Novel Therapeutics for Neonatal Seizures.
Ontology highlight
ABSTRACT:
SUBMITTER: Ziobro JM
PROVIDER: S-EPMC8608938 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neonatal encephalopathy (NE) is a major cause of neonatal mortality and morbidity. Therapeutic hypothermia (TH) is standard treatment for newborns at 36 weeks of gestation or greater with intrapartum hypoxia-related NE. Term and late preterm infants with moderate to severe encephalopathy show improved survival and neurodevelopmental outcomes at 18 months of age after TH. TH can increase survival without increasing major disability, rates of an IQ less than 70, or cerebral palsy. Neonates with severe NE remain at risk of death or severe neurodevelopmental impairment. This review discusses the evidence supporting TH for term or near term neonates with NE.
| S-EPMC4987711 | biostudies-literature
Project description:Benign familial neonatal seizures (BFNS) present a rare familial epilepsy syndrome caused by genetic alterations in the voltage-gated potassium channels Kv7.2 and Kv7.3, encoded by KCNQ2 and KCNQ3. While most BFNS families carry alterations in KCNQ2, mutations in KCNQ3 appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novel KCNQ3 variant, c.835G>T, cosegregating with seizures in 4 tested individuals. This variant results in a substitution of the highly conserved amino acid valine localized within the pore-forming transmembrane segment S5 (p.V279F). Functional investigations in Xenopus laevis oocytes revealed a loss of function, which supports p.V279F as a pathogenic mutation. When p.V279F was coexpressed with the wild-type (WT) Kv7.2 subunits, the resulting potassium currents were about 10-fold reduced compared to the WT Kv7.3 and Kv7.2 coexpression. Genotype-phenotype correlation shows an incomplete penetrance of p.V279F. Response to antiepileptic treatment was variable, but evaluation of treatment response remained challenging due to the self-limiting character of the disease. The identification of the pathogenic variant helped to avoid unnecessary investigations in affected family members and allowed guided therapy.
| S-EPMC5073621 | biostudies-literature
Project description:Many seizures in neonates are due to early-onset epilepsy, which is often difficult to diagnose, especially to explore the causes. Recently, the development of next-generation sequencing (NGS) has led to the discovery of a large number of genes involved in epilepsy. This may improve prompt detection of early-onset epilepsy in neonates. This study aimed at analyzing the genotype-phenotype correlations in neonates with seizures in a bid to improve the understanding of genetic diagnosis of early-onset epilepsy. Clinical features and prognosis of 15 children who underwent genetic testing having had unexplained seizures from February 2016 to May 2018 in Children's Hospital of Chongqing Medical University were analyzed retrospectively. The salient findings were: poor response to stimulus and abnormal electroencephalogram (EEG) in the initial period were observed in the group with concomitant genetic abnormalities. Despite the recent progress in genetic technology, molecular diagnosis for neonatal-onset epilepsy can be challenging due to genetic and phenotypic heterogeneities. However, some genotypes are associated with specific clinical manifestations and EEG patterns. Therefore, in-depth understanding of genotype-phenotype correlations would be useful to clinicians managing neonates with early-onset seizures.
| S-EPMC6888710 | biostudies-literature
Project description:Seizures occur in approximately 1 to 5 per 1000 live births and are among the most common neurologic conditions managed by a neonatal neurocritical care service. There are several, age-specific factors that are particular to the developing brain, which influence excitability and seizure generation, response to medications, and impact of seizures on brain structure and function. Neonatal seizures are often associated with serious underlying brain injury such as hypoxia-ischemia, stroke, or hemorrhage. Conventional, prolonged, continuous video electroencephalogram is the gold standard for detecting seizures, whereas amplitude-integrated EEG is a convenient and useful bedside tool.
| S-EPMC3925308 | biostudies-other
Project description:ObjectiveMany seizing neonates fail to respond to first-line anticonvulsant medications. Phenobarbital, an allosteric modulator of γ-aminobutyric acid type A (GABAA ) receptors, has low efficacy in treating neonatal seizures and causes neuronal apoptosis. Nonetheless, it is one of the most used anticonvulsants in this age group. In neonatal mice, phenobarbital's poor effectiveness is due in part to high intraneuronal chloride concentration, which causes GABA to exert depolarizing actions. Therefore, another approach to treat neonatal seizures could be to use anticonvulsants that do not rely on GABAergic modulation. We evaluated whether lacosamide decreases seizures in neonatal mice and whether it increases apoptosis in vitro and in vivo.MethodsIn vitro, we measured the effect of different lacosamide concentrations on seizure-like activity induced by the pro-convulsant drug 4-aminopyridine in neocortical brain slices (layer IV/V) from neonatal (postnatal day 8-11) and adult (1-1.6 months old) C57BL/6J mice. In vivo, we recorded the effect of different lacosamide concentrations on neonatal behavioral seizures induced by kainic acid. We studied neocortical apoptosis in vitro and in vivo, measuring terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling signal and cleaved-caspase 3.ResultsLacosamide reduced epileptiform activity in neocortical brain slices of neonates and adults in a concentration-dependent manner. In vivo, lacosamide reduced the duration and number of behavioral seizures. Lacosamide did not increase total or neuronal apoptosis in the neocortex in vitro or in vivo.SignificanceLacosamide reduces neocortical seizure-like activity in neonatal mice in vitro and in vivo without an acute increase in apoptosis. Our results support the use of lacosamide to treat neonatal seizures, with the advantage of not increasing apoptosis acutely.
| S-EPMC9742288 | biostudies-literature
Project description:Pharmacologic treatment options for neonatal seizures have expanded over the past 2 decades, and there is no consensus on optimal treatment strategy. We systematically reviewed the published literature to determine which medication(s) are most effective for treating neonatal seizures, by retrieving trials and observational investigations via PubMed (through August 2011) that focused on pharmacological seizure treatment of neonates (? 28 days old) and utilized continuous or amplitude-integrated EEG to confirm seizure diagnosis and cessation. Our search identified 557 initial articles and 14 additional studies after reference reviews, with 16 meeting inclusion criteria. Of these, 2 were randomized trials and only 3 additional investigations included comparison groups. We found limited evidence regarding the best pharmacologic treatment for neonatal seizures, but were able to devise a treatment algorithm from available data. These findings have the potential to serve as a clinical reference and to inform the design of comparative effectiveness investigations for neonatal antiepileptics.
| S-EPMC3805825 | biostudies-other
Project description:The lifespan risk of seizures is highest in the neonatal period. Current therapies have limited efficacy. Although the treatment of neonatal seizures has not changed significantly in the last several decades, there has been substantial progress in understanding developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. This article provides an overview of current approaches to the diagnosis and treatment of neonatal seizures, and some of the recent insights about the pathophysiology of neonatal seizures that may provide the foundation for better treatment are identified.
| S-EPMC2818833 | biostudies-literature
Project description:The majority of potent new biologics today are IgG-based molecules that have demonstrated tissue-targeting specificity with favorable clinical response. Several factors determine the efficacy of these products, including target specificity, serum half-life and effector functions via complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity or drug conjugates. In this review, we will focus on the interaction between therapeutic antibody and neonatal Fc receptor (FcRn), which is one of the critical factors in determining the circulating antibody half-life. Specifically, we will review the fundamental biology of FcRn, FcRn functions in various organs, Fc mutations designed to modulate binding to FcRn, IgG-based therapeutics that directly exploit FcRn functions and tools and strategies used to study FcRn-IgG interactions. Comprehensive understanding of FcRn-IgG interactions not only allows for development of effective therapeutics, but also avoidance of potential adverse effects.
| S-EPMC3225846 | biostudies-literature
Project description:To study the development of epilepsy following hypoxia-induced neonatal seizures in Long-Evans rats and to establish the presence of spontaneous seizures in this model of early life seizures.Long-Evans rat pups were subjected to hypoxia-induced neonatal seizures at postnatal day 10 (P10). Epidural cortical electroencephalography (EEG) and hippocampal depth electrodes were used to detect the presence of seizures in later adulthood (> P60). In addition, subdermal wire electrode recordings were used to monitor age at onset and progression of seizures in the juvenile period, at intervals between P10 and P60. Timm staining was performed to evaluate mossy fiber sprouting in the hippocampi of P100 adult rats that had experienced neonatal seizures.In recordings made from adult rats (P60-180), the prevalence of epilepsy in cortical and hippocampal EEG recordings was 94.4% following early life hypoxic seizures. These spontaneous seizures were identified by characteristic spike and wave activity on EEG accompanied by behavioral arrest and facial automatisms (electroclinical seizures). Phenobarbital injection transiently abolished spontaneous seizures. EEG in the juvenile period (P10-60) showed that spontaneous seizures first occurred approximately 2 weeks after the initial episode of hypoxic seizures. Following this period, spontaneous seizure frequency and duration increased progressively with time. Furthermore, significantly increased sprouting of mossy fibers was observed in the CA3 pyramidal cell layer of the hippocampus in adult animals following hypoxia-induced neonatal seizures. Notably, Fluoro-Jade B staining confirmed that hypoxic seizures at P10 did not induce acute neuronal death.The rodent model of hypoxia-induced neonatal seizures leads to the development of epilepsy in later life, accompanied by increased mossy fiber sprouting. In addition, this model appears to exhibit a seizure-free latent period, following which there is a progressive increase in the frequency of electroclinical seizures.
| S-EPMC3071424 | biostudies-literature
Project description:OBJECTIVE To investigate the accuracy of amplitude-integrated electroencephalography (aEEG) in detecting full-term neonatal seizures. METHODS Conventional EEG (cEEG) and aEEG were simultaneously applied to 62 full-term newborns with seizures and results were analyzed with different methods. RESULTS Of 876 seizures confirmed by cEEG, 21% were detected by clinical observation, 44.4% by aEEG and 85.7% by aEEG plus C3/C4 raw EEG. Of 531 seizures with a frequency higher than 5 times/h, 52.5% were detected by aEEG and 96.8% by aEEG plus C3/C4 raw EEG. Of 510 seizures lasting longer than 60 s, 50.6% were diagnosed by aEEG and 84.1% by aEEG plus C3/C4 raw EEG. Of 509 seizures originating in the central region, 57.9% were detected by aEEG and 90.9% by aEEG plus C3/C4 raw EEG. CONCLUSION Combination of aEEG with cEEG offers more accurate diagnosis, especially for detecting high-frequency, long-lasting and central region-generated seizures.
| S-EPMC5560306 | biostudies-other