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”?

Aragão, Máría de Fátima Viana Vasco; Holanda, Arthur Cesário de; Lima, Alessandra Cintia Mertens Brainer de Queiroz; Petribu, N C L; Castillo, Maurício; Linden, Vanessa van der; Serpa, Sarah Costa; Tenório, A G; Travassos, P; Cordeiro, Marli Tenório; Sarteschi, Camila; Valença, Marcelo Moraes; Costello, Anthony

doi:10.3174/ajnr.a5216

Cited by 131 publications

(162 citation statements)

References 25 publications

(22 reference statements)

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“…Consistent with our findings in mice, some human infants, without apparent microcephaly at birth, displayed postnatal syndromes of disproportionate head growth, while one baby developed difficulties moving its left hand months after birth. Not surprisingly, neuroimaging analyses suggested that babies who developed postnatal congenital ZIKV syndromes had a milder degree of brain damage compared to those with microcephaly at birth (Aragao et al, 2017). Our ZIKV infection model in immunocompetent C57BL/6J mice causes brain widespread astrogliosis and mild neurobehavioral deficits in pups, which can partially mimic congenital ZIKV-causing postnatal developmental deficits in humans.…”

Section: Resultsmentioning

confidence: 99%

Congenital Zika Virus Infection in Immunocompetent Mice Causes Postnatal Growth Impediment and Neurobehavioral Deficits

et al. 2018

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A small percentage of babies born to Zika virus (ZIKV)-infected mothers manifest severe defects at birth, including microcephaly. Among those who appeared healthy at birth, there are increasing reports of postnatal growth or developmental defects. However, the impact of congenital ZIKV infection in postnatal development is poorly understood. Here, we report that a mild congenital ZIKV-infection in pups born to immunocompetent pregnant mice did not display apparent defects at birth, but manifested postnatal growth impediments and neurobehavioral deficits, which include reduced locomotor and cognitive deficits that persisted into adulthood. We found that the brains of these pups were smaller, had a thinner cortical layer 1, displayed increased astrogliosis, decreased expression of microcephaly- and neuron development- related genes, and increased pathology as compared to mock-infected controls. In summary, our results showed that even a mild congenital ZIKV infection in immunocompetent mice could lead to postnatal deficits, providing definitive experimental evidence for a necessity to closely monitor postnatal growth and development of presumably healthy human infants, whose mothers were exposed to ZIKV infection during pregnancy.

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Section: Resultsmentioning

confidence: 99%

Congenital Zika Virus Infection in Immunocompetent Mice Causes Postnatal Growth Impediment and Neurobehavioral Deficits

et al. 2018

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“…The majority of research in newborns and infants has to date focused on the congenital ZIKV syndrome (1-3, 49), leaving the outcome of early postnatal infection on the developing infant brain uncertain. Reports of microcephaly developing after birth with congenital ZIKV infection (50, 51) suggest that the postnatal insult of ZIKV to the developing brain can be severe.…”

Section: Discussionmentioning

confidence: 99%

“…ZIKV has been linked with damage to the visual system, with ocular and brain visual system abnormalities seen in congenital ZIKV infection (50, 77, 78). Additionally, adults with Guillain-Barre Syndrome following ZIKV infection exhibit cytotoxic edema in the occipital lobe (79), the location of the visual cortex.…”

Section: Discussionmentioning

confidence: 99%

Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques

et al. 2018

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The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid- and neuro-tropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting state functional Magnetic Resonance Imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two out of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model impacts neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.

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“…(34) The CDC has defined a spectrum of birth defects thought to be potentially related to ZIKV infection for the purposes of birth defects surveillance (Box 1). (18) In many cases, the findings are similar to the CZS, but subtle and challenging to detect without access to prenatal or postnatal MRI imaging(34); the sensitivity of antenatal ultrasound may simply be insufficient to detect some fetal injuries. For example, sight-threatening ocular injuries have been described in infants without microcephaly (i.e.…”

Section: Broadening Spectrum Of Zikv-associated Fetal Injurymentioning

confidence: 99%

Zika virus and the nonmicrocephalic fetus: why we should still worry

Walker

Little²,

Roby

et al. 2019

American Journal of Obstetrics and Gynecology

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Zika virus (ZIKV) is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly due to a large outbreak in Northeastern Brazil. Although the ZIKV epidemic is now in decline, pregnancies in large parts of the Americas remain at risk due to ongoing transmission and the potential for new outbreaks. This review presents why Zika virus is still a complex and worrisome public health problem with an expanding spectrum of birth defects and why ZIKV and related viruses may evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with ZIKV exposure is broader and more complex than microcephaly alone and includes subtle fetal brain and ocular injuries; thus, the ability to prenatally diagnose fetal injury associated with ZIKV infection remains limited. New studies indicate that ZIKV imparts disproportionate effects on fetal growth with an unusual femur-sparing profile, potentially providing a new approach to identify viral injury to the fetus. Studies to determine the limitations of prenatal and postnatal testing for detection of ZIKV-associated birth defects and long-term neurocognitive deficits are needed to better guide counseling for women with a possible infectious exposure. It is also imperative that we investigate why ZIKV is so adept at infecting the placenta and the fetal brain to better predict other viruses with similar capabilities that may give rise to new epidemics. The efficiency with which ZIKV evades the early immune response to enable infection of the mother, placenta and fetus is likely critical for understanding why the infection may either be fulminant or limited. Furthermore, studies suggest that several emerging and related viruses may also cause birth defects, including West Nile virus, which is endemic in many parts of the United States. With mosquito-borne diseases increasing worldwide, there remains an urgent need to better understand the pathogenesis of ZIKV and related viruses to protect pregnancies and child health.

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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”?

Cited by 131 publications

References 25 publications

Congenital Zika Virus Infection in Immunocompetent Mice Causes Postnatal Growth Impediment and Neurobehavioral Deficits

Congenital Zika Virus Infection in Immunocompetent Mice Causes Postnatal Growth Impediment and Neurobehavioral Deficits

Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques

Zika virus and the nonmicrocephalic fetus: why we should still worry

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