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Contents lists available at ScienceDirect

Indian Journal of Medical Specialities

journal homepage: www.elsevier.com/locate/injms

Review article

Neurological manifestations in dengue

Ashok Kumar a,*, Shubha Laxmi Margekar b
a
b

Department of Medicine, Santosh Medical College and Hospital, No. 1, Ambedkar Road, Ghaziabad UP, India
Department of Medicine, Lady Hardinge Medical College, New Delhi, India

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 13 September 2016
Accepted 14 September 2016
Available online xxx

Dengue, an acute febrile illness caused by Flavivirus, is among the most frequent arbovirus in tropical
regions. Mostly infections are asymptomatic, but disease manifestations may range from minimal
symptoms to death. For the rst time in 2009, WHO has given importance to neurological manifestations
and considered this as criteria for severe dengue infection. Neurological complications are being seen
more frequently nowadays which were not seen during previous dengue virus outbreaks. Increasingly,
lot of unusual case reports, case series, and studies on neurological manifestations have been published
in the existing literature. The present review focuses on the recent insights on the neurological
manifestations and the pathogenesis of neural involvement of dengue virus. Neurological complications
of dengue virus infection can be categorised into dengue encephalopathy, encephalitis, immunemediated syndromes, muscle dysfunction, and neuro-ophthalmic disorders. The neurological
manifestations in dengue infection are primarily caused by DENV-2 and DENV-3. The neurological
involvement in dengue can be due to possible four mechanisms: (a) metabolic imbalance; (b)
haemorrhagic disturbance; (c) post-infectious autoimmune reaction; (d) direct infection by virus. There
is no specic treatment for dengue, but supportive and symptomatic management is essential with
emphasis on prompt uid resuscitation, along with early recognition of dengue and its complications.
2016 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Indian Journal of Medical
Specialities.

Keywords:
Dengue
Neurological manifestations
Arboviruses

1. Introduction
Dengue is a viral infection caused by members of the genus
Flavivirus and family Flaviviridae. These small viruses contain
single-strand RNA as genome. The virion consists of a nucleocapsid
with cubic symmetry enclosed in a lipoprotein envelope. There are
four virus subtypes known as DENV-1, DENV-2, DENV-3 and
DENV-4. The principal vectors of dengue virus are Aedes aegypti
and Aedes albopictus. As per WHO approximately 2.5 billion people
two fths of the worlds population in tropical and subtropical
countries are at risk [1]. Dengue fever is one of the leading causes
of hospitalisation and death among children [1,2]. Epidemics of
dengue are being seen in almost all countries located within the
tropical belt [3]. The relationship between haemorrhagic dengue
fever and neurological manifestations was rst described in
1976. In 1983, Gubler and others recorded neurological disorders
associated with dengue from 25 different countries across Asia, the
Pacic rim, the Americas, Mediterranean regions, and Africa [4].

For the rst time in 2009, the WHO endorsed guidelines for
clinical case denitions of dengue, included neurological manifestations for severe dengue [1]. However, from the time dengue was
recognised as a clinical entity, neurological manifestations of the
disease have been described [5,6]. Factors that might contribute to
neurological manifestations include prolonged shock, hyponatraemia, hepatic failure, or intracranial bleeding [5,7].
Why do most dengue virus infections lead to asymptomatic or
mild self-limiting disease, and some infected people develop severe
dengue? Subsequent (secondary or tertiary) infection with a
heterologous dengue virus serotype has been postulated to be
the main factor associated with severe disease, via antibodydependent enhancement [8,9]. According to this hypothesis, nonneutralising antibodies from a previous dengue virus infection
facilitate cell invasion, enhance viraemia, and initiate a selfamplifying cascade that can lead to release of cytokines and other
proinammatory mediators [10].
2. Neurological complications

* Corresponding author.
E-mail address: dr_ashk2006@yahoo.co.in (A. Kumar).

Neurological complications of dengue virus infection can be

categorised into dengue encephalopathy, encephalitis, immune-

http://dx.doi.org/10.1016/j.injms.2016.09.009
0976-2884/ 2016 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Indian Journal of Medical Specialities.

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mediated syndromes, dengue muscle dysfunction, and neuroophthalmic disorders. However, there is no strict classication and
some overlap does exist [11].

considered a benign condition differentiated from myopathy by

little ndings in electromyogram [23].
2.6. Neuro-ophthalmic complications

2.1. Dengue encephalopathy

Acute encephalopathy is the most commonly reported neurological disorder associated with dengue virus infection. Dengue
encephalopathy involves a diminished level of consciousness that
can be precipitated or caused by several factors, including
prolonged shock, anoxia, cerebral oedema, metabolic disturbances
(e.g., hyponatraemia), systemic or cerebral haemorrhages, acute
liver failure, or renal failure [7,12]. CSF analyses, including
measurements of protein, glucose, and cell count, are usually
normal [13]. Magnetic resonance imaging and CT scan imaging
may be normal or can show diffuse brain oedema [14].
2.2. Dengue encephalitis
Patients with dengue encephalitis can present with diminished
consciousness, headache, dizziness, disorientation, seizures, and
behavioural symptoms [15,16]. Quadriparesis might be seen in
severe cases [12]. Clinically it is difcult to differentiate
encephalitis from encephalopathy, the cause of encephalitis seems
to be same like prolonged shock, anoxia, cerebral oedema,
metabolic disturbances, etc.
As such there is no specic nding of dengue encephalitis
reported. Imaging may be normal or some focal abnormalities may
be seen [12,13], meningeal enhancement in post contrast imaging
[14], involvement of thalamus, pons, cerebellum cortex [17], and
symmetrical gyral oedema with involvement of bilateral temporal
lobe, hippocampi and cingulated gyrus [18] have been reported.

Neuro-ophthalmic manifestations of dengue typically entail the

posterior segment. Anterior uveitis without evidence of posterior
segment involvement can happen rarely and be associated with
progressive loss of vision [24]. Ocular complications include
dengue maculopathy, retinal oedema, retinal haemorrhages, optic
disc swelling, optic neuropathy, and vitreitis.
3. Pathogenesis of neurological involvement
The neurological manifestations in dengue infection are caused
mainly by DENV-2 and DENV-3. These serotypes are associated
with cases of encephalitis, meningitis and myelitis [15,25]. However, DENV-1 and DENV-4 are also identied in cases of
encephalitis [26]. About 121% of individuals with dengue present
with neurological abnormalities [15,27]. The prevalence of DENV
among viral infections in central nervous system (CNS) is reported
to be 5% and 6% in Vietnam [28,29], 15% in India [30] and 20% in
Thailand [31].
The central nervous system (CNS) involvement in dengue can
be due to possible four mechanisms: (a) metabolic imbalance; (b)
haemorrhagic disturbance (thrombocytopenia); (c) post-infectious
autoimmune reaction; (d) direct infection by dengue virus
[11,32,33]. A review by Puccioni-Sohler and Rosadas [34]
suggested recent advancements in neuropathogenesis elaborating
the viral characteristics like neuroinvasion, neurotropism, and
neurovirulence.
3.1. Neuroinvasion

2.3. Immune-mediated syndromes

Many of the post infectious dengue disorders have been
described in literature which can be immune mediated. Postdengue immune-mediated neurological syndromes include acute
transverse myelitis, acute disseminated encephalomyelitis, and
Guillain-Barre syndrome [11]. Reports are rare of neuromyelitis
optica, MillerFisher syndrome, and mononeuropathies such as
phrenic neuropathy, long thoracic neuropathy, isolated Bells
palsy, abducens nerve palsy, and oculomotor palsy.

Invading capacity of virus in CNS is known as neuroinvasion.

Haematological dissemination of virus after viraemia is the most
important route to CNS access. In animal studies, DENV has shown
to break the blood brain barrier. During the infection, there is an
over-expression of cytokines that alter the permeability of the
endothelium through the disturbance of the tight junctions [35
37]. Another hypothesis is that dengue virus can access the
nervous system, crossing the endothelial cells through transcytosis
and retrograde axonal transport as an alternative neuroinvasive
mechanism [38].

2.4. Cerebrovascular events

3.2. DENV neurotropism
In the cerebrovascular events reported with dengue, most
patients have intracranial bleeding a week after fever onset
[19]. Acute intracranial bleeding can arise without other (visible)
haemorrhagic manifestations. Basal ganglia haemorrhages and
multiple haemorrhagic foci in brain lobes are recorded [5]. Less
common presentations of intracranial bleeding include bilateral
cerebellar haemorrhage with oedema, mass effect, and obstructive hydrocephalus, pontine haemorrhage, acute subdural haematoma, multiple acute subdural haematomas [19], pituitary
adenoma haemorrhage, subarachnoid haemorrhage [5], and focal
subarachnoid haemorrhage associated with transient thrombocytopenia.
2.5. Muscle involvement
Muscles can also be involved in dengue infection. Dengue virus
infection can present with varying degrees of transient myalgia,
characterised by muscle tenderness on stretching, motor weakness, raised amounts of muscle enzymes, and in very severe cases
rhabdomyolysis [2022]. The muscle dysfunction is usually

Ability of virus to infect and replicate in neural cells is known as

neurotropism. Viral antigens and DENV RNA has been detected in
brain tissue of infected individuals [15,16,26]. More evidence of
CNS infection is the viral detection of DENV-2, -3 and -4 in the CSF
in cases of encephalitis, meningitis and myelitis.
3.3. DENV neurovirulence
Neurovirulence can be dened as the ability of the virus to
induce neurologic disease. In mouse models DENV has shown
apoptotic cell death. Nevertheless, when evaluating natural human
infections, those ndings were not observed. Complete genome
characterisation of DENV-4 did not reveal any of the described
mutations associated with neurological strains.
Recently in a retrospective study at tertiary care centre of
137 patients of serologically conrmed dengue by Mishra et al.
from northern India, neurological manifestations were present in
79% cases, including dengue encephalopathy in 17 (15%),
encephalitis in 22 (19%), dengue-associated transverse myelitis

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in one (1%), and muscle dysfunction in 52 (44%) patients. Authors

also reported that CNS manifestations were seen more frequently
in DHS/DHF than DF cases. Mortality is noted in 11 cases (9.5%), all
of them were dengue shock syndrome. Authors found that DEN3
and DEN4 serotype were most common in their study population
[39].
4. Conclusion
Of late, it is becoming obvious that dengue can involve nervous
system and any part of the CNS can be involved be it brain, nerves
or muscle. Pathogenesis of nervous system involvement is still
elusive and needs further human studies to establish pathogenesis
of DENV infection in CNS. Neurological involvement of dengue
confers the individuals at high risk of mortality as well as
morbidity. Therefore recognition of early signs and symptoms of
neurological involvement is required to prevent mortality and
morbidity associated with neurological manifestations of dengue.
Conicts of interest
The authors have none to declare.
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Please cite this article in press as: Kumar A, Margekar SL. Neurological manifestations in dengue. Indian J Med Spec. (2016), http://
dx.doi.org/10.1016/j.injms.2016.09.009