NMR-based metabolomics in pediatric drug resistant epilepsy \u2013 preliminary results

Łukasz Boguszewicz,Mateusz Ciszek,Maria Sokół,Ewa Jamroz,Marek Kijonka,Ewa Emich-Widera,Tomasz Banasik,Agnieszka Skorupa

doi:10.1038/s41598-019-51337-z

Abstract

Epilepsy in children is the most frequent, heterogeneous and difficult to classify chronic neurologic condition with the etiology found in 35–40% of patients. Our aim is to detect the metabolic differences between the epileptic children and the children with no neurological abnormalities in order to define the metabolic background for therapy monitoring. The studied group included 28 epilepsy patients (median age 12 months) examined with a diagnostic protocol including EEG, videoEEG, 24-hour-EEG, tests for inborn errors of metabolism, chromosomal analysis and molecular study. The reference group consisted of 20 patients (median age 20 months) with no neurological symptoms, no development delay nor chronic diseases. 1H-NMR serum spectra were acquired on 400 MHz spectrometer and analyzed using multivariate and univariate approach with the application of correction for age variation. The epilepsy group was characterized by increased levels of serum N-acetyl-glycoproteins, lactate, creatine, glycine and lipids, whereas the levels of citrate were decreased as compared to the reference group. Choline, lactate, formate and dimethylsulfone were significantly correlated with age. NMR-based metabolomics could provide information on the dynamic metabolic processes in drug-resistant epilepsy yielding not only disease-specific biomarkers but also profound insights into the disease course, treatment effects or drug toxicity.

Highlights

Based on the official International League against Epilepsy (ILAE) report, Fisher et al proposed the following clinical definition of epilepsy embracing occurrence of any of the following conditions: - at least two unprovoked seizures which occurred >24 hours apart; - one unprovoked seizure together with a probability of further seizures similar to the general recurrence risk after two unprovoked seizures, taking place over the 10 years; - diagnosis of an epilepsy syndrome[1]
The directions of the largest variation in the four types of the acquired NMR data was visualized using principal component analysis (PCA) method with the best separation between the Epilepsy Group (EG) and Reference Group (RG) groups observed in the CPMG spectra
The present study shows that the serum levels of NAG, creatine, lipids, glycine and lactate are increased in children with drug-resistant epilepsy, these metabolites might be considered as the systemic biomarkers of a diagnostic utility

Summary

Introduction

Based on the official International League against Epilepsy (ILAE) report, Fisher et al proposed the following clinical definition of epilepsy embracing occurrence of any of the following conditions: - at least two unprovoked seizures which occurred >24 hours apart; - one unprovoked (or reflex) seizure together with a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, taking place over the 10 years; - diagnosis of an epilepsy syndrome[1]. As reveals from the Ramos-Lizana et al study[3] the worse prognosis is expected in children below 12 months old suffering from symptomatic epilepsy accompanied with pathological neuroimaging study, or with frequent seizures before diagnosis of drug-resistant epilepsy. Another strong factors indicating poor prognosis are reported by Sillanpaa & Schmidt[9] and include seizures with weekly frequency during the first year of treatment or prior to treatment as well as diagnosis of remote symptomatic epilepsy. The latter, though valuable, comprise rather small and heterogeneous populations[14,15]

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