Epilepsia. Official Journal of the International League Against Epilepsy

Abstract

Objective

A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl⁻ importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl⁻ concentration ([Cl⁻]_i) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl⁻]_i with NKCC1, and ...

Abstract

Objective

In the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small-molecule, highly lipid-soluble drug, CBD is likely to distribute into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short-term placental effects, we conducted an ex vivo perfusion study in human placentas.

Methods

Placentas were obtained from healthy women ...

Abstract

Objective

Cognitive impairment often impacts quality of life in epilepsy even if seizures are controlled. Word-finding difficulty is particularly prevalent and often attributed to etiological (static, baseline) circuit alterations. We sought to determine whether interictal discharges convey significant superimposed contributions to word-finding difficulty in patients, and if so, through which cognitive mechanism(s).

Methods

Twenty-three patients undergoing intracranial monitoring for drug-resistant epilepsy participated in multiple tasks involving word-production (auditory naming, short-term verbal free recall, repetition) to probe word-finding difficulty across different cognitive domains. We ...

Abstract

Missense variants of HCN ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). While variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here, we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared ...

Abstract

Many patients suffering from epilepsy undergo exome or genome sequencing as part of a diagnostic work-up, however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for epilepsy patients; 1) the underlying cause is not genetic, 2) there is a complex polygenic explanation, 3) the illness is monogenic but the causative gene remains to be linked to a human disorder, 4) family segregation with reduced penetrance, 5) somatic mosaicism or the complexity of ...

Abstract

Objective

GABA_A receptor subunit gene mutations are major causes of various epilepsy syndromes, including severe kinds such as Dravet syndrome. Although the GABA_A receptor is a major target for antiseizure medications, treating GABA_A receptor mutations with the receptor channel modulators is ineffective. Here we determined the effect of a novel treatment with 4-phenylbutyrate (PBA) in the Gabrg2
^+/Q390X
knockin mice associated with Dravet syndrome.

Methods

We used biochemistry in conjunction with differential tagging of the wildtype and the mutant alleles, live brain ...

Abstract

Focal cortical dysplasia (FCD) is the most frequent etiology of operable pharmacoresistant epilepsy in children. There is burgeoning evidence that FCD-related epilepsy is a disorder that involves distributed brain networks. Functional magnetic resonance imaging (fMRI) is a tool that allows one to infer neuronal activity and to non-invasively map whole-brain functional networks. Despite its relative widespread availability at most epilepsy centers, the clinical application of fMRI remains mostly task-based in epilepsy. Another approach is to map and characterize cortical functional ...

Abstract

Objective

N-methyl-D-aspartate (NMDA) receptors are expressed at synaptic sites where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor are associated with severe neurological disorders that include epilepsy, intellectual disability and developmental delay. Here we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val [GluN1-3b(I481V)], p.Ala666Ser [GluN1-3b(A666S)] and p.Tyr668His [GluN1-3b(Y668H)].

Methods

Wild-type and variant-containing NMDA receptors were ...

Abstract

Background

With the unanimous approval of the Intersectoral Global Action Plan on epilepsy and other neurological disorders by the World Health Organization in May 2022, there are strong imperatives to work towards equitable neurological care.

Aims

Using epilepsy as an entry point to other neurologic conditions, we discuss disparities faced by marginalized groups including racial/ethnic minorities, Americans living in rural communities, and Americans with low socioeconomic status.

Materials and Methods

The National Institute on Minority Health Disparities Research Framework (NIMHD) was used to conduct a ...