Zika Virus as a Cause of Neurologic Disorders.

Z virus infections have been known in Africa and Asia since the 1940s, but the virus’s geographic range has expanded dramatically since 2007. Between January 1, 2007, and March 1, 2016, local transmission was reported in an additional 52 countries and territories, mainly in the Americas and the western Pacific, but also in Africa and southeast Asia. Zika virus infections acquired by travelers visiting those countries have been discovered at sites worldwide. Aedes aegypti mosquitoes are the principal vectors, though other mosquito species may contribute to transmission. The virus was found to be neurotropic in animals in experiments conducted in the 1950s, and recent experiments have shown how it can cause neural-cell death. A rise in the incidence of Guillain– Barré syndrome, an immunemediated flaccid paralysis often triggered by infection, was first reported in 2013 during a Zika outbreak in French Polynesia. An increase in the incidence of microcephaly, a clinical sign that can be caused by underdevelopment of the fetal brain, was first reported in northeastern Brazil in 2015, after Zika virus transmission had been confirmed there. These reports of excess cases of Guillain–Barré syndrome and microcephaly led the World Health Organization (WHO) to declare a Public Health Emergency of International Concern on February 1, 2016, and to recommend accelerated research into possible causal links between Zika virus and neurologic disorders.1 As researchers investigate whether and by what mechanisms Zika virus infections could affect the nervous system, there is a key question for public health: How can currently available evidence about causality guide the choice and implementation of interventions? For this purpose, the WHO is developing a framework for the systematic appraisal of evidence about these causal relationships. How does the available evidence inform current WHO recommendations, and what are the priorities for research going forward? Besides advancing scientific understanding, the main practical purpose of investigating causality is to evaluate, as accurately as possible, what reduction in the incidence of illness (here, especially neurologic disorders) can be expected from reducing human exposure to the putative cause (Zika virus infection). The conceptual framework is based on factors first proposed by Bradford Hill and commonly used to assess causality: temporality (cause precedes effect), biologic plausibility of causal mechanisms, consistency (same association found in different studies and populations), strength of association (as measured by risk ratio, rate ratio, or odds ratio in cohort or case–control studies), exclusion of alternative explanations, dose–response relationship, cessation (removing the supposed cause reverses the effect), and analogy to cause-and-effect relationships in other diseases.2 Temporality is the single necessary condition; none of the factors on its own is sufficient. Causal relationships cannot be proven with absolute certainty in epidemiologic studies, but these factors help analysts judge the existence and strength of possible causal links. Their assessment should be complemented by controlled experiments, the most robust approach to drawing inferences about cause and effect. A systematic strategy for identifying relevant evidence will enable a transparent and replicable approach that can be updated to capture new information. Study methods can be assessed for risks of selection and measurement bias, confounding, and the effect of chance. To illustrate the approach, we conducted a search of PubMed and selected journal and public health websites for information posted through March 4, 2016. The table and the Supplementary Appendix (available with the full text of this article at NEJM.org) provide a preliminary summary of populationand individuallevel studies on possible associations between Zika virus infection and Guillain–Barré syndrome or microcephaly. We found three published reports on Guillain–Barré syndrome studied at the population level. During the 2013–2014 outbreak in French Polynesia, the