Encephalitis is defined as an acute inflammation of the brain parenchyma, often with secondary meningeal involvement. Although some bacterial, fungal, and autoimmune disorders are capable of causing encephalitis, most cases are secondary to viruses. The incidence is 1 case per 200,000 population in the United States, with herpes simplex virus being the most prominent cause and arboviruses accounting for 10% (occasionally 50% during epidemic years) of cases. (See Epidemiology.)
Western equine encephalitis (WEE) is spread primarily by the vector mosquito Culex tarsalis. Other mosquitoes (eg, Aedes species) and, occasionally, small, wild mammals also have been known to spread the virus. C tarsalis is a mosquito that often is found on the West Coast of the United States and that prefers warm, moist environments. In these locations, cycles of wild bird and mosquito interactions and infectivity allow the virus to remain endemic. No cases of bird transmission of the disease have been reported, making mosquitoes the primary vector and birds simply reservoirs. Epidemic outbreaks in the equine or pheasant population often precede human epidemics of WEE. (See Pathophysiology and Etiology.)
WEE is a summertime infection found in the Western United States, and it is more common in rural areas. (See Epidemiology.)
WEE belongs to the genus Alphavirus, in the family Togaviridae. Togaviridae also encompasses Eastern equine encephalitis (EEE) and Venezuelan equine encephalitis (VEE). These alphaviruses are spherical and have a diameter of 60-65 nm. The outer layer consists of a glycoprotein shell with protruding glycoprotein spikes, beneath which lies the lipid bilayer. The nucleocapsid core contains the single-stranded ribonucleic acid (RNA) genome.[1, 2]
Of the alphaviruses, EEE virus most closely resembles WEE and may have been a genetic predecessor of WEE. The completed nucleotide sequence for WEE revealed an 11,508-nucleotide organism with an 84% concordance of protein similarity with EEE.[3] Additional cross-genetic research has revealed that the virus is an amalgamation of the EEE and Sindbis virus.
Further genetic research has differentiated the potential virulence of particular strains of WEE. Of 3 epizootic strains and 5 enzootic strains, researchers found that the enzootic strains were neither neurovirulent nor neuroinvasive but that the epizootic forms were virulent. Epizootic forms are believed to arise from nonpathogenic strains (eg, AG80-646), which are consistently maintained in enzootic cycles, allowing an opportunity for further screening of vectors with potential precursors of the virulent WEE strains.[4]
See the following for more information:
The primary complications other than death in WEE are variable levels of central nervous system (CNS) impairment. Numerous factors, including location and specific inflammatory cell response, may determine the resulting impairment.
Demyelination is a known byproduct of this disease, and it can be detected radiologically. Often, these areas heal quite well unless overlying fibrosis or cell death occurs.
Additional complications include mental retardation, behavioral changes, paralysis, permanent focal neurologic deficits, seizure disorders, cerebellar damage, and choreoathetosis. Cases of Parkinson syndrome have been reported in adults after WEE infection. (See History and Physical Examination.)
WEE can be reported electronically to a CDC-run site called ArboNet, which assists states in tracking mosquito-borne viruses.
For patient education information, see the Brain and Nervous System Center, as well as Encephalitis.
The WEE virus is a neurotropic alphavirus, which causes encephalitis and viral symptoms without an associated rash. The disease is usually subclinical and may mimic many viral and inflammatory syndromes.
Diffuse CNS involvement characterizes WEE in its more severe stages. Much of the damage is mediated by the large number of immunologically active cells that enter the brain parenchyma and perivascular areas. Focal necrosis is often found in the striatum, globus pallidus, cerebral cortex, thalamus, pons, and meninges. Neutrophils and macrophages may infiltrate the brain parenchyma and may cause neuronal destruction, neuronophagia, focal necrosis, and spotty demyelination. Vascular inflammation with endothelial proliferation, small vessel thrombosis, and perivascular cuffing may also occur. Cell death by apoptosis occurs primarily in the glial and inflammatory cells. Gross inspection during autopsy reveals edema, leptomeningeal vascular congestion, hemorrhage, and encephalomalacia. In infants or children who die of the disease, diffuse atrophy, particularly of the cortex, may be present.
The virus is transmitted from the mosquito into subcutaneous and cutaneous tissue of the host. It cannot be transmitted via the aerosol route. The virus can also be transferred transplacentally. In the fetus, infection often results in massive cerebral necrosis and death. Infection via contaminated blood transfusions is unlikely because the level of viremia in the donor is extremely low.
The infected individual usually develops a general viral prodrome with fevers, chills, weakness, headache, or myalgias. Viral replication in nonneural tissues, most often adjacent or lymphoid tissue, marks this period.
The virus binds to specific tissue receptors, undergoes endocytosis, and begins an RNA-dependent synthesis of RNA and protein. If the inoculum is high enough, a subsequent viremia develops, with eventual translocation to the CNS via cerebral capillary endothelial cells. The exact mechanism of this is not known but is believed to be secondary to vascular infiltration because factors that increase vascular permeability often facilitate neuroinvasion. Cell-to-cell spread in the CNS occurs via neighboring dendrites and axons.
The initial symptoms may progress rapidly to CNS symptoms of mental confusion, somnolence, coma, and death in 1-2 days, or they may resolve without sequelae.
During epidemics, a significant percentage of the population seroconverts, but the case-infection ratio is low in human adults (1:1000) and high in infants (1:1). Most infected individuals rarely experience severe CNS manifestations, and most infections are subclinical. An inverse ratio has been found between age and clinical CNS manifestations, including seizures and other sequelae.
Although no individual risk factors exist except for age, behavioral risk factors exist. Behavioral risk factors primarily include outdoor activities during peak mosquito activity, most often in rural areas.
Western equine encephalitis (WEE) often is found in states west of the Mississippi River, west of the Rocky Mountains, and in the corresponding Canadian provinces. The virus tends to have a sporadic or a consistent infectivity, based on the community. Sporadic cases have occurred in the Sacramento Valley, Calif, but infection is consistent in the nearby Imperial Valley, Calif. Additionally, local strains rarely extend into neighboring environments.
A study of WEE from 4 different regions of northern California revealed that the strains have evolved independently, with little movement between regions. However, in southern California, the virus tends to circulate more freely secondary to the movement of birds and mosquitoes. Most notably, WEE is able to survive a wintering effect and to reappear in a similar region because of an ability to survive in the immature Aedes larva and diapausing eggs. The summer bird– C tarsalis cycle that is then responsible for most infections is secondary to viral amplification during the spring.
WEE is most common between April and September, with peaks in July and August, which likely is due to the peak vector population during these periods.
Although weather plays an important role in the spread of WEE, geographic epidemiology has indicated vector spread via wind distribution is unlikely; thus, epidemic origins are difficult to judge. Warmth is an important factor in the promulgation of the virus, because it facilitates an alteration in the transmission rate such that a drop in temperature of a few degrees can differentiate between a 10-month and an 8-month transmission season. Heavy rainfalls or prominently snowy seasons also can increase the vector population.[5] An increase in global temperature may increase the duration of infectivity in the future.
The annual incidence of the virus varies greatly because of the presence of endemic and epidemic forms. The number of cases tends to increase during epidemic years, the worst of which occurred in the western United States and Canadian plains in 1941 and resulted in 300,000 cases of encephalitis in mules and horses and 3336 cases in humans. Because of the geographic and vector similarities between St. Louis encephalitis and WEE, epidemic outbreaks of both frequently overlap.
With the moderate prevalence of WEE in some California communities, neutralizing antibodies originally were believed to be widespread in this population. However, only a low percentage (>1%) of people with these antibodies has been discovered. This finding may be explained by the low rates of contact between infectious mosquitoes and humans.
A subtype of WEE in Argentina is a likely endemic reservoir in South America. Aedes albofasciatus, a neotropical flood mosquito, is the primary vector in this region. The mosquito is relatively ubiquitous and tends to have varied bursts of epidemic growth based on larval concentration factors and weather factors.
WEE has been found, based on cumulative cases, to be more common in males than in females, a situation that is believed to be secondary to frequent occupational exposure of rural land workers.
WEE is most common among infants because of the high case-infection ratio (1:1). Adults are often targets of the vector, but they have a very low infectivity rate (1:1000). However, older adults tend to develop more severe disease. Infants and children younger than 4 years also develop more severe disease and are more likely to develop CNS manifestations of infection with the virus.
Patients infected with Western equine encephalitis (WEE) who do not develop neurologic signs or symptoms have an excellent prognosis.
Patients with mild neurologic symptoms often rapidly recover.
Once adults recover, they often have very few residual effects.
Children who develop neurologic symptoms have a poorer prognosis.
In addition, patients who develop seizures are more likely to develop a subsequent lifetime seizure disorder.
Reported neurologic sequelae include developmental delay, motor impairments (pyramidal and extrapyramidal), and residual behavioral problems.
The case-fatality rates vary for adults and children. The fatality rate is 3-4%, in stark contrast to EEE, which has a 50-70% mortality rate.
The morbidity of such illnesses is higher in infants than in adults. Infected children have a 30% chance of developing neurologic sequelae, including retardation, seizures, spasticity, or behavioral disorders. The infectivity rate is 1:1000 in adults, 1:58 in children aged 1-4 years, and 1:1 in infants younger than 1 year.
Western equine encephalitis (WEE) is difficult to diagnose because of the lack of specificity in symptoms. Often, the goal in these situations is to determine the extent of the patient's illness and whether treatable CNS infection is a possibility. Most patients commonly present with the initial signs and symptoms of a viral prodrome. The prodromal phase is often short, averaging 1-4 days, and consists of fever, headache, chills, nausea, and vomiting. In many patients, especially adults, the disease may be subclinical, and these patients may never develop symptoms beyond that of the viral prodrome. Physicians must have a heightened awareness for neurologic symptoms and sequelae, especially in younger patients.
Once neurologic symptoms arise, patients have a poorer prognosis and decompensate rapidly. Neurologic symptoms may include the following:
Other associated symptoms may include the following:
Social history may include the following:
The findings on physical examination also are nonspecific and are similar to findings of many other encephalitides.
Changes in vital signs may include the following:
Neurologic findings may include the following:
Other findings may include the following:
Because of the large number of potential organisms that can be responsible for the signs and symptoms of Western equine encephalitis (WEE), diagnosis is often delayed and difficult. Laboratory confirmation is also difficult, because it requires either specific serologic findings or isolation of the virus in brain tissue or cerebrospinal fluid (CSF). However, isolation from either the blood or CSF is often difficult because of the low viremia associated with WEE.
The current guidelines from the Centers for Disease Control and Prevention (CDC) for diagnosis of an arbovirus infection require (1) an acute febrile illness with encephalitis during a time when transmission of the virus is likely and (2) one more of the following criteria:
Presumptive positive diagnoses can be made based on the remaining biochemical assays (eg, hemagglutinin inhibition, immunofluorescence, neutralization, complement fixation).
A leukocytosis with a left shift often is present but is less than that observed in EEE. Otherwise, no prominent laboratory anomalies are unique to WEE.
Encephalitis can be identified early with neuroimaging studies (eg, computed tomography [CT] scanning, magnetic resonance imaging [MRI]), which are routinely performed in patients with CNS symptoms.
Advances in imaging studies have shown that previous neuroradiographic manifestations of WEE were not precisely defined. Early studies revealed a predilection for the thalamic nuclei and the basal ganglia; however, these changes are also common with Japanese encephalitis, measles, mumps, echovirus-25 infection, Creutzfeldt-Jakob (CJ) disease, cyanide poisoning, and carbon monoxide poisoning and therefore are not entirely sensitive.
Of note, in patients who recover from WEE, most radiographic changes resolve.
Blood cultures are unlikely to help in these situations but may be performed if suspicion of bacterial meningitis is high.
Occasionally, the virus can be recovered by throat swab.
Electroencephalography (EEG) often reveals generalized slowing and disorganization of the background. This is often followed by epileptiform activity that varies from isolated discharges to gross seizure activity.
If suspicion is high, lumbar puncture is absolutely indicated as soon as possible. Assess the CSF for elevated opening pressures and send the CSF for a complete blood count (CBC) with differential; a Gram stain; glucose and protein levels; acid-fast bacillus; an India ink stain; a Venereal Disease Research Laboratory (VDRL) test; a herpes polymerase chain reaction (PCR) assay; and bacterial, viral, and fungal cultures.
Findings in CSF analysis (from lumbar puncture) include the following:
Biopsies are not frequently performed anymore, and these procedures are often a last resort.
The perikaryon and dendrites are primarily affected and demonstrate evidence of cytoplasmic swelling, eosinophilia, and nuclear pyknosis. Occasionally, mature viral particles are present in extracellular spaces. The brain is grossly edematous, and evidence of inflammation parenchymally and perivascularly is present. Perivascular inflammation, vasculitis, thrombi, neurolysis (cell membrane rupture), neuronophagia, and demyelination may be observed. The areas primarily affected grossly are the thalamic nuclei and basal ganglia.
Infants who die of WEE or neonates infected in utero often have massive neuroparenchymal destruction. Of those who survive, most have a normal brain grossly, but some cysts may be present.
The use of biochemical assays is most valuable for diagnosis. Obtain sera at 2- to 3-day intervals to assess for a potential outcome upon early suspicion. The potential drawbacks include an inability to rapidly receive the results of these tests.
Enzyme-linked immunosorbent assay (ELISA) is used to detect IgM, primarily during convalescent stages or prolonged courses, and is virus-specific.
ELISA may also reveal antiarboviral immunoglobulin G (IgG) and yields results similar to those of the neutralization assay. The current use of this assay is primarily as an adjunct to the IgM ELISA.[6]
A serum hemagglutinin inhibition titer of at least 1:320 is used most commonly and allows differentiation among EEE, WEE, and VEE.
A complement fixation titer of at least 1:128 is found primarily in convalescing patients.
An immunofluorescence titer of at least 1:256 is uncommon.
A neutralization assay titer of at least 1:160 is common.
Clinicians may document the presence of WEE in a specimen by inoculating mice or embryonated eggs (Vero cell plaque assay).
A final alternative study, which should provide rapid diagnosis in the future, is PCR analysis of the various organisms known to cause encephalitis. PCR analysis has been performed in WEE since 1996, but initial uses were primarily to differentiate between various cross-species of the virus.
Studies, however, indicate that PCR is much more accurate than the 10% likelihood of serologic diagnostics yielding positive results. Other advantages of PCR include the ability to target antiviral therapy, to reduce the need for brain biopsy, and to increase the speed of diagnosis (ie, the panel can often be run in 72 h). The current limitation of PCR is that it will likely require a state or national effort, which may not be available for WEE. The currently used assay is the TaqMan reverse transcriptase PCR assay.
This is an excellent modality for either monitoring the evolution of lesions or determining primary areas of disease.
The most common finding is a lesion of the basal ganglia. Lesions vary in size and may exhibit secondary mass effect with edema.
A CT scan may reveal areas of punctate hemorrhage, focal edema with mass effect, poorly marginated lesions, or interventricular hemorrhage.
In elderly patients, the findings could mimic early infarction or nonspecific common findings.
Occasionally, meningeal enhancement may also be observed and may indicate a subarachnoid hemorrhage or meningitis.
MRI is often sensitive to early changes secondary to EEE, but no studies have been completed with WEE. In EEE, MRI was more sensitive and revealed more abnormalities with increased detail compared with CT scan; these findings probably would be the same in studies of WEE.
The lesions are best observed with T2-weighted images and appear as areas of increased signal intensity.
The most commonly affected areas of the CNS include the basal ganglia (ie, unilateral or asymmetrical, with occasional internal capsule involvement) and thalamic nuclei. Other areas include the brain stem (often the midbrain), periventricular white matter, and cortex (most often temporally).
Focus initial medical care on a prompt diagnosis, with differentiation from other potentially treatable causes of the patient's symptoms. Because the disease mimics other encephalitides and meningitis or meningoencephalitis, implement prompt drug therapy. The physician should probably begin with triple antibiotic therapy for generalized bacterial coverage and begin acyclovir (10 mg/kg) to empirically treat herpes simplex virus.
As with all critically ill patients, take care to stabilize the patient first. Because of the similarity in presentation between encephalitis and meningitis, implement broad-spectrum antibiotics and an antiviral agent in these patients until more definitive tests are available.
Like all alphaviruses, Western equine encephalitis (WEE) has no specific treatment. Management remains focused primarily on supportive and preventive measures. Treatment also varies based on the stage of the disease. In the early stages of the viral prodrome, diagnosis is essential. Prophylactic use of steroids, ribavirin, or anticonvulsants in this early viremic stage has not been studied.
Once the patient is comatose, perform obvious measures (eg, respiratory maintenance with ventilator support). Ideally, maintain early awareness regarding whether the patient will require transfer to an appropriate level of care (eg, a critical care unit). In addition, appropriately maintain the patient's nutritional status.
Pharmacologic therapy consists primarily of antipyretics, analgesics, and anticonvulsants.
Surgical treatments for this disease are not available, except for appropriate neurologic procedures directed at a large CNS bleed or the consequences of markedly elevated CNS pressure. Rarely, brain biopsy may be performed.
Although no current medical therapies are available for WEE, research has revealed some possibilities, as follows:
Whether these therapies can be productive in humans remains to be elucidated.
The patient must be transferred to the ICU when appropriate.
Many issues are also secondary to the high mortality rate of the disease.
Social work services and other appropriate hospital services should be available to the patients' families.
See the following for more information:
If the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is present, treat it accordingly.
Undertake appropriate nutritional measures based on the patient's mental status.
Because of the potential for high neurologic morbidity, coordinated care and quality follow-up care must be arranged. Patients often require speech therapy, physical therapy, neurodiagnostic follow-up, and potential audiologic testing.
The primary care physician must also be aware of subtle changes in behavior, intelligence, and motor skills.
The potential exists for monitoring the sources of Western equine encephalitis (WEE) infection by assessing the serology of antibodies to WEE in certain wild birds or sentinel birds.
The virus may also be recovered from adult mosquitoes and may provide an opportunity for screening in possible vector habitats. Current screening is ongoing for other arthropod-borne illnesses, such as West Nile encephalitis and EEE.
Areas where the disease is endemic, where the virus has been isolated, or areas at high risk should have the vector mosquito population controlled.
An early outbreak of WEE should cause potential assessment for and deterrence of an epidemic. This should become easier for environmental screening agencies in the future with newly developed techniques, such as an indirect enzyme immunoassay, which has been developed to screen wild birds for antibodies against WEE.[7, 8]
Warn individuals who are at high risk in high-risk areas to take the necessary precautions against WEE. This includes the use of appropriate clothing (eg, long pants, long-sleeved shirts) and mosquito repellant and the avoidance of areas with high mosquito activity (especially during times of day when mosquitoes are most active).
Mosquito netting at nighttime also can be used if appropriate.
Permethrin 5% cream (marketed for scabies prevention) has been found to deter arthropod bites for up to a week. Treated skin is not an effective repellant, but it often causes the insect to die before biting. A permethrin rinse has also been used on clothing and has been proven effective for prevention.[9]
Currently, a vaccine for WEE is available, but it is not in widespread use and may not be effective against certain antigenic variants. The current use for the vaccine is for environmental workers with high exposure risk.
Consultations are primarily obtained for supportive measures.
Consultation with an infectious disease specialist is particularly relevant if the physician is unable to determine the etiology of the encephalitis or meningoencephalitis. The most important contribution is likely to be the ability to rapidly ascertain a potentially reversible cause of the patient's symptoms.
Neurologists also may provide early insightful information and aid in the diagnostics (eg, EEG) and treatment of complications.
If a general practitioner treats the patient, a critical care consultant is valuable to coordinate intensive care unit (ICU) treatment.
Consult a neurosurgeon only if needed for the treatment of complications.
The drugs currently used in cases of Western equine encephalitis (WEE) consist of agents capable of ameliorating neurologic complications. Antipyretics are used as needed. Additionally, suitable analgesics and amnestics are appropriate once the patient is intubated.
Antibiotics are of no value in this situation and may predispose the patients to superinfections. Once the physician determines that the patient does not have a bacterial infection, antibiotics are discontinued.
Initiate anticonvulsants either when a seizure has occurred or is probable, particularly in the pediatric population, in whom prevalence is high.
Corticosteroids are administered early and serve multiple functions. They decrease inflammation, decrease cerebral edema, and correct any adrenocortical insufficiency.
Clinical Context: Phenytoin may act in the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited.
Individualize the dose. Administer a larger dose before retiring if the dose cannot be divided equally. The rate of infusion must not exceed 50 mg per minute to avoid hypotension and arrhythmia.
Clinical Context: Diazepam depresses all levels of the CNS (eg, limbic, reticular formation), possibly by increasing the activity of gamma-aminobutyric acid (GABA). Alternatively, lorazepam can be used when indicated.
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Clinical Context: Dexamethasone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.
Clinical Context: Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context: This is a herpes virus–specific antiviral used for peripheral and systemic manifestations of acute viral illness.
These agents consist of acyclovir and valacyclovir and are often used as empiric treatments for possible herpes simplex encephalitis.
Clinical Context: 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.
These agents are helpful in relieving the associated lethargy, malaise, and fever associated with the disease.