COMMONLY AFFECTED BRAIN AREAS IN CHILDREN WITH CONGENITAL ZIKA SYNDROME: ANATOMICAL PATTERNS AND FUNCTIONAL CONSEQUENCES
DOI:
https://doi.org/10.56238/bocav25n77-023Keywords:
Microcephaly, Development, Zika Virus, BrainstemAbstract
Congenital Zika Syndrome (CZS) affects the fetal central nervous system (CNS) during pregnancy, resulting in specific neurological, cognitive and functional consequences. As this syndrome has only recently been identified, the full extent of its phenotypic and functional expression throughout childhood remains unclear. Objective: This review aims to explore anatomical patterns of major brain involvement in children with CZS, while also integrating emerging evidence on associated motor, cognitive and behavioural impairments. Methods: A review was conducted of studies involving children with microcephaly and confirmed Zika virus (ZIKV) infection. Neuroimaging findings were analyzed in relation to clinical advances, with particular attention to the CNS regions most and least affected by ZIKV. Results: Most studies report a predominance of major morphological anomalies in the cortical and subcortical regions, with the cerebellum and brainstem being relatively unaffected. Combined with the chronology of brain development and the possible differential expression of viral receptors, these findings reinforce the hypothesis that ZIKV's preference for certain cell populations plays a central role in the pathogenesis of the syndrome. Furthermore, the blood–brain barrier may contribute to the regional selectivity of the infection, providing partial protection to certain regions. Conclusions: A deeper understanding of the complex interplay between the pathophysiological mechanisms of the virus, neuroanatomical development and clinical manifestations is essential to improve our understanding of the CZS phenotype.
References
Almeida, I. M. L. M., et al. (2019). Clinical and epidemiological aspects of microcephaly in the state of Piauí, northeastern Brazil, 2015–2016. Journal of Pediatrics (Rio J.), 95(4), S6. https://doi.org/10.1016/j.jped.2018.04.013 DOI: https://doi.org/10.1016/j.jped.2018.04.013
Almeida, L. C., et al. (2022). Hearing and communicative skills in the first years of life in children with congenital Zika syndrome. Brazilian Journal of Otorhinolaryngology, 88(1), 112–117. https://doi.org/10.1016/j.bjorl.2020.05.007 DOI: https://doi.org/10.1016/j.bjorl.2020.05.007
Aragão, M. F. V. V., et al. (2016). Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ, 353, i1901. https://doi.org/10.1136/bmj.i1901 DOI: https://doi.org/10.1136/bmj.i1901
Aragão, M. F. V. V., et al. (2017). Nonmicrocephalic infants with congenital Zika syndrome suspected only after neuroimaging evaluation compared with those with microcephaly at birth and postnatally: how large is the Zika virus ‘iceberg’? AJNR American Journal of Neuroradiology, 38(7), 1427–1434. https://doi.org/10.3174/ajnr.A5216 DOI: https://doi.org/10.3174/ajnr.A5216
Campos, G. S., Bandeira, A. C., & Sardi, S. I. (2015). Zika virus outbreak, Bahia, Brazil. Emerging Infectious Diseases, 21(10), 1885–1886. https://doi.org/10.3201/eid2110.150847 DOI: https://doi.org/10.3201/eid2110.150847
Carvalho, M. D. C. G., et al. (2017). Sleep EEG patterns in children with congenital Zika virus syndrome. Clinical Neurophysiology, 128(9), 2040–2047. https://doi.org/10.1016/j.clinph.2016.11.004 DOI: https://doi.org/10.1016/j.clinph.2016.11.004
Castro, P. T., et al. (2023). Prenatal and postnatal Zika intrauterine infection: diagnostic imaging techniques and placental pathology. Fetal and Pediatric Pathology, 42(2), 207–215. https://doi.org/10.1080/15513815.2022.2118559 DOI: https://doi.org/10.1080/15513815.2022.2118559
Chen, J., et al. (2018). AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling. Nature Microbiology, 3(3), 302–309. https://doi.org/10.1038/s41564-017-0092-4 DOI: https://doi.org/10.1038/s41564-017-0092-4
Cho, H., et al. (2013). Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nature Medicine, 19(4), 458–464. https://doi.org/10.1038/nm.3108 DOI: https://doi.org/10.1038/nm.3108
Cumpston, M., et al. (2019). Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database of Systematic Reviews, 2019(10), ED000142. https://doi.org/10.1002/14651858.ED000142 DOI: https://doi.org/10.1002/14651858.ED000142
Das, S., et al. (2009). Heat shock protein 70 on Neuro2a cells is a putative receptor for Japanese encephalitis virus. Virology, 385(1), 47–57. https://doi.org/10.1016/j.virol.2008.10.025 DOI: https://doi.org/10.1016/j.virol.2008.10.025
Daza, M., et al. (2021). Clinical and neurodevelopmental outcomes based on brain imaging studies in a Colombian cohort of children with probable antenatal Zika virus exposure. Birth Defects Research, 113(18), 1299–1312. https://doi.org/10.1002/bdr2.1947 DOI: https://doi.org/10.1002/bdr2.1947
De Castro, J. D. V., et al. (2017). Presumed Zika virus-related congenital brain malformations: the spectrum of CT and MRI findings in fetuses and newborns. Arquivos de Neuro-Psiquiatria, 75(10), 703–710. https://doi.org/10.1590/0004-282X20170134 DOI: https://doi.org/10.1590/0004-282x20170134
Del Campo, M., et al. (2017). The phenotypic spectrum of congenital Zika syndrome. American Journal of Medical Genetics Part A, 173(4), 841–857. https://doi.org/10.1002/ajmg.a.38170 DOI: https://doi.org/10.1002/ajmg.a.38170
Dang, J., et al. (2016). Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell, 19(2), 258–265. https://doi.org/10.1016/j.stem.2016.04.014 DOI: https://doi.org/10.1016/j.stem.2016.04.014
Duarte, G., et al. (2017). Zika virus infection in pregnant women and microcephaly. Revista Brasileira de Ginecologia e Obstetrícia, 39(5), 235–248. https://doi.org/10.1055/s-0037-1603450 DOI: https://doi.org/10.1055/s-0037-1603450
Fensterl, V. L., et al. (2012). Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis. PLoS Pathogens, 8, e1002712. https://doi.org/10.1371/journal.ppat.1002712 DOI: https://doi.org/10.1371/journal.ppat.1002712
Hasan, S. S., et al. (2017). A human antibody against Zika virus crosslinks the E protein to prevent infection. Nature Communications, 8, 14722. https://doi.org/10.1038/ncomms14722 DOI: https://doi.org/10.2210/pdb5uhy/pdb
Hafizi, S., & Dahlbäck, B. (2006). Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine & Growth Factor Reviews, 17(4), 295–304. https://doi.org/10.1016/j.cytogfr.2006.04.004 DOI: https://doi.org/10.1016/j.cytogfr.2006.04.004
Hazin, A. N., et al. (2016). Computed tomographic findings in microcephaly associated with Zika virus. New England Journal of Medicine, 374, 2193–2195. https://doi.org/10.1056/NEJMc1603617 DOI: https://doi.org/10.1056/NEJMc1603617
Heukelbach, J., et al. (2016). Zika virus outbreak in Brazil. Journal of Infection in Developing Countries, 10(2), 116–120. https://doi.org/10.3855/jidc.8217 DOI: https://doi.org/10.3855/jidc.8217
Huang, Y. J., Higgs, S., & Vanlandingham, D. L. (2014). Flavivirus–mosquito interactions. Viruses, 6(11), 4703–4730. https://doi.org/10.3390/v6114703 DOI: https://doi.org/10.3390/v6114703
Kim, S. Y., Li, B., & Linhardt, R. J. (2017). Pathogenesis and inhibition of flaviviruses from the carbohydrate perspective. Pharmaceuticals (Basel), 10(2), Article 44. https://doi.org/10.3390/ph10020044 DOI: https://doi.org/10.3390/ph10020044
Krow-Lucal, E. R., et al. (2018). Association and birth prevalence of microcephaly attributable to Zika virus infection among infants in Paraíba, Brazil, in 2015–16: a case-control study. The Lancet Child & Adolescent Health, 2(3), 205–213. https://doi.org/10.1016/S2352-4642(18)30020-8 DOI: https://doi.org/10.1016/S2352-4642(18)30020-8
Lage, M.-L. C., et al. (2019). Clinical, neuroimaging, and neurophysiological findings in children with microcephaly related to congenital Zika virus infection. International Journal of Environmental Research and Public Health, 16(3), Article 309. https://doi.org/10.3390/ijerph16030309 DOI: https://doi.org/10.3390/ijerph16030309
Lazear, H. M., et al. (2016). A mouse model of Zika virus pathogenesis. Cell Host & Microbe, 19(5), 720–730. https://doi.org/10.1016/j.chom.2016.03.010 DOI: https://doi.org/10.1016/j.chom.2016.03.010
Leal, M. C., et al. (2017). Characteristics of dysphagia in infants with microcephaly caused by congenital Zika virus infection, Brazil, 2015. Emerging Infectious Diseases, 23(8), 1253–1259. https://doi.org/10.3201/eid2308.170354 DOI: https://doi.org/10.3201/eid2308.170354
Lemke, G., & Rothlin, C. V. (2008). Immunobiology of the TAM receptors. Nature Reviews Immunology, 8(5), 327–336. https://doi.org/10.1038/nri2303 DOI: https://doi.org/10.1038/nri2303
Li, C., Xu, D., & Sim, Q. (2016). Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell, 19(1), 120–126. https://doi.org/10.1016/j.stem.2016.04.017 DOI: https://doi.org/10.1016/j.stem.2016.04.017
Liebner, S., et al. (2018). Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathologica, 135(3), 311–336. https://doi.org/10.1007/s00401-018-1815-1 DOI: https://doi.org/10.1007/s00401-018-1815-1
Lima, P. H. M., et al. (2025). Perception of quality of life by primary caregivers of children with congenital Zika syndrome: a cross-sectional study. Maternal and Child Health Journal, 29(3), 363–375. https://doi.org/10.1007/s10995-025-04057-y DOI: https://doi.org/10.1007/s10995-025-04057-y
Meertens, L., et al. (2017). Axl mediates Zika virus entry in human glial cells and modulates innate immune responses. Cell Reports, 18(2), 324–333. https://doi.org/10.1016/j.celrep.2016.12.045 DOI: https://doi.org/10.1016/j.celrep.2016.12.045
Mehrjardi, M. Z., et al. (2017). Neuroimaging findings of congenital Zika virus infection: a pictorial essay. Japanese Journal of Radiology, 35(3), 89–94. https://doi.org/10.1007/s11604-016-0609-4 DOI: https://doi.org/10.1007/s11604-016-0609-4
Melo, A., et al. (2020). Motor function in children with congenital Zika syndrome. Developmental Medicine & Child Neurology, 62(2), 221–226. https://doi.org/10.1111/dmcn.14227 DOI: https://doi.org/10.1111/dmcn.14227
Mercer, J., Schelhaas, M., & Helenius, A. (2010). Virus entry by endocytosis. Annual Review of Biochemistry, 79, 803–833. https://doi.org/10.1146/annurev-biochem-060208-104626 DOI: https://doi.org/10.1146/annurev-biochem-060208-104626
Miner, J. J., et al. (2016). Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell, 165(5), 1081–1091. https://doi.org/10.1016/j.cell.2016.05.008 DOI: https://doi.org/10.1016/j.cell.2016.05.008
Moore, C. A., et al. (2017). Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatrics, 171(3), 288–295. https://doi.org/10.1001/jamapediatrics.2016.3982 DOI: https://doi.org/10.1001/jamapediatrics.2016.3982
Oh, Y., et al. (2017). Zika virus directly infects peripheral neurons and induces cell death. Nature Neuroscience, 20(9), 1209–1212. https://doi.org/10.1038/nn.4612 DOI: https://doi.org/10.1038/nn.4612
Oliveira-Szejnfeld, P. S., et al. (2016). Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology, 281(1), 203–218. https://doi.org/10.1148/radiol.2016161584 DOI: https://doi.org/10.1148/radiol.2016161584
Page, M. J., et al. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Revista Española de Cardiología, 74(9), 790–799. https://doi.org/10.1016/j.rec.2021.07.010 DOI: https://doi.org/10.1016/j.rec.2021.07.010
Page, M. J., et al. (2022). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews / Declaración PRISMA 2020. Revista Panamericana de Salud Pública, 46, e112. https://doi.org/10.26633/RPSP.2022.112 DOI: https://doi.org/10.26633/RPSP.2022.112
Peixoto Filho, A. A. A., et al. (2018). Computed tomography and magnetic resonance imaging findings in infants with microcephaly potentially related to congenital Zika virus infection. Radiologia Brasileira, 51(2), 119–122. https://doi.org/10.1590/0100-3984.2016.0135 DOI: https://doi.org/10.1590/0100-3984.2016.0135
Pinato, L., et al. (2018). Sleep findings in Brazilian children with congenital Zika syndrome. Sleep, 41(3), zsy009. https://doi.org/10.1093/sleep/zsy009 DOI: https://doi.org/10.1093/sleep/zsy009
Pires, P., et al. (2018). Neuroimaging findings associated with congenital Zika virus syndrome: case series at the time of first epidemic outbreak in Pernambuco State, Brazil. Child's Nervous System, 34(5), 957–963. https://doi.org/10.1007/s00381-017-3682-9 DOI: https://doi.org/10.1007/s00381-017-3682-9
Pool, K.-L., et al. (2019). Association between neonatal neuroimaging and clinical outcomes in Zika-exposed infants from Rio de Janeiro, Brazil. JAMA Network Open, 2(7), e198124. https://doi.org/10.1001/jamanetworkopen.2019.8124 DOI: https://doi.org/10.1001/jamanetworkopen.2019.8124
Quicke, K. M., et al. (2016). Zika virus infects human placental macrophages. Cell Host & Microbe, 20(1), 83–90. https://doi.org/10.1016/j.chom.2016.05.015 DOI: https://doi.org/10.1016/j.chom.2016.05.015
Regadas, V. C., et al. (2018). Microcephaly caused by congenital Zika virus infection and viral detection in maternal urine during pregnancy. Revista da Associação Médica Brasileira, 64(1), 11–14. https://doi.org/10.1590/1806-9282.64.01.11 DOI: https://doi.org/10.1590/1806-9282.64.01.11
Retallack, H., et al. (2016). Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proceedings of the National Academy of Sciences of the United States of America, 113(50), 14408–14413. https://doi.org/10.1073/pnas.1618029113 DOI: https://doi.org/10.1073/pnas.1618029113
Ribeiro, B. N. F., Muniz, B. C., & Marchiori, E. (2020). Evaluation of the frequency of neuroimaging findings in congenital infection by Zika virus and differences between computed tomography and magnetic resonance imaging. Revista da Sociedade Brasileira de Medicina Tropical, 53, e20190557. https://doi.org/10.1590/0037-8682-0557-2019 DOI: https://doi.org/10.1590/0037-8682-0557-2019
Ribeiro, C. T. M., et al. (2022). Gross motor function in children with congenital Zika syndrome from Rio de Janeiro, Brazil. European Journal of Pediatrics, 181(2), 783–788. https://doi.org/10.1007/s00431-021-04270-1 DOI: https://doi.org/10.1007/s00431-021-04270-1
Sahu, R. N., Kumar, R., & Mahapatra, A. K. (2009). Central nervous system infection in the pediatric population. Journal of Pediatric Neurosciences, 4(1), 20–24. https://doi.org/10.4103/1817-1745.49102 DOI: https://doi.org/10.4103/1817-1745.49102
Sanz-Cortés, M., et al. (2018). Clinical assessment and brain findings in a cohort of mothers, fetuses and infants infected with Zika virus. American Journal of Obstetrics and Gynecology, 218(4), 440.e1–440.e36. https://doi.org/10.1016/j.ajog.2018.01.012 DOI: https://doi.org/10.1016/j.ajog.2018.01.012
Schuler-Faccini, L., et al. (2016). Possible association between Zika virus infection and microcephaly — Brazil, 2015. MMWR Morbidity and Mortality Weekly Report, 65(3), 59–62. https://doi.org/10.15585/mmwr.mm6503e2 DOI: https://doi.org/10.15585/mmwr.mm6503e2
Sharon, M. K., & Pasko, R. (2022). Development of prefrontal cortex. Neuropsychopharmacology, 47(1), 41–57. https://doi.org/10.1038/s41386-021-01137-9 DOI: https://doi.org/10.1038/s41386-021-01137-9
Shi, Y., & Gao, G. F. (2017). Structural biology of the Zika virus. Trends in Biochemical Sciences, 42(6), 443–456. https://doi.org/10.1016/j.tibs.2017.02.009 DOI: https://doi.org/10.1016/j.tibs.2017.02.009
Tang, H., et al. (2016). Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell, 18(5), 587–590. https://doi.org/10.1016/j.stem.2016.02.016 DOI: https://doi.org/10.1016/j.stem.2016.02.016
Van der Linden, V., et al. (2016). Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morbidity and Mortality Weekly Report, 65(47), 1343–1348. https://doi.org/10.15585/mmwr.mm6547e2 DOI: https://doi.org/10.15585/mmwr.mm6547e2
Ventura, C. V., et al. (2016). Risk factors associated with the ophthalmologic findings identified in infants with presumed Zika virus congenital infection. JAMA Ophthalmology, 134(8), 912–918. https://doi.org/10.1001/jamaophthalmol.2016.1784 DOI: https://doi.org/10.1001/jamaophthalmol.2016.1784
Wang, Z.-Y., et al. (2017). Axl is not an indispensable factor for Zika virus infection in mice. Journal of General Virology, 98(8), 2061–2068. https://doi.org/10.1099/jgv.0.000886 DOI: https://doi.org/10.1099/jgv.0.000886
Werner, H., et al. (2016). First-trimester intrauterine Zika virus infection and brain pathology: prenatal and postnatal neuroimaging findings. Prenatal Diagnosis, 36(8), 785–789. https://doi.org/10.1002/pd.4860 DOI: https://doi.org/10.1002/pd.4860
Yan, Y., et al. (2019). Zika virus induces abnormal cranial osteogenesis by negatively affecting cranial neural crest development. Infection, Genetics and Evolution, 69, 176–189. https://doi.org/10.1016/j.meegid.2019.01.023 DOI: https://doi.org/10.1016/j.meegid.2019.01.023
Zegenhagen, L., et al. (2016). Brain heterogeneity leads to differential innate immune responses and modulates pathogenesis of viral infections. Cytokine & Growth Factor Reviews, 30, 95–101. https://doi.org/10.1016/j.cytogfr.2016.03.006 DOI: https://doi.org/10.1016/j.cytogfr.2016.03.006
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