Elsevier

The Lancet Neurology

Volume 12, Issue 9, September 2013, Pages 906-919
The Lancet Neurology

Review
Neurological complications of dengue virus infection

https://doi.org/10.1016/S1474-4422(13)70150-9Get rights and content

Summary

Dengue is the second most common mosquito-borne disease affecting human beings. In 2009, WHO endorsed new guidelines that, for the first time, consider neurological manifestations in the clinical case classification for severe dengue. Dengue can manifest with a wide range of neurological features, which have been noted—depending on the clinical setting—in 0·5–21% of patients with dengue admitted to hospital. Furthermore, dengue was identified in 4–47% of admissions with encephalitis-like illness in endemic areas. Neurological complications can be categorised into dengue encephalopathy (eg, caused by hepatic failure or metabolic disorders), encephalitis (caused by direct virus invasion), neuromuscular complications (eg, Guillain-Barré syndrome or transient muscle dysfunctions), and neuro-ophthalmic involvement. However, overlap of these categories is possible. In endemic countries and after travel to these regions, dengue should be considered in patients presenting with fever and acute neurological manifestations.

Introduction

Dengue is a mosquito-borne viral disease caused by one of four closely related dengue virus serotypes (DENV 1–4). It is the second most common mosquito-borne disease affecting human beings after malaria.1 Around 4 billion people are at risk of the disease, with about 100 million cases of symptomatic dengue occurring annually.2 Reported case-fatality rates of severe dengue range from less than 0·2% to 5%.1 Population growth, urbanisation, deterioration of mosquito-control programmes, and an increase in air travel and trade have contributed to the emergence and geographical spread of the disease over past decades.1, 3

In 2009, WHO released new dengue guidelines and a new case classification, which included CNS involvement in the definition of severe disease.1 From the time dengue was recognised as a clinical entity, neurological manifestations of the disease have been described.4, 5 Factors that might contribute to neurological manifestations include prolonged shock, hyponatraemia, hepatic failure, or intracranial bleeding.4, 6 Therefore, the noted abnormal neurological signs in patients with dengue could be due to encephalopathy and not encephalitis.4 Since the end of the 1990s, evidence of dengue virus neurotropism has increased and the number of reports on dengue patients with virus isolation from CSF or brain tissue has risen.7, 8, 9

We did a literature review of evidence for dengue virus neuroinvasion and the frequency either of neurological features in patients presenting with dengue or of dengue diagnosis in patients presenting with encephalitis-like illness, at hospitals in endemic areas. Here, we discuss the findings of our literature search and describe the epidemiology of dengue, its diagnosis, clinical manifestations, and treatment of the disease and its neurological features.

Section snippets

Epidemiology, virus, and vectors

Dengue viruses consist of single-stranded RNA and are members of the Flaviviridae family (genus Flavivirus). The RNA genome includes seven non-structural (NS) protein genes and three structural protein genes that encode the capsid, membrane, and envelope proteins.10 Four antigenically distinct serotypes (DENV 1–4) circulate simultaneously in endemic countries,11 and all can cause severe disease. Transmission occurs via aedes mosquitoes that feed during daytime, with Aedes aegypti and Aedes

Clinical findings

Most dengue virus infections are asymptomatic.14 Symptomatic infections were classified traditionally into undifferentiated fever, dengue fever, dengue haemorrhagic fever, and dengue shock syndrome.15

Fever, severe frontal and retro-ocular headache, muscle, bone and joint pain, abdominal pain, nausea, and vomiting are common during dengue fever. A mild transient skin rash can arise, and a maculopapular or scarlatiniform rash can be seen after the third or fourth day in half of infected people (

Neurological complications

Neurological complications of dengue virus infection can be categorised into dengue encephalopathy, encephalitis, immune-mediated syndromes, dengue muscle dysfunction, and neuro-ophthalmic disorders. However, in practice, classification can be difficult because these categories overlap and clinical data—eg, for CSF examinations—might be missing.

In our literature search, we identified 247 publications describing original studies or reports of dengue with neurological, neuromuscular, or

Dengue virus encephalitis

The pathogenesis of dengue neurological involvement and underlying virus–host interactions remain to be elucidated. For a long time, uncertainty surrounded whether dengue virus crossed the blood–brain barrier passively or whether active viral CNS invasion took place. Detection of dengue virus RNA in CSF, viral antigen in brain tissue, and concomitant pleocytosis lends support to the hypothesis of direct viral invasion of brain parenchyma (Table 1, Table 2, Table 3). Furthermore, the

Diagnosis

Clinical suspicion is essential for diagnosis of dengue because many symptoms are non-specific. Various methods are available for laboratory confirmation. During the first days of infection, dengue virus is present in blood; thus, at that time, detection of NS1 antigen or RNA by RT-PCR and viral culture are appropriate diagnostic methods.1 Dengue virus-specific IgM antibodies are present in serum samples 3–10 days after disease onset.1 IgM capture (MAC)-ELISA is the most widely used serological

Management

Currently, no effective antiviral agents are available to treat symptomatic dengue virus infection.140 Therefore, management remains supportive. In mild cases, antipyretic drugs and oral fluids could be useful. Acetyl-salicylic derivatives and other non-steroidal anti-inflammatory drugs should be avoided. Management of haemorrhagic complications should be initially conservative. Precise management of intravenous fluids is needed, and blood or platelet transfusion is only necessary when severe

Conclusions and future research

Dengue should be included in the differential diagnosis of acute febrile disease with neurological manifestations in dengue-endemic countries and in patients with a recent travel history to an endemic region. Many neurological manifestations of dengue have been recorded, ranging—with substantial overlap—from encephalitis and encephalopathy to immune-mediated syndromes and muscle involvement. Recent evidence suggests that dengue virus has neuroinvasive capacity. In several studies in endemic

Search strategy and selection criteria

We searched Pubmed and Scopus for reports published between January, 1960, and June, 2013, with the terms (“dengue”) AND (“neurolog*” or “encephal*” or “stroke” or “myositis” or “ophthalmic complications” or “ocular” or “unusual manifestations”). We did not include mental disorders after dengue virus infection in our search. We only considered original studies published in peer-reviewed journals in English, Spanish, Portuguese, German, or French. To verify our strategy, we hand-searched

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