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Bilateral FUS ET

Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor: An Open-Label Clinical Trial

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Year of Publication: 2024

Authors: Kaplitt MG, Krishna V, Eisenberg HM, ..., Murray AM

Journal: JAMA Neurology

Citation: JAMA Neurol. 2024;81(9):939-946

Link: https://doi.org/10.1001/jamaneurol.2024.2295

Clinical Question

Is staged, bilateral MRI-guided focused ultrasound thalamotomy safe and effective for treating bilateral essential tremor in patients who previously underwent successful unilateral treatment?

Bottom Line

Staged, bilateral MRgFUS thalamotomy significantly reduced tremor severity (66% improvement) and functional disability (73% improvement) in patients with essential tremor, with adverse events (speech, swallowing, ataxia) that were mostly mild and transient, leading to FDA approval of this approach.

Major Points

  • First multicenter trial evaluating staged bilateral MRgFUS thalamotomy with sufficient power for regulatory approval
  • 66% improvement in tremor/motor scores at 3 months, sustained through 12 months (62%)
  • 81% improvement in postural tremor and 73% improvement in functional disability at 3 months
  • Bilateral treatment effective for head tremor (71% responders) and voice tremor (67% responders)
  • Adverse events were 85% mild, 13% moderate: numbness/tingling, dysarthria, ataxia, taste disturbance
  • Most adverse events resolved by 12 months; persistent mild symptoms included numbness (n=8), dysarthria (n=7), ataxia (n=6)
  • Speech/swallowing dysfunction rates much lower than historical bilateral radiofrequency thalamotomy
  • First study to include formal pre- and post-procedure speech and language pathology assessment
  • Results led to FDA approval of staged bilateral MRgFUS ablation for essential tremor

Design

Study Type: Prospective, open-label, uncontrolled, single-arm, multicenter trial

Randomization:

Blinding: None (open-label)

Enrollment Period: July 2020 to October 2021

Follow-up Duration: 12 months

Centers: 7

Countries: United States

Sample Size: 51

Analysis: Modified intent-to-treat. Hierarchical testing design for primary and secondary endpoints (α=0.05)

Inclusion Criteria

  • Age ≥22 years
  • Essential tremor refractory to adequate trials of ≥2 medications (at least 1 first-line)
  • History of previous unilateral MRgFUS thalamotomy ≥9 months prior
  • Baseline CRST part A score ≥2 for postural or kinetic tremor in untreated upper extremity
  • Baseline CRST part C score ≥2 in any category

Exclusion Criteria

  • Persistence of neurological worsening following index MRgFUS procedure
  • Physical subscale score ≥16.5 on Dysphagia Handicap Index or diagnosis of dysphagia
  • Clinically significant abnormal speech function
  • Montreal Cognitive Assessment score <22
  • Pregnant or breastfeeding
  • Skull density ratio <0.40

Arms

FieldStaged Bilateral MRgFUS Thalamotomy
InterventionMRgFUS ablation of VIM thalamus contralateral to previous treatment using Exablate 4000 with 3T or 1.5T MRI. Peak temperatures >55°C for ablation.
DurationSingle procedure with 12-month follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline to 3 months in tremor/motor score (CRST parts A and B, range 0-32)PrimaryN/A (single-arm)Baseline 17.4 (5.4), 3 months 6.4 (5.3); 66% improvement (95% CI 59.8-72.2%)<0.001
Upper extremity postural tremor (CRST part A) at 3 monthsSecondaryN/ABaseline 2.5 to 3 months 0.6; 81% reduction<0.001
Functional disability (CRST part C) at 3 monthsSecondaryN/ABaseline 10.3 to 3 months 2.2; 73% improvement<0.001
Tremor/motor score at 12 monthsSecondaryN/A7.0 (5.6); 62% reduction from baseline<0.001
Voice tremor improvement (among 12 with baseline voice tremor)SecondaryN/A67% responders
Head tremor improvement (among 17 with baseline head tremor)SecondaryN/A71% responders
Numbness/tinglingAdverseN/A17 total; 8 at 12 months (all mild)
DysarthriaAdverseN/A15 total (14 mild, 1 moderate); 7 at 12 months (all mild)
AtaxiaAdverseN/A12 total (all mild); 6 at 12 months
Unsteadiness/imbalanceAdverseN/A10 total; 0 at 12 months
DysgeusiaAdverseN/A7 total; 3 at 12 months
DysphagiaAdverseN/A4 total (3 mild, 1 moderate); 3 at 12 months
Overall adverse event severityAdverseN/A159/188 (85%) mild, 25/188 (13%) moderate, 1 severe (UTI)

Subgroup Analysis

Among 6 participants taking primidone or propranolol at screening, all reduced doses by 6 months; 3 discontinued entirely by 3 months.

Criticisms

  • Open-label, single-arm design without sham control increases risk of bias
  • Participants had prior unilateral MRgFUS experience, limiting blinding
  • Population predominantly male (86.3%) and mostly non-Hispanic White
  • Skull density ratio requirements may have excluded certain racial groups
  • No long-term follow-up beyond 12 months
  • Strict exclusion criteria may limit real-world applicability

Funding

Insightec (device manufacturer and sponsor)

Based on: Bilateral FUS ET (JAMA Neurology, 2024)

Authors: Kaplitt MG, Krishna V, Eisenberg HM, ..., Murray AM

Citation: JAMA Neurol. 2024;81(9):939-946

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