The Immune System in Pediatric Seizures and Epilepsies

Christian M. Korff and Russell C. Dale
Pediatrics September 2017, 140 (3) e20163534; DOI:


The relation between the immune system and epilepsy has been studied for a long time. Immune activation may precede or follow the appearance of seizures. Depending on the situation, the innate and acquired immunity may be involved to various degrees. The intense, ongoing research has opened encouraging management and therapeutic perspectives for a significant number of patients suffering from seizures. These include the use of various drugs and less conventional approaches with anti-inflammatory or immunomodulatory properties. Data for children remain scarce, however, and the practical implications of recent discoveries in the field remain to be identified formally. The aim of this review is to present current knowledge of the role of immunity in relation to seizures, with a particular emphasis on clinical data available in childhood. More specifically, various autoantibodies involved in autoimmune encephalitis and epilepsy and general pathophysiological hypotheses on the role of immunity in seizure genesis are discussed, specific epilepsy syndromes in which autoimmune components have been studied are summarized, workup recommendations and therapeutic options are suggested, and finally, open questions and future needs are presented.

Various Mechanisms Link Immune Activation and Seizures

It is generally accepted that the activation of the immune system can be both the consequence and the cause of seizures, which in both cases can induce permanent functional changes in the CNS. These may themselves contribute to generate epileptic seizures.[91–93] Various pathways link the immune response and seizures. These include adaptive systemic responses, such as T- and B-cell activation and auto-AB production, and innate mechanisms of the CNS, like the increased production of cytokines by activated glial cells observed in response to various stimuli such as seizures. The latter mechanism is a recently identified process named neurogenic neuroinflammation, in which innate and adaptive inflammatory reactions and vascular cell activation within the CNS are triggered by activity in primary afferent nerve fibers or higher-order neurons.[94] On the basis of 5 recent overview articles,[91,94–97] one can attempt to summarize the most important steps that link the immune system and seizures with the following:

1. An initial injury occurs, in the CNS or in the periphery, and provokes an activation of the immune system in one or both compartments (systemic or neuroinflammatory). Various events have been identified as being able to play such a role, including peripheral infections, autoimmune diseases, CNS vascular disease (thrombosis, emboli, and hemorrhage), vasculitis, neurotrauma, metabolic disorders, CNS infections, seizures, and status epilepticus.

2. Inflammatory mediators are released in either compartment, or in both, depending on the nature of the initial injury. These mediators include various cytokines (such as interleukin [IL]-1β, IL-6, and tumor necrosis factor-α), complement proteins, so-called danger signals (molecules that alert the microenvironment to an ongoing injury, such as high-mobility-group box-1 and its activation of toll-like receptor 4 in neurons and glial cells), cell-adhesion molecules, prostaglandins produced by the activation of the cyclooxygenase-2 signaling pathway, and chemokines. The upregulation of these mediators and their release by lymphocytes in the periphery, or by activated glial and neuronal cells, may in turn provoke blood-brain barrier (BBB) breakdown, adhesion and penetration of activated peripheral lymphocytes, immunoglobulins and albumin into the brain (and, for the latter, subsequent activation of the transforming growth factor-β signaling pathway), increasing extracellular potassium concentration, as well as functional changes in neurons, glial cells, and astrocytes.

3. Neuronal functional changes occur, which increase seizure susceptibility. Examples of these functional changes include the increased expression of IL-1R1 (the target and mediator of the biological response to IL-1β) in neurons; the activation of various intracellular kinase families, such as inducing phosphorylation of a subunit of glutamatergic NMDA-R; the inhibition of the glutamate reuptake or the increase of glutamate release in the extracellular space by astrocytes; the promotion of synaptic reorganization; and the dysfunction of ion channels. Animal research studies also showed that certain genes that code for mediators of the inflammatory response, such as IL-1, IL-6 (and its receptor), and IL-1β are upregulated in the acute phase that follows status epilepticus or traumatic brain injury.[8,98]

4. All of these mechanisms increase neuronal excitability and lower the seizure threshold, which creates a vicious cycle of increased seizure susceptibility. Animal research has provided details regarding the various mechanisms for inflammation-induced epileptogenesis. These include the abovementioned increased adhesion of activated peripheral leukocytes to endothelial cells followed by their infiltration into the CNS through cytoskeletal reorganization.[99] These cells generate free radicals and cytotoxic enzymes, which, in addition to further production and secretion of cytokines and chemokines, participate in neuronal dysfunction or degeneration that contribute to the appearance of a subsequent chronic susceptibility to seizures.[95]

On the other hand, a neuroprotective role of CD3+ T cells of counterbalancing the innate inflammation has been shown in mice that suffer from kainic-acid–induced seizures and lesioned hippocampi,[100] thus leaving the question of the exact role of the adaptive response open.

From another standpoint, the relation between the BBB and the occurrence of epilepsy has been studied extensively for years,[101–105] but the way in which BBB disruption may provoke chronic epilepsy remains incompletely understood. It has been hypothesized, for example, that acute BBB disruption after initial seizures cause prolonged or permanent changes in brain permeability, which forms the basis of chronic surrounding neuronal excitability and further seizure genesis.[106–108] Recent advances in the BBB disruption theory will likely help our understanding of the process. Bargerstock et al[109] showed that S100B, an astrocytic protein, is released in the systemic circulation when the BBB endothelial tight-junctions are disrupted, for instance, during seizures. This release may in turn induce a systemic autoimmune reaction against the brain, which underlies the development of chronic conditions in the CNS, such as epilepsy and Alzheimer disease. These results need confirmation.


It is now clear that inflammation and autoimmunity play important roles in childhood seizures and epilepsies. These immune reactions can be the cause of seizures, such as when auto-ABs against various CNS targets involved in neuronal activation are produced. On the other hand, various CNS and peripheral immune responses are activated after seizures. The latter mechanisms are encompassed in the recently described concept of neurogenic neuroinflammation, which can result in the activation of an anti-inflammatory cascade and homeostatic mechanisms with subsequent neuroprotection and interruption of seizures or the perpetuation of a maladaptive and neurotoxic immune response as the basis of further epilepsy genesis.[94] Important questions that remain open include the understanding of the precise timing and sequence of elements of the immune response to seizures, the detection of reliable diagnostic biomarkers of CNS inflammation in children with epilepsies, the identification of specific clinical, radiologic, and electrophysiological features that may allow early suspicion of immune epilepsy, and the development of optimal therapeutic strategies and molecules targeted against the various inflammatory mediators described above through prospective-controlled studies.