Encephalitis is an acute inflammatory process that primarily involves the brain. The meninges are frequently involved (meningoencephalitis). Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases are viral in origin. The incidence of encephalitis is 1 case per 200,000 population in the United States, with herpes simplex virus (HSV) being the most common cause. The arboviruses account for 10% of cases; occasionally, during an epidemic, they can account for as many as 50%.
Five types of arborviral encephalitis are found in the United States: eastern equine encephalitis (EEE), western equine encephalitis (WEE), St Louis encephalitis, La Crosse encephalitis, and West Nile encephalitis (WNE).[1] This article focuses on EEE, which is caused by an arthropod-borne alphavirus. In equines, EEE is invariably fatal. In humans, EEE is uncommon but is likewise associated with a high rate of morbidity and mortality. Initial symptoms often progress rapidly to confusion, somnolence, or even coma.
In North America, the enzootic vector for EEE is the mosquito Culiseta melanura, which is responsible for the spring-summer amplification of the virus in the mosquito-bird-mosquito cycle. Occasionally, other mosquito types (eg, Coquillettidia perturbans and the ubiquitous Aedes canadensis species) may act as bridges in the horse-to-human transmission.
The viral reservoir varies depending on climate and habitat changes and often exhibits an annual fluctuation between avirulent and virulent strains. The degree of virulence is related to the host specifics of a given epizootic outbreak.
Initial medical care focuses on making a prompt diagnosis that differentiates EEE from potentially treatable causes. Like all diseases caused by alphaviruses, EEE has no specific treatment. Management of this condition primarily rests on supportive and preventive measures.
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For patient education resources, see the Brain and Nervous System Center, as well as Encephalitis.
EEE is characterized by diffuse central nervous system (CNS) involvement. A large number of immunologically active cells enter the brain parenchyma and perivascular areas and mediate much of the damage. Infiltrating neutrophils and macrophages cause neuronal destruction, neuronophagia, focal necrosis, and spotty demyelination. Vascular inflammation with endothelial proliferation, small vessel thrombosis, and perivascular cuffing may also develop.
Antigenic studies reveal that EEE primarily affects the perikaryon and dendrites of neurons, with minimal findings in glial cells. Occasionally, secondary glial proliferation and the formation of glial nodules occur. Cell death by apoptosis occurs primarily among the glial and inflammatory cells. Gross inspection on autopsy reveals edema, leptomeningeal vascular congestion, hemorrhage, and encephalomalacia. Patients who die late in the disease may exhibit diffuse cerebral atrophy, particularly of the cortex.
The mosquito injects the agent of EEE into the subcutaneous and cutaneous tissues of the host. EEE is not transmitted via the aerosol route. It may cross the placenta and infect the fetus. Because of low viral titers in the donor’s blood, EEE is unlikely to be transmitted via transfusion. The prodrome of fevers, chills, weakness, headache, and myalgias represents replication of the virus in nonneural tissues (tissue adjacent to the mosquito’s bite or the lymphatic system).
The virus then binds to specific tissue receptors, undergoes endocytosis, and initiates an RNA-dependent RNA and protein synthetic process.[2] If the original inoculum is large enough, secondary viremia occurs, with eventual viral migration into the CNS via cerebral capillary endothelial cells. Poorly described features of the virus increase microvascular permeability of the brain. Cell-to-cell spread then occurs via dendrites and axons.
EEE is caused by a virus from the Alphavirus genus, which is part of the antigenically similar family of viruses known as Togaviridae. (Alphaviruses are also responsible for WEE and 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 found beneath the lipid bilayer. The nucleocapsid core contains the single-stranded RNA genome.
The alphavirus that causes EEE is found mostly in the mosquito subtype C melanura; other infectious subtypes include the Aedes and Coquillettidia species. C melanura mosquitoes breed in freshwater swamps and feed on passerine birds. The infected birds subsequently exhibit high levels of viremia, which differs from human and equine cases, in which viremia is often low.
Passerine birds serve as an effective reservoir for continued mosquito infection. Regardless of the extent of viremia in the birds, the outcome varies, ranging from asymptomatic states to death. With low viremia in horses and humans, neither of these species acts as a reservoir for further viral distribution.
The only individual risk factor for EEE is age; however, certain behaviors can also be risk factors (eg, outdoor activities during peak mosquito activity, most often in rural areas).
EEE was first recognized in 1938. From 1955-1997, 256 cases, both sporadic and epidemic types, were reported to the US Centers for Disease Control and Prevention (CDC). From 2009-2018, 72 cases were reported to the CDC, averaging 7 cases per year (range, 3-15 annually).[3]
As of October 3, 2019, 30 cases of EEE had been reported in the United States for the year, including 11 deaths. Affected states have included Tennessee, Michigan, Massachusetts, North Carolina, Connecticut, New Jersey, and Rhode Island.[4]
Because alphaviruses depend on arthropod vectors, their distribution is geographically limited. The EEE virus is divided into North and South American variants on the basis of results from hemagglutinin inhibition testing. North American isolates have a highly conserved lineage, as noted in comparisons of outbreaks in Mexico and Texas.
In the United States, EEE is most common east of the Mississippi River (eg, in Michigan, Massachusetts, New York, New Jersey, North Carolina, South Carolina, Florida, Louisiana, and Georgia).[5] The prevalence is increased in environments with wooded areas adjacent to freshwater swamps and marshes.
Most infections occur in summer or early fall. The vector population usually dies in winter, and cases of EEE are almost nonexistent in winter months; however, after winter, a repetitive endemic locus of infection may persist. An additional risk increase occurs during epizootic outbreaks among horses or caged birds.
EEE also is prevalent in gulf coastal areas (eg, Mexico, northern coast of South America, Caribbean). The EEE virus in these regions is an antigenic variant of the North American form.
EEE is a summertime disease and most commonly affects people younger than 15 years and older than 55 years. The exact reason for this pattern is not known, but the preference for extremes of age is a characteristic common to many species of the alphavirus family. Patient age does not affect prognosis, but permanent neurologic impairment and death are more common in children.
No sexual or racial predilection exists for EEE.
EEE has an infection rate of 33%. The average duration of hospitalization is 16-20 days. The prognosis in infected patients is extremely poor; 50-70% of patients die. The morbidity rate is approximately 90%, representing a wide range of mild to severe impairment. Only 10% of patients fully recover.
Currently, no clinical or radiographic prognostic indicators are available for EEE. The location and the type of lesion on imaging do not correlate with long-term sequelae or mortality. Additionally, although younger patients with longer prodromes tend to have better outcomes, no study has proven any statistical significance. The initial history and physical examination often do not reveal any prognostic variables.
Changes in treatment regimens do not commonly affect outcome; in fact, one series revealed a poorer outcome with the use of steroids and anticonvulsants, but many confounding variables were involved in this determination.
Certain laboratory findings may have some significance. The expected outcome in a patient with an elevated white blood cell (WBC) count (>500/μL) in cerebrospinal fluid (CSF) is poorer than that in a patient with a lower CSF WBC count (ie, < 500 cells/μL). In addition, the prognosis in a hyponatremic patient with a sodium level lower than 130 mmol/L is poorer than that in a patient with a higher sodium level.
Because of the lack of specific symptoms, eastern equine encephalitis (EEE) is difficult to diagnose. A rewarding diagnostic approach is to determine the extent of the patient’s illness and to determine whether central nervous system (CNS) infection is present. The prodromal phase is often short (average, 5-10 days) and consists of fever, headache, and some abdominal pain with diarrhea. Compared with other alphavirus infections, EEE progresses more rapidly to both CNS involvement and death. Once symptoms arise, the patient often deteriorates rapidly.
Neurologic symptoms include the following:
Other associated symptoms include the following:
The following are other important factors to consider in the patient’s history:
The physical examination for EEE also is nonspecific, yielding findings similar to those seen with many other encephalitides.
Changes in vital signs may include the following:
Neurologic findings may include the following:
Other findings may include the following:
Possible pharyngeal erythema
The primary complication, other than death, is often a variable level of CNS impairment. Numerous factors, including location and specific inflammatory cell response, may determine the result.
Demyelination is a known by-product of this disease and can be radiologically detected. Often, these areas heal well, unless overlying fibrosis is present or cell death occurs.
Additional potential complications include the following:
Because of the numerous organisms that can produce signs and symptoms similar to those of eastern equine encephalitis (EEE), clinical diagnosis is difficult. Likewise, laboratory confirmation is challenging because it requires either specific serologic findings or virus isolation in brain tissue or cerebrospinal fluid (CSF). If the possibility of EEE is considered early, recovery of the virus from serum during the prodromal phase is possible; however, isolation from either blood or CSF is often difficult.
Neuroimaging studies (eg, computed tomography [CT] and magnetic resonance imaging [MRI]) may play an important role in the early identification of EEE virus and are routinely performed in patients with central nervous system (CNS) symptoms. Of note, most radiographic changes resolve in those patients who recover.
Relatively recent advances in imaging show that previous neuroradiographic manifestations of EEE were not precisely defined. Early studies (not entirely sensitive) revealed a predilection for the thalamic nuclei and the basal ganglia[6] ; however, these changes are also common in infections with Japanese encephalitis, measles, mumps, echovirus 25, conjunctivitis, cyanide poisoning, and carbon monoxide (CO) poisoning.
Brain biopsy is rarely indicated and is simply a last resort for diagnosis.
Few laboratory test abnormalities are particular to EEE. The following are abnormal findings:
Blood cultures reveal nothing in this particular disease but may be performed if suspicion of bacterial infection is high.
Biochemical assays are valuable for EEE diagnosis. With early suspicion, obtain sera at 2- to 3-day intervals. A potential drawback is the slow turnaround time for these test results. Additionally, VecTest antigen assays and Vero cell plaque assays have been in use for arthropod surveillance programs and have also been effective in human diagnosis.[7]
Potential assays for isolation include the following:
Obtain a lumbar puncture (LP) as soon as possible when EEE is strongly suspected. Assess the CSF for elevated opening pressures and obtain a complete blood count (CBC) with differential, Gram stain, glucose, protein, bacterial culture, viral culture, fungal culture, acid-fast bacillus, India ink stain, and Venereal Disease Research Laboratory (VDRL) test.
Increases in protein and protein concentration in the CSF (approximately 100 mg/dL) are common. The CSF red blood cell (RBC) count may be elevated. The CSF white blood cell (WBC) count may be elevated (initial WBC count, 500-2000/µL; median, 600/µL; neutrophils predominate). Hypoglycorrhachia is not present.
Previously, the recovery of EEE was limited because only a few facilities had the resources to amplify the virus. Recent studies indicate excellent growth of the virus recovered from patient CSF in A549 and MRC-5 cell cultures, which are mediums that virology laboratories routinely use to recover adenovirus, herpes simplex virus (HSV), and enterovirus.[9]
EEE-specific TaqMan reverse transcriptase polymerase chain reaction (PCR) analysis is used as a final alternative to analyze the various organisms known to cause encephalitis. It is hoped that this analysis will provide rapid diagnosis in the future.[10]
Recent studies are more promising for PCR because they indicate that it is more accurate than serologic diagnostics, which have a 10% likelihood of yielding positive virus results. Other current advantages include the ability to target antiviral therapy, the ability to reduce the need for brain biopsies, and the ability to increase the speed of diagnosis (obtaining the panel can occur in 72 hours).
The current limitation is that this study likely requires a state or national effort, which may not be available for EEE.
Perform CT scanning to monitor the evolution of lesions or to determine primary areas of disease. The most common finding is a lesion of the basal ganglia. Lesions vary in size and may exhibit a secondary mass effect with edema.
A CT scan may reveal areas of punctate hemorrhage, focal edema with a mass effect, poorly marginated lesions, or interventricular hemorrhage. In elderly patients, the findings can mimic early infarction or they may be nonspecific, which is common in elderly patients. Occasionally, meningeal enhancement may also be present, indicating a subarachnoid hemorrhage or meningitis.
MRI is often sensitive to early changes secondary to EEE, and it may help achieve a prompter diagnosis in as many as 60% of patients. Compared with CT scanning, MRI is more sensitive and reveals more abnormalities with increased detail. Use a T2-weighted image for optimal observation of the lesions, which appear as areas of increased signal intensity.
The most commonly affected areas of the CNS include the basal ganglia (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).
MRI findings are abnormal in all comatose patients, and normal MRI findings may indicate the need to consider another diagnosis.
MRI also provides critical information for differentiating EEE from herpes simplex encephalitis. EEE is common in the basal ganglia, whereas herpesvirus is not. If attenuation is present in the basal ganglia, herpesvirus tends to occur laterally, whereas EEE has a medial preponderance.
Electroencephalography (EEG) often reveals a generalized slowing and disorganization of the background. Later, this process is followed by epileptiform activity that may range from isolated discharges to gross seizure activity.
The perikaryon and dendrites are primarily affected and demonstrate evidence of cytoplasmic swelling, eosinophilia, and nuclear pyknosis. Occasionally, mature viral particles are observed in extracellular spaces. The brain is grossly edematous, and inflammation is evident both parenchymally and perivascularly.
Perivascular inflammation, vasculitis, thrombi, neurolysis, neuronophagia, and demyelination may be observed. The predominance of neutrophils in the inflammatory cell type is particularly important.
Like all disease caused by alphaviruses, eastern equine encephalitis (EEE) has no specific treatment.[11] Focus management primarily on supportive and preventive measures. Pharmacologic therapy consists primarily of antipyretics, analgesics, and anticonvulsants. If the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is present, treat accordingly.
Carefully stabilize the patient before any other activity. Once the patient is comatose, undertake obvious measures (eg, respiratory maintenance with ventilator support in a critical care unit [CCU]). Additionally, as with all critically ill patients, carefully provide adequate nutritional support. No special dietary restrictions exist. Transfer an infected patient to the intensive care unit (ICU) when appropriate.
Assess the many issues secondary to the high mortality of the disease. Ensure that a social worker and appropriate hospital services staff are available to the patient’s family.
No direct surgical treatments for this disease are available, except for the appropriate neurologic measures necessary to deal with significant central nervous system (CNS) bleeding or the consequences of markedly elevated CNS pressure.
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Consultations are obtained primarily for supportive measures. The following consultations may be helpful:
Patients who survive infection usually need extensive rehabilitation. On the basis of the duration of symptoms and the extent of neurospasticity, schedule the patient for physical therapy upon recovery. In addition, depending on the specific defect, a patient may need consultations with speech and auditory therapists.
Because of the potential for high neurologic morbidity, arrange coordinated care and quality follow-up care. Patients often require close neurodiagnostic follow-up care. The primary care physician must also be aware of subtle changes in behavior, intelligence, and motor skills.
There is no specific pharmacologic therapy for EEE. Drugs currently used are those capable of ameliorating neurologic complications (eg, anticonvulsants). No current studies provide convincing evidence for or against prophylactic use. Medications that may be given include phenytoin, phenobarbital, and a benzodiazepine drip.
Use antipyretics as needed. Additionally, appropriate analgesics and amnestics may be used once the patient is intubated. Antibiotics are not of value in these situations and may predispose patients to superinfections. After determining that the patient does not have a bacterial infection, discontinue antibiotics.
Because EEE can mimic other encephalitides, meningitis, or meningoencephalitis, empiric drug therapy for these conditions should be implemented promptly. Antibiotic therapy for generalized coverage of bacterial meningitis (as appropriate for age and antibiotic resistance patterns) and acyclovir to treat herpes simplex virus (HSV) infection should be started until these diseases are ruled out.
Although ribavirin has in vitro activity against this virus, the benefit of administering it in the early viremic stage has not been established.
Although no current medical therapies exist for EEE, recent research reveals some possibilities. An antibody with appropriate specificity attenuates the intracellular processes necessary for viral replication in animal models. The antibody binds to cell-specific markers of infected cells and initiates an intracellular cascade, which interferes with viral reproduction. Cytotoxic T cells also play an important part in the recovery from CNS lesions in mice.
Early studies attempted to use pyrimidine derivatives and isoprinosine, a derivative of inosine, for treatment, but in vivo results were poor.[12] Nucleoside analogs (eg, ribavirin) also have in vitro activity, but no clinical application is apparent.
Whether or not these therapies can be productive in humans remains questionable.
Monitoring the sources of infection may be possible by assessing the serology of anti-EEE antibodies in certain wild birds or in caged flocks of sentinel birds (eg, chickens). The virus may also be recovered from adult mosquitoes and may provide an opportunity for screening in possible vector habitats. Officials should control the vector mosquito population in areas where the virus has been isolated or where the risk of infection is high.
Global factors also play a role in future prevention and spread. If global temperatures continue to rise and sea levels rise, the swampy breeding habitat of the C melanura mosquito and other bridge vectors may expand.
Warn individuals who live in or travel to high-risk areas to take the necessary precautions.[13] This includes wearing appropriate clothing (eg, long pants, long-sleeved shirts), wearing mosquito repellent, avoiding areas with high mosquito activity, and avoiding outside activity during times of day when mosquitos are active. Mosquito netting at nighttime can also be used if appropriate.
Permethrin 5% cream on exposed skin areas can prevent arthropod bites for up to a week. The drug does not repel arthropods effectively, but it deters biting and causes the insects to die after contact with the treated skin.[14] Permethrin rinse in clothing has been shown to be partially effective in preventing arthropod bites.
Currently, a vaccine is available for the North American subtype of EEE; however, it is not in widespread use and may not be effective against certain antigenic variants that are found primarily in other countries. At present, its use is limited to environmental workers at high risk of exposure. Studies of advances in experimental vaccination have yielded equivocal results. The current vaccine has a weak antigen and requires multiple immunizations to achieve protection.
EEE is reportable under the National Notifiable Diseases Surveillance System. Additionally, electronic surveillance is conducted through ArboNet, a Centers for Disease Control and prevention (CDC) site used to assist states in tracking mosquito-borne viruses.
To enable appropriate precautions, states with known mosquito-borne illnesses are now also screening vectors to determine if certain counties contain an increased number of carriers.
Drugs currently used in the treatment of eastern equine encephalitis (EEE) are those capable of ameliorating neurologic complications. No current studies provide convincing evidence for or against prophylactic use. Potentially used medications include phenytoin, phenobarbital, or a benzodiazepine drip.
Use antipyretics as needed. Additionally, appropriate analgesics and amnestics can be used once the patient is intubated. Antibiotics are not of value in these situations and may predispose patients to superinfections. After determining that the patient does not have a bacterial infection, discontinue antibiotics.
Clinical Context: Phenytoin may act in the motor cortex, where it may inhibit spread of seizure activity. Activity of brain stem centers responsible for the tonic phase of grand mal seizures also may be inhibited. Individualize the dosage, and administer a larger dose before retiring if the dose cannot be divided equally. To avoid hypotension and arrhythmia, the rate of infusion must not exceed 50 mg/min.
Clinical Context: Any of the benzodiazepines may be effective in the short term. Most often, diazepam or lorazepam is recommended. Diazepam depresses all levels of the central nervous system (eg, limbic system, reticular formation), possibly by increasing the activity of gamma-aminobutyric acid (GABA). Individualize the dosage, and increase it cautiously to avoid adverse effects.
Because of the high prevalence of seizures in patients with EEE, anticonvulsants are appropriate.
Clinical Context: Dexamethasone is a potent corticosteroid usually administered intravenously (IV) in these situations. It is used for various allergic and inflammatory diseases. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Clinical Context: Methylprednisolone is an IV steroid often used early. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Early initiation serves multiple purposes (eg, decreases inflammation, decreases cerebral edema, treats potential adrenocortical dysfunction).
Clinical Context: Inhibits action of endogenous pyrogens on heat-regulating centers; reduces fever by a direct action on the hypothalamic heat-regulating centers, which, in turn, increase the dissipation of body heat via sweating and vasodilation.
These agents are used to reduce fever in patients with eastern equine encephalitis.