Study protocol: Neurological manifestations associated with Zika virus


Maria de Fatima Militão de Albuquerque, Maria Lúcia Brito Ferreira, Álvaro Moreira, Carlos Alexandre Brito, Ricardo Arraes de Alencar Ximenes, Celina Maria Turchi Martelli, Lindomar José Pena, Rafael França, Ernesto Marques and the Neuro Zika group


Zika virus is an arbovirus of the Flaviviridae family that has two main lineages – the Asian and African strains. Aedes aegypti and Aedes albopictus mosquitos are the principal transmission vectors. Following the initial description of Zika virus in 1947, there were few case reports until a large outbreak 2007. Since 2013, in French Polynesia, there have been a number of major outbreaks. From November 2014, Rio Grande do Norte and later Pernambuco reported a major outbreak of fever/rash cases that had a clinical pattern different from dengue, which was subsequently reported by the other states in the Northeast of Brazil. Zika virus has since been isolated from case samples in Northeastern Brazil.

In 2014 in French Polynesia, 72 cases of neurological disease were reported by the European Centre for Disease Control (ECDC). Among these, 40 Guillain-Barre syndrome (GBS) cases were diagnosed within three months (compared with only five diagnosed over the same period in the previous year). The remaining 32 cases had other neurological conditions such as encephalitis, meningo-encephalitis, paresthesia, facial paralysis and myelitis. All cases of GBS developed neurological symptoms following an episode of illness with symptoms compatible with Zika virus infection in previous days. Despite the likely association between infection and neurological disease, there was no specific laboratory test detection of Zika virus on reverse transcription polymerase chain reaction (RT-PCR) testing among these cases.

An increase in the number of neurological cases reported to epidemiological surveillance systems has recently been noticed in several cities in the Northeast. In Pernambuco, in a reference hospital in Neurology (Hospital da Restauração), several patients who presented with neurological manifestations had a preceding episode of illness that was consistent with Zika infection (fever, rash, etc). Zika infection was confirmed in the serum and CSF of five of the cases initially Clinical-epidemiological profile and neurological manifestations associated with Zika virus infection 3 investigated on RT-PCR testing or by isolation of the virus. These data have not yet been published, but they were notified, which has led the Ministry of Health to create protocols for diagnosing and investigating such cases.

Given the above situation, there is an urgent need to systematically investigate cases of Zika virus infection, so that we can better define the spectrum of associated neurological manifestations and elaborate a hypotheses of causality that could be tested in subsequent analytical studies. We therefore propose to study a series of cases of patients with neurological manifestations and a clinical and epidemiological suspicion of Zika virus infection. Neurological patients suspected of having Zika virus infection admitted to a neurology reference centre in the city of Recife (Hospital da Restauração), will be recruited, followed up in hospital and in an outpatient unit in subsequent consultations, where possible. The present study may provide additional information on neurotropism of the virus and the pathogenesis of neurological disease following Zika virus infection. This evidence can be further evaluated in analytical epidemiological studies.

Read the full protocol here.