Strongest Evidence Yet for Zika Link to Guillain-Barré

October 06, 2016

The strongest evidence yet that infection with the Zika virus can lead to the later development of Guillain-Barré syndrome has come from a new study.

Investigators conducted virologic polymerase chain reaction (PCR) testing in 42 Colombian patients with Guillain-Barré syndrome and found a positive result for Zika infection in 40%.

"This is very strong documentation of viral infection triggering Guillain-Barré syndrome," senior author, Carlos A. Pardo, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, commented to Medscape Medical News.

He explained that evidence from previous epidemiologic studies has suggested a temporal relationship between Zika infection and Guillain-Barré syndrome.

"There has been an increase in Guillain-Barré cases in areas where Zika infections have occurred, and a previous study from French Polynesia showed the possible presence of Zika in Guillain-Barré patients — reporting antibodies and a clinical profile highly suggestive of Zika. But this is the first demonstration using viral PCR testing that definitely shows the presence of Zika infection in patients with Guillain-Barré syndrome. This is biological proof that Zika infection is linked to Guillain-Barré syndrome."

The findings were published online October 5 in The New England Journal of Medicine.

Urine Test Best to Detect Zika

In terms of what this means for clinical practice, Dr Pardo said that "in the setting of Zika outbreaks, clinicians need to be aware of neurological complications, particularly Guillain-Barré syndrome, and patients with Guillain-Barré symptoms in Zika areas need to be tested for Zika infection."

He noted that Guillain-Barré syndrome often starts as weakness in the lower extremities. It can lead to serious problems because it can affect the muscles that control breathing and lead to respiratory failure.

"There are treatments available — immunoglobulins and plasmapheresis — so it is important to detect Guillain-Barré syndrome early and give treatment. Therefore, in areas where Zika infections are occurring we must be very aware of the possibility of Guillain-Barré syndrome developing. In countries now starting to see Zika outbreaks, such as Asia and Caribbean, there is very likely to be an increase in Guillain-Barré syndrome."

Other findings from the current study show that virologic testing for Zika seems to be most successful when urine samples are used.

"We did PCR testing of blood, urine, and spinal fluid in Guillain-Barré patients and we found the urine was the most efficient biological sample for detecting evidence of Zika infection. Our results indicate that PCR testing of urine is a valuable diagnostic tool for the identification of Zika infection in patients with Guillain-Barré syndrome," said Dr Pardo.

The researchers also found serologic, but not virologic, evidence of previous infections with other flaviviruses, such as dengue.

"This previous infection with dengue seems to be a risk factor for developing Guillain-Barré syndrome after Zika infection. Guillain-Barré syndrome is rare after dengue infection alone, so it may be that a previous dengue infection and then an infection with Zika is needed. These two viruses are closely related," said Dr Pardo.

For the current study, a total of 68 patients with Guillain-Barré syndrome from six Columbian hospitals were evaluated clinically, with 42 of them undergoing additional virologic testing. Of the 68 patients, 66 had symptoms compatible with Zika infection before the onset of Guillain-Barré syndrome, with a median time between onset of Zika symptoms and Guillain-Barré symptoms of 7 days.

Half the patients had bilateral facial paralysis, and among 46 patients who underwent nerve conduction studies, results in 78% were consistent with the acute inflammatory demyelinating polyneuropathy subtype of Guillain-Barré syndrome. This contrasts with the situation in French Polynesia, where the acute motor axonal neuropathy type has been reported, the researchers note.

Of the 42 patients who underwent PCR testing for Zika, the results were positive in 17 (40%). Most of the positive PCR results were from urine samples. In 18 of the 42 patients (43%) who underwent virologic testing, the presence of Zika was supported by clinical and immunologic findings.

In 20 of these 42 patients (48%), Guillain-Barré syndrome developed around the same time as the Zika infection. "This suggest a different temporal profile compared with Guillain-Barré syndrome associated with other infections, where there is generally a longer delay," Dr Pardo said.

All patients tested were negative for dengue virus infection, as assessed by PCR, but 32 of the 37 patients (86%) who were tested for flavivirus antibodies had results consistent with previous dengue infection.

Proving Causation a Challenge

In an accompanying editorial, Jennifer A. Frontera, MD, Cleveland Clinic, Ohio, and Ivan R.F. da Silva, MD, Fluminense Federal University, Niterói, Brazil, say the current study supports the association between Zika infection and Guillain-Barré syndrome. But they caution that proving a causal relationship is challenging and confirmation in another cohort would strengthen this assertion.

"Although high rates of seropositivity may prove protective against further waves of ZIKV [Zika virus]-related Guillain-Barré syndrome in Central and South America, the ZIKV pandemic is just beginning in North America and Africa, and an increase in the incidence of Guillain-Barré syndrome may follow," they conclude.

This study was supported by the Bart McLean Fund for Neuroimmunology Research; Johns Hopkins Project Restore; and VIREM, Virology Laboratory Fund, Universidad del Valle. Disclosures for the study authors and editorialists are available at nejm.org.

N Engl J Med. Published online October 5, 2016. Full text, Editorial

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