Sanne Hoeks

Restrained inflammation and neonatal WMI in viral encephalitis 73 5 Besides similarities in systemic immune responses in different viral CNS infections described in this study, shared characteristics of distribution of WMI in different viral CNS infections are remarkable. Adiffuse distribution of whitematter injurywith a frontal predominance characterizes CNS infections caused by EV and HPeV but also by Chikungunya virus and Rotavirus. 48 In HSV asymmetrical lesions with both grey and white matter injury has been reported, noticeably different from injury after the other neurotropic viruses. 10 Cerebral development progresses after birth and irreversible neuronal damage or different developmental pathways may be induced upon interference in this development. Remarkably, infants with WMI after EV or HPeV infections, without cystic evolution and without involvement of the central grey nuclei will have a better long term neurodevelopmental outcome than expected based on their MRI abnormalities. 49, 50 As the study design is of retrospective exploratory nature, the number of include patients was limited, and therefore not from all subjects both plasma an CSF was available. Furthermore, as expected, no references MRIs of healthy newborns are available due to ethical restrictions. Four infants were doing so well during admission (no convulsions, normal cerebral imaging) that follow up for neurodevelopmental outcome was discontinued during the first year. Despite these limitations associated with the study population, the present data enhances the understanding of neonatal immune responses upon viral invasion of the CNS. To conclude, our data indicate that different neurotropic viruses provoke rather identical immune responses and EV and HPeV share rather identical distribution of subsequent white matter injury upon viral invasion of the CNS but severity of cerebral injury seems to be dependent on the degree of immune activation. 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 biological improvement of immunity in neonates may reveal strategies to diminish white mater injury after viral encephalitis in neonates. Acknowledgements The authors wish to thank M.A. Verboon, MD PhD from the department of Neonatology, University Medical Center Utrecht, the Netherlands for her advice in conception and design of the study. Projka Piravalieva-Nikolova from the department of virology of the University Medical Center Utrecht for storage and assistance in acquisition of the samples. Mariska van Dijk and Rianne Scholman from the Multiplex Core Facility, Laboratory of Translational Immunology, University Medical Center Utrecht, The Netherlands for generating the immunological data.