Zika Virus Infection and Guillain-Barré Syndrome: The Evidence Grows

By Joseph E. Safdieh, MD

Vice Chair and Associate Professor, Weill Cornell Medical College

Dr. Safdieh reports no financial relationships relevant to this field of study.

SYNOPSIS: A recent Zika outbreak in Colombia was associated with a significant increase in Guillain-Barré syndrome (GBS) rates, with laboratory evidence of definite or probable Zika infection in more than half of the GBS cases.

SOURCE: Parra B, Lizarazo J, Jimenez-Arango JA, et al. Guillain-Barre syndrome associated with Zika virus infection in Colombia. N Engl J Med 2016;375:1513-1523.

Zika virus is a mosquito-born flavivirus that has recently emerged in Central and South America as well as the Caribbean and southern parts of the United States. Although humans typically are infected with Zika via a mosquito bite, Zika virus can be transmitted from an infected human to an uninfected human via sexual contact. Much attention has been paid to the Zika virus-associated microcephaly in children born to some mothers infected during pregnancy. During an earlier Zika virus outbreak in French Polynesia, there was an indication of an association with Guillain-Barré syndrome (GBS). As Zika has moved through the Americas, surveillance for GBS cases has been set up in a number of countries to document the case rate and to determine association with recent Zika virus infection. This paper presents data from the GBS surveillance program in Colombia.

Colombia reported its first case of Zika virus infection in October 2015, and by January 2016, cases were reported in most regions of the country. At the same time, hospitals were noting an uptick in the number of patients diagnosed with GBS. Surveillance of GBS cases was set up to track the number of GBS cases, the clinical features, and the laboratory testing to assess for recent or current Zika virus infection. GBS cases were diagnosed based on Brighton criteria. For Brighton criteria, level 1 requires both abnormal nerve conduction (NCS) studies and cerebrospinal fluid (CSF) cytoalbuminologic dissociation, level 2 requires either NCS or CSF abnormalities, and level 3 is based on clinical features alone without support from testing. Zika virus infection was categorized as definite (confirmed by Zika RNA-PCR in serum, urine, or CSF), probable (positive CSF and/or serum ELISA for flavivirus with negative Dengue serologies), or suspected (supportive clinical syndrome without supportive testing). Supportive clinical symptoms of Zika are quite nonspecific and include rash, fever, conjunctivitis, arthralgia, myalgia, and periarticular edema.

Parra et al reported on the results of GBS surveillance in Colombia from January through March 2016. Of note, 270 cases of GBS were reported throughout the country over these three months, as compared to an estimated baseline in Colombia of 250 cases per year. Sixty-eight GBS patients presented to the specialized centers that were involved for the purposes of this study. Of the 68 cases, 82% fulfilled Brighton criteria level 1 or 2 for the diagnosis of GBS. The majority of the patients had a typical ascending limb weakness pattern, with 50% developing bifacial paresis. A small number of cases of Miller Fisher variant also occurred. Median age of the patients was 47 years, with 56% male predominance. Eighty-two percent of those who underwent lumbar puncture demonstrated elevated CSF protein, with median CSF white blood cell count of 0 per CC. Seventy-eight percent of those who underwent electrophysiologic testing demonstrated features consistent with acute inflammatory demyelinating polyradiculopathy. Most patients were treated with intravenous immunoglobulin. Thirty-one percent of the patients required mechanical ventilation, and three patients died.

Of the 68 GBS patients included in this analysis, 97% had a recent illness suspicious for Zika virus infection in the previous four weeks. These symptoms lasted a median of four days and occurred a median of seven days before GBS symptom onset. Forty-two of the 68 patients with GBS underwent diagnostic testing for Zika virus. On laboratory testing, 17 (25%) of the patients had definite Zika infection, 18 (26%) of the patients had probable Zika infection, and the rest were considered suspected cases. Of note, 16 of the 17 patients with definite Zika virus demonstrated positive PCR in the urine, but only three in the CSF and one in the serum. Of the patients with definite and probable Zika infection, two developed GBS symptoms at the same time as the Zika symptoms, 20 (48%) patients developed GBS symptoms immediately after Zika infection with no post-Zika recovery period, and the remainder of the patients developed GBS with a more typical post-infectious course.

COMMENTARY

This is an important study because it offers more evidence of a possible connection between Zika virus and the development of GBS. Although it cannot be stated with certainty that Zika can trigger GBS, the evidence in this study, in addition to the previously described GBS outbreak after Zika infection in French Polynesia, lends further support to the association. It is worth noting that more than half of the GBS cases in this cohort had definite or probable Zika exposure. It is interesting that in some of the GBS cases, the symptoms developed either concurrently or immediately following the Zika symptoms, suggesting a possible para-infectious pathogenesis. This is distinct from the usual post-infectious temporal onset of GBS in patients with other known triggers such as Campylobacter jejuni. It is not known if the Zika virus is directly pathogenic to peripheral nervous system structures.

The symptoms, signs, and diagnostic testing findings in Zika-associated GBS are similar to the GBS typically seen in traditional clinical settings. The paper does not provide follow-up on outcomes, but it would be important to know whether these patients responded to therapy. Zika virus cases transmitted via mosquito vector already have been reported in Florida and Texas. Sexually transmitted cases of Zika have been reported in multiple states. U.S. neurologists should be familiar with the possible association between Zika and GBS and should ask about recent travel history (of the patient and any sexual partners) when encountering a patient with GBS.