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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 -
The Lancet. Neurology Jul 2017People with epilepsy who became seizure-free while taking antiepileptic drugs might consider discontinuing their medication, with the possibility of increased quality of... (Meta-Analysis)
Meta-Analysis Review
Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis.
BACKGROUND
People with epilepsy who became seizure-free while taking antiepileptic drugs might consider discontinuing their medication, with the possibility of increased quality of life because of the elimination of adverse events. The risk with this action, however, is seizure recurrence. The objectives of our study were to identify predictors of seizure recurrence and long-term seizure outcomes and to produce nomograms for estimation of individualised outcomes.
METHODS
We did a systematic review and meta-analysis, and identified eligible articles and candidate predictors, using PubMed and Embase databases with a last update on Nov 6, 2014. Eligible articles had to report on cohorts of patients with epilepsy who were seizure-free and had started withdrawal of antiepileptic drugs; articles also had to contain information regarding seizure recurrences during and after withdrawal. We excluded surgical cohorts, reports with fewer than 30 patients, and reports on acute symptomatic seizures because these topics were beyond the scope of our objective. Risk of bias was assessed using the Quality in Prognosis Studies system. Data analysis was based on individual participant data. Survival curves and proportional hazards were computed. The strongest predictors were selected with backward selection. Models were converted to nomograms and a web-based tool to determine individual risks.
FINDINGS
We identified 45 studies with 7082 patients; ten studies (22%) with 1769 patients (25%) were included in the meta-analysis. Median follow-up was 5·3 years (IQR 3·0-10·0, maximum 23 years). Prospective and retrospective studies and randomised controlled trials were included, covering non-selected and selected populations of both children and adults. Relapse occurred in 812 (46%) of 1769 patients; 136 (9%) of 1455 for whom data were available had seizures in their last year of follow-up, suggesting enduring seizure control was not regained by this timepoint. Independent predictors of seizure recurrence were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on electroencephalogram (EEG) before withdrawal. Independent predictors of seizures in the last year of follow-up were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, number of antiepileptic drugs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal. Adjusted concordance statistics were 0·65 (95% CI 0·65-0·66) for predicting seizure recurrence and 0·71 (0·70-0·71) for predicting long-term seizure freedom. Validation was stable across the individual study populations.
INTERPRETATION
We present evidence-based nomograms with robust performance across populations of children and adults. The nomograms facilitate prediction of outcomes following drug withdrawal for the individual patient, including both the risk of relapse and the chance of long-term freedom from seizures. The main limitations were the absence of a control group continuing antiepileptic drug treatment and a consistent definition of long-term seizure freedom.
FUNDING
Epilepsiefonds.
Topics: Adult; Anticonvulsants; Child; Humans; Outcome Assessment, Health Care; Recurrence; Remission Induction; Seizures
PubMed: 28483337
DOI: 10.1016/S1474-4422(17)30114-X -
The Indian Journal of Medical Research Nov 2016Epilepsy is a highly prevalent chronic neurologic disorder and leads to social, behavioural, health and economic consequences. 'Treatment gap' varies from 10 per cent in... (Review)
Review
Epilepsy is a highly prevalent chronic neurologic disorder and leads to social, behavioural, health and economic consequences. 'Treatment gap' varies from 10 per cent in developed countries to 75 per cent in low-income countries. Stigma and discrimination related to epilepsy are prevalent worldwide. Electroencephalography (EEG) is considered the most important tool for evaluating the patient with epilepsy. Video-EEG monitoring is an important tool for confirming the seizure type and estimating the epileptogenic zone in the brain. Neuroimaging evaluation is important to determine the aetiology of the epilepsies. Genetic testing has increased the probability of identifying the causes of some types of epilepsies. Epilepsy can be treated in an affordable way with low-cost medications. Refractory epilepsies occur in approximately one-third of recently diagnosed patients with epilepsy. For this group of patients, there are options of surgical treatment, diets and neurostimulation to improve seizure control and quality of life. In poorly organized societies, there is a lack of prioritization of epilepsy in national health policies, limited resources for trained personnel and a shortage of basic antiepileptic medications. There is evidence of improvement in the understanding of epilepsy and a clear progress in the management of epileptic seizures in recent times.
Topics: Anticonvulsants; Electroencephalography; Epilepsy; Humans; Seizures
PubMed: 28361817
DOI: 10.4103/ijmr.IJMR_1051_16 -
Epilepsia Apr 2010To consider the definition of acute symptomatic seizures for epidemiological studies, and to refine the criteria used to distinguish these seizures from unprovoked... (Review)
Review
PURPOSE
To consider the definition of acute symptomatic seizures for epidemiological studies, and to refine the criteria used to distinguish these seizures from unprovoked seizures for specific etiologies.
METHODS
Systematic review of the literature and of epidemiologic studies.
RESULTS
An acute symptomatic seizure is defined as a clinical seizure occurring at the time of a systemic insult or in close temporal association with a documented brain insult. Suggestions are made to define acute symptomatic seizures as those events occurring within 1 week of stroke, traumatic brain injury, anoxic encephalopathy, or intracranial surgery; at first identification of subdural hematoma; at the presence of an active central nervous system (CNS) infection; or during an active phase of multiple sclerosis or other autoimmune diseases. In addition, a diagnosis of acute symptomatic seizure should be made in the presence of severe metabolic derangements (documented within 24 h by specific biochemical or hematologic abnormalities), drug or alcohol intoxication and withdrawal, or exposure to well-defined epileptogenic drugs.
DISCUSSION
Acute symptomatic seizures must be distinguished from unprovoked seizures and separately categorized for epidemiologic purposes. These recommendations are based upon the best available data at the time of this report. Systematic studies should be undertaken to better define the associations in question, with special reference to metabolic and toxic insults, for which the time window for the occurrence of an acute symptomatic seizure and the absolute values for toxic and metabolic dysfunction still require a clear identification.
Topics: Acute Disease; Cross-Sectional Studies; Diagnosis, Differential; Humans; Seizures
PubMed: 19732133
DOI: 10.1111/j.1528-1167.2009.02285.x -
Seizure May 2019To summarize definitions, prevalence, risk factors, consequences, and acute management of seizure clusters using rescue medications.
PURPOSE
To summarize definitions, prevalence, risk factors, consequences, and acute management of seizure clusters using rescue medications.
METHODS
We searched MEDLINE for studies that assessed definitions, clinical characteristics, outcomes, and use of rescue medication for aborting seizure clusters.
RESULTS
Different clinical and statistical definitions for seizure clusters have been proposed, including: ≥3 seizures in 24 h, ≥2 seizures in 24 h, and ≥2 seizures in 6 h. Most studies of seizure clusters have been conducted in tertiary epilepsy centers, with refractory epilepsy patients. Patients with severe and poorly controlled epilepsy are more likely to experience seizure clusters. Seizure clusters can result in increased health care utilization and have negative impact on the quality of life of patients and caregivers. Use of benzodiazepine rescue medications in acute management of seizure clusters can help avoid progression to status epilepticus and reduce emergency room visits. Rescue medications are underutilized in seizure clusters. Currently, rectal diazepam gel is the only FDA approved rescue medication for seizure clusters. In addition, buccal midazolam is approved in European countries for treatment of prolonged seizures. However, various non-rectal non-IV benzodiazepines are safe and effective in treating acute seizures and clusters. Most patients and caregivers preferred non-rectal routes.
CONCLUSION
Identifying patients that are at high risk for seizure clusters, providing them with formal action plans and educating them about use of rescue medication for seizure clusters can help ameliorate the outcomes in this group of epilepsy patients.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Epilepsy; Humans; Infant; Middle Aged; Seizures; Young Adult
PubMed: 29871784
DOI: 10.1016/j.seizure.2018.05.013 -
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 -
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 -
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 -
Epilepsia Sep 1998We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as...
We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.
Topics: Electroencephalography; Epilepsy; Humans; Seizures; Syndrome; Terminology as Topic
PubMed: 9738682
DOI: 10.1111/j.1528-1157.1998.tb01452.x