Sanne Hoeks

Chapter 5 60 ABSTRACT Objective : Viral infections of the central nervous system (CNS) in neonates are associated with seizures and cerebral white matter injury (WMI), which are strong predictors of neurodevelopmental impairment. Especially neonates suffer from severe clinical symptoms and experience long-term consequences after neonatal viral encephalitis. In animals, activated immune cells in viral CNS infections contribute to neuropathology. However, the neonatal immune system is equipped with extensive immune regulatory mechanisms to support the unique demands for intrauterine survival and early postnatal life. Therefore, we studied the immune signature and its correlation with the development of WMI in neonatal viral encephalitis. Methods : We performed a multiplex immunoassay for 33 immune related proteins in cerebrospinal fluid (CSF) and plasma of 17 neonates with a viral encephalitis caused by Enterovirus (EV), Human Parechovirus (HPeV), or Herpes Simplex virus type I (HSV) confirmed with PCR. Neurodevelopmental outcome was assessed with the Griffiths Mental Development Scales and neuroimaging was performed with cerebral ultrasound and/or MRI. According to their neurodevelopmental outcome and abnormalities on neuroimaging, infants were categorized in three groups: favorable, uncertain and severely affected. Results : Frontal white matter injury characterizes EV and HPeV encephalitis. These neurotropic viruses also share similar serum immune profiles though in all neurotropic viruses, an impaired systemic immune activation is associated with severe white matter injury and a compromised neurodevelopmental outcome. Interpretation : We hypothesize that this failure to mount a proper immune response might be related to physiological adaptations of neonatal immune cells, virulence factors and/or immune escape mechanisms of neurotropic viruses. The complexity of the immune network ensuing viral invasion of the CNS and the vulnerability of neuronal and axonal cells suggest that more insight in physiological mechanisms that induce immune maturation in neonates may reveal strategies to diminish white mater injury following viral encephalitis in neonates and improve clinical outcome.