Neurodevelopmental outcomes of newborns and infants with parechovirus and enterovirus central nervous infection: a 5-year longitudinal study.

Though parechovirus (PeV) and enterovirus (EV) are common causes of central nervous system (CNS) infection in childhood, little is known about their long-term neurologic/neurodevelopmental complications. We investigated, longitudinally over a 5-year period, motor neurodevelopment in term-born newborns and infants with RT-qPCR-confirmed PeV- or EV-CNS infection. Motor neurodevelopment was assessed with standardized tests: Alberta Infant Motor Scale (AIMS), Bayley Scales of Infant and Toddler Development version-3 (Bayley-3-NL), and Movement Assessment Battery for Children version-2 (M-ABC-2-NL) at 6, 12, 24, and 60 months post-infection. Results of children with PeV-CNS infection were compared with those of peers with EV-CNS infection and with Dutch norm references. In the multivariate analyses adjustments were made for age at onset, gender, maternal education, and time from CNS infection Sixty of 172 eligible children aged ≤ 3 months were included. Children with PeV-CNS infection had consistently lower, non-significant mean gross motor function (GMF) Z-scores, compared with peers with EV-CNS infection and population norm-referenced GMF. Their GMF improved between 6 and 24 months and decreased at 5 years. Their fine motor function (FMF) scores fell within the population norm reference. CONCLUSION: These results suggest that the impact of PeV-A3-CNS infection on gross motor neurodevelopment in young children might manifest later in life. They highlight the importance of longitudinal neurodevelopmental assessments of children with PeV-A3-CNS infection up to school age. WHAT IS KNOWN: • Human parechovirus (PeV) is a major cause of central nervous system infection (CNS infection) in newborns and infants. • There is interest in the neurological and neurodevelopmental outcome of newborns and infants with PeV-A3-CNS infection. WHAT IS NEW: • This prospective study compares the motor neurodevelopment of term-born newborns and infants with PeV-A3-CNS infection with those with EV-CNS infection and with norm references. • The results support the importance of follow-up of newborns and infants with PeV-A3-CNS infection to detect subtle neurodevelopmental delay and start early interventions.

Neurological and neurodevelopmental outcomes after human parechovirus CNS infection in neonates and young children: a systematic review and meta-analysis.

BACKGROUND: Human parechoviruses are a major cause of CNS infection in neonates and young children. They have been implicated in neurological sequelae and neurodevelopmental delay. However, the magnitude of this effect has not been systematically reviewed or assessed with meta-analyses. We investigated short-term, medium-term, and long-term neurological sequelae and neurodevelopmental delay in neonates and young children after parechovirus-CNS-infection. METHODS: In this systematic review and meta-analyses of studies, we searched PubMed, Embase, and PsycInfo, from the inception of the database until March 18, 2019, for reviews, systematic reviews, cohort studies, case series, and case control studies reporting on neurological or neurodevelopmental outcomes of children 3 months or younger with parechovirus infection of the CNS. Studies that were published after Dec 31, 2007, assessed children younger than 16 years, detailed parechoviruses infection of the CNS (confirmed by PCR), and followed up on neurological and neurodevelopmental outcomes were included. Studies published before Dec 31, 2007, were excluded. The predefined primary outcomes were the proportions of children with neurological sequelae, impairment in auditory or visual functions, or gross motor function delay. The proportion of children in whom neurological or neurodevelopmental outcomes were reported was pooled in meta-analyses. For each outcome variable we calculated the pooled proportion with 95% CI. The proportion of children in whom neurological or neurodevelopmental outcomes were reported was extracted by one author and checked by another. Two authors independently assessed the methodological quality of the studies. FINDINGS: 20 studies were eligible for quantitative synthesis. The meta-analyses showed an increasing proportion of children with neurological sequelae over time: 5% during short-term follow-up (pooled proportion 0·05 [95% CI 0·03-0·08], I2=0·00%; p=0·83) increasing to 27% during long-term follow-up (0·27 [0·17-0·40], I2=52·74%; p=0·026). The proportion of children with suspected neurodevelopmental delay was 9% or more during long-term follow-up. High heterogeneity and methodological issues in the included studies mean that the results should be interpreted with caution. INTERPRETATION: This systematic review suggests the importance of long follow-up, preferably up to preschool or school age (5-6 years), of children with parechovirus infection of the CNS. Although not clinically severe, we found an increasing proportion of neonates and young children with CNS infection had associated neurological sequelae and neurodevelopmental delay over time. We recommend the use of standardised methods to assess neurological and neurodevelopmental functions of these children and to compare results with age-matched reference groups. FUNDING: No funding was received for this study.

Human parechovirus meningitis and gross-motor neurodevelopment in young children.

This multicenter prospective cohort study describes the impact of human parechovirus meningitis on gross-motor neurodevelopment of young children. Gross-motor function was measured using Alberta Infant Motor Scale. Of a total of 38 eligible children < 10 months of age at onset, nine cases had clinical evidence of meningitis and polymerase chain reaction positive for human parechovirus in cerebrospinal fluid; 11 had no meningitis and polymerase chain reaction positive for human parechovirus in nasopharyngeal aspirate, blood, urine, or feces; and in 18, no pathogen was identified (reference group).The children with human parechovirus meningitis showed more frequent albeit not statistically significant suspect gross-motor function delay (mean Z-score (standard deviation) - 1.69 (1.05)) than children with human parechovirus infection-elsewhere (- 1.38 (1.51)). The reference group did not fall in the range of suspect gross-motor function delay (- 0.96 (1.07)). Adjustment for age at onset and maternal education did not alter the results.Conclusion: Six months after infection, children with human parechovirus meningitis showed more frequent albeit not statistically significant suspect gross-motor function delay compared to the population norm and other two groups. Longitudinal studies in larger samples and longer follow-up periods are needed to confirm the impact and persistence of human parechovirus meningitis on neurodevelopment in young children. What is Known: • Human parechovirus is progressively becoming a major viral cause of meningitis in children. • There is keen interest in the development of affected infants with human parechovirus meningitis. What is New: • This study describes prospectively gross-motor functional delay in children with both clinical evidence of meningitis and polymerase chain reaction positive for human parechovirus in cerebrospinal fluid. • It shows the importance of screening young children for developmental delay in order to refer those with delay for early intervention to maximize their developmental potential.

Longitudinal Association Between Human Parechovirus Central Nervous System Infection and Gross-Motor Neurodevelopment in Young Children.

BACKGROUND: A paucity of studies investigated the association between human parechovirus (HPeV) central nervous system (CNS) infection and motor and neurocognitive development of children. This study describes the gross-motor function (GMF) in young children during 24 months after HPeV-CNS infection compared with children in whom no pathogen was detected. METHODS: GMF of children was assessed with Alberta Infant Motor Scale, Bayley Scales of Infant and Toddler Development or Movement Assessment Battery for Children. We conducted multivariate analyses and adjusted for age at onset, maternal education and time from infection. RESULTS: Of 91 included children, at onset <24 months of age, 11 had HPeV-CNS infection and in 47 no pathogen was detected. Nineteen children were excluded because of the presence of other infection, preterm birth or genetic disorder, and in 14 children, parents refused to consent for participation. We found no longitudinal association between HPeV-CNS infection and GMF (ß = -0.53; 95% confidence interval: -1.18 to 0.07; P = 0.11). At 6 months, children with HPeV-CNS infection had suspect GMF delay compared with the nonpathogen group (mean difference = 1.12; 95% confidence interval: -1.96 to -0.30; P = 0.03). This difference disappeared during 24-month follow-up and, after adjustment for age at onset, both groups scored within the normal range for age. Maternal education and time from infection did not have any meaningful influence. CONCLUSIONS: We found no longitudinal association between HPeV-CNS infection and GMF during the first 24-month follow-up. Children with HPeV-CNS infection showed a suspect GMF delay at 6-month follow-up. This normalized during 24-month follow-up.