Abstracts

Rationale: Acquired epilepsy is frequently followed traumatic, ischemic, infectious or inflammatory insults to the brain. Interestingly, these insults are frequently characterized by a dysfunctional blood-brain barrier (BBB). We recently showed that BBB injury is associated with albumin-mediated activation of the transforming growth factor β (TGF-β) signaling via activing-like kinase 5 (ALK5) in astrocytes, reactive astrogliosis, a local inflammatory response, followed by epileptiform discharges and delayed epileptic seizures. Importantly, we showed that the FDA-approved angiotensin II type I receptor antagonist, losartan, block albumin-induced TGF-β signaling and prevent epileptogenesis.Methods: To challenge the hypothesis that early BBB breakdown may serve as a biomarker for epileptogenesis, we performed a longitudinal study in rats exposed to paraoxon to induce status epilepticus (SE) and epileptogenesis. We performed repeated magnetic resonance imaging (MRI) - to quantitatively monitor BBB integrity (by following T2-weighted signal hyperintensity and T1-weighted contrast-enhancement). Continuous video-electrocorticographic (ECoG) recordings were acquired to monitor for seizures.Results: BBB breakdown was detected at day 2 after SE (n = 54), and often lasted for several weeks (Table 1). Analysis of the ECoG signals, using a home-made automated Matlab script, revealed that 59% (13 out of 22) of the rats presented ≥ 2 spontaneous seizures, and therefore were defined as epileptic. Signal analysis in 13 defined brain regions using logistic regression and forward selection suggested that focal BBB breakdown in olfactory brain regions (β = 1.433) increases the likelihood of a rat to become epileptic, while diffuse damage (in 3 brain regions including the diencephalon, internal capsule and septum, β = -0.672, -0.475 and -2.951 respectively) decreases this likelihood. We thus were able to predict epilepsy with high sensitivity and specificity (92.3% and 77.8%, respectively) with 12 out of 13 epileptic rats classified correctly and only 2 out of 9 non-epileptic falsely classified as epileptic.Conclusions: Our results demonstrate that increase in BBB permeability in specific brain regions may serve as a reliable biomarker for status epilepticus-induced epileptogenesis and together with our findings showing losartan as anti-epileptogenic drug, highlight the potential of specific anti-epileptogenic treatment in patients identified with high risk to develop epilepsy.