Summary: Purpose: To determine whether specific regions of cerebral cortex are activated at the onset and during the propagation of absence seizures. Methods: Twenty-five absence seizures were recorded in five subjects (all women; age 19‐58 years) with primary generalized epilepsy. To improve spatial resolution, all studies were performed with dense-array, 256-channel scalp EEG. Source analysis was conducted with equivalent dipole (BESA) and smoothed linear inverse (LORETA) methods. Analyses were applied to the spike components of each spike‐wave burst in each seizure, with sources visualized with standard brain models. Results :F or each patient, the major findings were apparent on inspection of the scalp EEG maps and waveforms, and the two methods of source analysis gave generally convergent results. The onset of seizures was typically associated with activation of discrete, often unilateral areas of dorsolateral frontal or orbital frontal lobe. Consistently across all seizures, the negative slow wave was maximal over frontal cortex, and the spike that appeared to follow the slow wave was highly localized over frontopolar regions of orbital frontal lobe. In addition, sources in dorsomedial frontal cortex were engaged for each spike‐wave cycle. Although each patient showed unique features, the absence seizures of all patients showed rapid, stereotyped evolution to engage both mesial frontal and orbital frontal cortex sources during the repeating cycles of spike‐wave activity. Conclusions: These data suggest that absence seizures are not truly “generalized,” with immediate global cortical involvement, but rather involve selective cortical networks, including orbital frontal and mesial frontal regions, in the propagation of ictal discharges. Ke yW ords: Absence seizures—EEG—Source analysis—Dipole—Cerebral cortex—Thalamus.

/pdf/are-generalized-seizures-truly-generalized-evidence-of-2amiwbrvq2.pdf

Are “Generalized” Seizures Truly Generalized? Evidence of Localized Mesial Frontal and Frontopolar Discharges in Absence

Dynamics of non-convulsive epileptic phenomena modeled by a bistable neuronal network.

The idiopathic generalized epilepsies encompass a class of epileptic seizure types that exhibit a polygenic and heritable etiology. Advances in molecular biology and genetics have implicated defects in certain types of voltage-gated calcium channels and their ancillary subunits as important players in this form of epilepsy. Both T-type and P/Q-type channels appear to mediate important contributions to seizure genesis, modulation of network activity, and genetic seizure susceptibility. Here, we provide a comprehensive overview of the roles of these channels and associated subunits in normal and pathological brain activity within the context of idiopathic generalized epilepsy.

https://www.physiology.org/doi/pdf/10.1152/physrev.00002.2006

Voltage-Gated Calcium Channels and Idiopathic Generalized Epilepsies

Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.

T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures

Cortical-area specific block of genetically determined absence seizures by ethosuximide

Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy

The treatment options for central chondrosarcoma are limited, and prognoses are generally unreliable. The presence and absence of mutations in IDH1, and IDH2 are defining events, and TERT mutations have been recently been associated with poor outcome. Despite this, molecular biomarkers are lacking. Here, analysing data from 356 patients, comprising results from whole genome sequencing (n=68), digital droplet PCR (n=346), and methylation arrays (n=57), we present a comprehensive genetic analysis of chondrosarcoma and suggest its clinical utility. Methylation profiles, TERT promoter mutations, genome doubling with prior haploidisation, and age at diagnosis of high grade, distinguish IDH1-mutant, IDH2-mutant and IDH wildtype tumours. The majority of IDH2-mutant tumours harbour TERT mutations, though a significant reduction in survival is only found in the less common mutational combination of IDH1 and TERT. We suggest that diagnostic testing for IDH1, IDH2 and TERT mutations could guide clinical monitoring and prognostication.

https://medrxiv.org/content/10.1101/2021.11.02.21265785v1.full.pdf

A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome

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Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy

A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome