Substantiating the Short Burst Duration in Cortical Myoclonus.

BACKGROUND: Myoclonus is characterized by involuntary, shock-like movements, of which cortical (CM) and non-cortical myoclonus (NCM) are most common. Electrophysiology can help differentiate between these subtypes; however, the diagnostic value of several features is largely unknown. OBJECTIVE: This study aims to determine the diagnostic value of the burst duration in distinguishing CM and NCM. METHODS: We manually identified the burst duration of 8 patients with CM, confirmed by electromyography-electroencephalography registration or somatosensory-evoked potentials, and 19 patients with NCM, suspected due to a myoclonus-dystonia phenotype (MYC/DYT-SGCE positive and negative). RESULTS: The sensitivity and specificity were calculated to assess the diagnostic value. The burst duration of CM (31.1 ms) was significantly shorter than that of NCM (56.7 ms), with a sensitivity of 100% and a specificity of 89.5% at a threshold of 45.0 ms. A minimum of 10 randomly selected bursts were sufficient for reliable diagnostic accuracy. CONCLUSION: The burst duration seems a valuable supportive diagnostic criterion for distinguishing CM and NCM. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Next move in movement disorders: neuroimaging protocols for hyperkinetic movement disorders.

Introduction: The Next Move in Movement Disorders (NEMO) study is an initiative aimed at advancing our understanding and the classification of hyperkinetic movement disorders, including tremor, myoclonus, dystonia, and myoclonus-dystonia. The study has two main objectives: (a) to develop a computer-aided tool for precise and consistent classification of these movement disorder phenotypes, and (b) to deepen our understanding of brain pathophysiology through advanced neuroimaging techniques. This protocol review details the neuroimaging data acquisition and preprocessing procedures employed by the NEMO team to achieve these goals. Methods and analysis: To meet the study's objectives, NEMO utilizes multiple imaging techniques, including T1-weighted structural MRI, resting-state fMRI, motor task fMRI, and 18F-FDG PET scans. We will outline our efforts over the past 4 years to enhance the quality of our collected data, and address challenges such as head movements during image acquisition, choosing acquisition parameters and constructing data preprocessing pipelines. This study is the first to employ these neuroimaging modalities in a standardized approach contributing to more uniformity in the analyses of future studies comparing these patient groups. The data collected will contribute to the development of a machine learning-based classification tool and improve our understanding of disorder-specific neurobiological factors. Ethics and dissemination: Ethical approval has been obtained from the relevant local ethics committee. The NEMO study is designed to pioneer the application of machine learning of movement disorders. We expect to publish articles in multiple related fields of research and patients will be informed of important results via patient associations and press releases.

Testing for Alcohol Responsiveness in Familial Essential Tremor.

Background: Essential tremor (ET) is the most common movement disorder in adults and is considered to be highly heritable. A reduction of the tremor amplitude after alcohol consumption is reported in approximately half of the patients. In this study, we describe the alcohol response in our familial ET cohort by employing an alcohol responsivity test designed by Knudsen et al. outside its original research group for the first time. Methods: We recruited families with at least three trembling family members and confirmed ET diagnoses. During the in-hospital alcohol responsivity test, tremor was measured using Archimedes spirals before alcohol consumption (T0), one hour after alcohol intake (T1), and the next morning (T2). The spirals were rated by two independent raters using the Bain Findley scale. The average of these two scores was calculated as the Archimedes Spiral Rating (ASR) for each time point. Results: Twenty-four confirmed ET patients were included for analysis. The median ASR at T0 (5.0) and T2 (4.75) were significantly higher than the median ASR at T1 (3.25) (both p < 0.001). In 67% of patients, a difference in ASR between T0 and T1 (dASR) ≥ 2 pointed towards an improvement of tremor after consuming alcohol. Discussion: We confirmed that the alcohol responsiveness test of Knudsen et al. is useful in determining objective alcohol responsivity. We established a significantly reduced ASR after alcohol consumption in 67% of familial ET patients in our cohort. In the future, a larger population is needed to establish whether familial aggregation of alcohol responsivity occurs in essential tremor patients. Highlights: The test designed by Knudsen et al. effectively established objective alcohol responsiveness outside its original research group.We found an objective alcohol response in 67% of our familial ET cohort.Subjective VAS scores were significantly lower after alcohol consumption.There was no correlation between the objective and subjective alcohol responsiveness.Familial aggregation of alcohol responsiveness in ET should be studied in a larger cohort.

The natural history of progressive myoclonus ataxia.

Progressive myoclonus ataxia (PMA) is a rare clinical syndrome characterized by the presence of progressive myoclonus and ataxia, and can be accompanied by mild cognitive impairment and infrequent epileptic seizures. This is the first study to describe the natural history of PMA and identify clinical, electrophysiological, and genetic features explaining the variability in disease progression. A Dutch cohort of consecutive patients meeting the criteria of the refined definition of PMA was included. The current phenotype was assessed during in-person consultation by movement disorders experts, and retrospective data was collected to describe disease presentation and progression, including brain imaging and therapy efficacy. Extensive genetic and electrophysiological tests were performed. The presence of cortical hyperexcitability was determined, by either the identification of a cortical correlate of myoclonic jerks with simultaneous electromyography-electroencephalography or a giant somatosensory evoked potential. We included 34 patients with PMA with a median disease duration of 15 years and a clear progressive course in most patients (76%). A molecular etiology was identified in 82% patients: ATM, CAMTA1, DHDDS, EBF3, GOSR2, ITPR1, KCNC3, NUS1, POLR1A, PRKCG, SEMA6B, SPTBN2, TPP1, ZMYND11, and a 12p13.32 deletion. The natural history is a rather homogenous onset of ataxia in the first two years of life followed by myoclonus in the first 5 years of life. Main accompanying neurological dysfunctions included cognitive impairment (62%), epilepsy (38%), autism spectrum disorder (27%), and behavioral problems (18%). Disease progression showed large variability ranging from an epilepsy free PMA phenotype (62%) to evolution towards a progressive myoclonus epilepsy (PME) phenotype (18%): the existence of a PMA-PME spectrum. Cortical hyperexcitability could be tested in 17 patients, and was present in 11 patients and supported cortical myoclonus. Interestingly, post-hoc analysis showed that an absence of cortical hyperexcitability, suggesting non-cortical myoclonus, was associated with the PMA-end of the spectrum with no epilepsy and milder myoclonus, independent of disease duration. An association between the underlying genetic defects and progression on the PMA-PME spectrum was observed. By describing the natural history of the largest cohort of published patients with PMA so far, we see a homogeneous onset with variable disease progression, in which phenotypic evolution to PME occurs in the minority. Genetic and electrophysiological features may be of prognostic value, especially the determination of cortical hyperexcitability. Furthermore, the identification of cortical and non-cortical myoclonus in PMA helps us gain insight in the underlying pathophysiology of myoclonus.

Stigma in functional neurological disorder (FND) - A systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate stigma and Functional Neurological Disorder (FND) regarding: 1) prevalence and associated factors, 2) the nature and context of stigma in FND, and 3) stigma-reduction interventions. METHODS: We searched four relevant databases from inception to December 2023, using search terms relevant to FND and stigma themes. We employed the method of synthesis by "aggregation and configuration" to synthesise and analyse the data into emergent themes. RESULTS: We found 127 studies, spanning 148 countries, involving 18,886 participants. Of these, 4889 were patients, 13,123 were healthcare professionals, and 526 were caregivers. Quantitatively, stigma has been mainly studied in patients with functional seizures, and was higher than patients with epilepsy in three studies. Stigma experienced by patients is associated with poorer quality of life and caregiver burden. We found 10 themes and 29 subthemes revealing stigma as a systemic process, with intrapersonal, interpersonal and structural aspects. Few studies examined the perspective of caregivers, the public or online community. We identified six anti-stigma interventions. CONCLUSION: Stigma in FND is a layered process, and affects patient quality of life and provision of care. Stigma needs to be addressed from the top structures, at governmental level, so that appropriate care pathways can be created, giving patients with FND parity of esteem with other medical conditions.

Conventional and novel anti-seizure medications reveal a particular role for GABAA in a North Sea progressive myoclonus Epilepsy Drosophila model.

OBJECTIVE: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model. METHOD: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls. RESULTS: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well. CONCLUSION: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABAA receptors. This suggests that GABAA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.

Negative Myoclonus: Neurophysiological Study and Clinical Impact in Progressive Myoclonus Ataxia.

INTRODUCTION: Negative myoclonus (NM) is an involuntary movement caused by a sudden interruption of muscular activity, resulting in gait problems and falls. OBJECTIVE: To establish frequency, clinical impact, and neurophysiology of NM in progressive myoclonus ataxia (PMA) patients. METHODS: Clinical, neurophysiological, and genetic data of 14 PMA individuals from University Medical Centre Groningen (UMCG) Expertise Center Movement Disorder Groningen were retrospectively collected. Neurophysiological examination included video-electromyography-accelerometry assessment in all patients and electroencephalography (EEG) examination in 13 individuals. Jerk-locked (or silent period-locked) back-averaging and cortico-muscular coherence (CMC) analysis aided the classification of myoclonus. RESULTS: NM was present in 6 (NM+) and absent in 8 (NM-) PMA patients. NM+ individuals have more frequent falls (100% vs. 37.5%) and higher scores on the Gross Motor Function Classification System (GMFCS) (4.3 ±0.74 vs. 2.5 ±1.2) than NM- individuals. Genetic background of NM+ included GOSR2 and SEMA6B, while that of NM- included ATM, KCNC3, NUS1, STPBN2, and GOSR2. NM was frequently preceded by positive myoclonus (PM) and silent-period length was between 88 and 194 ms. EEG epileptiform discharges were associated with NM in 2 cases. PM was classified as cortical in 5 NM+ and 2 NM- through EEG inspection, jerk-locked back-averaging, or CMC analysis. DISCUSSION: Neurophysiological examination is crucial for detecting NM that could be missed on clinical examination due to a preceding PM. Evidence points to a cortical origin of NM, an association with more severe motor phenotype, and suggests the presence of genetic disorders causing either a PMA or progressive myoclonus epilepsy, rather than pure PMA phenotype. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Efficacy of Hypnosis and Catalepsy Induction in Functional Neurological Disorders.

BACKGROUND: Patients with Functional Neurological Disorder (FND) experience complex patterns of motor and/or sensory symptoms. Treatment studies of psychological interventions are promising but limited. OBJECTIVES: The aim of the current pilot study is to investigate the effect of treatment consisting of a combination of hypnosis and catalepsy induction on FND symptom severity. METHODS: A within-subject waiting list-control design was used with 46 patients diagnosed with FND. The treatment consisted of 10 sessions. The primary outcome measure was FND symptom severity (The Psychogenic Movement Disorder Rating Scale; PMDRS). The secondary outcome measures were psychological distress and quality of life. RESULTS: The repeated measures (RM) ANOVA for the PMDRS as outcome measure revealed a significant effect for time with a large effect size (η2 = 0.679). Pairwise comparisons indicated that the effect of time in the treatment period was significant for the measure of FND symptom severity, whereas the waiting list period was not. The effect remained stable even at 8 weeks post treatment. As for the additional measurement, general psychological distress and quality of life, no statistically significant differences between individual time points were found. CONCLUSIONS: This pilot study showed that eight sessions of treatment consisting of a combination of hypnosis and catalepsy induction was effective in reducing FND symptom severity. Some explanations and limitations are provided in the paper as well as several avenues of future research.

Moving on with (social) cognition in idiopathic cervical dystonia.

OBJECTIVE: Cervical dystonia (CD) is a movement disorder characterized by involuntary muscle contractions causing sustained twisting movements and abnormal postures of the neck and head. Assumed affected neuronal regions are the cortico-striatal-thalamo-cortical circuits, which are also involved in cognitive functioning. Indeed, impairments in different cognitive domains have been found in CD patients. However, to date studies have only investigated a limited range of cognitive functions within the same sample. In particular, social cognition (SC) is often missing from study designs. Hence, we aimed to evaluate a broad range of cognitive functions including SC in CD patients. METHOD: In the present study 20 idiopathic CD patients and 40 age-, gender-, and IQ-matched healthy controls (HCs) were assessed with tests for non-SC (verbal memory, psychomotor speed, and executive functions) as well as for SC (emotion recognition, Theory of Mind (ToM), and empathy). RESULTS: CD patients scored on average significantly lower than HC on tests for non-SC, but did not show impairments on any of the tests for SC. CONCLUSIONS: The current study showed impairments in non-SC in CD, but intact social cognitive functions. These results underline the importance of recognizing non-motor symptoms in idiopathic CD patients, but emphasize a focus on identifying strengths and weaknesses in cognitive functioning as these influence daily life activities.

A Critical Appraisal of the Whack-a-Mole and Swivel Chair Signs in the Diagnosis of Functional Movement Disorders.

BACKGROUND: The demonstration of positive signs during neurological examination is a cornerstone of the diagnosis of functional movement disorders, however, the available data supporting the diagnostic value of some of these signs is limited. OBJECTIVES: To determine the diagnostic value (sensitivity and specificity) of the "whack-a-mole" (WAM) and "swivel chair" (SC) tests in patients with functional movement disorders (FMD). METHODS: We enrolled patients with functional and organic movements in the WAM test if they exhibited tremor, dystonia, myoclonus, chorea, or tics. For the SC test, patients with a gait disorder as their primary impairment were recruited. Two blinded movement disorder specialists rated the presence of these signs in edited videos. RESULTS: Inclusion criteria were met by 42 patients with FMD and 65 patients with organic movement disorders. Both tests demonstrated high specificity (means, 78% and 96%), but their sensitivity was low (means, 52% and 37%). Interobserver agreement for the WAM sign was 0.77 in the FMD group, against 0.28 in patients with organic movement disorders, whereas Movement Disorders Clinical Practice for Review Only for the SC sign was 0.69 in both groups. CONCLUSIONS: The present study indicates that physicians must be cautious in the application and interpretation of these clinical signs in the diagnosis of functional movement disorders, and they should be carefully considered and used as necessary.

Deep brain stimulation in dystonia: The added value of neuropsychological assessments.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is a recognized treatment for medication-refractory dystonia. Problems in executive functions and social cognition can be part of dystonia phenotypes. The impact of pallidal DBS on cognition appears limited, but not all cognitive domains have been investigated yet. In the present study, we compare cognition before and after GPi DBS. Seventeen patients with dystonia of various aetiology completed pre- and post-DBS assessment (mean age 51 years; range 20-70 years). Neuropsychological assessment covered intelligence, verbal memory, attention and processing speed, executive functioning, social cognition, language and a depression questionnaire. Pre-DBS scores were compared with a healthy control group matched for age, gender and education, or with normative data. Patients were of average intelligence but performed significantly poorer than healthy peers on tests for planning and for information processing speed. Otherwise, they were cognitively unimpaired, including social cognition. DBS did not change the baseline neuropsychological scores. We confirmed previous reports of executive dysfunctions in adult dystonia patients with no significant influence of DBS on cognitive functioning in these patients. Pre-DBS neuropsychological assessments appear useful as they support clinicians in counselling their patients. Decisions about post-DBS neuropsychological evaluations should be made on a case-by-case basis.

The Muddle of Myoclonus: Many Guises, 2 Disciplines, Consensus Needed.

Myoclonus is often approached in different ways by epileptologists and movement disorder specialists, leading to confusion in the literature. Multiplicity and inconsistency over the past 2 centuries resulted in a lack of precision and ambiguity of the terminology. We show that this is a current problem in which one phenomenon has been described with many terms and vice versa. Of more importance, we discuss the conceptualization of myoclonus from perspectives of both fields and focus on the borderland that exists, especially in the spectrum of cortical and epileptic myoclonus. By giving 2 examples, we illustrate the conundrum: the spectrum of progressive myoclonus epilepsies and progressive myoclonic ataxias and "cortical tremor" observed in familial cortical myoclonic tremor with epilepsy or familial adult myoclonic epilepsy. We attempt to facilitate to bridge these subspecialties and form the base for a uniform understanding to take this issue forward toward future classifications, discussions, and scientific research.

New developments in diagnostics and treatment of adult-onset focal dystonia.

PURPOSE OF REVIEW: The aim of this review is to showcase the recent developments in the field of diagnosis and treatment of adult-onset focal dystonia. RECENT FINDINGS: Accurate phenotyping of focal dystonia is essential in the process of finding an underlying cause, including acquired, genetic, and idiopathic causes. Motor symptoms as well as the associated nonmotor symptoms and their detrimental impact on quality of life have received increased interest over the last years. The diagnostic process is complicated by the steadily increasing numbers of newly discovered genes associated with dystonia. Recent efforts have been aimed at further developing recommendations and algorithms to aid in diagnosis and in navigating the use of diagnostic tools. In terms of treatment, research on DBS is advancing towards a better understanding of the most effective stimulation locations within the globus pallidus. Moreover, with the introduction of the LFP-recording devices, the search continues for an accurate electrophysiological biomarker for dystonia. SUMMARY: Accurate phenotyping and (sub)classification of patients with dystonia is important for improving diagnosis, subsequent treatment effect and population-based study outcomes in research. Medical practitioners should be attentive to the presence of nonmotor symptoms in dystonia.

Early onset ataxia with comorbid myoclonus and epilepsy: A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement.

OBJECTIVES: Early onset ataxia (EOA) concerns a heterogeneous disease group, often presenting with other comorbid phenotypes such as myoclonus and epilepsy. Due to genetic and phenotypic heterogeneity, it can be difficult to identify the underlying gene defect from the clinical symptoms. The pathological mechanisms underlying comorbid EOA phenotypes remain largely unknown. The aim of this study is to investigate the key pathological mechanisms in EOA with myoclonus and/or epilepsy. METHODS: For 154 EOA-genes we investigated (1) the associated phenotype (2) reported anatomical neuroimaging abnormalities, and (3) functionally enriched biological pathways through in silico analysis. We assessed the validity of our in silico results by outcome comparison to a clinical EOA-cohort (80 patients, 31 genes). RESULTS: EOA associated gene mutations cause a spectrum of disorders, including myoclonic and epileptic phenotypes. Cerebellar imaging abnormalities were observed in 73-86% (cohort and in silico respectively) of EOA-genes independently of phenotypic comorbidity. EOA phenotypes with comorbid myoclonus and myoclonus/epilepsy were specifically associated with abnormalities in the cerebello-thalamo-cortical network. EOA, myoclonus and epilepsy genes shared enriched pathways involved in neurotransmission and neurodevelopment both in the in silico and clinical genes. EOA gene subgroups with myoclonus and epilepsy showed specific enrichment for lysosomal and lipid processes. CONCLUSIONS: The investigated EOA phenotypes revealed predominantly cerebellar abnormalities, with thalamo-cortical abnormalities in the mixed phenotypes, suggesting anatomical network involvement in EOA pathogenesis. The studied phenotypes exhibit a shared biomolecular pathogenesis, with some specific phenotype-dependent pathways. Mutations in EOA, epilepsy and myoclonus associated genes can all cause heterogeneous ataxia phenotypes, which supports exome sequencing with a movement disorder panel over conventional single gene panel testing in the clinical setting.

Muscular and kinematic features in speed skaters indicate a task-specific dystonia.

OBJECTIVE: Skater's cramp is a movement disorder in speed skaters. We investigated whether affected skaters matched the disease profile of task-specific dystonia, specifically whether there was evidence of maladaptive muscle activity occurring simultaneously with aberrant movements (jerking). We further examined different skating intensities, positing no change would be more indicative of task-specific dystonia. METHODS: We analyzed video, kinematic and muscle activity in 14 affected skaters. We measured the angular velocity and electromyographic activity of normalized speed skating strokes using one dimensional statistical non-parametric mapping. Skaters were matched with comparably skilled controls, and filled out a bespoke clinical questionnaire. RESULTS: Skaters' impacted leg showed over-activation in the peroneus longus, tibialis anterior and gastrocnemius that coincided with higher foot movement compared to their healthy leg and controls. This pattern persisted regardless of skating intensity. Clinical features indicated it was task-specific and painless with common trigger factors including stress, equipment change, and falling. CONCLUSIONS: We showed aberrant muscular and kinematic activity in a movement disorder in speed skaters indicative of task-specific dystonia. SIGNIFICANCE: Understanding skater's cramp as a task-specific dystonia could reduce the damage that misdiagnosis and unsuccessful invasive operations have caused. Our quantitative method has value in testing future treatment efficacy.