Hyperkinetic Movement Research Articles

Inter-rater Agreement for Movement Disorder Classification in Children with Hyperkinetic Movement Disorders.

Accurate classification is essential for addressing childhood movement disorders (MD), but the common coexistence of multiple MDs complicates this process. The aim was to assess inter-rater agreement on classifying hyperkinetic MDs among pediatric neurologists with expertise in MDs. Five pediatric neurologists were requested to examine 112 videos of 66 pediatric patients. Based on the Movement Disorder-Childhood Rating Scale, 3 queries were posed: (Q1) Is there more than 1 MD? (Q2) What is the (predominant) MD? (Q3) What is the other MD (if present)? The final agreement rates were 57.5% for Q1, 66.6% for Q2, and 43.9% for absolute agreement. All videos with absolute agreement at the first evaluation featured 1 MD, whereas only 2 videos with multiple MDs could totally agree in the final review. This study reveals significant discordance in classification even among pediatric neurologists with expertise in MDs and highlights the necessity for a standardized approach.

Pallidal neuronal activity in Gilles de la Tourette syndrome and dystonic patients: A comparative study.

Gilles de la Tourette syndrome (GTS) and dystonia (DYS) are both hyperkinetic movement disorders effectively treated by deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi). In this study, we compared single-neuron activity in the GPi between 18 GTS patients (with an average of 41 cells per patient) and 17 DYS patients (with an average of 54 cells per patient), all of whom underwent bilateral pallidal stimulation surgery, under general anesthesia or while awake at rest. We found no significant differences in GPi neuronal activity characteristics between patients operated on under general anesthesia versus those who were awake, irrespective of their diagnosis (GTS or DYS). We found higher firing rates, firing rate in bursts, pause duration and interspike interval coefficient of variation in GTS patients compared to DYS patients. On the opposite, we found higher number of pauses and bursts frequency in DYS patients. Lastly, we found a higher proportion of GPi oscillatory activities in DYS compared to GTS patients, with predominant activity within the low-frequency band (theta/alpha) in both patient groups. These findings underscore the complex relationship between the different neuronal discharge characteristic such as oscillatory or bursting activity within the GPi in shaping the clinical phenotypes of hyperkinetic disorders. Further research is warranted to deepen our understanding of how neuronal patterns are transmitted within deep brain structures and to develop strategies aimed at normalizing these pathological activities, by refining DBS techniques to enhance treatment efficacy and individual outcomes.

Striato-pallidal oscillatory connectivity correlates with symptom severity in dystonia patients

Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes that allow for parallel recordings of several basal ganglia nuclei, namely the striatum, external and internal pallidum, that all displayed activity in the low frequency band (3–12 Hz). In addition to a correlation with low-frequency activity in the internal pallidum (R = 0.88, P = 0.001), we demonstrate that dystonic symptoms correlate specifically with low-frequency coupling between striatum and internal pallidum (R = 0.75, P = 0.009). This points towards a pathophysiological role of the direct striato-pallidal pathway in dystonia that is conveyed via coupling in the enhanced low-frequency band. Our study provides a mechanistic insight into the pathophysiology of dystonia by revealing a link between symptom severity and frequency-specific coupling of distinct basal ganglia pathways.

Non-ketotic hyperglycemia-induced hemichorea-hemiballism – A case presentation and literature review

Non-ketotic hyperglycemia-induced hemichorea-hemiballism (NKHHH) is an infrequent hyperkinetic movement disorder, also known as diabetic striatopathy or Chorea hyperglycemia basal ganglia syndrome (C-H-BG), characterized by repetitive, uncontrollable movements in the unilateral or bilateral limbs. An insult to the contralateral basal ganglia causes NKHHH to develop. NKHHH is caused by ischemia, followed by non-ketotic hyperglycemia and poorly controlled diabetes. NKHHH is a rare condition with a unique cause that only affects one side of the corpus striatum (caudate nucleus and putamen). Clinical events of hemichorea-hemiballism, laboratory tests (elevated blood glucose and hemoglobin A1c levels), and imaging modalities (computed tomography and magnetic resonance imaging) all contribute to diagnosing NKHHH. The objective of this case report is to represent cross-sectional imaging findings in a 55-year-old female who presented with hemichorea-hemiballism following non-ketotic hyperglycemia. In conclusion, the clinical manifestation of NKHHH and its computed tomography (CT) and magnetic resonance imaging (MRI) findings are crucial in determining the appropriate management.

Tetrabenazine, a vesicular monoamine transporter 2 inhibitor, inhibits vesicular storage capacity and release of monoamine transmitters in mouse brain tissue

AbstractBackground and PurposeTetrabenazine (TBZ), used for treating hyperkinetic disorders, inhibits vesicular monoamine transporter‐2 (VMAT‐2), which sequesters monoamines into vesicles for exocytosis. However, our knowledge of the effect of TBZ on monoaminergic transmission is limited. Herein, we provide neurochemical evidence regarding the effect of VMAT‐2 inhibition on vesicular neurotransmitter release from the prefrontal cortex (PFC) and striatum (STR) (brain regions involved in characteristic TBZ treatment side effects). The interaction between TBZ and MDMA was also assessed regarding motor behaviour in mice.Experimental ApproachVesicular storage capacity and release of [3H]‐noradrenaline ([3H]‐NA), [3H]‐dopamine ([3H]‐DA), [3H]‐serotonin ([3H]‐5‐HT), and [3H]‐acetylcholine ([3H]‐ACh) was studied in mouse PFC and STR ex vivo slice preparations using electrical field stimulation. Additionally, locomotor activity was assessed in vehicle‐treated mice and compared with that of MDMA, TBZ, and co‐administered animals (n = 6) using the LABORAS system.Key ResultsTBZ lowered the storage capacity and inhibited the vesicular release of [3H]‐NA and [3H]‐DA from the PFC, and [3H]‐DA and [3H]‐5‐HT from the STR in a concentration‐dependent manner. Unlike vesamicol (vesicular ACh uptake inhibitor), TBZ failed to inhibit the vesicular release of [3H]‐ACh from the PFC. When the vesicular storage of the investigated monoamines was inhibited by TBZ in the PFC and STR, MDMA induced the release of transmitters through transporter reversal; MDMA dose dependently increased locomotor activity in vivo.Conclusion and ImplicationsOur observations provide neurochemical evidence explaining the mechanism of VMAT‐2 inhibitors in the brain and support the involvement of dopaminergic and noradrenergic transmission in hyperkinetic movement disorders.

Vascular origin hemiballismus: A clinic case and literature review

Introduction: Post-stroke movement disorders (PSMD) represent an important proportion of secondary movement disorders. Although extrapyramidal structures are frequently affected by stroke, the incidence of post-stroke movement disorders is relatively low. Purpose: We report the case of a patient who developed hemiballismus of ischemic vascular origin, caused by a lacunar infarct in the right lenticular and capsular region. Case presentation: We present the case of an 82-year-old male who came to the emergency department with sudden-onset hyperkinetic movements on the left side of his body. Clinical history and diagnostic tests indicated a vascular origin. Conclusions: The sudden onset of movement disorders should alert healthcare personnel to the possibility of an ongoing cerebrovascular event.

Embolization of dissected and ruptured giant anterior cerebral artery aneurysm in a full-term neonate.

Intracranial aneurysms are rare in the pediatric age group, especially in neonates. This article presents a novel case of a neonate with a dissected and ruptured giant anterior cerebral artery aneurysm, focusing on diagnosis and endovascular treatment with a review of the literature. A full-term female neonate presented with projectile vomiting, fever, and hyperkinetic movements. Diagnostic workup revealed a giant dissecting and partially thrombosed aneurysm along the anterior cerebral artery. The neonate underwent successful endovascular coil embolization. The intervention led to the cessation of symptoms, and the patient was discharged and followed with mild hypotonia as the only neurological deficit at 9months. This case highlights the rarity and complexity of diagnosing and treating giant dissected anterior cerebral artery aneurysms in neonates. It underscores the importance of considering intracranial aneurysms in differential diagnosis for neonates with relevant symptoms and suggests endovascular embolization as an effective treatment option.

Extrapyramidal System/Symptoms/Signs Should Be Retired.

The term "extrapyramidal system/symptoms/signs" and the acronym "EPS" have been abundantly used in neurology and psychiatry literature for more than a century. However, EPS has been increasingly criticized, especially by movement disorder neurologists, for its lack of clinical, anatomical, and physiologic definition. Contrary to traditional assumptions, pyramidal and extrapyramidal systems are not mutually exclusive. The acronym EPS, commonly used to denote drug-induced movement disorders, lacks specificity in conveying the nature and severity of these and other movement disorders. Consequently, we propose that the term is retired from scientific literature and that clinicians use specific phenomenologic descriptors for the various hypokinetc and hyperkinetic movement disorders.

Gastrointestinal disorders in hyperkinetic movement disorders and ataxia

Disorders of the gastrointestinal tract in patients suffering from hypokinetic movement disorders, and in particular Parkinson's disease, have increasingly been the subject of more intensive neuromedical research. So far, few data are available for patients with hyperkinetic movement disorders and ataxias. This review article summarizes the currently available and relevant publications on this topic. The particular focus is on essential tremor, restless legs syndrome, Huntington's disease and the group of hereditary ataxias. Further intensive research will be necessary in the future to collect detailed information also for these disease symptoms about specific disturbance patterns, in order to understand the underlying pathological pathways and to derive specific treatment approaches.

Analysis of Brain, Blood, and Testis Phenotypes Lacking the Vps13a Gene in C57BL/6N Mice.

The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria-endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.

Mitochondrial targeted antioxidants as potential therapy for huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion in CAG repeat on huntington (Htt) gene, leading to a degeneration of GABAergic medium spiny neurons (MSNs) in the striatum, resulting in the generation of reactive oxygen species, and decrease antioxidant activity. These pathophysiological alterations impair mitochondrial functions, leading to an increase in involuntary hyperkinetic movement. However, researchers investigated the neuroprotective effect of antioxidants using various animal models. Still, their impact is strictly limited to curtailing oxidative stress and increasing the antioxidant enzyme in the brain, which is less effective in HD. Meanwhile, researchers discovered Mitochondria-targeted antioxidants (MTAXs) that can improve mitochondrial functions and antioxidant activity through the modulation of mitochondrial signaling pathways, including peroxisome proliferator-activated receptor (PPAR)-coactivator 1 (PGC-1α), dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), and Silent mating type information regulation 2 homolog 1 (SIRT-1), showing neuroprotective effects in HD. The present review discusses the clinical and preclinical studies that investigate the neuroprotective effect of MTAXs (SS31, XJB-5-131, MitoQ, bezafibrate, rosiglitazone, meldonium, coenzyme Q10, etc.) in HD. This brief literature review will help to understand the relevance of MTAXs in HD and enlighten the importance of MTAXs in future drug discovery and development.

Crossed-reflex in antiphospholipid chorea

Chorea is a hyperkinetic movement disorder associated with various underlyingconditions, including autoimmune diseases such as antiphospholipid syndrome (APS). APS can manifest with a wide range of neurological symptoms, including chorea. We present a case of a 77-year-old man with subacute generalized chorea secondary to primary APS. Notably, the patient exhibited a left patellar crossed-reflex, a phenomenon rarely documented in chorea cases, the pathophysiology of which has not yet been elucidated. In summary, this case challenges the traditional demographics of antiphospholipid syndrome (APS) by suggesting a potential link between APS and late-age patients. It emphasizes the importance of considering APS in late-onset chorea cases.

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment.

Chorea is a hyperkinetic movement disorder frequently observed in the pediatric population, and, due to advancements in genetic techniques, an increasing number of genes have been associated with this disorder. In genetic conditions, chorea may be the primary feature of the disorder, or be part of a more complex phenotype characterized by epileptic encephalopathy or a multisystemic syndrome. Moreover, it can appear as a persistent disorder (chronic chorea) or have an episodic course (paroxysmal chorea). Managing chorea in childhood presents challenges due to its varied clinical presentation, often involving a spectrum of hyperkinetic movement disorders alongside neuropsychiatric and multisystemic manifestations. Furthermore, during infancy and early childhood, transient motor phenomena resembling chorea occurring due to the rapid nervous system development during this period can complicate the diagnosis. This review aims to provide an overview of the main genetic causes of pediatric chorea that may manifest during infancy and early childhood, focusing on peculiarities that can aid in differential diagnosis among different phenotypes and discussing possible treatment options.

Paroxysmal Kinesigenic Dyskinesia Secondary to Novel Variant in PRRT2: A Case Report

AbstractParoxysmal kinesigenic dyskinesia (PKD) is a movement disorder characterized by frequent, brief episodes of choreiform or dystonic movements, often triggered by voluntary movement or a startle sensation. Here, we report a case of PKD associated with a novel variant in PRRT2 gene. A 19-year-old male with no medical history presented with hyperkinetic movement disorder symptoms consistent with PKD. Clinical evaluation, laboratory studies, and genetic testing were performed to confirm the diagnosis. Treatment with carbamazepine was initiated, and the patient's response was monitored over a 9-month period. The patient exhibited classic clinical criteria for PKD, including brief episode duration, an identified kinesigenic trigger, and responsiveness to pharmacological treatment. Genetic testing revealed a pathogenic variant in PRRT2 gene not previously reported in association with PKD. Treatment with carbamazepine led to complete resolution of symptoms, with sustained improvement observed during follow-up. This case highlights the importance of considering PKD in the differential diagnosis of hyperkinetic movement disorders and emphasizes the role of genetic testing in confirming the diagnosis. Furthermore, it underscores the efficacy of carbamazepine in managing PKD symptoms associated with PRRT2 gene. Further research is warranted to elucidate the underlying pathophysiological mechanisms and optimize treatment strategies for PKD.

Vigabatrin-associated hyperkinetic movements in two children with epileptic spasms: Case reports and video phenomenology description

Vigabatrin-associated hyperkinetic movements in two children with epileptic spasms: Case reports and video phenomenology description

Sleep and circadian rhythm dysfunctions in movement disorders beyond Parkinson's disease and atypical parkinsonisms.

This review aimed to comprehensively outline sleep and circadian rhythm abnormalities in hyperkinetic movement disorders beyond Parkinson's disease and atypical parkinsonisms, including tremor, dystonia, choreiform movements, tics, and ataxia disorders. Insomnia, poor sleep quality, and excessive daytime sleepiness (EDS) are commonly reported in essential tremor, Wilson's disease, tics or Tourette's syndrome, and spinocerebellar ataxia (SCA). REM sleep behavior disorder (RBD) have been observed in Wilson's disease and SCA. A combination of REM and non-REM parasomnias, along with nocturnal stridor with the initiation of sleep and re-entering after awakening, are characterized by undifferentiated Non-REM and poorly structured N2 in anti-IgLON5 disease. Restless legs syndrome (RLS) has been reported commonly in SCAs. Sleep-related dyskinesia has been reported in ADCY5-related disease and GNAO1-related movement disorder. Sleep problems can manifest as a result of movement disorders, either through direct motor disturbances or secondary nonmotor symptoms. Medication effects must be considered, as certain medications for movement disorders can exacerbate or alleviate sleep disturbances. Distinguishing sleep problems in some diseases might involve pathognomonic symptoms and signs, aiding in the diagnosis of movement disorders.

Unraveling progression subtypes in people with Huntington’s disease

BackgroundHuntington’s disease (HD) is a progressive neurodegenerative disease caused by a CAG trinucleotide expansion in the huntingtin gene. The length of the CAG repeat is inversely correlated with disease onset. HD is characterized by hyperkinetic movement disorder, psychiatric symptoms, and cognitive deficits, which greatly impact patient’s quality of life. Despite this clear genetic course, high variability of HD patients’ symptoms can be observed. Current clinical diagnosis of HD solely relies on the presence of motor signs, disregarding the other important aspects of the disease. By incorporating a broader approach that encompasses motor as well as non-motor aspects of HD, predictive, preventive, and personalized (3P) medicine can enhance diagnostic accuracy and improve patient care.MethodsMultisymptom disease trajectories of HD patients collected from the Enroll-HD study were first aligned on a common disease timescale to account for heterogeneity in disease symptom onset and diagnosis. Following this, the aligned disease trajectories were clustered using the previously published Variational Deep Embedding with Recurrence (VaDER) algorithm and resulting progression subtypes were clinically characterized. Lastly, an AI/ML model was learned to predict the progression subtype from only first visit data or with data from additional follow-up visits.ResultsResults demonstrate two distinct subtypes, one large cluster (n = 7122) showing a relative stable disease progression and a second, smaller cluster (n = 411) showing a dramatically more progressive disease trajectory. Clinical characterization of the two subtypes correlates with CAG repeat length, as well as several neurobehavioral, psychiatric, and cognitive scores. In fact, cognitive impairment was found to be the major difference between the two subtypes. Additionally, a prognostic model shows the ability to predict HD subtypes from patients’ first visit only.ConclusionIn summary, this study aims towards the paradigm shift from reactive to preventive and personalized medicine by showing that non-motor symptoms are of vital importance for predicting and categorizing each patients’ disease progression pattern, as cognitive decline is oftentimes more reflective of HD progression than its motor aspects. Considering these aspects while counseling and therapy definition will personalize each individuals’ treatment. The ability to provide patients with an objective assessment of their disease progression and thus a perspective for their life with HD is the key to improving their quality of life. By conducting additional analysis on biological data from both subtypes, it is possible to gain a deeper understanding of these subtypes and uncover the underlying biological factors of the disease. This greatly aligns with the goal of shifting towards 3P medicine.

Topological alterations in white matter anatomical networks in cervical dystonia

BackgroundAccumulating neuroimaging evidence indicates that patients with cervical dystonia (CD) have changes in the cortico-subcortical white matter (WM) bundle. However, whether these patients’ WM structural networks undergo reorganization remains largely unclear. We aimed to investigate topological changes in large-scale WM structural networks in patients with CD compared to healthy controls (HCs), and explore the network changes associated with clinical manifestations.MethodsDiffusion tensor imaging (DTI) was conducted in 30 patients with CD and 30 HCs, and WM network construction was based on the BNA-246 atlas and deterministic tractography. Based on the graph theoretical analysis, global and local topological properties were calculated and compared between patients with CD and HCs. Then, the AAL-90 atlas was used for the reproducibility analyses. In addition, the relationship between abnormal topological properties and clinical characteristics was analyzed.ResultsCompared with HCs, patients with CD showed changes in network segregation and resilience, characterized by increased local efficiency and assortativity, respectively. In addition, a significant decrease of network strength was also found in patients with CD relative to HCs. Validation analyses using the AAL-90 atlas similarly showed increased assortativity and network strength in patients with CD. No significant correlations were found between altered network properties and clinical characteristics in patients with CD.ConclusionOur findings show that reorganization of the large-scale WM structural network exists in patients with CD. However, this reorganization is attributed to dystonia-specific abnormalities or hyperkinetic movements that need further identification.

Myoclonus: an update.

Myoclonus, a common hyperkinetic movement disorder, can be disabling for patients. It is important to identify and classify myoclonus correctly to ensure appropriate workup and treatment. While the clinical history, examination, and process of classifying myoclonus remain largely unchanged, new causes and triggers for myoclonus are being elucidated, and new genetic causes have been found. Treatment can be challenging, though preliminary data about new options has been promising. In this article, we will briefly outline the process of classifying and treating myoclonus. We will then discuss three specific scenarios where myoclonus has been identified: myoclonus associated with SARS-CoV-2 infections, spinal myoclonus following surgery or anesthesia of the spine, and auricular myoclonus. We will also discuss new genetic findings associated with myoclonus-dystonia, and promising results regarding the use of perampanel in treating myoclonus. The process of describing unique scenarios associated with myoclonus has helped us build our understanding of the causes, genetic background, expected prognosis, and effective treatment of specific types of myoclonus. We hope that further studies on this topic will help tailor treatment.

Hyperkinetic movement disorder in FBXO28-related developmental and epileptic encephalopathy

Hyperkinetic movement disorder in FBXO28-related developmental and epileptic encephalopathy