Congenital Zika Infection and the Risk of Neurodevelopmental, Neurological, and Urinary Track Disorders in Early Childhood. A Systematic Review.

It was late 2015 when Northeast Brazil noticed a worrying increase in neonates born with microcephaly and other congenital malformations. These abnormalities, characterized by an abnormally small head and often neurological impairment and later termed Congenital Zika Syndrome, describe the severity of neurodevelopmental and nephrological outcomes in early childhood, and the implication of microcephaly at birth. The purpose of the study was to describe the neurodevelopmental outcomes in children exposed to Zika virus during fetal life, with and without microcephaly at birth. The systematic review included research studies about the neurodevelopmental outcomes with and without microcephaly, as well as nephrological outcomes in early childhood. We searched PubMed, Crossref, PsycINFO, Scopus, and Google Scholar publications and selected 19 research articles published from 2018 to 2021. Most studies have linked the severity of microcephaly in childbirth to the neurodevelopmental and urinary outcomes in early childhood. However, most children without microcephaly at birth develop typically, while others may be at risk for language impairment.

Desenvolvimento neuropsicomotor de crianças expostas à infecção congênita pelo Zika vírus / Neuropsychomotor development of children with congenital Zika virus infection

INTRODUÇÃO: A comprovação da associação de microcefalia no Brasil com a infecção congênita pelo Zika vírus, leva a necessidade de estudos sobre a repercussão no desenvolvimento das crianças decorrentes do comprometimento do sistema nervoso central (SNC). OBJETIVO: Avaliar o desenvolvimento neuropsicomotor (DNPM) de crianças expostas à infecção congênita pelo Zika vírus e sua associação com características e diagnósticos pré natais, neonatais e pós natais da mãe/criança. MÉTODOS: Estudo transversal com crianças de zero a três anos, nascidas entre 2015 e 2018, classificadas com infecção congênita pelo Zika vírus. Na coleta das características clínicas e sócio demográficas, utilizou-se um questionário semiestruturado e na avaliação do DNPM o Teste de Triagem de Denver II. Na associação, utilizou-se o teste exato de Fisher (p<0,05). RESULTADOS: Avaliou-se 30 crianças, 46,67% apresentavam alterações do DNPM, os maiores foram na linguagem (46,67%) e motricidade fina (43,33%). 23,33% tinham mais que 24 meses, idade que se associou a alterações do DNPM (p<0,012). A infecção predominou entre 4 e 12 semanas de gestação e obteve associação com os atrasos do DNPM (p<0,002). 46,67% das crianças apresentaram microcefalia e 40% calcificações cerebrais, ambos com associação a atrasos no DNPM (p<0,001). Em exame físico 36,7% apresentaram alterações de postura e persistência de reflexos primitivos, 40% hiperirritabilidade, 33,33% disfagia e deformidades articulares, todas com associação importante com as alterações no DNPM (p<0,001). CONCLUSÕES: Crianças expostas à infecção congênita pelo Zika vírus apresentaram atrasos no DNPM e quanto mais precoce a infecção na gravidez, maior o envolvimento do sistema nervoso central.

INTRODUCTION: The proof of the association of microcephaly in Brazil with congenital Zika virus infection leads to the need for studies on the impact on children's development resulting from the involvement of the central nervous system (CNS). OBJECTIVE: To evaluate the neuropsychomotor development (NPMD) of children exposed to congenital Zika virus infection and its association with prenatal, neonatal, and postnatal characteristics and diagnoses of the mother/child. METHODS: Cross-sectional study with children aged zero to three years, born between 2015 and 2018, classified with congenital Zika virus infection. In the collection of clinical and socio-demographic characteristics, a semistructured questionnaire was used, and the Denver II Screening Test was used to assess the DNPM. In the association, Fisher's exact test was used (p<0.05). RESULTS: Thirty children were evaluated; 46.67% had DNPM alterations, the greatest ones were in the language (46.67%) and fine motor skills (43.33%). 23.33% were older than 24 months, an age-associated with changes in DNPM (p<0.012). Infection predominated between 4 and 12 weeks of gestation and was associated with DNPM delays (p<0.002). 46.67% of children had microcephaly and 40% cerebral calcifications, both associated with DNPM delays (p<0.001). On physical examination, 36.7% had changes in posture and persistence of primitive reflexes, 40% hyperirritability, 33.33% dysphagia, and joint deformities, all with an important association with changes in DNPM (p<0.001). CONCLUSIONS: Children exposed to congenital Zika infection had developmental delays. It is noteworthy that the earlier the infection in pregnancy, the greater the involvement of the central nervous system of children.

An Examination of the Long-Term Neurodevelopmental Impact of Prenatal Zika Virus Infection in a Rat Model Using a High Resolution, Longitudinal MRI Approach.

Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.

Parent-administered Neurodevelopmental Follow up in Children After Picornavirus CNS Infections.

BACKGROUND: Data on the neurodevelopment of children who experienced central nervous system (CNS) infections with enteroviruses (EV) or parechoviruses (hPeV) is scarce and mostly limited to follow up of short-term outcomes. METHODS: Parents of children who presented between 2014 and 2019, underwent a lumbar puncture and whose cerebrospinal fluid was polymerase chain reaction positive for EV or hPeV, were asked to complete a care-giver-administered neurodevelopmental assessment tool (The Ages and Stages Instrument [ASQ3]). Clinical data of the infective episode were collected from patient notes. RESULTS: Of 101 children, 43 (10 hPeV+, 33 EV+) submitted ASQ3 results. Median age at assessment was 38.9 months (interquartile range, 15.4-54.8), the follow-up interval 3 years (median 37 months; interquartile range, 13.9-53.1). Age, inflammatory markers, and cerebrospinal fluid pleocytosis during the infective event were not associated with ASQ3 scores. In 23 children (17 EV+, 6 hPeV+), no neurodevelopmental concerns were reported. Two more had preexisting developmental delay and were excluded. Of the remaining, 18/41 (43.9%) reported ASQ3 scores indicating need for monitoring or professional review in at least 1 category, not differing by pathogen (EV 14/31, 45.2%; hPeV 4/10, 40%; P = 0.71). Seven children will require formal review, scoring ≥2 SD below the mean in at least 1 category (6/31 EV+, 1/10 hPeV+, P = 0.7), 3 scored ≥2 SD below the mean in more than 1 area. CONCLUSIONS: Parent-administered developmental assessment of children with a history of early picornavirus infection of the CNS identified a subgroup that requires formal neurodevelopmental review. Wider application of community-based developmental screening will complement our understanding of the impact of CNS infections in early childhood.

POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW.

OBJECTIVE: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. DATA: sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. DATA: synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. CONCLUSIONS: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

Plasma biomarker factors associated with neurodevelopmental outcomes in children with perinatal HIV infection and controlled viremia.

OBJECTIVE: We examined relationships between plasma biomarkers and neurodevelopment in children from sub-Saharan Africa with perinatal HIV (PHIV) with controlled viremia on antiretroviral therapy (ART). DESIGN: Longitudinal retrospective cohort study of children with controlled blood HIV replication. METHODS: Children (N = 213; 57% girls) started ART at less than 3 years of age, had neurodevelopmental assessments (cognition, attention/impulsivity, motor proficiency, global executive functions) at 5-11 years, and achieved controlled viremia (HIV-1 RNA <400 copies/ml for ≥9 months before initial assessment). Twenty-three plasma biomarkers were measured at onset of controlled viremia, week 0 (first neurodevelopmental assessment), and week 48 (second neurodevelopmental assessment). Factor analysis was conducted at each time point. Multivariable linear regressions assessed associations between factors and neurodevelopmental scores. RESULTS: Median age at week 0 was 7.0 years. Eighteen biomarkers loaded on six factors: a (L-10, IFNγ, IFNα2, IL-1ß, IL-6, IP-10, TNFα); B (sCD163, sICAM-1, sVCAM-1, CRP); C (sE-selectin, sP-selectin); D [MIP-1ß, vascular endothelial growth factor (VEGF)-A]; E (sCD14, CRP); and F (CX3CL1, MCP-1). Higher factor B scores were consistently associated with worse cognition and attention/impulsivity, and higher factor D scores with better attention/impulsivity. CONCLUSION: These results suggest a detrimental effect of increased endothelial cell activation (sICAM-1, sVCAM-1) and monocyte/macrophage scavenger function (sCD163) and a beneficial effect of increased CCR5 ligand and HIV entry blocker MIP-1ß and angiogenesis stimulant-VEGF concentrations on the neurodevelopment of children with PHIV. The model that emerges is of vascular inflammation leading to neurodevelopmental deficits. The role of persistent HIV replication in the central nervous system also needs to be further explored.

Long-term neurodevelopment outcomes of hand, foot and mouth disease inpatients infected with EV-A71 or CV-A16, a retrospective cohort study.

Hand, foot and mouth disease (HFMD) is a common infectious disease in western Asia area and the full range of the long-term sequelae of HFMD remains poorly described. We conducted a retrospective hospital-based cohort study of HFMD patients with central nervous system (CNS) complications caused by EV-A71 or CV-A16 between 2010 and 2016. Patients were classified into three groups, including CNS only, autonomic nervous system (ANS) dysregulation, and cardiorespiratory failure. Neurologic examination, neurodevelopmental assessments, Magnetic Resonance Imaging (MRI) and lung function, were performed at follow up. Of the 176 patients followed up, 24 suffered CNS only, 133 ANS dysregulation, and 19 cardiorespiratory failure. Median follow-up period was 4.3 years (range [1.4-8.3]). The rate of neurological abnormalities was 25% (43 of 171) at discharge and 10% (17 of 171) at follow-up. The rates of poor outcome were significantly different between the three groups of complications in motor (28%, 38%, 71%) domain (p=0.020), but not for cognitive (20%, 24%, 35%), language (25%, 36%, 41%) and adaptive (24%, 16%, 26%) domains (p = 0.537, p = 0.551, p = 0.403). For children with ventilated during hospitalization, 41% patients (14 of 34) had an obstructive ventilatory defect, and one patient with scoliosis had mixed ventilatory dysfunction. Persistent abnormalities on brain MRI were 0% (0 of 7), 9% (2 of 23) and 57% (4 of 7) in CNS, ANS and cardiorespiratory failure group separately. Patients with HFMD may have abnormalities in neurological, motor, language, cognition, adaptive behaviour and respiratory function. Long-term follow-up programmes for children's neurodevelopmental and respiratory function may be warranted.

Childhood Outcomes Following Parechovirus Infections in a US Young Infant Cohort.

BACKGROUND: Parechovirus A type 3 (PeV-A3) is associated with central nervous system infection in young infants. There are limited data regarding long-term outcomes, mostly reported from Australia and European populations. The objective of this study was to assess frequency of neurodevelopmental impairment (NDI) following PeV-A3 infection in our US cohort. METHODS: Infants hospitalized during the 2014 outbreak with laboratory-confirmed PeV-A3 infection were evaluated with medical history, neurologic examination, parental completion of Ages and Stages Questionnaire and developmental assessment using Bayley Scales of Infant and Toddler Development, Third Edition cognitive, motor and language quotients. Determination of NDI was based on published criteria. Relationship of severity of PeV disease to outcome measures was determined using Fisher exact, χ2 and Mann-Whitney U test as appropriate. RESULTS: Nineteen children, term gestation, were evaluated at ~3 years of age; PeV-A3 illness was uncomplicated for 6 (32%), complex, non-neurologic for 9 (47%) and encephalitis/seizures for 4 (21%). No differences were noted in mean Bayley Scales of Infant and Toddler Development, Third Edition quotients between infants by clinical presentation. Quotients for all were within 1 SD of population norms. Two (11%) children had mild NDI; 1 with mild cerebral palsy. Ages and Stages Questionnaire results included 11% at referral level and 37% suspect concern. Parents of 6 (32%) noted behavior concerns. These findings were unrelated to severity of the PeV-A3 illness. CONCLUSIONS: Parent concerns were identified frequently following infant PeV-A3 disease. Eleven percent had neurodevelopmental impairment at 3 years of age. Severity at presentation did not correlate with adverse childhood outcomes. Longitudinal developmental monitoring following infantile PeV-A3 disease is warranted.

Coronavirus Infections in the Nervous System of Children: A Scoping Review Making the Case for Long-Term Neurodevelopmental Surveillance.

BACKGROUND: The objective of this study was to describe the case literature of human coronavirus infections in the nervous system of children, including from SARS-CoV-2, and to provide guidance to pediatric providers for managing the potential long-term effects on neurodevelopment of human coronavirus infections in the nervous system. METHODS: Using a structured strategy, the PubMed and Ovid:Embase databases were queried for articles about the clinical presentation and pathophysiology of coronavirus infections in the nervous system of children and young adults, aged 0 to 24 years. RESULTS: Of 2302 articles reviewed, 31 described SARS-CoV-2 infections in the nervous system of children and 21 described other human coronaviruses: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1. Excepting MERS-CoV, we found cases of neurological disease in children from each human coronavirus. Children with non-SARS-CoV-2 infections have suffered acute flaccid paralysis, acute disseminated encephalomyelitis, encephalitis, and seizures. In addition, cases of ischemic, hemorrhagic, and microvascular strokes have occurred in children with SARS-CoV-2. Patients with multisystem inflammatory syndrome in children have suffered encephalitis, stroke, pseudotumor cerebri syndrome, and cytotoxic lesions of deep brain structures. Despite these reports, few articles evaluated the impact of human coronavirus infections on long-term neurodevelopmental domains including cognitive, language, academic, motor, and psychosocial outcomes. CONCLUSIONS: Neurological manifestations of human coronavirus infections can cause severe disease in children. The case literature suggests a critical gap in knowledge of the long-term effects on child neurodevelopment of these infections. As the current SARS-CoV-2 pandemic continues, this gap must be filled to facilitate optimal outcomes in recovering children.

Birth Defects and Long-Term Neurodevelopmental Abnormalities in Infants Born During the Zika Virus Epidemic in the Dominican Republic.

Background: When acquired during pregnancy, Zika virus (ZIKV) infection can cause substantial fetal morbidity, however, little is known about the long-term neurodevelopmental abnormalities of infants with congenital ZIKV exposure without microcephaly at birth. Methods: We conducted a cross sectional study to characterize infants born with microcephaly, and a retrospective cohort study of infants who appeared well at birth, but had possible congenital ZIKV exposure. We analyzed data from the Dominican Ministry of Health's (MoH) National System of Epidemiological Surveillance. Neurodevelopmental abnormalities were assessed by pediatric neurologists over an 18-month period using Denver Developmental Screening Test II. Results: Of 800 known live births from 1,364 women with suspected or confirmed ZIKV infection during pregnancy, 87 (11%) infants had confirmed microcephaly. Mean head circumference (HC) at birth was 28.1 cm (SD ± 2.1 cm) and 41% had a HC on the zero percentile for gestational age. Of 42 infants with possible congenital ZIKV exposure followed longitudinally, 52% had neurodevelopmental abnormalities, including two cases of postnatal onset microcephaly, during follow-up. Most abnormalities resolved, though two infants (4%) had neurodevelopmental abnormalities that were likely associated with ZIKV infection and persisted through 15-18 months. Conclusions: In the DR epidemic, 11% of infants born to women reported to the MoH with suspected or confirmed ZIKV during pregnancy had microcephaly. Some 4% of ZKV-exposed infants developed postnatal neurocognitive abnormalities. Monitoring of the cohort through late childhood and adolescence is needed.

Examining the Association of Socioeconomic Position with Microcephaly and Delayed Childhood Neurodevelopment among Children with Prenatal Zika Virus Exposure.

Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level; yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (-10.78, 95% CI: -19.87 to -1.69), motor (-10.45, 95% CI: -19.22 to -1.69), and cognitive (-17.20, 95% CI: -26.13 to -8.28) scores in children whose families participated in the Bolsa Família social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.

Neurological Findings in Children without Congenital Microcephaly Exposed to Zika Virus in Utero: A Case Series Study.

The Zika virus can induce a disruptive sequence in the fetal brain and is manifested mainly by microcephaly. Knowledge gaps still exist as to whether the virus can cause minor disorders that are perceived later on during the first years of life in children who are exposed but are asymptomatic at birth. In this case series, we describe the outcomes related to neurodevelopment through the neurological assessment of 26 non-microcephalic children who had intrauterine exposure to Zika virus. Children were submitted for neurological examinations and Bayley Scales-III (cognition, language, and motor performance). The majority (65.4%) obtained satisfactory performance in neurodevelopment. The most impaired domain was language, with 30.7% impairment. Severe neurological disorders occurred in five children (19.2%) and these were spastic hemiparesis, epilepsy associated with congenital macrocephaly (Zika and human immunodeficiency virus), two cases of autism (one exposed to Zika and Toxoplasma gondii) and progressive sensorineural hearing loss (GJB2 mutation). We concluded that non-microcephalic children with intrauterine exposure to Zika virus, in their majority, had achieved satisfactory performance in all neurodevelopmental domains. One third of the cases had some impairment, but the predominant group had mild alterations, with low occurrence of moderate to severe disorders, similar to other studies in Brazil.

In Utero HIV Exposure and the Early Nutritional Environment Influence Infant Neurodevelopment: Findings from an Evidenced Review and Meta-Analysis.

The developing brain is especially vulnerable to infection and suboptimal nutrition during the pre- and early postnatal periods. Exposure to maternal human immunodeficiency virus (HIV) infection and antiretroviral therapies (ART) in utero and during breastfeeding can adversely influence infant (neuro) developmental trajectories. How early life nutrition may be optimised to improve neurodevelopmental outcomes for infants who are HIV-exposed has not been well characterised. We conducted an up-to-date evidence review and meta-analysis on the influence of HIV exposure in utero and during breastfeeding, and early life nutrition, on infant neurodevelopmental outcomes before age three. We report that exposure to maternal HIV infection may adversely influence expressive language development, in particular, and these effects may be detectable within the first three years of life. Further, while male infants may be especially vulnerable to HIV exposure, few studies overall reported sex-comparisons, and whether there are sex-dependent effects of HIV exposure on neurodevelopment remains a critical knowledge gap to fill. Lastly, early life nutrition interventions, including daily maternal multivitamin supplementation during the perinatal period, may improve neurodevelopmental outcomes for infants who are HIV-exposed. Our findings suggest that the early nutritional environment may be leveraged to improve early neurodevelopmental trajectories in infants who have been exposed to HIV in utero. A clear understanding of how this environment should be optimised is key for developing targeted nutrition interventions during critical developmental periods in order to mitigate adverse outcomes later in life and should be a priority of future research.

Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes.

Neonatal herpes simplex virus type 1 (HSV-1) infections contribute to various neurodevelopmental disabilities and the subsequent long-term neurological sequelae into the adulthood. However, further understanding of fetal brain development and the potential neuropathological effects of the HSV-1 infection are hampered by the limitations of existing neurodevelopmental models due to the dramatic differences between humans and other mammalians. Here we generated in vitro neurodevelopmental disorder models including human induced pluripotent stem cell (hiPSC)-based monolayer neuronal differentiation, three-dimensional (3D) neuroepithelial bud, and 3D cerebral organoid to study fetal brain development and the potential neuropathological effects induced by the HSV-1 infections. Our results revealed that the HSV-1-infected neural stem cells (NSCs) exhibited impaired neural differentiation. HSV-1 infection led to dysregulated neurogenesis in the fetal neurodevelopment. The HSV-1-infected brain organoids modelled the pathological features of the neurodevelopmental disorders in the human fetal brain, including the impaired neuronal differentiation, and the dysregulated cortical layer and brain regionalization. Furthermore, the 3D cerebral organoid model showed that HSV-1 infection promoted the abnormal microglial activation, accompanied by the induction of inflammatory factors, such as TNF-α, IL-6, IL-10, and IL-4. Overall, our in vitro neurodevelopmental disorder models reconstituted the neuropathological features associated with HSV-1 infection in human fetal brain development, providing the causal relationships that link HSV biology with the neurodevelopmental disorder pathogen hypothesis.

Human Neural Stem Cell Systems to Explore Pathogen-Related Neurodevelopmental and Neurodegenerative Disorders.

Building and functioning of the human brain requires the precise orchestration and execution of myriad molecular and cellular processes, across a multitude of cell types and over an extended period of time. Dysregulation of these processes affects structure and function of the brain and can lead to neurodevelopmental, neurological, or psychiatric disorders. Multiple environmental stimuli affect neural stem cells (NSCs) at several levels, thus impairing the normal human neurodevelopmental program. In this review article, we will delineate the main mechanisms of infection adopted by several neurotropic pathogens, and the selective NSC vulnerability. In particular, TORCH agents, i.e., Toxoplasma gondii, others (including Zika virus and Coxsackie virus), Rubella virus, Cytomegalovirus, and Herpes simplex virus, will be considered for their devastating effects on NSC self-renewal with the consequent neural progenitor depletion, the cellular substrate of microcephaly. Moreover, new evidence suggests that some of these agents may also affect the NSC progeny, producing long-term effects in the neuronal lineage. This is evident in the paradigmatic example of the neurodegeneration occurring in Alzheimer's disease.

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.