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JAMA Neurol
JAMA Neurol
JAMA Neurology
2168-6149
2168-6157
American Medical Association

39073822
10.1001/jamaneurol.2024.2295
noi240043
Research
Research
Original Investigation
Online First
Comments
Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor
An Open-Label Clinical Trial
Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor
Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor
Kaplitt Michael G. MD PhD 1
Krishna Vibhor MD 2
Eisenberg Howard M. MD 3
Elias W. Jeffrey MD 4
Ghanouni Pejman MD PhD 5
Baltuch Gordon H. MD 6
Rezai Ali MD 7
Halpern Casey H. MD 8
Dalm Brian MD 9
Fishman Paul S. MD PhD 10
Buch Vivek P. MD 11
Moosa Shayan MD 4
Sarva Harini MD 12
Murray Ann Marie MD 13
1 Department of Neurological Surgery, Weill Cornell Medicine, New York, New York
2 Department of Neurosurgery, University of North Carolina, Chapel Hill
3 Department of Neurosurgery, University of Maryland, Baltimore
4 Department of Neurosurgery, University of Virginia, Charlottesville
5 Department of Radiology, Stanford University, Stanford, California
6 Columbia University, New York, New York
7 Department of Neurosurgery, West Virginia University, Morgantown
8 Department of Neurosurgery, University of Pennsylvania, Philadelphia
9 Department of Neurosurgery, The Ohio State University, Columbus
10 Department of Neurology, University of Maryland, Baltimore
11 Department of Neurosurgery, Stanford University, Stanford, California
12 Department of Neurology, Cornell University, New York, New York
13 Department of Neurology, West Virginia University, Morgantown
Article Information

Accepted for Publication: May 31, 2024.

Published Online: July 29, 2024. doi:10.1001/jamaneurol.2024.2295

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2024 Kaplitt MG et al. JAMA Neurology.

Corresponding Author: Howard M. Eisenberg, MD, Department of Neurosurgery, University of Maryland, 22 South Greene St, Baltimore, MD 21201 (heisenberg@som.umaryland.edu).
Author Contributions: Drs Kaplitt and Eisenberg had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kaplitt, Eisenberg, Elias, Rezai, Halpern, Fishman, Murray.

Acquisition, analysis, or interpretation of data: Kaplitt, Krishna, Eisenberg, Ghanouni, Baltuch, Rezai, Halpern, Dalm, Fishman, Buch, Moosa, Sarva, Murray.

Drafting of the manuscript: Kaplitt, Krishna, Eisenberg, Baltuch, Dalm, Fishman.

Critical review of the manuscript for important intellectual content: Kaplitt, Eisenberg, Elias, Ghanouni, Baltuch, Rezai, Halpern, Dalm, Fishman, Buch, Moosa, Sarva, Murray.

Statistical analysis: Eisenberg.

Administrative, technical, or material support: Eisenberg, Ghanouni, Baltuch, Halpern, Dalm, Fishman, Moosa, Sarva, Murray.

Supervision: Kaplitt, Krishna, Eisenberg, Elias, Ghanouni, Halpern, Fishman, Murray.

Conflict of Interest Disclosures: Dr Krishna reported grants the National Institutes of Health outside the submitted work. Dr Halpern reported consulting and speaking honoraria from Boston Scientific outside the submitted work; had a patent for tractography for circuit-based brain stimulation issued 63/210,472 and a patent for sensing and brain stimulation for the treatment of neuropsychiatric disorders issued (Stanford University 63/170,404 and 63/220,432); and serves as chairman of SynchNeuro. Dr Sarva reported clinical trial support from Blue Rock, Prevail, MeiraGTX, Biogen, Genentech, Neuroderm, Sun Pharma, Bukwang, Novo Nordisk, Cerevance, and the National Institutes of Health and personal fees from Novo Nordisk for consulting on study protocol completed outside the submitted work). No other disclosures were reported.

Funding/Support: This study was funded by Insightec.

Role of the Funder/Sponsor: The sponsor funded the study and provided general oversight for the management of the data collection. The sponsor funded the analysis, which was completed by an independent third-party statistical group. The sponsor did not design and conduct the study; the data were collected locally at each site and entered into an electronic data collection system managed by the sponsor; the sponsor did not do the analysis and interpretation of the data; the sponsor did not prepare, review, or approve the manuscript or make the decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We would like to thank Katie Gant, PhD, Insightec, for her help with administrative management of this submission. No compensation was provided.

29 7 2024
9 2024
29 7 2024
81 9 939946
14 2 2024
31 5 2024
Copyright 2024 Kaplitt MG et al. JAMA Neurology.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the CC-BY-NC-ND License.
jamaneurol-e242295.pdf

Key Points

Question

Is staged, bilateral magnetic resonance–guided focused ultrasound thalamotomy safe and effective for patients with essential tremor?

Findings

In this open-label trial, 51 patients with essential tremor treated successfully unilaterally underwent focused ultrasound thalamotomy on the opposite side. Tremor/motor, positional tremor, and functional disability improved significantly, and adverse events were almost always mild and frequently resolved.

Meaning

Magnetic resonance–guided focused ultrasound may be a safe and effective option for treating bilateral essential tremor.

This open-label clinical trial assesses the safety and efficacy of staged, bilateral focused ultrasound thalamotomy in essential tremor.

Importance

Unilateral magnetic resonance–guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option.

Objective

To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy.

Design, Setting, and Participants

This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category).

Intervention

A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation.

Main Outcomes and Measures

Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months.

Results

The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient.

Conclusions and Relevance

Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient.

Trial Registration

ClinicalTrials.gov Identifier NCT04112381.

Insightec
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pmcIntroduction

Essential tremor (ET) is one of the most common movement disorders.1 Surgery targeting the ventralis intermedius nucleus of the thalamus is an effective treatment for ET in patients with functionally significant tremors. Deep brain stimulation has been the established procedure for refractory ET as it can be adjusted to maximize efficacy and reduce off-target adverse effects.2,3

Alternatively, magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy uses intersecting ultrasound beams to ablate the ventralis intermedius to reduce contralateral tremors. A randomized, controlled, blinded trial of unilateral MRgFUS thalamotomy for ET showed sufficient efficacy and safety that the procedure was approved by the US Food and Drug Administration (FDA) in 2016.4

All the initial MRgFUS studies, as well as the first FDA approval, were for unilateral treatment for the dominant hand. However, most patients with ET have bilateral symptoms, and often require bilateral surgery.5 Also, for clinically significant head and voice tremors, unilateral surgery is usually inadequate to provide satisfactory control. Recently, a few small, single-center studies of staged bilateral MRgFUS thalamotomy for ET, have shown initial efficacy and safety similar to unilateral treatment.6,7,8,9

The growing acceptance of unilateral MRgFUS ablation has led to an interest in a bilateral option, but historically bilateral ablation was associated with higher risks, such as speech and language disturbance.10 Therefore, we designed a sufficiently robust study to allow regulatory evaluation of the safety and effectiveness of staged, bilateral MRgFUS thalamotomy. We now report the results of a multicenter trial of contralateral MRgFUS thalamotomy in individuals with ET with a previously successful unilateral MRgFUS thalamotomy. These results were used by the FDA to approve staged bilateral MRgFUS ablation for ET.

Methods

Trial Design and Oversight

The trial was performed under investigational device exemption and registered with ClinicalTrials.gov. Seven sites in the US recruited and treated participants between July 2020 and October 2021. Clinical oversight for each site was provided by the principal investigator and an independent centralized data and safety monitoring board. The sponsor and device manufacturer, Insightec, provided trial oversight for regulatory processes. The study investigators participated in statistical analysis in collaboration with an independent data analysis company (Technostat) contracted by the sponsor. The study protocol (Supplement 1) was approved by the institutional review boards at each institution, and written informed consent was signed by all participants. There were no confidentiality agreements between the sponsor and trial investigators. The trial was conducted in accordance with the Helsinki/Harmonization guidelines. Some features of the study design, including specific outcome scales, were chosen to conform with the preferences of regulatory bodies.

The study was a prospective, open-label, uncontrolled, single-arm, cohort, multicenter trial designed to evaluate the safety and effectiveness of staged, bilateral MRgFUS thalamotomy in individuals with medication-refractory ET. Individuals screened for eligibility had already undergone unilateral MRgFUS thalamotomy, 5 of whom participated in the earlier randomized study.4 MRgFUS thalamotomy for the untreated side was performed at least 9 months following initial treatment. Since participants had undergone a prior MRgFUS thalamotomy, it would make blinding of participants difficult, as they were fully aware of treatment-associated sensations and that expected improvement was virtually immediate.

Study Population

Sample size was based on the original unilateral study, accounting for a potential dropout rate of 20%. All participants consented and were screened, and those not meeting the following eligibility criteria were excluded: aged 22 years or older, diagnosis of ET that is refractory to adequate trials of at least 2 medications (at least 1 first line), history of previous MRgFUS thalamotomy procedure at least 9 months prior to enrollment, baseline Clinical Rating Scale for Tremor (CRST) part A score of 2 or higher for postural or kinetic tremor severity in the upper extremity for the untreated side, baseline CRST part C score of 2 or higher in any category. Exclusion criteria included persistence of any neurological worsening following the index procedure, a physical subscale score of 16.5 or greater on the Dysphagia Handicap Index or a diagnosis of dysphagia, clinically significant abnormal speech function, a score of less than 22 on the Montreal Cognitive Assessment, pregnant or breastfeeding, unstable cardiac status disease, prior deep brain stimulation or stereotactic ablation, coagulopathy, a skull density ratio (indicating the degree of penetrability of acoustic energy) less than 0.40, a structural brain lesion or a history of intracranial hemorrhage, multiple strokes, or a stroke within the past 6 months. Anticoagulation medications were stopped prior to and immediately after the MRgFUS procedure. Race and ethnicity data were gathered due to known differences in skull density ratio, but data are not reported here owing to small numbers.

Procedure

MRgFUS thalamotomy was performed using Exablate 4000 Neuro (Insightec) interfaced with a magnetic resonance imaging (MRI) machine (3 T or 1.5 T). The details of the MRgFUS thalamotomy procedure were previously described.4 Intraoperative anatomic images were acquired (typically T2) for treatment planning. These images were coregistered with the preoperative computed tomography and MRI, and no-pass regions were identified. Targeting was performed using a combination of stereotactic coordinates for the ventralis intermedius (generally 14 mm lateral to the midline, 25% of the intercommissural distance anterior to posterior commissure, and 1.5 to 2 mm superior to the intercommissural plane) or through the use of tractography to identify the dentatorubrothalamic tract.11,12

Low-energy sonications were initially delivered to the target for verification and subthreshold testing. These generated a 40 to 48 °C target temperature in an approximately 2-mm diameter volume of tissue. The ultrasound energy was gradually increased, progressing incrementally to higher temperatures, continually monitored with MR thermometry, with each sonication followed by patient evaluation to test for improvement in tremor and any off-target adverse effects, such as paresthesia, dysmetria, or speech difficulty. Any transient improvement without off-target effects was followed by increasing energy to cause permanent ablation (typically temperatures greater than 55 °C). In absence of tremor improvement or appearance of an off-target effect, the target was moved. The final ablation location and size were ultimately determined based upon clinical responses during treatment. For a more detailed discussion, see eMethods in Supplement 2. Putative treatment stopping points included the appearance of an off-target effect; a greater than 75% reduction of tremor; a postsonicaton MR signal change greater than 8 mm, and close proximity to an eloquent anatomic structure.

Patients were awake during the procedure but medicated as needed for discomfort, nausea, and blood pressure. Following the treatment, the stereotactic frame was removed. Patients were typically discharged from the hospital on the same day as the procedure. A postprocedure MRI of the brain was acquired within 24 hours to evaluate the location and size of the lesion, and all treated patients had a lesion detectable by MRI.

Follow-Up Assessments

Follow-up assessments were performed at 48 hours and months 1, 3, 6, and 12. Assessments included physical and neurological examinations (including walking and ataxia), CRST score, Dysphagia Handicap Index score, speech function assessments, Montreal Cognitive Assessment score, Epworth Sleepiness Scale (ESS) score, medication review, and adverse events.

Outcome Measures

All adverse events occurring during the study were recorded and assessed for causality and severity (mild, moderate, and severe; defined in the protocol according to FDA definitions). The primary study end point for safety was the incidence and severity of device- and treatment-related adverse events occurring through the 6-month time point and followed until the end of the study at 12 months.

The protocol-defined primary efficacy end point was the change from baseline to 3 months in tremor/motor function, measured with CRST parts A and B, for the treated side (ranges from 0-32, with a higher score indicating worse tremor).13 The tremor/motor score from the hand contralateral to the thalamotomy included 3 items from CRST part A (resting, postural, and kinetic tremor), and CRST part B (handwriting, drawing, and pouring assessments). Supporting secondary efficacy end points included the change from baseline to 3 months in upper extremity postural tremor (CRST part A) for the treated side, along with change from baseline to 3 months in functional disability score (CRST part C). Head and voice tremors were evaluated using the CRST scale, with treatment responsiveness defined as any participant with a head or voice tremor at baseline who experienced at least a 1-point improvement.

Speech was assessed by a speech-language pathologist to determine the presence of speech-language dysfunction at baseline and evaluate for any change in function at 3 months and categorize those into clinically significant or nonsignificant difficulty in phonation, articulation, and swallowing. Swallowing function was assessed using the Dysphagia Handicap Index.14 The Montreal Cognitive Assessment was used to identify cognitive impairment at baseline and estimate for any changes during study participation.15 The Epworth Sleepiness Scale assessed the propensity for dozing or falling asleep during common daily activities at baseline and each follow-up visit.16

Statistical Analysis

Data were analyzed using SAS version 9.4 (SAS Institute). Numerical variables were tabulated using means, SDs, and 95% CIs. Categorical variables were summarized using the number of observations and percentages. The study had 1 primary and 2 secondary efficacy end points. A hierarchical testing design was used to control for multiplicity across the end points. The primary efficacy analysis was performed with a significance level of α = .05. Testing of the 2 secondary efficacy end points proceeded with α = .05 if all previous tests were successful. Primary efficacy analyses were conducted on the modified intent-to-treat analysis set, which included all participants with baseline and at least 1 posttreatment measurement on the primary efficacy data. Primary and secondary end points were prespecified and approved by the FDA prior to initiation of the study. Data are reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Results

Study Population

Sixty-two individuals with a previous MRgFUS thalamotomy were recruited. Eleven were excluded (3 in whom CRST scores did not meet inclusion criteria, 3 with presence of dysphagia or elevated Dysphagia Handicap Index score, 1 with a low skull density ratio, 1 with clinically significant dysarthria, 1 with contraindicated medication use, 1 with a persistent neurological event, and 1 who withdrew consent during screening). Therefore, 51 individuals received a staged, bilateral MRgFUS ventralis intermedius thalamotomy. Of these, 50 completed follow-ups at both the 3-month primary end point and at 6 months follow-up, and 48 completed the 12-month visit (Figure 1).

Figure 1. Flowchart of Study Recruitment

CRST indicates Clinical Rating Scale for Tremor.

The mean (SD) duration between the first thalamotomy to the staged, contralateral procedure was 2.2 (1.6) years. All participants were treated on the nondominant side (left hemisphere n = 5; right n = 46). Twelve participants (23.5%) had voice tremor prior to the contralateral procedure, and 17 (33.3%) had head tremor. The mean skull density ratio was 0.54 (median, 0.52; range, 0.34-0.81). The mean (SD) age was 73 (9.3; range, 37ˑ5-93ˑ7) years. Forty-four participants (86.3%) were male, and 7 (13.7%) were female (Table 1).

Table 1. Demographic and Clinical Characteristicsa

Variable	Treatment group, No. (%)	
Age, mean (range), y	73.0 (37.5-93.7)	
Sex		
Female	7 (13.7)	
Male	44 (86.3)	
Raceb		
Asian	NR	
Black or African American	NR	
White	NR	
Ethnicityb		
Hispanic	NR	
Non-Hispanic	NR	
Total	49	
Time from initial ET symptoms, mean (SD) y (n = 50)	36.5 (18.1)	
Time from initial ET diagnosis, mean (SD) y (n = 50)	19.7 (14.9)	
Side of brain treated (all nondominant hand)		
Left	5 (9.8)	
Right	46 (90.2)	
Skull density ratio, mean (SD)	54.6 (10.1)	
Participants taking tremor-related medications at entry, No.	6	
Abbreviation: NR, not reported.

a N = 51 unless otherwise noted.

b Race and ethnicity data were collected via self-report (multiple choice) to understand treatment effects and generalizability of results. Because of low numbers in most represented groups, data have been obscured to protect participant privacy.

Despite exclusion of individuals with clinically notable dysphagia or dysarthria determined by the investigators, objective speech and swallowing evaluation found 10 participants (19.6%) with abnormal but nonsignificant phonation at baseline and 2 participants (3.9%) with significant abnormal phonation. There was 1 participant with significant articulation difficulty and 1 with nonsignificant articulation difficulty at baseline. The Dysphagia Handicap Index was also noted to be nonsignificantly abnormal in 2 participants at baseline, and no participant had a significant Dysphagia Handicap Index score. No participants had clinically significant ataxia at baseline.

Tremor Outcomes

At 3 months posttreatment, the primary outcome measured by CRST parts A and B reduced from a mean (SD) score of 17.4 (5.4; 95% CI, 15.9 to 18.9) to 6.4 (5.3; 95% CI, 4.9-7.9; 66% reduction in the CRST parts A and B; 95% CI, 59.8-72.2; P < .001) (Figure 2A). Mean (SD) postural tremor improved from 2.5 (0.8; 95% CI, 2.3-2.7) to 0.6 (0.9; 95% CI, 0.3-0.8; 81% reduction in the CRST part A; P < .001) (Figure 2B). These decreases in scores were similar at 6 and 12 months posttreatment (Figure 2), with CRST A and B mean (SD) tremor scores of 6.9 (5.0; 63% reduction) at 6 months and 7.0 (5.6; 62% reduction) at 12 months. Mean (SD) postural tremor scores also improved at 6 (0.5 [0.7]; 81.2% reduction in CRST part A) and 12 (0.6 [0.8]; 80.2% reduction in CRST part A) months (P < .001 for all).

Figure 2. Tremor/Motor Scores, Postural Tremor Scores, and Tremor Disability Scores at Baseline and Follow-up After Staged Bilateral Focused Ultrasound Ablation

The number of participants assessed at baseline, month 3, month 6, and month 12 visits are 51, 50, 50, and 45, respectively.

For the CRST part C, which reflects functional disability, the mean (SD) scores improved from 10.3 (4.7; 95% CI, 9.0-11.6) prior to the second side treatment to 2.2 (2.8; 95% CI, 1.4-2.9; 73% improvement in CRST part C; P < .001) (Figure 2C). Again, this was consistent across all the time points (mean [SD] 6-month score: 2.3 [3.9]; improvement of 73.1%; 12-month score: 2.4 [3.8]; 73.3% improvement in CRST part C; P < .001 for all) (Figure 2). Those participants who were taking primidone or propranolol at the time of screening for this study (n = 6) all reduced their doses by 6 months following the treatment (eFigure in Supplement 2). In 3 of these 6 patients, tremor medications were discontinued entirely by 3 months posttreatment.

Participant-Reported Adverse Events

Adverse events were 85% mild (159 of 188), 13% moderate (25 of 188), and 2% severe (1 severe urinary tract infection related to catheter use during procedure). The most common participant-reported adverse events within 30 days were numbness or tingling (mild, n = 17), dysarthria (mild, n = 14; moderate, n = 1), ataxia (mild, n = 12), unsteadiness/imbalance (mild, n = 9; moderate, n = 1), dysgeusia (mild, n = 6; moderate, n = 1), gait disturbance (mild, n = 5), and dysphagia (mild, n = 3; moderate, n = 1) (Table 2). At 3 months, 9 participants continued to experience numbness (all mild), 8 reported dysarthria (all mild), 8 reported ataxia (all mild), 3 reported unsteadiness/imbalance (mild, n = 2; moderate, n = 1), 7 reported dysgeusia (mild, n = 6; moderate, n = 1), 3 reported dysphagia (mild, n = 2; moderate, n = 1), and 2 reported gait disturbance (all mild). At 12 months, 8 participants continued to experience numbness (all mild), 7 reported dysarthria (all mild), 6 reported ataxia (all mild), none reported unsteadiness/imbalance, 3 reported change in taste (mild, n = 2; moderate, n = 1), and 1 reported gait disturbance (mild). One severe event, a urinary tract infection due to catheter use during the treatment, was noted.

Table 2. Adverse Events Associated With Staged, Bilateral Focused Ultrasound Ablation

Event	No.	
Total (N = 51)	1 mo (n = 51)	3 mo (n = 50)	6 mo (n = 50)	12 mo (n = 47)	
Numbness/tingling	17	11	9	8	8	
Dysarthriaa	15	10	8	7	7	
Ataxia	12	9	8	7	6	
Unsteadiness/imbalancea	10	5	3	0	0	
Dysgeusiaa	7	7	7	3	3	
Gait disturbance	5	3	2	1	1	
Hypogeusia	4	4	4	4	3	
Dysphagiaa	4	4	3	3	3	
Fatigue	2	1	1	0	0	
Dysmetria	2	1	1	1	0	
Facial droop	1	0	0	0	0	
Weakness	1	1	1	1	0	
Decrease in synchronicityb	1	1	1	1	1	
Diplopia, intermittent	1	0	0	0	0	
Dizziness	1	0	0	0	0	
Dry mouth	1	1	1	1	0	
Hypoesthesia	1	1	1	1	1	
Sialorrhea	1	1	1	1	1	
Voice change	1	1	0	0	0	
Headachea	1	0	0	0	0	
UTIc	1	0	0	0	0	
a All events were mild, except for 1 moderate event each for dysarthria (resolved by 1 month), unsteadiness/imbalance (resolved by 6 months), dysgeusia (ongoing at 12 months), dysphagia (ongoing at 12 months), and headache (resolved by 1 month).

b Mild difficulty in coordinating the right and left hand when playing the guitar.

c There was 1 severe event, a urinary tract infection due to catheter use during the treatment.

Speech and Language Pathology Assessment

The assessment by the speech and language pathologist identified that phonation shifted from baseline nonsignificantly abnormal to significantly abnormal in 1 participant at 1 month and 3 participants at 6 months. No other participants developed new difficulties with phonation.

At 1 month posttreatment, articulation in 1 participant changed from nonsignificant to significant, and 4 additional participants developed significant slurred/slow speech. By 3 months, 3 participants had ongoing, abnormal, significant articulation difficulty.

Nine participants were observed to have significant abnormal dysphagia at 1 month (2 at baseline and 7 additional participants developed abnormal dysphagia). By 6 months, the number of dysphagia abnormalities reduced to 3 participants with significant abnormal dysphagia and 1 with nonsignificant abnormal dysphagia. No participant had worsening in all 3 speech and language measures.

Additional Safety Assessments

Among other clinical evaluations, there were no significant changes in cognition as measured by the Montreal Cognitive Assessment (mean [SD] at baseline, 26.5 [1.9], 6 months, 27.3 [2.6]), and Epworth Sleepiness Scale results remained unchanged (participants with reported normal sleep at baseline, n = 46; 3 months, n = 43; and 6 months, n = 46).

Secondary Outcomes

Among participants with baseline voice tremor, 8 of 12 (67%) were considered treatment responsive, and there was a mean (SD) improvement from 1.2 (0.5) at baseline to 0.2 (0.4) at 3 months, 0.4 (0.5) at 6 months, and 0.3 (0.5) at 12 months (Figure 3). For participants with head tremor prior to contralateral treatment, 12 of 17 (71%) were responders, with a mean (SD) improvement from the head tremor score at baseline of 1.1 (0.3) to 0.4 (0.6) at 3 months, 0.4 (0.6) at 6 months, and 0.2 (0.4) at 12 months.

Figure 3. Head and Voice Tremor Scores at Baseline and Follow-Up After Staged Bilateral Focused Ultrasound Ablation

The number of participants assessed at baseline, month 3, month 6, and month 12 visits are 17, 17, 17, and 16 for head tremor and 12, 12, 12, and 11 for voice tremor, respectively.

Discussion

In this multicenter, open-label trial of 51 participants with ET, staged bilateral MRgFUS thalamotomy significantly reduced limb, head, and voice tremor and improved tremor-related disability. These improvements were associated with adverse events similar in frequency and severity to those that occurred in the pivotal trial of unilateral treatment,4 with the exception of mild dysarthrias, which were reported more frequently in this study. These data led to regulatory approval by the US FDA, yet this is the first report of these data from the study.

Unilateral MRgFUS thalamotomy is increasingly used for patients with tremor refractory to medical therapy due to its less invasive nature and elimination of hardware implants. However, a PubMed search revealed 87 publications reporting MRgFUS thalamotomy outcomes, and most were unilateral procedures. Most patients with ET have bilateral symptoms, and the untreated limb can be a continuing source of disabling symptoms after successful unilateral treatment for the many daily tasks requiring the use of both hands, as indicated by the ongoing baseline mean disability score in this study prior to contralateral treatment.

This is the first study that we are aware to include a pre- and post-MRgFUS thalamotomy formal speech and language assessment. After MRgFUS thalamotomy, we observed adverse events related to speech and swallowing function, which were much less frequent than the reported rates of speech dysfunction after bilateral radiofrequency thalamotomy.10 However, there were no clear patterns to predict which participants might be more prone to a decline. While the frequency of these adverse events was greater than prior reports of unilateral treatment, most were sufficiently mild that they were not considered to be a source of clinical disability for participants. Adverse events in these domains have also been reported in studies of bilateral deep brain stimulation for ET.17,18

At 1 month following the procedure, approximately 20% of participants reported sensory changes (numbness or tingling), dysarthria, or ataxia, and a loss or change in taste (dysgeusia/hypogeusia). More than 60% of these resolved by 12 months. Nonetheless, at 12 months, 10% to 15% of participants reported some residual sensory changes, dysarthria, or gait ataxia, all of which were reported as mild and were thus defined as changes that did not interfere with everyday activities. Moderate dysphagia and dysgeusia were observed at 12 months in 1 participant each. The 1 severe event was a urinary tract infection due to catheter use during the treatment. Differences in these adverse effects compared with prior studies may be due to intrinsic differences in cohorts or treatment.19

The magnitude and stability of tremor relief over 1 year is similar to the reported results from unilateral MRgFUS and the few studies of staged, bilateral MRgFUS thalamotomy.7,8,9 For those with head or voice tremors, there was a considerable reduction in tremor in most participants. These results are consistent with observations that bilateral deep brain stimulation treatment often better controls head and voice tremor.20 Participants were motivated to undergo contralateral treatment, suggesting that the ongoing contralateral tremor was sufficiently influencing their quality of life to justify undergoing a second procedure with limited safety and efficacy data prior to enrollment in this study. Thus, the significant improvement in functional scores following successful contralateral treatment confirms that even with an excellent result from unilateral therapy, staged bilateral treatment should be considered in patients with ongoing disability from contralateral tremor.

Limitations

A sham control group was considered, as was done in the unilateral ET trial4 and the unilateral pallidotomy trial (n = 94).21 In the pallidotomy trial, patients were assigned to 2 groups, treatment and sham. Although none of these participants had ever been treated with MRgFUS, 95% correctly believed that they had received active treatment, while in the sham group, 58% believed incorrectly that they were treated. But perhaps more relevant, the trial investigators correctly guessed 79% in the active group and 83% in the sham group. Given this experience, and considering this study population had already undergone unilateral treatment, we proceeded with an open-label study, recognizing this limitation. The nature of the study population, with improvement following unilateral MRgFUS thalamotomy and being mostly non-Hispanic White and mostly male, is another limitation. The skull density ratio has been noted to be lower on average in certain racial groups,22 which could have skewed the treatment population. The lack of other underrepresented groups may also reflect disparities in health care access.

Conclusions

In this open-label study of 51 participants, staged, bilateral MRgFUS thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient.

Supplement 1. Trial protocol

Supplement 2. eMethods

eFigure

Supplement 3. Data sharing statement
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