Epilepsia
Steroid hormones, such as progestogens and androgens, influence seizures. Progestogens and androgens exert organizational and/or activational effects that may mitigate vulnerability to, and/or expression of, some seizure disorders. Progestogens, such as progesterone (P4) and its 5α‐reduced metabolite, 5α‐pregnan‐3α‐ol‐20‐one (3α,5α‐THP), which vary across the reproductive cycle and lifespan, may protect...
Tuberous sclerosis complex (TSC) and severe cortical dysplasia (CD), or CD type II according to Palmini classification, share histopathologic similarities, specifically the presence of cytomegalic neurons and balloon cells. In this study we examined the morphologic and electrophysiologic properties of cells in cortical tissue samples from pediatric patients with TSC and CD type II who underwent surgery...
One of the major challenges in developing novel therapeutics for human epileptic disorders comes from the wide range of brain abnormalities capable of producing epilepsy. In children and adults that undergo epilepsy surgery for treatment of refractory seizures, these abnormalities range from developmental defects to injuries, infections, tumors, and ischemia. Given the many molecular mechanisms likely...
Pretreatment with the endocannabinoid‐receptor antagonist, SR141716, has been reported to suppress the long‐lasting hyperexcitability and increased seizure susceptibility present after 30 min of hyperthermia‐induced convulsions in immature rats, an animal model of complex febrile seizures in children, which may be a cause of temporal lobe epilepsy. The present experiments tested the hypothesis that...
Neurosteroids such as allopregnanolone (THP) act as positive allosteric modulators of γ‐aminobutyric acid (GABA)A receptors and have exerted anticonvulsant properties. However, their role in the regulation of epileptogenesis is unclear. It has been shown that circulating levels of THP fluctuate during development and seizure episodes. Furthermore, both chronic administration of THP and its withdrawal...
Interneurons, γ‐aminobutyric acid (GABA)A receptor density, and subunit composition determine inhibitory function in pyramidal neurons and control excitability in cortex. Abnormalities in GABAergic cells or GABAA receptors could contribute to seizures in malformations of cortical development. Herein we review data obtained in resected cortex from pediatric epilepsy surgery patients with type I and...
Brain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during...
Inflammatory signaling in the central nervous system (CNS) has been shown to exacerbate both seizure activity and seizure‐induced neuronal injury. However, it has not been firmly established whether neurodegeneration is a prerequisite of proconvulsant effect of neuroinflammation, or whether the latter may facilitate seizures without involving neuronal injury. We examined effects of inflammation in...
γ‐Aminobutyric acid (GABA) has an important role in the mechanism of epilepsy. Cell grafts from different sources have been performed to modulate local circuits or increase GABAergic inhibition in animal models of epilepsy. Among the different transplanted cell types, the medial ganglionic eminence (MGE)–derived cells present the best properties to be used in cell‐based therapy. In this work we review...
Cortical dysplasia is often associated with intractable seizures. Studies in animal models have described changes in inhibitory and excitatory synaptic function that contribute to hyperexcitability. The role of changes in intrinsic excitability and abnormal dendritic properties has received less attention. Changes in hyperpolarization‐activated nonselective cation (HCN) channels have been implicated...
Migraine and epilepsy are comorbid conditions that have many clinical similarities. There are also cellular physiologic similarities, and some antiepileptic drugs are prophylactic in migraine, suggesting common pathophysiologic elements. The most compelling evidence comes from familial hemiplegic migraine, in which migraine and epilepsy can be caused by mutations in the same gene. For an expanded...
Lafora disease (EPM2A and EPM2B genes); myoclonus epilepsy with ragged red fibers; or MERRF (mtDNA tRNA genes), and Dentatorubral‐pallidoluysian atrophy or DRPLA (ATN1 gene) are three severe forms of progressive myoclonus epilepsy. The corresponding gene defects have been identified and molecular diagnosis is now widely available. Recent advances in genetics and molecular biology offer promising venues...
Findings obtained from surgical specimens of epilepsy patients and animal models of epilepsy demonstrate dysfunction of astrocytes in epilepsy. Specifically, gap junction coupling, glutamate uptake, and K+ buffering are compromised. In epilepsy models, astroglial alterations occur very early after status epilepticus, suggesting their crucial involvement in the process of epileptogenesis. For an expanded...
Spontaneous mutation of the gene encoding theP/Q voltage‐gated calcium ion channel alpha subunit proved to be the first identified cause of absence epilepsy, and subsequent exploration of other members within this gene family has had a major impact on our understanding of how inherited errors of single genes lead to specific epileptic phenotypes. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
The onset, progression, and severity of epilepsy vary between family members with identical mutations in primary disease genes. The background of genetic variation unique to each individual genome contributes to clinical variation. Known examples of gene interactions in human families and mouse models provide insight into underlying molecular mechanisms. For an expanded treatment of this topic see...
Mutations in the Aristaless‐related homeobox gene (ARX) are linked to infantile spasms and other developmental epilepsies. How loss of Arx leads to epilepsy is not well understood. This review will discuss the spectrum of Arx disorders and the emerging evidence, from animal models, of the function of Arx during development and the potential role in generating an epilepsy phenotype. For an expanded...
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of brief motor seizures. This rare syndrome is caused by mutations in at least two subunit genes of the neuronal nicotinic acetylcholine receptor (nAChR). Some of these mutations seem to increase the risk for additional neurologic symptoms. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
γ‐Aminobutyric acid (GABA)A receptors are ligand‐gated chloride channels that mediate fast synaptic inhibition in the brain. Recently, loss‐of‐function mutations have been identified in four different GABAA subunits, in rare but distinct forms of familial idiopathic generalized epilepsy. These results provide important insights into the pathogenesis of the disease. For an expanded treatment of this...