Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

Abstract

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

Keywords: cerebral palsy; epilepsy; eye; microcephaly; neurodevelopement; zika (ZIKV).

FIGURE 1

Dysmorphic features in the CZS. Dysmorphic physical features characteristic of the CZS. One year old boy with craniofacial disproportion, and marked reduction of the volume of the cranial vault, including lateral depressions of the frontal bone (A) and an occipital prominence (B). These severe features have remained visible since birth. Skin redundance in frontal and glabellar area with vertical folds in a 3 month old (C) and multiple folds across the scalp, called cutis rugata in a 1 month old (D). Generalized contractures of large and small joints (E). Contractures of all fingers (F). Abnormal single transverse palmar crease (G). Club foot (H). Deep dimple at the knee (I).

FIGURE 2

Neurological examination findings in the CZS. Common findings in the neurological examination of infants with CZS. (A) Irritability with constant inconsolable cry. (B) Swan neck position of the second finger caused by dystonic hyperextension. (C) Marked hypertonia leading to an almost stable sitting position right after birth. (D) Dystonic position of the fingers, with flexion of 2–3 and extension of 3–4.

FIGURE 3

Brain neuroimaging studies in an infant with microcephaly and prenatal Zika infection. Head ultrasound image of a prefrontal coronal plane showing dilated frontal horns and cerebral calcifications below the subcortical border (A). CT axial image showing ventriculomegaly, calcifications predominantly located in the cortical-subcortical border and simplified gyral pattern (B). MRI- T2-weigthed axial image showing a very simplified frontal gyral pattern, ventriculomegaly, germinolytic pseudocysts in the caudothalamic groove, an open operculum, reduced white matter volume and absence of myelin in the posterior limb of the internal capsule (C). Gradient Echo T2* axial MRI image showing cerebral calcifications seeb as small, rounded, homogeneous, dark dot-like lesions (D).

FIGURE 4

Changes in brain imaging observed during the first year of life. CT of the brain of the same patient in the first month of life in the upper row in (A,C,E), at 6 months of age in lower rows (B,D), and at 13 months of age in (F). Calcifications are more difficult to visualize at 6 months of age (B,D) than at birth (A,B). We observed increases in volume of intraventricular and extra-axial fluids (bottom pictures) in comparison to the initial exam (top pictures). The increasing ventricular dilatation did not show clinical or imaging signs of increased intracranial pressure at 6 months (B,D), but a high tentorium confirmed progressive hydrocephalus requiring surgical shunting at 13 months (F).

FIGURE 5

Eye findings in children with prenatal Zika infection. (A) Exotropia. (B) Esotropia. (C) Microphthalmia. (D) Optic nerve hypoplasia. (E) Chorio-retinal scarring. (F) Pigmentary macular mottling.

FIGURE 6

Correlation of differentially expressed genes (DEGs) in ZIKV infection and molecular markers of neurological conditions and brain diseases found in the human disease database MalaCards (https://www.malacards.org). (A) Clinical outcomes associated with ZIKV infection. (B) Most frequent neurodegenerative and neuropsychiatric diseases in global population. The ZIKV infection DEGs were found in ZIKAVID database (https://zikavid.org). Elite genes are those likely to be associated with causing the disease, according to MalaCards database.