eMedicine Specialties > Infectious Diseases > CNS Infections

Western Equine Encephalitis

Mohan Nandalur, MD, Staff Physician, Department of Internal Medicine, Section of Cardiovascular Medicine, Washington Hospital Center
Andrew W Urban, MD, Chief, Section of Infectious Diseases, Middleton Memorial Veterans Hospital; Clinical Assistant Professor, Department of Internal Medicine, University of Wisconsin at Madison

Updated: Oct 31, 2007

Introduction

Background

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.

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 prefers warm and 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.

WEE is of the genus Alphavirus and in the family Togaviridae. WEE is a summertime infection found in the western United States, and it is more common in rural areas.

WEE is a member of the antigenically similar group of viruses known as Togaviridae, which 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 RNA genome.

Of the alphaviruses, EEE virus most closely resembles WEE and may have been a genetic predecessor of WEE. The recently completed nucleotide sequence for WEE revealed an 11,508-nucleotide organism with an 84% concordance of protein similarity with EEE.¹ Additional cross-genetic research reveals 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 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.²

Pathophysiology

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.

Pathogen invasion

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.

Frequency

United States

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 both a sporadic and 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.³

The annual incidence of the virus varies greatly because of the presence of both 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.

International

A subtype of WEE found in Argentina has indicated a likely endemic reservoir in South America. Aedes albifasciatus, 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.

Mortality/Morbidity

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.

Race

No racial predilection for WEE exists.

Sex

Based on cumulative cases, WEE is more common in males than in females, which is believed to be secondary to frequent occupational exposure of rural land workers.

Age

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.

Clinical

History

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.

• Neurologic symptoms: Once these symptoms arise, patients have a poorer prognosis and decompensate rapidly.
  • Headache - Often the most prevalent symptom
  • Nausea or vomiting - Present in both the prodromal and the active stages of illness
  • Confusion
  • Focal neurologic deficits (ie, sensory or motor loss in 1 distribution) - Low prevalence
  • Seizures (most commonly of the general tonic-clonic or partial complex) - Greater frequency in very young children
  • Somnolence
  • Neck stiffness
  • Malaise and weakness
  • Cranial nerve palsies (rare)
  • Photophobia
• Other associated symptoms
  • Vertigo (common)
  • Abrupt fever - Almost invariably present at some point
  • Chills
  • Abdominal pain
  • Diarrhea
  • Sore throat (common)
  • Arthralgias or myalgias
  • Respiratory difficulty (common)
• Social history
  • Recent travel to endemic areas
  • Outdoor exposure history
  • Work related to the care of horses
  • Recent insect bites
  • Recent illnesses
  • Recent ill contacts
  • Locations of home and work

Physical

The findings on physical examination also are nonspecific and are similar to findings of many other encephalitides.

• Changes in vital signs
  • Fever
  • Tachycardia
  • Possibly tachypneic
• Neurologic findings
  • Bilateral papilledema
  • Nuchal rigidity
  • Focal sensory or motor deficit
  • Depressed or hyperactive reflexes
  • Tremors
  • Fasciculations
  • Seizure activity
  • Spastic paralysis
• Other findings
  • Cyanosis, if respiratory compromise is present
  • Facial, periorbital, or generalized edema
  • Lymphadenopathy (not necessarily present)
  • Possible pharyngeal erythema
  • Infants - Bulging fontanelles (possibly)

Causes

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.

Differential Diagnoses

Other Problems to Be Considered

Infective endocarditis
Mumps
Rabies virus
Stroke
Metabolic encephalopathy
Reye syndrome
Epstein-Barr virus (EBV)

Workup

Laboratory Studies

• Because of the large number of potential organisms that can be responsible for the signs and symptoms of this disease, 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 western equine encephalitis (WEE).
• The current guidelines of the Centers for Disease Control and Prevention (CDC) for diagnosis of an arbovirus require an acute febrile illness with encephalitis during a time when transmission of the virus is likely and 1 more of the following criteria:
  • A greater than 4-fold increase in the viral antibody titer between acute and convalescent sera (often 10 wk apart)
  • Viral isolation from the CSF, blood, or tissue
  • Immunoglobulin M (IgM) positive to the organism in the CSF
• Presumptive positive diagnoses can be made based on the remaining biochemical assays (eg, hemagglutinin inhibition, immunofluorescence, neutralization, complement fixation).
• Blood cultures are unlikely to help in these situations but may be performed if suspicion of bacterial meningitis is high.
• 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. Potential assays for isolation include the following:
  • 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.⁴
  • 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 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.
• CSF findings (from lumbar puncture) 
  • Increased protein and protein concentration in CSF: This is often present (approximately 90-110 mg/dL) and occurs with a high prevalence.
  • Elevated CSF RBC count
  • Elevated CSF WBC count: Initial WBC count is 50-500/µL, with a median of 350/µL and a predominance of lymphocytes.
  • No hypoglycorrhachia
  • Occasional viral isolation
  • Occasional IgM positivity, which can provide a presumptive diagnosis
• A final alternative study, which should provide rapid diagnosis in the future, is polymerase chain reaction (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. Recent studies, however, are more promising for PCR because they indicate that it is much more accurate than the 10% likelihood of serological 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.

Imaging Studies

Encephalitis can be identified early with neuroimaging studies (eg, CT scanning, MRI), which are routinely performed in patients with CNS symptoms.

Recent 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 in infections with Japanese encephalitis, measles, mumps, echovirus 25, Creutzfeldt-Jakob (CJ) disease, cyanide poisoning, and carbon monoxide poisoning and therefore are not entirely sensitive. Both CT scanning and MRI may play an important part in the early identification of WEE. Of note, in patients who recovered, most radiographic changes resolved.

• CT scanning
• 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
• 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 to CT scan, and 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 asymmetric 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).

Other Tests

• Throat swab: Occasionally, the virus can be recovered by this method.
• EEG: 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.
• Lumbar puncture: If suspicion is high, lumbar puncture is absolutely indicated as soon as possible. Assess the CSF for elevated opening pressures and send CSF for a CBC count with differential; Gram stain; glucose and protein levels; acid-fast bacillus; India ink stain; Venereal Disease Research Laboratory (VDRL) test; herpes PCR; and bacterial, viral, and fungal culture.
• Brain biopsies: Biopsies are not frequently performed anymore, and these procedures are often a last resort.

Histologic Findings

CNS histopathology

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 both 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.

Treatment

Medical Care

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.

• 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.
• If the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is present, treat accordingly (see Syndrome of Inappropriate Antidiuretic Hormone Secretion).
• Pharmacologic therapy consists primarily of antipyretics, analgesics, and anticonvulsants.
• Although no current medical therapies are available for WEE, recent research has revealed some possibilities.
  • Viral envelope proteins are capable of being functionally expressed in culture and in the future may lead to a subunit vaccine for WEE.
  • An antibody with appropriate specificity attenuates the intracellular processes necessary for viral replication in animal models.
  • Cytotoxic T cells play an important part in the recovery from CNS lesions in mice.
  • Nucleoside analogs (eg, ribavirin) have in vitro activity, but no clinical application is yet apparent.
  • Additionally, a repertoire of mouse monoclonal antibodies (MAbs) against WEE currently exists; these are currently not in clinical practice and may eventually become a form of immunodetection or immunotherapy.
  • Whether these therapies can be productive in humans remains to be elucidated.

Surgical Care

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.

Consultations

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.
• Similar to the reasons for obtaining a consultation with an infectious disease specialist, neurologists 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 ICU care.
• Consult a neurosurgeon only if needed for treatment of complications.

Diet

Undertake appropriate nutritional measures based on the patient's mental status.

Medication

The drugs currently used 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.

Anticonvulsant agents

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Phenytoin (Dilantin)

May act in motor cortex, where it may inhibit spread of seizure activity. Activity of brain stem centers responsible for tonic phase of grand mal seizures may also be inhibited.
Individualize the dose. Administer a larger dose before retiring if dose cannot be divided equally. Rate of infusion must not exceed 50 mg/min to avoid hypotension and arrhythmia.

Dosing

Adult

Loading dose: 15-20 mg/kg PO/IV once or as divided doses, followed by 100-150 mg per dose at 30-min intervals
Initial dose: 100 mg (125 mg susp) PO/IV tid
Maintenance dose: 300-400 mg/d PO/IV divided tid or qd/bid if using ER; increase to 600 mg/d (625 mg/d susp) may be necessary; not to exceed 1500 mg/24h

Pediatric

Loading dose: 15-20 mg/kg PO/IV once or as divided doses
Initial dose: 5 mg/kg/d PO/IV divided bid/tid
Maintenance dose: 4-8 mg/kg PO/IV divided bid/tid
>6 years: May require minimum adult dose (300 mg/d); not to exceed 300 mg/d

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimide, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid

Contraindications

Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if a skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood sugars); discontinue use if hepatic dysfunction occurs

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic, reticular formation), possibly by increasing activity of GABA. Alternatively, lorazepam can be used when indicated.

Dosing

Adult

5-15 mg IV q5min, repeat prn; not to exceed 30 mg in 8 h

Pediatric

0.05-0.3 mg/kg/dose IV/IM over 2-3 min q15-30min; repeat in 2-4 h prn; not to exceed 10 mg

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Dexamethasone (Decadron, Baldex, AK-Dex)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Dosing

Adult

16 mg PO/IV, followed by 4-10 mg PO/IV q6h

Pediatric

0.08-0.3 mg/kg/d or 2.5-10 mg/m²/d PO/IV divided q6-12h

Interactions

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

3 mg/kg IV over 15 min, followed in 45 min with 5.4 mg/kg/h IV

Pediatric

0.5-1.7 mg/kg/d or 5-25 mg/m²/d PO/IV/IM divided q6-12h

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Antiviral agents

These agents consist of acyclovir or valacyclovir and are often used as empiric treatments for possible herpes simplex encephalitis.

Acyclovir (Zovirax)

This is a herpes virus–specific antiviral used for peripheral and systemic manifestations of acute viral illness.

Dosing

Adult

5-10 mg/kg IV q8h; PO not recommended

Pediatric

Administer as in adults

Interactions

Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal failure or when using nephrotoxic drugs

Follow-up

Further Inpatient Care

• 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.

Further Outpatient Care

• 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 audiology testing. The primary care physician must also be aware of subtle changes in behavior, intelligence, and motor skills.

Deterrence/Prevention

• Environmental animal control
• The potential exists for monitoring the sources of infection by assessing serology of antibodies to western equine encephalitis (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.⁵
• Global environmental factors: Global factors also play a role in prevention and spread. As noted above, the transmission rate increases during warm seasons, and an increase in global temperature may increase the duration of infectivity in the future.
• Public information
• Warn individuals who are at high risk in high-risk areas to take the necessary precautions. This includes appropriate clothing (eg, long pants, long-sleeved shirts), mosquito repellant, and 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.
• Having air conditioning in the home has been found to decrease the transmission of the disease. Behavioral patterns such as these have reduced the incidence of disease, even in peak mosquito seasons.⁶
• 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.⁷
• Surveillance: WEE can be reported electronically to a CDC-run site called ArboNet, which assists states in tracking mosquito-borne viruses.
• Future prevention: 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.

Complications

• The primary complications other than death are variable levels of 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.

Prognosis

• Patients infected with 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 (both pyramidal and extrapyramidal), and residual behavioral problems.

Patient Education

• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Encephalitis.

Miscellaneous

Medicolegal Pitfalls

• As with all critically ill patients, take care to stabilize the patient first. As mentioned above, 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.

References

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Keywords

western equine encephalitis, WEE, inflammation of the brain parenchyma, meninges, herpes simplex virus, arbovirus, Culex tarsalis, C tarsalis, Aedes species, eastern equine encephalitis, EEE, Venezuelan equine encephalitis, VEE, Sindbis virus, neurotropic alphavirus, diffuse CNS involvement, meningitis, meningoencephalitis, St. Louis encephalitis, Aedes albifasciatus, A albifasciatus, encephalitides

Contributor Information and Disclosures

Author

Mohan Nandalur, MD, Staff Physician, Department of Internal Medicine, Section of Cardiovascular Medicine, Washington Hospital Center
Mohan Nandalur, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians-American Society of Internal Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Andrew W Urban, MD, Chief, Section of Infectious Diseases, Middleton Memorial Veterans Hospital; Clinical Assistant Professor, Department of Internal Medicine, University of Wisconsin at Madison
Andrew W Urban, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine
Disclosure: Nothing to disclose.

Medical Editor

Kenneth C Earhart, MD, FACP, Deputy Head, Disease Surveillance Program, United States Naval Medical Research Unit #3
Kenneth C Earhart, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Undersea and Hyperbaric Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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