Abstracts

Rationale: The blood-brain barrier (BBB) contributes to brain homeostasis necessary for the correct function of neurons. Disturbance of this delicate equilibrium can be a cause or consequence of central nervous system (CNS) diseases, including seizures and epileptic syndromes. Symptomatic epilepsies are the result of well-defined brain pathologies (e.g. malformations of brain development) but also occur in response to events initiated extra-parenchymally (e.g., stroke) or following traumatic brain injury associated with edema. Seizures can be transitory events observed in the time-frame of acute systemic pathologies (e.g., infection) or during iatrogenic vascular intervention. We examined the role of BBB damage in favoring seizures by using: 1) Osmotic opening of the BBB, 2) Pilocarpine model of Temporal lobe epilepsy (TLE), 3) Lithium-Pilocarpine model of TLE and 4) rodent model (MAM) of malformation of cortical development (MCD). Methods: 1) Osmotic opening of the BBB was performed in rats and pigs using intracarotid injection of mannitol 1.4M. Seizures occurrence was monitored by video-EEG. 2) Occurrence of opening of the BBB was evaluated in rats after injection of pilocarpine and before the onset of status epilepticus (SE). 3) Occurrence of opening of the BBB was evaluated 20hrs after the injection of lithium chloride (3meq/L). 4) BBB status was evaluated in the MAM model of malformation of cortical development. Association between neuronal and vascular dysplasia were examined. BBB damage was assessed by micro-angiography using FITC-Albumin and Evans Blue and examined by fluorescent microscopy. Results: Acute, hemispherical opening of the BBB was achieved by osmotic shock with mannitol. Identical results were obtained when using either a rodent or a porcine model. Behavioral seizures occurred only when the BBB was successfully and maximally breached (25% of the procedures). EEG recordings revealed additional subtle pro-epileptogenic changes not associated with change in behavior. In the pilocarpine model, areas of patchy leakage of the BBB were observed before onset of SE. Lithium-induced damage of the BBB was observed in the temporal cortex, including the hippocampus. Leakage of the BBB was associated with regions of reactive gliosis and enlargement of the ventricles. In MAM-treated rats, morphological analysis revealed leaky vessels often characterized by tortuous and interrupted branches. Vascular dysmorphism was observed in association with ectopic neurons.Conclusions: A complete hemispheric opening of the BBB is sufficient to provoke acute seizures in pigs and rodents. Partial opening of the BBB occurred before SE in the pilocarpine and the lithium-pilocarpine model of TLE. Chronic BBB damage, as observed in MAM-treated rats, is associated with low seizure threshold to several pro-convulasant agents. We suggest that seizure threshold can be decreased by pre-existent BBB damage. Different extent of cerebrovascular damage can contribute to the occurrence of seizures when a second hit is administrated.