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Developmental Medicine and Child... Jan 2022To explore the genotypes and phenotypes of CACNA1A variants in children with epilepsy.
AIM
To explore the genotypes and phenotypes of CACNA1A variants in children with epilepsy.
METHOD
Eighteen children (six males, 12 females) with CACNA1A variants were identified using next-generation sequencing.
RESULTS
There were 14 missense variants, two nonsense variants, one frameshift variant, and one splice site variant. Sixteen variants were de novo. Age at seizure onset ranged from 1 day to 8 years; median age was 8 months. Multiple seizure types were observed, including focal, generalized tonic-clonic, myoclonic, and absence seizures, as well as epileptic spasms and tonic seizures. Focal motor status epilepticus occurred in 10 individuals and generalized motor status epilepticus occurred in two individuals. All 18 children showed developmental delay. Focal motor status epilepticus resulted in cerebral atrophy in five individuals, mainly on the contralateral side. Interictal electroencephalogram showed focal discharges in 12 individuals, whereas five individuals had generalized discharges. Three individuals were seizure-free, whereas 15 still had seizures and five had recurrent status epilepticus at last follow-up.
INTERPRETATION
Most children with epilepsy and CACNA1A variants had early seizure onset and developmental delay. Focal seizure was the most common seizure type. Most patients experienced status epilepticus. Unilateral cerebral atrophy could occur after focal motor status epilepticus. Patients with CACNA1A variants located in the transmembrane region may be at high risk of status epilepticus.
Topics: Calcium Channels; Child; Epilepsy; Female; Genetic Association Studies; Genotype; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Male; Mutation; Phenotype; Seizures
PubMed: 34263451
DOI: 10.1111/dmcn.14985 -
IEEE Transactions on Neural Systems and... 2022Absence seizure as a generalized onset seizure, simultaneously spreading seizure to both sides of the brain, involves around ten-second sudden lapses of consciousness....
Absence seizure as a generalized onset seizure, simultaneously spreading seizure to both sides of the brain, involves around ten-second sudden lapses of consciousness. It common occurs in children than adults, which affects living quality even threats lives. Absence seizure can be confused with inattentive attention-deficit hyperactivity disorder since both have similar symptoms, such as inattention and daze. Therefore, it is necessary to detect absence seizure onset. However, seizure onset detection in electroencephalography (EEG) signals is a challenging task due to the non-stereotyped seizure activities as well as their stochastic and non-stationary characteristics in nature. Joint spectral-temporal features are believed to contain sufficient and powerful feature information for absence seizure detection. However, the resulting high-dimensional features involve redundant information and require heavy computational load. Here, we discover significant low-dimensional spectral-temporal features in terms of mean-standard deviation of wavelet transform coefficient (MS-WTC), based on which a novel absence seizure detection framework is developed. The EEG signals are transformed into the spectral-temporal domain, with their low-dimensional features fed into a convolutional neural network. Superior detection performance is achieved on the widely-used benchmark dataset as well as a clinical dataset from the Chinese 301 Hospital. For the former, seven classification tasks were evaluated with the accuracy from 99.8% to 100.0%, while for the latter, the method achieved a mean accuracy of 94.7%, overwhelming other methods with low-dimensional temporal and spectral features. Experimental results on two seizure datasets demonstrate reliability, efficiency and stability of our proposed MS-WTC method, validating the significance of the extracted low-dimensional spectral-temporal features.
Topics: Adult; Algorithms; Child; Electroencephalography; Epilepsy; Humans; Reproducibility of Results; Seizures; Signal Processing, Computer-Assisted
PubMed: 35245199
DOI: 10.1109/TNSRE.2022.3156931 -
Current Neuropharmacology 2021A dysfunction in glutamate neurotransmission is critical for seizure. Glutamate is the major excitatory drive in the cerebral cortex, where seizures occur. Glutamate... (Review)
Review
BACKGROUND
A dysfunction in glutamate neurotransmission is critical for seizure. Glutamate is the major excitatory drive in the cerebral cortex, where seizures occur. Glutamate acts via (i) ionotropic (iGlu) receptors, which are ligand-gated ion channels mediating fast excitatory synaptic transmission; and (ii) G proteins coupled metabotropic (mGlu) receptors.
OBJECTIVE
To overview the evidence on the role of iGlu receptors in the onset, duration, and severity of convulsive and non-convulsive seizures to lay the groundwork for novel strategies for drug-resistant epilepsy.
METHODS
We used PubMed crossed-search for "glutamate receptor and epilepsy" (sorting 3,170 reports), searched for "ionotropic glutamate receptors", "AMPA receptors", "NMDA receptors", "kainate receptors", "convulsive seizures", "absence epilepsy", and selected those papers focusing this Review's scope.
RESULTS
iGlu receptor antagonists inhibit, whereas agonists worsen experimental seizures in various animal species. Clinical development of iGlu receptor antagonists has been limited by the occurrence of adverse effects caused by inhibition of fast excitatory synaptic transmission. To date, only one drug (perampanel) selectively targeting iGlu receptors is marketed for the treatment of focal epilepsy. However, other drugs, such as topiramate and felbamate, inhibit iGlu receptors in addition to other mechanisms.
CONCLUSION
This review is expected to help dissect those steps induced by iGlu receptors activation, which may be altered to provide antiepileptic efficacy without altering key physiological brain functions, thus improving the safety and tolerability of iGlu-receptor directed antiepileptic agents. This effort mostly applies to drug resistant seizures, which impact the quality of life and often lead to status epilepticus, which is a medical urgency.
Topics: Animals; Anticonvulsants; Epilepsy, Absence; Quality of Life; Receptors, Ionotropic Glutamate; Seizures
PubMed: 32867642
DOI: 10.2174/1570159X18666200831154658 -
Seizure Aug 2023Dissociation is a "disruption of the usually integrated functions of consciousness, memory, identity or perception of the environment" according to DSM-5. It is... (Review)
Review
Dissociation is a "disruption of the usually integrated functions of consciousness, memory, identity or perception of the environment" according to DSM-5. It is commonly seen in psychiatric disorders including primary dissociative disorders, post-traumatic stress disorder, depression, and panic disorder. Dissociative phenomena are also described in the context of substance intoxication, sleep deprivation and medical illnesses including traumatic brain injury, migraines, and epilepsy. Patients with epilepsy have higher rates of dissociative experiences as measured on the Dissociative Experiences Scale compared to healthy controls. Ictal symptoms, especially in focal epilepsy of temporal lobe origin, may include dissociative-like experiences such as déjà vu/jamais vu, depersonalization, derealization and what has been described as a "dreamy state". These descriptions are common in the setting of seizures that originate from mesial temporal lobe epilepsy and may involve the amygdala and hippocampus. Other ictal dissociative phenomena include autoscopy and out of body experiences, which are thought to be due to disruptions in networks responsible for the integration of one's own body and extra-personal space and involve the temporoparietal junction and posterior insula. In this narrative review, we will summarize the updated literature on dissociative experiences in epilepsy, as well as dissociative experiences in functional seizures. Using a case example, we will review the differential diagnosis of dissociative symptoms. We will also review neurobiological underpinnings of dissociative symptoms across different diagnostic entities and discuss how ictal symptoms may shed light on the neurobiology of complex mental processes including the subjective nature of consciousness and self-identity.
Topics: Humans; Seizures; Epilepsy; Epilepsy, Temporal Lobe; Dissociative Disorders; Stress Disorders, Post-Traumatic
PubMed: 37433243
DOI: 10.1016/j.seizure.2023.06.020 -
Expert Opinion on Drug Discovery Oct 2019: Epilepsy affects over 65 million people worldwide, and despite the numerous therapies that are currently available for the symptomatic management of chronic seizures,...
: Epilepsy affects over 65 million people worldwide, and despite the numerous therapies that are currently available for the symptomatic management of chronic seizures, a substantial proportion of the population has not achieved adequate seizure control. Developing more effective and better-tolerated therapies will benefit patients worldwide. : This article will discuss the relevant preclinical models that have been instrumental to the development of over 20 antiseizure drugs (ASDs) currently on the market today. While there have been meaningful therapies already developed over the last several decades, this article will highlight remaining areas of unmet medical need. Innovative models of pharmacoresistant epilepsy may advance therapies for patients who currently do not attain sufficient seizure control in the absence of adverse effects. There also remains a need to identify improved therapies for special patient populations, including the very young and old. : ASD development will still find utility in the established models that have been instrumental to the identification of impactful therapies. However, there should now be greater emphasis to implement those models in young and aged rodents to advance novel therapies for patients who are still in need of better tolerated or more effective therapies, such as pediatric and elderly patients.
Topics: Aged; Animals; Anticonvulsants; Child; Disease Models, Animal; Drug Development; Drug Evaluation, Preclinical; Epilepsy; Humans; Rodentia; Seizures
PubMed: 31248287
DOI: 10.1080/17460441.2019.1636782 -
Neurology Aug 2017To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes. (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.
METHODS
For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.
RESULTS
Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%-84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern.
CONCLUSIONS
Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Electroencephalography; Epilepsy, Absence; Eye Movements; Female; Follow-Up Studies; Humans; Male; Outcome Assessment, Health Care; Seizures
PubMed: 28724582
DOI: 10.1212/WNL.0000000000004226 -
Epilepsia Jul 2021Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access...
OBJECTIVE
Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access program (EAP). Most studies report efficacy over short time periods (<1 year), with little published on longer term efficacy. Here, we investigate the efficacy of CBD for a treatment period of up to 60 months (median = 45.5 months).
METHODS
We conducted a retrospective review of patient-reported seizure logs and medical records for 54 subjects with refractory epilepsy who enrolled in the Massachusetts General Hospital's open-label EAP for CBD as a new treatment for epilepsy. We analyzed the effect of CBD on seizure frequencies and concomitant antiepileptic drug (AED) use at 1 year after starting treatment and the most recent study visit.
RESULTS
Our results indicate that CBD maintains its efficacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7%-42.6%), and the seizure response rate was also maintained (p = .12). Efficacy was also seen over a broad dose range, and up to 50 mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic spasms and absence seizures. Although CBD use did not lead to an overall decrease in concomitant AEDs, most subjects reduced the dose of at least one concomitant AED compared to baseline. CBD was generally well tolerated, with drowsiness and diarrhea as the primary adverse reactions.
SIGNIFICANCE
This study demonstrates CBD does not lose its efficacy in controlling seizures over a treatment period of up to 60 months. Taken alongside other results on the efficacy and tolerability of CBD in the treatment of refractory epilepsies, our results provide evidence that CBD is an effective, safe, and well-tolerated AED for long-term use.
Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Clobazam; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Drug Therapy, Combination; Female; Humans; Kaplan-Meier Estimate; Male; Retrospective Studies; Seizures; Treatment Outcome; Tuberous Sclerosis; Young Adult
PubMed: 34050682
DOI: 10.1111/epi.16936 -
Seizure Aug 2020The aim of our study was to evaluate the relationship between seizure semiology and etiological factors in our population of neonates, in pointing out that specific...
OBJECTIVE
The aim of our study was to evaluate the relationship between seizure semiology and etiological factors in our population of neonates, in pointing out that specific kinds of clinical presentation are strictly related to specific etiologies.
METHODS
We selected neonates which presented clinical seizures during video-EEG monitoring performed in Neonatal and Neurological Units between 2010 and 2017. We excluded patients with electrographic seizures only or video-EEGs of poor quality. Seizures were divided into the main subgroups "motor" (focal clonic, focal tonic and myoclonic) and "non motor". For each patient we evaluated etiology, considering two major categories: acute and remote symptomatic.
RESULTS
The study included 65 patients, including 44 with an acute symptomatic cause and 21 with remote symptomatic etiology. Focal motor clonic seizures were almost exclusively associated to acute symptomatic etiology (p < 0.05), mainly to stroke and infective causes. Focal motor tonic seizures were the prevalent type of seizures in remote symptomatic etiologies (p < 0.05). They were observed mainly in patients with Developmental Epileptic Encephalopathy. Focal non motor seizures were more represented in acute symptomatic causes (p = 0.01) and were the main type of seizure in HIE.
CONCLUSIONS
Seizure semiology in neonates may help physicians in the early recognition of specific etiologies. In particular, focal clonic seizures are strongly suggestive of acute symptomatic causes, allowing an early diagnosis and treatment.
Topics: Electroencephalography; Epilepsy; Epilepsy, Generalized; Humans; Infant, Newborn; Infant, Newborn, Diseases; Seizures
PubMed: 32585613
DOI: 10.1016/j.seizure.2020.06.025 -
Journal of Veterinary Internal Medicine Jul 2021Many studies of epilepsy in veterinary medicine use subjective data (eg, caregiver-derived histories) to determine seizure frequency. Conversely, in people, objective...
BACKGROUND
Many studies of epilepsy in veterinary medicine use subjective data (eg, caregiver-derived histories) to determine seizure frequency. Conversely, in people, objective data from electroencephalography (EEG) are mainly used to diagnose epilepsy, measure seizure frequency and evaluate efficacy of antiseizure drugs. These EEG data minimize the possibility of the underreporting of seizures, a known phenomenon in human epileptology.
OBJECTIVE
To evaluate the correlation between reported seizure frequency and EEG frequency of ictal paroxysmal discharges (PDs) and to determine whether seizure underreporting phenomenon exists in veterinary epileptology.
ANIMALS
Thirty-three ambulatory video-EEG recordings in dogs showing ≥1 ictal PD, excluding dogs with status epilepticus.
METHODS
Retrospective observational study. Ictal PDs were counted manually over the entire recording to obtain the frequency of EEG seizures. Caregiver-reported seizure frequency from the medical record was categorized into weekly, daily, hourly, and per minute seizure groupings. The Spearman rank test was used for correlation analysis.
RESULTS
The coefficient value (r ) comparing reported seizure to EEG-confirmed ictal PD frequencies was 0.39 (95% confidence interval [CI] = 0.048-0.64, P = .03). Other r values comparing history against various seizure types were: 0.36 for motor seizures and 0.37 for nonmotor (absence) seizures.
CONCLUSIONS AND CLINICAL IMPORTANCE
A weak correlation was found between the frequency of reported seizures from caregivers (subjective data) and ictal PDs on EEG (objective data). Subjective data may not be reliable enough to determine true seizure frequency given the discrepancy with EEG-confirmed seizure frequency. Confirmation of the seizure underreporting phenomenon in dogs by prospective study should be carried out.
Topics: Animals; Dog Diseases; Dogs; Electroencephalography; Epilepsy; Prospective Studies; Seizures; Status Epilepticus
PubMed: 34002887
DOI: 10.1111/jvim.16158 -
Epileptic Disorders : International... Apr 2022To characterize in detail the electroclinical features of typical absence seizures and elucidate whether EEG or semiology features, alone or in combination, can predict...
OBJECTIVE
To characterize in detail the electroclinical features of typical absence seizures and elucidate whether EEG or semiology features, alone or in combination, can predict long-term therapeutic outcome.
METHODS
We analysed video-EEG recordings from 213 typical absence seizures from 61 patients with idiopathic generalized epilepsy. We extracted semiological features, in addition to hallmark manifestations (motor/behavioural arrest, non-responsiveness), their location, timing and frequency. We evaluated the duration and frequency of generalized spike-wave discharges and the presence of polyspikes. We used a supervised machine-learning approach (random forest) to search for classifier features for long-term therapeutic outcome (>one year).
RESULTS
Besides the hallmark manifestations, additional semiological features were identified in 87% of patients (75% of seizures). The most common additional semiological features were automatisms and eye blinking (observed in 45% and 41.5% of seizures, respectively). Automatisms were associated with longer seizure duration, and oral automatisms occurred earlier compared to limb automatisms (4.03 vs. 6.19 seconds; p=0.005). The mean duration of the ictal spike-wave discharges was nine seconds, and the median frequency was 3 Hz. Polyspikes occurred in 46 seizures (21.6%), in 19 patients (31%). Median follow-up was five years, and 73% of the patients were seizure-free at the end of the follow-up. None of the semiological features, alone or in combination, were predictors of therapeutic outcome. The only significant classifier was the presence of polyspikes, predicting a non-seizure-free outcome with an accuracy of 73% (95% CI: 70-77%), positive predictive value of 92% (95% CI: 84-98%) and negative predictive value of 60% (95% CI: 39-81%).
SIGNIFICANCE
Semiological features, in addition to behavioural arrest and non-responsiveness, are common in typical absence seizures, but they do not predict long-term therapeutic outcome. The presence of polyspikes has a high positive predictive value for unfavourable therapeutic outcome, and their presence should therefore be included when reporting EEGs in patients with typical absence seizures.
Topics: Automatism; Electroencephalography; Epilepsy, Absence; Humans; Predictive Value of Tests; Seizures
PubMed: 34859792
DOI: 10.1684/epd.2021.1392