Journal of Clinical Virology 77 (2016) 29–31

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Journal of Clinical Virology

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

Case report

Early Guillain–Barré Syndrome associated with acute dengue fever

O. Simon a,∗ , S. Billot a , D. Guyon a , M. Daures b , E. Descloux c , A.C. Gourinat d , N. Molko a ,
M. Dupont-Rouzeyrol e
a
Department of Neurology, Territorial Hospital, Noumea, New Caledonia
b
New Caledonia Health Department, Noumea, New Caledonia
c
Department of Internal Medicine and Infectious Diseases, Territorial Hospital, Noumea, New Caledonia
d
Immuno-Serology and Molecular Biology Lab, Institut Pasteur in New Caledonia, Institut Pasteur International Network, Noumea, New Caledonia
e
Dengue and Arboviruses Expertise and Research Unit, Institut Pasteur in New Caledonia, Institut Pasteur International Network, Noumea, New Caledonia

a r t i c l e i n f o a b s t r a c t

Article history: Various forms of neurological manifestations are reported in dengue fever. We describe here three cases
Received 18 September 2015 of concomitant Guillain–Barré syndrome and dengue virus (DENV) infection during the largest DENV-1
Received in revised form outbreak in New Caledonia. Research of viral RNA was positive in both blood and CSF samples. All patients
16 December 2015
were treated with intravenous polyvalent immunoglobulins and recovered without sequelae within one
Accepted 29 January 2016
week.
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Dengue
Guillain–Barré Syndrome
Acute
Infectious disease
Neurology

1. Why this case is important? 2. Case description

We report herein three cases of concomitant Guillain–Barré syn-
drome (GBS) and dengue fever during the largest dengue virus
(DENV) outbreak ever reported in New Caledonia (2012–2013) [1].
To our knowledge, these cases represent the first description of
concomitant GBS and DENV infection diagnosed by RT-PCR. In our
cases both sera and cerebrospinal fluid (CSF) taken before two and
after three days of the onset of neurological symptoms were pos-
itive for DENV. The three patients were treated with intravenous
polyvalent immunoglobulins and recovered without sequelae.
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DENV,
dengue virus; DF, dengue fever; EMG, electroneuromyography; GBS, Guillain–Barré
syndrome; HIV, human immunodeficiency virus; IVIg, intravenous polyvalent
immunoglobulins; MRI, magnetic resonance imaging; RNA, ribonucleic acid;
RT-PCR, reverse transcriptase polymerase chain reaction; WHO, World Health Orga-
nization.
∗ Corresponding author at: Department of Neurology, Gaston Bourret Territorial
Hospital, BP J5, 98849 Noumea, New Caledonia.
E-mail address: o.simon@cht.nc (O. Simon).
The three patients were two males and one female with a mean
age of sixty years old (range 55–68). They were from various origins,
Melanesian, Indonesian and Caucasian. One of them had a signif-
icant medical history of Basedow disease but without treatment
(Table 1).
Dengue fever (DF) symptoms included acute fever, headaches,
muscle and joint pains without any haemorrhagic signs. Mean
latency between fever and the neurological symptoms was 2 days
(range 1–3). Only in case 2 the diagnosis of DF was confirmed by
DENV RT-PCR two days before the beginning of the neurological
symptoms. The ascendant course of the neurological symptoms
was fast and within the first seventy-two hours all of the patients
had areflexic tetraparesis with gait disorder and two of them had
multiple cranial nerves palsies with dysphagia and bilateral facial
palsy (Table 1).
Blood tests revealed initial lymphopenia then thrombopenia
(Table 1). CSF analysis performed within 3 days after the onset of
the neurological symptoms was normal without pleocytosis nor
hyperproteinorachy. Research of DENV on both serum and CSF by
RT-PCR was positive for DENV-1 for all patients. Viral loads were
lower in CSF than in serum samples. Earliest blood samples were
assessed for DENV IgG. All patients were IgG negative, suggesting
primary dengue infection.

http://dx.doi.org/10.1016/j.jcv.2016.01.016
1386-6532/© 2016 Elsevier B.V. All rights reserved.
30 O. Simon et al. / Journal of Clinical Virology 77 (2016) 29–31

Table 1
Clinical and biological features among the three cases infected by dengue virus with concomitant Guillain–Barré syndrome, New Caledonia, 2012–2013.
Number in brackets: day of analysis expressed in days from the onset of dengue disease

Cases

1 2 3

Sex Male Female Male

Age 68 55 58
Medical history Mitral prolapse with flail leaflet Depressive symptoms Basedow disease, Gout

Clinical description
Delay between onset of dengue 1 2 3
and onset neurological
manifestations (day)
Neurological signs Tetraparesis with distal Tetraparesis with upper limb Tetraparesis with proximal
predominance and proximal predominance predominance
Deep tendon reflexes Brachioradialis and ankle Upper limb reflexes abolished, All abolished
reflexes abolished, others lower limb reflexes diminished
diminished
Sensory involvement Upper and lower limb distal Hypoesthesia of both hands No
hypoesthesia
Cranial Yes No Yes
nerves Bilateral VII Bilateral VII
palsy Bilateral IX Left IX
Left XII Left III
Breathing dysfunction No No No
Autonomic nervous system No No No
dysfunction
Neurological evolution Complete recovery Complete recovery Complete recovery
IVIg treatment Yes Yes Yes

Laboratory abnormalities
Leucopenia (N = 4–10 × 109 /L) 1.5 × 109 /L [3] 2.1 × 109 /L [2] 1.5 × 109 /L [6]
Lymphopenia (N = 1–4 × 109 /L 0.51 × 109 /L [3] 0.52 × 109 /L [2] 0.6 × 109 /L [6]
Thrombopenia 23 × 109 /L [5] 30 × 109 /L [6] 23 × 109 /L [7]
(N = 150–400 × 109 /L)

Diagnostic
DENV RT-PCR (Serum/CSF) Positive/positive Positive/positive Positive/positive
Antigangliosides antibodies Negative Negative AntiGD1b strongly positive
EMG Demyelinating Demyelinating Quite normal
polyradiculopathy polyradiculopathy

Electroneuromyography (EMG) was performed within 5 days
after the beginning of the acute paralysis and revealed for 2
patients demyelinating disorders according to Cornblath criterias
[2]: motor conduction velocity were slowed with distal motor
latencies prolonged in one case, F waves latencies were prolonged
and conduction blocs were observed in two cases. For the third
case, electroneuromyography was slightly disturbed but he had
anti-gangliosides antibodies anti-GD1b strongly positives. All other
etiologies of acute polyradiculitis were ruled out by history and rel-
evant investigations including serum electrolytes and creatinine
phosphokinase, antinuclear antibodies, anti-cytoplasmic polynu-
clear antibodies, serum protein electrophoresis and serological
tests for Campylobacter jejuni, Cytomegalovirus, Epstein–Barr virus,
human immunodeficiency virus (HIV), hepatitis B and C viruses
and leptospirosis. The two patients with multiple cranial nerve
palsy had normal brain magnetic resonance imaging (MRI). Medical
treatment consisted in intravenous polyvalent immunoglobulins
(IVIg) 2 g/kg over 2 or 3 days. None of them required intensive
cares. All patients recovered within one week and were discharged
at home. None of them had sequelae after 2 months of follow-up
(Table 1).
Regarding our investigation, we proposed a diagnostic of GBS
for our three patients (Table 1). The high level of anti-gangliosides
antibodies found in case 3 was in favor of GBS. Other complica-
tions of DF were ruled out including acute dengue myositis and
hypokalemic paralysis. In the two other patients, multiple cranial
palsies, associated with a normal brain MRI were suggestive of a
peripheral neuropathy.
3. Other similar and contrasting cases in the literature
Dengue is the most prevalent arthropod-borne human viral
infection in tropical and subtropical countries. DENV is a
single-stranded, positive-sense RNA virus of the genus Flavivirus
transmitted by Aedes mosquitoes. Infection with one of the four
distinct serotypes (DENV-1 to DENV-4) does not provide long-
term cross-protective immunity against the three others. Incidence
of dengue has grown dramatically over the last decades [3].
Over 40% of the world’s population is now at risk. WHO cur-
rently estimates there may be 50–100 million dengue infections
worldwide every year. DENV infection can cause a wide range
of diseases in humans even though DENV infections may also
be asymptomatic. The diseases range in severity from undiffer-
entiated acute febrile illness, classical DF, to the life-threatening
dengue haemorrhagic fever and dengue shock syndrome. Clas-
sical symptoms include headaches, retro-orbital pain, myalgia,
arthralgia and rash [1]. In 2009, WHO endorsed new guidelines
that, for the first time, consider neurological manifestations in
the clinical case classification for severe dengue [4]. A recent
review indicates that the proportion of DF with neurological
manifestations ranged between 0.5% and 5.4% in four studies
from Southeast Asia and was found to be 21% in a prospective
study from Brazil [5]. Neurological complications of DENV infec-
tion can be categorized into dengue encephalopathy, encephalitis,
immune-mediated syndromes, dengue muscle dysfunction, and
neuro-ophthalmic disorders [5]. Another review indicates that the
peripheral nervous system manifestations account for 5% of neuro-
logical manifestations of DF and occur later than the central nervous
system (CNS) manifestations [6].
 O. Simon et al. / Journal of Clinical Virology 77 (2016) 29–31
The Guillain–Barré syndrome (GBS) is characterized by acute
areflexic paralysis with albuminocytologic dissociation in cere-
brospinal fluid (CSF) [2]. A history of upper respiratory infectious
symptoms or diarrhea 3 days–6 weeks before the onset is found
in two third of cases with a peak incidence between one and
two weeks. The autoimmune cause of this syndrome is well
established. The classification of GBS subtypes includes acute
inflammatory demyelinating polyneuropathy and acute motor
axonal neuropathy. It is important to notice that the albuminocyto-
logic dissociation is present in only 50% of patients during the first
week of illness.
DF preceding GBS has been described in case reports and case
series of patients presenting various neurological manifestations.
About 20 cases of GBS following DF infection have been described
[5,6]. Usually acute onset of limb weakness and areflexia were
noted at least one week after the onset of symptoms. The mean
latency cannot be calculated. In almost all cases, it has been con-
sidered as a post infectious disease due to the immune mediated
disorder. Both axonal and demyelinating polyradiculoneuropathy
were described.
To our knowledge, one case of concomitant SGB and DF has been
described but RT-PCR for DENV in both blood and CSF samples were
negative [7]. A second case has been reported but viral RT-PCR was
not performed [8]. For both cases, the diagnosis was based only
on the detection of IgM in the serum. One case of Miller Fisher
syndrome following DF infection has been reported with a latency
of only 2 days. Research of viral RNA was positive in both serum
and CSF samples and the patient recovered in one week [9].
4. Discussion
These three cases of GBS with DENV RT-PCR positive in both
serum and CSF are original. The simultaneous occurrence of GBS
and DF has only been described in two cases [7,8] but the diagnostic
has not been confirmed by RT-PCR, NS1 antigen or cell culture. In
all others cases of GBS, DF occurred at least one week after the
beginning of DF and after the viremic phase that is usually lasting
7 days after the disease onset [3]. In our cases, detection of viral
RNA in both serum and CSF samples confirms that neurological
manifestations started very early after the onset of DF.
As all our patients were primary dengue infection, this early neu-
rological complication cannot be related to antibody-dependant
enhancement as often described in secondary dengue hemorrhagic
fever [10]. The timing between the beginning of DF and GBS, the
detection of the viral RNA in CSF and the complete regression of
the neurological symptoms in one week suggest that these cases
may have an infectious origin rather than a post-infectious ori-
gin such as in GBS. However, the fast and complete recovery did
not allow us to perform nerve biopsy to confirm this hypothesis.
The neurotropism of dengue virus is well established for the CNS
but has not been studied for the peripheral nervous system. DENV
could actively enter in the CNS and the presence of the virus in the
CNS would not result from passive crossing of the blood–brain bar-
rier [11]. Viral infection of Schwann cell has only been studied for
Theiler’s Myeloencephalitis virus. In this study it has been observed
in a murine model demyelination coincident with viral replication
within the nerve [12]. In contrast to cases 1 and 2, the high level
of antiganglioside antibodies found in case 3 suggests an immune
mediated disorder rather than an infectious mechanism.
In our three cases, IVIg appeared to be a safe and effective
treatment. Other cases of GBS and acute virus infection treated
with efficient IVIg therapy have been reported in literature. Some
authors recommend the use of IVIg for SGB in cases of acute HIV
infection. Sloan et al. have reported one case and review five oth-
ers cases of GBS occurring at early stage of HIV infection [13]. The
31
patients were previously anti-retroviral naïve so no drug toxicity
can be evoked. Possible mechanisms include direct HIV neurotoxi-
city or autoimmunity. Half of them were treated with IVIg therapy
before starting highly active anti-retroviral therapy and completely
recovered.
These case reports highlight that GBS can occur very early dur-
ing DF with atypical evolution and that IVIg represents a safe and
effective treatment.
Conflict of interest
None to declare.
Funding
None.
Ethical approval
None.
Acknowledgments
We would like to thank the personnel from Gaston Bourret Hos-
pital and Institut Pasteur in New Caledonia for their work during
this dengue outbreak.
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