Sepsis modulates cortical excitability and alters the local and systemic hemodynamic response to seizures

Non-convulsive seizures and status epilepticus are frequent and associated with increased mortality in septic patients. However, the mechanism through which seizures impact outcome in these patients is unclear. As previous studies yielded an alteration of neurovascular coupling (NVC) during sepsis, we hypothesized that non-convulsive seizures, might further impair NVC, leading to brain tissue hypoxia. We used a previously developed ovine model of sepsis. Animals were allocated to sham procedure or sepsis; septic animals were studied either during the hyperdynamic phase (sepsis group) or after septic shock occurrence (septic shock group). After allocation, seizures were induced by cortical application of penicillin. We recorded a greater seizure-induced increase in the EEG gamma power in the sepsis group than in sham. Using a neural mass model, we also found that the theoretical activity of the modeled inhibitory interneurons, thought to be important to reproduce gamma oscillations, were relatively greater in the sepsis group. However, the NVC was impaired in sepsis animals, despite a normal brain tissue oxygenation. In septic shock animals, it was not possible to induce seizures. Cortical activity declined in case of septic shock, but it did not differ between sham or sepsis animals. As the alteration in NVC preceded cortical activity reduction, we suggest that, during sepsis progression, the NVC inefficiency could be partially responsible for the alteration of brain function, which might prevent seizure occurrence during septic shock. Moreover, we showed that cardiac output decreased during seizures in sepsis animals instead of increasing as in shams. The alteration of the seizure-induced systemic hemodynamic variations in sepsis might further affect cerebrovascular response to neuronal activation. Our findings support the hypothesis that anomalies in the cerebral blood flow regulation may contribute to the sepsis-associated encephalopathy and that seizures might be dangerous in such a vulnerable setting.