West Nile Virus (WNV) Infection and Encephalitis (WNE) 

Updated: Nov 30, 2018
Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

West Nile virus (WNV) was first described in 1937 and is named for the West Nile district of Uganda, where it was discovered.[1] In the United States, the virus has been detected in each of the lower 48 states plus 9 Canadian provinces.[2]

The disease is caused by the West Nile virus, a positive-strand RNA flavivirus.[3] It is transmitted via the bite from the Culex mosquito and is known to infect humans, birds, horses, and other mammals. Birds act as a primary reservoir and means of viral replication, with high levels of viremia observed in infected crows, sparrows, blue jays, and other passerine birds.[4] WNV infection manifests as two clinical syndromes: West Nile fever (WN fever) and West Nile encephalitis (WNE).

WNE can be defined as disease that causes encephalitis, meningitis, or acute flaccid paralysis.[5] When the virus infects these structures of the central nervous system, it may be described as neuroinvasive disease.

West Nile fever can be defined as WNV disease that causes fever and nonspecific symptoms (eg, headache, muscle aches, rash, neck stiffness, vomiting) without any evidence of brain/meningeal involvement.[5] West Nile fever is generally less severe than WNE and produces symptoms in only about 25% of cases.[6] WNE, however, is generally a much more severe form of WNV infection, especially in elderly individuals, and carries a mortality rate of approximately 8%.[7]

The Culex mosquito, common in the eastern United S The Culex mosquito, common in the eastern United States, is the primary vector responsible for infecting humans with West Nile virus. Prevention of West Nile virus is primarily directed at reducing the mosquito population from May to October and by taking precautions to limit human exposure during these months of high mosquito activity. Image courtesy of the Centers for Disease Control and Prevention.

See 7 Bug Bites You Need to Know This Summer, a Critical Images slideshow, for helpful images and information on various bug bites.

For more information, see the Centers for Disease Control and Prevention (CDC) fact sheet on West Nile virus, links to state and local government web sites on West Nile virus, and the Environmental Protection Agency (EPA) article on mosquito control.

For current and up to date information on disease activity from the CDC, see https://www.cdc.gov/westnile/index.html

Prognosis

West Nile fever generally has an excellent prognosis. Most WNV infections (60%-75%) are asymptomatic and self-limited. Cases that prove to be symptomatic may produce symptoms that range from a mild febrile illness to a severe lethal encephalitis.[5] As reported by the CDC in 2016, the case fatality rate associated with WNE was approximately 8%.[7] These findings were similar to the range of 7%-10% as reported in prior years.[7]

The most important predictor of mortality in patients with WNE is advanced age. The median age in fatal cases in 2016 was 75 years, with an interquartile range of 62-82 years.[7] Besides this, age-adjusted risk factors positively correlated with death due to WNE include chronic kidney disease, hepatitis C virus infection, and immunosuppression.[8] Significant risk factors associated with development of WNE (as opposed to West Nile fever), as well as increased mortality risk, includes advanced age, malignancy, or organ transplant recipient status.[9] Other important risk factors for development of WNE include hypertension, cardiac disease, diabetes, alcohol abuse, and male sex.[10, 8]

Patients who recover from WNE may be left with considerable long-term morbidity and functional deficits.[11] About two-thirds of patients who develop paralysis during the disease course retain significant weakness in that extremity.[11] Besides muscle weakness, other, more complex, neurocognitive deficits may develop, including memory loss.[12] A small case series showed that symptoms such as fatigue, headache, and myalgias tended to persist at 8 months postinfection, with roughly 40% maintaining their gait or movement symptoms.[13] Those with WNE who developed meningitis or encephalitis had better neurological recovery at 8 months than those with acute flaccid paralysis.[13]

Epidemiology

In 2000, the CDC established ArboNet, an online epidemiologic surveillance system for the tracking of infections reported throughout the year.[14] From 1999 through the end of 2016, 46,086 cases of WNV disease were reported in the United States. Of these, 21,574 were categorized as neuroinvasive disease. There were 2,017 deaths reported over the same time period, 1,888 from neuroinvasive disease (9% case fatality rate), and 129 from non-neuroinvasive disease (< 1% case fatality rate). The five states with the highest number of overall cases were California (6,031), Colorado (5,362), Texas (5,277), Nebraska (3,653), and Illinois (2,368). The five states with the highest number of neuroinvasive cases were California (3,390), Texas (3,171), Illinois (1,481), Colorado (1,249), and Louisiana (1,009).[7]

In 2016, of all cases reported (2,150), 39% were non-neuroinvasive disease, 32% involved encephalitis, 22% involved meningitis, and 4% involved acute flaccid paralysis. Of patients with acute flaccid paralysis, 56% also had concomitant encephalitis or meningitis. Of the cases reported in 2016, 97% of cases were in adults (54% aged 18-59 years and 44% >60 years).[7]

The peak month for WNV disease is August, with 83% infections occurring from July-September and 95% of infections occurring from July through the end of October.[7]

The three largest outbreaks in the United States occurred in 2002 (2,946 cases), 2003 (2,866 cases), and 2012 (2,873 cases). The 2012 outbreak saw an above-average incidence of neuroinvasive disease throughout the country.[15] More than half of the WNE cases in 2012 were reported from only four states, and 29% of the overall WNE cases were reported from Texas alone.[15] That year, the incidence of WNE was 7.3 per 100,000 in Dallas County, Texas, significantly higher than the previous record rate for the county (2.91 per 100,000).[16] This outbreak was associated with an unusually warm winter and correlated strongly with the local infected-mosquito population.[16]

For current ongoing disease activity information, please see https://wwwn.cdc.gov/arbonet/maps/ADB_Diseases_Map/index.html

Patient Education

Avoidance of mosquito exposure, particularly around dawn and dusk, may help mitigate the risk of exposure to WNV. Mosquito repellents, such as DEET, as well as barrier netting, are helpful. 

Pathophysiology

The WNV vector is the Culex mosquito, which typically feeds around dusk and dawn. Virus-laden saliva from the carrier mosquito infects the host. Dissemination occurs stepwise from replication in local subcutaneous tissues, and the virus spreads via lymphatics and blood vessels to solid organs and the CNS.[2]

WNV may spread to multiple host species, most commonly to horses, dogs, and other mammals. Horses can be severely affected, with a 30% mortality rate reported during a 2002 outbreak.[2] These animals, including humans, may be described as “dead end” hosts, as the levels of viremia do not facilitate high enough animal-to-mosquito transmission to perpetuate the replication cycle.[5]

More than 150 bird species have been reported as WNV-positive in CDC surveillance programs.[4] However, passerine birds (eg, species of jay, sparrow, crow, songbirds) have been shown the most competent in acting as disease reservoirs, demonstrating high levels of viremia for up to 1 week.[4] Bird-to-bird oral transmission has been demonstrated among birds kept in close contact, but bird-to-human transmission has not been reported.[3] However, standard precautions are still recommended when handling dead birds.

In addition to mosquito-borne transmission, the virus may be transmitted via solid organ transplant, trans-placental, and via blood transfusion.[17, 18, 19] Transfusion-related transmission was first described in 2002, and enhanced nucleic acid–based testing was instituted in 2003 and is now a part of routine screening to prevent transmission.[17] Laboratory-technician transmission has also been documented.[20]

The Culex mosquito, common in the eastern United S The Culex mosquito, common in the eastern United States, is the primary vector responsible for infecting humans with West Nile virus. Prevention of West Nile virus is primarily directed at reducing the mosquito population from May to October and by taking precautions to limit human exposure during these months of high mosquito activity. Image courtesy of the Centers for Disease Control and Prevention.
 

Presentation

History

Patients with West Nile virus (WNV) infection may or may not report a mosquito bite history, although the higher frequency of bites results in a higher probability of encountering the virus. The incubation period is typically 2-6 days but may range up to 14 days and may be longer in immunocompromised patients.[21, 20] West Nile encephalitis (WNE) may start with constitutional symptoms, including the nonspecific symptoms of West Nile fever (eg, fever, headaches, muscle aches, joint pain, vomiting). Clinically, WNE is indistinguishable from other forms of viral aseptic meningitis.[20]

Neuroinvasive disease manifests as fever and neurologic symptoms. A meningeal-type infection may manifest as typical meningeal symptoms (eg, neck stiffness, photophobia, headache).[13, 20] Encephalitis may be more varied, possibly featuring mental status changes, confusion, lethargy, seizures, local paresthesia, and/or movement disorders.[13, 20] These can manifest as extrapyramidal symptoms—coarse tremor, myoclonus, parkinsonian features such as bradykinesia, rigidity, and postural instability.[13, 20]

In children and adolescents, neuroinvasive WNV disease most commonly manifests as meningitis-type symptoms; however, encephalitis-type symptoms are more common in older adults and elderly individuals.[22]

Physical Examination

Most patients with symptomatic WNV infection are febrile.

Neurological examination findings may vary depending on the severity and manifestations of the disease. The presence of Kernig or Brudzinski signs may indicate meningeal irritation in patients with meningitis. Tremor, either fine or coarse, may be encountered. Mental status is likely to be depressed in patients with encephalitis and can manifest as subtle increased sleepiness to frank coma. Confusion or neurocognitive signs may be present. Acute flaccid paralysis results in a poliomyelitis-like loss of tone and strength and may affect one or more extremities.

Examination findings may be remarkable for diffuse maculopapular rash.

Ocular findings may include chorioretinitis featuring “target-like” lesions, retinal hemorrhages, and vitreitis.[23, 24, 25]

 

DDx

Diagnostic Considerations

The most important infection to exclude in the differential diagnoses of West Nile encephalitis (WNE) is herpes simplex virus type 1 (HSV-1) encephalitis, because it is the only viral encephalitis that can be treated pharmacologically, and early appropriate intervention will benefit the patient. HSV-1 encephalitis is suggested by temporal lobe abnormalities on electroencephalography (EEG) and later on CT scanning and MRI.

Early in the course of HSV-1 encephalitis, cerebrospinal fluid (CSF) may show a polymorphonuclear predominance but most frequently features a high red blood cell (RBC) count. CSF glucose levels may be increased in HSV-1 encephalitis. CSF studies in patients with WNE generally do not show this finding.

HSV-1 encephalitis is the most common cause of non–arthropod-borne (nonseasonal) encephalitis in the United States. HSV-1 infection usually manifests as encephalitis, uncommonly as meningoencephalitis, or rarely as aseptic meningitis. Differential diagnoses of meningoencephalitis, including the HSV-1 type, are listed in the chart below.

Differential diagnoses of meningoencephalitis. Differential diagnoses of meningoencephalitis.

Encephalopathy due to systemic illnesses

Encephalopathy is a feature of many systemic illnesses that the clinician should consider in patients presenting with encephalitis. Most of these patients have extra-CNS findings that suggest the underlying disease process. Common disorders with CNS manifestations that may mimic WNE include subacute bacterial endocarditis, Legionnaires disease, Rocky Mountain spotted fever, Epstein-Barr virus infectious mononucleosis, human herpesvirus type 6 (HHV-6) infection, and systemic lupus erythematosus cerebritis. Other noninfectious causes of encephalopathy to consider initially may include uremia, hyperammonemia, intoxication or ingestion, or other metabolic derangement.

Other arthropod-borne viral encephalitides

The clinical presentation of WNE is not unlike other causes of arthropod-borne viral encephalitis (eg, Japanese encephalitis, equine encephalitis), including mental confusion, stupor, or coma. However, the clinical presentation of arthropod-borne viral encephalitis is characterized by rapid onset and severe headache. Arthropod-borne viral encephalitis has some distinctive features that indicate a presumptive clinical diagnosis (as seen in the charts below).

Common encephalitis associations. Common encephalitis associations.
Clinical features of arboviral encephalitis. Clinical features of arboviral encephalitis.

Enteroviral aseptic meningitis

The most common cause of aseptic meningitis encountered during the summer months, particularly in late August or early September, is enteroviral meningitis. Enteroviral aseptic meningitis is most commonly due to coxsackieviruses but may also be due to enterocytopathogenic human orphan virus or nonparalytic strains of poliovirus. Enteroviral meningitis may occur after water exposure in swimming pools, lakes, streams, or oceans, as well as after contact with infected individuals.

Acute enteroviral CNS infections usually manifest as aseptic meningitis, uncommonly as meningoencephalitis, or, rarely, as encephalitis. Nonexudative pharyngitis, maculopapular extremity rash, loose stools, and even diarrhea often accompany enteroviral aseptic meningitis, which provides clues to its presence.

Excluding enterovirus 71, enteroviral meningitis is not accompanied by paralysis or prolonged and/or profound relative lymphopenia. Enterovirus D68 may also be associated with the above symptoms with a transverse myelitis syndrome and may present similarly to acute flaccid paralysis.

Differential Diagnoses

 

Workup

Laboratory Studies

A laboratory diagnosis of WNV infection is based on isolation of the virus antigen or RNA in tissue, blood, CSF, or other body fluid. Diagnosis can also be made based on four-fold antibody titer increase or detection of viral-specific IgM antibody in CSF or serum.[5] The presence of WNV IgM almost always indicates recent WNV infection; however, because of cross-reactivity with IgM, this sometimes indicates recent infection with another flavivirus. The IgM antibodies are usually short-lived, lasting weeks to months; however, in cases of reinfection, it is important to measure titers approximately 2-3 weeks apart to establish a diagnosis.[20] Detection of IgM in CSF is presumptive of recent neuroinvasive disease.

Nucleic acid testing, if positive, is also diagnostic of active disease. However, negative results may reflect viremia that is inadequate for detection, especially in immunocompetent patients.[20] Therefore, RNA PCR is not recommended for diagnosis in immunocompetent patients.[20]

Leukopenia

West Nile encephalitis (WNE), as with many viral illnesses, may feature mild leukopenia. Leukocytosis usually suggests another diagnosis.

Lymphopenia

Although relative lymphopenia is not specific for WNE, it is a helpful diagnostic finding if present in a patient with aseptic meningitis, meningoencephalitis, or, particularly, encephalitis of unknown cause.

Although patients with HIV infection or Venezuelan equine encephalitis often present with relative lymphopenia, the relative lymphopenia of WNE is usually more profound and may be prolonged, which should be suggestive.

ESR/CRP ratio

An ESR/CRP ratio of less than 1 suggests WNE in adults with encephalitis.

Serum transaminases

Mild elevations of serum glutamic-pyruvic transaminase (SGPT) levels are not a feature of most arboviral encephalitides.

In addition to WNE, mild elevations of serum glutamic-oxaloacetic transaminase (SGOT)/SGPT levels in a patient with encephalitis should suggest Epstein-Barr virus, Rocky Mountain spotted fever, ehrlichiosis, HHV-6 infection, or Legionnaires disease.

Serum ferritin levels

Serum ferritin levels are usually elevated in WNE and not in other causes of encephalitis. The magnitude/duration of serum ferritin elevations also has prognostic importance.

Imaging Studies

Imaging studies may be helpful, especially during the early phases of an evaluation. It may facilitate exclusion of other causes of encephalopathy.

Imaging findings in patients with WNE vary wildly and, when present, are nonspecific. Imaging results may be normal even in severe WNE.[26, 27] No particular MRI or CT findings are specific for WNE.[26, 27]

Patients with MRI abnormalities of the nerve roots or spinal cord were found to be more likely to have residual neurological deficits upon resolution of acute illness, and those with normal findings were found to be more likely to have a favorable prognosis.[27]

EEG may be used as an adjunctive study but is not likely sufficient for confirmation. EEG may show generalized continuous slowing, particularly in the anterior (frontal, temporal) regions, consistent with a nonspecific encephalopathy.[28] However, not all patients with WNE have generalized slowing, and generalized slowing is not specific to WNE.

Procedures

Lumbar puncture

CSF reveals mild to moderate pleocytosis with a lymphocytic predominance in WNE.[17, 29] CSF protein levels are variably elevated, and the CSF glucose level is not decreased.

The CSF lactic acid level is not elevated, and RBCs, excluding traumatic taps, are not present in WNE. CSF Gram stain and bacterial culture findings are negative.

CSF testing for immunoglobulin M (IgM) antibodies against West Nile virus (WNV) should be performed (in addition to testing of the patient’s serum).

Histologic Findings

Brain biopsy findings exhibit diffuse encephalitis, which is nonspecific and nondiagnostic for WNE.

 

Treatment

Approach Considerations

Treatment of West Nile encephalitis (WNE) consists of prevention, followed then by supportive care. The mainstay of prevention is limiting personal mosquito-bite exposure. Mosquito netting and barrier protection are most helpful and may be augmented by mosquito repellents.

Initially, it is important to exclude herpes simplex virus (HSV) encephalitis among the differential diagnoses, as this is the only viral encephalitis for which there is a treatment, and prompt intervention will likely be beneficial to the patient.

Supportive care focuses on minimizing the potential for cerebral edema by electrolyte flux of fluid shift in patients with WNE.

No proven benefit has been observed in small numbers of patients treated with interferon, ribavirin, or intravenous immunoglobulin (IVIG).

Consultation with an infectious disease specialist and a neurologist should be considered. A repeat lumbar puncture is usually unnecessary. Further outpatient care is usually unnecessary; however, follow-up and rehabilitation of neurologic deficits will likely be beneficial.

Prevention

Avoidance of mosquito exposure, particularly around dawn and dusk, may help mitigate the risk of exposure to West Nile virus (WNV). Mosquito repellents, such as DEET, as well as barrier netting, are helpful. Mosquito-control programs are also able to reduce rates of human infection and are typically employed when surveillance identifies increased local risk. A 2005 study found that the odds of infection were 6-fold higher in untreated areas than in areas treated with aerosolized pyrethrin spraying.[30] Routine local control, such as limiting stagnant areas of water collection, may also be beneficial.

No vaccine is currently FDA-approved for WNV, although studies of live attenuated vaccines are ongoing (up to phase II clinical trials), which have shown safety and tolerability, as well as immunogenicity.[31, 32] Currently, no clinical trials for WNV vaccine are in phase III.

 

Medication

Medication Summary

No specific drug treatment exists for West Nile encephalitis (WNE). Supportive care is the mainstay of treatment.

Vaccine development has been in process since the mid-2000s. NIH-funded vaccine development entered clinical trial in 2015. However, no vaccine has been FDA-approved to prevent WNE.

Analgesics/Antipyretics

Class Summary

These agents are helpful in relieving the associated lethargy, malaise, and fever associated with the disease.

Acetaminophen (Acephen, FeverAll, Tylenol)

Acetaminophen inhibits the action of endogenous pyrogens on heat-regulating centers; it reduces fever by a direct action on the hypothalamic heat-regulating centers, which, in turn, increases the dissipation of body heat via sweating and vasodilation. It is effective in relieving mild to moderate acute pain; however, it has no peripheral anti-inflammatory effects. Acetaminophen may be preferred in elderly patients because of fewer GI and renal side effects.

 

Questions & Answers

Overview

What are West Nile virus (WNV) infection and encephalitis (WNE)?

What is the prognosis of West Nile virus (WNV) infection and encephalitis (WNE)?

What is the prevalence of West Nile virus (WNV) infection and encephalitis (WNE)?

What is included in patient education about West Nile virus (WNV) infection and encephalitis (WNE)?

What is the pathophysiology of West Nile virus (WNV) infection and encephalitis (WNE)?

Presentation

Which clinical history findings are characteristic of West Nile virus (WNV) infection and encephalitis (WNE)?

Which physical findings are characteristic of West Nile virus (WNV) infection and encephalitis (WNE)?

DDX

How is herpes simplex virus type 1 (HSV-1) encephalitis differentiated from West Nile virus (WNV) infection and encephalitis (WNE)?

How is encephalopathy due to systemic illnesses differentiated from West Nile virus (WNV) infection and encephalitis (WNE)?

How are other arthropod-borne viral encephalitides differentiated from West Nile virus (WNV) infection and encephalitis (WNE)?

How is enteroviral aseptic meningitis differentiated from West Nile virus (WNV) infection and encephalitis (WNE)?

What are the differential diagnoses for West Nile Virus (WNV) Infection and Encephalitis (WNE)?

Workup

How is West Nile virus (WNV) infection and encephalitis (WNE) diagnosed?

What is the role of leukocyte count in the workup of West Nile virus (WNV) infection and encephalitis (WNE)?

What is the role of lymphocyte count in the workup of West Nile virus (WNV) infection and encephalitis (WNE)?

Which erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) ratio suggests West Nile virus (WNV) infection and encephalitis (WNE)?

What is the role of serum glutamic-pyruvic transaminase (SGPT) measurement in the workup of West Nile virus (WNV) infection and encephalitis (WNE)?

What is the role of serum ferritin measurement in the workup of West Nile virus (WNV) infection and encephalitis (WNE)?

What is the role of imaging studies in the workup of West Nile virus (WNV) infection and encephalitis (WNE)?

What is the role of lumbar puncture in the workup of West Nile virus (WNV) infection and encephalitis (WNE)?

Which histologic findings are characteristic of West Nile virus (WNV) infection and encephalitis (WNE)?

Treatment

How are West Nile virus (WNV) infection and encephalitis (WNE) treated?

How are West Nile virus (WNV) infection and encephalitis (WNE) prevented?

Medications

What is the role of medications in the treatment of West Nile virus (WNV) infection and encephalitis (WNE)?

Which medications in the drug class Analgesics/Antipyretics are used in the treatment of West Nile Virus (WNV) Infection and Encephalitis (WNE)?