Metabolomic changes in adults with status epilepticus: A human case–control study

Abstract

ObjectiveStatus epilepticus (SE) is a life‐threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long‐term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury.MethodsWe conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high‐resolution mass spectrometry (LC‐HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways.ResultsWe identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N‐acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N‐methyl‐d‐aspartate (NMDA) receptor agonist with pro‐inflammatory properties.SignificanceThis study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.

Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug‐resistant epilepsy

“…However, it is clear that the blood metabolome of someone experiencing status epilepticus is significantly different from someone with control epilepsy patients. 51 Future work need to validate identified biomarkers externally in an independent cohort. It will also be important to explore the applicability of the NMR blood test in identifying other AE subtypes, seronegative AE patients and whether the AE metabolomic signature might be used to predict the persistence of AE.…”

Role of inflammatory cytokine in mediating the effect of plasma lipidome on epilepsy: a mediation Mendelian randomization study

“…Subsequent animal research demonstrated that subchronic administration of palmitoylethanolamide markedly diminished seizure intensity and fostered neuroprotection, which can also modulate plasma and hippocampal endocannabinoid and eicosanoid levels in systemic KA-injected mice ( 12 ). An investigation into metabolomic alterations in adult status epilepticus (SE) patients showed that metabolic dysregulation primarily impacted amino acid metabolism, pyrimidine metabolism and lipid homeostasis ( 13 ). The existing association between epilepsy and plasma liposomes primarily arises from observational studies characterized by limited sample sizes and numerous confounding variables.…”