Essential Tremor Rating Assessment Scale Research Articles

Non-motor symptoms in patients with Spinocerebellar ataxia type 12.

Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by abnormal CAG repeat expansion in the PPP2R2B gene. This disease is classically characterized by action tremor, dysarthria, ataxia, and hyperreflexia. There are limited reports regarding the non-motor symptoms in patients with SCA 12. We investigated the frequency and factors associated with the selected non-motor symptoms in patients with SCA 12. Genetically diagnosed (CAG repeats > 43) and symptomatic cases of SCA 12 were included in the study. Motor severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and The Essential Tremor Rating Assessment Scale (TETRAS). Non-motor symptoms such as depression, autonomic function, and cognition were assessed using the Hamilton Depression Rating Scale (HAM-D), the Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT), and the Montreal Cognitive Assessment (MoCA), respectively. The mean age of the cohort with 34 SCA12 patients was 64.87 years (standard deviation 6.844). In this study, 21 patients (61.76%) had either mild or moderate cognitive impairment, almost equally frequent in early and advanced cases. Similarly a number of patients demonstrated evidence of moderate and severe depression. The SARA score was strongly associated with the MoCA score, and CAG repeat length could independently predict the MoCA score in this cohort. Autonomic symptoms were commonly present, with the majority of the patients experiencing urinary symptoms. Non-motor symptoms are common in SCA12 patients, even in the early stages of the condition. Timely detection and treatment of these symptoms may improve the therapeutic outcome and quality of life for SCA12 patients. The diverse symptoms of SCA12 perhaps indicate a widespread neurodegeneration beyond the cerebellum or its direct connections.

An Algorithm for Automated Measurement of Kinetic Tremor Magnitude Using Digital Spiral Drawings

Introduction: Essential tremor is a common movement disorder. Numerous validated clinical rating scales exist to quantify essential tremor severity by employing rater-dependent visual observation but have limitations, including the need for trained human raters and the lack of precision and sensitivity compared to technology-based objective measures. Other continuous objective methods to quantify tremor amplitude have been developed, but frequently provide unitless measures (e.g., tremor power), limiting real-world interpretability. We propose a novel algorithm to measure kinetic tremor amplitude using digital spiral drawings, applying the V3 framework (sensor verification, analytical validation, and clinical validation) to establish reliability and clinical utility. Methods: Archimedes spiral drawings were recorded on a digitizing tablet from participants (n = 7) enrolled in a randomized placebo control double-blinded crossover pilot trial evaluating the efficacy of oral cannabinoids in reducing essential tremor. We developed an algorithm to calculate the mean and maximum tremor amplitude derived from the spiral tracings. We compared the digitally measured tremor amplitudes to manual measurement to evaluate sensor reliability, determined the test-retest reliability of the digital output across two short-interval repeated measures, and compared the digital measure to kinetic tremor severity graded using The Essential Tremor Rating Assessment Scale (TETRAS) score for spiral drawings. Results: This algorithm for automated assessment of kinetic tremor amplitude from digital spiral tracings demonstrated a high correlation with manual spot measures of tremor amplitude, excellent test-retest reliability, and a high correlation with human ratings of the TETRAS score for spiral drawing severity when the tremor severity was rated “slight tremor” or worse. Discussion: This digital measure provides a simple and clinically relevant evaluation of kinetic tremor amplitude that shows promise as a potential future endpoint for use in clinical trials of essential tremor.

Estimating Disability in Patients with Essential Tremor: Comparison of Tremor Rating Scale, Spiral Drawing, and Accelerometric Tremor Power.

Although performance rating scales, spiral drawing, water pouring, and accelerometry are commonly used to assess tremor severity, the extent to which their results correlate with impairment in activities of daily living (ADL) remains unclear. The aim was to identify the most effective predictors of ADL in essential tremor (ET). Forty ET patients were examined using The Essential Tremor Rating Assessment Scale (TETRAS), spiral drawing, volume of water spilled, and accelerometric tremor power. Root-mean-square error, R2, and F-test were calculated for models predicting TETRAS ADL subscore. TETRAS Performance Subscale explained the variability in TETRAS ADL with an R2 value of 0.686. Models incorporating spiral rating and accelerometric tremor power (R2 = 0.731) and water spillage volume (R2 = 0.756) were not statistically superior. TETRAS performance subscore predicted nearly 70% ADL impairment in ET patients. Incorporating the spiral rating, accelerometric tremor power, and water pouring test did not enhance ADL estimation.

Ayurvedic Management of Kampavata

Kampavata is one among Vataja nanatmaja vyadhis. Acharya Charaka, Susrutha, Vagbhata, Madhavakara, Kashyapa mentioned Kampavata as Vepathu. It can be correlated with “Tremors” in modern science which is the most common movement disorder. The total number of people suffering from ET worldwide was 24.91 million in 2020 and incidence increases with age. Kampa is the prominent feature in Kampavata which is categorized as Sarvanga-kampa and Shiro-kampa. Kampa occurs due to Prakopa of Chalaguna which is the inherent quality of Vata dosha. The management of essential tremors in the conventional system of medicine is decreasing quality of life of patient with certain side effects like fatigue, impotence, bradycardia, reduced blood pressure, drowsiness, nausea, dizziness, ataxia, confusion, vertigo, paresthesia etc. By Ayurvedic intervention patient quality of life can be preserved. In the present clinical study patient was treated with Snehana and Brmhana line of management in the form of Shirodhara, Nasya and Samana oushadies like Sarvamayantakaghrta etc. The outcome of the study revealed good therapeutic efficacy and patient got remarkable relief in symptoms, that are assessed by TRG Essential tremor rating assessment scale (TETRAS©) V 3.1.

Validation of a New Patient-Reported Outcome Measure of the Functional Impact of Essential Tremor on Activities of Daily Living.

The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Develop and validate a TETRAS PRO subscale. Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.

Associations Among Tremor Amplitude, Activities of Daily Living, and Quality of Life in Patients with Essential Tremor.

Essential tremor (ET) is a disabling syndrome consisting of tremor, primarily in the upper limbs. We assessed the correlation of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Item 4 ratings of upper limb tremor with the TETRAS activities of daily living (ADL) subscale and with 2 quality of life (QoL) scales. This noninterventional, cross-sectional, point-in-time survey of neurologists(n = 60), primary care physicians (n = 38), and their patients with ET (n = 1,003) used real-world data collected through the Adelphi ET Disease Specific Programme™. Physician-reported measures (TETRAS Performance Item 4 and TETRAS ADL total) and patient-reported QoL measures (generic EuroQol-5 Dimension 5 Level [EQ-5D-5 L] and ET-specific Quality of Life in Essential Tremor Questionnaire (QUEST)) were assessed with bivariate and multivariable analyses. Sensitivity analyses were also conducted. The bivariate association between TETRAS Performance Item 4 score and TETRAS ADL total score was high (Pearson r = 0.761, P < 0.001). The bivariate associations between TETRAS Performance Item 4 score and EQ-5D-5 L index score (r = -0.410, P < 0.001) and between TETRAS ADL total score and EQ-5D-5 L index score (r = -0.543, P < 0.001) were moderate. The bivariate associations between TETRAS Performance Item 4 score and QUEST total score (r = 0.457, P < 0.001), and between TETRAS ADL total score and QUEST total score (r = 0.630, P < 0.001) were also moderate. These associations were unaltered by the inclusion of covariates. This study showed that greater tremor severity (TETRAS Performance Item 4) was positively correlated with ADL impairment (TETRAS ADL) and negatively associated with QoL (EQ-5D-5 L and QUEST). TETRAS Performance Item 4 score is a robust predictor of TETRAS ADL total score, and TETRAS Performance Item 4 and TETRAS ADL total scores were robust predictors of the 2 QoL scales. The results demonstrate the value of TETRAS scores as valid endpoints for future clinical trials. This real-world study assessed TETRAS scores as predictors of impaired QoL in ET. TETRAS Performance Item 4 and ADL were associated with EQ-5D-5 L and QUEST. TETRAS scores may serve as valid endpoints for future clinical trials.

Impact of biologically effective dose on tremor decrease after stereotactic radiosurgical thalamotomy for essential tremor: a retrospective longitudinal analysis

Stereotactic radiosurgery (SRS) is one of the surgical alternatives for drug-resistant essential tremor (ET). Here, we aimed at evaluating whether biologically effective dose (BEDGy2.47) is relevant for tremor improvement after stereotactic radiosurgical thalamotomy in a population of patients treated with one (unplugged) isocenter and a uniform dose of 130 Gy. This is a retrospective longitudinal single center study. Seventy-eight consecutive patients were clinically analyzed. Mean age was 69.1 years (median 71, range 36–88). Mean follow-up period was 14 months (median 12, 3–36). Tremor improvement was assessed at 12 months after SRS using the ET rating assessment scale (TETRAS, continuous outcome) and binary (binary outcome). BED was defined for an alpha/beta of 2.47, based upon previous studies considering such a value for the normal brain. Mean BED was 4573.1 Gy2.47 (median 4612, 4022.1–4944.7). Mean beam-on time was 64.7 min (median 61.4; 46.8–98.5). There was a statically significant correlation between delta (follow-up minus baseline) in TETRAS (total) with BED (p = 0.04; beta coefficient − 0.029) and beam-on time (p = 0.03; beta coefficient 0.57) but also between TETRAS (ADL) with BED (p = 0.02; beta coefficient 0.038) and beam-on time (p = 0.01; beta coefficient 0.71). Fractional polynomial multivariate regression suggested that a BED > 4600 Gy2.47 and a beam-on time > 70 min did not further increase clinical efficacy (binary outcome). Adverse radiation events (ARE) were defined as larger MR signature on 1-year follow-up MRI and were present in 7 out of 78 (8.9%) cases, receiving a mean BED of 4650 Gy2.47 (median 4650, range 4466–4894). They were clinically relevant with transient hemiparesis in 5 (6.4%) patients, all with BED values higher than 4500 Gy2.47. Tremor improvement was correlated with BED Gy2.47 after SRS for drug-resistant ET. An optimal BED value for tremor improvement was 4300–4500 Gy2.47. ARE appeared for a BED of more than 4500 Gy2.47. Such finding should be validated in larger cohorts.

Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Cognitive impairment in essential tremor assessed by the cerebellar cognitive affective syndrome scale.

Essential tremor (ET) is a movement disorder characterized by cerebellar neurodegenerative changes. ET is also associated with non-motor symptoms including cognitive impairment. The neuropsychologic profile of a patient with ET could relate to cerebellar cognitive affective syndrome (CCAS). This study aimed to assess the prevalence of cognitive impairment in patients with ET and identify whether the cognitive impairment in ET corresponds to a CCAS. Cognitive functions were evaluated with the CCAS-Scale (CCAS-S) in 20 patients with ET and 20 controls matched for age, sex, and level of education. The results of the CCAS-S were compared between patients and controls. The underlying determinant of CCAS inpatients with ET was identified through the correlation between the results of the CCAS-S and age at onset of symptoms, disease duration, and the Essential Tremor Rating Assessment Scale (TETRAS). On a group level, ET patients performed significantly worse than matched controls. In total, 13 individuals with ET had a definite CCAS (CCAS-S failed items ≥ 3). ASO and TETRAS scores significantly correlated with CCAS-S performances in ET patients. CCAS is highly prevalent in patients with ET which supports the cerebellar pathophysiology of associated cognitive impairment and supports a more systematic use of the CCAS-S to cognitively assessed patients with ET.

Medication Status and Related Factors in Essential Tremor Patients: A Cross-Sectional Study in China

Introduction: Essential tremor (ET) is one of the most common movement disorders. Oral drugs play a crucial role in treating ET, with various available options such as propranolol, primidone, and topiramate. However, the medication status and related factors among Chinese ET patients are unknown yet. Methods: This study used the baseline data from the National Survey of Essential Tremor Plus in China cohort. ET patients with information related to medication intake were included. Medication patients were defined as patients who were taking medication at the time of the survey. We further defined recommended medication users according to Chinese guideline recommendations and clinical knowledge. We used mean and standard deviation (SD), median and interquartile range (IQR), or frequencies and percentages when appropriate for descriptive analysis. We used multivariate logistic regression analyses to explore factors related to medication intake in all ET patients and in recommended medication users. Results: Of 1,153 included ET participants, 207 (18.0%) took medication. Arotinolol (115, 55.6%) and propranolol (63, 30.4%) were the top 2 used medicines. Patients with middle school education (odds ratio 0.57, 95% confidence interval 0.39–0.83), college or higher level education (0.46, 0.28–0.76), and late-onset ET (LO-ET) (0.38, 0.23–0.63) were less likely to take medication. Patients with intention tremor (1.90, 1.38–2.62), every 10-unit increase in age (1.10, 1.00–1.21), Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Part 1 (1.63, 1.37–1.93), and TETRAS Part 2 (1.81, 1.48–2.22) were more likely to take medication. Among 332 recommended medication users, only 104 (31.3%) took medicine. The associations of LO-ET (0.36, 0.17–0.75), intention tremor (2.27, 1.35–3.81), TETRAS Part 1 (1.52, 1.09–2.13), and TETRAS Part 2 (1.59, 1.15–2.20) with medication were similar to all ET patients. Conclusion: The proportion of medication intake is low among both all ET patients and recommended medication users. The top 2 commonly used medications among all ET patients are arotinolol and propranolol. Influencing factors of medication intake are different between all ET patients and recommended medication users. Clinicians are suggested to provide counseling and education on ET medication to promote medication intake.

510 Prospective, Multicenter, International Outcomes Study of Deep Brain Stimulation for Essential Tremor

INTRODUCTION: Essential Tremor (ET) treatment is focused on medical management of motor symptoms and includes pharmacotherapy and ventral intermediate nucleus (VIM) thalamotomy, which is being largely replaced by thalamic Deep Brain Stimulation (DBS) as the surgical treatment of choice. DBS of the VIM thalamus is recommended as a therapeutic option for appropriate subjects with ET (Elble RJ., et al. Expert Rev Neurother. 2018). METHODS: This is a prospective, on-label, multi-center, international DBS outcomes study conducted at up to 50 implanting centers. All participants are implanted with a multiple-source, constant-current directional DBS system (Vercise, Boston Scientific). Subjects are followed for up to 3-years post implantation where their overall improvement in quality of life and ET symptoms are evaluated. Clinical endpoints evaluated at baseline and follow-up timepoints include: The Essential Tremor Rating Assessment Scale (TETRAS), Quality of Life in Essential Tremor Questionnaire (QUEST), Fahn-Tolosa-Marin Rating Scale (TRS), and Global Impression of Change. Adverse events also collected. RESULTS: To date, 18-implanted subjects with a mean disease duration of 15.1 ± 14.6-years and a baseline QUEST Summary Index score of 35.0 ± 12.4. At 6-months post-DBS, a clinically significant improvement in quality of life (∆ = 19.5-point change in QUEST SI score) was reported. In addition, a mean 9-hours of tremor reduction was noted (14-hours at Baseline, 6.9-hours at 6-months) in a typical day at 6-months. All subjects (100%) reported mild disability, and no subject reported moderate or marked disability (89% at baseline) as reported by TRS at 6 months. CONCLUSIONS: This work represents the first comprehensive, large scale collection of real-world outcomes and evaluation of safety and effectiveness of a multiple-source, constant-current DBS system capable of providing directionality for use in treatment of Essential Tremor.

Chronic inflammatory demyelinating polyradiculoneuropathy-associated tremor: Phenotype and pathogenesis.

Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP-related tremor is more variable than other tremor disorders. Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross-sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t-test was used for comparisons between groups. Twenty-four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high-frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F-wave latency and median nerve sensory amplitude. TSI (2.3± 0.1) was significantly higher than essential tremor. Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat-to-beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.

Tremor, Gait, and Balance Disorders in Essential Tremor and the Efficacy of Atenolol

ABSTRACT Background: To assess gait and balance in patients with essential tremor (ET), which is the most common tremor disorder characterized by bilateral action tremor of the hands with possible involvement of further tremor locations and to test the efficacy of atenolol on tremor and gait and balance. Methods: In this prospective study, gait and balance were evaluated by static posturography in addition to International Cooperative Ataxia Rating Scale (ICARS) in 22 ET patients without any additional neurologic signs on examination. Tremor severity was assessed by The Essential Tremor Rating Assessment Scale (TETRAS). The efficacy of atenolol 100 mg/day both on tremor and gait and balance was investigated. Posturographic recordings were performed in gender, age-, and height-matched healthy volunteers who constituted the control group. Results: The mean center of gravity sway velocity of the ET patients recorded on firm and foam surfaces with eyes open and closed was not significantly different from the healthy controls but sway velocity on tandem stance was significantly increased (P = 0.032). Gait speed (P = 0.015) was decreased and step width was increased (P = 0.001). An improvement in TETRAS scores was recorded with atenolol treatment (P = 0.046). An improvement not reaching statistical significance was present in ICARS scores (P = 0.059). However, posturographic parameters did not change significantly (P &gt; 0.05). Conclusion: Increased sway velocity on tandem stance, decreased gait speed and increased step width are consistent with midline cerebellar dysfunction in ET patients with no obvious gait and balance deficits on clinical examination. Atenolol seems to be effective on tremor but does not cause a significant improvement in gait and balance deficits.

MRI-guided focused-ultrasound thalamotomy in essential tremor: Immediate and delayed changes in cortico-muscular coherence and cortico-cortical out-strength

ObjectiveDrug-resistant essential tremor (ET) can be treated by Magnetic-Resonance-guided Focused-Ultrasound (MRgFUS) targeted to thalamic ventralis-intermediate nucleus (ViM). We are presenting the results obtained in ET patients by evaluating the cortico-muscular coherence (CMC) and the out-strength among cortical areas. MethodsWe recorded MEG-EMG signals in 16 patients with predominant tremor on the right upper limb. The examination was performed the day before MRgFUS (T0) treatment, 24 hours (T1), and 3-months (T2) after lesioning the left ViM. Normalized CMC (nCMC) and cortico-cortical out-strength among cortical areas were assessed during isometric extension of the right hand. ResultsAccording to the Essential Tremor Rating Assessment Scale, 13 of 16 patients were considered responders. At T1, in the beta-band, nCMC increased in the left hemisphere, namely in the areas directly involved in motor functions. At T2, the nCMC in non-motor areas decreased and the out-strength from other examined cortical areas toward the left motor-area decreased. ConclusionsIn patients positively responding to MRgFUS, the CMC increased in the motor-area of the treated hemisphere immediately after the treatment, while the reorganization of CMC and cortico-cortical out-strength toward the cortical motor area occurred with a delay. SignificanceThe effective treatment with MRgFUS corresponds with a readjustment of the CMC and of the communication between cortical areas.

Locus coeruleus degeneration and cerebellar gray matter changes in essential tremor.

The pathophysiology of essential tremor (ET) is not fully understood, and studies suggest pathological changes mainly occur in the cerebellum and locus coeruleus (LC). Fifty-three ET patients, including 30 patients with head tremor (h-ET), 23 patients without head tremor (nh-ET), 71 age and education matched healthy controls (HCs) were enrolled. All participants underwent Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and T1 scans on a 3-Tesla MR system. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume. Significant difference of CNRLC was found between ET and HC groups. The CNRLC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNRLC in nh-ET was significantly lower than HCs (p = 0.016). Compared to HCs, h-ETs showed marked atrophy in the cerebellum: the vermis IV-V and lobule VI (GRF corrected, p < 0.05). A significant negative correlation was found between CNRLC and the vermis lobule IV-V in h-ETs (r = -0.651, p < 0.001). No significant correlation was found between CNRLC and TETRAS scores. The LC and the cerebellum might both involve in the pathophysiology of ET. LC evaluation using NM-MRI might be an effective tool for us to explore the pathophysiology of ET further.

Clinical features and reclassification of essential tremor with NOTCH2NLC GGC repeat expansions based on a long‐term follow‐up

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.

A Wearable In-home Tremor Assessment System via Virtual Reality Environment for the Activities in Daily Lives (ADLs).

Currently available diagnostic methods for tremor movements are mostly subjective measurements, and clinicians and researchers typically diagnose patients' symptoms with provocative maneuvers, and the inter-rater and intra-rater variabilities of those methods have been always reported. Even though various sensor-based quantitative approaches have been explored, most of the tools are limited to the tremor metrics (i.e., severity and frequency). A consistent environment that can provide a test setup to evaluate how their performance is affected by the tremor movement for activities of daily living would be needed for a smart tremor diagnosis. Therefore, we developed a virtual reality environment with a custom designed wearable sensor module to quantify tremor characteristics with performance-based assessment while they perform the activities of daily living, and correlated the performance to existing tremor scores (i.e., The Essential Tremor Rating Assessment Scale (TETRAS)). We evaluated this approach with five healthy participants (no tremor), and applied an artificial tremor using a vibration motor to mimic tremor movements as a pilot study. We analyzed three categorized tremor scenarios: resting, postural, and kinetic tremor tasks using six different tasks in virtual 3D space. All the artificial tremor was score as TETRAS=1, and we successfully analyzed the tremor metrics for different tasks by comparing them with TETRAS score, and verified the different tremor characteristics with the artificial tremor. Additionally, we analyzed the performance of 3D spiral drawing on the virtual reality track using "outside area" and "completion time" as the accuracy and speed of the performance. Clinical Relevance- This can be applied to quantify and track the tremor symptom at the patients' home, and ultimately this method can be synchronized with their current treatment parameters (i.e., dosage of medication, and parameters of the stimulation) to optimize/maximize the effect of treatment.

Fitts' Law Based Performance Metrics to Quantify Tremor in Individuals With Essential Tremor.

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 tasks-a 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 individual's 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.

Age and Sex Affect Essential Tremor (ET) Plus: Clinical Heterogeneity in ET Based on the National Survey in China.

The new term essential tremor (ET) plus was proposed in the 2018 tremor consensus criteria. The National Survey of Essential Tremor Plus in China, a large multicenter registry study, aimed to evaluate the clinical features of pure ET and ET plus and explore possible factors related to ET plus. All patients with ET underwent neurological examination and neuropsychological assessment at 17 clinical sites. The diagnosis was made according to the 2018 consensus criteria. Clinicodemographic characteristics were analyzed. A total of 1160 patients were included, including 546 patients with pure ET and 614 patients with ET plus. The proportion of females was significantly higher in the ET plus than that in the pure ET (P = 0.001). The age at onset (AAO) of pure ET showed a bimodal distribution, with peaks in the 2nd and 5th decades. However, the AAO of the ET plus group demonstrated a skewed distribution, with a single peak in the 6th decade. Female sex (OR=1.645, P<0.001), older age (OR=1.023, P<0.001), lower educational level (OR=0.934, P<0.001), head tremor (OR=1.457, P<0.001), and higher the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-II scores (OR=1.134, P<0.001) were significantly associated with ET plus. Old age and female sex may contribute to ET plus development. Pure ET showed a bimodal distribution for AAO, whereas ET plus showed a unimodal distribution. It remains unclear whether pure ET and ET plus are merely different stages of a single disease or represent distinct disease entities.

Brain Metabolic Changes with Longitudinal Transcutaneous Afferent Patterned Stimulation in Essential Tremor Subjects.

Background:Non-invasive peripheral nerve stimulation, also referred to as transcutaneous afferent patterned stimulation (TAPS), reduces hand tremor in essential tremor (ET) subjects. However, the mechanism of action of TAPS is unknown. Here, we investigated changes in brain metabolism over three months of TAPS use in ET subjects.Methods:This was an interventional, open label, single group study enrolling 5 ET subjects. They received 40 minutes of TAPS treatment twice daily for 90 days. Brain metabolic activity and tremor severity were measured using 18F-fluorodeoxyglucose (FDG) PET/CT, and the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), respectively, at baseline and after 90 days. Tremor power and frequency was measured before and after all TAPS sessions using an onboard three-axis accelerometer.Results:FDG PET/CT revealed areas of hypermetabolism in ipsilateral cerebellar hemisphere and hypometabolism in contralateral cerebellar hemisphere following 90 days of TAPS treatment, compared to day one (uncorrected p value <0.05). Paired pre-post kinematic measurements over 90 days showed significantly decreased tremor power (p < 0.0001) but no change in tremor frequency. The TETRAS score on day 1 decreased from 6.5 ± 2.5 to 4.1 ± 1.8 following TAPS (p = 0.05). The pre-post TETRAS scores on day 90: 4.9 ± 1.5 and 4.1± 1 were lower than pre-TAPS TETRAS score on day 1 (p = 0.14 and 0.05, respectively).Conclusions:Our results suggest that longitudinal TAPS of the median and radial nerves modulates brain metabolism in areas instrumental to motor coordination and implicated in ET. Clinically, TAPS reduced tremor power, but had no effect on tremor frequency. This study paves the way for comprehensive studies in larger cohorts to further elucidate the mechanism of TAPS.Highlights:Non-invasive peripheral nerve stimulation, also referred to as transcutaneous afferent patterned stimulation (TAPS), reduces hand tremor in essential tremor subjects. Longitudinal TAPS therapy alters cerebellar metabolism, which can be a cause or consequence of tremor reduction. Cerebellar-premotor region connectivity may play a role in the anti-tremor effects of TAPS.