The spectrum of neuropathological changes associated with congenital Zika virus infection

Abstract

A major concern associated with ZIKV infection is the increased incidence of microcephaly with frequent calcifications in infants born from infected mothers. To date, postmortem analysis of the central nervous system (CNS) in congenital infection is limited to individual reports or small series. We report a comprehensive neuropathological study in ten newborn babies infected with ZIKV during pregnancy, including the spinal cords and dorsal root ganglia (DRG), and also muscle, pituitaries, eye, systemic organs, and placentas. Using in situ hybridization (ISH) and electron microscopy, we investigated the role of direct viral infection in the pathogenesis of the lesions. Nine women had Zika symptoms between the 4th and 18th and one in the 28th gestational week. Two babies were born at 32, one at 34 and 36 weeks each and six at term. The cephalic perimeter was reduced in four, and normal or enlarged in six patients, although the brain weights were lower than expected. All had arthrogryposis, except the patient infected at 28 weeks gestation. We defined three patterns of CNS lesions, with different patterns of destructive, calcification, hypoplasia, and migration disturbances. Ventriculomegaly was severe in the first pattern due to midbrain damage with aqueduct stenosis/distortion. The second pattern had small brains and mild/moderate (ex-vacuo) ventriculomegaly. The third pattern, a well-formed brain with mild calcification, coincided with late infection. The absence of descending fibres resulted in hypoplastic basis pontis, pyramids, and cortico-spinal tracts. Spinal motor cell loss explained the intrauterine akinesia, arthrogryposis, and neurogenic muscle atrophy. DRG, dorsal nerve roots, and columns were normal. Lympho-histiocytic inflammation was mild. ISH showed meningeal, germinal matrix, and neocortical infection, consistent with neural progenitors death leading to proliferation and migration disorders. A secondary ischemic process may explain the destructive lesions. In conclusion, we characterized the destructive and malformative consequences of ZIKV in the nervous system, as reflected in the topography and severity of lesions, anatomic localization of the virus, and timing of infection during gestation. Our findings indicate a developmental vulnerability of the immature CNS, and shed light on possible mechanisms of brain injury of this newly recognized public health threat.

Human Zika and West Nile virus neurological infections: What is the difference?

“…Infection later in pregnancy can still cross the placenta but fetal infection appears limited to systemic organs and meninges. The meningitis is clearly not benign and instead associated with severe destructive ischemic lesions as has been seen with other viruses in newborns …”

“…We have recently had the opportunity to investigate the autopsies of 10 pregnancies in Zika infected mothers . There was a broad spectrum of neuropathological findings encompassing both developmental and destructive lesions.…”

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

“…Placentas from infants carried to term were small and showed chronic villitis, chorionitis, deciduitis and stromal fibrosis (Chimelli et al, 2017). In monkeys, ZIKV was most abundant in the chorionic villous tissue (Adams Waldorf et al, 2016).…”

“…Histopathology of these cases showed abnormal neuronal migration with polymicrogyria, meningeal glioneuronal heterotopia, and motor neuron loss and cerebellar cortical dysplasia. Viral antigen was most often detected in the meninges and inflammation was not prominent (Chimelli et al, 2017). Pups born to Swiss Jim Lambert (SJL), but not C57BL/6, mice intravenously infected with large amounts [4 × 10 10 –10 12 plaque-forming units (pfu)] of ZIKV at 10–13 days gestation displayed intrauterine growth restriction and abnormal brains with cortical thinning and evidence of neuronal cell death (Cugola et al, 2016).…”

Descripción de la experiencia en RM cerebral fetal en Cali - Colombia

“…Los hallazgos por imágenes pueden ser: microcefalia, calcificaciones cerebrales subcorticorticales, alteraciones en el patrón de los giros, ventriculomegalia, anormalidades del cuerpo calloso, disminución de los volúmenes cerebrales y agrandamiento de la cisterna magna y espacio subaracnoideo extraaxial 13,14 . En este estudio se encontraron tres casos con sospecha de infección por Zika, dos se confirmaron por reacción en cadena de la polimerasa (PCR) para Zika en cordón umbilical y líquido amniótico.…”