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Since the initial description of glucose transporter-1 deficiency syndrome (Glut1-DS) the phenotype of the condition has expanded, even leading to the recognition of atypical manifestations. We report on eight patients with Glut1-DS who experienced at least one episode of acute focal neurological deficits. We conducted a retrospective analysis, collecting clinical, electrophysiological, neuroradiological, and genetic information. We focused in particular on three well-documented cases. Among 42 patients with Glut1-DS, eight individuals aged between six and 38 years presented with an acute onset of neurological disturbances: dysarthria/aphasia, oral dyskinesia, swallowing difficulties, paresthesia, facial palsy, hemi/monoplegia, vomiting, headache, and behavioral disturbances. When performed, magnetic resonance imaging (MRI) revealed signs of venous congestion and hypoperfusion and electroencephalography showed focal contralateral slowing. Deficits were transient in all patients but one. Four patients (50%) were on a ketogenic diet (KD), and two of these patients had lower than usual ketonemia levels during the episode. In two patients, MRI demonstrated the presence of an ischemic brain lesion. In Glut1-DS, stroke-like episodes are a recurrent manifestation, particularly during early adulthood, and they were reported in 19% of the patients in our cohort. Stroke mimics should be considered a key feature of Glut1-DS, as other paroxysmal disorders. It remains to be established whether a KD can prevent the recurrence of episodes and, if so, at what level of ketosis. Further observations are needed to confirm the correlation between Glut1-DS and ischemic stroke. [ABSTRACT FROM AUTHOR]

Functional neurosurgery involves the surgical management of a wide range of neurological diseases with the aim of treating conditions such as movement disorders, spasticity, epilepsy and intractable pain. Functional neurosurgery began with ablative surgical techniques involving destruction of neural structures responsible for the aberrant neural pathways/networks causing pathology. In more recent years there has been a move away from the creation of permanent destructive lesions towards modulation of the neural networks utilizing neuro-modulation. Neuromodulation therapies include invasive (e.g. deep brain stimulators, cortical stimulators, vagal nerve stimulators and spinal cord stimulators) and non-invasive (e.g. transcranial magnetic stimulation) approaches that involve the application of electrical stimulation to drive or inhibit neural function within a circuit. Most implantable neuromodulation systems include three primary components: stimulating electrode(s) with contacts at the tip through which electricity is delivered, an implantable pulse generator (IPG) that serves as a signal generator/battery pack, and the extension cable(s) to subcutaneously connect the electrode(s) to the IPG. In this article we primarily focus on the current role of neuromodulation in treating movement disorders, epilepsy and pain, and also consider emerging and evolving applications. [ABSTRACT FROM AUTHOR]

Sunflower syndrome is a rare photosensitive pediatric epilepsy characterized by stereotyped hand-waving in response to bright lights. These stereotyped movements with maintained awareness can be mistaken for a movement disorder. This study assessed neurology providers' diagnostic reasoning, evaluation, and treatment of Sunflower syndrome. A 32-question anonymized electronic survey, including a clinical vignette and video of hand-waving in sunlight, was distributed to child neurology providers to assess (1) initial diagnosis and evaluation based on clinical information, (2) updated diagnosis and management after electroencephalography (EEG), and (3) prior experience with Sunflower syndrome. Among 277 viewed surveys, 211 respondents provided information about initial diagnosis and evaluation, 200 about updated diagnosis, 191 about management, and 189 about prior clinical experience. Most providers (135, 64%) suspected seizure, whereas fewer suspected movement disorders (29, 14%) or were unsure of the diagnosis (37, 22%). EEG was recommended by 180 (85%). After EEG, 189 (95%) diagnosed epilepsy, 111 of whom specifically diagnosed Sunflower syndrome. The majority (149, 78%) recommended antiseizure medications (ASMs) and sun avoidance (181, 95%). Only 103 (55%) had managed Sunflower syndrome. Epileptologists and those with prior clinical experience were more likely to suspect a seizure, order an EEG, and offer ASMs than those without prior experience. Although many providers had not managed Sunflower syndrome, the majority recognized this presentation as concerning for epilepsy. Epilepsy training and prior clinical experience are associated with improved recognition and appropriate treatment. Educational initiatives that increase awareness of Sunflower syndrome may improve patient care. [ABSTRACT FROM AUTHOR]

Many alternating hemiplegia of childhood (AHC) patients have received Cannabidiol (CBD) but, to our knowledge, there are no published data available. Test the hypothesis that CBD has favorable effects on AHC spells. Retrospective review of available data of AHC patients who received CBD. Primary analysis: Clinical Global Impression Scale of Improvement (CGI-I) score for response of AHC spells to CBD with calculation of 95% confidence interval (CI) for rejection of the null hypothesis. Secondary analyses, performed to achieve an understanding of the effect of CBD as compared to flunarizine, were CGI-I scores of 1) epileptic seizures to CBD, 2) AHC spells to flunarizine, 3) epileptic seizures to flunarizine. Also, Mann-Whitney test was done for comparison of CGI-I scores of CBD and flunarizine to both AHC spells and seizures. We studied 16 AHC patients seen at Duke University and University of Lyon. CI of CGI-I scores for AHC spells in response to CBD and to flunarizine, each separately, indicated a positive response to each of these two medications: neither overlapped with the null hypothesis score, 4, indicating significant positive responses with p < 0.05 for both. These two scores also did not differ (p = 0.84) suggesting similar efficacy of both: CBD score was 2 ± 1.1 with a 95% CI of 1.5–2.6 and flunarizine score was 2.3 ± 1.3 with a 95% CI of 1.7–3.1. In patients who had seizures, CI calculations indicated a positive effect of CBD on seizure CGI scores but not of flunarizine on seizure scores. CBD was well tolerated with no patients discontinuing it due to side effects and with some reporting positive behavioral changes. Our study indicates a real-life positive effect of CBD on AHC type spells. • Real life study of 16 Alternating Hemiplegia of Childhood (AHC) patients • Response of AHC spells to cannabidiol was assessed • We determined the Clinical Global Impression Scale of Improvement scores • Scores showed significant response and cannabidiol was well tolerated [ABSTRACT FROM AUTHOR]

Humans use different types of eye movements to look at points of interest in the visual scene, to optimize visual processing, and to guide hand and body movements. Eye movements have the potential to reveal sensorimotor and cognitive processes in healthy and pathological brains. Eye movement abnormalities are common in Parkinson's disease (PD) and can provide clues as to the identity of neuronal populations, mechanisms, and pathways that contribute to disease processes. Eye movements may aid biomarker-based diagnosis and quantification of PD when combined with other biomarkers, although they currently appear to lack sensitivity and specificity to serve as a standalone diagnostic tool. Therapeutic approaches such as deep brain stimulation, in addition to their clinical utility, offer a unique opportunity to systematically probe the brain networks that underlie human oculomotor control. Movement disorders such as Parkinson's disease (PD) impact oculomotor function – the ability to move the eyes accurately and purposefully to serve a multitude of sensory, cognitive, and secondary motor tasks. Decades of neurophysiological research in monkeys and behavioral studies in humans have characterized the neural basis of healthy oculomotor control. This review links eye movement abnormalities in persons living with PD to the underlying neurophysiological mechanisms and pathways. Building on this foundation, we highlight recent progress in using eye movements to gauge symptom severity, assess treatment effects, and serve as potential precision biomarkers. We conclude that whereas eye movements provide insights into PD mechanisms, based on current evidence they appear to lack sufficient sensitivity and specificity to serve as a standalone diagnostic tool. Their full potential may be realized when combined with other disease indicators in big datasets. [ABSTRACT FROM AUTHOR]

[Display omitted] Two recently discovered DRD2 mutations, c.634A > T, p.Ile212Phe and c.1121T > G, p.Met374Arg, cause hyperkinetic movement disorders that have overlapping features but apparently differ in severity. The two known carriers of the Met374Arg variant had early childhood disease onset and more severe motor, cognitive, and neuropsychiatric deficits than any known carriers of the Ile212Phe variant, whose symptoms were first apparent in adolescence. Here, we evaluated if differences in the function of the two variants in cultured cells could explain differing pathogenicity. Both variants were expressed less abundantly than the wild type receptor and exhibited loss of agonist-induced arrestin binding, but differences in expression and arrestin binding between the variants were minor. Basal and agonist-induced activation of heterotrimeric G i/o/z proteins, however, showed clear differences; agonists were generally more potent at Met374Arg than at the Ile212Phe or wild type variants. Furthermore, all Gα subtypes tested were constitutively activated more by Met374Arg than by Ile212Phe. Met374Arg produced greater constitutive inhibition of cyclic AMP accumulation than Ile212Phe or the wild type D2 receptor. Met374Arg and Ile212Phe were more sensitive to thermal inactivation than the wild type D2 receptor, as reported for other constitutively active receptors, but Ile212Phe was affected more than Met374Arg. Additional pharmacological characterization suggested that the mutations differentially affect the shape of the agonist binding pocket and the potency of dopamine, norepinephrine, and tyramine. Molecular dynamics simulations provided a structural rationale for enhanced constitutive activation and agonist potency. Enhanced constitutive and agonist-induced G protein-mediated signaling likely contributes to the pathogenicity of these novel variants. [ABSTRACT FROM AUTHOR]

The advent of computer vision technology and increased usage of video cameras in clinical settings have facilitated advancements in movement disorder analysis. This review investigated these advancements in terms of providing practical, low-cost solutions for the diagnosis and analysis of movement disorders, such as Parkinson's disease, ataxia, dyskinesia, and Tourette syndrome. Traditional diagnostic methods for movement disorders are typically reliant on the subjective assessment of motor symptoms, which poses inherent challenges. Furthermore, early symptoms are often overlooked, and overlapping symptoms across diseases can complicate early diagnosis. Consequently, deep learning has been used for the objective video-based analysis of movement disorders. This study systematically reviewed the latest advancements in automatic two-dimensional & three-dimensional video analysis using deep learning for movement disorders. We comprehensively analyzed the literature published until September 2023 by searching the Web of Science, PubMed, Scopus, and Embase databases. We identified 68 relevant studies and extracted information on their objectives, datasets, modalities, and methodologies. The study aimed to identify, catalogue, and present the most significant advancements, offering a consolidated knowledge base on the role of video analysis and deep learning in movement disorder analysis. First, the objectives, including specific PD symptom quantification, ataxia assessment, cerebral palsy assessment, gait disorder analysis, tremor assessment, tic detection (in the context of Tourette syndrome), dystonia assessment, and abnormal movement recognition were discussed. Thereafter, the datasets used in the study were examined. Subsequently, video modalities and deep learning methodologies related to the topic were investigated. Finally, the challenges and opportunities in terms of datasets, interpretability, evaluation methods, and home/remote monitoring were discussed. [ABSTRACT FROM AUTHOR]

Background: Harmonic ratios (HRs), recurrence quantification analysis in the antero-posterior direction (RQAdetAP), and stride length coefficient of variation (CV) have recently been shown to characterize gait abnormalities and fall risk in people with Parkinson's disease (pwPD) at moderate disease stages.Research Question: This study aimed to i) assess the internal and external responsiveness to rehabilitation of HR, RQAdetAP, and CV, ii) identify the baseline predictors of normalization of the gait stability indexes, and iii) investigate the correlations between the gait indexes modifications (∆) and clinical and kinematic ∆s in pwPD at Hoehn and Yahr disease staging classification 3.Methods: The trunk acceleration patterns of 21 pwPD and 21 age- and speed-matched healthy subjects (HSmatched) were acquired during gait using an inertial measurement unit at baseline (T0). pwPD were also assessed after a 4-week rehabilitation period (T1). Each participant's HR in the antero-posterior (HRAP), medio-lateral (HRML), and vertical directions, RQAdetAP, CV, spatio-temporal, and kinematic variables were calculated.Results: At T1, HRAP and HRML improved to normative values and showed high internal and external responsiveness. Lower HRs and higher pelvic rotation values at baseline were predictors of ∆HRs. A minimal clinically important difference (MCID) ≥ 21.5 % is required to normalize HRAP with 95 % probability. MCID ≥ 36.9 % is required to normalize HRML with 92 % probability. ∆HRAP correlated with ∆HRML and both correlated with ∆stride length and ∆pelvic rotation, regardless of ∆gait speed. RQAdetAP and step length CV were not responsive to rehabilitation.Significance: When using inertial measurement units, HRAP and HRML can be considered as responsive outcome measures for assessing the effectiveness of rehabilitation on trunk smoothness during walking in pwPD at moderate disease stages. [ABSTRACT FROM AUTHOR]

Pathogenic variants in ATP1A3 cause various phenotypes of neurological disorders, including alternating hemiplegia of childhood 2, CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and rapid-onset dystonia-parkinsonism (RDP). Early developmental and epileptic encephalopathy has also been reported. Polymicrogyria has recently been added to the phenotypic spectrum of ATP1A3 -related disorders. Case report. We report here a male patient with early developmental delay who at 12 months presented dystonia of the right arm which evolved into hemidystonia at the age of 2. A cerebral MRI showed bilateral perisylvian polymicrogyria with intact basal ganglia. Whole-exome and whole-genome sequencing analyses identified a de novo new ATP1A3 missense variant (p.Arg914Lys) predicted pathogenic. Hemidystonia was thought not to be due to polymicrogyria, but rather a consequence of this variant. This case expands the phenotypic spectrum of ATP1A3 -related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition. [ABSTRACT FROM AUTHOR]

To explore neurological factors affecting quality of life (QoL) in children and young people with ataxia-telangiectasia (A-T), from both child and parent perspective. 24 children/young people with A-T (mean age 11.2 ± 3.5 years; 13 males) and 20 parents were recruited, and 58% were reassessed after an average interval of 3.4 years. Participants completed the PedsQL QoL assessment. Participants with A-T underwent structured neurological examination. QoL data from 20 healthy controls and their parents was used for comparison. Children/young people with A-T rated their QoL higher than parental ratings across time points, with no longitudinal change. Higher age of the child participant correlated with lower parental (r = −0.43, p =.008) but not child ratings of QoL (r = −0.16, p =.380). Child and parent QoL ratings from the A-T group were lower than respective ratings from controls (η p 2 = 0.44 and η p 2 = 0.75 respectively, both p <.0005, controlled for socioeconomic status). Parental, but not child, ratings of QoL was predicted by a regression model based on neurological scores (R 2 = 0.44, p =<.001). Neurological disability does not determine child/young person QoL ratings in A-T. While certain aspects of neurological disability predict parent-proxy ratings, there is no decline in QoL over time. These results may reflect resilience in the face of a complex life-limiting disorder. [Display omitted] • Child ratings of QoL in A-T are significantly higher than parental ratings. • Age negatively correlated with parent QoL ratings, but there was no relationship between age and child QoL self-ratings. • Neurological function significantly predicts parental, but not the child's own ratings of their QoL. • Over time, QoL ratings did not decline with increasing disability reflecting high levels of resilience in this sample. [ABSTRACT FROM AUTHOR]

Recent neuroscientific models suggest that functional bodily symptoms can be attributed to perceptual dysregulation in the central nervous system. Evidence for this hypothesis comes from patients with functional dizziness, who exhibit marked sensorimotor processing deficits during eye-head movement planning and execution. Similar findings in eye-head movement planning in patients with irritable bowel syndrome confirmed that these sensorimotor processing deficits represent a shared, transdiagnostic mechanism. We now examine whether erroneous sensorimotor processing is also at play in functional movement disorder. We measured head movements of 10 patients with functional movement disorder (F44.4, ICD-10), 10 patients with functional dizziness (F45.8, ICD-10), and (respectively) 10 healthy controls during an eye-head experiment, where participants performed large gaze shifts under normal, increased, and again normal head moment of inertia. Head oscillations at the end of the gaze shift served as a well-established marker for sensorimotor processing problems. We calculated Bayesian statistics for comparison. Patients with functional movement disorder (Bayes Factor (BF) 10 = 5.36, BF incl = 11.16; substantial to strong evidence) as well as patients with functional dizziness (BF 10 = 2.27, BF incl = 3.56; anecdotal to substantial evidence) showed increased head oscillations compared to healthy controls, indicating marked deficits in planning and executing movement. We replicate earlier experimental findings on erroneous sensorimotor processing in patients with functional dizziness, and show that patients with functional movement disorder show a similar impairment of sensorimotor processing during large gaze shifts. This provides an objectively measurable, transdiagnostic marker for functional disorders, highlighting important implications for diagnosis, treatment, and de-stigmatization. • Patients with functional disorders are an underserved and stigmatized group. • Experimentally testable explanatory models lack, impeding diagnostics and treatment. • Functional disorders may be seen as a sensorimotor processing disorder in the brain. • Head instability is an objectively measurable marker of functional disorders. [ABSTRACT FROM AUTHOR]

Falls are a serious health threat for people with Parkinson's disease. Dynamic gait stability has been associated with fall risk. Developing effective fall prevention interventions requires a sound understanding of how Parkinson's disease affects dynamic gait stability. This study compared dynamic gait stability within the Feasible Stability Region framework between people with and without Parkinson's disease during level walking at a self-selected speed. Twenty adults with Parkinson's disease and twenty age- and gender-matched healthy individuals were recruited. Dynamic gait stability at two gait instants: touchdown and liftoff, was assessed as the primary outcome measurement. Spatiotemporal gait parameters, including stance phase duration, step length, gait speed, and cadence were determined as explanatory variables. People with Parkinson's disease walked more slowly (p < 0.001) with a shorter step (p = 0.05), and prolonged stance phase (p = 0.04) than their healthy peers with moderate to large effect sizes. Dynamic gait stability did not show any group-associated differences (p > 0.36). Despite the different gait parameters between groups, people with Parkinson's disease exhibited similar dynamic gait stability to their healthy counterparts. To compensate for the potential dynamic gait stability deficit resulting from slow gait speed, individuals with Parkinson's disease adopted a short step length to shift the center of mass motion state closer to the Feasible Stability Region. Our findings could provide insight into the impact of Parkinson's disease on the control of dynamic gait stability. • Dynamic gait stability is similar between Parkinson's disease and healthy adults. • People with Parkinson's walked slower with shorter steps than healthy controls. • Parkinson's is related to a lower cadence and a longer stance phase than controls. [ABSTRACT FROM AUTHOR]

To improve the initiation and speed of intended action, one of the crucial mechanisms is suppressing unwanted movements that interfere with goal-directed behavior, which is observed relatively aberrant in Parkinson's disease patients. Recent research has highlighted that dopamine deficits in Parkinson's disease predominantly occur in the caudal lateral part of the substantia nigra pars compacta (SNc) in human patients. We previously found two parallel circuits within the basal ganglia, primarily divided into circuits mediated by the rostral medial part and caudal lateral part of the SNc dopamine neurons. We have further discovered that the indirect pathway in caudal basal ganglia circuits, facilitated by the caudal lateral part of the SNc dopamine neurons, plays a critical role in suppressing unnecessary involuntary movements when animals perform voluntary goal-directed actions. We thus explored recent research in humans and non-human primates focusing on the distinct functions and networks of the caudal lateral part of the SNc dopamine neurons to elucidate the mechanisms involved in the impairment of suppressing involuntary movements in Parkinson's disease patients. • Parkinson's disease (PD) is the most prevalent neurodegenerative movement disorder. • A crucial obstruction in PD is the inability to suppress unwanted movements. • PD presents region-specific damage in the caudal lateral dopamine neurons (cdlSNc). • cdlSNc forms a distinct caudal basal ganglia circuit to control involuntary actions. • The distinct cdlSNc networks will be central to treating individual symptoms of PD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Parkinson's Disease impacts audiovisual temporal discrimination, reflecting altered multisensory integration. • The order of stimuli presentation influences temporal discrimination in Parkinson's Disease, with auditory-first trials showing enhanced performance over visual-first trials. • Parkinson's Disease significantly affects reaction times in audiovisual temporal discrimination tasks. Cognitive deficits are prevalent in Parkinson's disease (PD), ranging from mild deficits in perception and executive function to severe dementia. Multisensory integration (MSI), the ability to pool information from different sensory modalities to form a combined, coherent perception of the environment, is known to be impaired in PD. This study investigated the disruption of audiovisual MSI in PD patients by evaluating temporal discrimination ability between auditory and visual stimuli with different stimulus onset asynchronies (SOAs). The experiment was conducted with Fifteen PD patients and fifteen age-matched healthy controls where participants were requested to report whether the audiovisual stimuli pairs were temporal simultaneous. The temporal binding window (TBW), the time during which sensory modalities are perceived as synchronous, was adapted as the comparison index between PD patients and healthy individuals. Our results showed that PD patients had a significantly wider TBW than healthy controls, indicating abnormal audiovisual temporal discrimination. Furthermore, PD patients had more difficulty in discriminating temporal asynchrony in visual-first, but not in auditory-first stimuli, compared to healthy controls. In contrast, no significant difference was observed for auditory-first stimuli. PD patients also had shorter reaction times than healthy controls regardless of stimulus priority. Together, our findings point to abnormal audiovisual temporal discrimination, a major component of MSI irregularity, in PD patients. These results have important implications for future models of MSI experiments and models that aim to uncover the underlying mechanism of MSI in patients afflicted with PD. [ABSTRACT FROM AUTHOR]

PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability. • PCDH12 mutations associated with spectrum of epilepsy-dyskinesia disorders. • Five new cases, three novel PCDH12 mutations and review of the literature. • Novel observation: malformations of medulla oblongata in PCDH12 patients. • Novel observation: clinical overlap with interferonopathies and. • Increased interferon signature as potential hint to underlying disease mechanism. [ABSTRACT FROM AUTHOR]

Mutations in the X-linked gene DDX3X account for approximately 2% of intellectual disability in females, often comorbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. We generated a Ddx3x haploinsufficient mouse (Ddx3x +/− females) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. Ddx3x +/− females showed physical, sensory, and motor delays that evolved into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments in specific tasks (e.g., contextual fear memory but not novel object recognition memory), and motor deficits. Motor function declined with age but not if mice were previously exposed to behavioral training. Developmental and behavioral changes were associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning was accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. These data shed new light on the developmental mechanisms driving DDX3X syndrome and support construct and face validity of this novel preclinical mouse model. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal (GI) disorders have been thoroughly investigated in hypokinetic disorders such as Parkinson's disease, but much less is known about GI disorders in hyperkinetic movement disorders and ataxia. The aim of this review is to draw attention to the GI disorders that are associated with these movement disorders.Methods: References for this systematic review were identified by searches of PubMed through May 2020. Only publications in English were reviewed.Results: Data from 249 articles were critically reviewed, compared, and integrated. The most frequently reported GI symptoms overall in hyperkinetic movement disorders and ataxia are dysphagia, sialorrhea, weight changes, esophago-gastritis, gastroparesis, constipation, diarrhea, and malabsorption. We report in detail on the frequency, characteristics, pathophysiology, and management of GI symptoms in essential tremor, restless legs syndrome, chorea, and spinocerebellar ataxias. The limited available data on GI disorders in dystonias, paroxysmal movement disorders, tardive dyskinesias, myoclonus, and non-SCA ataxias are also summarized.Conclusion: The purpose of our systematic review is to draw attention that, although primarily motor disorders, hyperkinetic movement disorders and ataxia can involve the GI system. Raising awareness about the GI symptom burden in hyperkinetic movement disorders and ataxia could contribute to a new research interest in that field, as well as improved patient care. [ABSTRACT FROM AUTHOR]

Background: We sought to expand our knowledge of the clinical spectrum of GNAO1-related neurodevelopmental disorders through a caregiver survey reviewing medical and developmental history and development of epilepsy and movement disorders.Methods: An online survey was administered to caregivers of individuals diagnosed with GNAO1 pathogenic variants.Results: Eighty-two surveys were completed. Nearly all (99%) reported the first symptom of concern by age one year with the most frequently identified concerns as hypotonia (68%), developmental delay (67%), seizures (29%), difficulty feeding (23%), and abnormal movements (20%). All caregivers reported developmental delays with a spectrum of severity. Movement disorders (76%) were more common than epilepsy (52%), although 33% reported both. The onset of seizures tended to be earlier than abnormal movements. Nearly half (48%) of those with any seizures, reported they were no longer having recurrent seizures. No single most effective medication for movement disorders or epilepsy was noted. Ten participants have had deep brain stimulator for their movement disorder, and all indicated positive effects.Conclusions: GNAO1-related neurodevelopmental disorders most often present within the first year of life with nonspecific symptoms of hypotonia or developmental delay. Although associated epilepsy and movement disorders can be severe, GNAO1-associated epilepsy may not always be medically refractory or lifelong. [ABSTRACT FROM AUTHOR]

Functional neurosurgery involves the surgical management of a wide range of neurological diseases with the aim of treating conditions such as movement disorders, spasticity, epilepsy and intractable pain. Functional neurosurgery began with ablative surgical techniques involving destruction of neural structures responsible for the aberrant neural pathways/networks causing pathology. In more recent years there has been a move away from the creation of permanent destructive lesions towards modulation of the neural networks utilizing neuromodulation. Neuromodulation therapies include invasive (e.g. deep brain stimulators, cortical stimulators, vagal nerve stimulators and spinal cord stimulators) and non-invasive (e.g. transcranial magnetic stimulation) approaches that involve the application of electrical stimulation to drive or inhibit neural function within a circuit. Most implantable neuromodulation systems include three primary components: stimulating electrode(s) with contacts at the tip through which electricity is delivered, an implantable pulse generator (IPG) that serves as a signal generator/battery pack, and the extension cable(s) to subcutaneously connect the electrode(s) to the IPG. In this article we primarily focus on the current role of neuromodulation in treating movement disorders, epilepsy and pain, and also consider emerging and evolving applications. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) may negatively influence the rehabilitative course after total knee arthroplasty (TKA). However, functional outcomes in this select group remain poorly defined. We compared complication, mortality and revision rates, as well as patient-reported outcomes, and satisfaction between patients with PD and controls after TKA.Methods: Patients with PD who underwent primary unilateral TKA were identified and matched 1:1 with a control group using propensity scores adjusting for age, sex, body mass index, Charlson Comorbidity Index, baseline range of motion, Knee Society Knee Score, Knee Society Function Score, Oxford Knee Score, and 36-item Short-Form Health Survey Mental and Physical Component Summary. Functional outcomes and patient satisfaction were assessed at 6 months and 2 years. Complications, survivorship, and all-cause mortality were analyzed.Results: In total, 114 patients were included. Majority of PD patients had Hoehn and Yahr stage 1 or 2 disease. Overall complication rate was 26.3% in the PD group and 10.5% in the control group (P = .030). There was no difference in transfusions, length of stay, and discharge to rehabilitation or readmissions. Patients with PD had more flexion contractures, poorer Knee Society Function Score and Oxford Knee Score at 2 years, and poorer 36-item Short-Form Health Survey Physical Component Summary at 6 months. 80.4% of patients with PD were satisfied compared with 85.5% of controls (P = .476). At follow-up of 8.5 ± 2.7 years, one TKA was revised in each group. All-cause mortality was higher in the PD group (15.8% vs 5.3%, P = .067).Conclusion: Although patients with PD had relatively poorer knee function and quality of life, these patients still experienced significant functional gains compared with their preoperative status, and high satisfaction was achieved.Level Of Evidence: III. [ABSTRACT FROM AUTHOR]

• Reaction time was slower in FMD group compared to control group. • The relationship between accuracy and reaction time was the same in both FMD and control groups. • Findings may suggest a role of distributed sensory processing in motor execution in people with FMD. Functional movement disorder (FMD) presents as disabling motor symptoms that cannot be explained by organic processes. Despite the lack of lesion or known central nervous system dysfunction, distortion in sensorimotor processing in movement generation and execution is often observed. A person's capacity to judge laterality of a body part requires processing of sensorimotor information. This prospective observational study compared reaction time (RT) and accuracy (ACC) of hand laterality recognition between 30 people diagnosed with FMD and 30 age-matched healthy control participants. The association of RT and ACC with severity of FMD as measured by the Simplified Functional Movement Disorders Rating Scale (SFMDRS) was also explored. RT was on average 0.6 s slower (95% CI 0.4 – 0.8 s, p < 0.001) in patients with FMD (mean 2.2 s, standard deviation (SD) 0.5) than controls (mean 1.7 s, SD 0.3). ACC was on average 8.9% lower (95% CI −15.7 – −2.2, p = 0.01) in patients with FMD (mean 79.6%, SD 16.6) than controls (mean 88.5%, SD 8.1). When adjusted for SFMDRS using robust regression, RT was 0.3 s slower (95% CI 0.01 – 0.5, p = 0.04) in cases than in controls, but ACC was no longer different between groups. There was a moderate negative correlation between RT and ACC in FMD patients (ρ −0.58, p < 0.001 but not in controls (ρ −0.26, p = 0.17). People with FMD had significantly slower RT and lower ACC compared to the control group. These results provide new insights into underlying sensorimotor processing deficits in those with FMD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's Disease (PD) is among one of the common comorbidities in older patients. People with PD may be more vulnerable to severe pneumonia, due to the impairment of pulmonary function. Currently, the association between PD and COVID-19 is not yet established. This study aims to analyze the relationship between PD and in-hospital outcomes of COVID-19.Materials and Methods: We systematically searched the PubMed and Europe PMC database using specific keywords related to our aims until December 25th, 2020. All articles published on COVID-19 and Parkinson's Disease were retrieved. The quality of the study was assessed using the Newcastle Ottawa Scale (NOS) tool for observational studies and Joanna Briggs Institute (JBI) Critical Appraisal Tools for cross-sectional studies. Statistical analysis was done using Review Manager 5.4 software.Results: A total of 12 studies with 103,874 COVID-19 patients were included in this meta-analysis. This meta-analysis showed that Parkinson's Disease was associated with poor in-hospital outcomes [[OR 2.64 (95% CI 1.75-3.99), p < 0.00001, I2 = 81%] and its subgroup which comprised of severe COVID-19 [OR 2.61 (95% CI 1.98-3.43), p < 0.00001, I2 = 0%] and mortality from COVID-19 [RR 2.63 (95% CI 1.50-4.60), p = 0.0007, I2 = 91%]. Meta-regression showed that the association was influenced by age (p = 0.05), but not by gender (p = 0.46) and dementia (p = 0.23).Conclusions: Extra care and close monitoring should be provided to Parkinson's Disease patients to minimize the risk of infections, preventing the development of severe and mortality outcomes. [ABSTRACT FROM AUTHOR]

Acute onset de novo movement disorder is an increasingly recognized, yet undereported complication of diabetes. Hyperglycemia can give rise to a range of different movement disorders, hemichorea-hemiballism being the commonest. This article delves into the current knowledge about this condition, its diverse presentations, ongoing debates regarding its underlying mechanisms, disparities between clinical and radiological findings, and challenges related to its management. PubMed and Google Scholar were searched with the following key terms- "diabetes", "striatopathy", "hyperglycemia", "striatum", "basal ganglia", "movement disorder", "involuntary movement". Case reports, systematic reviews, meta-analysis, and narrative reviews published in English literature related to the topic of interest from January 1, 1950, to October 20, 2023, were retrieved. The references cited in the chosen articles were also examined, and those considered relevant were included in the review. Diabetic striatopathy is the prototype of movement disorders associated with hyperglycemia with its characteristic neuroimaging feature (contralateral striatal hyperdensitity on computed tomography or hyperintensity on T1-weighted magnetic resonance imaging). Risk factors for diabetic striatopathy includes Asian ethnicity, female gender, prolonged poor glycemic control, and concurrent retinopathy. Several hypotheses have been proposed to explain the pathophysiology of movement disorders induced by hyperglycemia. These hypotheses are not mutually exclusive; instead, they represent interconnected pathways contributing to the development of this unique condition. While the most prominent clinical feature of diabetic striatopathy is a movement disorder, its phenotypic expression has been found to extend to other manifestations, including stroke, seizures, and cognitive and behavioral symptoms. Fortunately, the prognosis for diabetic striatopathy is generally excellent, with complete resolution achievable through the use of anti-hyperglycemic therapy alone or in combination with neuroleptic medications. Hyperglycemia is the commonest cause of acute onset de novo movement disorders presenting to a range of medical specialists. So, it is of utmost importance that the physicians irrespective of their speciality remain aware of this clinical entity and check blood glucose at presentation before ordering any other investigations. Prompt clinical diagnosis of this condition and implementation of intensive glycemic control can yield significant benefits for patients. • Hemichorea-hemiballism is the commonest among all the movement semiologies described in relation with hyperglycemia. • For patients with new onset abnormal movement, blood glucose is to be checked first irrespective of history of diabetes. • Dagnosis of diabetic striatopathy relies on the presence of typical clinical symptoms and poor glycemic control. • Distinctive neuroimaging findings are contralateral striatal hyper-attenuation on CT or hyperintensity on T1-weighted MRI. • Intensive glycemic control with occasional use of neuroleptics leads to rapid resolution of abnormal movements in majority. [ABSTRACT FROM AUTHOR]

Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators. The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely. In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed. [ABSTRACT FROM AUTHOR]

• Biological actions are produced by changes of parameters in biology-specific laws of nature. • These parameters are spatial referent coordinates for the involved effectors. • Perception is measurement of sensory signals within a frame of reference provided by the efferent process. • Stability of actions and percepts is a reflection of stable manifolds in corresponding high-dimensional spaces. • This framework offers interpretation of new experimental findings in healthy persons and patients with movement disorders. We describe a physical approach to biological functions, with the emphasis on the motor and sensory functions. The approach assumes the existence of biology-specific laws of nature uniting salient physical variables and parameters. In contrast to movements in inanimate nature, actions are produced by changes in parameters of the corresponding laws of nature. For movements, parameters are associated with spatial referent coordinates (RCs) for the effectors. Stability of motor actions is ensured by the abundant mapping of RCs across hierarchical control levels. The sensory function is viewed as based on an interaction of efferent and afferent signals leading to an iso-perceptual manifold where percepts of salient sensory variables are stable. This approach offers novel interpretations for a variety of known neurophysiological and behavioral phenomena and makes a number of novel testable predictions. In particular, we discuss novel interpretations for the well-known phenomena of agonist-antagonist co-activation and vibration-induced illusions of both position and force. We also interpret results of several new experiments with unintentional force changes and with analysis of accuracy of perception of variables produced by elements of multi-element systems. Recently, this approach has been expanded to interpret motor disorders including spasticity and consequences of subcortical disorders (such as Parkinson's disease). We suggest that the approach can be developed for cognitive functions. [ABSTRACT FROM AUTHOR]

Congenital Zika Virus Syndrome (CZVS) denotes the neurologic and developmental sequelae of congenital infection of the Zika virus. While prior studies have detailed the associated clinical phenotypes, new findings continue to be identified. Abnormal postures and movements have been previously described in children with CZVS, but not in detail. To examine a cohort of infants with CZVS and characterize the spectrum of motor abnormalities, especially movement disorders. Cross-sectional prospective study of 21 infants with confirmed CZVS. Single-center cohort of 32 patients with serologically confirmed CZVS cared for in a referral center in Brazil. 21 children (67% female), evaluated by two child neurologists and one movement disorders specialist, with clinical and laboratory diagnosis of CZVS aged between 16 and 30 months, with a mean age of 16 months at the time of the last examination. Prospective neurologic examination by a team of three neurologists, including one movement disorders specialist. Sixteen (76.2%) children had a longitudinal evaluation with a six-month interval. The same team of experts analyzed recorded videos of all patients to characterize motor abnormalities and movement disorders. Neuroimaging findings were also analyzed to correlate with clinical findings. Twenty (95.2%) patients presented with dystonic postures, including "125" posture of the fingers in 17 (80.1%), "swan neck" posture of the fingers in three (18.8%), oromandibular dystonia in nine (42.9%), extensor axial hypertonia in eight (38.1%) and internal rotation of the shoulder posture in two (9.5%). Four (19%) patients had tremor. All children had malformations of cortical development, and in 13 (61.9%), the pattern was consistent with a severe and diffuse gyral simplification. Seventeen children (81%) had calcification in the transition of grey and white matter, whereas 11 (52.4%) patients had basal ganglia calcifications. In our series, dystonic postures and other extrapyramidal signs were frequent and potentially disabling. Although children with CZVS are assessed and treated for spasticity, dystonia and other movement disorders remain neglected. This study emphasizes that extrapyramidal findings may potentially influence optimal strategies for rehabilitation and management. [ABSTRACT FROM AUTHOR]

Recently, the herbal medicine Ukgansan (Yigansan in China, Yokukansan in Japan) was reported to be effective in the management of movement disorders. We report the case of a 62-year-old woman with herpes simplex encephalitis exhibiting atypical abnormal movements in the chronic stage. While controlling the abnormal movements with haloperidol, an antipsychotic agent, we prescribed Ukgansan-gami, an extract of a variant of Ukgansan, at a dose of 12 g/day to prevent the recurrence of abnormal movements and allow for the discontinuation of haloperidol. The patient was successfully treated with Ukgansan-gami, with no further recurrence of symptoms, making the use of haloperidol no longer necessary. The potential mechanism of action of Ukgansan involves the inhibition of nervous system hyperexcitability through the suppression of glutamate sodium channels, as well as attenuation of hypermotility through serotonin regulation. The present case suggests that herbal medicine therapy was likely to be an alternative to antipsychotics. [ABSTRACT FROM AUTHOR]

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. This document summarizes the imaging appropriateness data for rapidly progressive dementia, chorea, Parkinsonian syndromes, suspected neurodegeneration with brain iron accumulation, and suspected motor neuron disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. [ABSTRACT FROM AUTHOR]

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. This document summarizes the imaging appropriateness data for rapidly progressive dementia, chorea, Parkinsonian syndromes, suspected neurodegeneration with brain iron accumulation, and suspected motor neuron disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. [ABSTRACT FROM AUTHOR]

Introduction: Clinical neurophysiology constitutes a potentially useful aid in differentiating hyperkinetic movement disorders (HMD). Parameters including presence of a Bereitschaftspotential on back-averaged electroencephalography (EEG) have been demonstrated to help distinguish between these disorders. In 2008, a Movement Disorder neurophysiology service was established in Greater Manchester to aid in the diagnostic process.Methods: We retrospectively reviewed records of patients with HMD who underwent EEG back-averaging through this service from January 2009 until January 2018. The aim was (i) to characterise the clinical features of our patient cohort and (ii) to determine how frequently neurophysiological testing altered the final diagnosis.Results: A total of 39 patients (23 females, 16 males), with a mean age at onset of 42.6 years and mean disease duration of 2.0 years underwent neurophysiological examination. The clinical diagnosis was changed in 16 cases (41%) and refined in a further seven. Distractibility (P = 0.001), variability (P = 0.002), the presence of a Bereitschaftspotential (P < 0.0001), and electromyography burst duration > 300 ms (P = 0.012) were more frequent in those with an eventual diagnosis of functional movement disorder (n = 24) compared to other HMDs (n = 15).Conclusion: Neurophysiology is an invaluable adjunct in complex HMD, altering the diagnosis and treatment options for a significant proportion of patients. Our data also demonstrate, consistent with previous studies, that the majority of patients referred for jerky HMDs to a tertiary movement disorder service have a functional movement disorder. [ABSTRACT FROM AUTHOR]

Introduction: Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD.Method: We examined amplicons encompassing the coding region of GBA (8.9 kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation.Results: We detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408 M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C > T or p.(L335 = ), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants.Conclusion: This work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments. [ABSTRACT FROM AUTHOR]

3-acetylpyridine (3-AP) is a neurotoxin that is known to mainly affect the inferior olivary nucleus (ION) in the brain stem. Although several studies have explored the effect of this neurotoxin, still further investigation is required to understand the impact of this toxin on different parts of the brain. In this research, two groups of rats were studied, the 3-AP-treated and the control groups. Behavioral, stereological, and immunohistochemical analyses were performed. The locomotor activity of the 3-AP-treated rats decreased whereas their anxiety levels were higher than in normal controls. Also, memory performance was impaired in animals in the 3-AP group. Microscopic observations showed a decline in the numerical density of neurons in the hippocampus and striatum along with gliosis. Although this toxin is used to affect the ION, it exerts a neurotoxic effect on different brain regions. [ABSTRACT FROM AUTHOR]

Genetic diagnosis of childhood epilepsy is crucial to provide disease-specific treatments. This report describes the genetic landscape of childhood epilepsy revealed by targeted next-generation sequencing panels for epilepsy (TNGSP-E) and whole exome sequencing (WES). In this retrospective cohort study, TNGSP-E and/or WES were applied to identify underlying genetic diagnoses in children seen in a single Pediatric Epilepsy Genetics Clinic. We reviewed electronic patient charts for phenotypes and biochemical, genetic, and neuroimaging investigations. Forty-four different genetic diagnoses were confirmed in 71 of 197 patients (36%; 95% CI 29.3%–43.2%). The diagnostic yield of WES (37%) was 1.9-fold greater than the diagnostic yield of TNGSP-E (19.0%; P =.0018). The number of genes included in TNGSP-E was not correlated with whether or not the test resulted in a diagnosis (Pearson's R = -0.02, P =.8). Inherited metabolic disorders accounted for 13% of the genetic diagnoses, despite abnormal metabolic investigations being an exclusion criteria. There was a direct treatment implication in 6% of patients with inherited metabolic disorders including pyridoxine dependent epilepsy, glucose transporter 1 deficiency and neuronal ceroid lipofuscinosis type 2. Additionally, there might be some treatment implications in 30% of patients with genetic diagnoses including SCN1A, SCN2A, SCN8A , and KCNQ2 associated epilepsies by application of effective anti-epileptic drugs or the ketogenic diet therapy. The high diagnostic yield of clinical molecular genetic investigations and their disease-specific treatment implications highlight the importance of genetic diagnosis in childhood epilepsy. We recommend a stepwise diagnostic algorithm including metabolic investigations for treatable disorders, chromosomal microarray analysis, TNGSP-E, and WES. • Forty-four different genetic diagnoses using targeted next-generation sequencing panels for epilepsy and whole exome sequencing. • The diagnostic yield of targeted next-generation sequencing panels for epilepsy was 19%. • The diagnostic yield of whole exome sequencing was 37%. • Inherited metabolic disorders were present in 13% of the patients with normal metabolic investigations. • Direct treatment implication of a genetic diagnosis in 6% of the patients with inherited metabolic disorders. [ABSTRACT FROM AUTHOR]

The clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy remain to be elucidated. We describe here the clinical features of 14 patients with GFAP astrocytopathy confirmed by detection of GFAP-IgG in cerebrospinal fluid (CSF). The novel findings of this study are as follows. First, over half of the patients presented with movement disorders (tremor, myoclonus, and ataxia), autonomic dysfunction (mainly urinary dysfunction), and hyponatremia. Second, most patients showed transient elevation of adenosine deaminase activity levels in CSF. Finally, some patients showed bilateral hyperintensities in the posterior part of the thalamus on brain magnetic resonance imaging. Unlabelled Image • We described patients with autoimmune GFAP astrocytopathy in Japan. • They presented with movement disorders, urinary dysfunction, and hyponatremia. • Brain MRI showed the bilateral hyperintensities of posterior part of the thalamus. • The CSF ADA levels were transiently elevated during early stage of this disease. • They were treated with corticosteroid and had a good outcome without relapse. [ABSTRACT FROM AUTHOR]

Introduction: Ataxias are heterogeneous disorders that are caused by variants in a large number of genes. The study was conducted to identify the molecular basis of a movement disorder in a consanguineous Pakistani family.Methods: We performed clinical assessments and magnetic resonance imaging of the older of two siblings affected with a movement disorder. Molecular analyses included whole-exome sequencing in order to delineate the underlying pathology of the disorder. Segregation of variants with the phenotype was checked by Sanger sequencing.Results: Symptoms of the two affected subjects were consistent with cerebellar ataxia with dysarthria. Magnetic resonance imaging did not reveal brain abnormalities. The levels of low density lipid proteins were elevated in blood samples of both affected individuals. Whole-exome sequencing data analyses identified a frameshift variant, c.4993delG:p.(Val1665TyrfsTer36) in ABCA2 (NM_212533.2) which segregated with the disorder and was absent from all publicly available databases and ethnically matched controls. Although recessively inherited ABCA2 variants have been reported in two patients who had intellectual disability with global developmental delays, our study demonstrates the role of an ABCA2 variant in the pathogenesis of ataxia with dysarthria. The phenotype observed in our patients shows high concordance with that observed in Abca2 knockout mice.Conclusion: Our research links an ABCA2 variant with a distinct form of ataxia with dysarthria in humans and demonstrates pleiotropic effects due to the gene mutation. The findings further delineate the importance of low density lipid metabolism and intracellular sterol trafficking in brain function. [ABSTRACT FROM AUTHOR]

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype–genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3. • RECA is defined by recurring episodes of hypotonia and ataxia triggered by fever. • RECA symptoms can be mistaken for recurrent decompensations of metabolic disorders. • RECA is consistently associated with mutations of the Arg756 in the ATP1A3 protein. • Different ATP1A3 ion pump dysfunctions lead to different clinical phenotypes. [ABSTRACT FROM AUTHOR]

Highlights • Deep brain stimulation normalizes abnormal cortical excitability and circuits in movement disorders. • Single-pulse deep brain stimulation modulates the motor cortical circuits. • Repetitive deep brain stimulation with motor cortical stimulation produces cortical plastic changes. Abstract Deep brain stimulation (DBS) implanted in different basal ganglia nuclei regulates the dysfunctional neuronal circuits and improves symptoms in movement disorders. However, the understanding of the neurophysiological mechanism of DBS is at an early stage. Transcranial magnetic stimulation (TMS) can be used safely in movement disorder patients with DBS, and can shed light on how DBS works. DBS at a therapeutic setting normalizes the abnormal motor cortical excitability measured with motor evoked potentials (MEP) produced by primary motor cortical TMS. Abnormal intracortical circuits in the motor cortex tested with paired-pulse TMS paradigm also show normalization with DBS. These changes are accompanied with improvements in symptoms after chronic DBS. Single-pulse DBS produces cortical evoked potentials recorded by electroencephalography at specific latencies and modulates motor cortical excitability at certain time intervals measured with MEP. Combination of basal ganglia DBS with motor cortical TMS at stimulus intervals consistent with the latency of cortical evoked potentials delivered in a repetitive mode produces plastic changes in the primary motor cortex. TMS can be used to examine the effects of open and closed loop DBS. Patterned DBS and TMS delivered in a repetitive mode may be developed as a new therapeutic method for movement disorder patients. [ABSTRACT FROM AUTHOR]

Abstract We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p < 0.001) and PKD/IC in two (p = 0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2 -related phenotypes. [ABSTRACT FROM AUTHOR]

Introduction: Huntington's Disease (HD) cognitive dysfunction occurs before unequivocal motor signs become apparent. The predominant early cognitive abnormal domains may include deficits in psychomotor speed, negative emotion recognition and executive functioning. Our study is aimed to investigate the executive control of cognition in pre-manifest (pre) HD subjects, by means of a task-switching protocol.Methods: We recruited 30 pre-HD subjects and 18 age-, sex- and education-matched Healthy Controls (HC). Subjects were assigned to two experimental groups: 15 pre-HD1 with a Total Motor Score (TMS) ≤4 (far from onset) and 15 pre-HD2 with a 5 ≤ TMS≤9 (near to onset and Diagnostic Confidence Level (DCL) still<4). Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called Switch Cost (SC).Results: Pre-HD subjects had worse performance than HC in the switch and repetition trials, as indicated by increased SC and reaction times. In particular, pre-HD2 showed impaired switching abilities with reaction times slower than pre-HD1 and HC.Conclusions: Our study highlighted a task-switching impairment since HD was still at a pre-manifest stage. Such abnormalities worsen when pre-HD subjects start to show subtle motor manifestations, still nonspecific and insufficient to define the clinical diagnosis of HD (DCL<4). Considering that such abilities have obvious implications for activities of daily living, early cognitive rehabilitation programs addressing such deficits might be useful in the premanifest stage of the disease. [ABSTRACT FROM AUTHOR]

Highlights • We screened 362 patients with encephalitis of unknown aetiology for a panel of antibodies for autoimmune encephalitis. • Out of the 41 patients, 21 (51.2%) patients presented with movement disorder. • The commonest movement disorder encountered in our cohort was orofaciolingual dyskinesia (OFLD) 57.1%. • The hyperkinetic movement disorders were more commonly seen compared to hypokinetic disorders. • On follow, 17 (80.1%) patients had good response with total remission of the movement disorder. Abstract We aimed to study the proportion of patients with movement disorders in seropositive autoimmune encephalitis of non-neoplastic aetiology and also to describe the spectrum of movement disorders in them. We prospectively screened 362 patients of age >12 years with encephalitis of unknown aetiology for a panel of antibodies for autoimmune encephalitis. Demographic and clinical characteristics with focus on the movement disorders were recorded. We also evaluated the differences in the spectrum of movement disorder based on various age groups and antibody positivity. Patients were treated with immune modulating drugs and were followed up for 6 months. Out of the 41 patients, 21 (51.2%) patients presented with movement disorder as a part of their clinical presentation. The commonest movement disorder encountered in our cohort was orofaciolingual dyskinesia (OFLD) 57.1% followed by tremor (38.1%), choreoathetosis (33.3%), paroxysmal dyskinesia (23.8%) stereotypies (14.3%), bradykinesia (13.1%), followed by dystonia (13.1%), catatonia (4.7%), neuromyotonia (4.7%) ballism (4.7%), ataxia (4.7%) and stiff person phenotype (4.7%). The hyperkinetic movement disorders were more commonly seen compared to hypokinetic disorders. All patients received immunomodulatory therapy. On follow, 17 (80.1%) patients had good response with total remission of the movement disorder. Four patients did not have total remission but significant improvement in the symptoms after 6 months of follow up. Our study shows that >50% of patients with antibody positive autoimmune encephalitis have movement disorder as a part of their clinical feature. Timely institution of immunotherapy leads to good outcome in majority of patients. [ABSTRACT FROM AUTHOR]

Abstract On the basis of the findings that the rapid influx of extracellular Zn2+ into nigral dopaminergic neurons causes dopaminergic neurodegeneration, here we report that AMPA causes movement disorder in rats. AMPA markedly increased turning behavior in response to apomorphine 1 and 2 weeks after AMPA injection into the substantia nigra pars compacta (SNpc), while AMPA-induced movement disorder was suppressed by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and TPEN, suggesting that AMPA-induced movement disorder is due to intracellular Zn2+ dysregulation. Furthermore, AMPA markedly induced loss of nigrostriatal dopaminergic neurons 2 weeks after AMPA injection into the SNpc, while AMPA-induced neurodegeneration was also suppressed in the SNpc and the striatum by co-injection of ZnAF-2DA and TPEN. AMPA rapidly increased nigral intracellular Zn2+ after AMPA injection into the SNpc and this increase was blocked by co-injection of TPEN. These results indicate that AMPA receptor activation rapidly increases influx of extracellular Zn2+ into nigral dopaminergic neurons and causes nigrostriatal dopaminergic neurodegeneration, resulting in movement disorder in rats. The evidence that AMPA-induced intracellular Zn2+ dysregulation causes movement disorder via nigrostriatal dopaminergic neurodegeneration suggests that AMPA receptors, probably Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors are potential targets for overcoming Parkinson's syndrome. [ABSTRACT FROM AUTHOR]

[Display omitted] • Parkin and Pink1 are important regulators of the mitochondrial quality control process. • Rab11, a recycling endocytic protein, plays an essential role in vesicular trafficking and function in the same pathway of mitophagy. • Loss of Rab11 function causes muscle degeneration and synaptic defects. • Rab11 acts as a novel regulator of Bruchpilot expression at synapse. • Overexpression of Rab11 improves the muscle and synaptic organization at the neuromuscular junction in Parkinson's disease. Mutation in parkin and pink1 is associated with Parkinson's disease (PD), the most common movement disorder characterized by muscular dysfunction. In a previous study, we observed that Rab11, a member of the small Ras GTPase family, regulates the mitophagy pathway mediated by Parkin and Pink1 in the larval brain of the Drosophila PD model. Here, we describe that the expression and interaction of Rab11 in the PD model of Drosophila is highly conserved across different phylogenic groups. The loss of function in these two proteins, i.e., Parkin and Pink1, leads to mitochondrial aggregation. Rab11 loss of function results in muscle degeneration, movement disorder and synaptic morphological defects. We report that overexpression of Rab11 in park13 heterozygous mutant improves muscle and synaptic organization by reducing mitochondrial aggregations and improving cytoskeleton structural organization. We also show the functional relationship between Rab11 and Brp, a pre-synaptic scaffolding protein, required for synaptic neurotransmission. Using park13 heterozygous mutant and pink1RNAi lines, we showed reduced expression of Brp and consequently, there were synaptic dysfunctions including impaired synaptic transmission, decreased bouton size, increase in the bouton numbers, and the length of axonal innervations at the larval neuromuscular junction (NMJ). These synaptic alterations were rescued with the over-expression of Rab11 in the park13 heterozygous mutants. In conclusion, this work emphasizes the importance of Rab11 in rescuing muscle degeneration, movement dysfunction and synaptic morphology by preserving mitochondrial function in the PD model of Drosophila. [ABSTRACT FROM AUTHOR]

Abstract Functional neurosurgery involves the surgical management of a wide range of neurological diseases with the aim of treating conditions such as movement disorders, spasticity, epilepsy and intractable pain. Functional neurosurgery began with ablative surgical techniques involving destruction of neural structures responsible for the aberrant neural pathways/networks causing pathology. In more recent years there has been a move away from the creation of permanent destructive lesions towards modulation of the neural networks utilizing neuromodulation. Neuromodulation therapies include invasive (e.g. deep brain stimulators, cortical stimulators, vagal nerve stimulators and spinal cord stimulators) and non-invasive (e.g. transcranial magnetic stimulation) approaches that involve the application of electrical stimulation to drive or inhibit neural function within a circuit. Most implantable neuromodulation systems include three primary components: stimulating electrode(s) with contacts at the tip through which electricity is delivered; an implantable pulse generator (IPG) that serves as a signal generator/battery pack; and the extension cable(s) to subcutaneously connect the electrode(s) to the IPG. In this article we primarily focus on the current role of neuromodulation in treating movement disorders, epilepsy and pain, and also consider emerging and evolving applications. [ABSTRACT FROM AUTHOR]

Abstract Normal pressure hydrocephalus (NPH) is generally treated with ventriculoperitoneal shunts (VPS), with improved symptoms in the majority of patients. We performed a retrospective chart review study in order to describe patterns of, and risk factors for, delayed symptom progression after initially successful VPS placement. 69 consecutive patients underwent VPS placement for NPH, and were followed for a minimum of 12 months postoperatively. 55 patients (80%) had objective improvement in their NPH symptoms after surgery. Of these, 27 patients (49%) developed delayed deterioration of at least one of their NPH symptoms, at a mean of 28.3 months postoperatively (range, 3–77). 1 of the 27 patients was found to have shunt malfunction; 19 had specific clinical or imaging evidence of shunt function. 6/19 patients had transient improvement in their symptoms (lasting 30 days or more) after adjustment of their programmable shunt valves (32%), although symptoms in all of these patients later worsened. During a mean follow up period of 44.4 months (range, 15–87), 12 patients (44%) received other neurological diagnoses felt to at least partially explain their symptoms. Increased patient age was associated with likelihood of delayed symptom progression. We conclude that delayed symptom progression is common after VPS placement for NPH, including after initial symptom improvement; that symptom progression can often be temporarily palliated by shunt valve pressure adjustment; and that older patients are more likely to experience delayed symptom progression. We suggest that patients and their families be counselled accordingly before surgery. Highlights • Patients with NPH may have symptomatic improvement after VPS, but show delayed symptomatic progression • Delayed symptomatic progression occurs at an average of 2 years postoperatively and may respond to valve pressure changes • Many patients receive neurological diagnoses other than NPH [ABSTRACT FROM AUTHOR]

Objective Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood. Methods The patients’ DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported. Results Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3 . These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing. Significance Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively. [ABSTRACT FROM AUTHOR]

Abstract Movement disorders are increasingly identified in infantile encephalopathies due to single gene disorders (e.g. SCN2A, CDKL5, ARX). The associated movement disorder can be challenging to recognise and treat. We report a 2 year-old boy with a background history of Ohtahara syndrome due to a missense variant in ARX (the aristaless-related homeobox gene) who subsequently developed status dystonicus. ARX is a transcription factor that plays a critical role in cortical neuronal development and is associated with a range of important neurodevelopmental disorders depending on the site of the pathogenic variant. Cases of status dystonicus are described with variants affecting the polyalanine expansion region of ARX but have not been reported previously with variants affecting the aristaless domain of ARX as in this case. Dystonic episodes posed a challenge in recognition and treatment, including confusion with status epilepticus. We discuss the difficulties in diagnosis and management of status dystonicus, an underreported life-threatening emergency in children. Highlights • Variants in ARX are an important cause of severe early-onset epilepsy, developmental delay and dystonia. • We report status dystonicus in male with Ohtahara syndrome due to a missense variant in ARX , expanding the genotype-phenotype. • Status dytonicus is a “ medical emergency”, requiring early recognition, supportive and dystonia-specific treatments. [ABSTRACT FROM AUTHOR]