19 research outputs found
Autoimmune Epilepsy: Some Epilepsy Patients Harbor Autoantibodies to Glutamate Receptors and dsDNA on both Sides of the Blood-brain Barrier, which may Kill Neurons and Decrease in Brain Fluids after Hemispherotomy
Purpose: Elucidating the potential contribution of specific autoantibodies (Ab's)
to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy
patients with Rasmussen's encephalitis (RE) and 71 patients with other epilepsies
were tested for Ab's to the âBâ peptide (amino acids 372-395) of the glutamate/AMPA
subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and
additional autoimmune disease-associated autoantigens, and for the ability of their
serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B
Ab's were found in serum and CSF of most RE patients, and in serum of 17/71
(24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab's
decreased drastically in CSF following functional-hemispherotomy, in association
with seizure cessation and neurological improvement. Serum and CSF of two RE
patients, and serum of 12/71 (17%) patients with other epilepsies, contained
elevated anti-dsDNA Ab's, the hallmark of systemic-lupus-erythematosus. The sera
(but not the CSF) of some RE patients contained also clinically elevated levels of
âclassicalâ autoimmune Ab's to glutamic-acid-decarboxylase,
cardiolipin,
ÎČ2-glycoprotein-I and nuclear-antigens SS-A and RNP-70. Sera and CSF of some
RE patients caused substantial death of hippocampal neurons. Conclusions: Some
epilepsy patients harbor Ab's to GluR3 and dsDNA on both sides of the blood-brain
barrier, and additional autoimmune Ab's only in serum. Since all these Ab's may
be detrimental to the nervous system and/or peripheral organs, we recommend
testing
for their presence in epilepsy, and silencing their activity in Ab-positive patients
International consensus recommendations on the diagnostic work-up for malformations of cortical development
Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCDÂ subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk
Ultra-rare genetic variation in common epilepsies: a case-control sequencing study
BACKGROUND:Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS:We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS:We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1âĂâ10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1âĂâ10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8âĂâ10-8) that were lower than expected from a random sampling of genes. INTERPRETATION:We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING:National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK
Spontaneous dissection of the extra-and intracranial internal carotid artery
info:eu-repo/semantics/nonPublishe
Dissection spontanée de l'artÚre carotide interne chez une adolescente
info:eu-repo/semantics/nonPublishe
MRI of acute disseminated encephalomyelitis after Coxsackie B infection
SCOPUS: ar.jinfo:eu-repo/semantics/publishe
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Sodium Channel SCN3A (Na(V)1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development
Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel Na(V)1.3. Pathogenic Na(V)1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (Na(V)1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.Peer reviewe
Autoimmune Epilepsy: Some Epilepsy Patients Harbor Autoantibodies to Glutamate Receptors and dsDNA on both Sides of the Bloodâbrain Barrier, which may Kill Neurons and Decrease in Brain Fluids after Hemispherotomy
Purpose: Elucidating the potential contribution of specific autoantibodies (Abâs) to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy patients with Rasmussenâs encephalitis (RE) and 71 patients with other epilepsies were tested for Abâs to the âB â peptide (amino acids 372â395) of the glutamate/AMPA subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and additional autoimmune disease-associated autoantigens, and for the ability of their serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B Abâs were found in serum and CSF of most RE patients, and in serum of 17/71 (24%) patients with other epilepsies. In two RE patients, anti-GluR3B Abâs decreased drastically in CSF following functional-hemispherotomy, in association with seizure cessation and neurological improvement. Serum and CSF of two RE patients, and serum of 12/71 (17%) patients with other epilepsies, contained elevated anti-dsDNA Abâs, the hallmark of systemic-lupus-erythematosus. The sera (but not the CSF) of some RE patients contained also clinically elevated levels of âclassical