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Introduction Unilateral Gamma Knife™ stereotactic radiosurgery on the ventral-intermediate nucleus of the thalamus is a minimally invasive neurosurgical option for refractory tremor. We describe the experience of Gamma Knife™ thalamotomy (GKT) in patients with essential tremor (ET) and tremor-dominant Parkinson's disease (PD) at our specialised stereotactic neurosurgery unit. Methods We reviewed the cases of patients treated with GKT between January 2014 and February 2018 with a minimum of 12 months' follow-up. We analysed clinical and demographic variables, indication, radiation dose, effectiveness (based on subscales of the Fahn-Tolosa-Marin [FTM] scale and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] motor score), and adverse events. Results Thirteen patients were registered, 6 with a diagnosis of tremor-dominant PD, four with refractory ET, and three with ET and PD. Median age was 78 years (range, 62-83), with seven patients aged over 75 years. Four patients were receiving anticoagulants and two had history of stroke. The maximum radiation dose administered was 130 Gy. Mean (standard deviation) follow-up duration was 30.0 (14.5) months. Significant tremor improvement was observed on the FTM subscales: 63.6% at 12 months and 63.5% at the end of follow-up; MDS-UPDRS tremor items showed improvements of 71.3% at 12 months and 60.3% at the end of follow up. Eleven patients reported significant improvements in quality of life, and 3 reported mild and transient adverse effects. Conclusions This is the largest series of patients with essential and parkinsonian tremor treated with GKT and followed up in the long term in Spain. GKT can be safe and effective in the long term in patients with refractory tremor, including in elderly patients and those receiving anticoagulants.

Objective: Essential tremor (ET) is a common neurological disorder that has been associated with 60% increased risk of developing dementia. The goals of the present study were to: (a) learn whether individuals with advanced ET symptoms seeking deep brain stimulation (DBS) surgery would fall into distinct cognitive subgroups, and (b) learn how empirically derived subgroups map onto criteria for mild cognitive impairment (MCI). Method: Patients with ET (N = 201; mean age = 68.9 ± 8.9 years) undergoing pre-surgical evaluation for DBS completed a multi-domain neurocognitive assessment consisting of memory, executive function, visuospatial skill, language, and processing speed. Two cluster analytic approaches (K-means, hierarchical) were independently conducted to classify cognitive patterns using domain composites. Demographics, clinical characteristics, and proportion of cases meeting neuropsychologically defined criteria for MCI were examined among clusters. Results: A three-cluster solution reflected a Low Executive group (N = 64), Low Memory Multi-Domain group (N = 41), and Cognitively Normal group (N = 96). The Cognitively Normal group was older and more educated, with a higher Dementia Rating Scale-2 score. In total, 27.4% of participants met criteria for MCI. Of the MCI cases, most were in the Low Executive (41.8%) or Low Memory Multi-Domain groups (49.1%). In the latter, 65.9% of its members were classified as MCI versus 35.9% in the Low Executive group. Conclusions: Our study identified three cognitive subtypes of ET patients presenting for DBS. Future work should examine the subgroups for progression to dementia, particularly the Low Memory Multi-Domain subgroup which may be at highest risk.

and objective: Tremor is a disabling symptom of PD that usually responds poorly to available standard pharmacological agents. This study aimed to assess the effect of Zonisamide 25 mg on tremor in tremor-dominant PD patients as compared to placebo.This was a randomized, placebo-controlled, double-blind study. Parkinson's disease patients were allocated either to the intervention group (standard treatment along with Zonisamide 25 mg add-on) or the placebo group (standard treatment along with placebo). Baseline Unified Parkinson's Disease Rating Scale (UPDRS) and Tremor Research Group Essential Tremor Rating Scale (TETRAS) scores, as well as accelerometric tremor analysis were done and follow-up assessments of the same were done after 12 weeks of intervention. Percentage change from baseline in the UPDRS tremor score was the primary outcome whereas percentage change from baseline of total UPDRS score, UPDRS rigidity and bradykinesia scores, TETRAS score, and accelerometric tremor analysis values were the secondary outcomes.There was no significant difference in the percentage change from baseline UPDRS tremor scores between the two groups (placebo: 8.33 [-19.89-23.86] vs drug: 26.14 [-35.58 to -16.07], p-value: 0.164, CI: 0.157-0.171). Best-case analysis for missing values showed a significant improvement in the drug group, compared to the placebo group (p-value:0.001, CI:0.001 -0.001).Zonisamide at a dose of 25 mg per day did not improve tremor in tremor-dominant PD patients, however, a positive trend was seen as compared to Placebo in the UPDRS tremor score. Larger studies are required to confirm this finding.

Essential tremor (ET) is one of the most common neurological disorders, affecting an estimated 2.2% of the entire US population. Despite its high prevalence and associated morbidity and mortality, there are no published data on the medical costs associated with ET care.This is a retrospective secondary data analysis using the 5% Medicare claims data from 2016 to study age-eligible Medicare beneficiaries diagnosed with ET (diagnostic code G250) relative to a propensity score-matched group of comparison beneficiaries without ET (27,081 in each arm). Comparisons were matched within age strata and on the full set of Charlson comorbidity indicators, race, and sex. We examined encounter-level costs (amounts paid) and total annual costs of care (in constant $2021 dollars) adjusting for age, sex, race/ethnicity, provider specialty, setting, and the most common comorbidities, using a generalized linear model.The final sample included 54,162 total beneficiaries, with an average age of 75, 65% female and 94% Non-Hispanic White. On average, Medicare beneficiaries with at least one outpatient or physician office visit with an ET diagnosis have $1068 (95% CI: $981, $1154) in additional direct medical care expenditures per year relative to statistically similar comparison beneficiaries of the same age. Across the population, we predicted aggregated additional spending attributable to ET among Medicare beneficiaries between $1.5 billion and $5.4 billion per year.The estimated direct medical costs among Medicare beneficiaries with an ET diagnosis aggregated to the population-level are non-trivial. These data begin to fill a gap in knowledge.

Peripheral tremor suppression has the potential to reduce tremor, but we do not currently know where best to intervene. The purpose of this study was to characterize the distribution of tremorogenic activity among upper-limb muscles.Surface electromyography was recorded from the 15 major superficial muscles of the upper limb while 25 patients with Essential Tremor performed postural and kinetic tasks. We defined tremorogenic activity as power in the tremor band (4-8 Hz) and determined the distribution of this power among muscles.The distribution varied considerably between patients (mean r = 0.58), but on average, the greatest power was found in the anterior deltoid and extensor carpi ulnaris muscles. Other muscles with high power included the extensor carpi radialis, pectoralis major, lateral deltoid, and brachialis muscles. This distribution was similar (mean r ≥ 0.88) for postural and kinetic tremor, various limb configurations, repetitions, and patient characteristics (sex, tremor severity, age of onset, and duration).We identified a rough pattern in which muscles opposing gravity appeared to have the highest tremor-band power; we hypothesize that the distribution of tremorogenic muscle activity depends in part on the distribution of voluntary activity required by the task.Understanding which muscles exhibit the most tremorogenic activity is one of the steps in the pursuit of optimizing peripheral tremor suppression.

The objective of this study was to evaluate the accuracy of the SureTune3 postoperative imaging software in determining the location of a deep brain stimulation (DBS) electrode based on clinical outcomes and the adverse effects (AEs) observed.Twenty-six consecutive patients with Parkinson disease (n = 17), essential tremor (n = 8), and dystonia (n = 1) who underwent bilateral DBS surgery (52 electrodes) were included in this study. Presurgical assessments were performed in all patients prior to surgery and at 3 and 6 months after surgery, using quality-of-life and clinical scales in each case. The SureTune3 software was used to evaluate the anatomical positioning of the DBS electrodes.Following DBS surgery, motor and quality-of-life improvement was observed in all patients. Different AEs were detected in 12 patients, in 10 of whom (83.3%) SureTune3 related the symptoms to the positioning of an electrode. A clinical association was observed with SureTune3 for 48 of 52 (92.3%) electrodes, whereas no association was found between the AEs or clinical outcomes and the SureTune3 reconstructions for 4 of 52 electrodes (7.7%) from 4 different patients. In 2 patients, the contact chosen was modified based on the SureTune3 data, and in 2 cases, the software helped determine that second electrode replacement surgery was necessary.The anatomical position of electrodes analyzed with SureTune3 software was strongly correlated with both the AEs and clinical outcomes. Thus, SureTune3 may be useful in clinical practice, and it could help improve stimulation parameters and influence decisions to undertake electrode replacement surgery.

The Essential Tremor Centralized Brain Repository is the largest repository of prospectively collected essential tremor (ET) brains (n = 231). Hence, we are uniquely poised to address several questions: What proportion of ET cases has Lewy pathology (LP)? What is the nature of that pathology and how does it relate to other comorbidities? Each brain had a complete neuropathological assessment, including α-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of Parkinson disease (PD). LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of 5 or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. In summary, 1 in 4 ET cases had LP-a proportion that seems higher than expected based on studies among control populations. Heterogeneous LP likely reflects clinical associations between ET and PD, and ET with Alzheimer disease-type neuropathology. These data further our understanding of ET and its relatedness to other degenerative diseases.

NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non-expansions and describe distinctive clinical features of repeat expanded patients with long-term follow-up according to the new tremor classification.Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients.In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate-length GGC repeats (41-59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non-Motor Symptoms Scale scores and lower Mini-Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET-plus (11/46) and ET-neuronal intranuclear inclusion disease (10/46) subgroups at 2-8 years of follow-up.Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non-motor symptoms. Further long-term follow-up and subtype studies will help to define the role of NOTCH2NLC in ET.

Essential tremor (ET) is characterized by action tremor, although rest tremor may also occur. Despite this, rest tremor has not been studied extensively. A dearth of studies compare the relationship of rest tremor to other types of tremors in ET.Two-hundred-and-thirteen ET cases underwent detailed neurological examination, including evaluations of rest, simple kinetic, postural, and intention tremors. A movement disorders neurologist assessed the prevalence of each type of tremor. Each instance of tremor was classified as either symmetrical (present and equally severe on both sides of the body) or asymmetrical (only present on or more severe on one side of the body). Asymmetrical rest tremor that co-occurred with other types of asymmetrical tremors in a given case was further classified as either concordant (i.e., asymmetry on the same side of the body) or discordant (i.e., asymmetry on opposite sides of the body). Chi-square analyses examined the prevalence of concordant versus discordant pairings.Sixty-two cases (29.2%) had rest tremor while seated. Fifteen (7.4%) had rest tremor while standing. Among asymmetric tremor pairings, concordant pairings occurred 2-2.7 times more frequently than discordant pairings - for pairings involving rest tremor while seated, 73.2% were concordant and 26.8% discordant (p 0.001); for pairings involving rest tremor while standing, 66.7% were concordant and 33.3% were discordant (p = 0.25).Rest tremor often lateralized with other tremor types. These data add to our knowledge of the phenotypic manifestations of ET.

Deep brain stimulation (DBS) is a pivotal surgical treatment for movement disorders. However, men and women have had differing opinions and referral experiences related to DBS, leading us to assess whether a gender disparity exists in the interval from a movement disorder diagnosis to DBS usage.We performed a single-center, retrospective cohort study of 105 patients who had undergone DBS surgery for either Parkinson disease (PD) or essential tremor (ET). We compared gender differences in the median interval between the diagnosis date, DBS consultation date, and DBS surgery dates. Additionally, the patient demographics, baseline clinical characteristics, and DBS outcomes were compared between men and women.We found no significant differences between genders in the interval from the diagnosis to DBS surgery for ET or PD. At the DBS consultation for ET, the women had had significantly greater disease severity compared with the men (P = 0.029). The baseline motor impairment without medication was similar between the men and women with PD. However, female patients with PD had experienced a significantly greater reduction compared with male patients in baseline motor impairment with medication versus without medication (P = 0.042). No minority populations were represented within the female ET and PD subgroups.Our study detected no gender differences in the DBS implantation timeline but alluded to a gender-specific discrepancy in DBS referral for ET. The female patients did not have a shorter duration from the ET diagnosis to DBS, despite experiencing significantly greater baseline ET severity compared with their male counterparts. Furthermore, the women with ET more often used Medicaid insurance and were without minority representation.

OBJECTIVE To assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care. MATERIALS AND METHODS Patients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables. RESULTS Fifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation. CONCLUSIONS Directional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation.

OBJECTIVES To determine change in restless legs syndrome (RLS) symptoms in essential tremor (ET) patients undergoing bilateral thalamic ventral intermedius (VIM) deep brain stimulation (DBS) surgery. MATERIALS AND METHODS We retrospectively reviewed our database of ET patients with RLS who had undergone VIM DBS for tremor from 2012 to 2020. We reviewed the patients with available International Restless Leg Syndrome Study Group RLS scale scores before and after DBS. Percentage of responders, defined as proportion of patients experiencing three or more point improvement of RLS scores post-DBS, was calculated. We performed two-tailed t-test of pre-DBS and post-DBS RLS scores. RESULTS We identified 13 patients with ET and RLS who had undergone bilateral VIM DBS, of whom nine (69%) were responders post-DBS. Five of 13 patients (38%) had complete resolution of RLS post-DBS. For all patients, mean pre-DBS RLS score was 15.8 ± 7.9 which improved by 46% post-DBS to a mean of 8.5 ± 8.8 (p = 0.007). Four patients rated their RLS scale one night with the stimulator OFF and another night with the stimulator ON. The mean RLS score with stimulator ON was 15.5 ± 7.6 which improved by 53% to a mean of 6.25 ± 7.8 (p = 0.008), with two having complete resolution of RLS with stimulator ON. Of the nine responders, six preferred to keep their stimulator ON at night due to relief of RLS and better subjective quality of sleep. CONCLUSIONS We report for the first time improvement of RLS in patients with ET after bilateral thalamic DBS. Although many ET patients with nonrechargeable DBS systems switch off their stimulator at night to conserve battery life, those with RLS may potentially benefit from keeping their stimulator ON at night to relieve their RLS.

Imaging studies investigating cerebellar gray matter (GM) in essential tremor (ET) showed conflicting results. Moreover, no large study explored the cerebellum in ET patients with resting tremor (rET), a syndrome showing enhanced blink reflex recovery cycle (BRrc).To investigate cerebellar GM in ET and rET patients using voxel-based morphometry (VBM) analysis.Seventy ET patients with or without resting tremor and 39 healthy controls were enrolled. All subjects underwent brain 3 T-MRI and BRrc recording. We compared the cerebellar GM volumes between ET (n = 40) and rET (n = 30) patients and controls through a VBM analysis. Moreover, we investigated possible correlations between cerebellar GM volume and R2 component of BRrc.rET and ET patients had similar disease duration. All rET patients and none of ET patients had enhanced BRrc. No differences in the cerebellar volume were found when ET and rET patients were compared to each other or with controls. By considering together the two tremor syndromes in a large patient group, the VBM analysis showed bilateral clusters of reduced GM volumes in Crus II in comparison with controls. The linear regression analysis in rET patients revealed a cluster in the left Crus II where the decrease in GM volume correlated with the R2BRrc increase.Our study suggests that ET and rET are different tremor syndromes with similar mild cerebellar gray matter involvement. In rET patients, the left Crus II may play a role in modulating the brainstem excitability, encouraging further studies on the role of cerebellum in these patients.

Midline essential tremor (Mid-ET) is a distinctive group of essential tremor (ET) in which tremor affects the neck, jaw, tongue, and/or voice. For long, it has been considered as an ultimate stage of the disease and a marker of its severity. However, recent studies pointed its complexity in terms of non-motor presentation. Thus, we aimed to investigate the non-motor signs (NMS) in Mid-ET.We conducted a cross-sectional study in a tertiary neurology referral center including ET patients classified into two groups based on the presence or not of midline tremor (Mid-ET vs. No-Mid-ET). We assessed NMS using the non-motor severity scale (NMSS), a large battery of cognitive tests, clinical and electrophysiological study of the autonomic nervous system along with the evaluation of sleep disturbances.A total of 163 patients were included: Mid-ET (n = 79) and No-Mid-ET (n = 84) matched in gender and age of onset. Mid-ET patients had higher proportion of late-onset ET ( 60 years old, p = 0.002) and more extrapyramidal signs (p = 0.005). For NMS, Mid-ET was marked with cognitive dysfunction (p = 0.008). The hallmarks of the neuropsychiatric profile of Mid-ET were executive dysfunction (p = 0.004), attention problems (p 0.000), episodic memory impairment (p = 0.003), and greater depression (p = 0.010). The presence of RBD was a trait of Mid-ET (p = 0.039). In both Mid-ET and No-Mid-ET phenotypes, clinical and neurophysiological dysautonomia correlated with cognitive dysfunction.Mid-ET patients had greater cognitive dysfunction, depression, RBD, higher proportion of late-onset ET, and more extrapyramidal signs. Taken all together, these findings could provide a redesigned insight into the underlying physiopathology of Mid-ET indicative of a greater cerebellar dysfunction.

Contains fulltext : 282588.pdf (Publisher’s version ) (Open Access) PURPOSE OF REVIEW: Tremor is one of the most prevalent movement disorders in clinical practice. Here, we review new insights in the pathophysiology of tremor. We focus on the three most common tremor disorders: essential tremor (ET), dystonic tremor syndrome (DTS), and Parkinson's disease (PD) tremor. RECENT FINDINGS: Converging evidence suggests that ET, DTS, and PD tremor are all associated with (partly) overlapping cerebral networks involving the basal ganglia and cerebello-thalamo-cortical circuit. Recent studies have assessed the role of these networks in tremor by measuring tremor-related activity and connectivity with electrophysiology and neuroimaging, and by perturbing network components using invasive and noninvasive brain stimulation. The cerebellum plays a more dominant and causal role in action tremors than in rest tremor, as exemplified by recent findings in ET, DTS, and re-emergent tremor in PD. Furthermore, the role of the cerebellum in DTS is related to clinical differences between patients, for example, whether or not the tremor occurs in a dystonic limb, and whether the tremor is jerky or sinusoidal. SUMMARY: Insight into the pathophysiological mechanisms of tremor may provide a more direct window into mechanism-based treatment options than either the etiology or the clinical phenotype of a tremor syndrome.

Essential tremor (ET) is one of the most common neurological diseases. Despite this high prevalence, treatment options remain limited. Recent advances in mechanistic research have led to renewed interest in developing newer pharmacotherapeutic agents. Although this is promising, there remains surprisingly little knowledge of the magnitude of the vast ET patient population who would benefit from and/or engage with such agents. This is because the vast bulk of ET patients in the population has milder tremor and does not seek medical care for their tremor. How many of these would be interested in taking a new agent? Hence, the level of unmet need, from the patient perspective and from a public health perspective, is totally unclear. In this article, the author systematically reviews peer-reviewed data on several pertinent questions that relate to this unmet need. The questions are as follows: (1) What proportion of the population of ET cases sees a health care provider for their tremor? (2) What proportion of the ET population has a tremor that is severe enough for them to want to take a medication for their tremor? (3) How do other factors such as age, sex, education, health literacy, and locale affect the receptivity to treatment in ET? (4) What is the patient use of the current ET medications? (5) Is the unmet need greater in some groups of ET cases than others? For each of these questions, available data are carefully reviewed and analyzed, and gaps in knowledge identified for further investigation.

Since the initial description of Essential Tremor (ET), the entity of ET with rest tremor has proven to be a controversial concept. Some authors argued it could be a late manifestation of ET, others suggested it could be a variant of ET, yet others suggested it could represent a transitional state between ET and Parkinson's disease. The novel tremor classification has proposed the construct of ET-plus to differentiate patients with rest tremor from pure ET. However, there is no clarity of what ET-plus rest tremor represents. With the aim of shedding light on this controversial entity, we have, therefore, systematically reviewed all clinical, electrophysiological, imaging and anatomopathological studies indexed in the Medline database published both before and after the new tremor classification and involving patients with ET-plus rest tremor. Forty-four studies involving 4028 patients were included in this review and analyzed in detail by means of descriptive statistics. The results of the current review suggest that ET-plus rest tremor is a heterogenous group of conditions: thus, rest tremor might represent a late feature of ET, might reflect a different disorder with higher age at onset and lower dependance on genetic susceptibility than ET, might suggest the development of Parkinson's disease or might indicate a misdiagnosis of ET. The reviewed lines of evidence refuse recent claims arguing against the construct of ET-plus, which should be viewed as a syndrome with different possible underpinnings, and highlights methodological issues to be solved in future research.

Micrographia is a common symptom of Parkinson’s disease (PD), and it may precede other motor symptoms. Despite the high prevalence of micrographia in PD, its neurobiological mechanisms are not known. Given that levodopa may alleviate consistent micrographia and that nondopaminergic essential tremor (ET) is not associated with micrographia, micrographia could possibly be used as an ancillary diagnostic method that reflects nigrostriatal dopamine function. We evaluated the usefulness of micrographia as a simple one-sentence writing test in differentiating PD from ET. A total of 146 PD patients, 42 ET patients and 38 healthy controls provided writing samples and were scanned with brain [123I]FP-CIT dopamine transporter (DAT) SPECT imaging with ROI-based and voxelwise analyses. The diagnostic accuracy of micrographia was evaluated and compared to that of DAT binding. Compared to ET and healthy controls, PD patients showed micrographia (consistent, 25.6% smaller area of handwriting sample in PD compared to ET, p = 0.002, and 27.2% smaller area of handwriting compared to healthy controls, p = 0.004). PD patients showed 133% more severe progressive micrographia compared with ET patients (median b = − 0.14 in PD, b = − 0.06 in ET, p = 0.021). In early unmedicated cognitively normal patients, consistent micrographia showed 71.2% specificity and 87.5% sensitivity in PD versus ET differentiation, but micrographia had no correlation with striatal or extrastriatal [123I]FP-CIT binding in patients with PD. The one-sentence micrographia test shows moderately good accuracy in PD versus ET differentiation. The severity of micrographia has no relationship with DAT binding, suggesting nondopaminergic mechanism of micrographia in PD.ClinicalTrials.gov identifier: NCT02650843 (NMDAT study).

INTRODUCTION: Essential tremor (ET), a common movement disorder, is characterized by motor, cognitive and psychiatric symptoms. Depressed mood, a symptom of ET, has historically been viewed as a psychological response to disability. However, depressive symptoms are emerging as a predictor of cognitive decline across several clinical populations. We examined if depressive symptoms predict decline in global cognition, memory, and executive functioning among older adults with ET. METHODS: 125 cognitively normal participants with ET completed three in-person assessments of cognition, mood, and motor symptoms at baseline, 18 months, and 36 months; baseline data were collected from July 2014-July 2016. Depressive symptoms were measured with the Geriatric Depression Scale. Cognitive functioning was measured via a 3–4-hour neuropsychological evaluation. Generalized linear regression models examined depressive symptoms as a predictor of decline in global cognition, executive functioning (EF), and memory. RESULTS: Participants were grouped according to a median split (GDS =5) due to the bimodal distribution of the data. In unadjusted models, depressive symptoms did not predict change in global cognition (b = −.002, p = .502) or EF (b = .000, p = .931), however individuals with GDS >=5 demonstrated faster memory decline in unadjusted (b = −.008, p =.039) and adjusted models (b = −.009, p = .019). CONCLUSION: The presence of 5 or more depressive symptoms predicted mildly faster memory decline in cognitively normal older adults with ET over 36 months. We discuss potential mechanisms and clinical implications.

OBJECTIVE Stereotactic radiosurgery (SRS) treats severe, medically refractory essential tremor and tremor-dominant Parkinson disease. However, the optimal target for SRS treatment within the thalamic ventral intermediate nucleus (VIM) is not clearly defined. This work evaluates the precision of the physician-selected VIM target, and determines the optimal SRS target within the VIM by correlation between early responders and nonresponders. METHODS Early responders and nonresponders were assessed retrospectively by Elements Basal Ganglia Atlas autocontouring of the VIM on the pre–SRS-treatment 1-mm slice thickness T1-weighted MRI and correlating the center of the post–SRS-treatment lesion. Using pre- and posttreatment diffusion tensor imaging, the fiber tracking package in the Elements software generated tremor-related tracts from autosegmented motor cortex, thalamus, red nucleus, and dentate nucleus. Autocontouring of the VIM was successful for all patients. RESULTS Among 23 patients, physician-directed SRS targets had a medial–lateral target range from +2.5 mm to −2.0 mm from the VIM center. Relative to the VIM center, the SRS isocenter target was 0.7–0.9 mm lateral for 6 early responders and 0.9–1.1 mm medial for 4 nonresponders (p = 0.019), and without differences in the other dimensions: 0.2 mm posterior and 0.6 mm superior. Dose–volume histogram analyses for the VIM had no significant differences between responders and nonresponders between 20 Gy and 140 Gy, mean or maximum dose, and dose to small volumes. Tractography data was obtained for 4 patients. CONCLUSIONS For tremor control in early responders, the Elements Basal Ganglia Atlas autocontour for the VIM provides the optimal SRS target location that is 0.7–0.9 mm lateral to the VIM center.

Current methods of evaluating essential tremor (ET) either rely on subjective ratings or use limited tremor metrics (i.e., severity/amplitude and frequency). In this study, we explored performance metrics from Fitts law tasks that replicate and expand existing tremor metrics, to enable low-cost, home-based tremor quantification and analyze the cursor movements of individuals using a 3D mouse while performing a collection of drawing tasks. We analyzed the 3D mouse cursor movements of 11 patients with ET and three controls, on three computer-based tasksa spiral navigation (SPN) task, a rectangular track navigation (RTN) task, and multi-directional tapping/clicking (MDT)with several performance metrics (i.e., outside area (OA), throughput (TP in Fitts law), path efficiency (PE), and completion time (CT)). Using an accelerometer and scores from the Essential Tremor Rating Assessment Scale (TETRAS), we correlated the proposed performance metrics with the baseline tremor metrics and found that the OA of the SPN and RTN tasks were strongly correlated with baseline tremor severity (R2=0.57 and R2=0.83). We also found that the TP in the MDT tasks were strongly correlated with tremor frequency (R2=0.70). In addition, as the OA of the SPN and RTN tasks was correlated with tremor severity and frequency, it may represent an independent metric that increases the dimensionality of the characterization of an individuals tremor. Thus, this pilot study of the analysis of those with ET-associated tremor performing Fitts law tasks demonstrates the feasibility of introducing a new tremor metric that can be expanded for repeatable multi-dimensional data analyses.

Essential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello-thalamo-cortical circuitry and may be dependent on T-type calcium channel activity. T-type calcium channels regulate sigma band electroencephalogram (EEG) power during non-rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX-944 is a novel T-type calcium channel blocker in development for essential tremor.Using a rat tremor model and sigma-band EEG power, we assessed pharmacodynamically-active doses of PRAX-944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials.Harmaline-induced tremor and spontaneous locomotor activity were used to assess PRAX-944 efficacy and tolerability, respectively, in rats. Sigma-power was used as a translational biomarker of T-type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants.In rats, PRAX-944 dose-dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma-power by ~30% to 50% in rats. In healthy participants, sigma-power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated.In rats, PRAX-944 reduced sigma-power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma-power indicate that robust T-type calcium channel blockade was achieved at well-tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) has proven to be an effective therapy of some treatment-resistant psychiatric disorders and movement disorders. Comorbid depressive symptoms are common and difficult to manage. Treatment with electroconvulsive therapy (ECT) may be required. There are few published cases describing the safety and efficacy of ECT for patients with DBS implants, and there are no available guidelines for administration of ECT in patients with DBS and mood disorders. The current study had 3 aims: (i) to conduct a systematic review of case reports on patients with DBS implants who received ECT; (ii) to report the case of a 69-year-old man with a DBS implant for essential tremor, who required ECT; and (iii) to provide practical recommendations for ECT in patients with DBS implants.We conducted a systematic review, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, of existing case reports on patients with DBS implants administered ECT for psychiatric disorders.Our search yielded 25 cases of ECT in patients implanted with DBS systems. In addition, we here describe successful ECT management of major depressive disorder in a patient treated by DBS. We also set forth ECT management guidelines based on points of consensus. The 2 most important practical recommendations are to make sure the DBS system is set to 0 V and turned off before ECT, and to avoid sites near the DBS electrodes.Electroconvulsive therapy may be an effective and safe treatment for DBS patients with MDD.

OBJECTIVE To obtain individual clinical and neuroimaging data of patients undergoing Deep Brain Stimulation for essential tremor from five different European centers to identify predictors of outcome and to identify an optimal stimulation site. METHODS We analysed retrospectively baseline covariates, pre- and postoperative clinical tremor scores (12-month) as well as individual imaging data from 119 patients to obtain individual electrode positions and stimulation volumes. Individual imaging and clinical data was used to calculate a probabilistic stimulation map in normalized space using voxel-wise statistical analysis. Finally, we used this map to train a classifier to predict tremor improvement. RESULTS Probabilistic mapping of stimulation effects yielded a statistically significant cluster that was associated with a tremor improvement greater than 50%. This cluster of optimal stimulation extended from the posterior subthalamic area to the ventralis intermedius nucleus and coincided with a normative structural-connectivity-based cerebello-thalamic tract (CTT). The combined features "distance between the stimulation volume and the significant cluster" and "CTT activation" were used as a predictor of tremor improvement. This correctly classified a greater than 50% tremor improvement with a sensitivity of 89% and a specificity of 57%. INTERPRETATION Our multicentre ET probabilistic stimulation map identified an area of optimal stimulation along the course of the CTT. The results of this study are mainly descriptive until confirmed in independent datasets, ideally through prospective testing. This target will be made openly available and may be used to guide surgical planning and for computer-assisted programming of deep brain stimulation in the future. This article is protected by copyright. All rights reserved.

Generation of functional tremor relies on the structures involved in the control of voluntary movements. The clinical diagnosis is based on the presence of "positive signs", which are expression of cognitive and motor distractibility and reflect functional tremor dependence on explicit motor control. In patients who manifest less distractibility, habitual (implicit) control may be of greater significance. Habitual behaviours are inflexible and difficult to eradicate.To investigate if motor and cognitive distractibility predicts response to treatment with repetitive transcranial magnetic stimulation.21 patients with functional tremor underwent 5-day repeated sessions of continuous theta burst stimulation over primary motor cortex. A battery of tests to provoke positive signs was performed during accelerometry recordings and the total functional tremor accelerometry score was calculated for each patient. Response to treatment was measured as change in tremor amplitude, expressed as total power of the spectra between 1 and 30 Hz.On the group level, cTBS significantly changed postural tremor amplitude (Z = -1.9; p = 0.05), with the median decrease of 40%, IQR (-90-(+24)). There was a positive correlation between the functional tremor accelerometry score and reduction of postural tremor amplitude with treatment (rPatients who are more distractible are better candidates for treatment with transcranial magnetic stimulation. The likely explanation is the between-subjects differences on the reliance of functional tremor generation on explicit vs. implicit motor network.

Major progress has occurred during the last decade in the field of tremor. From the clinical standpoint, a new classification has completely revised the nosology of tremor syndromes and has re-conceptualized essential tremor as a syndrome rather than a single disease entity, fueling an ongoing enlightened debate. Significant advances have been obtained in terms of instrumental measurement of tremor, remarking on the possibility of developing novel treatment strategies based on tremor characteristics, namely tremor-phase. Moreover, a better understanding of the pathophysiological mechanisms has further led to the suggestion of refining the classification of tremor syndromes according to their driving underpinnings. Finally, surgical options such as deep brain stimulation and focused ultrasound thalamotomy are now part of the therapeutic portfolio for tremor, but several oral drugs, including long-chain alcohols, T-channel blockers, allosteric modulators of potassium channels, and of GABA-A receptors, are currently being tested and hold promise. This review will discuss the key milestones in tremor research of the last 10 years, with a focus on the most common tremor syndromes, namely essential tremor, dystonic tremor, and Parkinsonian tremor.

Surgical targeting of the ventral intermediate nucleus of the thalamus (VIM) has been historically done using indirect strategies. Here we depict the cerebello-thalamo-cortical tract (CTCT) through 3 T proton density (PD) in a cohort of patients who underwent high-intensity focus ultrasound (HIFUS) thalamotomy. Forty-seven patients treated in our institution with MR-guided HIFUS VIM thalamotomy were included in this study. PD weighted 3 T MRI used for presurgical planning was compared with postoperative MRI obtained 1 month after surgery. Images were processed with ISTX software (Brain lab, Munich, Germany). The coordinates of the VIM lesion concerning the inter-commissural line (ICL) were annotated. Deterministic tractographies using three ROIs were used to verify the different tracts. The triangle seen in the 3 T PD sequence at the level of the mesencephalic-diencephalic junction was systematically recognized. The posterior angle of this triangle at the junction of the CTCT and the ZI was denominated as "point P." The area of this triangle corresponds to the posterior subthalamic area (PSA) harboring the Raprl fibers. The CTCT was visible from 1 to 2.5 mm below the ICL. The average center of the final HIFUS lesion (point F) was 11 mm from the medial thalamic border of the thalamus (14.9 mm from the midline), 6.4 mm anterior to PC, and 0.6 mm above the ICL. The FUS point was consistently 1-2 mm directly above point P. The anterior border of the external angle of this triangle (point P) can be used as an intraparenchymal point for targeting the ventral border of the VIM. Three ROIs placed in a single slice around this triangle are a fast way to originate tractography of the CTCT, lemniscus medialis, and pyramidal tract.

Despite substantial clinical and pathophysiological differences, the characteristics of tremor in Parkinson's disease (PD) and essential tremor (ET) patients bear certain similarities. The presented study delineates tremor-related structural networks in these two disorders.42 non-advanced PD patients (18 tremor-dominant, 24 without substantial tremor), 17 ET, and 45 healthy controls underwent high-angular resolution diffusion-weighted imaging acquisition to reconstruct their structural motor connectomes as a proxy of the anatomical interconnections between motor network regions, implementing state-of-the-art globally optimised probabilistic tractography.When compared to healthy controls, ET patients exhibited higher structural connectivity in the cerebello-thalamo-cortical network. Interestingly, the comparison of tremor-dominant PD patients and PD patients without tremor yielded very similar results - higher structural connectivity in tremor-dominant PD sharing multiple nodes with the tremor network detected in ET, despite the generally lower structural connectivity between basal ganglia and frontal cortex in the whole PD group when compared to healthy controls.The higher structural connectivity of the cerebello-thalamo-cortical network seems to be the dominant tremor driver in both PD and ET. While it appears to be the only tremor-related network in ET, its combination with large scale hypoconnectivity in the frontal cortico-subcortical network in PD may explain different clinical features of tremor in these two disorders.

The new essential tremor (ET)-plus nomenclature was proposed by the 2018 Tremor Consensus Criteria. However, few studies have adopted this usage and the clinical differences between ET and ET-plus remains unclear. To address this issue, we reclassified and compared the characteristics of ET and ET-plus patients in a large Chinese tremor cohort.In this cross-sectional observational study, 766 patients originally diagnosed with ET underwent neurological examination. Scale ratings were used to evaluate motor and non-motor symptoms, and quality of life (QoL). We then reclassified the ET cohort and compared demographic and clinical characteristics between ET and ET-plus patients. A logistic regression analysis was used to explore whether the presence of neurological soft signs in ET-plus was associated with tremor severity or QoL.Among 665 clinically confirmed ET syndrome patients, 274 were ET and 391 were ET-plus. The most prevalent neurological soft sign was resting tremor. ET-plus patients were older, had older age at onset and longer disease duration. ET-plus patients recorded higher scores in tremor severity evaluations and lower in cognitive evaluations, whereas a higher proportion of patients presented with depression or anxiety symptoms. Resting tremor and questionable cerebellar signs were associated with tremor severity. Cognitive impairment was associated with worse QoL.ET-plus patients were older, had longer disease durations, worse tremor manifestations, and more distinct non-motor symptoms. Certain additional soft signs of ET-plus were associated with tremor severity or worse QoL. ET-plus patients may include advanced ET patients with additional neurological soft signs presenting along with disease progression.

The ventral intermediate (VIM) thalamic nucleus is the main target for the surgical treatment of refractory tremor. Initial targeting traditionally relies on atlas-based stereotactic targeting formulas, which only minimally account for individual anatomy. Alternative approaches have been proposed, including direct targeting of the dentato-rubro-thalamic tract (DRTT), which, in clinical settings, is generally reconstructed with deterministic tracking. Whether more advanced probabilistic techniques are feasible on clinical-grade magnetic resonance acquisitions and lead to enhanced reconstructions is poorly understood. OBJECTIVE: To compare DRTT reconstructed with deterministic vs probabilistic tracking. METHODS: This is a retrospective study of 19 patients with essential tremor who underwent deep brain stimulation (DBS) with intraoperative neurophysiology and stimulation testing. We assessed the proximity of the DRTT to the DBS lead and to the active contact chosen based on clinical response. RESULTS: In the commissural plane, the deterministic DRTT was anterior (P < 10(−4)) and lateral (P < 10(−4)) to the DBS lead. By contrast, although the probabilistic DRTT was also anterior to the lead (P < 10(−4)), there was no difference in the mediolateral dimension (P = .5). Moreover, the 3-dimensional Euclidean distance from the active contact to the probabilistic DRTT was smaller vs the distance to the deterministic DRTT (3.32 ± 1.70 mm vs 5.01 ± 2.12 mm; P < 10(−4)). CONCLUSION: DRTT reconstructed with probabilistic fiber tracking was superior in spatial proximity to the physiology-guided DBS lead and to the empirically chosen active contact. These data inform strategies for surgical targeting of the VIM.

Dysgeusia, or distorted taste, has recently been acknowledged as a complication of thalamic ablation or thalamic deep brain stimulation as a treatment of tremor. In a unique patient, left-sided MR-guided focused ultrasound thalamotomy improved right-sided essential tremor but also induced severe dysgeusia. Although dysgeusia persisted and caused substantial weight loss, tremor slowly relapsed. Therefore, 19 months after the first procedure, the patient underwent a second focused ultrasound thalamotomy procedure, which again improved tremor but also completely resolved the dysgeusia. On the basis of normative and patient-specific whole-brain tractography, the authors determined the relationship between the thalamotomy lesions and the medial border of the medial lemniscus—a surrogate for the solitariothalamic gustatory fibers—after the first and second focused ultrasound thalamotomy procedures. Both tractography methods suggested partial and complete disruption of the solitariothalamic gustatory fibers after the first and second thalamotomy procedures, respectively. The tractography findings in this unique patient demonstrate that incomplete and complete disruption of a neural pathway can induce and resolve symptoms, respectively, and serve as the rationale for ablative procedures for neurological and psychiatric disorders.

We aimed to study the cortical and intracortical functions in patients of ET using transcranial magnetic stimulation (TMS) and to evaluate the effect of continuous theta burst stimulation (cTBS) on the tremor characteristics.Ten ET and 20 healthy controls were included in the study. All the participants were evaluated with TMS with recording of resting motor threshold (RMT), central motor conduction time, contralateral silent period (cSP), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Subsequently only ET patients underwent cTBS of the motor cortex (M1) followed by repeat TMS.The mean age of the patients (46.5 ± 17.2 years) was comparable to healthy controls (55.4 ± 9.2 years; p = 0.16). There was a non-significant increase in RMT in ET patients (44 ± 12.5%) when compared to healthy controls (40.9 ± 6.9%; p = 0.48). There was a significant reduction of cSP in the ET group (102.03 ± 15.26 msec) compared to healthy controls (116.1 ± 15.2, p = 0.03). In addition, a significant reduction in ICF was observed in ET patients (0.9 ± 0.7) compared to healthy controls (1.8 ± 0.8, p = 0.01). Following cTBS there was a significant reduction in the tremor scores [FTMRS (Pre-cTBS: 29.3 ± 18.7, Post-cTBS: 25.3 ± 16.8; p 0.001) and TETRAS (pre-cTBS: 34.4 ± 16.2, post-cTBS: 29.8 ± 12.1; p = 0.01)] and improvement (increase) of the duration of cSP (pre-cTBS: 102.03 ± 15.3 msec., post-cTBS: 119.4 ± 12.03 msec; p = 0.05).Patients with ET have GABAergic and glutaminergic dysfunction as demonstrated by reduced cSP and ICF. However, only the cSP improved following cTBS of M1 region, with a corresponding improvement of tremor severity suggesting the effect of cTBS on the cerebello-thalamo-cortical network.

Background: Essential tremor (ET) is the most common adult movement disorder. For the relatively large group of patients who do not respond adequately to pharmacological therapy, deep brain stimulation (DBS) is a well-established treatment option. Most ET patients will have bilateral symptoms, and many of them receive bilateral DBS. Unilateral DBS is however still the most common procedure, and some papers suggest an ipsilateral effect in these patients. Objectives: The aim of this study was to analyze if there is an ipsilateral effect of DBS for ET. Method: We retrospectively analyzed our patient cohort with DBS surgery from 1996 to 2017, selecting patients with ET that underwent surgery with unilateral DBS without previous DBS or lesional surgery. A total number of 68 patients (39 males, 29 females) were identified. The patients were evaluated twice: first, at a mean time of 12 months after surgery defined as short-term follow-up and then again at a mean time of 49 months after surgery defined as long-term follow-up, using the clinical rating scale for tremor (CRST). Results: The total CRST score was reduced from mean 49.5 points at baseline before surgery to 20.2 (p < 0.001) at short-term and 28.3 (p < 0.001) at long-term follow-up. Contralateral tremor was reduced from mean 6.1 to 0.4 (p < 0.001) and 1.2 (p < 0.001), respectively. Contralateral hand function was reduced from 11.5 to 2.6 (p < 0.001) and 4.6 (p < 0.001), respectively. Ipsilateral hand function scored 9 at baseline, 8.3 at 1 year, and then again 9.4 at long-term follow-up. Ipsilateral tremor scored 4.0 at baseline, 3.7 at 1 year, and 4.3 at long-term follow-up. Neither ipsilateral hand function nor ipsilateral tremor showed significant difference. Conclusions: There was no difference in severity of ipsilateral tremor, neither at 1 year nor in the long term. We believe ipsilateral effects of DBS for ET merits limited consideration regarding decision-making or patient counseling before surgery.

Contains fulltext : 252111.pdf (Publisher’s version ) (Open Access) The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review.

Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Here, we address the relationship between single-neuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinson’s disease ( n = 19) and essential tremor ( n = 16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic single-neuron bursts encode both pathophysiological beta (13 to 33 Hz; STN) and tremor (4 to 10 Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phase-coupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phase-coupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic single-neuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile “rate” and “oscillation” models of Parkinson’s disease and shed light on the single-neuron basis and origin of pathophysiological oscillations in movement disorders.

Aims Deep brain stimulation (DBS) in the ventral intermediate nucleus (Vim‐DBS) is the preferred surgical therapy for essential tremor (ET). Tolerance and disease progression are considered to be the two main reasons underlying the loss of long‐term efficacy of Vim‐DBS. This study aimed to explore whether Vim‐DBS shows long‐term loss of efficacy and to evaluate the reasons for this diminished efficacy from different aspects. Methods In a repeated‐measures meta‐analysis of 533 patients from 18 studies, Vim‐DBS efficacy was evaluated at ≤6 months, 7–12 months, 1–3 years, and ≥4 years. The primary outcomes were the score changes in different components of the Fahn‐Tolosa‐Marin Tremor Rating Scale (TRS; total score, motor score, hand‐function score, and activities of daily living [ADL] score). Secondary outcomes were the long‐term predictive factors. Results The TRS total, motor, and ADL scores showed significant deterioration with disease progression (p = 0.002, p = 0.047, and p, The firstly reported ventral intermediate nucleus has different effects on different aspects and provides high‐level evidence of the long‐term efficacy change of Vim‐DBS.

Tremor disorders are diverse and complex. Historical clues and examination features play a major role in diagnosing these disorders, but diagnosis can be challenging due to phenotypic overlap. Ancillary testing, such as neuroimaging or laboratory testing, is driven by the history and examination, and should be performed particularly when there are other neurological or systemic manifestations. The pathophysiology of tremor is not entirely understood, but likely involves multiple networks along with the cerebello-thalamo-cortical pathways. Treatment options include medications, botulinum toxin, surgery, and nonpharmacologic interventions utilizing physical and occupational therapies and assistive devices. Further work is needed in developing accurate diagnostic tests and better treatment options for tremor disorders.

BACKGROUND AND PURPOSE The GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion-positive patients presenting with tremor-dominant symptoms. This study aimed to clarify the clinical phenotype in tremor-dominant patients who have the GGC repeat expansion in the NOTCH2NLC gene. METHODS We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically re-evaluated the clinical features of the expansion-positive probands and their family members. RESULTS Pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in 10 probands (1.66%). Seven of these probands were re-evaluated and found to have systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of the probands had typical hyperintensity in the corticomedullary junction on diffusion-weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. CONCLUSIONS The NIID tremor-dominant subtype can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. Systemic areflexia could be an important clinical clue suggesting that cranial magnetic resonance imaging examination, or even further genetic testing and skin biopsy examination, should be used to confirm the diagnosis of NIID.

Background Deep brain stimulation (DBS) is an effective surgical therapy for individuals with essential tremor (ET). However, DBS operates continuously, resulting in adverse effects such as postural instability or dysarthria. Continuous DBS (cDBS) also presents important practical issues including limited battery life of the implantable neurostimulator (INS). Collectively, these shortcomings impact optimal therapeutic benefit in ET. Objective The goal of the study was to establish a physiology-driven responsive DBS (rDBS) system to provide targeted and personalized therapy based on electromyography (EMG) signals. Methods Ten participants with ET underwent rDBS using Nexus-D, a Medtronic telemetry wand that acts as a direct conduit to the INS by modulating stimulation voltage. Two different rDBS paradigms were tested: one driven by one EMG (single-sensor) and another driven by two or more EMGs (multi-sensor). The feature(s) used in the rDBS algorithms was the pow2er in the participant's tremor frequency band derived from the sensors controlling stimulation. Both algorithms were trained on kinetic and postural data collected during DBS off and cDBS states. Results Using established clinical scales and objective measurements of tremor severity, we confirm that both rDBS paradigms deliver equivalent clinical benefit as cDBS. Moreover, both EMG-driven rDBS paradigms delivered less total electrical energy translating to an increase in the battery life of the INS. Conclusions The results of this study verify that EMG-driven rDBS provides clinically equivalent tremor suppression compared to cDBS, while delivering less total electrical energy. Controlling stimulation using a dynamic rDBS paradigm can mitigate limitations of traditional cDBS systems.

Introduction Non-motor DBS outcomes have received little attention in ET relative to PD. This study examines neuropsychological outcomes in ET following thalamic VIM DBS. Methods Fifty patients completed neuropsychological evaluations preoperatively and approximately seven months postoperatively. Cognition and mood changes were analyzed at the group level and individual level. Additional associations with treatment, disease, and demographic characteristics were assessed. Results Significant cognitive decline was not observed at the group level. At the individual level, 46% of patients demonstrated at least subtle overall cognitive decline (≥1SD on at least one test within at least two domains). Mild decline (≥1SD) was seen in 10%–29.17% of patients on individual tests across all cognitive domains, with highest rates in verbal memory. Substantial cognitive decline (≥2SD) occurred in less than 9% of the sample across all tests. Factors related to cognitive decline included higher DBS parameter settings, older age of ET onset, intracranial complications, and inability to reduce ET medications postoperatively. Depression and anxiety did not change when accounting for questionnaire items that could be falsely elevated by tremor. Conclusion Substantial cognitive decline after VIM DBS is rare in patients with ET. However, subtle decrements can occur across cognitive domains and particularly in verbal memory. DBS parameter settings may relate to cognitive decline. Further research is needed to better understand possible associations with electrode lateralization and other variables that could also relate to disease progression and test-retest effects. Symptoms of depression and anxiety remain stable.

Investigation of associated risk factors of valproic acid (VPA)–induced tremor helped in increasing tolerance and optimizing treatment scheme individually. To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations. Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. One hundred and eighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p = 0.014), family history of tremor (OR = 7.595, p = 0.003), treatment duration (> 24 months; OR = 3.294, p = 0.002), and daily dosage (> 1,000 mg/d; OR = 19.801, p = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER (p = 0.030) and carbamazepine combination (p = 0.040) reduced the incidence of tremor. One hundred and seventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values (p > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p = 0.001), reduced cerebellar hemisphere thickness (p = 0.025), and right cerebellar hemisphere longitudinal diameter (p = 0.047). Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000 mg and treatment duration > 24 months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor.

Objective: This report describes the case of a patient with essential tremors of the mouth and hands, which were improved by Yeokhan-san treatment.Methods: To relieve the symptoms, Korean medicine treatments, including Yeokhan-san, Ohaeng-Hwa acupuncture, and electronic moxibustion, were performed. To evaluate the effects of the treatments, the visual analog scale and Fahn-Tolosa-Marin clinical rating scale for tremor were used.Results: After the treatment, the patient's clinical symptoms were improved. The visual analog scale score decreased from 10 to 2 for the hand tremor and from 10 to 1 for the mouth tremor. The Fahn-Tolosa-Marin tremor scores decreased from 3 to 1 for both the hand and mouth tremors.Conclusions: The present case suggests that Yeokhan-san and Ohaeng-Hwa acupuncture are effective for the treatment of essential tremor.

PURPOSE OF REVIEW The optimal diagnosis and management of dystonic voice disorders are rooted in the nuanced understanding of their phenomenology. Distinguishing between subtypes of vocal dystonia is challenging, not only because the audible and physical presentations of these dystonia's can seem similar, but also because there is a lack of scientific consensus regarding the diagnostic criteria for these conditions. To help improve the clinician's acumen we focus on outlining the classification of the top three neurological voice disorders, notably: spasmodic dysphonia, (2) spasmodic dysphonia with tremor, and essential tremor of the voice. We also provide an algorithmic approach based on current evidence-based literature to guide practitioners through the clinical diagnosis and management of each possible etiology. RECENT FINDINGS Much remains unknown about the subtypes of vocal dystonia, and this gap in our knowledge likely limits our ability to advance clinical management. Still, continued experience evaluating and treating these patients yields refined clinical evaluations and decision making. SUMMARY Improvements in our clinical decision-making can be made by acknowledging that our limited understanding of vocal dystonia may hinder what therapeutic interventions we can offer, yet our ability to accurately diagnose the dystonia is central to providing optimal patient management.

Deep brain stimulation (DBS) is an effective treatment of several types of neurological conditions, including Parkinson’s disease, essential tremor, dystonia, and epilepsy. Despite technological progress in the past 10 years, the number of studies reporting side effects of DBS has increased, mainly due to hardware failures. This review investigated studies published between 2017 and 2021 to identify the prevalence of distinct types of hardware failures related to DBS. In total, fifteen studies were selected for the estimate of the prevalence of five distinct types of hardware failures: high impedance, fracture or failure of the lead or other parts of the implant, skin erosion and infection, lead malposition or migration, and implantable pulse generator (IPG) malfunction. The quality evaluation of the studies suggests a need to report results including populations from distinct regions of the world so that results can be generalized. The objective analysis of the prevalence of hardware failures showed that skin erosion and infection presented the highest prevalence in relation to other hardware failures. Despite the sophistication of the surgical technique of DBS over time, there is a considerable complication rate, about 7 per 100 individuals ( $$\mathrm{prevalence}=6.67\%, CI = [2.26\%,12.49\%]$$ , in which CI is the confidence interval). Future research can also include correlation analysis with the aim of understanding the correlation between distinct hardware failures and variables such as gender, type of disorder, and age.

MRgFUS Vim thalamotomy is a novel, effective, minimally invasive therapeutic option for patients with essential tremor (ET). Among the selection criteria, some parameters related to the patient's anatomy, such as the skull density ratio (SDR), are well recognized. The role of brain tissue interposed between the target and the ultrasound transducers has never been explored. Therefore, the purpose of our study was to evaluate the correlation and the possible predictive value between brain tissue volumes (grey matter - GM, white matter - WM, and cerebrospinal fluid - CSF) and several treatment-related variables (periprocedural parameters, MRI imaging findings, and the clinical outcome). We analysed data from thirty ET patients previously submitted to MRgFUS thalamotomy. Pre-treatment images were automatically segmented in sopra-tentorial (ST) WM, GM, and CSF using SPM 12. The most significant findings were a positive correlation of the ST-GM with the Accumulated Thermal Dose (ATD) (p 0,001) and a negative correlation of the ATD temperature with ST-CSF and ST-TIV (p 0,001). Ultrasound propagation speed is lower in fluids than brain tissues. Also, WM has an attenuation rate of 1.5 higher than the GM. Therefore, the difference in the ATD may be explained by the different acoustic properties of normal brain tissues interposed between the transducers and the VIM.