Cellular injury and neuroinflammation in children with chronic intractable epilepsy

Abstract

ObjectiveTo elucidate the presence and potential involvement of brain inflammation and cell death in neurological morbidity and intractable seizures in childhood epilepsy, we quantified cell death, astrocyte proliferation, microglial activation and cytokine release in brain tissue from patients who underwent epilepsy surgery.MethodsCortical tissue was collected from thirteen patients with intractable epilepsy due to focal cortical dysplasia (6), encephalomalacia (5), Rasmussen's encephalitis (1) or mesial temporal lobe epilepsy (1). Sections were processed for immunohistochemistry using markers for neuron, astrocyte, microglia or cellular injury. Cytokine assay was performed on frozen cortices. Controls were autopsy brains from eight patients without history of neurological diseases.ResultsMarked activation of microglia and astrocytes and diffuse cell death were observed in epileptogenic tissue. Numerous fibrillary astrocytes and their processes covered the entire cortex and converged on to blood vessels, neurons and microglia. An overwhelming number of neurons and astrocytes showed DNA fragmentation and its magnitude significantly correlated with seizure frequency. Majority of our patients with abundant cell death in the cortex have mental retardation. IL-1beta, IL-8, IL-12p70 and MIP-1beta were significantly increased in the epileptogenic cortex; IL-6 and MCP-1 were significantly higher in patients with family history of epilepsy.ConclusionsOur results suggest that active neuroinflammation and marked cellular injury occur in pediatric epilepsy and may play a common pathogenic role or consequences in childhood epilepsy of diverse etiologies. Our findings support the concept that immunomodulation targeting activated microglia and astrocytes may be a novel therapeutic strategy to reduce neurological morbidity and prevent intractable epilepsy.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…As discussed above, the activation of inflammatory pathways and the consequent release of inflammatory molecules alter neural network excitability, inducing various mechanisms, with either a direct or indirect impact on neuronal functions (for reviews see [71][72][73][74]). Activation of cells of the microglia/macrophage lineage and astrocytes and concomitant induction of various inflammatory pathways have also been observed in FCD with activation of both innate and the adaptive immune response [77,120,172,173]. In a cohort of FCD II patients, the density of activated microglial cells correlated significantly with the duration of epilepsy, as well as with the frequency of seizures prior to surgical resection [172].…”

Immunity and Inflammation in Epilepsy

“…Neuropathological examination of surgical specimens from patients with FCD provides evidence of activation of both the innate and adaptive immune responses and concomitant induction of various inflammatory pathways Ravizza et al 2006;Choi et al 2009;Iyer et al 2010a). Moreover, in a cohort FCD II case, the density of activated microglial cells significantly correlates with the duration of epilepsy, as well as with the frequency of seizures before surgical resection .…”

Rasmussen encephalitis and comorbid autoimmune diseases

“…Subsequently, serum IgG autoantibodies against a7 nicotinic acetylcholine receptors (a7nAChR) were reported in a subset of patients with RE and described as specifically blocking the function of the neuronal a7nAChR, 16 an inflammatory regulator thought to play a role in blood-brain barrier regulation, which is likely to be damaged in RE. 17,18 In 2 independent studies, serum antibodies against the presynaptic SM (Sec1/Munc18-like) protein Munc-18 were found in a subset of patients with RE during early disease stages, with description of altered neurotransmitter release. 19,20 In addition to the potential contribution of B cells/plasma cells and antibodies, involvement of effector T cells has been suggested based on immunohistochemical analysis of the RE inflammatory lesion, highlighting that most of the infiltrating lymphocytes were cytotoxic CD8…”