MRGFUS BILATERAL ET
(2026)Objective
To evaluate the efficacy and safety of staged bilateral MRgFUS thalamotomy in medication-refractory essential tremor patients undergoing a second-side procedure, and to perform a systematic review and meta-analysis of the available literature.
Study Summary
• Functional disability (CRST C) improved 74.2% (7.3→1.9) and QoL (QUEST) improved 68.7% (30.5→9.5) at 12 months (both p<0.001)
• Head tremor reduced 73.8% and voice tremor 40.3% at 12 months; 100% of patients reported they would undergo the procedure again
• 42 adverse events across 15 patients: 95.2% grade 1, 88% transient; persistent AEs at 12 months limited to dysarthria, dysgeusia, and finger hypoesthesia
• Cognition globally preserved at 12 months with a selective decline in verbal episodic memory only
• Meta-analysis confirmed significant improvement in tremor severity across published bilateral MRgFUS cohorts
Intervention
Second-side MRgFUS thalamotomy (FUS2) using Exablate Neuro 4000 system integrated with 3T MRI, targeting the mirror image of the first-side lesion refined by real-time clinical response
Inclusion Criteria
ET patients with minimum 9-month interval since first-side MRgFUS, CRST part A ≥2 in untreated upper limb, CRST part C ≥2 in at least one item, MoCA ≥18, no clinically significant persistent AEs from first procedure
Study Design
Arms: Second-side MRgFUS Thalamotomy (FUS2) (n=15) — single-arm observational study
Patients per Arm: 15
Outcome
• CRST C (functional disability): 7.3 → 1.3 at 1 month (−82.7%), 1.9 at 12 months (−74.2%; p<0.001); QUEST (QoL): 30.5 → 9.5 (−68.7%) at 1 month, stable at 12 months (p<0.001)
• Head tremor CRST A: 1.7 → 0.5 at 12 months (−73.8%); voice tremor CRST A: 1.6 → 1.0 (−40.3%); both p<0.001
• SARA axial score transiently rose 0.5→2.1 at 1 month, returned to 0.7 at 12 months; gait disturbance most frequent AE (53.3% at 1 month, resolving to 0% at 12 months)
Bottom Line
Staged bilateral MRgFUS thalamotomy achieved approximately 58% reduction in hand tremor and over 70% improvement in functional disability and QoL at 12 months, with a predominantly mild and transient adverse event profile and preserved cognition, supporting its use as a therapeutic option in carefully selected medication-refractory essential tremor patients who have residual disability after unilateral treatment.
Major Points
- Staged bilateral MRgFUS (FUS2) produced a 58% reduction in CRST A+B for the treated hand at 12 months (21.0 → 8.8; p<0.001), with effect established by 1 month and sustained throughout follow-up.
- Midline tremor improved significantly: head tremor reduced 73.8% and voice tremor 40.3% at 12 months — notably, head tremor showed minimal response to FUS1 but significant improvement after FUS2.
- Functional disability (CRST C) improved 74.2% (7.3 → 1.9) and quality of life (QUEST) improved 68.7% (30.5 → 9.5) at 12 months, with all patients reporting they would undergo the procedure again.
- The adverse event profile was favorable: 95.2% of 42 AEs were grade 1, 88% were transient. Gait disturbance was most frequent (53.3% at 1 month), resolving completely by 12 months. Only 5 mild AEs persisted at 12 months.
- Axial function (SARA) showed transient worsening at 1 month (0.5 → 2.1) with near-complete recovery by 12 months (0.7).
- Cognition was globally preserved at 12 months; a selective, statistically significant decline was observed only in verbal episodic memory (Rey Auditory Verbal Learning Test).
- First-side thalamic lesion maintained durable benefit: 81% CRST A+B improvement at last pre-FUS2 assessment, remaining stable throughout follow-up.
- Systematic review and random-effects meta-analysis of published bilateral MRgFUS series confirmed significant improvement in tremor severity across cohorts.
Study Design
- Study Type
- Prospective single-centre observational cohort study with systematic review and meta-analysis
- Randomization
- No
- Blinding
- None (open-label observational study)
- Sample Size
- 15
- Follow-up
- 12 months after second-side procedure (FUS2)
- Centers
- 1
- Countries
- Italy
Primary Outcome
Definition: Longitudinal change in CRST A+B composite score for the hand treated by FUS2 (all left hands, treated via right thalamic FUS2) from baseline pre-FUS2 to post-FUS2 follow-up timepoints
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Not applicable (single-arm study); baseline pre-FUS2: 21.0 | 1 month: 7.1; 6 months: 8.5; 12 months: 8.8 | - (12-month: −13.9 to −10.5) | <0.001 at all timepoints vs. baseline; no significant differences between post-treatment timepoints |
Limitations & Criticisms
- Small sample size (n=15) limits generalizability and statistical power for subgroup analyses
- Single-centre observational design without control group precludes causal inference
- 10-month follow-up data available for only 10 of 15 patients, introducing potential attrition bias
- Heterogeneous interval between FUS1 and FUS2 (10–69 months) may confound results
- One patient lacked FUS1 baseline data (performed at another site)
- Long-term durability beyond 12 months not assessed in this cohort
- No sham or active comparator arm; natural history of ET progression not accounted for
Citation
Paio F, Ricciardi GK, Bulgarelli G, et al. Staged Bilateral Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor: Prospective Single-Centre Cohort and Systematic Review With Meta-Analysis. Eur J Neurol. 2026;33:e70535.