First Strong Sign That Zika Can Cause the Debilitating Guillain–Barré Syndrome

Scientists agree that it’s a good idea for countries prone to Zika infections to be prepared for more cases of the rare neurological disease that causes rapid-onset paralysis.

A scanning electron microscope-derived image of Campylobacter jejuni, which triggers about 30% of cases of Guillain–Barré syndrome. Caption & credit: Wikimedia Commons

A scanning electron microscope-derived image of Campylobacter jejuni, which triggers about 30% of cases of Guillain–Barré syndrome. Caption & credit: Wikimedia Commons

A group of scientists from French Polynesia, France and Glasgow claims to have, for the first time confirmed the link between Zika and Guillain-Barré syndrome, a neurological disease that causes rapid-onset paralysis. The results of their observational study were published in The Lancet on February 29.

French Polynesia, a group of islands in the Pacific Ocean, is where the first large outbreak of Zika virus occurred between November 2013 and April 2014. Before that, though Zika cases cropped up now and then primarily in Africa and South East Asia, and the symptoms had been relatively non-alarming – such as fever, rashes and muscle pain. The French Polynesian outbreak brought to notice Zika’s apparent association with the otherwise-rare Guillain-Barré syndrome (GBS).

The number of GBS cases in French Polynesia was five, ten, three and three in 2009, 2010, 2011 and 2012 respectively. However, it spiked to 42 between November 2013 and February 2014. These four months coincided with a nasty Zika outbreak in the region that saw 32,000 patients assessed for suspected Zika infections.

A public health emergency

With Zika’s foray into the Americas in 2015 and 2016, and the possibility that it causes another neurological disease called microcephaly (characterised by babies born with small heads), the need for confirmation studies to establish these links is more urgent than ever. The World Health Organisation (WHO) on February 1 had declared these suspected links a Public Health Emergency of International Concern and urged further research to confirm these theories. In a situation report released on February 26, WHO stated that the evidence that neurological disorders, including microcephaly and GBS, are linked to Zika virus infection remains circumstantial.

While the role of microcephaly is still debated, the new study by Van-Mai Cao-Lormeau, from the Institut Louis Malardé in Tahiti, and her team presents statistical evidence that GBS is indeed linked to the Zika virus. Their study is the first to assess the role of Zika virus infections in a large number of patients with GBS diagnosed during a Zika outbreak.

The scientists conducted a case-control study involving all 42 GBS cases during the outbreak period in French Polynesia. This was possible because all suspected GBS cases were required to be referred to a single hospital, Centre Hospitalier de Polynésie Française (the 42 patients were the cases in this study). Two control groups were designated: the first comprised 98 patients who had come in with non-febrile (without fever) illnesses. The second control group was made of 70 Zika virus infected patients who hadn’t developed GBS.

A challenging study

As Zika has a short viraemic period (the amount of time viruses are present in the bloodstream) of just five days and the samples were collected weeks after, none of the 42 GBS cases still had the Zika virus itself. Urine samples, the next best alternative, weren’t available either, so the scientists had to rely on serological evidence. They looked for specific anti-Zika immune cells that would be present in the blood serum of a person who had had Zika in the past. It turned out that in the group of 42 GBS cases, 98% had anti-Zika immunoglobulins G and M circulating in their blood. Some 88% had reported a fever preceding the GBS onset. These figures were significantly higher than in control group 1, where only 36% had anti-Zika immunoglobulins G and M. This suggested that a GBS patient is almost thrice as likely to have had a past Zika infection as a non-GBS patient.

However, there was an important factor to be considered before any of this could be used as useful evidence. “There is a high background of dengue infection in this population,” say Australian scientists David W. Smith and John Mackenzie in a comment article in The Lancet. The Zika virus belongs to a group called flaviviruses, to which the dengue virus also belongs. Antibodies against flaviviruses are widely cross-reactive, meaning the dengue virus could trigger an immune response against Zika virus and vice-versa. Hence, even though anti-Zika antibodies were detected, this could have been due to a Zika infection or a dengue infection.

To eliminate this dengue noise, the team also assessed the cases for dengue immunity. They found that 95% of the GBS patients had dengue immunity but this was not significant as the two control groups were not far behind (89% and 83% respectively). Moreover, 74% of the GBS cases had only Zika immunity, whereas none had only dengue immunity, indicating that the dengue antibodies probably were a result of cross-reactivity during their Zika fever.

Decoding the nature of the disease

Clinically, a number of different types of GBS are recognised. It is obviously vital to have information about which type is associated Zika-driven GBS. Cao-Lormeau & co. found that most had the acute motor axonal neuropathy (AMAN) type of the syndrome, and though the disease evolved rapidly, the prognosis was favourable. Most patients could walk without assistance three months after discharge.

The team did not meet with much success in finding out the biological mechanism by which the Zika infection was causing GBS, however. Zika is not the only infection known to cause GBS. Seventy-five percent of the AMAN-type of Guillane Barre Syndrome sufferers show intestinal infection by a bacteria called Campylobacter jejuni. Notably, none of the studied cases had this infection, nor did they have herpes or Epstein-Barr virus infections, both also known to be associated with GBS. In case of most of these infections, the antibodies produced to fight the pathogens wrongly recognise certain components of neurons as the enemy. The resultant destruction of neurons is what causes neurological symptoms like paralysis. However, the scientists could not find such antibodies in the GBS cases.

The road ahead

In light of their results, the scientists conclude that Zika virus should be added to the list of infectious pathogens able to cause GBS. And conversely, they advise that countries at risk for Zika need to be prepared to have adequate intensive care beds capacity to manage patients with GBS.

While WHO has called for similar research into microcephaly, they have conceded that this could be a tougher task as it involves tracking pregnant women until they deliver babies. “It will probably be somewhere around four to six months before we can say with some certainty,” said Bruce Aylward, WHO’s executive director of outbreaks and health emergencies, at a recent press conference.

Dr. Tarun Dua, a WHO brain disorder and mental health expert, emphasised that just case-control studies are not adequate. “Cohort studies, where a set of subjects are identified and their progress tracked over a period of time, are also required to answer questions such as temporal association, biological plausibility, consistency, and if there are any alternative explanations,” she said.