Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data from the Neonatal Research Network Hypothermia Trial

Departments of Neurology and Pediatrics, University of Rochester, Rochester, New York 14642, USA.
Journal of child neurology (Impact Factor: 1.72). 10/2010; 26(3):322-8. DOI: 10.1177/0883073810380915
Source: PubMed


It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.

    • "Studies in both human neonates and animal models suggest that seizures themselves may independently contribute to brain injury and poor neurological outcome [5] [18] [29] [31] (but also see Refs. [25] [41]). Unfortunately, neonatal seizures are often resistant to treatment with approved antiepileptic drugs [15]. "
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    ABSTRACT: Current first-line drugs for the treatment of neonatal seizures have limited efficacy and are associated with side effects. Uncontrolled seizures may exacerbate brain injury and contribute to later-life neurological disability. Therefore, it is critical to develop a treatment for neonatal seizures that is effective and safe. In early-life, when the γ-aminobutyric acid (GABA) inhibitory system is not fully developed, potassium channels play an important role in controlling excitability. An earlier study demonstrated that flupirtine, a KCNQ potassium channel opener, is more efficacious than diazepam and phenobarbital for the treatment of chemoconvulsant-induced neonatal seizures. In newborns, seizures are most commonly associated with hypoxic-ischemic encephalopathy (HIE). Thus, in the present study, we examined the efficacy of flupirtine to treat neonatal seizures in an animal model of global hypoxia. Our results showed that flupirtine dose dependently blocks the occurrence of behavioral seizures in pups during hypoxia. Additionally, flupirtine inhibits the development of hypoxia-induced clinical seizures and associated epileptiform discharges, as well as purely electrographic (subclinical) seizures. These results suggest that flupirtine is an effective anti-seizure drug, and that further studies should be conducted to determine the time window within which it's administration can effectively treat neonatal seizures.
    No preview · Article · Sep 2015 · Neuroscience Letters
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    • "c o m / l o c a t e / y e x n r demonstrated that a higher seizure burden in neonates with hypoxic/ ischemic encephalopathy was correlated with greater damage on MRI. On the other hand, the multicenter study reported by Kwon et al. (2011) came to the conclusion that clinical seizures in neonatal hypoxic/ischemic encephalopathy have no independent impact on neurodevelopmental outcome. Experimental studies have been equally inconclusive. "
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    ABSTRACT: The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of the endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40pmol/1μl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70nmol/1μl) or ETB receptors (BQ788; 70nmol/1μl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40pmol/1μl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10mM PBS or 0.01% DMSO-PBS solution; pH 7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptors antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 level. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizures duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET-1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures following the application of ET-1 in immature rats. The dissociation between the ischemic-producing and seizure-producing processes suggests that damage is not necessary to induce seizures, although it may exacerbate them. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Experimental Neurology
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    • "There is however still an unresolved controversy whether seizures worsen outcome by themselves or whether they are associated to those with a more severe degree of encephalopathy, hence the higher mortality and morbidity [126, 127]. The molecular and cellular mechanisms underlying birth-asphyxia seizures are unknown, but understanding the seizure-triggering mechanisms plays a key role in the design of novel therapeutic strategies. "
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    ABSTRACT: Encephalopathy consequent on perinatal hypoxia-ischemia occurs in 1-3 per 1,000 term births in the UK and frequently leads to serious and tragic consequences that devastate lives and families, with huge financial burdens for society. Although the recent introduction of cooling represents a significant advance, only 40 % survive with normal neurodevelopmental function. There is thus a significant unmet need for novel, safe, and effective therapies to optimize brain protection following brain injury around birth. The Na(+)/H(+) exchanger (NHE) is a membrane protein present in many mammalian cell types. It is involved in regulating intracellular pH and cell volume. NHE1 is the most abundant isoform in the central nervous system and plays a role in cerebral damage after hypoxia-ischemia. Excessive NHE activation during hypoxia-ischemia leads to intracellular Na(+) overload, which subsequently promotes Ca(2+) entry via reversal of the Na(+)/Ca(2+) exchanger. Increased cytosolic Ca(2+) then triggers the neurotoxic cascade. Activation of NHE also leads to rapid normalization of pHi and an alkaline shift in pHi. This rapid recovery of brain intracellular pH has been termed pH paradox as, rather than causing cells to recover, this rapid return to normal and overshoot to alkaline values is deleterious to cell survival. Brain pHi changes are closely involved in the control of cell death after injury: an alkalosis enhances excitability while a mild acidosis has the opposite effect. We have observed a brain alkalosis in 78 babies with neonatal encephalopathy serially studied using phosphorus-31 magnetic resonance spectroscopy during the first year after birth (151 studies throughout the year including 56 studies of 50 infants during the first 2 weeks after birth). An alkaline brain pHi was associated with severely impaired outcome; the degree of brain alkalosis was related to the severity of brain injury on MRI and brain lactate concentration; and a persistence of an alkaline brain pHi was associated with cerebral atrophy on MRI. Experimental animal models of hypoxia-ischemia show that NHE inhibitors are neuroprotective. Here, we review the published data on brain pHi in neonatal encephalopathy and the experimental studies of NHE inhibition and neuroprotection following hypoxia-ischemia.
    Full-text · Article · Jan 2014 · Translational Stroke Research
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