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ObjectiveZika virus (ZIKV) targets neural stem cells in the developing brain. However, the majority of ZIKV-exposed children are born without apparent neurological manifestations. It remains unclear if these children were protected from ZIKV neurotropism or if they harbour subtle pathology that is disruptive to brain development. We assess this by comparing neurodevelopmental outcomes in normocephalic ZIKV-exposed children relative to a parallel control group of unexposed controls.DesignCohort study.SettingPublic health centres in Grenada, West Indies.Patients384 mother–child pairs were enrolled during a period of active ZIKV transmission (April 2016–March 2017) and prospectively followed up to 30 months. Child exposure status was based on laboratory assessment of prenatal and postnatal maternal serum.Main outcome measuresThe INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) package and Cardiff Vision Tests, administered and scored by research staff masked to child’s exposure status.ResultsA total of 131 normocephalic ZIKV exposed (n=68) and unexposed (n=63) children were assessed between 22 and 30 months of age. Approximately half of these children completed vision testing. There were no group differences in sociodemographics. Deficits in visual acuity (31%) and contrast sensitivity (23%) were apparent in the ZIKV-exposed infants in the absence of cognitive, motor, language or behavioural delays.ConclusionsOverall neurodevelopment is likely to be unaffected in ZIKV-exposed children with normal head circumference at birth and normal head growth in the first 2 years of life. However, the visual system may be selectively vulnerable, which indicates the need for vision testing by 3 years of age.

Background Adaptation of standardized early child development (ECD) assessments to low- and middle-income countries can be challenging because of culture-specific factors relating to language, content, context, and tool administration, and because the reliance of these tests on specialist healthcare professionals limits their scalability in low resource settings. Methods We report the cross-cultural adaptation of an international, standardized ECD instrument, the INTERGROWTH-21st Project Neurodevelopment Assessment (INTER-NDA), measuring cognitive, language, motor and behavioural outcomes in 2-year-olds, from a UK-based English-speaking population to the English-speaking Caribbean. Children aged 22-30 months were recruited from a pre-existing randomized controlled neurodevelopment intervention study in Grenada, West Indies. Results Eight of 37 INTER-NDA items (22%) were culturally and linguistically adapted for implementation in the Caribbean context. Protocol adherence across seven newly-trained non-specialist child development assessors was 89.9%; six of the seven assessors scored ≥80%. Agreement between the expert assessor and the non-specialist child development assessors was substantial (κ = 0.89 to 1.00 (95% CI [0.58, 1.00]). The inter-rater and test-retest reliability for non-specialist child development assessors was between κ = 0.99 -1.00 (95% CI [0.98, 0.99]) and κ = 0.76 - 1.00 (95% CI [0.33, 1.00]) across all INTER-NDA domains. Conclusions The current study provides evidence to support the use of the adapted INTER-NDA by trained, non-specialist assessors to measure ECD prevalence in the English-speaking Caribbean. It also provides a methodological template for the adaptation of child developmental measures to cultural and linguistic contexts that conform to the cultural standards of the countries in which they are utilized to aid in the measurement of neurodevelopmental impairments (NDIs) in a variety of global clinical settings.

Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003–0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings., Author summary Epilepsy is a clinical concern in children with Congenital Zika Syndrome and microcephaly; however, it is unknown whether epilepsy rates are elevated in normocephalic children with prenatal Zika virus exposure. We found a modest elevation of epilepsy rates in the first year of life of exposed, relative to unexposed, children, despite no other neurological manifestations. Seizures in exposed children had features of focal, rather than generalized, epilepsy and were well controlled with carbamazepine. Our findings suggest that epilepsy surveillance should be included in the neurodevelopmental assessment of children with prenatal Zika virus exposure, even in the absence of neurologic manifestations at birth.

Highlights • Congenital Zika Syndrome with microcephaly can present with focal seizures. • TeleEEG can augment epilepsy care in Zika-endemic resource limited settings. • A seizure questionnaire can prompt caregiver report of relevant seizure features., Zika virus (ZIKV) is a mosquito-borne, single-stranded DNA flavivirus that is teratogenic and neurotropic. Similar to the teratogenic effects of other TORCH infections, ZIKV infection during pregnancy can have an adverse impact on fetal and neonatal development. Epilepsy is detected in 48–96% of children with Congenital Zika Syndrome (CZS) and microcephaly. Early epilepsy surveillance is needed in children with prenatal ZIKV exposure; yet, most ZIKV-endemic regions do not have specialist epilepsy care. Here, we describe the demographic, clinical, imaging, and EEG characteristics of a 2-year-old child with CZS and microcephaly who presented with focal epileptiform activity, suboptimal growth, and severe neurodevelopmental delays. Administration of a brief seizure questionnaire by allied health professionals to the patient’s caregiver helped to characterize the child’s seizure semiology and differentiate focal from generalized seizure features. A telemedicine EEG interpretation platform provided valuable diagnostic information for the patient’s local pediatrician to integrate into her treatment plan. This case illustrates that CZS can present with focal epilepsy features and that a telemedicine approach can be used to bridge the gap between epilepsy specialists and local care providers in resource limited ZIKV-endemic regions to achieve better seizure control in children with CZS.

Background: The Zika virus (ZIKV) targets neural stem cells in the developing brain. It remains unclear whether ZIKV-Exposed Children (ZEC) with no apparent neurological manifestations at birth were protected from ZIKV neurotropism during gestation or harbor subtle pathology that might disrupt neurodevelopment. In this prospective study, we tracked a cohort of normocephalic ZIKV-exposed children (NZEC) in parallel with normocephalic unexposed controls (UC) from birth to 30 months of age to determine whether NZEC show higher rates of neurodevelopmental delays relative to UC. Methods: A total of 384 pregnant women were recruited from public health centers in Grenada, West Indies and enrolled between April 2016 and March 2017, which was a period of active ZIKV transmission. Serum samples were collected from mothers during the prenatal and postnatal period and assessed for ZIKV antibodies using a plasmonic-gold platform. Infants were classified as NZEC if their mothers tested positive for ZIKV infection during pregnancy and they were normocephalic, as defined by World Health Organization Child Growth Standards. Children were classified as UC if their mothers tested negative for ZIKV infection during and following pregnancy. Outcome measures included the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) package and Cardiff Vision Tests, which were administered and scored by research staff blinded to participants’ exposure status. Findings: A total of 68 NZEC and 63 UC completed outcome measures between 22 to 30 months of age. There were no group differences in socio-demographics. Visual acuity deficits were apparent in NZEC in the absence of any other cognitive, motor, language, or behavioral delays. Interpretation: The presence of visual acuity deficits in NZEC suggests that the visual system may be selectively vulnerable in otherwise normally developing children. Continued neurocognitive surveillance of this cohort will address whether early vision problems place NZEC at risk for future deficits in visuo-spatial functions and learning disorders. Funding Statement: TWINDREF GSP-SRGI-18009 (KB); USAID AID-OAA-A-14-00028 (ADL), NIH R21HD093551-01 (RW, BL, MF), Stanford Maternal Child Health Research Institute (ADL). MF is supported by an Academic Clinical Fellowship in Paediatrics from the National Institute for Health Research, UK, to the University of Southampton. Declaration of Interests: None of the authors have any conflicts of interest to disclose. Ethics Approval Statement: Institutional Review Board approval was obtained at St George’s University (IRB#16061) and Stanford University (IRB#45242). Informed consent was obtained from all mothers who participated in this study. There was no financial compensation.

Background The 2005–06 chikungunya virus (CHIKV) outbreak in La Réunion suggested that mothers could transmit CHIKV to their neonates while viremic during the intrapartum period, and more than half of the infected neonates showed impaired neurodevelopment at two years of age. However, data sparsity precluded an overview of the developmental impact of vertical infection within the whole prenatal period. Objective & methods The current study assessed two-year old children born to mothers who were infected during the 2014 CHIKV outbreak in Grenada to determine the neurodevelopmental impact of perinatal CHIKV infection throughout gestation. Mother and child infection status were confirmed by serologic testing (IgG and IgM) for CHIKV. Cognitive, fine motor, gross motor, language and behavioral outcomes were assessed at two years of age on the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA). Results No differences in neurodevelopmental outcomes were observed between two-year-old children born to mothers infected with CHIKV during gestation (n = 149) and those born to mothers not infected with CHIKV (n = 161). No differences were found in INTER-NDA scores between children infected with CHIKV (n = 47) and children not infected with CHIKV (n = 592). Likewise, there were no differences between children infected with CHIKV post-partum (n = 19) versus children not infected with CHIKV (n = 592). Conclusion Our findings suggest that children exposed and/or infected with CHIKV outside of the intrapartum period experience no significant neurodevelopmental delay at two years of age, as measured by the INTER-NDA, compared to their unexposed and/or uninfected peers. These results complement those of previous studies which showed a neurodevelopmental risk only for children infected during the intrapartum period, while the mother was highly viremic. These results might be reassuring for women of childbearing age and public health officials in CHIKV-endemic regions., Author summary The Chikungunya virus (CHIKV) can negatively impact fetal neurodevelopment and consequent neurocognitive functioning in young children. Studies from La Réunion island demonstrated that, compared to their uninfected counterparts, children infected by CHIKV during the intrapartum period were at increased risk for deficiencies in the frontal lobes where the language and coordination centers are located, as well as slight deficits in other neurocognitive skills like sociability, movement and posture. The current study assessed two-year old children born to mothers infected during the 2014 CHIKV outbreak in Grenada to determine the neurodevelopmental impact of perinatal infection throughout gestation. No differences in neurodevelopmental outcomes were observed between two-year-old children born to mothers infected with CHIKV during gestation and those born to mothers not infected with CHIKV, nor between children infected with CHIKV and children not infected with CHIKV. Our results support previous findings that a small proportion of children born in CHIKV-endemic regions are at risk as only mothers viremic during the intrapartum period are at risk of infecting their neonates. Healthcare providers in CHIKV-endemic regions may wish to monitor for CHIKV symptoms when pregnant women are near term. The relatively high symptomatic rate seen with CHIKV infection (75%) makes such monitoring feasible.