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Nature Reviews. Neurology Jun 2022The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent... (Review)
Review
The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy.
Topics: Brain; Energy Metabolism; Epilepsy; Humans; Seizures; Status Epilepticus
PubMed: 35361967
DOI: 10.1038/s41582-022-00651-8 -
Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures.Brain : a Journal of Neurology Aug 2020Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in... (Review)
Review
Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.
Topics: Adolescent; Animals; Child; Comorbidity; Humans; Seizures
PubMed: 32437558
DOI: 10.1093/brain/awaa072 -
Drugs & Aging Apr 2021Stroke is the leading cause of seizures and epilepsy in older adults. Patients who have larger and more severe strokes involving the cortex, are younger, and have acute... (Review)
Review
Stroke is the leading cause of seizures and epilepsy in older adults. Patients who have larger and more severe strokes involving the cortex, are younger, and have acute symptomatic seizures and intracerebral haemorrhage are at highest risk of developing post-stroke epilepsy. Prognostic models, including the SeLECT and CAVE scores, help gauge the risk of epileptogenesis. Early electroencephalogram and blood-based biomarkers can provide information additional to the clinical risk factors of post-stroke epilepsy. The management of acute versus remote symptomatic seizures after stroke is markedly different. The choice of an ideal antiseizure medication should not only rely on efficacy but also consider adverse effects, altered pharmacodynamics in older adults, and the influence on the underlying vascular co-morbidity. Drug-drug interactions, particularly those between antiseizure medications and anticoagulants or antiplatelets, also influence treatment decisions. In this review, we describe the epidemiology, risk factors, biomarkers, and management of seizures after an ischaemic or haemorrhagic stroke. We discuss the special considerations required for the treatment of post-stroke epilepsy due to the age, co-morbidities, co-medication, and vulnerability of stroke survivors.
Topics: Aged; Biomarkers; Epilepsy; Humans; Risk Factors; Seizures; Stroke
PubMed: 33619704
DOI: 10.1007/s40266-021-00837-7 -
Clinical Medicine (London, England) Jan 2021We present a practical overview of functional neurological disorder (FND), its epidemiology, assessment and diagnosis, diagnostic pitfalls, treatment, aetiology and... (Review)
Review
We present a practical overview of functional neurological disorder (FND), its epidemiology, assessment and diagnosis, diagnostic pitfalls, treatment, aetiology and mechanism. We present an update on functional limb weakness, tremor, dystonia and other abnormal movements, dissociative seizures, functional cognitive symptoms and urinary retention, and 'scan-negative' cauda equina syndrome. The diagnosis of FND should rest on clear positive evidence, typically from a combination of physical signs on examination or the nature of seizures. In treatment of FND, clear communication of the diagnosis and the involvement of the multidisciplinary team is beneficial. We recommend that patients with FND are referred to specialists with expertise in neurological diagnosis. FND is a common presentation in emergency and acute medical settings and there are many practical elements to making a positive diagnosis and communication which are useful for all physicians to be familiar with.
Topics: Conversion Disorder; Emergency Service, Hospital; General Practitioners; Humans; Nervous System Diseases; Seizures; Tremor
PubMed: 33479065
DOI: 10.7861/clinmed.2020-0987 -
JAMA Neurology Apr 2021Focal epilepsy is characterized by the cyclical recurrence of seizures, but, to our knowledge, the prevalence and patterns of seizure cycles are unknown.
IMPORTANCE
Focal epilepsy is characterized by the cyclical recurrence of seizures, but, to our knowledge, the prevalence and patterns of seizure cycles are unknown.
OBJECTIVE
To establish the prevalence, strength, and temporal patterns of seizure cycles over timescales of hours to years.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study analyzed data from continuous intracranial electroencephalography (cEEG) and seizure diaries collected between January 19, 2004, and May 18, 2018, with durations up to 10 years. A total of 222 adults with medically refractory focal epilepsy were selected from 256 total participants in a clinical trial of an implanted responsive neurostimulation device. Selection was based on availability of cEEG and/or self-reports of disabling seizures.
EXPOSURES
Antiseizure medications and responsive neurostimulation, based on clinical indications.
MAIN OUTCOMES AND MEASURES
Measures involved (1) self-reported daily seizure counts, (2) cEEG-based hourly counts of electrographic seizures, and (3) detections of interictal epileptiform activity (IEA), which fluctuates in daily (circadian) and multiday (multidien) cycles. Outcomes involved descriptive characteristics of cycles of IEA and seizures: (1) prevalence, defined as the percentage of patients with a given type of seizure cycle; (2) strength, defined as the degree of consistency with which seizures occur at certain phases of an underlying cycle, measured as the phase-locking value (PLV); and (3) seizure chronotypes, defined as patterns in seizure timing evident at the group level.
RESULTS
Of the 222 participants, 112 (50%) were male, and the median age was 35 years (range, 18-66 years). The prevalence of circannual (approximately 1 year) seizure cycles was 12% (24 of 194), the prevalence of multidien (approximately weekly to approximately monthly) seizure cycles was 60% (112 of 186), and the prevalence of circadian (approximately 24 hours) seizure cycles was 89% (76 of 85). Strengths of circadian (mean [SD] PLV, 0.34 [0.18]) and multidien (mean [SD] PLV, 0.34 [0.17]) seizure cycles were comparable, whereas circannual seizure cycles were weaker (mean [SD] PLV, 0.17 [0.10]). Across individuals, circadian seizure cycles showed 5 peaks: morning, mid-afternoon, evening, early night, and late night. Multidien cycles of IEA showed peak periodicities centered around 7, 15, 20, and 30 days. Independent of multidien period length, self-reported and electrographic seizures consistently occurred during the days-long rising phase of multidien cycles of IEA.
CONCLUSIONS AND RELEVANCE
Findings in this large cohort establish the high prevalence of plural seizure cycles and help explain the natural variability in seizure timing. The results have the potential to inform the scheduling of diagnostic studies, the delivery of time-varying therapies, and the design of clinical trials in epilepsy.
Topics: Adolescent; Adult; Aged; Circadian Rhythm; Cohort Studies; Electrocorticography; Epilepsies, Partial; Female; Humans; Implantable Neurostimulators; Male; Middle Aged; Retrospective Studies; Seizures; Young Adult
PubMed: 33555292
DOI: 10.1001/jamaneurol.2020.5370 -
Seizure Feb 2021Neonatal seizures occur in their majority in close temporal relation to an acute brain injury or systemic insult, and are accordingly defined as acute symptomatic or... (Review)
Review
Neonatal seizures occur in their majority in close temporal relation to an acute brain injury or systemic insult, and are accordingly defined as acute symptomatic or provoked seizures. However less frequently, unprovoked seizures may also present in the neonatal period as secondary to structural brain abnormalities, thus corresponding to structural epilepsies, or to genetic conditions, thus corresponding to genetic epilepsies. Unprovoked neonatal seizures should be thus considered as the clinical manifestation of early onset structural or genetic epilepsies that often have the characteristics of early onset epileptic encephalopathies. In this review, we address the conundrum of neonatal seizures including acute symptomatic, remote symptomatic, provoked, and unprovoked seizures, evolving to post-neonatal epilepsies, and neonatal onset epilepsies. The different clinical scenarios involving neonatal seizures, each with their distinct post-neonatal evolution are presented. The structural and functional impact of neonatal seizures on brain development and the concept of secondary epileptogenesis, with or without a following latent period after the acute seizures, are addressed. Finally, we underline the need for an early differential diagnosis between an acute symptomatic seizure and an unprovoked seizure, since it is associated with fundamental differences in clinical evolution. These are crucial aspects for neonatal management, counselling and prognostication. In view of the above aspects, we provide an outlook on future strategies and potential lines of research in this field.
Topics: Diagnosis, Differential; Epilepsy; Humans; Infant, Newborn; Infant, Newborn, Diseases; Seizures
PubMed: 33418166
DOI: 10.1016/j.seizure.2020.12.023 -
Brain and Behavior Sep 2022Epilepsy is one of the most common neurological conditions worldwide. As a chronic condition, epilepsy imposes a significant burden on people with epilepsy and society.... (Review)
Review
BACKGROUND
Epilepsy is one of the most common neurological conditions worldwide. As a chronic condition, epilepsy imposes a significant burden on people with epilepsy and society. We aimed to assess the burden and unmet need of individuals with epilepsy and their caregivers, focusing on focal seizures, the main type of seizure in adults and children.
METHODS
A targeted evidence review of the burden of epilepsy, focusing on focal seizures, was conducted to identify articles reporting: epidemiology, mortality, morbidity, quality of life (QoL), and costs.
RESULTS
Focal seizures affect up to ∼61% of people with epilepsy. They are associated with an increased risk of injury and premature death than the general population. People with epilepsy also have high comorbidity, particularly depression, anxiety, and cognitive impairments. Higher seizure frequency, adverse treatment events, and employment concerns reduce QoL. A reduction in caregivers' QoL is also often reported. Epilepsy requires long-term treatment accounting for high individual costs. Hospitalizations and antiseizure medications (ASMs) are the leading cost drivers of inpatient management and indirect costs with high unemployment rates, particularly in drug-resistant populations. Despite the advent of new treatments, a high unmet need remains unaddressed; approximately 40% of people with epilepsy are drug-resistant, further increasing the risks associated with epilepsy.
CONCLUSIONS
Our findings highlight a substantial burden of illness and unmet needs in individuals with focal seizures, especially those with drug-resistant epilepsy. Suboptimal treatment options negatively impact QoL and, consequently, a sizeable economic burden indicating the need for new treatments and prioritizing this condition.
Topics: Adult; Anticonvulsants; Child; Drug Resistant Epilepsy; Epilepsy; Humans; Quality of Life; Seizures
PubMed: 36017757
DOI: 10.1002/brb3.2589 -
Seizure Aug 2021First seizures are always challenging for physicians. Determining etiology, risk of recurrence, need for diagnostic electroencephalogram (EEG) or neuroimaging, balancing... (Review)
Review
OBJECTIVE
First seizures are always challenging for physicians. Determining etiology, risk of recurrence, need for diagnostic electroencephalogram (EEG) or neuroimaging, balancing starting anti-seizure medication (ASM) versus its potential adverse effects, and addressing patient and family concerns about social or emotional impact in lifestyle issues is always demanding.
METHOD
a narrative review providing information from a database search between January 1970 to November 2020 was conducted, with the following search terms: first seizure, epidemiology, treatment, neuroimaging, electroencephalogram, impact, lifestyle.
RESULTS
Incidence rates of single unprovoked seizures range from 23 to 64.1 /100000/person-years. The risk of recurrence depends on several clinical, etiological, EEG, and neuroimaging findings that should be approached on an individual basis. Initiating ASM is not generally advised, but shall be considered in individual situations. The emotional and social impact of single seizures must not be underestimated. Some interesting clues are pointing out at risks to present or prevent a first seizure.
CONCLUSION
Presentation of first seizure, diagnostic workup, treatment, and impact should be considered individually based on continuously updated knowledge of treating physicians.
Topics: Adult; Anticonvulsants; Carbamazepine; Child; Electroencephalography; Epilepsies, Partial; Epilepsy, Generalized; Humans; Recurrence; Seizures
PubMed: 33840584
DOI: 10.1016/j.seizure.2021.03.027 -
JCI Insight Dec 2022Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy with...
Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, which encodes for sodium activated potassium channel protein KNa1.1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene-silencing antisense oligonucleotide (ASO) approach. We generated a mouse model carrying the KCNT1 p.P924L pathogenic variant; only the homozygous animals presented with the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared with mice treated with a control ASO (nonhybridizing sequence). ASO administration at neonatal age was also well tolerated and effective in controlling seizures and extending the life span of treated animals. The data presented here provide proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.
Topics: Mice; Animals; Brain Diseases; Seizures
PubMed: 36173683
DOI: 10.1172/jci.insight.146090 -
Emergencias : Revista de La Sociedad... Oct 2020This consensus statement was developed to optimize the emergency management of epileptic seizures in prehospital and hospital settings. A list of clinical questions was...
This consensus statement was developed to optimize the emergency management of epileptic seizures in prehospital and hospital settings. A list of clinical questions was drafted and the literature on the emergency treatment of epileptic seizures was reviewed by a multidisciplinary team of emergency physicians, neurologists, and pediatric neurologists from 3 associations: the Spanish Epilepsy Society (SEEP), the Spanish Society of Emergency Medicine (SEMES), and the Spanish Neurology Society (SEN). The team members first answered the questions individually and then discussed them during a meeting of experts from the 3 associations, to reach consensus on the content of the present statement. The recommendations and protocols proposed attempt to standardize the emergency management epileptic seizures. Earlier concepts and definitions are reviewed, a new definition of an epileptic seizure emergency is proposed, treatment options are described for different clinical scenarios, and a crisis code for seizures is also set out.
Topics: Child; Consensus; Emergency Service, Hospital; Epilepsy; Humans; Seizures
PubMed: 33006837
DOI: No ID Found