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.
Highlights
The deleterious contribution of inflammation has been well established for a growing number of neurological disorders such as cerebral ischemia, traumatic brain injury, multiple sclerosis, and HIV encephalitis [1]
Pro-inflammatory cytokines, NF-κB, interleukin (IL)-1β and its signaling receptor IL-1R1 are highly expressed by neurons and glia in temporal lobe epilepsy [3,4], focal cortical dysplasia [5], glioneuronal tumor [6], and in tuberous sclerosis complex [7]
There was a tendency toward younger age of seizure onset (4.2 years ± 2.1 vs. 6.6 years ± 1.8, p < 0.43) and shorter duration of seizures (3.7 years ± 1.2 vs. 9.0 years ± 2.8, p < 0.098) for patients with cortical dysplasia compared to encephalomalasia group
Summary
The deleterious contribution of inflammation has been well established for a growing number of neurological disorders such as cerebral ischemia, traumatic brain injury, multiple sclerosis, and HIV encephalitis [1]. Involvement of inflammation in the pathogenesis of epilepsy and seizure-induced brain damage, has only recently been explored [2,3]. Active inflammation has been detected in prototypical inflammatory epilepsies such as Rasmussen's encephalitis or limbic encephalitis, and in patients with pharmacoresistant epilepsy of diverse causes [2,3,4,5,6,7]. Increased levels of cytokines such as IL-6 [8], IL-1β [9] and IL-1-receptor antagonist [10] have been detected in plasma and cerebrospinal fluid from patients with recent seizures without evidence of infection. Whether cytokines contribute directly to pathogenesis of seizures and chronic epilepsy, or the high levels of cytokines merely reflect activation following seizures, cannot be determined from these clinical observations. The causative role of neuroinflammation in the development of chronic epilepsy remains unclear
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