Dengue in patients with central nervous system manifestations, Brazil.
or breakbone fever or dandy fever
Infectious, disabling mosquito-borne fever. Other symptoms include extreme joint pain and stiffness, intense pain behind the eyes, a return of fever after brief pause, and a characteristic rash. is the most prevalent arboviral infection in humans (1). Since the reintroduction of dengue virus (DENV DENV Department of Environment (Canada) ) into Brazil in the 1980s, >60% of the reported dengue cases in this region of the Western Hemisphere have occurred there (2). As the disease has become more common, unusual clinical signs, some of which involve the central nervous system, have been observed in dengue patients (2-4). We therefore assessed prevalence of dengue neurologic cases from Ceara State, Brazil, a region where dengue is endemic.
We enrolled 183 patients with suspected viral meningitis/meningoencephalitis admitted to Sao Jose Hospital of Infectious Disease and 26 deceased patients with suspected fatal meningitis who had been sent to the city of Fortaleza Coroner's Office. Cerebrospinal fluid (CSF Cerebrospinal Fluid (CSF) Analysis Definition
Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord. ) was collected from all 209 patients. Study inclusion criteria were suspicion of viral meningitis/meningoencephalitis, a CSF cell count <500 cells/[mm.sup.3], and negative results of culture and microscopic examination for bacteria and fungi. The CSF samples were not contaminated with blood. The study was performed retrospectively and used samples from patients who had been treated for meningitis during 2005-2008, a period during which a dengue epidemic may have occurred in Ceara. This study was approved by the Ethics Committee of Sao Jose Hospital of Infectious Disease (protocol no. 005/2009; Certificado de Apresentacao para Apreciacao Etica [Proof of Application for Ethical Review] 0005.0.042.000-09).
Dengue meningitis was suspected when a patient had fever and symptoms of irritation of the meninges meninges (mĭnĭn`jēz), three membranous layers of connective tissue that envelop the brain and spinal cord (see nervous system). The outermost layer, or dura mater, is extremely tough and is fused with the membranous lining of the skull. , such as headache and neck stiffness; a diagnosis of dengue meningoencephalitis meningoencephalitis /me·nin·go·en·ceph·a·li·tis/ (me-ning?go-en-sef?ah-li´tis) inflammation of the brain and meninges.
toxoplasmic meningoencephalitis was established when the patient showed signs of focal involvement of the central nervous system (CNS See Continuous net settlement.
See continuous net settlement (CNS). ). A diagnosis of dengue was confirmed with a DENV-positive CSF result by reverse transcription PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) (RT-PCR), nonstructural protein (NS) 1, or IgM against DENV (3,4).
Samples were analyzed by using RT-PCR, ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.
n. for NS1, and IgM monoclonal antibody and a rapid immunochromatography test for IgG (3-5).Viral RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic for the nested RT-PCR was extracted from 140 [micro]L of the CSF samples by using the QIAamp Viral RNA Mini Kit (QIAGEN, Valencia, CA, USA), following the manufacturer's protocol, and stored at -80[degrees]C until tested. The RT-PCR for DENV was performed on 209 CSF samples, as described (5).
The NS1Ag Pan-E Dengue Early ELISA kit (Panbio Diagnostics, Brisbane, Queensland, Australia) was used to detect the dengue NS1 in 209 CSF specimens in accordance with the manufacturers' instructions (4). The Dengue IgM Capture ELISA (Panbio Diagnostics) was performed on 209 CSF samples, according to the manufacturer's instructions. The Panbio Dengue Duo Cassette rapid test was performed, according to the manufacturer's instructions, with CSF specimens that were positive for DENV in any of the other tests used.
Of 209 CSF samples studied, 8 (3.8%) showed positive results in [greater than or equal to] 1 test: 5 from the group admitted to Sao Jose Hospital of Infectious Disease and 3 deceased patients examined at the Fortaleza Coroner's Office (Table 1). Reviewed literature showed that the etiologic agents of most cases of viral meningitis in Brazil are enterovirus enterovirus /en·tero·vi·rus/ (en´ter-o-vi?rus) any virus of the genus Enterovirus. enterovi´ral
Enterovirus /En·tero·vi·rus/ (en´ter-o-vi?rus and herpesvirus herpesvirus, any of the family (Herpesviridae) of common DNA-containing viruses, many of which are associated with human disease. See cytomegalovirus; Epstein-Barr virus; herpes simplex; herpes zoster. ; cytomegalovirus and dengue viruses are each responsible for 10% (2/20) (6).
DENV as a causal agent for meningitis has been rarely reported, although some cases have been described in the literature. In Jamaica, a study of 401 patients with suspected cases of viral infection of the CNS showed that 54 (13.5%) were positive for dengue; 18 (33.3%) of those patients showed clinical signs of meningitis (7). However, when we included patients in the cohort who were initially suspected of having CNS infection, the frequency of meningitis in this study was 18/401 (4.5%).
An investigation of dengue patients with suspected CNS infection conducted in Vietnam found 4.2% (16/378) of persons positive for DENV; 1 (0.3%) patient had meningitis (3). The frequency of finding dengue virus in patients with suspected cases of meningitis found in this study corroborated what was hypothesized in the literature: neurologic manifestations in patients with DENV have been reported in Ceara, but previous studies based laboratory diagnosis on serum, not on CSF as in our study, which indicated a relationship between dengue and CNS manifestations (8).
Of 5 patients treated at Sao Jose Hospital of Infectious Disease (Table 1), 3 recovered, 1 was given a diagnosis of a brain tumor, and 1 died. The patient who died was the only person of 5 with dengue fever dengue fever (dĕng`gē, –gā), acute infectious disease caused by four closely related viruses and transmitted by the bite of the Aedes mosquito; it is also known as breakbone fever and bone-crusher disease. who had signs and symptoms of fatal dengue hemorrhagic fever (DHF DHF dihydrofolate or dihydrofolic acid. ) (such as intense malaise, dry cough with dyspnea, and abdominal pain) (9). Of the 3 deceased patients (Table 1), only 1 had signs of severe dengue, including myalgia, abdominal pain, asthenia, somnolence somnolence /som·no·lence/ (som´no-lens) drowsiness or sleepiness, particularly in excess.
1. A state of drowsiness; sleepiness.
2. , and confusion. Suspected cases of meningitis with other pathologic changes might also be confused with dengue cases with CNS involvement (10). Of 8 dengue patients, 2 had signs and symptoms of dengue infection. In Brazil, meningitis was confirmed for patients with oligosymptomatic dengue infection in the cities of Vitoria and Rio de Janeiro (10,11).
The presence of DENV NS1 antigen (NS1Ag) has been associated with virus replication and viremia viremia /vi·re·mia/ (vi-re´me-ah) the presence of viruses in the blood.
The presence of viruses in the bloodstream. with the risk for development of DHF (12). The NS1Ag was detected in 4 of the fatal cases reported here, but because none fulfilled the World Health Organization criteria for DHF, they were considered to have been cases of severe dengue because the patients died (1) (Table 1). Detection of dengue IgM in CSF has shown a high specificity (97%) for diagnosing neurologic dengue and might be associated with the neurovirulence of DENV and its ability to cause encephalitis (13). Prior to the 1996 publication of findings by Lum et al., involvement of the CNS in dengue infection had been thought to be secondary to vasculitis Vasculitis Definition
Vasculitis refers to a varied group of disorders which all share a common underlying problem of inflammation of a blood vessel or blood vessels. The inflammation may affect any size blood vessel, anywhere in the body. only; direct involvement of the brain by DENV was thought to be unlikely (14),. The literature has reported detection of DENV in the brain and CSF by PCR and virus isolation and detection of NS1 and dengue IgM, providing strong evidence that DENV has neurovirulent properties (3,4,11,13-15). Meningeal me·nin·ge·al
Of, relating to, or affecting the meninges.
pertaining to the meninges.
meningeal hemorrhage lesions, neuronal damage, and evidence of DENV in CSF by RT-PCR and ELISA (NS1/IgM) found in this study are consistent with CNS infection (Table 1).
The prevalence of CNS involvement in patients with dengue infection seems to vary with severity of dengue cases (11). Mortality rates also vary among studies; the reported rate of neurologic dengue was found to be 3.7% (2/54) in a study in Jamaica (7). In another study conducted in Vietnam, no patients with the neurologic form of dengue died (3); our study found a mortality rate of 1.9% (4/209). However, the proportional positivity was higher for the group of patients who died (4/27, 14.8%) than for those who recovered (4/182, 2.2%) (Table 2). The relative risk for identifying DENV-positive CSF in patients who died was 6.74x greater than that for patients who recovered (95% CI 1.79x-25.38x; p<0.0109). No patients had DHF or a concurrent condition to predict deterioration to death, thus suggesting that patients with meningitis/meningoencephalitis and DENV-positive CSF may have higher risk for development of severe forms of dengue infection.
The high risk for death among patients with dengue meningitis/meningoencephalitis in this study supports the need for increased surveillance. Dengue should be suspected in patients with neurologic manifestations in dengue-endemic areas, and appropriate treatment should be given to prevent death.
This study was supported by the Brazilian National Research Council, process MCT/CNPq 14/2009, and by the Ceara State Scientific Development Foundation, process FUNCAP 09100097-1.
Dr Araujo is a researcher in the dengue reference laboratory in the State Health Secretariat in Ceara. Her research interest and work for the past 23 years is in dengue viruses in Brazil.
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(2.) Nogueira RMR RMR Resting Metabolic Rate
RMR Registered Merit Reporter
RMR Reliability Must-Run (electric generation plant's status to maintain grid voltage/reliability)
RMR Recurring Monthly Revenue (finance) , Araujo JMG JMG Journal of Medical Genetics
JMG Junior Master Gardener
JMG Journal of Metamorphic Geology
JMG Junior Maine Guide
JMG Joint Meteorological Group
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Enzyme-linked immunosorbent assay (ELISA)
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A condition resulting in massive, difficult-to-control bleeding.
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Author affiliations: State Health Secretariat of Ceara, Fortaleza, Ceara, Brazil (F.M.C. Araujo, A.C.B. Perdigao, D.C.L. Feitosa Vilar, S.G. Silveira Holanda and D.N. de Melo Braga); Oswaldo Cruz Institute, Rio de Janeiro, Rio de Janeiro, Brazil (R.M.R. Nogueira); Dr. Jose Frota Institute, Fortaleza (M. de Sousa Araujo); Federal University of Ceara, Fortaleza (L.P.G., Cavalcanti, F.M. de Carvalho Araujo, J.J. da Costa Sidrim, R.S.N. Brilhante, M.F.G. Rocha); State University of Ceara, Fortaleza (A.C.B. Perdigao); College Christus, Fortaleza (L.P.G. Cavalcanti)
DOI: http://dx.doi.org/ 10.3201/eid1804.111522
Address for correspondence: Fernanda Araujo, Av. Barao de Studart, 2405, 60120-002, Fortaleza, CE, Brazil; email: fernanda.montenegro@ lacen.ce.gov.br
Table 1. Clinical features and virologic findings for 8 patients with meningitis-meningoencephalitis and confirmed cases of dengue, Brazil, 2005-2008 * Patient Age, Initial symptoms and no. y/sex signs Progress and outcome 1 45/M Fever, headache, Cerebral edema and sweating, thorax pain, congestion; mononuclear seizure, coma, chronic cells in meninges; hypertension. death after 6 d 2 32/F Fever, vomiting, neck Meningitis, sixth nerve stiffness, myalgia, palsy; death after 14 d abdominal pain, asthenia, somnolence, confusion 3 1/M Fever, tremors, Intracranial rigidity of limbs, hypertension, otitis meningitis; death after 24 h 4 6/F Fever, headache, CSF: clear, 133 cells/ malaise, vomiting, [mm.sup.3], 42% drowsiness, neck lymphocytes, 2% stiffness monocytes, 53% neutrophils, 3% eosinophils; protein 58 g/L, glucose 54 g/L; recovery after 9 d 5 58/M Fever, headache, severe CSF: 300 cells/ malaise, vomiting, [mm.sup.3]; lowering of lymphocytes, 87%, consciousness, delirium monocytes 5%, neutrophils 4%, protein 112 g/L, glucose 59 g/ L; serum: AST 127 U/L, ALT 74 U/L; CT scan: expansible lesion measuring 4 x 2 x 2.3 cm; referred for surgical treatment 6 5/F Fever, headache, CSF: 490 cells/ vomiting, neck [mm.sup.3], 2% stiffness monocytes, 5% lymphocytes, 93% neutrophils, protein 45 g/L, glucose 110 g/L; recovery after 8 d 7 15/M Fever, headache, IHC result positive for arthralgia, severe dengue. CSF: clear; malaise, dry cough, cerebrum and cerebellum dyspnea, epigastric with marked edema and pain vasocongestion of meninges and nerve tissue; death after 5 d 8 24/M Fever, headache, CSF: 426 cells/ vomiting, and neck [mm.sup.3]; protein 136 stiffness g/L, glucose 55 g/L; recovery Patient no. RT-PCR NS1Ag IgM IgG ND 1 - + - - ME 2 DENV-3 + - - ME 3 - + + - M 4 - - + + M 5 - - + + Brain tumor; M 6 - - + M 7 - + - - ME 8 - - + + M * RT-PCR, reverse transcription PCR; NS1Ag, nonstructural protein 1 antigen; ND, neurologic diagnosis; -, negative; +, positive; ME, meningoencephalitis; DENV, dengue virus; M, meningitis; CSF, cerebrospinal fluid; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CT, computed tomography; IHC, immunohistochemical test. Table 2. Risk for death among patients with meningitis/ meningoencephalitis with DENV+ versus DENV- cerebrospinal fluid test results, Brazil, 2005-2008 * Outcome DENV+ DENV- Total Death 4 (14.8) 23 (85.2) 27 (100) Recovery 4 (2.2) 178 (97.8) 182 (100) * Values are no. (%) patients. Relative risk 6.74 (95% CI 1.79- 25.38); p<0.0109. DENV, dengue virus; -, negative; +, positive.