Encephalitis is a devastating neurologic syndrome that is characterized by inflammation of the brain parenchyma. While infectious encephalitis is most often identified, the cause remains unknown in up to 50% of cases. An acute clinical presentation may suggest more virulent viruses and bacteria, while a subacute presentation is more often associated with indolent bacteria, fungi, parasites, and autoimmune and paraneoplastic causes. More than 90% of viral encephalitis is caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and enteroviruses (Venkatesan, 2014), with typical bacterial causes of cerebritis and abscesses consisting of polymicrobial streptococci, gram-negative bacilli, and Staphylococcus aureus infections. Early recognition and treatment for HSV, bacterial, Plasmodium falciparum, and rabies infections are critical and potentially life saving. Diagnosis requires a combination of clinical, laboratory, and neuroimaging findings (Venkatesan, 2014).
Diagnosis
Indications for Testing
- Focal neurologic signs
- Confusion, altered mental status, or behavioral changes
- Fever
- Seizure
Criteria for Diagnosis
Major Criterion (required) | Minor Criterion (2 required for possible encephalitis, ≥3 required for probable or confirmed encephalitis) |
---|---|
Patient presenting for medical attention with altered mental status (defined as decreased or altered level of consciousness, lethargy, or personality change) lasting ≥24 hours with no alternative cause identified |
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CSF, cerebrospinal fluid; EEG, electroencephalography; WBC, white blood cell Source: Venkatesan, 2013 |
Laboratory Testing
- Initial, nonspecific testing
- CBC – usually not helpful
- Leukocytosis suggests a bacterial etiology
- Relative lymphocytosis suggests a viral etiology
- Electrolyte panel, liver function studies – useful to rule out metabolic encephalopathy
- Elevated transaminases – consider tickborne disease testing if appropriate clinical history
- C-reactive protein (CRP)
- Indicated to detect inflammatory process
- If CRP not available, order erythrocyte sedimentation rate (ESR)
- Non-CSF cultures – relatively poor sensitivity
- Blood – two to three sets from separate venipuncture sites prior to the administration of antibiotics
- Other site cultures may be helpful based on other symptoms suggesting infection – sputum, urine, pleural/peritoneal/synovial fluid, stool, skin lesions
- CBC – usually not helpful
- Routine studies for encephalitis workup
- CSF analysis – critical for diagnosis unless contraindicated (Zunt, Infectious Diseases Society of America [IDSA], 2008; Venkatesan, 2014)
- Glucose – collect concomitantly for comparison
- Low or normal glucose – suggests bacterial, fungal, or mycobacterial infection
- Protein
- Gram stain and bacterial culture
- Nucleic acid amplification testing (eg, polymerase chain reaction [PCR])
- HSV 1/2, enterovirus, and VZV
- Most commonly identified etiologic agents in acute encephalitis (Venkatesan, 2014)
- HSV – should be performed on all CSF specimens in patients with encephalitis (Zunt, IDSA, 2008)
- Consider retesting in 3-7 days if signs and symptoms suggest high probability or if temporal lobe localization on neuroimaging (Zunt, IDSA, 2008)
- Enterovirus – more commonly positive in meningitis
- HSV 1/2, enterovirus, and VZV
- Serology – viral IgM antibodies in CSF specimen considered diagnostic for many diseases (eg, primary VZV and many arboviruses) (Zunt, IDSA, 2008)
- Other tests, if indicated – Cryptococcal antigen or India ink staining
- Venereal Disease Research Laboratory (VDRL) testing – syphilis
- Glucose – collect concomitantly for comparison
- Routine blood culture
- Serum (Venkatesan, 2014)
- HIV serology (consider RNA)
- Treponemal testing – rapid plasma reagin (RPR), specific treponemal test
- CSF analysis – critical for diagnosis unless contraindicated (Zunt, Infectious Diseases Society of America [IDSA], 2008; Venkatesan, 2014)
- Examples of conditional studies – for more comprehensive listing, refer to 2008 IDSA guidelines, or Venkatensan, 2014
- Host factors (eg, immunocompromised) – CMV or HHV6/7 PCR testing, West Nile virus
- Geographic factors
- North America – geographically appropriate arboviruses
- Africa – malaria, dengue
- Asia – Japanese encephalitis virus
- Europe – tickborne encephalitis virus
- Seasonal factors
- Tick exposure (consider tickborne disease testing), animal bite (eg, if bat, consider rabies testing), swimming or diving in warm freshwater (consider Naegleria fowleri testing)
Histology
Brain biopsy – not routinely recommended, but may be indicated if patient continues to decline and no etiology has been established (Zunt, IDSA, 2008)
Imaging Studies
- Magnetic resonance imaging (MRI) – most sensitive neuroimaging test to evaluate patients with encephalitis (Zunt, IDSA, 2008)
- Evaluate for abscess, tumor, subdural or subarachnoid bleed, other structural lesions, demyelination, and cerebral edema
- Computed tomography (CT), with and without contrast enhancement, should be used only if MRI is not available (Zunt, IDSA, 2008)
Other Tests
EEG – may demonstrate seizure activity; most useful in HSV
Differential Diagnosis (Noninfectious)
- Vascular disease
- Stroke
- Subarachnoid or subdural hemorrhage
- Autoimmune or paraneoplastic
- Autoimmune central nervous system (CNS) disease (most commonly systemic lupus erythematosus [SLE])
- CNS vasculitis
- Anti-NMDA receptor syndrome
- Paraneoplastic neurological syndromes
- Toxin-induced disorder
- Drug overdose
- Alcohol
- Adverse drug reactions (eg, cyclosporine)
- Metabolic derangement
- Metabolic acidosis
- Hyperglycemia/hypoglycemia
- Hepatic encephalitis
- Renal encephalitis
- Malignant disease
- Primary tumor
- Metastatic tumors
- Paraneoplastic syndromes
- Neurodegenerative disease
- Frontotemporal dementia
- Prion disease (eg, Creutzfeldt-Jakob)
- Demyelinating disease
- Endocrine disease
- Addisonian crisis
- Hyperthyroid storm
- Psychiatric disorder
- Psychosis
- Catatonia
Background
Epidemiology
- Incidence – 0.7-13.8/100,000 for all ages (Solomon, 2012)
- Increased incidence (10.5-13.8/100,000) in children
- Age – peaks at >65 years and <1 year
- Sex – M>F (minimal)
Organisms
Viral | Bacterial | Parasitic | Fungal |
---|---|---|---|
Adenovirus Enterovirus Human herpesvirus 6 and 7 Lymphocytic choriomeningitis Rabies virus |
Actinomyces odontolyticus Bartonella spp Borrelia burgdorferi, B. miyamotoi Brucella spp Chlamydia spp Legionella spp Leptospira spp Listeria monocytogenes Nocardia spp Rickettsia spp Tropheryma whipplei |
Acanthamoeba spp Naegleria fowleri Trypanosoma spp |
Blastomyces dermatitidis Candida spp Cryptococcus neoformans Histoplasma capsulatum |
Clinical Presentation
- Constitutional – fever, fatigue, myalgias
- Neurologic – headache, altered consciousness, focal neurologic findings, seizures, coma
- Dermatologic – skin rashes (eg, Rickettsia spp), skin lesions (VZV, HSV), bite-site paresthesias (rabies virus)
- Gastroenterologic – nausea, emesis (enterovirus)
- Pulmonary – cough, dyspnea (Mycobacterium spp, Mycoplasma spp)
ARUP Laboratory Tests
Use to rapidly detect a panel of common viruses, bacteria, and fungi associated with meningitis and encephalitis
Do NOT use as a replacement for CSF bacterial and/or fungal culture and cryptococcal antigen testing for at-risk patients
A negative result does not exclude a diagnosis of meningitis or encephalitis due to infection
Qualitative Polymerase Chain Reaction
Aid in differentiation of viral from bacterial etiology
Enzymatic
Reflectance Spectrophotometry
Identify Cryptococcus as an etiological agent of meningitis
CAP requires confirmation by culture for this test
When test is ordered by the University of Utah Hospital, Huntsman Cancer Hospital, or VA Hospital of SLC, CSF culture will be ordered automatically; other clients should order culture separately
Semi-Quantitative Enzyme Immunoassay
Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)
Quantitative Immunoturbidimetry
Gold standard; most sensitive test for diagnosing mycobacteria
The laboratory should be notified when the presence of Mycobacterium genavense is suspected, as this organism will not grow on media routinely used for Mycobacterium isolation
Susceptibility testing will be performed on organisms isolated from a sterile source and for isolates of M. chelonae, M. abscesses, M. fortuitum complex, M. immunogenum, M. mucogenicum; susceptibility testing will be performed by request only on M. kansaii and M. marinum; susceptibility testing of M. gordonae is inappropriate
Stain/Culture/Identification/Susceptibility/Polymerase Chain Reaction
Use to detect aerobic actinomycetes (Nocardia and Gordonia spp, etc) in clinical specimens
Stain/Microscopy
Diagnose anaerobic bacterial infections
Stain/Culture/Identification
Gold standard test to diagnose fungi as agent of infection
Culture/Identification
Gold standard test to diagnose fungi as agent of infection in blood
Continuous Monitoring Blood Culture/Identification
Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Components: Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo, Tr/DNER); amphiphysin antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; NDMA receptor antibody, IgG with reflex to titer; glutamic acid decarboxylase (GAD) antibody; voltage-gated potassium channel (VGKC) antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; leucine-rich, glioma-inactivated protein 1 antibody, IgG with reflex to titer; contactin-associated protein-2 antibody, IgG with reflex to titer; acetylcholine receptor binding antibody; striated muscled antibody; AMPA receptor antibody, IgG by IFA with reflex to titer; GABA-BR antibody IgG by IFA with reflex to titer; MOG antibody, IgG by IFA with reflex to titer; SOX1 antibody, IgG by immunoblot; P/Q type voltage-gated calcium channel (VGCC) antibody; ganglionic acetylcholine receptor antibody; dipeptidyl aminopeptidase-like protein 6 (DPPX) antibody, IgG by IFA with reflex to titer, serum
Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Radioimmunoassay/Semi-quantitative Enzyme-Linked Immunosorbent Assay
Panel includes Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo, Tr/DNER); amphiphysin antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; NDMA receptor antibody, IgG with reflex to titer; GAD antibody; VGKC antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; LGI1 antibody, IgG with reflex to titer; CASPR2 antibody, IgG with reflex to titer; N-type voltage-gated calcium channel (VGCC) antibody; P/Q type VGCC antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; striated muscled antibody; SOX1 antibody, IgG; dipeptidyl aminopeptidase-like protein 6 (DPPX) antibody, IgG with reflex to titer; and amphiphysin antibody, IgG
Detect Acanthamoeba spp and N. fowleri in various specimen types
Qualitative Culture/Microscopy
Useful if Giemsa stain is negative, but high suspicion of babesiosis exists
Will not detect Babesia duncani or strain MO-1
Semi-Quantitative Indirect Fluorescent Antibody
Detect Bartonella species in blood, CSF, or tissue
Qualitative Polymerase Chain Reaction
Use in conjunction with positive serologic testing for the workup of suspected acute Lyme neuroborreliosis
Do not order in the absence of clinical symptom
Qualitative Immunoblot
Preferred reflex test to detect Lyme disease in individuals with ≤4 weeks of clinical symptoms or exposure to tick
Positive/equivocal screen confirmed by immunoblot
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Immunoblot
Reflex pattern: if enzyme-linked immunosorbent assay (ELISA) result is 1.00 LIV or greater, then IgG and IgM immunoblot will be added
Not a first-line test for Lyme disease; may be useful if strong suspicion of Lyme disease persists in spite of persistent negative serologic testing
Qualitative Polymerase Chain Reaction
Detect C. pneumoniae in bronchoalveolar lavage (BAL), nasal wash, nasopharyngeal swab, or pleural fluid
Qualitative Polymerase Chain Reaction
Identify Cryptococcus neoformans as the infectious agent of invasive cryptococcal disease
Semi-quantitative Enzyme Immunoassay
Aid in discriminating between current and past CMV infection in immunocompetent individuals
Semi-Quantitative Chemiluminescent Immunoassay
Detects CMV but does not quantify viral load; potentially useful for specimen types other than blood
CMV by quantitative PCR on plasma is preferred for most clinical indications
Qualitative Polymerase Chain Reaction
Adjunct to other diagnostic tests (eg, imaging) for echinococcosis
Patient's travel history is necessary to aid in test interpretation
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Diagnose infection from E. chaffeensis
Semi-Quantitative Indirect Fluorescent Antibody
Detect enterovirus in blood, CSF, or nasopharyngeal specimens
Qualitative Polymerase Chain Reaction
Aid in diagnosis of primary EBV infectious mononucleosis after a suspected false-negative heterophile antibody (Monospot) test
Semi-Quantitative Chemiluminescent Immunoassay
Panel includes EBV antibody to viral capsid antigen, IgG and IgM; nuclear antigen, IgG; early D antigen (EA-D), IgG
Aid in determining past or present EBV infection as well as susceptibility to future EBV infection
May be used in conjunction with EBV nuclear antigen to diagnose primary EBV infectious mononucleosis
Semi-Quantitative Chemiluminescent Immunoassay
Panel includes EBV antibody to viral capsid antigen, IgG and IgM
Do not use for diagnosis of infectious mononucleosis
Order to detect EBV in individuals suspected of having EBV-related disease
Qualitative Polymerase Chain Reaction
Preferred test for detecting antibodies during acute or convalescent phase
Convalescent sera may be required for diagnosis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Detect antibodies during convalescent phase
Convalescent sera may be required for diagnosis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Detect antibodies during convalescent phase
Convalescent sera may be required for diagnosis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Traditional gold standard test for identifying acute HSV infection in active lesions (eg, vesicles, ulcers, inflamed mucous membranes)
Molecular testing is generally preferred (refer to HSV by PCR)
Cell Culture/Immunoassay
Preferred test for detecting HSV infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary
Qualitative Polymerase Chain Reaction
Recommend testing in conjunction with the combined complement fixation and immunodiffusion antibody and urine galactomannan antigen tests
Quantitative Enzyme Immunoassay
Detect and quantify HHV6 subtypes A and B in immunocompromised patients
A negative result (<3.0 log copies/mL or <1,000 copies/mL) does not rule out the presence of PCR inhibitors in the patient specimen or HHV6 DNA in concentrations below the level of detection of the test
Quantitative Polymerase Chain Reaction
2014 CDC Recommended Algorithm for Laboratory Diagnosis of HIV infection
Fourth generation test screens for HIV-1 p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2
Not available to New York clients; refer to New York HIV combo antigen/antibody (HIV-1/O/2) reflexive panel
Qualitative Chemiluminescent Immunoassay/Qualitative Immunoassay/Quantitative Transcription-Mediated Amplification
Reflex pattern: repeatedly reactive HIV-1, 2 antigen/antibody screening results are confirmed with an HIV-1/ HIV-2 antibody differentiation test; negative or indeterminate results for HIV-1, 2 antibody differentiation are confirmed with a quantitative NAAT test
Qualitative Transcription-Mediated Amplification
Detect Legionella species
Qualitative Polymerase Chain Reaction
May provide definitive diagnosis, but sensitivity is low and culture may take several weeks to yield result
Semi-Quantitative Complement Fixation
Aid in the diagnosis of lymphocytic choriomeningitis (LCM) viral infection
Semi-Quantitative Indirect Fluorescent Antibody
Aid in the diagnosis of LCM viral infection in CNS
Semi-Quantitative Indirect Fluorescent Antibody
Culture test for detecting measles virus in specimens other than CSF
Cell Culture/Immunofluorescence
Aid in the diagnosis of measles infection
Test may not be helpful in patients who have recently received an MMR vaccination
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay
Aid in the diagnosis of measles infection
Test may not be helpful in patients who have recently received an MMR vaccination
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Not recommended
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Detect M. pneumoniae bacteria
Qualitative Polymerase Chain Reaction
Confirm diagnosis of anti-NMDAR encephalitis
May be used in monitoring treatment response in individuals who are antibody positive
Semi-Quantitative Indirect Fluorescent Antibody
Reflex pattern: if NMDA antibody IgG is positive, then an NMDA antibody IgG titer is reported
CDC-recommended screening test for syphilis
May use to confirm reactive treponemal test (eg, enzyme immunoassay [EIA], chemiluminescence immunoassay [CIA]) if using so-called reverse algorithm testing
Preferred test for monitoring treatment response in established syphilis
Semi-Quantitative Charcoal Agglutination
Reflex pattern: if RPR is reactive, then a titer will be added
Confirm toxoplasmosis infection in immunocompromised hosts as well as fetuses and newborns
May be used to confirm equivocal antibody testing
Qualitative Polymerase Chain Reaction
Aid in the diagnosis of nonacute (chronic phase) Chagas disease (T. cruzi)
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Generally not recommended for the diagnosis of acute disease/encephalitis
May aid in diagnosing VZV vasculopathy
Semi-Quantitative Chemiluminescent Immunoassay
Detect VZV
Negative or inadequate direct fluorescent antibody (DFA) results are confirmed with culture
DFA sensitivity is highest when performed on scraping from the base of lesions; culture sensitivity is highest when specimens are collected soon after onset of symptoms
Molecular testing is generally preferred; refer to VZV by PCR
Direct Fluorescent Antibody Stain/Cell Culture
Reflex pattern: If DFA is negative or inadequate, then a VZV culture will be added
Detect VZV in blood, CSF, ocular fluid, tissue, or vesicle fluid
Qualitative Polymerase Chain Reaction
Preferred test for diagnosing West Nile encephalitis
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Detect presence of IgG and IgM antibodies in individuals with a clinical suspicion of West Nile virus
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Medical Experts
Fisher

Hillyard

Klonoski
Palmer

References
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases
Bennett J, Dolin R, Blaser M. Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 8th ed. Elsevier Churchill Livingston; 2014.
26295485
Bloch KC, Glaser CA. Encephalitis Surveillance through the Emerging Infections Program, 1997-2010. Emerg Infect Dis. 2015;21(9):1562-1567.
27106239
Bradshaw MJ, Venkatesan A. Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management. Neurotherapeutics. 2016;13(3):493-508.
25955462
Britton PN, Eastwood K, Paterson B, et al. Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand. Intern Med J. 2015;45(5):563-576.
Choosing Wisely
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Dec 2020]
25192177
George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010. PLoS One. 2014;9(9):e104169.
12627357
Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000. Clin Infect Dis. 2003;36(6):731-742.
21047030
Hunt G. Meningitis and encephalitis in adolescents. Adolesc Med State Art Rev. 2010;21(2):287-317, ix-x.
18514730
Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet. 2008;371(9627):1861-1871.
21120725
Long SS. Encephalitis diagnosis and management in the real world. Adv Exp Med Biol. 2011;697:153-73.
Greenfield’s Neuropathology - Ninth Edition
Love S, Perry A, Ironside J, et al. Greenfield's Neuropathology. 9th ed. CRC Press; 2015.
Practical Surgical Neuropathology - A Diagnostic Approach
Perry A, Brat, DJ. Practical Surgical Neuropathology: A Diagnostic Approach. 2nd ed. Elsevier; 2018.
18582201
Tunkel AR, Glaser CA, Bloch KC , et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47(3):303-27.
20236175
Steiner I, Budka H, Chaudhuri A , et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2010;17(8):999-e57.
23861361
Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):1114-1128.
25110619
Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis: A practical approach. Neurol Clin Pract. 2014;4(3):206-215.
24384647
Vora NM, Holman RC, Mehal JM, et al. Burden of encephalitis-associated hospitalizations in the United States, 1998-2010. Neurology. 2014;82(5):443-451.
Panel includes Cryptococcus neoformans/gattii, CMV, enterovirus, Escherichia coli K1, Haemophilus influenzae, HSV-1, HSV-2, human herpesvirus 6 (HHV-6), human parechovirus, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, and VZV