SCN1A/NaV1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models

Summary

Pathogenic SCN1A/NaV1.1 mutations cause well‐defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, SCN1A/NaV1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/NaV1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene‐targeted animal models, and the induced pluripotent ...

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SCN8A encephalopathy: Mechanisms and models

Summary

De novo mutations of the neuronal sodium channel SCN8A have been identified in approximately 2% of individuals with epileptic encephalopathy. These missense mutations alter the biophysical properties of sodium channel Nav1.6 in ways that lead to neuronal hyperexcitability. We generated two mouse models carrying patient mutations N1768D and R1872W to examine the effects on neuronal function in vivo. The conditional R1872W mutation is activated by expression of CRE recombinase, permitting characterization of the effects of the mutation on different classes ...

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Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults

Abstract

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed ...

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Impaired vigilance networks in temporal lobe epilepsy: Mechanisms and clinical implications

Abstract

Mesial temporal lobe epilepsy (mTLE) is a neurological disorder in which patients suffer from frequent consciousness‐impairing seizures, broad neurocognitive deficits, and diminished quality of life. Although seizures in mTLE originate focally in the hippocampus or amygdala, mTLE patients demonstrate cognitive deficits that extend beyond temporal lobe function—such as decline in executive function, cognitive processing speed, and attention—as well as diffuse decreases in neocortical metabolism and functional connectivity. Given prior observations that mTLE patients exhibit impairments in vigilance, and that seizures ...

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Ensembling crowdsourced seizure prediction algorithms using long‐term human intracranial EEG

Abstract

Seizure prediction is feasible, but greater accuracy is needed to make seizure prediction clinically viable across a large group of patients. Recent work crowdsourced state‐of‐the‐art prediction algorithms in a worldwide competition, yielding improvements in seizure prediction performance for patients whose seizures were previously found hard to anticipate. The aim of the current analysis was to explore potential performance improvements using an ensemble of the top competition algorithms. The results suggest that minor increments in performance may be possible; however, the ...

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Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country‐, center‐, and age‐specific variation

Abstract

Objective

To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015.

Methods

We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries.

Results

We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial ...

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Oligodendrocyte lineage and myelination are compromised in the gray matter of focal cortical dysplasia type IIa

Abstract

Objectives

Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of medically intractable epilepsy. FCDs are characterized by local architectural disturbances of the neocortex and often by a blurred gray‐white matter boundary indicating abnormal white matter myelination. We have recently shown that myelination is also compromised in the gray matter of dysplastic areas, since transcripts encoding factors for oligodendrocyte differentiation and myelination are downregulated and myelin fibers appear fractured and disorganized.

Methods

Here, we characterized the gray ...

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Hippocampal profiling: Localized magnetic resonance imaging volumetry and T2 relaxometry for hippocampal sclerosis

Abstract

Objective

Hippocampal sclerosis (HS) is the most common cause of drug‐resistant temporal lobe epilepsy, and its accurate detection is important to guide epilepsy surgery. Radiological features of HS include hippocampal volume loss and increased T2 signal, which can both be quantified to help improve detection. In this work, we extend these quantitative methods to generate cross‐sectional area and T2 profiles along the hippocampal long axis to improve the localization of hippocampal abnormalities.

Methods

T1‐weighted and T2 relaxometry data from 69 HS patients (32 ...

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Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study

Abstract

Objective

In tuberous sclerosis complex (TSC)‐associated drug‐resistant epilepsy, the optimal invasive electroencephalographic (EEG) and operative approach remains unclear. We examined the role of stereo‐EEG in TSC and used stereo‐EEG data to investigate tuber and surrounding cortex epileptogenicity.

Methods

We analyzed 18 patients with TSC who underwent stereo‐EEG (seven adults). One hundred ten seizures were analyzed with the epileptogenicity index (EI). In 13 patients with adequate tuber sampling, five anatomical regions of interest (ROIs) were defined: dominant tuber (tuber with highest median EI), perituber ...

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