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Background: Invasive treatments like radiofrequency stereotactic lesioning or deep brain stimulation of the globus pallidus internus can resolve drug-resistant status dystonicus (SD). However, these open procedures are not always feasible in patients with SD., Objective: The aim was to report the safety and efficacy of simultaneous asleep bilateral transcranial magnetic resonance-guided focused ultrasound (MRgFUS) pallidotomy for life-threatening SD., Methods: We performed bilateral simultaneous MRgFUS pallidotomy under general anesthesia in 2 young patients with pantothenate kinase-associated neurodegeneration and GNAO1 encephalopathy. Both patients had medically refractory SD and severe comorbidities contraindicating open surgery., Results: SD resolved at 4 and 12 days after MRgFUS, respectively. Adverse events (intraoperative hypothermia and postoperative facial paralysis) were mild and transient., Conclusion: Bilateral simultaneous MRgFUS pallidotomy under general anesthesia is safe and may be a valid alternative therapeutic option for fragile patients. Further studies are needed to assess long-term efficacy of the procedure., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: To investigate cortical network changes using Magnetoencephalography (MEG) signals in Parkinson's disease (PD) patients undergoing Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy., Methods: We evaluated the MEG signals in 16 PD patients with drug-refractory tremor before and after 12-month from MRgFUS unilateral lesion of the ventralis intermediate nucleus (Vim) of the thalamus contralateral to the most affected body side. We recorded patients 24 h before (T0) and 24 h after MRgFUS (T1). We analyzed signal epochs recorded at rest and during the isometric extension of the hand contralateral to thalamotomy. We evaluated cortico-muscular coherence (CMC), the out-strength index from non-primary motor areas to the pre-central area and connectivity indexes, using generalized partial directed coherence. Statistical analysis was performed using RMANOVA and post hoc t -tests., Results: Most changes found at T1 compared to T0 occurred in the beta band and included: (1) a re-adjustment of CMC distribution; (2) a reduced out-strength from non-primary motor areas toward the precentral area; (3) strongly reduced clustering coefficient values. These differences mainly occurred during motor activation and with few statistically significant changes at rest. Correlation analysis showed significant relationships between changes of out-strength and clustering coefficient in non-primary motor areas and the changes in clinical scores., Discussion: One day after MRgFUS thalamotomy, PD patients showed a topographically reordered CMC and decreased cortico-cortical flow, together with a reduced local connection between different nodes. These findings suggest that the reordered cortico-muscular and cortical-networks in the beta band may represent an early physiological readjustment related to MRgFUS Vim lesion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Visani, Panzica, Franceschetti, Golfrè Andreasi, Cilia, Rinaldo, Rossi Sebastiano, Lanteri and Eleopra.)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal., Objectives: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET., Methods: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response., Results: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events., Conclusions: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA -related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF)., Methods and Analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat., Ethics and Dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences., Trial Registration Numbers: NCT05287503, EudraCT 2021-004565-13., Competing Interests: Competing interests: RC has received speaking honoraria from Zambon Italia; Zambon SAU; Bial Italia Srl; advisory board fees from Bial; research support from the Italian Ministry of Health; he is Editor-in-Chief of the neuromuscular and movement disorders section of Brain Sciences (MDPI); Associate Editor of Parkinsonism and Related Disorders (Elsevier) and Frontiers in Ageing Neuroscience., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches., Objectives: To estimate LED of safinamide 50 and 100 mg., Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg ( N  = 130), safinamide 50 mg ( N  = 144), or rasagiline 1 mg ( N  = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B ( N  = 129)., Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED., Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD)., Objective: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy., Methods: We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy., Results: We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy., Conclusions: In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Osmotic demyelination syndrome (ODS) is caused by damage to the pons myelin sheath and nerve cells. Although the pathophysiological mechanism responsible for the damage is not yet fully understood, it is currently believed that osmotic-type changes (especially if they are massive and too rapid) cause oedema that leads to compression and, subsequently, demyelination of white matter fibres. It generally manifests with acute paraparesis/tetraparesis, dysphagia, dysarthria, diplopia, and loss of consciousness, as well as hallucinations, spasms, and other neurological symptoms related to brainstem damage. In extreme cases, the locked-in syndrome may also appear. Of note, in some cases an association between osmotic demyelinating damage and the onset of movement disorders has been documented and, although the pathophysiology is still unknown, a correlation has been postulated between ODS and movement disorders. Here, we present a patient with ODS who developed parkinsonism, thus supporting the hypothesis of a correlation between these pathological events.

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with Parkinson's disease (PD) with motor complications; the contribution of sex in determining the outcome is still not understood., Methods: We included 107 patients (71 males) with PD consecutively implanted with STN-DBS at our center. We reviewed patient charts from our database and retrospectively collected demographical and clinical data at baseline and at three follow-up visits (1, 5 and 10 years)., Results: We found a long-lasting effect of DBS on motor complications, despite a progressive worsening of motor performances in the ON medication condition. Bradykinesia and non-dopaminergic features seem to be the major determinant of this progression. Conversely to males, females showed a trend towards worsening in bradykinesia already at 1-year follow-up and poorer scores in non-dopaminergic features at 10-year follow-up. Levodopa Equivalent Daily Dose (LEDD) was significantly reduced after surgery compared to baseline values; however, while in males LEDD remained significantly lower than baseline even 10 years after surgery, in females LEDD returned at baseline values. Males showed a sustained effect on dyskinesias, but this benefit was less clear in females; the total electrical energy delivered was consistently lower in females compared to males. The profile of adverse events did not appear to be influenced by sex., Conclusion: Our data suggest that there are no major differences on the motor effect of STN-DBS between males and females. However, there may be some slight differences that should be specifically investigated in the future and that may influence therapeutic decisions in the chronic follow-up., (© 2021. Fondazione Società Italiana di Neurologia.)

Magnetic Resonance-guided high-intensity Focused Ultrasound (MRgFUS) of the thalamic ventral intermediate nucleus (Vim) for tremor has increasingly gained interest as a new non-invasive alternative to standard neurosurgery. Resting state functional connectivity (rs-FC) correlates of MRgFUS have not been extensively investigated yet. A region of interest (ROI)-to-ROI rs-FC MRI "connectomic" analysis focusing on brain regions relevant for tremor was conducted on 15 tremor-dominant patients with Parkinson's disease who underwent MRgFUS. We tested whether rs-FC between tremor-related areas was modulated by MRgFUS at 1 and 3 months post-operatively, and whether such changes correlated with individual clinical outcomes assessed by the MDS-UPDRS-III sub items for tremor. Significant increase in FC was detected within bilateral primary motor (M1) cortices, as well as between bilateral M1 and crossed primary somatosensory cortices, and also between pallidum and the dentate nucleus of the untreated hemisphere. Correlation between disease duration and FC increase at 3 months was found between the putamen of both cerebral hemispheres and the Lobe VI of both cerebellar hemispheres, as well as between the Lobe VI of untreated cerebellar hemisphere with bilateral supplementary motor area (SMA). Drop-points value of MDS-UPDRS at 3 months correlated with post-treatment decrease in FC, between the anterior cingulate cortex and bilateral SMA, as well as between the Lobe VI of treated cerebellar hemisphere and the interpositus nucleus of untreated cerebellum. Tremor improvement at 3 months, expressed as percentage of intra-subject MDS-UPDRS changes, correlated with FC decrease between bilateral occipital fusiform gyrus and crossed Lobe VI and Vermis VI. Good responders (≥50% of baseline tremor improvement) showed reduced FC between bilateral SMA, between the interpositus nucleus of untreated cerebellum and the Lobe VI of treated cerebellum, as well as between the untreated SMA and the contralateral putamen. Good responders were characterized at baseline by crossed hypoconnectivity between bilateral putamen and M1, as well as between the putamen of the treated hemisphere and the contralateral SMA. We conclude that MRgFUS can effectively modulate brain FC within the tremor network. Such changes are associated with clinical outcome. The shifting mode of integration among the constituents of this network is, therefore, susceptible to external redirection despite the chronic nature of PD., Competing Interests: GF was employed by company InSightec Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Stanziano, Golfrè Andreasi, Messina, Rinaldo, Palermo, Verri, Demichelis, Medina, Ghielmetti, Bonvegna, Nigri, Frazzetta, D'Incerti, Tringali, DiMeco, Eleopra and Bruzzone.)

Objective: Bilateral globus pallidus internus deep brain stimulation (GPi-DBS) is an established and effective therapy for primary refractory dystonia. However, the comparison of frameless vs . frame-based DBS surgery technique is still controversial. This retrospective study aims to compare the clinical outcome of two GPi-DBS surgical techniques for patients affected by primary generalized or multi-segmental dystonia. Methods: For lead's stereotaxic placement, 10 patients underwent frame-based surgery and the other 10 subjects DBS surgery with a frameless technique. Clinical features were evaluated at baseline and 6 and 12 months after surgery by means of the Burke-Fahn-Marsden Dystonia Rating Scale. Results: Frame-based GPi-DBS and frameless stereotaxic group revealed a comparable clinical outcome with no surgical complications. Conclusions: Frameless technique is safe and well-tolerated by patients and showed similar effectiveness of the frame-based stereotaxic surgery during GPi-DBS for primary dystonia. Notably, it could be a valid alternative solution because of the great advantage in improving the patient's discomfort during awake surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eleopra, Rinaldo, Devigili, Mondani, D'Auria, Golfrè Andreasi, Skrap and Lettieri.)