A Randomized Phase 2 KINETIC Trial Evaluating SAGE-324/BIIB124 in Individuals with Essential Tremor.

BACKGROUND: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABAA receptors. OBJECTIVE: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET). METHODS: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo. RESULTS: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder. CONCLUSION: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Movement Disorder Specialists Survey Regarding Use of Telemedicine During the COVID-19 Pandemic.

Aim: To assess the overall satisfaction level of movement disorder specialists using a virtual platform during the COVID-19 pandemic. Methods: This was a multicenter cross-sectional survey for a 6-month period during the beginning of the COVID-19 pandemic. Movement disorder specialists, who utilized telehealth visits from March 2020 to August 2020, were included. The study surveys, including provider's satisfaction with the care that they were able to provide and visit quality, were completed by the provider after each visit. Results: A total of 206 visits, provided by movement disorder specialists, were analyzed. Zoom was the most popular platform used for remote visits (70, 34%). A backup platform was not needed in the majority of movement disorder visits (171, 83%). The majority of physicians were very satisfied or satisfied with the care provided (72.9%) and visit quality (61%). Conclusions: The satisfaction level of specialists using telemedicine during COVID-19 was high despite having encounters with elderly patients with cognitive impairment or lacking advanced skills with technology.

A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Reliability and Validity of Pupillary Response During Dual-Task Balance in Parkinson Disease.

OBJECTIVE: To investigate the reliability and validity of pupillary response during dual-task balance conditions in individuals with Parkinson disease (PD). DESIGN: Cross-sectional study. SETTING: University of Kansas Medical Center Parkinson's Disease and Movement Disorder Center. PARTICIPANTS: Participants (N=68) included individuals with PD (n=33) and healthy controls (n=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pupillary response was the main outcome measure that was measured during the following conditions: single-task balance eyes open, single-task balance eyes occluded, dual-task eyes open, and dual-task eyes occluded. After each condition, the National Aeronautics and Space Administration-Task Load Index (NASA-TLX) was administered to assess self-reported cognitive workload. To examine the test-retest reliability of the pupillary response, the conditions were administered twice for each individual within 2 hours. Intraclass correlation coefficients (ICC) were used to analyze the test-retest reliability of pupillary response in each condition for both groups. Pearson's r correlation was used to assess the convergent validity of pupillary response against the NASA-TLX. RESULTS: The test-retest reliability was excellent for both groups in almost all conditions (ICC>0.75). There were no correlations between pupillary response and the NASA-TLX. However, increased mental demand (a subitem of the NASA-TLX) significantly correlated with increased pupillary response in individuals with PD (r=0.38; P=.03). CONCLUSIONS: Pupillary response showed excellent test-retest reliability and validity during dual-task balance for individuals with PD and healthy controls. Overall, these results suggest that pupillary response represents a stable index of cognitive workload during dual-task balance in individuals with PD.

Cognitive workload during verbal abstract reasoning in Parkinson's disease: a pilot study.

BACKGROUND: Pupillary response reflects cognitive workload during processing speed, working memory, and arithmetic tasks in Parkinson's disease (PD). Abstract reasoning, a higher-order cognitive function that relates different objects, events, or thoughts in a similar manner, may also be compromised in PD. The aim of this study was to compare pupillary response as a measure of cognitive workload while completing a verbal abstract reasoning test between patients with PD and age-matched controls. METHODS: Nineteen non-demented individuals with PD (66.6 ± 8.9 years) and 10 healthy controls (65.3 ± 7.3 years) were recruited. A remote eye tracker recorded the pupillary response at 60 Hz, while the participants were performing the Similarities test of Wechsler Adult Intelligence Scale-IV. Outcome measures included pupillary response, evaluated by the Index of Cognitive Activity (ICA), and behavioral responses of the Similarities test. RESULTS: The PD group (scaled scores = 8.9 ± 2.2) did not show impairment in behavioral performance on Similarities test compared with healthy controls (scaled scores = 8.8 ± 2.3; p = .91). However, the PD group (ICA = .32 ± .09) demonstrated significantly greater cognitive workload during the Similarities test compared to controls (ICA = .24 ± .08; p = .03). CONCLUSIONS: Non-demented individuals with PD exerted greater cognitive workload to complete a verbal abstract reasoning task despite similar behavioral performance compared to healthy controls. Clinical utilities of pupillary response to detect and monitor early impairment in higher-order executive function will be the subject of further study in the PD population.

Classification of Parkinson's disease and essential tremor based on balance and gait characteristics from wearable motion sensors via machine learning techniques: a data-driven approach.

BACKGROUND: Parkinson's disease (PD) and essential tremor (ET) are movement disorders that can have similar clinical characteristics including tremor and gait difficulty. These disorders can be misdiagnosed leading to delay in appropriate treatment. The aim of the study was to determine whether balance and gait variables obtained with wearable inertial motion sensors can be utilized to differentiate between PD and ET using machine learning. Additionally, we compared classification performances of several machine learning models. METHODS: This retrospective study included balance and gait variables collected during the instrumented stand and walk test from people with PD (n = 524) and with ET (n = 43). Performance of several machine learning techniques including neural networks, support vector machine, k-nearest neighbor, decision tree, random forest, and gradient boosting, were compared with a dummy model or logistic regression using F1-scores. RESULTS: Machine learning models classified PD and ET based on balance and gait characteristics better than the dummy model (F1-score = 0.48) or logistic regression (F1-score = 0.53). The highest F1-score was 0.61 of neural network, followed by 0.59 of gradient boosting, 0.56 of random forest, 0.55 of support vector machine, 0.53 of decision tree, and 0.49 of k-nearest neighbor. CONCLUSIONS: This study demonstrated the utility of machine learning models to classify different movement disorders based on balance and gait characteristics collected from wearable sensors. Future studies using a well-balanced data set are needed to confirm the potential clinical utility of machine learning models to discern between PD and ET.

Khodakarami, H., et al., Prediction of the Levodopa Challenge Test in Parkinson's Disease Using Data from a Wrist-Worn Sensor. Sensors 2019, 19, 5153.

The authors wish to make the following erratum to this paper [...].

MDS evidence-based review of treatments for essential tremor.

BACKGROUND: Essential tremor is one of the most prevalent movement disorders. Many treatments for essential tremor have been reported in clinical practice, but it is uncertain which options have the most robust evidence. The International Parkinson and Movement Disorder Society commissioned a task force on tremor to review clinical studies of treatments for essential tremor. OBJECTIVES: To conduct an evidence-based review of current pharmacological and surgical treatments for essential tremor, using standardized criteria defined a priori by the International Parkinson and Movement Disorder Society. METHODS: We followed the recommendations of the International Parkinson and Movement Disorder Society Evidence Based Medicine Committee. RESULTS: Sixty-four studies of pharmacological and surgical interventions were included in the review. Propranolol and primidone were classified as clinically useful, similar to Topiramate, but only for doses higher than 200 mg/day. Alprazolam and botulinum toxin type A were classified as possibly useful. Unilateral Ventralis intermedius thalamic DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy were considered possibly useful. All the above recommendations were made for limb tremor in essential tremor. There was insufficient evidence for voice and head tremor as well as for the remaining interventions. CONCLUSION: Propranolol, primidone, and topiramate (>200 mg/day) are the pharmacological interventions in which the data reviewed robustly supported efficacy. Their safety profile and patient preference may guide the prioritization of these interventions in clinical practice. MRI-guided focused ultrasound thalamotomy was, for the first time, assessed and was considered to be possibly useful. There is a need to improve study design in essential tremor and overcome the limitation of small sample sizes, cross-over studies, short-term follow-up studies, and use of nonvalidated clinical scales. © 2019 International Parkinson and Movement Disorder Society.

Prediction of the Levodopa Challenge Test in Parkinson's Disease Using Data from a Wrist-Worn Sensor.

The response to levodopa (LR) is important for managing Parkinson's Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson's Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies.

An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor.

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

Improving Communication Between Health Care Providers, Families, and Children with Autism Spectrum Disorder: The Linked Program.

PURPOSE: To provide easy-to-use tools and skills to decrease stress in the perioperative period for families and their children with autism spectrum disorder (ASD). DESIGN: Evidence-based practice project. METHODS: After literature review, a perioperative assessment and management program was developed to guide and individualize the care of pediatric patients with ASD. The program was piloted on a convenience sample of 31 pediatric patients diagnosed with ASD. FINDINGS: Most patients were back to their baseline behavior according to their families or caregivers within 120 minutes of the procedure (n = 29, 93.5%), with two needing more than 24 hours (6.5%). CONCLUSIONS: The Linked Program has enabled staff to be effective in meeting the perioperative needs of families and their children with ASD. Families have expressed great appreciation that they are able to share their knowledge of what their children need.

"Mild" hyperphenylalaninemia? A case series of seven treated patients following newborn screening.

Hyperphenylalaninemia (HPA) is a disorder diagnosed only incidentally by newborn screening, a by-product of screening for classic phenylketonuria (PKU) which, if untreated, causes irreversible neurologic sequelae. In contrast, HPA is thought to have a benign phenotype because phenylalanine (Phe) levels are insufficiently elevated to cause neurological damage, obviating the need for rigorous dietary protein restriction. Phenylalanine below 360µmol/L is generally considered safe, thus this threshold is both the upper therapeutic range for treated PKU and the highest Phe expected to be possible for most individuals with HPA. However, the published literature and even expert consensus provides limited guidance on long-term follow-up of Phe after this diagnosis. In particular, how frequently and vigilantly to monitor levels to evaluate for subsequent elevations above the 'safe' range. Upon retrospective review we identified 22 patients with HPA, ascertained via newborn screen and currently aged two to thirty-six years. All patients had an initial untreated Phe between 90µmol/L (our upper limit of normal) and 360µmol/L. Of these patients, seven subsequently demonstrated either fluctuating or sustained increases in Phe above 360µmol/L. Five have been treated successfully with sapropterin therapy without dietary intervention and two have been treated with mild to moderate protein restriction. Our experience demonstrates successful treatment of these children without the traditional highly restrictive PKU diet. However, a better understanding of this disorder is necessary to more safely and appropriately identify, monitor and manage children with HPA. SYNOPSIS: One clinics' experience with diagnostic differences in a population of Hyperphenylalaninemia patients that required treatment.

Outpatient titration of carbidopa/levodopa enteral suspension (Duopa).

Carbidopa/levodopa enteral suspension (CLES; Duopa) is a suspension or gel formulation of carbidopa/levodopa that is approved by the USA Food and Drug Administration for the treatment of advanced Parkinson's disease patients with motor fluctuations. CLES is delivered at a constant rate continuously throughout the day into the jejunum through an infusion pump via a PEG-J tube implanted surgically. The efficacy of CLES was established in the USA based on a randomized, double-blind, double-dummy, active controlled, parallel group and 12-week study, in which mean daily OFF time was reduced by 4.0 h, compared to 1.9 h with oral immediate release carbidopa/levodopa. The CLES hardware consists of a cassette containing the drug, a pump to deliver the drug and tubing to connect the PEG-J to the pump. It is critical to understand the appropriate conversion of the carbidopa/levodopa daily dosages to the CLES dosage and how to program the pump and titrate CLES to achieve the most effective dose. We describe one methodology for patient selection, outpatient titration and pump programming.

Transducer-based evaluation of tremor.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

MDS-UPDRS to assess non-motor symptoms after STN DBS for Parkinson's disease.

OBJECTIVE: To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). METHODS: Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. RESULTS: One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. CONCLUSIONS: This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.

The characterization of a base-width neutral step as the first step for balance recovery in moderate Parkinson's disease.

PURPOSE: The purpose of this study is to characterize the base-width neutral step (BNS) as the first step in a compensatory step response in persons with moderate Parkinson's disease (PD), and its effect on balance recovery. MATERIALS AND METHODS: Ten PD and 10 healthy controls (HCs) responded to a posterior waist pull. A BNS was defined if the first step was less than 50 mm. The length, height, duration and velocity of the BNS and its effect on balance recovery time and center of mass location at recovery were compared to the first step within other stepping strategies (single step (SS), multiple step (MS)). A linear mixed model was used to compare across strategies. RESULTS: Six of ten persons with PD compared to zero HC used a BNS. The BNS was shorter in length and duration compared to MS responses in HC, and shorter in duration compared to MS responses in PD. The BNS was slower in velocity compared to every other strategy. BNS use resulted in a longer recovery time compared to all strategies in HC and SS responses in PD, and trended toward a longer recovery time compared to MS responses in PD. CONCLUSIONS: The BNS as the first step in a MS response may be an unreported strategy for compensatory stepping in PD. This study suggests that the cost of utilizing the BNS may be a longer time for recovery, but further work is necessary to understand the progression of the BNS as PD severity increases.

Validation of the QUEST for German-speaking countries.

OBJECTIVE: To explore the clinimetric attributes of the German version of the quality of life in essential tremor (ET) questionnaire (QUEST) as a tremor-specific measure of quality of life. METHODS: This was an observational, cross-sectional study. The QUEST German version was obtained by translation-back translation procedure. ET cases were diagnosed according to the tremor investigation group criteria. Assessments included Archimedes spirals rating, EQ-5D, Beck Depression Inventory (BDI-II) and QUEST German version. Missing data were imputed for those cases in which the loss of data for one domain of the QUEST was <30%. RESULTS: Ninety three patients out of 138 (67.4%) with definite or probable ET had complete QUEST data after 43 item imputations and they constituted the sample for this study. The QUEST summary index (QSI) displayed no floor or ceiling effects. QUEST internal consistency (Cronbach's alpha) ranged between 0.50 and 0.89. Item-total domain correlations ranged from 0.26 to 0.82 and the item homogeneity indexes were satisfactory (range: 0.28-0.60). The QSI correlated weakly with the EQ-5D (rS=0.20) and moderately with the BDI-II (rS = 0.31) and the QUEST self-evaluation of tremor severity (rS = 0.44). CONCLUSIONS: The QUEST German version has, despite recognized data quality problems, satisfactory acceptability and internal consistency as a whole. The correlation analysis showed that tremor in the head, voice and right hand was moderately associated with quality of life.

Paradoxical effect of dopamine medication on cognition in Parkinson's disease: relationship to side of motor onset.

Parkinson's disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n = 36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n = 42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing.

Qigong exercise may improve sleep quality and gait performance in Parkinson's disease: a pilot study.

PURPOSE: Parkinson's disease (PD) involves a variety of motor and non-motor symptoms, several of which, including gait abnormalities and sleep disorders, are generally not adequately managed with standard therapy. This study aimed to determine the impact of Qigong as a potential complementary therapy in the management of gait and sleep-related symptoms in PD. METHODS: Seven subjects (aged 66.9 ± 8.1 years) with PD participated in a six-week Qigong exercise intervention. Pre- and post-intervention testing was performed to assess sleep quality, cognitive function, fatigue, quality of life, gait performance (stride time, stride length, double support time, and velocity), and gait variability (stride time and length variability). RESULTS: Following Qigong, subjects showed improvement in some aspects of sleep quality. Fatigue remained unchanged. Gait function was improved by a significant reduction of stride time and a slight increase in stride length. Together these changes resulted in significant improvements to gait velocity. In addition, time spent in double limb support was reduced following the intervention. Overall gait variability improved significantly, particularly in the reduction of stride time variability. CONCLUSIONS: These results suggest that Qigong may provide benefit for gait performance and sleep quality in PD patients. However, larger, controlled studies are required to determine the immediate and long-term benefits of Qigong for PD sleep and gait problems as well as the impact on other aspects of the disease.

Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What's in the Pipeline.

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.