Cognitive impairment following status epilepticus and recurrent seizures during early development: support for the “two-hit hypothesis”

Hoffmann, Alexandra; Zhao, Qian; Holmes, Gregory L.

doi:10.1016/j.yebeh.2004.09.005

Cited by 38 publications

(17 citation statements)

References 41 publications

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“…Flurothyl-induced seizure latencies were measured using procedures previously described 30, 31. P10 rat pups were placed in an air-tight cylindrical plastic chamber (radius, 7.5 cm; height, 18 cm) within a fume hood.…”

Section: Methodsmentioning

confidence: 99%

A KCNQ channel opener for experimental neonatal seizures and status epilepticus

Raol

Lapides

Keating

et al. 2009

Annals of Neurology

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Objective-Neonatal seizures occur frequently, are often refractory to anticonvulsants, and are associated with considerable morbidity and mortality. Genetic and electrophysiological evidence indicates that KCNQ voltage-gated potassium channels are critical regulators of neonatal brain excitability. This study tests the hypothesis that selective openers of KCNQ channels may be effective for treatment of neonatal seizures.Methods-We induced seizures in postnatal day 10 rats with either kainic acid or flurothyl. We measured seizure activity using quantified behavioral rating and electrocorticography. We compared the efficacy of flupirtine, a selective KCNQ channel opener, with phenobarbital and diazepam, two drugs in current use for neonatal seizures.Results-Unlike phenobarbital or diazepam, flupirtine prevented animals from developing status epilepticus (SE) when administered prior to kainate. In the flurothyl model, phenobarbital and diazepam increased latency to seizure onset, but flupirtine completely prevented seizures throughout the experiment. Flupirtine was also effective in arresting electrographic and behavioral seizures when administered after animals had developed continuous kainate-induced SE. Flupirtine caused doserelated sedation and suppressed EEG activity, but did not result in respiratory suppression or result in any mortality.Interpretation-Flupirtine appears more effective than either of two commonly used anti-epileptic drugs, phenobarbital and diazepam, in preventing and suppressing seizures in both the kainic acid and flurothyl models of symptomatic neonatal seizures. KCNQ channel openers merit further study as potential treatments for seizures in infants and children.Epileptic seizures occur commonly in the first days after birth. 1 Such neonatal seizures are usually symptomatic, arising as a result of developmental abnormalities, in utero injuries, perinatal hypoxia-ischemia, infection, and other causes. Patients experiencing neonatal seizures are at substantial risk of mortality and long-term morbidity, including static encephalopathy, cerebral palsy, and chronic epilepsy. 2, 3 The first-line drugs given to neonates, phenobarbital and phenytoin, are effective in less than 50% of cases 4 . Moreover, phenobarbital, benzodiazepines and phenytoin have been shown to cause widespread neuronal apoptosis when given to young rodents, raising concerns about administration of these drugs in human infants. Genetic, physiological, and pharmacological evidence calls attention to KCNQ potassium channels (also termed Kv7 and M-channels) as potential molecular targets for treatment of neonatal seizures. 9 Loss-of-function mutations in the KCNQ2 and KCNQ3 genes cause benign familial neonatal seizures (BFNS), an uncommon but highly penetrant, dominantly-inherited syndrome characterized by seizures that recur frequently over the first weeks of life. 10-12 Experimental inhibition of KCNQ channels in rodents, by pharmacological and genetic methods, dramatically promotes neuronal and network hyperexcitabi...

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Section: Methodsmentioning

confidence: 99%

A KCNQ channel opener for experimental neonatal seizures and status epilepticus

Raol

Lapides

Keating

et al. 2009

Annals of Neurology

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“…Many of the pathophysiological changes observed in epileptic human brain tissue have been shown to be present in pilocarpineinduced epileptic mice, including hippocampal neuronal death, sclerosis and axon reorganization, in particular, mossy fiber sprouting [64][65]. Behavioral and cognitive changes occur soon after pilocarpine induced status epilepticus [33,41,59,61,77]. It has been known that this model develops refractoriness to many first-line treatments as seizure duration increases, rendering it a good model for drug screening [59], and fully satisfying the criteria for an "ideal model of epilepsy" proposed by White [76].…”

Section: Agonists and Antagonists Of Mglurs As Candidate Drugs To Prementioning

confidence: 99%

Agonists and Antagonists of Metabotropic Glutamate Receptors: Anticonvulsants and Antiepileptogenic Agents?

Tang

2005

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Anticonvulsant and neuroprotective effects of agonist and antagonist of metabotropic glutamate receptors (mGluRs) have been known for more than 10 years from multiple studies. However, it is not certain whether these candidate drugs are also antiepileptic and antiepileptogenic, as few studies included the chronic stages to determine whether spontaneous recurrent seizures could be prevented or stopped. Even in the acute stage, differences in experimental design such as timing and route of administration of candidate drugs, age, species and strain of experimental animal and experimental model make it difficult to determine the anticonvulsant and neuroprotective effects of each candidate drug. This paper, reviews in vivo neuropharmacological studies on agonsists and antagonists of mGluRs in different seizure and epilepsy models in last more than ten years. By combining with our neuropharmacological studies on the effect of mGluR agonists and antagonists in the mouse pilocarpine model of temporal lobe epilepsy, an ideal model for future development of mGluR agonists and antagonists as antiepileptogenic drugs will be proposed.

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“…Etiology of the seizures, seizure type, frequency and duration of seizures, genetics, and antiepileptic drugs are but a few of these variables. The use of animal models allows the investigator to stringently control many of these variables and provides insight into the behavioral consequences of early-life seizures (Huang et al, 1999; de Rogalski Landrot et al, 2001; Cha et al, 2002; Hoffmann et al, 2004; Zhao et al, 2005). …”

Section: 0 Introductionmentioning

confidence: 99%

Effect of age on cognitive sequelae following early life seizures in rats

et al. 2009

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Purpose-Clinical studies have suggested that seizures in newborns are more damaging that seizures occurring in older children. However, these studies are difficult to interpret for a variety of factors including differing etiologies of seizures across ages. Animal studies can provide insights into the question of whether age of seizure onset in children is a factor in cognitive outcome.Methods-To evaluate effect of age on seizure-induced cognitive impairment we subjected rats to 50 seizures from postnatal day (P) 0 to P10 or P15-P25. As adults the rats were studied in the Morris water maze, radial-arm water maze, open field, and active avoidance. To assess synaptic strength and network excitatory and inhibitory function animals were evaluated with long-term potentiation (LTP) and paired-pulse facilitation/inhibition.Results-Compared to controls, both groups of rats with recurrent seizures were impaired in spatial memory in both water maze tests, had altered activity in the open field, and did not differ from controls in active avoidance. Rats with recurrent seizures had impaired LTP but showed no deficits in pairedpulse facilitation or inhibition. While rats with later onset showed a trend to worse performance than rats with earlier seizures, the differences were not substantial.Conclusions-Recurrent seizures during development are associated with long-term behavioral deficits in learning, memory and activity level as well as impaired synaptic efficiency. Age of seizure onset was not a strong predictor of outcome. KeywordsDevelopment; seizures; radial-arm water maze; open field; active avoidance; paired pulse; long term potentiation IntroductionAge plays a major role in virtually all aspects of epilepsy (Hauser, 1992). Children are at substantially higher risk for epilepsy than young and middle aged adults (Hauser, 1994;1995;Forsgren et al., 2005). In addition to the higher incidence of epilepsy in children than adults, precipitating factors such as fever are far more likely to induce a seizure in a young child than Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Hauser, 1992;Fetveit, 2008). Age is also a determinant for prognosis. Intellectual impairment (Huttenlocher and Hapke, 1990;Glosser et al., 1997;Bulteau et al., 2000;Bjornaes et al., 2001;Hermann et al., 2002;Cormack et al., 2007), learning disabilities (Sillanpaa, 2004;Soria et al., 2007;Fastenau et al., 2008),social outcome (Lindsay et al., 1979;Sillanpaa, 1983) and medical refractoriness (Berg et al., 1996;Casetta et al., 1999;Camfield and Camfield, 2007) all appear to be influenced by age of onset. ...

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Cognitive impairment following status epilepticus and recurrent seizures during early development: support for the “two-hit hypothesis”

Cited by 38 publications

References 41 publications

A KCNQ channel opener for experimental neonatal seizures and status epilepticus

A KCNQ channel opener for experimental neonatal seizures and status epilepticus

Agonists and Antagonists of Metabotropic Glutamate Receptors: Anticonvulsants and Antiepileptogenic Agents?

Effect of age on cognitive sequelae following early life seizures in rats

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