The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4⁺ and CD8⁺ T cells. Significantly, proinflammatory (IL-17– and GM-CSF–producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell– and IL-17RA–deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.

Background: Explosive synaptogenesis and synaptic pruning occur in the hippocampus during the first two weeks of postnatal life, coincident with a heightened susceptibility to seizures in rodents. To determine the temporal correlation between microglial development and age‐dependent susceptibility and response to seizures, we quantified developmental changes in basal microglia levels and seizure‐induced microglial activation in the hippocampus of Cx3Cr1^GFP/+transgenic mice.Methods: Basal levels of microglia were quantified in the hippocampi of Cx3Cr1^GFP/+mice at P0, P5, P10, P15, P20, P25, P30, P40, and P60. Seizure susceptibility and seizure‐induced microglial activation were assessed in response to febrile seizures (lipopolysaccharide followed by hyperthermia) and kainic acid‐induced status epilepticus.Results: The density of microglia within the hippocampus increased rapidly after birth, reaching a peak during the second week of life – the age at which the animals became most vulnerable to seizure triggers. In addition, this peak of microglial development and seizure vulnerability during the second postnatal week represented the time of maximal seizure‐induced microglia activation.Conclusions: Overreactive innate immunity mediated by activated microglia may exacerbate acute injury to neuronal synapses and contribute to the long‐term epileptogenic effects of early‐life seizures. Anti‐inflammatory therapy targeting excessive production of inflammatory mediators by activated microglia, therefore, may be an effective age‐specific therapeutic strategy to minimize neuronal dysfunction and prevent increases in susceptibility to subsequent seizures in developing animals.

Febrile infection‐related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL‐1 receptor antagonist that blocks biologic activity of IL‐1β) are recommended.

Until a decade ago, epilepsy research had focused mainly on alterations of neuronal activities and excitability. Such neurocentric emphasis has neglected the role of glia and involvement of inflammation in the pathogenesis of epilepsy. It is becoming clear that immune and inflammatory reactions do occur in the brain despite the brain’s lack of conventional lymphatic drainage and graft acceptance and the presence of vascular brain barrier that tightly regulates infiltration of blood monocytes and lymphocytes. The critical roles of brain-resident immune mediators and of brain-infiltrating peripheral leukocytes are increasingly recognized. Inflammatory processes, including activation of microglia and astrocytes and production of proinflammatory cytokines and related molecules, occur in human epilepsy as well as in experimental models of epilepsy. Immune mechanism that underlies evolution of drug-resistant epilepsy and epileptic encephalopathy represents a new target and will aid in development of novel immunotherapeutic drugs and therapies against the key constituents in immune pathways.