关键词： Movement disorders   Neurodegenerative diseases   Neurodevelopmental disorders  

关键词： astrocytes   behaviour   calcium signalling   development   IP(3)R2  

摘要： Astrocytes are key players in the regulation of brain development and function. They sense and respond to the surrounding activity by elevating their intracellular calcium (Ca2+) levels. These astrocytic Ca2+ elevations emerge from different sources and display complex spatio-temporal properties. Ca2+ elevations are spatially distributed in global (soma and main processes) and/or focal regions (microdomains). The inositol 1,4,5-trisphosphate receptor type 2 knockout (IP(3)R2 KO) mouse model lacks global Ca2+ elevations in astrocytes, and it has been used by different laboratories. However, the constitutive deletion of IP(3)R2 during development may trigger compensating phenotypes, which could bias the results of experiments using developing or adult mice. To address this issue, we performed a detailed neurodevelopmental evaluation of male and female IP(3)R2 KO mice, during the first 21 days of life, as well as an evaluation of motor function, strength and neurological reflexes in adult mice. Our results show that male and female IP(3)R2 KO mice display a normal acquisition of developmental milestones, as compared with wild-type (WT) mice. We also show that IP(3)R2 KO mice display normal motor coordination, strength and neurological reflexes in adulthood. To exclude a potential compensatory overexpression of other IP(3)Rs, we quantified the relative mRNA levels of all 3 subtypes, in brain tissue. We found that, along with the complete deletion of Itpr2, there is no compensatory expression of Itpr1 or Itrp3. Overall, our results show that the IP(3)R2 KO mouse is a reliable model to study the functional impact of global IP(3)R2-dependent astrocytic Ca2+ elevations.

关键词： Synapse   Cell adhesion molecules   Nectin   Necl   Afadin   Puncta adherentia junction  

摘要： Synapses are interneuronal junctions which form neuronal networks and play roles in a variety of functions, including learning and memory. Two types of junctions, synaptic junctions (SJs) and puncta adherentia junctions (PAJs), have been identified. SJs are found at all excitatory and inhibitory synapses whereas PAJs are found at excitatory synapses, but not inhibitory synapses, and particularly well developed at hippocampal mossy fiber giant excitatory synapses. Both SJs and PAJs are mediated by cell adhesion molecules (CAMs). Major CAMs at SJs are neuroligins-neurexins and Nectin-like molecules (Necls)/CADMs/SynCAMs whereas those at PAJs are nectins and cadherins. In addition to synaptic PAJs, extrasynaptic PAJs have been identified at contact sites between neighboring dendrites near synapses and regulate synapse formation. In addition to SJs and PAJs, a new type of cell adhesion apparatus different from these junctional apparatuses has been identified and named nectin/Necl spots. One nectin spot at contact sites between neighboring dendrites at extrasynaptic regions near synapses regulates synapse formation. Several members of nectins and Necls had been identified as viral receptors before finding their physiological functions as CAMs and evidence is accumulating that many nectins and Necls are related to onset and progression of neurological diseases. We review here nectin and Necls in synapse formation and involvement in neurological diseases.

关键词： CIDP   diagnosis   GRADE   guideline   treatment  

摘要： To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term "atypical CIDP" was replaced by "CIDP variants" because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants;(b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective;(c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point);(d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended;(e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point);and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).

关键词： Sturge-weber syndrome   Intellectual disability   Language disorder   Angioma   Epilepsy   Port-wine stain  

摘要： Introduction: This study of children with Sturge-Weber syndrome (SWS) profiled neurological presentations;compared patients with (+) and without (-) port-wine stain (PWS);and determined risk factors for intellectual and language impairments. Methods: A retrospective case note review was conducted at a national centre. Results: This cohort (n = 140, male 72, median follow up 114 months) showed sex parity. Intellectual disability ("ID": IQ < 70) affected half (66), being severe (IQ < 40) in two-fifths (27) with ID. Language disorder (core score<70) affected half (57). Neurological presentations were: status epilepticus 57% (80), hemiplegia 58% (81), headaches 36% (50) and acutely acquired neurological deficits lasting over 24 h 40% (56). One-seventh (20) were PWS(-). This group had: fewer lobes with angioma (p < 0.0001);and less frequent ID (p = 0.002) or language disorder (p = 0.013). Seizure frequency and status epilepticus prevalence did not differ from PWS(+). ID and language disorder were associated with: more lobes with angioma;earlier seizure onset;more frequent status epilepticus and seizure clusters. On multivariable analysis recurrent status epilepticus (p = 0.037) and multi-lobe involvement (p = 0.002) increased the risk of severe intellectual disability. Active epilepsy was associated with language disorder (p = 0.030). Conclusions: This is the largest reported series documenting detailed developmental profiles of children with SWS, including ID and ASD. PWS(+) shows high rates of ID and language disorder. PWS(-) SWS has a more favourable outcome. Cognitive outcome is contingent on number of affected lobes and bilateral involvement. Epilepsy exerts an additional deleterious effect on language and cognition. A high percentage of children have a history of status epilepticus, with evidence that this impacts language and cognitive outcomes. Acutely acquired neurological deficits did not penalise either. Regular structured clinical and developmental assessment

关键词： EEG reactivity   Cardiac arrest   Prognostication   Machine learning   Predictive modeling  

摘要： Objective: To test whether 1) quantitative analysis of EEG reactivity (EEG-R) using machine learning (ML) is superior to visual analysis, and 2) combining quantitative analyses of EEG-R and EEG background pattern increases prognostic value for prediction of poor outcome after cardiac arrest (CA). Methods: Several types of ML models were trained with twelve quantitative features derived from EEG-R and EEG background data of 134 adult CA patients. Poor outcome was a Cerebral Performance Category score of 3-5 within 6 months. Results: The Random Forest (RF) trained on EEG-R showed the highest AUC of 83% (95-CI 80-86) of tested ML classifiers, predicting poor outcome with 46% sensitivity (95%-CI 40-51) and 89% specificity (95%-CI 86-92). Visual analysis of EEG-R had 80% sensitivity and 65% specificity. The RF was also the best classifier for EEG background (AUC 85%, 95%-CI 83-88) at 24 h after CA, with 62% sensitivity (95%-CI 57-67) and 84% specificity (95%-CI 79-88). Combining EEG-R and EEG background RF classifiers reduced the number of false positives. Conclusions: Quantitative EEG-R using ML predicts poor outcome with higher specificity, but lower sensitivity compared to visual analysis of EEG-R, and is of some additional value to ML on EEG background data. Significance: Quantitative EEG-R using ML is a promising alternative to visual analysis and of some added value to ML on EEG background data. (C) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

关键词： Neurogenic bladder   Spinal cord diseases  

摘要： Study design Cross-sectional study. Objectives To evaluate if specific definitions of detrusor sphincter dyssynergia (DSD) might distinguish between individuals with spinal cord injury (SCI) and those with no underlying neurological disorder (NO ND). Setting Single tertiary university SCI center. Methods A series of 153 individuals, 81 with traumatic SCI and 72 with NO ND, were prospectively evaluated and included in this study. All individuals underwent a clinical neuro-urological examination, a neurophysiological work-up and a video-urodynamic investigation and were diagnosed with DSD as defined by the International Continence Society (ICS). We determined the DSD grades/types according to the classifications by Yalla (grade 1-3), Blaivas (type 1-3) and Weld (type 1-2). Distribution of the DSD grades/types were compared between SCI and NO ND individuals. Associations between the various DSD grades/types and clinical parameters, such as risk factors for upper urinary tract damage (all individuals) or lower extremity motor scores, SCI injury levels and severity scores (only SCI group), were assessed. Results The distribution of all DSD types were similar between groups (p > 0.05). None of the DSD classifications allowed risk assessment for upper urinary tract damage. A significant association between DSD type and other clinical parameters could not be found (p > 0.05). Conclusions None of the investigated DSD definitions can distinguish between patients with SCI and with NO ND. The more complex DSD classifications by Yalla, Blaivas or Weld cannot compete with the ICS binary yes-no definition which is pragmatic and straightforward for managing patients in daily clinical practice. Sponsorship None.

摘要： This commentary is on the original article by Maddison et al. on pages 1099–1106 of this issue.

摘要： In the era of genomic medicine, diagnoses of rare paediatric neurological diseases are increasing. Many are untreatable and life-limiting, leading to an exceptional increase in gene therapy development. It is estimated that 20 gene therapy products will have received approval from the US Food and Drug Administration by 2025. With viral gene therapy considered a potential single-dose cure for patients with spinal muscular atrophy type 1 as one example, and contemporaneously tragically resulting in the deaths of three male children with X-linked myotubular myopathy receiving high-dose gene therapy in 2020, what is the current state of gene therapy? What is behind the decades of hype around viral gene therapy and is it high impact, but high risk? In this review, we outline principles of viral gene therapy development and summarize the most recent clinical evidence for the therapeutic effect of gene therapy in paediatric neurological diseases. We discuss adeno-associated virus and lentiviral vectors, antisense oligonucleotides, emerging genetic editing approaches, and current limitations that the field still faces.