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Quick Consult: Lethargy, Headache, Fever, Confusion

Wiler, Jennifer L. MD, MBA

doi: 10.1097/01.EEM.0000370750.01920.f2
Quick Consult
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A middle-aged man presents to the ED in early autumn with a complaint of increasing lethargy, headache, and fever for three days. One week earlier, he was camping, and sustained multiple mosquito bites on his legs, like the one shown. He has a nonfocal neurological examination, but is confused, which is new, according to his wife.

What illness are you concerned about, and how would you make the diagnosis?

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Diagnosis: West Nile Virus

West Nile virus (WNV) is an RNA arbovirus and a member of the Japanese encephalitis virus antigenic complex and of the Flaviviridae family. The infection is spread by transmission to humans by mosquito (more than 60 species have been identified as carriers) who become infected after feeding on an infected bird. More than 320 bird species have been identified as amplification vectors. Infected birds are asymptomatic, but the American crow in the northern United States and the blue jay in the southern part of the country have a disproportionately high mortality rate from WN viremia. WNV infection or disease also has been identified in 20 mammalian species including humans and horses. (www.cdc.gov/ncidod/dvbid/westnile/resources/wnv-guidelines-aug-2003.pdf.)

WNV transmission also can occur by transfusion of blood products, but universal screening via nucleic acid detection tests (NAT) have made this occurrence negligible. (N Engl J Med 2005;353[5]:516.) In 2009, 109 presumptive cases of WN viremia were identified by routine screening of donor blood products. (www.cdc.gov/ncidod/dvbid/westnile/Mapsviremic/surv&control09Maps_Viremic.htm.) WNV transmission can occur by breastfeeding, transplacental exposure, conjunctival exposure, percutaneous exposure, or organ transplantation, but these events are rare.

First identified in 1937 in Uganda, the first reported cases occurred in New York in 1999. (N Engl J Med 2001;344[24]:1807.) Although initial reports of outbreaks from Africa and the Middle East were a mild self-limited disease of fever, rash, and polyarthralgias, more deadly outbreaks later followed across the globe, resulting in death in nearly seven percent of all cases and in 10 percent of those with neuroinvasive disease. Today, WNV infection has been identified in every state.

More cases of WNV occur in the summer and continue into late fall. For 2009, 663 cases of WN have been reported to the Centers for Disease Control and Prevention via ArboNET, of which 335 (51%) cases were diagnosed as neuroinvasive (meningitis or encephalitis). Thirty cases resulted in death. (www.cdc.gov/ncidod/dvbid/westnile/surv&controlCaseCount09_detailed.htm.) States with the highest incidence of reported cases, by a factor of nearly 10 were Texas (104 cases), California (103), and Colorado (101). (www.cdc.gov/ncidod/dvbid/westnile/Mapsactivity/surv&control09Maps.htm.) These numbers may represent reporting bias, however, because those patients' with mild West Nile fever (the self-limiting, febrile illness form) may not present for evaluation, as compared with those with a debilitating neuroinvasive manifestation.

WNV infection tends to occur three days to two weeks after a bite by an infected mosquito. Arboviral infection, including WNV, can have a variety of clinical presentations based on the extent of infection. Most patients infected with WNV are asymptomatic (80%) or have a febrile illness of varying severity (up to 20%). (www.CDC.gov.) Flu-like symptoms such as myalgias, arthralgias, skin rash (50% cases), anorexia, fatigue (96%), and lymphadenopathy are also common. Other nonspecific viral syndrome symptoms such as pharyngitis, abdominal pain, diarrhea, nausea, and vomiting are less common. (Ann Intern Med 2004;141[5]:360.) Dengue fever can be clinically indistinguishable from WNV fever so a travel history is prudent.

Approximately one in 150 people will develop neuroinvasive WNV illnesses including aseptic meningitis, myelitis, and encephalitis, all of which are clinically indistinguishable from those caused by more common viruses. Patients with neuroinvasive WN infection can present with fever, headache, stiff neck, generalized weakness, vertigo, altered mental status, or coma. Cranial or peripheral neuropathies, acute flaccid paralysis, seizure, myoclonus, Parkinsonian features, optic neuritis, chorioretinitis, and sensory or motor deficits are possible physical examination findings. Patients over age 50 appear to be at greatest risk for neuroinvasive disease based on assessment of previous outbreaks.

If neuroinvasive WN infection is suspected, lumbar puncture with open pressure and cerebrospinal fluid (CSF) analysis should be performed. Pleocytosis with a predominance of lymphocytes, elevated protein, and normal CSF glucose is typical. Serum total leukocyte counts can be normal or elevated. Brain CT is often normal, but MRI may highlight abnormalities that are nonspecific.

The differential diagnosis of WNV infection includes other viral syndromes, and is extensive. Numerous arbovirus illnesses have been reported, including the California serogroup, Eastern equine encephalitis, St. Louis encephalitis, Powassan, and Western equine encephalitis virus disease.

The CDC laboratory criteria for diagnosis of arboviral infection, including WNV infection are fourfold or greater virus-specific serum antibody titer; or isolation of the virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid, or other body fluid; or elevated virus-specific immunoglobulin antibodies in the acute or convalescent serum specimen as measured by VN or HI; or IgG enzyme immunoassay; or virus-specific immunoglobulin M antibodies demonstrated in serum by IgM antibody-capture enzyme immunoassay. (www.cdc.gov/ncphi/disss/nndss/casedef/arboviral_current.htm.) False-positive enzyme testing can occur after recent yellow fever or Japanese encephalitis immunizations or with current flaviviruses infections. (Clin Diagn Lab Immunol 2002;9[3]:544.)

Unfortunately, there is no treatment for WNV infection, only supportive care, but most WNV fever infections are self-limited, lasting weeks before resolution. Case reports describe the use of ribaviron, IVIG, and interferon alfa-2b for neuroinvasive WN, but no randomized trials of therapeutic agents have been completed to date. Serious adverse outcomes are limited to those with neuroinvasive disease, with death occurring in patients with meningitis (2%) or encephalitis (12%). (Vector Borne Zoonotic Dis 2004;4[1]:61.) Studies have found mixed results with regard to achieving baseline cognitive and physical functional capacity. More studies are needed to determine long-term outcomes after neuroinvasive WN infection.

This patient was found to have West Nile meningitis/encephalitis via CSF confirmatory enzyme immunoassay studies and MRI (asymmetric increased T2 signal intensities in left putamen and caudate). On discharge from the hospital, he had a new and persistent mild tremor, word-finding difficulty, and slow gait.

Dr. Wiler

Dr. Wiler

© 2010 Lippincott Williams & Wilkins, Inc.