Showing papers in "Epilepsy Currents in 2014"

Epilepsy and inflammation in the brain: overview and pathophysiology.

Abstract: The possibility that inflammatory processes in the brain contribute to the etiopathogenesis of seizures and the establishment of a chronic epileptic focus is increasingly recognized as a result of supportive evidence in experimental models and in the clinical setting. Prototypical inflammatory cytokines (such as IL-1beta) and “danger signals” (such as HMGB1 and S100beta) are overexpressed in human and experimental epileptogenic tissue, prominently by glia. Neurons and endothelial cells of the blood–brain barrier contribute to inflammatory processes. All these cell types also express receptors for inflammatory mediators, suggesting that inflammatory molecules in the brain exert both autocrine and paracrine activation of intracellular signaling cascades; thus, they may act as soluble mediators of cell communication in diseased tissue. In experimental models, seizures also trigger brain inflammation in the absence of cell loss; in human epileptogenic tissue, the type of neuropathology associated with chronic...

Closing the Major Gap in PNES Research Finding a Home for a Borderland Disorder

Abstract: Psychogenic nonepileptic seizures (PNES) are events commonly encountered by primary care physicians, neurologists, pediatricians, and emergency medicine physicians in their practices, yet there continues to be significant variability in the way they are evaluated, diagnosed, and treated. Lack of understanding this condition and limited data on long-term outcome from current treatment paradigms have resulted in an environment with iatrogenic injury, morbidity, and significant costs to the patient and healthcare system. This article will review the current state of research addressing PNES treatment both in the adult and pediatric populations.

Inflammatory Processes, Febrile Seizures, and Subsequent Epileptogenesis

Abstract: Febrile seizures (FS) are the most common type of seizures in infants and preschool children. Inflammatory mediators, which are known triggers of fever, have also been implicated as contributors to the onset of these seizures. Evidence that inflammation is present following FS and during established epilepsy suggests that it could also influence epileptogenesis. However, the potential involvement of inflammatory mediators to the epileptogenic process that may follow prolonged FS has yet to be fully determined. This article reviews the current state of our knowledge and major gaps that remain by focusing on four questions: Does inflammation contribute to the generation of FS? Does prolonged FS or febrile status epilepticus (SE) cause temporal lobe epilepsy in the absence of predisposing factors? Does inflammation contribute to the process by which febrile SE causes limbic epilepsy? And finally, can inflammation be a foundation for biomarkers and therapy for FS-induced epileptogenesis?

Cannabidiol: promise and pitfalls.

Abstract: Over the past few years, increasing public and political pressure has supported legalization of medical marijuana. One of the main thrusts in this effort has related to the treatment of refractory epilepsy—especially in children with Dravet syndrome—using cannabidiol (CBD). Despite initiatives in numerous states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available to prove or disprove the efficacy and safety of CBD in patients with epilepsy. This review highlights some of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for epilepsy, and highlights issues related to the use of currently available CBD products. Cannabidiol is the major nonpsychoactive component of Cannabis sativa. Over the centuries, a number of medicinal preparations derived from C. sativa have been employed for a variety of disorders, including gout, rheumatism, malaria, pain, and fever. These preparations were widely employed as analgesic...

Untangling the dravet syndrome seizure network: the changing face of a rare genetic epilepsy.

Abstract: Dravet syndrome (also known as Severe Myoclonic Epilepsy of Infancy) is a rare genetic epilepsy syndrome commonly associated with loss-of-function mutations in SCN1A, the gene encoding the α subunit of the voltage-gated sodium channel NaV1.1, resulting in haploinsufficiency. Like other voltage-gated sodium channels, NaV1.1 function contributes to the rising phase of the neuronal action potential; thus, the observation that loss-of-function mutations in this channel gene are associated with seizures has created a paradox for the field. Major work has been done to untangle this paradox during the past decade, resulting in the development of two distinct hypotheses to explain seizures in Dravet syndrome. Here, we review the history of these two hypotheses and speculate as to what the history of Dravet syndrome research might tell us about its future.

Seizing an Opportunity for the Endocannabinoid System

Abstract: Exogenous cannabinoids can limit seizures and neurodegeneration, and their actions are largely mimicked by endogenous cannabinoids (endocannabinoids). Endocannabinoids are mobilized by epileptiform activity and in turn influence this activity by inhibiting synaptic transmission; both excitatory and some inhibitory synapses can be suppressed, leading to potentially complex outcomes. Moreover, the endocannabinoid system is not a fixed entity, and its strength can be enhanced or reduced. Endocannabinoids and their receptors are altered by epileptic seizures in ways that can reduce the efficacy of both exogenous and endogenous cannabinoids in sometimes unexpected ways.

P-glycoprotein Expression and Pharmacoresistant Epilepsy: Cause or Consequence?

Abstract: Commentary Since the 1990s, more than a dozen new medications have been introduced for the treatment of epilepsy. Many of these newer molecules have unique pharmacological mechanisms, and most have significantly improved pharmacokinetic profiles as compared to their predecessors. Despite these advances, however, a frustrating statistic remains: Approximately one-third of patients with epilepsy will ultimately inadequately respond to antiepileptic drug (AED) treatment (1). Pharmacoresistance is, by international consensus, defined as a failure of two or more AEDs, given in an appropriate manner, to achieve seizure freedom. While the reasons for this drug resistance is no doubt multifactorial, there is a growing body of evidence— derived from both animal models, as well as examinations in brain tissue of patients undergoing surgical resection—that drug resistance might be explained by a failure of AEDs to reach their molecular targets (1). P-glycoprotein (Pgp) is a member of the ATP-binding cassette proteins. This transmembrane transporter is found in a number of tissues, including endothelial cells of the blood brain barrier (BBB), and functions as an efflux transporter, pumping both xenobiotics and other toxic substrates from the intracellular space back into the capillary lumen. P-glycoproP-glycoprotein Expression and Pharmacoresistant Epilepsy: Cause or Consequence?

Neurocysticercosis and epilepsy.

Abstract: . NCC is the most common parasitic disease of the nervous system. It accounts for about 50,000 deaths per year and many times this number of people with active epilepsy (1, 2). The disease is endemic in Central and South America, sub-Saharan Africa, and in some regions of the Far East, including the Indian subcontinent, Indonesia, and China. It is rare in Europe, in North America (with the exception of the southwest United States), Australia, Japan, and New Zealand, except among immigrants. It is non-existent in Israel and the Muslim countries of Africa and Asia (Figure 1) (1, 3). With increased travel to disease-endemic areas and the migration of tapeworm carriers or people infected with the disease, NCC is becoming increasingly prevalent in industrialized countries, particularly the United States (4). In a recent systematic review, the frequency of NCC in people with epilepsy was found to have a large variability. The authors selected a total 565 articles from PubMed and 23 international databases, from January 1, 1990, to June 1, 2008 (5). The pooled estimate for this population was found to be 29% (95% confidence interval [CI]: 22.9–35.5%).

Advanced Imaging Techniques in the Diagnosis of Nonlesional Epilepsy: MRI, MRS, PET, and SPECT.

Abstract: Once patients have a diagnosis of localization related epilepsy (LRE), it is critical to further classify those patients into lesional or nonlesional for treatment and prognostic reasons. An individual with LRE may be classified as nonlesional for two reasons: 1) a lesion may not exist; that is, the structural abnormality that gives rise to seizures may be at the channel level or be spatially distributed in such a way that it would not be accurately termed a lesion, or 2) a lesion exists but is so subtle that standard clinical imaging is not sensitive enough to discriminate between the lesion and surrounding healthy brain tissue. As with any technology and disease process, this definition is dynamic, as we know that future imaging techniques will be developed and new disease mechanisms will be discovered, making detection of the epileptogenic underlying abnormality an ever-changing target.

Timing of surgery in rasmussen syndrome: is patience a virtue?

Abstract: Rasmussen syndrome affects previously normal people and forever changes their lives and the lives of their families. Although understood as a probable autoimmune condition, medical treatment remains limited and surgery remains the only cure, although with inevitable functional consequences. Difficulties remain in deciding on the optimal timing of surgery. Here, we review data available to aid clinicians faced with making the decision of when to recommend hemispherectomy. Not all patients have rapidly progressive disease, however, and such patients may benefit from immunomodulatory treatment. Thus, a patient's clinical course requires careful evaluation in order to identify those who would benefit most from early surgery.

Seizures and epileptiform activity in early Alzheimer disease: how hard should we be looking?

Abstract: Commentary My standard epilepsy talk for medical students used to include the following: The incidence of epilepsy has a bimodal distribution, and the causes of epilepsy in children are different from those in older adults. New-onset epilepsy in the elderly is often a consequence of accumulated injuries to the brain, including from stroke, brain tumors, and neurodegenerative diseases. Although I did not explicitly say that epilepsy was an end-stage feature of Alzheimer disease (AD)—the result of advanced neuronal and synaptic loss—I implied that this was the case and made that implicit assumption myself. Clearly, this thinking needed revision. There is now substantial and growing literature addressing the interface between Alzheimer disease and epilepsy. Epidemiological studies clearly indicate that Alzheimer disease confers an increased risk of seizures and epilepsy: The incidence rate is increased about sevenfold in patients with AD compared to non-demented controls (1). A number of potential risk factors for developing seizures in AD have been identified, including antipsychotic drug use, African-American race, epileptiform findings on EEG, and greater cognitive impairment at baseline (2, 3). However, the most robust association has been with young age at dementia onset (4). While seizures can appear at any stage of the disease, the odds of developing epilepsy in AD are highest in young patients with AD and early in the disease course. Those with genetic causes of AD, who also have earlier onset of disease, appear to be at especially high risk of developing comorbid epilepsy. Patients with the most common Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease.

Epilepsy and viral infections.

Abstract: Viral infections may cause seizures via several pathogenetic mechanisms. Systemic infections, such as influenza, can lead to metabolic compromise, as well as occasional direct central nervous system (CNS) invasion—even though not usually neurotrophic. Although viral infection confined to the meninges rarely causes seizures and does not increase risk for later epilepsy, encephalitis is a major cause of seizures and subsequent epilepsy (1). In addition to the acute pathogens, syndromes caused by “unconventional” agents, such as Creutzfelt–Jacob disease or progressive multifocal leukoencephalopathy, often are associated with seizures or myoclonus at some time in their course. Seizures are caused by direct CNS infection by human immune deficiency virus (HIV), as well as with the secondary infections associated with acquired immune deficiency syndrome (AIDS). In addition, recent data suggest that persistent infection with a latent agent, human herpesvirus 6, may be associated with development of mesial temporal sclerosis.

Hope for New Treatments for Acute Repetitive Seizures

Abstract: Commentary Acute repetitive seizures (ARS) are also sometimes termed serial, repetitive, recurrent, cluster, or crescendo seizures (1). Although there is not a universally agreed upon definition, the essential features of ARS include multiple seizures (usually three or more) over a relatively short period of time (usually <24 hours). The seizures that compose ARS may be different from the patient’s usual isolated seizures, and the patient or family may be able to use these features to identify the onset of ARS. The type, duration, or severity of seizure may be characteristic at onset of ARS, or alternatively, ARS may be identified simply by increased frequency of typical seizures. ARS are distinguished from status epilepticus by recovery between the discrete seizures. ARS may be seen with nearly any seizure type, but the term is less often applied to myoclonic or absence seizures, which prototypically involve multiple seizures. The prevalence of ARS is not well known. Certain epilepsy syndromes are more likely to include ARS, namely symptomatic generalized and refractory localization-related epilepsy syndromes. A population-based study of ARS in the United Kingdom estimated that the crude prevalence in the general population was 2.3 per 10,000 (2). The prevalence was highest in the very young (ages, 0–4) at 5.9 per 10,000, and declined with age to 0.5 per 10,000 in those aged 70 and older. They estimated that ARS affect about 3 percent of the epilepsy population, which corresponds to about 0.02 percent of the general population. There is evidence that the prevalence of ARS in A Double-Blind, Randomized, Placebo-Controlled Trial of a Diazepam Auto-Injector Administered by Caregivers to Patients With Epilepsy Who Require Intermittent Intervention for Acute Repetitive Seizures.

Status epilepticus in the setting of acute encephalitis.

Abstract: Ms. Q, a 29-year-old woman, began to behave strangely, claiming to see and hear imaginary people. The following day, she was confused and somnolent in the morning. In the late morning, she had a generalized tonic-clonic seizure and was transported to the hospital. Her past medical and developmental histories were unremarkable. She took a daily oral contraceptive and had no drug allergies. She worked as a teacher and had been married for one year. On initial examination, blood pressure was 129/82, pulse 88, respiratory rate 16, temperature 37.5 °C. She was stuporous, moving her arms appropriately in response to a painful stimulus. Pupils were 2 mm and reactive. There was no gaze preference, and the rest of the examination was nonfocal. About 30 minutes after her first seizure, she had a second GTCS and was given 4 mg lorazepam intravenously. She had a third GTCS 6 min after her second seizure and received a second dose of lorazepam. Initial blood tests-including complete blood count, comprehensive metabolic panel, urinalysis, and toxic screen-were normal. Head CT was normal. She remained stuporous. EEG demonstrated waxing and waning electrographic ictal activity, and she was loaded with fosphenytoin. Intermittent electrographic seizure activity persisted, and a continuous infusion of intravenous propofol was administered. After 24 hr, propofol was weaned, but electrographic seizures recurred and it was restarted.

Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial.

Abstract: Commentary Despite the availability of multiple AEDs, many patients with epilepsy continue to have refractory seizures as well as debilitating side effects. As such, there continues to be a need to explore and investigate new AEDs. Brivaracetam is a novel compound that has been studied extensively in preclinical, phase II, and now phase III trials. The results of three phase III, prospective multicenter randomized, double-blind placebocontrolled, parallel-group trials have recently been published (1–3) and yield mixed results. Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand. It is not entirely clear how SV2A affects neurotransmission, but animal studies suggest that it is potentially a good target for seizure control. Mice deficient in SV2A have seizures (4). Among animal models of epileptogenesis as well Brivaracetam as Adjunctive Treatment for Uncontrolled Partial Epilepsy in Adults: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial.

Parasitic Diseases that Cause Seizures

Abstract: The propensity of parasites to invade the brain, cause disease, and give rise to seizures and epilepsy varies greatly. This reflects the wide diversity of parasites that differ in fundamental ways. This manuscript reviews parasites that invade the brain or its vasculature and give rise to seizures.

Lennox-lombroso lecture, 2013: psychiatric comorbidities through the life of the seizure disorder: a complex relation with a not so complex solution.

Abstract: Psychiatric comorbidities are relatively frequent in people with epilepsy, occurring in one of every three patients, with mood and anxiety disorders predominating. They are the expression of a complex interaction between a previous psychiatric history (and/or genetic predisposition for psychiatric disorder), neurobiologic changes associated with the underlying epilepsy, peri-ictal phenomena, iatrogenic and reactive processes. Furthermore, a bidirectional relation between psychiatric disorders and epilepsy has added another level of complexity, while at the same time opening an opportunity of the recognition of potential pathogenic mechanisms that are responsible for the high comorbid occurrence of these disorders. This article highlights the clinical implications of understanding the course of psychiatric comorbidities relative to the onset of the seizure disorder to minimize their risk of recurrence and their interference in the management of the seizure disorder.

The New Ketone Alphabet Soup: BHB, HCA, and HDAC.

Abstract: Commentary After nearly a century of clinical use, the mechanisms underlying the anti-seizure effects of the ketogenic diet (KD) remain unclear. Notwithstanding this dearth of knowledge, the KD’s clinical utility appears to be expanding, as there is increasing evidence of its broad neuroprotective properties (1, 2). For both anti-seizure and neuroprotective actions, there have emerged a broad array of proposed mechanisms, and more recently, biochemical and cellular effects that would not necessarily be predicted for bioenergetic substrates and enzymes (3). However, it is uncertain which putative mechanisms are relevant in the clinical context. Clearly, as perturbations in cellular metabolism are increasingly linked to the pathogenesis of neurologic disorders (4), a better mechanistic understanding of the KD (and indeed its variants, such as the modified Atkins diet and the low-glycemic index therapy), would potentially lead to more effective dietary/metabolic treatments, and even perhaps a “KD in a pill,” although the evidence thus far suggests that modulation of a single target mechanism is unlikely to recapitulate the entire clinical profile of the KD (5). Not surprising, some investigators have taken a simple reductionist approach to studying KD mechanisms and asked whether the principal by-products of fatty acid oxidation (i.e., ketone bodies such as β-hydroxybutyrate [BHB], acetoacetate [ACA], and acetone) might exert direct effects on brain network excitability, beyond their well-established role as alternative fuels for bodily tissues under conditions of decreased bioavailability of glucose. Thus far, the preclinical data support the notion that ACA and acetone can exert antiseizure effects when acutely administered in vivo, but whether BHB possesses antiseizure activity remains unknown (3). And unfortunately, Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor.

Danger in the pipeline for the ketogenic diet

Abstract: Commentary The popularity of ketogenic diets for children and adults with epilepsy in the modern era is at an all-time high. Effective in approximately half of those who try them, it is difficult to argue dietary therapy should be offered earlier in the course of refractory epilepsy. The recent emergence of alternative variants of the diet, computer programs for recipe building, and creative dietitians and parents have made dietary therapies easier and more palatable than ever before (1, 2). Unfortunately, these medical treatments have very real side effects. Several are more benign and often treatable, including constipation, hypoglycemia, and gastroesophageal reflux (3). However, others such as kidney stones, growth disturbance, and acidosis can be potentially more problematic (3). Many parents and patients are particularly concerned about the effects of hypercholesterolemia, especially in the long term (4). It is not unusual for a family to ask: “ will my child have a heart attack from this diet?” Preliminary data suggests that although serum lipid values increase in the first several months on the ketogenic diet, they decline to normal values The Impact of the Ketogenic Diet on Arterial Morphology and Endothelial Function in Children and Young Adults With Epilepsy: A Case-Control Study.

MRI (minimum recommended imaging) in epilepsy.

Abstract: Commentary When patients are told that they will undergo an MRI and an EEG to evaluate their epilepsy, I imagine that they think of these studies as standard practice. There will be a “picture of the brain” and a look at the “brain wave activity” to assist with epilepsy diagnosis, classification, and management. Neurologists know that the product is far from standard. Some aspects of EEG recording are relatively uniform. Development of the International 10-20 system of electrode placement and dissemination of published guidelines have led to the widespread use of standardized electrode placement and a standard number of recording channels at most centers (1). High-density EEG arrays are rarely used, even at specialized epilepsy centers. However, differences in recording quality can result from variability in the training and experience of EEG technologists, and differences in interpretation quality may vary based on the qualifications and experience of the interpreting neurologist. Several reports describe the misdiagnosis of epilepsy based on false-positive findings on EEG interpretations (2, 3). Inter-rater reliability for some EEG features can be poor, and a recent supplement of Neurology (“How not to read an EEG” [4]) was devoted to examining the sources of this variability and potential solutions. The field also lacks a uniform electronic format standard for EEG comparable to the Digital Imaging and Communications in Medicine (DICOM) standard that facilitates sharing of medical images in a common electronic format. Although some “universal EEG reader” programs are available, most clinical neurophysiologists must still cross some technical barriers created by proprietary software to share or review studies recorded elsewhere. Although the field of MRI has solved some of these data sharing issues [studies can be electronically “pushed” into and reviewed in compatible picture archiving and communication systems (PACS)], MRI for the evaluation of epilepsy is far from a standard product. Von Oertzen and colleagues (5) highlighted this point in their insightful 2002 paper examining factors influencing detection of epileptogenic lesions. A “standard” MRI read by a “nonexpert” radiologist was much less likely to reveal a relevant epileptogenic lesion (39% detection rate) than an “expert” reader reviewing images generated using a dedicated epilepsy protocol (91%). The combination of clinical expertise (people) and optimized protocols (technology) resulted in the best outcomes. Importantly, an experienced reader reviewing Proposal for a Magnetic Resonance Imaging Protocol for the Detection of Epileptogenic Lesions at Early Outpatient Stages.

Do We Need Seizure Prophylaxis for Brain Tumor Surgery

Abstract: Commentary Seizures constitute very serious complications of brain tumor surgery as they often delay recovery and even cause death. Seizures occur in 20 to 40 percent of patients with brain tumors (1, 2). Frontal and parietal tumor location is more likely to be associated with seizures, as are slowly growing tumors (3). Craniotomies or biopsies, often done for diagnoses, may also increase risk of seizures. Previous retrospective studies reported no significant reduction of seizure incidence with prophylactic antiepileptic medications in patients with supratentorial gliomas (4) and provided conflicting results on the role of seizure prophylaxis in patients with metastatic brain tumors (1). On the other hand, prospective studies have not specifically recruited patients with gliomas or metastatic supratentorial tumors needing craniotomy to study the efficacy of antiepileptic drug (AED) prophylaxis in reducing postoperative seizures. Such studies either focused on brain tumor patients with or without craniotomy (2), or on craniotomy patients with or without brain tumors (5). Thus, the debate continues about seizure prophylaxis after craniotomy for intraparenchymal tumor resection. Wu et al. conducted a prospective randomized trial in patients with intraparenchymal brain tumors undergoing craniotomy to examine the use of phenytoin for postoperative seizure prevention (6). Eligible patients were ones with primary or metastatic supratentorial brain tumors who had not had seizures prior to surgery. They were randomized to a 7-day A Prospective Randomized Trial of Perioperative Seizure Prophylaxis in Patients with Intraparenchymal Brain Tumors.

Epilepsy is not resolved.

Abstract: Commentary The ILAE has re-defined epilepsy: epilepsy is a disease of the brain causing at least two unprovoked or reflex seizures occurring more than 24 hours apart or after one seizure if risks of recurrence are “high” (>60%). Conversely—and making a change that carries significant implications—they also now define epilepsy as “resolved” if an individual has outgrown their age-dependent syndrome or if they are seizure free for 10 years and off AEDs for 5 years. Overall, the ILAE committee report is a useful and sophisticated practical definition of epilepsy that helps guide the clinical evaluation of patients with seizures: epilepsy implies a risk for seizure recurrence and may require treatment while clinical monitoring and safety restrictions can end when epilepsy is resolved. Their definition incorporates a number of points that are clearly reviewed and justified in the ILAE report. It is important, however, to note what this “practical clinical” definition of epilepsy “is” and “is not” and to note controversial aspects of the report. First, unlike the 2005 conceptual definition of epilepsy, this is a clinical and not a neurobiological definition. The 2005 conceptual definition of epilepsy is “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological and social consequences of this condition.” While the new “practical clinical” definition of epilepsy is not intended to replace the 2005 conceptual definition, its use may deemphasize important links between brain disorders, epilepsy and associated emotional, cognitive and neurologic symptoms that are important to assess in patients with epilepsy (1, 2). Secondly, the new definition of epilepsy incorporates several controversies: 1) Epilepsy is defined as a disease. Although epilepsy meets the broad definition of disease as any condition that impairs normal function, it is more precisely a “disorder” with seizures representing functional disturbances caused by multiple diseases. The practical elements of a broad definition for epilepsy won out; similar to “heart disease,” advocacy for epilepsy research funding and epilepsy awareness may be enhanced by terming epilepsy a disease. It may be less stigmatizing; however, to call epilepsy a “disorder” than a “disease” if this helps distinguish patients with benign and disabling etiologies for epilepsy; 2) patients diagnosed with an epilepsy syndrome are defined as having epilepsy, since “it makes little sense to say that someone has an epilepsy syndrome, but not epilepsy” (3, 4). This is a practical point, but may detract conceptually from emerging evidence that epilepsy is often a trait (e.g., genetic generalized epilepsy) with limited expression (3, 4) and that epilepsy may be only one of several phenotypes associated with single gene variants (e.g., recurrent copy number variants may be associated with multiple neuropsychiatric disorders and epilepsy [5]); 3) Epilepsy may be clinically defined as present following a single seizure if recurrence risks are high (>60%). This is reasonable in that most patients with single unprovoked seizures have low to intermediate risks for recurrence (20–50%); however, some paA Practical Clinical Definition of Epilepsy.

Sudden unexpected death in the epilepsy monitoring unit.

Abstract: Commentary Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among persons with chronic refractory epilepsy (1). The current accepted definition is a sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death, occurring in benign circumstances in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (2). SUDEP typically affects patients with drug-resistant epilepsy. The average incidence is 4 deaths per 1,000 patient-years; for patients with uncontrolled childhood-onset epilepsy, there is a 12% cumulative risk over 40 years. Epidemiologic risk factors include generalized tonic-clonic seizures, particularly nocturnal; male sex; age of onset of epilepsy <16 years; duration of epilepsy >15 years; and polytherapy (3,4). Other than identifying risk factors, there has been limited progress in our understanding of SUDEP. Most cases are thought to be peri-ictal (1). Putative mechanisms fall into 1 of 3 camps: cardiac, pulmonary, or cerebral (“cerebral shutdown”) causes. Further study is difficult as SUDEP is relatively rare and inherent within the name itself, cases are unpredictable. Prior information comes from either witnessed reports, typically family members, or published reports (9 in the literature) of cases occurring within epilepsy monitoring units (EMUs). These cases are important as through careful analysis of video-EEG monitoring, a better understanding of pathophysiological mechanisms may be elucidated. Ryvlin and colleagues through the MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) gathered an international cohort of such cases. They performed a systematic retrospective survey of EMUs located in Europe, Israel, Australia, and New Zealand; collected data of all cardiorespiratory arrests; estimated incidence of cardiorespiratory arrests in surveyed EMUs; analyzed patterns; and explored mechanisms to explain SUDEP. Previously published cases were included. Incidence and Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS): A Retrospective Study.

Epi4K Phase I: Gene Discovery in Epileptic Encephalopathies by Exome Sequencing.

Abstract: Commentary The Epi4K Consortium was launched in 2011 in response to a National Institute of Neurological Disorders and Stroke (NINDS) Funding Opportunity Announcement soliciting applications for “Centers Without Walls for Collaborative Research in the Epilepsies: Genetics and Genomics of Human Epilepsies.” This large-scale collaborative effort leverages large sample cohorts to increase statistical power and accelerate epilepsy gene discovery. The ultimate goal of the Epi4K Center without Walls is to sequence the genomes of at least 4,000 individuals with epilepsy using next-generation sequencing (NGS) (1). NGS technology has revolutionized our ability to efficiently and inexpensively sequence individuals at the whole exome or whole genome level. The cost of whole exome sequencing is now under $1000 per sample. Whole exome sequencing studies have been quite successful for identifying de novo dominant mutations in individuals with profound neurodevelopmental phenotypes (2, 3). This approach relies on a simple genetic model in which the causative mutation is assumed to be present in the genome of the affected child but absent in the unaffected parents. On average, each individual carries a mutation in one of their genes that was not present in their parents (4) and, thus, is denoted as a de novo mutation. The occurrence of de novo mutations in the same gene in two or more unrelated individuals with similar clinical phenotypes supports a potential pathogenic contribution to the disease. The first project tackled by the Epi4K Consortium focused on discovery of de novo mutations in two well-defined epileptic encephalopathies: Lennox–Gastaut syndrome and infantile spasms. Patients were ascertained by the NINDS-funded Epilepsy Phenome/Genome Project, a multi-center collaborative effort designed to collect detailed, high-quality phenotype information for genetic studies (5). The Epi4K Consortium performed whole exome sequencing on 264 patient–parent trios, of which 149 were classified as infantile spasms and 115 were Lennox–Gastaut syndrome. They identified 329 confirmed de novo mutations. On average, each patient harbored 1.25 de novo mutations, which is consistent with other studies reported in the literature (4, 6). The majority of the mutations De Novo Mutations in Epileptic Encephalopathies.

The more, the better: modeling dravet syndrome with induced pluripotent stem cell-derived neurons.

Abstract: Commentary Advances in cellular reprogramming have made it possible to generate virtually any cell type from pluripotent stem cells. Initially, embryonic stem cells were the only source of truly pluripotent cells. However, in 2007, it was reported that induced pluripotent stem cells (iPSCs) could be generated from human somatic cells (1, 2). This discovery enabled iPSCs generated from patients to be used as an in vitro model for studying disease mechanisms and testing therapeutics. Patient cells obtained from skin biopsy can be reprogrammed to pluripotency by addition of the four factors: Oct3/4, Sox2, Klf4, and cMYC (1). These iPSCs have infinite capacity for self-renewal and are pluripotent, making them an unlimited resource for differentiating any cell type for experimental studies. iPSCs provide a particularly attractive model for neurologic disease, where access to live human tissue suitable for culture is extremely limited. In this study, Liu and colleagues generated iPSC-derived neurons to model Dravet syndrome, a catastrophic, infantonset epileptic encephalopathy with pharmacoresistant seizures, developmental regression, and increased mortality (3). In over 80% of patients, Dravet syndrome is caused by heterozygous mutation of SCN1A, which encodes the voltagegated sodium channel Nav1.1 (4). Most Dravet syndrome mutations result in loss of Nav1.1 function, suggesting that SCN1A is haploinsufficient. Initially, it was puzzling that loss of a voltage-gated sodium channel, which underlies action potentials, could lead to hyperexcitability. However, results from mice with targeted deletion of Scn1a or from mice engineered with a human nonsense mutation suggested that loss of Nav1.1 predominantly affected GABAergic inhibitory neurons (5, 6). These observations led to the hypothesis that Dravet syndrome is an “interneuronopathy,” with hyperexcitability and seizures resulting from loss of inhibitory input onto excitatory principal neurons (pyramidal cells). Liu and colleagues sought to determine the effects of SCN1A mutations on human neuronal function using iPSCderived neurons from Dravet syndrome patients. They generated iPSCs from three unaffected controls and two patients, Dravet Syndrome Patient-Derived Neurons Suggest a Novel Epilepsy Mechanism.

“It Was the Interneuron With the Parvalbumin in the Hippocampus!” “No, It Was the Pyramidal Cell With the Glutamate in the Cortex!” Searching for Clues to the Mechanism of Dravet Syndrome – The Plot Thickens

Abstract: Viewer/Itinerary Planner Washington, DC: Society for Neuroscience. 2004; Program No. 479.5. 8. Liautard C, Scalmani P, Carriero G, de Curtis M, Franceschetti S, Mantegazza M. Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Epilepsia

The Face (and Arm) of Treatment for Seizures in VGKC/LGI1 Antibody-Associated Limbic Encephalitis.

Abstract: Commentary The occurrence of symptomatic seizures in the setting of underlying neurologic and systemic medical conditions that have their own specific therapies apart from AEDs often raises clinical questions with regard to the choice and timing of treatments. In cases of autoimmune epilepsy associated with antineuronal antibodies, for example, these questions concern the relative importance and sequence of immunomodulatory therapies (corticosteroids, intravenous immunoglobulin [IVIg], and plasma exchange) as compared with AEDs. A distinctive form of autoimmune epilepsy is now known to be associated with antibodies directed against the voltagegated potassium channel complex (VGKC), and in particular the leucine-rich glioma inactivated 1 (LGI1) protein component of this complex (1). Frequent, brief episodes of posturing, Faciobrachial Dystonic Seizures: The Influence of Immunotherapy on Seizure Control and Prevention of Cognitive Impairment in a Broadening Phenotype

mTOR Strikes Again: mTORC1 Activation Causes Epilepsy Independent of Overt Pathological Changes

Abstract: Commentary The mammalian target of rapamycin (mTOR) is a ubiquitous protein kinase that has received extensive attention in recent years as a potential mediator of epilepsy. mTOR, particularly a specific complex of proteins called mTORC1, regulates numerous cellular and physiologic functions, including protein synthesis, cell growth, proliferation, autophagy, and metabolism. Abnormal regulation of mTORC1 is most strongly implicated in promoting epilepsy in the genetic disease, tuberous sclerosis complex (TSC). However, there is now abundant evidence that mTORC1 may be involved in epileptogenesis in a variety of other types of epilepsies, including infantile spasms, neonatal hypoxic seizures, absence epilepsy, posttraumatic epilepsy, and acquired temporal lobe epilepsy (1). In TSC, the association between mTORC1 and epilepsy is strongly rooted in the primary genetic defect that causes this disease. Two genes, TSC1 and TSC2, have been linked to TSC. Since the protein products of TSC1 and TSC2, hamartin and tuberin, normally function to inhibit mTORC1, mutations in TSC1 or TSC2 lead to disinhibited or abnormally elevated mTORC1 activity. Given the role of mTORC1 in stimulating cell growth and proliferation, hyperactivation of mTORC1 promotes excessive cell growth and tumor formation in various organs in TSC patients, including the skin, heart, kidneys, and brain. Identification of this pathophysiological mechanism has already led to the use of mTORC1 inhibitors for treating brain and kidney tumors in TSC patients. While the relationship of mTORC1 to tumors is relatively straightforward, the link to epilepsy in TSC is more complicated (1). Cortical tubers, the pathological hallmark of TSC, are most closely associated with epilepsy, as surgical removal of tubers can eliminate seizures in some TSC patients. Cortical tubers are considered malformations of cortical development, akin to focal cortical dysplasia. While tubers do not grow like true tumors, they do feature some tumor-like cellular features, such as glial proliferation and poorly differentiated cytomegalic cells, as well as biochemical evidence of increased mTORC1 activity. Although mTORC1 might also promote epileptogenesis through tuber-independent mechanisms, the connection TORC1-Dependent Epilepsy Caused by Acute Biallelic Tsc1 Deletion in Adult Mice.

Prediction and Prevention of Verbal Memory Decline After Temporal Lobectomy

Abstract: Functional magnetic resonance imaging has demonstrated reorganization of memory encoding networks within the temporal lobe in temporal lobe epilepsy, but little is known of the extra-temporal networks in these patients. We investigated the temporal and extra-temporal reorganization of memory encoding networks in refractory temporal lobe epilepsy and the neural correlates of successful subsequent memory formation. We studied 44 patients with unilateral temporal lobe epilepsy and hippocampal sclerosis (24 left) and 26 healthy control subjects. All participants performed a functional magnetic resonance imaging memory encoding paradigm of faces and words with subsequent out-ofscanner recognition assessments. A blocked analysis was used to investigate activations during encoding and neural correlates of subsequent memory were investigated using an event-related analysis. Event-related activations were then correlated with out-of-scanner verbal and visual memory scores. During word encoding, control subjects activated the left prefrontal cortex and left hippocampus whereas patients with left hippocampal sclerosis showed significant additional right temporal and extra-temporal activations. Control subjects displayed subsequent verbal memory effects within left parahippocampal gyrus, left orbitofrontal cortex and fusiform gyrus whereas patients with left hippocampal sclerosis activated only right posterior hippocampus, parahippocampus and fusiform gyrus. Correlational analysis showed that patients with left hippocampal sclerosis with better verbal memory additionally activated left orbitofrontal cortex, anterior cingulate cortex and left posterior hippocampus. During face encoding, control subjects showed right lateralized prefrontal cortex and bilateral hippocampal activations. Patients with right hippocampal sclerosis showed increased temporal activations within the superior temporal gyri bilaterally and no increased extra-temporal areas of activation compared with control subjects. Control subjects showed subsequent visual memory effects within right amygdala, hippocampus, fusiform gyrus and orbitofrontal cortex. Patients with right hippocampal sclerosis showed subsequent visual memory effects within right posterior hippocampus, parahippocampal and fusiform gyri, and predominantly left hemisphere extra-temporal activations within the insula and orbitofrontal cortex. Correlational analysis showed that patients with right hippocampal sclerosis with better visual memory activated the amygdala bilaterally, right anterior parahippocampal gyrus and left insula. Right sided extra-temporal areas of reorganization observed in patients with left hippocampal sclerosis during word encoding and bilateral lateral temporal reorganization in patients with right hippocampal sclerosis during face encoding were not associated with subsequent memory formation. Reorganization within the medial temporal lobe, however, is an efficient process. The orbitofrontal cortex is critical to subsequent memory formation in control subjects and patients. Activations within anterior cingulum and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment.