Approach Considerations

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

Polymerase chain reaction (PCR) for the diagnosis of La Crosse encephalitis and Metagenomic next-generation sequencing (NGS) of the CSF has the potential to identify a broad range of pathogens in a single test (ref DOI: 10.1056/NEJMoa1803396). This studies 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]

CT Scanning and MRI

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.

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).

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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.

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.

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Treatment & Management

HAMMON WM, REEVES WC. California encephalitis virus, a newly described agent. Calif Med. 1952 Nov. 77 (5):303-9. [QxMD MEDLINE Link].
Watts DM, Thompson WH, Yuill TM, DeFoliart GR, Hanson RP. Overwintering of La Crosse virus in Aedes triseriatus. Am J Trop Med Hyg. 1974 Jul. 23 (4):694-700. [QxMD MEDLINE Link].
McJunkin JE, de los Reyes EC, Irazuzta JE, Caceres MJ, Khan RR, Minnich LL, et al. La Crosse encephalitis in children. N Engl J Med. 2001 Mar 15. 344 (11):801-7. [QxMD MEDLINE Link].
Sokol DK, Kleiman MB, Garg BP. LaCrosse viral encephalitis mimics herpes simplex viral encephalitis. Pediatr Neurol. 2001 Nov. 25(5):413-5. [QxMD MEDLINE Link].
Wurtz R, Paleologos N. La Crosse encephalitis presenting like herpes simplex encephalitis in an immunocompromised adult. Clin Infect Dis. 2000 Oct. 31(4):1113-4. [QxMD MEDLINE Link].
Hubalek Z, Sebesta O, Pesko J, Betasova L, Blazejova H, Venclikova K, et al. Isolation of Tahyna Virus (California Encephalitis Group) From Anopheles hyrcanus (Diptera, Culicidae), a Mosquito Species New to, and Expanding in, Central Europe. J Med Entomol. 2014 Nov 1. 51 (6):1264-7. [QxMD MEDLINE Link].
Jones TF, Erwin PC, Craig AS, Baker P, Touhey KE, Patterson LE, et al. Serological survey and active surveillance for La Crosse virus infections among children in Tennessee. Clin Infect Dis. 2000 Nov. 31 (5):1284-7. [QxMD MEDLINE Link].
de los Reyes EC, McJunkin JE, Glauser TA, Tomsho M, O'Neal J. Periodic lateralized epileptiform discharges in La Crosse encephalitis, a worrisome subgroup: clinical presentation, electroencephalogram (EEG) patterns, and long-term neurologic outcome. J Child Neurol. 2008 Feb. 23(2):167-72. [QxMD MEDLINE Link].
McJunkin JE, Khan R, de los Reyes EC, Parsons DL, Minnich LL, Ashley RG, et al. Treatment of severe La Crosse encephalitis with intravenous ribavirin following diagnosis by brain biopsy. Pediatrics. 1997 Feb. 99 (2):261-7. [QxMD MEDLINE Link].
Sandler ZJ, Firpo MR, Omoba OS, Vu MN, Menachery VD, Mounce BC. Novel Ionophores Active against La Crosse Virus Identified through Rapid Antiviral Screening. Antimicrob Agents Chemother. 2020 May 21. 64 (6):[QxMD MEDLINE Link].
Conti B, Benelli G, Leonardi M, Afifi FU, Cervelli C, Profeti R, et al. Repellent effect of Salvia dorisiana, S. longifolia, and S. sclarea (Lamiaceae) essential oils against the mosquito Aedes albopictus Skuse (Diptera: Culicidae). Parasitol Res. 2012 Jul. 111(1):291-9. [QxMD MEDLINE Link].

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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 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).
La Crosse virus neuroinvasive disease cases reported in the United states from 2010-2019. Courtesy of CDC and ArboNET (https://www.cdc.gov/lac/tech/epi.html).
La Crosse virus neuroinvasive disease cases reported by state, 2010-2019. Courtesy of CDC and ArboNET (https://www.cdc.gov/lac/tech/epi.html).

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Author

Folusakin O Ayoade, MD Assistant Professor of Clinical Medicine, Division of Infectious Diseases, Department of Medicine, University of Miami, Leonard M Miller School of Medicine; Attending Physician in Infectious Diseases, Jackson Health System; Attending Physician in Infectious Diseases, University of Miami Hospital

Folusakin O Ayoade, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Medical Association, Infectious Diseases - International Research Initiative, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Leopoldo Cordova G, MD Fellow in Infectious Diseases, University of Miami, Leonard M Miller School of Medicine

Leopoldo Cordova G, MD is a member of the following medical societies: American College of Physicians, Venezuelan Society of Infectious Diseases, Venezuelan Society of Internal Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Joseph F John, Jr, MD, FACP, FIDSA, FSHEA is a member of the following medical societies: Charleston County Medical Association, Infectious Diseases Society of America, South Carolina Infectious Diseases Society

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

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

Wayne E Anderson, DO, FAHS, FAAN is a member of the following medical societies: American Academy of Neurology, American Headache Society, California Medical Association, California Neurology Society, International Headache Society, San Francisco Medical Society, San Francisco Neurological Society

Disclosure: Nothing to disclose.

Norvin Perez, MD Medical Director, Juneau Urgent and Family Care

Norvin Perez, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association

Disclosure: Nothing to disclose.

Mary D Nettleman, MD, MS, MACP Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine

Mary D Nettleman, MD, MS, MACP is a member of the following medical societies: American College of Physicians, Association of Professors of Medicine, Central Society for Clinical and Translational Research, Infectious Diseases Society of America, Society of General Internal Medicine

Disclosure: Nothing to disclose.

Emad Fahmi Soliman, MD, MSc Consulting Staff, Department of Neurology, St John's Riverside Hospital

Emad Fahmi Soliman, MD, MSc is a member of the following medical societies: American Academy of Neurology, American Medical Association

Disclosure: Nothing to disclose.

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

Mohammad J Alam, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Society of Critical Care Medicine, Southern Medical Association

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.