Zika: The Expanding and Deepening Threat

Marc Gozlan, MD

Disclosures

November 14, 2016

March 2016

March 10, 2016. An article[25] from Slovenian researchers using molecular genetic and electron-microscopic data reinforced the biological association between Zika virus and microcephaly. They presented a case of vertical transmission of Zika virus in a 25-year-old European woman who had a febrile illness with rash at the end of the first trimester of pregnancy while she was working in northeastern Brazil. She chose a late-pregnancy termination after ultrasound performed at 29 weeks of gestation showed microcephaly with calcifications in the brain and the placenta.

At fetal autopsy, the brain was very small, with complete absence of cerebral gyri, severe dilatation of both lateral ventricles, and diffuse calcifications in the brain and the spinal cord. Zika virus particles were visualized. The presence of Zika virus was also found by reverse-transcriptase (RT) PCR in fetal brain tissue, showing a strong neurotropism of the virus, but no virus and no pathologic changes were detected in any other fetal organs. The complete genome of the Zika virus, similar to that of other recent Zika viral isolates, was recovered from the fetal brain.

Published in the New England Journal of Medicine,[25] this Slovenian article, together with previous documented cases in Brazil[13] and one in Hawaii[26] (the first congenital Zika virus infection in the United States, confirmed by high Zika virus immunoglobulin [Ig] M antibody titers in serum and cerebrospinal fluid), made the link between Zika and microcephaly even stronger. It added more evidence that transplacental infections with Zika virus could cause severe CNS damage and microcephaly.

In other developments, it appeared that many fetuses and infants with presumed congenital Zika virus infection who presented with severe microcephaly, intracranial calcifications, and other brain anomalies also had ocular findings, redundant scalp skin (a finding not typically observed in other forms of microcephaly), arthrogryposis (multiple congenital joint contractures), and clubfoot. In articles published online in mid-February and early March 2016, a new term appeared to describe these clinical abnormalities: "congenital Zika syndrome."[27,28,29]

At the same time, another term emerged in the medical literature on Zika virus disease: "fetal brain disruption sequence" (FBDS). It described infants with congenital Zika virus infection who had a particular phenotype involving a microcephaly, overlapping of cranial sutures, a prominent occipital bone, redundant and wrinkled skin over the scalp (cutis gyrata), and deep neurologic impairment.[21,22,23,24,25,26,27,28,29,30] (Figure 2)

Figure 2. Characteristic phenotype of fetal brain disruption sequence in infant with congenital Zika virus syndrome. (A) Craniofacial disproportion and biparietal depression. (B) Prominent occiput. Courtesy of the Centers for Disease Control and Prevention.

In addition to congenital microcephaly and ocular disease in fetuses and infants, another neurologic illness was associated with Zika virus in adults: GBS, an acute immune-mediated muscle weakness damaging the peripheral nervous system. Before the current epidemic, this acute motor axonal neuropathy had been reported during a Zika outbreak in French Polynesia in 2014.[31]

During the outbreak in this French Pacific territory (when more than 32,000 suspected cases of Zika virus infection were reported), a Polynesian woman developed GBS (bilateral paresthesias and ascending muscle weakness, followed by tetraparesis, diffuse myalgia, and peripheral facial palsy) 7 days after an acute febrile illness attributed to Zika virus.[31] This was the first published report of a GBS case, based on serology, occurring during an ongoing Zika outbreak.

At the same time that evidence grew to incriminate Zika virus in congenital neurologic malformations, an increase was observed in the number of reported cases of GBS in adults with previous clinical Zika infection. During the Zika epidemics in French Polynesia, an increase in GBS cases had been noticed, but a case/control study, published online in the Lancet[32] on February 29, 2016, unequivocally implicated Zika virus infection in triggering GBS.

GBS is the most common peripheral nervous system disease associated with Zika virus infection. However, all cases of GBS occurred during the postinfectious period, the onset being delayed by days or weeks. During the outbreak in French Polynesia, in the 4 months between November 2013 and April 2014, 42 patients were diagnosed with GBS among 28,000 people seeking medical care. This represented a marked increase from the three to 10 cases detected annually in the previous 4 years.[33]

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