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Abstract Deep Learning (DL) has the potential to enhance patient outcomes in healthcare by implementing proficient systems for disease detection and diagnosis. However, the complexity and lack of interpretability impede their widespread adoption in critical high-stakes predictions in healthcare. Incorporating uncertainty estimations in DL systems can increase trustworthiness, providing valuable insights into the model’s confidence and improving the explanation of predictions. Additionally, introducing explainability measures, recognized and embraced by healthcare experts, can help address this challenge. In this study, we investigate DL models’ ability to predict sex directly from electroencephalography (EEG) data. While sex prediction have limited direct clinical application, its binary nature makes it a valuable benchmark for optimizing deep learning techniques in EEG data analysis. Furthermore, we explore the use of DL ensembles to improve performance over single models and as an approach to increase interpretability and performance through uncertainty estimation. Lastly, we use a data-driven approach to evaluate the relationship between frequency bands and sex prediction, offering insights into their relative importance. InceptionNetwork, a single DL model, achieved 90.7% accuracy and an AUC of 0.947, and the best-performing ensemble, combining variations of InceptionNetwork and EEGNet, achieved 91.1% accuracy in predicting sex from EEG data using five-fold cross-validation. Uncertainty estimation through deep ensembles led to increased prediction performance, and the models were able to classify sex in all frequency bands, indicating sex-specific features across all bands.

Abstract Objective The Salzburg EEG criteria for nonconvulsive status epilepticus (NCSE) have been proposed as consensus criteria for NCSE. We aimed to perform an independent study of their diagnostic accuracy. Methods A prospective study was carried out at Oslo University Hospital, including all consecutive patients ≥15 years old who were referred for an EEG with an explicit or implicit question of NCSE from February 2020 to February 2022. Two independent EEG readers scored the included EEGs according to the Salzburg criteria and blinded to the clinical data. The reference standard was defined as the clinical diagnosis the patient received based on all available clinical and paraclinical data. Diagnostic accuracy in identifying “certain/possible NCSE” was assessed by calculating sensitivity, specificity, positive predictive value, and negative predictive value with their 95% confidence intervals. Results In total, 469 patients/EEGs were included in the study. The prevalence of NCSE according to the reference standard was 11% (n = 53). The criteria showed a sensitivity of 94% (95% CI: 92–96%), a specificity of 77% (95% CI: 73–81%), a positive predictive value of 34% (95% CI: 30–39%), and a negative predictive value of 99% (95% CI: 98–100%). False positives for “certain NCSE” (n = 16) included many serial seizures and stimulus‐induced rhythmic and periodic discharges (SIRPIDs), as well as a focal cortical dysplasia. False positives for “possible NCSE” (n = 79) were mainly represented by different encephalopathies and postictality. Interpretation The low specificity of the Salzburg criteria calls for refinement before implementation into daily clinical practice.

BackgroundPost-traumatic epilepsy (PTE) is a well-known complication of traumatic brain injury (TBI). Although several risk factors have been identified, prediction of PTE is difficult. Changing demographics and advances in TBI treatment may affect the risk of PTE. Our aim was to provide an up-to-date estimate of the incidence of PTE by linking multiple nationwide registers.MethodsPatients with TBI admitted to hospital 2015–2018 were identified in the Norwegian Trauma Registry and matched to trauma-free controls on sex and birth year according to a matched cohort design. They were followed up for epilepsy in nationwide registers 2015–2020. Cumulative incidence of epilepsy in TBI patients and controls was estimated taking competing risks into account. Analyses stratified by the Abbreviated Injury Scale (AIS) severity score, Glasgow Coma Scale score and age were conducted for the TBI group. Occurrence of PTE in different injury types was visualized using UpSet plots.ResultsIn total, 8,660 patients and 84,024 controls were included in the study. Of the patients, 3,029 (35%) had moderate to severe TBI. The cumulative incidence of epilepsy in the TBI group was 3.1% (95% Confidence Interval [CI] 2.8–3.5%) after 2 years and 4.0% (3.6–4.5%) after 5 years. Corresponding cumulative incidences in the control group were 0.2% (95% CI 0.2–0.3%) and 0.5% (0.5–0.6%). The highest incidence was observed in patients with severe TBI according to AIS (11.8% [95% CI 9.7–14.4%] after 2 years and 13.2% [10.8–16.0%] after 5 years) and in patients >40 years of age.ConclusionPatients with TBI have significantly higher risk of developing epilepsy compared to population controls. However, PTE incidence following moderate–severe TBI was notably lower than what has been reported in several previously published studies.

Abstract Background Status Epilepticus (SE) is a common neurological emergency associated with a high rate of functional decline and mortality. Large randomized trials have addressed the early phases of treatment for convulsive SE. However, evidence regarding third-line anesthetic treatment and the treatment of nonconvulsive status epilepticus (NCSE) is scarce. One trial addressing management of refractory SE with deep general anesthesia was terminated early due to insufficient recruitment. Multicenter prospective registries, including the Sustained Effort Network for treatment of Status Epilepticus (SENSE), have shed some light on these questions, but many answers are still lacking, such as the influence exerted by distinct EEG patterns in NCSE on the outcome. We therefore initiated a new prospective multicenter observational registry to collect clinical and EEG data that combined may further help in clinical decision-making and defining SE. Methods Sustained effort network for treatment of status epilepticus/European Academy of Neurology Registry on refractory Status Epilepticus (SENSE-II/AROUSE) is a prospective, multicenter registry for patients treated for SE. The primary objectives are to document patient and SE characteristics, treatment modalities, EEG, neuroimaging data, and outcome of consecutive adults admitted for SE treatment in each of the participating centers and to identify factors associated with outcome and refractoriness. To reach sufficient statistical power for multivariate analysis, a cohort size of 3000 patients is targeted. Discussion The data collected for the registry will provide both valuable EEG data and information about specific treatment steps in different patient groups with SE. Eventually, the data will support clinical decision-making and may further guide the planning of clinical trials. Finally, it could help to redefine NCSE and its management. Trial registration NCT number: NCT05839418.

Abstract Objective Ketogenic diets like the modified Atkins diet (MAD) are increasingly used in patients with refractory epilepsy. For epilepsy patients, stress is a well‐known seizure‐precipitating factor. New possibilities for measuring biomarkers of stress are now available. The purpose of this study was to investigate the impact of MAD on endocrine stress biomarkers. Methods Forty‐nine patients with drug‐resistant epilepsy were investigated at baseline and after 12 weeks on MAD. Cortisol and cortisol‐binding globulin (CBG) were measured and free cortisol index (FCI) calculated. We also measured metanephrine, normetanephrine, and methoxytyramine, all markers of epinephrine, norepinephrine, and dopamine, respectively. Changes were analyzed according to sex and antiseizure medications. The different markers at baseline and after 12 weeks of MAD treatment were correlated with seizure frequency and weight loss, respectively. Results The change in total cortisol was modest after 12 weeks on the diet (from 432.9 nmol/L (403.1–462.7)) to 422.6 nmol/L (384.6–461.0), P = 0.6). FCI was reduced (from 0.39 (0.36–0.42) to 0.34 (0.31–0.36), P = 0.001). CBG increased during the study (from 1126.4 nmol/L (1074.5–1178.3) to 1272.5 nmol/L (1206.3–1338.7), P

The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic–clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have been suggested to increase the risk. However, the prevailing viewpoint is that the choice of antiseizure medication (ASM) does not influence the occurrence. We have explored the approach to addressing this question in relevant studies to evaluate the validity of the conclusions reached. A systematic search was performed in PubMed to identify all controlled studies on SUDEP risk in individuals on CBZ or LTG. Studies were categorized according to whether idiopathic generalized epilepsy (IGE) or females were considered separately, and whether data were adjusted for seizure frequency. Eight studies on CBZ and six studies on LTG were identified. For CBZ, one study showed a significantly increased risk of SUDEP without adjustment for seizure frequency. Another study found significantly increased risk after statistical adjustment for seizure frequency and one study found increased risk with high blood levels. Five other studies found no increase in risk. For LTG, one study showed a significantly increased risk in patients with IGE as opposed to focal epilepsy, and another study showed a significantly increased risk in females. None of the subsequent studies on LTG and none of the studies on CBZ considered females with IGE separately. Taken together the available studies suggest that LTG, and possibly CBZ, may increase occurrence of SUDEP when used in females with IGE. Additional studies with sub-group analysis of females with IGE are needed.

Status epilepticus (SE) is a critical medical emergency that demands immediate and effective intervention. We report a unique case involving a 21-year-old woman with left hemimegalencephaly who was hospitalized for super-refractory status epilepticus (SRSE) that persisted for 8 weeks. Despite extensive treatment efforts including multiple anti-seizure medications, anesthetics, high-dose methylprednisolone, anakinra, magnesium infusion, and a ketogenic diet, her condition remained unchanged. Ultimately, a left functional hemispherotomy was performed, informed by MRI findings and EEG results showing predominantly left-sided epileptic activity. This decision was made collaboratively when all other therapeutic options had been exhausted. Postoperatively, the patient recovered with manageable neurological deficits and a satisfactory quality of life. To our knowledge, this is the first reported case of acute functional hemispherotomy in an adult with hemimegalencephaly and SRSE.

Approximately one-third of patients with epilepsy are drug-refractory, necessitating novel treatment approaches. Chronopharmacology, which adjusts pharmacological treatment to physiological variations in seizure susceptibility and drug responsiveness, offers a promising strategy to enhance efficacy and tolerance. This narrative review provides an overview of the biological foundations for rhythms in seizure activity, clinical implications of seizure patterns through case reports, and the potential of chronopharmacological strategies to improve treatment. Biological rhythms, including circadian and infradian rhythms, play an important role in epilepsy. Understanding seizure patterns may help individualize treatment decisions and optimize therapeutic outcomes. Altering drug concentrations based on seizure risk periods, adjusting administration times, and exploring hormone therapy are potential strategies. Large-scale randomized controlled trials are needed to evaluate the efficacy and safety of differential and intermittent treatment approaches. By tailoring treatment to individual seizure patterns and pharmacological properties, chronopharmacology offers a personalized approach to improve outcomes in patients with epilepsy.

High frequency of convulsive seizures and long-lasting epilepsy are associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). Structural changes in the myocardium have been described in SUDEP victims. It is speculated that these changes are secondary to frequent convulsive seizures and may predispose to SUDEP. The aim of this cross-sectional study was to investigate the impact of chronic drug-resistant epilepsy on cardiac function and structure in patients with a high frequency of convulsive seizures. We consecutively included 21 patients (17 women, 4 men) aged 18–40 years, with at least 10 years with epilepsy and a minimum of six convulsive seizures in the last year and without a history of status epilepticus or nonepileptic events. A complete clinical examination, resting 12-lead electrocardiogram, 72-h Holter monitoring, and echocardiography were recorded in all patients. Ten patients were assessed by 3-Tesla cardiac magnetic resonance imaging. Echocardiography and MRI data were compared with those from age- and sex-matched healthy control individuals. No significant changes in cardiac structure or function were found among patients with chronic drug-resistant epilepsy and high frequency of convulsive seizures. However, we cannot exclude that there are subgroups of patients who are more prone to epilepsy-associated cardiac alterations.

Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures—the process of epileptogenesis—could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis.

ObjectiveEpilepsy is associated with both changes in brain connectivity and memory function, usually studied in the chronic patients. The aim of this study was to explore the presence of connectivity alterations measured by EEG in the parietofrontal network in patients with temporal lobe epilepsy (TLE), and to examine episodic memory, at the time point of diagnosis.MethodsThe parietofrontal network of newly diagnosed patients with TLE (N = 21) was assessed through electroencephalography (EEG) effective connectivity and compared with that of matched controls (N = 21). Furthermore, we assessed phenomenological aspects of episodic memory in both groups. Association between effective connectivity and episodic memory were assessed through correlation.ResultsPatients with TLE displayed decreased episodic (p ≤ 0.001, t = −5.18) memory scores compared with controls at the time point of diagnosis. The patients showed a decreased right parietofrontal connectivity (p = 0.03, F = 4.94) compared with controls, and significantly weaker connectivity in their right compared with their left hemisphere (p = 0.008, t = −2.93). There were no significant associations between effective connectivity and episodic memory scores.ConclusionsWe found changes in both memory function and connectivity at the time point of diagnosis, supporting the notion that TLE involves complex memory functions and brain networks beyond the seizure focus to strongly interconnected brain regions, already early in the disease course. Whether the observed connectivity changes can be interpreted as functionally important to the alterations in memory function, it remains speculative.

Neuroinflammation has been considered an important pathophysiological process involved in epileptogenesis and may provide possibilities for new treatment possibilities. We present the case of a 45-year-old female with drug resistant epilepsy and progressive right-sided cerebral hemiatrophy associated with adult onset Rasmussen’s encephalitis. Over a period of 26 years, she was treated with 14 different antiseizure medications, intravenous immunoglobulins, glucocorticosteroids, underwent two operations with focal resection and subpial transections, and tried out trigeminal nerve stimulation. Extensive blood tests, including antibodies relevant for autoimmune encephalitis, and brain biopsy did not show any signs of neuroinflammation.Eventually, the patient received the interleukin-1 receptor antagonist, anakinra. Within 1–2 days after injection, seizure frequency decreased significantly, and, after one week, the seizures stopped completely. Anakinra treatment was continued for 2 months. Stopping medication led to a relapse of seizures after 2 weeks, with a frequency of up to 45 seizures per day. Reintroduction of anakinra led to rapid recovery. Treatment with anakinra was continued for 7 months. The treatment was discontinued in April 2020, and the patient has been completely seizure free since then. There have been no other changes in antiseizure medication.

Background and Aims: Morphological changes in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) are well-characterized. Yet, it remains elusive whether these are a consequence of seizures or originate from a hitherto unknown underlying pathology. We recently published data on changes in gene expression and DNA methylation in the ipsilateral hippocampus (ILH) using the intracortical kainate mouse model of mTLE-HS. In order to explore the effects of epileptic activity alone and also to further disentangle what triggers morphological alterations, we investigated glial and neuronal changes in gene expression and DNA methylation in the contralateral hippocampus (CLH).Methods: The intracortical kainic acid mouse model of mTLE-HS was used to elicit status epilepticus. Hippocampi contralateral to the injection site from eight kainate-injected and eight sham mice were extracted and shock frozen at 24 h post-injection. Glial and neuronal nuclei were sorted by flow cytometry. Alterations in gene expression and DNA methylation were assessed using reduced representation bisulfite sequencing and RNA sequencing. The R package edgeR was used for statistical analysis.Results: The CLH featured substantial, mostly cell-specific changes in both gene expression and DNA methylation in glia and neurons. While changes in gene expression overlapped to a great degree between CLH and ILH, alterations in DNA methylation did not. In the CLH, we found a significantly lower number of glial genes up- and downregulated compared to previous results from the ILH. Furthermore, several genes and pathways potentially involved in anti-epileptogenic effects were upregulated in the CLH. By comparing gene expression data from the CLH to previous results from the ILH (featuring hippocampal sclerosis), we derive potential upstream targets for epileptogenesis, including glial Cox2 and Cxcl10.Conclusion: Despite the absence of morphological changes, the CLH displays substantial changes in gene expression and DNA methylation. We find that gene expression changes related to potential anti-epileptogenic effects seem to dominate compared to the pro-epileptogenic effects in the CLH and speculate whether this imbalance contributes to prevent morphological alterations like neuronal death and reactive gliosis.

The congenital long QT syndrome (cLQTS) is an inherited cardiac disorder and is associated with sudden cardiac death. We describe a Norwegian family with mutations within the KCNQ1 gene causing cLQTS type 1 (LQT1) and epilepsy. The index patient had Jervell and Lange-Nielsen-syndrome (JLNS) with deafness and recurrent episodes of cardiac arrhythmia. The mother and the brother have Romano-Ward syndrome (RWS) with recurrent arrhythmias. Whereas the father has focal epilepsy and genetically verified LQT1, the sister has both focal epilepsy and RWS.Our findings are consistent with the notion that mutations in the KCNQ1 gene can cause epilepsy. Keywords: Long QT syndrome, SUDEP, EEG, Channelopathies, Seizures, Syncope

BACKGROUND AND AIMS:Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia. METHODS:We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package. RESULTS:We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided. CONCLUSION:We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.