Three-Year Post-Neonatal Intensive Care Unit Health Care Utilization Among Infants with Congenital Anomalies.

OBJECTIVE: To describe 3-year post-neonatal intensive care unit (NICU) health care use among children with congenital anomalies discharged home from a level IV NICU. STUDY DESIGN: Retrospective chart review of children with congenital anomalies enrolled in a previous prospective cohort study from 201 to 2020. We assessed hospital readmission rate, number of surgeries, and durable medical equipment (DME) use by type of anomaly. RESULTS: Among 166 infants enrolled in the original study, 158 survived to NICU discharge. One-third of the cohort had a genetic anomaly. Six of 158 patients (4%) died before 3 years of age. More than one-half the children were readmitted within the first 2 years of life, and one-third were readmitted in the third year of life. Readmissions were greatest for those with multiple, musculoskeletal, and central nervous system anomalies and lowest for abdominal-wall defects. Approximately one-half the children underwent surgeries, and this proportion remained constant over the 3-year time. Sixty-two percent of patients received DME at discharge, with gastrostomy tubes being the most common. Gastrostomy tubes were still present in 75% of the patients at 3 years of age. CONCLUSION: Children with congenital anomalies are at risk for increased health care use during early childhood. Those with multiple anomalies, a genetic syndrome, musculoskeletal, and central nervous system anomalies and those discharged with DME are at greatest risk whereas those with abdominal-wall defects are at lowest risk. Provider awareness, high-quality discharge training, parent psychological support, greater assimilation of families in the NICU, and telehealth may be some strategies to better support these families.

Neuroimaging Findings in Fetal Hemimegalencephaly: Case Study and Review.

BACKGROUND: Limited information exists in the prenatal literature regarding the neuroimaging features of fetal hemimegalencephaly. SUMMARY: This report describes ultrasound and magnetic resonance imaging (MRI) findings in a second-trimester fetus with an isolated, severe form of hemimegalencephaly. The most prominent imaging findings included unilateral enlarged cerebral hemisphere and ipsilateral ventriculomegaly causing cerebral asymmetry, midline shift, and macrocephaly. Abnormal cortical development imaging signs were also evident. A literature review encompassing 23 reports describing 36 cases, including ours, is presented. KEY MESSAGES: Characteristic ultrasound findings for the diagnosis of hemimegalencephaly are not always apparent prenatally. Asymmetric ventriculomegaly emerges as the most common but nonspecific presenting feature during routine second- or third-trimester ultrasound scans. Subsequent high-resolution prenatal neurosonography and fetal MRI facilitate definitive prenatal diagnosis, showcasting associated features primarily related to cortical migration, differentiation, and maturation. Postnatally, the prognosis is poor due to intractable seizures, hemiplegia, and progressive neurodevelopmental delay.

Epidemiological trends of isolated and non-isolated central nervous system congenital malformations in live births in a middle-income setting.

OBJECTIVES: This study aimed to analyze, in the São Paulo state of Brazil, time trends in prevalence, neonatal mortality, and neonatal lethality of central nervous system congenital malformations (CNS-CM) between 2004 and 2015. METHODS: Population-based study of all live births with gestational age ≥22 weeks and/or birthweight ≥400 g from mothers living in São Paulo State, during 2004-2015. CNS-CM was defined by the presence of International Classification Disease 10th edition codes Q00-Q07 in the death and/or live birth certificates. CNS-CM was classified as isolated (only Q00-Q07 codes), and non-isolated (with congenital anomalies codes nonrelated to CNS-CM). CNS-CM associated neonatal death was defined as death between 0 and 27 days after birth in infants with CNS-CM. CNS-CM prevalence, neonatal mortality, and lethality rates were calculated, and their annual trends were analyzed by Prais-Winsten Model. The annual percent change (APC) with 95% confidence interval (95%CI) was obtained. RESULTS: 7,237,628 live births were included in the study and CNS-CM were reported in 7526 (0.1%). CNS-CM associated neonatal deaths occurred in 2935 (39.0%). Isolated CNS-CM and non-isolated CNS-CM were found respectively in 5475 and 2051 livebirths, with 1525 (28%) and 1410 (69%) neonatal deaths. CNS-CM prevalence and neonatal lethality were stationary, however neonatal mortality decreased (APC -1.66; 95%CI -3.09 to -0.21) during the study. For isolated CNS-CM, prevalence, neonatal mortality, and lethality decreased over the period. For non-isolated CNS-CM, the prevalence increased, neonatal mortality was stationary, and lethality decreased during the period. The median time of CNS-CM associated neonatal deaths was 18 h after birth. CONCLUSIONS: During a 12-year period in São Paulo State, Brazil, neonatal mortality of infants with CNS-CM in general and with isolated CNS-CM showed a decreasing pattern. Nevertheless CNS-CM mortality remained elevated, mostly in the first day after birth.

Congenital Zika Virus Infection Impairs Corpus Callosum Development.

Congenital Zika syndrome (CZS) is a set of birth defects caused by Zika virus (ZIKV) infection during pregnancy. Microcephaly is its main feature, but other brain abnormalities are found in CZS patients, such as ventriculomegaly, brain calcifications, and dysgenesis of the corpus callosum. Many studies have focused on microcephaly, but it remains unknown how ZIKV infection leads to callosal malformation. To tackle this issue, we infected mouse embryos in utero with a Brazilian ZIKV isolate and found that they were born with a reduction in callosal area and density of callosal neurons. ZIKV infection also causes a density reduction in PH3+ cells, intermediate progenitor cells, and SATB2+ neurons. Moreover, axonal tracing revealed that callosal axons are reduced and misrouted. Also, ZIKV-infected cultures show a reduction in callosal axon length. GFAP labeling showed that an in utero infection compromises glial cells responsible for midline axon guidance. In sum, we showed that ZIKV infection impairs critical steps of corpus callosum formation by disrupting not only neurogenesis, but also axon guidance and growth across the midline.

Clinical and Acoustic Alterations of Swallowing in Children Exposed to Zika Virus during Pregnancy in a Cohort in Amazonas, Brazil: A Case Series Study.

Oropharyngeal dysphagia (OD) is a swallowing disorder that involves difficulty in safely passing the food bolus from the oral cavity to the stomach. OD is a common problem in children with congenital Zika virus syndrome (CZS). In this case series, we describe the clinical and acoustic alterations of swallowing in children exposed to the Zika virus during pregnancy in a cohort from Amazonas, Brazil. From July 2019 to January 2020, 22 children were evaluated, 6 with microcephaly and 16 without microcephaly. The mean age among the participants was 35 months (±4.6 months). All children with microcephaly had alterations in oral motricity, mainly in the lips and cheeks. Other alterations were in vocal quality, hard palate, and soft palate. Half of the children with microcephaly showed changes in cervical auscultation during breast milk swallowing. In children without microcephaly, the most frequently observed alteration was in lip motricity, but alterations in auscultation during the swallowing of breast milk were not observed. Regarding swallowing food of a liquid and pasty consistency, the most frequent alterations were incomplete verbal closure, increased oral transit time, inadequacy in capturing the spoon, anterior labial leakage, and increased oral transit time. Although these events are more frequent in microcephalic children, they can also be seen in non-microcephalic children, which points to the need for an indistinct evaluation of children exposed in utero to ZIKV.

Does Intra-Uterine Exposure to the Zika Virus Increase Risks of Cognitive Delay at Preschool Ages? Findings from a Zika-Exposed Cohort from Grenada, West Indies.

Maternal infection with Zika virus (ZIKV) is associated with a distinct pattern of birth defects, known as congenital Zika syndrome (CZS). In ZIKV-exposed children without CZS, it is often unclear whether they were protected from in utero infection and neurotropism. Early neurodevelopmental assessment is essential for detecting neurodevelopmental delays (NDDs) and prioritizing at-risk children for early intervention. We compared neurodevelopmental outcomes between ZIKV-exposed and unexposed children at 1, 3 and 4 years to assess exposure-associated NDD risk. A total of 384 mother-child dyads were enrolled during a period of active ZIKV transmission (2016-2017) in Grenada, West Indies. Exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. Neurodevelopment was assessed using the Oxford Neurodevelopment Assessment, the NEPSY® Second Edition and Cardiff Vision Tests, at 12 (n = 66), 36 (n = 58) and 48 (n = 59) months, respectively. There were no differences in NDD rates or vision scores between ZIKV-exposed and unexposed children. Rates of microcephaly at birth (0.88% vs. 0.83%, p = 0.81), and childhood stunting and wasting did not differ between groups. Our results show that Grenadian ZIKV-exposed children, the majority of whom were without microcephaly, had similar neurodevelopmental outcomes to unexposed controls up to at least an age of 4 years.

Role of Fetal Magnetic Resonance Imaging in Differentiating Isolated Septal Agenesis from Septo-Optic Dysplasia: Case Study and Review.

INTRODUCTION: The detection of absent septi pellucidi (ASP) during obstetric ultrasound is a rare event. However, the clinical implications of this finding are significant. ASP can be associated with severe central nervous system anomalies such as holoprosencephaly, agenesis/dysgenesis of the corpus callosum, schizencephaly, severe ventriculomegaly, and open neural tube defects. In such cases, the prognosis is poor. When no such anomalies are identified, isolated ASP usually carries a good prognosis. However, some fetuses thought to have isolated ASP actually have septo-optic dysplasia (SOD), which is associated with optic nerve hypoplasia, hypothalamic-pituitary dysfunction, and developmental delay. CASE PRESENTATION: A case in which fetal 3.0 Tesla magnetic resonance imaging (MRI) was considered crucial to definitively diagnose isolated ASP is presented. A review of the literature was conducted and analyzed to determine the role of MRI in the evaluation of fetuses with ASP, with special consideration on the differential diagnosis between isolated ASP and SOD. CONCLUSION: Differentiating isolated ASP from SOD is imperative for adequate prenatal counseling. Unfortunately, making a prenatal diagnosis of SOD requires visualization and evaluation of the fetal optic nerves, chiasm, and pituitary gland, which is very demanding and not always possible using ultrasound. Fetal MRI has the potential of obtaining high-quality images of the fetal brain, and therefore this technique can be used for establishing the differential diagnosis in utero.

Case report: double dermal sinus tracts of the cervical and thoracic spine associated with congenital intracranial pathology (hydrocephalus and an interhemispheric cyst) in a newborn patient.

INTRODUCTION: A dermal sinus tract (DST) is an uncommon type of spinal dysraphisms characterized by a tract lined with stratified squamous epithelium that extends from the subcutaneous tissue to the underlying thecal sac or neural tube. These developmental anomalies can present asymptomatically with cutaneous abnormalities or with devastating complications. Usually, it is presented as a unique lesion, and there are only a few reports that show multiple sinuses, and none of them associated with midline brain malformations. METHODS: We present the case of a 3-day-old girl with an antenatal diagnosis of hydrocephalus who was diagnosed with double dermal sinus tracts of the cervical and thoracic regions at admission. The patient presented signs of elevated intracranial pressure (ICP), which imposed a challenge in the management of the case. RESULTS: Our patient was successfully treated initially with a lumbar puncture in order to discard a cerebrospinal fluid (CSF) infection. With negative CSF cultures, a ventriculoperitoneal shunt (VPS) was placed. Nine days after the VPS surgery and without signs of infection, the DST was excised in a single procedure, without follow-up complications. CONCLUSION: To our knowledge, this is the first description of a patient with multiple midline neural tube defects (NTDs) associated with congenital intracranial pathology. Although there are no guidelines regarding the best treatment for this complex associated pathology, the patient was treated, without follow-up complications.

Causes of death in children with congenital Zika syndrome in Brazil, 2015 to 2018: A nationwide record linkage study.

BACKGROUND: Children with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018. METHODS AND FINDINGS: In a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother's infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother's infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls. CONCLUSION: The sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika.

Molecular Mechanisms of ZIKV-Induced Teratogenesis: A Systematic Review of Studies in Animal Models.

Zika virus (ZIKV) is a teratogen that causes congenital anomalies, being linked to microcephaly in children exposed during pregnancy. Animal studies have been conducted to investigate the molecular mechanisms related to ZIKV teratogenesis. Although animal models can mimic the effects of ZIKV in human embryo development, few in vivo studies have addressed molecular changes following ZIKV infection in embryos. Moreover, few literature reviews have been conducted with these studies. The aim of this systematic review is to evaluate the molecular mechanisms of ZIKV teratogenesis determined from studies in animal models. PubMed/MEDLINE, EMBASE, Web of Science, and Scopus as well as grey literature were searched for studies that evaluated molecular alterations related to ZIKV teratogenesis which occurred during embryonic development. Nine studies were included: six with mice, one with mice and guinea pigs, one with pigs and one with chickens. In general, studies presented an unclear or high risk of bias for methodological criteria. Most of studies reported embryos exposed to ZIKV presenting microcephaly, reduced cortex thickness, and growth restriction. Different techniques were used to evaluated molecular changes in the animals following ZIKV infection: RNA sequencing, RT-qPCR, and in situ hybridization. It was found that common pathways are changed in most studies, being pathways related to immune response upregulated and those involved to neurodevelopment downregulated.

Prenatal and Postnatal Zika Intrauterine Infection: Diagnostic Imaging Techniques and Placental Pathology.

Introduction: Zika virus (ZIKV) is an arbovirus (arthropod-borne virus) in the genus Flavivirus and Flaviviridae family. In November 2015, several cases of microcephaly in Northeastern of Brazil suggested ZIKV involvement. Case Report: A 33-year-old primigravida developed fever and cutaneous rash at 7th week of gestation (WGA). The ultrasound and MRI examination showed head circumference < 5th centile and enlargement of lateral ventricles. The infant was delivered at 39th WGA with microcephaly. Microscopy of the placenta showed chronic villitis and intervillitis, nodular stromal fibrosis in the stem villi, and vascular thickening. Postnatal CT showed collapsed cranium due to growth impairment of the suprathalamic brain, multiple cerebral calcifications, parenchymal atrophy, and ventricular dilatation. Now, at 6 years old, the child suffers from severe neurologic symptoms, including seizures. Conclusion: This case gathers images of prenatal and postnatal period, and placental histopathology. The long-term follow-up highlights the dramatic neurological sequelae induced by ZIKV.

Intervenções psicológicas necessárias: a prática como residente no serviço de medicina fetal / Necessary psychological interventions: the practice as a resident in the fetal medicine service / Intervenciones psicológicas necesarias: la práctica como residente en el servicio de medicina fetal

Com os avanços tecnológicos e o aprimoramento da prática médica via ultrassonografia, já é possível detectar possíveis problemas no feto desde a gestação. O objetivo deste estudo foi analisar a prática do psicólogo no contexto de gestações que envolvem riscos fetais. Trata-se de um estudo qualitativo sob formato de relato de experiência como psicólogo residente no Serviço de Medicina Fetal da Maternidade Escola da Universidade Federal do Rio de Janeiro (UFRJ). Os registros, feitos por observação participante e diário de campo, foram analisados em dois eixos temáticos: 1) intervenções psicológicas no trabalho em equipe em consulta de pré-natal, exame de ultrassonografia e procedimento de amniocentese; e 2) intervenções psicológicas em casos de bebês incompatíveis com a vida. Os resultados indicaram que o psicólogo nesse serviço é essencial para atuar de forma multiprofissional na assistência pré-natal para gravidezes de alto risco fetal. Ademais, a preceptoria do residente é relevante para sua formação e treinamento para atuação profissional no campo da psicologia perinatal.(AU)

Face to the technological advances and the improvement of medical practice via ultrasound, it is already possible to detect possible problems in the fetus since pregnancy. The objective of this study was to analyze the psychologist's practice in the context of pregnancies which involve fetal risks. It is a qualitative study based on an experience report as a psychologist trainee at the Fetal Medicine Service of the Maternity School of UFRJ. The records, based on the participant observation and field diary, were analyzed in two thematic axes: 1) psychological interventions in the teamwork in the prenatal attendance, ultrasound examination and amniocentesis procedure; and 2) psychological interventions in cases of babies incompatible to the life. The results indicated that the psychologist in this service is essential to work in a multidisciplinary way at the prenatal care for high fetal risk pregnancies. Furthermore, the resident's preceptorship is relevant to their education and training for professional performance in the field of Perinatal Psychology.(AU)

Con los avances tecnológicos y la mejora de la práctica médica a través de la ecografía, ya se puede detectar posibles problemas en el feto desde el embarazo. El objetivo de este estudio fue analizar la práctica del psicólogo en el contexto de embarazos de riesgos fetal. Es un estudio cualitativo basado en un relato de experiencia como residente de psicología en el Servicio de Medicina Fetal de la Escuela de Maternidad de la Universidade Federal do Rio de Janeiro (UFRJ). Los registros, realizados en la observación participante y el diario de campo, se analizaron en dos ejes temáticos: 1) intervenciones psicológicas en el trabajo en equipo, en la consulta prenatal, ecografía y los procedimientos de amniocentesis; y 2) intervenciones psicológicas en casos de bebés incompatibles con la vida. Los resultados señalaron como fundamental la presencia del psicólogo en este servicio trabajando de forma multidisciplinar en la atención prenatal en el contexto de embarazos de alto riesgo fetal. Además, la tutela del residente es relevante para su educación y formación para el desempeño profesional en el campo de la Psicología Perinatal.(AU)

Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review.

The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis. WES revealed two pathogenic and homozygous variants: a c.4174C>T variant in the ASPM gene and a c.382C>T variant in the CTNS gene, explaining the complex phenotype. The literature review showed that most of the patients harboring two variants in recessive disease genes are born to consanguineous parents. To the best of our knowledge, the patient herein described is the first one harboring pathogenic variants in both the ASPM and CTNS genes. These findings highlight the importance of searching for MPV in patients with complex phenotypes investigated by genome-wide testing methods, especially for those patients born to consanguineous parents.

Characteristics associated with drug resistant epilepsy in children up to 36 months old with Congenital Zika Syndrome.

OBJECTIVES: To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS). METHODS: This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected. RESULTS: Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months. CONCLUSIONS: The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum.

Characteristics of children of the Microcephaly Epidemic Research Group Pediatric Cohort who developed postnatal microcephaly.

The number of studies published on postnatal microcephaly in children with Congenital Zika Syndrome is small, clinical presentations vary and aspects of the evolution of these children remain unclarified. The present case series examined clinical characteristics and assessed the growth velocity of the head circumference, weight and height Z-scores in 23 children who developed postnatal microcephaly during follow-up in the Microcephaly Epidemic Research Group Pediatric Cohort. To estimate the change in the head circumference, weight and height Z-scores over time and compare the mean difference between sexes, we used multilevel mixed-effects linear regressions with child-specific random effects. Among these children, 60.9% (n = 14/23) presented with craniofacial disproportion, 60.9% (n = 14/23) with strabismus, 47.8% (n = 11/23) with early onset seizures, 47.8% (n = 11/23) with dysphagia and 43.5% (n = 10/23) with arthrogryposis. Of the 82.7% (n = 19/23) children who underwent neuroimaging, 78.9% (n = 15/19) presented with alterations in the central nervous system. Monthly growth velocity, expressed in Z-scores, of the head circumference was - 0.098 (95% CI % - 0.117 to - 0.080), of weight was: - 0.010 (95%-CI - 0.033 to 0.014) and of height was: - 0.023 (95%-CI - 0.046 to 0.0001). Postnatal microcephaly occurred mainly in children who had already presented with signs of severe brain damage at birth; there was variability in weight and height development, with no set pattern.

microRNAs Control Antiviral Immune Response, Cell Death and Chemotaxis Pathways in Human Neuronal Precursor Cells (NPCs) during Zika Virus Infection.

Viral infections have always been a serious burden to public health, increasing morbidity and mortality rates worldwide. Zika virus (ZIKV) is a flavivirus transmitted by the Aedes aegypti vector and the causative agent of severe fetal neuropathogenesis and microcephaly. The virus crosses the placenta and reaches the fetal brain, mainly causing the death of neuronal precursor cells (NPCs), glial inflammation, and subsequent tissue damage. Genetic differences, mainly related to the antiviral immune response and cell death pathways greatly influence the susceptibility to infection. These components are modulated by many factors, including microRNAs (miRNAs). MiRNAs are small noncoding RNAs that regulate post-transcriptionally the overall gene expression, including genes for the neurodevelopment and the formation of neural circuits. In this context, we investigated the pathways and target genes of miRNAs modulated in NPCs infected with ZIKV. We observed downregulation of miR-302b, miR-302c and miR-194, whereas miR-30c was upregulated in ZIKV infected human NPCs in vitro. The analysis of a public dataset of ZIKV-infected human NPCs evidenced 262 upregulated and 3 downregulated genes, of which 142 were the target of the aforementioned miRNAs. Further, we confirmed a correlation between miRNA and target genes affecting pathways related to antiviral immune response, cell death and immune cells chemotaxis, all of which could contribute to the establishment of microcephaly and brain lesions. Here, we suggest that miRNAs target gene expression in infected NPCs, directly contributing to the pathogenesis of fetal microcephaly.

Accuracy of the Hammersmith infant neurological examination for the early detection of neurological changes in infants exposed to Zika virus: A case-cohort study.

ABSTRACT: The Hammersmith infant neurological examination (HINE) is a highly predictive tool for the easy and low-cost detection of cerebral palsy. Between 2015 and 2016, the rapid spread of the Zika virus (ZIKV) in Brazil was responsible for an increase in microcephaly cases. This study aimed to verify the accuracy of the HINE for the early detection of neurological problems in Brazilian babies exposed to ZIKV.This was a cross sectional case-control study of children exposed to ZIKV. This study was part of the Jundiaí ZIKV Cohort. Of a total sample of 782 children, 98 were evaluated (26 in the exposed group and 63 in the control group). We included late preterm infants and term infants who were exposed to the ZIKV and were participants in the ZIKV Cohort study. Student's t-test and stepwise multivariate logistic regression were used to compare groups.Of the 26 items evaluated in the five scored categories of the HINE (cranial nerve function, posture, movements, tone, reflexes, and reactions), only the difference in ankle dorsiflexion between the exposed and the control groups was statistically significant. However, some items showed a significant trend in relation to the control group.Our results demonstrated the importance of early neurological assessment of infants exposed to ZIKV, even in those without a microcephaly diagnosis.

Neurodevelopmental outcome of infants without central nervous system anomalies born to symptomatic RT-PCR ZIKV positive women.

An epidemic of Zika virus (ZIKV) infection began in Colombia in October 2015. Previous studies have identified a cause-effect relationship between fetal exposure to the ZIKV and the development of microcephaly and other central nervous system (CNS) anomalies with variable degrees of neurodevelopmental delay. Less is known about the neurodevelopmental outcome of infants without CNS anomalies born to symptomatic ZIKV RT-PCR-positive women. We aimed to compare the neurodevelopmental outcome of these infants to a control group of infants without CNS anomalies born to asymptomatic ZIKV RT-PCR negative women who did not seroconvert during pregnancy. Participating infants were categorized according to ZIKV maternal exposure. Women with symptomatology suggestive of ZIKV infection and a positive RT-PCR for ZIKV were categorized as ZIKV-exposed. Maternal controls (ZIKV unexposed) from the same geographic area were subsequently captured during the tail end of the epidemic through a partner project, the ZIKAlliance, whose aim was to determine the prevalence of ZIKV in pregnant women. Infant survivors from these two groups of pregnant women had a neurodevelopmental evaluation at 12, 18, and 24 months corrected age (CA). The ZIKV-exposed women were found to be older, had less subsidized health care, had a higher percentage of women in middle-class socioeconomic strata, had higher technical and university education, were less likely to be living with a partner, and had higher rates of pregnancy comorbidity and premature births than ZIKV unexposed women. Compared to infants born to ZIKV unexposed women (unexposed), infants born to ZIKV exposed women (exposed) were of lower gestational age and required more speech and occupational therapy services. No differences between groups were observed in the proportion of cut-off scores <70 on the Bayley-III Scale at 12, 18, and 24 months for motor, language, and cognitive domains. When a cut-off of <85 was used, a higher percentage of motor and cognitive impairment was observed in unexposed infants at 12 and 24 months CA, respectively. Median and IQR score on the Bayley-III scale showed higher scores in favor of exposed infants for motor development at 12 and 18 months CA, language at 12 months, and cognitive domain at 12, 18, and 24 months. The adjusted median and IQR compound score of the difference between exposed and unexposed was higher in favor of exposed infants at 12 to 24 months CA for motor (3.8 [95% CI 1.0 to 6.7]) and cognitive domains (10.6 [95% CI 7.3 to 13.9]). We observed no differences in the language domain (1.9 [95% CI -1.2 to 5.0]). We conclude that infants with no evidence of microcephaly or other CNS anomalies born to ZIKV-exposed women had normal neurodevelopment up to 24 months of CA, supporting an all-or-nothing effect with maternal ZIKV exposure. Long-term follow-up to evaluate school performance is required. Clinical Trial Registration: www.clinicaltrials.gov, NCT02943304.

Clinical and Financial Impact of a Diagnostic Stewardship Program for Children with Suspected Central Nervous System Infection.

OBJECTIVE: To investigate the optimal implementation and clinical and financial impacts of the FilmArray Meningitis Encephalitis Panel (MEP) multiplex polymerase chain reaction testing of cerebrospinal fluid (CSF) in children with suspected central nervous system infection. STUDY DESIGN: A pre-post quasiexperimental cohort study to investigate the impact of implementing MEP using a rapid CSF diagnostic stewardship program was conducted at Children's Hospital Colorado (CHCO). MEP was implemented with electronic medical record indication selection to guide testing to children meeting approved use criteria: infants <2 months, immunocompromised, encephalitis, and ≥5 white blood cells/µL of CSF. Positive results were communicated with antimicrobial stewardship real-time decision support. All cases with CSF obtained by lumbar puncture sent to the CHCO microbiology laboratory meeting any of the 4 aforementioned criteria were included with preimplementation controls (2015-2016) compared with postimplementation cases (2017-2018). Primary outcome was time-to-optimal antimicrobials compared using log-rank test with Kaplan-Meier analysis. RESULTS: Time-to-optimal antimicrobials decreased from 28 hours among 1124 preimplementation controls to 18 hours (P < .0001) among 1127 postimplementation cases (72% with MEP testing conducted). Postimplementation, time-to-positive CSF results was faster (4.8 vs 9.6 hours, P < .0001), intravenous antimicrobial duration was shorter (24 vs 36 hours, P = .004), with infectious neurologic diagnoses more frequently identified (15% vs 10%, P = .03). There were no differences in time-to-effective antimicrobials, hospital admissions, antimicrobial starts, or length of stay. Costs of microbiologic testing increased, but total hospital costs were unchanged. CONCLUSIONS: Implementation of MEP with a rapid central nervous system diagnostic stewardship program improved antimicrobial use with faster results shortening empiric therapy. Routine MEP testing for high-yield indications enables antimicrobial optimization with unchanged overall costs.