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  • American Epilepsy Society (AES): Written Comments to Norman E. “Ned” Sharpless, MD, Acting Commissioner of Food and Drugs, U.S. Food and Drug Administration (FDA), Department of Health and Human Services (HHS): on Docket ID# FDA-2019-N-1482, Scientific Data and Information about Products Containing Cannabis or Cannabis-Derived Compounds; Public Hearing; Request for Comments: Submitted on: July 16, 2019
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-10-22
    Timothy E. Welty; Kevin E. Chapman; R. Edward Faught, Jr; Robert J. Kotloski

    On April 3, 2019, the US Food and Drug Administration (FDA) announced a public hearing on May 31, 2019 and a call for written comments on the topic of cannabis and cannabis-derived compounds.1 Kevin Chapman, MD, spoke on behalf of the American Epilepsy Society (AES) at the public hearing. Transcripts of comments, including those by Dr Chapman, are available through the FDA website.2

    更新日期:2019-11-13
  • EEG Reactivity in Coma After Cardiac Arrest: Is it Enough to Wake Up the Dead?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-16
    Jong Woo Lee

    A variety of tools have been developed to aid in the prognosis of comatose patients after cardiac arrest (CA), particularly since the advent of targeted temperature management, which has rendered clinical examination less predictive than in the past. Among the most promising and widely used is electroencephalogram reactivity, defined as change in electroencephalogram (EEG) frequency or amplitude in response to an external stimulus; the absence of reactivity 72 hours after CA as a poor prognostic marker is included in the American Heart Association Guidelines for post-CA care.1 However, there are no definite standards for delivering or assessing EEG reactivity, there have been concerns for substantial interrater disagreement,2 and there are marked variations in practice across institutions.3

    更新日期:2019-11-13
  • Guilty by Association: KCTD16 and GABABR Antibodies in Paraneoplastic Limbic Encephalitis
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-10-02
    Nicolas Gaspard

    Since its seminal description in the 1960s,1 the spectrum of limbic encephalitis (LE) has considerably expanded. So has our understanding of its causes, with the establishment of a link with cancer and the identification of onconenural antibodies in the 1990s, followed by the identification of sporadic autoimmune cases and of antibodies to neuronal surface antigens in the 2000s. There are currently more than a dozen antibodies associated with idiopathic and paraneoplastic LE (Table 1). The γ-aminobutyric acid B receptor (GABABR) antibody is a relatively recent addition to this expanding list. With around 150 cases reported prior to this series2–11 (Table 2), this entity is rare—approximately 20 times less frequent than the anti-NMDAR syndrome,2 for instance—although it is likely underdiagnosed.

    更新日期:2019-11-13
  • Is Spontaneity Overrated? The Value of Cortical Stimulation–Induced Seizures
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-10-09
    Naymee Velez-Ruiz

    Cortical stimulation (CS)–induced seizures were first reported during the early days of neurosurgery when intraoperative electrical CS elicited patient’s habitual auras.1,2 Since then CS has been used to delineate the epileptogenic zone (EZ) in patients undergoing invasive presurgical investigations for pharmacoresistant epilepsy. The EZ has been defined as the region that produces the complete ictal electroclinical pattern.3 Most of the data published on CS-induced seizures are restricted to anecdotal reports, and what is available relates mostly to stimulation studies using stereoelectroencephalography (SEEG). Until now the clinical utility of CS-elicited seizures to delineate the EZ was not well established because it had not been methodically investigated.

    更新日期:2019-11-13
  • Seizing the Neuroinflammatory Target: The Quest Continues
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-05
    Ayushe A. Sharma; Jerzy P. Szaflarski

    The relationship between epilepsy and neuroinflammation is no longer being questioned. In fact, studies have shown that, in response to tissue insult, the neuroinflammatory cascade starts with microglial activation, which then may continue even when the original insult has been removed. Neuroinflammation may underlie neurological diseases that have evaded scientists for years, with current investigations focusing on its role in multiple sclerosis, Alzheimer disease, and, of greatest significance to us, epilepsy. In the case of epilepsy, perpetual activation of the neuroinflammatory cascade likely results in dysfunction of the blood–brain barrier, giving rise to chronic neuronal hyperexcitability.1,2 This lowers seizure threshold and promotes aberrant epileptic activity, eventually resulting in the process of epileptogenesis and the development of clinical seizures.1,2 Prior to the dawn of advanced neuroimaging, studying neuroinflammation in humans depended on probing postmortem (or surgical) tissue samples. However, the development of modern neuroimaging techniques has allowed us targeted imaging of microglial activation via positron emission tomography (PET). Positron emission tomography imaging that utilizes specific tracers allows visualizing biochemical properties of neuroinflammation in vivo and may hold promise for localizing ictal onset zone(s) in patients with lesional and nonlesional epilepsy.

    更新日期:2019-11-13
  • How High Can Patients Get on CBD?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-16
    Angela Birnbaum

    There is interest in identifying drugs that have a potential for abuse before they become widely available so that safeguards can be put into place before distribution. The Food and Drug Administration defines drug abuse “as the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desired psychological or physiological effect”.1 The determination of abuse potential aims to identify the liklihood that a particular compound will be abused. On a federal level, medications with abuse potential are typically placed into one of 4 schedules (II-V) as schedule I compounds are reserved for those with the potential for abuse and that have no medical benefit.2 As medications that treat epilepsy act in the central nervous system, they are a natural target for potential drug abuse and may require drug abuse reliability testing.1 In the past, most antiepileptic drugs (AEDs) have not been scheduled substances. However, in recent years, several AEDs have been determined to have the potential for abuse.3-5

    更新日期:2019-11-13
  • Delay of Treatment, After Diagnosis, as a Contributor to the “Treatment Gap” in Epilepsy
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-17
    R. Edward Hogan

    The “treatment gap” (the difference between people with active epilepsy and people who receive appropriate treatment)1 in epileptic seizures presents challenges on several levels. Past studies addressing the “treatment gap” have focused on the initial diagnosis of epilepsy.2,3 Conceptually, focal seizures can originate from any region of the cortex, and the associated signs and symptoms of seizures are unique to each individual. Therefore, theoretically, the semiology of seizures spans the spectrum of any sensory or motor phenomenon an individual can experience, which is different for each patient. Unsurprisingly, given the complexity of signs and symptoms related to epileptic seizures, there is a lengthy differential diagnosis of patients presenting with the possible diagnosis of epilepsy. These broad categories of differential diagnoses are appropriately called “imitators” of epilepsy.4 Fortunately, the stereotypical patterns of epileptic seizures within individuals help in establishing a diagnosis. While seizure semiology differs between individuals, within a single individual, seizures tend to be stereotypical, sharing a common, reproducible pattern of signs and symptoms. Diagnosis of epilepsy calls for a detailed history to look for patterns of seizures.5

    更新日期:2019-11-13
  • Finally, Some Neurophysiologic Good News—Favorable Prognosis in Coma
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-10-13
    Aatif M. Husain

    Families of patients in coma often feel that their loved ones can hear them, even if medical professionals find no outward signs of such sensory perception. There are many news reports of patients “waking up” after weeks or months of coma and confirming that they could hear harrowing conversations of their own condition. Such reports have fueled the desire to have better and more accurate tools for coma prognostication.

    更新日期:2019-11-13
  • Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-16
    Rui Li; Gordon F. Buchanan

    Epilepsy affects more than 70 million people globally.1 Although seizures can be fatal in several ways,2 sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of death in patients with epilepsy.3 Sudden unexpected death in epilepsy is second only to stroke in potential life-years lost due to neurological disease.4 Sudden unexpected death in epilepsy is defined as the sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death in a patient with epilepsy, excluding known status epilepticus and in who the postmortem examination provides no structural or toxicological causes of death.5 Sudden unexpected death in epilepsy most commonly follows a seizure, especially a generalized one.6 Other risk factors include young age of onset, poor medication compliance, nocturnal seizures, sleeping prone, long seizure duration, and long epilepsy history.7, 8 The landmark MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) demonstrates a cascade of cardiorespiratory events preceding death,9 suggesting SUDEP is the consequence of a complex and heterogeneous process. Proposed pathophysiological mechanisms for SUDEP include respiratory, cardiac, and arousal dysregulation and have implicated several neurotransmitter and neuromodulator systems.2,7,10-12 The unpredictable and largely unwitnessed nature of SUDEP poses a great challenge to studies in patients. Herein, we will review basic science developments in SUDEP research, focusing primarily on animal models (Table 1) in the context of etiology they recapitulate and preventative strategies these models may reveal.

    更新日期:2019-11-13
  • More Is More: Potential Benefits of Characterizing High-Frequency Activity Over Long Durations
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-16
    Shyam Kumar Sudhakar; Omar J. Ahmed

    In patients with intractable focal epilepsy, pathological high-frequency activity (pHFA), when carefully analyzed, can help identify the seizure onset zone (SOZ).1-4 This information, together with traditional SOZ markers, can then potentially help clinicians decide exactly what tissue should be resected to try to ensure the highest likelihood of postsurgical seizure freedom. Although pHFA clearly holds great promise as a biomarker of epileptic tissue, the correlations are not always consistent in all patients.5 There are many potential reasons for this, including the type of epilepsy each patient has, the anatomical location and high-frequency activity (HFA)–generating capabilities of the patient-specific SOZ, the fact that it is hard to know which high-frequency events are physiological versus pathological, and the precise methods used to analyze the properties of the HFA. As discussed below, HFA—be it physiological or pathological—can be highly variable over time.6 Despite this fact, many studies have used short 10-minute epochs of data for HFA analysis. There have been good reasons for using a short time period: it is better to manually (via the trained eyes of a human expert) verify each potential high-frequency event on each channel as being real and nonartefactual, rather than analyzing massive amounts of automated, unverified, and potentially flawed detections. However, improved automated HFA detection algorithms have made it possible to more reliably analyze longer data sets.7-9 A recent paper by Gliske et al now uses such automated algorithms to show that there is a large degree of variation in both the timing and location of detected HFA across hours and days, emphasizing the importance of longer duration analyses before making HFA-dependent decisions regarding the SOZ.

    更新日期:2019-11-13
  • An Ancient Enzyme Takes a Hit in Epilepsy
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-17
    Tore Eid

    Glutamine synthetase (GS, glutamate-ammonia ligase, E.C. 6.3.1.2), which catalyzes the condensation of ammonia and glutamate to glutamine, is a fascinating enzyme because of its ancient origin, ubiquitous presence in nature, and emerging involvement in several diseases, including epilepsy. GS is encoded by one of the oldest genes known to exist, likely originating more than 3500 million years ago in the “pre-prokaryotic” era, that is, the period between the origin of life and the divergence of prokaryotes and eukaryotes.1 Moreover, all extant organisms express GS, and absent or reduced enzyme levels are respectively deadly, or sometimes associated with a variety of pathological conditions such as Alzheimer disease,2 schizophrenia,3 and epilepsy.4–7 Even though GS is widely distributed in nature, the expression in mammals is restricted to a surprisingly small number of cell types. In the central nervous system, for instance, GS is almost exclusively found in astrocytes8 and is thought to play a critical role in ammonia detoxification and in regulation of the excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid (reviewed in the study by Eid et al9).

    更新日期:2019-11-13
  • What Do We Want? INHIBITION. When Do We Want it? NOW
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-05
    Jamie L. Maguire

    Inhibition has been a focus of antiepileptic drug (AED) pharmacology since the discovery of the anticonvulsant actions of phenobarbital, a barbiturate that acts on GABAA receptors (GABAARs), in the early 20th century. Recently, efforts have diverted from classic pharmacological targeting of GABAARs toward manipulating interneurons and their function. For instance, cell-based therapies involving transplantation of interneuron progenitors have shown promise in animal models of epilepsy,1,2 and this approach is under further development for translational implementation. In addition, optogenetic manipulation of interneurons has demonstrated utility for seizure control in animal models and the therapeutic potential is currently being explored.3 Here, Acker et al demonstrate a novel antiseizure approach involving rapid inhibitory synaptogenesis, which may be a novel mechanism for enhancing inhibitory signaling to exploit for therapeutics.

    更新日期:2019-11-13
  • Blocking TrkB’s Effectors Reveal Benefits of the Road Not Taken
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-09
    Steve C. Danzer

    Despite the introduction of dozens of medications that can control seizures in many patients with epilepsy, the development of a therapy that can prevent epilepsy development or improve disease course remains elusive. Animal studies targeting the brain-derived neurotrophic factor (BDNF) receptor tropomyosin-related tyrosine kinase B (TrkB) have shown promising results in epilepsy models. Brain-derived neurotrophic factor is released following epileptogenic brain injuries, such as status epilepticus, leading to a dramatic increase in TrkB activation.1 Activated TrkB, in turn, can act through a variety of signaling pathways that promote neuronal remodeling, increase synaptic strength, and enhance neuronal activity. Furthermore, infusing BDNF directly into the brains of normal rodents can promote seizures,2 and enhancing TrkB activation can facilitate epileptogenesis.3 Decreasing BDNF signaling and blocking TrkB activation, on the other hand, has antiepileptogenic effects in the kindling, traumatic brain injury, and status epilepticus models of epilepsy.4-7

    更新日期:2019-11-13
  • Moving Metabolism to Make Inroads in a Model of Mitochondrial Epilepsy
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-09
    Kyle A. Lyman; Dane M. Chetkovich

    Working out the enzymatic reactions that comprise metabolism is one of the hallmark accomplishments of modern biology.1 However, despite the formulaic description provided in textbooks, the workings of metabolism in vivo, especially in the brain, remain poorly understood. Broadly, adenosine triphosphate (ATP) is generated through 2 groups of reactions: glycolysis and oxidative phosphorylation. Glycolysis refers to the breakdown of glucose into pyruvate in order to generate a relatively limited quantity of ATP. Pyruvate can then be taken up by the mitochondria in order to drive the Krebs cycle forward to generate additional ATP as well as provide the substrates for synthetic reactions.1 Within the mitochondria, the key enzyme that allows the pyruvate derived from glycolysis to enter the Krebs cycle is pyruvate dehydrogenase (PDH). As a result, PDH plays a central role in regulating both the production of ATP and the synthesis of new molecules whose substrates are derived from the Krebs cycle.1 In the brain, the Krebs cycle is essential to the production of both glutamate and γ-aminobutyric acid (GABA), which puts PDH in the critical position of linking metabolism to the excitatory–inhibitory balance.2

    更新日期:2019-11-13
  • Rise and Fall of the Empire: Conquering Alzheimer’s Disease by Targeting Adult Neurogenesis
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-16
    Parul Varma; Jenny Hsieh

    Alzheimer's disease (AD) is a neurodegenerative disorder and contributes to more than two-thirds of dementia cases all over the world. Ever since its first description in a lecture delivered by Alois Alzheimer (a psychiatrist) in 1906, a century has been spent investigating the pathology, etiology, mechanisms, and treatment strategies for AD. At the histopathological level, AD is characterized by deposition of plaques and tangles in brain and extensive neuronal loss. While plaques are a result of accumulation of abnormally folded Aβ (amyloid-beta) peptides (a cleavage product of amyloid precursor proteins [APP]), neuronal tangles are formed by intracellular connections of hyperphosphorylated cytoskeletal tau proteins.1 Moreover, a review of clinical literature shows that epileptiform activity is also often associated with AD and the appearance of seizures has been reported to happen as early as in the age-group of 50 to 60 years.2-4 The association between AD and epilepsy has also been shown in mouse models of AD.5,6 This early association of seizures in AD raises the possibility of their crucial role in the progression of the disease.

    更新日期:2019-11-13
  • One Seizure Please, Hold the Sprouts: The Role of Hippocampal Mossy Fiber Sprouting in Epilepsy
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-09-26
    Mark Beenhakker; Matthew Ritger

    When scientists first began looking at neurons under the microscope, they did what humans are good at doing; namely, they began sorting what they saw into categories. When classifying neurons in the hippocampus, Ramon y Cajal noted that certain cells and nearby axons had messy outgrowths resembling moss.1 As hippocampal mossy cells have been reviewed previously,2 the remainder of this commentary will focus on the separate entity of mossy fibers. Mossy fibers are the axons originating from dentate granule cells and are morphologically distinct from other neuronal axons in that they possess a variety of synaptic terminals.3 Mossy fibers form synapses onto neurons of the CA3 region of the hippocampus, a connection mediated by glutamate. The mossy fiber-CA3 synapse is a “detonator synapse,” which means it robustly and reliably activates postsynaptic CA3 neurons; however, this detonation is conditional insofar a brief burst of presynaptic activity is required for expression.4 In contrast, the more prevalent CNS connection is the nondetonator synapse, which has a low success rate of triggering spikes in postsynaptic targets, and often requires teamwork (from neighboring synapses) to evoke a robust postsynaptic response.5

    更新日期:2019-11-13
  • When Monogenic Isn’t Monogenic—Unravelling the Oligogenic Architecture of the Developmental and Epileptic Encephalopathies
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-10-11
    Ingrid E. Scheffer; Jianxiang Liao

    Our understanding of the etiologies of the developmental and epileptic encephalopathies (DEEs) has exploded in recent years.1 Developmental and epileptic encephalopathies are the most severe group of epilepsies, typically beginning in early life. They are characterized by frequent uncontrolled seizures, often of multiple types, and developmental delay or intellectual disability. A key concept underpinning the term “epileptic encephalopathy” (EE) is the presence of frequent epileptiform activity that itself contributes to developmental slowing or regression.2 The term was recently expanded to include “developmental” in recognition that many of the underlying etiologies of the DEEs result in developmental impairment in their own right, with the superimposed EE process further adversely impacting an individual’s development.

    更新日期:2019-11-13
  • 更新日期:2019-11-01
  • From Point A to Point B, and What it Means for Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : null
    Esther Krook-Magnuson

    [Box: see text].

    更新日期:2019-11-01
  • Emerging Roles for Microglial Phagocytic Signaling in Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : null
    Season K Wyatt-Johnson,Amy L Brewster

    Microglia are the resident immune cells and professional phagocytes of the central nervous system. However, little is known about the contribution of their phagocytic signaling to the neuropathology and pathophysiology of epilepsy. Here, we summarize and discuss the implications of recent evidence supporting that aberrant microglia phagocytic activity and alterations in phagocytosis signaling molecules occur in association with microglia-neuronal contacts, neuronal/synaptic loss, and spontaneous recurrent seizures in human and preclinical models of epilepsy. This body of evidence provides strong support that the microglial contribution to epileptogenic networks goes beyond inflammation, and suggests that phagocytic signaling molecules may be novel therapeutic targets for epilepsy.

    更新日期:2019-11-01
  • Ketogenic Dietary Therapy Controversies for Its Second Century.
    Epilepsy Curr. (IF 6.909) Pub Date : null
    Eric Kossoff,Mackenzie Cervenka

    As the ketogenic diet approaches 100 years of continuous use, we reflect on its successes and consider new avenues of research for the next century. One controversial question is regarding whether ketogenic dietary therapies could be successful first-line treatments for epilepsy. Second, is it possible to mimic the mechanisms of action of ketogenic dietary therapy with a drug (eg, a tablet formulation)? A third controversy worthy of future study involves its expanded usage in adults with refractory epilepsy and its role in treating women of childbearing age. Finally, as flexible, alternative diets have recently become widely available, is it feasible and safe to have families and patients start ketogenic dietary therapy successfully on their own with limited medical supervision?

    更新日期:2019-11-01
  • Show Me the Meaning of Being Lonely (and Its Effects on Seizure Burden and Comorbidities).
    Epilepsy Curr. (IF 6.909) Pub Date : null
    Lola Lozano,Catherine A Christian

    [Box: see text].

    更新日期:2019-11-01
  • Network Changes after Epilepsy Surgery: It's Time to Reconnect.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-11-22
    Dario J Englot

    [Box: see text].

    更新日期:2019-11-01
  • Mechanisms of Epilepsy and Neuronal Synchronization Gordon Research Conference Power Hour Summary.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-07-10
    Lori L Isom,Karen S Wilcox,Amy Brooks-Kayal

    更新日期:2019-11-01
  • A new policy for disclosure of competing interests.
    Epilepsy Curr. (IF 6.909) Pub Date : 2011-04-05
    Michael A Rogawski

    更新日期:2019-11-01
  • Epileptogenic role of astrocyte dysfunction.
    Epilepsy Curr. (IF 6.909) Pub Date : 2008-03-12
    Annamaria Vezzani

    更新日期:2019-11-01
  • Seizing Sequencing Data to Consider Cell and Circuit Complexity.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-04-09
    Zoé Christenson Wick,Esther Krook-Magnuson

    Classes and Continua of Hippocampal CA1 Inhibitory Neurons Revealed by Single-Cell Transcriptomics Harris K, Hochgerner H, Skene NG, et al. PLoS Biol. 2018;16(6):e2006387. doi:10.1371/journal.pbio.2006387. Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neurons have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of cortical inhibitory neurons or whether continuous modes of variability are also required. We studied the transcriptomes of 3663 CA1 inhibitory cells, revealing 10 major GABAergic groups that divided into 49 fine-scale clusters. All previously described and several novel cell classes were identified, with 3 previously described classes unexpectedly found to be identical. A division into discrete classes, however, was not sufficient to describe the diversity of these cells, as continuous variation also occurred between and within classes. Latent factor analysis revealed that a single continuous variable could predict the expression levels of several genes, which correlated similarly with it across multiple cell types. Analysis of the genes correlating with this variable suggested it reflects a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells to slower-spiking cells targeting distal dendrites or interneurons. These results elucidate the complexity of inhibitory neurons in one of the simplest cortical structures and show that characterizing these cells require continuous modes of variation as well as discrete cell classes.

    更新日期:2019-11-01
  • cPLA2 in Epilepsy: Shutting Down the Leaker at Its Source.
    Epilepsy Curr. (IF 6.909) Pub Date : 2018-11-23
    Christina Gross

    更新日期:2019-11-01
  • Risk of Unnatural Mortality in Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2018-12-21
    Mohamad Koubeissi

    更新日期:2019-11-01
  • Women With Epilepsy and Control Women: Two Peas in a WEPOD.
    Epilepsy Curr. (IF 6.909) Pub Date : 2018-11-23
    Mohamad Koubeissi

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Pannexin1 as a Possible Panacea for Intractable Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2018-12-21
    Kyle A Lyman,Dane M Chetkovich

    更新日期:2019-11-01
  • "Chance Takers Are Accident Makers": Are Patients With Epilepsy Really Taking a Chance When They Drive?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-07-23
    Charuta N Joshi,David G Vossler,Marianne Spanaki,Joseph F Draszowki,Alan R Towne,

    This review compiles scientific data about the real dangers faced by people with epilepsy (PWE) who drive. Those include risks of motor vehicle accidents (MVA) in PWE as compared with controls (individuals without epilepsy) and as compared with persons with other medical conditions that impact fitness to drive. Data regarding Accident rates as related to seizure free intervals (SFI), single vs. multiple seizure events, and/or antiseizure drug (ASD) taper and reintroduction are discussed. Variation in state, national, and international laws and guidance for non-commercial and commercial drivers is highlighted, along with some related reasons for driving restrictions. The review concludes by emphasizing the importance of physicians educating patients about local driving laws and about risks of ASD non-adherence. The need for a broader, multi-stakeholder re-examination of driving regulations for PWE is noted.

    更新日期:2019-11-01
  • SCN8A: When Neurons Are So Excited, They Just Can't Hide It.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-07-11
    Tracy S Gertler,Gemma L Carvill

    Prominent role of forebrain excitatory neurons in SCN8A encephalopathy. Bunton-Stasyshyn RKA, Wagnon JL, Wengert ER, Barker BS, Faulkner A, Wagley PK, Bhatia K, Jones JM, Maniaci MR, Parent JM, Goodkin HP, Patel MK, Meisler MH. Brain. 2019;142(2):362-375. doi:10.1093/brain/awy324. De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early-onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.

    更新日期:2019-11-01
  • Beyond Dravet Syndrome: Characterization of a Novel, More Severe SCN1A-Linked Epileptic Encephalopathy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-07-02
    Veronica C Beck,Jacob M Hull,Lori L Isom

    Not All SCN1A Epileptic Encephalopathies Are Dravet Syndrome: Early Profound Thr226Met Phenotype Sadleir LG, Mountier EI, Gill D, et al. Neurology. 2017;89(10):1035-1042. OBJECTIVE To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met. SCN1A Gain of Function in Early Infantile Encephalopathy Berecki G, Bryson A, Terhag J, et al. Ann Neurol. 2019; 85:514-525. OBJECTIVE To elucidate the biophysical basis underlying the distinct and severe clinical presentation in patients with the recurrent missense SCN1A variant, p.Thr226Met. Patients with this variant show a well-defined genotype-phenotype correlation and present with developmental and early infantile epileptic encephalopathy that is far more severe than typical SCN1A Dravet syndrome. METHODS Whole cell patch clamp and dynamic action potential clamp were used to study T226M Nav 1.1 channels expressed in mammalian cells. Computational modeling was used to explore the neuronal scale mechanisms that account for altered action potential firing. RESULTS T226M channels exhibited hyperpolarizing shifts of the activation and inactivation curves and enhanced fast inactivation. Dynamic action potential clamp hybrid simulation showed that model neurons containing T226M conductance displayed a left shift in rheobase relative to control. At current stimulation levels that produced repetitive action potential firing in control model neurons, depolarization block and cessation of action potential firing occurred in T226M model neurons. Fully computationally simulated neuron models recapitulated the findings from dynamic action potential clamp and showed that heterozygous T226M models were also more susceptible to depolarization block. INTERPRETATION From a biophysical perspective, the T226M mutation produces gain of function. Somewhat paradoxically, our data suggest that this gain of function would cause interneurons to more readily develop depolarization block. This "functional dominant negative" interaction would produce a more profound disinhibition than seen with haploinsufficiency that is typical of Dravet syndrome and could readily explain the more severe phenotype of patients with T226M mutation.

    更新日期:2019-11-01
  • Bringing EEG Back to the Future: Use of cEEG in Neurocritical Care.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-07-02
    Adriana Bermeo-Ovalle

    Continuous EEG Is Associated With Favorable Hospitalization Outcomes for Critically Ill Patients. Hill CE, Blank LJ, Thibault D, et al. Willis Neurology. 2018. doi: https://doi.org/10.1212/WNL.0000000000006689 Objective: To characterize continuous electroencephalography (cEEG) use patterns in the critically ill and to determine the association with hospitalization outcomes for specific diagnoses. METHODS We performed a retrospective cross-sectional study with National Inpatient Sample data from 2004 to 2013. We sampled hospitalized adult patients who received intensive care and then compared patients who underwent cEEG to those who did not. We considered diagnostic subgroups of seizure/status epilepticus, subarachnoid or intracerebral hemorrhage, and altered consciousness. Outcomes were in-hospital mortality, hospitalization cost, and length of stay. RESULTS In total, 7 102 399 critically ill patients were identified, of whom 22 728 received cEEG. From 2004 to 2013, the proportion of patients who received cEEG increased from 0.06% (95% confidence interval [CI]: 0.03%-0.09%) to 0.80% (95% CI: 0.62%-0.98%). While the cEEG cohort appeared more ill, cEEG use was associated with reduced in-hospital mortality after adjustment for patient and hospital characteristics (odds ratio [OR]: 0.83, 95% CI: 0.75-0.93, P < .001). This finding held for the diagnoses of subarachnoid or intracerebral hemorrhage and for altered consciousness, but not for the seizure/status epilepticus subgroup. Cost and length of hospitalization were increased for the cEEG cohort (OR: 1.17 and 1.11, respectively, P < .001). CONCLUSIONS There was a >10-fold increase in cEEG use from 2004 to 2013. However, this procedure may still be underused; cEEG was associated with lower in-hospital mortality but used for only 0.3% of the critically ill population. While administrative claims analysis supports the utility of cEEG for critically ill patients, our findings suggest variable benefit by diagnosis, and investigation with greater clinical detail is warranted.

    更新日期:2019-11-01
  • Heartbreakers-Cardiac Stress After Uncomplicated Generalized Convulsive Seizures.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-07-02
    Nicolas Gaspard

    Blood Markers of Cardiac Stress After Generalized Convulsive Seizures. Nass RD, Motloch LJ, Paar V, Lichtenauer M, Baumann J, Zur B, Hoppe UC, Holdenrieder S, Elger CE, Surges R. Epilepsia. 2019;60(2):201-210. doi:10.1111/epi.14637. Epub 2019 Jan 15. PMID: 30645779 Objective: Generalized convulsive seizures (GCS) are associated with high demands on the cardiovascular system, thereby facilitating cardiac complications. To investigate occurrence, influencing factors, and extent of cardiac stress or injury, the alterations and time course of the latest generation of cardiac blood markers were investigated after documented GCS. METHODS Adult patients with refractory epilepsy who underwent video-electroencephalography monitoring along with simultaneous one-lead electrocardiography recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high-sensitivity troponin T [hsTNT]; N-terminal prohormone of brain natriuretic peptide; copeptin; suppression of tumorigenicity-2 [SST-2]; growth differentiation factor 15, [GDF-15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart-type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Peri-ictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals (QTc). RESULTS Thirty-six GCS (6 generalized-onset tonic-clonic seizures and 30 focal to bilateral tonic-clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than 2-fold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 (10%) of 30 patients and 6 (26%) of 23 patients, respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST-2, HFABP, and GDF-15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient. SIGNIFICANCE The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. Soluble urokinase plasminogen activator receptor may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS but specificity needs to be tested.

    更新日期:2019-11-01
  • The Dentate Gyrus and Temporal Lobe Epilepsy: An "Exciting" Era.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-25
    Helen E Scharfman

    This review describes developments in epilepsy research during the last 3 to 4 decades that focused on the dentate gyrus (DG) and its role in temporal lobe epilepsy (TLE). The emphasis is on basic research in laboratory animals and is chronological, starting with hypotheses that attracted a lot of attention in the 1980s. Then experiments are described that addressed the questions, as well as new methods that often made the experiments possible. In addition, where new questions arose and the implications for clinical epilepsy are discussed.

    更新日期:2019-11-01
  • Epilepsy Did it Again: Memory and Model-Based Planning Studied in Patients After Epilepsy Surgery.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-22
    Libor Velíšek

    Hippocampal Contributions to Model-Based Planning and Spatial Memory. Vikbladh OM, Meager MR, King J, et al. Neuron. 2019;102:1-11. pii: S0896-6273(19)30123-0. doi: 10.1016/j.neuron.2019.02.014. [Epub ahead of print] PMID: 30871859 Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and patients with epilepsy treated using unilateral anterior temporal lobectomy with hippocampal resection. Both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, although planning and boundary-driven place memory covaried in the control group, this relationship was attenuated in patients, consistent with both functions relying on the same structure in the healthy brain. These findings clarify both the neural mechanism of model-based planning and the scope of hippocampal contributions to behavior.

    更新日期:2019-11-01
  • fMRI Language Activation-If You See It Don't Resect It….
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-22
    Jerzy P Szaflarski

    fMRI Prediction of Naming Change After Adult Temporal Lobe Epilepsy Surgery: Activation Matters. You X, Zachery AN, Fanto EJ, et al. Epilepsia. 2019. doi:10.1111/epi.14656. [Epub ahead of print] PMID: 30740666 . OBJECTIVE We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability. METHOD Thirty-five adults (mean age: 37.5 ± 10.9 years, 13 males) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative magnetic resonance imaging tissue map comparison. This mask provided the following: (a) resection volume, (b) overlap between resection and preoperative activation, and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance. RESULTS Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r2 = 0.28, P = .012). The percentage of top 10% fMRI activation resected (P = .017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality). SIGNIFICANCE Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.

    更新日期:2019-11-01
  • Cutting the Losses of Pregnant Women With Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-19
    Naymee Velez-Ruiz

    Association of Unintended Pregnancy With Spontaneous Fetal Loss in Women With Epilepsy: Findings of the Epilepsy Birth Control RegistryHerzog AG, Mandle HB, MacEachern DB. JAMA Neurol. 2018. doi:10.1001/jamaneurol.2018.3089. [Epub ahead of print] PMID: 30326007. IMPORTANCE If unintended pregnancy is common among women with epilepsy and is associated with increased risk of spontaneous fetal loss (SFL), it is important to develop guidelines for safe and effective contraception for this community. OBJECTIVE To assess whether planned pregnancy is a determinant of SFL in women with epilepsy. DESIGN, SETTING, AND PARTICIPANTS The Epilepsy Birth Control Registry conducted this web-based, retrospective survey between 2010 and 2014. It gathered demographic, epilepsy, antiepileptic drug (AED), contraceptive, and reproductive data from 1144 women with epilepsy in the community between ages 18 and 47 years. Data were analyzed between March 2018 and May 2018. Main outcomes and measures The primary outcome was the risk ratio (RR) with 95% confidence intervals (CIs) for SFL in unplanned versus planned pregnancies. The secondary outcome was the identification of some potentially modifiable variables (maternal age, pregnancy spacing, and AED category) of SFL versus live birth using binary logistic regression. RESULTS The participants were proportionally younger (mean [standard deviation] age, 28.5 [6.8] years), and 39.8% had household incomes of $25 000 or less. Minority women represented only 8.7% of the participants. There were 530 (66.8%) of 794 unplanned pregnancies and 264 (33.2%) of 794 planned pregnancies. The risk of SFL in 653 unaborted pregnancies in women with epilepsy was greater for unplanned (n = 137 of 391; 35.0%) than planned (n = 43 of 262; 16.4%) pregnancies (RR: 2.14; 95% CI: 1.59-2.90; P < .001). Regression analysis found that the risk of SFL was greater when planning was entered alone (odds ratio [OR], 2.75; 95% CI: 1.87-4.05; P < .001) and more so when adjusted for maternal age, interpregnancy interval, and AED category (OR: 3.57; 95% CI: 1.54-8.78; P = .003). Interpregnancy interval (OR: 2.878; 95% CI: 1.8094-4.5801; P = .008) and maternal age (OR: 0.957; 95% CI: 0.928-0.986 for each year from 18 to 47 years; P = .02), but not AED category, were also associated. The risk was greater when interpregnancy interval was less than 1 year (n = 56 of 122; 45.9%) versus greater than 1 year (n = 56 of 246; 22.8%; RR: 2.02; 95% CI: 1.49-2.72; P < .001). Relative to the younger than 18 years cohort (n = 15 of 29; 51.7%), the risks were lower for the intermediate older cohort aged 18 to 27 years (n = 118 of 400; 29.5%; RR: 0.57; 95% CI: 0.39-0.84; P < .004) and the cohort aged 28 to 37 years (n = 44 of 212; 20.8%; RR: 0.40; 95% CI: 0.26-0.62; P < .001) but not significantly different for the small number of participants in the aged 38 to 47 years cohort (n = 3 of 12; 25.0%). No individual AED category's SFL frequency differed significantly from the no AED category. CONCLUSIONS AND RELEVANCE The Epilepsy Birth Control Registry retrospective survey finding that unplanned pregnancy in women with epilepsy may double the risk of SFL warrants prospective investigation with outcome verification.

    更新日期:2019-11-01
  • A Hit, a Hit-A Very Palpable Hit: Mild TBI and the Development of Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-19
    Steve C Danzer

    Repetitive Diffuse Mild Traumatic Brain Injury Causes An Atypical Astrocyte Response and Spontaneous Recurrent Seizures Shandra O, Winemiller AR, Heithoff BP, et al. J Neurosci. 2019;39(10):1944-1963. doi:10.1523/JNEUROSCI.1067-18.2018. Epub 2019 Jan 21. PMID: 30665946 . Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins, and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human patients with TBI. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI. Traumatic brain injury is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.

    更新日期:2019-11-01
  • The EEG Ictal-Interictal Continuum-A Metabolic Roar But a Whimper of a Functional Outcome.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-15
    Jong Woo Lee

    Lateralized Periodic Discharges Frequency Correlates With Glucose Metabolism Subramaniam T, Jain A, Hall LT, Cole AJ, Westover MB, Rosenthal ES, Struck AF. Neurology. 2019;92(7):e670-e674. OBJECTIVE To investigate the correlation between characteristics of lateralized periodic discharges (LPDs) and glucose metabolism measured by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). METHODS We retrospectively reviewed medical records to identify patients who underwent FDG-PET during electroencephalography (EEG) monitoring with LPDs present during the FDG uptake period. Two blinded board-certified neurophysiologists independently interpreted EEGs. (18)F-fluorodeoxyglucose uptake was measured using standardized uptake value (SUV). Structural images were fused with PET images to aid with localization of SUV. Two PET readers independently measured maximum SUV. Relative SUV values were obtained by normalization of the maximum SUV to the SUV of pons (SUVRpons). Lateralized periodic discharge frequency was analyzed both as a categorical variable and as a continuous measure. Other secondary variables included duration, amplitude, presence of structural lesion, and "plus" EEG features such as rhythmic or fast sharp activity. RESULTS Nine patients were identified and 7 had a structural etiology for LPDs. Analysis using frequency as a categorical variable and continuous variable showed an association between increased LPD frequency and increased ipsilateral SUVRpons (P = .02). Metabolism associated with LPDs (0.5 Hz as a baseline) increased by a median of 100% at 1 Hz and for frequencies >1 Hz increased by a median of 309%. There were no statistically significant differences in SUVRpons for other factors including duration (P = .10), amplitude (P = .80), structural etiology (P = .55), or "plus" features such as rhythmic or fast sharp activity (P = .84). CONCLUSIONS Metabolic activity increases monotonically with LPD frequency. Lateralized periodic discharge frequency should be a measure of interest when developing neuroprotection strategies in critical neurologic illness. Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury Lee H, Mizrahi MA, Hartings JA, Sharma S, Pahren L, Ngwenya LB, Moseley BD, Privitera M, Tortella FC, Foreman B. Crit Care Med. 2019;47(4):574-582. OBJECTIVES After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate to severe traumatic brain injury, and to correlate continuous electroencephalography features with functional outcome. DESIGN Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID study ( ClinicalTrials.gov : NCT00805818). Continuous electroencephalography was initiated upon admission to the intensive care unit. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as "ictal-interictal continuum"; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. SETTING Twenty US level I trauma centers. PATIENTS Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4 to 12 were included. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Among 152 patients with continuous electroencephalography (age = 34 ± 14 years; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in 4 (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; P = .01) and Injury Severity Score (r = 0.49; P = .01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% confidence interval, 1.30-9.09), absence of N2 sleep transients (3.69; 1.69-8.20), predominant delta activity (2.82; 1.32-6.10), and discontinuous background (5.33; 2.28-12.96) within the first 72 hours of monitoring. CONCLUSIONS Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate to severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

    更新日期:2019-11-01
  • Not Just Where, But How Does a Seizure Start?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-14
    Jean Gotman

    The Repertoire of Seizure Onset Patterns in Human Focal Epilepsies: Determinants and Prognostic Values Lagarde S, Buzori S, Trebuchon A, Carron R, Scavarda D, Milh M, McGonigal A, Bartolomei F. Epilepsia. 2019;60(1):85-95. doi: 10.1111/epi.14604. PMID: 30426477 Objective: In this study, we seek to analyze the determinants of the intracranial electroencephalography seizure onset pattern (SOP) and the impact of the SOP in predicting postsurgical seizure outcome. METHODS To this end, we analyzed 820 seizures from 252 consecutive patients explored by stereoelectroencephalography (total of 2148 electrodes), including various forms of focal refractory epilepsies. We used a reproducible method combining visual and time-frequency analyses. RESULTS We described 8 SOPs: low-voltage fast activity (LVFA), preictal spiking followed by LVFA, burst of polyspikes followed by LVFA, slow wave/DC shift followed by LVFA, sharp theta/alpha waves, beta sharp waves, rhythmic spikes/spike-waves, and delta-brush. Low-voltage fast activity occurred in 79% of patients. The SOP was significantly associated with (1) underlying etiology (burst of polyspikes followed by LVFA with the presence of a focal cortical dysplasia, LVFA with malformation of cortical development, postvascular and undetermined epilepsies), (2) spatial organization of the epileptogenic zone (EZ; burst of polyspikes followed by LVFA with focal organization, slow wave/DC shift followed by LVFA with network organization), and (3) postsurgical seizure outcome (better outcome when LVFA present). SIGNIFICANCE This study demonstrates that the main determinants of the SOP are the underlying etiology and the spatial organization of the EZ. Concerning the postsurgical seizure outcome, the main determinant factor is the spatial organization of the EZ, but the SOP plays also a role, conferring better prognosis when LVFA is present.

    更新日期:2019-11-01
  • Psychiatric Residue of Epilepsy Surgery: De Novo or Not.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-14
    Jay Salpekar

    Predicting De Novo Psychopathology After Epilepsy Surgery: A 3-Year Cohort Study Novais F, Pestana LC, Loureiro S, Andrea M, Figueira ML, Pimentel J. Epilepsy Behav. 2019;90:204-208. doi:10.1016/j.yebeh.2018.11.037. PMID: 30573340. OBJECTIVE The aim of this study was to determine the potential risk factors for de novo psychiatric syndromes after epilepsy surgery. METHODS Refractory epilepsy surgery candidates were recruited from our Refractory Epilepsy Reference Centre. Psychiatric evaluations were made before surgery and every year, during a 3-year follow-up period. Demographic, psychiatric, and neurological data were recorded. The types of surgeries considered were resective surgery (resection of the epileptogenic zone) and palliative surgery (deep brain stimulation of the anterior nuclei of the thalamus [ANT-DBS]). A survival analysis model was used to determine pre- and postsurgical predictors of de novo psychiatric events after surgery. RESULTS One hundred and six people with refractory epilepsy submitted to epilepsy surgery were included. Sixteen (15%) people developed psychiatric disorders that were never identified before surgery. Multilobar epileptogenic zone (P = .001) and DBS of the ANT-DBS (P = .003) were found to be significant predictors of these events. CONCLUSION People with more generalized epileptogenic activity and those who undergo ANT-DBS seem to present an increased susceptibility for the development of mental disorders, after neurosurgical interventions, for the treatment of refractory epilepsy. People considered to be at higher risk should be submitted to more frequent routine psychiatric assessments."

    更新日期:2019-11-01
  • Biomarkers for SUDEP: Are We There Yet?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-14
    David King-Stephens

    Postconvulsive Central Apnea as a Biomarker for Sudden Unexpected Death in Epilepsy (SUDEP) Laura Vilella, MD, Nuria Lacuey, MD, Johnson P. Hampson, MSBME, M. R. Sandhya Rani, PhD, Rup K. Sainju, MBBS, Daniel Friedman, MD, Maromi Nei, MD, Kingman Strohl, MD, Catherine Scott, MPhil, Brian K. Gehlbach, MD, Bilal Zonjy, MD, Norma J. Hupp, Anita Zaremba, BA, Nassim Shafiabadi, MD, Xiuhe Zhao, MD, Victoria Reick-Mitrisin, MS, Stephan Schuele, MD, MPH, Jennifer Ogren, PhD, Ronald M. Harper, PhD, Beate Diehl, MD, PhD, FRCP, Lisa Bateman, MD, Orrin Devinsky, MD, George B. Richerson, MD, PhD, Philippe Ryvlin, MD, PhD, and Samden D. Lhatoo, MD, FRCP. Neurology. 2019;92:e171-e182. OBJECTIVE To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. METHODS This was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video electroencephalography, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and electrocardiogram were analyzed. RESULTS We studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy, 65 had focal epilepsy, 1 had both, and the epileptogenic zone was unknown in 2. Ictal central apnea (ICA) preceded GCS in 49 (40.4%) of 121 seizures in 23 patients, all with focal epilepsy. Postconvulsive central apnea (PCCA) occurred in 31 (22.1%) of 140 seizures in 22 patients, with generalized, focal, or unknown epileptogenic zones. In 2 patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2 per 1000 patient-years. One patient with PCCA died of probable SUDEP during follow-up, suggesting a SUDEP incidence rate 5.1 per 1000 patient-years. No cases of laryngospasm were detected. Rhythmic muscle artifact synchronous with breathing was present in 75 of 147 seizures and related to stertorous breathing (odds ratio: 3.856, 95% confidence interval: 1.395-10.663, P = .009). CONCLUSIONS Postconvulsive central apnea occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. Postconvulsive central apnea was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm. Hypoxemia Following Generalized Convulsive Seizures: Risk Factors and Effect of Oxygen Therapy Sylvain Rheims, MD, PhD, Blanca Mercedes Alvarez, MD, Veriano Alexandre, MD, PhD, Jonathan Curot, MD, Louis Maillard, MD, PhD, Fabrice Bartolomei, MD, PhD, Philippe Derambure, MD, PhD, Edouard Hirsch, MD, PhD, V´eronique Michel, MD, Francine Chassoux, MD, PhD, Didier Tourniaire, MD, Arielle Crespel, MD, Arnaud Biraben, MD, Vincent Navarro, MD, PhD, Philippe Kahane, MD, PhD, Bertrand De Toffol, MD, PhD, Pierre Thomas, MD, PhD, Sarah Rosenberg, MD, PhD, Luc Valton, MD, PhD, Laurent Bezin, PhD, and Philippe Ryvlin, MD, PhD, on behalf of the REPO2MSE Study Group. Neurology. 2019;92:e183-e193. OBJECTIVE To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS). METHODS We reviewed the video electroencephalography (EEG) recordings of 1006 patients with drug-resistant focal epilepsy included in the REPO2MSE study to identify those with ≥1 GCS and pulse oximetry (SpO2) measurement. Factors determining recovery of SpO2 ≥ 90% were investigated using Cox proportional hazards models. Association between SpO2 nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures. RESULTS A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 (86%) GCS. Rate of GCS with SpO2 < 70% dropped from 40% to 21% when oxygen was administered early (P = .046). Early recovery of SpO2 ≥ 90% was associated with early administration of oxygen (P = .004), absence of postictal generalized EEG suppression (PGES; P = .014), and extratemporal lobe epilepsy (P = .001). Lack of early administration of O2 (P = .003), occurrence of PGES (P = .018), and occurrence of ictal hypoxemia during the focal phase (P = .022) were associated with lower SpO2 nadir. CONCLUSION Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS, but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.

    更新日期:2019-11-01
  • Casting a Wide Net to Catch Seizures.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-14
    Adam C Lu,Mark Beenhakker

    Network Properties Revealed During Multi-Scale Calcium Imaging of Seizure Activity in Zebrafish Liu J, Baraban SC. eNeuro. 2019;6(1):ENEURO.0041-19.2019. doi:10.1523/ENEURO.0041-19.2019. eCollection 2019 Jan-Feb. PMID: 30895220. Seizures are characterized by hypersynchronization of neuronal networks. Understanding these networks could provide a critical window for therapeutic control of recurrent seizure activity, that is, epilepsy. However, imaging seizure networks have largely been limited to microcircuits in vitro or small "windows" in vivo. Here, we combine fast confocal imaging of genetically encoded calcium indicator-expressing larval zebrafish with local field potential recordings to study epileptiform events at whole-brain and single-neuron levels in vivo. Using an acute seizure model (pentylenetetrazole, PTZ), we reliably observed recurrent electrographic ictal-like events associated with generalized activation of all major brain regions and uncovered a well-preserved anterior to posterior seizure propagation pattern. We also examined brain-wide network synchronization and spatiotemporal patterns of neuronal activity in the optic tectum microcircuit. Brain-wide and single-neuronal level analysis of PTZ-exposed and 4-aminopyridine-exposed zebrafish revealed distinct network dynamics associated with seizure and nonseizure hyperexcitable states, respectively. Neuronal ensembles, comprised of coactive neurons, were also uncovered during interictal-like periods. Taken together, these results demonstrate that macro- and micro-network calcium motifs in zebrafish may provide a greater understanding of epilepsy.

    更新日期:2019-11-01
  • When a Good Cop Turns Bad: The Pro-Ictal Action of Parvalbumin Expressing Interneurons During Seizures.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-06-05
    Joseph V Raimondo,Chris Dulla

    KCC2 Overexpression Prevents the Paradoxical Seizure-Promoting Action of Somatic Inhibition Magloire, V., Cornford, J., Lieb, A., Kullmann, D. M., and Pavlov, I. Nat. Commun. 10, 1225. doi:10.1038/s41467-019-08933-4. Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain a trans-membrane chloride gradient in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.

    更新日期:2019-11-01
  • Irritable No More: Activating Mossy Cells for the Treatment of Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2018-09-27
    Young J Kim,Robert F Hunt

    更新日期:2019-11-01
  • Astrocyte Receptor Rebirth.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-10
    Kathryn Salvati,Mark Beenhakker

    Conditional Knockout of mGluR5 From Astrocytes During Epilepsy Development Impairs High-Frequency Glutamate Uptake Umpierre AD, West PJ, White JA, et al. J Neurosci. 2019;39(4):727-742. doi:10.1523/JNEUROSCI.1148-18.2018 Astrocyte expression of metabotropic glutamate receptor 5 (mGluR5) is consistently observed in resected tissue from patients with epilepsy and is equally prevalent in animal models of epilepsy. However, little is known about the functional signaling properties or downstream consequences of astrocyte mGluR5 activation during epilepsy development. In the rodent brain, astrocyte mGluR5 expression is developmentally regulated and confined in expression/function to the first weeks of life, with similar observations made in human control tissue. Herein, we demonstrate that mGluR5 expression and function dramatically increase in a mouse model of temporal lobe epilepsy. Interestingly, in both male and female mice, mGluR5 function persists in the astrocyte throughout the process of epileptogenesis following status epilepticus. However, mGluR5 expression and function are transient in animals that do not develop epilepsy over an equivalent time period, suggesting that patterns of mGluR5expression may signify continuing epilepsy development or its resolution. We demonstrate that, during epileptogenesis, astrocytes reacquire mGluR5-dependent calcium transients following agonist application or synaptic glutamate release, a feature of astrocyte-neuron communication absent since early development. Finally, we find that the selective and conditional knockout of mGluR5 signaling from astrocytes during epilepsy development slows the rate of glutamate clearance through astrocyte glutamate transporters under high-frequency stimulation conditions, a feature that suggests astrocyte mGluR5 expression during epileptogenesis may recapitulate earlier developmental roles in regulating glutamate transporter function.

    更新日期:2019-11-01
  • Finding the Sweet Spot: Fine-Tuning DBS Parameters to Cure Seizures While Avoiding Psychiatric Complications.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-10
    Daniel L Drane,Nigel P Pedersen

    Reversible Psychiatric Adverse Effects Related to Deep Brain Stimulation of the Anterior Thalamus in Patients With Refractory Epilepsy Järvenpää S, Peltola J, Rainesalo S, et al. Epilepsy Behav. 2018;88:373-379. OBJECTIVE Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) is becoming a more common treatment for drug-resistant epilepsy. Epilepsy and depression display a bidirectional association. Anterior nucleus of thalamus has connections to anterior cingulate cortex and orbitomedial prefrontal cortex, hence, a possible role in emotional and executive functions, and thus, ANT DBS might exert psychiatric adverse effects. Our aim was to evaluate previous and current psychiatric symptoms in patients with epilepsy undergoing ANT DBS surgery and assess the predictability of psychiatric adverse effects. Programming-related psychiatric adverse effects are also reported. METHOD Twenty-two patients with ANT DBS for retractable epilepsy were examined, and a psychiatric evaluation of depressive and other psychiatric symptoms was performed with Montgomery-Åsberg Depression Rating Scale, Beck Depression Inventory, and Symptom Checklist prior to surgery, concentrating on former and current psychiatric symptoms and medications. The follow-up visit was 1 year after surgery. RESULTS At the group level, no changes in mood were observed during ANT DBS treatment. Two patients with former histories of depression experienced sudden depressive symptoms related to DBS programming settings; these were quickly alleviated after changing the stimulation parameters. In addition, 2 patients with no previous histories of psychosis gradually developed clear paranoid and anxiety symptoms that also relieved slowly after changing the programming settings. CONCLUSION The majority of our ANT DBS patients did not experience psychiatric adverse effects. Certain DBS parameters might predispose to sudden depressive or slowly manifesting paranoid symptoms that are reversible via programming changes.

    更新日期:2019-11-01
  • Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-09
    Gemma L Carvill

    De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy With Contractures, Macrocephaly, and Dyskinesias Helbig KL, Lauerer RJ, Bahr JC, et al. Am J Hum Genet. 2019;104(3):562. Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on electroencephalogram (EEG), and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high-voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all 4 S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the antiepileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

    更新日期:2019-11-01
  • Infantile Spasms of Unknown Cause: Who Can Have a Good Outcome?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-08

    Infantile spasms of unknown cause: predictors of outcome and genotype-phenotype correlation Yuskaitis CJ, Ruzhnikov MRZ, Howell KB, et al. Pediatr Neurol. 2018;87:48-56. doi:10.1016/j.pediatrneurol.2018.04.012. Epub 2018 May 7. BACKGROUND No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project (EPGP) aimed to characterize IS of unknown cause by phenotype and genotype analysis. METHODS We undertook a retrospective multicenter observational cohort of 133 individuals within the EPGP database met criteria for IS of unknown cause with at least 6 months of follow-up data. Clinical medical records, imaging, and electroencephalography were examined. RESULTS Normal development occurred in only 15% of IS of unknown cause. The majority (85%) had clinically documented developmental delay (15% mild, 20% moderate, and 50% severe) at last assessment (median 2.7 years; interquartile interval 1.71-6.25 years). Predictors of positive developmental outcomes included no delay prior to IS ( P < .001), older age of IS onset (median 6 months old), and resolution of IS after initial treatment ( P < .001). Additional seizures after IS occurred in 67%, with predictors being seizures prior to IS ( P = .018), earlier age of IS onset (median 5 months old), and refractory IS ( P = .008). On a research basis, whole exome sequencing identified 15% with de novo variants in known epilepsy genes. Individuals with a genetic finding were more likely to have poor developmental outcomes ( P = .035). CONCLUSIONS The current study highlights the predominately unfavorable developmental outcomes and that subsequent seizures are common in children with IS of unknown cause. Ongoing genetic evaluation of IS of seemingly unknown cause is likely to yield a diagnosis and provide valuable prognostic information.

    更新日期:2019-11-01
  • Highlights From the Annual Meeting of the American Epilepsy Society 2018.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-03
    Barbara C Jobst,Elinor Ben-Menachem,Kevin E Chapman,Aradia Fu,Alica Goldman,Lawrence J Hirsch,Lara E Jehi,Eric H Kossoff,Madona Plueger,Jong M Rho,Catherine A Schevon,Shlomo Shinnar,Michael R Sperling,Timothy A Simeone,Janelle L Wagner,Fred Lado

    The American Epilepsy Society Meeting in New Orleans attracted more than 5900 attendees. There was a lively exchange of new science, innovation, education, clinical practice, and many other items related to epilepsy. Educational symposia were a major part of the meeting and explored varying topics of interest for all types of epilepsy professionals. This article reviews highlights of the meeting presented in major symposia. Topics ranged from how to treat varying aspects of epilepsy as a consultant in the hospital to finding the scientific underpinning of the interaction between sleep and epilepsy. Pros and cons of novel antiseizure medications, dietary, and stimulation treatments were discussed. Epilepsy may impair memory and we need to learn what is the pathophysiologic relationship. Febrile status epilepticus may have severe consequences for a later life with seizures. Epilepsy professionals should be very well aware of the ethical implications of devasting seizures and their associated disability. These are just a few select topics of the many that we need to study further to archive the final goal to improve the lives of patients with epilepsy.

    更新日期:2019-11-01
  • The Roof is Leaking and a Storm is Raging: Repairing the Blood-Brain Barrier in the Fight Against Epilepsy.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-01
    J A Gorter,E Aronica,E A van Vliet

    A large body of evidence that has accumulated over the past decade strongly supports the role of both blood-brain barrier (BBB) dysfunction and perivascular inflammation in the pathophysiology of epilepsy. Recent preclinical studies indicate that prolonged seizure- or brain injury-induced BBB dysfunction and subsequent perivascular inflammation may play an important role in post-traumatic epileptogenesis. In turn, perivascular inflammation can further sustain BBB dysfunction. In genetic epilepsies, such as tuberous sclerosis complex and other related epileptogenic developmental pathologies, there is an association between the underlying gene mutation, BBB dysfunction, and perivascular inflammation, but evidence for a causal link to epilepsy is lacking. Future neuroimaging studies might shed light on the role of BBB function in different epilepsies and address the potential for disease modification by targeting both the BBB and perivascular inflammation in acquired and genetic epilepsies.

    更新日期:2019-11-01
  • Are Antidepressant Medications Safe for Pregnant Women With Epilepsy? The Signs Point to Yes.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-01
    Katherine Noe

    The Use of Antidepressant Drugs in Pregnant Women With Epilepsy: A Study From the Australian Pregnancy Register Sivathamboo N, Hitchcock A, Graham J, et al. Epilepsia. 2018;59(9):1696-1704. OBJECTIVE To study interactions between first-trimester exposure to antidepressant drugs (ADDs) and antiepileptic drugs (AEDs) and a history of clinical depression and/or anxiety on pregnancy outcomes and seizure control in pregnant women with epilepsy (WWE). METHODS We examined data from the Australian Pregnancy Register of Antiepileptic Drugs in Pregnancy, collected from 1999 to 2016. The register is an observational, prospective database, from which this study retrospectively analyzed a cohort. Among the AED-exposed outcomes, comparisons were made among 3 exposure groups: (1) pregnancy outcomes with first-trimester exposure to ADDs, (2) outcomes with mothers diagnosed with depression and/or anxiety but who were not medicated with an ADD, and (3) those with mothers who were not diagnosed with depression and/or anxiety and were not medicating with ADD. Prevalence data were analyzed using Fisher exact test. RESULTS A total of 2124 pregnancy outcomes were included in the analysis; 1954 outcomes were exposed to AEDs in utero, whereas 170 were unexposed. Within the group of WWE taking AEDs, there was no significant difference in the prevalence of malformations in infants who were additionally exposed to ADDs (10.2%; 95% confidence interval [CI]: 3.9-16.6), compared to individuals in the non-ADD-medicated depression and/or anxiety group (7.7%, 95% CI: 1.2-14.2), or those without depression or anxiety (6.9%, 95% CI: 5.7-8.1; P = .45). The malformation rates in pregnancy outcomes unexposed to AEDs were also similar in the above groups ( P = .27). In WWE medicated with AEDs and ADDs, the frequency of convulsive seizures ( P = .78), or nonconvulsive seizures ( P = .45) throughout pregnancy, did not differ across comparative groups. SIGNIFICANCE Comedicating with ADDs in WWE taking AEDs does not appear to confer a significant added teratogenic risk, and it does not affect seizure control.

    更新日期:2019-11-01
  • Is Targeting of Compensatory Ion Channel Gene Expression a Viable Therapeutic Strategy for Dravet Syndrome?
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-01
    Lori L Isom

    Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome Ritter-Makinson S, Clemente-Perez A, Higashikubo B, Cho FS, Holden SS, Bennett E, Chkhaidze A, Eelkman Rooda OHJ, Cornet MC, Hoebeek FE, Yamakawa K, Cilio MR, Delord B, Paz JT. Cell Rep. 2019;26(1):54-64.e6. doi:10.1016/j.celrep.2018.12.018. Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the nonconvulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote nonconvulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

    更新日期:2019-11-01
  • Good Outcome in Cardiac Arrest Patients in Refractory Status Epilepticus: A Result of Aggressive Treatment or EEG Reclassification.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-01
    Jong Woo Lee

    Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment. Beretta S, Coppo A, Bianchi E, et al. Neurology. 2018;91(23):e2153-e2162. doi:10.1212/WNL.0000000000006615. Epub October 31, 2018. OBJECTIVE To investigate neurologic outcome of patients with cardiac arrest with refractory status epilepticus (RSE) treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics compared to patients with other electroencephalogram (EEG) patterns. METHODS In the prospective cohort study, 166 consecutive patients with cardiac arrest in coma were stratified according to 4 independent EEG patterns (benign, RSE, generalized periodic discharges [GPDs], malignant nonepileptiform) and multimodal prognostic indicators. Primary outcomes were survival and cerebral performance category (CPC) at 6 months. RESULTS The RSE occurred in 36 (21.7%) patients and was treated with an aggressive standardized protocol as long as multimodal prognostic indicators were not unfavorable. The RSE started 3 ± 2.3 days after cardiac arrest and lasted 4.7 ± 4.3 days. A benign EEG pattern was recorded in 76 (45.8%) patients, a periodic pattern (GPDs) was seen in 13 (7.8%) patients, and a malignant nonepileptiform EEG pattern was recorded in 41 (24.7%) patients. The 4 EEG patterns were highly associated with different prognostic indicators (low-flow time, clinical motor seizures, N20 responses, neuron-specific enolase, neuroimaging). Survival and good neurologic outcome (CPC 1 or 2) at 6 months were 72.4% and 71.1% for benign EEG pattern, 54.3% and 44.4% for RSE, 15.4% and 0% for GPDs, and 2.4% and 0% for malignant nonepileptiform EEG pattern, respectively. CONCLUSIONS Aggressive and prolonged treatment of RSE may be justified in patients with cardiac arrest with favorable multimodal prognostic indicators.

    更新日期:2019-11-01
  • CRAFTing a New Approach to Antiepileptic Drug Discovery.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-01
    Kyle A Lyman,Dane M Chetkovich

    Srivastava PK, van Eyll J, Godard P, Mazzuferi M, Delahaye-Duriez A, Steenwinckel JV, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun. 2018;9(1):3561. doi:10.1038/s41467-018-06008-4. The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ("Causal Reasoning Analytical Framework for Target discovery"-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in 3 preclinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. The CRAFT is applicable to disease settings other than epilepsy.

    更新日期:2019-11-01
  • Don't Just Stand There: Do Something! The Case for Peri-Ictal Intervention.
    Epilepsy Curr. (IF 6.909) Pub Date : 2019-05-01
    Prakash Kotagal

    Hypoxemia Following Generalized Convulsive Seizures: Risk Factors and Effect of Oxygen Therapy Rheims S, Alvarez BM, Alexandre V, Curot J, Maillard L, Bartolomei F, et al; the REPO2MSE Study Group. Hypoxemia following generalized convulsive seizures: risk factors and effect of oxygen therapy . Neurology. 2019;92(3):e183-e193 Objective: To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS). METHODS We reviewed the video-electroencephalogram (EEG) recordings of 1006 patients with drug-resistant focal epilepsy included in the REPO2MSE study to identify those with ≥1 GCS and pulse oximetry (SpO2) measurement. Factors determining recovery of SpO2 ≥90% were investigated using Cox proportional hazards models. Association between SpO2 nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures. RESULTS A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 (86%) GCS. Rate of GCS with SpO2 <70% dropped from 40% to 21% when oxygen was administered early ( P = .046). Early recovery of SpO2 ≥90% was associated with early administration of oxygen ( P = .004), absence of postictal generalized EEG suppression (PGES; P = .014), and extratemporal lobe epilepsy ( P = .001). Lack of early administration of O2 ( P = .003), occurrence of PGES ( P = .018), and occurrence of ictal hypoxemia during the focal phase ( P = .022) were associated with lower SpO2 nadir. CONCLUSION Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS, but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.

    更新日期:2019-11-01
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