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MRGFUS

Safety and efficacy of staged, bilateral magnetic resonance-guided focused ultrasound pallidothalamic tractotomy for motor complications of Parkinson's disease: a prospective, multicentre, single-arm trial

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Year of Publication: 2026

Authors: Arif Dalvi, Howard M Eisenberg, Peihan Wu, ..., Michael G Kaplitt

Journal: Lancet Neurology

Citation: Lancet Neurol 2026; 25: 654-63

Clinical Question

Does staged, bilateral MRgFUS pallidothalamic tractotomy offer a favorable risk-benefit profile for advanced Parkinson's disease with motor complications?

Bottom Line

Unilateral MRgFUS pallidothalamic tractotomy is safe and effective for Parkinson's disease motor complications. Adding contralateral (bilateral) treatment provides only small incremental motor benefit while substantially increasing the rate of persistent moderate/severe speech, gait, and balance complications (25% at 12 months vs 2% with unilateral). Bilateral procedures demand rigorous patient selection and counselling regarding cumulative risks.

Major Points

  • First prospective multicentre trial to systematically evaluate staged bilateral MRgFUS pallidothalamic tractotomy for Parkinson's disease motor complications
  • Primary endpoint met: 32% median improvement (IQR 18-52) in bilateral off-medication ULE motor score at 3 months post-bilateral treatment (p<0.0001)
  • Median ULE motor score fell from 33.0 (IQR 28.0-40.5) at baseline to 21.0 (15.0-25.5) at 3 months post-bilateral; benefits seen within 1 month of first procedure and durable through 12 months after second procedure
  • Unilateral treatment had excellent safety: 39% any treatment-related AE, only 2% persistent moderate AE at 6 months
  • Bilateral treatment showed less favourable risk-benefit: 55% AE rate, 25% persistent moderate/severe AEs at 12 months (predominantly speech, gait, balance), including one case of severe persistent anarthria
  • Incremental motor benefit of contralateral treatment beyond the unilateral plateau was small
  • Data contributed to FDA approval (July 8, 2025) of staged bilateral MRgFUS pallidothalamic tractotomy using Exablate Neuro for Parkinson's disease with motor fluctuations or dyskinesia
  • Findings echo historical lessons from bilateral radiofrequency ablation: bilateral irreversible lesions require careful patient selection and thorough counselling

Design

Study Type: Prospective, open-label, single-arm, multicentre interventional trial

Randomization:

Blinding: Open-label; independent monitoring of speech, vision, and cognitive function

Allocation: Single-arm (no allocation)

Enrollment Period: July 12, 2021 to November 1, 2023

Follow-up Duration: 12 months after each procedure (unilateral and bilateral)

Centers: 9

Countries: USA, Spain, Taiwan

Sample Size: 54

Analyzed: 40

Analysis: Unilateral ITT and safety populations: all patients receiving ≥1 sonication during first procedure (n=54). Bilateral modified ITT (mITT) and safety populations: ≥1 sonication during second procedure, baseline motor assessment, and at least one post-bilateral motor assessment (n=40); 36 completed 12-month follow-up after second procedure.

Power Calculation: Performance threshold of 5.6% derived from sham-group result in a prior trial. Assuming mean treatment effect ≥25.6% (SD 32%), 29 bilateral-treated patients would provide 90% power (two-sided α=0.05); target increased to 40 (with ~60 unilateral) to support prespecified subgroup and cross-site poolability analyses.

Registration: ClinicalTrials.gov NCT04728295 (active, not recruiting)

Inclusion Criteria

  • Men and women aged ≥30 years
  • Desiring bilateral treatment
  • Idiopathic Parkinson's disease per MDS clinical diagnostic criteria
  • Levodopa responsiveness (≥30% reduction in MDS-UPDRS part III motor score, on vs off medication)
  • Motor complications (dyskinesia, fluctuations, or both) affecting daily function (MDS-UPDRS part IV item 4.2 or 4.4 score ≥2) on optimum medical treatment
  • Skull density ratio ≥0.40

Exclusion Criteria

  • Clinical features suggestive of an alternative parkinsonian syndrome (early recurrent falls, autonomic failure disproportionate to idiopathic PD, supranuclear gaze palsy, cerebellar signs, poor/absent levodopa response)
  • Severe premorbid risks per MDS-UPDRS part II (balance, speech, swallowing impairment)
  • Significant cognitive impairment per neuropsychologist assessment
  • Skull density ratio <0.40
  • For contralateral treatment: persistent moderate or severe neurological event after first MRgFUS procedure (dysphagia, speech, gait imbalance, cognitive impairment, visual field deficit)

Baseline Characteristics

Age, years — Unilateral (n=54): 63.8 (SD 8.7)

Age, years — Bilateral (n=40): 63.0 (SD 8.5)

Male — Unilateral: 37 (69%)

Female — Unilateral: 17 (31%)

Male — Bilateral: 26 (65%)

Female — Bilateral: 14 (35%)

White — Unilateral / Bilateral: 40 (74%) / 30 (75%)

Time from PD diagnosis, years — Unilateral (mean, SD): 7.7 (4.0), range 0.8-17.0

Time from initial PD symptoms, years — Unilateral (mean, SD): 10.1 (6.7), range 2.2-43.9

Baseline LEDD, mg (mean, SD): 1067.0 (765.9), range 400-4488

Median MDS-UPDRS part III off-medication bilateral ULE motor score: 33.0 (IQR 28.0-40.5)

Arms

FieldUnilateral MRgFUS pallidothalamic tractotomy (symptom-dominant side)Staged bilateral MRgFUS pallidothalamic tractotomy
N5440
InterventionUnilateral MRgFUS pallidothalamic tractotomy using Exablate Neuro 4000 system (Insightec) to the symptom-dominant side; followed at 1 week and months 1, 3, and 6Contralateral MRgFUS pallidothalamic tractotomy performed ≥6 months after first procedure in eligible patients; followed at week 1 and months 1, 3, 6, and 12 after second procedure
DurationSingle procedure with 12-month follow-upTwo staged procedures with 12-month follow-up after second procedure

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Percent change from baseline in MDS-UPDRS part III off-medication summed bilateral upper and lower extremity (ULE) motor scorePrimaryBaseline median ULE score 33.0 (IQR 28.0-40.5)Post-bilateral median ULE score 21.0 (IQR 15.0-25.5) at 3 months; median within-patient change 10.5 points (IQR 5.7-20.0)32% median improvement (IQR 18-52)<0.0001
Confirmatory secondary: percent change in MDS-UPDRS part IV total motor complication score at 3 months post-bilateralSecondaryMedian part IV score fell from 12.0 (IQR 8.5-13.0) at baseline to 4.1 (2.0-7.0) at 3 months post-unilateral and 3.9 (0.0-5.0) at 3 months post-bilateral — a 67% improvement (IQR 50-100), p<0.0001; sustained through 12 months
Confirmatory secondary: percent change in MDS-UPDRS part III off-medication total motor score at 3 months post-bilateralSecondaryMedian total score fell from 49.5 (IQR 43.0-56.5) at baseline to 36.0 (27.5-43.5) at 3 months post-unilateral (30% [14-45] improvement, p<0.0001) and 32.7 (25.5-40.5) at 3 months post-bilateral — 16.0-point change (7.5-23.9), 33% improvement (IQR 15-42), p<0.0001; sustained through 12 months
Unilateral treated-side MDS-UPDRS part III off-medication ULE motor scoreSecondaryMedian score fell from 20.0 (IQR 18.0-24.0) at baseline to 9.5 (7.0-14.0) at 3 months post-unilateral — median within-patient change 11.0 points (5.0-16.0), 53% improvement (IQR 27-67), p<0.0001; sustained through 12 months
Durability of motor benefitSecondaryBenefits became apparent within 1 month of the first procedure and were sustained through 12 months after the second procedure
Post-hoc matched-subset (n=40): incremental benefit of second-side vs unilateral plateau at month 6SecondaryMedian motor scores fell from 26 (IQR 19-32) at unilateral month 6 to 21 (16-26) at bilateral month 3 — an additional 19% improvement, indicating modest incremental gain from contralateral treatment
Treatment-related adverse events after unilateral treatmentSafety21/54 (39%) had treatment-related AEs (30 events total: 87% mild, 13% moderate, no severe); 1/54 (2%) had a persistent moderate AE (dyskinesia) at 6 months
Treatment-related adverse events after bilateral treatmentSafety22/40 (55%) had treatment-related AEs (43 events total: 70% mild, 28% moderate, 2% severe); 10/40 (25%) had persistent moderate or severe AEs at 12 months, mainly affecting speech, gait, and balance
Severe persistent anarthriaSafety1/40 (3%) developed severe persistent anarthria after bilateral treatment (onset at week 1; remained severely affected at 12 months despite gradual improvement)
Most common bilateral AE terms (≥2 patients)SafetyDysarthria (n=5), imbalance (n=3), gait abnormality (n=3), hypophonia (n=3), slurred speech (n=2), drooling (n=2), dysphagia (n=2)
Unilateral any treatment-related AEAdverse21/54 (39%)
Unilateral persistent moderate AE at 6 monthsAdverse1/54 (2%)
Bilateral any treatment-related AEAdverse22/40 (55%)
Bilateral persistent moderate/severe AE at 12 monthsAdverse10/40 (25%)
Severe persistent anarthria after bilateral treatmentAdverse1/40 (3%)
Predominant AE domains after bilateralAdverseSpeech, gait, and balance

Criticisms

  • Open-label, single-arm design with no comparator (no sham, no DBS control)
  • No independent data safety monitoring board; safety monitored by sponsor-assigned clinical monitor
  • Industry-sponsored (Insightec); most senior authors have Insightec-related honoraria, grants, or consultancies
  • Selection bias: only patients without persistent moderate/severe AE after unilateral treatment proceeded to bilateral, potentially understating bilateral risk in less selected populations
  • Small bilateral cohort (n=40) with only 36 completing 12-month follow-up
  • Incremental motor benefit of contralateral treatment beyond the unilateral plateau was modest (~19% in matched-subset), raising questions about clinical value relative to added risk
  • Regulatory-driven delays produced highly variable inter-procedural intervals (0-371 days); no repeat baseline before contralateral treatment, so PD progression and second-ablation effects cannot be fully separated
  • Generalisability limited by predominantly White male cohort; three centres treated 70% of patients (learning-curve concern)

Funding

Insightec

Based on: MRGFUS (Lancet Neurology, 2026)

Authors: Arif Dalvi, Howard M Eisenberg, Peihan Wu, ..., Michael G Kaplitt

Citation: Lancet Neurol 2026; 25: 654-63

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