Inflammatory pathways of seizure disorders

Abstract

Epilepsy refers to a cluster of neurological diseases characterized by seizures. Although many forms of epilepsy have a well-defined immune etiology, in other forms of epilepsy an altered immune response is only suspected. In general, the hypothesis that inflammation contributes to seizures is supported by experimental results. Additionally, antiepileptic maneuvers may act as immunomodulators and anti-inflammatory therapies can treat seizures. Triggers of seizure include a bidirectional communication between the nervous system and organs of immunity. Thus, a crucial cellular interface protecting from immunological seizures is the blood-brain barrier (BBB). Here, we summarize recent advances in the understanding and treatment of epileptic seizures that derive from a non-neurocentric viewpoint and suggest key avenues for future research.

Keywords: antiepileptic drugs; blood–brain barrier; corticosteroids; immunomodulatory axis; infection; inflammation; vagus nerve stimulation.

Figure 1. Schematic representation of the immunological players involved in seizure disorders

Coexistence of central and peripheral inflammatory mechanisms which are potentially epileptogenic requires numerous checkpoints to ensure that infectious or other pro-inflammatory signals are fully activated only under extreme conditions. In this scenario, electrophysiological control of seizure threshold (e.g., endowment of neuronal ion channels) interacts with ictogenic alterations of the brain milieu (soluble inflammatory factors). The latter either directly (potassium ions) or indirectly (albumin) affect neuronal firing. CNS levels of these factors are ultimately controlled by the blood-brain barrier. The most commonly reported excitability changes occur when potassium or glutamate homeostasis is altered [7]. A typical downstream event of inflammation (increased vascular permeability – dotted arrow) will not only alter immediate gene expression or cause sudden excitability changes but also sustain gliosis and activation of microglia [3]. Both principal neurons and interneurons are prone to electrophysiological changes facilitated by pro-inflammatory signals (e.g., COX-2 and IL-1β) or by an abnormal angiogenesis (Ang-2, VEGF). Other brain cells (astrocyte and microglia) contribute to delay recovery from pathologic interstitial homeostasis (e.g., albumin and IgG extravasation). Please see Table 1 for a summary of the molecular players involved.

Figure 2. Proposed routes of brain-periphery immune communication in seizure disorders

Pro-inflammatory events occurring peripherally (experimentally induced or infectious: e.g., LPS, clinically relevant: e.g., colitis) are transmitted to the brain (afferent vagus – red line, and circulating cytokines) possibly tilting the neurons toward a pro-seizure condition. Conversely, a brain-derived stress signal stimulates the adrenal glands (via hypothalamic-pituitary-adrenal gland (HPA) and sympathetic adrenal-medullary (SAM) axes); activation of these results in secretion of pro- (red) and anti-inflammatory (blue) factors. The brain-peripheral cross talk comprises peripheral organ of immune competency (e.g., spleen, lymph nodes, bone marrow, resident cells in gut [43]) and activation of circulating leukocytes. In the inflammatory reflex, a centripetal sensory input travels after infection or injury through the afferent vagus nerve to the brainstem; the efferent vagus carries centrifugal spleen-bound signals that modulates acetylcholine-release, transmitting neural signals to other immune cells by action on α-7 nicotinic receptors (see asterisk and [46]). Glucocorticosteroids can reduce seizures while commonly prescribed anti-epileptic drugs (e.g., phenytoin and diazepam, indicated in blue) have anti-inflammatory properties. Other anti-seizure therapeutic intervention (ketogenic diet, KD and hypothermia, HT) have anti-inflammatory effects. See also Table 2.