Seizure Onset Research Articles

Circulating miR-134 in mesial temporal lobe epilepsy: implications in hippocampal sclerosis development and drug resistance

AimmiR-134 has been widely reported as upregulated in experimental and human studies of Mesial Temporal Lobe Epilepsy the most common drug-resistant epilepsy (DRE). Studies have shown that the use of antagomirs, anti-miR-134, may be a promising therapeutic approach to these epilepsies. However, data on miR-134 in other epileptic syndromes is scarce. In this study, we aimed to quantify serum levels of miR-134 in a cohort of patients with Mesial Temporal Lobe Epilepsy-Hippocampal Sclerosis (MTLE-HS) and with Genetic Generalized Epilepsies (GGE). Additionally, we explored the correlation between miR-134 serum levels and clinical parameters, such as age at onset or febrile seizures antecedents, to evaluate its potential as a biomarker and therapeutic target in epilepsy.MethodsmiR-134 levels were evaluated in cell-free serum of 131 patients with epilepsy (75 women, 56 men; age 41.10 ± 13.12 years; 72 with DRE) and 42 healthy individuals (25 women, 17 men; age 42.40 ± 9.80 years). The epilepsy cohort included 77 MTLE-HS patients and 54 GGE patients.ResultsPatients with elevated miR-134 circulating levels were at higher risk of drug-resistant epilepsy (OR [95% CI] = 2.246 [1.111–4.539], p = 0.021). Other risk factors included an older age (OR [95% CI] = 1.032 [1.004–1.061], p = 0.025), history of febrile seizures (OR [95% CI] = 2.994 [1.385–6.471], p = 0.005) and higher disease duration (OR [95% CI] = 1.038 [1.011–1.066], p = 0.006). The strongest predictor of DRE was hippocampal sclerosis (OR [95% CI] = 10.338 [4.566–23.404], p < 0.001). Circulating miR-134 levels were significantly higher in MTLE-HS patients compared to controls (p < 0.05) and GGE patients (p < 0.05). However, the clinical utility of miR-134 in discriminating MTLE-HS patients from controls was only moderated (AUC = 0.651 ± 0.051 95% CI 0.551–0.751, p = 0.007).ConclusionWe show that miR-134 circulating levels are associated with DRE, especially in MTLE-HS, a syndrome characterized by severe hippocampal damage, consistent with activity-regulated miR-134 expression. This overexpression likely contributes to disease progression and our results support the potential of targeting miR-134 as a novel therapeutic approach for refractory epilepsy.

Seizure Detection and Lateralization Using Thalamic Deep Brain Stimulator Recordings.

The lack of reliable seizure detection remains a significant challenge for epilepsy care. A clinical deep brain stimulation (DBS) system provides constrained ambulatory brain recordings; however, limited data exist on the use of DBS recordings for seizure detection and lateralization. We present the case of an 18-year-old patient with drug-resistant focal epilepsy, who had seizure detection and lateralization by DBS recordings. Prior stereotactic-EEG, including a thalamus lead, identified independent left orbitofrontal and mesial temporal onset seizures. Notably, low-frequency thalamic ictal power was significantly elevated relative to baseline awake and sleep states. The patient was subsequently implanted with an anterior nucleus of the thalamus DBS system. Postimplantation, low-frequency power-in-band (5.3-10.3 Hz) recordings were initiated. Nursing staff identified four typical clinical seizures during the inpatient DBS recording period. Thalamic DBS trends contained relative peaks that were coincident with each nurse-reported seizure. Peri-ictal power was uniformly maximal ipsilateral to the seizure network. This case demonstrates the feasibility of seizure detection and lateralization by a thalamic DBS system for some individuals, and suggests DBS sensing parameter selection may be guided by thalamic stereotactic EEG. Further research is necessary to assess the generalizability of DBS seizure detection across individuals and diverse seizure networks.

Resting-state fMRI seizure onset localization meta-analysis: comparing rs-fMRI to other modalities including surgical outcomes

ObjectiveResting-state functional MRI (rs-fMRI) may localize the seizure onset zone (SOZ) for epilepsy surgery, when compared to intracranial EEG and surgical outcomes, per a prior meta-analysis. Our goals were to further characterize this agreement, by broadening the queried rs-fMRI analysis subtypes, comparative modalities, and same-modality comparisons, hypothesizing SOZ-signal strength may overcome this heterogeneity.MethodsPubMed, Embase, Scopus, Web of Science, and Google Scholar between April 2010 and April 2020 via PRISMA guidelines for SOZ-to-established-modalities were screened. Odd ratios measured agreement between SOZ and other modalities. Fixed- and random-effects analyses evaluated heterogeneity of odd ratios, with the former evaluating differences in agreement across modalities and same-modality studies.ResultsIn total, 9,550 of 14,384 were non-duplicative articles and 25 met inclusion criteria. Comparative modalities were EEG 7, surgical outcome 6, intracranial EEG 5, anatomical MRI 4, EEG-fMRI 2, and magnetoencephalography 1. Independent component analysis 9 and seed-based analysis 8 were top rs-fMRI methods. Study-level odds ratio heterogeneity in both the fixed- and random-effects analysis was significant (p < 0.001). Marked cross-modality and same-modality systematic differences in agreement between rs-fMRI and the comparator were present (p = 0.005 and p = 0.002), respectively, with surgical outcomes having higher agreement than EEG (p = 0.002) and iEEG (p = 0.007). The estimated population mean sensitivity and specificity were 0.91 and 0.09, with predicted values across studies ranging from 0.44 to 0.96 and 0.02 to 0.67, respectively.SignificanceWe evaluated centrality and heterogeneity in SOZ agreement between rs-fMRI and comparative modalities using a wider variety of rs-fMRI analyzing subtypes and comparative modalities, compared to prior. Strong evidence for between-study differences in the agreement odds ratio was shown by both the fixed- and the random-effects analyses, attributed to rs-fMRI analysis variability. Agreement with rs-fMRI differed by modality type, with surgical outcomes having higher agreement than EEG and iEEG. Overall, sensitivity was high, but specificity was low, which may be attributed in part to differences between other modalities.

Budget impact analysis of cenobamate for epilepsy patients with drug-resistant focal onset seizures in the Netherlands

Objective The objective of this study was to explore the financial consequences of adopting cenobamate as a treatment alternative in epilepsy patients with drug-resistant focal onset seizures (FOS) from a societal perspective in the Netherlands. Methods A previous budget impact model with a 5-year time horizon was adapted to the Dutch setting accounting for the eligible population, real-world market shares, treatment effectiveness and resource use in two scenarios: cenobamate with constant market share versus cenobamate with linearly increased market share up to 20%. Clinical inputs included treatment response, seizure reduction and adverse events. Costs consisted of drugs, medical and non-medical costs. One-way sensitivity analysis and scenario analysis were conducted to test the robustness of our results. Results 14,723 patients were eligible for cenobamate in 2022. Although cenobamate adds a gross budget impact of €12,686,30, the displacement of other drugs yields a total impact on the drug budget of €3,722,596 over 5 years. Adopting cenobamate resulted in a medical cost savings of €13,499,498 due to less resource use, and non-medical cost savings of €22,144,054 due to reduced productivity losses. Overall, savings generated at medical and non-medical cost level offset the gross drug budget impact of cenobamate, resulting in a saving of €31,920,955 over 5 years. Results were robust in the sensitivity/scenario analyses. Conclusion Treatment with cenobamate is associated with both medical and non-medical cost savings, which offset the increase in drug budget and result in a significant potential budget saving. The higher the market share of cenobamate, the larger the budget savings. We acknowledge several limitations; Complex scenarios such as drug interactions, stopping/switching drugs, and multiple drug use were not taken into account. The long-term efficacy and safety of cenobamate and its comparators remains uncertain. Future real-world data are needed to confirm our findings.

A Prospective Single-Arm Cohort Study of Immune-mediated Seizures/Epilepsy Without Encephalopathy (ISEWE) in Children from a Tertiary Care Hospital in South India.

Acute-onset seizures in children pose a diagnostic and therapeutic dilemma. Some epilepsy cases presenting with seizures but without encephalopathy, though treatable with immunotherapy, are often missed due to lack of suspicion of immune mechanism in the context of absent encephalitis. A prospective study was conducted on premorbidly normal children with new-onset seizures occurring in clusters, with normal neuroimaging. Investigations included electroencephalogram (EEG), cerebrospinal fluid examination, and testing for autoantibodies. All cases received methylprednisolone pulse therapy along with antiseizure medications (ASMs), followed by monthly dexamethasone oral pulse therapy. Fifteen cases were enrolled (11 males, four females). Mean age at seizure onset was 4.6 years. Focal seizures were present in 13/15 (86.7%) cases. Magnetic resonance imaging of the brain was normal in all. EEG showed interictal epileptiform discharges in 12 cases (focal in nine) and ictal record in two cases. On monthly oral steroids, number of ASMs could be reduced. Eight cases never had a relapse, while seven did have it. Relapses were more common if more than three ASMs were tried and less if steroids were started within 30 days. Immune-mediated seizures/epilepsy without encephalopathy is a new, important, and treatable entity. Early diagnosis and institution of immunotherapy results in significant improvement in seizure control and also reduces the need for long-term polytherapy. Awareness of this entity is crucial, especially when premorbidly normal children present with new-onset clusters of refractory seizures.

Ictal Involvement of the Pulvinar and the Anterior Nucleus of the Thalamus in Patients With Refractory Epilepsy.

Deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT) has been shown to be effective in treating some patients with medically refractory epilepsy. However, it remains unknown how seizures spread through the ANT relative to other thalamic nuclei. This study aimed to investigate, through simultaneous recordings from both ANT and pulvinar (PLV) nucleus, their roles in seizure propagation. Our goal was to determine whether the ANT is the primary site of seizure propagation in the human thalamus, especially for focal seizure originating in the medial temporal lobe. In a retrospective design, we studied EEGs and clinical notes of patients with refractory epilepsy who were implanted with stereo-EEG (sEEG) electrodes across cortical regions, some of which were extended to reach various sites of the thalamus (i.e., multisite thalamic recordings). We selected patients from the Stanford Comprehensive Epilepsy Center with both ANT and PLV electrodes and collected information about the timing and anatomy of seizure activity in the seizure onset zones, usually temporal, and the 2 thalamic sites. We recruited 17 (5 female, mean age 32 years) adult patients with simultaneous ipsilateral ANT and PLV recordings. In all patients, the procedure was safe without any complications. In 100% of patients, the thalamus was involved during seizures (in 88% both ANT and PLV and in 82% first the PLV). In patients with confirmed hippocampal or amygdalar onset seizures, 62% had initial involvement and 100% had subsequent involvement of the PLV nucleus. Only 31% showed initial propagation to ANT. All focal-to-bilateral tonic-clonic seizures and most of the focal impaired awareness seizures had early involvement of both ANT and PLV, with rapid spread to the contralateral nuclei. sEEG of thalamic nuclei simultaneously provides an opportunity to understand propagation patterns of seizures with respect to each thalamic subdivision at the individual level. The patterns of seizure propagation, as we report here, provide insights about the prominent involvement of the PLV nucleus during seizure propagation. This may motivate future prospective work in larger cohorts of patients to understand how thalamic propagation may predict response to resective/ablative surgery or whether personalization of DBS (for instance, PLV instead of, or together with, ANT) could improve clinical outcomes.

Stereoelectroencephalography (SEEG)-guided insula resections: is it "Reily" worth it?

Stereoelectroencephalography (SEEG) is widely used to characterise epileptic networks and guide resection in paediatric epilepsy surgery programmes. The insula, with its extensive connectivity with temporal and extratemporal structures, has increasingly been seen as a possible surgical target. We report our seizure outcomes after SEEG-guided resection of the insula in a paediatric cohort. From our paediatric epilepsy surgery database of patients aged 0-19 years, we analysed demographic and clinical data of those who underwent SEEG-guided insula cortex resection. In total, 11 children (7 females, 4 males) who underwent SEEG-guided resection were identified. The mean age at first SEEG was 13 years old. Mean age at seizure onset was 4.3 years; seizure frequency ranged from 50/day to 2/week. Four children required 1 SEEG study, 6 children 2 SEEG, and 1 child underwent 3 SEEG recordings. The mean follow-up duration was 2.1 years; at the latest follow-up, three children had Engel I, 2 children Engel III, and 6 children Engel IV. One child classified as an Engel IV outcome for insular surgery had Engel class I after 2 failed insula surgeries, after an occult frontal focal cortical dysplasia was later identified and resected. No major complications were noted. In our paediatric series, one third of the patients undergoing insula cortex surgery after SEEG became seizure free but this may require repeat SEEG implantation, repeat resective surgery and the possibility of changing hypothesis from the insula cortex to nearby foci.

Ictal onset zone localization by using ECOG signals

The diagnosis of seizure onset zone is crucial in epilepsy surgery for patients having pharmacoresistant, that the localization of ictal onset zone (IOZ) is associated with epileptiform activity region, by using intracranial strip and grid electrodes of electrocorticography (ECOG). Thus, these ECOG signals determine areas of the brain which can be surgically removed by visual inspection, especially in partial epilepsy named focal seizure. However, this paper investigates recent automatic IOZ localization, based on recurrent neural network (RNN) to improve the performance of identification of IOZ. Therefore, statistical patterns in time-frequency domains are extracted after applying hybrid empirical mode decomposition (EMD) and variational mode decomposition (VMD) methods. In addition, the evaluation of this work is performed by implementation of several indicators to distinct between focal and non focal ECOG signals. Moreover, the experiment results using Bern– Barcelona dataset indicated the effectiveness of using hybrid EMD-VMD method and RNN, that the proposed model achieve better classification performance reached 100% of accuracy. Hence, by comparison with other studies in the literature review, ECoG recordings provide best localization of IOZ by using this system. Finally, this developed method shows accurate results to help clinical experts in seizure resection, and indicates localization of IOZ which can be removed from brain area.

Understanding paralogous epilepsy–associated GABAA receptor variants: Clinical implications, mechanisms, and potential pitfalls

Recent discoveries have revealed that genetic variants in γ-aminobutyric acid type A (GABAA) receptor subunits can lead to both gain-of-function (GOF) and loss-of-function (LOF) receptors. GABAA receptors, however, have a pseudosymmetrical pentameric assembly, and curiously diverse functional outcomes have been reported for certain homologous variants in paralogous genes (paralogous variants). To investigate this, we assembled a cohort of 11 individuals harboring paralogous M1 proline missense variants in GABRA1, GABRB2, GABRB3, and GABRG2. Seven mutations (α1P260L, α1P260S, β2P252L, β3P253L, β3P253S, γ2P282A, and γ2P282S) in α1β2/3γ2 receptors were analyzed using electrophysiological examinations and molecular dynamics simulations. All individuals in the cohort were diagnosed with developmental and epileptic encephalopathy, with a median seizure onset age of 3.5 mo, and all exhibited global developmental delay. The clinical data for this cohort aligned with established GABAA receptor GOF but not LOF cohorts. Electrophysiological assessments revealed that all variants caused GOF by increasing GABA sensitivity by 3- to 23-fold. In some cases, this was accompanied by LOF traits such as reduced maximal current amplitude and enhanced receptor desensitization. The specific subunit mutated and whether the mutation occurred in one or two subunits within the pentamer influenced the overall effects. Molecular dynamics simulations confirmed similar structural changes from all mutations, but with position-dependent asymmetry. These findings establish that paralogous variants affecting the 100% conserved proline residue in the M1 transmembrane helix of GABAAR subunits all lead to overall GOF traits. The unexpected asymmetric and mixed effects on receptor function have broader implications for interpreting functional analyses for multimeric ion-channel proteins.

Peak width of skeletonized mean diffusivity as a marker of small vessel disease in patients with temporal lobe epilepsy with hippocampal sclerosis.

White matter abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) are well known. Peak width of skeletonized mean diffusivity (PSMD) is a novel marker for quantifying white matter integrity that may reflect small vessel disease. In this study, we aimed to quantify the extent of white matter damage in patients with TLE and HS by using PSMD. We enrolled 52 patients with TLE with HS and 54 age- and sex-matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3-T magnetic resonance imaging scanner. We measured PSMD using DTI findings and compared PSMD between patients with TLE with HS and healthy controls. We also evaluated the correlation between PSMD and clinical factors in patients with TLE and HS. PSMD differed significantly between healthy controls and patients with TLE and HS, and it was higher in the patients (2.375 × 10-4 mm2/s vs. 2.108 × 10-4 mm2/s, p < .001). Furthermore, PSMD in the ipsilateral hemisphere of the HS was higher than in the contralateral hemisphere of the HS (2.472 × 10-4 mm2/s vs. 2.258 × 10-4 mm2/s, p = .040). PSMD was positively correlated with age (r = .512, p < .001) and age at seizure onset (r = .423, p = .002) in patients with TLE and HS. Patients with TLE and HS had higher PSMD values than healthy controls, and PSMD was positively correlated with age. These findings provide evidence of white matter damage probably due to small vessel disease in patients with TLE and HS and support the feasibility of PSMD as a promising imaging marker for epileptic disorders.

Preictal period optimization for deep learning-based epileptic seizure prediction.

Accurate seizure prediction could prove critical for improving patient safety and quality of life in drug-resistant epilepsy. While deep learning-based approaches have shown promising performance using scalp electroencephalogram (EEG) signals, the incomplete understanding and variability of the preictal state imposes challenges in identifying the optimal preictal period (OPP) for labeling the EEG segments. This study introduces novel measures to capture model behavior under different preictal definitions and proposes a data-driven methodology to identify the OPP. &#xD;&#xD;Approach: We employed a competent subject-specific CNN-Transformer model (Area Under the Curve [AUC] of 99.35\% and F1-score of 97.46\%) to accurately detect preictal EEG segments using the open-access CHB-MIT dataset. To capture the temporal dynamics of the model's predictions, we fitted a sigmoidal curve to the model outputs obtained from uninterrupted multi-hour EEG recordings prior to seizure onset. From this fitted curve, we derived key performance measures reflecting the timing of predictions, including classifier convergence, average error, output stability, and the transition between interictal and preictal states. These measures were then combined to synthesize the Continuous Input-Output Performance Ratio (CIOPR), a novel metric designed to suggest the OPP for each patient.&#xD;&#xD;Significance: The newly developed metrics demonstrate that varying the preictal period significantly (p<0.001) impacts the timing of predictions in ways not captured by conventional accuracy-related metrics. Understanding this impact is essential for developing intelligent systems tailored to individual patient needs and for underlining practical limitations in detecting the preictal period in real-world clinical applications.

Methodological insights from the EPISTOP trial to designing clinical trials in rare diseases-A secondary analysis of a randomized clinical trial.

In clinical research, the most appropriate way to assess the effect of an intervention is to conduct a randomized controlled trial (RCT). In the field of rare diseases, conducting an RCT is challenging, resulting in a low rate of clinical trials, with a high frequency of early termination and unpublished trials. The aim of the EPISTOP trial was to compare outcomes in infants with tuberous sclerosis (TSC) who received vigabatrin preventively before the seizures onset with those who received it conventionally after. The study was designed as a prospective, multicentre, randomized clinical trial. However, ethics committees at four centres did not approve this RCT design, resulting in an open-label trial (OLT) in these four centres and an RCT in the other six centres. In this paper, we re-analyse the data from the EPISTOP trial using methods to investigate the influence of allocation bias on the results of the EPISTOP trial. A bias-corrected analysis is used to support and strengthen the published results. We included a term representing the effect of selection bias as an influencing factor on the corresponding endpoint in the statistical model. Thus, the treatment effect estimates for the primary endpoint of time to first seizure and additional secondary endpoints are adjusted for the bias effect. The bias-corrected analyses for the primary endpoint show that the estimated hazard ratio and associated confidence intervals are in a very similar range (original analysis: HR 2.91, 95%-CI [1.11 to 7.67], p-value 0.0306; bias-corrected analysis: HR 2.89, 95%-CI [1.10 to 7.58], p-value 0.0316). This was also the case for the secondary endpoints. The statistical re-analysis of the raw trial data therefore supports the published results and confirms that there is no additional bias introduced by randomization, thereby increasing the value of the results. However, this highlights that this aspect needs to be considered in future trials, especially in rare diseases, to avoid additional biases in an already small sample size where it may be difficult to reach significance.

A universal method for seizure onset zone localization in focal epilepsy using standard deviation of spike amplitude

BackgroundPrecisely localizing the seizure onset zone (SOZ) is critical for focal epilepsy surgery. Existing methods mainly focus on high-frequency activities in stereo-electroencephalography, but often fail when seizures are not driven by high-frequency activities. Recognized as biomarkers of epileptic seizures, ictal spikes in SOZ induce epileptiform discharges in other brain regions. Based on this understanding, we aim to develop a universal algorithm to localize SOZ and investigate how ictal spikes within the SOZ induce seizures. MethodsWe proposed a novel metric called standard deviation of spike amplitude (SDSA) and utilized channel-averaged SDSA to describe seizure processes and detect seizures. By integrating SDSA values in specific intervals, the score for each channel located within SOZ was calculated. Channels with high SOZ scores were clustered as SOZ. The localization accuracy was asserted using area under the receiver operating characteristic (ROC) curve. Further, we analyzed early ictal signals from SOZ channels and investigated factors influencing their duration to reveal the seizure inducing conditions. ResultsWe analyzed data from 15 patients with focal epilepsy. The channel-averaged SDSA successfully detected all 28 seizures without false alarms. Using SDSA integration, we achieved precise SOZ localization with an average area under ROC curve (AUC) of 0.96, significantly outperforming previous methods based on high-frequency activities. Further, we discovered that energy of ictal spikes in SOZ was concentrated at a specific frequency distributed in [6, 12Hz]. Additionally, we found that the higher the energy per second in this frequency band, the faster ictal spikes could induce seizures. ConclusionThe SDSA metric offered precise SOZ localization with robustness and low computational cost, making it suitable for clinical practice. By studying the propagation patterns of ictal spikes between the SOZ and non-SOZ, we suggest that ictal spikes from SOZ need to accumulate energy at a specific central frequency to induce epileptic spikes in non-SOZ, which may have significant implications for understanding the seizure onset pattern.

Association between Frequency of Seizures and Number of Antiseizure Medications (ASM) in Patients with Epilepsy.

The literature has shown the relevance of nutritional and metabolic aspects in patients with epilepsy. This study evaluated the relationship between clinical variables and plasma proteins and compared the variables between seizure frequency and neurological examination. A pilot study was carried out with eighty-four (n = 84) adults patients with epilepsy. The relationship between clinical variables of the disease (age at disease onset, neurological examination, current type and frequency of seizures, duration of disease, amount of antiseizure medications-ASM used and type and etiology of epilepsy) and plasma proteins (albumin and transferrin) was investigated. In the statistical analysis, the chi-square, Fisher, Mann-Whitney, Kruskal-Wallis tests, Spearman coefficient and univariate logistic regression were used. There was a significant association between the use of antiseizure medications (ASM) (p = 0.0105) and altered neurological examination (p = 0.0049), compared with the frequency of seizures, and between albumin and gender (p = 0.0005), and albumin and etiology of epilepsy (p = 0.0186). There was a significant low-intensity and inverse linear correlation (coefficient = -0.31363, p = 0.0037) between albumin and disease duration. In the logistic regression model, a significant association was only observed between the number of ASM and the frequency of seizures (p = 0.0120; OR = 3.368; 95% CI = 1.305-8.691). There was no association between plasma proteins and the outcomes of seizure frequency and neurological examination. The number of ASM and not protein metabolism was associated with frequency of seizures in patients with epilepsy.

New onset seizures in Octogenarians.

The occurrence of new seizure(s) in older adults is two- to three-fold higher as compared to the younger population, and previous studies have characterized the clinical features of seizures in patients beyond 60 or 65 years. This study, in response to the recent ILAE task force on epilepsy in the elderly (2023), has assessed the clinical characteristics of individuals who are over 85 years old. Data was collected from prospectively maintained electronic medical records, and the participants were divided into seizure-free and seizure-recurrence groups, and their clinical characteristics were compared. Over a 30-year period, a single comprehensive epilepsy care center included a total of 40 patients, with a mean age of 88.7 ± 2.79 years - most common seizure type was generalized tonic-clonic seizures (45%), with a positive neuroimaging yield of 42.5% and an EEG showing specific abnormalities in 50% of cases. Etiology was unidentified in 50%, while stroke was the most common among identified etiologies (27.5%). Over a mean follow-up of 1.4 [0.2-5.8] years, monotherapy effectively controlled 62.5% of patients, but 47.5% experienced recurrence. When compared to the non-recurrence group, these patients showed significant risk factors such as a history of prior stroke [47.3% versus 23.8%, p = 0.031], use of phenytoin [68.4% versus 33.3%, p = 0.056], and clobazam [42.1% vs. 19%, p = 0.049]. This study contributes to better identification and improved characterization of late-onset seizures and adds that appropriate, timely management results in better outcomes.

Chemogenetic silencing of the subiculum blocks acute chronic temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy. Subicular hyperexcitability is frequently observed with TLE, presumably caused by impaired inhibition of local excitatory neurons. Here, we evaluated the effectiveness of silencing subicular pyramidal neurons to treat a rodent model of TLE. First, we generated a chronic TLE mouse model via initial intrahippocampal kainic acid (IHKA) injection. In the chronic state after first IHKA injection, behavioral seizures and histological abnormalities were reliably observed. We then injected an adeno-associated viral (AAV) vector carrying an inhibitory chemogenetic element, hM4Di, directly into the subiculum. Eight weeks after the first IHKA injection, acute seizures were induced by giving a second dose of kainic acid (KA), which mimicked generalized tonic–clonic seizures. Herein, precise control over generalized tonic–clonic seizure onset was achieved via this two-step process. We found that chemogenetic suppression of subicular pyramidal neurons had a robust anti-epileptogenesis effect in this acute-chronic model of TLE. These data confirm a crucial role of the subiculum in the propagation of hippocampal seizures and highlight the potential for using subicular chemogenetic manipulation to treat generalized tonic–clonic seizures.

Diagnostic value of EEG after a first unprovoked seizure in adults – A population-based study

ObjectiveElectroencephalography (EEG) is a standard investigation after a first unprovoked seizure but the diagnostic value in adults remains unclear. Our objective was to investigate the diagnostic value of EEG after a first unprovoked seizure in a population-based cohort in Gothenburg, Sweden. MethodsThis retrospective population-based study included adult patients referred by a neurologist for EEG after a first unprovoked seizure from August 2016 - December 2019 in the greater Gothenburg catchment area. In total 520 patients were included and followed in medical records for a median of 4.42 years (range 0.33–6.93). Primary outcome measures were epileptiform activity. Medical records were reviewed for the influence of EEG on clinical management. The frequency of epileptiform activity was calculated and compared in different subgroup analyses. ResultsEEGs were recorded after a median of 70 days from the seizure. In total, 7.7 % had epileptiform activity, and 27.9 % had pathological slowing on their EEG. Seizure recurrence occurred in 33.7 % (29.6–37.8). Epileptiform activity predicted seizure recurrence with a recurrence risk of 82.5 % (70.7–94.3). The sensitivity of epileptiform activity was only 19.2 % (13.6–25.9) but the specificity was 98.0 % (95.9–99.2) and the relative risk of recurrence in presence of such activity was 2.8 (2.3–3.5). The EEG findings resulted in an alteration of diagnosis and/or medication in 4.4 % of the patients. Factors associated with epileptiform activity on EEG were younger age, EEG including sleep recording, generalized onset seizure, shorter time from seizure to EEG and longer duration of EEG recording. SignificanceThe yield of EEG recorded with a longer latency after a first unprovoked seizure in adults was low. However, epileptiform activity highly predicted seizure recurrence and our results suggest that epileptiform activity on EEG could be explored further as a biomarker for defining epilepsy already after a first seizure.

A Retrospective Study Reviewing Timing to Onset of Habitual Psychogenic Non-Epileptic Seizures in a Home Video Telemetry Cohort

Objectives: This study aimed to investigate the onset time to habitual psychogenic non-epileptic seizures (PNES) in adults referred to Guy’s and St Thomas’ Neurophysiology Department for home video telemetry (HVT) with a clinical question of PNES. The primary objective was to determine the optimal time window for HVT recording for patients with suspected PNES to try to improve the allocation of clinical resources. The secondary objective was to explore any potential association between time to habitual PN ES onset and demographic indexes and other clinical, neuro-radiological and semiological findings. Methods: We performed a retrospective analysis of our XLTEK database between 2019 and 2020. A multifactorial analysis of PNES semiologic subtypes, patient demographics, psychiatric comorbidities and neuroimaging was conducted to explore their impact on time to PNES within an HVT study. People who had at least one typical PNES during their recording were included. The exclusion criteria included people who had the test performed without video recording. The total number of participants was 37. The data were extracted from our local XLTEK database. Statistical analyses using Mann–Whitney U and Fischer exact tests were carried out. Results: The mean time to first habitual PNES onset was seven hours, with a mean recording duration of 46 h. The most commonly occurring event type was blank spells (12, 32%), with the least common presentation being déjà vu (1, 3%). There was a significant association between time to PNES onset and male sex (p = 0.04). There was a significant association between time to PNES onset and abnormal MRI findings (p = 0.02). Particular PNES semiologic subtypes were not significantly linked with PNES onset time. Conclusions: Our study highlights that on average, patients with PNES will rapidly have their first habitual event within an HVT study (mean time to event onset of seven hours), consistent with the current literature. This raises the question of whether HVT study duration could be reduced to release study resources and aid departmental efficiencies. We also observe the novel finding that men presented significantly earlier with their habitual PNES event than women, and that abnormal imaging findings were also significantly associated with an earlier time to event onset, although the reason for this association is yet to be determined.

Application of TCM network pharmacology and experimental verification to explore the mechanism of kaempferol against epilepsy

BackgroundKaempferol (KF), the main active ingredient in identifying the authenticity of safflower, has a variety of pharmacological activities and neuroprotective effects. However, the mechanism of KF in the treatment of epilepsy remains unclear. This study aimed to investigate the protective effects of KF on epilepsy and its related mechanisms. MethodsNetwork pharmacology was used to explore the targets and mechanisms of safflower antiepileptic action. The protective effect of KF on epilepsy was assessed in the behavior and tissues of epileptic mice. Additionally, the impact of KF on the excitability and calcium transients of rat cortical neurons and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) were investigated using patch clamp and calcium imaging techniques. ResultsNetwork pharmacology indicated safflower could be involved in calcium signaling pathways and calcium channel inhibitor activity. Experimental validation demonstrated that KF delayed seizure onset and mitigated neuronal damage in the prefrontal cortex of mice. It also reduced neuronal excitability, as indicated by action potential parameters, and suppressed Glutamate (Glu)-induced calcium transients. In tsA201 cells, KF inhibited AMPAR-mediated currents, suggesting a role in regulating [Ca2+]i homeostasis. ConclusionThese results indicate that KF's anticonvulsant properties may arise from its neuroprotection against cell injury, edema, and necrosis, its reduction of neuronal hyperexcitability, and its prevention of calcium-induced cytotoxicity, potentially involving AMPAR modulation. This study positions KF as a promising candidate for epilepsy therapy, offering a scientific foundation for its clinical investigation.

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy: QARS1 variants associated with a severe phenotype in a patient

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy is a rare disease due to QARS1 pathogenic variants altering the Glutaminyl-tRNA synthetase 1 activity. We report a Tunisian child presenting with neonatal onset seizures, severe psychomotor delay, retinal abnormalities and MRI cerebral supratentorial atrophy lesions. Whole exome and Sanger sequencing revealed two compound heterozygous variants of QARS1. Three-dimensional analysis of the mutant Glutaminyl-tRNA synthetase 1 predicted altered catalytic and tRNA-binding functions. Genotype–phenotype correlations emphasize the combined effect of the zygosity and the location of the pathogenic variants within the protein domains on the severity of the disease.