Seizure‐related death exhibits a circadian rhythm independent of seizure timing or sleep in a mouse model of Dravet syndrome

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Июнь 2, 2025

Abstract Sudden unexpected death in epilepsy (SUDEP) is the most extreme consequence of epilepsy. SUDEP typically occurs at night. Because humans sleep night, these nighttime deaths are often attributed to seizures arising from sleep. Nocturnal mice also experience more seizure‐associated during nighttime. This could represent timing that under circadian control. To examine this, male and female Scn1a R1407X/+ mice, a model epileptic encephalopathy Dravet syndrome, which patients spontaneous result death, were housed constant darkness seizure associated was assessed. We found sudden following persists peaks subjective rhythm independent potentially fatal frequently occurred while awake. Potentially resulted prolonged unconsciousness, exhibited peaking These findings provide support for regulation, sleep, risk death. Nighttime may increase via multiple mechanisms, as evident by peak profoundly impaired consciousness image Key points epilepsy, or SUDEP, devastating outcome intractable Converging lines evidence indicate there time‐of‐day preference with occurring Several animal models syndrome (DS), including one employed our study, recapitulate key features DS patients, high rate seizure‐related Here, we removed light/dark photocycles, housing animals darkness, identify preponderance suggesting this regulation. further carefully characterize vs . non‐fatal prove be useful biomarkers predict become fatal.

Язык: Английский

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Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

Epilepsia, Год журнала: 2023, Номер 65(1), С. 9 - 25

Опубликована: Ноя. 2, 2023

Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of sudden and unexpected death in epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting limitations these intrinsic difficulties investigating SUDEP. The interpretation preclinical data their translation diagnostic therapeutic developments patients thus require a high level confidence relevance model human situation. Preclinical SUDEP heterogeneous include rodent nonrodent species. A critical aspect is whether animals isolated seizures exclusively induced by trigger, such as where elicited electrical stimulation, pharmacological intervention, or DBA mouse strains, they suffer from with spontaneous seizures, without SUDEP, either nongenetic etiology genetically based developmental epileptic encephalopathies. All advantages potential disadvantages, but it important be aware interpret appropriately translational perspective. majority genetic basis, whereas cases basis represent only small proportion total number. In almost all models, cardiorespiratory arrest occurs during course seizure, contrary that observed at time death, raising issue we studying periseizure death. However, some impossible avoid can part dependent on features which may difficult model. Several tools available address certain gaps pathophysiology, used further validate current models.

Язык: Английский

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Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures

Epilepsia, Год журнала: 2023, Номер 64(9), С. 2373 - 2384

Опубликована: Июнь 24, 2023

Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In mouse model of seizure-induced death, increased interictal variability was reported mice that later died arrest after GCS. We studied patients as predictive tool severity postictal hypoxemia, potential biomarker SUDEP risk. then explored the relationship between and central CO

Язык: Английский

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Divergent Causes and Convergent Mechanisms of SUDEP

Annals of Neurology, Год журнала: 2023, Номер 94(5), С. 809 - 811

Опубликована: Сен. 16, 2023

Язык: Английский

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Wearable detection of tonic seizures in childhood epilepsy: An exploratory cohort study

Epilepsia, Год журнала: 2023, Номер 64(11), С. 3013 - 3024

Опубликована: Авг. 21, 2023

To investigate the performance of a multimodal wearable device for offline detection tonic seizures (TS) in pediatric childhood epilepsy cohort, with focus on patients Lennox-Gastaut syndrome.Parallel prolonged video-electroencephalography (EEG), Plug 'n Patch system, using Sensor Dot and replaceable electrode adhesives, was used to detect TS. Multiple biosignals were recorded: behind-the-ear EEG, surface electromyography, electrocardiography, accelerometer/gyroscope. Biosignals annotated blindly by neurologist. Seizure characteristics described, assessed sensitivity, positive predictive value (PPV), F1 score, false alarm rate (FAR) per hour. Performance compared seizure diaries kept caretaker.Ninety-nine TS detected 13 patients. Seven (54%) had syndrome six (46%) other forms (developmental) epileptic encephalopathies or drug-resistant epilepsy. All but one patient intellectual disability. Overall sensitivity 41%, PPV 9%, an score 14%, median FAR hour 0.75. increased 66% nightly lasting at least 10 s (sensitivity 66%, 66%) 71% 20 62%, 82%). For these there no alarms Sensitivity reached maximum 52% (≥20 s) seizures, even though caretakers slept same room.We showed that it is feasible use multiple adhesive sites children manual outperformed diaries. The recognition seizure-specific signatures modalities can help development automated algorithms.

Язык: Английский

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Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

Опубликована: Июнь 21, 2024

Developmental and Epileptic Encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures exacerbated disruptions to excitatory/inhibitory balance in the brain, are commonly caused mutations ion channels. Disruption of, or variants in, FGF13 were implicated as causal for set DEEs, but underlying mechanisms clouded because is expressed both excitatory inhibitory neurons, undergoes extensive alternative splicing producing multiple isoforms with distinct functions, overall roles neurons incompletely cataloged. To overcome these challenges, we generated novel cell type-specific conditional knockout mice. Interneuron-targeted deletion Fgf13 led perinatal mortality associated impaired hippocampal inhibitory/excitatory while neuron-targeted no detectable survival deficits. While best studied voltage-gated sodium channel (Na v ) regulator, observed effect ablation interneurons on Na s rather marked reduction K + currents. Re-expressing different splice could partially rescue deficits interneuron excitability restore current amplitude. These results enhance our understanding molecular that drive pathogenesis Fgf13- related expand functions neuron subsets.

Язык: Английский

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Disruption of adenosine metabolism increases risk of seizure‐induced death despite decreased seizure severity

Epilepsia, Год журнала: 2024, Номер 65(9), С. 2798 - 2811

Опубликована: Июль 17, 2024

Abstract Objective Respiratory arrest plays an important role in sudden unexpected death epilepsy (SUDEP). Adenosine is of interest SUDEP pathophysiology due to its influence on seizures and breathing. The objective this investigation was examine the adenosine seizure severity, seizure‐induced respiratory disruption, using mouse models. Understanding adenosinergic contributions cessation may provide insights into how can be prevented while avoiding increased severity. Methods Our approach examine: (1) severity after 15 mA electroshock during repeated pentylenetetrazol (PTZ) administration wild‐type mice ( Adk +/+ ) transgenic with reduced metabolism +/− ); (2) postictal hypercapnic ventilatory response (HCVR) (the HCVR could not examined their high mortality rate); (3) effects drugs following maximal (MES). Results were more vulnerable PTZ Despite mortality, had comparable model model. Breathing suppressed by mice. Pharmacological inhibition decreased MES but did increase mortality. A 1 selective nonselective receptor antagonists MES. Significance has opposing death. On one hand, our data highlight importance suppression. other indicate that excessive extracellular signaling risk arrest.

Язык: Английский

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Sudden unexpected death in epilepsy: respiratory vs. cardiac contributions

Cardiovascular Research, Год журнала: 2024, Номер unknown

Опубликована: Авг. 7, 2024

Abstract Sudden unexpected death in epilepsy (SUDEP) poses a significant risk to life expectancy for individuals with epilepsy. Mechanistic insight, while incomplete, has advanced through clinical observational studies and animal models. Yet we lack preventative therapies, which will depend on understanding SUDEP mechanisms. Recurrent convulsive seizures are the major factor. Cardiorespiratory dysfunction precedes SUDEP, but whether cardiac arrhythmias proximate culprits remains be determined. Here, highlight recent data from mouse models that provide increasing support respiratory depression decreasing evidence tachyarrhythmia-induced SUDEP. Further, review genetic chemoconvulsant have enabled deeper how initiated central nervous system propagate autonomic drive seizure-induced subsequent rather than supporting arrhythmia cause. Ongoing research continue identify predictive biomarkers, improve models, translate basic into precision medicine approaches. Identifying brainstem circuits vulnerable apnoea enable therapeutic interventions enhance quality of

Язык: Английский

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Challenges and future directions of SUDEP models

Lab Animal, Год журнала: 2024, Номер 53(9), С. 226 - 243

Опубликована: Авг. 26, 2024

Язык: Английский

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The future treatment of status epilepticus

Epilepsy & Behavior, Год журнала: 2024, Номер 161, С. 110146 - 110146

Опубликована: Ноя. 13, 2024

Язык: Английский

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