The developmental spectrum of prenatal Zika virus exposure
2020; Elsevier BV; Volume: 4; Issue: 5 Linguagem: Inglês
10.1016/s2352-4642(20)30071-7
ISSN2352-4650
AutoresChrista Einspieler, Peter B. Marschik,
Tópico(s)Virology and Viral Diseases
Resumo5 years after the 2015–16 Zika virus epidemic in Brazil, the first medium-term outcome studies provided insights into the effect of prenatal exposure to Zika virus infection on the developing nervous system. The spectrum of outcomes ranges from normal development,1Gerzson LR de Almeida CS Silva JHD et al.Neurodevelopment of nonmicrocephalic children, after 18 months of life, exposed prenatally to Zika virus.J Child Neurol. 2020; 35: 278-282Crossref PubMed Scopus (14) Google Scholar below-average language, cognitive, and motor development,2Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (71) Google Scholar, 3Nielsen-Saines K Brasil P Kerin T et al.Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.Nat Med. 2019; 25: 1213-1217Crossref PubMed Scopus (132) Google Scholar, 4Faiçal AV de Oliveira JC Oliveira JVV et al.Neurodevelopmental delay in normocephalic children with in utero exposure to Zika virus.BMJ Paediatr Open. 2019; 5e000486Google Scholar and hearing and visual dysfunctions3Nielsen-Saines K Brasil P Kerin T et al.Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.Nat Med. 2019; 25: 1213-1217Crossref PubMed Scopus (132) Google Scholar to severe neurodevelopmental impairment often corresponding with non-ambulatory cerebral palsy.2Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (71) Google Scholar, 5Carvalho AL Ventura P Taguchi T et al.Cerebral palsy in children with congenital Zika syndrome: a 2-year neurodevelopmental follow-up.J Child Neurol. 2020; 35: 202-207Crossref PubMed Scopus (18) Google Scholar Severe neurodevelopmental impairment, or congenital Zika syndrome, is associated with microcephaly, cortical malformations and calcifications at the cortical and subcortical junction and the basal ganglia. In their Article in The Lancet Child and Adolescent Health, Heloisa Viscaino Fernandes Souza Pereira and colleagues6Souza Pereira HVFS dos Santos SP Amâncio APRL et al.Neurological outcome of the congenital Zika syndrome in toddlers and pre-schoolers.Lancet Child Adolesc Health. 2020; (published online March 18.)https://doi.org/10.1016/S2352-4642(20)30041-9Google Scholar categorised 75 children with congenital Zika syndrome into two clinical groups. The children either had signs related to damage of the corticospinal tract (such as hypertonicity, scissoring legs, and hyperreflexia), or neuromuscular dysfunctions characterised by hypotonicity and abnormal postures. Dyskinetic signs (such as dystonia or chorea) were observed in children in both the neuromuscular and corticospinal groups and also occurred in isolation. However, how these neurofunctional impairments relate to specific neuroimaging findings is still unclear. Prins and colleagues7Prins JR Eskandar S Eggen BJL et al.Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment?.J Reprod Immunol. 2018; 126: 18-22Crossref PubMed Scopus (36) Google Scholar proposed an immunologically secure milieu in the fetal brain in which the Zika virus directly targets neuronal progenitor and microglia cells. The vulnerability of the child to the effects of Zika virus is higher if maternal infection occurs during the first trimester of pregnancy, explaining the stunted growth of neuronal progenitor cells that results in microcephaly.8Garcez PP Correia Loiola E Madeiro da Costa R et al.Zika virus impairs growth in human neurospheres and brain organoids.Science. 2016; 352: 816-818Crossref PubMed Scopus (814) Google Scholar Although microcephaly is one of the most prominent signs of congenital Zika syndrome, and the media recorded and reported on this aspect with great detail; it is only one effect of Zika virus-related neurological impairments. The same is true for less severe sequelae, which occur more frequently if the maternal infection with Zika virus occurred during the first trimester of pregnancy.2Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (71) Google Scholar Direct effects of the virus on the developing microglia and the maternal immune activation itself are thought to lead to alterations in neurodevelopment7Prins JR Eskandar S Eggen BJL et al.Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment?.J Reprod Immunol. 2018; 126: 18-22Crossref PubMed Scopus (36) Google Scholar although the cause of the range of severity is still unclear. In another Brazilian cohort9Brasil P Pereira JP Moreira ME et al.Zika virus infection in pregnant women in Rio de Janeiro.N Engl J Med. 2016; 375: 2321-2334Crossref PubMed Scopus (1281) Google Scholar of infants born to mothers who had been infected by Zika virus, the number of children born without microcephaly was relatively high. Assessment of the movements and posture of children showed that they were more often atypical at age 3–5 months if mothers were infected with Zika virus during the first trimester of pregnancy compared with infections later in pregnancy.2Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (71) Google Scholar This finding was associated with poor cognitive and language performance as the children aged.2Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (71) Google Scholar, 3Nielsen-Saines K Brasil P Kerin T et al.Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.Nat Med. 2019; 25: 1213-1217Crossref PubMed Scopus (132) Google Scholar The description of the spectrum of congenital Zika syndrome phenotype by Pereira and colleagues6Souza Pereira HVFS dos Santos SP Amâncio APRL et al.Neurological outcome of the congenital Zika syndrome in toddlers and pre-schoolers.Lancet Child Adolesc Health. 2020; (published online March 18.)https://doi.org/10.1016/S2352-4642(20)30041-9Google Scholar is of utmost importance for parental counselling and targeted intervention. Furthermore, children who are not microcephalic but were exposed to Zika virus during gestation might benefit from early identification of eventual atypical signs. For more than 20 years, the General Movement Assessment has repeatedly proven to be a powerful tool for predicting neurodevelopmental outcomes.10Prechtl HFR Einspieler C Cioni G Bos AF Ferrari F Sontheimer D An early marker for neurological deficits after perinatal brain lesions.Lancet. 1997; 349: 1361-1363Summary Full Text Full Text PDF PubMed Scopus (476) Google Scholar By evaluating spontaneous (general) movements during the first months of life, we were able to predict adverse neurodevelopmental outcomes with 96% specificity and 70% sensitivity in infants who were non-microcephalic born to mothers who were Zika virus positive. In the case of congenital or secondary microcephaly, predictive values increased to 100%.2Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (71) Google Scholar Further longitudinal research is needed to show whether earlier differentiation between the congenital Zika syndrome subgroups described by Pereira and colleagues6Souza Pereira HVFS dos Santos SP Amâncio APRL et al.Neurological outcome of the congenital Zika syndrome in toddlers and pre-schoolers.Lancet Child Adolesc Health. 2020; (published online March 18.)https://doi.org/10.1016/S2352-4642(20)30041-9Google Scholar is possible by means of structural (eg, MRI) and early functional assessments (eg, general movements assessment). Zika virus infections lead to a spectrum of structural and functional atypicalities and impairments with tendencies to deteriorate, but also to improve or even normalise. However, the effect of Zika virus exposure during development needs further investigation, from early gestation throughout the vulnerable period of infancy. We are compelled to thoroughly document developmental traits, learn to interpret classical and neurofunctional biomarkers that allow the prediction of developmental trends, and consequently start to intervene as early as possible to target the most efficient time window for neurorecovery. CE is a certified tutor of the Prechtl General Movement Assessment. PBM declares no competing interests. Neurological outcomes of congenital Zika syndrome in toddlers and preschoolers: a case seriesWe describe distinct neurological profiles in the congenital Zika syndrome spectrum, with functional outcomes tending to correlate with these groups. The clinical division of children based on the disease signs proposed here is supported by the literature on central and peripheral nervous system pathology in congenital Zika syndrome. The high prevalence of dyskinetic symptoms merits special attention. Full-Text PDF
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