Highlights This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TET-RAS) and 68% (BF-ADL) of 'severe' or 'moderate' patients improving to 'mild' or 'slight'. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.

IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.OBJECTIVE To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.DESIGN, PARTICIPANTS, AND SETTING Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURESThe primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTSBased on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine 11.1 [95% CI,] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

Background: Progression of neurological deficit (PND) is a frequent complication of acute subcortical ischemic stroke (SCS). The role of intracranial atherosclerosis (IAS) in PND is controversial. Our goal was to evaluate IAS on admission, as predictor of PND in SCS patients. Methods: SCS patients were identified from our prospective database from 2004 to 2008. Clinical and laboratory data were collected from charts, and radiographic data from original radiographs. The proximal intracranial arteries were graded as patent, irregular, stenotic, or occlusion. IAS was defined as irregularity or stenosis. PND was defined as a change in the National Institutes of Health Stroke Scale >1 point. Results: Two hundred and two SCS patients were identified. In 14%, PND occurred at a median of 2 days from onset. Univariate analysis by infarct location showed the following to be associated with PND: for anterior circulation infarcts (centrum semiovale/basal ganglia), M1 atherosclerosis (p = 0.042); for posterior circulation infarcts, vertebral artery atherosclerosis (p = 0.018). For both groups, we found a non-significant association with age (p = 0.2) and HbA1c levels (p = 0.095). No association was found with admission glucose levels. Multivariate analysis showed the following association with PND: for anterior circulation infarcts, M1 atherosclerosis (OR 4.7; 95% CI 1.2–18.8; p = 0.03); for pontine infarcts, vertebral artery atherosclerosis (OR 5.8; 95% CI 1.1–29.4; p = 0.033). There was an increase in PND likelihood with an increasing number of atherosclerotic vessels. Discussion: In our cohort of SCS patients, PND was associated with IAS of the responsible vessels. These results suggest a role for IAS in the pathogenesis of PNF in SCS patients.

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Background: Little is known about caregiver burden in Parkinson disease (PD) patients undergoing brain stimulation (DBS) surgery.Objective: The aim of this exploratory analysis was to evaluate whether caregiver burden improves after bilateral subthalamic nucleus (STN) DBS for PD patients and identify baseline factors associated with caregiver burden. Methods: We analyzed the motor, cognitive and behavioral data of 12 PD patients (9 men/3 women) who underwent bilateral STN DBS and whose caregivers completed the Caregiver Burden Inventory (CBI) both before and approximately 6 months after bilateral STN DBS. Results: Total CBI score did not change from baseline (17.8 ± 10.7) to the 6 month evaluation (18.7 ± 13.1), despite a 29% improvement in the MDS-UPDRS motor score (baseline 40.3 ± 12.1 compared to 28.7 ± 8.4 at 6 months, p = 0.01). Change in total CBI score did not correlate with change in MDS-UPDRS Parts I-IV or MoCA from baseline to 6 months. In post-hoc analyses looking at baseline characteristics that may correlate with caregiver burden, only the disinhibition subscore on the Frontal Systems Behavioral Scale correlated positively with the baseline total CBI score (ρ = 0.763, p = 0.004). Conclusion: Caregiver burden for PD patients (as measured by the CBI) does not change 6 months after bilateral STN DBS, despite significant improvement in motor function. Only baseline behavioral problems, specifically disinhibition, correlated with higher baseline caregiver burden. Clinicians may need to better counsel patients on expectations for caregiver burden after DBS.