Código encefalopatía hipóxico-isquémica: revisión sistematizada para entornos con recursos limitados / Hypoxic-ischaemic encephalopathy code: a systematic review for resource-limited settings

Se estima que el 96% de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) nacen en entornos con recursos limitados (ERL) sin capacidad para ofrecer el estándar asistencial vigente desde hace cerca de 15 años en los países con altos recursos y que incluye hipotermia terapéutica, neuromonitorización continua electroencefalográfica y resonancia magnética, además de un control intensivo de las constantes vitales y del equilibrio homeostático. Esta situación no parece estar cambiando; sin embargo y aún con estas limitaciones, el conocimiento actualmente disponible permite mejorar la asistencia de los pacientes con EHI atendidos en ERL. El propósito de esta revisión sistematizada es ofrecer, bajo el término «código EHI», recomendaciones de prácticas asistenciales basadas en evidencia científica y factibles en ERL, que permitan optimizar la atención del RN con EHI y ayuden potencialmente a reducir los riesgos asociados a la comorbilidad y a mejorar los resultados neuroevolutivos. El contenido del código EHI se agrupó en nueve epígrafes: 1) prevención de la EHI, 2) reanimación, 3) primeras seis horas de vida, 4) identificación y graduación de la EHI, 5) manejo de las convulsiones, 6) otras intervenciones terapéuticas, 7) disfunción multiorgánica, 8) estudios complementarios, y 9) atención a la familia. (AU)

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia, continuous electroencephalographic monitoring and magnetic resonance imaging in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term «HIE Code», evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: 1) prevention of HIE, 2) resuscitation, 3) first 6hours post birth, 4) identification and grading of encephalopathy, 5) seizure management, 6) other therapeutic interventions, 7) multiple organ dysfunction, 8) diagnostic tests and 9) family care. (AU)

Efficacy and Safety of Levetiracetam for Childhood Epilepsies.

Background: Levetiracetam (LEV) is a broad spectrum second-generation antiepileptic drug (AED). Objective: The objective of the study was to investigate the efficacy and safety of levetiracetam for childhood epilepsies. Methods: This is single, tertiary centre observational, prospective study, that included paediatric patients who were treated with levetiracetam at Paediatric hospital University Clinical Centre Sarajevo, during the period of 15 years (2008-2022). Inclusion criteria were: paediatric patients age > 1 month, diagnosed with epilepsy according to International League Against Epilepsy. After the introduction of levetiracetam, each patient has been followed up at least 12 months. According to the outcome the patients were divided into 5 groups: seizure reduction >50%, seizure reduction <50%, complete seizure freedom, the same number of seizures and increased number of seizures. From these groups two intergroups have been formed: responders (seizure reduction >50% and complete seizure freedom) and non-responders (seizure reduction <50%, the same number of seizures and increased number of seizures). Results: The study enrolled 259 patients (141 female and 118 male), with mean age 7 years (3,0-12.0). Comorbidities were present at 129/259 (49.8%) patients. After 12 months of treatment, 25/259 (9.7%) patients had seizure reduction >50%, 30/259 (11.6%) patients had seizure reduction <50%, 154/259 (56.5%) patients had achieved seizure freedom, 31/259 (12%) patients had same number of seizures, while 19/259 (7.3%) patients had increased number of seizures. Seizure frequency between responders and non-responders, before treatment and after 12 months of treatment was statistically significant (p<0.001). Discussion: Non responders had the best outcome with ditherapy (30/79; 38%), while responders had the best outcome with monotherapy (161/180;89.4%). Conclusion: Levetiracetam is efficient antiepileptic drug for different types of epilepsies in childhood, used as mono, di or polytherapy.

Very Long-Term Functional Outcomes and Dependency in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: To assess the daily function of children with anti-N-methyl-d-aspartate receptor encephalitis (NMDARe) after a minimal follow-up of 5 years. METHODS: Patients 18 years and younger by the time of disease onset, whose serum and CSF were studied in our center between 2013 and 2017, were included in the study. Patients' daily life function was assessed by their physicians using a 15-domain question format (Liverpool Outcome Score). RESULTS: Of 76 patients, 8 (11%) died and 68 were followed for a mean of 7.1 years (SD 1.5 years, range: 5.0-10.1). Three outcome patterns were identified: full recovery (50; 73%); behavioral and school/working deficits (12; 18%); and multidomain deficits (6; 9%) involving self-care ability, behavioral-cognitive impairment, and seizures. Younger age of disease onset was significantly associated with multidomain deficits (OR 1.6, 95% CI 1.02-2.4, p = 0.04), particularly in children younger than 6 years, among whom 8 of 23 (35%) remained sociofamiliar dependent. DISCUSSION: After a minimal follow-up of 5 years, most children with NMDARe had substantial or full functional recovery, but approximately one-fifth remained with behavioral and school/working deficits. The younger the patient at disease onset, the more probable it was to remain with multidomain deficits and dependent on sociofamiliar support.

Seizure as the main presenting manifestation of three patients with acute glufosinate-ammonium poisoning.

Glufosinate-ammonium herbicides are the most widely used broad-spectrum, non-selective herbicides in the world. Glufosinate-ammonium is a structural analogue of glutamate (Glu) which can irreversibly inhibit the activity of glutamine synthetase (GS) and Glu decarboxylase in plants, thereby blocking the synthesis of glutamine (Gln) from Glu and ammonia (Hoerlein, 1994). This causes the plants to die because of the nitrogen metabolism disorder and subsequent intracellular accumulation of ammonia. In humans, the characteristic features of glufosinate-ammonium herbicide poisoning include gastrointestinal symptoms and neurotoxicity (Watanabe and Sano, 1998). Currently, there are no antidotes for glufosinate-ammonium herbicide poisoning, and thus supportive care is the key treatment.

Seizures in febrile children with SARS-CoV-2 infection: clinical features, short-term follow-up.

BACKGROUND: As the Omicron variant of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerges, the neurological manifestations correlated with this epidemic have garnered increasing attention. This study was primarily intended to compare seizures in febrile children with and without SARS-CoV-2 infection and to conduct short-term follow-up of the SARS-CoV-2-infected patients. METHODS: Retrospective analysis of patients admitted to the Children's Hospital of Chongqing Medical University for fever and seizures between October 1 and December 30, 2022. Based on the results of SARS-CoV-2 Reverse Transcription-Polymerase Chain Reaction(RT-PCR) at the time of admission, the patients were divided into a Coronavirus disease 2019(COVID-19) positive group and a COVID-19 negative group. Aside from that, we followed up COVID-19-positive patients for 3 months after their discharge from the hospital. The follow-up included monitoring for post-discharge seizures. RESULTS: Compared with the COVID-19-negative group, the COVID-19-positive group had a higher proportion of seizure duration ≥ 15 min(18.7%VS5.1%;P = 0.001), seizure ≥ 2 time(54.4%VS41.0%; P = 0.024), status epilepticus(15.4%VS5.1%; P = 0.005), and Electroencephalogram (EEG) abnormalities(29.4%VS13.6%; P = 0.016). Among the 161 individuals under follow-up, 21 (13.0%)experienced a recurrence of seizures. CONCLUSIONS: Although the incidence of seizure duration ≥ 15 min, number of seizures ≥ 2 time, and status epilepticus was higher in the COVID-19-positive group, the majority of patients had a favorable prognosis. Nonetheless, patients with COVID-19 who present with seizures and persistent impaired consciousness need to be alerted to serious neurological disorders such as acute necrotizing encephalopathy. Owing to the consideration that some patients may experience a recurrence of seizures within a short period of time, it is paramount to provide guardians with education about the emergency management of seizures and to follow up with patients over time.

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population.

Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug-drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.

Emotional State Transitions in Trauma-Exposed Individuals With and Without Posttraumatic Stress Disorder.

Importance: Posttraumatic stress disorder (PTSD) is marked by the contrasting symptoms of hyperemotional reactivity and emotional numbing (ie, reduced emotional reactivity). Comprehending the mechanism that governs the transition between neutral and negative emotional states is crucial for developing targeted therapeutic strategies. Objectives: To explore whether individuals with PTSD experience a more pronounced shift between neutral and negative emotional states and how the intensity of emotional numbing symptoms impacts this shift. Design, Setting, and Participants: This cross-sectional study used hierarchical bayesian modeling to fit a 5-parameter logistic regression to analyze the valence ratings of images. The aim was to compare the curve's slope between groups and explore its association with the severity of emotional numbing symptoms. The study was conducted online, using 35 images with a valence range from highly negative to neutral. The rating of these images was used to assess the emotional responses of the participants. The study recruited trauma-exposed individuals (witnessed or experienced life-threatening incident, violent assault, or someone being killed) between January 17 and March 8, 2023. Participants completed the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) (PCL-5). Exposure: On the basis of DSM-5 criteria (endorsing at least 1 symptom from clusters B and C and 2 from D and E), participants were categorized as having probable PTSD (pPTSD) or as trauma-exposed controls (TECs). Main Outcomes and Measures: The main outcome was the slope parameter (b) of the logistic curve fitted to the valence rating. The slope parameter indicates the rate at which emotional response intensity changes with stimulus valence, reflecting how quickly the transition occurs between neutral and negatively valenced states. The secondary outcome was the association between emotional numbing (PCL-5 items 12-14) and the slope parameter. Results: A total of 1440 trauma-exposed individuals were included. The pPTSD group (n = 445) was younger (mean [SD] age, 36.1 [10.9] years) compared with the TEC group (mean [SD] age, 41.5 [13.3] years; P < .001). Sex distribution (427 women in the TEC group vs 230 in the pPTSD group) did not significantly differ between groups (P = .67). The pPTSD group exhibited a steeper slope (mean slope difference, -0.255; 89% highest posterior density [HPD], -0.340 to -0.171) compared with the controls. Across all individuals (n = 1440), a robust association was found between the slope and emotional numbing severity (mean [SD] additive value, 0.100 [0.031]; 89% HPD, 0.051-0.15). Additional analysis controlling for age confirmed the association between emotional numbing and transition sharpness (mean [SD] additive value, 0.108 [0.032]; 89% HPD, 0.056-0.159), without evidence of an age-related association (mean [SD] additive value, 0.031 [0.033]; 89% HPD, -0.022 to 0.083). Conclusions and Relevance: These findings support that individuals with PTSD undergo rapid transitions between neutral and negative emotional states, a phenomenon intensified by the severity of emotional numbing symptoms. Therapeutic interventions aimed at moderating these swift emotional transitions could potentially alleviate PTSD symptoms.

Concept-drifts adaptation for machine learning EEG epilepsy seizure prediction.

Seizure prediction remains a challenge, with approximately 30% of patients unresponsive to conventional treatments. Addressing this issue is crucial for improving patients' quality of life, as timely intervention can mitigate the impact of seizures. In this research field, it is critical to identify the preictal interval, the transition from regular brain activity to a seizure. While previous studies have explored various Electroencephalogram (EEG) based methodologies for prediction, few have been clinically applicable. Recent studies have underlined the dynamic nature of EEG data, characterised by data changes with time, known as concept drifts, highlighting the need for automated methods to detect and adapt to these changes. In this study, we investigate the effectiveness of automatic concept drift adaptation methods in seizure prediction. Three patient-specific seizure prediction approaches with a 10-minute prediction horizon are compared: a seizure prediction algorithm incorporating a window adjustment method by optimising performance with Support Vector Machines (Backwards-Landmark Window), a seizure prediction algorithm incorporating a data-batch (seizures) selection method using a logistic regression (Seizure-batch Regression), and a seizure prediction algorithm with a dynamic integration of classifiers (Dynamic Weighted Ensemble). These methods incorporate a retraining process after each seizure and use a combination of univariate linear features and SVM classifiers. The Firing Power was used as a post-processing technique to generate alarms before seizures. These methodologies were compared with a control approach based on the typical machine learning pipeline, considering a group of 37 patients with Temporal Lobe Epilepsy from the EPILEPSIAE database. The best-performing approach (Backwards-Landmark Window) achieved results of 0.75 ± 0.33 for sensitivity and 1.03 ± 1.00 for false positive rate per hour. This new strategy performed above chance for 89% of patients with the surrogate predictor, whereas the control approach only validated 46%.

Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure.

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.

A systematic review and meta-analysis of factors related to first line drugs refractoriness in patients with juvenile myoclonic epilepsy (JME).

INTRODUCTION: Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients. MATERIAL AND METHODS: The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis. RESULTS: A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity. CONCLUSION: In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.

Clinical-functional correlation with brain volumetry in severe perinatal asphyxia: a case report.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental. CASE PRESENTATION: A comprehensive analysis of a term infant with perinatal asphyxia using longitudinal 3D brain information from Machine Learning Models is presented. The clinical analysis revealed the perinatal asphyxia diagnosis with APGAR <5 at 5 and 10 minutes, umbilical arterial pH of 7.0 BE of -21.2 mmol / L), neonatal seizures, and invasive ventilation mechanics. Therapeutic interventions: physical, occupational, and language neurodevelopmental therapies. Epilepsy treatment: vagus nerve stimulation, levetiracetam, and phenobarbital. Furthermore, the 3D analysis showed how the volume decreases due to age, exhibiting an increasing asymmetry between hemispheres. The results of the basal ganglia area showed that thalamus asymmetry, caudate, and putamen increase over time while globus pallidus decreases. CLINICAL OUTCOMES: spastic cerebral palsy, microcephaly, treatment-refractory epilepsy. CONCLUSIONS: Slight changes in the basal ganglia and cerebellum require 3D volumetry for detection, as standard MRI examinations cannot fully reveal their complex shape variations. Quantifying these subtle neurodevelopmental changes helps in understanding their clinical implications. Besides, neurophysiological evaluations can boost neuroplasticity in children with neurological sequelae by stimulating new neuronal connections.

Inhibition of neuronal pentraxin 2 relieved epileptic seizure via reducing GluA1 phosphorylation.

Neuronal pentraxin 2 (Nptx2), a member of the synaptic protein family linked to excitatory synaptic formation, is found to be upregulated in epileptic mice, yet its role in epilepsy has been unclear. In vivo, we constructed a mouse model of epilepsy by using kainic acid induction. In vitro experiments, a Mg2+-free medium was used to induce epileptiform discharges in neurons. The results showed that the Nptx2 was upregulated in epileptic mice. Moreover, Nptx2 knockdown reduced the number of seizures and seizure duration. Knocking down Nptx2 not only reduced the number and duration of seizures but also showed a decrease in electroencephalogram amplitude. Behavioral tests indicated improvements in learning and memory abilities after Nptx2 knockdown. The Nissl staining and Timms staining revealed that Nptx2 silencing mitigated epilepsy-induced brain damage. The immunofluorescence staining revealed that Nptx2 absence resulted in a reduction of apoptosis. Nptx2 knockdown reduced Bax, cleaved caspase3, and cleaved caspase9 expression, while increased Bcl-2 expression. Notably, Nptx2 knockdown inhibited GluA1 phosphorylation at the S831 site and reduced the GluA1 membrane expression. The PSD95 expression declined in the epilepsy model, while the Nptx2 knockdown reversed it. Collectively, our study indicated that Nptx2 silencing not only alleviated brain damage and neuron apoptosis but also improved learning and memory ability in epileptic mice, suggesting Nptx2 as a promising target for epilepsy treatment.

[An increasing prevalence of epilepsy and stagnating or decreasing health care resources makes nationwide implementation challenging]. / Följsamhet till ordination en av utmaningarna i epilepsivården.

The Swedish national guidelines for epilepsy stipulate regular health care contacts in the years following diagnosis, referral for epilepsy surgery in cases of pharmacoresistant epilepsy, multidisciplinary teams, and adequate patient information particularly for women of childbearing age. The last years have seen advances in many research areas of relevance for the basic epilepsy care, and Sweden has contributed regarding pharmacotherapy, seizure-related risks, sudden unexpected death in epilepsy (SUDEP), and digital tools. An increasing prevalence of epilepsy and stagnating or decreasing health care resources makes nationwide implementation of this knowledge challenging and increases the risk of unequal access to care. Innovation and focus on prioritized groups, such as newly diagnosed and persons with pharmacoresistant epilepsy or comorbidities, will be needed.

Perifocal edema is a risk factor for preoperative seizures in patients with meningioma WHO grade 2 and 3.

BACKGROUND: Patients with intracranial meningiomas frequently suffer from tumor-related seizures prior to resection, impacting patients' quality of life. We aimed to elaborate on incidence and predictors for seizures in a patient cohort with meningiomas WHO grade 2 and 3. METHODS: We retrospectively searched for patients with meningioma WHO grade 2 and 3 according to the 2021 WHO classification undergoing tumor resection. Clinical, histopathological and imaging findings were collected and correlated with preoperative seizure development. Tumor and edema volumes were quantified. RESULTS: Ninety-five patients with a mean age of 59.5 ± 16.0 years were included. Most tumors (86/95, 90.5%) were classified as atypical meningioma WHO grade 2. Nine of 95 tumors (9.5%) corresponded to anaplastic meningiomas WHO grade 3, including six patients harboring TERT promoter mutations. Meningiomas were most frequently located at the convexity in 38/95 patients (40.0%). Twenty-eight of 95 patients (29.5%) experienced preoperative seizures. Peritumoral edema was detected in 62/95 patients (65.3%) with a median volume of 9 cm3 (IR: 0-54 cm3). Presence of peritumoral edema but not age, tumor localization, TERT promoter mutation, brain invasion or WHO grading was associated with incidence of preoperative seizures, as confirmed in multivariate analysis (OR: 6.61, 95% CI: 1.18, 58.12, p = *0.049). Postoperative freedom of seizures was achieved in 91/95 patients (95.8%). CONCLUSIONS: Preoperative seizures were frequently encountered in about every third patient with meningioma WHO grade 2 or 3. Patients presenting with peritumoral edema on preoperative imaging are at particular risk for developing tumor-related seizures. Tumor resection was highly effective in achieving seizure freedom.

Expression of GCaMP6s in the dentate gyrus induces tonic-clonic seizures.

GCaMP is a genetically encoded calcium indicator (GECI) widely used in neuroscience research. It measures intracellular Ca2+ level by fluorescence changes as it directly binds to Ca2+. In this process, the effect of this calcium buffer on the intracellular calcium signaling and cell physiology is often not taken into consideration. However, growing evidence from calcium imaging studies shows GCaMP expression under certain conditions can generate aberrant activity, such as seizures. In this study, we examined the effect of GCaMP6 expression in the dentate gyrus (DG) on epileptogenesis. We found that viral expression of GCaMP6s but not GCaMP6f in the DG induces tonic-clonic seizures several weeks after viral injection. Cell-type specific expression of GCaMP6s revealed the granule cells (GCs) as the key player in GCaMP6s-induced epilepsy. Finally, by using slice electrophysiology, we demonstrated that GCaMP6s expression increases neuronal excitability in the GCs. Together, this study highlights the ability of GCaMP6s in DG-associated epileptogenesis.

Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

[Saikosaponin a alleviates pentylenetetrazol-induced acute epileptic seizures in mouse models of depression by suppressing microglia activation-mediated inflammation].

OBJECTIVE: To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism mediating this effect. METHODS: Male C57BL/6J mouse models of depression was established by oral administration of corticosterone via drinking water for 3 weeks, and acute epileptic seizures were induced by intraperitoneal injection of a single dose of pentylenetetrazole. The effect of intraperitoneal injection of SSa prior to the treatment on depressive symptoms and epileptic seizures were assessed using behavioral tests, epileptic seizure grading and hippocampal morphology observation. ELISA was used to detect blood corticosterone levels of the mice, and RTqPCR was performed to detect the pro- and anti-inflammatory factors. Microglia activation in the mice was observed using immunofluorescence staining. RESULTS: The mouse model of corticosterone-induced depression showed body weight loss and obvious depressive behaviors with significantly increased serum corticosterone level (all P < 0.05). Compared with those with pentylenetetrazole-induced epilepsy alone, the epileptic mice with comorbid depression showed significantly shorter latency of epileptic seizures, increased number, grade and duration of of seizures, reduced Nissl bodies in hippocampal CA1 and CA3 neurons, increased number of Iba1-positive cells, and significantly enhanced hippocampal expressions of IL-1ß, IL-10, TNF-α and IFN-γ. Pretreatment of the epileptic mice with SSa significantly prolonged the latency of epileptic seizures, reduced the number, duration, and severity of seizures, increased the number of Nissl bodies, decreased the number of Iba1-positive cells, and reduced the expression levels of IL-1ß, IL-10, TNF-α, and IFN-γ in the hippocampus (P < 0.05). CONCLUSION: Depressive state aggravates epileptic seizures, increases microglia activation, and elevates inflammation levels. SSA treatment can alleviate acute epileptic seizures in mouse models of depression possibly by suppressing microglia activation-mediated inflammation.

Anticonvulsant effects of Paeonia daurica subsp. macrophylla root extracts in pentylenetetrazol-induced seizure models in mice.

INTRODUCTION: In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl3, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice. METHODS: HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests. RESULTS: All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures. CONCLUSIONS: It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.