Zika virus and neurological disease: is there evidence for causality?

Arun Krishnan and Steve Vucic, Neurologists and JNNP web editors, discuss recent data on possible Zika virus-induced neurological disease.

There has been considerable worldwide coverage documenting the impact of the recent Zika virus epidemic which spread through South America and more recently the Carribean. While infection with Zika is of little consequence in most people but there have been major concerns with infection in pregnant women and most of the interest has focussed on the nervous system. The most marked congenital neurological abnormality has been the development of microcephaly in newborns and this was most clearly brought out in the large spike in cases of microcephaly in Brazil in 2016. There have however been concerns about attributing causality based on epidemiological data alone and a recent paper in the New England Journal of Medicine noted that there were methodological concerns in some of the studies and that it may be premature to invoke causality [1]. A more recent report in the same journal has laid out the case for and against a causal effect [2]. In this paper, the authors test current scientific knowledge concerning Zika against accepted criteria for proof of human teratogenicity. Interestingly, the case for causality appears strong when assessed in this manner. Of note, the spike in cases of microcephaly in South America was not the first time that it has been associated with a Zika outbreak: a previous Zika epidemic in French Polynesia in 2013-2014 was also associated with an increase in microcephaly. In both South America and French Polynesia, the Zika outbreak preceded the spike in microcephaly cases and neonates who were affected also manifested other signs that are consistent with Zika exposure. The authors also provide references to studies that have outlined the mechanisms of Zika-induced neurotoxicity, with changes noted in neural progenitor cells that are exposed to the virus, providing evidence of biological plausibility.

In addition to the neonatal neurological manifestations, Zika virus infections have been associated with the occurrence of Guillain Barre Syndrome (GBS) [3-7], an acute immune-mediatied polyradiculoneuropathy with a heterogeneous phenotype[8], that causes acute weakness and impaired sensation. The first case of ZIKA related GBS was reported in 2013 in a French Polynesian lady, clinically presenting as global tetraparesis, facial paralysis, and autonomic nervous system dysfunction[4].  Subsequently, a further 42 GBS cases secondary to Zika virus infection have been reported, with Zika virus infection preceding the onset of GBS by 6 days [5].  Most patients exhibited a rapid disease course, severe tetraparesis and bilateral facial weakness, with an elevated CSF protein level.  Respiratory dysfunction, requiring intensive care management, was evident in 38% of patients, although all responded to therapy with intravenous immunoglobulin or plasmapheresis.  Importantly, no patients died as a result of Zika virus infection related GBS, and over half the patients exhibited good clinical recovery  at 3 months post infection.  Neurophysiological studies disclosed a predominantly distal demyelinating motor neuropathy which improved on follow-up [5].   The pathophysiological mechanisms by which Zika virus infection underlies the development of GBS remains to be fully elucidated, although antigenic mimicry against yet to be identified axonal targets, or direct viral infection of nerves has been invoked.  Given the rapid reversal of clinical and neurophysiological findings, the possibility of an antibody-mediated blockade of nodal Na+ channels leading to failure of distal neurotransmission, should also be explored.

In conclusion, Zika virus infections can lead to severe neurological syndromes including neonatal microcephaly and GBS.  Since the Zika virus infection is spreading rapidly across the South America countries, physicians need to be vigilant about the possibility of neurological sequalae and resources need to be allocated to the management of neurological complications of Zika virus infection.


  1. Broutet N, Krauer F, Riesen M, Khalakdina A, Almiron M, Aldighieri S, et al. Zika Virus as a Cause of Neurologic Disorders. The New England journal of medicine. 2016. Epub 2016/03/10. doi: 10.1056/NEJMp1602708. PubMed PMID: 26959308.
  2. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects – Reviewing the Evidence for Causality. The New England journal of medicine. 2016. Epub 2016/04/14. doi: 10.1056/NEJMsr1604338. PubMed PMID: 27074377.
  3. Roze B, Najioullah F, Ferge JL, Apetse K, Brouste Y, Cesaire R, et al. Zika virus detection in urine from patients with Guillain-Barre syndrome on Martinique, January 2016. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2016;21(9). Epub 2016/03/12. doi: 10.2807/1560-7917.es.2016.21.9.30154. PubMed PMID: 26967758.
  4. Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, et al. Zika virus infection complicated by Guillain-Barre syndrome–case report, French Polynesia, December 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2014;19(9). Epub 2014/03/15. PubMed PMID: 24626205.
  5. Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016. Epub 2016/03/08. doi: 10.1016/s0140-6736(16)00562-6. PubMed PMID: 26948433.
  6. Anaya JM, Ramirez-Santana C, Salgado-Castaneda I, Chang C, Ansari A, Gershwin ME. Zika virus and neurologic autoimmunity: the putative role of gangliosides. BMC medicine. 2016;14(1):49. Epub 2016/03/24. doi: 10.1186/s12916-016-0601-y. PubMed PMID: 27001187; PubMed Central PMCID: PMCPmc4802632.
  7. Araujo LM, Ferreira ML, Nascimento OJ. Guillain-Barre syndrome associated with the Zika virus outbreak in Brazil. Arq Neuropsiquiatr. 2016;74(3):253-5. Epub 2016/04/07. doi: 10.1590/0004-282×20160035. PubMed PMID: 27050856.
  8. Vucic S, Kiernan MC, Cornblath DR. Guillain-Barre syndrome: an update. J Clin Neurosci. 2009;16(6):733-41. Epub 2009/04/10. doi: S0967-5868(08)00527-4 [pii]10.1016/j.jocn.2008.08.033 [doi]. PubMed PMID: 19356935.

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