Severe peri-ictal respiratory dysfunction is common in Dravet syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Kim Y
PROVIDER: S-EPMC5824857 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
Publications
Severe peri-ictal respiratory dysfunction is common in Dravet syndrome.
Kim YuJaung Y Bravo Eduardo E Thirnbeck Caitlin K CK Smith-Mellecker Lori A LA Kim Se Hee SH Gehlbach Brian K BK Laux Linda C LC Zhou Xiuqiong X Nordli Douglas R DR Richerson George B GB
The Journal of clinical investigation 20180212 3
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutat ...[more]
Similar Datasets
Project description:ObjectiveIctal vocalizations have shown diagnostic utility in epilepsy patients. Audio recordings of seizures have also been used for seizure detection. The present study aimed to determine whether generalized tonic-clonic seizures in the Scn1a+/- mouse model of Dravet syndrome are associated with either audible mouse squeaks or ultrasonic vocalizations.MethodsAcoustic recordings were captured from group-housed Scn1a+/- mice undergoing video-monitoring to quantify spontaneous seizure frequency. We generated audio clips (n = 129) during a generalized tonic-clonic seizure (GTCS) that included 30 seconds immediately prior to the GTCS (preictal) and 30 seconds following the conclusion of the seizure (postictal). Nonseizure clips (n = 129) were also exported from the acoustic recordings. A blinded reviewer manually reviewed the audio clips, and vocalizations were identified as either an audible (<20 kHz) mouse squeak or ultrasonic (>20 kHz).ResultsSpontaneous GTCS in Scn1a+/- mice were associated with a significantly higher number of total vocalizations. The number of audible mouse squeaks was significantly greater with GTCS activity. Nearly all (98%) the seizure clips contained ultrasonic vocalizations, whereas ultrasonic vocalizations were present in only 57% of nonseizure clips. The ultrasonic vocalizations emitted in the seizure clips were at a significantly higher frequency and were nearly twice as long in duration as those emitted in the nonseizure clips. Audible mouse squeaks were primarily emitted during the preictal phase. The greatest number of ultrasonic vocalizations was detected during the ictal phase.SignificanceOur study shows that ictal vocalizations are exhibited by Scn1a+/- mice. Quantitative audio analysis could be developed as a seizure detection tool for the Scn1a+/- mouse model of Dravet syndrome.
| S-EPMC10472354 | biostudies-literature
Project description:Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that is mainly associated with variants in SCN1A. While drug-resistant epilepsy is the most notable feature of this syndrome, numerous symptoms are present that have significant impact on patients' quality of life. In spite of novel, third-generation anti-seizure treatment options becoming available over the last several years, seizure freedom is often not attained and non-seizure symptoms remain. Precision medicine now offers realistic hope for seizure freedom in DS patients, with several approaches demonstrating preclinical success. Therapeutic approaches such as antisense oligonucleotides (ASO) and adeno-associated virus (AAV)-delivered gene modulation have expanded the potential treatment options for DS, with some of these approaches now transitioning to clinical trials. Several of these treatments may risk the exacerbation of gain-of-function variants and may not be reversible, therefore emphasizing the need for functional testing of new pathogenic variants. The current absence of treatments that address the overall disease, in addition to seizures, exposes the urgent need for reliable, valid measures of the entire complement of symptoms as outcome measures to truly know the impact of treatments on DS. Additionally, with so many treatment options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.
| S-EPMC8608987 | biostudies-literature
Project description:Dravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder, and increased risk of sudden death. Convergent data suggest hippocampal dentate gyrus (DG) pathology in DS (Scn1a+/-) mice. We performed two-photon calcium imaging in brain slice to uncover a profound dysfunction of filtering of perforant path input by DG in young adult Scn1a+/- mice. This was not due to dysfunction of DG parvalbumin inhibitory interneurons (PV-INs), which were only mildly impaired at this timepoint; however, we identified enhanced excitatory input to granule cells, suggesting that circuit dysfunction is due to excessive excitation rather than impaired inhibition. We confirmed that both optogenetic stimulation of entorhinal cortex and selective chemogenetic inhibition of DG PV-INs lowered seizure threshold in vivo in young adult Scn1a+/- mice. Optogenetic activation of PV-INs, on the other hand, normalized evoked responses in granule cells in vitro. These results establish the corticohippocampal circuit as a key locus of pathology in Scn1a+/- mice and suggest that PV-INs retain powerful inhibitory function and may be harnessed as a potential therapeutic approach toward seizure modulation.
| S-EPMC8920506 | biostudies-literature
Project description:Relatively few SCN1A mutations associated with genetic epilepsy with febrile seizures-plus (GEFS+) and Dravet syndrome (DS) have been functionally characterized. In contrast to GEFS+, many mutations detected in DS patients are predicted to have complete loss of function. However, functional consequences are not immediately apparent for DS missense mutations. Therefore, we performed a biophysical analysis of three SCN1A missense mutations (R865G, R946C and R946H) we detected in six patients with DS. Furthermore, we compared the functionality of the R865G DS mutation with that of a R859H mutation detected in a GEFS+ patient; the two mutations reside in the same voltage sensor domain of Na(v) 1.1. The four mutations were co-expressed with ?1 and ?2 subunits in tsA201 cells, and characterized using the whole-cell patch clamp technique. The two DS mutations, R946C and R946H, were nonfunctional. However, the novel voltage sensor mutants R859H (GEFS+) and R865G (DS) produced sodium current densities similar to those in wild-type channels. Both mutants had negative shifts in the voltage dependence of activation, slower recovery from inactivation, and increased persistent current. Only the GEFS+ mutant exhibited a loss of function in voltage-dependent channel availability. Our results suggest that the R859H mutation causes GEFS+ by a mixture of biophysical defects in Na(v) 1.1 gating. Interestingly, while loss of Na(v) 1.1 function is common in DS, the R865G mutation may cause DS by overall gain-of-function defects.
| S-EPMC3195841 | biostudies-literature
Project description:Focal seizures originating from the temporal lobe are commonly associated with peri-ictal hypoxemia (PIH). During the course of temporal lobe seizures, epileptic discharges often not only spread within various parts of the temporal lobe but also possibly insula and frontal lobe. The link between spatial propagation of the seizure discharges and PIH is still unclear. The present study investigates the involvement of several brain structures including medial temporal structures, temporal pole, anterior insula, and frontal cortex in the occurrence of PIH. Using quantitative indices obtained during SEEG (stereoencephalography) recordings in 38 patients, we evaluated the epileptogenicity, the spatial propagation, and functional connectivity between those structures during seizures leading to PIH. Multivariate statistical analyses of SEEG quantitative indices showed that temporal lobe seizures leading to PIH are characterized by a strong involvement of amygdala and anterior insula during seizure propagation and a more widespread involvement of medial temporal lobe structures, lateral temporal lobe, temporal pole, and anterior cingulate at the end of the seizures. On the contrary, seizure-onset zone was not associated with PIH occurrence. During seizure propagation, anterior insula, temporal pole, and temporal lateral neocortex activities were correlated with intensity of PIH. Lastly, PIH occurrence was also related to a widespread increase of synchrony between those structures. Those results suggest that PIH occurrence during temporal lobe seizures may be related to the activation of a widespread network of cortical structures, among which amygdala and anterior insula are key nodes.
| S-EPMC9491280 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus first identified in December 2019. Notable features that make SARS-CoV-2 distinct from most other previously identified betacoronaviruses include a receptor binding domain and a unique insertion of 12 nucleotides or 4 amino acids (PRRA) at the S1/S2 boundary. In this study, we identified two deletion variants of SARS-CoV-2 that either directly affect the polybasic cleavage site itself (NSPRRAR) or a flanking sequence (QTQTN). These deletions were verified by multiple sequencing methods. In vitro results showed that the deletion of NSPRRAR likely does not affect virus replication in Vero and Vero-E6 cells; however, the deletion of QTQTN may restrict late-phase viral replication. The deletion of QTQTN was detected in 3 of 68 clinical samples and 12 of 24 in vitro-isolated viruses, while the deletion of NSPRRAR was identified in 3 in vitro-isolated viruses. Our data indicate that (i) there may be distinct selection pressures on SARS-CoV-2 replication or infection in vitro and in vivo; (ii) an efficient mechanism for deleting this region from the viral genome may exist, given that the deletion variant is commonly detected after two rounds of cell passage; and (iii) the PRRA insertion, which is unique to SARS-CoV-2, is not fixed during virus replication in vitro These findings provide information to aid further investigation of SARS-CoV-2 infection mechanisms and a better understanding of the NSPRRAR deletion variant observed here.IMPORTANCE The spike protein determines the infectivity and host range of coronaviruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has two unique features in its spike protein, the receptor binding domain and an insertion of 12 nucleotides at the S1/S2 boundary resulting in a furin-like cleavage site. Here, we identified two deletion variants of SARS-CoV-2 that either directly affect the furin-like cleavage site itself (NSPRRAR) or a flanking sequence (QTQTN), and we investigated these deletions in cell isolates and clinical samples. The absence of the polybasic cleavage site in SARS-CoV-2 did not affect virus replication in Vero or Vero-E6 cells. Our data indicate the PRRAR sequence and the flanking QTQTN sequence are not fixed in vitro; thus, there appears to be distinct selection pressures on SARS-CoV-2 sequences in vitro and in vivo Further investigation of the mechanism of generating these deletion variants and their infectivity in different animal models would improve our understanding of the origin and evolution of this virus.
| S-EPMC7431800 | biostudies-literature
Project description:BackgroundDespite considerable evidence for the efficacy and safety of stiripentol in Dravet syndrome (DS), some aspects of stiripentol use remain challenging in clinical practice, such as dose titration and the adjustment of concomitant antiseizure medications (ASMs) to prevent potential adverse effects.AimTo (1) provide practical recommendations on the initiation of stiripentol treatment in patients with DS, (2) evaluate its effectiveness in the patient, and (3) guide the management of drug interactions and other aspects of treatment monitoring.MethodsSix Spanish neurologists (the authors) with expertise in the management of pediatric and adult patients with DS held a meeting in early 2024 to develop expert recommendations regarding the use of stiripentol in DS, based on a review of the literature and their common clinical experience.ResultsAccording to these recommendations, stiripentol can be administered to patients with DS of any age, although its initiation and titration vary according to age group. Individualized adjustment of concomitant ASMs, such as valproic acid and clobazam or drugs specifically for DS (i.e., fenfluramine), at initiation and during stiripentol treatment, can mitigate drug interactions, thereby increasing the long-term tolerability of stiripentol treatment. In specific cases, stiripentol doses of > 50 mg/kg/day may be contemplated, and acute stiripentol administration may be considered to control refractory status epilepticus. Blood tests should be performed before starting stiripentol, at 3, 6, and 12 months after starting treatment, and then annually, except in the event of adverse effects, when additional testing may be necessary. Most adverse effects can be adequately managed by adjusting concomitant medications.ConclusionThese practical recommendations may be easily adapted for use in different countries, and should increase physicians' confidence in the initiation and monitoring of stiripentol treatment, thus facilitating effective management of patients with DS and improving clinical outcomes.
| S-EPMC11762041 | biostudies-literature
Project description:Severe acute respiratory syndrome (SARS) is a new human disease caused by an animal coronavirus that adapted to efficient human-to-human transmission. The disease first emerged in November 2002 in Guangdong Province, China and spread globally within months. The SARS coronavirus (SARS CoV) affects multiple organ systems with severe viral pneumonia as its main clinical manifestation but with diarrhea, lymphopenia, and mild liver dysfunction being common extra-pulmonary manifestations. Increasing age and the presence of underlying respiratory diseases worsens the prognosis. Unlike other respiratory viral infections, transmission of SARS was less frequent in the first 5 days of illness and correlated with low viral load in the upper respiratory tract at this stage of the illness. This fortuitous feature of the disease allowed the public health measures of case detection and patient isolation to interrupt virus transmission in the community and abort the SARS outbreak. Bats are a reservoir of a virus closely related to SARS CoV and this may be the likely precursor from which the human-adapted SARS CoV emerged. Small mammals such as ‘civet-cats’ (Paguma larvata) within live animal markets in southern China serve as amplifiers of infection and these markets were the likely interface where zoonotic transmission occurred. The viral spike protein is necessary and sufficient for inducing protective antibody responses and has been a key target in the development of candidate vaccines.
| S-EPMC7149687 | biostudies-literature
Project description:Sudden unexpected death in epilepsy (SUDEP) accounts for the deaths of 8-17% of patients with epilepsy. Although the mechanisms of SUDEP are unknown, one proposed mechanism is abnormal control of the heart by the autonomic nervous system (ANS). Our objective was to determine whether the broad changes in ictal heart rate experienced by mouse models of SUDEP are (1) due to the ANS and (2) contribute to seizure-induced death. Seizures were induced by electrical stimulation of the hippocampus of a mouse carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D; "D/+ mice"). Using standard autonomic pharmacology, the relative roles of the parasympathetic and sympathetic nervous systems on heart rate changes associated with seizures were determined. All induced seizures had pronounced ictal bradycardia and postictal tachycardia. Seizure susceptibility or severity were unchanged by the pharmacological agents. Administration of Atropine, a muscarinic antagonist, eliminated ictal bradycardia, while carbachol, a muscarinic agonist, had no effect on ictal bradycardia, but reduced postictal tachycardia. Sotalol, an adrenergic β-receptor antagonist, had no effect on ictal bradycardia, but did suppress postictal tachycardia. Isoproterenol, a β-receptor agonist, had no effect on either ictal bradycardia or postictal tachycardia. Administration of the α1-receptor antagonist prazosin increases the incidence of seizure-induced death in D/+ mice. Although postictal heart rate was lower for these fatal seizures in the presence of prazosin, rates were not as low as that recorded for carbachol treated mice, which all survived. Both ictal bradycardia and postictal tachycardia are manifestations of the ANS. Bradycardia is mediated by a maximal activation of the parasympathetic arm of the ANS, and tachycardia is mediated by parasympathetic inactivation and sympathetic activation. While the changes in heart rate during seizures are profound, suppression of postictal heart rate did not increase seizure mortality.
| S-EPMC8813980 | biostudies-literature
Project description:ObjectiveWe aimed to conduct an umbrella review to summarize the existing evidence regarding the prevalence of peri-ictal psychiatric manifestations (PM) in people with epilepsy (PWE) including pre-ictal, ictal, and postictal stages.MethodsDatabases were searched up to June 2023 for systematic reviews (SR) of observational studies that included patients with epilepsy peri-ictal PM. Data selection, data extraction, and risk of bias assessment (with the AMSTAR-2 instrument) were performed by two independent reviewers. We performed a narrative synthesis using previous guidelines. We used a self-developed decision table according to the GRADE system adapted for narrative outcomes if the certainty of outcomes was not determined by systematic review authors.ResultsFour SRs were included comprising 66 primary studies (n = 10 217). Three SRs evaluated one period (pre-ictal, ictal, and postictal), and one did not determine it. During the pre-ictal period, the more prevalent symptom was confusion, although with a low certainty (due to the heterogeneity and serious risk of bias). One systematic review that only included case reports evaluated the ictal period, finding mood/anxiety disorders, psychosis, and personality changes. The postictal period included the most PM (anxiety: 45.0% and depressive symptoms: 43.0%), with very low certainty, due to risk of bias, potential publication bias, heterogeneity, and failure to report the confidence intervals.SignificanceWith very low certainty, epileptic periods are characterized by a wide spectrum of PM, being postictal symptoms the most prevalent, predominantly anxiety, and depressive symptoms. Further understanding of these PM of epilepsy could improve the attention of the people with epilepsy.Plain language summaryIn this review of reviews, we summarize the frequency in which psychiatric manifestations occur in relation to an epileptic seizure. A total of 10 217 patients were reported in the reviews. The most common manifestations included symptoms of anxiety and depression, as well as changes in the normal behavior of the patient. These manifestations occurred most frequently right after the seizure finished.
| S-EPMC11296096 | biostudies-literature