Abstract
Background and Objective: One third of children with epilepsy are refractory to medications. Growing data support a role of common childhood infections with neurotropic viruses and inflammation in epileptogenesis. Our objective was to determine the frequency of Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) infection and cytokine levels in saliva from children with seizures compared to healthy controls and to controls with a febrile illness without seizures.Methods: In this cross-sectional multi-center study, we collected saliva from 115 consecutive children with acute seizures (cases), 51 children with a fever and no seizures or underlying neurological disease (fever controls) and 46 healthy children (healthy controls). Specimens were analyzed by a novel droplet digital PCR for HHV-6 and EBV viral DNA and a bead-based immunoassay for neuroinflammatory cytokines.Results: Cases included febrile seizures (n = 30), acute seizures without (n = 53) and with fever (n = 4) in chronic epilepsy, new onset epilepsy (n = 13), febrile status epilepticus (n = 3), and first lifetime seizure (n = 12). HHV-6 DNA was found in 40% of cases vs. 37% fever controls and 35% healthy controls, with no statistically significant differences. EBV DNA was also detected with no differences in 17% cases, 16% fever controls, and 28% healthy controls. IL-8 and IL-1β were increased in saliva of 32 random samples from cases compared with 30 fever controls: IL-8 cases mean (SD): 1158.07 pg/mL (1427.41); controls 604.92 (754.04); p = 0.02. IL-1β 185.76 (230.57); controls 86.99 (187.39); p = 0.0002. IL-1β level correlated with HHV6 viral load (p = 0.007).Conclusion: Increase in inflammatory cytokines may play a role in the onset of acute seizures and saliva could represent an inexpensive and non-invasive method for detection of viral DNA and cytokines.
Highlights
Experimental and clinical findings suggest a crucial role of inflammation in epileptogenesis [1]
Studies investigating cytokine profiles in serum and cerebrospinal fluid (CSF) from children with human herpesvirus-6 (HHV-6) encephalopathy revealed an increase in IL-6, IL-8, Interleukin-10 (IL-10), and Matrix Metalloproteinase-9 (MMP-9), compared to healthy children [20]
46/115 cases of children with seizures of any etiology tested positive for HHV-6B DNA in saliva (40%) (Table 1)
Summary
Experimental and clinical findings suggest a crucial role of inflammation in epileptogenesis [1]. Host gene expression analysis of brain samples of patients with MTLE revealed expression of monocyte chemoattractant protein 1 (MCP-1) and glial fibrillary acidic protein (GFAP) in the HHV6–positive vs HHV-6–negative amygdala tissues, with positive correlation with viral load, suggesting an inflammatory process triggered by the virus [17]. Inflammatory cytokines such as IL-1β and HHV-6 infection can both induce dysregulation of glutamate homeostasis in astrocytes and contribute to epileptogenesis [18, 19]. Our objective was to determine the frequency of Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) infection and cytokine levels in saliva from children with seizures compared to healthy controls and to controls with a febrile illness without seizures
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