Focused Ultrasound Thalamotomy for Tremor Relief in Atypical Parkisnsonism

Background Magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) VIM-thalamotomy has established efficacy and safety in tremor relief in patients with essential tremor and Parkinson's disease. The efficacy and safety in patients with atypical parkinsonism have not been reported. Objective To report on the efficacy and safety of FUS VIM-thalamotomy in 8 patients with parkinsonism, multiple system atrophy-Parkinsonian type (MSA-P) (n = 5), and dementia with Lewy bodies (DLB) (n = 3). Methods Tremor was assessed in the treated hemibody using the Clinical Rating Scale for Tremor (CRST). The motor Unified MSA Rating Scale (UMSAR) was used in the MSA-P and motor sections of the Unified Parkinson's Disease Rating Scale (UPDRS-III) in DLB patients. Cognition was measured using the Montreal Cognitive Assessment (MoCA). Results In MSA-P and DLB patients, there was immediate tremor relief. CRST scores measured on the treated side improved compared to baseline. During the follow-up of up to 1 year tremor reduction persisted. The change in CRST scores at different time points did not reach statistical significance, probably due to the small sample size. Adverse events were transient and resolved within a year. Conclusions In our experience, FUS VIM-thalamotomy was effective in patients with MSA-P and DLB. Larger, controlled studies are needed to verify our preliminary observations.

MSA with predominant parkinsonism (MSA-P) is characterized by rigidity, akinesia/bradykinesia, postural instability, and tremor.Te European MSA-Study Group found that postural tremor was present in 52% of patients and rest tremor in 36%.[15] Te motor symptoms, including tremor, are generally resistant to pharmacological treatment [16].Although some patient with clinically probable MSA may respond to levodopa, the response is typically poor or unsustained.Amantadine has also shown some efcacy, similar to levodopa [16,17].Deep brain stimulation in MSA-P to relieve motor symptoms showed unfavorable results and therefore is not recommended in these patients [18][19][20].Tus, a large majority of MSA-P patients do not get tremor relief with the current available treatments.
Dementia with Lewy bodies is one of the most common types of degenerative dementia.In addition to progressive dementia, patients sufer from parkinsonian symptoms including bradykinesia, rigidity, and tremor.Te prevalence of rest tremor and action tremor in DLB is not clear.In some studies, it was uncommon, while others reported a prevalence of 44.8% [21,22].Treatment of tremor and other parkinsonian symptoms in DLB is generally similar to that for PD, if somewhat less successful [23][24][25].In these patients, medications are used with caution and given at smaller doses and with slower upward titration, in order not to exacerbate psychotic symptoms.In DLB patients, levodopa seems to be more efective than dopamine agonists and produces fewer side efects [26] while anticholinergic agents are generally avoided because they may worsen the cognitive state.Neurosurgical intervention with deep brain stimulation was attempted in these patients with the aim of relieving cognitive decline, not tremor, but was abandoned due to a lack of efcacy.Tus, treatment of tremor in DLB patients is currently limited.
Patients with atypical parkinsonism may be misdiagnosed at the onset of their disease as sufering from PD.Among patients that were referred to our center for FUS VIM thalamotomy, there were a few that were misdiagnosed as sufering from tremor-dominant PD, and their diagnosis was later changed to MSA-P and DLB.We report on our experience in treating these patients with atypical parkinsonism with FUS thalamotomy.To the best of our knowledge, this is the frst report of FUS thalamotomy in MSA and DLB patients.

Methods
2.1.Patients.Among 177 patients that underwent FUS VIM-thalamotomy for tremor at Rambam Health Care Campus, Haifa, Israel, between November 2013 and January 2023, 8 were diagnosed with atypical parkinsonism including possible MSA-P (n � 5) and probable DLB (n � 3).MSA-P was diagnosed according to the Gilman and the Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy criteria [27,28].DLB was diagnosed according to the revised criteria for the clinical diagnosis of DLB [29].Te diagnosis was confrmed by a movement disorder neurologist (IS or MN).Te aim of FUS was to improve daily function by reducing arm tremor in the dominant hand, which could not be controlled with medication.All patients were able to provide informed consent for treatment.
Patients were examined on the day before the procedure, at the end of the procedure, and during follow-up visits at 1 month, 6 months, and 1 year.

Assessments.
Tremor in the treated hemi-body was assessed using the Clinical Rating Scale for Tremor (hemi-CRST) (items 5-6, 8-9, 11-15; scores ranging from 0 to 36 with higher scores indicating more severe tremor) [30].Reemergent tremor was rated as rest tremor.Te motor function unifed MSA rating scale (UMSAR) [31] was used in the MSA-P and motor sections of the Unifed Parkinson's Disease Rating Scale (UPDRS-III) in DLB patients.Cognition was measured using the Montreal Cognitive Assessment (MoCA).
Adverse events were documented by the neurologists after a thorough neurological examination and rated according to the Clavien-Dindo criteria (range 1 to 5; higher scores represent increased severity) [32].
Tis study of data collection was approved by the Rambam Health Care Campus review board.Data will be available upon request.

FUS Talamotomy.
In brief, patients underwent preprocedural MRI and CT.CT images were used to assess ultrasound penetration.FUS for VIM ablation was performed using 3-T MRI and an ExAblate Neuro system (650-kHz system, Insightec LTD, Tirat Hacarmel, Israel).Te procedure was performed in a staged manner in order to verify its efectiveness and avoid adverse efects.Te initial brain sonication target coordinates for the VIM were calculated to be located at 25% of the AC-PC distance anterior to the PC and 14 mm lateral to the AC-PC line.When there was third ventricle enlargement, the initial target was between 14 mm lateral to the AC-PC line and 11.5 mm lateral to the third ventricle wall.Te treatment was staged with a gradual increase in energy.At low temperatures of 45-50 °C degree a transient or mild efect on tremor was the goal, and once achieved, the energy was gradually increased until a target temperature of 55-60 °C.Treatment at the target temperature was repeated 2-3 times when possible in order to increase the probability of a longterm efect.When tremor was not totally abolished or if adverse events occurred, the target was moved according to the VIM homunculus [33].Te energy used during treatment depended on the individual's skull properties of ultrasound penetration.

Statistical Analysis.
Hemi-CRST scores, UMSAR scores, UPDRS scores, and MoCA scores before and after the procedure were compared using Wilcoxon signed-rank tests for each time point.Adverse events included transient objective and subjective gait ataxia, lip paresthesiae, and asthenia that resolved within 1-12 months (Table 1).

Discussion
In this paper, we report improvement in tremor following FUS VIM-thalamotomy in patients with possible MSA-P and probable DLB.To the best of our knowledge, this is the frst report of the efcacy and safety of FUS VIM-thalamotomy in DLB and MSA-P.
Te treatment was safe for all patients with mild and transient adverse efects.
Previously, FUS VIM-thalamotomy demonstrated tremor relief in PD, a synucleinopathy [8][9][10][11][12].Here we report that in other synucleinopathies, MSA-P and DLB, FUS VIM thalamotomy can improve tremor as well.Te favorable results could be attributed to a common pathophysiology or to a common abnormal pathway generating tremor.Since symptomatic treatment in MSA-P and DLB is limited and deep brain stimulation showed unfavorable results [18][19][20], our fnding of long term suppression of tremor may ofer patients a new treatment option.Our limited number of patients did not enable the detection of a possible efect of FUS treatment on disease progression, and this remains to be seen.
In this paper, we report on the efect of FUS on tremor.Te improvement in tremor translated to improvements in both UMSAR and UPDRS scores.However, the treatment was symptomatic, and thus the disease continued to progress.Terefore, whether the improvement in tremor translates to an improvement in quality of life remains to be seen.Te possibility of improving other symptoms of these disorders has not been explored; however, in PD patients, pallidotomy using FUS has shown promising results [34,35].
It should be noted that in MSA patients, UMSAR scores were reduced over time.Te reduction in UMSAR score at 1 month follow-up can be attributed to the FUS treatment.Te continued reduction in scores may be explained by Parkinson's Disease 3 missing information in patients lost to follow-up due to disease progression.Tus, patients with a lower UMSAR came for follow-up visits, resulting in a pseudo-improvement of the UMSAR over time.We report a few, mild, transient adverse events, less than in other series, probably because of our large experience with the procedure.Te possibility of treatment with this technology should be carefully considered in centers where serious adverse efects are more prevalent.
Te main limitation of this report is the small number of patients treated with some lost to follow-up.Te number of patients at each time point was reduced over time.Tus, though improvement in tremor was evident, statistical analysis could not reach statistical signifcance.In some measurements, a so-called "improvement" in the scale was documented.Tis is probably due to the fact that patients who had a higher score were lost to follow-up maybe due to disease progression.A placebo efect cannot be ruled out.Hence, our observation should be viewed as preliminary and precludes generalization.

Conclusion
Our results ofer new hope for tremor relief in MSA and DLB patients treated with unilateral FUS VIM-thalamotomy.Te mild and transient adverse efects observed emphasize the safety of the procedure.Additional studies are needed to substantiate our preliminary results.
.1.Patients.Eight patients are included in this case series (six male) with a median age of 70.0 years (range 67-84).

Table 1 :
Tremor scores and adverse events following focused ultrasound thalamotomy.