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Epileptogenesis

About: Epileptogenesis is a research topic. Over the lifetime, 4218 publications have been published within this topic receiving 170809 citations.


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TL;DR: Autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice and impaired autophagy contributes to epileptogenesis, which may be of interest as a potential therapeutic target for epilepsy treatment and/or prevention.
Abstract: Certain mutations within the mammalian target of rapamycin (mTOR) pathway, most notably those affecting the tuberous sclerosis complex (TSC), lead to aberrant activation of mTOR and result in a high incidence of epilepsy in humans and animal models. Although hyperactivation of mTOR has been strongly linked to the development of epilepsy and, conversely, inhibition of mTOR by rapamycin treatment is protective against seizures in several models, the downstream epileptic mechanisms have remained elusive. Autophagy, a catabolic process that plays a vital role in cellular homeostasis by mediating the turnover of cytoplasmic constituents, is negatively regulated by mTOR. Here we demonstrate that autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice, both of which display aberrant mTOR activation and seizures. In addition, we also discovered that autophagy is suppressed in the brains of human TSC patients. Moreover, conditional deletion of Atg7, an essential regulator of autophagy, in mouse forebrain neurons is sufficient to promote development of spontaneous seizures. Thus, our study suggests that impaired autophagy contributes to epileptogenesis, which may be of interest as a potential therapeutic target for epilepsy treatment and/or prevention.

122 citations

Journal ArticleDOI
TL;DR: In this article, the authors discuss five clinical syndromes that have seizures as a prominent manifestation: mutation of a specific family of ion (potassium) channels in benign familial neonatal convulsions, deficiency of the protein that transports glucose into the CNS in Glut-1 deficiency, aberrantly formed local neural circuits in focal cortical dysplasia, synaptic reorganization of limbic circuitry in temporal lobe epilepsy, and abnormal thalamocortical circuit function in childhood absence epilepsy.
Abstract: Epilepsy is a common neurologic disorder that manifests in diverse ways. There are numerous seizure types and numerous mechanisms by which the brain generates seizures. The two hallmarks of seizure generation are hyperexcitability of neurons and hypersynchrony of neural circuits. A large variety of mechanisms alters the balance between excitation and inhibition to predispose a local or widespread region of the brain to hyperexcitability and hypersynchrony. This review discusses five clinical syndromes that have seizures as a prominent manifestation. These five syndromes differ markedly in their etiologies and clinical features, and were selected for discussion because the seizures are generated at a different 'level' of neural dysfunction in each case: (1) mutation of a specific family of ion (potassium) channels in benign familial neonatal convulsions; (2) deficiency of the protein that transports glucose into the CNS in Glut-1 deficiency; (3) aberrantly formed local neural circuits in focal cortical dysplasia; (4) synaptic reorganization of limbic circuitry in temporal lobe epilepsy; and (5) abnormal thalamocortical circuit function in childhood absence epilepsy. Despite this diversity of clinical phenotype and mechanism, these syndromes are informative as to how pathophysiological processes converge to produce brain hyperexcitability and seizures.

121 citations

Journal ArticleDOI
TL;DR: There is evidence that defects in synapse elimination and remodeling during early “critical periods” can trigger hyperexcitability later in life, and further clarification of the developmental pathways to epilepsy has important implications for disease prevention and therapy.
Abstract: Epilepsy is characterized by spontaneous recurrent seizures and comprises a diverse group of syndromes with different aetiologies. Epileptogenesis refers to the process whereby the brain becomes epileptic and can be related to several factors, such as acquired structural brain lesions, inborn brain malformations, alterations in neuronal signalling and defects in maturation and plasticity of neuronal networks. In this review, we will focus on alterations of brain development that lead to an hyperexcitability phenotype in adulthood, providing examples from both animal and human studies. Malformations of cortical development (including focal cortical dysplasia, lissencephaly, heterotopia, and polymicrogyria) are frequently epileptogenic and result from defects in cell proliferation in the germinal zone and/or impaired neuronal migration and differentiation. Delayed or reduced arrival of inhibitory interneurons into the cortical plate is another possible cause of epileptogenesis. GABAergic neurons are generated during early development in the ganglionic eminences, and failure to pursue migration towards the cortex alters the excitatory/inhibitory balance resulting in aberrant network hyperexcitability. More subtle defects in the developmental assembly of excitatory and inhibitory synapses are also involved in epilepsy. For example, mutations in the presynaptic proteins synapsins and SNAP-25 cause derangements of synaptic transmission and plasticity which underlie appearance of an epileptic phenotype. Finally, there is evidence that defects in synapse elimination and remodelling during early “critical periods” can trigger hyperexcitability later in life. Further clarification of the developmental pathways to epilepsy has important implications for disease prevention and therapy.

121 citations

Journal ArticleDOI
01 Dec 2007-Brain
TL;DR: Results for the first time demonstrate that quantitative diffusion MRI can serve as a tool to facilitate prediction of increased seizure susceptibility in a clinically relevant model of human PTE.
Abstract: The need to use animal models to develop imaging markers that could be linked to electrophysiological abnormalities in epilepsy and able to predict epileptogenicity in human studies is widely acknowledged. This study aimed to investigate the value of early magnetic resonance imaging (MRI) in predicting the long-term increased seizure susceptibility in the clinically relevant model of post-traumatic epilepsy (PTE). Moderate traumatic brain injury (TBI) was induced by lateral fluid-percussion in two groups of adult rats (34 injured, 16 controls). In Experiment 1, MRI follow-up was performed using a 4.7 T magnet at 3 h, 3 days, 9 days, 23 days, 2 months, 3 months and 6 months after TBI. T2 and 1/3 of the trace of the diffusion tensor ( D av) were quantified from a single slice using a fast spin-echo sequence. In Experiment 2, MRI was performed at 7 and 11 months post-injury. In both groups, seizure susceptibility was tested by injecting a single dose of pentylenetetrazol at 12 months post-injury. Electrographic and behavioural responses were monitored for 1 h. Total number of spikes, total number of epileptiform discharges (EDs) and latency to first spike were measured. Finally, the severity of mossy fibre sprouting was evaluated. In both experiments, EEG parameters such as total number of spikes or EDs proved to be reliable indicators of increased seizure susceptibility in injured animals when compared to controls ( P < 0.05). In the hippocampus ipsilateral to TBI, D av correlated with these EEG parameters at both early (3 h), and chronic (23 days, 2, 3, 6, 7 and 11 months) time points after TBI, as well as with the density of mossy fibre sprouting. These results for the first time demonstrate that quantitative diffusion MRI can serve as a tool to facilitate prediction of increased seizure susceptibility in a clinically relevant model of human PTE.

121 citations

Journal ArticleDOI
TL;DR: Continuous radiotelemetric electroencephalography and video monitoring are used along with automated computer detection of EEG spikes and seizures to test the hypothesis that EEG spikes precede and are correlated with subsequent spontaneous recurrent seizures.
Abstract: Summary Purpose: Chronic epilepsy frequently develops after brain injury, but prediction of which individual patient will develop spontaneous recurrent seizures (i.e., epilepsy) is not currently possible. Here, we use continuous radiotelemetric electroencephalography (EEG) and video monitoring along with automated computer detection of EEG spikes and seizures to test the hypothesis that EEG spikes precede and are correlated with subsequent spontaneous recurrent seizures. Methods: The presence and pattern of EEG spikes was studied during long recording epochs between the end of status epilepticus (SE) induced by three different doses of kainate and the onset of chronic epilepsy. Results: The presence of spikes, and later spike clusters, over several days after SE before the first spontaneous seizure, was consistently associated with the development of chronic epilepsy. The rate of development of epilepsy (i.e., increase in seizure frequency) was strongly correlated with the frequency of EEG spikes and the cumulative number of EEG spikes after SE. Conclusions: The temporal features of EEG spikes (i.e., their presence, frequency, and pattern [clusters]) when analyzed over prolonged periods, may be a predictive biomarker for the development of chronic epilepsy after brain injury. Future clinical trials using prolonged EEG recordings may reveal the diagnostic utility of EEG spikes as predictors of subsequent epilepsy in brain-injured humans.

121 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023181
2022348
2021245
2020219
2019210
2018209