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Proceedings of the National Academy of... Mar 2022A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying...
A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here, we utilized a knock-in mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and dyskinesia. The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits and dyskinesia-like behaviors. The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia. A BK channel blocker, paxilline, potently suppresses BK-D434G–induced hyperexcitability and effectively mitigates absence seizures and locomotor deficits in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and dyskinesia. Our findings also suggest that BK inhibition is a promising therapeutic strategy for mitigating BK GOF-induced neurological disorders.
Topics: Animals; Channelopathies; Dyskinesias; Epilepsy, Absence; Humans; Large-Conductance Calcium-Activated Potassium Channels; Mice; Neurons; Seizures
PubMed: 35286197
DOI: 10.1073/pnas.2200140119 -
Neurophysiologie Clinique = Clinical... Aug 2022To analyze the ictal and interictal electroencephalographic (EEG) features in newly diagnosed childhood absence epilepsy (CAE) and determine the association between...
OBJECTIVE
To analyze the ictal and interictal electroencephalographic (EEG) features in newly diagnosed childhood absence epilepsy (CAE) and determine the association between seizure onset topography, interictal focal spike-wave discharges (FSWDs) and accompanying clinical features of absence seizures.
METHODS
The authors searched the EEG database for a definite diagnosis of CAE according to ILAE 2017 criteria. Video-EEGs of untreated pediatric patients during sleep and wakefulness were evaluated retrospectively.
RESULTS
The study included 47 patients (25 males, 22 females). Interictal FSWDs were observed in 49% of patients with CAE during wakefulness and in 85.1% during sleep (p = 0.001). Interictal FSWDs were most frequently observed in the frontal regions (awake: 34%; asleep: 74.5%), followed by the posterior temporoparietooccipital region (awake: 21.2%; asleep: 36.1%), and the centrotemporal region (awake: 6.4%; asleep: 8.5%). Eleven patients (23.4%) had polyspikes during sleep. Both bilateral symmetric and asymmetric seizure onset were noted in 32%, whereas focal seizure onset was observed in 14.9% of the patients. Absence seizures with and without motor components were seen in 72.3% and 61.7% of patients, respectively, and in 33% of patients both occurred. There were no associations between the existence of interictal FSWDs, focal/asymmetric seizure onset, and absence seizures with and/or without motor components.
CONCLUSION
Asymmetric and/or focal seizure onset, interictal FSWDs, and absence seizures with motor components are commonly observed in drug-naive CAE. This study found no association between seizure onset topography, interictal FSWDs, and semiological features of absence seizures.
Topics: Child; Electroencephalography; Epilepsy, Absence; Female; Humans; Male; Retrospective Studies; Seizures; Sleep
PubMed: 35953417
DOI: 10.1016/j.neucli.2022.07.003 -
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 -
Dental Clinics of North America Jul 2023All dentists should be trained in the diagnosis and management of seizures in a dental chair. Although epilepsy is a common etiological factor, there are other medical... (Review)
Review
All dentists should be trained in the diagnosis and management of seizures in a dental chair. Although epilepsy is a common etiological factor, there are other medical situations whereby seizures are manifested. Once a seizure is suspected and other causes of altered consciousness or involuntary motor movements are ruled out, proper management should commence immediately. The first step in management is to immediately remove/stop all provocative factors, like bright flashing lights, drill sounds, and such. Benzodiazepines remain as the first-line treatment for patients with continued seizures before activating emergency medical services.
Topics: Humans; Oral Hygiene; Epilepsy; Seizures; Anticonvulsants
PubMed: 37244727
DOI: 10.1016/j.cden.2023.02.031 -
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 -
The Turkish Journal of Pediatrics 2021Seizures are one of the most common causes of pediatric admissions to hospitals in children. This study aims to identify the clinical profile and outcome of first...
BACKGROUND
Seizures are one of the most common causes of pediatric admissions to hospitals in children. This study aims to identify the clinical profile and outcome of first seizures in children.
METHODS
Children who presented to the pediatric neurology outpatient clinic and pediatric emergency service with a first-time seizure and aged one month through 18 years old were enrolled to the study. At the time of the study, enrolled children were categorized into three study groups according to seizure characteristics: febrile seizure, nonfebrile-provoked seizure and, unprovoked seizure.
RESULTS
The study group consisted of 138 children. Of the 138 patients, 60 (43%) had febrile first seizures, 23 (17%) had nonfebrile-provoked first seizures, and 55 (40%) had unprovoked first seizures. The patients did not experience the recurrence of a seizure by the treatment of underlying cause at the eighteenth month and the eighth year follow-up in the nonfebrile-provoked seizure group. Among the children admitted for unprovoked first seizures, 33 (60%) patients had seizure recurrence during 18 month follow-up and 36 (82%) patients had seizure recurrence during eight year follow-up. Seizure recurrence rate was statistically higher in patients with abnormal EEG and cranial MRI findings in the unprovoked seizure group (p < .05).
CONCLUSIONS
The patients with provoked first seizure did not develop epilepsy during eight year follow-up. However, 36 patients with unprovoked seizures were diagnosed with epilepsy during eight year follow-up. It is essential to determine the causes of the seizures and treat the condition.
Topics: Aged; Child; Electroencephalography; Emergency Service, Hospital; Epilepsy; Humans; Infant; Recurrence; Seizures; Seizures, Febrile
PubMed: 34449143
DOI: 10.24953/turkjped.2021.04.008 -
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