Children with seizures are at risk for long-term cognitive deficits. Similarly, recurrent seizures in developing rats are associated with deficits in spatial learning and memory. However, the pathophysiological bases for these deficits are not known. Hippocampal place cells, cells that are activated selectively when an animal moves through a particular location in space, provides the animal with a spatial map. We hypothesized that seizure-induced impairment in spatial learning is a consequence of the rat's inability to form accurate and stable hippocampal maps. To directly address the cellular concomitants of spatial memory impairment, we recorded the activity of place cells from hippocampal subfield CA1 in freely moving rats subjected to 100 brief flurothyl-induced seizures during the first weeks of life and then tested them in the Morris water maze and radial-arm water maze followed by place cell testing. Compared to controls, rats with recurrent seizures had marked impairment in Morris water maze and radial-arm water maze. In parallel, there were substantial deficits in action potential firing characteristics of place cells with two major defects: i) the coherence, information content, center firing rate, and field size were reduced compared to control cells; and ii) the fields were less stable than those in control place cells. These results show that recurrent seizures during early development are associated with significant impairment in spatial learning and that these deficits are paralleled by deficits in the hippocampal map. This study thus provides a cellular correlate for how recurrent seizures during early development lead to cognitive impairment.

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. ...

Purpose Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an antiepileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. Methods We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 minutes after the onset of behavioral status epilepticus, animals were treated with LEV (200–1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. Results When administered 30 minutes after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4 minutes to 23.6 minutes. When administered 10 minutes after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Conclusions Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG.