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Focused Ultrasound Subthalamotomy for Parkinson Disease

Year of Publication: 2020

Authors: Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R, ..., Obeso JA

Journal: New England Journal of Medicine

Citation: 10.1056/NEJMoa2016311

Link: https://doi.org/10.1056/NEJMoa2016311

Clinical Question

To evaluate the efficacy and safety of MRI-guided focused ultrasound subthalamotomy performed in one hemisphere for treating motor features of Parkinson's disease in patients with markedly asymmetric motor signs

Bottom Line

Unilateral MRgFUS subthalamotomy improved contralateral motor scores by 36% at 4 months in PD (MDS-UPDRS III contralateral -8.1 vs -0.4 sham; P<0.001). Asymmetric/tremor-dominant patients benefited most. Dyskinesia occurred in 48% (transient in most). Published NEJM 2020 (Martínez-Fernández et al.). 40 patients, single-center, Spain.

        Major Points
        MDS-UPDRS III contralateral: -8.1 (FUS) vs -0.4 (sham) at 4 months off-medication (P<0.001).
MDS-UPDRS III total off-med: -10.4 vs -1.9 (P<0.001).
40 patients randomized 2:1 (27 FUS, 13 sham). Double-blind. Sham crossed at 4 months.
Unilateral subthalamotomy targeting STN via transcranial MRgFUS.
Dyskinesia in 48% of FUS group (contralateral) — mostly resolved or mild by 12 months.
Tremor improved most: -4.3 vs +0.5 (P<0.001). Rigidity and bradykinesia also improved.
On-medication: less improvement (already partially treated state).
AEs: dyskinesia (48%), speech impairment (8%), gait/balance (8%). Most transient.
First sham-controlled RCT of FUS subthalamotomy for PD.
Published NEJM 2020 (Martínez-Fernández et al.). Single-center, HM CINAC Madrid.

      

Design

Study Type: Randomized, double-blind, sham-controlled trial with 2:1 randomization ratio

Randomization: 1

Blinding: Double-blind

Enrollment Period: Enrollment March 2018 to May 2019. Primary endpoint at 4 months

Follow-up Duration: 4 months (primary endpoint), with extension to 12 months for active treatment group

Centers: 2

Countries: Spain, USA

Sample Size: 40

Inclusion Criteria

Parkinson's disease per U.K. Brain Bank criteria
highly asymmetric parkinsonism (asymmetry index >1.5, ratio of MDS-UPDRS III score for more affected side to less affected side)
motor signs not well controlled on more affected side despite optimal dopaminergic medication
declined deep-brain stimulation or ineligible

Exclusion Criteria

Modified Hoehn and Yahr score ≥2.5 in on-medication state
severe levodopa-induced dyskinesia
history of stereotactic surgery or brain hemorrhage
cognitive impairment or serious neuropsychiatric/medical condition
claustrophobia preventing MRI
skull density ratio <0.35

Arms

Field	Control
Intervention	Identical preparation with power disengaged
Duration	4 months (primary endpoint), with extension to 12 months for active treatment group

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change from baseline to 4 months in MDS-UPDRS III motor score for more affected side (off-medication)	Primary	18.7 → 17.1 (1.7-point decrease)	19.9 → 9.9 (9.8-point decrease)	8.1	<0.001
MDS-UPDRS III total off-medication at 4 months	Secondary	-1.9	-10.4		<0.001
Tremor subscore	Secondary	+0.5	-4.3		<0.001
PDQ-39 quality of life	Secondary	-1.6 points	-7.4 points
Patient Global Impression of Change (improved)	Secondary	15%	85%
Speech disturbance	Adverse		56% (persistent 11% at 4mo)
Dyskinesia (off-medication)	Adverse		22% (persistent 11% at 4mo, 0% at 12mo)
Gait disturbance	Adverse		48% (persistent 7% at 4mo)
Weakness	Adverse		19% (persistent 7% at 4mo)

Criticisms

Small sample size (40 patients) limits generalizability
Nearly single-center trial (36/40 patients from one site)
Blinding ineffective - patients and assessors correctly guessed assignments
Limited to highly selected patients with asymmetric disease
Unilateral procedure may have limited applicability as disease progresses bilaterally
High frequency of neurologic adverse events raises safety concerns

Funding

Insightec (trial sponsor, provided ultrasound device and funding), Focused Ultrasound Foundation, Fundación MAPFRE, Fundación Hospitales de Madrid, University of Virginia Center of Excellence

Based on: Focused Ultrasound Subthalamotomy for Parkinson Disease (New England Journal of Medicine, 2020)

Authors: Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R, ..., Obeso JA

Citation: 10.1056/NEJMoa2016311

Content summarized and formatted by NeuroTrials.ai.

Focused Ultrasound Subthalamotomy for Parkinson Disease

(2020)

Objective

To evaluate the efficacy and safety of unilateral focused ultrasound subthalamotomy compared to sham procedure for treating motor features of Parkinson's disease in patients with markedly asymmetric disease

Study Summary

• Focused ultrasound subthalamotomy significantly improved motor scores on the more affected side (8.1-point between-group difference, P<0.001)
• MDS-UPDRS III score decreased from 19.9 to 9.9 at 4 months in active treatment vs 18.7 to 17.1 in sham
• Benefit sustained at 12 months with mean reduction of 11.6 points

Intervention

Unilateral MRI-guided focused ultrasound subthalamotomy targeting the dorsolateral subthalamic nucleus and pallidothalamic tract

Inclusion Criteria

Parkinson's disease with highly asymmetric motor signs (asymmetry index >1.5), inadequate symptom control despite optimal medication, declined or ineligible for deep-brain stimulation

Study Design

Arms: Active treatment (focused ultrasound subthalamotomy) vs Sham procedure

Patients per Arm: 27 active treatment, 13 sham

Outcome

• Primary: Between-group difference in MDS-UPDRS III score for more affected side at 4 months: 8.1 points (95% CI 6.0-10.3, P<0.001)
• Secondary: Improvement in rigidity, bradykinesia, tremor, quality of life, and reduction in levodopa dose

Bottom Line

Major Points

MDS-UPDRS III contralateral: -8.1 (FUS) vs -0.4 (sham) at 4 months off-medication (P<0.001).
MDS-UPDRS III total off-med: -10.4 vs -1.9 (P<0.001).
40 patients randomized 2:1 (27 FUS, 13 sham). Double-blind. Sham crossed at 4 months.
Unilateral subthalamotomy targeting STN via transcranial MRgFUS.
Dyskinesia in 48% of FUS group (contralateral) — mostly resolved or mild by 12 months.
Tremor improved most: -4.3 vs +0.5 (P<0.001). Rigidity and bradykinesia also improved.
On-medication: less improvement (already partially treated state).
AEs: dyskinesia (48%), speech impairment (8%), gait/balance (8%). Most transient.
First sham-controlled RCT of FUS subthalamotomy for PD.
Published NEJM 2020 (Martínez-Fernández et al.). Single-center, HM CINAC Madrid.

Study Design

Study Type: Randomized, double-blind, sham-controlled trial with 2:1 randomization ratio
Randomization: Yes
Blinding: Double-blind
Sample Size: 40
Follow-up: 4 months (primary endpoint), with extension to 12 months for active treatment group
Centers: 2
Countries: Spain, USA

Primary Outcome

Definition: Change from baseline to 4 months in MDS-UPDRS III motor score for more affected side (off-medication)

Control	Intervention	HR/OR	P-value
18.7 → 17.1 (1.7-point decrease)	19.9 → 9.9 (9.8-point decrease)	- (6.0–10.3)	<0.001

Limitations & Criticisms

Small sample size (40 patients) limits generalizability
Nearly single-center trial (36/40 patients from one site)
Blinding ineffective - patients and assessors correctly guessed assignments
Limited to highly selected patients with asymmetric disease
Unilateral procedure may have limited applicability as disease progresses bilaterally
High frequency of neurologic adverse events raises safety concerns

Citation

10.1056/NEJMoa2016311

View Original Publication →

Focused Ultrasound Subthalamotomy for Parkinson Disease

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Criticisms

Funding

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