Intrauterine Zika Virus Infection Research Articles

Oligodendrocytes are susceptible to Zika virus infection in a mouse model of perinatal exposure: Implications for CNS complications.

Some children with proven intrauterine Zika virus (ZIKV) infection who were born asymptomatic subsequently manifested neurodevelopmental delays, pointing to impairment of development perinatally and postnatally. To model this, we infected postnatal day (P) 5–6 (equivalent to the perinatal period in humans) susceptible mice with a mammalian cell‐propagated ZIKV clinical isolate from the Brazilian outbreak in 2015. All infected mice appeared normal up to 4 days post‐intraperitoneal inoculation (dpi), but rapidly developed severe clinical signs at 5–6 dpi. All nervous tissue examined at 5/6 dpi appeared grossly normal. However, anti‐ZIKV positive cells were observed in the optic nerve, brain, and spinal cord; predominantly in white matter. Co‐labeling with cell type specific markers demonstrated oligodendrocytes and astrocytes support productive infection. Rarely, ZIKV positive neurons were observed. In spinal cord white matter, which we examined in detail, apoptotic cells were evident; the density of oligodendrocytes was significantly reduced; and there was localized microglial reactivity including expression of the NLRP3 inflammasome. Together, our observations demonstrate that a clinically relevant ZIKV isolate can directly impact oligodendrocytes. As primary oligodendrocyte cell death can lead later to secondary autoimmune demyelination, our observations may help explain neurodevelopmental delays in infants appearing asymptomatic at birth and commend lifetime surveillance.

Intrauterine Zika virus infection: review of the current findings with emphasis in the prenatal and postnatal brain imaging diagnostic methods

Zika virus (ZIKV) is a widespread flavivirus transmitted to humans through the bite of Aedes mosquitoes. The number of ZIKV cases increased significantly between 2015 and 2016, and Brazil was the first to report autochthonous transmission of infection. The main neurological disorder related to ZIKV infection is microcephaly. Fetal magnetic resonance imaging (MRI) is the gold standard examination for the analysis of fetal brain infection, followed by obstetric ultrasonography. Cerebral atrophy, intracranial calcifications, ventriculomegaly, cerebellar, and brain gyrus abnormalities are some of the most common findings. Postnatal MRI shows high sensitivity and specificity. Corpus callosum abnormalities, cerebellar hypoplasia, and choroid plexus dilation can be also observed. We present a review of congenital ZIKV infection with emphasis on pre and postnatal brain findings using ultrasonography, MRI, computed tomography, and three-dimensional reconstruction models.

Dental care for children with Congenital Zika Syndrome

ABSTRACT There was a large increase in the number of newborns with microcephaly in Brazil between 2015 and 2017, mainly in the Northeast. This increase was associated with intrauterine Zika virus infection, which causes a congenital syndrome characterized by neurological, musculoskeletal, and sensory abnormalities. Despite the great worldwide repercussion, few studies about oral conditions in children with the syndrome have been published. This work aims to propose a guide for the dental care of these individuals on the basis of a literature review. Children with congenital Zika syndrome have a number of systemic comorbidities that affect their oral health and can compromise dental care. To date, no clinical protocol has been established for the dental care of children with congenital Zika syndrome. This is a pioneering study of great importance to orient dental professionals and promote the dental health of these children.

Evaluation of the frequency of neuroimaging findings in congenital infection by Zika virus and differences between computed tomography and magnetic resonance imaging in the detection of alterations.

INTRODUCTION: Congenital infection by the Zika virus (ZIKV) is responsible for severe abnormalities in the development of the central nervous system. The aim of this study was to evaluate and compare the ability of computed tomography (CT) and magnetic resonance (MR) to detect patterns of involvement of the central nervous system in congenital ZIKV syndrome. METHODS: We retrospectively analyzed CT and MR images from 34 patients with congenital ZIKV syndrome and evaluated the differences between the two methods in detecting alterations. RESULTS: The predominant radiographic finding was a simplified gyral pattern, present in 97% of cases. The second most common finding was the presence of calcifications (94.1%), followed by ventriculomegaly (85.3%), dysgenesis of the corpus callosum (85.3%), craniofacial disproportion and redundant scalp (79.4%), complete opercular opening (79.4%), occipital prominence (44.1%), cerebellar hypoplasia (14.7%), and pontine hypoplasia (11.8%). The gyral pattern was extensively simplified in most cases, and calcifications were located predominantly at the cortical-subcortical junction. CT was able to better identify calcifications (94.1% × 88.2%), while MRI presented better spatial resolution for the characterization of gyral pattern (97% × 94.1%) and corpus callosum dysgenesis (85.3% × 79.4%). CONCLUSIONS: Although congenital ZIKV syndrome does not present pathognomonic neuroimaging findings, some aspects, such as calcifications at the cortical-subcortical junction, especially when associated with compatible clinical and laboratory findings, are suggestive of intrauterine ZIKV infection.

Zika Virus Infection in Pregnancy: Maternal, Fetal, and Neonatal Considerations.

An infection with the Zika virus (ZIKV) is usually mild, with nonspecific symptoms and most often asymptomatic. However, because of its causal relationship with severe congenital malformations, the ZIKV epidemic became an imperative for mobilization, renewed strategies for vector control, and biomedical research. A congenital Zika syndrome (CZS) has been characterized with 5 distinctive features that focus on brain development abnormalities (including microcephaly and brain calcifications), retinal manifestations, and defects on extremities including congenital contractures and hypertonia. The CZS could be just "the tip of the iceberg", pending the documentation of a spectrum of disease that could manifest later in life, from mild dysfunction to severe disease. It will be a matter of time for neurodevelopmental abnormalities, learning disabilities, and other unknown but yet-to-be-described outcomes to be associated with intrauterine ZIKV infection. In addition, ZIKV infection during pregnancy has been associated with other adverse outcomes. Reports mostly include ZIKV-affected pregnancies, and it will be difficult to clearly establish causality without appropriate control groups. We are summarizing some of the known or reported consequences of such infection during pregnancy. Women of reproductive age and particularly pregnant women are the most vulnerable to the adverse consequences of the ZIKV epidemic. Vector control programs need to be expanded to curtail new infections. Research is needed to develop safe and effective treatments, a preventive or therapeutic vaccine, and specific and sensitive tests and to diagnose and identify correlates of long-term immunity. Vaccines and treatments should be safe to be used in pregnancy. To do nothing would allow thousands of pregnant women to expose their fetuses to an infection that causes birth defects and other problems. Prenatal diagnosis technology development is necessary to be able to predict or diagnose adverse fetal outcomes related to ZIKV. Moreover, these tests should be used in a manner similar to the testing/screening method for neural tube defects and common chromosomal anomalies during prenatal care.

Neuroimaging findings using transfontanellar ultrasound in newborns with microcephaly: a possible association with congenital Zika virus infection

Objective: The objective of this study is to determine the main neuroimaging findings of microcephalic newborns with possible Zika virus (ZIKV) intrauterine infection using transfontanellar cranial ultrasound.Methods: We performed a retrospective study to describe the main neuroimaging findings in newborns with microcephaly and possible association with congenital ZIKV infection. Microcephaly was defined in the postnatal period using transfontanellar cranial examination which was performed using both two- (2D) and three-dimensional (3D) ultrasound.Results: One hundred and fifty newborns with microcephaly were identified during the study period. The mean ± (standard deviation - SD) of cephalic perimeter was 28.5 ± 4.2 cm (range, 25–38 cm). Transfontanellar neuroimaging patterns detected cerebral calcifications, neuronal migrational abnormalities, dysgenesis of the corpus callosum, and cerebellar atrophy in 34.9%, 31.1%, 26%, and 16.2%, respectively. Hydrocephalus was seen in 28% of overall newborns. A history of maculopapular rash was present in almost half of the mothers (46.1%).Conclusion: Neuroimaging patterns by means of transfontanellar ultrasound are accurate and diagnostic investigations of brain pathology in newborns affected by microcephaly and possible intrauterine ZIKV infection.

Differential neuronal susceptibility and apoptosis in congenital Zika virus infection.

To characterize the mechanism of Zika virus (ZIKV)-associated microcephaly, we performed immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. Although ZIKV demonstrated a wide range of neuronal and non-neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV-associated microcephaly, and may provide insights into the design and best timing of future therapy. Ann Neurol 2017;82:121-127.

Prenatal imaging findings in fetal Zika virus infection

The aim of this review is to report the most recent observations concerning intrauterine Zika virus (ZIKV) infection and associated neuroimaging. ZIKV outbreak in Brazil in 2015 was associated with an impressive registration of cases of congenital microcephaly in women with symptoms suggestive of ZIKV infection. Clinical and laboratory testing for ZIKV and hypothetic etiopathogenetic mechanisms are described. Diagnostic tests on blood, urine and amniotic fluid should be performed in all mothers with symptoms suggestive of intrauterine ZIKV infection. ZIKV causes multiple teratogenic malformations, mainly affecting the developing brain. Neuroimaging investigation contributes to the prenatal detection of microcephaly and other brain abnormalities in cases of intrauterine ZIKV infection. Neuroimaging is based antenatally on two-dimensional and three-dimensional ultrasound and fetal MRI, whereas computed tomography scan is performed postnatally. Although neuropathology associated with intrauterine ZIKV infection is characterized by nonspecific findings of brain disorder, reduced cortical gyration and white-matter hypomyelination or dysmyelination and cerebellar hypoplasia have been consistently observed in the majority of fetuses and newborns. Prenatal or postnatal genetic workup should be carried out to exclude cases of primary microcephaly. Follow-up should rely upon MRI and computed tomography scan as well as neuropediatrician to better define developmental outcome in survivors.

Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes

Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction and reduces neonatal brain cortical thickness, which is associated with increased activation of microglia. Viral antigen localizes in trophoblast and endothelial cells in the placenta, and endothelial, microglial and neural progenitor cells in the fetal brain. ZIKV infection of the placenta increases production of IFNβ and expression of IFN-stimulated genes 48 h after infection. This mouse model provides a platform for identifying factors at the maternal–fetal interface that contribute to adverse perinatal outcomes in a host with an intact immune system.

EP01.08: Intrauterine Zika virus infection in Brazil: main central nervous system findings

EP01.08: Intrauterine Zika virus infection in Brazil: main central nervous system findings

Autopsy and Postmortem Studies Are Concordant: Pathology of Zika Virus Infection Is Neurotropic in Fetuses and Infants With Microcephaly Following Transplacental Transmission.

-Pathology studies have been important in concluding that Zika virus infection occurring in pregnant women can result in vertical transmission of the agent from mother to fetus. Fetal and infant autopsies have provided crucial direct evidence that Zika virus can infect an unborn child, resulting in microcephaly, other malformations, and, in some cases, death. -To better understand the etiologic role and mechanism(s) of Zika virus in causing birth defects such as microcephaly, this communication analyzes the spectrum of clinical and autopsy studies reported from fetuses and infants who developed intrauterine Zika virus infection, and compares these findings with experimental data related to Zika virus infection. -Retrospective analysis of reported clinical, autopsy, pathology, and related postmortem studies from 9 fetuses and infants with intrauterine Zika virus infection and microcephaly. -All fetuses and infants examined demonstrated an overlapping spectrum of gross and microscopic neuropathologic abnormalities. Direct cytopathic effects of infection by the Zika virus were confined to the brain; in cases where other organs were evaluated, no direct viral effects were identified. -There is concordance of the spectrum of brain damage, reinforcing previous data indicating that the Zika virus has a strong predilection for cells of the fetal central nervous system following vertical transmission. The occurrence of additional congenital abnormalities suggests that intrauterine brain damage from Zika virus interferes with normal fetal development, resulting in fetal akinesia. Experimental in vitro and in vivo studies of Zika virus infection corroborate the human autopsy findings of neural specificity.

Microcefalia e Zika Vírus: características e associações

Objetivo: Discutir a associação entre microcefalia e a infecção materna por Zika Vírus. A microcefalia é o tamanho da cabeça menor do que o esperado em comparação com bebês do mesmo sexo e idade. Entre as causas conhecidas, estão as infecções congênitas. O aumento de casos entre outubro e novembro de 2015 no nordeste brasileiro, que coincidiu com a presença da circulação de novo vírus no país, em maio do mesmo ano, criou a hipótese de associação entre a microcefalia e a infecção materna durante a gravidez. O Zika Vírus é um arbovírus similar ao da Febre Amarela e da Dengue, transmitido principalmente através da picada do Aedes aegypti. A provável transmissão por relação sexual e transfusão de sangue, além de outros vetores como o Aedes albopictus e possivelmente até o pernilongo (Culex sp) aumentam a necessidade de cuidados preventivos em relação à infecção. O exame para detecção viral idealmente é realizado até o quinto dia após o início dos sintomas. Sorologias ainda não são amplamente disponíveis no Brasil. Métodos: Revisão narrativa da literatura. Conclusão: A associação entre casos de microcefalia e o Zika Vírus é embasada nos relatos de relação têmporo-espacial, padrão de alterações neurológicas associado a malformações congênitas, presença do RNA viral no líquido amniótico e nos tecidos de fetos. As respostas definitivas de causalidade serão possíveis após pesquisas e disponibilidade de exames laboratoriais. As evidências até agora apoiam fortemente esta hipótese e todas as medidas preventivas devem ser estimuladas.

Defining the syndrome associated with congenital Zika virus infection.

Zika virus infection in humans is usually mild or asymptomatic. However, some babies born to women infected with Zika virus have severe neurological sequelae. An unusual cluster of cases of congenital microcephaly and other neurological disorders in the WHO Region of the Americas, led to the declaration of a public health emergency of international concern by the World Health Organization (WHO) on 1 February 2016. By 5 May 2016, reports of newborns or fetuses with microcephaly or other malformations – presumably associated with Zika virus infection – have been described in the following countries and territories: Brazil (1271 cases); Cabo Verde (3 cases); Colombia (7 cases); French Polynesia (8 cases); Martinique (2 cases) and Panama (4 cases). Additional cases were also reported in Slovenia and the United States of America, in which the mothers had histories of travel to Brazil during their pregnancies.1 Zika virus is an intensely neurotropic virus that particularly targets neural progenitor cells but also – to a lesser extent – neuronal cells in all stages of maturity. Viral cerebritis can disrupt cerebral embryogenesis and result in microcephaly and other neurological abnormalities.2 Zika virus has been isolated from the brains and cerebrospinal fluid of neonates born with congenital microcephaly and identified in the placental tissue of mothers who had had clinical symptoms consistent with Zika virus infection during their pregnancies.3–5 The spatiotemporal association of cases of microcephaly with the Zika virus outbreak and the evidence emerging from case reports and epidemiologic studies, has led to a strong scientific consensus that Zika virus is implicated in congenital abnormalities.6,7 Existing evidence and unpublished data shared with WHO highlight the wider range of congenital abnormalities probably associated with the acquisition of Zika virus infection in utero. In addition to microcephaly, other manifestations include craniofacial disproportion, spasticity, seizures, irritability and brainstem dysfunction including feeding difficulties, ocular abnormalities and findings on neuroimaging such as calcifications, cortical disorders and ventriculomegaly.3–6,8–10 Similar to other infections acquired in utero, cases range in severity; some babies have been reported to have neurological abnormalities with a normal head circumference. Preliminary data from Colombia and Panama also suggest that the genitourinary, cardiac and digestive systems can be affected (Pilar Ramon-Pardo, unpublished data). The range of abnormalities seen and the likely causal relationship with Zika virus infection suggest the presence of a new congenital syndrome. WHO has set in place a process for defining the spectrum of this syndrome. The process focuses on mapping and analysing the clinical manifestations encompassing the neurological, hearing, visual and other abnormalities, and neuroimaging findings. WHO will need good antenatal and postnatal histories and follow-up data, sound laboratory results, exclusion of other etiologies and analysis of imaging findings to properly delineate this syndrome. The scope of the syndrome will expand as further information and longer follow-up of affected children become available. The surveillance system that was established as part of the epidemic response to the outbreak initially called only for the reporting of microcephaly cases. This surveillance guidance has been expanded to include a spectrum of congenital malformations that could be associated with intrauterine Zika virus infection.11 Effective sharing of data is needed to define this syndrome. A few reports have described a wide range of abnormalities,3–6,8–10 but most data related to congenital manifestations of Zika infection remain unpublished. Global health organizations and research funders have committed to sharing data and results relevant to the Zika epidemic as openly as possible.12 Further analysis of data from cohorts of pregnant women with Zika virus infection are needed to understand all outcomes of Zika virus infection in pregnancy. Thirty-seven countries and territories in the Region of the Americas now report mosquito-borne transmission of Zika virus and risk of sexual transmission. With such spread, it is possible that many thousands of infants will incur moderate to severe neurological disabilities. Therefore, routine surveillance systems and research protocols need to include a larger population than simply children with microcephaly. The health system response, including psychosocial services for women, babies and affected families will need to be fully resourced. The Zika virus public health emergency is distinct because of its long-term health consequences and social impact. A coordinated approach to data sharing, surveillance and research is needed. WHO has thus started coordinating efforts to define the congenital Zika virus syndrome and issues an open invitation to all partners to join in this effort.

Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil

The Zika virus (ZIKV) has rapidly reached epidemic proportions, especially in northeastern Brazil, and has rapidly spread to other parts of the Americas. A recent increase in the prevalence of microcephaly in newborn infants and vision-threatening findings in these infants is likely associated with the rapid spread of ZIKV. To evaluate the ocular findings in infants with microcephaly associated with presumed intrauterine ZIKV infection in Salvador, Bahia, Brazil. Case series at a tertiary hospital. Twenty-nine infants with microcephaly (defined by a cephalic circumference of ≤32 cm) with a presumed diagnosis of congenital ZIKV were recruited through an active search and referrals from other hospitals and health unities. The study was conducted between December 1 and December 21, 2015. All infants and mothers underwent systemic and ophthalmic examinations from December 1 through December 21, 2015, in the Roberto Santos General Hospital, Salvador, Brazil. Anterior segment and retinal, choroidal, and optic nerve abnormalities were documented using a wide-field digital imaging system. The differential diagnosis included toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and human immunodeficiency virus, which were ruled out through serologic and clinical examinations. Ocular abnormalities associated with ZIKV. Twenty-three of 29 mothers (79.3%) reported suspected ZIKV infection signs and symptoms during pregnancy, 18 in the first trimester, 4 in the second trimester, and 1 in the third trimester. Of the 29 infants (58 eyes) examined (18 [62.1%] female), ocular abnormalities were present in 17 eyes (29.3%) of 10 children (34.5%). Bilateral findings were found in 7 of 10 patients presenting with ocular lesions, the most common of which were focal pigment mottling of the retina and chorioretinal atrophy in 11 of the 17 eyes with abnormalities (64.7%), followed by optic nerve abnormalities in 8 eyes (47.1%), bilateral iris coloboma in 1 patient (2 eyes [11.8%]), and lens subluxation in 1 eye (5.9%). Congenital infection due to presumed ZIKV exposure is associated with vision-threatening findings, which include bilateral macular and perimacular lesions as well as optic nerve abnormalities in most cases.

Intrauterine Zika virus infection and microcephaly: correlation of perinatal imaging and three-dimensional virtual physical models

Intrauterine Zika virus infection and microcephaly: correlation of perinatal imaging and three-dimensional virtual physical models