NEURO-ZIKA: Neurological Manifestations of Zika

Key Results & Achievements

The results from the work carried out across the four-year period have furthered understanding of the spectrum of ZIKV-associated neurological disease and provided valuable information on diagnostic assays, viral epidemiology, characteristic systemic and neurological features, responses to treatment and clinical outcomes. NEURO-ZIKA’s work has informed the development of guidelinesandsupported on-going educational activities to improve the management of neurological disease associated with ZIKV and other arboviruses globally.

This collaborative effort has led to successful applications for further funding from the UK National Institute of Health Research (NIHR) for ULIV and Fiocruz and the US National Institute of Health (NIH) for UVAL and Johns Hopkins. The studies carried out by NEURO-ZIKA in both Brazil and Colombia have helped create close collaboration through a large network of hospitals. Supported by ULIV, the NeuroZika network linked with hospitals and academic centres around the world as part of the Brain Infections Global network. As the COVID-19 pandemic has evolved Brain Infections Global provided critical capacity and infrastructure for establishing the COVID-Neuro Global network, which is studying neurological disease associated with COVID-19. Thanks to recent fundings form GBS-CIDP Foundation International and the Dutch ‘Prinses Beatrix Spierfonds’, the IGOS cohort study in GBS will continue with new patient inclusions and specified research projects.

Strengthened diagnostic capacity for ZIKV

This work was led by Fundação Oswaldo Cruz (Fiocruz) in collaboration with ZikAction and informed the selection of the most accurate available assays for subsequent clinical and seroepidemiological studies.

The group adapted and developed training materials and practical recommendations to support clinical practice in Latin America and to improve patient management. Working alongside ZikAction, local and international staff were trained and local testing protocols with optimised molecular and serological diagnostic assays for Zika, Chikungunya and Dengue were implemented. Educational workshops were held, and presentations given on ZIKV-associated neurological disease. Support and leadership were also provided for public engagement work.

Recognition of the co-circulation of other arboviruses that may cause neurological disease

The importance of investigating for Chikungunya (CHIKV) or dengue virus (DENV) in patients with suspected arbovirus-associated neurological disease was identified, as a high number of patients in the retrospective study in Rio de Janeiro and a prospective study in Recife had evidence of infection with one of more of these viruses. Importantly, in our larger Recife study, dual infection with more than one arbovirus appeared to be linked to more severe disease in Guillain Barré Syndrome (GBS) patients. Dual infection was also more frequently seen in patients with stroke.

Enhanced understanding of the spectrum of ZIKV-associated neurological disease

The Rio de Janeiro study identified that patients infected with ZIKV may have a mixed picture of simultaneous central and peripheral neurological disease, which had not been seen in previous studies. The prospective study conducted during the Zika outbreak in Recife further contributed to our understanding of the broad spectrum of Zika-associated neurological disease. As in Rio, we saw patients with mixed central and peripheral nervous system disease, as well as a number of cases of stroke – which have not been widely reported previously - and neuromuscular conditions such as myositis.

Case-control studies in Latin America and Asia

A new prospective case-control study on GBS was developed, based on the largest ongoing observational study on GBS; the International GBS Outcome Study (IGOS). This study, called IGOS-Zika, was set up and conducted across Brazil, Argentina and further afield through the IGOS network with incorporation of pre-existing Asian IGOS sites. Beyond this, we conducted two case-control studies in parallel that aimed to study the association between arboviral infection and a broader range of neurological manifestations, including encephalitis, myelitis and stroke. These multicentre prospective case-control studies included the NEAS study in Colombia and the Zika Neurology Network study in Brazil. Patient follow up in these studies continued until December 2019. Diagnostic testing of samples collected from patients has commenced.

Use of on-line platforms for data collection

Online platforms are being used for data collection, to build capacity for clinical research into neurological disease. This includes use of the REDCap platform by University of Liverpool, Fiocruz and Universidad del Valle and the development of a web-based data entry support system by Erasmus Universitair Medisch Centrum (EMC) for the IGOS study, where local investigators can upload and organize their research data. This system is free to use by the local institutes.

Maintaining biobanks

Sample biobanks were established and maintained with on-going sample collection in Brazil and Colombia. These samples will be used for diagnostic purposes and for other research into the neuropathogenesis of ZIKV performed by NEURO-ZIKA Pathogenesis (WP4).

Publication of collaborative work

The analysis of data from a large neuro arbovirus case series in Brazil was completed and written up for publication. Two high-impact studies, a retrospective one from Rio de Janeiro and prospective one from Recife, were published in PLOS NTD and The Lancet Neurology respectively. In addition, an international consensus guideline on GBS management was produced. The aim of this guideline, based on current literature and international expert consensus, is to contribute to the improvement of patient management.  It presents a 10-step approach to facilitate use in clinical practice. "Diagnosis and management of Guillain–Barré syndrome in ten steps" was published in the high-impact journal ‘Nature Reviews Neurology’ on September 20, 2019.

Dissemination activities

Activities, to increase awareness of the potential for ZIKV to cause neurological disease, included attendance and presentations at international conferences. In addition, alongside engagement with UK, Colombian and Brazilian policymakers, presentations were given at a UK-Brazilian government science and innovation seminar titled ‘Zika virus: Three years after the Epidemic’ held in Recife, Brazil, 12 March 2019, which was covered widely by the Brazilian media.

MERG and NEURO-ZIKA Networks

Participating Organisations

Group leader: Prof. Tom Solomon, The University of Liverpool

• Umeå University
• University of Glasgow
• University of Oxford
• Erasmus Universitair Medisch Centrum Rotterdam
• Universidad del Valle
• Fundação de Apoio à Universidade de São Paulo
• Fundação Oswaldo Cruz (Fiocruz)