Mechanisms Of Epileptogenesis Research Articles

N-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis.

Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues.

Diffuse low grade glioma after the 2016 WHO update, seizure characteristics, imaging correlates and outcomes

ObjectivesThe majority of patients with supratentorial diffuse grade II glioma present with seizures, which adversely affect quality of life. The exact mechanism of epileptogenesis is unknown and the influence of tumour characteristics, radiological and histological, are not well studied, particularly following the introduction of molecular genetics in the 2016 WHO reclassification of gliomas. We sought to define predictors of seizure development and outcome in low grade glioma. Patients and MethodsA retrospective review of patients who underwent resection of a supratentorial grade II glioma in a single institution. All patients underwent surgery at initial presentation with the aim of maximal safe resection. Presenting symptoms and radiological variables were recorded, including eloquent location, cortical involvement, tumour margins and tumour volume. Extent of resection (EOR), surgery type (awake vs asleep) and seizure outcome were analysed. Using molecular genetics data the original histology was reclassified according to the 2016 WHO update. Results63 patients were included, 45 (71%) presented with seizures. 36 (57%) had oligodendroglioma and 27 astrocytoma. IDH-1 mutation was present in 53 (84%). 18 (29%) had tumour in an eloquent location. 33 (73%) were Engel class I following surgery at median follow up of 43 months. 6 patients were Engel II, 6 class III. Complete and near total resection were associated with improved Engel class compared to subtotal resection. No factors such as age, tumour location, tumour margins or tumour molecular genetics (including IDH-1 mutation) predicted better seizure outcome. Updated histological subtype did not predict the presence of seizures at initial diagnosis, only tumour heterogeneousity on initial MRI (p = 0.043). More patients who underwent awake craniotomy with intraoperative mapping were Engel class 1 post-operatively than those operated under general anaesthetic (84% vs 65%). Tumour volume at presentation did not correlate with seizure outcome but impacts on the EOR. ConclusionSeizure outcome is directly related to EOR in low grade glioma, which can be predicted by the initial tumour volume. Tumour histological subtype, including updated molecular genetic classification did not predict seizure development or outcome in this series. The use of awake craniotomy results in greater EOR and improved Engel Class following surgery.

Voltage-Dependent Calcium Channels, Calcium Binding Proteins, and Their Interaction in the Pathological Process of Epilepsy.

As an important second messenger, the calcium ion (Ca2+) plays a vital role in normal brain function and in the pathophysiological process of different neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy. Ca2+ takes part in the regulation of neuronal excitability, and the imbalance of intracellular Ca2+ is a trigger factor for the occurrence of epilepsy. Several anti-epileptic drugs target voltage-dependent calcium channels (VDCCs). Intracellular Ca2+ levels are mainly controlled by VDCCs located in the plasma membrane, the calcium-binding proteins (CBPs) inside the cytoplasm, calcium channels located on the intracellular calcium store (particular the endoplasmic reticulum/sarcoplasmic reticulum), and the Ca2+-pumps located in the plasma membrane and intracellular calcium store. So far, while many studies have established the relationship between calcium control factors and epilepsy, the mechanism of various Ca2+ regulatory factors in epileptogenesis is still unknown. In this paper, we reviewed the function, distribution, and alteration of VDCCs and CBPs in the central nervous system in the pathological process of epilepsy. The interaction of VDCCs with CBPs in the pathological process of epilepsy was also summarized. We hope this review can provide some clues for better understanding the mechanism of epileptogenesis, and for the development of new anti-epileptic drugs targeting on VDCCs and CBPs.

Neuroimaging in epilepsy.

Epilepsy neuroimaging is important for detecting the seizure onset zone, predicting and preventing deficits from surgery and illuminating mechanisms of epileptogenesis. An aspiration is to integrate imaging and genetic biomarkers to enable personalized epilepsy treatments. The ability to detect lesions, particularly focal cortical dysplasia and hippocampal sclerosis, is increased using ultra high-field imaging and postprocessing techniques such as automated volumetry, T2 relaxometry, voxel-based morphometry and surface-based techniques. Statistical analysis of PET and single photon emission computer tomography (STATISCOM) are superior to qualitative analysis alone in identifying focal abnormalities in MRI-negative patients. These methods have also been used to study mechanisms of epileptogenesis and pharmacoresistance.Recent language fMRI studies aim to localize, and also lateralize language functions. Memory fMRI has been recommended to lateralize mnemonic function and predict outcome after surgery in temporal lobe epilepsy. Combinations of structural, functional and post-processing methods have been used in multimodal and machine learning models to improve the identification of the seizure onset zone and increase understanding of mechanisms underlying structural and functional aberrations in epilepsy.

Seizure-induced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis

Brain glucose hypometabolism is an early symptom of acquired epilepsy, its causative mechanism yet unclear. We suggest that a bidirectional positive feedback linking seizures and hypometabolism (hypometabolism induces seizures while seizures disrupt glucose metabolism) may be a primary cause for acquired epileptogenesis. We reported recently that chronic partial inhibition of brain glycolysis triggers epileptogenesis in healthy rats. Here, by monitoring dynamic electrical and multiple metabolic parameters before and following seizure generation in mouse hippocampal slices using the 4-aminopyridine model of epileptiform activity, we show that in turn seizures are followed by a long-lasting glucose hypometabolism, indicating possible existence of a positive feedback in the mechanism of epileptogenesis. Seizures were associated with acute oxidative stress that may contribute to the subsequent glucose metabolism impairment, since exogenous application of H2O2 replicated the post-seizure metabolic effects. Exogenous pyruvate, the principal mitochondrial energy substrate with a broad spectrum of neuroprotective properties, effectively normalized the post-seizure glucose consumption. We have shown recently that pyruvate exhibited a strong antiepileptic action in three rodent chronic epilepsy models, while in the present study we find that pyruvate effectively normalizes impaired glucose metabolism following seizures. Together, our results provide the mechanistic basis for the metabolic concept of acquired epileptogenesis and an efficient treatment strategy.

S1-4. PET imaging of epilepsy

If we can visualize the epileptogenic lesion, the intractable epilepsy might be cured by the resective surgery. PET is a common clinical imaging tool, and it can evaluate and visualize brain function quantitatively and multidimensionally with various radio ligands. (18) FDG-PET and (11) C-flumazenil-PET are mainly used in the clinical settings, and they showed the decrease of glucose metabolism and binding in the epilepsy focus. In this decade, many PET radio-ligands are developed for positive imaging of epileptogenic lesion. The first target is neuroinflammation, such as 18 kDa-translocator protein (TSPO). (11) PK-11195-PET showed increase of TSPO binding in the focus in animal model, however, this alteration is unclear in human clinical study. Glutamate receptors are believed to be a novel biomarkers of epileptogenesis in future, and our experimental study showed the possibility that it could be a positive marker. Furthermore, other PET studies for neurotransmitters reported the role of opioids, cannabinoids, acetylcholine, and dopamine in modulating neuronal hyperexcitability. PET has the possibility not only to visualize the epileptic foci, but also elucidate of the mechanism of epileptogenesis.

Intrinsic Inflammation Is a Potential Anti-Epileptogenic Target in the Organotypic Hippocampal Slice Model

Understanding the mechanisms of epileptogenesis is essential to develop novel drugs that could prevent or modify the disease. Neuroinflammation has been proposed as a promising target for therapeutic interventions to inhibit the epileptogenic process that evolves from traumatic brain injury. However, it remains unclear whether cytokine-related pathways, particularly TNFα signaling, have a critical role in the development of epilepsy. In this study, we investigated the role of innate inflammation in an in vitro model of post-traumatic epileptogenesis. We combined organotypic hippocampal slice cultures, representing an in vitro model of post-traumatic epilepsy, with multi-electrode array recordings to directly monitor the development of epileptiform activity and to examine the concomitant changes in cytokine release, cell death, and glial cell activation. We report that synchronized ictal- and interictal-like activities spontaneously evolve in this culture. Dynamic changes in the release of the pro-inflammatory cytokines IL-1β, TNFα, and IL-6 were observed throughout the culture period (3 to 21 days in vitro) with persistent activation of microglia and astrocytes. We found that neutralizing TNFα with a polyclonal antibody significantly reduced ictal discharges, and this effect lasted for 1 week after antibody washout. Neither phenytoin nor an anti-IL-6 polyclonal antibody was efficacious in inhibiting the development of epileptiform activity. Our data show a sustained effect of the anti-TNFα antibody on the ictal progression in organotypic hippocampal slice cultures supporting the critical role of inflammatory mediators in epilepsy and establishing a proof-of-principle evidence for the utility of this preparation to test the therapeutic effects of anti-inflammatory treatments.

Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis.

In many patients who suffer from epilepsies, recurrent epileptic seizures do not start at birth but develop later in life. This holds particularly true for epilepsies with a focal seizure origin including focal cortical dysplasias and temporal lobe epilepsy (TLE). TLE most frequently has its seizure onset in the hippocampal formation. Hippocampal biopsies of pharmacoresistant TLE patients undergoing epilepsy surgery for seizure control most frequently reveal the damage pattern of hippocampal sclerosis, that is, segmental neuronal cell loss and concomitant astrogliosis. Many TLE patients report on transient brain insults early in life, which is followed by a 'latency' period lacking seizure activity of months or even years before chronic recurrent seizures start. The plethora of structural and cellular mechanisms that convert the hippocampal formation to become chronically hyperexcitable after a transient insult to the brain are summarized under the term epileptogenesis. In contrast to the obstacles arising for experimental studies of epileptogenesis aspects in human surgical hippocampal tissue, recent animal model approaches allow insights into mechanisms of epileptogenesis. Relevant models of transient brain insults in this context comprise several distinct types of lesions including excitoxic status epilepticus (SE), electrical seizure induction, traumatic brain injury, induction of inflammatory processes by hyperthermia and viral inflammation and others. In pathogenetic terms, aberrant transcriptional and epigenetic reprogramming, acquired channel- and synaptopathies, neuronal network and blood-brain barrier dysfunction as well as innate and adaptive immunity-mediated damage play major roles. In subsequent steps, respective animal models have been used in order to test whether this dynamic process can be either retarded or even abolished by interfering with epileptogenic mechanisms. Well-controlled subsequent analyses of epileptogenic cascades characterized in animal models using carefully stratified human hippocampal biopsies to exploit the unique opportunities given by these rare and precious brain tissue samples aim to translate into novel antiepileptogenic approaches. Respective preclinical tests can open entirely new perspectives for tailor-made treatments in patients with the potential to avoid the emergence of chronic focal seizure events.

Progress in synaptic mechanism in epileptogenesis

Recurrent seizures lead to abnormal expression of synaptic proteins, reorganization of synapse and formation of abnormal neuron network. Recently, it is identified that the synaptic proteins are involved in epileptogenesis. The abnormal expression of several synaptic regulatory proteins and postsynaptic membrane receptor proteins may result in epilepsy. The ion channels usually are the action target of most antiepileptic drugs. However, carbamazepine and zonisamide may interact with syntaxin and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex to exert its function of anti-epilepsy. The synaptic vesicle protein 2A is the action target for new anti-epileptic drugs, including levetiracetam, brivaracetam and seletracetam.

SERUM BRAIN DERIVED NEUROTROPHIC FACTOR AS BIOMARKER FOR EPILEPSY DIAGNOSIS IN EGYPTIAN CHILDREN WITH EPILEPSY; RELATIONSHIP TO DISEASE SEVERITY AND COGNITIVE FUNCTION.

Objectives: This study was designed to estimate serum brain-derived neurotrophic factor (BDNF) concentration in a group of Egyptian children with epilepsy to clarify its utility as a biomarker for epilepsy diagnosis and to evaluate its relationship with their cognitive function and disease severity. Methods: Intelligence was assessed using Arabic version of the WISC-R test. Serum concentration of BDNF was assessed using enzyme-linked immunosorbent assay in 40 children with epilepsy and 40 apparently healthy children of matched age and sex controls. Results: Of total 40 epileptic patients aged 6–12 years, the mean age was 8.32 ± 0.7 years and male to female ratio was 1.5:1. The mean serum BDNF concentration and cognitive IQ scores were statistically significantly reduced in the studied patient’s group versus to controls (p<0.001). There were highly significant differences in serum BDNF concentration as regards epileptic severity. Serum concentration of BDNF showed significantly positive correlation with cognitive, verbal, performance, and totals IQ scores and negative correlation with the age at the onset of seizures, and duration of therapy. The linear regression analysis showed a statistically significant association between age at the onset of seizures, duration of therapy, cognitive function, and serum BDNF concentrations among the studied patients. Conclusions: Concentration of BDNF in serum is involved in the mechanism of epileptogenesis in children with epilepsy. It should be used as a helpful marker for epilepsy diagnosis and detection of severity.

Uloga glija ćelija, krvno-moždane barijere i citokina u nastanku konvulzija - implikacije za terapeutske modalitete

Epilepsy is a chronic, common, neurological disorder marked by transient, paroxysmal and hypersynchronous activity of the brain neurons, behaviorally manifested as seizures. It is developed through the process of epileptogenesis which alters neuronal excitability, establishes critical interconnections and develop neuronal hyperexcitability and degeneration, as well as the neuronal network reorganization as its main mechanisms. There are a number of different mechanisms of epileptogenesis, including neuroinflammation as a recently highlighted important novel mechanism. In this review paper, our focus will be to light up the latest findings about neuroinflammation as a pathogenic factor in epileptogenesis. Neuroinflammation is characterized by the structural and functional alteration of the CNS glial cells and peripherally derived immune cells with the presence of blood-brain barrier (BBB) dysfunction as main mechanisms. Disequilibrium in the CNS microenvironment is often followed by increased synthesis of proinflammatory cytokines (IL-6, IL-1β, TNF-α, IFN-γ) and chemokines. The interplay between glial alteration, BBB dysfunction, cytokines and chemokines establish a positive feedback cascade for further epileptogenesis. It is still unclear if neuroinflammation is causing epileptogenesis or whether in a consequence of that, but, there are clear findings about positive feedback between these two processes. This interconnection could be a helpful key to better target therapeutic treatment of neuroinflammation for providing beneficial effects for patients with epilepsy.

SERUM BRAIN DERIVED NEUROTROPHIC FACTOR AS BIOMARKER FOR EPILEPSY DIAGNOSIS IN EGYPTIAN CHILDREN WITH EPILEPSY; RELATIONSHIP TO DISEASE SEVERITY AND COGNITIVE FUNCTION.

Objectives: This study was designed to estimate serum brain-derived neurotrophic factor (BDNF) concentration in a group of Egyptian children with epilepsy to clarify its utility as a biomarker for epilepsy diagnosis and to evaluate its relationship with their cognitive function and disease severity. Methods: Intelligence was assessed using Arabic version of the WISC-R test. Serum concentration of BDNF was assessed using enzyme-linked immunosorbent assay in 40 children with epilepsy and 40 apparently healthy children of matched age and sex controls. Results: Of total 40 epileptic patients aged 6–12 years, the mean age was 8.32 ± 0.7 years and male to female ratio was 1.5:1. The mean serum BDNF concentration and cognitive IQ scores were statistically significantly reduced in the studied patient’s group versus to controls (p<0.001). There were highly significant differences in serum BDNF concentration as regards epileptic severity. Serum concentration of BDNF showed significantly positive correlation with cognitive, verbal, performance, and totals IQ scores and negative correlation with the age at the onset of seizures, and duration of therapy. The linear regression analysis showed a statistically significant association between age at the onset of seizures, duration of therapy, cognitive function, and serum BDNF concentrations among the studied patients. Conclusions: Concentration of BDNF in serum is involved in the mechanism of epileptogenesis in children with epilepsy. It should be used as a helpful marker for epilepsy diagnosis and detection of severity.

Neurophysiological Analysis of the Genesis Mechanism of EEG During the Interictal and Ictal Periods Using a Multiple Neural Masses Model.

Electroencephalography (EEG) is an important method to investigate the neurophysiological mechanism underlying epileptogenesis to identify new therapies for the treatment of epilepsy. The neurophysiologically based neural mass model (NMM) can build a bridge between signal processing and neurophysiology, which can be used as a platform to explore the neurophysiological mechanism of epileptogenesis. Most EEG signals cannot be regarded as the outputs of a single NMM with identical model parameters. The outputs of NMM are simple because the diversity of neural signals in the same NMM is ignored. To improve the simulation of EEG signals, a multiple NMM is proposed, the output of which is the linear combination of the outputs of all NMMs. The NMM number is not fixed and is minimized under the premise of guaranteeing the fitting effect. Orthogonal matching pursuit is used to solve a constrained [Formula: see text] norm minimization problem for NMM number and the strength of every NMM. The results showed that the NMM number was significantly lower during the ictal period than during the interictal period, and the strength of major NMMs increased. This indicates that neural masses fuse into fewer larger neural masses with greater strength. The distribution of excitatory and inhibitory strength during the ictal and interictal periods was similar, whereas the excitation/inhibition ratio was higher during the ictal period than during the interictal period.

Influence of the epileptiform discharge microenvironment on the differentiation of oligodendrocyte precursor cells

The use of related cell cultured models to investigate the genesis and development of epilepsy is beneficial for exploring the mechanism of epileptogenesis. Recent reports have described the myelination damage caused by epilepsy in animal models; however, limited reports have focused on the influence of epilepsy on remyelination in vitro. The current study was designed to investigate the effect of the epileptiform discharge microenvironment on the differentiation of oligodendrocyte precursor cells (OPCs). Neurons with epileptiform discharge released more glutamic acid than normal neurons, which was detected by HPLC. The RT-qPCR, immunofluorescence and Western Blot results showed myelin basic protein (MBP) loss in the epileptiform discharge neuron microenvironment, with increased GluR2 subunit expression. In addition, an α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor antagonist altered the influence of epilepsy on OPC differentiation. This study confirmed the positive effect of epilepsy on the differentiation of OPCs and verified the critical role of glutamic acid and the AMPA receptor in this process, which provides a potential treatment strategy for epilepsy.

Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy.

Epilepsy is a chronic brain disease characterized by repeated unprovoked seizures. Currently, no drug therapy exists for curing epilepsy or disease modification in people at risk. Despite several emerging mechanisms, there have been few studies of epigenetic signaling in epileptogenesis, the process whereby a normal brain becomes progressively epileptic because of precipitating factors. Here, we report a novel role of histone deacetylation as a critical epigenetic mechanism in epileptogenesis. Experiments were conducted using the histone deacetylase (HDAC) inhibitor sodium butyrate in the hippocampus kindling model of temporal lobe epilepsy (TLE), a classic model heavily used to approve drugs for treatment of epilepsy. Daily treatment with butyrate significantly inhibited HDAC activity and retarded the development of limbic epileptogenesis without affecting after-discharge signal. HDAC inhibition markedly impaired the persistence of seizure expression many weeks after epilepsy development. Moreover, subchronic HDAC inhibition for 2 weeks resulted in a striking retardation of epileptogenesis. HDAC inhibition, unexpectedly, also showed erasure of the epileptogenic state in epileptic animals. Finally, butyrate-treated animals exhibited a powerful reduction in mossy fiber sprouting, a morphologic index of epileptogenesis. Together these results underscore that HDAC inhibition prevents the development of TLE, indicating HDAC's critical signaling role in epileptogenesis. These findings, therefore, envisage a unique novel therapy for preventing or curing epilepsy by targeting the epigenetic HDAC pathway.

Inhibitory synapse deficits caused by familial α1 GABAA receptor mutations in epilepsy

Epilepsy is a spectrum of neurological disorders with many causal factors. The GABA type-A receptor (GABAAR) is a major genetic target for heritable human epilepsies. Here we examine the functional effects of three epilepsy-causing mutations to the α1 subunit (α1T10’I, α1D192N and α1A295D) on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic GABAAR isoform, α1β2γ2L. We employed a neuron - HEK293 cell heterosynapse preparation to record IPSCs mediated by mutant-containing GABAARs in isolation from other GABAAR isoforms. IPSCs were recorded in the presence of the anticonvulsant drugs, carbamazepine and midazolam, and at elevated temperatures (22, 37 and 40°C) to gain insight into mechanisms of febrile seizures. The mutant subunits were also transfected into cultured cortical neurons to investigate changes in synapse formation and neuronal morphology using fluorescence microscopy. We found that IPSCs mediated by α1T10’Iβ2γ2L, α1D192Nβ2γ2L GABAARs decayed faster than those mediated by α1β2γ2L receptors. IPSCs mediated by α1D192Nβ2γ2L and α1A295Dβ2γ2L receptors also exhibited a heightened temperature sensitivity. In addition, the α1T10’Iβ2γ2L GABAARs were refractory to modulation by carbamazepine or midazolam. In agreement with previous studies, we found that α1A295Dβ2γ2L GABAARs were retained intracellularly in HEK293 cells and neurons. However, pre-incubation with 100nM suberanilohydroxamic acid (SAHA) induced α1A295Dβ2γ2L GABAARs to mediate IPSCs that were indistinguishable in magnitude and waveform from those mediated by α1β2γ2L receptors. Finally, mutation-specific changes to synaptic bouton size, synapse number and neurite branching were also observed. These results provide new insights into the mechanisms of epileptogenesis of α1 epilepsy mutations and suggest possible leads for improving treatments for patients harbouring these mutations.

Neurostimulation as a promising epilepsy therapy.

SummaryThe revolution in theory, swift technological developments, and invention of new devices have driven tremendous progress in neurostimulation as a third‐line treatment for epilepsy. Over the past decades, neurostimulation took its place in the field of epilepsy as an advanced treatment technique and opened up a new world. Numerous animal studies have proven the physical efficacy of stimulation of the brain and peripheral nerves. Based on this optimistic fundamental research, new advanced techniques are being explored in clinical practice. Over the past century, drawing on the benefits brought about by vagus nerve stimulation for the treatment of epilepsy, various new neurostimulation modalities have been developed to control seizures. Clinical studies including case reports, case series, and clinical trials have been booming in the past several years. This article gives a comprehensive review of most of these clinical studies. In addition to highlighting the advantages of neurostimulation for the treatment of epilepsy, concerns with this modality and future development directions are also discussed. The biggest advantage of neurostimulation over pharmacological treatments for epilepsy is the modulation of the epilepsy network by delivering stimuli at a specific target or the “hub.” Conversely, however, a lack of knowledge of epilepsy networks and the mechanisms of neurostimulation may hinder further development. Therefore, theoretical research on the mechanism of epileptogenesis and epilepsy networks is needed in the future. Within the multiple modalities of neuromodulation, the final choice should be made after full discussion with a multidisciplinary team at a presurgical conference. Furthermore, the establishment of a neurostimulation system with standardized parameters and rigorous guidelines is another important issue. To achieve this goal, a worldwide collaboration of epilepsy centers is also suggested in the future.

Neural stem cells and epilepsy: functional roles and disease-in-a-dish models.

Epilepsy is a disorder of the central nervous system characterized by spontaneous recurrent seizures. Although current therapies exist to control the number and severity of clinical seizures, there are no pharmacological cures or disease-modifying treatments available. Use of transgenic mouse models has allowed an understanding of neural stem cells in their relation to epileptogenesis in mesial temporal lobe epilepsy. Further, with the significant discovery of factors necessary to reprogram adult somatic cell types into pluripotent stem cells, it has become possible to study monogenic epilepsy-in-a-dish using patient-derived neurons. This discovery along with some of the newest technological advances in recapitulating brain development in a dish has brought us closer than ever to a platform in which to study and understand the mechanisms of this disease. These technologies will be critical in understanding the mechanism of epileptogenesis and ultimately lead to improved therapies and precision medicine for patients with epilepsy.

Nicotinamide adenine dinucleotide suppresses epileptogenesis at an early stage

The pathophysiologic mechanisms of epileptogenesis are poorly understood, and no effective therapy exists for suppressing epileptogenesis. Numerous reports have shown that nicotinamide adenine dinucleotide (NAD+) has neuroprotective effects, suggesting its potential use for treating epileptogenesis. Here we evaluated the effects of NAD+ on epileptogenesis and the mechanisms underlying these effects. In pilocarpine-induced status epilepticus (SE) model mice, NAD+ was injected three times within 24.5 h after SE. NAD+ intervention significantly reduced the incidence of spontaneous recurrent seizure (SRS) and abnormal electroencephalogram (EEG) activity, rescued contextual fear memory formation, reduced neuronal loss in the CA1 region of the hippocampus at SRS stage. Furthermore, exogenous supply of NAD+ distinctly reversed the seizure-induced depletion of endogenous NAD+, reduced neuronal apoptosis in the CA1 region of the hippocampus, and reversed the augmented Acp53/p53 ratio at the early stage of epileptogenesis. Our findings demonstrated that early-stage intervention with NAD+ prevents epileptogenesis in pilocarpine-induced SE mice by suppressing neuronal apoptosis.

Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies.

The prevalence of epilepsy is estimated 5-10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds.