Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island

Abstract

Background: Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection.

Methods: The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ ≤ 85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms.

Results: The mean DQ score was 86.3 (95%CI: 81.0-91.5) in infected children compared to 100.2 (95%CI: 98.0-102.5) in uninfected peers (P<0.001). Fifty-one percent (n = 17) of infected children had a GND compared to 15% (n = 21) of uninfected children (P<0.001). Specific neurocognitive delays in p-CHIKV-infected children were as follows: coordination and language (57%), sociability (36%), movement/posture (27%). After adjustment for maternal social situation, small for gestational age, and head circumference, p-CHIKV infection was found associated with GND (incidence rate ratio: 2.79, 95%CI: 1.45-5.34). Further adjustments on gestational age or breastfeeding did not change the independent effect of CHIKV infection on neurocognitive outcome. The mean DQ of p-CHIKV-infected children was lower in severe encephalopathic children than in non-severe children (77.6 versus 91.2, P<0.001). Of the 12 cases of CHIKV neonatal encephalopathy, five developed a microcephaly (head circumference <-2 standard deviations) and four matched the definition of cerebral palsy. MRI scans showed severe restrictions of white matter areas, predominant in the frontal lobes in these children.

Conclusions: The neurocognitive outcome of children exposed to perinatal mother-to-child CHIKV infection is poor. Severe CHIKV neonatal encephalopathy is associated with an even poorer outcome.

Figure 1. Study population.

− : seronegative for CHIKV-specific IgM and IgG antibodies ; + : seropositive for CHIKV-specific IgG antibodies; M24: 24^th month, end of follow-up ; Unexposed - Uninfected and Exposed - Uninfected children were pooled as the Uninfected group (grey lozenge) and compared with Exposed - infected children as the Infected group (white lozenge) for RBL (Revised Brunet-Lézine) performance.

Figure 2. MRI scans of a four-month child with CHIKV neonatal encephalopathy.

- Child n°4 of Table 5. Full-term small for gestational age 38-week neonate. m5-Apgar score: 10/10. Encephalopathy with sepsis and DIC on day 4. Global developmental delay with DQ = 77 and microcephaly (head circumference 43 cm, −1.5 z-score SD) at 20 months. Axial sections via the interventricular foramen at day 15 on the left side: Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) map (Fig. 2a), and T2-weighted imaging (T2WI) (Fig. 2b). Axial sections via the body of third ventricular at month 4 on the right side: DWI with ADC map (Fig. 2c), and T2-weighted imaging (Fig. 2d). MRI scans show scattered areas of cytotoxic edema (violet circles) with decreased-diffusion signals on the ADC map or normal-appearing white matter (green circles) at 15-day scans, absence of persistent brain swelling (normal ADC) but scattered demyelination with scalloped-appearance of white matter atrophy (green triangles) including thinning of the corpus callosum (double red lines), passive dilatation of supratentorial interhemispheric subarachnoïd spaces (double yellow arrows). Anatomic abbreviations: WM: white matter; frontal lobes: superior frontal (F1), cingular (CingG), inferior frontal (F3), post-central (PoC), Th: thalamus, hCN: head of the caudate nucleus; parietal lobes: supra marginalis (SuMa), angular (Ang), superior parietal (P1) gyri; genu (gCC) and splenium (sCC) of the corpus callosum; occipital lobe (Cuneus); aLV: atrium of the lateral ventricule containing the choroid plexuses.