Is dengue virus neurotropic?

Abstract

Dengue viral infection is on the rise in tropical urban and semi-urban parts of the world. WHO fact sheet- N°117 updated in May 2015 estimates 390 million dengue infections per year and that 3900 million people, in 128 countries, are at risk. The WHO case definition of severe dengue includes organ impairment, but does not describe neurological manifestations as a separate entity. Earliest reports on neurological manifestations came from Indonesia 35 to 40 years back. Abundant literature is available on diverse neurological manifestations in dengue from India and other parts of the world. Encephalopathy, aseptic meningitis, papilledema, stroke, intracranial and sub- arachnoid haemorrhage (ICH/ SAH), Acute Disseminated Encephalomyelitis (ADEM), opsoclonus- myoclonus syndrome, myelitis cranial nerve palsies, polyneuropathies, Guillain-Barre syndrome (GBS), polymyositis, and hypokalemic paralysis are all reported. Long-term sequelae recorded are Parkinsonism, dystonias, cognitive changes, behavioural disorders, depression, amnesia, dementia and psychosis. The neurological manifestations in dengue can be grouped into 3 categories – (I) those related to the neuro-myotropic effects of the virus (II) those related to the systemic complications of dengue infection like vascular leakage, hemoconcentration, haemorrhage and dyselectrolytemia; and (III) Post- infectious manifestations like ADEM, encephalomyelitis, myelitis, optic neuritis, GBS and mono and polyneuropathies. Dengue virus belongs to the flaviviridae family, several members of which have proven neurotropism and propensity for the sub- cortical nucleii. CNS invasion, either through neurotropism or vascular leakage is supported by inconsistent evidence including animal experiments. Presence of virus and IgM- dengue in the CSF of some encephalopathy cases suggests capability, but not invariability of CNS invasion. Glycosylation of the envelope protein, increased inflammatory cytokines disrupting the blood brain barrier (BBB) allowing free virus access to the CNS and non-specific cellular virus attachment factors are all implicated. Some authors recommend a high index of suspicion for dengue in CNS infections occurring in endemic countries. Three tetravalent live-attenuated vaccines are under development in phase II and phase III clinical trials, and 3 other vaccine candidates (based on subunit, DNA and purified inactivated virus platforms) are at earlier stages of clinical development. Their immunogenicity may be implicated in neurological manifestations in the future.