CNS autoimmune response in the MAM/pilocarpine rat model of epileptogenic cortical malformation.

The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical alterations resulting from abnormal network excitability. However, recent analyses at single-cell resolution of human brain samples from MCD patients have indicated the possible involvement of adaptive immunity in the pathogenesis of these disorders. By exploiting the MethylAzoxyMethanol (MAM)/pilocarpine (MP) rat model of drug-resistant epilepsy associated with MCD, we show here that the occurrence of status epilepticus and subsequent spontaneous recurrent seizures in the malformed, but not in the normal brain, are associated with the outbreak of a destructive autoimmune response with encephalitis-like features, involving components of both cell-mediated and humoral immune responses. The MP brain is characterized by blood-brain barrier dysfunction, marked and persisting CD8+ T cell invasion of the brain parenchyma, meningeal B cell accumulation, and complement-dependent cytotoxicity mediated by antineuronal antibodies. Furthermore, the therapeutic treatment of MP rats with the immunomodulatory drug fingolimod promotes both antiepileptogenic and neuroprotective effects. Collectively, these data show that the MP rat could serve as a translational model of epileptogenic cortical malformations associated with a central nervous system autoimmune response. This work indicates that a preexisting brain maldevelopment predisposes to a secondary autoimmune response, which acts as a precipitating factor for epilepsy and suggests immune intervention as a therapeutic option to be further explored in epileptic syndromes associated with MCDs.

Involvement of GABAergic Interneuron Subtypes in 4-Aminopyridine-Induced Seizure-Like Events in Mouse Entorhinal Cortex in Vitro.

Single-unit recordings performed in temporal lobe epilepsy patients and in models of temporal lobe seizures have shown that interneurons are active at focal seizure onset. We performed simultaneous patch-clamp and field potential recordings in entorhinal cortex slices of GAD65 and GAD67 C57BL/6J male mice that express green fluorescent protein in GABAergic neurons to analyze the activity of specific interneuron (IN) subpopulations during acute seizure-like events (SLEs) induced by 4-aminopyridine (4-AP; 100 µm). IN subtypes were identified as parvalbuminergic (INPV, n = 17), cholecystokinergic (INCCK), n = 13], and somatostatinergic (INSOM, n = 15), according to neurophysiological features and single-cell digital PCR. INPV and INCCK discharged at the start of 4-AP-induced SLEs characterized by either low-voltage fast or hyper-synchronous onset pattern. In both SLE onset types, INSOM fired earliest before SLEs, followed by INPV and INCCK discharges. Pyramidal neurons became active with variable delays after SLE onset. Depolarizing block was observed in ∼50% of cells in each INs subgroup, and it was longer in IN (∼4 s) than in pyramidal neurons (<1 s). As SLE evolved, all IN subtypes generated action potential bursts synchronous with the field potential events leading to SLE termination. High-frequency firing throughout the SLE occurred in one-third of INPV and INSOM We conclude that entorhinal cortex INs are very active at the onset and during the progression of SLEs induced by 4-AP. These results support earlier in vivo and in vivo evidence and suggest that INs have a preferential role in focal seizure initiation and development.SIGNIFICANCE STATEMENT Focal seizures are believed to result from enhanced excitation. Nevertheless, we and others demonstrated that cortical GABAergic networks may initiate focal seizures. Here, we analyzed for the first time the role of different IN subtypes in seizures generated by 4-aminopyridine in the mouse entorhinal cortex slices. We found that in this in vitro focal seizure model, all IN types contribute to seizure initiation and that INs precede firing of principal cells. This evidence is in agreement with the active role of GABAergic networks in seizure generation.

Ictal fast activity chirps as markers of the epileptogenic zone.

The identification of the epileptogenic zone (EZ) boundaries is crucial for effective focal epilepsy surgery. We verify the value of a neurophysiological biomarker of focal ictogenesis, characterized by a low-voltage fast-activity ictal pattern (chirp) recorded with intracerebral electrodes during invasive presurgical monitoring (stereoelectroencephalography [SEEG]). The frequency content of SEEG signals was retrospectively analyzed with semiautomatic software in 176 consecutive patients with focal epilepsies that either were cryptogenic or presented with discordant anatomoelectroclinical findings. Fast activity seizure patterns with the spectrographic features of chirps were confirmed by computer-assisted analysis in 95.4% of patients who presented with heterogeneous etiologies and diverse lobar location of the EZ. Statistical analysis demonstrated (1) correlation between seizure outcome and concordance of sublobar regions included in the EZ defined by visual analysis and chirp-generating regions, (2) high concordance in contact-by contact analysis of 68 patients with Engel class Ia outcome, and (3) that discordance between chirp location and the visually outlined EZ correlated with worse seizure outcome. Seizure outcome analysis confirms the fast activity chirp pattern is a reproducible biomarker of the EZ in a heterogeneous group of patients undergoing SEEG.

Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Limbic and olfactory cortical circuits in focal seizures.

Epilepsies affecting the limbic regions are common and generate seizures often resistant to pharmacological treatment. Clinical evidence demonstrates that diverse regions of the mesial portion of the temporal lobe participate in limbic seizures; these include the hippocampus, the entorhinal, perirhinal and parahippocampal regions and the piriform cortex. The network mechanisms involved in the generation of olfactory-limbic epileptiform patterns will be here examined, with particular emphasis on acute interictal and ictal epileptiform discharges obtained by treatment with pro-convulsive drugs and by high-frequency stimulations on in vitro preparations, such as brain slices and the isolated guinea pig brain. The interactions within olfactory-limbic circuits can be summarized as follows: independent, region-specific seizure-like events (SLE) are generated in the olfactory and in the limbic cortex; SLEs generated in the hippocampal-parahippocampal regions tend to remain within these areas; the perirhinal region controls the neocortical propagation and the generalization of limbic seizures; interictal spiking in the olfactory regions prevents the invasion by SLEs generated in limbic regions. The potential relevance of these observations for human focal epilepsy is discussed.

Ligand-gated mechanisms leading to ictogenesis in focal epileptic disorders.

We review here the neuronal mechanisms that cause seizures in focal epileptic disorders and, specifically, those involving limbic structures that are known to be implicated in human mesial temporal lobe epilepsy. In both epileptic patients and animal models, the initiation of focal seizures - which are most often characterized by a low-voltage fast onset EEG pattern - is presumably dependent on the synchronous firing of GABA-releasing interneurons that, by activating post-synaptic GABAA receptors, cause large increases in extracellular [K+] through the activation of the co-transporter KCC2. A similar mechanism may contribute to seizure maintenance; accordingly, inhibiting KCC2 activity transforms seizure activity into a continuous pattern of short-lasting epileptiform discharges. It has also been found that interactions between different areas of the limbic system modulate seizure occurrence by controlling extracellular [K+] homeostasis. In line with this view, low-frequency electrical or optogenetic activation of limbic networks restrain seizure generation, an effect that may also involve the activation of GABAB receptors and activity-dependent changes in epileptiform synchronization. Overall, these findings highlight the paradoxical role of GABAA signaling in both focal seizure generation and maintenance, emphasize the efficacy of low-frequency activation in abating seizures, and provide experimental evidence explaining the poor efficacy of antiepileptic drugs designed to augment GABAergic function in controlling seizures in focal epileptic disorders.

A debate on the neuronal origin of focal seizures.

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.

Can in vitro studies aid in the development and use of antiseizure therapies? A report of the ILAE/AES Joint Translational Task Force.

In vitro preparations (defined here as cultured cells, brain slices, and isolated whole brains) offer a variety of approaches to modeling various aspects of seizures and epilepsy. Such models are particularly amenable to the application of anti-seizure compounds, and consequently are a valuable tool to screen the mechanisms of epileptiform activity, mode of action of known anti-seizure medications (ASMs), and the potential efficacy of putative new anti-seizure compounds. Despite these applications, all disease models are a simplification of reality and are therefore subject to limitations. In this review, we summarize the main types of in vitro models that can be used in epilepsy research, describing key methodologies as well as notable advantages and disadvantages of each. We argue that a well-designed battery of in vitro models can form an effective and potentially high-throughput screening platform to predict the clinical usefulness of ASMs, and that in vitro models are particularly useful for interrogating mechanisms of ASMs. To conclude, we offer several key recommendations that maximize the potential value of in vitro models in ASM screening. This includes the use of multiple in vitro tests that can complement each other, carefully combined with in vivo studies, the use of tissues from chronically epileptic (rather than naïve wild-type) animals, and the integration of human cell/tissue-derived preparations.

Distinctive electro-clinical, neuroimaging and histopathological features of temporal encephaloceles associated to epilepsy.

OBJECTIVE: Encephaloceles (ENCs) may cause clinical complications, including drug-resistant epilepsy that can be cured with epilepsy surgery. METHODS: We describe clinical, diagnostic, and neuropathological findings of 12 patients with temporal ENC and epilepsy evaluated for surgery and compare them with a control group of 26 temporal lobe epilepsy (TLE) patients. RESULTS: Six patients had unilateral and 6 bilateral temporal ENCs. Compared to TLEs, ENCs showed i) later epilepsy onset, ii) higher prevalence of psychiatric comorbidities, iii) no history of febrile convulsions, and iv) ictal semiology differences. Seven patients had MRI signs of gliosis, and 9 of intracranial hypertension. Interictal EEG analysis in ENCs demonstrated significant differences with controls: prominent activity in the beta/gamma frequency bands in frontal regions, interictal short sequences of low-voltage fast activity, and less frequent and more localized interictal epileptiform discharges. Ictal EEG patterns analyzed in 9 ENCs showed delayed and slower contralateral spread compared to TLEs. All ENCs that underwent surgery (7 lobectomies and 1 lesionectomy) are in Engel class I. Neuropathological examination revealed 4 patterns: herniated brain fragments, focal layer I distortion, white matter septa extending into the cortex, and altered gyral profile. CONCLUSIONS AND SIGNIFICANCE: The described peculiarities might help clinicians to suspect the presence of largely underdiagnosed ENCs.

Dendritic pathology, spine loss and synaptic reorganization in human cortex from epilepsy patients.

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 analysed 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 aetiologies: 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.

Seizure activity and brain damage in a model of focal non-convulsive status epilepticus.

AIMS: Focal non-convulsive status epilepticus (FncSE) is a common emergency condition that may present as the first epileptic manifestation. In recent years, it has become increasingly clear that de novo FncSE should be promptly treated to improve post-status outcome. Whether seizure activity occurring during the course of the FncSE contributes to ensuing brain damage has not been demonstrated unequivocally and is here addressed. METHODS: We used continuous video-EEG monitoring to characterise an acute experimental FncSE model induced by unilateral intrahippocampal injection of kainic acid (KA) in guinea pigs. Immunohistochemistry and mRNA expression analysis were utilised to detect and quantify brain injury, 3-days and 1-month after FncSE. RESULTS: Seizure activity occurring during the course of FncSE involved both hippocampi equally. Neuronal loss, blood-brain barrier permeability changes, gliosis and up-regulation of inflammation, activity-induced and astrocyte-specific genes were observed in the KA-injected hippocampus. Diazepam treatment reduced FncSE duration and KA-induced neuropathological damage. In the contralateral hippocampus, transient and possibly reversible gliosis with increase of aquaporin-4 and Kir4.1 genes were observed 3 days post-KA. No tissue injury and gene expression changes were found 1-month after FncSE. CONCLUSIONS: In our model, focal seizures occurring during FncSE worsen ipsilateral KA-induced tissue damage. FncSE only transiently activated glia in regions remote from KA-injection, suggesting that seizure activity during FncSE without local pathogenic co-factors does not promote long-lasting detrimental changes in the brain. These findings demonstrate that in our experimental model, brain damage remains circumscribed to the area where the primary cause (KA) of the FncSE acts. Our study emphasises the need to use antiepileptic drugs to contain local damage induced by focal seizures that occur during FncSE.

A hypothesis for the role of axon demyelination in seizure generation.

Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies (such as focal cortical dysplasias and tuberous sclerosis) and in animal models of focal epilepsy. Moreover, seizures are a frequent symptom in demyelinating diseases, such as multiple sclerosis, and in animal models of demyelination and oligodendrocyte dysfunction. Finally, the excessive activity reported in demyelinated axons may promote hyperexcitability. We hypothesize that the extracellular potassium rise generated during epileptiform activity may be amplified by the presence of axons without appropriate myelin coating and by alterations in oligodendrocyte function. This process could facilitate the triggering of recurrent spontaneous seizures in areas of altered myelination and could result in further demyelination, thus promoting epileptogenesis.

Peripheral blood mononuclear cell activation sustains seizure activity.

OBJECTIVE: The influx of immune cells and serum proteins from the periphery into the brain due to a dysfunctional blood-brain barrier (BBB) has been proposed to contribute to the pathogenesis of seizures in various forms of epilepsy and encephalitis. We evaluated the pathophysiological impact of activated peripheral blood mononuclear cells (PBMCs) and serum albumin on neuronal excitability in an in vitro brain preparation. METHODS: A condition of mild endothelial activation induced by arterial perfusion of lipopolysaccharide (LPS) was induced in the whole brain preparation of guinea pigs maintained in vitro by arterial perfusion. We analyzed the effects of co-perfusion of human recombinant serum albumin with human PBMCs activated with concanavalin A on neuronal excitability, BBB permeability (measured by FITC-albumin extravasation), and microglial activation. RESULTS: Bioplex analysis in supernatants of concanavalin A-stimulated PBMCs revealed increased levels of several inflammatory mediators, in particular interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (INF)-γ, IL-6, IL-10, IL-17A, and MIP3α. LPS and human albumin arterially co-perfused with either concanavalin A-activated PBMCs or the cytokine-enriched supernatant of activated PBMCs (1) modulated calcium-calmodulin-dependent protein kinase II at excitatory synapses, (2) enhanced BBB permeability, (3) induced microglial activation, and (4) promoted seizure-like events. Separate perfusions of either nonactivated PBMCs or concanavalin A-activated PBMCs without LPS/human albumin (hALB) failed to induce inflammatory and excitability changes. SIGNIFICANCE: Activated peripheral immune cells, such as PBMCs, and the extravasation of serum proteins in a condition of BBB impairment contribute to seizure generation.

Molecular Chaperones and miRNAs in Epilepsy: Pathogenic Implications and Therapeutic Prospects.

Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.

The understanding of mental states and the cognitive phenotype of frontal lobe epilepsy.

OBJECTIVE: Previous studies of frontal lobe epilepsy (FLE) have documented different impairments of theory of mind (ToM), while the study of frontal lobe (FL) lesion without seizures has produced inconsistent results. Given the role played by the FLs in ToM, we evaluated this and other functions in patients with FLE with and without FL lesions. The main objective was to clarify the salience of ToM impairment in the cognitive pattern of FLE and its capacity to discriminate these patients from healthy subjects. The effects of FL lesions on ToM were also explored. METHODS: Seventy-five adult patients with FLE (40 cases with FL lesions) were compared with 42 healthy controls. The Faux Pas Task (FPT) and other neuropsychological tests were utilized to assess ToM, reasoning, language, memory, praxis, attention, and executive abilities. RESULTS: The patients obtained lower z scores for the FPT than for other tests. The ToM, Executive, and Verbal factors discriminated patients from healthy subjects. The patients with or without FL lesion showed significant impairments in recognizing and understanding others' epistemic and affective mental states, but adequate capacity to exclude inexistent mental states was retained. In comparison with controls, the patients with FL lesions obtained lower scores for lexical, memory, praxis, attention, and executive functions, whereas those without lesion only showed attention and initiative deficits. Schooling was the major predictor of ToM, whereas the capacity to exclude inexistent mental states was related to seizure onset age and epilepsy duration. Other cognitive functions were related to schooling, age, or FLE laterality. SIGNIFICANCE: Impaired understanding of real mental states is a specific, salient, and discriminating cognitive aspect of FLE. Poor education is a risk factor for ToM deficit, whereas the clinical variables and FL lesions have no impact. These results suggest that impaired ToM may be a marker of FLE neurobehavioral phenotype.

Quality of life, psychiatric symptoms, and stigma perception in three groups of persons with epilepsy.

OBJECTIVE: The current study aimed to describe quality of life (QoL) levels, psychiatric symptoms prevalence, and perceived stigma levels in persons with either drug-resistant epilepsy (DRE) or drug-sensitive epilepsy (DSE) and in persons with epilepsy (PwE) with DRE that underwent epilepsy surgery (DREES). METHODS: Persons with epilepsy diagnosed as having DRE according to International League Against Epilepsy (ILAE) criteria, DSE, and DREES were enrolled at the Epilepsy Unit of the Neurological Institute Carlo Besta of Milan. Sociodemographic and clinical data, Quality of Life in Epilepsy Inventory (QOLIE-31), Symptom Checklist-90 (SCL-90), and the Epilepsy Stigma Scale (ESS) were collected based on self-reported information and on medical records. RESULTS: Sociodemographic, medical, and psychological data were obtained from 181 PwE: 80 with DRE, 31 with DSE, and 70 with DREES. We found that QoL is higher and psychiatric symptoms are lower in persons with DSE compared with DRE and that patients with DREES, who were drug-resistant before surgery, are in between DSE and DRE for both measures. Perceived stigma level is different in DSE and in DRE, that report the highest levels of stigma, and is between the other two groups in DREES. SIGNIFICANCE: This study suggests that low QoL levels and high psychiatric symptoms prevalence in drug-resistant PwE may be significantly improved after epilepsy surgery and suggests the importance of a biopsychosocial approach when planning therapeutic intervention.

Epilepsy course during COVID-19 pandemic in three Italian epilepsy centers.

During epidemic outbreaks, epilepsy course can be modified by different physical and psychological stressors and, most importantly, by irregular therapy intake. The effect of COVID-19 and quarantine isolation on the course of epilepsy and on incidence of new-onset seizures is still unclear. With the aim of managing epilepsy in quarantined patients, three Italian Epilepsy Centers set up telephone consultations using a semistructured interview, allowing a prospective collection of data on seizure course and other seizure-related problems during pandemic. The collected data on seizure course were compared with the analogous period of 2019. The level of patients' concern relating to the COVID-19 pandemic was also assessed using a numeric rating scale. To address the effect of COVID-19 pandemic on seizure incidence, data collection included the number of consultations for first seizures, relapse seizures, and status epilepticus (SE) in the emergency department of one of the participating centers. Clinical telephone interviews suggest the absence of quarantine effect on epilepsy course in our cohort. No differences in incidence of emergency consultations for seizures over a two-month period were also observed compared with a control period. As demonstrated in other infective outbreaks, good antiepileptic drug (AED) supplying, precise information, and reassurance are the most important factors in chronic conditions to minimize psychological and physical stress, and to avoid unplanned treatment interruptions.

GABAA receptor-mediated networks during focal seizure onset and progression in vitro.

Focal seizures are triggered by the pathological synchronization of a functionally altered group of neurons. In vivo and in vitro results in rodents and single unit studies in humans suggest that seizure can be initiated by increased activity in interneuronal networks. We review here the data derived from in vitro perparations to describe the function of GABAergic network in different phases of focal seizures. The data demonstrate that GABA-mediated synchronization of interneuronal activity has an active role in shaping focal seizure dynamics.

Two main focal seizure patterns revealed by intracerebral electroencephalographic biomarker analysis.

OBJECTIVE: Long-term recording with intracerebral electrodes is commonly utilized to identify brain areas responsible for seizure generation (epileptogenic zone) and to tailor therapeutic surgical resections in patients with focal drug-resistant epilepsy. This invasive diagnostic procedure generates a wealth of data that contribute to understanding human epilepsy. We analyze intracerebral signals to identify and classify focal ictal patterns. METHODS: We retrospectively analyzed stereo-electroencephalographic (EEG) data in a cohort of patients either cryptogenic (magnetic resonance imaging negative) or presenting with noncongruent anatomoelectroclinical data. A computer-assisted method based on EEG signal analysis in frequency and space domains was applied to 467 seizures recorded in 105 patients submitted to stereo-EEG presurgical monitoring. RESULTS: Two main focal seizure patterns were identified. P-type seizures, typical of neocortex, were observed in 73 patients (69.5%), lasted 22 ± 13 seconds (mean +SD), and were characterized by a sharp-onset/sharp-offset transient superimposed on low-voltage fast activity (126 ± 19 Hz). L-type seizures were observed in 43 patients (40.9%) and consistently involved mesial temporal structures; they lasted longer (93 ± 48 second), started with 116 ± 21 Hz low-voltage fast activity superimposed on a slow potential shift, and terminated with large-amplitude, periodic bursting activity. In 23 patients (21.9%), the L-type seizure was preceded by a P seizure. Spasmlike and unclassifiable EEG seizures were observed in 11.4% of cases. SIGNIFICANCE: The proposed computer-assisted approach revealed signal information concealed to visual inspection that contributes to identifying two principal seizure patterns typical of the neocortex and of mesial temporal networks.

Epileptiform activity contralateral to unilateral hippocampal sclerosis does not cause the expression of brain damage markers.

OBJECTIVE: Patients with epilepsy often ask if recurrent seizures harm their brain and aggravate their epileptic condition. This crucial question has not been specifically addressed by dedicated experiments. We analyze here if intense bilateral seizure activity induced by local injection of kainic acid (KA) in the right hippocampus produces brain damage in the left hippocampus. METHODS: Adult guinea pigs were bilaterally implanted with hippocampal electrodes for continuous video-electroencephalography (EEG) monitoring. Unilateral injection of 1 µg KA in the dorsal CA1 area induced nonconvulsive status epilepticus (ncSE) characterized by bilateral hippocampal seizure discharges. This treatment resulted in selective unilateral sclerosis of the KA-injected hippocampus. Three days after KA injection, the animals were killed, and the brains were submitted to ex vivo magnetic resonance imaging (MRI) and were processed for immunohistochemical analysis. RESULTS: During ncSE, epileptiform activity was recorded for 27.6 ± 19.1 hours in both the KA-injected and contralateral hippocampi. Enhanced T1-weighted MR signal due to gadolinium deposition, mean diffusivity reduction, neuronal loss, gliosis, and blood-brain barrier permeability changes was observed exclusively in the KA-injected hippocampus. Despite the presence of a clear unilateral hippocampal sclerosis at the site of KA injection, no structural alterations were detected by MR and immunostaining analysis performed in the hippocampus contralateral to KA injection 3 days and 2 months after ncSE induction. Fluoro-Jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining at the same time points confirmed the absence of degenerating cells in the hippocampi contralateral to KA injection. SIGNIFICANCE: We demonstrate that intense epileptiform activity during ncSE does not cause obvious brain damage in the hippocampus contralateral to unilateral hippocampal KA injection. These findings argue against the hypothesis that epileptiform activity per se contributes to focal brain injury in previously undamaged cortical regions.