Neurological manifestations of dengue

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1 Pediatric Infectious Disease 2012 December Volume 4, Number 4; pp. 160e164 Review Article Neurological manifestations of dengue Preeti Singh a, *, S. Aneja b ABSTRACT Dengue, the most common arboviral disease is fast emerging as a global health problem. The incidence and geographical distribution of dengue have greatly increased in recent years. Neurological manifestations are considered a rare complication of dengue infection, although a wide range of them have been reported in literature. The exact incidence of various neurological complications is uncertain. The pathogenesis of neurological complications can be related to the systemic effects of the infection, neurotropic effect of the virus and immune mediated. Detection of IgM in CSF using ELISA has a high specificity. Mortality due to neurological involvement is low and patients die due to other multisystem involvement. In dengue-endemic areas, it is prudent and justified to include dengue in the differential diagnosis of patients with fever and acute neurological manifestations. Copyright 2012, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved. Keywords: Dengue, Neurological manifestations, Encephalitis, CSF examination EPIDEMIOLOGY Dengue viruses are single stranded RNA viruses belonging to the family Flaviviridae. Dengue virus infections cause a spectrum of illnesses e classical dengue fever (DF), DF with haemorrhagic manifestations, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). There are four antigenically related but distinct dengue virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4) all of which can cause DF and DHF. The infection is transmitted by infected female Aedes mosquitoes. Incubation period of these viruses ranges from 2 to 7 days after which they cause a range of similar clinical syndromes. 1 Infection with one serotype is thought to produce lifelong immunity to that serotype but only a few months immunity to the others. Dengue fever is one of the leading causes of hospitalization and death among children. 2 Epidemics of dengue are being seen in almost all countries located within the tropical belt. 3 The increasing incidence of flavivirus infection has been linked to explosive population growth, unplanned urban overpopulation with inadequate public health systems, resurgence of the vector Aedes aegypti, as well as to increasing travel. Dengue has been regarded as a nonneurotropic virus. In recent years, unusual manifestations of dengue infection, including neurological syndromes, have been described. Sanguansermsri et al first reported this association in Since then there have been various case reports and original articles published on this subject. All ages and both sexes are affected by the neurological complications. Cases have been reported among ages ranging from 3 months to 60 years. 4 However, there is a greater incidence among children. In dengue-endemic areas, this infectious agent must be kept in mind when exploring causes of encephalitis and encephalopathy. The incidence of neurological symptoms among dengue patients varies from 1% to 25% of all dengue admission. 3e5 a Assistant Professor, Pediatrics, Chacha Nehru Bal Chikitsalaya, Geeta Colony, b Director, Professor and Head, Department of Pediatrics, Kalawati Saran Childrens Hospital, New Delhi, India. * Corresponding author. Tel.: þ (mobile), drpreetisingh3@gmail.com Received: ; Accepted: ; Available online: Copyright Ó 2012, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.

2 Neurological manifestations of dengue Review Article 161 PATHOGENESIS AND CLINICAL FEATURES Three types of neurological manifestations have been associated with confirmed dengue infection: a) Neurological manifestations secondary to prolonged DHF/DSS: altered consciousness, convulsions, and coma have been ascribed to an encephalopathy, 6e10 resulting from the leakage of plasma into serous spaces, haemorrhage, shock, and metabolic disturbances. b) Classical signs with acute infection which are related to neurotropic effect of virus: encephalitis, 3 meningitis, 11 myositis. 6 c) Post infection disorders: ADEM (acute disseminated encephalomyelitis), 3 encephalomyelitis, 3 transverse myelitis, 3 GBS, 12e14 Reye s syndrome, 15 Bell s palsy, and amnesia. 16 There has been convincing evidence of dengue neurovirulence. Given lack of evidence supporting viral invasion of the CNS, the term encephalopathy instead of encephalitis has been used previously. The involvement of central nervous system has always been thought to be secondary to vacuities and leaky capillary syndrome with resultant fluid extravasations, cerebral oedema, hypoperfusion, hyponatremia, liver failure and or renal failure. It was called as dengue encephalopathy. 3,17e20 Encephalitis can only be said to have occurred when a histological diagnosis is available. 3,21 Several studies have however based their diagnosis of encephalitis on indirect evidence, including absence of other explanations for encephalopathy, isolation of virus in CSF or its serological evidence, CSF pleocytosis or focal neurological signs. 3 Certain case reports have indicated that dengue viruses can cross the blood brain barrier and set up infection in the central nervous system as demonstrated by virus isolation from brain tissue and CSF of patients with dengue and neurological manifestations. 3,17e19,22 Animal studies have shown a virus mediated breakdown of blood brain barrier. The infiltration of virus-infected macrophages could also be one of the pathways by which the virus enters the brain in dengue encephalitis. 19 The incidence of neurological manifestations in patients diagnosed with dengue haemorrhagic fever (DHF) and severe dengue has been documented to vary from 3% in prospective DHF studies to 25% in retrospective studies. 23,24 Dengue neurological presentation is most commonly seen with paediatric age group as with earlier studies. 23 A paediatric study from Thai children reported the incidence of neurological manifestations of dengue to be 5.4% with encephalopathy and seizure as common presentations. 21 Encephalitis is also known to be one of the frequent presenting manifestations of dengue neurological disease. 23 DEN-2 and DEN-3, especially can cause dengue encephalitis in the form of both primary and secondary infections. 18 There are not many studies documenting meningitis as a feature of dengue neurological disease. 21,23 Clinical signs noted among such patients include drowsiness and nuchal rigidity as a feature of meningitis or meningoencephalitis. In India, headache was reported in 34 and drowsiness in 28 in a prospective study based on a total of 59 children seropositive for dengue. 25 Dengue patients with neurological manifestations often present with convulsions. 17 Seizures and pyramidal tract signs have been documented to occur in 43e63.3% and 16.7e36.7% of dengue neurological disease respectively. 21,23 Seizures occurring in dengue infected patients have been associated with intracerebral haemorrhages. 26 Seet et al 27 postulated that flaccid paralysis may be associated with acute parainfectious dengue infection and spastic weakness with postinfectious dengue infection. Acute hepatic failure has been reported as a part of dengue viral syndrome. The association between severe liver disease and encephalopathy has been described in paediatric and adult patients with DF 10,28 and DHF. In a study by Misra et al, 6 out of 17 patients with neurological syndrome associated with dengue infection, 11 patients had febrile encephalopathy and 6 had acute pure motor weakness. In the patients with encephalopathy, 3 presented with seizures, 1 had myoclonus, CSF pleocytosis and EEG slowing were present in 8 each and globus pallidus and thoracic spinal cord involvement on MRI in 1 patient each. In the pure motor weakness group, CK was elevated in 5 and EMG and muscle biopsy were consistent with myositis in 1 patient each. Acute muscle weakness was attributed to myositis because of reduced or normal reflexes, raised CK, myopathic EMG and suggestive histopathology. GB syndrome was ruled out because of presence of fever at time of weakness, normal nerve conduction studies and absence of albumin-cytological dissociation. The patients with pure motor weakness improved completely but in the encephalopathy group 3 died, 2 had partial, 1 poor and 5 complete recovery by 1 month. Dengue myositis has been reported in 2 other patients who were also diagnosed on the basis of raised CK. 29 In all flavivirus infections involving the nervous system, a small proportion has a lower motor neuron syndrome with their other manifestations. INVESTIGATIONS Investigations in dengue with CNS involvement include complete blood count, serology in blood and CSF, CSF examination (cell count including the differential, protein glucose and viral culture), EEG, and finally the imaging

3 162 Pediatric Infectious Disease 2012 December; Vol. 4, No. 4 Singh and Aneja (CT/MRI). Laboratory diagnosis of dengue is established directly by detection of viral components in serum or indirectly by serologic means. Blood During the febrile phase, detection of viral nucleic acid in serum by reverse-transcriptase-polymerase-chain reaction (RT-PCR) assay or detection of the virus expressed soluble nonstructural protein 1 (NS1) by means of enzyme-linked immunosorbent assay (ELISA) is sufficient for a confirmatory diagnosis. 30 For primary infections diagnostic sensitivity of NS1 detection in the febrile phase can exceed 90%, and antigenemia may persist for several days after the resolution of fever, while it is lower (60%e80%) for secondary infections. 31 It is known that dengue IgM appears in serum as early as 4 days after the onset of fever, and in the case of a second infection, achieves low levels. 2 Titre of antibodies in serum usually persists for 30e90 days, although it has been reported to be detectable as long as 252 days after onset. IgM seroconversion between paired samples is considered confirmatory, whereas detection of IgM in a single specimen obtained from a patient with a clinical syndrome that is consistent with dengue is widely used to establish a presumptive diagnosis. 30 CSF examination including CSF serology CSF examination in a case of dengue with neurological syndrome reveals high opening pressure, CSF protein above 45 mg/dl (80%) and CSF pleocytosis (87%). 32 Neurological and cerebrospinal fluid (CSF) findings of 13 patients with dengue infection were studied by Soares et al. 32 High protein concentration was the most common CSF alteration found in 47% of the cases whereas the CSF was normal in 57% of the patients with encephalitis. The GBS and myelitis patients had a high Alb Q (> ), indicating a bloodecsf barrier dysfunction. The ELISA test for dengue specific IgM antibodies on CSF revealed 46% sensitivity and 97% specificity in patients with neurological symptoms associated with dengue infection. 32 A survey describing 9 patients with encephalitis in association with dengue infection, detected the presence of virus or dengue specific IgM antibodies in CSF (using double sandwich capture ELISA) in 4 patients. 3 In another study, dengue virus was observed in the CSF in 5 of 6 patients presenting with encephalitis, indicating that virus may cross the bloodebrain barrier and directly invade the brain. 18 Search for viral RNA or viral isolation was negative in the remaining patient, but specific IgM was found in the CSF. 18 Detection of IgM in CSF is indicative of viral replication in CNS, but the titre is generally lower and short-lived when compared with serum. 30 Sensitivity of the ELISA test for dengue specific IgM antibodies on CSF depends upon time of onset of the symptoms until the lumbar puncture, the CSF dilution and the presence of primary or secondary infection. 32 Antibodies in the CSF however, usually disappear within a month after onset of illnesses. 33 Electroencephalography Neurological dengue infections have resulted in nonspecific electroencephalographic slowing 34 ; however other conditions such as seizures, metabolic encephalopathy or structural brain lesions may also cause these changes. Imaging CT scan has been reported to show cerebral oedema in patients with dengue associated encephalopathy. 3 The study on MR imaging in dengue encephalitis is by Cam et al 17 who reported MRI findings in 18 patients of which only 2 patients showed encephalitis like changes and rest showed only cerebral oedema. MRI findings in other arboviral infections like Japanese encephalitis 6 and eastern equine encephalitis includes involvement of thalamus, basal ganglia and brainstem. Bilateral symmetrical thalamic involvement is suggestive of Japanese encephalitis but similar MRI finding has been reported in dengue encephalitis. 35 Prognosis Most patients completely recover by the time of hospital discharge. Mortality rates reported in cases of neurological dengue and severe dengue ranged from 5% to 8.35%. 21,23,24 Causes of death include multi-organ failure, haemorrhagic complications, and circulatory collapse. The median coma recovery time for admitted patients with reduced consciousness was 3.5 days (range 1e45) days. 3 Neurological sequelae reported in literature include spastic paresis, static myelopathy following transverse myelitis, prolonged drowsiness, abnormal affect and altered personality 3 and residual paralysis. However, developmental assessments were normal in all children at follow up. 3 Dengue fever should be included in the differential diagnosis of a person presenting with fever and neurological symptoms. This becomes especially important in endemic areas or during epidemics in other areas.

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