Bilateral Simultaneous Magnetic Resonance-Guided Focused Ultrasound Pallidotomy for Life-Threatening Status Dystonicus.

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.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy May Spare Dopaminergic Therapy in Early-Stage Tremor-Dominant Parkinson's Disease: A Pilot Study.

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.

Short- and long-term motor outcome of STN-DBS in Parkinson's Disease: focus on sex differences.

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.

Early cortico-muscular coherence and cortical network changes in Parkinson's patients treated with MRgFUS.

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 hoct-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.

The Optimal Targeting for Focused Ultrasound Thalamotomy Differs between Dystonic and Essential Tremor: A 12-Month Prospective Pilot Study.

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.

Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme ß-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.

Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case-Control Study.

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.