vs 52%), especially gait difficulty and dysarthria |
| Unilateral RF thalamotomy | 1 RCT + 1 case series (34 total patients) | Likely efficacious — possibly useful | Tremor improvement maintained at 12 months; Vim-DBS showed greater functional improvement in head-to-head RCT (6.6-point difference); more AEs with thalamotomy (P = .024) |
| Unilateral MRI-guided FUS thalamotomy | 1 RCT (81 patients) | Likely efficacious — possibly useful | 47% tremor reduction at 3 months; improvement in function and QoL; paresthesia/numbness in 38%, gait impairment in 36% |
| Gamma-knife thalamotomy | Limited data | Insufficient evidence — investigational | — |
Practical Treatment Algorithm for ET
- Step 1: Trial of propranolol or primidone monotherapy (or both combined if monotherapy insufficient)
- Step 2: Topiramate >200 mg/day if first-line agents fail or are not tolerated
- Step 3: Alprazolam or botulinum toxin A (second-line options for refractory limb tremor)
- Step 4 (medically refractory): Surgical referral — unilateral Vim-DBS, RF thalamotomy, or MRI-guided FUS thalamotomy
- Vim-DBS has advantage of adjustability and reversibility; FUS thalamotomy is noninvasive but lesional
- The RCT comparing DBS vs thalamotomy showed greater functional improvement with DBS and fewer AEs
Head and Voice Tremor
A few studies specifically assessed head tremor (including propranolol, primidone, and botulinum toxin A injections into cervical muscles). Data were limited to small studies with insufficient evidence to support any specific treatment recommendation.
- Botulinum toxin A for head tremor: No reported benefit (1 study targeting sternocleidomastoid and splenius capitis) — insufficient evidence
- Vim-DBS for head tremor: Sequential bilateral Vim-DBS did not improve head or voice tremor in 1 case series
- Voice tremor: No included study specifically assessed voice tremor
Limitations and Research Gaps
- Most pharmacological studies were short-term (mean 3.5–10.5 weeks); only 1 study assessed 12-month efficacy (primidone)
- Predominance of small sample sizes and crossover designs without carryover assessment
- Nonvalidated clinical rating scales used in many studies
- Clinical relevance of tremor score changes is poorly defined — improvement in severity often did not translate to functional improvement
- No head-to-head comparisons between surgical procedures (DBS vs FUS) except DBS vs RF thalamotomy
- All surgical interventions require additional Level-I evidence to be upgraded to “clinically useful”
Reference
Ferreira JJ, Mestre TA, Lyons KE, et al. MDS Evidence-Based Review of Treatments for Essential Tremor. Mov Disord. 2019;34(7):950-958. doi: 10.1002/mds.27700