scholarly journals Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model

2020 ◽  
Author(s):  
Brennan J. Sullivan ◽  
Pavel A. Kipnis ◽  
Brandon M. Carter ◽  
Shilpa D. Kadam
Keyword(s):  
Mouse Model ◽  
Neonatal Seizure ◽  
Seizure Susceptibility ◽  
Neonatal Seizures ◽  
First Line ◽  
Chloride Homeostasis ◽  
Epilepsy Models ◽  
And Function ◽  
Ischemic Encephalopathy

AbstractNeonatal seizures pose a clinical challenge for their early detection, acute management, and mitigation of long-term comorbidities. A major cause of neonatal seizures is hypoxic-ischemic encephalopathy that results in seizures that are frequently refractory to the first-line anti-seizure medication phenobarbital (PB). One proposed mechanism for PB-inefficacy during neonatal seizures is the reduced expression and function of the neuron-specific K+/Cl− cotransporter 2 (KCC2), the main neuronal Cl− extruder that maintains chloride homeostasis and influences the efficacy of GABAergic inhibition. To determine if PB-refractoriness after ischemic neonatal seizures is dependent upon KCC2 hypofunction and can be rescued by KCC2 functional enhancement, we investigated the recently developed KCC2 functional enhancer CLP290 in a CD-1 mouse model of refractory ischemic neonatal seizures quantified with vEEG. We report that acute CLP290 intervention can rescue PB-resistance, KCC2 expression, and the development of epileptogenesis after ischemic neonatal seizures. KCC2 phosphorylation sites have a strong influence over KCC2 activity and seizure susceptibility in adult experimental epilepsy models. Therefore, we investigated seizure susceptibility in two different knock-in mice in which either phosphorylation of S940 or T906/T1007 was prevented. We report that KCC2 phosphorylation regulates both neonatal seizure susceptibility and CLP290-mediated KCC2 functional enhancement. Our results validate KCC2 as a clinically relevant target for refractory neonatal seizures and provide insights for future KCC2 drug development.

Efficacy of Fosphenytoin as First-Line Antiseizure Medication for Neonatal Seizures Compared to Phenobarbital

2020 ◽  
Vol 36 (1) ◽  
pp. 30-37 ◽  
Author(s):  
Veronica Alix ◽  
Mansi James ◽  
Anthony H. Jackson ◽  
Paul F. Visintainer ◽  
Rachana Singh
Keyword(s):  
Negative Impact ◽  
Study Groups ◽  
Neonatal Seizure ◽  
Neonatal Seizures ◽  
First Line ◽  
Neurodevelopmental Outcomes ◽  
Treatment Protocols ◽  
Neurodevelopmental Delay ◽  
Observational Cohort

Currently used treatment protocols for neonatal seizures vary among centers with limited evidence to support the choice of a given antiseizure medication. Because of concerns about the potential negative impact of phenobarbital on long-term neurodevelopment outcomes, our unit transitioned to fosphenytoin as the first-line antiseizure medication. A retrospective observational cohort study was conducted to compare the acute and long-term outcomes of fosphenytoin and phenobarbital as first-line antiseizure medication for neonatal seizure treatment. The 2 study groups had similar baseline characteristics for neonatal variables as well as maternal antenatal complications. We did not find any differences in the acute outcomes between the 2 groups. However, significantly fewer infants in the fosphenytoin group had moderate-to-severe neurodevelopmental delay at the 18- and 24-month assessments. In conclusion, although both medications were equally efficacious for acute neonatal seizure control, fosphenytoin had the potential for significantly better neurodevelopmental outcomes at 18-24 months of age.

Neonatal Antiepileptic Medication Treatment Patterns: A Decade of Change

2019 ◽  
Author(s):  
Vi T. Le ◽  
Hibo H. Abdi ◽  
Pablo J. Sánchez ◽  
Lina Yossef ◽  
Patricia B. Reagan ◽  
...  
Keyword(s):  
Neonatal Period ◽  
Health Information System ◽  
Neonatal Seizure ◽  
Long Term Outcomes ◽  
Adjusted Risk ◽  
Antiepileptic Medication ◽  
Anticonvulsant Medication ◽  
Risk Ratios ◽  
Ischemic Encephalopathy

Abstract Objective This article aims to describe the frequency and characteristics of anticonvulsant medication treatments initiated in the neonatal period. Study Design We analyzed a cohort of neonates with a seizure diagnosis who were discharged from institutions in the Pediatric Health Information System between 2007 and 2016. Adjusted risk ratios and 95% confidence intervals for characteristics associated with neonatal (≤ 28 days postnatal) anticonvulsant initiation were calculated via modified Poisson regression. Results A total of 6,245 infants from 47 institutions were included. There was a decrease in both phenobarbital initiation within the neonatal period (96.9 to 91.3%, p = 0.015) and continuation at discharge (90.6 to 68.6%, p <0.001). Levetiracetam (7.9 to 39.6%, p < 0.001) initiation within the neonatal period and continuation at discharge (9.4 to 49.8%, p < 0.001) increased. Neonates born at ≥ 37 weeks' gestation and those diagnosed with intraventricular hemorrhage, ischemic/thrombotic stroke, other hemorrhagic stroke, and hypoxic ischemic encephalopathy (HIE) had a higher probability of anticonvulsant administration. The most prevalent diagnosis was HIE (n = 2,223, 44.4%). Conclusion Phenobarbital remains the most widely used neonatal seizure treatment. Levetiracetam is increasingly used as a second line therapy. Increasing levetiracetam use indicates a need for additional study to determine its effectiveness in reducing seizure burden and improving long-term outcomes.

scholarly journals Clinical profile, etiology, type and outcome of neonatal seizures: a hospital-based study

2021 ◽  
Vol 9 (1) ◽  
pp. 104
Author(s):  
Mohmad Saleem Chesti ◽  
Naveed Shahzad ◽  
Shilakha Chaman ◽  
Sheenam Gazala
Keyword(s):  
Birth Asphyxia ◽  
Clinical Profile ◽  
Neonatal Seizure ◽  
Neonatal Seizures ◽  
Medical Sciences ◽  
Long Term Outcomes ◽  
Acute Symptomatic Seizure ◽  
Ethical Clearance ◽  
Common Infections

Background: Our study was undertaken to study the etiological factor, clinical profile, types and outcome of newborn with neonatal seizures (NNS).Methods: Our study was hospital based prospective study was done in Sheri Kashmir institute of medical sciences (SKIMS) Bemina from April 2013 to April 2015 in NICU, after obtaining ethical clearance from institutional ethical committee. All neonates fulfilling inclusion criteria were included in our study.Results: In our study, 80 neonates with seizures were included in our study, among them 48 were males and 32 were females. Majority of neonates (57.5%) developed seizures during first 72 hours of life due to birth asphyxia. Commonest types of neonatal seizures observed in our study were subtle observed in 46 cases, followed by tonic (21.2 %), clonic (14.9 %) and mixed (6.2%) seizures. Birth asphyxia was commonest cause (57.5%) of NNS, sepsis with meningitis (18.7%) followed by hypoglycemia (13.7%) and hypocalcemia (5%). Cases of birth asphyxia were associated with higher mortality (58.3%) as compared to cases with metabolic seizures.Conclusions: From our study we conclude that commonest cause of neonatal seizure was birth asphyxia occurring within 72 hours of birth. Sepsis and meningitis were also common infections resulting in neonatal seizure, while as hypoglycaemia and hypocalcemia were common biochemical abnormalities leading to NNS. Early identification and treatment are likely important for long-term outcomes in acute symptomatic seizure.

Levetiracetam for the Treatment of Seizures in Neonatal Hypoxic Ischemic Encephalopathy

2016 ◽  
Vol 32 (2) ◽  
pp. 210-214 ◽  
Author(s):  
Charu Venkatesan ◽  
Sarah Young ◽  
Mark Schapiro ◽  
Cameron Thomas
Keyword(s):  
Hypoxic Ischemic Encephalopathy ◽  
Loading Dose ◽  
Efficacy And Safety ◽  
Neonatal Seizures ◽  
First Line ◽  
Single Center Study ◽  
The Mean ◽  
Negative Side Effects ◽  
Ischemic Encephalopathy ◽  
Center Study

The objective of this study was to determine the efficacy and safety of levetiracetam in treatment of neonatal seizures due to hypoxic ischemic encephalopathy. Seizures often persist in neonates with hypoxic ischemic encephalopathy despite phenobarbital. A retrospective single-center study was conducted in neonates ≥36 weeks gestation with hypoxic ischemic encephalopathy. A total of 127 neonates were identified born 2008-2015. Clinical seizures occurred in 83 infants. Fifty-one neonates (61%) had cessation of seizures with only phenobarbital. Thirty-two neonates received levetiracetam after phenobarbital, and the seizures stopped in 27 of these neonates. The mean total loading dose of levetiracetam was 63 mg/kg. Mean maintenance dose of levetiracetam was 65 mg/kg/d. We found no negative side effects in neonates following levetiracetam use. Our study finds that levetiracetam is an efficacious medication in treatment of seizures in the setting of neonatal hypoxic ischemic encephalopathy. Future prospective studies should explore its use as a first-line medication.

scholarly journals Long-term effects of losartan on structure and function of the thoracic aorta in a mouse model of Marfan syndrome

2009 ◽  
Vol 158 (6) ◽  
pp. 1503-1512 ◽  
Author(s):  
HH Clarice Yang ◽  
Jong Moo Kim ◽  
Elliott Chum ◽  
Cornelis van Breemen ◽  
Ada WY Chung
Keyword(s):  
Mouse Model ◽  
Marfan Syndrome ◽  
Thoracic Aorta ◽  
Structure And Function ◽  
Long Term Effects ◽  
And Function

scholarly journals Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease

PLoS ONE ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. e0178753 ◽  
Author(s):  
Susanne C. Beck ◽  
Yuxi Feng ◽  
Vithiyanjali Sothilingam ◽  
Marina Garcia Garrido ◽  
Naoyuki Tanimoto ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinal Vessel ◽  
Norrie Disease ◽  
Long Term Consequences ◽  
And Function

scholarly journals ETIOLOGICAL PROFILE OF NEONATAL SEIZURES WITH SPECIAL REFERENCE TO BIOCHEMICAL ABNORMALITIES

2019 ◽  
Vol 8 (6) ◽  
Author(s):  
Gurdeep Singh Dhanjal ◽  
Vikramjot Singh ◽  
Gurnoor Singh
Keyword(s):  
Seizure Activity ◽  
Early Recognition ◽  
Birth Asphyxia ◽  
Neurological Dysfunction ◽  
Neonatal Seizure ◽  
Neonatal Seizures ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Biochemical Abnormalities

Introduction: Neonatal seizure are the most frequent manifestation of neurological dysfunction in a neonate.  Detection of seizure and its etiology is important for guiding therapy. In the presence of biochemical abnormalities, it is difficult to control seizures and there is a risk of further brain damage. Early recognition and treatment of biochemical abnormalities are essential for optimal management and satisfactory long term outcome. The aim was to determine the etiology of neonatal seizures and to study the biochemical abnormalities. Material and Methods: The present study included 70 inborn neonates presenting with seizures admitted to the neonatal unit in MMIMSR, Mullana, Ambala, Haryana, India over a period of one and a half years. A detailed history was taken and clinical examination of the neonate was done. Etiological causes and various biochemical parameters were evaluated. Results:  Neonatal seizures occurred more commonly in males. The most common cause of neonatal seizures was birth asphyxia seen in 26 (37.1%) neonates followed by sepsis in 24 (34.3%) neonates. The Primary Biochemical abnormalities were seen in 12 (17.1%) neonates with seizures. Among these neonates, hypoglycemia was most commonly seen in 4 (33.3%) neonates followed by hypocalcemia seen in 3 (25%) neonates. Conclusion: Biochemical abnormalities are common in neonatal seizures and often go unrecognized. These abnormalities may significantly contribute to seizure activity and hence a biochemical workup is necessary for all cases of neonatal seizures.

Efficacy and Safety of Phenobarbitone as First-Line Treatment for Neonatal Seizure: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 67 (1) ◽  
Author(s):  
Jogender Kumar ◽  
Jitendra Meena ◽  
Jaivinder Yadav ◽  
Lokesh Saini
Keyword(s):  
Seizure Control ◽  
Meta Analysis ◽  
Random Effect ◽  
Neurodevelopmental Outcome ◽  
Neonatal Seizure ◽  
Efficacy And Safety ◽  
First Line ◽  
Neurodevelopmental Outcomes ◽  
First Line Therapy

Abstract Background and objective Phenobarbitone is used as a first-line drug for neonatal seizures. However, its poor short- and long-term safety profile is concerning. We aim to systematically synthesize the data on the efficacy and safety of phenobarbitone as a first-line agent and compare it against other anti-epileptic drugs (AEDs) in neonates. Methods Using keywords related to the study population (neonatal seizure) and intervention (phenobarbitone), we searched CENTRAL, Embase, PubMed and Web of Science until 15 December 2020. Randomized controlled trials (RCTs) comparing phenobarbitone with any other AED as first-line therapy for seizure control in the neonates were considered eligible. The random-effect meta-analysis was done using RevMan 5.3 software. Results We screened through 443 records and identified nine eligible studies (719 participants). Five RCTs comparing phenobarbitone with levetiracetam did not find any difference in seizure control with the first dose [risk ratio (RR) 1.43, 95% CI 0.79–2.57] or adverse effects (RR 4.66; 95% CI 0.33–65.83). Two trials comparing phenobarbitone and phenytoin also did not find any difference in seizure control with the first dose (RR 2.09; 95% CI 0.31–14.03) and other outcomes. Only one RCT compared phenobarbitone and lorazepam and found lorazepam to be more efficacious in seizure control with the first dose (RR 0.71; 95% CI 0.53–0.94). Three trials compared neurodevelopmental outcomes, in which levetiracetam was better in two, whereas one did not find any difference. Conclusion Phenobarbitone is at least as efficacious and safe as other drugs like phenytoin and levetiracetam. The data over the long-term neurodevelopmental outcome are lacking. The existing evidence is insufficient to recommend other drugs over phenobarbitone.

Seizure Susceptibility Correlates with Brain Injury in Male Mice Treated with Hypothermia after Neonatal Hypoxia-Ischemia

2018 ◽  
Vol 40 (5-6) ◽  
pp. 576-585 ◽  
Author(s):  
Melanie A. McNally ◽  
Raul Chavez-Valdez ◽  
Ryan J. Felling ◽  
Debra L. Flock ◽  
Frances J. Northington ◽  
...  
Keyword(s):  
Brain Injury ◽  
Seizure Susceptibility ◽  
Neonatal Seizures ◽  
Sex Dimorphism ◽  
Significant Morbidity ◽  
Neonatal Brain ◽  
Cortical Injury ◽  
Hypoxia Ischemia ◽  
Underlying Mechanisms ◽  
Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy is a common neonatal brain injury associated with significant morbidity and mortality despite the administration of therapeutic hypothermia (TH). Neonatal seizures and subsequent chronic epilepsy are frequent in this patient population and current treatments are partially effective. We used a neonatal murine hypoxia-ischemia (HI) model to test whether the severity of hippocampal and cortical injury predicts seizure susceptibility 8 days after HI and whether TH mitigates this susceptibility. HI at postnatal day 10 (P10) caused hippocampal injury not mitigated by TH in male or female pups. TH did not confer protection against flurothyl seizure susceptibility at P18 in this model. Hippocampal (R2 = 0.33, p = 0.001) and cortical (R2 = 0.33, p = 0.003) injury directly correlated with seizure susceptibility in male but not female pups. Thus, there are sex-specific consequences of neonatal HI on flurothyl seizure susceptibility in a murine neonatal HI model. Further studies are necessary to elucidate the underlying mechanisms of sex dimorphism in seizure susceptibility after neonatal HI.

scholarly journals A study of biochemical abnormalities and manifestations of neonatal seizures

2019 ◽  
Vol 6 (5) ◽  
pp. 1867
Author(s):  
Sahaya Nirmala ◽  
Sahana Giliyaru ◽  
S. C. Karat
Keyword(s):  
Neonatal Period ◽  
Neonatal Seizure ◽  
Neonatal Seizures ◽  
Central Nervous System Disorder ◽  
Biochemical Abnormality ◽  
Neurological Problem ◽  
System Disorder ◽  
Work Up ◽  
Ischemic Encephalopathy ◽  
Biochemical Abnormalities

Background: Neonatal seizure is a common neurological problem in the neonatal period with a frequency of 1.5 to 14/1000 neonates1. Neonatal seizures have always been a topic of particular interest because of their universal occurrence. A varied number of conditions are capable of causing seizures in the neonatal period. The presence of a seizure does not constitute a diagnosis but is a symptom of an underlying central nervous system disorder due to systemic or biochemical disturbances. This study aims to study the various clinical types of seizures and the biochemical abnormalities associated with them.Methods: This prospective study was conducted in the neonatology unit, department of pediatrics, C.S.I. Holdsworth Memorial Hospital, Mysore. Details of history, examination and investigations were recorded on predesigned proforma.Results: Out of total 54 cases, 47(87%) cases had seizures during first 3 days of life and hypoxic ischemic – encephalopathy (HIE) remains the main etiological factor in 20 (37.04%) cases. More than one metabolic abnormality was present in 6 cases. Hypoglycemia & hypomagnesemia were the commonest abnormality in neonates having seizures.Conclusions: A biochemical work up is necessary for all cases of neonatal seizures. The type of seizure does not give much information as to whether the seizures are purely metabolic or organic or about the type of biochemical abnormality.

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