Epilepsia
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Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. ⋯ In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl(-)](i)) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl(-)](i) that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs.
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Several factors contribute to epileptogenesis in patients with brain tumors, including reduced γ-aminobutyric acid (GABA)ergic inhibition. In particular, changes in Cl(-) homeostasis in peritumoral microenvironment, together with alterations of metabolism, are key processes leading to epileptogenesis in patients afflicted by glioma. It has been recently proposed that alterations of Cl(-) homeostasis could be involved in tumor cell migration and metastasis formation. In neurons, the regulation of intracellular Cl(-) concentration ([Cl(-) ](i) ) is mediated by NKCC1 and KCC2 transporters: NKCC1 increases while KCC2 decreases [Cl(-) ](i) . Experiments were thus designed to investigate whether, in human epileptic peritumoral cortex, alterations in the balance of NKCC1 and KCC2 activity may decrease the hyperpolarizing effects of GABA, thereby contributing to epileptogenesis in human brain tumors. ⋯ We report that the positive shift of E(GABA) in epileptic peritumoral human cortex is due to an altered expression of NKCC1 and KCC2, perturbing Cl(-) homeostasis, which might lead to a consequent reduction in GABAergic inhibition. These findings point to a key role of Cl(-) transporters KCC2 and NKCC1 in tumor-related epilepsy, suggesting a more specific drug therapy and surgical approaches for the epileptic patients afflicted by brain tumors.
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Because more selective and individual versus extended standard surgery in the treatment of epilepsy appears to result in similar seizure outcomes, the issue of sparing nonlesional and hypothetically still-functioning tissues has become a central topic in epilepsy surgery. Within this framework we hypothesized that surgery in magnetic resonance imaging (MRI)- and histopathologically negative patients with temporal lobe epilepsy (TLE) may serve as a proof of principle about the negative cognitive consequences of resecting nonlesional tissue. ⋯ Preoperative group differences in memory and the finding that, after surgery, both groups had comparably poor performance levels indicate a major relevance of morphologic structural lesions for memory impairment in TLE. The findings in particular confirm the negative impact of the resection of nonlesional functional tissue for cognitive surgical outcome. Absence of MRI lesion and unimpaired memory appear as significant risk factors for postoperative memory loss in temporal lobe surgery.
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Although gamma-knife radiosurgery (GKS) has proved efficacious in temporal lobe epilepsy (TLE), its antiepileptic mechanism of action remains elusive. Human and experimental data suggest that subnecrotic radiation-induced tissue changes might contribute to the antiepileptic effect of GKS. However, there are no data regarding the evolution of electroencephalography (EEG) activity within GKS-treated hippocampus, information that aid in better understanding both the mechanism of action and the reason for failure of GKS treatment. ⋯ Our study shows that mesial temporal structures previously treated with GKS can demonstrate a persistent high degree of epileptiform activity in patients who failed to respond to that treatment. Although this persistent EEG activity appears likely to reflect GKS-induced brain changes, its relation to GKS seizure outcome remains unclear.
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Lennox-Gastaut syndrome (LGS) is an intractable childhood-onset epileptic encephalopathy. Seizure freedom is rare in LGS. One of the hallmarks of LGS is medical intractability, with generally poor response to antiepileptic drugs (AEDs). ⋯ New AEDs have been validated in randomized, controlled trials for the treatment of seizures in LGS. In some cases, nonpharmacologic options may be effective, although more data are needed to confirm efficacy outcomes. Comprehensive patient assessments are critical to achieve an optimal AED treatment regimen and minimize the potential for adverse effects.