Neurodevelopmental outcomes following severe hand foot and mouth disease in Vietnam

Abstract

In 2011, more than 160 children died in an unprecedented outbreak of Hand foot and mouth disease (HFMD) in Vietnam, predominantly associated with enterovirus 71 (EV-A71). The occurrence of encephalitis outbreaks in children at vulnerable developmental stages raised concerns of long-term consequences. Limited retrospective outcome studies in the literature lack either a healthy comparison group or a locally validated neurodevelopmental assessment tool. Brain MRI retrospective observations identified stereotypical patterns of brainstem lesions predominantly in severe EV-A71 HFMD cases with conflicting opinions on the prognostic role of MRI. I adapted the “Bayley Scales of Infant and Toddler Development (3rd edition)” for Vietnam and demonstrated that the adaptation was reliable and valid. I conducted a prospective observational cohort study to test the hypothesis that children with severe HFMD, graded per Vietnam Ministry of Health classification, would have lower cognitive, language and motor Z scores than a healthy comparison group. All HFMD cases had virological samples taken and a sample of severe HFMD cases had brain MRI scans. All Z score 95% confidence intervals were within 2 standard deviations of the comparative healthy cohort mean suggesting outcomes at six months were not significantly lower than the healthy comparative group. I identified novel nonspecific brain white matter abnormalities on MRI in all severity grades, lower motor Z scores in grade 2b children with MRI abnormalities and that Coxsackievirus A10 (CV-A10) was significantly associated with MRI abnormalities. These findings support surveillance of all enteroviruses during HFMD outbreaks and suggest MRI may be predictive of motor impairment in a subset of severe HFMD cases. No significant impairment was identified at six months follow-up, but more complex developmental skills are yet to emerge. Hence the study continues for an eighteen-month follow up to robustly determine emergence of long-term sequelae.