PDF: MRgFUS Thalamotomy for ET
(2016)Objective
To evaluate the efficacy and safety of MRI-guided focused ultrasound thalamotomy for the treatment of medication-refractory essential tremor
Study Summary
• Improvement sustained at 12 months (40% reduction; 18.1 to 10.9; P<0.001)
• Total tremor score improved 41% at 3 months (50.1 to 29.6) and 35% at 12 months
• Disability score (CRST Part C) improved 62% vs 3% with sham at 3 months (P<0.001)
• Quality of life (QUEST) improved 46% vs 3% (P<0.001)
• Adverse events: gait disturbance 36%, paresthesias/numbness 38%; persisting at 12 months in 9% and 14% respectively
Intervention
Unilateral MRI-guided focused ultrasound thalamotomy (targeting ventral intermediate nucleus) vs sham procedure (identical setup without acoustic energy delivery), with crossover option at 3 months
Inclusion Criteria
• Essential tremor diagnosed by movement disorder specialist
• Moderate-to-severe hand tremor (CRST tremor score ≥2)
• Disabling tremor (CRST disability ≥2 on any item)
• Refractory to ≥2 trials of medical therapy including ≥1 first-line agent (propranolol or primidone)
• Stable medications ≥30 days
• No neurodegenerative disease
• No prior brain procedure (TMS, DBS, stereotactic lesioning, ECT)
• Skull density ratio ≥0.45
• MMSE ≥24
• No severe depression (PHQ-9 ≥20)
Study Design
Arms: Array
Patients per Arm: Thalamotomy: 56; Sham: 20 (3:1 randomization)
Outcome
• Hand tremor score at 3 months: 9.6 (thalamotomy) vs 15.8 (sham)
• Hand tremor at 12 months: 10.9 (40% improvement from baseline 18.1; P<0.001)
• Total CRST tremor score at 3 months: 29.6 (41% improvement from 50.1) vs 43.1 (2% change; P<0.001)
• CRST disability (Part C) at 3 months: 6.2 (62% reduction from 16.5) vs 15.6 (3% reduction; P<0.001)
• QUEST quality of life at 3 months: 23.1 (46% improvement from 42.6) vs 41.4 (3% reduction; P<0.001)
• Gait disturbance: 36%; Paresthesias/numbness: 38%; persisting at 12 months in 9% and 14%
Bottom Line
MRI-guided focused ultrasound thalamotomy significantly reduced hand tremor by 47% at 3 months and 40% at 12 months compared with a sham procedure, with corresponding improvements in disability and quality of life. The procedure was noninvasive (no craniotomy), but gait disturbance (36%) and paresthesias (38%) were common, persisting in 9-14% at one year.
Major Points
- First sham-controlled randomized trial of focused ultrasound thalamotomy, leading to FDA approval of the InSightec Exablate Neuro system in 2016.
- Primary endpoint met: hand tremor score improved 8.3 points more with thalamotomy vs sham (95% CI 5.9-10.7, P<0.001) at 3 months.
- Hand tremor improved 47% at 3 months (18.1→9.6) and 40% at 12 months (18.1→10.9), demonstrating durable benefit.
- Total tremor score (CRST overall) improved 41% at 3 months and 35% at 12 months; sham showed only 2% change.
- Disability improved 62% (CRST Part C) and quality of life improved 46% (QUEST) at 3 months, both highly significant vs sham (P<0.001).
- The sham-crossover cohort (19 patients) showed similar 55% improvement at 3 months, confirming the treatment effect.
- Adverse events were notable: gait disturbance 36%, paresthesias/numbness 38%, with persistence at 12 months in 9% and 14% respectively.
- Unilateral procedure only — treats the contralateral hand. The ipsilateral hand showed no significant change (P=0.50).
Study Design
- Study Type
- Phase 3, multicenter, double-blind, sham-controlled, randomized trial. 3:1 randomization to thalamotomy vs sham. Crossover allowed at 3 months. 12-month follow-up. 8 international centers.
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 76
- Centers
- 8
- Countries
- USA, Canada, South Korea, Japan
Primary Outcome
Definition: Change from baseline to 3 months in hand tremor score (CRST Part A + Part B, contralateral hand, 0-32 scale)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 16.0 → 15.8 (0.1% change) | 18.1 → 9.6 (47% improvement) | - (5.9–10.7) | <0.001 |
Citation
N Engl J Med 2016;375:730-9