RESUMO
Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment.
Assuntos
Encéfalo , Células-Tronco Pluripotentes Induzidas , Transmissão Vertical de Doenças Infecciosas , Sinapses , Infecção por Zika virus , Zika virus , Humanos , Infecção por Zika virus/virologia , Infecção por Zika virus/patologia , Feminino , Zika virus/patogenicidade , Sinapses/patologia , Sinapses/metabolismo , Encéfalo/virologia , Encéfalo/patologia , Gravidez , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/virologia , Neurônios/virologia , Neurônios/metabolismo , Neurônios/patologia , Masculino , Astrócitos/virologia , Astrócitos/metabolismo , Doenças Neuroinflamatórias/virologia , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismo , Complicações Infecciosas na Gravidez/virologia , Complicações Infecciosas na Gravidez/patologia , Brasil , Recém-Nascido , Transtorno do Espectro Autista/virologia , CriançaRESUMO
Dengue is an infectious disease of global health concern that continues to require surveillance. Serological testing has been used to investigate dengue-infected patients, but specificity is affected by the co-circulation of ZIKA virus (ZIKV), which shares extensive antigen similarities. The goal of this study was the development of a specific dengue virus (DENV) IgG ELISA based on a multi-epitope NS1-based antigen for antibody detection. The multi-epitope protein (T-ΔNS1), derived from a fragment of the NS1-protein of the four DENV serotypes, was expressed in Escherichia coli and purified via affinity chromatography. The antigenicity and specificity were evaluated with sera of mice infected with DENV-1-4 or ZIKV or after immunization with the recombinant ΔNS1 proteins. The performance of the T-ΔNS1-based IgG ELISA was also determined with human serum samples. The results demonstrate that the DENV T-ΔNS1 was specifically recognized by the serum IgG of dengue-infected mice or humans but showed no or reduced reactivity with ZIKV-infected subjects. Based on the available set of clinical samples, the ELISA based on the DENV T-ΔNS1 achieved 77.42% sensitivity and 88.57% specificity. The results indicate that the T-ΔNS1 antigen is a promising candidate for the development of specific serological analysis.
RESUMO
Importance: Hydrocephalus is a treatable but potentially fatal complication that has not been previously described in congenital Zika syndrome (CZS). Objective: To describe the clinical features and imaging findings in 24 patients with congenital Zika syndrome (CZS) who developed hydrocephalus. Design, Setting, and Participants: This case series included patients with hydrocephalus who were born in October and November 2015 and followed up until mid-2017 in the 2 largest national referral centers for CZS in Brazil. The participants included consecutively enrolled children with a clinical and laboratorial diagnosis of CZS who developed clinical and/or image findings suggestive of hydrocephalus and who were confirmed to experience increased intracranial hypertension during ventriculoperitoneal shunt procedures. Main Outcomes and Measures: To retrospectively describe clinical and image findings in these 24 patients. Results: This multicenter cohort included 308 patients with CZS; 24 consecutive children were enrolled in this study. These children were aged between 3 to 18 months, and 13 of 24 (54%) were female. All patients presented with at least 1 positive test result for anti-Zika antibodies in cerebrospinal fluid or serum and had classic signs of CZS. At the time of hydrocephalus diagnosis, only 14 of 24 patients (58%) had symptoms and signs suggestive of hydrocephalus (mainly worsening seizures, vomiting, irritability, and/or sudden increase of head circumference percentile). Two of 24 patients (8%) had no symptoms suggestive of hydrocephalus but were found to have reduced brain volume on repeated imaging. Cerebellar or brainstem hypoplasia on baseline imaging were found in 18 of 23 patients (78%). At the second computed tomographic scan, all patients showed a marked increase of ventricular volume, compatible with communicating hydrocephalus, and reduction of brain tissue that was visibly worse than on baseline imaging for the 23 patients with repeated scans. Conclusions and Relevance: We present evidence that hydrocephalus is a complication of CZS in at least a proportion of patients. The clinical spectrum of this condition continues to evolve, but given that presenting signs and symptoms of hydrocephalus can be challenging to recognize in CZS, we provisionally recommend that high suspicion and appropriate monitoring for hydrocephalus should be part of the standard care of patients with CZS.
Assuntos
Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Infecção por Zika virus/congênito , Infecção por Zika virus/complicações , Brasil , Feminino , Seguimentos , Humanos , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Lactente , Masculino , Estudos RetrospectivosRESUMO
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.
Assuntos
Fontanelas Cranianas/diagnóstico por imagem , Microcefalia/diagnóstico , Neuroimagem/métodos , Complicações Infecciosas na Gravidez , Infecção por Zika virus/complicações , Infecção por Zika virus/diagnóstico , Fontanelas Cranianas/patologia , Feminino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/virologia , Recém-Nascido , Masculino , Microcefalia/virologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Estudos Retrospectivos , Ultrassonografia/métodos , Zika virus/fisiologia , Infecção por Zika virus/congênitoRESUMO
PURPOSE: This study aimed to describe the prenatal and postnatal neuroimaging and clinical findings in a clinical series following congenital Zika virus syndrome during the first epidemic Zika virus (ZIKV) outbreak in the State of Pernambuco, Brazil. METHODS: We (the authors) conducted a retrospective study of a prospectively collected case series of fetuses and neonates with microcephaly born to mothers with presumed/confirmed congenital ZIKV syndrome. Prenatal ultrasound findings were reviewed to identify potential central nervous system (CNS) abnormalities. Neonates underwent postnatal neuroimaging follow up by computed tomography (CT)-scan or magnetic resonance (MR) imaging. RESULTS: The prenatal and postnatal outcomes of eight fetuses/neonates born to mothers with presumed/confirmed congenital ZIKV syndrome were examined. The mean gestational age at ultrasound was 31.3 weeks. Severe microcephaly was identified in seven fetuses (87.5%), while ventriculomegaly and brain calcifications were detected in all fetuses. The mean gestational age at delivery and head circumference were 38 weeks and 30.2 cm, respectively. All cases of microcephaly but one was confirmed postnatally. Brain CT scans or MRIs were performed in seven newborns, and all had periventricular and/or parenchymal calcifications, symmetrical or asymmetrical ventriculomegaly, pachygyria, and reduced sulcation and gyration. MR imaging aided the detection of one undetected case of corpus callosum dysgenesis and was essential in documenting reduced mantel of the cerebral cortex and reduced gyration and sulcation, especially involving the parietal lobe. In addition, MR imaging was also able to display irregular interfaces with the subcortical white matter, a finding consistent with polymicrogyria, more frequently seen at the level of the frontal lobe and atrophic and thinned pons. CONCLUSION: Severe microcephaly and CNS abnormalities may be associated with congenital ZIKV syndrome.
Assuntos
Encéfalo/diagnóstico por imagem , Surtos de Doenças/estatística & dados numéricos , Microcefalia/etiologia , Neuroimagem , Infecção por Zika virus/diagnóstico por imagem , Infecção por Zika virus/epidemiologia , Encéfalo/anormalidades , Encéfalo/virologia , Brasil/epidemiologia , Feminino , Idade Gestacional , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/virologia , Diagnóstico Pré-Natal , Estudos Retrospectivos , Infecção por Zika virus/complicaçõesRESUMO
Objective To compare initial brain computed tomography (CT) scans with follow-up CT scans at one year in children with congenital Zika syndrome, focusing on cerebral calcifications.Design Case series study.Setting Barão de Lucena Hospital, Pernambuco state, Brazil.Participants 37 children with probable or confirmed congenital Zika syndrome during the microcephaly outbreak in 2015 who underwent brain CT shortly after birth and at one year follow-up.Main outcome measure Differences in cerebral calcification patterns between initial and follow-up scans.Results 37 children were evaluated. All presented cerebral calcifications on the initial scan, predominantly at cortical-white matter junction. At follow-up the calcifications had diminished in number, size, or density, or a combination in 34 of the children (92%, 95% confidence interval 79% to 97%), were no longer visible in one child, and remained unchanged in two children. No child showed an increase in calcifications. The calcifications at the cortical-white matter junction which were no longer visible at follow-up occurred predominately in the parietal and occipital lobes. These imaging changes were not associated with any clear clinical improvements.Conclusion The detection of cerebral calcifications should not be considered a major criterion for late diagnosis of congenital Zika syndrome, nor should the absence of calcifications be used to exclude the diagnosis.
Assuntos
Encéfalo/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Infecção por Zika virus/diagnóstico , Zika virus/isolamento & purificação , Encéfalo/patologia , Encéfalo/virologia , Brasil , Calcinose/virologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/metabolismo , Microcefalia/virologia , Neuroimagem/métodos , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico por imagem , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/virologia , Síndrome , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/virologia , Zika virus/imunologia , Infecção por Zika virus/congênito , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologiaRESUMO
Fetal infection by the Zika virus has been implicated in the exceptional rise in the number of microcephalic newborns recorded by the end of 2015 in Brazil. The mechanism by which this teratogenic effect is produced in the developing brain has not been fully established. Very early in the outbreak, we addressed this question by evaluating available initial data from a gestational and postnatal clinical investigation in the Brazilian state of Pernambuco. The present study was undertaken to test the hypothesis that the subtractive dysmorphic brain malformations observed in Zika-related microcephaly are primarily due to the massive induction of apoptosis of neuroprogenitor cells. We designed a physiopathological algorithm based on the examination of the following medical findings: epidemiological data, ultrasound images, computed tomography scans, placental tissue, cerebral fluid analysis, eye fundoscopy, neurological examination and necroscopy findings.
Assuntos
Surtos de Doenças , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus/patogenicidade , Apoptose , Brasil/epidemiologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Feminino , Humanos , Recém-Nascido , Microcefalia/fisiopatologia , Gravidez , Teratogênicos/toxicidadeRESUMO
Starting with the outbreak in Brazil, Zika virus (ZIKV) infection has been correlated with severe syndromes such as congenital Zika syndrome and Guillain-Barré syndrome. Here, we review the status of Zika virus pathogenesis in the central nervous system (CNS). One of the main concerns about ZIKV exposure during pregnancy is abnormal brain development, which results in microcephaly in newborns. Recent advances in in vitro research show that ZIKV can infect and obliterate cells from the CNS, such as progenitors, neurons, and glial cells. Neural progenitor cells seem to be the main target of the virus, with infection leading to less cell migration, neurogenesis impairment, cell death and, consequently, microcephaly in newborns. The downsizing of the brain can be directly associated with defective development of the cortical layer. In addition, in vivo investigations in mice reveal that ZIKV can cross the placenta and migrate to fetuses, but with a significant neurotropism, which results in brain damage for the pups. Another finding shows that hydrocephaly is an additional consequence of ZIKV infection, being detected during embryonic and fetal development in mouse, as well as after birth in humans. In spite of the advances in ZIKV research in the last year, the mechanisms underlying ZIKV infection in the CNS require further investigation particularly as there are currently no treatments or vaccines against ZIKV infection.
Assuntos
Encéfalo/embriologia , Hidrocefalia/virologia , Microcefalia/virologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Animais , Encéfalo/virologia , Movimento Celular/fisiologia , Feminino , Humanos , Camundongos , Células-Tronco Neurais/virologia , Gravidez , Complicações Infecciosas na Gravidez , Infecção por Zika virus/virologiaRESUMO
Os tumores de intestino delgado são considerados raros, representando apenas 3-6% das neoplasias gastrointestinais. Em geral, possuem sintomatologia inespecífica, diagnóstico difícil e prognóstico ruim. A falta de especificidade dos sintomas e a maior dificuldade de avaliação do intestino delgado têm sido considerados como fatores que contribuem para as apresentações tardias da doença e atraso no diagnóstico. A ressecção cirúrgica é mandatória e as terapias adjuvantes trazem poucos benefícios. Relataremos o caso de uma paciente submetida à enteroscopia de duplo balão por quadro clínico de hemorragia digestiva obscura, sendo diagnosticada uma lesão neoplásica em jejuno proximal.
The small bowel tumors are considered rare, only representing 3-6% of gastrointestinal neoplasms. In general, they exhibit nonspecific symptomatology, difficult diagnosis and a bad prognosis. The lack of symptoms specificity and the small intestine evaluation difficulties are contributing factors to the late appearance of the disease as well as a late diagnosis. The surgical resection is mandatory and the adjuvant therapy offers little benefit. We report a case with clinical presentation of obscure digestive bleeding, submitted to capsule endoscopy followed by double-balloon enteroscopy being diagnosed neoplastic lesion in the proximal jejunum.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Gastrointestinais , Intestino Delgado/patologia , Endoscopia por Cápsula , Cápsulas Endoscópicas , Enteroscopia de Duplo Balão , Hemorragia GastrointestinalRESUMO
Schwannoma é um tumor neurogênico benigno raro, originário das células de Schwann da bainha de mielina dos nervos periféricos. Sua localização nos tecidos oculares não é comum, sendo a órbita o local afetado com maior frequência e o acometimento das pálpebras é muito raro. Há poucos relatos descritos na literatura sobre Schwannoma palpebral, apenas dois em crianças. Este é, em nosso conhecimento, o primeiro caso relatado no Brasil.
Schwannoma is a rare benign neurogenic tumor. It arises from Schwann cells located at the myelin sheath of peripheral nerves. Its incidence is frequently associated with the orbit. Ocular tissues in general and eyelids in particular are rarely affected. Very few reports can be found in the literature describing eyelid schwannomas. Amongst these, we have found only two describing it affecting children. To our knowledge, this is the first case report about eyelid schwanomma in Brazil - and it involves a child.