Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study

Abstract

Background: Since 2015, the arthropod-borne viruses (arboviruses) Zika and chikungunya have spread across the Americas causing outbreaks, accompanied by increases in immune-mediated and infectious neurological disease. The spectrum of neurological manifestations linked to these viruses, and the importance of dual infection, are not known fully. We aimed to investigate whether neurological presentations differed according to the infecting arbovirus, and whether patients with dual infection had a different disease spectrum or severity.

Methods: We report a prospective observational study done during epidemics of Zika and chikungunya viruses in Recife, Pernambuco, a dengue-endemic area of Brazil. We recruited adults aged 18 years or older referred to Hospital da Restauração, a secondary-level and tertiary-level hospital, with suspected acute neurological disease and a history of suspected arboviral infection. We looked for evidence of Zika, chikungunya, or dengue infection by viral RNA or specific IgM antibodies in serum or CSF. We grouped patients according to their arbovirus laboratory diagnosis and then compared demographic and clinical characteristics.

Findings: Between Dec 4, 2014, and Dec 4, 2016, 1410 patients were admitted to the hospital neurology service; 201 (14%) had symptoms consistent with arbovirus infection and sufficient samples for diagnostic testing and were included in the study. The median age was 48 years (IQR 34-60), and 106 (53%) were women. 148 (74%) of 201 patients had laboratory evidence of arboviral infection. 98 (49%) of them had a single viral infection (41 [20%] had Zika, 55 [27%] had chikungunya, and two [1%] had dengue infection), whereas 50 (25%) had evidence of dual infection, mostly with Zika and chikungunya viruses (46 [23%] patients). Patients positive for arbovirus infection presented with a broad range of CNS and peripheral nervous system (PNS) disease. Chikungunya infection was more often associated with CNS disease (26 [47%] of 55 patients with chikungunya infection vs six [15%] of 41 with Zika infection; p=0·0008), especially myelitis (12 [22%] patients). Zika infection was more often associated with PNS disease (26 [63%] of 41 patients with Zika infection vs nine [16%] of 55 with chikungunya infection; p≤0·0001), particularly Guillain-Barré syndrome (25 [61%] patients). Patients with Guillain-Barré syndrome who had Zika and chikungunya dual infection had more aggressive disease, requiring intensive care support and longer hospital stays, than those with mono-infection (median 24 days [IQR 20-30] vs 17 days [10-20]; p=0·0028). Eight (17%) of 46 patients with Zika and chikungunya dual infection had a stroke or transient ischaemic attack, compared with five (6%) of 96 patients with Zika or chikungunya mono-infection (p=0·047).

Interpretation: There is a wide and overlapping spectrum of neurological manifestations caused by Zika or chikungunya mono-infection and by dual infections. The possible increased risk of acute cerebrovascular disease in patients with dual infection merits further investigation.

Funding: Fundação do Amparo a Ciência e Tecnologia de Pernambuco (FACEPE), EU's Horizon 2020 research and innovation programme, National Institute for Health Research.

Translations: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Figure 1

Study population Eligible patients presented with neurological disease to the hospital neurology service in Recife between Dec 4, 2014, and Dec 4, 2016. CHIKV=chikungunya virus. DENV=dengue virus. PNS=peripheral nervous system. ZIKV=Zika virus.

Figure 2

Epidemiological data Map of neurological disease case locations in Pernambuco state, Brazil (A), and patient recruitment rate per month over the study period, grouped according to arbovirus laboratory diagnosis (B). Mono-infection was defined as laboratory test evidence of infection with a single virus; dual infection was defined as evidence of infection with more than one virus on the basis of a positive PCR or IgM test, in whom infection might be concurrent or sequential. Additionally, there were two patients with dengue mono-infection in 2015; four patients with chikungunya and dengue dual infection between November, 2015, and April, 2016; and 53 patients without laboratory evidence of arbovirus infection recruited over the study period.

Figure 3

Neuroimaging findings (A) FLAIR MRI of the brain showing bilateral asymmetric hyperintense signal changes in the cortex, most likely representing acute demyelination, in a 57-year-old woman with acute disseminated encephalomyelitis. The patient presented 14 days after having systemic symptoms of arboviral infection with a reduced level of consciousness, bilaterally reduced visual acuity, bilateral lower limb weakness with brisk reflexes, and a T6 sensory level; MRI imaging was done on the day of admission. CSF samples were positive for Zika and chikungunya viruses on PCR and IgM testing, and serum samples were positive for Zika virus on PCR testing. (B) Coronal FLAIR MRI of the brain of the same patient. (C) T2-weighted MRI of the spinal cord of the same patient showing a longitudinally extensive intramedullary signal change within the lower thoracic cord extending to the conus (indicated by arrows). T2-weighted MRI (D) and DWI MRI (E) of a 78-year-old man positive for chikungunya virus with a stroke. The patient, with a history of hypertension, developed left-sided hemiparesis and dysarthria 7 days after onset of systemic symptoms of rash, myalgia, arthralgia, and joint oedema. Serum was positive for chikungunya virus IgM antibodies. MRI shows features of acute ischaemia, including an area of restricted diffusion involving the left PCA territory (medial temporal lobe and the left occipital lobe acute medially, including the lingual gyrus). (F) Follow-up CT at 6 weeks in the same patient, showing an established left PCA territory infarct with involution. CT of the head (G), T2-weighted MRI (H), and DWI MRI of the brain (I) of a patient positive for Zika and chikungunya virus with a stroke. The patient, a 64-year-old woman with hypertension, developed a left-sided hemiparesis 12 weeks after onset of systemic viral symptoms. Serum was positive for Zika virus on PCR and IgM testing, and chikungunya virus on IgM testing. She presented at hospital again 3 months after neurological symptom onset and imaging was done. (G) CT showing an area of gyral hyperdensity with surrounding low density change in the left frontal lobe and a mass effect. (H, I) MRI imaging showing an area of signal abnormality in the left frontal lobe (middle frontal gyrus) with restricted diffusion and areas of susceptibility. These features are suggestive of ischaemia with areas of haemorrhage within it, indicative of a subsequent, more recent event after the initial presentation 3 months before. DWI=diffusion-weighted imaging. FLAIR=transverse fluid attenuated inversion recovery. PCA=posterior cerebral artery.