Nearly all patients in a small, case-control study who developed Guillain-Barré syndrome also tested positive for Zika virus, according to data from a Zika outbreak in French Polynesia.
Described as the first study to assess the role of Zika virus in patients with Guillain-Barré syndrome during a Zika virus outbreak, Van-Mai Cao-Lormeau, MD, of the Institut Louis Malardé in Papeete, Tahiti, and colleagues, reported a statistically significant difference in the incidence of Zika virus antibodies between a small group of patients diagnosed with Guillain-Barré syndrome and a control group with a nonfebrile illness (P<0.0001).

Of the 42 patients diagnosed with Guillain-Barré syndrome during the Zika virus outbreak, 41 of them had anti-Zika virus IgM or IgG compared with about a third (36%) of 98 age-matched, sex-matched and residence-matched controls, they wrote in the Lancet.

In addition, all 42 patients (100%) had evidence of any antibodies ("a neutralizing response") against the Zika virus compared with a little over half (56%) of the control group (P<0.0001).

"Although it is unknown whether attack rates of Zika virus epidemics will be as high in affected regions in Latin America than in the Pacific Islands, high numbers of cases of Guillain-Barré syndrome might be expected in the coming months as the result of this association," said co-author Arnaud Fontanet, MD, of the Institut Pasteur in Paris in a statement. "The results of our study support that Zika virus should be added to the list of infectious pathogens susceptible to cause Guillain-Barré syndrome."



The incidence of Guillain-Barré syndrome during this outbreak (October 2013 to August 2014) was estimated to be 0.24 per 1,000 Zika virus infections. By comparison, the rate of Guillain-Barré syndrome following C jejuni infections -- a form of bacteria associated with food poisoning -- ranges from 0.25 to 0.65 per 1,000 cases.
The potential link between Guillain-Barré syndrome and Zika virus was also addressed by Thomas Frieden, MD, director, CDC in a media conference call recently.

"We would not be the least bit surprised if Guillain-Barré is definitely associated with Zika, and given the time course of clusters of Guillain-Barre' after peak Zika virus infection, I think most epidemiologists would say it's certainly related," he said.

But in an accompanying editorial by David W. Smith, MD, of the University of Western Australia in Nedlands and John Mackenzie, MD of Curtin University in Bentley, Australia, pointed out that the authors faced "major challenges" in proving this association.

"Unfortunately the patients were no longer [viremic] at the time of presentation, and urine samples, which remain PCR positive for longer, were not available for testing," they wrote. "They relied on serological criteria for diagnosis, a tricky procedure when there is a high background of dengue infection in this population."

Cao-Lormeau's team investigated the possibility that incidence of Guillain-Barré may have been due to dengue, which was also circulating at the time of the Zika outbreak. They found about three quarters (74%) of those patients with Guillain-Barré syndrome had IgM against Zika virus, but not dengue.

There were 19% of patients with both anti-Zika and anti-dengue IgM, but the authors suggested that was potentially due to cross-reactivity and not because of dengue infection.

Guillain-Barré syndrome is the leading global cause of nontraumatic paralysis. Its risk tends to increase with age and typically affects men more than women. In addition to the association with Zika virus, the authors noted the research provided useful findings about the clinical characteristics of Guillain-Barré syndrome cases.

As suggested by other epidemiologists, symptoms of Guillain-Barré manifest after a mild viral or bacterial infection (such as Zika virus). The Guillain-Barré group here seemed to support this finding. There were 39 patients (93%) who had anti-Zika virus IgM (evidence of more recent infection), and a large majority (88%) who reported "transient viral syndrome compatible with Zika virus" prior to the onset of Guillain-Barré symptoms.

The most common symptoms were generalized muscle weakness (74%) and facial palsy (64%). A little under half (44%) also reported incapacity to walk. There were 16 patients (38%) who were admitted to hospital ICUs and a little under a third (29%) required respiratory assistance and there were no deaths.

There were electrophysiological findings compatible with the acute motor axonal neuropathy type of Guillain-Barré syndrome cases, the authors noted. This included rapid evolution of disease, with a median of 6 (IQR 4-9) days installation phase and a median 4 day (IQR 3-10) plateau phase.

Four months later, researchers found an improvement in electrophysiological testing results in a cohort of 19 patients (P<0.05), which they cite as suggestive of acute motor axonal neuropathy. However, they noted that the typical anti-ganglioside antibodies, which are generally indicative of Guillain-Barré syndrome, were rarely present. "These findings suggest that there might be autoantibodies in this post-Zika virus Guillain-Barré syndrome cohort that cannot be fully identified by current methods," they wrote.

A potential limitation of the study was that almost all the patients were of Polynesian origin, which could suggest a possible link to ethnicity. But there have been similar incidence rates of Guillain-Barré syndrome in Brazil, El Salvador, and Colombia following outbreaks of Zika virus, the authors noted.

In the U.S., the CDC continues to add to its guidance about Zika virus, recently adding two more tropical destinations to its travel advisory warning list, as well as announcing the emergency authorization of a new diagnostic test to detect Zika.