Zika Fallout: More Than Just Microcephaly

Pauline Anderson

October 07, 2016

A new investigation of the Zika virus in Brazil has produced additional insights about the neurologic manifestations in babies exposed to this virus.

The analysis of 11 confirmed fetal cases of Zika determined that the babies had neurologic changes in addition to microcephaly.

The study, published October 3 in JAMA Neurology, highlights the importance of imaging at about 18 weeks of gestation in suspected cases of Zika infection, said study author Amilcar Tanuri, MD, PhD, professor, Universidade Federal do Rio de Janeiro, Brazil.

As with yellow fever, dengue, and West Nile viruses, the Zika virus is an arthropod-borne flavivirus transmitted mostly through the bite of an Aedes mosquito. The Zika virus, which can be found in body fluids, is spread through the placenta, during sexual intercourse, or via blood transfusions.

Patients with the infection can present with low-grade fever, arthralgia, rash, headache, and/or myalgia, but most infections are asymptomatic. In addition to congenital abnormalities, the virus infection has been associated with Guillain-Barré syndrome (GBS).

The current study included pregnant mothers referred to the fetal medicine service of the Instituto Paraibano de Pesquisa Professor Joaquim Amorim Neto in Brazil between October 2015 and February 2016.

The fetuses of these women had abnormalities in brain development, as shown by ultrasound imaging. Investigators performed amniocentesis in all women for laboratory confirmation of Zika infection by polymerase chain reaction.

Researchers observed the women until they gave birth. After birth, they did additional imaging and collected samples of amniotic fluid, cord blood, and placenta.

By these means, Zika diagnoses were confirmed in all but two patients. Both these patients were included in the study on the basis of a strong IgG anti-Zika immune profile.

"This means that we were sure that the 11 cases were infected by Zika, and we focused our attention on the kinds of lesions that showed up on images," said Dr Tanuri.

Three of the 11 babies died after birth. Two mothers consented to autopsies, which were performed less than 8 hours after death.

The surviving infants were followed from gestation to age 6 months.

The median cephalic perimeter at birth was 31 cm, which the authors said is lower than the limit for considering microcephaly. But they noted that some infants had a head circumference measure that was consistent with their gestational age.

Universal Neurologic Impairment

The researchers found neurologic impairments in all cases. There was a common pattern of brain atrophy and changes associated with disturbances in neuronal migration.

Dr Tanuri pointed out that Zika induced "very specific lesions," with the difference in severity being based on where the virus replicates in the brain.

"We saw two different patterns: one where the whole brain is smaller and the other pattern with ventriculomegaly and water inside the brain. Both patterns are induced by the same virus."

If the virus replicates in important structures, such as the brain stem or cerebellum, the outcome seems to be much worse than if it replicates in the cortex. In all babies who died, the virus had attacked the brain stem, said Dr Tanuri.

Evaluating the brainstem on fetal MRI may help predict the likelihood of survival of the newborn, he added.

It's unclear what factors determine where in the brain the virus will replicate, said Dr Tanuri.

Results of testing for other causes of microcephaly, such as drug use, alcohol consumption, smoking, and medications, were negative. Tests for other arboviruses, including the dengue virus, also had negative results.

New Nomenclature

Most of the women in the study demonstrated symptoms of Zika infection in the first trimester, which could be associated with the disturbance in neuronal migration processes and the formation of the neural tube, write the authors. All but one of the mothers had a skin rash at the beginning of the pregnancy.

Unlike authors of other reports, Dr Tanuri and his colleagues did not observe changes in umbilical and cerebral blood flow, even in the most serious cases.

The authors made several conclusions. One was that because microcephaly isn't the only Zika manifestation, the term "congenital Zika syndrome" should be used instead of "microcephaly associated with Zika virus infection."

"What seems to be universal is that microcephaly is not the sole finding but is a consequence of several brain injuries," write the authors. "Growth restriction and other damages, such as ophthalmologic alterations, were observed in neonates. Indeed, we observed a pronounced ventriculomegaly in most patients that could influence the observed microcephaly."

Dr Tanuri stressed the importance of ultrasound around the third semester "to report or to isolate or identify babies or fetuses" who are infected.

"If I am following up a pregnant woman, and I do ultrasound at 18 weeks and some lesions show up, this is a sign" that will identify babies already infected with Zika.

The problem in Brazil and other low-income countries is that routine ultrasound is not widely available, said Dr Tanuri.

Collecting amniotic fluid during gestation is another valuable tool for prenatal diagnosis, he said.

Another Surge on the Way?

As summer will soon arrive in Brazil, Dr Tanuri is concerned about a surge in Zika cases. From November to January, temperatures can get extremely high in the region and mosquitoes are much more prevalent.

"I hope that things are settled, but we have to be vigilant."

He said he's also worried about an epidemic in Puerto Rico. "I heard that nearly 2000 pregnant women there are infected with Zika."

Dr Tanuri is hopeful that an antiviral drug will soon be developed to block transmission of the virus through the placenta to the fetus.

"If an antivirus is effective and not toxic, you can give it to moms in endemic areas."

However, he said he has "some doubts" about the development of a Zika vaccine.

"You need to know much more about the virus before proposing a vaccine; we know nothing about the immune response" to this virus.

Vaccine on the Way?

In an accompanying editorial, Raymond P. Roos, MD, Department of Neurology, University of Chicago, Illinois, said that although it's "reassuring" that at least 18 manufacturers and institutions are pursuing a vaccine, "issues may complicate the development of a successful Zika virus vaccine."

One such issue, said Dr Roos, is that there may be difficulty in raising Zika virus–neutralizing antibodies in dengue virus–endemic areas because of the serologic cross-reactivity between these two viruses.

He noted that many questions related to the Zika virus infection remain unanswered. Among these, he said, are the following:

"How frequently does asymptomatic infection or second- and third-trimester infection lead to CNS [central nervous system] disease? Is Zika virus-induced GBS the typical immune-mediated disease or is there a direct virus invasion? What are the long-term sequelae of intrauterine Zika virus infection? What is the reason for the substantial size, severity, and unexpected complications of the recent Zika virus outbreak in the Americas compared with what has been seen with this virus in the past?"

Another important question is what neurologists can do regarding the Zika situation, said Dr Roos. It would be "valuable" to have adult and pediatric neurologists network with the Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus–induced GBS and CNS disease.

"This would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiological studies."

According to background in the editorial, the Zika virus was first isolated in the Zika forest of Uganda in 1947 from rhesus monkeys being investigated for the yellow fever virus. The first major outbreak was recognized in the Yap Islands in Micronesia in 2007, followed by an outbreak in French Polynesia.

(All Zika genomes sequenced from the 11 current cases belonged to the Zika Asian lineage. These were all related to the viruses identified in the French Polynesian outbreak.)

The recent outbreak in Brazil began in April 2015. Since then, thousands of cases of microcephaly and CNS developmental abnormalities associated with the Zika virus have been reported in the Americas. Cases have now been reported in 23 countries and territories in this region.

Earlier this year, the World Health Organization designated the Zika virus epidemic as a public health emergency of international concern.

Medscape Medical News approached Kate Russell, MD, MPH, epidemic intelligence service officer, Centers for Disease Control and Prevention, for her views of the new findings.

"This series adds to the growing literature that microcephaly is one of multiple neurologic consequences of congenital Zika virus infection," said Dr Russell.

"We know that Zika virus infection during pregnancy is a cause of microcephaly and other severe brain defects; however, more information is needed to understand the full clinical spectrum of the effects of Zika virus infection during pregnancy."

Because it's difficult to predict at birth what problems infants will have from exposure to Zika virus during gestation, "close follow-up of infants with and without microcephaly whose mothers have evidence of Zika infection are needed" to better understand the impact of the infection, added Dr Russell.

The authors and editorial writer have disclosed no relevant financial relationships.

JAMA Neurol. Published online October 3, 2016. Abstract, Editorial

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