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A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor

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Year of Publication: 2016

Authors: Elias WJ, Lipsman N, Ondo WG, ..., Huss D

Journal: New England Journal of Medicine

Citation: 10.1056/NEJMoa1600159

Link: https://doi.org/10.1056/NEJMoa1600159

Clinical Question

To evaluate efficacy and safety of MRI-guided focused ultrasound thalamotomy compared to sham procedure for medication-refractory essential tremor

Bottom Line

MRI-guided focused ultrasound (MRgFUS) thalamotomy significantly reduced hand tremor in essential tremor: CRST hand tremor score improved 47% at 3 months (P<0.001 vs sham). 76 patients randomized 3:1 (FUS:sham). Published NEJM 2016 (Elias et al.). Led to FDA approval of Insightec Exablate Neuro system.

Major Points

  • CRST hand tremor score improved 47% at 3 months with FUS vs 0.1% sham (P<0.001).
  • CRST Part A (tremor) improved from 18.1 to 9.6 (FUS) vs 16.0 to 15.8 (sham).
  • 76 patients randomized 3:1 (56 FUS, 20 sham). Sham group crossed over at 3 months.
  • Unilateral Vim thalamotomy via transcranial MRI-guided focused ultrasound. No incision.
  • Disability rating (CRST Part C): improved 62% at 3 months (P<0.001).
  • Quality of life (QUEST): improved from 34.4 to 17.4 at 3 months.
  • AEs: sensory (14%), gait disturbance (36% at 3mo → 9% at 12mo), paresthesias.
  • Effect durable: maintained at 12-month follow-up (crossover group also improved).
  • First RCT of incisionless focused ultrasound for any neurological condition.
  • Published NEJM 2016 (Elias et al.). Led to FDA approval August 2016.

Design

Study Type: Prospective, multicenter, randomized, double-blind, sham-controlled trial (3:1 randomization)

Randomization: 1

Blinding: Double-blind

Enrollment Period: August 2013 to September 2014 (enrollment)

Follow-up Duration: 12 months

Centers: 8

Countries: USA, Canada, South Korea, Japan

Sample Size: 76

Inclusion Criteria

  • ET diagnosed by movement disorder specialist
  • postural/intention tremor CRST ≥2
  • disability subsection ≥2
  • refractory to ≥2 medications including propranolol or primidone
  • stable meds 30 days
  • skull density ratio ≥0.45

Exclusion Criteria

  • Neurodegenerative condition
  • unstable cardiac
  • coagulopathy
  • depression PHQ-9 ≥20
  • MMSE <24
  • previous brain procedure

Arms

FieldFUS ThalamotomyControl
InterventionUnilateral MRI-guided FUS thalamotomy targeting VIM nucleus; temperature 55-60°CIdentical stereotactic frame and MRI protocol with acoustic power disengaged
Duration12 months12 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline to 3 months in hand tremor score (CRST A+B, contralateral hand, 0-32 scale)Primary16.0 → 15.8 (0.1% change)18.1 → 9.6 (47% improvement)8.3<0.001
CRST Part C disability score at 3 monthsSecondaryNo significant change62% improvement (16.5 → 6.2)<0.001
QUEST quality of life at 3 monthsSecondary3% change46% improvement<0.001
Hand tremor durability at 12 monthsSecondary40% improvement maintained<0.001
Total CRST scoreSecondary41% at 3 months, 35% at 12 months
Paresthesias/numbnessAdverse38% (persistent 14% at 12mo)
Gait disturbanceAdverse36% (persistent 9% at 12mo)
Head discomfort (intraprocedural)Adverse30%
VertigoAdverse21%
NauseaAdverse20%

Criticisms

  • Unilateral only - no ipsilateral or axial tremor reduction
  • Permanent lesion cannot be adjusted like DBS
  • No direct DBS comparison
  • Blinding compromised - 95% FUS and 80% sham correctly guessed assignment
  • Industry funded

Funding

InSightec, Focused Ultrasound Foundation, BIRD Foundation

Based on: A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor (New England Journal of Medicine, 2016)

Authors: Elias WJ, Lipsman N, Ondo WG, ..., Huss D

Citation: 10.1056/NEJMoa1600159

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