Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis.

Background: Neonatal seizures are a common neurological emergency in newborns. Phenobarbital (PB) is the first-line antiepileptic drug (AED). However, PB has some side effects, such as hypotension and respiratory depression, and it can accelerate neuronal apoptosis in the immature brain. Levetiracetam (LEV), a new antiepileptic drug, has been used as a second-line drug for the treatment of neonatal seizures. Compared with PB, LEV has many advantages, including a low incidence of side effects and better neurodevelopmental outcomes. However, there are only a few systematic reviews of LEV for the treatment of neonatal seizures. Objective: To evaluate the efficacy and safety of LEV for neonatal seizures and to compare the efficacy, side effects, and neurological outcomes between LEV and PB in the treatment of neonatal seizures. Methods: The keywords LEV, PB, and neonatal seizure were searched in the MEDLINE, Cochrane Library, Web of Science, EMBASE, clinicaltrials.gov, and China National Knowledge Internet (CNKI) databases with a last update in July 2021 to collect high-quality studies. We collected studies studying the efficacy or safety of LEV and PB in the treatment of neonatal seizures applying strict inclusion and exclusion criteria. The data were extracted and outcome measures, including efficacy, side effect rate, neurological score, and mortality rate, were analyzed with RevMan 5.3 software. Results: Ten articles were finally included in the meta-analysis. The meta-analysis showed that there was no difference in efficacy between LEV and PB in the treatment of neonatal seizures. Compared with PB, the incidence of side effects of LEV was lower. The incidence of hypotension and respiratory depression in the LEV group was significantly lower than that in the PB group. In terms of long-term neurodevelopmental outcomes, there was no significant difference in the Bayley Scales of Infant Development (BSID) scores between LEV and PB. Conclusion: PB is still the first-line AED recommended by the WHO for the treatment of neonatal seizures. The new AEDs LEV may not have better efficacy than PB. At the same time, LEV is associated with better neurodevelopment outcomes and a lower risk of adverse effects. In addition, continuous EEG monitoring should be used to diagnose neonatal seizures to evaluate the severity of the seizures, remission, and drug efficacy. Systematic Review Registration: PROSPERO, identifier: CRD42021279029.

Comparative efficacy of anti-epileptic drugs for neonatal seizures: A network meta-analysis.

BACKGROUND: Anti-epileptic drugs have different effects on neonatal seizures, and new agents have been widely used in recent years. Meanwhile, significant differences still exist in the treatment for neonatal seizures, whether in choice of drug or in duration of treatment. And with the increase in options for treatment, the best choice of second-line treatment has not been recommended. METHODS: The MEDLINE, the Cochrane Library, Web of Science, Embase and clinicaltrials.gov databases were searched (January 1, 1960 to October 20, 2020). Randomized controlled trials (RCTs) or observational investigations studying anti-epileptic drugs for neonatal seizures were selected. And then we conducted a network meta-analysis and examined comparative efficacy of the first-line and second-line anti-epileptic drugs for neonatal seizures. RESULTS: Data were extracted from 11 included studies by 2 independent investigators. Random effects models were used to estimate odds ratios (ORs). We performed direct meta-analyses with a random effects model and network meta-analyses for first-line and second-line drugs. Five published RCTs and 6 observational investigations with 1333 patients and 6 interventions contributed to the analysis. CONCLUSION: We recommend phenobarbital as the first-line drug for neonatal seizures. In addition, there is a tendency for levetiracetam to be an effective second-line treatment for neonatal seizures after failure of first-line drugs.

How to Early Identify and Prevent the SARS-CoV-2 Infection in Children for Families?

Importance: COVID-19 has become a worldwide pandemic. Many countries have reported cases of infection in children and newborns, and there is a trend of significantly increasing infections among these populations. Therefore, it is important to provide advice and guidance for the prevention and control of COVID-19 in children. Observations: Children are as susceptible to SARS-CoV-2 infection as adults. The manifestations in children are atypical, and children are much less likely to have critical cases. If children are infected, they may play an important role in the spread of SARS-CoV-2 because their symptoms are less obvious and less likely to be detected. To prevent COVID-19 from spreading among children, efforts to prevent, and control the infection should be increased by controlling the source of infection, blocking the route of transmission and protecting the susceptible population. Conclusions and Relevance: The early identification of the COVID-19 in children and the protection of families are important measures to prevent the continued spread of SARS-CoV-2.

Intranasal IL-4 Administration Alleviates Functional Deficits of Periventricular Leukomalacia in Neonatal Mice.

Background: Periventricular leukomalacia (PVL) is the major form of brain injury in premature infants. Currently, there are no therapies to treat PVL. Several studies suggested that polarization of microglia, a resident macrophage-like immune cell in the central nervous system, plays a vital role in brain injury and recovery. As an important mediator of immunity, interleukin-4 (IL-4) has critical effects on many immune cells, such as astrocytes and microglia. Increasing evidence shows that IL-4 plays a well-established role in attenuating inflammation in neurological disorders. Additionally, as a noninvasive and highly effective method, intranasal drug administration is gaining increasing attention. Therefore, in our study, we hypothesized that intranasal IL-4 administration is a promising strategy for PVL treatment. Methods: The therapeutic effects of IL-4 on neuroprotection were evaluated using a Control group, Hypoxia group, and Hypoxia + IL-4 treatment group. The PVL mouse model was established by a severe acute hypoxia (SAH) protocol. Exogenous IL-4 was intranasally administered to investigate its neuroprotective effects. A functional study was used to investigate neurological deficits, immunohistochemical technology and Western blotting were used to detect protein levels, and electron microscopy was used to evaluate myelination. Results: The results suggested that hypoxia stimulated Iba1+ microglial activation, downregulated myelin-related gene (NG2, MAG, and MBP) expression, reduced MBP protein levels, and caused neurological deficits. However, the intranasal administration of exogenous IL-4 partially inhibited Iba1+ microglial activation, improved myelination, and alleviated neurological deficits. The mechanistic study showed that IL-4 improved myelination possibly through the IL-4Ra-mediated polarization of microglia from the M1 phenotype to the M2 phenotype. Conclusion: In summary, our findings demonstrated that the intranasal administration of exogenous IL-4 improves myelination and attenuates functional deficits in a hypoxia-induced PVL model. Intranasal IL-4 administration may be a promising strategy for PVL treatment, for which further mechanistic studies are urgent.

Corrigendum: Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis-A Systematic Review.

[This corrects the article DOI: 10.3389/fneur.2018.00929.].

Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis-A Systematic Review.

Background: Neonatal bacterial meningitis is a severe infection with high mortality and morbidity. It is necessary to identify factors associated with a high risk of a poor prognosis so that we can prevent them with more appropriate treatments. This study was performed to summarize the prognostic factors known to predict adverse outcomes in neonatal bacterial meningitis. Methods: The Medline/PubMed, Cochrane Library and Embase databases were searched for studies of prognostic risk factors in neonates with bacterial meningitis. Studies published from the initiation of the database to April 30th, 2017 were included. The quality of cohort studies was assessed by the Newcastle-Ottawa Scale (NOS). The quality of cross-section studies was assessed by the Agency for Healthcare Research and Quality (AHRQ) scale. Each prognostic factor known to cause adverse outcomes is summarized. Results: Sixteen studies were identified, including 7 cohort studies and 9 cross section studies. Seizure and high protein levels in the cerebrospinal fluid (CSF) predict a poor prognosis in this disease. Coma, the need for ventilation support, and leukopenia also had some value for predicting poor prognoses. A bulging anterior fontanelle was valuable for predicting mortality. Low CSF glucose levels, thrombocytopenia, gestational age (GA) < 37 weeks and an altered sensorium were correlated with a poor prognosis. A birth weight < 2500 g, early onset meningitis and positive CSF cultures were correlated with mortality. Conclusions: This study provides a preliminary exploration of prognostic factors in neonatal bacterial meningitis and thereby fills some of the gaps in the study of prognoses in this disease. These prognostic factors can be used to predict and estimate outcomes in neonatal bacterial meningitis. Without a meta-analysis, the reliability of these factors cannot be assured. In addition, these results emphasize that there is an urgent need for a standardized protocol for follow-up and well-designed prognostic studies in neonatal bacterial meningitis.

Determination of optimal cutoff value to accurately identify glucose-6-phosphate dehydrogenase-deficient heterozygous female neonates.

BACKGROUND: Conventional screening tests to assess G6PD deficiency use a low cutoff value of 2.10 U/gHb which may not be adequate for detecting females with heterozygous deficiency. The aim of present study was to determine an appropriate cutoff value with increased sensitivity in identifying G6PD-deficient heterozygous females. METHODS: G6PD activity analysis was performed on 51,747 neonates using semi-quantitative fluorescent spot test. Neonates suspected with G6PD deficiency were further analyzed using quantitatively enzymatic assay and for common G6PD mutations. The cutoff values of G6PD activity were estimated using the receiver operating characteristic curve. RESULTS: Our results demonstrated that using 2.10 U/g Hb as a cutoff, the sensitivity of the assay to detect female neonates with G6PD heterozygous deficiency was 83.3%, as compared with 97.6% using 2.55 U/g Hb as a cutoff. The high cutoff identified 21% (8/38) of the female neonates with partial G6PD deficiency which were not detected with 2.10 U/g Hb. Our study found that high cutoffs, 2.35 and 2.55 U/g Hb, would increase assay's sensitivity to identify male and female G6PD deficiency neonates, respectively. CONCLUSIONS: We established a reliable cutoff value of G6PD activity with increased sensitivity in identifying female newborns with partial G6PD deficiency.

Anticonvulsant activity of acute and chronic treatment with a-asarone from Acorus gramineus in seizure models.

For centuries, extracts of Acorus gramineus have been used extensively in traditional Chinese medicine for the treatment, management, and/or control of human ailments, including central nervous system disorders such as convulsions and epilepsy. In the present study, we investigated the anticonvulsant activity of chronic treatment with the plant's major essential oil component (a-asarone, 50-200 mg/kg, per os (p.o.)) against maximal electroshock seizure (MES), pentylenetetrazole (PTZ)-induced seizures in mice, lithium-pilocarpine (LI-PILO)-induced status epilepticus (SE), and spontaneous recurrent seizures (SRSs) in rats and determined whether a single acute administration of a-asarone at various doses could produce anticonvulsant activity. As the standard antiepileptic drugs used, chronically administered a-asarone (50-200 mg/kg, p.o.) significantly delayed (p<0.05) the onset of, and antagonized maximal electroshock seizure and PTZ-induced seizures. Chronically administered a-asarone (50-200 mg/kg) also profoundly antagonized LI-PILO-induced seizures. The SE incidence, SE latency and seizure severity as well as mortality were significantly reduced after treatment with a-asarone at different doses. Higher doses of a-asarone (100-200 mg/kg) significantly reduced spontaneous recurrent seizure incidence, severity, and seizure frequency during treatment in LI-PILO-induced SRSs rats. On the other hand, a single acute administration of a-asarone (50-200 mg/kg) produced weak anticonvulsant activity in MES and PTZ-induced seizures. The results of this laboratory animal study indicate that chronically administered a-asarone possesses anticonvulsant activity in the mammalian experimental model used, and thus suggest that a-asarone may be used as a natural supplementary remedy in the management of convulsions and epilepsy.