California encephalitis (CE) is a relatively common, reportable, childhood central nervous system (CNS) disease transmitted by mosquito bite. It is second in importance to West Nile viral encephalitis among the mosquito-borne viral diseases in the United States, with about 80-100 cases reported yearly. See the image below.
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Range of California encephalitis cases reported in the United states from 2004-2013. Courtesy of CDC and ArboNET.
Most infections are asymptomatic, and the majority of infected individuals who develop symptoms recover completely; however, up to 10% of patients develop behavioral problems or recurrent seizures. Severe disease often manifests as encephalitis (inflammation of the brain) and can cause seizures, coma, and paralysis. Mortality rates are low (< 1%).
The condition was named California encephalitis after the first human case (caused by a virus called California virus) was described in Kern County, California, in 1946.[1] Since then, most cases have been associated with La Crosse (LAC) virus. La Crosse virus was first isolated from the brain of a 4-year-old boy who died of encephalitis in La Crosse County, Wisconsin.
California encephalitis (CE) is caused by a group of viruses that belong to the genus Bunyavirus and the family Bunyaviridae. This largest family of RNA viruses has more than 350 named isolates with worldwide distribution. Bunyaviruses are spherical, lipid membrane–enclosed viruses that are 90-110 nm in diameter. They contain 3 negative-sense RNA segments and an enveloped nucleocapsid. The nucleocapsid protein is believed to be immunogenic.
Most cases of California encephalitis are caused by La Crosse virus, although a number of other antigenically related viruses make up the California encephalitis group, including California and Jamestown Canyon viruses.
La Crosse virus is the most common cause of arboviral-induced pediatric encephalitis in the United States. The principal vector is Aedes triseriatus, a forest-dwelling, tree-hole–breeding mosquito of the north central and northeastern regions of the United States. La Crosse virus is maintained in the mosquito via transovarial transmission supplemented by venereal transmission and amplification during summer by mosquitoes feeding on viremic chipmunks, foxes, squirrels, and woodchucks. During winter, the virus survives in infected mosquito eggs.[2]
Alternating cycles of infection occur between the mosquito and the vertebrate hosts, including humans. The mosquitoes obtain the virus after a blood meal from hosts who are in the viremia stage. The transmission cycle for La Crosse virus is demonstrated in the diagram below.
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La Crosse virus transmission cycle. The virus is maintained by vertical transmission in Aedes triseriatus mosquitoes; the virus winters in infected eg....
After inoculation via a mosquito bite (usually the female mosquito), the virus undergoes a local replication at the original skin site. A primary viremia occurs, with seeding of the reticuloendothelial system, mainly the liver, spleen, and lymph nodes.
With continued virus replication, a secondary viremia occurs, with seeding of the CNS. The probability of CNS infection depends on the efficiency of viral replication at the extraneural sites and the degree of viremia. The virus invades the CNS through either the cerebral capillary endothelial cells or the choroid plexus. Rarely, the virus is isolated from brain tissue.
Antibodies against the G1 part of the virus neutralize the virus, block fusion, and inhibit hemagglutination. They are also important in virus clearance and recovery and in prevention of reinfection.
Several epidemiologic factors influence arboviral encephalitis, including (1) the season, (2) the geographic location, (3) the regional climate conditions (eg, spring rainfall), and (4) patient age.
The highest incidence of arboviral encephalitis in the United States is in the midwestern states. Most cases occur in the late summer to early fall, although, in subtropical endemic areas (eg, the Gulf States), some cases occur in winter. Outdoor activities, especially in woodland areas, are associated with an increased risk of infection.
Historically, La Crosse encephalitis has been reported in 28 states, mostly from the northern Midwestern states (Minnesota, Wisconsin, Iowa, Illinois, Indiana, and Ohio). Recently, more cases have been reported from mid-Atlantic and southeastern states (West Virginia, Virginia, Kentucky, North Carolina, and Tennessee). See the image below.
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La Crosse virus neuroinvasive disease cases reported by state, 2004-2013. Courtesy of CDC and ArboNET.
In areas where the disease is endemic, the incidence exceeds that of bacterial meningitis before the introduction of the Haemophilus influenzae vaccine. La Crosse encephalitis may be underrecognized, not only in terms its prevalence but also in terms of severity.
California encephalitis is more common in males than in females, probably because of more outdoor exposure. Clinical disease occurs almost exclusively in children aged 6 months to 16 years (peak, 4-10 y). The older the patient, the less likely he or she is to develop the clinical illness.
The incubation period of California encephalitis is usually 3-7 days. A prodromal phase of 1-4 days commonly precedes the onset of encephalitis. This phase manifests as any or all of the following:
Fever
Chills
Nausea
Vomiting
Headache
Abdominal pain
The encephalitis is characterized by fever and somnolence, which may progress to obtundation. Although most patients make uneventful recoveries, electroencephalographic findings are abnormal 1-5 years later in 75% of cases, emotional lability is persistent in 10%, and epilepsy is a chronic problem in 6%-10% of all diagnosed cases. Although uncommon, frank neurologic deficit can also occur.[3] Twenty percent of children develop focal neurologic signs (eg, asymmetrical reflexes, Babinski signs), and 10% of patients develop coma. Periodic lateralizing epileptiform discharges (PLEDS) can be seen in the temporal lobe. The total duration of illness rarely exceeds 10-14 days.
Two reports in the literature have described LaCrosse encephalitis manifesting as signs and symptoms of herpes simplex encephalitis.[4, 5]
In adults, infection is asymptomatic or causes a benign febrile illness or aseptic meningitis.
The diagnosis of California encephalitis is based on immunology, because the virus is not present in blood or secretions during clinical CNS disease. The diagnosis can be established as follows:
Specific immunoglobulin M (IgM) and neutralizing antibodies to the virus in serum or cerebrospinal fluid (CSF) using enzyme-linked immunosorbent assay (ELISA) technique: IgM is usually but not always present during acute illness.
A 4-fold increase in the antivirus antibody titer between the acute and the convalescent periods, although this may not be observed in every case[7]
In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry and virus culture of autopsy tissues can also be useful. Only a few state laboratories or other specialized laboratories, including those at the Centers for Disease Control and Prevention (CDC), are capable of performing this specialized testing.
Antibody studies
Significant antibody titers include levels of more than 320 by hemagglutination inhibition, more than 128 by complement fixation, more than 256 by immunofluorescence, or more than 160 by plaque reduction neutralization test.
A licensed indirect fluorescent antibody test is available for IgG and IgM antibodies to La Crosse virus and may be useful in diagnosis.[7]
CSF examination
In general, the findings are nonspecific and similar to other presentations of viral meningoencephalitis.
CSF examination may reveal the following:
Normal to mildly elevated pressure level
Normal glucose level and normal to mildly elevated protein level
Initially, a polymorphonuclear leukocytic pleocytosis followed by lymphocytic or monocytic leukocytosis is present.
Complete blood count and chemistry
The complete blood count (CBC) is usually within the reference range or might show mild leukocytosis. Peripheral leukocytosis in excess of 15,000 WBCs/µL is not uncommon. Chemistry findings are usually within the reference range, but hyponatremia (low serum sodium level) has been observed in up to 20% of patients in at least one case series.[3]
Polymerase chain reaction
Use of the polymerase chain reaction for the diagnosis of La Crosse encephalitis is still in the research stage.
Electroencephalography
De los Reyes and colleagues found that children with La Crosse encephalitis who have PLEDS on electroencephalograms have a higher rate of complications.[8]
Neuroimaging using conventional computed tomography (CT) scanning and magnetic resonance imaging (MRI) is not helpful in establishing the diagnosis of California encephalitis. In very severe cases, CT scanning might show nonspecific enhancement. (See the image below.)
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Left image of a CT scan of an 8-year-old boy with severe La Crosse encephalitis complicated by uncal herniation (obtained on the second hospital day) ....
Histologic Findings
On pathologic examination, as with all viral encephalitides, there is a widespread degeneration of single nerve cells, with neuronophagia and scattered foci of inflammatory necrosis involving the gray and white matter. The brain stem is relatively spared. Perivascular cuffing with lymphocytes and plasma cells occurs, as well as patchy infiltration of the meninges. (See the image below.)
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Brain biopsy specimen from a 7-year-old boy with severe La Crosse encephalitis (hematoxylin and eosin stain, 200X). Perivascular infiltration with mon....
No specific antiviral treatment for California encephalitis is approved at this time. Supportive care is therefore the mainstay of management. La Crosse virus has in vitro sensitivity to ribavirin, and treatment of one unusual case diagnosed with brain biopsy has been reported.[9] Since neurologic complications are the most severe and closely linked to disease mortality, control of seizures and optimal neurologic support are vital components of management. Patient isolation during acute illness is unnecessary. Bed rest is always recommended until recovery.
Prevention
No vaccines are available at this time.
Preventive measures include the following:
Insect repellents
Mosquito control by controlling the breeding sites, including elimination of manufactured containers and use of spray insecticides.
Wearing long sleeves for outdoor activities
Mosquito prevention techniques, possibly including the repellant effect of certain essential oils[10]
Supportive care is the mainstay of treatment. The drugs in supportive care consist of agents capable of ameliorating neurologic complications. Antipyretics are used as needed. No antiviral agent is available, and no vaccine is available for preexposure protection.
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.
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.
Folusakin O Ayoade, MD, Clinical Fellow, Division of Infectious Diseases, LSU Health Science Center
Disclosure: Nothing to disclose.
Coauthor(s)
Mohammad J Alam, MD, Assistant Professor of Medicine, Departments of Internal Medicine, Infectious Disease, and Emergency Medicine, University Health, Louisiana State University School of Medicine in Shreveport; Affiliate Staff Physician, Department of Internal Medicine (Infectious Disease), Schumpert Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Joseph F John, Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
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
Disclosure: Nothing to disclose.
Additional Contributors
Emad Fahmi Soliman, MD, MSc, Consulting Staff, Department of Neurology, St John's Riverside Hospital
Disclosure: Nothing to disclose.
Mary D Nettleman, MD, MS, MACP, Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine
Disclosure: Nothing to disclose.
Norvin Perez, MD, Medical Director, Juneau Urgent and Family Care
Disclosure: Nothing to disclose.
Wayne E Anderson, DO, FAHS, FAAN, Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors gratefully acknowledge the contributions of previous authors Eleftherios Mylonakis, MD, and Eduardo Gotuzzo, MD, to the development and writing of the source article.
Range of California encephalitis cases reported in the United states from 2004-2013. Courtesy of CDC and ArboNET.
La Crosse virus transmission cycle. The virus is maintained by vertical transmission in Aedes triseriatus mosquitoes; the virus winters in infected eggs that are usually deposited in tree holes or in artificial containers holding rainwater. Horizontal transmission (by viral amplification in small vertebrates, eg, squirrels and chipmunks, and venereally among adult mosquitoes) is required to supplement vertical transmission. The role of deer in viral amplification is uncertain. Human infections are incidental to the transmission cycle.
La Crosse virus neuroinvasive disease cases reported by state, 2004-2013. Courtesy of CDC and ArboNET.
Left image of a CT scan of an 8-year-old boy with severe La Crosse encephalitis complicated by uncal herniation (obtained on the second hospital day) reveals brain edema with associated obliteration of perimesencephalic cisterns (arrows). On the right, a T2-weighted magnetic resonance image obtained from a 7-year-old boy with severe La Crosse encephalitis shows focal areas of increased signal intensity in the right temporoparietal and left frontotemporal regions (arrows).
Brain biopsy specimen from a 7-year-old boy with severe La Crosse encephalitis (hematoxylin and eosin stain, 200X). Perivascular infiltration with mononuclear cells is present on light microscopy. This biopsy material tested positively for La Crosse virus antigen on direct immunofluorescence assay.
La Crosse virus transmission cycle. The virus is maintained by vertical transmission in Aedes triseriatus mosquitoes; the virus winters in infected eggs that are usually deposited in tree holes or in artificial containers holding rainwater. Horizontal transmission (by viral amplification in small vertebrates, eg, squirrels and chipmunks, and venereally among adult mosquitoes) is required to supplement vertical transmission. The role of deer in viral amplification is uncertain. Human infections are incidental to the transmission cycle.
Brain biopsy specimen from a 7-year-old boy with severe La Crosse encephalitis (hematoxylin and eosin stain, 200X). Perivascular infiltration with mononuclear cells is present on light microscopy. This biopsy material tested positively for La Crosse virus antigen on direct immunofluorescence assay.
Left image of a CT scan of an 8-year-old boy with severe La Crosse encephalitis complicated by uncal herniation (obtained on the second hospital day) reveals brain edema with associated obliteration of perimesencephalic cisterns (arrows). On the right, a T2-weighted magnetic resonance image obtained from a 7-year-old boy with severe La Crosse encephalitis shows focal areas of increased signal intensity in the right temporoparietal and left frontotemporal regions (arrows).
Range of California encephalitis cases reported in the United states from 2004-2013. Courtesy of CDC and ArboNET.
La Crosse virus neuroinvasive disease cases reported by state, 2004-2013. Courtesy of CDC and ArboNET.
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