Abstract
Drug refractory epilepsy (RE) is a chronic neurological disease with varied etiology that represents a group of patients whose seizures do not respond to antiepileptic drugs. The immune system may have a role in seizure and epilepsy development, but the specific mechanisms of inflammation that lead to epileptogenesis and contribute to RE are unknown. Here, we used mass cytometry to comprehensively study the immune system of pediatric patients with RE and compared their immune profile and function with patients with age-matched autoimmune encephalitis (AIE) and healthy controls. Patients with RE and AIE displayed similar immune profiles overall, with changes in CD4+ and CD8+ T cell subsets and an unbalance toward proinflammatory IL-17 production. In addition, patients with RE uniquely showed an altered balance in NK cell subsets. A systems-level intercellular network analysis identified rewiring of the immune system, leading to loss of inhibitory/regulatory intercellular connections and emergence of proinflammatory pathogenic functions in neuroinflammatory immune cell networks in patients with AIE and RE. These data underscore the contribution of systemic inflammation to the pathogenesis of seizures and epileptogenesis and have direct translational implications in advancing diagnostics and therapeutics design.
Highlights
Epilepsy affects more than 50 million people worldwide, and onset typically occurs in childhood
While the distribution of CD4+ and CD8+ T cells was similar between the autoimmune encephalitis (AIE) and the refractory epilepsy (RE) patients, the distribution of NK cells differed, with a lower frequency of NK cells in AIE compared with RE or healthy controls (HC) (Figure 1A, map region 4)
We investigated the immunome of pediatric patients with RE and AIE at the single-cell level using cytometry by TOF (CyTOF)
Summary
Epilepsy affects more than 50 million people worldwide, and onset typically occurs in childhood. AIE responds well to immunotherapy and children with epileptic encephalopathies and refractory seizures are treated with steroids, there is little evidence for the efficacy of corticosteroids in RE as a whole [3, 4]. Recent studies have shown association of inflammation with seizures and epileptogenesis, even in the absence of an underlying inflammatory disorder [5,6,7,8]. Animal models of epilepsy show inflammation and a perturbed immune response, and inflammation has been identified in surgically resected brain tissue from human patients with RE [8,9,10,11,12]. Rasmussen’s encephalitis — a chronic inflammatory brain disorder — predominantly affects children with onset of frequent seizure that often progress to RE.
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