Focused Ultrasound Lesioning of the Subthalamic Nucleus for Asymmetric Parkinson's Disease in Japan

Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been a standard treatment for Parkinson's disease (PD). Despite its established efficacy, it is an invasive treatment carrying risks of procedure- and hardware-related adverse events (AEs).1 In recent years, magnetic resonance-guided focused ultrasound lesioning (MRgFUS) has emerged as a promising, incisionless alternative. Previous studies have shown the efficacy of unilateral MRgFUS of the STN (STN-FUS), although some AEs, such as dyskinesia, were observed.2, 3 The skull shape and structure affect ultrasound transmission; the skull density ratio (SDR) correlates with target temperature and sonication energy requirement during MRgFUS.4 Notably, there are differences in skull morphology between Asian and Caucasian populations, and it has been suggested that Asians have lower SDR, leading to potentially reduced ultrasound transmission.5, 6 This can affect the risk of unsuccessful lesioning and AEs. We report the first feasibility trial evaluating the safety and clinical response to unilateral STN-FUS performed in Asians. This prospective, open-label, single-arm, feasibility trial, sponsored by Insightec (Haifa, Israel), was conducted at Osaka University Hospital and Saito Yukoukai Hospital between May 2019 and July 2022. Patients with PD exhibiting markedly asymmetric symptoms were recruited. Supplementary Methods 1 details the inclusion and exclusion criteria. STN-FUS was performed as previously described.7 Each subject was assessed at baseline, followed up at 24-h, 1-week, 2-month, and 4-month. The primary outcome was safety, while the secondary outcome was efficacy against motor symptoms at 4 months, assessed by the improvement in total Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores in ON- and OFF-medication, and those on the treated side in OFF-medication. Supplementary Methods 2 details clinical evaluation and statistics. Thirteen patients were enrolled. One patient was excluded owing to incidental ischemic stroke and two patients withdrew their consent before the treatment. Then, 10 patients underwent STN-FUS. Table S1 describes the baseline characteristics. Ultrasound sonication reached a definitive ablation temperature (≥55°C) in the target in all subjects, except for one (subject 7, SDR 0.34) who experienced headache at a maximum temperature of 52°C. Nonetheless, post-FUS MR imaging confirmed successful lesioning in the target for all subjects, including subject 7. Details for sonication are shown in Table S2. AEs are shown in Table S3. One subject experienced a severe AE, exacerbated lumbar canal stenosis after 4 months, deemed unrelated to treatment. AEs included dyskinesia (30%), exacerbated preprocedural dyskinesia (20%), truncal ataxia (30%), transient headache, diplopia, scalp edema, upper limb weakness and transient hypersexuality. During OFF-medication, the total MDS-UPDRS part III scores improved from baseline to 4 months, from 35 [27–41] (median [interquartile range]) to 25 [18–31] (r = 0.69, p < 0.05). Those scores also improved during ON-medication from 27 [22–34] to 17.5 [13–22] (r = 0.69, p < 0.05) (Fig. 1A,B). MDS-UPDRS part III scores on the treated side in OFF-medication improved from 18 [12–21] to 11 [8–13] (r = 0.69, p < 0.05) (Fig. 1C). Improvement rates ranged from 21.1% to 72.7% (Fig. 1D). The levodopa equivalent dose (LED) was reduced from 435 [300–540] mg to 250 [150–420] mg (r = 0.56, p < 0.05). All patients showed subjective improvement in Patient Global Impression of Change at 4 months. Table S1 details clinical evaluations. This trial showed that the safety of STN-FUS in Asian patients with asymmetric PD aligned those in Western patients from current literatures. Notably, all patients showed successful STN lesioning and clinical response, indicating the feasibility of unilateral STN-FUS in Asian population. However, the subjects with low SDR required higher sonication energy (shown in Table S2), resulting in AEs such as headache (Subjects 3 and 7) and scalp edema (Subject 7). While recent MRgFUS studies in Asian populations have reported safety with SDR between 0.40 and 0.45,8, 9 our results underscore the importance of careful consideration of skull structure. Dyskinesia was mild and non-troublesome. Reducing dopaminergic medications helped control dyskinesia, but doses were often reverted due to symptoms on the untreated side (Table S4). Motor symptoms in the ON-medication improved concurrently with medication reduction, indicating that STN-FUS exerts alternative levodopa effects similar to STN-DBS.10 However, this study included patients with relatively low LED, as some patients may not have received sufficient dose escalation owing to adverse effects or mild symptoms on the less affected side. A long-term study showed sustained efficacy of unilateral STN-FUS, suggesting better control of PD symptoms.11 Considering dyskinesia risks, the optimal pharmacological treatment after STN-FUS warrants further investigation. This study has several limitations, including the exploratory nature of efficacy assessment due to the open-label design and small sample size. As we focused on unilateral treatment, long-term observations are needed to assess symptom progression on the untreated side. In conclusion, STN-FUS is a safe and feasible treatment option for Asian patients with PD, warranting further investigation in larger, international clinical trials. None. Ethical Compliance Statement: This study, conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines, was approved by the Osaka University Graduate School of Medicine Ethics Committee (approval number: 191001-B). The protocol synopsis is available at the National Library (clinicaltrials.gov; NCT04744493). Written informed consent was obtained from all participants. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: Insightec provided financial, regulatory, and technical support for the ultrasound devices. The sponsor did not play any role in the data analysis or interpretation. HK reports honoraria from Insightec Japan. Financial Disclosures for the Previous 12 Months: CS, KB, XH, NT, and MK have nothing to disclose. YK, KK, NH, KH, and HK were supported by the Japan Society for the Promotion of Science (JSPS). NH has received honoraria from Otsuka Pharmaceutical Co., Ltd. and Daiichi Sankyo Company, Ltd. KH was supported by the Japan Agency for Medical Research and Development (AMED); has received lecture fees from Daiichi Sankyo Co., Ltd., Boston Scientific Japan, and Nippon Zoki Pharmaceutical Co., Ltd.; and has received consulting fees from Daiichi Sankyo Co., Ltd. SO has received honoraria for lectures from Insightec Japan, Teijin Pharma Ltd., UCB Japan Co. Ltd., Daiichi Sankyo Co., Ltd., and Eisai Co. Ltd. HK was supported by the Japan Agency for Medical Research and Development (AMED) and Sysmex Co., and has received honoraria from Insightec Japan, Boston Scientific Japan, Abbott, and Medtronic Japan. HM was supported by Grants from Japan Blood Products Organization and has received payment for expert testimony from Sumitomo Pharma Co. Ltd., Eisai Co. Ltd., and Takeda Pharmaceutical Co. Ltd. (1) Research project: A. Conception, B. Methodology, C. Data curation, D. Visualization, E, Statistical analysis, F. Project administration, G. Supervision. (2) Manuscript preparation: A. Writing of the first draft, B. Review and critique. C.S.: 1C, 1E, 2A, 1D. Y.K.: 1A, 1B, 1E, 2A, 1D, 1F. K.K.: 1C, 2B. K.B.: 1C, 2B, 1G. N.H.: 1A, 1B, 2B. X.H.: 1C, 1B, 2B. N.T.: 1B, 1F, 2B. K.H.: 1B, 1F, 2B. S.O.: 1B, 1F, 2B, 1G. M.K.: 1C, 1F, 2B, 1F. H.K.: 1B, 1F, 2B, 1G, 1F. H.M.: 1A, 1B, 2B, 1G, 1F. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supplementary Appendix Table S1. Demographic of subjects. Table presents the subjects' baseline characteristics, with data expressed as median [interquartile range]. (minimum—maximum values). M, male; F, female; R, right; L, left; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Table S2. Procedure details for focused ultrasound lesioning of subthalamic nucleus Initial target location, sonication dose and obtained temperature are shown in Table. Target locations are shown with positive values for lateral (L), anterior (A) and superior (S), and negative value for medial (M), posterior (P), and inferior (I). SDR, skull density ratio; MCP, midcommissural point; AC-PC, anterior commissure-posterior commissure; M, male; F, female; R, right; L, left. Table S3. Adverse events. Table shows the severity, course and outcome on all AEs. The severity of AEs was categorized into three grades: Mild (asymptomatic or mild symptoms), Moderate (minimal, local or non-invasive intervention indicated), Severe (disruption of activities of daily living). POD, postoperative day; MRI. Magnetic resonance imaging. Table S4. Details of dyskinesia and medication adjustment. Table details the clinical course of dyskinesia and medication adjustments. Dyskinesia subscores were calculated using the sum of MDS-UPDRS part IV item 4.1 and 4.2 (scores ranged from 0 to 8; higher scores indicate more severe symptom). POD, postoperative day; FUS, focused ultrasound, LED, levodopa equivalent dose; MDS-UPDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale. Table S5. Changes in clinical and neuropsychiatric assessments. Table details clinical and neuropsychiatric assessments at each visit. All outcomes were shown as median [interquartile range]. NA, not available; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; MoCA-J, Japanese version of Montreal Cognitive Assessment; WMS-R, Wechsler Memory Scale—Revised; BDI, Beck Depression Inventory; NPI; JART, Japanese adult reading test. 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