Abstracts

Rationale: Status epilepticus (SE) in humans may be associated with acute hippocampal injury that may progress onto mesial temporal sclerosis (MTS) and temporal lobe epilepsy. However, the mechanisms that underlie these events remain unclear. Clinical and experimental MRI studies have demonstrated that acute and transient MRI changes occur in the hippocampus after SE, but the relationships between these early changes and MTS are not known. Therefore we used MRI to characterise these early hippocampal changes after SE with quantitative T₂, apparent diffusion coefficient (ADC) and cerebral blood flow (CBF) in the rat lithium-pilocarpine model. We measured these parameters over a period of 21 days and investigated the relationships between these early changes and brain injury. Methods: Sixteen adult Sprague-Dawley rats were given lithium chloride (3mEq/kg) intraperitoneally (i.p.) 18 to 20h prior to either pilocarpine (30mg/kg) (n=9) or saline (n=7). Methylscopolamine i.p. (1mg/kg) was given to reduce mortality. Diazepam (10mg/kg) was administered i.p. 90min after SE onset. Imaging was performed on a 2.35T MRI scanner. Quantitative T₂, CBF and ADC were measured before injections and on days 0, 1, 2, 3, 7, 14, 21 after SE. High-resolution anatomical spin-echo images were acquired on day 21 for assessing whole brain injury and these were scored from 1 (no injury) to 5 (severe injury) by 3 independent assessors. The sum of the scores was used to give a final brain injury score.Results: In the pilocarpine animals, hippocampal T₂ increases were first detected on day 0, and reached a peak on day 2, before returning to pre-SE levels on day 7. CBF followed a similar pattern. In contrast, ADC decreased on days 2 and 3 only, in a region localised to the CA1 subfield. Furthermore, our analysis indicated that there was a strong relationship between T₂ on day 2 and brain injury on day 21 (R² = 0.70, p = 0.005). No significant MR changes were observed in the saline-injected animals.Conclusions: In the SE-injured hippocampus, we observed T₂, ADC and CBF changes that occur within the first few days after SE, which is similar to the pattern seen in humans. The T₂ and ADC changes are thought to reflect oedema formation and energy failure respectively, and these are consistent with previous reports that have demonstrated that cell death and mitochondrial dysfunction occur during this period. In addition, inflammation has also been reported at this time and may be driving the observed increase in CBF. All of these changes peaked on day 2. Furthermore, the T₂ measurements made on day 2 were clearly associated with the degree of damage on day 21. Further studies are necessary to elucidate the mechanisms that underlie this period and also the role that this period may play in epileptogenesis. In conclusion, we have used MRI to characterise early SE-induced hippocampal injury in the lithium-pilocarpine rat model and we have identified an early biomarker of subsequent injury. This project was funded by the Epilepsy Research Foundation UK.