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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...
Epilepsy often results from a brain insult. Herein, I describe the complex time‐dependent alterations in glutamatergic and γ‐aminobutyric acid (GABA)ergic circuitry triggered by the initial insult. I will relate these modifications to the occurrence of the first spontaneous seizure, the development of epileptogenic networks, and associated cognitive deficits. For an expanded treatment of this topic...
Posttraumatic epilepsy (PTE) is defined as a recurrent seizure disorder due to injury to the brain following head trauma. Traumatic brain injury (TBI) accounts for 20% of symptomatic epilepsy in the general population and 5% of all epilepsy. Prevention or suppression of the development of PTE is a major unmet challenge in medicine. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Neonatal hypoxic/ischemic encephalopathy is the most common cause of neonatal seizures, and these seizures are refractory to conventional antiseizure drugs and can lead to later life epilepsy and congitive deficits. Data from human tissue studies as well as rodent models suggest unique age‐specific mechanisms underlying these neonatal seizure and their consequences, and are leading to a number of...
Epilepsy research is undergoing a conceptual shift that is moving away from preventing seizures to preventing epilepsy by treatments that modify the epileptogenic process induced by a variety of brain insults. Evidence from animal experiments suggests that epilepsy prevention or modification is possible, but translating laboratory findings into successful therapies will require more scientific discoveries...
Two electron‐neutral, cation‐chloride cotransporters control intraneuronal chloride ion concentration (Cl−). The Na‐K‐2Cl cotransporter‐1 mediates Cl− influx while the K‐Cl cotransporter‐2 (KCC2) extrudes Cl−, assuring that γ‐aminobutyric acid (GABA)ergic signals hyperpolarize neurons. KCC2 is downregulated in pyramidal cells from human temporal lobe epilepsy and experimental focal epilepsy, inducing...
The neurobiologic basis for infantile spasms has long been debated but with little resolution. The very recent development of several animal models of this disorder should provide a paradigm shift in our understanding of this disorder. This chapter outlines unresolved questions and suggests experimental approaches to answering them. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Seizures and epilepsy are fundamentally neuronal circuit phenomena. This article describes the development and application of multiple dynamic imaging techniques that, in combination, facilitate the elucidation of hippocampal circuit function in animal models of epilepsy. This combined approach has significant promise in furthering our understanding of the mechanisms underlying epilepsy. For an expanded...
Some have questioned whether research into basic mechanisms of the epilepsies can have a significant impact on the development of better treatments and cures for patients with epilepsy. In that context, it is helpful to develop clear expectations about what we can accomplish in the laboratory, and how to optimize our contributions. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
The development of any new therapy for the treatment of a human disorder or disease depends heavily on the demonstration of efficacy in a validated animal model. The need for finding a therapy that would prevent or delay the development of epilepsy in the susceptible individual is evident, and many of the required tools have been developed in recent years. However, there are many practical challenges...
The study of depression as a comorbidity of epilepsy in humans is limited by the attendant iatrogenic and psychosocial variables. In order to study the neurobiology of this clinically important phenomenon without the above‐mentioned confounding factors, we have studied the behavioral and biochemical correlates of epilepsy‐associated depression in two rodent models of limbic epileptogenesis. For an...
Levetiracetam’s (Keppra) binding site and its subsequent identification as the synaptic vesicle protein 2A (SV2A) enabled the discovery of high affinity SV2A ligands with promising anticonvulsant properties. Among these, brivaracetam was selected for further development. SV2A represents an important antiepileptic drug target validated in both preclinical and clinical studies. For an expanded treatment...
Purpose: Absence epilepsies are common, with a major genetic contribution to etiology. Certain environmental factors can influence absence occurrence but a complete understanding of absence precipitation is lacking. Herein we investigate if lowering blood glucose increases spike‐wave activity in mouse models with varying seizure susceptibility.
Methods: Three mouse models were used: an absence seizure...
Purpose: Mutations in the SCN1A gene, which encodes the α1 subunit of voltage‐gated sodium channels, cause generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). N1417H‐Scn1a mutant rats are considered to be an animal model of human FS+ or GEFS+. To assess the pharmacologic validity of this model, we compared the efficacies of eight different antiepileptic...
Selective serotonin reuptake inhibitors (SSRIs) can reduce seizure frequency in humans, but no large‐scale clinical trials have been done to test the utility of SSRIs as potential antiepileptic drugs. This may be caused in part by a small number of reports on seizures triggered by SSRI treatment. The preclinical literature on SSRIs is somewhat conflicting, which is likely to contribute to the hesitance...
Purpose: Mossy fiber sprouting (MFS) is a frequent finding following status epilepticus (SE). The present study aimed to test the feasibility of using manganese‐enhanced magnetic resonance imaging (MEMRI) to detect MFS in the chronic phase of the well‐established pilocarpine (Pilo) rat model of temporal lobe epilepsy (TLE).
Methods: To modulate MFS, cycloheximide (CHX), a protein synthesis inhibitor,...
Many symptoms of neurologic or psychiatric illness—such as cognitive impairment, depression, anxiety, attention deficits, and migraine—occur more frequently in people with epilepsy than in the general population. These diverse comorbidities present an underappreciated problem for people with epilepsy and their caregivers because they decrease quality of life, complicate treatment, and increase mortality...
A working group was created to address clinical “gaps to care” as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease‐modifying or antiepileptogenic effect...
Gene therapy in human disease has expanded rapidly in recent years with the development of safer and more effective viral vectors, and presents a novel approach to the treatment of epilepsy. Studies in animals models have demonstrated that overexpression of inhibitory peptides can modify seizure threshold, prevent the development of epilepsy, and modify established epilepsy. More recently there has...
The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically...
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