Magnetic resonance-guided focused ultrasound for essential tremor: a prospective, single center, singlearm study

Rui Zong, Xuemei Li, Chunyu Yin, Jianfeng He, Dekang Zhang, Xiangbing Bian, Lichao Huang, Jiayou Zhou, Zhipei Ling,Lin Ma, Xin Lou,*, Longsheng Pan,*, Xinguang Yu,*

Abstract The safety and effectiveness of magnetic resonance-guided focused ultrasound thalamotomy has been broadly established and validated for the treatment of essential tremor.In 2018, the first magnetic resonance-guided focused ultrasound system in Chinese mainland was installed at the First Medical Center of the PLA General Hospital.This prospective, single center, open-label, single-arm study was part of a worldwide prospective multicenter clinical trial (ClinicalTrials.gov Identifier: NCT03253991) conducted to confirm the safety and efficacy of magnetic resonance-guided focused ultrasound for treating essential tremor in the local population.From 2019 to 2020, 10 patients with medication refractory essential tremor were recruited into this open-label, single arm study.The treatment efficacy was determined using the Clinical Rating Scale for Tremor.Safety was evaluated according to the incidence and severity of adverse events.All of the subjects underwent a unilateral thalamotomy targeting the ventral intermediate nucleus.At the baseline assessment, the estimated marginal mean of the Clinical Rating Scale for Tremor total score was 58.3 ± 3.6, and this improved after treatment to 23.1 ± 6.4 at a 12-month follow-up assessment.A total of 50 adverse events were recorded, and 2 were defined as serious.The most common intraoperative adverse events were nausea and headache.The most frequent postoperative adverse events were paresthesia and equilibrium disorder.Most of the adverse events were mild and usually disappeared within a few days.Our findings suggest that magnetic resonance-guided focused ultrasound for the treatment of essential tremor is effective, with a good safety profile, for patients in Chinese mainland.

Key Words: efficacy; essential tremor; magnetic resonance-guided focused ultrasound (MRgFUS); movement disorder; safety; stereotactic therapy;thalamotomy; ventral intermediate nucleus

Introduction

Essential tremor (ET) is a common movement disorder characterized by postural and intentional tremor, often involving the upper limbs, with a frequency of 8–12 Hz.Although ET can be treated using pharmaceutical means, approximately 50% of patients eventually discontinue medications because they are ineffective or intolerable.In the 1990s, the thalamic ventral intermediate nucleus (Vim) was introduced as a treatment target for medication refractory tremor (Israel, 2003).Improvements in magnetic resonance (MR) imaging and electrophysiological localization methods over the past two decades have confirmed that the Vim nucleus is an effective target for tremor treatment (Brodkey et al., 2004; Milosevic et al., 2018).Both lesioning and deep brain stimulation (DBS) targeting the Vim have been found to effectively control tremor symptoms (Schreglmann et al., 2018).Surgical interventions include Vim radiofrequency ablation, stereotactic radiosurgery,or DBS.However, many patients are reluctant to undergo invasive surgery or ionizing irradiation therapy (Haubenberger and Hallett, 2018).

Magnetic resonance-guided focused ultrasound (MRgFUS) is a newly developed therapeutic technology for the treatment of ET.In this technique,a helmet-shaped phased-array transducer emits high intensity focused ultrasound (FUS) waves transcranially into the defined target under continuous anatomical MR guidance and monitoring.The thermal effect of ultrasonic energy is used to ablate the target (Wang et al., 2018).MRgFUS does not require a craniotomy, hardware implantation, or ionizing radiation,and has the advantage of an extremely low risk of postoperative infection or bleeding.Furthermore, the MRI component is used to obtain continuous thermal feedback regarding the real-time treatment effect.The patient is awake during the treatment, and is able to provide physiological and clinical feedback regarding the targeting accuracy.

The safety and effectiveness of MRgFUS for ET have been broadly validated.Regulatory authorities in the United States, Europe, Japan, South Korea,Israel, and other countries and regions have approved the use of transcranial MRgFUS for the treatment of ET (Fishman, 2017).A series of clinical studies demonstrated the feasibility, safety, and effectiveness of transcranial MRgFUS for the treatment of tremor.Specifically, an open-label pilot study evaluated the effects of MRgFUS for unilateral Vim thalamotomy in 15 patients with severe medication-refractory ET, and found that it safely improved the mean Clinical Rating Scale for Tremor (CRST) score for hand tremor from a baseline of 20.4 to 5.2 at 12 months after the initial treatment, while the total tremor score improved from 54.9 to 24.3 (Elias et al., 2013a).In a separate proof of concept study, Lipsman et al.(2013) used MRgFUS to treat 4 patients with chronic drug-resistant ET.The mean decrease from baseline in the treatedhand tremor score was 89.4% at 1 month and 81.3% at 3 months.Chang et al.(2015) attempted MRgFUS thalamotomy in 11 ET patients.Only 8 patients completed the MRgFUS treatment because the temperature at the target was insufficient in 3 patients.For the 8 successfully treated patients, the mean CRST Part A and CRST Part B scores were remarkably improved from 5.1 at baseline to 1.4 at 6 months, and from 13 at baseline to 2.6 at 6 months,respectively.Furthermore, the improvement in the mean CRST total score in these patients at 6 monthsvs.baseline was 80.43%.

Several studies have described attempts to treat individuals with tremordominant Parkinson’s disease via MRgFUS by targeting the Vim.In 2018,Zaaroor et al.reported that in 9 patients with Parkinson’s disease, MRgFUS treatment led to a reduction in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS; Goetz et al., 2007) motor score from 24.9 ± 8.0 to 13.4 ± 9.2 after 6 months.In a randomized controlled study of 27 subjects, there was a 62% post-treatment improvement in the treatment arm hand tremor score (CRST part A+B, ON state), while the quality of life score (CRST part C) decreased from 12.5 to 1.0.The therapeutic effect of MRgFUS-induced Vim ablation was reaffirmed in 65% of a patient group,with an improvement in hand tremor score of at least 50% after 1 year (Bond et al., 2017).Previously, we reported the outcomes of 9 tremor-dominant Parkinson’s patients treated with MRgFUS.In that sample, the preoperative MDS-UPDRS III score had decreased from 55.0 (OFF) and 26.0 (ON) to 40.0(OFF) and 21.0 (ON), respectively, at 1 year after the operation.Furthermore,the levodopa equivalent dose had decreased from 600 mg/d to 575 mg/d.The total MDS-UPDRS III score, as well as the MDS-UPDRS III tremor,bradykinesia, and rigidity scores of the contralateral limbs in the OFF state,had all significantly improved at 1 year (Yin et al., 2022).

In August 2018, the People’s Liberation Army (PLA) General Hospital installed the first MRgFUS system in Chinese mainland.Immediately after the installation of the equipment, the center initiated a clinical trial.The aim of the current trial was to verify the safety and effectiveness of MRgFUS for the treatment of medication-refractory ET in individuals living in Chinese mainland.The study objective was to test the efficacy of treatment conducted using the MRgFUS system and to further demonstrate its safety for treating medication-refractory tremor in subjects with ET.We hypothesized that the study subjects would achieve treatment effects consistent with those at other clinical centers.

Methods

Study design and oversight

This study was part of a worldwide prospective multicenter clinical trial(ClinicalTrials.gov Identifier: NCT03253991) sponsored by InSightec Co.Ltd.,and was reported according to the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement.Given that the U.S.FDA has approved the indication for MRgFUS for ET, our center, as the first clinical trial center in Chinese mainland, primarily aims to provide Chinese patients with a portion of the clinical treatment.In terms of sample size, the main consideration at that time was to distribute it equally across multiple hospitals, ensuring that physicians would go through the learning curve phase to obtain more stable and reliable treatment results and ensure that all centers could master this treatment protocol.Finally, the results of the multicenter treatment in Chinese mainland were combined with the results of foreign clinical trials and jointly declared for approval of the Chinese clinical license.Therefore, the sample size is not statically required.Ultimately, the sponsor determined that our center would receive a quota of 10 samples.This prospective, single center, open-label, single-arm study was conducted at the First Medical Center of the PLA General Hospital and approved by the Ethics Committee of the PLA General Hospital (approval No.2018-021) on October 11, 2018.Subject screening was performed at our center’s outpatient clinic, and the investigator covered the costs of the subject examination and treatment.There were no other incentives for study participation.Subjects were screened and evaluated independently by 2 non-blinded experienced movement disorder specialists using a consensus approach.Subjects who met the eligibility criteria were enrolled and underwent the treatment.All subjects sign an informed consent form.Post-treatment follow-up assessments were scheduled at 1, 3, 6, and 12 months after treatment.Treatment efficacy was determined according to the change in CRST score from baseline (Stacy et al., 2007).Safety was assessed by the incidence and severity of MRgFUS treatment-related adverse events (AE).

Patient selection

The main eligibility criteria are as follows:

- Men and women aged 22 years or older.

- Subjects who were able and willing to give consent and to attend all study sessions.

- An ET diagnosis via clinical history and examination by a neurologist or neurosurgeon specialized in movement disorders (Bhatia et al., 2018;Haubenberger and Hallett, 2018).

- A history of an inadequate response to 1 or 2 oral doses of medication, per local standards.An inadequate response was defined as an instance where a therapeutic dose of a medication elicited a poor response or the development of side effects as the medication dose was titrated.

- Immediately following the date of provision of study consent, the subjects were required to complete a 1-month medication stability period, during which they were on stable medication for tremor.

- The Vim nucleus of the thalamus was the target of the MRgFUS treatment.Accordingly, the thalamic region needed to be apparent on MR imaging such that targeting could be performed by measuring distances from a line connecting the anterior and posterior commissures of the brain.

- Able to communicate sensations during the MRgFUS treatment.

- A postural or intention tremor severity score of greater than or equal to 2 in the dominant hand/arm as measured by the CRST rating scale while stable on medication.

- Subjects with unilateral and bilateral tremor both included.

- Significant disability caused by essential tremor despite medical treatment.This was identified as a CRST score of 2 or above for any one of items 16–23 from the Disability subsection of the CRST (speaking, feeding other than liquids, bringing liquids to mouth, hygiene, dressing, writing, working, and social activities).

- Adherence with the inclusion and exclusion criteria was assessed by two members of the medical team, who made decisions according to consensus.

- Individuals who had been on stable antidepressant medication for at least 3 months could participate in this study (i.e., no change in medication drug or dosage for 3 months).

Individuals were excluded from study participation if they had severe systemic disease (e.g., unstable cardiac status, severe hypertension, severely impaired renal function); a history of abnormal bleeding and/or coagulopathy or were at risk for bleeding; contraindications for MR imaging; an inability or unwillingness to tolerate the required prolonged stationary supine position during treatment; any other neurodegenerative diseases, significant cognitive impairment, or a history of psychosis; cerebrovascular disease, brain tumors,seizure, or other maladies of the brain; a history of deep brain stimulation or prior stereotactic ablation; an overall skull density ratio (SDR) of 0.3 ± 0.05 or lower as calculated from the screening computerized tomography (CT) scan(Tsai et al., 2021).

Treatment procedure

All subjects underwent MRgFUS unilateral Vim-thalamotomy using the Exablate system (ExAblate, InSightec, Tirat Carmel, Israel).The initial target coordinates were located at the anterior commissure-posterior commissure(AC-PC) plane, 25% of the intercommissural distance anterior to the posterior commissure (PC), and 14 mm lateral to the AC-PC line.If the third ventricle was larger, the target was set at 11.5 mm lateral to the wall of the third ventricle.

The treatment procedure followed a standard workflow (Wang et al., 2018).After affixing a stereotactic head-frame to the patient’s shaved head, an elastic membrane was attached to their scalp and connected to the helmet-shaped FUS transducer to enable the interface between the transducer and the scalp to be filled with chilled, degassed water.Then, the patient was asked to adopt a supine position, and was oriented head-first on the system’s treatment table in the MR bore.Following a 3-dimentional localizer MR scan, a series of anatomical MR sequences were acquired and fused with a pre-operative CT scan to identify the target volume and plan the actual treatment with a skull-correction algorithm.The treatment started with low power sonications,which were intended to produce temperatures of 40–45°C.This enabled us to confirm accurate focusing in the 3 orthogonal planes.When correct focusing was verified according to the MR imaging data and the patient’s feedback, the power was increased to achieve temperatures expected to result in permanent thermal ablation.Before each consecutive sonication,the physician examined the subject for tremor suppression and for potential neurological signs of off-target focusing.The treatment was concluded if we observed tremor improvement, patient-reported intolerance, or 3 or more attempts to perform sonications over 54°C.Generally speaking, disappearance of tremor in the treated hand could be observed during the treatment session.Dexamethasone was given postoperatively to minimize symptomatic edema.

Clinical evaluation

The primary endpoint was the evaluated safety and efficacy of the treatment.The safety of the ExAblate procedure was determined by evaluating the incidence and severity of device/treatment-related complications that occurred from the first treatment day through the follow-up assessments.Adverse events were reported and categorized by the investigators.An AE was judged to be a serious adverse event (SAE) if it resulted in death, was life-threatening, required hospitalization or prolonged hospitalization, led to,or possibly led to permanent impairment of a body structure or function, or led to, or possibly led to fetal disease, congenital disease, or abnormalities in offspring.Primary effectiveness was evaluated using the CRST.The secondary endpoints of the study were subject daily functionalities as measured by the CRST part C (subscales) at month 12 compared with the baseline assessment(Elias et al., 2016).The CRST is composed of 3 parts: CRST part A focuses on rating tremor severity and involved body parts; CRST part B addresses specific motor tasks/functions; and CRST part C rates functional disabilities resulting from tremor.The total score ranges from 0 to 160, and a higher score indicates more severe tremor.Clinical assessments were made at the following time points: baseline, with subjects on confirmed stable medication(1-month post screening), and post-treatment at 1, 3, 6, and 12 months.We used a repeated-measures analysis of variance to test mean differences among the following repeatedly measured variables: the total CRST score,hand tremor score (including item 5 for part A and the right-hand part for part B), and the part C score.The validated tremor assessment was administered by a movement disorder specialist.

Sonications

All study participants were right-hand dominant.Thus, all subjects underwent a left thalamotomy for treatment of tremor in the right hand.The total number of emitted sonications ranged from 7 to 19.The maximum energy was between 5702 J and 24,895 J.The highest temperatures achieved were between 52°C and 60°C.Detailed treatment parameters for each subject are displayed in Figure 1.

Statistical analysis

We analyzed the patient data from the baseline to one year postoperatively using a linear mixed-effects model.Data were expressed as means ± SD.The CRST tremor scores were presented as estimated marginal means values with a 95% confidence interval.The percentage improvement was calculated using the following equation: (baseline score - postoperative score)/baseline score× 100.Statistical analysis was performed using SPSS 17.0 software (SPSS Inc.,Chicago, IL, USA).P< 0.05 was considered significant (two-tailed).

Results

Patient characteristics

From 2019 to 2020, 10 subjects were enrolled according to the eligibility criteria (Figure 2).There were seven men and three women; the mean age was 65.2 ± 5.2 years, and the mean disease duration was 18.4 ± 9.9 years.Other baseline demographics are shown in Table 1.

CRST tremor scores

The CRST total score data are given in Figure 3A.In our study sample,seven patients showed a good clinical response to the treatment while the other three had partial tremor recurrence.The baseline scores for the three patients with tremor recurrence were clearly higher than those of the other seven patients.Starting from the 1-month follow-up visit through to the 12-month follow-up, the CRST part C scores of the seven patients who experienced good tremor control on the treated side were nearly 0, i.e., they experienced no disabilities related to functional or social daily activities.This improvement in daily functional disabilities was not seen in the three patients with tremor recurrence (Figure 3B).

The clinical outcomes are summarized in Table 1.The estimated marginal mean of the CRST total score was improved from the baseline (estimated marginal mean value [95% confidence interval]; 58.3 ± 3.6 [50.4–66.2]) to the 12-month follow-up (23.1 ± 6.4 [8.9–37.3]), with a 60.4% improvement (Figure

Safety

Overall, 50 adverse events (AEs) were recorded, and 2 of these were defined as SAEs.The most common intraprocedural AEs that occurred were nausea or vomiting (six patients) and headache (three patients).These AEs typically occurred during energy transmission to the Vim; and once the sonication ended, the symptoms were quickly alleviated.The most common post-procedural AEs were tongue or cheek numbness (six patients), scalp numbness (four patients), scalp hyperalgesia (two patients), and balance disorder (four patients).At the 12-month follow-up visit, tongue or cheek numbness had subsided in four patients, and was completely resolved in the other two patients.In three out of the four patients with balance issues, these side effects had completely resolved within several days.In the 4thpatient,imbalance issues lasted 5 months and required rehabilitation training for complete recovery.Other reported AEs included limb spasms, compression pain caused by the pressure of the membrane on the scalp, voice hoarseness,and excessive salivation (Table 2).All of these AEs were mild.

Two SAEs occurred.One patient experienced transient right upper limb weakness that was attributed to an inner capsule edema (strength score IV+).After administration of mannitol and dexamethasone, the weakness subsided and the limb strength returned to normal 8 days later.The second SAE was unrelated to the thalamotomy; i.e., new onset of angina pectoris with myocardial infarction reported by the patient 9 months after treatment.The patient underwent uneventful coronary artery stenting leading to symptom relief (Table 2).

Discussion

3C).Furthermore, the hand score was improved from the baseline (22.8 ± 1.4[16.9–26.0]) to the 12-month follow-up (6.5 ± 2.5 [0.9–12.1]) , with a 71.5%improvement (Figure 3D), as was the part-C score (baseline: 16.0 ± 1.0 [13.7–18.3]; 12-month follow-up: 3.9 ± 1.8 [–0.0–7.8]), with a 75.6% improvement(Figure 3E).

Since the installation of the MRgFUS system, multiple Vim-thalamotomies have been performed at the centre and the patients have been followed-up for at least 12 months.Here, we report the preliminary clinical results.

As an important milestone in the application of this treatment, the American Food and Drug Administration approved the Exablate device for the treatment of refractory ET (Fishman, 2017).The approval was based on a multinational(multi-center), double-blind, randomized controlled trial in which 76 patients were randomized to either a thalamotomy group or a sham group at a 3:1 ratio (56:20) (Elias et al., 2016).The mean score for hand tremor improved by 47% in the treatment group at 3 months post thalamotomy, while the tremor score improved by 0.1% in the sham group.This improvement was maintained at 12 months in the thalamotomy group.

Since that pivotal trial, additional medical centers have reproducibly demonstrated the effectiveness of MRgFUS for the treatment of drug-resistant ET.In a single-center trial including 20 patients with medication refractory ET, Jung et al.(2018) reported a mean improvement in the CRST total score of 67.3% at one year following MRgFUS thalamotomy.Furthermore, Zaaroor et al.(2018) evaluated the effects of MRgFUS thalamotomies performed at a single center, 18 of them for intractable ET.The mean CRST score of the ET patients dropped from 40.7 ± 11.6 to 8.2 ± 5.0 at 6-month post-treatment.A meta-analysis of 8 studies with 154 ET patients who underwent MRgFUS Vimthalamotomy (Mohammed et al., 2018) found that the CRST total score, CRST part A score, and CRST part C score was improved after treatment by 62.2%,62.4%, and 69.1%, respectively.

Elias et al.(2013b) compared the lesioning effects of FUS, radiofrequency,and stereotactic radiosurgery in swine models and found that the MR and histological lesion characteristics of the FUS and radiofrequency treatments had similar immediate development patterns with sharp margins, while stereotactic radiosurgery lesions were delayed, less circumscribed, and had a larger penumbra.

Harary et al.(2019) used data from two published RCTs to compare the clinical outcomes of unilateral Vim-DBS and MRgFUS thalamotomy for the treatment of refractory ET.They found that the one-year effectiveness of the therapeutic modalities was comparable.

Therapeutic results for the study cohort

We reported herein the 1-year results and assessed the safety and effectiveness of MRgFUS thalamotomy for the treatment of refractory ET.At 12 months follow-up, the mean CRST total score was improved by 60.4%compared with the baseline score.Immediately after the treatment, all of the subjects experienced complete tremor suppression in the treated hand.At the 12-month follow-up assessment, the mean improvement was 71.5%.

Recent publications support the effectiveness of MRgFUS-thalamotomy in terms of tremor control.Chang et al.(2018) reported the two-year follow-up results of a pivotal randomized controlled trial (Elias et al., 2016).The mean hand tremor score improved from the baseline by 55% at 6 months, by 53%at 12 months, and by 56% at 2 years post-treatment.In the same cohort, the 3-year hand tremor improvement from baseline ranged from 38% to 50%(Halpern et al., 2019).Park et al.(2019) conducted a 4-year assessment of the treatment effects in a sub-cohort of 12 patients from the original trial,conducted in a single center in South Korea (Elias et al., 2016).Among these patients, the mean improvement in the hand tremor score from baseline to 4 years post-treatment was 56%, that of the disability score was 63%, that of the postural score was 70%, and that of the action score was 63%.Abe et al.(2021) conducted a prospective, multicenter, single-arm confirmatory trial with a Japanese patient cohort.They found that compared with the baseline value, there was a significant decrease of 56.4% (95% CI: 46.7–66.1%;P<0.001) in the mean postural tremor score for the treated hand at 12 months,which was maintained at the last follow-up assessment.Sinai et al.(2019) evaluated the sustained effectiveness of MRgFUS thalamotomies for ET in a single center in Haifa (Israel) with up to 5 years of follow-up.CRST scores in the treated hand at baseline (median 19; range 7–32,44 patients) improved by a median of 16 at 1 month (44 patients;P< 0.0001),17 at 6 months (31 patients;P< 0.0001), 15 at 1 year (24 patients;P< 0.0001),18 at 2 years (15 patients;P< 0.0001), 19 at 3 years, (10 patients;P< 0.0001),21 at 4 years (6 patients;P< 0.01), and 23 at 5 years (2 patients, significance not tested).From the above reports, as well as from our study cohort, it seems that the degree of tremor control measured after the first 6 followup months could predict the expected long-term tremor control.Therefore,in our cohort, the patients who maintained good tremor suppression at 12-months post-treatment will likely maintain beneficial treatment effects in the following years.We summarized the enrollment criteria, demographic characteristics, treatment measures, efficacy, and safety in this and previous studies in Table 3.

Table 1 ｜Baseline data and Clinical Rating Scale for Tremor (CRST) total scores of enrolled subjects

Figure 1 ｜Treatment parameters listed by case.Red columns represent sonications and achieved temperatures.Blue dots represent sonication energy (J).The red line marks 54°C.

Figure 2 ｜CONSORT Flow Diagram.MRgFUS: Magnetic resonance-guided focused ultrasound; SDR: skull density ratio.

Figure 3 ｜Clinical Rating Scale for Tremor (CRST) scores of 10 subjects before and after treatment.(A and B) CRST total score (A) and part-C score (B) in each subject at follow-up visits, up to 12 months.Significant improvement was observed in 7 subjects (cases 2–7 and 10),and 3 subjects (cases 1, 8, and 9) experienced tremor recurrence.(C–E) Error bar graphs(95% CI) summarize the CRST total score (C), hand score (D), and part C score (E) for subject groups.Bars represent estimated marginal means and 95% confidence interval for the mean.

Table 2 ｜Adverse events

Tremor recurrence

In our cohort, 3 patients experienced various degrees of tremor recurrence within the first 6 months post treatment.Other researchers have noticed cases of decay in the therapeutic effect.Meng et al.(2018) assessed the 2-year outcomes of 37 ET patients who underwent unilateral MRgFUS thalamotomy.The CRST total score improved from the baseline by 42.35% at 1 year and by 43.4% at 2 years, but the proportion of patients with significant improvement(i.e., ≥ 50% score reduction from baseline) decreased from 45.7% to 35.3% at 2 years.Sinai et al.(2019) reported that tremor returned during the followup period in 11% (n= 5) of 44 ET patients who underwent commercial treatment.Previous studies have shown that younger age and lower baseline CRST score were favorable outcome factors (Fukutome et al., 2020).And the thermal doses were confirmed to be sufficient, we speculate that the tremor recurrences in our group may be related to the high CRST scores at baseline(Fukutome et al., 2020).Another potential explanation is that the pathological tremor in the present patient group was related to more complex motor circuits in the brain (Buijink et al., 2015a, b; Nieuwhof et al., 2018), and that Vim ablation alone was insufficient for complete tremor elimination.For patients with tremor recurrence, further MRgFUS ablation could be considered as a remedial treatment (Weidman et al., 2019).

Quality of life

Successful unilateral MRgFUS thalamotomy with good tremor control in the treated hand usually leads to a sustainable improvement in quality of life greater than 50% (Halpern et al., 2019; Sinai et al., 2019).In our cohort, the improvement in the CRST part C mean score was 75.6% at the 12-month follow-up assessment, which represents a meaningful functional improvement in patients’ daily activities and social life.Patients with successful treatment had good unilateral tremor control that dramatically improved their quality of life and reported patient satisfaction.

Safety

The most common intraoperative AEs in our patient group were nausea and headache.These AEs often occurred during energy transmission and subsided immediately after the energy was stopped.However, these symptoms could affect the patient’s treatment experience and affect the tolerability of the procedure.

The most common postoperative AE was numbness, including numbness of the scalp and the tip of tongue.These side effects may result from the extension of the lesion or edema to the medial lemniscus.These symptoms did not cause a significant decline in the quality of life, and were frequently resolved within 3 months.Another common postoperative AE was imbalance.Most balance disorders were mild and usually disappeared within a few days.However, in 1 patient, the imbalance disorder was associated with gait disturbances, and the patient required walking rehabilitation training.These imbalance and gait disturbances had completely resolved by the 6-month follow-up.The impaired balance could be related to the extension of the lower part of the lesion or edema into the subthalamic nucleus.The latter patient also experienced transient muscle weakness in the upper limb on the treated side.Although the muscle weakness subsided within a few days, it was considered a SAE because of the extended hospital stay for observation.We speculate that this transient paresis was caused by extension of the perilesional edema into the internal capsule.

Table 3 ｜Comparison of enrollment criteria, demographic characteristics, treatment measures, efficacy, and safety among this study and previous studies

The AEs that occurred in our study resemble those described in previous studies.Fishman et al.(2018) analyzed the safety profile of MRgFUS thalamotomies performed to treat 186 ET patients under 5 clinical trials.The overall incidence of SAEs was 1.6%.There were no serious complications such as cerebral hemorrhage or infection.Most of the AEs were temporary and mild (79%), and abnormal sensation and balance disorders were the most common side effects.

In a meta-analysis that included 154 ET patients who underwent MRgFUS Vim thalamotomies in 8 studies, the most common side effects were ataxia (32.8%)and numbness (25.1%).At the 12-month follow-up, ataxia had resolved in all patients, while 15.3% of the patients still had some numbness (Mohammed et al., 2018).

Although AEs such as numbness, balance disorders, and muscle weakness frequently resolve with time, these should be avoided as much as possible because lesion location and volume correlate with the occurrence of side effects.For example, Boutet et al.(2018) found that complications usually involved lesions that extended into surrounding vital structures.Lesions larger than 170 mm3may be associated with an increased risk of acute adverse effects.Other authors found that larger ablation volumes predicted better clinical outcomes (Federau et al., 2018; Pineda-Pardo et al., 2020), while additional evidence indicates that the lesion location is more important than its size (Fukutome et al., 2020).Therefore, it is necessary to develop a method for predicting ablation volume to optimize the therapeutic effect of this treatment (Bond and Elias, 2018).Tractography-based methods could be carefully explored to assist precise target positioning at an individual level(Krishna et al., 2019).

This study had several limitations.First, the study design was a singlearm clinical trial.Second, the sample size was small.Given that the cranial skull features of the yellow race, such as the rounded shape of the head circumference and the distribution of cranial density, are different from those of the white race, there are also special considerations for the precise localization of targets and the efficiency of energy transfer in their treatment.Therefore, multi-center and large-sample studies are still necessary to address the therapeutic characteristics of the yellow race, especially the Chinese, who are mainly composed of the Han population.Third, the followup time was relatively short, and it did not fully reflect the long-term effects.Long-term efficacy is a primary concern for patients.Moreover, in the past experience with radiofrequency ablation, the biggest challenge with this type of thalamotomy is the potential recurrence in some patients.Therefore, it is essential to increase the follow-up time to obtain long-term results.Fourth,this is the first batch of treatments applied in our center, and there may be a learning curve that affects the treatment results.With more experience in treatment, treatment times can be shortened and complications reduced.Thus, the results of subsequent treatment may surpass those of the first 10 cases.

In conclusion, in the Chinese population, MRgFUS for drug-refractory ET can achieve relatively good results with high treatment safety.The present results indicated that MRgFUS is thus an option for the treatment of drug-refractory ET.

Author contributions:XL, XY, LP, ZL, and LM designed the study.RZ and LP performed surgery and wrote the paper.XL and CY conducted subject screening and evaluation.JH, DZ, XB, LH, and JZ provided assistance in technique application.All of these authors approved the final version of the paper.

Conflicts of interest:All authors declare that there is no conflict of interest in this paper.No conflicts of interest exist between Insightec Co.Ltd.(Israel) and publication of this paper.

Data availability statement:No additional data are available.

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