A case report of IPEX syndrome in Palestine: detailed family identification and breadth of disorders with the same defect.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by multi-systemic autoimmunity secondary to loss-of-function mutations in the gene coding the forkhead box P3 (FOXP3) transcription factor which is important for the development, maturation, and maintenance of CD4 + regulatory T (T-reg) cells. Fewer than 300 affected individuals have been identified worldwide. The occurrence of IPEX is below 1:1,000,000. Herein we present a case of a 15-day-old male who was admitted to NICU 15 days after delivery due to respiratory distress. He was found to have metabolic acidosis due to DKA. During his stay in the NICU, he experienced seizures and was intubated for a month. He was diagnosed with neonatal diabetes. He also experienced recurrent respiratory infections and multiple episodes of diarrhea rash, and meningitis. At the age of 7 months, genetic testing confirmed IPEX with FOXP3 mutation, specifically the p.(Pro75Leu) variant of the FOXP3 gene. Subsequently, multiple family members were diagnosed. The unique variability observed in organ involvement and presentation timing among individuals within the same family, despite carrying an identical mutation, is a distinctive aspect, particularly considering the monoallelic expression of the FOXP3 gene in males. This phenomenon strongly suggests the presence of modifying genes that play a significant role in the pathogenesis of IPEX syndrome. The case presentation underscores the importance of clinical suspicion of IPEX in cases of neonatal DM. It also highlights the challenges associated with managing rare genetic disorders in pediatric patients. It also emphasizes that the IPEX genotype has a wide phenotype. This case is considered the first documented case of IPEX in Palestine.

Connectivity of high-frequency bursts as SOZ localization biomarker.

For patients with refractory epilepsy, the seizure onset zone (SOZ) plays an essential role in determining the specific regions of the brain that will be surgically resected. High-frequency oscillations (HFOs) and connectivity-based approaches have been identified among the potential biomarkers to localize the SOZ. However, there is no consensus on how connectivity between HFO events should be estimated, nor on its subject-specific short-term reliability. Therefore, we propose the channel-level connectivity dispersion (CLCD) as a metric to quantify the variability in synchronization between individual electrodes and to identify clusters of electrodes with abnormal synchronization, which we hypothesize to be associated with the SOZ. In addition, we developed a specialized filtering method that reduces oscillatory components caused by filtering broadband artifacts, such as sharp transients, spikes, or direct current shifts. Our connectivity estimates are therefore robust to the presence of these waveforms. To calculate our metric, we start by creating binary signals indicating the presence of high-frequency bursts in each channel, from which we calculate the pairwise connectivity between channels. Then, the CLCD is calculated by combining the connectivity matrices and measuring the variability in each electrode's combined connectivity values. We test our method using two independent open-access datasets comprising intracranial electroencephalography signals from 89 to 15 patients with refractory epilepsy, respectively. Recordings in these datasets were sampled at approximately 1000 Hz, and our proposed CLCDs were estimated in the ripple band (80-200 Hz). Across all patients in the first dataset, the average ROC-AUC was 0.73, and the average Cohen's d was 1.05, while in the second dataset, the average ROC-AUC was 0.78 and Cohen's d was 1.07. On average, SOZ channels had lower CLCD values than non-SOZ channels. Furthermore, based on the second dataset, which includes surgical outcomes (Engel I-IV), our analysis suggested that higher CLCD interquartile (as a measure of CLCD distribution spread) is associated with favorable outcomes (Engel I). This suggests that CLCD could significantly assist in identifying SOZ clusters and, therefore, provide an additional tool in surgical planning for epilepsy patients.

Effects of epileptic seizures on the quality of biosignals recorded from wearables.

OBJECTIVE: Wearable nonelectroencephalographic biosignal recordings captured from the wrist offer enormous potential for seizure monitoring. However, signal quality remains a challenging factor affecting data reliability. Models trained for seizure detection depend on the quality of recordings in peri-ictal periods in performing a feature-based separation of ictal periods from interictal periods. Thus, this study aims to investigate the effect of epileptic seizures on signal quality, ensuring accurate and reliable monitoring. METHODS: This study assesses the signal quality of wearable data during peri-ictal phases of generalized tonic-clonic and focal to bilateral tonic-clonic seizures (TCS), focal motor seizures (FMS), and focal nonmotor seizures (FNMS). We evaluated accelerometer (ACC) activity and the signal quality of electrodermal activity (EDA) and blood volume pulse (BVP) data. Additionally, we analyzed the influence of peri-ictal movements as assessed by ACC (ACC activity) on signal quality and examined intraictal subphases of focal to bilateral TCS. RESULTS: We analyzed 386 seizures from 111 individuals in three international epilepsy monitoring units. BVP signal quality and ACC activity levels differed between all seizure types. We found the largest decrease in BVP signal quality and increase in ACC activity when comparing the ictal phase to the pre- and postictal phases for TCS. Additionally, ACC activity was strongly negatively correlated with BVP signal quality for TCS and FMS, and weakly for FNMS. Intraictal analysis revealed that tonic and clonic subphases have the lowest BVP signal quality and the highest ACC activity. SIGNIFICANCE: Motor elements of seizures significantly impair BVP signal quality, but do not have significant effect on EDA signal quality, as assessed by wrist-worn wearables. The results underscore the importance of signal quality assessment methods and careful selection of robust modalities to ensure reliable seizure detection. Future research is needed to explain whether seizure detection models' decisions are based on signal responses induced by physiological processes as opposed to artifacts.

Clinical characteristics and serum 25-hydroxyvitamin D levels in children with febrile seizures in China.

The aim of this study was to evaluate the serum level of 25-hydroxyvitamin D (25(OH)D) in children with febrile seizures (FS) in Luzhou, Sichuan Province, China, and in particular its association with gender and age. This should inform possible strategies for supplementation with vitamin D, and hence for prevention of FS in the local pediatric population. The Febrile seizures group consisted of 747 children hospitalized with FS at the Southwest Medical University Affiliated Hospital from January 2020 to January 2024. The healthy control group was comprised of 750 children aged from 0 to 8 years who underwent health checkups during this period. The serum 25(OH)D level was analyzed in relation to gender and age to explore its association with FS. The median serum vitamin D level in the FS group (28.8 ng/mL; IQR 21.64, 33.64) was significantly lower than in the healthy control group (37.51 ng/mL; IQR 31.05, 37.51). The incidence of vitamin D deficiency in the FS group was 10.8%, which was significantly higher than in the healthy control group (P < 0.05). In addition, the serum vitamin D level in children with FS varied in different age groups, with significantly lower levels observed in older children (P < 0.05). ROC curve analysis revealed that a serum vitamin D level of 35.28 ng/mL showed 60.0% sensitivity and 84.7% specificity for predicting FS (P < 0.05). In this study cohort, the serum vitamin D level in children with FS was at the lower limit of the physiological range, and significantly lower than in healthy children. Furthermore, this level decreased with age in children with FS. Regular supplementation with vitamin D for 6 months after birth and outdoor sun exposure for more than 2 h per day can improve the serum vitamin D level in children with FS.

Imipenem-Cilastatin-Induced Seizures: A Case Report.

BACKGROUND: Imipenem-cilastatin, a carbapenem antibiotic, is commonly used for severe bacterial infections. While generally well-tolerated, it can rarely cause central nervous system toxicity, including seizures. We have, herein, reported a case of imipenem-cilastatin-induced seizure in a 20-year-old patient. CASE PRESENTATION: A 20-year-old male was admitted to the intensive care unit for febrile status epilepticus and acute respiratory distress syndrome. Initial evaluations ruled out underlying causes and anti-epileptic treatment has been initiated. Despite having an effective anti-epileptic treatment for three months of hospitalization, seizure recurrence occurred, leading to antibiotic regimen adjustment as the imputability of imipenem-cilastatin was suspected. After discontinuation of the involved drug, the patient remained neurologically stable. Previous literature has reported cases of imipenem-cilastatin-induced seizures, particularly in elderly patients or at higher dosages. The causality assessment was conducted using the updated French method, which rated the chronological criterion as C2 and the semiological criterion as S2. The intrinsic imputability score was I3, indicating plausible causality, and the extrinsic bibliographic score was B3. CONCLUSION: Our case has highlighted the importance of promptly recognizing imipenem-cilastatin- induced epileptic seizures in order to treat them more effectively and thus optimize the patient's care. Therefore, we emphasize that clinicians be vigilant about the side effects of its use, particularly in patients with neurological susceptibilities. We also advocate a personalized choice of antibiotics, taking into account both antimicrobial efficacy and potential adverse effects, for better outcomes with fewer risks.

Association of preoperative seizures with reduced expression of soluble CD163, an M2 macrophage marker, in the cerebrospinal fluid in isocitrate dehydrogenase wild-type glioblastoma.

PURPOSE: To investigate the relationship between the tumor microenvironment (TME), tumor-related seizures (TRS), and cerebrospinal fluid (CSF) markers that predict preoperative seizures in patients with glioblastoma. METHODS: In total, 47 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma who underwent preoperative CSF examination, 3-T magnetic resonance spectroscopy (MRS), and neurological surgery between January 2017 and December 2023 were included. We measured the concentrations of soluble CD163 (sCD163), a soluble form of the M2 macrophage marker, in the CSF, the metabolite concentration on MRS, and the number of CD163-positive M2 macrophages in the tumor tissue. Factors associated with preoperative seizures were examined. RESULTS: Twelve patients (25.5%) had preoperative seizures. sCD163 levels in the CSF were positively correlated with the number of CD163-positive M2 macrophages in the tumor tissue, and both were significantly lower in the preoperative seizure group than in the non-preoperative seizure group (p = 0.0124 and p < 0.0001, respectively). MRS indicated that only glutathione (GSH) concentrations were higher in the preoperative seizure group than in the non-preoperative seizure group (2.55 mM and 1.87 mM, respectively; p = 0.0171). CD163-positive M2 macrophages were inversely correlated with GSH levels. sCD163 in the CSF had a high predictive accuracy (sensitivity, 91.7%; specificity, 54.3%; and area under the receiver operator curve, 0.745) for preoperative seizures. CONCLUSIONS: The CSF level of sCD163 is useful for predicting the TME and preoperative seizures in IDH wild-type glioblastoma.

Management of non-lesional super-refractory status epilepticus: a rare case report.

Introduction and importance: Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the initiation of anesthetic therapy(continuum), a serious medical emergency with a potential for significant morbidity and mortality. Cortisectomy with invasive EEG recording electrocorticography (ECoG) can be a successful treatment option for super-refractory status epilepticus in selected cases after medical management has failed. Case presentation: The authors present a case of a young lady who suffered a super-refractory status epilepticus and failed five different anti-seizure medications, coma-producing agents, IVIG. After failure of multiple medical and sedative therapy cortisectomy was done with the use of invasive EEG recording electrocorticography (ECoG) to tailor and localize the epileptogenic zone. Clinical discussion: When dealing with status epilepticus (SE) that is refractory to treatment, early surgical intervention should be taken into consideration as a viable option. Although there are only a few published cases of SE treated with epilepsy surgery, these cases have shown positive outcomes. In fact, one study demonstrated a significant improvement in seizure control for patients with SE who underwent surgical treatment using these techniques. Conclusion: Cortisectomy, which is a rare and invasive procedure, could be considered as a potential treatment for patients who have not responded to multiple medical and sedative therapies.

Short-term effectiveness and side effects of ketogenic diet for drug-resistant epilepsy in children with genetic epilepsy syndromes.

Background: Drug-resistant epilepsy (DRE) impacts a significant portion, one-third, of individuals diagnosed with epilepsy. In such cases, exploring non-pharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs). Objective: This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs. Materials and methods: This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly. Results: We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet. Conclusion: The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles.

Seizure recurrence following the first unprovoked seizure: Risk factors among children in UAE.

In a retrospective study of paediatric and adolescent patients in Abu Dhabi, UAE, who experienced their first unprovoked seizure between March 2016 and March 2020, with a minimum one-year follow-up, we identified significant risk factors associated with seizure recurrence. Among 317 patients, 96.2% experienced seizure recurrence, with the majority (68.8%) occurring within the first 6-month follow-up period. Notable risk factors for recurrence included focal seizures, symptomatic seizure causes, abnormal initial electroencephalogram (EEG) findings, abnormal brain magnetic resonance imaging results, and the presence of neurological disorders. Interestingly, the type of epileptiform activity in the initial EEG did not predict recurrence risk. Over a 3-year period, the overall recurrence risk was 98.4%, particularly higher in cases with symptomatic seizures compared to idiopathic (genetic) ones. These findings underscore the importance of vigilant monitoring, particularly in the early post-seizure follow-up period, and advocate for initial EEG assessments, especially in cases of remote symptomatic first unprovoked seizures.

Generalized spike-waves in idiopathic generalized epilepsies: Does their frequency matter?

OBJECTIVES: We hypothesized that the frequency (in Hertz) of generalized spike-waves (GSWs) in patients with idiopathic generalized epilepsy (IGE) has associations with the syndromic diagnosis as well as with the prognosis of patients (their response to medical treatment). METHODS: This was a retrospective study of a prospectively developed database. All patients with a diagnosis of IGE were studied at the epilepsy center at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2022. Patients were classified into four IGE syndromes: childhood absence epilepsy; juvenile absence epilepsy; juvenile myoclonic epilepsy; and generalized tonic-clonic seizures alone. RESULTS: Five hundred and eighty-three patients were studied. GSWs were commonly observed in all four syndromes of IGE. Frequency of GSW (in Hertz) did not have a significant association with the syndromic diagnosis of the patients (p = .179). The presence of GSW did not have a significant association with the seizure outcome (becoming seizure free or not) of the patients (p = .416). Frequency of GSW did not have a significant association with the seizure outcome of the patients either (p = .574). CONCLUSION: GSWs are the hallmark electroencephalographic footprints of idiopathic generalized epilepsies; however, neither their presence nor their frequency has practical associations with the syndromic diagnosis of IGEs or their outcome (response to treatment).

Therapeutic potential of ketamine in management of epilepsy: Clinical implications and mechanistic insights.

Epilepsy, a widespread neurological disorder, affects approximately 50 million people worldwide. This disorder is typified by recurring seizures due to abnormal neuron communication in the brain. The seizures can lead to severe ischemia and hypoxia, potentially threatening patients' lives. However, with proper diagnosis and treatment, up to 70 % of patients can live without seizures. The causes of epilepsy are complex and multifactorial, encompassing genetic abnormalities, structural brain anomalies, ion channel dysfunctions, neurotransmitter imbalances, neuroinflammation, and immune system involvement. These factors collectively disrupt the crucial balance between excitation and inhibition within the brain, leading to epileptic seizures. The management of treatment-resistant epilepsy remains a considerable challenge, necessitating innovative therapeutic approaches. Among emerging potential treatments, ketamine-a drug traditionally employed for anesthesia and depression-has demonstrated efficacy in reducing seizures. It is noteworthy that, independent of its anti-epileptic effects, ketamine has been found to improve the balance between excitatory and inhibitory (E/I) activities in the brain. The balance is crucial for maintaining normal neural function, and its disruption is widely considered a key driver of epileptic seizures. By acting on N-methyl-D-aspartate (NMDA) receptors and other potential mechanisms, ketamine may regulate neuronal excitability, reduce excessive synchronized neural activity, and counteract epileptic seizures. This positive impact on E/I balance reinforces the potential of ketamine as a promising drug for treating epilepsy, especially in patients who are insensitive to traditional anti-epileptic drugs. This review aims to consolidate the current understanding of ketamine's therapeutic role in epilepsy. It will focus its impact on neuronal excitability and synaptic plasticity, its neuroprotective qualities, and elucidate the drug's potential mechanisms of action in treating epilepsy. By scrutinizing ketamine's impact and mechanisms in various types of epilepsy, we aspire to contribute to a more comprehensive and holistic approach to epilepsy management.

A cortical field theory - dynamics and symmetries.

We characterise cortical dynamics using partial differential equations (PDEs), analysing various connectivity patterns within the cortical sheet. This exploration yields diverse dynamics, encompassing wave equations and limit cycle activity. We presume balanced equations between excitatory and inhibitory neuronal units, reflecting the ubiquitous oscillatory patterns observed in electrophysiological measurements. Our derived dynamics comprise lowest-order wave equations (i.e., the Klein-Gordon model), limit cycle waves, higher-order PDE formulations, and transitions between limit cycles and near-zero states. Furthermore, we delve into the symmetries of the models using the Lagrangian formalism, distinguishing between continuous and discontinuous symmetries. These symmetries allow for mathematical expediency in the analysis of the model and could also be useful in studying the effect of symmetrical input from distributed cortical regions. Overall, our ability to derive multiple constraints on the fields - and predictions of the model - stems largely from the underlying assumption that the brain operates at a critical state. This assumption, in turn, drives the dynamics towards oscillatory or semi-conservative behaviour. Within this critical state, we can leverage results from the physics literature, which serve as analogues for neural fields, and implicit construct validity. Comparisons between our model predictions and electrophysiological findings from the literature - such as spectral power distribution across frequencies, wave propagation speed, epileptic seizure generation, and pattern formation over the cortical surface - demonstrate a close match. This study underscores the importance of utilizing symmetry preserving PDE formulations for further mechanistic insights into cortical activity.

Seizure forecasting with ultra long-term EEG signals.

OBJECTIVE: The apparent randomness of seizure occurrence affects greatly the quality of life of persons with epilepsy. Since seizures are often phase-locked to multidien cycles of interictal epileptiform activity, a recent forecasting scheme, exploiting RNS data, is capable of forecasting seizures days in advance. METHODS: We tested the use of a bandpass filter to capture the universal mid-term dynamics enabling both patient-specific and cross-patient forecasting. In a retrospective study, we explored the feasibility of the scheme on three long-term recordings obtained by the NeuroPace RNS System, the NeuroVista intracranial, and the UNEEG subcutaneous devices, respectively. RESULTS: Better-than-chance forecasting was observed in 15 (83 %) of 18 patients, and in 16 (89 %) patients for daily and hourly forecast, respectively. Meaningful forecast up to 30 days could be achieved in 4 (22 %) patients for hourly forecast frequency. The cross-patient performance decreased only marginally and was patient-wise strongly correlated with the patient-specific one. Comparable performance was obtained for NeuroVista and UNEEG data sets. SIGNIFICANCE: The feasibility of cross-patient forecasting supports the universal importance of mid-term dynamics for seizure forecasting, demonstrates promising inter-subject-applicability of the scheme on ultra long-term EEG recordings, and highlights its huge potential for clinical use.

Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy.

Epilepsy and Alzheimer's disease share some common pathologies such as neurodegeneration, seizures and impaired cognition. However, the molecular mechanisms of these changes are still largely unknown. Fyn, a Src-family non-receptor tyrosine kinase (SFK), and its interaction with tau in mediating brain pathology in epilepsy and Alzheimer's disease can be a potential therapeutic target for disease modification. Although Fyn and tau pathology occurs in both Alzheimer's disease and epilepsy, the dynamics of Fyn-tau and PSD95-NR2B interactions affected by seizures and their impact on brain pathology in epilepsy have not been investigated. In this study, we demonstrate a significant increase of Fyn-tau interactions following seizure induction by kainate in both acute and chronic rodent models and in human epilepsy. In the early phase of epileptogenesis, we show increased Fyn/tau/NR2B/PSD95/neuronal nitric oxide synthase complexes after status epilepticus and a postsynaptic increase of phosphorylated tau (pY18 and AT8), Fyn (pSFK-Y416), NMDAR (pNR2B-Y1472) and neuronal nitric oxide synthase. Hippocampal proximity ligation assay and co-immunoprecipitation revealed a sustained increase of Fyn-tau and NR2B-PSD95 complexes/binding in rat chronic epilepsy at 3 months post-status epilepticus. Enhanced Fyn-tau complexes strongly correlated with the frequency of spontaneously recurring convulsive seizures and epileptiform spikes in the chronic epilepsy model. In human epileptic brains, we also identified increased Fyn-tau and NR2B-PSD95 complexes, tau phosphorylation (pY18 and AT8) and Fyn activation (pSFK-Y416), implying the translational and therapeutic potential of these molecular interactions. In tau knockout mice and in rats treated with a Fyn/SFK inhibitor saracatinib, we found a significant reduction of phosphorylated Fyn, tau (AT8 in saracatinib-treated), NR2B and neuronal nitric oxide synthase and their interactions (Fyn-tau and NR2B-PSD95 in saracatinib-treated group; NR2B-PSD95 in tau knockout group). The reduction of Fyn-tau and NR2B-PSD95 interactions in the saracatinib-treated group, in contrast to the vehicle-treated group, correlated with the modification in seizure progression in the rat chronic epilepsy model. These findings from animal models and human epilepsy provide evidence for the role of Fyn-tau and NR2B-PSD95 interactions in seizure-induced brain pathology and suggest that blocking such interactions could modify the progression of epilepsy.

Sudden death in epilepsy: the overlap between cardiac and neurological factors.

People with epilepsy are at risk of premature death, of which sudden unexpected death in epilepsy (SUDEP), sudden cardiac death (SCD) and sudden arrhythmic death syndrome (SADS) are the primary, partly overlapping, clinical scenarios. We discuss the epidemiologies, risk factors and pathophysiological mechanisms for these sudden death events. We reviewed the existing evidence on sudden death in epilepsy. Classification of sudden death depends on the presence of autopsy and expertise of the clinician determining aetiology. The definitions of SUDEP, SCD and SADS lead to substantial openings for overlap. Seizure-induced arrhythmias constitute a minority of SUDEP cases. Comorbid cardiovascular conditions are the primary determinants of increased SCD risk in chronic epilepsy. Genetic mutations overlap between the states, yet whether these are causative, associated or incidentally present is often unclear. Risk stratification for sudden death in people with epilepsy requires a multidisciplinary approach, including a review of clinical history, toxicological analysis and complete autopsy with histologic and, preferably, genetic examination. We recommend pursuing genetic testing of relatives of people with epilepsy who died suddenly, mainly if a post-mortem genetic test contained a Class IV/V (pathogenic/likely pathogenic) gene variant. Further research may allow more precise differentiation of SUDEP, SCD and SADS and the development of algorithms for risk stratification and preventative strategies.

Multistability of bursting rhythms in a half-center oscillator and the protective effects of synaptic inhibition.

For animals to meet environmental challenges, the activity patterns of specialized oscillatory neural circuits, central pattern generators (CPGs), controlling rhythmic movements like breathing and locomotion, are adjusted by neuromodulation. As a representative example, the leech heartbeat is controlled by a CPG driven by two pairs of mutually inhibitory interneurons, heart interneuron (HN) half-center oscillators (HCO). Experiments and modeling indicate that neuromodulation of HCO navigates this CPG between dysfunctional regimes by employing a co-regulating inverted relation; reducing Na+/K+ pump current and increasing hyperpolarization-activated (h-) current. Simply reducing pump activity or increasing h-current leads to either seizure-like bursting or an asymmetric bursting dysfunctional regime, respectively. Here, we demonstrate through modeling that, alongside this coregulation path, a new bursting regime emerges. Both regimes fulfill the criteria for functional bursting activity. Although the cycle periods and burst durations of these patterns are roughly the same, the new one exhibits an intra-burst spike frequency that is twice as high as the other. This finding suggests that neuromodulation could introduce additional functional regimes with higher spike frequency, and thus more effective synaptic transmission to motor neurons. We found that this new regime co-exists with the original bursting. The HCO can be switched between them by a short pulse of excitatory or inhibitory conductance. In this domain of coexisting functional patterns, an isolated cell model exhibits only one regime, a severely dysfunctional plateau-containing, seizure-like activity. This aligns with widely reported notion that deficiency of inhibition can cause seizures and other dysfunctional neural activities. We show that along the coregulation path of neuromodulation, the high excitability of the single HNs induced by myomodulin is harnessed by mutually inhibitory synaptic interactions of the HCO into the functional bursting pattern.

Propagation of transient explosive synchronization in a mesoscale mouse brain network model of epilepsy.

Generalized epileptic attacks, which exhibit widespread disruption of brain activity, are characterized by recurrent, spontaneous, and synchronized bursts of neural activity that self-initiate and self-terminate through critical transitions. Here we utilize the general framework of explosive synchronization (ES) from complex systems science to study the role of network structure and resource dynamics in the generation and propagation of seizures. We show that a combination of resource constraint and adaptive coupling in a Kuramoto network oscillator model can reliably generate seizure-like synchronization activity across different network topologies, including a biologically derived mesoscale mouse brain network. The model, coupled with a novel algorithm for tracking seizure propagation, provides mechanistic insight into the dynamics of transition to the synchronized state and its dependence on resources; and identifies key brain areas that may be involved in the initiation and spatial propagation of the seizure. The model, though minimal, efficiently recapitulates several experimental and theoretical predictions from more complex models and makes novel experimentally testable predictions.

Understanding seizure dynamics at the whole-brain level is crucial for controlling abnormal hypersynchronous activity. Currently, complete brain coverage recordings are lacking in both patients and animal models. We employ network science tools to investigate epileptic seizure-like synchronization in a mouse whole-brain network, leveraging network structure and supported dynamics as the basis for seizure evolution. Our results align with experimental findings, suggesting that seizure activity initiates in the cortico-thalamic circuit. Importantly, our novel analysis identifies key nodes, primarily in the cortex, driving this hypersynchronous activity. Our findings highlight the network structure's role in shaping seizure dynamics, and the techniques developed here could enhance our ability to control generalized seizures when combined with patient-specific data.

Sturge weber syndrome: A case report.

This report presents a 14-year-old male with seizures and facial port-wine stains, who upon further evaluation was found to have SWS. Early diagnosis and consistent treatment of Sturge-Weber syndrome in children are essential to prevent seizures and improve quality of life. Anti-seizure medications play a crucial role in preventing and controlling seizures.

A single exposure to brivaracetam or perampanel does not cause cell death in neonatal rats.

Introduction: Exposure to a range of anti-seizure medications (ASMs) during early brain development adversely impacts neurodevelopmental outcomes in both animal models and in clinical studies. Many ASMs, including phenobarbital, phenytoin, valproate (VPA), and benzodiazepines, are associated with acute neurotoxicity (cell death), impaired synaptic development, and long-term behavioral changes following gestational or neonatal exposure in animals. This is mirrored in clinical studies which show lasting neurodevelopmental deficits following early-life or gestational exposure to these drugs. Brivaracetam (BRV) and perampanel (PER) are two newer generation anti-seizure medications and are of interest based on their mechanisms of action (SV2A modulator, AMPA antagonist, respectively), as other drugs with these mechanisms of action do not trigger acute neurotoxicity. Both BRV and PER show anti-seizure efficacy in developing animals, but potential neurotoxicity of these drugs is unexplored. Methods: To address this gap, we treated postnatal day (P)7 Sprague-Dawley rats with BRV (20, 40, 80 mg/kg) and PER (0.1, 0.9, 2.7 mg/kg), and assessed the induction of cell death across a range of vulnerable brain regions 24 h after exposure. Cell death was assessed using pathogreen staining. Results: In each of the regions examined (dorsal striatum, nucleus accumbens, motor cortex, cingulate cortex, lateral thalamus, septum, hippocampus), VPA, which served as a positive control, significantly increased cell death as measured by the numer of pathogreen positive cells. By contrast, neither BRV nor PER increased the number of pathogreen positive cells in any region examined. Discussion: Our results suggest that BRV and PER may have a positive safety profile-at least with respect to acute induction of cell death - and therefore may offer a safer option for the treatment of early life seizures.

Neural dynamics and seizure correlations: Insights from neural mass models in a Tetanus Toxin rat model of epilepsy.

This study focuses on the use of a neural mass model to investigate potential relationships between functional connectivity and seizure frequency in epilepsy. We fitted a three-layer neural mass model of a cortical column to intracranial EEG (iEEG) data from a Tetanus Toxin rat model of epilepsy, which also included responses to periodic electrical stimulation. Our results show that some of the connectivity weights between different neural populations correlate significantly with the number of seizures each day, offering valuable insights into the dynamics of neural circuits during epileptogenesis. We also simulated single-pulse electrical stimulation of the neuronal populations to observe their responses after the connectivity weights were optimized to fit background (non-seizure) EEG data. The recovery time, defined as the time from stimulation until the membrane potential returns to baseline, was measured as a representation of the critical slowing down phenomenon observed in nonlinear systems operating near a bifurcation boundary. The results revealed that recovery times in the responses of the computational model fitted to the EEG data were longer during 5 min periods preceding seizures compared to 1 hr before seizures in four out of six rats. Analysis of the iEEG recorded in response to electrical stimulation revealed results similar to the computational model in four out of six rats. This study supports the potential use of this computational model as a model-based biomarker for seizure prediction when direct electrical stimulation to the brain is not feasible.