Superficial and deep white matter diffusion abnormalities in focal epilepsies.

OBJECTIVE: This study was undertaken to evaluate superficial-white matter (WM) and deep-WM magnetic resonance imaging diffusion tensor imaging (DTI) metrics and identify distinctive patterns of microstructural abnormalities in focal epilepsies of diverse etiology, localization, and response to antiseizure medication (ASM). METHODS: We examined DTI data for 113 healthy controls and 113 patients with focal epilepsies: 51 patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) refractory to ASM, 27 with pharmacoresponsive TLE-HS, 15 with temporal lobe focal cortical dysplasia (FCD), and 20 with frontal lobe FCD. To assess WM microstructure, we used a multicontrast multiatlas parcellation of DTI. We evaluated fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), and assessed within-group differences ipsilateral and contralateral to the epileptogenic lesion, as well as between-group differences, in regions of interest (ROIs). RESULTS: The TLE-HS groups presented more widespread superficial- and deep-WM diffusion abnormalities than both FCD groups. Concerning superficial WM, TLE-HS groups showed multilobar ipsilateral and contralateral abnormalities, with less extensive distribution in pharmacoresponsive patients. Both the refractory TLE-HS and pharmacoresponsive TLE-HS groups also presented pronounced changes in ipsilateral frontotemporal ROIs (decreased FA and increased MD, RD, and AD). Conversely, FCD patients showed diffusion changes almost exclusively adjacent to epileptogenic areas. SIGNIFICANCE: Our findings add further evidence of widespread abnormalities in WM diffusion metrics in patients with TLE-HS compared to other focal epilepsies. Notably, superficial-WM microstructural damage in patients with FCD is more restricted around the epileptogenic lesion, whereas TLE-HS groups showed diffuse WM damage with ipsilateral frontotemporal predominance. These findings suggest the potential of superficial-WM analysis for better understanding the biological mechanisms of focal epilepsies, and identifying dysfunctional networks and their relationship with the clinical-pathological phenotype. In addition, lobar superficial-WM abnormalities may aid in the diagnosis of subtle FCDs.

Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology.

OBJECTIVE: Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS: We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS: The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE: This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.

Transsylvian amygdalohippocampectomy for mesial temporal lobe epilepsy: Comparison of three different approaches.

OBJECTIVE: This study's objective was to compare the transinsular (TI-AH), transuncus (TU-AH), and temporopolar (TP-AH) amygdalohippocampectomy approaches regarding seizure control, temporal stem (TS) damage, and neurocognitive decline. METHODS: We included 114 consecutive patients with unilateral hippocampal sclerosis (HS) who underwent TI-AH, TU-AH, or TP-AH between 2002 and 2017. We evaluated seizure control using Engel classification. We used diffusion tensor imaging and postoperative Humphrey perimetry to assess the damage of the TS. We also performed pre- and postoperative memory performance and intelligence quotient (IQ). RESULTS: There were no significant differences in the proportion of patients free of disabling seizures (Engel IA+IB) among the three surgical approaches in the survival analysis. However, more patients were free of disabling seizures (Engel IA+IB) at 2 years of postsurgical follow-up with TP-AH (69.5%) and TI-AH (76.7%) as compared to the TU-AH (43.5%) approach (p = .03). The number of fibers of the inferior fronto-occipital fasciculus postoperatively was reduced in the TI-AH group compared with the TU-AH and TP-AH groups (p = .001). The rate of visual field defects was significantly higher with TI-AH (14/19, 74%) in comparison to the TU-AH (5/15, 33%) and TP-AH (13/40, 32.5%) approaches (p = .008). Finally, there was a significant postoperative decline in verbal memory in left-sided surgeries (p = .019) and delayed recall for both sides (p < .001) regardless of the surgical approach. However, TP-AH was the only group that showed a significant improvement in visual memory (p < .001) and IQ (p < .001) for both right- and left-sided surgeries. SIGNIFICANCE: The TP-AH group had better short-term seizure control than TU-AH, a lower rate of visual field defects than TI-AH, and improved visual memory and IQ compared to the other groups. Our findings suggest that TP-AH is a better surgical approach for temporal lobe epilepsy with HS than TI-AH and TU-AH.

Interactions between in vivo neuronal-glial markers, side of hippocampal sclerosis, and pharmacoresponse in temporal lobe epilepsy.

OBJECTIVE: To evaluate the interactions of metabolic neuronal-glial changes with the presence and hemispheric-side of hippocampal sclerosis (HS) and its potential role in predicting pharmacoresistance in temporal lobe epilepsy (TLE). METHODS: We included structural magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1 H-MRS) metabolic data for 91 patients with unilateral TLE and 50 healthy controls. We measured the values of total N-acetyl aspartate/total creatine (tNAA/tCr), glutamate/tCr (Glu/tCr), and myo-inositol/tCr (mIns/tCr). To assess the influence of the pharmacoresponse and hemispheric-side of HS on metabolic data, the relationship between clinical and MRI data, and the predictive value of NAA/Cr, we used analysis of variance/covariance and built a logistic regression model. We used bootstrap simulations to evaluate reproducibility. RESULTS: Bilateral tNAA/tCr reduction was associated with pharmacoresistance and with left HS, a decrease of Glu/tCr ipsilateral to the seizure focus was associated with pharmacoresistance, and ipsilateral mIns/tCr increase was related to pharmacoresistance and the presence of left HS. The logistic regression model containing clinical and 1 H-MRS data discriminated pharmacoresistance (area under the curve [AUC] = 0.78). However, the reduction of tNAA/tCr was the main predictor, with the odds 2.48 greater for pharmacoresistance. SIGNIFICANCE: Our study revealed a spectrum of neuronal-glial changes in TLE, which was associated with pharmacoresistance, being more severe in left-sided HS and less severe in MRI-negative TLE. These noninvasive, in vivo biomarkers provide valuable additional information about the interhemispheric differences in metabolic dysfunction, seizure burden, and HS, and may help to predict pharmacoresistance.

MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy.

Epilepsy is misdiagnosed in up to 25% of patients, leading to serious and long-lasting consequences. Recently, circulating microRNAs have emerged as potential biomarkers in a number of clinical scenarios. The purpose of this study was to identify and to validate circulating microRNAs that could be used as biomarkers in the diagnosis of epilepsy. Quantitative real-time PCR was used to measure plasma levels of three candidate microRNAs in two phases of study: an initial discovery phase with 14 patients with mesial temporal lobe epilepsy (MTLE), 13 with focal cortical dysplasia (FCD) and 16 controls; and a validation cohort constituted of an independent cohort of 65 patients with MTLE and 83 controls. We found hsa-miR-134 downregulated in patients with MTLE (p = 0.018) but not in patients with FCD, when compared to controls. Furthermore, hsa-miR-134 expression could be used to discriminate MTLE patients with an area under the curve (AUC) of 0.75. To further assess the robustness of hsa-miR-134 as a biomarker for MTLE, we studied an independent cohort of 65 patients with MTLE, 27 of whom MTLE patients were responsive to pharmacotherapy, and 38 patients were pharmacoresistant and 83 controls. We confirmed that hsa-miR-134 was significantly downregulated in the plasma of patients with MTLE when compared with controls (p < 0.001). In addition, hsa-miR-134 identified patients with MTLE regardless of their response to pharmacotherapy or the presence of MRI signs of hippocampal sclerosis. We revealed that decreased expression of hsa-miR-134 could be a potential non-invasive biomarker to support the diagnosis of patients with MTLE.

Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy.

We previously described - studying transcriptional signatures of hippocampal CA3 explants - that febrile (FS) and afebrile (NFS) forms of refractory mesial temporal lobe epilepsy constitute two distinct genomic phenotypes. That network analysis was based on a limited number (hundreds) of differentially expressed genes (DE networks) among a large set of valid transcripts (close to two tens of thousands). Here we developed a methodology for complex network visualization (3D) and analysis that allows the categorization of network nodes according to distinct hierarchical levels of gene-gene connections (node degree) and of interconnection between node neighbors (concentric node degree). Hubs are highly connected nodes, VIPs have low node degree but connect only with hubs, and high-hubs have VIP status and high overall number of connections. Studying the whole set of CA3 valid transcripts we: i) obtained complete transcriptional networks (CO) for FS and NFS phenotypic groups; ii) examined how CO and DE networks are related; iii) characterized genomic and molecular mechanisms underlying FS and NFS phenotypes, identifying potential novel targets for therapeutic interventions. We found that: i) DE hubs and VIPs are evenly distributed inside the CO networks; ii) most DE hubs and VIPs are related to synaptic transmission and neuronal excitability whereas most CO hubs, VIPs and high hubs are related to neuronal differentiation, homeostasis and neuroprotection, indicating compensatory mechanisms. Complex network visualization and analysis is a useful tool for systems biology approaches to multifactorial diseases. Network centrality observed for hubs, VIPs and high hubs of CO networks, is consistent with the network disease model, where a group of nodes whose perturbation leads to a disease phenotype occupies a central position in the network. Conceivably, the chance for exerting therapeutic effects through the modulation of particular genes will be higher if these genes are highly interconnected in transcriptional networks.