Abstracts

Rationale: After a precipitating brain insult, only a proportion of patients develop acquired epilepsy. Although genetic and epigenetic variation is likely at the origin of this dichotomy, our aim was to investigate the pathological phenotype associated with the epilepsy outcome by means of two approaches. Firstly, we studied brain pathology in two submodels of post-kainic acid-induced status epilepticus (KASE) which result in a different seizure outcome. In a second experiment, non-invasive 18F-PBR111 (microglia activation) PET and T2 MRI were performed to evaluate the link between early brain damage and inflammation with seizure outcome on the long term.Methods: Status epilepticus (SE) was induced in male Wistar rats (Charles River, W/CR) and Sprague Dawleys (Harlan, SD/H) by low-dose subcutaneous injection of kainic acid. Animals were sacrificed in the latent period (D7, n= 11-12 per model) and chronic period (W12, n= 9-12 per model). Microglia activation (Ox42) and cell loss (NeuN) were investigated post-mortem. Secondly, brain inflammation was determined in vivo during the latent phase (W2, n= 13) or saline injection (n= 8) in the W/CR KASE model with non-invasive 18F-PBR111 PET. MRI scans were obtained for assessment of structural brain damage and PET coregistration. Animals from the W12 time-point and from the imaging study were followed to assess spontaneous recurrent seizures in the chronic period using video-EEG.Results: None of the groups differed in the severity of the SE. Interestingly, the two KASE models (W/CR and SD/H) significantly differed in seizure number in the chronic epilepsy phase (p< 0.01). Whereas W/CR KASE had none to few seizures/day, the SD/H experienced up to 20 seizures/day. Surprisingly, significantly higher cell loss and Ox42 staining was observed in the W/CR KASE compared to the SD/H group in the hippocampus. The PET study in the W/CR showed a significant increase in 8F-PBR111 binding at W2 post SE in the KASE animals that did not develop seizures (n=3) compared to the KASE animals with seizures (n=10) in the chronic phase.Conclusions: It is generally well accepted that a more severe brain insult increases the risk for acquired epilepsy. On the contrary, data from our experiments suggests that cell loss and microglia activation in KASE animals with less seizure burden or no seizures is higher compared to KASE animals with higher seizure burden. Although this may seem counter intuitively, a possible explanation might be that this results in increased homeostatic mechanisms. An alternative hypothesis may be that when neurons survive the insult they become dysfunctional and contribute to the increased hyperexcitability. Lastly, 18F-PBR111 PET scans might discriminate subjects with or without epilepsy. However, the limited number of KASE rats without seizures in the chronic epilepsy period warrant caution when interpretation the results. Further studies will be needed to investigate these hypotheses and to confirm our results.