Generalized Seizures Research Articles

Resting-state brain activity distinguishes patients with generalised epilepsy from others

PurposeEpilepsy is a prevalent neurological disorder characterised by repetitive seizures. It is categorised into three types: generalised epilepsy (GE), focal epilepsy (FE), and combined generalised and focal epilepsy. Correctly subtyping the epilepsy is important to select appropriate treatments. The types are mainly determined (i.e., diagnosed) by their semiologies supported by clinical examinations, such as electroencephalography and magnetoencephalography (MEG). Although these examinations are traditionally based on visual inspections of interictal epileptic discharges (IEDs), which are not always visible, alternative analyses have been anticipated. We examined if resting-state brain activities can distinguish patients with GE, which would help us to diagnose the type of epilepsy. MethodsThe 5 min resting-state brain activities acquired using MEG were obtained retrospectively from 15 patients with GE. The cortical source of the activities was estimated at each frequency band from delta to high-frequency oscillation (HFO). These estimated activities were compared with reference datasets from 133 healthy individuals and control data from 29 patients with FE. ResultsPatients with GE showed larger theta in the occipital, alpha in the left temporal, HFO in the rostral deep regions, and smaller HFO in the caudal ventral regions. Their area under the curves of the receiver operating characteristic curves was around 0.8–0.9. The distinctive pattern was not found for data from FE. ConclusionPatients with GE show distinctive resting-state brain activity, which could be a potential biomarker and used complementarily to classical analysis based on the visual inspection of IEDs.

EEG Temporal-Spatial Feature Learning for Automated Selection of Stimulus Parameters in Electroconvulsive Therapy.

The risk of adverse effects in Electroconvulsive Therapy (ECT), such as cognitive impairment, can be high if an excessive stimulus is applied to induce the necessary generalized seizure (GS); Conversely, inadequate stimulus results in failure. Recent efforts to automate this task can facilitate statistical analyses on individual parameters or qualitative predictions. However, this automation still significantly lags behind the requirements in clinical practices. This study addresses this issue by predicting the probability of GS induction under the joint restriction of a patient's EEG (electroencephalogram) and the stimulus parameters, sustained by a two-stage learning model (namely ECTnet): 1) Temporal-Spatial Feature Learning. Channel-wise convolution via multiple convolution kernels first learns the deep features of the EEG, followed by a "ConvLSTM" constructing the temporal-spatial features aided with the enforced convolution operations at the LSTM gates; 2) GS Prediction. The probability of seizure induction is predicted based on the EEG features fused with stimulus parameters, through which the optimal parameter setting(s) may be obtained by minimizing the stimulus charge while ensuring the probability above a threshold. Experiments have been conducted on EEG data from 96 subjects with mental disorders to examine the performance and design of ECTnet. These experiments indicate that ECTnet can effectively automate the selection of optimal stimulus parameters: 1) an AUC of 0.746, F1-score of 0.90, a precision of 89% and a recall of 93% in the prediction of seizure induction have been achieved, outperforming the state-of-the-art counterpart, and 2) inclusion of parameter features increases the F1-score by 0.054.

Pannexin1 Mediates Early-Life Seizure-Induced Social Behavior Deficits.

There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.

Manifestações neurológicas da Síndrome de Ogden: relato de caso

INTRODUCTION: The syndrome related to a mutation in the N-alpha-acetyltransferase 10 (NAA10) gene, an X-linked recessive disorder, Ogden Syndrome, presents in boys with severe developmental delay, central hypotonia, dysmorphic features, cardiac malformations, and early death in the first months of life. CASE REPORT: Male infant with hypotonia and craniofacial dysmorphisms: prominent forehead, triangular facies, bilateral microphthalmia, superior oblique palpebral fissure and epicanthus, increased nasolabial filter, tapered upper lip, sparse blond hair, long and light eyelashes. Delay in neuropsychomotor development, brief episodes of oromasticatory movements, sialorrhea, horizontal nystagmus, excessive sleepiness, and hypo-responsiveness, with oxygen saturation drop and bradycardia. Electroencephalogram: bursts of diffuse slow waves. Echocardiogram and electrocardiogram without alterations. Cranial resonance: cortical thickening in the right frontal lobe, small encephalomalacic area; signs of previous ischemic insult in the territory of the right posterior cerebral artery; areas of signal alteration in the central and deep white matter adjacent to the lateral ventricles with mild compensatory dilation of the same; and diffuse thinning of the corpus callosum of undetermined nature, treatment initiated. Genome identified a likely pathogenic variant in the NAA10 gene. Under treatment with phenobarbital and oxcarbazepine, and multiprofessional follow-up. DISCUSSION/CONCLUSION: Many patients present neuroimaging alterations, mainly: corpus callosum hypoplasia and microcephaly. Epilepsy around 69%, generalized, described eyelid myoclonias or spasms, or as identified in this patient: oromasticatory automatism. There is a need to include Ogden Syndrome in differential diagnoses and investigate the NAA10 gene in epilepsy and intellectual disability panels, even without multisystemic manifestations.

PERCEIVED SOCIAL SUPPORT WITH EARLY MALADAPTIVE SCHEMAS AMONG MALE AND FEMALE EPILEPTICS.

Abstract Background of study: Individuals with epilepsy face number of psychological and physical challenges in their daily life. One of the issues is the faulty thought processes, such as disturbed thinking, holding negative beliefs about their selves, lack of social support from their family. Objectives: To examine (a) Younger epileptics will exhibit more early maladaptive schemas, and perceived low social support as compare to older epileptics.(b) Female epileptics will have more early maladaptive schemas, and perceived more social support as compared to male epileptics. (c) Married epileptics will experience less early maladaptive schemas, and perceived more social support as compared to unmarried epileptics. Methodology: This Correlational study was conducted on epileptic patients from March 2021 to December 2021. Sample of the current study was comprised of 200 epileptic patients. The sample was purposefully selected from hospitals and clinics of Lahore Pakistan. The questionnaire, Urdu version of young schema questionnaire short form (YSQ-SF), Urdu version of the multidimensional scale of perceived social support (MSPSS), were used to analyze the effect of early maladaptive schemas on perceived social support and quality of life among epileptics. Result: Results of the current study concluded that old-aged epileptics have less early maladaptive schemas, and perceived more social support as compared to young-aged epileptic. It is also concluded that female epileptics exhibited more maladaptive schemas, and perceived social support, as compared to male epileptics. Unmarried epileptics suffering from generalized seizure scored higher on early maladaptive schema and perceived low social support. While married epileptics suffering from generalized epileptic seizure and have perceived low social support. Conclusion: The results of study confirm the hypothesis by establishing examine the effect of early maladaptive schemas with perceived social support. Early maladaptive schemas have negative affect with perceived social support. Generalize seizure have high scores on early maladaptive schema and low score on perceived social support as compared to focal seizure epileptics. Key Word: Early Maladaptive Schemas, Perceived Social Support, and Quality of Life.

The Association Between Serum Levels of Glial Biomarkers, Clinical Severity and Electro-encephalography Features in Idiopathic West and Lennox-Gastaut Syndromes.

Although the contribution of enhanced glial activity in seizure induction is increasingly recognized, the role of glia-induced neuroinflammation in the physiopathology of epileptic encephalopathy (EE) has been scarcely investigated. To delineate the contribution of glial activity in EE, we measured levels of glia-derived mediators with previously described biomarker value, including glial fibrillary acidic protein (GFAP), high mobility group box 1 (HMGB1), chitinase-3-like protein 1 (CHI3L1), soluble CD163 (sCD163) and triggering receptor expressed on myeloid cells 2 (TREM2) by ELISA in sera of patients with idiopathic West syndrome (WS, n=18), idiopathic Lennox-Gastaut syndrome (LGS, n=13) and healthy controls (n=31). Patients with EE showed significantly higher CHI3L1 levels compared to healthy controls. Levels of HMGB1, CHI3L1, sCD163 and TREM2 were higher in LGS patients than WS patients and/or healthy controls. One or more of the investigated mediators were associated with treatment responsiveness, disease severity and presence of pathological features on electroencephalography (EEG). To our knowledge, our findings provide the initial patient-based evidence that astrocyte- and microglia-mediated neuroinflammation might be involved in the pathogenesis of LGS and WS. Moreover, glial mediators may serve as prognostic biomarkers in patients with idiopathic EE.

Ictal activity is sustained by the estrogen receptor β during the estrous cycle

Catamenial epilepsy, defined as a periodicity of seizure exacerbation during the menstrual cycle, affects up to 70 % of epileptic women. Seizures in these patients are often non-responsive to medication; however, our understanding of the relation between menstrual cycle and seizure generation (i.e. ictogenesis) remains limited. We employed here field potential recordings in the in vitro 4-aminopyridine model of epileptiform synchronization in female mice (P60–P130) and found that: (i) the estrous phase favors ictal activity in the entorhinal cortex; (ii) these ictal discharges display an onset pattern characterised by the presence of chirps that are thought to mirror synchronous interneuron firing; and (iii) blocking estrogen receptor β-mediated signaling reduces ictal discharge duration. Our findings indicate that the duration of 4AP-induced ictal discharges, in vitro, increases during the estrous phase, which corresponds to the human peri-ovulatory period. We propose that these effects are caused by the presumptive enhancement of interneuron excitability due to increased estrogen receptor β-mediated signaling.

Targeted sonogenetic modulation of GABAergic interneurons in the hippocampal CA1 region in status epilepticus.

Rationale: Sonogenetics is an advanced ultrasound-based neurostimulation approach for targeting neurons in specific brain regions. However, the role of sonogenetics in treating status epilepticus (SE) remains unclear. Here, we aimed to investigate the effects of ultrasound neurostimulation and MscL-G22S (a mechanosensitive ion channel that mediates Ca2+ influx)-mediated sonogenetics (MG-SOG) in a mouse model of kainic acid (KA)-induced SE. Methods: For MG-SOG, a Cre-dependent AAV expressing MscL-G22S was injected into parvalbumin (PV)-cre and somatostatin (SST)-cre mice to induce the expression of MscL-G22S-EGFP in PV interneurons (PV-INs) and SST interneurons (SST-INs), respectively; mice were stimulated with continuous pulses of ultrasound stimulation during the latency of generalized seizures (GSs), the latency to SE, in SE model mice. We performed calcium fiber photometry, patch-clamp recording, local field potential recording, and SE monitoring to investigate the role of MG-SOG in treating SE. Results: First, we observed obvious neuronal activation in the hippocampal CA1 region in SE model mice. Both excitatory neurons (ENs) and GABAergic interneurons (GABA-INs) in the CA1 region were activated in SE model mice; however, the inhibitory effect of GABA-INs on ENs seemed to be insufficient to reduce EN excitability despite the increased activation of GABA-INs in SE model mice. Thus, we speculated that MG-SOG-induced activation of GABA-INs, mainly SST-INs and PV-INs, in the CA1 region may protect against SE. We found that MG-SOG-mediated PV-IN activation in the CA1 region ameliorated SE and changed SE-related electrophysiological abnormalities in the CA1 region; however, MG-SOG-induced SST-IN activation in the CA1 region did not ameliorate SE. Conclusions: MG-SOG-mediated activation of PV-INs had a positive effect on relieving SE. Our work may promote the development of sonogenetic neurostimulation techniques for treating SE.

Isolation of Salmonella enterica Serovar Typhi from Infected Intracranial Dermoid Cyst: A Case Report

Salmonella Typhi is a versatile pathogen that can infect almost all organs of its host. There has been an increase in the number of cases of extraintestinal infection caused by Salmonella species during the past decade. Present case is of a 17-year-old immunocompetent female admitted to the hospital with complaints of a general tonic-clonic seizure and diagnosed with a Suprasellar hypodense lesion with Hydrocephalus (HCP) documented on a Computed Tomography (CT) scan of the head. Magnetic Resonance Imaging (MRI) revealed signs of an intracranial dermoid cyst. Placement of a right Ventriculoperitoneal (VP) Shunt was performed, followed by a right craniotomy with decompression, during which 5 mL of pus was collected from the lesion. The pus was received in the Department of Microbiology and subjected to culture, which grew Salmonella enterica serovar Typhi. The patient had been empirically receiving injection cefoperazone-sulbactam 2g/2g twice daily and injection vancomycin 1g 12 hourly before the isolation of Salmonella Typhi. She had also been receiving injection levetiracetam 500 mg i.v. twice a day and inj. phenytoin 500 mg i.v. thrice a day. Following the positive culture report, injection ceftriaxone 2 g daily was started. The patient was discharged on the fifth postoperative day while on injection ceftriaxone, oral levetiracetam 500 mg, and phenytoin 100 mg and was asked to report to the neurosurgery department after seven days for follow-up. On follow-up, she showed improvement, and there were no complaints of fever, seizure, or loss of consciousness. In conclusion, proper clinical, radiological, and microbiological evaluation is very much necessary, and clinicians should be aware of the relatively rare manifestations of Salmonella Typhi infections.

Epilepsy insights revealed by intravital functional optical imaging.

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.

Supramolecular delivery of dinuclear ruthenium and osmium MCU inhibitors.

The transmembrane protein known as the mitochondrial calcium uniporter (MCU) mediates the influx of calcium ions (Ca2+) into the mitochondrial matrix. An overload of mitochondrial Ca2+ ( m Ca2+) is directly linked to damaging effects in pathological conditions. Therefore, inhibitors of the MCU are important chemical biology tools and therapeutic agents. Here, two new analogues of previously reported Ru- and Os-based MCU inhibitors Ru265 and Os245, of the general formula [(C10H15CO2)M(NH3)4(μ-N)M(NH3)4(O2CC10H15)](CF3SO3)3, where M = Ru (1) or Os (2), are reported. These analogues bear adamantane functional groups, which were installed to act as guests for the host molecule cucurbit-[7]-uril (CB[7]). These complexes were characterized and analyzed for their efficiency as guests for CB[7]. As shown through a variety of spectroscopic techniques, each adamantane ligand is encapsulated into one CB[7], affording a supramolecular complex of 1 : 2 stoichiometry. The biological effects of these compounds in the presence and absence of two equiv. CB[7] were assessed. Both complexes 1 and 2 exhibit enhanced cellular uptake compared to the parent compounds Ru265 and Os245, and their uptake is increased further in the presence of CB[7]. Compared to Ru265 and Os245, 1 and 2 are less potent as m Ca2+ uptake inhibitors in permeabilized cell models. However, in intact cell systems, 1 and 2 inhibit the MCU at concentrations as low as 1 μM, marking an advantage over Ru265 and Os245 which require an order of magnitude higher doses for similar biological effects. The presence of CB[7] did not affect the inhibitory properties of 1 and 2. Experiments in primary cortical neurons showed that 1 and 2 can elicit protective effects against oxygen-glucose deprivation at lower doses than those required for Ru265 or Os245. At low concentrations, the protective effects of 1 were modulated by CB[7], suggesting that supramolecular complex formation can play a role in these biological conditions. The in vivo biocompatibility of 1 was investigated in mice. The intraperitoneal administration of these compounds and their CB[7] complexes led to time-dependent induction of seizures with no protective effects elicited by CB[7]. This work demonstrates the potential for supramolecular interactions in the development of MCU inhibitors.

Intraoperative changes in large-scale thalamic circuitry following laser ablation of hypothalamic hamartomas

Background and objectivesGelastic seizures due to hypothalamic hamartomas (HH) are challenging to treat, in part due to an incomplete understanding of seizure propagation pathways. Although magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) is a promising intervention to disconnect HH from ictal propagation networks, the optimal site of ablation to achieve seizure freedom is not known. In this study, we investigated intraoperative post-ablation changes in resting-state functional connectivity to identify large-scale networks associated with successful disconnection of HH. MethodsChildren who underwent MRgLITT for HH at two institutions were consecutively recruited and followed for a minimum of one year. Seizure freedom was defined as Engel score of 1A at the last available follow-up. Immediate pre- and post- ablation resting-state functional MRI scans were acquired while maintaining a constant depth of general anesthetic. Multivariable generalized linear models were used to identify intraoperative changes in large-scale connectivity associated with seizure outcomes. ResultsTwelve patients underwent MRgLITT for HH, five of whom were seizure-free at their last follow-up. Intraprocedural changes in thalamocortical circuitry involving the anterior cingulate cortex were associated with seizure-freedom. Children who were seizure-free demonstrated an increase and decrease in connectivity to the pregenual and dorsal anterior cingulate cortices, respectively. In addition, children who became seizure-free demonstrated increased thalamic connectivity to the periaqueductal gray immediately following MRgLITT. DiscussionSuccessful disconnection of HH is associated with intraoperative, large-scale changes in thalamocortical connectivity. These changes provide novel insights into the large-scale basis of gelastic seizures and may represent intraoperative biomarkers of treatment success.

Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability.

Epilepsy, a complex neurological condition marked by recurring seizures, is increasingly recognized for its intricate relationship with mitochondria, the cellular powerhouses responsible for energy production and calcium regulation. This review offers an in-depth examination of the interplay between epilepsy, mitochondrial function, and aging. Many factors might account for the correlation between epilepsy and aging. Mitochondria, integral to cellular energy dynamics and neuronal excitability, perform a critical role in the pathophysiology of epilepsy. The mechanisms linking epilepsy and mitochondria are multifaceted, involving mitochondrial dysfunction, reactive oxygen species (ROS), and mitochondrial dynamics. Mitochondrial dysfunction can trigger seizures by compromising ATP production, increasing glutamate release, and altering ion channel function. ROS, natural byproducts of mitochondrial respiration, contribute to oxidative stress and neuroinflammation, critical factors in epileptogenesis. Mitochondrial dynamics govern fusion and fission processes, influence seizure threshold and calcium buffering, and impact seizure propagation. Energy demands during seizures highlight the critical role of mitochondrial ATP generation in maintaining neuronal membrane potential. Mitochondrial calcium handling dynamically modulates neuronal excitability, affecting synaptic transmission and action potential generation. Dysregulated mitochondrial calcium handling is a hallmark of epilepsy, contributing to excitotoxicity. Epigenetic modifications in epilepsy influence mitochondrial function through histone modifications, DNA methylation, and non-coding RNA expression. Potential therapeutic avenues targeting mitochondria in epilepsy include mitochondria-targeted antioxidants, ketogenic diets, and metabolic therapies. The review concludes by outlining future directions in epilepsy research, emphasizing integrative approaches, advancements in mitochondrial research, and ethical considerations. Mitochondria emerge as central players in the complex narrative of epilepsy, offering profound insights and therapeutic potential for this challenging neurological disorder.

Insular lobe epilepsy. Part 1: semiology

The insula is often referred to as "the fifth lobe" of the brain, and its accessibility used to be very limited due to the deep location under the opercula as well as the sylvian vasculature. It was not until the availability of modern stereo-electroencephalography (SEEG) technique that the intracranial electrodes could be safely and chronically implanted within the insula, thereby enabling anatomo-electro-clinical correlations in seizures of this deep origin. Since the first report of SEEG-recorded insular seizures in late 1990s, the knowledge of insular lobe epilepsy (ILE) has rapidly expanded. Being on the frontline for the diagnosis and management of epilepsy, neurologists should have a precise understanding of ILE to differentiate it from epilepsies of other lobes or non-epileptic conditions. Owing to the multimodal nature and rich anatomo-functional connections of the insula, ILE has a wide range of clinical presentations. The following symptoms should heighten the suspicion of ILE: somatosensory symptoms involving a large/bilateral cutaneous territory or taking on thermal/painful character, and cervico-laryngeal discomfort. The latter ranges from slight dyspnea to a strong sensation of strangulation (laryngeal constriction). Other symptoms include epigastric discomfort/nausea, hypersalivation, auditory, vestibular, gustatory, and aphasic symptoms. However, most of these insulo-opercular symptoms can easily be masked by those of extra-insular seizure propagation. Indeed, sleep-related hyperkinetic (hypermotor) epilepsy (SHE) is a common clinical presentation of ILE, which shows predominant hyperkinetic and/or tonic-dystonic features that are often indistinguishable from those of fronto-mesial seizures. Subtle objective signs, such as constrictive throat noise (i.e., laryngeal constriction) or aversive behavior (e.g., facial grimacing suggesting pain), are often the sole clue in diagnosing insular SHE. Insular-origin seizures should also be considered in temporal-like seizures without frank anatomo-electro-clinical correlations. All in all, ILE is not the epilepsy of an isolated island but rather of a crucial hub involved in the multifaceted roles of the brain.

Seizure Pathways Changes at the Subject-Specific Level via Dynamic Step Effective Network Analysis.

The variability in the propagation pathway in epilepsy is a main factor contributing to surgical treatment failure. Ways to accurately capture the brain propagation network and quantitatively assess its evolution remain poorly described. This work aims to develop a dynamic step effective network (dSTE) to obtain the propagation path network of multiple seizures in the same patient and explore the degree of dissimilarity. Multichannel stereo-electroencephalography (sEEG) signals were acquired with ictal processes involving continuous changes in information propagation. We utilized high-order dynamic brain networks to obtain propagation networks through different levels of linking steps. We proposed a dissimilarity index based on singular value decomposition to quantitatively compare seizure pathways. Simulated data were generated through The Virtual Brain, and the reliability of this method was verified through ablation experiments. By applying the proposed method to two datasets consisting of 29 patients total, the evolution processes of each patient's seizure networks was obtained, and the within-patient dissimilarities were quantitatively compared. Finally, three types of brain network connectivity patterns were found. Type I patients have a good prognosis, while type III patients are prone to postoperative recurrence. This method captures the evolution of seizure propagation networks and assesses their dissimilarity more reliably than existing methods, demonstrating good robustness for studying the propagation path differences for multiple seizures in epilepsy patients. The three different patterns will be important considerations when planning epilepsy surgery under sEEG guidance.

Touch-screen automatisms in the digital age

ObjectiveTo describe a novel set of gestural automatisms related to the use of digital screens on smartphones and tablets in patients with epilepsy. MethodsRepresentative patients were selected from among those admitted to the Epilepsy Monitoring Unit at the Toronto Western Hospital between April 2016 and January 2020, and included if they exhibited automatisms clearly related to or mimicking digital device use. ResultsIn total 5 patients were included, 4 female. All had temporal lobe epilepsy: 2 had left mesial temporal sclerosis and 3 had normal imaging. Nearly equal numbers of seizures began with right (5/9) and left (4/9) temporal onsets, with most automatisms occurring after seizure propagation to bilateral temporal involvement (6/9). Left-handed automatisms were most common (8/9). The majority of the automatisms (7/9) were perseverative on device usage prior to the seizure. ConclusionGestural automatisms appear related to the contemporary lived experience, culture, and habitual behaviour of patients with epilepsy. In the modern era, the use of smartphones and tablets are both common and habitual for many, and this case series shows that touch-screen automatisms may be added to the semiological panoply of temporal lobe seizures.

Perampanel increases seizure threshold in pentylenetetrazole-kindled mice and improves behavioral dysfunctions by modifying mRNA expression levels of BDNF/TrkB and inflammatory markers

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects.

KRM–II–81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM–II–81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM–II–81 might reduce seizure burden in pharmacoresistant patients.

Alcohol for seizure induction in the epilepsy monitoring unit

Rationale: Seizure induction techniques are used in the epilepsy monitoring unit (EMU) to increase diagnostic yield and reduce length of stay. There are insufficient data on the efficacy of alcohol as an induction technique. MethodsWe performed a retrospective cohort study using six years of EMU data at our institution. We compared cases who received alcohol for seizure induction to matched controls who did not. The groups were matched on the following variables: age, reason for admission, length of stay, number of antiseizure medications (ASM) at admission, whether ASMs were tapered during admission, and presence of interictal epileptiform discharges. We used both propensity score and exact matching strategies. We compared the likelihood of epileptic seizures and nonepileptic events in cases versus controls using Kaplan-Meier time-to-event analysis, as well as odds ratios for these outcomes occurring at any time during the admission. ResultsWe analyzed 256 cases who received alcohol (median dose 2.5 standard drinks) and 256 propensity score-matched controls. Cases who received alcohol were no more likely than controls to have an epileptic seizure (X2(1) = 0.01, p = 0.93) or nonepileptic event (X2(1) = 2.1, p = 0.14) in the first 48 h after alcohol administration. For the admission overall, cases were no more likely to have an epileptic seizure (OR 0.89, 95 % CI 0.61–1.28, p = 0.58), nonepileptic event (OR 0.97, CI 0.62–1.53, p = 1.00), nor require rescue benzodiazepine (OR 0.63, CI 0.35–1.12, p = 0.15). Stratified analyses revealed no increased risk of epileptic seizure in any subgroups. Sensitivity analysis using exact matching showed that results were robust to matching strategy. ConclusionsAlcohol was not an effective induction technique in the EMU. This finding has implications for counseling patients with epilepsy about the risks of drinking alcohol in moderation in their daily lives.

Multilevel Mathematical Model of Epileptic Seizures

The paper presents novel developed modular mathematical model of epileptic seizures, obtained by combining and modifying existing models of epilepsy, which for the first time makes it possible to simulate the dynamics of seizure onset, propagation and termination simultaneously at the cellular and regional levels of brain organization. At the level of individual cells, the dynamics of AMPA receptor trafficking, changes in the concentrations of intra- and extracellular ions, membrane depolarization, and other biophysical processes responsible for the development of ictal activity were calculated. Local field potentials of brain regions were modeled at the regional level taking into account cellular processes and the large-scale structure of the brain network. It is shown that the dynamics of submodels used in the structure of the multilevel model corresponds to the dynamics of the original models, the authors of which validated them with experimental data. The theoretical justification of the connections between submodels was given.