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Objective: To observe and measure the morphological and temporal evolutionary features of the hypersynchronous (HYP) pattern in the mesial temporal seizure. Methods: The HYP patterns during preictal and interictal states of 16 mesial temporal epileptic patients were analyzed. The wave components of the HYP transients were firstly observed and measured. The dynamic deformations and parameter changes of the components were further analyzed along the preictal-ictal axis. The difference of emergence rate of HYP transients and typical interictal spike during interictal periods was also compared. Results: The HYP transients were invariably composed of slow-wave proper, sharp wave and post-slow component among studied patients for all the 93 seizures. During preictal epoch, all of the seizures incorporated present evolutionary manner of type 1 characterized by smooth modification of HYP transients in morphology, including gradual shortening of the inter-transient interval, increase of amplitude and time duration of slow-wave proper and sharp wave, amplitude decrease of the post-slow component, as well as amplitude increases of ripple and fast ripple, and 2/3 seizures showed some more sophisticated transitional manners (type 2) following type 1, including reduction in amplitude with decrease of inter-transient intervals, superimposed or followed by the emergent low amplitude rhythmic activities, or both of them. The HYP transients and typical interictal spikes were found to mutually "repelling" each other in interictal period. Conclusion: The HYP transients showed a combinational feature and temporal evolution manners during preictal state. The emergence of HYP transients in cluster reflects the transitional trend from interictal to ictal state. Significance: HYP should be viewed as an index of ictogenesis in the mesial temporal seizure. [ABSTRACT FROM AUTHOR]

Intracranial potentials are used as functional biomarkers of neural networks. As potentials spread away from the source populations, they become mixed in the recordings. In humans, interindividual differences in the gyral architecture of the cortex pose an additional challenge, as functional areas vary in location and extent. We used source separation techniques to disentangle mixing potentials obtained by exploratory deep arrays implanted in epileptic patients of either sex to gain access to the number, location, relative contribution, and dynamics of coactive sources. The unique spatial profiles of separated generators made it possible to discern dozens of independent cortical areas for each patient, whose stability maintained even during seizure, enabling the follow up of activity for days and across states. Through matching these profiles to MRI, we associated each with limited portions of sulci and gyri and determined the local or remote origin of the corresponding sources. We also plotted source-specific 3D coverage across arrays. In average, individual recording sites are contributed to by 3–5 local and distant generators from areas up to several centimeters apart. During seizure, 13–85% of generators were involved, and a few appeared anew. Significant bias in location assignment using raw potentials is revealed, including numerous false positives when determining the site of origin of a seizure. This is not amended by bipolar montage, which introduce additional errors of its own. In this way, source disentangling reveals the multisource nature and far intracranial spread of potentials in humans, while efficiently addressing patient-specific anatomofunctional cortical divergence. [ABSTRACT FROM AUTHOR]

Dendritic Pathology, Spine Loss and Synaptic Reorganization in Human Cortex From Epilepsy Patients Rossini L, De Santis D, Mauceri RR, Tesoriero C, Bentivoglio M, Maderna E, Maiorana A, Deleo F, de Curtis M, Tringali G, Cossu M, Tumminelli G, Bramerio M, Spreafico R, Tassi L, Garbelli R. Brain. 2021;144(1):251-265. doi:10.1093/brain/awaa387 Neuronal dendritic arborizations and dendritic spines are crucial for a normal synaptic transmission and may be critically involved in the pathophysiology of epilepsy. Alterations in dendritic morphology and spine loss mainly in hippocampal neurons have been reported both in epilepsy animal models and in human brain tissues from patients with epilepsy. However, it is still unclear whether these dendritic abnormalities relate to the cause of epilepsy or are generated by seizure recurrence. We investigated fine neuronal structures at the level of dendritic and spine organization using Golgi impregnation, and analyzed synaptic networks with immunohistochemical markers of glutamatergic (vGLUT1) and GABAergic (vGAT) axon terminals in human cerebral cortices derived from epilepsy surgery. Specimens were obtained from 28 patients with different neuropathologically defined etiologies: type Ia and type II focal cortical dysplasia, cryptogenic (no lesion) and temporal lobe epilepsy with hippocampal sclerosis. Autoptic tissues were used for comparison. Three-dimensional reconstructions of Golgi-impregnated neurons revealed severe dendritic reshaping and spine alteration in the core of the type II focal cortical dysplasia. Dysmorphic neurons showed increased dendritic complexity, reduction of dendritic spines, and occasional filopodia-like protrusions emerging from the soma. Surprisingly, the intermingled normal-looking pyramidal neurons also showed severe spine loss and simplified dendritic arborization. No changes were observed outside the dysplasia (perilesional tissue) or in neocortical postsurgical tissue obtained in the other patient groups. Immunoreactivities of vGLUT1 and vGAT showed synaptic reorganization in the core of type II dysplasia characterized by the presence of abnormal perisomatic baskets around dysmorphic neurons, in particular those with filopodia-like protrusions, and changes in vGLUT1/vGAT expression. Ultrastructural data in type II dysplasia highlighted the presence of altered neuropil engulfed by glial processes. Our data indicate that the fine morphological aspect of neurons and dendritic spines are normal in epileptogenic neocortex, with the exception of type II dysplastic lesions. The findings suggest that the mechanisms leading to this severe form of cortical malformation interfere with the normal dendritic arborization and synaptic network organization. The data argue against the concept that long-lasting epilepsy and seizure recurrence per se unavoidably produce a dendritic pathology. [ABSTRACT FROM AUTHOR]

Rasmussen encephalitis (RE) is a rare and progressive form of chronic encephalitis that typically affects one hemisphere of the brain and primarily occurs in pediatric individuals. The current study aims to narratively review the literature about RE, including historical information, pathophysiology, and management of this condition. RE often occurs in individuals with normal development, and it is estimated that only a few new cases are identified each year in epilepsy centers. Approximately 10% of cases also occur in adolescents and adults. The hallmark feature of RE is drug-resistant focal seizures that can manifest as epilepsia partialis continua. Also, patients with RE usually develop motor and cognitive impairment throughout the years. Neuroimaging studies show progressive damage to the affected hemisphere, while histopathological examination reveals T-cell-dominated encephalitis with activated microglial cells and reactive astrogliosis. The current therapy guidelines suggest cerebral hemispherotomy is the most recommended treatment for seizures in RE, although significant neurological dysfunction can occur. Another option is pharmacological management with antiseizure medications and immunomodulatory agents. No significant progress has been made in understanding the pathophysiology of this condition in the last decades, especially regarding genetics. Notably, RE diagnosis still depends on the criteria established by Bien et al., and the accuracy can be limited and include genetically different individuals, leading to unexpected responses to management. [ABSTRACT FROM AUTHOR]

Although perampanel (PER) has received approval as an antiseizure medication, reports quantifying its antiseizure effects using electroencephalography (EEG) remain scarce. In a previous study, we demonstrated that the interictal high gamma oscillation regularity (GOR) on scalp EEG is an excellent marker of epileptogenicity. Herein, we investigated whether the antiseizure effect of PER could be quantified through interictal GOR analysis of scalp EEG data. To investigate this, we examined the interictal GOR from 20 s of scalp EEG data before and after PER administration collected from five patients with epilepsy with focal seizures. Prior to PER administration, each patient presented with localized areas with high GOR consistent with brain lesions or seizure semiology. In all patients, the seizures improved following PER administration, and the localized high GOR, which is considered an epileptogenic focus, disappeared. These results indicate that interictal GOR analysis may be a useful tool for the quantitative assessments of the antiseizure effects of PER in focal epilepsy. Plain Language Summary: This study explored whether perampanel (PER)'s antiseizure effects can be quantified using interictal high gamma oscillation regularity (GOR) analysis from scalp EEG data. Analyzing 20‐second EEG segments before and after PER administration in five patients with focal epilepsy, we found that high GOR areas, indicative of epileptogenic foci, disappeared following PER administration. The results suggest that interictal GOR analysis could effectively quantify the antiseizure effects of PER. [ABSTRACT FROM AUTHOR]

Introduction: Seizures are common reasons to call an ambulance, and this study aims to analyze the burden of seizures in the prehospital setting based on incidence, hospital admission rate, and costs. Methods: This was a population-based, cross-sectional analysis of prehospital emergency medical services (EMS) data on suspected seizure cases from the federal state of Hesse, Germany, in 2019. Results: A total of 6534 suspected seizure cases were identified, of which most were those with a known seizure disorder. Incidence rate for epilepsy-related seizures (ES; pediatric epilepsy, first seizure [1stS], seizure with known seizure disorder [SEPI]) was 205.7 per 100,000 inhabitants and incidence rate for pediatric febrile seizures (PFS) was 36.7 per 100,000 inhabitants, corresponding to 171,275 ES and 28,500 PFS (99.3% < 18 years) cases in Germany. A prehospital EMS physician was involved in 40.0% (SEPI) to 54.4% (PFS) of suspected seizure cases. Depending on the type of seizure, 70.7% (SEPI) to 80.9% (1stS) were admitted to hospital for inpatient stay of ≥ 24 h. An additional 4% (PFS) to 16% (1stS) of cases needed immediate intervention at hospital. Prehospital EMS staff needed 8:24 min:s (SD 7:24; n = 5004) after the emergency call to arrive at the scene of the ES and 10:58 min:s (SD 27:39; n = 321) for PFS. ES and PFS cases caused estimated costs of 48.5 and 8.1 million euros for Germany in 2019, respectively, not including hospital treatment-related costs. Conclusion: This study identified a high number of suspected seizure-related emergency cases and proportion of patients admitted to hospitals, as well as high associated costs in Germany. [ABSTRACT FROM AUTHOR]

Despite an abundance of pharmacologic and surgical epilepsy treatments, there remain millions of patients suffering from poorly controlled seizures. One approach to closing this treatment gap may be found through a deeper mechanistic understanding of the network alterations that underly this aberrant activity. Functional optical imaging in vertebrate models provides powerful advantages to this end, enabling the spatiotemporal acquisition of individual neuron activity patterns across multiple seizures. This coupled with the advent of genetically encoded indicators, be them for specific ions, neurotransmitters or voltage, grants researchers unparalleled access to the intact nervous system. Here, we will review how in vivo functional optical imaging in various vertebrate seizure models has advanced our knowledge of seizure dynamics, principally seizure initiation, propagation and termination. [ABSTRACT FROM AUTHOR]

Epilepsy is a common yet complex neurological disorder. Historically, antiseizure medications (ASMs) have faced challenges in crossing the blood-brain barrier (BBB) and targeting the epileptogenic zone, creating a bottleneck in seizure management. Certain nanomaterials can facilitate drug penetration through the BBB and enable stimulus-responsive drug release, thereby enhancing targeted and efficient drug utilization while reducing adverse reactions in other brain tissues and peripherally. This article reviews the current researches on stimulus-responsive nanosystems applicable in antiepileptic therapy, as well as nanotechnology applications that improve the brain delivery of ASMs. [ABSTRACT FROM AUTHOR]

Electroencephalogram (EEG) plays a pivotal role in the detection and analysis of epileptic seizures, which affects over 70 million people in the world. Nonetheless, the visual interpretation of EEG signals for epilepsy detection is laborious and time-consuming. To tackle this open challenge, we introduce a straightforward yet efficient hybrid deep learning approach, named ResBiLSTM, for detecting epileptic seizures using EEG signals. Firstly, a one-dimensional residual neural network (ResNet) is tailored to adeptly extract the local spatial features of EEG signals. Subsequently, the acquired features are input into a bidirectional long short-term memory (BiLSTM) layer to model temporal dependencies. These output features are further processed through two fully connected layers to achieve the final epileptic seizure detection. The performance of ResBiLSTM is assessed on the epileptic seizure datasets provided by the University of Bonn and Temple University Hospital (TUH). The ResBiLSTM model achieves epileptic seizure detection accuracy rates of 98.88–100% in binary and ternary classifications on the Bonn dataset. Experimental outcomes for seizure recognition across seven epilepsy seizure types on the TUH seizure corpus (TUSZ) dataset indicate that the ResBiLSTM model attains a classification accuracy of 95.03% and a weighted F1 score of 95.03% with 10-fold crossvalidation. These findings illustrate that ResBiLSTM outperforms several recent deep learning state-of-the-art approaches. [ABSTRACT FROM AUTHOR]

Epilepsy is a common chronic neurologic disorder, with about 30%‐40% of patients suffering from recurrent seizures despite receiving enough antiseizure medication. Growing evidence of extensive structural and functional research has revealed that epilepsy is a network disorder, and the network investigation is crucial in the presurgical evaluation. This narrative review is aimed at providing an overview of the conceptual development of epileptic surgery, the epileptic network formation, and the network‐oriented strategy in clinical practice. We searched the PubMed database before October 2022 with no language or regional restrictions for studies of network exploration in epilepsy patients. The study eligibility criteria were original connectivity or network research studies using neuroimaging or neurophysiological approaches, focusing on seizure localization, neuropsychological evaluation, neuromodulation, or surgical prognosis. The initial search revealed 2046 studies. The selection process presented 746 papers that meet the inclusion criteria. The results indicated that epilepsy was characterized by the alternation of brain networks, which account for the clinical, electrographic, and neurocognitive phenomena related to human seizures and changes across different disease stages. Hubs have garnered significant attention due to their extensive connections, which make them prone to facilitating the spread of seizures to various brain regions. Unlike the seizure onset zone, the removal of the majority of these ictogenic nodes demonstrated a significant correlation with positive outcomes. Therefore, performing a network analysis during the epilepsy presurgical evaluation seems essential and will influence surgical decisions. It is hoped that studying the network of epilepsy will enhance our ability to determine the most appropriate surgical strategy for patients with epilepsy, thus contributing to success in terms of effective seizure control with maximal sparing or even improvement of brain functioning. [ABSTRACT FROM AUTHOR]

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a+/- and Scn1aRH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers. [ABSTRACT FROM AUTHOR]

Background: Senile epilepsy and its comorbidities pose a tremendous burden on patients and the society. This study was aimed to investigate the clinical characteristics and comorbidities of senile epilepsy, as well as the impact of comorbidities on the prognosis of senile epilepsy. Methods: Information of patients with senile epilepsy was retrospectively collected from three tertiary hospitals in Southwest China between December 2014 and December 2022. A total of 154 patients met the inclusion criteria and were divided into two groups based on the presence or absence of comorbidities. The prevalence, type, characteristics, and impacts of the comorbidities were investigated. The characteristics of patients with and without comorbidities were also compared. Results: Eighty-one percent of patients with senile epilepsy had at least one comorbidity, and 36% had three or more comorbidities. Eighteen different types of comorbidities were identified. The most common comorbidities were neurological (61%), followed by cardiovascular (45%) and psychiatric (26%) comorbidities. More than one-third of patients had bidirectional comorbidities, whereas more than half of the patients had additional causal comorbidities. Among all types of comorbidities, neurological and psychiatric comorbidities were found to be associated with an increased risk of recurrent seizures. Compared to patients without bidirectional comorbidities, those with at least one bidirectional comorbidity had a lower rate of achieving seizure freedom. The higher the number of bidirectional comorbidities, the lower the seizure-free rate. Survival analysis revealed that patients with neurological comorbidities had a higher risk of death. Conclusions: This study revealed a high comorbidity rate and a low seizure-freedom rate among patients with senile epilepsy. In particular, neuropsychiatric comorbidities can increase the risk of seizures and affect the survival rate of patients with senile epilepsy. Therefore, preventing and managing these comorbidities may improve seizure outcomes and reduce mortality in this special population. [ABSTRACT FROM AUTHOR]

Mean-field models have been developed to replicate key features of epileptic seizure dynamics. However, the precise mechanisms and the role of the brain area responsible for seizure onset and propagation remain incompletely understood. In this study, we employ computational methods within The Virtual Brain framework and the Epileptor model to explore how the location and connectivity of an Epileptogenic Zone (EZ) in a mouse brain are related to focal seizures (seizures that start in one brain area and may or may not remain localized), with a specific focus on the hippocampal region known for its association with epileptic seizures. We then devise computational strategies to confine seizures (prevent widespread propagation), simulating medical-like treatments such as tissue resection and the application of an anti-seizure drugs or neurostimulation to suppress hyperexcitability. Through selectively removing (blocking) specific connections informed by the structural connectome and graph network measurements or by locally reducing outgoing connection weights of EZ areas, we demonstrate that seizures can be kept constrained around the EZ region. We successfully identified the minimal connections necessary to prevent widespread seizures, with a particular focus on minimizing surgical or medical intervention while simultaneously preserving the original structural connectivity and maximizing brain functionality. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent cell death mechanism involving the accumulation of lipid peroxides. As a critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be downregulated in epilepsy. However, the mechanism of ferroptosis in epilepsy remains unclear. In this study, bioinformatics analysis, analysis of epilepsy patient blood samples and cell and mouse experiments revealed strong associations among epilepsy, ferroptosis, microRNA-211-5p and purinergic receptor P2X 7 (P2RX7). P2RX7 is a nonselective ligand-gated homotrimeric cation channel, and its activation mainly increases neuronal activity during epileptic seizures. In our study, the upregulation of P2RX7 in epilepsy was attributed to the downregulation of microRNA (miR)-211-5p. Furthermore, P2RX7 has been found to regulate GPX4/HO-1 by alleviating lipid peroxidation induced by suppression of the MAPK/ERK signaling pathway in murine models. The dynamic decrease in miR-211-5p expression induces hypersynchronization and both nonconvulsive and convulsive seizures, and forebrain miR-211-5p suppression exacerbates long-lasting pentylenetetrazole-induced seizures. Additionally, in this study, induction of miR-211-5p expression or genetic-silencing of P2RX7 significantly reduced the seizure score and duration in murine models through the abovementioned pathways. These results suggest that the miR-211-5p/P2RX7 axis is a novel target for suppressing both ferroptosis and epilepsy. Highlights: We first utilized bioinformatics technology to screen microRNA-211-5p reduction in epileptic patients and verified this in epileptic patient blood samples and mice hippocampal tissue. We first uncovered a significant interaction exists between microRNA-211-5p and P2RX7. We first verify that microRNA-211-5p exerts an influence on epilepsy by regulating ferroptosis through targeting P2RX7. Our data provide comprehensive evidence that microRNA-211-5p/P2RX7/ERK/GPX4 pathway could be a promising target for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Several studies have attributed epileptic activities in temporal lobe epilepsy (TLE) to the hippocampus; however, the participation of nonhippocampal neuronal networks in the development of TLE is often neglected. Here, we sought to understand how these nonhippocampal networks are involved in the pathology that is associated with TLE disease. Methods: A kainic acid (KA) model of temporal lobe epilepsy was induced by injecting KA into dorsal hippocampus of C57BL/6J mice. Network activation after spontaneous seizure was assessed using c‐Fos expression. Protocols to induce seizure using visual or auditory stimulation were developed, and seizure onset zone (SOZ) and frequency of epileptic spikes were evaluated using electrophysiology. The hippocampus was removed to assess seizure recurrence in the absence of hippocampus. Results: Our results showed that cortical and hippocampal epileptic networks are activated during spontaneous seizures. Perturbation of these networks using visual or auditory stimulation readily precipitates seizures in TLE mice; the frequency of the light‐induced or noise‐induced seizures depends on the induction modality adopted during the induction period. Localization of SOZ revealed the existence of cortical and hippocampal SOZ in light‐induced and noise‐induced seizures, and the development of local and remote epileptic spikes in TLE occurs during the early stage of the disease. Importantly, we further discovered that removal of the hippocampi does not stop seizure activities in TLE mice, revealing that seizures in TLE mice can occur independent of the hippocampus. Significance: This study has shown that the network pathology that evolves in TLE is not localized to the hippocampus; rather, remote brain areas are also recruited. The occurrence of light‐induced or noise‐induced seizures and epileptic discharges in epileptic mice is a consequence of the activation of nonhippocampal brain areas. This work therefore demonstrates the fundamental role of nonhippocampal epileptic networks in generating epileptic activities with or without the hippocampus in TLE disease. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder characterized by benign tumor growth in multiple organs, including the brain, kidneys, heart, eyes, lungs, and skin. Pathogenesis stems from mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR pathway, a critical regulator of cell growth and proliferation. Disruption of the tuberin–hamartin complex leads to overactivation of mTOR signaling and uncontrolled cell growth, resulting in hamartoma formation. Neurological manifestations are common in TSC, with epilepsy developing in up to 90% of patients. Seizures tend to be refractory to medical treatment with anti-seizure medications. Infantile spasms and focal seizures are the predominant seizure types, often arising in early childhood. Drug-resistant epilepsy contributes significantly to morbidity and mortality. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, clinical manifestations, and treatment approaches for epilepsy and other neurological features of TSC. While narrative reviews on TSC exist, this review uniquely synthesizes key advancements across the areas of TSC neuropathology, conventional and emerging pharmacological therapies, and targeted treatments. The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients. [ABSTRACT FROM AUTHOR]

The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Seizures beget seizures is a longstanding theory that proposed that seizure activity can impact the structural and functional properties of the brain circuits in ways that contribute to epilepsy progression and the future occurrence of seizures. Originally proposed by Gowers, this theory continues to be quoted in the pathophysiology of epilepsy. We critically review the existing data and observations on the consequences of recurrent seizures on brain networks and highlight a range of factors that speak for and against the theory. The existing literature demonstrates clearly that ictal activity, especially if recurrent, induces molecular, structural, and functional changes including cell loss, connectivity reorganization, changes in neuronal behavior, and metabolic alterations. These changes have the potential to modify the seizure threshold, contribute to disease progression, and recruit wider areas of the epileptic network into epileptic activity. Repeated seizure activity may, thus, act as a pathological positive‐feedback mechanism that increases seizure likelihood. On the other hand, the time course of self‐limited epilepsies and the presence of seizure remission in two thirds of epilepsy cases and various chronic epilepsy models oppose the theory. Experimental work showed that seizures could induce neural changes that increase the seizure threshold and decrease the risk of a subsequent seizure. Due to the complex nature of epilepsies, it is wrong to consider only seizures as the key factor responsible for disease progression. Epilepsy worsening can be attributed to the various forms of interictal epileptiform activity or underlying disease mechanisms. Although seizure activity can negatively impact brain structure and function, the "seizures beget seizures" theory should not be used dogmatically but with extreme caution. [ABSTRACT FROM AUTHOR]

A critical question regarding how focal seizures start is whether we can identify particular cell classes that drive the pathological process. This was the topic for debate at the recent International Conference for Technology and Analysis of Seizures (ICTALS) meeting (July 2022, Bern, CH) that we summarize here. The debate has been fueled in recent times by the introduction of powerful new ways to manipulate subpopulations of cells in relative isolation, mostly using optogenetics. The motivation for resolving the debate is to identify novel targets for therapeutic interventions through a deeper understanding of the etiology of seizures. [ABSTRACT FROM AUTHOR]

CA3 Principal Cell Activation Triggers Hypersynchronous-Onset Seizures in a Mouse Model of Mesial Temporal Lobe Epilepsy Wang S, Lévesque M, Fisher TAJ, Kennedy TE, Avoli M. J Neurophysiol. 2023;130(4):1041-1052. doi:10.1152/jn.00244.2023 Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy, and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250–500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region. NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone. [ABSTRACT FROM AUTHOR]

This document is a letter published in the journal Neurological Sciences. It discusses a case of drug refractory epilepsy in a 10-year-old female with MOG antibody-associated disorders (MOGAD). The patient presented with seizures and behavioral abnormalities, and had been previously treated with multiple antiepileptic drugs. The letter describes the patient's medical history, examination findings, and diagnostic tests, including brain MRI, CSF examination, and antibody testing. The patient was treated with steroids and immunosuppressants, which resulted in a decrease in seizure frequency. The authors emphasize the expanding spectrum of MOGAD and the potential role of immunotherapy in epilepsy associated with anti-MOG antibodies. [Extracted from the article]

Background: Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods: This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results: Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05). Conclusions: The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate (R2*), we investigated regional brain susceptibility changes in 36 patients with left‐sided (LTLE) or right‐sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and R2* with age of epilepsy onset, frequency of focal‐to‐bilateral tonic–clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak‐harmonic QSM (WH‐QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left‐versus‐right hippocampal susceptibility. Significant R2* changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R2* was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and R2* were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with R2* in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with R2* in the caudate. Susceptibility and R2* changes observed in TLE groups suggest selective loss of low‐myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and R2* in the thalamus and putamen suggest increased iron content and reflect disease severity. [ABSTRACT FROM AUTHOR]

Seizures are caused by increased neuronal firing activity resulting from reduced inhibitory effect and enhancement of inhibitory modulation to suppress this activity is used as a therapeutic tool. However, recent experiments have shown a counterintuitive phenomenon that inhibitory modulation does not suppress but elicit post-inhibitory rebound (PIR) spike along with seizure to challenge the therapeutic tool. The nonlinear mechanism to avoid the PIR spike can present theoretical guidance to seizure treatment. This paper focuses on identifying credible bifurcations that underlie PIR spike by modulating multiple parameters in multiple theoretical models. The study identifies a codimension-2 bifurcation called saddle--node homoclinic orbit (SNHOB), which is an intersection between saddle node bifurcation on invariant cycle (SNIC) and other two bifurcations. PIR spike cannot be evoked for the SNIC far from the SNHOB but induced for the SNIC close to the SNHOB, which extends the bifurcation condition for PIR spike from the well-known Hopf to SNIC. Especially, in a thalamic neuron model, increases of conductance of T-type Ca2+ (T Ca) channel induce SNIC bifurcation approaching to the SNHOB to elicit PIR spikes, closely matching experimental results of the absence seizure or Parkinson diseases. Such results imply that, when inhibition is employed to relieve absence seizure and Parkinson diseases related to PIR spike, modulating SNIC to get far from the SNHOB to avoid PIR spike is the principle. The study also addresses the complex roles of T Ca current and comprehensive relationships between PIR spike and nonlinear conceptions such as bifurcation types and shapes of threshold curve. [ABSTRACT FROM AUTHOR]

Seizure patterns identified in focal epilepsies caused by diverse etiologies are likely due to different pathogenic mechanisms. We describe here a novel, region-specific focal seizure pattern that mimics seizure activity observed in a subpopulation of patients submitted to presurgical monitoring with intracerebral electrodes. Distinctive seizure-like events (SLEs) are induced in the olfactory regions by acute treatment of both tangential brain slices and the isolated guinea pig brain with the potassium channel blocker 4-aminopyridine. Analysis of field potentials, intracellular activities, and extracellular potassium changes demonstrates that SLEs in the piriform cortex initiate in the superficial layer 1 lacking principal neurons with an activity-dependent increase of extracellular potassium. SLE progression (but not onset) does not require the participation of synaptic transmission and is mediated by diffusion of potassium to deep cortical layers. The novel seizure pattern here described is not observed in other cortical regions; it is proposed to rely on the peculiar organization of the superficial piriform cortex layers, which are characterized by unmyelinated axons and perisynaptic astroglial envelopes. This study reveals a sequence of ictogenic events in the olfactory cortex that were never described before in other cortical structures and supports the notion that altered potassium homeostasis and unmyelinated fibers may represent a potential vehicle for focal ictogenesis. [ABSTRACT FROM AUTHOR]

Although the piriform cortex (PC) has been previously implicated as a critical node for seizure generation and propagation, the underlying neural mechanism has remained unclear. Here, we found increased excitability in PC neurons during amygdala kindling acquisition. Optogenetic or chemogenetic activation of PC pyramidal neurons promoted kindling progression, whereas inhibition of these neurons retarded seizure activities induced by electrical kindling in the amygdala. Furthermore, chemogenetic inhibition of PC pyramidal neurons alleviated the severity of kainic acid‐induced acute seizures. These results demonstrate that PC pyramidal neurons bidirectionally modulate seizures in temporal lobe epilepsy, providing evidence for the efficacy of PC pyramidal neurons as a potential therapeutic target for epileptogenesis. Key points: While the piriform cortex (PC) is an important olfactory centre critically involved in olfactory processing and plays a crucial role in epilepsy due to its close connection with the limbic system, how the PC regulates epileptogenesis is largely unknown.In this study, we evaluated the neuronal activity and the role of pyramidal neurons in the PC in the mouse amygdala kindling model of epilepsy.PC pyramidal neurons are hyperexcited during epileptogenesis.Optogenetic and chemogenetic activation of PC pyramidal neurons significantly promoted seizures in the amygdala kindling model, whereas selective inhibition of these neurons produced an anti‐epileptic effect for both electrical kindling and kainic acid‐induced acute seizures.The results of the present study indicate that PC pyramidal neurons bidirectionally modulate seizure activity. [ABSTRACT FROM AUTHOR]

Absence seizures--generalized rhythmic spike-and-wave discharges (SWDs) are the defining property of childhood (CAE) and juvenile (JAE) absence epilepsies. Such seizures are the most compelling examples of pathological neuronal hypersynchrony. All the absence detection algorithms proposed so far have been derived from the properties of individual SWDs. In this work, we investigate EEG phase synchronization in patients with CAE/JAE and healthy subjects to explore the possibility of using the wavelet phase synchronization index to detect seizures and quantify their disorganization (fragmentation). The overlap of the ictal and interictal probability density functions was high enough to preclude effective seizure detection based solely on changes in EEG synchronization. We used a machine learning classifier with the phase synchronization index (calculated for 1 s data segments with 0.5 s overlap) and the normalized amplitude as features to detect generalized SWDs. Using 19 channels (10-20 setup), we identified 99.2% of absences. However, the overlap of the segments classified as ictal with seizures was only 83%. The analysis showed that seizures were disorganized in approximately half of the 65 subjects. On average, generalized SWDs lasted about 80% of the duration of abnormal EEG activity. The disruption of the ictal rhythm can manifest itself as the disappearance of epileptic spikes (with high-amplitude delta waves persisting), transient cessation of epileptic discharges, or loss of global synchronization. The detector can analyze a real-time data stream. Its performance is good for a six-channel setup (Fp1, Fp2, F7, F8, O1, O2), which can be implemented as an unobtrusive EEG headband. False detections are rare for controls and young adults (0.03% and 0.02%, respectively). In patients, they are more frequent (0.5%), but in approximately 82% cases, classification errors are caused by short epileptiform discharges. Most importantly, the proposed detector can be applied to parts of EEGwith abnormal EEGactivity to quantitatively determine seizure fragmentation. This property is important because a previous study reported that the probability of disorganized discharges is eight times higher in JAE than in CAE. Future research must establish whether seizure properties (frequency, length, fragmentation, etc.) and clinical characteristics can help distinguish CAE and JAE. [ABSTRACT FROM AUTHOR]

Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague–Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. Results: In Sprague–Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. Conclusions: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors. [ABSTRACT FROM AUTHOR]

Objective: We aim to determine whether automatically detected ripple rate (ADRR) of 10‐min scalp electroencephalography (EEG) during slow‐wave sleep can be a useful tool for rapid epilepsy differentiation and seizure activity assessment, and we analyze the clinical factors that may affect the scalp ripple rates. Methods: We retrospectively included 336 patients who underwent long‐term video‐EEG with a sampling rate ≥1000 Hz, and three groups were established based on their final clinical diagnosis (non‐epilepsy; non‐active epilepsy [epilepsy being seizure‐free for at least 1 year]; and active epilepsy [epilepsy with one or more seizures in the past year]). ADRRs between groups were compared and diagnostic thresholds set according to the maximum of Youden index with the receiver‐operating characteristic curve. Results: The 336 patients comprised 49 non‐epilepsy and 287 epilepsy patients (95 non‐active epilepsy and 192 active epilepsy). The median ADRR of the epilepsy group was significantly greater than in the non‐epilepsy group, with a diagnostic threshold of 4.25 /min (specificity 89.8%, sensitivity 47.74%, p<.001). Following stratification by age, the area under the curve was greatest in the 0–20 year subgroup, threshold 4.10 /min (specificity 100%, sensitivity 52.47%, p<.001). Regarding distinguishing active epilepsy from non‐active epilepsy patients, the area under the curve was also greatest in patients 0–20 years of age, threshold 13.05/min (specificity 98.36%, sensitivity 35.64%, p<.001). Following stratification by epilepsy type, the diagnostic efficiency was best in children with developmental and epileptic encephalopathies/epileptic encephalopathies (DEEs/EEs) (threshold 5.20/min, specificity 100%, sensitivity 100%) and self‐limited focal epilepsies (SeLFEs) (threshold 5.45/min, specificity 80%, sensitivity 100%). Multivariate analysis revealed that the influential factors of ADRRs were age, depth of epileptogenic lesion, and seizure frequency. Significance: ADRR of scalp EEG can be a rapid and specific method to differentiate epilepsy and evaluate seizure activity. This method is especially suitable for young patients. [ABSTRACT FROM AUTHOR]

Focal epileptic seizures are characterized by abnormal neuronal discharges that can spread to other cortical areas and interfere with brain activity, thereby altering the patient's experience and behavior. The origin of these pathological neuronal discharges encompasses various mechanisms that converge toward similar clinical manifestations. Recent studies have suggested that medial temporal lobe (MTL) and neocortical (NC) seizures are often underpinned by two characteristic onset patterns, which, respectively, affect and spare synaptic transmission in cortical slices. However, these synaptic alterations and their effects have never been confirmed or studied in intact human brains. To fill this gap, we here evaluate whether responsiveness of MTL and NC are differentially affected by focal seizures, using a unique data set of cortico‐cortical evoked potentials (CCEPs) collected during seizures triggered by single‐pulse electrical stimulation (SPES). We find that responsiveness is abruptly reduced by the onset of MTL seizures, despite increased spontaneous activity, whereas it is preserved in the case of NC seizures. The present results provide an extreme example of dissociation between responsiveness and activity and show that brain networks are diversely affected by the onset of MTL and NC seizures, thus extending at the whole brain level the evidence of synaptic alteration found in vitro. [ABSTRACT FROM AUTHOR]

Background: Focal motor seizures that originate in the motor region are a considerable challenge because of the high risk of permanent motor deficits after resection. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a potential treatment for motor epilepsy that may enhance the antiepileptic actions of the substantia nigra pars reticulata (SNr). Orexin and its receptors have a relationship with both STN-DBS and epilepsy. We aimed to investigate whether and how STN inputs to the SNr regulate seizures and the role of the orexin pathway in this process. Methods: A penicillin-induced motor epileptic model in adult male C57BL/6J mice was established to evaluate the efficacy of STN-DBS in modulating seizure activities. Optogenetic and chemogenetic approaches were employed to regulate STN-SNr circuits. Selective orexin receptor type 1 and 2 antagonists were used to inhibit the orexin pathway. Results: First, we found that high-frequency ipsilateral or bilateral STN-DBS was effective in reducing seizure activity in the penicillin-induced motor epilepsy model. Second, inhibition of STN excitatory neurons and STN-SNr projections alleviates seizure activities, whereas their activation amplifies seizure activities. In addition, activation of the STN-SNr circuits also reversed the protective effect of STN-DBS on motor epilepsy. Finally, we observed that STN-DBS reduced the elevated expression of orexin and its receptors in the SNr during seizures and that using a combination of selective orexin receptor antagonists also reduced seizure activity. Conclusion: STN-DBS helps reduce motor seizure activity by inhibiting the STN-SNr circuit. Additionally, orexin receptor antagonists show potential in suppressing motor seizure activity and may be a promising therapeutic option in the future. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorders (ASDs) are one of the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact on society. Interestingly, several systematic reviews and meta-analyses documented a bidirectional link between epilepsy and ASD, supporting the hypothesis that both disorders may have common neurobiological pathways. According to this hypothesis, an imbalance of the excitatory/inhibitory (E/I) ratio in several brain regions may represent a causal mechanism underpinning the co-occurrence of these neurological diseases. Methods: To investigate this bidirectional link, we first tested the seizure susceptibility to chemoconvulsants acting on GABAergic and glutamatergic systems in the BTBR mice, in which an imbalance between E/I has been previously demonstrated. Subsequently, we performed the PTZ kindling protocol to study the impact of seizures on autistic-like behavior and other neurological deficits in BTBR mice. Results: We found that BTBR mice have an increased susceptibility to seizures induced by chemoconvulsants impairing GABAA neurotransmission in comparison to C57BL/6J control mice, whereas no significant difference in seizure susceptibility was observed after administration of AMPA, NMDA, and Kainate. This data suggests that deficits in GABAergic neurotransmission can increase seizure susceptibility in this strain of mice. Interestingly, BTBR mice showed a longer latency in the development of kindling compared to control mice. Furthermore, PTZ-kindling did not influence autistic-like behavior in BTBR mice, whereas it was able to significantly increase anxiety and worsen cognitive performance in this strain of mice. Interestingly, C57BL/6J displayed reduced sociability after PTZ injections, supporting the hypothesis that a tight connection exists between ASD and epilepsy. Conclusion: BTBR mice can be considered a good model to study epilepsy and ASD contemporarily. However, future studies should shed light on the mechanisms underpinning the co-occurrence of these neurological disorders in the BTBR model. [ABSTRACT FROM AUTHOR]

Neuronal activity propagates through the network during seizures, engaging brain dynamics at multiple scales. Such propagating events can be described through the avalanches framework, which can relate spatiotemporal activity at the microscale with global network properties. Interestingly, propagating avalanches in healthy networks are indicative of critical dynamics, where the network is organized to a phase transition, which optimizes certain computational properties. Some have hypothesized that the pathologic brain dynamics of epileptic seizures are an emergent property of microscale neuronal networks collectively driving the brain away from criticality. Demonstrating this would provide a unifying mechanism linking microscale spatiotemporal activity with emergent brain dysfunction during seizures. Here, we investigated the effect of drug-induced seizures on critical avalanche dynamics, using in vivo whole-brain two-photon imaging of GCaMP6s larval zebrafish (males and females) at single neuron resolution. We demonstrate that single neuron activity across the whole brain exhibits a loss of critical statistics during seizures, suggesting that microscale activity collectively drives macroscale dynamics away from criticality. We also construct spiking network models at the scale of the larval zebrafish brain, to demonstrate that only densely connected networks can drive brain-wide seizure dynamics away from criticality. Importantly, such dense networks also disrupt the optimal computational capacities of critical networks, leading to chaotic dynamics, impaired network response properties and sticky states, thus helping to explain functional impairments during seizures. This study bridges the gap between microscale neuronal activity and emergent macroscale dynamics and cognitive dysfunction during seizures. [ABSTRACT FROM AUTHOR]

While seizure activity may be electrographically widespread, increasing evidence has suggested that ictal discharges may in fact represent travelling waves propagated from a focal seizure source. Interictal epileptiform discharges (IEDs) are an electrographic manifestation of excessive hypersynchronization of cortical activity that occur between seizures and are considered a marker of potentially epileptogenic tissue. The precise relationship between brain regions demonstrating IEDs and those involved in seizure onset, however, remains poorly understood. Here, we hypothesize that IEDs likewise reflect the receipt of travelling waves propagated from the same regions which give rise to seizures. Forty patients from our institution who underwent invasive monitoring for epilepsy, proceeded to surgery and had at least one year of follow-up were included in our study. Interictal epileptiform discharges were detected using custom software, validated by a clinical epileptologist. We show that IEDs reach electrodes in sequences with a consistent temporal ordering, and this ordering matches the timing of receipt of ictal discharges, suggesting that both types of discharges spread as travelling waves. We use a novel approach for localization of ictal discharges, in which time differences of discharge receipt at nearby electrodes are used to compute source location; similar algorithms have been used in acoustics and geophysics. We find that interictal discharges co-localize with ictal discharges. Moreover, interictal discharges tend to localize to the resection territory in patients with good surgical outcome and outside of the resection territory in patients with poor outcome. The seizure source may originate at, and also travel to, spatially distinct IED foci. Our data provide evidence that interictal discharges may represent travelling waves of pathological activity that are similar to their ictal counterparts, and that both ictal and interictal discharges emerge from common epileptogenic brain regions. Our findings have important clinical implications, as they suggest that seizure source localizations may be derived from interictal discharges, which are much more frequent than seizures. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease frequently develop neurological complications including confusion and altered consciousness. Non-convulsive status epilepticus, which is characterized by a change in behavior and/or mental process accompanied by epileptiform discharges on electroencephalogram in the absence of convulsive seizures, is one of the overlooked causes of altered consciousness. The incidence and precise pathophysiological mechanism of non-convulsive status epilepticus in patients with kidney disease, and especially in patients with electrolyte disturbances, remains unknown. We recently treated an older patient with chronic kidney disease and severe hyperkalemia in whom non-convulsive status epilepticus developed following a correction of severe hyperkalemia. Case presentation: An 82-year-old male was admitted to our hospital at midnight because of weakness of all four limbs (Day 1). He underwent urgent hemodialysis for severe hyperkalemia (9.84 mEq/L) and his serum potassium concentration decreased to 4.97 mEq/L. He regained full consciousness and his limb weakness improved on the morning of Day 2, but he became confused in the evening. Electroencephalogram revealed repeated low-voltage ictal discharges in the right occipital region and a diagnosis of non-convulsive status epilepticus was made. Following medication with fosphenytoin and phenytoin, the patient became fully alert and orientated on Day 8. Conclusion: We speculate that a rapid correction of hyperkalemia was the possible cause of non-convulsive status epilepticus development. To our knowledge, this is the first report of non-convulsive status epilepticus from a potassium abnormality. We described a case of this condition in detail and summarized 78 previous case reports of non-convulsive status epilepticus with kidney disease or electrolyte disturbances. [ABSTRACT FROM AUTHOR]

Long-term home monitoring of people living with epilepsy cannot be achieved using the standard full-scalp electroencephalography (EEG) coupled with video. Wearable seizure detection devices, such as behind-the-ear EEG (bte-EEG), offer an unobtrusive method for ambulatory follow-up of this population. Combining bte-EEG with electrocardiography (ECG) can enhance automated seizure detection performance. However, such frameworks produce high false alarm rates, making visual review necessary. This study aimed to evaluate a semi-automated multimodal wearable seizure detection framework using bte-EEG and ECG. Using the SeizeIT1 dataset of 42 patients with focal epilepsy, an automated multimodal seizure detection algorithm was used to produce seizure alarms. Two reviewers evaluated the algorithm's detections twice: (1) using only bte-EEG data and (2) using bte-EEG, ECG, and heart rate signals. The readers achieved a mean sensitivity of 59.1% in the bte-EEG visual experiment, with a false detection rate of 6.5 false detections per day. Adding ECG resulted in a higher mean sensitivity (62.2%) and a largely reduced false detection rate (mean of 2.4 false detections per day), as well as an increased inter-rater agreement. The multimodal framework allows for efficient review time, making it beneficial for both clinicians and patients. [ABSTRACT FROM AUTHOR]

Physiological parameters that predict electroconvulsive therapy (ECT) effectiveness may reflect propagation of the induced epileptic seizure. As an indication of seizure propagation to the diencephalon, we here examined the correlation between prolactin increase after ECT and clinical seizure evaluation parameters, focusing on peak heart rate. As a proxy for peripheral endocrine stress response, we examined the correlation to postictal cortisol increase. Participants were consecutively recruited from clinical ECT patients (n = 131, age 18–85 years). The first ECT session in a series was examined. For each participant, blood serum concentrations of prolactin and cortisol were measured immediately before and within 30 min after the seizure. Physiological parameters were extracted from clinical records: peak heart rate (HR) during seizure, electroencephalography (EEG) seizure duration, and motor seizure duration. Correlations were calculated using non-parametric tests. Serum prolactin increased after ECT and correlated with peak HR, EEG seizure duration, and motor seizure duration. Peak HR during seizure also correlated positively with both EEG seizure duration and motor seizure duration. Correlations were unaffected by age, sex, baseline prolactin levels, antipsychotics, or beta-blocking agents. Serum cortisol increased after ECT but did not correlate with the seizure evaluation parameters, nor with prolactin concentrations. Our findings of a positive correlation between peak HR and prolactin that was independent from the peripheral endocrine stress response might be in line with the idea that tachycardia during ECT seizures reflects seizure propagation to the diencephalon. This supports the practice of monitoring cardiovascular response for ECT seizure evaluation. [ABSTRACT FROM AUTHOR]

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1β concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1β concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation. [ABSTRACT FROM AUTHOR]

Blood–brain barrier (BBB) dysfunction emerges as one of the mechanisms underlying the induction of seizures and epileptogenesis. There is growing evidence that seizures also affect BBB, yet only scarce data is available regarding serum levels of BBB-associated proteins in chronic epilepsy. In this study, we aimed to assess serum levels of molecules associated with BBB in patients with epilepsy in the interictal period. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2, S100B, CCL-2, ICAM-1, P-selectin, and TSP-2 were examined in a group of 100 patients who were seizure-free for a minimum of seven days and analyzed by ELISA. The results were compared with an age- and sex-matched control group. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B were higher in patients with epilepsy in comparison to control group (p < 0.0001; <0.0001; 0.001; <0.0001; <0.0001, respectively). Levels of CCL-2, ICAM-1, P-selectin and TSP-2 did not differ between the two groups. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B are elevated in patients with epilepsy in the interictal period, which suggests chronic processes of BBB disruption and restoration. The pathological process initiating epilepsy, in addition to seizures, is probably the factor contributing to the elevation of serum levels of the examined molecules. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS), as an emerging non - invasive neuromodulation technology, has high safety and provides a choice for intractable epilepsy patients without surgical indications or unable to benefit from surgical treatment. Among them, negative electrode tDCS can reduce epileptic discharge and seizure frequency by inhibiting abnormal cortical excitation in epilepsy patients, restoring the balance of brain functional network. However, due to the heterogeneity among the results of various studies, its application in the treatment of epilepsy still needs further exploration. This article reviews the principle of tDCS, its potential mechanism in the treatment of epilepsy and its clinical application in intractable epilepsy in the past three years, providing evidence for the potential and safety of tDCS in the clinical treatment of intractable epilepsy. [ABSTRACT FROM AUTHOR]

Investigations into seizure initiation, in recent years, have focused almost entirely upon alterations of interneuronal function, chloride homeostasis, and extracellular potassium levels. In contrast, little attention has been directed toward a possible role of dendritic plateau potentials in the actual ictogenic transition, despite a substantial literature dating back 40 years regarding its importance generally in epilepsy. Here, we argue that an increase in dendritic excitability, coordinated across the population of pyramidal cells, is a key stage in ictogenesis. [ABSTRACT FROM AUTHOR]

Hemimegalencephaly (HME) is a rare brain congenital malformation, consisting in altered neuronal migration and proliferation within one hemisphere, which is responsible for early onset drug-resistant epilepsy. Hemispherotomy is an effective treatment option for patients with HME and drug-resistant epilepsy. Surgical outcome may be variable among different surgical series, and the long-term neuropsychological trajectory has been rarely defined using a standardized neurocognitive test. We report the epileptological and neuropsychological long-term outcomes of four consecutive HME patients, operated on before the age of three years. All patients were seizure-free and drug-free, and the minimum follow-up duration was of five years. Despite the excellent post-surgical seizure outcome, the long-term developmental outcome is quite variable between patients, ranging from mild to severe intellectual disabilities. Patients showed improvement mainly in communication skills, while visuo-perceptive and coordination abilities were more impaired. Epileptological outcome seems to be improved in early treated patients; however, neuropsychological outcome in HME patients may be highly variable despite early surgery. [ABSTRACT FROM AUTHOR]

Automatic detection of epileptic seizures is important in epilepsy control and treatment, and specific feature extraction assists in accurate detection. We developed a feature extraction method for seizure detection based on multi-site synchronous changes and an edge detection algorithm. We investigated five chronic temporal lobe epilepsy rats with 8- and 12-channel detection sites in the hippocampus and limbic system. Multi-site synchronous changes were selected as a specific feature and implemented as a seizure detection method. For preprocessing, we used magnitude-squared coherence maps and Canny edge detection algorithm to find the frequency band with the most significant change in synchronization and the important channel pairs. In detection, we used the maximal cross-correlation coefficient as an indicator of synchronization and the correlation coefficient curves' average value and standard deviation as two detection features. The method achieved high performance, with an average 96.60% detection rate, 2.63/h false alarm rate, and 1.25 s detection delay. The experimental results show that synchronization is an appropriate feature for seizure detection. The magnitude-squared coherence map can assist in selecting a specific frequency band and channel pairs to enhance the detection result. We found that individuals have a specific frequency band that reflects the most significant synchronization changes, and our method can individually adjust parameters and has good detection performance. [ABSTRACT FROM AUTHOR]

Growing studies indicate that vigilance states and circadian rhythms can influence seizure occurrence in patients with epilepsy and rodent models of epilepsy. Electrical kindling, referred to brief, repeated stimulations of a limbic structure, is a commonly used model of temporal lobe epilepsy. Kindling via the classic protocol lasting a few weeks does not generally induce spontaneous recurrent seizures (SRS), but extended kindling that applies over the course of a few months has shown to induce SRS in several animal species. Kindling-induced SRS in monkeys and cats were observed mainly during resting wakefulness or sleep, but the behavioral activities associated with SRS in rodent models of extended kindling remain unknown. We aimed to add information in this area using a mouse model of extended hippocampal kindling. Middle-aged C57 black mice experienced ≥80 hippocampal stimulations (delivered twice daily) and then underwent continuous 24 h electroencephalography (EEG)-video monitoring for SRS detection. SRS were recognized by EEG discharges and associated motor seizures. The five stages of the modified Racine scale for mice were used to score motor seizure severities. Seizure-preceding behaviors were assessed in a 3 min period prior to seizure onset and categorized as active and inactive. Three main observations emerged from the present analysis. (1) SRS were found to predominantly manifest as generalized (stage 3-5) motor seizures in association with tail erection or Straub tail. (2) SRS occurrences were not significantly altered by the light on/off cycle. (3) Generalized (stage 3-5) motor seizures were mainly preceded by inactive behaviors such as immobility, standing still, or apparent sleep without evident volitional movement. Considering deeper subcortical structures implicated in genesis of tail erection in other seizure models, we postulate that genesis of generalized motor seizures in extended kindled mice may involve deeper subcortical structures. Our present data together with previous findings from post-status epilepticus models support the notion that ambient cage behaviors are strong influencing factors of SRS occurrence in rodent models of temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Sleep disorders are common comorbidities in patients with temporal lobe epilepsy (TLE), but the underlying mechanisms remain poorly understood. Since the lateral hypothalamic (LH) and the perifornical orexinergic (ORX) and melanin-concentrating hormone (MCH) neurons are known to play opposing roles in the regulation of sleep and arousal, dysregulation of ORX and MCH neurons might contribute to the disturbance of sleep-wakefulness following epileptic seizures. Methods: To test this hypothesis, rats were treated with lithium chloride and pilocarpine to induce status epilepticus (SE). Electroencephalogram (EEG) and electromyograph (EMG) were recorded for analysis of sleep-wake states before and 24 h after SE. Double-labeling immunohistochemistry of c-Fos and ORX or MCH was performed on brain sections from the epileptic and control rats. In addition, anterograde and retrograde tracers in combination with c-Fos immunohistochemistry were used to analyze the possible activation of the amygdala to ORX neural pathways following seizures. Results: It was found that epileptic rats displayed prolonged wake phase and decreased non-rapid eye movement (NREM) and rapid eye movement (REM) phase compared to the control rats. Prominent neuronal activation was observed in the amygdala and the hypothalamus following seizures. Interestingly, in the LH and the perifornical nucleus, ORX but not MCH neurons were significantly activated (c-Fos+). Neural tracing showed that seizure-activated (c-Fos+) ORX neurons were closely contacted by axon terminals originating from neurons in the medial amygdala. Discussion: These findings suggest that the spread of epileptic activity from amygdala to the hypothalamus causes selective activation of the wake-promoting ORX neurons but not sleep-promoting MCH neurons, which might contribute to the disturbance of sleep-wakefulness in TLE. [ABSTRACT FROM AUTHOR]

Under physiological conditions, neuronal network synchronization leads to different oscillatory EEG patterns that are associated with specific behavioral and cognitive functions. Excessive synchronization can, however, lead to focal or generalized epileptiform activities. It is indeed well established that in both epileptic patients and animal models, focal epileptiform EEG patterns are characterized by interictal and ictal (seizure) discharges. Over the last three decades, employing in vitro and in vivo recording techniques, several experimental studies have firmly identified a paradoxical role of GABAA signaling in generating interictal discharges, and in initiating—and perhaps sustaining—focal seizures. Here, we will review these experiments and we will extend our appraisal to evidence suggesting that GABAA signaling may also contribute to epileptogenesis, i.e., the development of plastic changes in brain excitability that leads to the chronic epileptic condition. Overall, we anticipate that this information should provide the rationale for developing new specific pharmacological treatments for patients presenting with focal epileptic disorders such as mesial temporal lobe epilepsy (MTLE). [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders, characterized by the occurrence of repeated seizures. Given that epilepsy is considered a network disorder, tools derived from network neuroscience may confer the valuable ability to quantify the properties of epileptic brain networks. In this study, we use well-established brain network metrics (i.e., mean strength, variance of strength, eigenvector centrality, betweenness centrality) to characterize the temporal evolution of epileptic functional networks over several days prior to seizure occurrence. We infer the networks using long-term electroencephalographic recordings from 12 people with epilepsy. We found that brain network metrics are variable across days and show a circadian periodicity. In addition, we found that in 9 out of 12 patients the distribution of the variance of strength in the day (or even two last days) prior to seizure occurrence is significantly different compared to the corresponding distributions on all previous days. Our results suggest that brain network metrics computed fromelectroencephalographic recordings could potentially be used to characterize brain network changes that occur prior to seizures, and ultimately contribute to seizure warning systems. [ABSTRACT FROM AUTHOR]

Seizure is one of the manifestations of central nervous system inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody‐positive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). Acute symptomatic seizures secondary to MS/AQP4‐NMOSD/MOGAD occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent nonprovoked seizures, mainly attributed to autoimmune‐associated epilepsy, occur in the nonacute phase of the diseases. Seizures in MS/AQP4‐NMOSD/MOGAD mostly have a focal onset. MS patients with concomitant systemic infections, earlier onset, and greater disease activity are more likely to have seizures, whereas factors such as greater MS severity, the presence of status epilepticus, and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis and acute disseminated encephalomyelitis (ADEM)‐like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a greater seizure risk. Multiple relapses with ADEM‐like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction, and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS/AQP4‐NMOSD/MOGAD consists of immunotherapy along with antiseizure medications. This critical review discusses the most‐updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS/AQP4‐NMOSD/MOGAD. Treatment cautions including drug‐drug interactions and the impact of treatments on the diseases are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions. [ABSTRACT FROM AUTHOR]

Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guineapig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4-aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure. [ABSTRACT FROM AUTHOR]

Epilepsy is considered a circuit-level dysfunction associated with imbalanced excitation-inhibition, it is therapeutically necessary to identify key brain regions and related circuits in epilepsy. The subiculum is an essential participant in epileptic seizures, but the circuit mechanism underlying its role remains largely elusive. Here we deconstruct the diversity of subicular circuits in a mouse model of epilepsy. We find that excitatory subicular pyramidal neurons heterogeneously control the generalization of hippocampal seizures by projecting to different downstream regions. Notably, anterior thalamus-projecting subicular neurons bidirectionally mediate seizures, while entorhinal cortex-projecting subicular neurons act oppositely in seizure modulation. These two subpopulations are structurally and functionally dissociable. An intrinsically enhanced hyperpolarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission, thus contributing to the generalization of hippocampal seizures. These results demonstrate that subicular circuits have diverse roles in epilepsy, suggesting the necessity to precisely target specific subicular circuits for effective treatment of epilepsy. The subiculum is known to contribute to seizures in epilepsy. Here the authors investigate the circuit mechanism by which the subiculum contributes to initiation and propagation of hippocampal seizures in a mouse model. [ABSTRACT FROM AUTHOR]