Respiratory Dysfunction in Epileptic Encephalopathies: Insights and Challenges

Cureus, Год журнала: 2023, Номер unknown

Опубликована: Сен. 29, 2023

Epileptic encephalopathies constitute a group of severe epileptic disorders characterized by intractable seizures and cognitive regression. Beyond the hallmark neurological manifestations, these frequently exhibit associated respiratory dysfunction, which is increasingly recognized as critical aspect their pathophysiology. Respiratory abnormalities in encompass spectrum ranging from subtle alterations breathing patterns to life-threatening events such apneas hypoventilation. These disturbances often occur during seizures, interictal period, or even persist chronically, leading significant morbidity mortality. We explore varied clinical presentations implications on patient outcomes, emphasizing need for heightened awareness among clinicians. This review unravels intricate mechanisms linking epilepsy dysfunction. GABAergic glutamatergic imbalances, central centers, abnormal autonomic control are key factors contributing patients. elucidate neurobiological intricacies that underlie processes relevance therapeutic interventions. Accurate diagnosis dysfunction hindered its diverse phenotypes absence routine screening protocols. scrutinize diagnostic hurdles, highlighting necessity comprehensive assessments managing Timely recognition issues may guide treatment decisions mitigate complications. Management complex necessitates multidisciplinary approach. various modalities, including antiepileptic drugs (AEDs), ventilatory support, novel interventions like neuromodulation techniques. The emphasizes individualized nature strategies tailored each patient's specific needs. In conclusion, this narrative offers overview encephalopathies, shedding light importance, underlying mechanisms, challenges, considerations. By addressing insights we hope inspire further research innovation enhance care outcomes patients with encephalopathies.

Язык: Английский

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Response to Singh et al. 2023: It is premature for a unified hypothesis of sudden unexpected death in epilepsy: A great amount of research is still needed to understand the multisystem cascade

Epilepsia, Год журнала: 2023, Номер 64(9), С. 2256 - 2259

Опубликована: Июнь 30, 2023

In response to the comments by Singh and colleagues about our recent paper proposing a unified hypothesis of SUDEP, we definitely agree that more research is needed. This should include studies in other models, including Dravet mice, emphasized et al. However, strongly believe timely, because it based on continuing progress SUDEP-related serotonin (5-HT) adenosine as well neuroanatomical findings.We propose testing 5-HT enhancing drugs, neurotoxicity blocking such N-methyl-D-aspartate (NMDA) antagonists periaqueductal gray (PAG) electrical stimulation for SUDEP prevention. There are FDA-approved drugs enhance action 5-HT, fluoxetine fenfluramine, which approved syndrome. NMDA antagonists, memantine ketamine, also disorders. PAG stimulation, proposed activate suffocation alarm, treat conditions known respiration. Experiments using these methods currently being carried out animal studies. If approaches validated treatments could be evaluated relatively quickly patients with epilepsy (PWE) who exhibit biomarker high risk, peri-ictal respiratory abnormalities. An example study ongoing clinical trial selective reuptake inhibitor PWE. Although, gene-based therapies may ultimately become choice prevent al suggested, one or temporizing before can available. Establishing genetic would require extensive time each abnormalities associated too many PWE likely die meantime.The help reduce incidence sooner, urgently

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 18, 2024

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

eLife, Год журнала: 2024, Номер 13

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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Modulation Of SUDEP By Central Serotonergic Cooperating with Noradrenergic Circuits: A Synergistic-Dependent Manner

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 23, 2024

Abstract Sudden unexpected death in epilepsy (SUDEP) is the leading cause of refractory patients. Despite previous accumulating evidence has shown that seizure-induced respiratory arrest (S-IRA) may play main contributor to SUDEP as an initiating event preeminent mortality, specific underlying mechanism action remains unclear. Based on our work, serotonin (5-HT) signaling dorsal raphe nucleus (DRN) strongly implicated S-IRA animal models, including DBA/1 mice, meanwhile, norepinephrine (NE) neurons locus coeruleus (LC) also plays a vital role regulating function its own. Superficially, monoaminergic neuron, important neurotransmitters central nervous system, have similar modes maintenance system balance, and each them regulatory effect SUDEP. However, it be investigated whether neuron family (NE 5-HT) are related SUDEP, what even more curious two intrinsically linked. Thus, we hypothesize neural noradrenergic serotonergic circuits modulating synergistic-dependent manner, this endeavor will culminate significant breakthrough elucidating precise In study, use chemogenetics, optogenetics, calcium signal recording, bidirectional tracing explore internal DR-LC occurrence by specifically injecting 5-HT2AR antagonist Ketanserin (KET) and/or NEα-1R Prazosin into pre-Bötzinger complex (PBC), was finally elucidate DR-LC-PBC network can effectively reduce incidence SIRA. We firstly proposed powerful target for exploring reduction which great clinical translation potential.

Язык: Английский

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