Neurologic Complications of Zika Include More Than Microcephaly

The tragic hallmark of Zika virus infection during pregnancy is the occurrence of microcephaly in some newborns. However, as cases have mounted and analyses have been more finely tuned, other neurologic consequences are being recognized.

One of these, as discussed by James Sejvar, MD, a neuroepidemiologist at the Centers for Disease Control and Prevention, is Guillain-Barré Syndrome (GBS). GBS refers to a group of autoimmune polyneuropathies that can cause progressive weakness and respiratory difficulties that can progress and will require use of a mechanical ventilator. Globally, with some local variations, GBS is rare, with an annual diagnosis rate of 1 to 2 cases per 100,000 people.

“Epidemiologically, almost all estimates have been conducted in North America and Europe. We have less understanding of the epidemiology in Africa, South and Southwest Asia, and the Middle East. The other challenge is that there is no clear biological marker, so this can lead to misclassification and a lack of understanding or standardization of diagnosis,” said Dr. Sejvar in his session.

In the 2007 outbreak in Yap, there were no reports of neurologic events. In the 2013 outbreak in French Polynesia, an increase in the expected number of cases of GBS was noted. Tragically, as more data has become available with the large 2015 South American outbreak, Zika virus infection has been linked to GBS, meningoencephalitis, and myelitis, with a direct causal association concluded for microcephaly.

In the 2015 outbreak, the temporal pattern of a spike in cases of Zika infection followed several weeks later by a spike in GBS cases in Brazil and Columbia is compelling. In contrast to the expected worldwide GBS incidence of 1.1 to 1.8 cases per 100,000 people per year, during the outbreak, within 1 to 2 months, the number of cases in Brazil and Columbia translated to 5.8 and 7.2 cases per 100,000 per year, respectively. “In both of these instances, not only did GBS occur, but its occurrence was much higher in magnitude than we would expect,” Dr. Sejvar said.

The epidemiologic evidence indicates an association between Zika virus infection and the development of GBS. However, it is far too early to conclude that Zika is a neurotropic virus that is capable of causing GBS.

The sole causal association that has been demonstrated with the Zika virus is with microcephaly. This association was detailed by Sonja Rasmussen, MD, MS one of the authors on the publication that described the causal connection. Besides microcephaly and GBS, other possible adverse outcomes of pregnancy include fetal death early and late in pregnancy, brain anomalies that are less severe, developmental disabilities, and preterm birth. At the moment, all of these outcomes are more in the realm of speculation.

Microcephaly is a component of several events that include skull collapse and scalp rugae, due to the normal growth of the skull in anticipation of a normal-size brain, and neurologic impairment. All events have been observed in infants of Zika-infected mothers; they are collectively termed fetal brain disruption sequence.

“Prenatal Zika virus infection can result in congenital Zika syndrome, which involves destruction of existing central nervous system tissue with loss of brain volume and disruption of future developmental processes due to neurologic dysfunction,” explained Dr. Rasmussen in her talk.

Consequences of neurologic dysfunction in other diseases include problems in hearing, vision, and swallowing, as well as epilepsy. Only longer term follow-up in survivors will establish if this is also true in congenital Zika syndrome. Ocular abnormalities that have been observed in affected infants include anterior and posterior eye anomalies. Chorioretinitis has not been reported so far.

Surveillance programs in the continental US, Puerto Rico, and Columbia, will hopefully provide clarity concerning the longer-term consequences. As of October 20, 2016, 953 pregnant women in the continental US and 2,027 in US territories had been confirmed to be infected with Zika virus, the latter overwhelmingly in Puerto Rico.

Co-infections with Zika virus have been documented and their significance with respect to infection-related death was discussed by Alfonso Rodriguez-Morales, MD, MSc, DTM&H, FRSTM&H, FFTM RCPS, PhD, Universidad Tecnológica de Pereira, Pereira, Columbia.

A raft of case studies from Dr. Rodriguez-Morales and colleagues have reported co-infections (or co-detections) of Zika that involve dengue and chikungunya, just dengue, and just chikungunya. While it is possible that what are considered co-infections are really co-detection of coincidental, but pathologically separate, infections, next-generation sequencing data from one case favors co-infection.

The case studies have also described severe abdominal pain and fatal sickle cell disease in different patients.

DISCLOSURES

James Sejvar: None

Sonja Rasmussen: none

Alfonso Rodriguez-Morales: Member, Scientific Expert Panel: Sanofi Pastuer, Johnson & Johnson, Global Disease Research

SOURCES

• Photos and tape of IDSA presentations
• Laxminarayan R et al. Lancet 2015 387:168-175
• Fairall L et al. Lancet 2012 380:889-898
• Rasmussen SA et al. New Engl J Med 374:1981-1987
• Villamil-Gómez WE AJ et al. Inter J Infect Dis 2016 51:135-138

PRESENTATIONS

Zika Symposium II: Post-Infectious Sequelae and Clinical Guidance

• Neurologic manifestations of Zika virus: Clinical, epidemiologic, and outcomes of a new emerging infection; James Sejvar, MD, US Centers for Disease Control and Prevention
• Zika virus infection and microcephaly; perspective; Sonja Rasmussen, MD, MS, Centers for Disease Control and Prevention
• Zika: What about co-infections and deaths? Experience in Columbia; Alfonso Rodriguez-Morales, MD, MSC, Universidad Tecnológica de Pereira, Pereira, Columbia

​Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.