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Neurological manifestations of dengue infection

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  • Neurological manifestations of dengue infection

    The Lancet 2000; 355:1053-1059
    Neurological manifestations of dengue infection

    Tom SolomonMRCP a e , Nguyen Minh DungMD b, David W VaughnMD c, Rachel KneenMRCP a e, Le Thi Thu ThaoMD b, Boonyos RaengsakulrachPhD c, Ha Thi LoanMD b, Nicholas PJ DayMRCP a e, Jeremy FarrarMRCP a e, Khin SA MyintMD c, Mary J WarrellMRCPath d, William S JamesDPhil d, Amanda NisalakMD c and Prof Nicholas J WhiteFRCP a e

    Patients and methods


    BackgroundSevere forms of dengue, the most important arboviral infection of man, are associated with haemorrhagic disease and a generalised vascular leak syndrome. The importance of dengue as a cause of neurological disease is uncertain.

    MethodsDuring 1995, all patients with suspected CNS infections admitted to a referral hospital in southern Vietnam were investigated by culture, PCR, and antibody measurement in serum and CSF for dengue and other viruses.

    FindingsOf 378 patients, 16 (4?2%) were infected with dengue viruses, compared with four (1?4%) of 286 hospital controls (odds ratio [95% CI] 3?1 [1?7?5?8]). Five additional dengue positive patients with CNS abnormalities were studied subsequently. No other cause of CNS infection was identified. Seven infections were primary dengue, 13 secondary, and one was not classified. Ten patients had dengue viruses isolated or detected by PCR, and three had dengue antibody in the CSF. 12 of the 21 had no characteristic features of dengue on admission. The most frequent neurological manifestations were reduced consciousness and convulsions. Nine patients had encephalitis. No patient died, but six had neurological sequelae at discharge. Phylogenetic analysis of the four DEN-2 strains isolated mapped them with a DEN-2 strain isolated from a patient with dengue haemorhagic fever, and with other strains previously isolated in southern Vietnam.

    InterpretationIn dengue endemic areas patients with encephalitis and encephalopathy should be investigated for this infection, whether or not they have other features of the disease.
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    Dengue is the most important arboviral infection of man, with an estimated 100 million cases per year and 2?5 billion people at risk.1,2 Infection presents classically as dengue fever, a self-limiting but severe influenza-like illness, or dengue haemorrhagic fever (DHF). In southeast Asia, this is a disease predominantly of children and characterised by increased vascular permeability, plasma leakage, haemorrhagic manifestations, and thrombocytopenia.2 Epidemiological evidence suggests that DHF is most likely when infection with one dengue serotype is followed by a secondary infection with a different serotype. Because of controversy over whether dengue viruses cause neurological disease,3?6 we investigated prospectively the role of dengue in acute nervous system infections in southern Vietnam.
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    Patients and methods


    The study was conducted on the intensive-care units at the Centre for Tropical Diseases, Ho Chi Minh City, an infectious disease referral hospital for much of southern Vietnam, a region where dengue and Japanese encephalitis are endemic. The study protocol was approved by the hospital's scientific and ethical committee, and consent was obtained from the patient or accompanying relative.
    From Jan 1 to Dec 31, 1995, all children (under 15) and adults with a suspected CNS infection were studied. CNS infections were suspected in patients with a fever or history of fever, and at least one of the following: reduced level of consciousness (Glasgow coma score ≤14, or for children below 6 years, Blantyre coma score ≤4);7 severe headache; neck stiffness; focal neurological signs; tense fontanelle; or convulsions. Patients with slide-positive cerebral malaria or clinical features of tetanus were admitted to specialised wards and were not included in this series. Nor were children between 6 months and 5 years of age with a simple febrile convulsion (defined as a single convulsion lasting less than 15 min with recovery of consciousness within 60 min).
    A full history included details of drugs and other potential CNS toxins (alcohol, recreational drugs). A detailed clinical examination, including full neurolgical examination, was done every day by a member of the study team until the patient's discharge. At lumbar puncture opening pressures were measured, and CSF was taken for cell count and differential, protein, glucose, Gram stain, and bacterial and viral culture. Blood was taken for haematocrit, examination for malaria parasites, platelet count, differential white cell count, blood cultures, biochemical screen, and viral serology.8
    Patients with reduced consciousness were defined clinically as having encephalitis if there was no metabolic abnormality or other apparent explanation, and if they had any of the following: CSF pleocytosis (corrected white cell count >5/μL), focal neurological signs, or convulsions other than simple febrile convulsions.9 If they had none of these features they were considered to have an acute encephalopathy.9 Convulsions were treated with intravenous diazepam; repeated convulsions were treated with intravenous phenobarbitone. Patients with clinical signs of raised intracranial pressure were treated with mannitol. Suspected septicaemia was treated with a third-generation cephalospoin and gentamicin.
    Patients admitted with DHF and no CNS abnormalities were graded I?IV using WHO criteria, modified to allow for manual platelet counting. Patients with dengue shock syndrome (DHF grades III and IV) were given Ringer's lactate and dextran 40.2
    Following the one year study, when computer tomography became available, five further patients with neurological manifestations of dengue were investigated, and are included in this report.

    Virological and serological studies

    IgM and IgG antibodies to dengue and to Japanese encephalitis virus were measured in acute and convalescent sera and in CSF using a double sandwich capture ELISA.10 For single serum samples 40 units of IgM to dengue (with dengue IgM greater than Japanese encephalitits virus IgM), or for paired samples a rise from less than 15 to more than 30 units was considered evidence of acute dengue infection.10 An IgM/IgG ratio of 1?8/1 or more was considered evidence for a primary dengue infection, whilst a ratio below 1?8 was considered evidence for a secondary infection.10 IgG >100 units with IgM between 20 and 40 units was considered evidence of recent secondary dengue infection.
    For serological studies we recruited as controls 120 children with diphtheria and 166 adults with typhoid sequentially admitted to specialised wards. At this hospital both diseases have geographical distributions and referral patterns similar to those for CNS infections.
    To type the dengue infections, virus isolation and nucleic acid amplification were performed on sera and CSF. About 15 live Toxorrhyncites splendens mosquitoes were injected with 0?34 μL of undiluted sample. After 14 days about 10 surviving mosquitoes were tested for flavivirus antigen by indirect fluorescent antibody assay of the head.11 Virus positive mosquitoes were used to infect Aedes albopictus C6/36 cell cultures for identification of virus type using a panel of monoclonal antibodies against dengue and Japanese encephalitis virus in an ELISA.12 Dengue virus RNA was amplified by reverse transcriptase nested PCR of CSF and serum.13 Isolation of or PCR detection of dengue viruses in CSF or a CSF anti-dengue IgM titre above 30 units were considered diagnostic of CNS infection.14,15 Culture and PCR were not done on controls.
    To exclude other viral causes of CNS infection, CSF was inoculated into Vero cells and rhesus monkey kidney (LLCMK2) cells, and examined by nested PCR for evidence of enteroviruses, herpes, measles, mumps, or Epstein-Barr virus, and cytomegalovirus.16 CSF and acute serum were also examined for Leptospira by PCR.17 Paired sera were assayed for antibodies to enteroviruses, herpes, measles, and mumps virus, cytomegalovirus, and Mycoplasma pneumoniae using complement fixation tests; for leptospirosis using the microagglutination test; and for Salmonella typhi using the Widal test. Single serum samples were assayed for Epstein-Barr virus and HIV by IgM ELISAs.
    Sera from patients with raised bilirubin and liver transaminases were tested for hepatitis A virus IgM; IgM to hepatitis B virus core and surface antigens; and hepatitis C virus total immunoglobulins using enzyme immunoassays (HAVABM EIA; Corzyme-M, and AUSYME monoclonal assays; HCV EA 2nd Generation [Abbott Laboratories]).

    Phylogenetic analysis

    To investigate whether DEN-2 isolates in this study were likely to represent strains circulating in southern Vietnam or new imported strains, we contructed phylogenetic trees for isolates of DEN-2 viruses cultured from the CSF and serum of two patients. A 240 base-pair fragment encoding the junction between the envelope and NS1 (non-structural) protein genes was sequenced18 from published primer pairs.19 Fragments were compared with those of a DEN-2 isolate from a child with classical DHF, and with 181 homologous sequences of DEN-2 viruses in the GenBank database using the program ClustalX. Phylogenetic trees were displayed using NJPlot.


    The odds ratio (OR) with 95% confidence interval (CI) was used to express the strength of the association between a neurological presentation and the dengue result. Diferences between proportions were tested by Fisher's exact test (Statview 4.02; Abacus Concepts).
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    378 patients (228 adults 150 children) with suspected CNS infections were admitted to the hospital. 16 (4?2%; nine adults and seven children) were infected with dengue viruses compared with four (1?4%, all children with diphtheria) of 286 matched hospital controls (OR 3?1 [1?7?5?8], p=0?039). CNS patients with other diagnoses have been reported previously.8,20 During the same period 1675 patients (1405 children) were admitted with clinically diagnosed DHF of whom 296 (18%, 277 children) had dengue shock syndrome, including 10 (0?6%, 9 children) with DHF grade IV. Thus a neurological presentation occurred in 16 (1%) of 1691 patients admitted with suspected dengue infection.

    Virology and serology

    The 21 patients (16 from the one year study and the five subsequent patients) are summarised in table 1. DEN-3 was isolated from the serum of three patients, DEN-2 from the serum of one and from serum and CSF of two patients, and DEN-1 from the serum of one patient. In six cases dengue virus RNA was detected by PCR. The CSF samples positive for dengue virus were not bloody except for one sample which contained 2 red cells/μL. 20 of the 21 patients had serological evidence of dengue infection and six had evidence of CNS infection by dengue viruses. Seven infections were classed as primary and 13 as secondary; one patient could not be classified serologically. Six patients seroconverted during their first week in hospital. No patient had Japanese encephalitis virus cultured from CSF or serum. Patient 12 had HBsAg and patient 4 had antibodies to HBsAg in serum. Patient 6 had Leptospira detected in the serum by PCR but not in the CSF. No other viruses or bacteria were isolated or detected, serologically or by PCR.

    Click to view table

    Table 1. Virological studies on 21 patients with neurological manifestations of dengue infection

    Clinical and demographic features

    Eight patients were from Ho Chi Minh City; 16 patients were admitted during the rainy season (May to October) (table 2). One child (patient 14) had had a convulsion in the past. Five patients had received antibiotics (cephalosporins) and one had received artesunate. All 21 patients were febrile on admission. 18 patients had a reduced level of consciousness; three were fully conscious, one with a severe headache, meningism, and vomiting, and two with a spastic paraparesis.

    Click to view table

    Table 2. Clinical features

    In seven patients neurological manifestations coincided with clinical features of DHF: one patient had haemoconcentration (haematocrit 38% on admission, 33?5% at discharge) and a petechial rash, five had bleeding or petechiae and a narrow pulse pressure, and one had grade IV dengue shock. Two patients had manifestations of dengue fever without significant vascular leak (one with petechial rash, the other with bruising). In patient 10 a spastic paraparesis followed a dengue-like illness by 2 weeks.
    In 12 patients there were no characteristic features of dengue on admission. Seven of these were children, who presented typically with a short febrile prodrome of headache, vomiting, cough, and coryza, followed by a reduced level of consciousness, often heralded by convulsions. Three adults with abnormal behaviour were initially thought to have hysteria. Eight patients had generalised convulsions, and one had right-sided focal convulsions of the arm and leg. Eight of the unconscious patients had focal neurological signs on admission.

    Laboratory findings

    Three patients had CSF opening pressures above 20 cm; three had CSF pleocytosis (>5/μL) and seven had CSF protein above 45 mg/dL. CSF to plasma glucose ratios were normal. Three patients had a peripheral leukocytosis (>11?109/mL), and two had leukopenia (<4?109/mL). No patient had hypoglycaemia. Five encephalopathic patients had liver transaminases more than 10 times normal with raised total bilirubin and a bleeding diathesis. Prothrombin time was measured in two of these, and was prolonged (30 s and 34 s). One of these also had moderate hyponatraemia (128 mmol/L). Five further patients had mild hyponatraemia (130?135 mol/L). Acute CT scans were possible on three patients. Patients 13 and 21 had normal scans. Patient 20 had diffuse brain swelling; and an EEG on admission was abnormal, with high-amplitude periodic slow wave complexes (2?3 Hz) on a featureless background.


    Three patients with severe DHF deteriorated. Patient 4 developed arm dyskinesias and lipsmacking, pleural effusions, and a bleeding diathesis. She became anaemic and required 2 units of blood before eventually recovering fully. Patient 8 developed disseminated intravascular coagulation and oliguric acute renal failure, requiring peritoneal dialysis. Her coma score deteriorated to 5, with tremors of the right arm and downward deviation of the eyes (figure 1). Patient 12 had further generalised convulsions and developed rigidity spasms. Of the 12 patients with purely neurological presentations, one subsequently developed DHF grade III, and three developed a dengue recovery rash just before discharge (figure 2), but in the other eight patients there were no features of dengue at any time in the illness.

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    Figure 1. Downward deviation of eyes in a comatose 19-year-old woman with acute secondary dengue 3 infection

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    Figure 2. Fine maculopapular dengue recovery rash; only clinical feature of dengue in a 12-year-old boy with encephalitis and primary dengue 3 infection

    The median coma recovery time for those admitted with a reduced level of consciousness was 3?5 days (range 1?45) days. No patient died. At discharge 15 patients had fully recovered but six had neurological sequelae. Patients 6 and 10, with transverse myelitis, had a mild spastic paraparesis, but could walk independently; patient 9, who had presented with encephalitis, had residual spasticity; patient 13 remained confused; patients 8 and 20 had abnormal affect and altered personality. Six patients were followed up 2?24 months later (median 20?5 months). Patients 13 and 17 were completely normal. Patients 8 and 20 still had altered personality with labile mood; patient 20 also had poor short-term memory but his follow-up EEG was normal. Two children (patients 14 and 15) had had further convulsions associated with febrile illness, but follow-up EEGs were normal. Developmental assessments were normal in all children at follow up.
    Nine patients met the case definition of encephalitis; nine were diagnosed as acute encephalopathy and two as transverse myelitis; one with meningism but no CSF pleocytosis (patient 3) did not fit into any case definition.

    Dengue virus genotypes

    The four DEN-2 virus sequences obtained from patients 2 and 3 grouped together with the sequence from the patient with DHF, within genotype IIIb of DEN-221 (figure 3). Within this genotype the isolates from CNS patients were most closely related to the DHF isolate, two Vietnamese sequences isolated in 198718 and a Chinese isolate of 1985.

    Click to enlarge image

    Figure 3. Phylogenetic analysis of DEN-2 strains describedFigure represents the portion of derived tree corresponding to genotype IIIb. Genetic distance indicated with bar. Strains are represented by GenBank sequence filename and country and year of isolation. Strains not identified (fuller versions of tree obtainable from author) are from Central and South America. Genbank accession numbers for the five new sequences (boxed) are: for BD48, AJ272016; for CNS 504, AJ272015 (serum) and AJ272018 (CSF); and for CNS 36, AJ272014 (serum) and AJ272017 (CSF).

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    Dengue viruses now affect almost every country between the tropics of Capricorn and Cancer. The expansion of this flavivirus infection has been linked to resurgence of the mosquito vector Aedes aegypti, to overcrowding, and increasing travel.22 Following massive epidemics of DHF in Thailand in the 1950s and 1960s, the WHO adopted criteria for diagnosing and treating dengue fever and DHF.23 Neurological manifestations received little attention initially, but in the last twenty years there has been increasing recognition of their possible importance.
    Neurological findings reported in association with dengue include mononeuropathies, polyneuropathies, and Guillain-Barr? syndrome.24 Two patients in our study had transverse myelitis. In one, the history of a dengue-like illness 2 weeks previously suggested a post-infectious aetiology. However the high fever, rigors, headache and muscle pain during the acute presentation are consistent with an acute dengue, and this was supported by the serology. The fact that both patients improved spontaneously without antibiotics or other therapy supports a diagnosis of para-infectious transverse myelitis.
    Whilst few doubt that dengue infection can be associated with clouding of consciousness, until now it was not clear whether this represents CNS invasion by the virus, a non-specific complication of severe dengue disease, or even coincident infection with another, unidentified arbovirus. Most published data consist of case-reports or reviews of patients admitted to dengue wards with classical features of dengue infection,6,25,26 and there has been no previous attempt to assess prospectively dengue as a cause of neurological disease.
    We found that 4% of patients with suspected CNS infecions admitted to a referral centre were infected with dengue viruses. Although these accounted for only 1% of all dengue admissions to our referral hospital there were more patients with neurological manifestations of dengue than patients with DHF grade IV. Serological evidence of dengue infection may persist for some weeks but dengue infection is unlikely to be fortuitous in all cases. CNS patients had three times the risk of dengue infection compared with hospital controls. Ten patients had virus detected or isolated, and six seroconverted in hospital. Other causes of CNS syndromes were excluded except that one encephalopathic patient was positive for hepatitis B. One other patient with a spastic paraparesis was seropositive for leptospirosis but, as far as we are aware, acute transverse myelitis has not been described among the neurological complications of leptospirosis.27
    Complications of severe dengue implicated as possible causes of dengue encephalopathy include hypotension, cerebral oedema,24 microvascular or frank haemorrhage,28 hyponatraemia29 and fulminant hepatic failure30?which may be part of a Reye-like syndrome.31 Liver-function tests may be abnormal in 90% of dengue infected patients.32 Five of our encephalopathic patients with severe DHF had greatly raised transaminases. Although we were unable to investigate fully every patient, the findings were consistent with fulminant hepatic failure. In the remaining two DHF patients raised CSF opening pressures may have reflected cerebral oedema. Intracranial haemorrhage has been postulated as a cause of coma in DF patients bleeding from other sites.6 However, in patient 13 a normal CT scan excluded this; and in patient 3 intracranial haemorrhage seems unlikely given the presenting features, normal CSF, and full recovery.
    In ten encephalopathic patients there were no characteristic features of dengue fever or DHF, and no metabolic explanations for the coma. Should such patients be considered to have dengue encephalitis? In our study it is hard to explain the detection of dengue viruses and IgM antibody in the CSF in some patients other than by viral invasion across the blood-brain barrier. The CSF cell counts indicate that none of the lumbar punctures was traumatic?. Strictly speaking, encephalitis should only be diagnosed with histological confirmation.3 However, brain biopsy and necropsy is not possible in many areas where dengue occurs. Most published post-mortem series are on patients who died from DHF, rather than encephalitis, and lesions in the brain have been non-specific (oedema, vascular congestion, and focal haemorrhages).28,33 However, perivenous encephalitis was seen in one patient.34 Because of the difficulties in obtaining a pathological diagnosis we used a clinical case definition based on the surrogate indicators of CSF pleocytosis or focal neurological signs.35 Although three patients had a CSF pleocytosis, the CSF can be acellular in a variety of viral encephalitides.35
    Dengue first appeared in southern Vietnam in the 1960s and there are major epidemics every 3?4 years. All four serotypes are endemic but DEN-1 and DEN-2, and DEN-3 have been most frequently isolated in recent years.36 Dual infection, as seen in one of our patients, had been reported previously.37 DEN-3 has been associated with neurological presentations most frequently and in our study was implicated in six of 10 cases where the serotype was known. Whether this represents a higher transmission rate, easier isolation, or different virulence is not known. The phylogenetic data suggest that the viruses associated with CNS disease described here were drawn from the contemporary pool of locally circulating viruses causing dengue fever.
    The neurological manifestations of dengue infection were similar to Japanese encephalitis. Many areas that are endemic for dengue viruses are also endemic for Japanese encephalitis virus. Antibodies to the two viruses are cross-reactive, and encephalopathic patients with anti-flavivirus antibody in the CSF were assumed to have Japanese encephalitis. However diagnostic tests that separate these two viruses have now been adapted for field use,38 and neurological manifestations of dengue infection are likely to be recognised more often. In a study in Thailand, four of 44 patients with suspected Japanese encephalitis were shown to have dengue infection by IgM capture ELISA.30
    In summary, we found a variety of pathophysiological processes may interact to cause coma in some dengue patients but in others no toxic, metabolic, pathophysiological, or infectious cause of coma could be identified, other than dengue virus itself. Although it remains possible that an as yet unidentified viral agent is causing encephalitits in patients who are also infected with dengue, our findings suggest that dengue viruses can cause encephalitis. In endemic areas dengue should be considered in patients who present with the clinical features of encephalitis, whether or not classical manifestations of dengue are present. The WHO adoption of standard definitions for dengue encephalopathy and encephalitis would help clarify the importance world-wide.
    Tom Solomon, Nguyen Minh Dung, Rachel Kneen, Le Thi Thu Thao, Ha Thi Loan, Nicholas Day, Jeremy Farrar and Nicholas White designed the clinical study and collected the data and the samples. Tom Solomon, Boonyos Raengsakulrach, Khin S A Myint, Ananda Nisalak, and David Vaughn were responsible for the virological and immunological studies, and their interpretation. Mary Warrell, William James, and Tom Solomon performed the phylogenetic analysis. All authors contributed to the overall data analysis and intrepretation, and writing the paper.
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    We thank the director and staff of the Centre for Tropical Diseases for their support, in particular Tran Tinh Hien and the doctors and nurses of the adult and paediatric intensive care units, Delia Bethell, Mary Gainsborough, Bridget Wills, Deborah House, Christopher Parry, and John Wain; Tim Endy, Jane Cardosa, Fenella Kirkham, Bruce Innis, and John Newsom-Davis for helpful discussions; Philippe Perolat, Panor Srisongkram, Ann Taylor, Annie Siemieniuk, Steven Read, Jamal Ibrahim, Abdessamad Tahiri-Alaoui, Tipawan Kungvanrattana, Naowayubol Nutkumhaeng, Somkiat Changnak, Somsak Imlarp, Chonticha Klungthong, Vipa Thirawuth for laboratory support; Shelagh Smith for neurophysiological advice. This work was funded by The Wellcome Trust of Great Britain.
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    Uncited reference

    <!--start ce:further-reading-sec=--> 39. Burke DS, Lorsumrudee W, Leake CJ, Hoke Nisalak A, Laorakpongse T. Fatal outcome in Japanese encephalitis. Am J Trop Med Hyg 1985; 34: 1203-1209.

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        Figure 3

        Figure 3. Phylogenetic analysis of DEN-2 strains described
        Figure represents the portion of derived tree corresponding to genotype IIIb. Genetic distance indicated with bar. Strains are represented by GenBank sequence filename and country and year of isolation. Strains not identified (fuller versions of tree obtainable from author) are from Central and South America. Genbank accession numbers for the five new sequences (boxed) are: for BD48, AJ272016; for CNS 504, AJ272015 (serum) and AJ272018 (CSF); and for CNS 36, AJ272014 (serum) and AJ272017 (CSF).