Pharmacoresponse, hippocampal sclerosis and inflammation in mesial temporal lobe epilepsy: influence on metabolites measured by proton magnetic resonance spectroscopy

Author(s)

Luciana Ramalho Pimentel da Silva

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2018-02-16

Examining board members

Fernando Cendes; Ana Carolina Coan; Marcondes Cavalcante Franca Junior; Luiz Eduardo Betting; Carlos Eduardo Soares Silvado

• Advisor: Fernando Cendes

Abstract

Introduction: Mesial temporal lobe epilepsy (MTLE) is an heterogenous disease which usually present with a detectable underlying lesion by magnetic resonance imaging (MRI). The most frequent is hippocampal sclerosis (HS). Nearly 70% of TLE patients do not achieve seizure control with available antiepileptic drugs, i.e., they are pharmacoresistant and surgical candidates. However, MTLE profiles include MRI-negative and seizure free patients (SzF). The pharmacoresistance mechanisms are not fully understood. Metabolic and inflammatory processes have been implicated in focal seizures mechanisms and might have a role in pharmacoresistance. Proton-magnetic resonance spectroscopy (1H-MRS) is a in vivo non-invasive technique able to quantify markers of neuronal and inflammatory processes. The better understanding of the mechanisms involved in MTLE features such as pharmacoresponse, presence and side of HS and inflammation is important to develop therapy strategies targeting different MTLE profiles. Objectives: To evaluate the impact of typical features of mesial TLE (MTLE), such as pharmacoresistance and the presence and side of hippocampal sclerosis (HS) on n-acetylaspartate (NAA, a neuron marker), myo-inositol (mIns, a gliosis marker) and glutamate (Glx, the main excitatory neurotransmitter, often implicated in epileptogenesis and excitoxicity); to investigate the relationship between inflammation and pharmacoresistance and to analyze metabolic predictors of pharmacoresponse. Methods: It were acquired data on: 1H-MRS (total NAA, mIns and Glx ratios to total creatine [Cr] using the LCmodel), automatic hippocampal volumetry (using Freesurfer) and peripheral inflammatory mediators (tumor necrosis factor alpha [TNF-?], interleukin 1? [IL1?] and IL6 using multiplex assay. Data were analyzed according to: 1) pharmacoresponse, divided into pharmacoresistant (AED-R), seizure-free (SzF) and controls; 2) presence and side of HS, divided into MRI-negative, right- and left-HS; or 3) the combination of both. Results: The data showed that pharmacoresponse and HS independently affect the NAA and mIns values. However, the results suggest that left-HS presents with bilateral and more widespread alterations than right-HS and MRI negative MTLE patients, thus reflecting structural and functional damage to the neuroglial complex. We found no difference in the inflammatory mediators levels studied here and the pharmacoresponse. The NAA/Cr abnormality predicted AED-R patients with 72.3% accuracy overall. The presence of HS was confirmed on the histopathological analysis of 13 tissue samples from patients operated on during the study. Conclusions: The findings suggest structural and functional damage to the neuroglial complex. It was demonstrated that the pharmacoresistance and side of HS independently affect the metabolic quantification of neuronal-glial markers. Moreover, there is a spectrum of metabolic changes across different subsets of MTLE patients (AU)

• FAPESP's process: 13/21056-4 - Proton MRS evaluation of inflammatory and drug refractoriness biomarkers in temporal lobe epilepsy.
• Grantee: Luciana Ramalho Pimentel da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate