Pro- and Anti-inflammatory Neurovascular Processes in Epilepsy: A Fragile and Dynamic Equilibrium

The relationship between epilepsy and inflammation dates back to 1958 when inflammation in the epileptic brain was first recognized in Rasmussen’s encephalitis. In the last two decades, preclinical and clinical studies provided growing evidence to support a link between brain or peripheral inflammation, seizures, and epileptogenesis. Inflammation is activated to restore tissue homeostasis and to initiate repair programs by the activation of pro-resolving mediators. Inflammation is based on early activation of innate immunity mechanisms (e.g., macrophages), which may successively recruit adaptive immunity effectors (e.g., lymphocytes). An incomplete or defective resolution of this complex homeostatic mechanism can lead to chronic inflammation, histological damage, and autoimmunity. In the brain, the inflammatory response to injuries involves brain-resident cells and leukocyte recruited from the bloodstream in complex crosstalk tightly regulated by the blood-brain barrier (BBB). Two distinct inflammatory processes have been linked to seizures: neuroinflammation and systemic inflammation. Seizures can be triggered by a pathogen or dysregulated sterile immunity. Neuroinflammation is an intrinsic brain response that involves the activation of innate immunity mechanisms in glia, neurons, and the microvasculature. Systemic inflammation, whose effects on the brain are primarily mediated by impairment of BBB, can induce neuron hyperexcitability through loss of ionic and neurotransmitter homeostasis. It is traditionally considered that activation of innate immunity and brain-resident cells leading to neuroinflammation has a pivotal role in structural epilepsies. In contrast, a prominent role of adaptive immunity in triggering or perpetuating the inflammatory response relates to epileptic encephalitis and systemic or neurological autoimmune conditions associated with the development of epilepsy. In this chapter we will summarize current knowledge on systemic and neuroinflammation and on the BBB which, when intact, separates the periphery from the brain.