Epilepsy Currents最新文献

People with epilepsy have a markedly increased risk of premature mortality, with sudden unexpected death in epilepsy (SUDEP) accounting for approximately half of epilepsy-related deaths. Although rarely witnessed, converging evidence indicates that SUDEP arises from seizure-triggered cardiorespiratory failure mediated by central and peripheral mechanisms. In this article, we explore mechanisms of SUDEP related to respiratory, cardiac, and autonomic control of vital functions. Specifically, we examine how seizure propagation to a discrete amygdala subregion can induce profound ictal and postictal apnea; how complementary genetic and animal studies reveal that ion channelopathies affecting genes expressed in both brain and heart produce intrinsic neuronal and cardiac electrical dysfunction; and how emerging evidence implicates stress physiology and hypothalamic-pituitary-adrenal axis dysfunction as underrecognized contributors to SUDEP risk. Together, these findings support a multifactorial model in which respiratory suppression, cardiac vulnerability, autonomic dysregulation, and stress-responsive mechanisms converge to produce fatal outcomes.

Sudden unexpected death in epilepsy (SUDEP) is the most catastrophic complication associated with epileptic seizures. Despite its devastating impact, the mechanistic underpinnings of SUDEP remain poorly understood, limiting the development of effective preventive strategies. Animal models have proven indispensable in understanding the complex pathophysiology of SUDEP, offering controlled systems to dissect potential causes of these fatal events. This review provides a comprehensive overview of the current landscape of SUDEP animal models, with an emphasis on key experimental variables that impact SUDEP outcome in animal studies. In particular, this review focuses on how the animals' genetic background, age, sex, vigilance state, and time of day influence their phenotypic variability. We also report the major discrepancies in terminal seizure characteristics between mice and humans and highlight the necessity to segregate "anti-SUDEP" effects from potential "antiseizure" effects. From a regulatory and animal welfare perspective, we discuss the challenges of studying SUDEP as an endpoint and outline the critical steps to implement the preclinical SUDEP common data element, thereby promoting consistency, reproducibility, and interoperability across preclinical studies. By synthesizing insights across critical experimental variables and remaining challenges in SUDEP preclinical studies, this review aims to promote rigorous experimental design in animal SUDEP studies, with the long-term goal of facilitating translational insights into human SUDEP prevention.

Drug-induced liver injury remains a major concern in the pharmacological management of epilepsy. Antiseizure medication (ASM)-related liver injury has multiple phenotypes, and in the majority of cases it is "idiosyncratic," involving hypersensitivity reactions. Awareness of drug- and patient-related risk factors can help direct treatment selection, monitoring, and ASM discontinuation, when necessary. This article examines the typical patterns of ASM-induced liver injury, from mild elevations of hepatic enzymes to life-threatening conditions. We also discuss risk factors, means for preventing liver injury in people with epilepsy treated with ASMs, and emerging biomarkers.

Objective: Autoimmune encephalitis is a cause of brain inflammation characterized by auto-antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto-antibodies to leucine-rich glioma-inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto-antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen (HLA) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry-matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual.

Methods: To investigate this, we studied 42 patients with LGI1-antibody encephalitis (LGI1-Ab-E) and 27 familial/environmentally matched controls and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome.

Results: We observed that LGI1-Ab-E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1-Ab-E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short-chain fatty acids (SCFAs) in LGI1-Ab-E patients.

Significance: Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1-Ab-E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.