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Second-trimester Ultrasound and Neuropathologic Findings in Congenital Zika Virus Infection

Ho, Cheng-Ying, MD*; Castillo, Nicolas, MD; Encinales, Liliana, MD; Porras, Alexandra, PhD§; Mendoza, Alejandro Rico, PhD§; Lynch, Rebecca, PhD; Nemirovsky, Amy, BA*; Mantus, Grace, BS; DeBiasi, Roberta L., MD‖,**,††; Bethony, Jeffrey M., PhD; Simon, Gary L., MD††; Chang, Aileen Y., MD††

The Pediatric Infectious Disease Journal: December 2018 - Volume 37 - Issue 12 - p 1290–1293
doi: 10.1097/INF.0000000000002080
Maternal-Neonatal Reports

Zika virus is a mosquito-borne virus that causes congenital Zika syndrome, characterized by microcephaly and other fetal brain anomalies. This case report presents a case of Zika virus–related fetal brain anomalies including pathologic evidence of cerebral neuronal apoptosis and macrophage infiltrates and intracerebral calcification, ventriculomegaly and corpus callosum dysgenesis detected by ultrasound at 18 weeks of pregnancy.

From the *Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland

Department of Maternal Fetal Health

Department of Medicine, Allied Research Society LLC, Baranquilla, Atlántico, Colombia

§Grupo de Medicina Comunitaria, Universidad El Bosque, Bogotá, Colombia

Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, District of Columbia

Division of Pediatric Infectious Diseases, Children’s National Health System, Washington District of Columbia

**Department of Pediatrics

††Department of Medicine, The George Washington University, Washington, District of Columbia.

Accepted for publication January 8, 2018.

Supported by the National Institutes of Health U19 AI131130 (awarded to C.-Y.H.) and UL1TR001876 and KL2TR001877 from the NIH National Center for Advancing Translational Sciences (awarded to A.Y.C.). Its contents are solely the responsibility of the authors and do not necessary represent the official views of the National Center for Advancing Translational Science or the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have no conflicts of interest to disclose.

C.-Y.H. and N.C. contributed equally to this work.

Address for correspondence: Aileen Y. Chang, MD, MSPH, George Washington University, 2150 Pennsylvania Ave 5–416, Washington, DC 20037. E-mail:

Zika virus (ZIKV) is a single-stranded RNA virus of the family Flaviviridae.1 The virus is transmitted to humans primarily by the Aedes mosquito.2 Although the majority of the individuals infected with ZIKV are asymptomatic, some individuals may experience fever, rash and myalgias. Conjunctival injection may also be present in ZIKV, as well as dengue infection. Guillian–Barré syndrome may follow ZIKV infection in a small number of patients.3 The most concerning complication of ZIKV infection is the congenital Zika syndrome characterized by microcephaly and/or an expanding list of fetal brain defects including intracranial calcifications, ventriculomegaly, corpus callosum abnormalities and cerebellar hypoplasia.4 , 5 This is the earliest ultrasound-diagnosed case of Zika-associated microcephaly, which is also the first ZIKV-associated neuropathology report from Colombia. The mother gave consent for her case details to be published.

A 23-year-old woman from Barranquilla, Colombia, with no significant medical history or prior pregnancy complications presented to clinic in her second trimester of pregnancy for routine prenatal ultrasound. She did not report a history of dengue or chikungunya virus infection. During her 8th week of pregnancy, she developed fever, bilateral conjunctivitis, peripheral edema and arthralgia.

Prenatal ultrasound performed at 18-weeks-and-2-days gestation revealed abnormal findings in the central nervous system, including microcephaly, ventriculomegaly with asymmetric anterior horns of lateral ventricles (Fig. 1A and B), dysgenesis of corpus callosum (Fig. 1C), multiple cerebellar (Fig. 1D) and periventricular calcifications (Fig. 1E) and hypoplasia of cerebellar vermis. Limb abnormalities, including claw-like appearances of the hands and hyperextension of the lower extremities (Fig. 1F), were also detected. The placenta, amniotic fluid, umbilical artery Doppler and uterine artery Doppler were normal.



Given these abnormal ultrasound findings, the patient elected to terminate her pregnancy at 19 weeks. A brief gross examination was performed on the fetus. The gender of the fetus was undetermined. The crown-heel length was normal (22 cm; reference range, 18.8–21.4 cm). The head was disproportionally small compared with the trunk and extremities. There were no abnormal facies or other gross abnormalities. Other organ systems including the placenta were grossly unremarkable. The brain weight was not available, but the hemispheres appeared appropriately formed. Assessment of the gross brain anatomy was difficult because of extreme softening of the structures. Further laboratory testing confirmed that the amniotic fluid was positive for anti-ZIKV IgM and IgG antibodies, and ZIKV RNA by real-time polymerase chain reaction. The mother’s plasma was positive for anti-ZIKV IgM and IgG antibody binding to the ZIKV envelope protein and indicated high IgG titers with a reciprocal EC50 titer of 5697.

Histologic sections of the cerebral cortical plate showed abundant cellular apoptosis and macrophage infiltrates (Figs. 2A and 1C), whereas the ventricular and subventricular zone germinal matrix appeared morphologically intact (Fig. 2B and D). ZIKV infection was confirmed in both cortical plate and germinal matrix by immunofluorescent staining for flavivirus envelope protein (Fig. 2C and F).



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Since the outbreak in 2015 and 2016, there have been >8000 reported cases of microcephaly from Brazil,6 >500 cases from Colombia,7 and a variable numbers of cases from other countries in the Americas. The rapid spread of the virus and its complications prompted the World Health Organization to declare a global public health emergency between February and November 2016.8

According to recent studies, symptomatic maternal ZIKV infection during all trimesters can be associated with adverse pregnancy outcomes.9 , 10 The incidence of fetal brain abnormalities is highest when infection occurs in the first trimester.10–13 However, the period between the end of the first trimester and the beginning of the second trimester is when neuronal proliferation and migration peak. This may be a period of unique vulnerability, because mild perturbations in the maternal–fetal environment can be amplified during this period and significantly alter the structure and function of the brain.14 Given the critical nature of this time window, studies of infected fetuses at this gestational age may provide insight into the pathogenesis of ZIKV-associated microcephaly.

Although a number of congenital Zika syndrome cases have been reported, most are neuroimaging studies.4 , 15 , 16 To date, there have been only a handful of neuropathologic studies.5 , 17–19 , 20 In addition, all but one neuropathologic report described findings in the third trimester, when neuronal proliferation and migration has slowed or ceased.17 , 20 The overall pathologic findings identified in the third trimester, for example, intraparenchymal calcifications, cortical thinning and migrational disturbances, are likely a manifestation of the neural injuries that may have occurred earlier in gestation.

We present the earliest ultrasound-diagnosed case of Zika-associated microcephaly, which is also the first ZIKV-associated neuropathology report from Colombia. Microcephaly is usually diagnosed at a mean gestational age of 28 weeks18 and often is not clinically evident at the early stage that was seen in this patient. Notably, the neuropathology of the current case shares many similarities to another fetus who was infected by the Guatemalan variant of virus.17 , 20 The most important finding of these 2 cases is the presence of cellular apoptosis and macrophage infiltrates in the cerebral cortex but not in the germinal matrix, despite the detection of ZIKV in both brain regions. These findings suggest that ZIKV-associated injuries may preferentially affect postmigratory immature neurons, which are most abundant in the second trimester. Furthermore, similarities in the second-trimester pathology of cases from Guatemala and Colombia suggests that a common pathogenic mechanism of microcephaly exists among Asian-lineage strains.21

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This study was made possible by Allied Research Society, the Universidad El Bosque, and La Fundación Santa Fe. We would also like to thank Dr Raul Garcia Tolosa for his role preparation of the specimen.

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Zika; microcephaly; fetal brain anomalies; congenital infection; neuronal apoptosis

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