Epileptogenesis

Pitkänen, Asla; Łukasiuk, Katarzyna; Dudek, F. Edward; Staley, Kevin J.

doi:10.1101/cshperspect.a022822

Cited by 252 publications

(180 citation statements)

References 124 publications

(114 reference statements)

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“…Even in the normal developing brain, excitatory synaptic function develops before inhibitory synaptic function, favoring enhanced excitation and seizure generation. In addition, early in life, the neurotransmitter GABA causes excitation rather than inhibition (BenAri 2002;Pitkänen et al 2015). These observations partly explain why the very young brain is especially susceptible to seizures.…”

Section: Pathophysiology and Geneticsmentioning

confidence: 99%

“…Phenobarbital or phenytoin sometimes suppresses clinical seizures, but electrographic seizures continue ("uncoupling"). Any drug that targets GABA receptors (barbiturates, benzodiazepines) may be ineffective or even exacerbate seizures because of the depolarizing action of GABA in the neonatal brain (Staley 2006;Berkovic 2015;Pitkänen et al 2015). Active research is attempting to untangle the role of potassium-chloride cotransporters and their developmental profile in the GABA depolarizing-to-hyperpolarizing switch; inhibitors of these cotransporters might have clinical utility (Löscher et al 2013).…”

Section: Neonatal Seizuresmentioning

confidence: 99%

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Seizures and Epilepsy: An Overview for Neuroscientists

Stafstrom

Carmant²

2015

Cold Spring Harbor Perspectives in Medicine

567

421

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Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.T his article provides an overview of seizures and epilepsy for neuroscientists. We focus on broad concepts, rather than clinical details, and raise questions related to mechanisms, epileptogenesis, and therapeutic approaches that might generate interest among basic researchers. Further information about differential diagnosis, drug doses, and clinical management are available from numerous resources (Engel and Pedley 2008;Duchowny et al. 2012;Engel 2013).We first define seizures and epilepsy and summarize their classification, pathophysiology, and genetics. Diagnostic methods are then considered, including the importance of an accurate historical description of an event suspected to be a seizure and the appropriate use of ancillary/confirmative tests, such as electroencephalogram (EEG), neuroimaging, and genetic studies. These modalities enable the clinician to differentiate epilepsy from numerous clinical conditions that mimic seizures, but have a nonepileptic pathophysiological basis. Examples of epilepsy syndromes are then described, selected based on their frequency in the population or because they embody scientific questions that warrant elucidation. Finally, we provide an overview of treatment options and prognosis, including a consideration of conditions that accompany epilepsy (comorbidities) and complicate the daily lives of people with epilepsy. Subsequent articles in this collection explore the scientific basis of many of the clinical concepts introduced here. DEFINITIONS AND EPIDEMIOLOGYA "seizure" is a paroxysmal alteration of neurologic function caused by the excessive, hyper-

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Section: Pathophysiology and Geneticsmentioning

confidence: 99%

Section: Neonatal Seizuresmentioning

confidence: 99%

Seizures and Epilepsy: An Overview for Neuroscientists

Stafstrom

Carmant²

2015

Cold Spring Harbor Perspectives in Medicine

567

421

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“…In contrast, antiepileptogenic screening in animal models of chronic epilepsy can take several months 57, 58. The second stage of screening was also accomplished in a matter of weeks.…”

Section: Discussionmentioning

confidence: 99%

Staged anticonvulsant screening for chronic epilepsy

Berdichevsky

Saponjian

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveCurrent anticonvulsant screening programs are based on seizures evoked in normal animals. One‐third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high‐throughput in vitro models to low‐throughput in vivo models.MethodsEpileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure‐like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings.ResultsWe screened 407 compound‐concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy.InterpretationThe use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure‐like activity and seizure‐induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models.

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“…As per the new guidelines of ILAE, the epileptogenesis extends from the time of first brain insult, such as SE, with a consequence of structural (cellular and molecular) and functional changes in the brain, leading to a decreased seizure threshold for onset of spontaneous recurrent seizures, which continue to progress thereafter (Hellier et al 1998; Williams et al 2009; Kadam et al 2010; Goldstein and Coulter 2013; Pitkanen and Engel, 2014; Pitkanen et al, 2015). The process of epileptogenesis follows immediately after SE and the brain changes continue to progress beyond the first couple of spontaneous seizures.…”

Section: The Hallmarks Of Epileptogenesismentioning

confidence: 99%

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

Sharma

Puttachary

Thippeswamy

2017

J of Neuroscience Research

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Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease-modifying agents. For translational studies, SE targets are appropriate for screening anticonvulsive drugs prior to their advancement as therapeutic agents, while targets of epileptogenesis are relevant for identification and development of therapeutic agents that can either prevent or modify the disease or its onset. The acute seizure models do not reveal antiepileptogenic properties of anticonvulsive drugs. This review highlights the important components of epileptogenesis and the long-term impact of intervening one of these components, nitric oxide (NO), in rat and mouse kainate models of TLE. NO is a putative pleotropic gaseous neurotransmitter and an important contributor of nitro-oxidative stress that coexists with neuroinflammation and epileptogenesis. The long-term impact of inhibiting the glial source of NO during early epileptogenesis in the rat model of TLE is reviewed. The importance of sex as a biological variable in disease modification strategies in epilepsy is also briefly discussed.

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Epileptogenesis

Cited by 252 publications

References 124 publications

Seizures and Epilepsy: An Overview for Neuroscientists

Seizures and Epilepsy: An Overview for Neuroscientists

Staged anticonvulsant screening for chronic epilepsy

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

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