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.

Objective To evaluate the safety and effectiveness of a wrist‐worn peripheral nerve stimulation device in patients with essential tremor (ET) in a single in‐office session. Methods This was a randomized controlled study of 77 ET patients who received either treatment stimulation (N = 40) or sham stimulation (N = 37) on the wrist of the hand with more severe tremor. Tremor was evaluated before and immediately after the end of a single 40‐minute stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral scores in treatment and sham groups. Additional endpoints included TETRAS upper limb tremor scores, subject‐rated tasks from the Bain and Findley activities of daily living (ADL) scale before and after stimulation as well as clinical global impression‐improvement (CGI‐I) rating after stimulation. Results Subjects who received peripheral nerve stimulation did not show significantly larger improvement in the Archimedes spiral task compared to sham but did show significantly greater improvement in upper limb TETRAS tremor scores (p = 0.017) compared to sham. Subject‐rated improvements in ADLs were significantly greater with treatment (49% reduction) than with sham (27% reduction; p = 0.001). A greater percentage of ET patients (88%) reported improvement in the stimulation group as compared to the sham group (62%) according to CGI‐I ratings (p = 0.019). No significant adverse events were reported; 3% of subjects experienced mild adverse events. Conclusions Peripheral nerve stimulation in ET may provide a safe, well‐tolerated, and effective treatment for transient relief of hand tremor symptoms.

Background Background: The cerebellum's role in dystonia is increasingly recognized. Dystonia can be a disabling and refractory condition; deep brain stimulation can help many patients, but it is traditionally less effective in acquired dystonia. New surgical targets would be instrumental in providing treatment options and understanding dystonia further. Objective Objective: To evaluate the efficacy of deep brain stimulation of the cerebellum in acquired dystonia. Methods Methods: We report our management of a 37-year-old woman with severe left arm and leg dystonia, a complication of an ischemic stroke in childhood. She had already had 2 thalamotomies with only transient benefit. These procedures, in addition to her initial stroke that had damaged the basal ganglia, left traditional deep brain stimulation targets unavailable. ResultsResults: After implantation of bilateral deep cerebellar nuclei, dystonia improved with a 40% reduction in severity on scales and subjective reports of improved posturing, gait, and pain. This improvement has been maintained for almost 2 years after implantation. Conclusion Conclusion: Cerebellar stimulation has potential for therapeutic benefit in acquired dystonia and should be further explored.Although dystonia was classically thought to arise from basal ganglia pathology, increasing evidence supports a critical role of the cerebellum in its pathophysiology as well. 1 Through pharmacologic or genetic alteration of cerebellar output pathways, irregular cerebellar activity leads to high-frequency burst firing of the basal ganglia and is associated with dystonic posturing in mice. 2-4 Subsequent inhibition of cerebellar outflow, either electrically or pharmacologically, reduces the abnormal basal ganglia activity and improves dystonia. 3,4 Whereas classically the cerebellum and basal ganglia communicate through rubro-thalamo-cortical connections, rapid modulation may occur through a more direct, disynaptic pathway, with 1 relay in the thalamus. This pathway has recently been identified in rodents and nonhuman primates 5-8 and, in animal models, conveys the aberrant activity that underlies dystonic posturing. 3 In humans, structural abnormalities in the cerebellum or its afferent pathways have been implicated as the cause of dystonia in several cases. 9,10 Similarly, in a small autopsy study, a reduced density of cerebellar Purkinje cells was found in patients with cervical dystonia when compared with healthy controls. 11 The role of the cerebellum in dystonia indicates its potential as a therapeutic target for deep brain stimulation (DBS). In mouse models of dystonia, DBS of cerebellar output nuclei improved dystonic posturing and general mobility. 4 In humans, the invasive stimulation of the cerebellar hemispheres has been described previously for spasticity and dystonia with variable effect. 12,13 Recently, stimulation of the deep cerebellar nuclei has been employed for spasticity and dystonia as a result of cerebral palsy. 14,15 Identifying a new target would be clinically very use...

Background: Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson's disease (PD) differed from those in patients with other neurodegenerative disorders. Methods: We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. Results: In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from − 17 to − 47 pg/ml/year, much greater than that reported for the elderly population. Conclusions: Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders.