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ABSTRACT This review aimed to provide an update on the morphological and/or functional abnormalities related to congenital Zika virus (ZIKV) infection, based on primary data from studies conducted in Brazil since 2015. During the epidemic years (2015-2016), case series and pediatric cohort studies described several birth defects, including severe and/or disproportionate microcephaly, cranial bone overlap, skull collapse, congenital contractures (arthrogryposis and/or clubfoot), and visual and hearing abnormalities, as part of the spectrum of Congenital Zika Syndrome (CZS). Brain imaging abnormalities, mainly cortical atrophy, ventriculomegaly, and calcifications, serve as structural markers of CZS severity. Most case series and cohorts of microcephaly have reported the co-occurrence of epilepsy, dysphagia, orthopedic deformities, motor function impairment, cerebral palsy, and urological impairment. A previous large meta-analysis conducted in Brazil revealed that a confirmed ZIKV infection during pregnancy was associated with a 4% risk of microcephaly. Additionally, one-third of children showed at least one abnormality, predominantly identified in isolation. Studies examining antenatally ZIKV-exposed children without detectable abnormalities at birth reported conflicting neurodevelopmental results. Therefore, long-term follow-up studies involving pediatric cohorts with appropriate control groups are needed to address this knowledge gap. We recognize the crucial role of a national network of scientists collaborating with international research institutions in understanding the lifelong consequences of congenital ZIKV infection. Additionally, we highlight the need to provide sustainable resources for research and development to reduce the risk of future Zika outbreaks.

We assessed the development, sensory status, and brain structure of children with congenital Zika virus (ZIKV) infection (CZI) at two years and preschool age. CZI was defined as either ZIKV RNA detection or positive ZIKV IgM and neutralization test in the cord or neonatal blood. Twelve children with CZI born in 2017–2018 in Vietnam, including one with Down syndrome, were assessed at 23–25.5 months of age, using Ages and Stages Questionnaire (ASQ-3), ASQ:Social-Emotional (ASQ:SE-2), Modified Checklist for Autism in Toddlers, automated auditory brainstem response (AABR), and Spot Vision Screener (SVS). They underwent brain CT and MRI. They had detailed ophthalmological examinations, ASQ-3, and ASQ:SE-2 at 51–62 months of age. None had birthweight or head circumference z-score < −3 except for the one with Down syndrome. All tests passed AABR (n = 10). No ophthalmological problems were detected by SVS (n = 10) and detailed examinations (n = 6), except for a girl's astigmatism. Communication and problem-solving domains in a boy at 24 months, gross-motor area in a boy, and gross-motor and fine-motor areas in another boy at 59–61 months were in the referral zone. Brain CT (n = 8) and MRI (n = 6) revealed no abnormalities in the cerebrum, cerebellum, or brainstem other than cerebellar hypoplasia with Down syndrome. The CZI children were almost age-appropriately developed with no brain or eye abnormalities. Careful and longer follow-up is necessary for children with CZI. [ABSTRACT FROM AUTHOR]

• Congenital Zika virus infection caused offspring's neurobehavioral development delay. • Gestational Zika virus damaged the offspring's blood–brain barrier. • Gestational Zika virus infection causes progeny's oxidative stress imbalance. Zika virus (ZIKV) is a mosquito-borne flavivirus associated with several neurodevelopmental outcomes after in utero infection. Here, we studied a congenital ZIKV infection model with immunocompetent Wistar rats, able to predict disabilities and that could pave the way for proposing new effective therapies. We identified neurodevelopmental milestones disabilities in congenital ZIKV animals. Also, on 22nd postnatal day (PND), blood–brain barrier (BBB) proteins disturbances were detected in the hippocampus with immunocontent reduction of β_Catenin, Occludin and Conexin-43. Besides, oxidative stress imbalance on hippocampus and cortex were identified, without neuronal reduction in these structures. In conclusion, even without pups' microcephaly-like phenotype, congenital ZIKV infection resulted in neurobehavioral dysfunction associated with BBB and oxidative stress disturbances in young rats. Therefore, our findings highlighted the multiple impact of the congenital ZIKV infection on the neurodevelopment, which reinforces the continuity of studies to understand the spectrum of this impairment and to provide support to future treatment development for patients affected by congenital ZIKV. [ABSTRACT FROM AUTHOR]

Brazil reported 18,282 suspected congenital Zika syndrome (CZS) cases up to 2018 and accounts for 61.4% of the total reported Zika cases in the Americas in the period. To detect high-risk areas for children with CZS in the city of Rio de Janeiro, we used cluster detection and thematic maps. We analyzed data using a Poisson model in Satscan 10.1.3 software. We also analyzed the records of children with CZS from 2015 to 2016 to describe the clinical and epidemiological maternal and child profile, as well as live births in 2016 and the social development index (SDI) by neighborhood. In 2015 and 2016, the incidence rates of CZS were 8.84 and 46.96 per 100,000 live births in the city, respectively. Severe congenital findings such as microcephaly and brain damage, osteoarticular impairment, ocular abnormalities, and hearing loss were observed in 47 children. The spatial distribution of CZS was concentrated in the north and west zones in heterogeneous neighborhoods. The neighborhoods with the highest occurrence of CZS cases were found to have the worst SDIs. Stascan detected three spatial clusters in the north zone, where the SDI is lower. The clusters presented high relative risks for CZS (7.86, 1.46, and 2.08), although they were not statistically significant. Our findings highlight a higher occurrence of CZS in areas with less favorable socioeconomic conditions.

To compare cell adhesion molecules levels in cerebrospinal fluid (CSF) between Zika virus (ZIKV)‐exposed neonates with/without microcephaly (cases) and controls, 16 neonates (cases), 8 (50%) with and 8 (50%) without microcephaly, who underwent lumbar puncture (LP) during the ZIKV epidemic (2015–2016) were included. All mothers reported ZIKV clinical symptoms during gestation, all neonates presented with congenital infection findings, and other congenital infections were ruled out. Fourteen control neonates underwent LP in the same laboratory (2017–2018). Five cell adhesion proteins were measured in the CSF using mass spectrometry. Neurexin‐1 (3.50 [2.00–4.00] vs. 7.5 [5.00–10.25], P = 0.001), neurexin‐3 (0.00 [0.00–0.00] vs. 3.00 [1.50–4.00], P = 0.001) and neural cell adhesion molecule 2 (NCAM2) (0.00 [0.00–0.75] vs. 1.00 [1.00–2.00], P = 0.001) were significantly lower in microcephalic and non‐microcephalic cases than in controls. When these two sub‐groups of prenatally ZIKA‐exposed children were compared to controls separately, the same results were found. When cases with and without microcephaly were compared, no difference was found. Neurexin‐3 (18.8% vs. 78.6%, P = 0.001) and NCAM2 (25.0% vs. 85.7%, P = 0.001) were less frequently found among the cases. A positive correlation was found between cephalic perimeter and levels of these two proteins. Neurexin‐2 and neurexin‐2b presented no significant differences. Levels of three cell adhesion proteins were significantly lower in CSF of neonates exposed to ZIKV before birth than in controls, irrespective of presence of congenital microcephaly. Moreover, the smaller the cephalic perimeter, the lower CSF cell adhesion protein levels. These findings suggest that low CSF levels of neurexin‐1, neurexin‐3 and NCAM2 may reflect the effects of ZIKV on foetal brain development. [ABSTRACT FROM AUTHOR]

Purpose: To describe epilepsy after congenital Zika virus infection (ZIKV) and its relationship with structural neuroimaging findings.Methods: This was a cross-sectional study in children (aged 13-42 months) who were born with microcephaly due to ZIKV infection between 2015-2017. Patients underwent a brain imaging scan (magnetic resonance) and a video-EEG study.Results: Among the patients (n = 43), 55.8 % were male, 88.4 % were born at term, mean head circumference at the birth was 29.7 ± 1.8 cm, and 44.8 % were infected in the first trimester of pregnancy. Neuroimaging was moderately abnormal in 30.2 % and severely abnormal in 46.5 % of patients. Early seizures (<6 months of age) were observed in 41.9 %. EEG background was abnormal when asleep or awake in 72.1 % and during sleep in 62.8 %. The interictal epileptogenic activity was recorded on 41/43 of the EEGs and was predominantly multifocal (62.8 %). An ictal EEG was obtained in 22 patients and 31.8 % had more than one seizure type. Sleep EEG (background) patterns, interictal epileptogenic activity (p = 0.046), interictal discharge localization (p = 0.015), type of ictal epileptogenic activity (p = 0.002), and localization of ictal discharge (p = 0.024) were significantly different between neuroimaging groups. The mild neuroimaging group had a higher chance of having more frequently normal sleep EEG patterns, no interictal epileptogenic activity and a further increase in the probability of walking without limitations, and less neurodevelopment delay.Conclusion: In patients with congenital Zika virus syndrome, epilepsy tended to be early and refractory. EEG features correlated with degree of neuroimaging abnormalities. [ABSTRACT FROM AUTHOR]

Congenital Zika virus (ZIKV) infection can cause lifelong medical and developmental conditions and management needs. There is limited information on the strengths and weaknesses of the systems of care for addressing ZIKV and other neurodevelopmental disabilities (NRD) in the United States (US) Affiliated Pacific Island Territories. Therefore, the purpose of the study was to assess the quality of the chronic illness systems of care for children with congenital ZIKV and other NRD in the US Pacific Island Territories. A cross-sectional study was conducted among health professionals from American Samoa, Guam, and Commonwealth of the Northern Mariana Islands. Participants completed an adapted version of the Assessment of Chronic Illness Care 3.5 (ACIC), which is based on the Chronic Care Model. The median Total Program Score was calculated, which ranged from limited support (0-2), basic support (3-5), reasonably good support (6-8), to fully developed support for care (9-11). Among the 17 health professionals who completed the survey, 47% were Guamanian/Chamorro, 24% were Samoan, 12% were Filipino, and 6% were Other Pacific Islanders. The median (25th percentile, 75th percentile [interquartile range]) Total Program Score was 5 (3, 6 [3]), indicating basic support for ZIKV and other NRD care for children. As more is learned about the full spectrum of clinical findings related to ZIKV, it is critical to continue to build an interdisciplinary maternal and child health workforce with the capacity and preparation to adequately address the special needs of children with ZIKV and other NRD. [ABSTRACT FROM AUTHOR]

Objective: To compare immunoglobulin levels in cerebrospinal fluid (CSF) of neonates exposed to Zika virus (ZIKV) during foetal life (cases) with levels in CSF of control neonates.Methods: We identified 16 neonates who underwent lumbar puncture (LP), during the ZIKV epidemic (December/2015 to March/2016) whose mothers reported ZIKV clinical symptoms during gestation (cases). Congenital microcephaly was defined as head circumference ≤31.9 cm (boys) and ≤31.5 cm (girls) for term neonates, or ≤2 standard deviations below the mean for premature (<37 weeks) neonates. Subsequently, we identified neonates who underwent LP in the same lab and fulfilled criteria to be controls: age ≤4 days, CSF white blood cell count ≤8/mm3, CSF protein ≤132 mg/dL, CSF red blood cell count ≤1,000/mm3, neither central nervous system illness, nor congenital infection, nor microcephaly. CSF immunoglobulin concentrations were measured by mass spectrometry.Results: 13 controls were included. IgM, IgA, IgG, IgK, and IgL were significantly higher among cases (p < 0.001). Eight (50%) ZIKV exposed infants had congenital microcephaly. These showed the strongest immunoglobulin elevation of the IgM and IgA classes.Conclusion: Neonates exposed to ZIKV infection during gestation present with elevated distinct immunoglobulins in CSF, both in cases that developed microcephaly and in cases that did not. [ABSTRACT FROM AUTHOR]

We report the results of pathologic examinations of 2 fetuses from women in Colombia with Zika virus infection during pregnancy that revealed severe central nervous system defects and potential associated abnormalities of the eye, spleen, and placenta. Amniotic fluid and tissues from multiple fetal organs tested positive for Zika virus.

Background: Identifying infants with congenital infection for early intervention will likely be challenging in future Zika virus outbreaks. We investigated indicators of risk for developmental delay among children born with and without obvious manifestations of congenital Zika virus infection. Methods: We evaluated 120 children conceived during the 2015−2016 Zika virus outbreak in Paraíba, Brazil. We analyzed data from children at birth; ages 1−7 months and approximately 24 months, using medical records (i.e., anthropometric measurements diagnoses), medical evaluation (i.e., Zika/other laboratory tests, dysmorphic features), and parent report (seizures, developmental delay). We used a Bayesian modeling approach to identify predictors of developmental delay. Results: Head circumference (HC) and length at birth and rates of growth for HC and length at follow-up were consistent across domains of developmental delay; (e.g., for every 1 cm per month decrease in HC growth rate; there was a corresponding decrease in the gross motor z-score). Modeling results indicated that HC and length at birth, and follow-up HC and length rates of growth, were predictive of developmental delay. Conclusion: These findings suggest that accurate measurement and frequent monitoring of HC and length, especially in the first few months of life, may be useful for identifying children possibly congenitally exposed to Zika virus who could benefit from early intervention services.

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. [ABSTRACT FROM AUTHOR]

The spread of Zika virus to the Americas was accompanied by surge in the number of infants with CNS abnormalities leading to a declaration of a health emergency by the WHO. This was accompanied by significant responses from governmental health agencies in the United States and Europe that resulted in significant new information described in the natural history of this perinatal infection in a very short period of time. Although much has been learned about Zika virus infection during pregnancy, limitations of current diagnostics and the challenges for accurate serologic diagnosis of acute Zika virus infection has restricted our understanding of the natural history of this perinatal infection to infants born to women with clinical disease during pregnancy and to Zika exposed infants with obvious clinical stigmata of disease. Thus, the spectrum of disease in infants exposed to Zika virus during pregnancy remains to be defined. In contrast, observations in informative animal models of Zika virus infections have provided rational pathways for vaccine development and existing antiviral drug development programs for other flaviviruses have resulted in accelerated development for potential antiviral therapies. This brief review will highlight some of the current concepts of the natural history of Zika virus during pregnancy. [ABSTRACT FROM AUTHOR]

Background: A relationship between Zika virus (ZikV) infection in pregnancy and the occurrence of microcephaly was established during the Zika outbreak in Brazil (2015-2016). Neuropathological findings in congenital Zika syndrome helped to understand its pathogenetic mechanisms. Results: The most relevant postmortem findings in the central nervous system (CNS) of fetuses and neonates infected with ZikV early in gestation are microcephaly with ex-vacuo ventriculomegaly and large head circumference associated with obstructive hydrocephalus due to severe midbrain and aqueduct distortion. Babies with severe brain lesions are born with arthrogryposis. Histologically, there is extensive destruction of the hemispheric parenchyma, calcifications, various disturbances of neuronal migration, reactive gliosis, microglial hyperplasia and occasional perivascular cuffs of lymphocytes, also in the meninges. Hypoplastic lesions secondary to the lack of descending nerve fibers include small basis pontis, pyramids and spinal corticospinal tracts. Cerebellar hypoplasia is also common. Severe nerve motor nerve cell loss is observed in the anterior horn of the spinal cord. Conclusion: A spectrum of neuropathological changes, from severe microcephaly to obstructive hydrocephalus was observed. The severity of the lesions is directly related to the gestational age, the most severe occurring when the mother is infected in the first trimester. Infection of progenitor cells at the germinal matrix was demonstrated. The lack of spinal motor neurons is responsible for fetal acynesia and consequent arthrogryposis. [ABSTRACT FROM AUTHOR]

We report the results of pathologic examinations of 2 fetuses from women in Colombia with Zika virus infection during pregnancy that revealed severe central nervous system defects and potential associated abnormalities of the eye, spleen, and placenta. Amniotic fluid and tissues from multiple fetal organs tested positive for Zika virus. [ABSTRACT FROM AUTHOR]

Background: As a new disease, some features of the congenital Zika virus infection are not yet fully understood. The current Brazilian outbreak brought up an unexpected increase in the number of microcephaly cases as this strain is essentially neurotropic and associated with devastating effects on the developing central nervous system. Object: This focus session aims to discuss the several issues related to the epidemiology, diagnosis, clinical features, and treatment of the congenital Zika virus infection. [ABSTRACT FROM AUTHOR]