Experimental and clinical evidence have demonstrated aberrant expression of cytokines/chemokines and their receptors in patients with hippocampal sclerosis (HS) and focal cortical dysplasia (FCD). However, there is limited information regarding the modulation of cytokine/chemokine-regulatory networks, suggesting contribution of miRNAs and downstream transcription factors/receptors in these pathologies. Hence, we studied the levels of multiple inflammatory mediators (IL1β, IL1Ra, IL6, IL10, CCL3, CCL4, TNFα and VEGF) along with transcriptional changes of nine related miRNAs and mRNA levels of downstream effectors of significantly altered cytokines/chemokines in brain tissues obtained from patients with HS (n = 26) and FCD (n = 26). Up regulation of IL1β, IL6, CCL3, CCL4, STAT-3, C-JUN and CCR5, and down regulation of IL 10 were observed in both HS and FCD cases (p < 0.05). CCR5 was significantly up regulated in FCD as compared to HS (p < 0.001). Both, HS and FCD presented decreased miR-223-3p, miR-21-5p, miR-204-5p and let-7a-5p and increased miR-155-5p expression (p < 0.05). As compared to HS, miR-204-5p (upstream to CCR5 and IL1β) and miR-195-5p (upstream to CCL4) were significantly decreased in FCD patients (p < 0.01). Our results suggest differential alteration of cytokine/chemokine regulatory networks in HS and FCD and provide a rationale for developing pathology specific therapy.

Hippocampal sclerosis (HS), the most common subset of drug-resistant epilepsy (DRE), is associated with large-scale network abnormalities, even under resting state. We studied the excitatory postsynaptic currents (EPSCs) recorded from pyramidal neurons in resected samples under resting conditions from the hippocampal and anterior temporal lobe (ATL) obtained from patients with HS (n = 14) undergoing resective surgery. We observed higher frequency and amplitude of spontaneous EPSCs in both the samples compared to non-seizure control samples. Application of tetrodotoxin (TTX) reduced the frequency of spontaneous EPSCs by 49.6 ± 4.3% and 61.8 ± 6.2% in the hippocampal and ATL samples, respectively. The magnitude of reduction caused by TTX with respect to non-seizure controls was significantly higher in the ATL samples than in the hippocampal samples. The magnitude of the change in the expression of the NR2A subunit of the NMDA receptors also varied in these two regions. Thus, the mechanism of hyperexcitabilty mediated by glutamatergic network reorganization in the hippocampal region is different from that in the ATL region of patients with HS, suggesting two independent resting-state networks at the cellular level. Taken together, these findings will improve the understanding of the broadly distributed resting-state networks in HS.

Despite great advances in our understanding of the process of epileptogenesis we are yet to develop reliable biomarkers that have the potential to accurately localize the epileptogenic zone (EZ), and to resolve the issue of heterogeneity in epilepsy surgery outcome. Inability to precisely localize the epileptogenic foci is one of the reason why more than 30% of these DRE patients are not benefited. Molecular and cellular biomarkers in combination with imaging and electrical investigations will provide a more specific platform for defining epileptogenic zone. Potential molecular biomarkers of epileptogenesis including markers of inflammation, synaptic alterations and neurodegeneration may also have the potential for localizing EZ. At molecular level components derived from epileptogenic tissues, such as metabolites, proteins, mRNAs and miRNAs that are significantly altered can serve as biomarkers and can be clubbed with existing techniques to preoperatively localize the EZ. Neurosurgeons across the world face problems while defining the margins of the epileptogenic tissues to be resected during surgery. In this review we discuss molecular biomarkers reported so far in the context of epileptogenesis and some of the unexplored markers which may have the potential to localize EZ during surgery. We also discuss "Intelligent knife" technique that couples electrosurgery and mass spectrometry allowing near-real-time characterization of human tissue and may prove to be instrumental in defining the margins of the epileptogenic zone during surgery.