Posts Tagged SUDEP

[ARTICLE] Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions – Full Text

Abstract

The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016.

Introductory Vignette by Lizbeth Carmichael. Epilepsy, Depression, and SUDEP—A Parent’s Perspective

My son John developed epilepsy in his late teens, and despite medications, his seizures remained severe and uncontrolled. John was a talented and creative musician and a caring and thoughtful brother and son. He had many friends, and he desperately wanted an independent life. As John’s epilepsy progressed, he also experienced declining mental health. John, who was normally a very peaceful individual, had periods of severe irritability and rage. He also became very anxious at times, and this was a sign of an impending seizure. John heard voices and developed paranoia, hallucinations, and depression. Our family was told to see specialists, but we found that the communication and coordination of care between epileptologists and mental health professionals was impossible, even when he was hospitalized and referrals were made. Ultimately, his mental health issues were not understood or addressed and contributed significantly to his decline. John died of sudden unexpected death in epilepsy (SUDEP) in 2012. Our family’s wish is that those around John had been more attuned to the mental health comorbidities that he was experiencing, and that his medical issues were jointly managed as the outcome for him might have been different.

Significant comorbidities often accompany epilepsy and can be more debilitating than the seizures themselves. A better understanding of the underlying mechanisms of epilepsy-associated comorbidities and appropriate clinical care is critical for increased quality of life for those impacted by epilepsy and their families.

Lizbeth Carmichael. Forever John’s Mom. Citizens United for Research in Epilepsy (CURE).

Introduction

In this review, we provide an update on preclinical and clinical advances into our understanding of the many etiologies of the epilepsies, as well as progress in assigning etiology to epilepsy-related neuropsychiatric and somatic comorbidities. Since the most recent summary in this area,1 expansion in our knowledge of epilepsy genetics and autoimmune epilepsies has continued to result in fewer individuals being labeled with epilepsy of unknown etiology. With the advent of next-generation sequencing technologies, the number of “epilepsy genes” continues to expand. Assigning a causative role to such genes requires verification in not only larger cohorts with statistical rigor but also a number of criteria that take into account normal variation, determination of how a genetic change leads to altered molecular function, and the demonstration of an epilepsy or epilepsy-related phenotype in genetically manipulated model organisms.2 Similar considerations apply for autoimmune epilepsies, for which the relative epileptogenic effects of T-cell infiltration and circulating antibodies continue to be clarified.

Preclinical models of genetic, autoimmune, and brain injury-related epilepsies have been essential to advance our knowledge into upstream and downstream cellular and neurophysiological perturbations that may promote hypersynchrony and the transition to the ictal state. It is only with this type of knowledge that we will be able to better inform treatment of epilepsy related to these types of epilepsy. Incomplete penetrance and variable phenotypes in both humans and animal models strongly implicate genetic modifiers of susceptibility, which need to be identified and validated so as to appreciate mechanisms by which epilepsy may be therapeutically modulated.

In parallel with efforts to address the causes of epilepsy and epileptogenesis, there has been an expansion in efforts designed to unravel the genesis of epilepsy’s various psychiatric comorbidities. Generally, these are etiologically related to broad network dysfunction that may be secondary to the underlying epileptogenic lesion (genetic, structural, or unknown) and actively modulated by the burden of ongoing seizures (if present) and antiseizure medications. Animal models of monogenic epilepsies provide the most tractable route to assigning etiology to epilepsy-associated comorbidities, albeit with some limitations in the ability to assess psychiatric comorbidities in various models. Incorporating optogenetic and chemogenetic strategies in these models affords the ability to definitively test whether specific network abnormalities affect seizure risk or impact limbic function or cognitive function or both.

We conclude our review with a set of general recommendations for future research into the causes of epilepsy spectrum disorders that will guide our understanding into epilepsy prevention (area II), treatment options (area III), and the adverse consequences of seizures themselves (area IV).

Key Advances in Area I

Epilepsy Genetics

Advances in our understanding of the genetics of the epilepsies have continued to accrue since the last Benchmarks update and have been reviewed in several excellent publications.36 Many new variants associated with epilepsy are identified as “de novo dominant,” meaning that they are present in the heterozygous state in sporadically affected individuals. At a cellular level, these genes encode proteins that display a broad range of functions that extend well beyond ion channels, including cell adhesion (eg, PCDH19), DNA binding and chromatin remodeling (eg, CHD2), and neurotransmitter release (eg, STXBP1).7 The importance of genetic etiologies in focal epilepsy in particular has become even more clear, with the involvement of DEPDC5 and associated GATOR1-complex mTOR repressors in epileptogenic cortical malformations being notable examples.8

De novo postzygotic (somatic) mutation has been increasingly recognized to play a role in focal epilepsy, largely involving the mTOR pathway in the pathogenesis of lesional epilepsies such as focal cortical dysplasia and hemimegalencephaly, with a majority of cases explained by this mechanism.911 Extending the discovery of somatic mutation to a new pathway and, interestingly, to both focal cortical dysplasia (type I) and nonlesional focal epilepsy was a report on mosaic variants in the gene SLC35A2, which encodes an UDP-galactose transporter previously associated in nonmosaic form with developmental and epileptic encephalopathy.12 The discovery of these 2 distinct pathways may point to very different targeted therapies after further study, which is promising but also demands attention to precision in classifying individuals with focal epilepsy and establishing a molecular diagnosis before pursuing experimental therapy.

Although most newly discovered pathogenic variants each seem to be causative in only a small number of individuals, taken together their combined impact is substantial. From the perspective of practicing epileptologists, we now benefit from a relatively high rate of identifiable genetic causes in neonatal and early childhood epilepsies, particularly in those individuals with comorbid intellectual disability, so that more routine usage of next-generation sequencing methods in this population may be warranted.13,14 Much more research is needed, however, to separate out the effects of seizures, genetic changes, and treatments on the intellectual impairments that are found in the epileptic encephalopathies.15

Animal models have permitted important insights into the specific mechanisms by which genetic aberrations may promote hyperexcitability. In additional to conventional “knockout” mice, mutants with conditional gene deletions (permitted via Cre-LoxP technology) have helped dissect the individual contributions of specific neuronal populations to seizure generation. For example, mice with a conditional deletion of Lgi1 in parvalbumin-positive interneurons alone are devoid of spontaneous seizures, while conditional deletions of Lgi1 in forebrain glutamatergic neurons result in frequent early-life seizures and premature death,16 just as in Lgi1 knockout mice.17 These results not only provide guidance to future gene replacement strategies but also show that while Lgi1 is an extracellularly secreted protein that is expressed in both GABAergic and glutamatergic neurons, restoring Lgi1 expression in glutamatergic neurons may be more likely to ameliorate seizures. The lack of spontaneous seizures in mice with heterozygous deletions of Lgi1 (recapitulating the haploinsufficiency of LGI1 mutation-related lateral temporal lobe epilepsy [TLE]) illustrates an important point with regard to gene dosage in animal models. Similar findings exist with other epilepsy genes, including KCNQ2,18 CDKL5,19 and DEPDC5. 20 Heterozygous DEPDC5 variants are found in cases of familial focal epilepsy as well as focal cortical dysplasia–associated epilepsy.20,21 Mice or rats with homozygous germ line deletions of Depdc5 had embryonic lethality,2224 which is itself etiologically nonspecific and may even reflect placental pathology.25 In contrast, rats with heterozygous deletions of Depdc5 do not display spontaneous seizures.24 Mice with a conditional brain-specific homozygous deletion of Depdc5 display extremely rare seizures, together with macrocephaly, impaired survival, and biochemical evidence of mTOR1 complex activation.22 Thus, it appears that for certain genetic variants strongly associated with epilepsy in humans, mice with corresponding gene deletions or transgenic “knock-ins” of variants seen in individuals with the specific epilepsy syndrome may not display spontaneous seizures or even reflex audiogenic seizures, a common expression of epilepsy in mice. This phenomenon may reflect the influences of variations in genetic background or fundamental differences in mechanisms of genetic epileptogenesis between mice and humans.

Confirming the epilepsy-inducing or epilepsy-modifying effects of specific variants may be greatly aided through the use of other vertebrate models, such as zebrafish (Danio rerio). Classically employed as a model to study embryology and development, zebrafish has now been adopted to study a variety of neurological disorders, including epilepsy. This species is amenable to exon deletion via homologous recombination, and specific single-nucleotide variants can be introduced via CRISPR-Cas9 technology.2628 As with mice, stereotyped spontaneous or induced seizures can be identified by video tracking and/or electroencephalography. The small size and rapid development of zebrafish also permit high-throughput drug screening29 that may be individualized to identify a treatment for a specific variant.30

Despite the impressive array of genetic advances, the translation of these findings into gene-related or pathway-based clinical treatments has had mixed results.31 There are genetic diagnoses for which specific antiepileptic therapies are either indicated or relatively contraindicated (eg, GLUT1 deficiency, pyridoxine dependency, SCN1A-related epilepsy), and mTOR inhibitors are now known to be at least partially effective for tuberous sclerosis complex–associated epilepsy.32 By contrast, the use of quinidine for KCNT1-related epilepsy, initially thought to be promising following the report of a single case,33 has not been shown to reduce seizure frequency in subsequent studies.34 Overall, these and other findings suggest that simply modulating a causative pathway featuring a rational drug target can lead to variable responses. More work is clearly necessary to bring genetic discoveries from the bench successfully to therapeutic application at the bedside.

Interneuronopathy-Related Epilepsies

Interneuronopathies can be broadly defined as those conditions in which epilepsy or neuropsychiatric comorbidities arise as a consequence of either developmental or functional changes in interneurons. Alterations in interneuron migration or numbers have been identified in multiple epilepsy mouse models, including mice with deletions of Cntnap2,35 Wwox,36 and Syngap1,37 as well as in certain models of acquired epilepsy,38,39 and after traumatic brain injury.40,41 Epilepsy that occurs in Dravet syndrome associated with pathogenic variants in SCN1A may also be classified in this category based on evidence that interneurons in Scn1a heterozygous mice display a selective decrease in excitability, and selective deletions of Scn1a in interneurons are sufficient to recapitulate the spectrum of Dravet-related phenotypes.4244 The term “interneuronopathy” was first used in the setting of a very severe genetic epilepsy syndrome (X-linked lissencephaly with ambiguous genitalia, XLAG) caused by pathogenic variants in ARX, with significant reductions in interneuron density in hippocampal and cortical regions observed in this condition.4547

A more detailed understanding of interneuron development and migration patterns will be critical for developing novel treatments for these specific genetic epilepsy syndromes and will guide our explorations into the therapeutic potential of either transplantation48,49 and/or optogenetic/chemogenetic manipulations of interneurons.

Tumor-Related Epilepsies

The incidence of epilepsy in individuals with brain tumors ranges from 70% to 80% in glioneuronal tumors (including gangliogliomas and dysembryoplastic neuroepithelial tumors) to 20% to 35% in individuals with brain metastases.50 Epileptogenesis associated with gliomas, the most common malignant primary brain tumor, has been a focus of intense research, with 2 nonmutually exclusive mechanisms explored extensively.

For some neurodevelopmental tumors such as ganglioglioma, a genetic profile has become apparent in the form of a BRAF V600E variant, suggesting the possibility of treatment with BRAF inhibitors.51 Furthermore, in some tumors, malignant glial cells release excessive amounts of glutamate through the cystine/glutamate transporter (SLC7A11), a gene whose expression is upregulated in at least half of all glial tumors.52 SLC7A11-mediated glutamate release results in hyperexcitability that spreads to adjacent tissues,53 and in preclinical studies, a currently available SLC7A11 inhibitor (sulfasalazine, utilized in the treatment of Crohn disease) resulted in improved seizure frequency and prolonged survival.54 Mutations in isocitrate dehydrogenase (IDH1) are a strong predictor of epilepsy in patients with low-grade glial tumors.55 Mutant IDH1 converts isocitrate to 2-hydroxyglutarate (instead of α-ketoglutarate), which is structurally similar to glutamate and sufficient to lengthen burst duration in cultured rat cortical neurons in an NMDA-receptor-dependent fashion.55

A second potential mechanism involves the dysregulation of chloride homeostasis in peritumoral cortical neurons through the aberrant downregulation of KCC2 (potassium chloride cotransporter) and upregulation of NKCC1 (sodium potassium chloride cotransporter) within these cells.56 Under these conditions, γ-aminobutyric acid (GABA) binding to ionotropic receptors results in depolarization, and inhibitors of NKCC1 (which reverse altered chloride gradients) in preclinical glioma models improve seizure susceptibility.57 It remains to be seen whether similar mechanisms of epileptogenesis may be involved in epilepsies related to meningiomas or metastatic lesions, for which preclinical models are less well developed. Clearly, cortically based or invading tumors seem to possess the greatest risk of epilepsy.50

Autoimmune Epilepsies

As of 2019, antibodies to at least 11 different antigens have been associated with epilepsy occurring in the context of encephalitis. Antibodies against extracellular antigens raise neuronal excitability and impose synaptic dysfunction either by disrupting specific protein interactions (eg, LGI1, NMDAR), enhancing receptor internalization (AMPAR), or by functioning as an antagonist (GABA-BR).58 In contrast, antibodies against intracellular antigens are thought to produce epilepsy as a consequence of direct cytotoxic T-cell infiltration (eg, amphiphysin, GAD-65). The clinical presentation of autoimmune encephalitides is highly variable (signs and symptoms of limbic or motor dysfunction may or may not be present), and seizures may be the presenting symptom, a late symptom, or absent entirely.59

Establishing a direct causative link between individual antibodies and their specific mechanisms of epileptogenesis has been possible through experiments in which patient-derived antibodies are infused into mouse or rat models. For example, hippocampal specimens from mice that received intracerebroventricularly infused LGI1 antibodies over 14 days displayed reduced synaptic expression of the voltage-gated potassium channel KV1.1 (KCNA1) together with increases in presynaptic-release probability and postsynaptic current amplitudes, as well as diminished long-term potentiation and impairments in learning and memory.60 These mice did not develop spontaneous seizures, suggesting that at least in mice, either longer durations of anti-LGI1 antibody exposure or higher antibody titers may be necessary for seizure generation. In contrast, similar infusions of anti-NMDAR antibodies in mice produced spontaneous seizures without impairments in memory or motor function.61

Recent genome-wide association studies have revealed that particular human leukocyte antigen (HLA) haplotypes may increase the risk of specific antibody-mediated encephalitides,59,62,63 just as with other autoimmune conditions such as type I diabetes mellitus or ankylosing spondylitis; these HLA associations provide pathophysiological insights into the genesis of these antibodies. Fortunately, only a minority of patients who display acute symptomatic seizures during active encephalitis go on to develop epilepsy.58 Early immunomodulatory therapy appears to be critical to avoid future drug resistance, while other factors, such as medical complications or hypoxia, may also contribute to long-term seizure risk.58,59

Epilepsy-Related Conditions

Adults have a median of 2 chronic medical conditions, but this number rises to 6 in individuals older than 65 years.64 Thus, “comorbidities” are a central aspect of all chronic medical conditions, and epilepsy is no exception. In epilepsy, comorbidities can be broadly divided into those which affect mental health (including sleep), general physical health (including trauma), and reproductive health.65,66 Together, these comorbidities contribute tremendously to overall disability, impairments in quality of life, and premature mortality.67,68 Outside of chance or artifactual comorbidities that may reflect various forms of bias,64 4 main mechanisms of comorbidity have been proposed69: (1) independent comorbidity (etiologically unrelated to epilepsy), (2) consequent comorbidity (a direct consequence of epilepsy), (3) iatrogenic comorbidity (treatment related), and (4) shared risk factor (in which epilepsy and its comorbidity independently arise from a single etiology). Importantly, shared risk factors may epidemiologically resemble a bidirectional association (in which each condition causes the other).

Psychiatric comorbidities in epilepsy have received the greatest emphasis. Epilepsy is associated with significantly higher rates of mood and anxiety disorders,70,71 psychosis,72 fatigue,73 and autism spectrum disorder.74 These entities are each independently associated with varying degrees of intellectual disability. Cross-sectional and/or prospective human data provide a framework for mechanistic hypotheses into their etiology; ultimately, these hypotheses require verification in animal models. Unfortunately, this schema is inherently limited since many psychiatric endophenotypes are either absent entirely (eg, suicidality) or difficult to measure (eg, depressed mood, psychosis) in animal models.

Depression, or major depressive disorder, has and will continue to be a major focus of comorbidity research. Individuals with epilepsy are twice as likely to develop depression over their lifetime,70 and either entity can occur first.75 The severity of depression is associated with the risk of epilepsy.76 Depression and suicidality tend to be more prominent in individuals with TLE compared with those who have genetic generalized epilepsies,77,78 and within TLE, depression severity correlates with pharmacoresistance but does not correlate with the side57 or the extent of hippocampal atrophy,79 if present. Improvements in depression that follow temporal lobectomy are strongly associated with improvements in seizure control.80 To date, there has been no high-quality evidence to suggest that antidepressants (in conjunction with standard anticonvulsant therapy) are sufficient to either impact epilepsy risk or reduce seizure frequency.81 On the other hand, behavioral interventions such as cognitive behavioral therapy or mindfulness training have been shown to improve both seizure control and quality of life.82 Overall, this body of evidence argues strongly for the presence of shared noniatrogenic neurobiological risk factors that simultaneously raise the risk of depression and epilepsy.

What are these risk factors? Genetic or epigenetic factors may play only a modulatory role since major depression and epilepsy display little to no evidence of genetic overlap (unlike autism and epilepsy).78 The roots of epilepsy–depression comorbidity may be related to changes in network functional connectivity. In major depression, such functional rearrangements are broad, bilateral, and vary by depression subtype.83,84 At least within TLE circuits,85 hyperexcitability within the anterior hippocampus (corresponding to the ventral hippocampus in rodents) may be one such anatomical substrate for comorbidity. In mice, ventral hippocampal injections of kainic acid produce epileptic seizures together with memory impairments and anhedonic behavior; these behavioral comorbidities were not observed in mice that received dorsal kainic acid injections.86 Hypersynchrony in the anterior/ventral hippocampus region may contribute to depressive symptoms by compromising functional connectivity to ipsilateral frontal regions.87

Testing these hypotheses in preclinical models is now possible with optogenetics, in which an anatomically or molecularly defined neuronal population is genetically or virally transduced to express an excitatory or inhibitory ion channel that is activated by light of a specific wavelength. Bilateral optogenetic activations of ventral hippocampal afferent pathways in nonepileptic mice are sufficient to produce depression and anxiety-like symptoms.88,89 Similarly, the optogenetic inhibition of mossy cells within the dentate gyrus (simulating mossy fiber loss) is sufficient to produce impairments in object memory in mice.90 Aside from these focal network derangements, aberrations in a variety of other neuromolecular axes have been proposed as substrates that may raise seizure risk and compromise mood, including disturbances in neurotransmitter signaling (glutamate, GABA, serotonin), dysfunctional hypothalamo–pituitary–adrenal axis signaling, and a host of cellular and secreted mediators of neuroinflammation.57,91

Looking Forward: Opportunities and Challenges

Given the progress over the past several years and the remaining gaps in knowledge in the field, we have identified some ambitious but feasible future priorities in epilepsy research that we believe should guide our scientific efforts in this area over the next decade. First, it is notable that a large portion of this update has been devoted to genetic advances, given the substantial work in this area. We also recognize that many patients worldwide have epilepsy primarily caused by infection, head injury, birth trauma, hypoxic–ischemic insult, or any of a number of other perturbations of nervous system function. We support an increased focus on investigating the underlying causes and mechanisms of all forms of epilepsy, including these acquired forms of epilepsy, in order to improve our ability to prevent and treat these conditions successfully.

We also support further work on the cognitive and behavioral deficits that accompany epilepsy through experimental animal models, including further use of chemogenetic and optogenetic strategies to study specific cellular populations in the pathogenesis of epilepsy and related conditions. An important question with direct clinical relevance centers on the transition to the ictal state: Since seizures occur only in discrete episodes in most instances, we need a better understanding of what allows them to arise at any particular time and what limits transition to an ictal state at other times.92

We support continued attention on interneuron pathology, central neuronal signaling pathways, and autoimmune factors as underlying mechanistic factors in both genetic and acquired epilepsy syndromes. Further, invoking another less well-studied cell type in the nervous system, we support evaluation of the role of glia in epileptogenesis and seizure propagation. The pathogenesis of infection-related epilepsy, including virus-induced epilepsy and parasite-induced epilepsy, the latter of which is a leading cause of epilepsy worldwide but lacks a relevant animal model, needs further exploration. In general, the links between the brain and immune system and the relationship between inflammation and neural excitability should be critical targets of investigation. Despite the large volume of new advances in epilepsy genetics, we believe there needs to be further characterization of genes associated with the most prevalent early-life syndromes and further research on the use of “rational” therapy design to modulate known pathogenic pathways.

Although some work has been devoted to understanding the causality behind some of the most common epilepsy-related comorbidities, much more is required. We would support further research aimed at disentangling the effects of seizures, genetic changes, and antiseizure medication in contributing to the intellectual impairments that are present in patients with epileptic encephalopathies. In addition, we believe that further timely study of epilepsy etiologies in elderly individuals, who represent a second peak of epilepsy incidence after early childhood, could be highly impactful. Recent findings related to hippocampal hyperexcitability in individuals with Alzheimer disease93 and the discovery of associations between lifestyle risk factors and late-onset epilepsy94 provide tantalizing suggestions of important etiological connections in older adults who had multiple medical conditions.

“Doctor, what is causing my seizures?” At the current time, in a significant majority of individuals, including those without a definite brain lesion, an encephalitic prodrome, evidence for a familial epilepsy syndrome, or a comorbid neurodevelopmental syndrome, the answer to this question remains unknown. Fortunately, 65% of individuals will experience seizure freedom with 1 or more currently available antiseizure medications.95 To improve the lives of all individuals affected by epilepsy, however, we must address the fundamental causes of epilepsy and its associated conditions. As demonstrated in the introductory vignette, we also have a responsibility to translate our scientific advances toward the treatment of epilepsy and fcognitive and psychiatric comorbidities in a coordinated fashion.

Source: https://doi.org/10.1177/1535759719895280

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[WEB SITE] New epilepsy warning device could save thousands of lives — ScienceDaily

Nightwatch bracelet on the arm of a young epilepsy patient.
Credit: LivAssured

A new high-tech bracelet, developed by scientists from the Netherlands detects 85 percent of all severe night-time epilepsy seizures. That is a much better score than any other technology currently available. The researchers involved think that this bracelet, called Nightwatch, can reduce the worldwide number of unexpected night-time fatalities in epilepsy patients. They published the results of a prospective trial in the scientific journal Neurology.

SUDEP, sudden unexpected death in epilepsy, is a major cause of mortality in epilepsy patients. People with an intellectual disability and severe therapy resistant epilepsy, may even have a 20% lifetime risk of dying from epilepsy. Although there are several techniques for monitoring patients at night, many attacks are still being missed.

Consortium researchers have therefore developed a bracelet that recognizes two essential characteristics of severe attacks: an abnormally fast heartbeat, and rhythmic jolting movements. In such cases, the bracelet will send a wireless alert to carers or nurses.

The research team prospectively tested the bracelet, known as Nightwatch, in 28 intellectually handicapped epilepsy patients over an average of 65 nights per patient. The bracelet was restricted to sounding an alarm in the event of a severe seizure. The patients were also filmed to check if there were any false alarms or attacks that the Nightwatch might have missed. This comparison shows that the bracelet detected 85 percent of all serious attacks and 96% of the most severe ones (tonic-clonic seizures), which is a particularly high score.

For the sake of comparison, the current detection standard, a bed sensor that reacts to vibrations due to rhythmic jerks, was tested at the same time. This signalled only 21% of serious attacks. On average, the bed sensor therefore remained unduly silent once every 4 nights per patient. The Nightwatch, on the other hand, only missed a serious attack per patient once every 25 nights on average. Furthermore, the patients did not experience much discomfort from the bracelet and the care staff were also positive about the use of the bracelet.

These results show that the bracelet works well, says neurologist and research leader Prof. Dr. Johan Arends. The Nightwatch can now be widely used among adults, both in institutions and at home. Arends expects that this may reduce the number of cases of SUDEP by two-thirds, although this also depends on how quickly and adequately care providers or informal carers respond to the alerts. If applied globally, it can save thousands of lives.

Watch the video here: https://youtu.be/0G_BQK4LK88

Story Source:

Materials provided by Eindhoven University of TechnologyNote: Content may be edited for style and length.


Journal Reference:

  1. Johan Arends, Roland D. Thijs, Thea Gutter, Constantin Ungureanu, Pierre Cluitmans, Johannes Van Dijk, Judith van Andel, Francis Tan, Al de Weerd, Ben Vledder, Wytske Hofstra, Richard Lazeron, Ghislaine van Thiel, Kit C.B. Roes, Frans Leijten. Multimodal nocturnal seizure detection in a residential care settingNeurology, 2018; 10.1212/WNL.0000000000006545 DOI: 10.1212/WNL.0000000000006545

via New epilepsy warning device could save thousands of lives — ScienceDaily

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[WEB SITE] New Epilepsy Bracelet Could Save Thousands of Lives

High-Tech “Nightwatch” is Capable of Detecting 85 Percent of Severe Night-Time Epileptic Seizures

Scientists in the Netherlands are optimistic that their new device will reduce the number of sudden unexpected death in epilepsy (SUDEP) patients worldwide. Currently, for people with an intellectual disability and severe treatment-resistant epilepsy, the outlook is poor, with a possible 20 percent lifetime risk of dying from epilepsy. While several techniques exist for monitoring patients at night, many seizures are still being missed.

With this in mind, a consortium of researchers (from Kempenhaeghe epilepsy centre, Eindhoven University of Technology, the Foundation for Epilepsy Institutions in the Netherlands (SEIN), UMC Utrecht, the Epilepsy Fund, patient representatives, and LivAssured) developed Nightwatch, a bracelet that recognizes unusually fast heartbeat and rhythmic jolting movements, two critical characteristics of severe attacks. When these occur, the device sends a wireless alert to caregivers or nurses.

In a test among 28 intellectually handicapped patients with epilepsy, over an average of 65 nights, Nightwatch detected 85 percent of all serious attacks and 96 percent of the most severe ones (tonic-clonic seizures). In comparison, a bed sensor, which is the current detection standard, sounded the alarm for only 21 percent of serious attacks. While the bed sensor was silent once every four nights per patient, the Nightwatch only missed a serious attack once every 25 nights, on average.

Prof. Dr. Johan Arends, neurologist and research leader, expects that the bracelet may reduce the number of SUDEP cases by two-thirds, although this also depends on the speed and efficiency with which caregivers respond to the alerts.

Source: MedicalXpress.com, October 29, 2018

 

via New Epilepsy Bracelet Could Save Thousands of Lives | Managed Care magazine

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[Abstract] Dead in the water: Epilepsy‐related drowning or sudden unexpected death in epilepsy?

Summary

Objective

Both drowning and sudden unexpected death in epilepsy (SUDEP) are diagnoses of exclusion with predominantly nonspecific autopsy findings. We hypothesized that people with epilepsy found dead in water with no clear sign of submersion could be misdiagnosed as SUDEP.

Methods

All reported seizure‐related deaths undergoing medicolegal investigation in three medical examiner’s offices (New York City, Maryland, San Diego County) over different time periods were reviewed to identify epilepsy‐related drownings and SUDEPs. Drowning cases that fulfilled inclusion criteria were divided into two groups according to the circumstances of death: definite drowning and possible drowning. The SUDEP group included two sex‐ and age (±2 years)‐matched definite SUDEP/definite SUDEP plus cases for each drowning case.

Results

Of 1346 deaths reviewed, we identified 36 definite (76.6%) and 11 possible drowning deaths (23.4%), most of which occurred in a bathtub (72.3%). There were drowning‐related findings, including fluid within the sphenoid sinuses, foam in the airways, clear fluid in the stomach content, and lung hyperinflation in 58.3% (21/36) of the definite drowning group, 45.5% (5/11) of the possible drowning group, and 4.3% of the SUDEP group (4/92). There was no difference in the presence of pulmonary edema/congestion between the definite drowning group, possible drowning group, and SUDEP group. The definite drowning group had a higher mean combined lung weight than the SUDEP group, but there was no difference in mean lung weights between the possible drowning and SUDEP groups or between the possible drowning and definite drowning groups.

Significance

No distinguishable autopsy finding could be found between SUDEPs and epilepsy‐related drownings when there were no drowning‐related signs and no clear evidence of submersion. SUDEP could be the cause of death in such possible drowning cases. As most drowning cases occurred in the bathtub, supervision and specific bathing precautions could be effective prevention strategies.

 

via Dead in the water: Epilepsy‐related drowning or sudden unexpected death in epilepsy? – Cihan – – Epilepsia – Wiley Online Library

 

 

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[WEB SITE] Mechanisms of Ketogenic Diet Identify Novel Targets for AED Development

Diet restriction is an ancient method for control of epileptic seizures, though a precise understanding of how it mediates seizure suppression is still unknown. Development of the high-fat, low-carbohydrate, protein-adequate ketogenic diet (KD) was based on the hypothesis that ketone production induced by glucose deprivation is responsible for the historic seizure-suppressing effect of fasting. Recently, several key findings regarding how the ketogenic diet suppresses seizures in patients with refractory epilepsy have revealed new targets for anti-epileptic drug design as well as novel therapeutic approaches for epilepsy.

The traditional KD involves a strict 4:1 ratio by weight of fat to combined carbohydrate and protein. A more recently developed modified KD- the medium-chain triglyceride (MCT) diet- is more ketogenic, and thus allows greater intake of carbohydrates and proteins, easing compliance and improving nutrition. Despite this modification, adherence is so difficult that the KD is reserved for use in patients whose seizures do not respond to anti-epileptic drug (AED) treatment.1


While most epileptics become seizure free with AED treatment, roughly 30% of patients will continue to have seizures despite taking multiple AEDs.Uncontrolled seizures not only limit quality of life, but are also associated with risk of sudden unexpected death in epilepsy (SUDEP),highlighting the need for improved understanding of alternative interventions.

Medically refractory epileptics have few treatment options, including brain surgery, vagus nerve stimulation, and KD. While numerous clinical reports indicate the efficacy of KD for treatment of drug-resistant epilepsy, few high-quality controlled studies exist.The most recent Cochrane Review of KD for treatment of epilepsy states that seizure freedom rates after 3 months on a 4:1 classic KD can reach up to 55%, while rates of seizure reduction reach as high as 85%.However, compliance is difficult, emphasizing the need to better understand how the KD works to facilitate development of supplements that may provide the “ketogenic diet in a pill.”4

General mechanism of action of the ketogenic diet

The KD imparts its effect via multiple pathways. In general, it is believed that the KD works by decreasing neuronal excitability, decreasing inflammation, and improving mitochondrial function, either through the direct action of ketone bodies and fatty acids, or through downstream changes in metabolic and inflammatory pathways.

Several specific mechanisms have been suggested by studies performed in vitro or in animal models of epilepsy, including: 1) direct action of ketone bodies; 2) direct action of fatty acids; 3) glycolic restriction or diversion; 4) altered neurotransmitter systems involving GABA, glutamate, and adenosine; 5) changes in ion channel regulation; 6) improved mitochondrial function and cellular bioenergetics; 7) a reduction in oxidative stress; and 8) enhancement of the tricarboxylic acid (TCA) cycle.While data support a role for each of these pathways in seizure control, several recent studies have identified precise molecules that regulate specific pathways involved in seizure suppression. These molecules may thus serve as targets for drug development that could provide the same effects as the KD without the need for diet restriction.

 

Direct inhibition of AMPA receptors by decanoic acid controls seizures

Decanoic acid, a medium-chain fatty acid that penetrates the blood-brain barrier, has previously been shown to 1) improve mitochondrial biogenesis through a peroxisome proliferator-activated receptors (PPAR)y-mediated mechanism; 2) increase transcription of genes regulating fatty acid metabolism while downregulating genes involved in glucose metabolism; and 3) modulate astrocyte metabolism and affect the glial/neuronal shuttle system by supplying neurons with ketones and lactate for fuel.However, a recent seminal study by Chang et al has now delineated a specific protein target of decanoic acid- the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and has shown decanoic acid to have anti-seizure effects at clinically relevant doses.Using rat hippocampal slices and whole cell patch-clamp measurements, Chang et al demonstrated that decanoic acid, but not ketone bodies, had an inhibitory effect on neurotransmission, and that this effect is mediated through postsynaptic excitatory AMPA receptors. Importantly, this inhibitory effect was found at physiological serum concentration (0.3mM; 52 µg/ml) of decanoic acid, similar to that measured in children on the MCT diet, and below serum and brain concentrations that suppress seizures in mouse models of epilepsy. Also of note was that decanoic acid selectively blocks excitatory synaptic activity while not affecting inhibitory synaptic currents.5

Furthermore, by expressing AMPA receptor subunits in Xenopus oocytes and testing neuronal excitability in the presence of decanoic acid ± glutamate, the authors were able to conclude that decanoic acid inhibits the AMPA receptor by binding to a site that does not compete with glutamate binding.5

This binding is unique to decanoic acid, while octanoic acid and valproic acid do not interact with AMPA receptors.“If it were possible to replace the diet with an AMPA receptor antagonist, this would enormously simplify therapy, avoid the poor palatability and gastrointestinal side effects of the diet, and therefore make treatment available to a broader group of patients,” wrote Dr. Michael Rogawski in a commentary on the findings of Chang et al.5,6 As such, a comparative trial between the MCT KD diet and parampanel warrants consideration.

Inhibition of lactate dehydrogenase results in seizure suppression

While it is well known that the KD affects energy metabolism, metabolic enzymes that control epilepsy have not yet been identified. Similarly, no AEDs are known to directly impact metabolic pathways, though the mechanism of action of many AEDs remains unclear.In a landmark study published in Science, Sada et al investigated the mechanism by which glucose deprivation leads to neuronal hyperpolarization and subsequent seizure suppression. By simply switching the energy source from glucose to ketone bodies (as occurs on the KD), neurons from the subthalmic nucleus of the basal ganglia were dramatically hyperpolarized. However, addition of ketone bodies alone did not hyperpolarize the neurons; instead, Sada et al were able to show that glucose deprivation resulted in inhibition of lactate dehydrogenase (LDH), an enzyme that converts glucose to lactate in astrocytes, and that this inhibition alone is responsible for neuron hyperpolarization. Therefore, this study suggests it is the inhibition of LDH, and not activation of the tricarboxylic acid (TCA) cycle by ketone bodies, that mediates anti-seizure effects. Sada et al demonstrated that direct inhibition of LDH could suppress seizures both in vitro and in vivo (mouse), confirming LDH as a valid target for development of AEDs.

Taking their study one step further, the authors determined that a clinically used AED, stiripentol, binds to LDH and inhibits its activity. Sada et al were able to modify stiripentol into a derivative that more potently inhibited LDH and could suppress seizures in mice, suggesting that LDH inhibitors should be further explored as drugs that can mimic effects of the ketogenic diet.7

Epigenetic changes induced by the KD confer long-term seizure protection

While acute prevention of drug-refractory seizures is the primary goal of the KD, study of children following the diet suggests that KD may confer protection against seizures even after its discontinuation.8 A proposed mechanism has been recently outlined by Lusardi et al, who demonstrated that the KD reduced hippocampal DNA methylation to levels found in non-epileptic controls, resulting in delayed onset of severe seizures and slower disease progression.9 Importantly, this reduction was maintained over at least 8 weeks after diet reversal, suggesting a “recalibration” of brain chemistry. Similarly, another study found that the KD delayed disease progression and increased longevity by 47% and in mouse models of SUDEP.3 Since hypermethylation of hippocampal DNA is a hallmark of the epileptic brain, the finding that long-lasting epigenetic changes can be maintained in animals predisposed to severe epilepsy suggests that “recalibration” of the epileptic brain is possible. Drugs that increase hippocampal adenosine concentration to that achieved by the KD may prove effective at decreasing DNA methylation status in the epileptic brain,10 and should be pursued for treatment of drug-resistant epilepsy.

Ketogenic diet modification of gut microbiota

A new, recently identified physiologic change induced by the KD is alteration of the gut microbiome. Using a mouse model of Autism Spectrum Disorder (ASD), in which the KD has been shown to limit symptoms,11 Newell et al demonstrated remodeling of the gut microbiota, leading to lower bacterial load and altered composition.12 Interestingly, the authors point out a 2- to 3- fold increase in bacterial species that generate short-chain fatty acids (SCFAs) that actively communicate with the brain. Given the increasing evidence of a “gut-brain axis” and the knowledge that fatty acids play an active role in the epileptic brain, it will be important to determine what role this change in gut microbial composition may play in regulation of seizures.

 

Published: April 28, 2017

 

References

via Mechanisms of Ketogenic Diet Identify Novel Targets for AED Development

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[WEB SITE] Wristband devices may improve detection and characterization of epileptic seizures

New research published in Epilepsia (http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1528-1167), a journal of the International League Against Epilepsy (ILAE), indicates that wristband devices may improve the detection and characterization of seizures in patients with epilepsy.

New devices are needed for monitoring epileptic seizures, especially those that can lead to sudden death. While rare, “sudden unexpected death in epilepsy” (SUDEP) is the most common cause of death in epilepsy, and it often occurs at night. The gold standard for monitoring seizures-video-electroencephalography- is available in epilepsy monitoring units but is an impractical procedure for daily life use. Therefore, clinicians often rely on patients and caregivers to report seizure counts, which are often inaccurate.

In their attempts to develop a better monitoring method, Giulia Regalia, PhD and Francesco Onorati, PhD, of Empatica Inc. in Milan, Italy and Cambridge, Massachusetts, and their colleagues examined the potential of automated, wearable systems to detect and characterize convulsive epileptic seizures. The researchers used three different wristbands to record two signals-called electrodermal activity and accelerometer signals-that usually exhibit marked changes upon the onset of convulsive seizures, obtaining 5928 hours of data from 69 patients, including 55 convulsive epileptic seizures from 22 patients.

The wristband detectors showed high sensitivity (95% of seizures were detected) while keeping the false alarm rate at a bearable level (on average, one false alarm every four days), which improves a pioneering 2012 study led by MIT professor Rosalind Picard, now chief scientist at Empatica.

In addition to detecting seizures, the method also revealed certain characteristics of the seizures, which may help alert clinicians and patients to seizures that are potentially dangerous and life-threatening.

“The present work provides significant improvements for convulsive seizure detection both in clinical and ambulatory real-life settings,” said Dr. Regalia. “Accurate seizure counts with real-time alerts to caregivers allows an early application of aid, which can be protective against SUDEP risk.” She noted that the wristband detectors do not require caregivers to be near patients continuously, which could significantly improve patients and caregivers’ quality of life.

Source: Wristband devices may improve detection and characterization of epileptic seizures

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[WEB SITE] A Look at Epilepsy – Electrical Outbursts in the Brain

Illustration of a man holding a child; a doctor and patient; and a brain.When you hear the word epilepsy, you might think of intense seizures with muscle spasms and loss of consciousness. But most epilepsy seizures are surprisingly subtle and may be hard to recognize. These little spells can be an early warning sign of epilepsy, a brain disorder that strikes an estimated 1 in 26 Americans at some point in their lives. The sooner epilepsy is recognized, the sooner it can be treated and seizures prevented.

Most people know surprisingly little about epilepsy, even though it’s the nation’s 4th most common neurological disorder, after migraine, stroke, and Alzheimer’s disease. Epilepsy is marked by repeated, unpredictable seizures that may last for seconds or minutes. Seizures arise from abnormal bursts of electrical activity in the brain that trigger jerky movements, strange emotions or sensations, falls, or passing out.

“Epilepsy can strike people of all ages, from the moment of birth—even in the delivery room—up to older ages,” says Dr. Jeffrey Noebels, an epilepsy expert at Baylor College of Medicine. The condition is most likely to first arise in children and in adults over age 60. “Most types of epilepsy last a lifetime, but some are self-limited, meaning they can go away on their own,” Noebels adds.

The causes of epilepsy are varied. “Defects in genes are probably responsible for the largest fraction of epilepsy cases,” Noebels says. Scientists so far have linked more than 150 genes to epilepsy. “Other types of epilepsy can be acquired through trauma (such as head injury or stroke), infections, brain tumors, or other factors.”

Anything that disrupts the normal pattern of brain activity—from illness to brain damage to faulty brain development—can lead to seizures. But for up to half of people with epilepsy, the underlying cause is simply not known.

Types of seizures can also vary widely, which is why epilepsy is sometimes called a “spectrum disorder.” In some people, seizures may appear only occasionally. At the other end of the spectrum, a person may have hundreds of seizures a day. The seizures can be severe, with convulsions, loss of consciousness, or even sudden death in rare cases. Or seizures may be barely noticeable.

Such subtle seizures—sometimes called partial or focal seizures—can cause feelings of déjà vu (feeling that something has happened before); hallucinations (seeing, smelling, or hearing things that aren’t there); or other seemingly mild symptoms. During some seizures, a person may stop what they’re doing and stare off into space for a few seconds without being aware of it.

“These little spells or seizures can sometimes occur for years before they’re recognized as a problem and diagnosed as epilepsy,” says Dr. Jacqueline French, who specializes in epilepsy treatment at the New York University Langone Medical Center. “They can be little spells of confusion, little spells of panic, or feeling like the world doesn’t look real to you.”

The symptoms of these small seizures generally depend on which brain regions are affected. Over time, these types of seizures can give rise to more severe seizures that affect the whole brain. That’s why it’s important to get diagnosed and begin epilepsy treatment as soon as possible. “If you notice a repeating pattern of unusual behaviors or strange sensations that last anywhere from a few seconds to a few minutes, be sure to mention it to your doctor or pediatrician,” French says.

Over the past few decades, NIH-funded scientists have been working to develop better approaches for diagnosing, treating, and understanding epilepsy. The condition can now be diagnosed through imaging tools like MRI or CT scans, by testing blood for defective genes, or by measuring the brain’s electrical activity. Seizures can often be controlled with medications, special diets, surgery, or implanted devices. But there’s still a need for improved care.

“Traditional medications for treating epilepsy are effective but problematic,” says Dr. Ivan Soltesz, who studies epilepsy at Stanford University. “About 1 in 3 patients has drug-resistant epilepsy, meaning that available drugs can’t control the seizures. In these cases, surgical removal of brain tissue may be the best option.” When the drugs do work, he explains, they can also cause numerous side effects, including fatigue, abnormal liver function, and thinking problems.

One issue with today’s medicines is they aren’t targeted to the malfunctioning brain cells. Rather, they tend to affect the whole brain. “The drugs are also not specific in terms of the timing of treatment,” Soltesz says. “The medications are always in the body, even when the seizures are not occurring.”

He and other researchers are working to create highly targeted epilepsy therapies that are delivered only to malfunctioning brain regions and only when needed to block a seizure. So far, they’ve developed an experimental approach that can stop epilepsy-like seizures as they begin to occur in a mouse. The scientists hope to eventually translate those findings for use in people who have epilepsy.

In another line of NIH-funded research, a team of scientists is studying a deadly and poorly understood condition called SUDEP (for sudden unexpected death in epilepsy). “Most people with epilepsy live long and happy lives. But SUDEP is the most common cause of the shorter lifespan that can occur with epilepsy,” says Noebels. “It’s been a real mystery. We haven’t known who’s at greatest risk for this premature death. It can happen to different people who have epilepsy, from all walks of life.”

Noebels and his colleagues have identified several mouse genes that seem related to both sudden-death seizures and heart rhythm problems. The researchers are now searching for similar human genes that may help predict who’s most at risk for SUDEP. “We believe that SUDEP doesn’t have to happen—that we can learn about it, predict it, and eventually find better ways to prevent it in every patient,” Noebels says.

You can take steps to reduce some risk factors for epilepsy. Prevent head injuries by wearing seatbelts and bicycle helmets, and make sure kids are properly secured in car seats. Get proper treatment for disorders that can affect the brain as you age, such as cardiovascular disease or high blood pressure. And during pregnancy, good prenatal care can help prevent brain problems in the developing fetus that could lead to epilepsy and other problems later in life.

“We’ve made exciting advances to date in our understanding of epilepsy, its prevention, and treatment,” says French. “But there’s still much we have to learn, and much we’re actively working to improve.”

References:
The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia. Jehi L, Friedman D, Carlson C, Cascino G, et al. Epilepsia. 2015 Oct;56(10):1526-33. doi: 10.1111/epi.13116. Epub 2015 Aug 7. PMID: 26250432.

On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Krook-Magnuson E, Armstrong C, Oijala M, Soltesz I. Nat Commun. 2013;4:1376. doi: 10.1038/ncomms2376. PMID: 23340416.

Sudden unexpected death in epilepsy: Identifying risk and preventing mortality. Lhatoo S, Noebels J, Whittemore V; NINDS Center for SUDEP Research. Epilepsia. 2015 Nov;56(11):1700-6. doi: 10.1111/epi.13134. Epub 2015 Oct 23. PMID: 26494436.

NIH News in Health, November 2015

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