bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potassium Channels (Including KCNQ) and Epilepsy
Authors: Cooper Edward C. 
Published: May 2013

Abstract
This chapter aims to provide a perspective on the achievements and future potential of studies of potassium channels in epilepsy research. The thesis is that the understanding obtained from recent studies justifies continued investment in K+ channels by academic and industry-based researchers. We first reintroduce the K+ channels, highlighting progress that appears particularly relevant to epilepsy. Then, as an example, we provide a detailed account of one K+ channel subfamily, the KCNQ/Kv7 family. Members of this family are mutated in benign familial neonatal seizures, an autosomal dominant syndrome. Moreover, these channels have been found to be practical targets for antiepileptic drug development, perhaps providing a model for studies of other K+ channel subgroups. We conclude with a discussion of directions for future work.
Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Ion Channelopathy in Epilepsy
Authors: Poolos Nicholas P. 
Published: May 2013

Abstract
This chapter describes how the unique biophysical properties of HCN channels lead to an influential role in seizure generation; whether recent evidence truly supports the existence of HCN channelopathy in human epilepsy; and how the mechanisms underlying acquired HCN dysfunction could be targeted by antiepileptic therapies.
Neuronal Synchronization and Thalamocortical Rhythms during Sleep, Wake, and Epilepsy
Authors: Timofeev Igor , Bazhenov Maxim , Seigneur Josée , Sejnowski Terrence 
Published: May 2013

Abstract
Neuronal synchronization can be divided into long-range and local synchrony. Long-range synchrony is usually detected with two or more electrodes placed some distance apart. It leads to brain activity that is correlated at long distances and may be seen using both local field potential (LFP) and electroencephalogram (EEG) recordings. The first tool (i.e., the LFP) provides a microscopic measure of brain activity summarizing electrical activities of possibly thousands of neurons 1–4. The second type of recording (i.e., the EEG) is a result of changes in electrical activity of multiple sources and ultimately represents activity patterns of large populations of neurons and glial cells in the brain. Local or short-range synchrony can be detected either with one relatively large field potential electrode or with two or more small [intracellular or extracellular unit (action potential) recording] electrodes located at short (less than 1 mm) distances from each other. Synchronous activity of a few neurons does not necessarily lead to measurable EEG signals, but this can be seen using LFP recordings. Because of the low-pass filtering properties of the extracellular media,5 high-frequency electric fields associated with action potentials steeply attenuate and large-amplitude slow LFP and EEG potentials are mainly generated from nearly simultaneously occurring de- and hyperpolarizing events in a large number of neighboring cells with a major contribution from large pyramidal neurons.6
Brainstem Networks
Authors: Faingold Carl L. 
Published: May 2013

Abstract
Penfield and Jasper1 proposed that generalized seizures involve the brainstem reticular formation (BRF) and other brain sites that are extensively connected to most other brain regions as a centrencephalic system. Considerable subsequent research has confirmed a major role for the BRF in the neuronal networks that subserve generalized convulsive seizure generation. The BRF has been defined to include the core of the brainstem in the medulla, pons, and midbrain. The projections between brainstem nuclei, as well as those to and from the BRF, are massive, including all levels of the central nervous system (CNS) from spinal cord to cerebral cortex. Recent research on the anatomical and neurochemical diversity of nuclei within the BRF has been extensive, leading to a more complex view of the functions of the brainstem. However, these observations have not invalidated the original concept that the BRF has the potential to act as an extremely large network (reticulum) capable of “mass action” under certain circumstances, such as arousal or generalized convulsive seizure.2–4 Depression of BRF neurons was originally and is still implicated as a major mechanism of action for depressant and anesthetic drugs.2,5
On the Basic Mechanisms of Infantile Spasms
Authors: Swann John W. , Moshe Solomon L. 
Published: May 2013

Abstract
We are at a very early stage in studying the basic mechanisms of infantile spasms. However, features of several promising animal models have been described, and more may be forthcoming in the near future. Technical challenges are substantial in studying seizures in infant rodents, but they are not insurmountable. The basic science and clinical communities need to evaluate each of the proposed animal models and develop minimal criteria for what they consider to be a valid animal model of this disorder. Once validated, models should provide an unprecedented opportunity to study the mechanisms responsible for this catastrophic epilepsy and hopefully provide new avenues for effective therapies.
Head Trauma and Epilepsy
Authors: Pitkänen Asla , Bolkvadze Tamuna 
Published: May 2013

Abstract
Recent advances in model development provide a platform for studies that are aimed at understanding the post-TBI molecular and cellular alterations leading to epilepsy. Undoubtedly, the search for surrogate markers that identify subjects with the highest risk for posttraumatic epileptogenesis will benefit from novel possibilities for following candidate epileptogenic changes in neuronal circuits in vivo using structural and functional imaging. Some proof-of-principle trials already suggest that post-TBI seizure susceptibility can be favourably modified.
Role of Blood-Brain Barrier Dysfunction in Epileptogenesis
Authors: Friedman Alon , Heinemann Uwe 
Published: May 2013

Abstract
Focal epilepsy typically arises from neuronal tissue either within or adjacent to a cortical lesion. About 30% of epilepsies are caused by acquired etiologies such as traumatic brain injury, stroke, infection, or prolonged febrile seizures.1 Injury-related acquired epilepsy is frequently resistant to medications and may be associated with other neurological impairments. In most animal models of acquired epilepsy (similar to the situation in humans), a period of days to weeks is required for the development of seizures.2,3 Typically, the initial insult is followed by a latent interval, referred to as epileptogenesis, in which cellular and structural reorganization occurs that ultimately leads to chronic recurrent epileptic seizures. While the molecular, anatomical, and electrophysiological activities in the epileptic focus have been described in great details (e.g., in refs. 4–8), the critical changes occurring following injury and before epileptic activity develops are mostly unknown. A better understanding of the molecular and physiological events during epileptogenesis is essential for the targeted development of preventive therapeutic approaches that are presently unavailable.1
Histopathology of Human Epilepsy
Authors: de Lanerolle Nihal C. , Lee Tih-Shih , Spencer Dennis D. 
Published: May 2013

Abstract
Histopathological lesions that are associated with seizures are described in several neurological disease states. Such histopathological lesions are found in developmental disorders, neoplasms, microbial diseases, cerebrovascular diseases, trauma, and immune-mediated disorders, as well as in disorders primarily related to seizures such as temporal lobe epilepsy (TLE). General descriptions of these lesions have been the subject of several reviews.1,2 Temporal lobe epilepsy, a major seizure disorder that affects over 40 million people worldwide, has received the most study in relation to its histopathology, and the histological lesion is thus best understood in relation to epilepsy. This chapter will review the state of our knowledge in the histopathology of TLE.
Alterations in Synaptic Function in Epilepsy
Authors: Bernard Christophe 
Published: May 2013

Abstract
How do alterations in synaptic function relate to seizures and their comorbidities? This question has been particularly difficult to address since epilepsy is often a time-dependent disorder, involving (for example) an initial insult (which may involve genetic alterations, meningitis, brain trauma, etc.) and the subsequent trigger of a number of network modifications. Ultimately, some of these modifications may be directly linked to seizure generation and/or comorbidities. It is therefore important to understand the time course of these changes. This issue has been extensively investigated in experimental models of temporal lobe epilepsy, which are characterized by a latent seizure-free period of about 2 weeks following the initial insult (usually a period of status epilepticus). We will use these models to describe synaptic remodeling and its possible functional consequences in the adult brain, focusing on the hippocampus.
Neurogenesis and Epilepsy
Authors: Parent Jack M. , Kron Michelle M. 
Published: May 2013

Abstract
Medial temporal lobe epilepsy (mTLE) is a common and often intractable form of epilepsy. Approximately 50 million people suffer from different epilepsies worldwide,1 30%–40% of whom may continue to have poorly controlled seizures despite therapy.2,3 Medial TLE is estimated to be the most common cause of intractable epilepsy in this population.4 In addition to chronic seizures, the long-term morbidity of mTLE includes an increased incidence of depression5,6 and problems with learning and memory7,8 that may progress despite adequate seizure control.9 Thus, progress in the study of mTLE is critical for developing better therapies to ease the large burden of this disorder. Humans with mTLE often have an initial precipitating event, followed by a latent period and subsequent development of epilepsy later in life. This knowledge has led to the development of the most common animal models of mTLE. In these models, a prolonged seizure (termed status epilepticus, SE) is induced by either electrical stimulation or a chemoconvulsant, leading to injury as the initial precipitating event. After a seizure-free latent period, spontaneous seizures develop and persist for the lifetime of the animal.10,11 The two most commonly used chemconvulsant-induced SE models of mTLE are the kainic acid and pilocarpine models.
GABAA Receptor Plasticity during Status Epilepticus
Authors: Joshi Suchitra , Kapur Jaideep 
Published: May 2013

Abstract
Status epilepticus (SE) is a prolonged, self-sustained seizure that can manifest as a prolonged convulsion, subtle facial or limb twitching, or simply altered mental status, always in association with a persistent electroencephalographic (EEG) seizure pattern. In clinical trials, convulsive seizures lasting longer than 5 min are often treated as SE,1 whereas epidemiological studies have defined 30 min of continuous convulsive seizures or intermittent seizures without recovery of consciousness as SE.2 There are 126,000 to 195,000 episodes of SE associated with 22,000 to 42,000 deaths each year in the United States when SE is defined as 30 min of seizures.2 As many as 50% of patients older than 65 years of age who suffer from SE die within 30 days of the episode. Although mortality is far less common in younger patients, they are at risk for neurological morbidity, such as injury to the hippocampus3 and neuropsychological dysfunction.4 Prolonged seizures can also lead to significant systemic complications, including pulmonary congestion and edema, cardiac arrhythmias, hypotension, elevation of body temperature, hypoglycemia, acidosis, and rhabdomylosis. These systemic complications tend to worsen as more seizures occur.5 It has long been recognized that SE is a dynamic and rapidly evolving condition.5,6 Ongoing seizures rapidly modify neuronal activity and synaptic function.7 This rapid neuronal plasticity is manifest in changes in behavioral seizures, EEG patterns, sensitivity to drugs, and evolution of neuronal injury and death. Although these changes are continuous, it is convenient to divide SE into stages for the purposes of investigation and treatment (Table 41–1).
Astrocytes and Epilepsy
Authors: Clasadonte Jerome , Haydon Philip G. 
Published: May 2013

Abstract
Glia, Greek for “glue,” was discovered by Rudolph Virchow, a German anatomist, in the mid-nineteenth century. The name reflects the original view that glia played merely a structural or metabolic support role for neurons. Glial cells, especially astrocytes, are much more than glue or merely quiescent and display their own set of activities. Studies over the last 20 years show that astrocytes perform a series of complex functions that go well beyond the uptake and recycling of neurotransmitters and the buffering of extracellular potassium.1,2
Astrocyte Dysfunction in Epilepsy
Authors: Steinhäuser Christian , Seifert Gerald 
Published: May 2013

Abstract
The novel view of astrocytes as communication partners of neurons rather than “brain glue” has rekindled the question regarding the role of these cells in neurological disorders such as epilepsy. Indeed, an increasing body of evidence has documented astroglial dysfunction, and even dysregulation of astroglia-specific functions, in human and experimental epilepsy. This particularly concerns impaired uptake/conversion of glutamate and removal/redistribution of K+, as observed in MTLE-HS. However, a number of key questions need to be addressed before a unifying picture can be proposed. For example, it is still unclear whether the reported glial alterations are a cause or a consequence of the condition. In addition, difficulties arise from the fact that the term astrocyte covers a heterogeneous group of cells, and this complicates comparison of individual studies. It is worthwhile, however, to emphasize that the molecular, functional, and structural characterization of astroglial heterogeneity is a rapidly evolving field that may soon lead to a better definition of astroglial subtypes. In a comprehensive approach that uses modern molecular genetics and in vivo models, we may now have the opportunity to clarify the specific roles of astroglia in epilepsy and to develop novel therapeutic approaches to fight this disorder.
Mutated GABAA Receptor Subunits in Idiopathic Generalized Epilepsy
Authors: Cossette Patrick , Lachance-Touchette Pamela , Rouleau Guy A. 
Published: May 2013

Abstract
An increasing number of genes predisposing to epilepsy have been identified over the past 10 years. Among these genes, mutations in four subunits of the GABAA receptor appear to be important causes of familial epilepsy. So far, the majority of these mutations have been associated with a dramatic decrease of GABA-evoked currents in recombinant receptors. Because GABA is the main inhibitory transmitter in the adult brain, it is generally believed that this loss of function would cause abnormal excitability of cortical neurons, thereby leading to clinical seizures. However, in contrast to the mature central nervous system, GABA is excitatory in the developing brain. This apparent paradox is caused by an inversion in the chloride gradient across the cell membrane that occurs during the first days of life. There is now increasing evidence supporting the hypothesis that excitatory GABA transmission plays a key role in various aspects of brain development, such as neuronal migration, shaping of dendritic trees, and synaptogenesis. It is thus very likely that epilepsy-causing mutations in GABAA receptors would be associated with abnormal development of neuronal networks, which may be one of the critical mechanisms leading to the disease. However, so far, this hypothesis has not been examined. Should it be validated, it would provide an unparalleled advance in our comprehension of the IGEs.
GABAA Receptor Subunit Mutations and Genetic Epilepsies
Authors: Macdonald Robert L. , Kang Jing-Qiong , Gallagher Martin J. 
Published: May 2013

Abstract
Idiopathic epilepsy syndromes (IES) are common and constitute about 50% of the epilepsies diagnosed worldwide.1 They vary in severity from the relatively benign febrile seizures (FS) and childhood absence epilepsy (CAE) to the severe epilepsy syndrome Dravet syndrome. A common IES is FS plus (FS+), which develops early in childhood with multiple FS that continue to occur beyond 6 years of age or are associated with afebrile seizures.2 Generalized epilepsy with FS plus (GEFS+) is a familial epilepsy syndrome in which multiple family members have either FS, FS+, myoclonic-astatic epilepsy (MAE), and DS.2
Rare Genetic Causes of Lissencephaly May Implicate Microtubule-Based Transport in the Pathogenesis of Cortical Dysplasias
Authors: Liu Judy S. , Schubert Christian R. , Walsh Christopher A. 
Published: May 2013

Abstract
Disruption of early neural development can cause severe forms of mental retardation and epilepsy associated with defects in cortical structure, such as lissencephaly (“smooth brain”), a disorder resulting from abnormal neuronal migration. Of the six causative genes for classical lissencephaly, three—LIS1, DCX, and TUBA1A—encode for microtubule-related proteins, indicating the importance of this pathway for neuronal migration (Table 60–1). The lissencephaly 1 (LIS1) protein is an adaptor for dynein, a microtubule motor protein.1 Doublecortin (DCX) encodes a microtubule-associated protein (MAP).2,3 Finally, tubulin α1a (TUBA1A) is a gene that encodes an α-tubulin subunit that is enriched during brain development.4 These lissencephalic syndromes clinically all share a widespread disruption of lamination in the cerebral cortex (Fig. 60–1). Since all three genes appear to regulate microtubule-based transport, their functional relation and regulation during development is an area of active investigation with implications that may be significant for a wider cohort of patients with focal cortical dysplasias. Cortical dysplasias are a common cause of refractory epilepsy and share some of the histological features of lissencephaly, including the dyslamination and abnormal neuronal morphology.5 Disruption of microtubule-based pathways may lead to cortical dysplasias, and the causative genes for lissencephaly are a starting point for further investigation.
The Generation of Cortical Interneurons
Authors: Gelman Diego M. , Marín Oscar , Rubenstein John L.R. 
Published: May 2013

Abstract
Most, if not all, mouse pallial interneurons are derived from three progenitor regions in the embryonic subpallium: MGE, CGE, and POA (Fig. 61–3). While there is controversy about this in the human, there is strong evidence that the ganglionic eminences are fundamental sources for pallial interneurons in all vertebrates. Development of these regions is regulated by multiple transcription factors. Arx, Ascl1, and Dlx1,2,5&6 have roles in all of these regions, whereas MGE development is regulated by Nkx2-1, Lhx6, Lhx8, and Sox6, and CGE development is regulated by Gsx2. Future studies should aim at elucidating the molecular mechanisms downstream of these transcription factors that regulate cell fate specification and differentiation of specific interneuron subtypes. Furthermore, because many of the transcription factors that regulate early interneuron development are expressed in mature interneurons (e.g., Arx, Dlx1,2,5&6, Lhx6, and Sox6), it is likely that they have roles in controlling interneuron function and/or survival, such as Dlx1.36 As interneuron defects that could contribute to epilepsy include abnormalities in their production, migration, differentiation, function, and survival, the mechanisms gleaned from basic studies should provide insights into the molecular, cellular, and histological underpinnings of epileptogenesis.
Haploinsufficiency of STXBP1 and Ohtahara Syndrome
Authors: Saitsu Hirotomo , Kato Mitsuhiro , Matsumoto Naomichi 
Published: May 2013

Abstract
Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy with suppression-burst, is one of the most severe and earliest forms of epilepsy.1 It is characterized by early onset of tonic seizures, seizure intractability, characteristic suppression-burst patterns on the electroencephalogram (EEG), and a poor outcome with severe psychomotor retardation.2,3 Brain malformations, such as cerebral dysgenesis or hemimegalencephaly, are often associated with OS, but cryptogenic or idiopathic OS is found in a subset of OS patients, in whom genetic aberrations might be involved.4 Although mutations of the ARX gene have been found in several male patients with OS,5–8 the genetic causes are unexplained in most cryptogenic OS cases. We have recently found de novo mutations in STXBP1 (encoding syntaxin binding protein 1, also known as MUNC18-1) in individuals with cryptogenic OS.9 Here we present all the mutations in STXBP1 found to date in OS patients, as well as some evidence of mutations leading to haploinsufficiency.
mTOR and Epileptogenesis in Developmental Brain Malformations
Authors: Wong Michael , Crino Peter B. 
Published: May 2013

Abstract
Malformations of cortical development (MCDs) are among the most common causes of epilepsy. While a wide variety of types and classifications of MCDs exists,1 a subset of focal cortical malformations (FCMs), including tuberous sclerosis complex (TSC), focal cortical dysplasia, ganglioglioma, and hemimegalencephaly, is associated with an especially high incidence of epilepsy and other neurological deficits, such as cognitive dysfunction and autism.2,3 Epilepsy related to these focal developmental brain malformations is often refractory to medical therapy. Even in patients whose seizures are well controlled with medications, currently available drugs are only symptomatic treatments that help suppress seizures; they have not been demonstrated to have antiepileptogenic or disease-modifying properties in preventing or altering the long-term prognosis of epilepsy. Although epilepsy surgery may eliminate seizures in some medically intractable cases, many patients are not good candidates for surgery or continue to have seizures despite surgical intervention. Thus, novel therapeutic strategies are needed to reduce the burden of seizures and other neurological symptoms caused by MCDs or, ideally, to prevent the development of epilepsy in the first place.