Metabolomics of cerebrospinal fluid reveals prognostic biomarkers in pediatric status epilepticus

Abstract

AimsStatus epilepticus (SE) is the most common neurological emergency in pediatric patients. This study aimed to screen for prognostic biomarkers of SE in the cerebrospinal fluid (CSF) using metabolomics.MethodsUltra‐performance liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry (UPLC‐QTOF‐MS) was conducted to identify prognostic biomarkers in CSF metabolomics by comparing the poor outcome group (N = 13) with the good outcome group (N = 15) of children with SE. Differentially expressed metabolites were identified using Mann–Whitney U test corrected by Benjamini‐Hochberg and partial least squares discriminant analysis (PLS‐DA).ResultsThe PLS‐DA model identified and validated significant metabolic differences between the poor and good outcome groups of children with SE (PLS‐DA with R2Y = 0.992 and Q2 = 0.798). A total of 49 prognosis‐related metabolites were identified. Of these metabolites, 20 including glutamyl‐glutamine, 3‐iodothyronamine, and L‐fucose had an area under the curve (AUC) ≥ 80% in prognostic prediction of SE. The logistic regression model combining glutamyl‐glutamine and 3‐iodothyronamine produced an AUC value of 0.976, with a sensitivity of 0.863 and specificity of 0.956. Pathway analysis revealed that dysregulation of the citrate cycle (TCA) and arginine biosynthesis may contribute to poor SE prognosis.ConclusionsThis study highlighted the prognosis‐related metabolomic disturbances in the CSF of children with SE and identified potential prognostic biomarkers. A prognostic prediction model combining glutamyl‐glutamine and 3‐iodothyronamine with high predictive value was established.

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

“…17 This metabolism was found altered in pediatric SE and associated with poor outcomes. 10 The most prevalent dipeptide in the brain, NAAG, plays a crucial role in modulating glutamatergic synapses. NAAG can regulate excessive glutamate signaling by activating presynaptic metabotropic glutamate receptor 3 (mGluR3) and providing postsynaptic neurons with a negative feedback mechanism to inhibit excessive glutamate signaling.…”

“…7,8 Numerous metabolomic studies involving patients with epilepsy, animal models of epilepsy, and SE have been conducted in recent years. 9,10 The primary types of metabolites that change in patients with epilepsy and epilepsy models are amino acids and organic acids. 9 Specifically, elevated levels of glutamate and lactate, [11][12][13] as well as variations in purine levels, 11,14,15 have been observed in patients with epilepsy and animals with seizures compared to controls.…”

“…16 In addition, a recent study conducted in pediatric SE revealed prognosisrelated metabolomic disturbances in the cerebrospinal fluid (CSF) and suggested the interest in combining glutamylglutamine and 3-iodothyronamine to predict outcomes. 10 Analyses of metabolic pathways have indicated that affected metabolisms varied among models. 9 However, all patients and epileptic models exhibited abnormal alanine, aspartate, and glutamate metabolism.…”

“…9 However, all patients and epileptic models exhibited abnormal alanine, aspartate, and glutamate metabolism. 9,10 The recent study conducted in a cohort of 28 children with SE emphasized the predictive prognostic significance of alanine, aspartate, and glutamate metabolism. 10 Seizures can lead to metabolic alterations.…”

“…9,10 The recent study conducted in a cohort of 28 children with SE emphasized the predictive prognostic significance of alanine, aspartate, and glutamate metabolism. 10 Seizures can lead to metabolic alterations. 17 For instance, when the availability of glucose is limited, medium-chain fatty acids, lactate, and ketone bodies may be overproduced to meet the needs of neuronal demands.…”