Abstracts

In a recent pediatric series, we noted a high incidence of focal cortical dysplasia and microdysgenesis in children who underwent surgery for refractory temporal lobe epilepsy. We suggested that the presence of an underlying focal neocortical lesion predisposes children to limbic seizures and dual pathology. Previous experimental models of focal cortical dysplasia or prolonged febrile seizures have not been associated with definitive structural hippocampal changes. But hippocampal damage was observed following hyperthermic seizures in rats with a diffuse neuronal migration disorder secondary to MAM exposure. The goal of the present study was to evaluate if hippocampal changes would be seen following hyperthermic seizures in rat pups bearing a more circumscribed abnormality of cortical dyplasia.
Focal cortical lesions were induced at P1 using a modification of the freeze lesion technique initially described by Dvor[aacute]k and Feit. Sham-operated littermates received anesthesia, skin incision but did not receive the freeze lesion. At P10 hyperthermia was induced in lesioned, sham operated and na[iuml]ve control littermates. Rats were placed in a large plexi-glass box through which warm dry air (45-50[deg]C) was circulated. Each pup remained in the box until they had a generalized convulsion after which time they were removed to a cool surface for 20 min of observation. A subgroup of these rats was sacrificed at P20 to assess early hippocampal anatomical changes. The other animals were monitored 4-8 hours per day for 60 days following exposure to hyperthermia using a video camera. Animals that developed abnormal behaviours were implanted with a stainless steel bipolar electrode into the right amygdala and video-EEG recordings were performed for 1-2 hours per day over the ensuing 30 days.
Exposure to hyperthermia led to seizures with a shorter latency and a lower temperature threshold in lesioned rats with more persistent EEG ictal discharges at the end of the hyperthermia exposure. At P20, a number of lesioned pups with HS showed a failure of brain growth involving the ipsilateral hemisphere and this was associated with dentate granule cell layer hyperplasia and hypercellularity of the CA4 region. In monitored animals, prolonged episodes of freezing were observed. These episodes correlated on EEG with rhythmic epileptic discharges, consistent with spontaneous recurrent seizures.
Our model shows that the presence of a pre-existing focal cortical microgyrus leads to atypical seizures upon exposure to hyperthermia. A significant proportion of these animals develop seizure-induced neuronal damage and go on to develop limbic seizures. These findings further support a link between a focal cortical developmental lesion and the development of mesial temporal epilepsy.
[Supported by: CIHR/Epilepsy Canada, The Hospital For Sick Children Foundation, The Saint Justine Research Foundation]