Encephalitis, Infectious

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Altered state of consciousness in appropriate clinical setting

Criteria for Diagnosis – International Encephalitis Consortium (Venkatesan 2013)

  • Major (required)
    • Patient presenting to 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
  • Minor (2 required for possible encephalitis; ≥3 required for probable or confirmed encephalitis)
    • Documented fever ≥38° C (100.4° F) within the 72 hours before or after presentation
    • Generalized or partial seizures not fully attributable to a preexisting seizure disorder
    • New onset of focal neurologic findings
    • CSF WBC count ≥5/cubic mm
    • Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onset
    • Abnormality on electroencephalography that is consistent with encephalitis and not attributable to another cause

Laboratory Testing

  • CBC – usually not helpful
    • Leukocytosis suggests a bacterial etiology
    • Relative lymphocytosis suggests a viral etiology
    • Peripheral smear
  • Electrolyte panel, liver function studies – useful to rule out metabolic encephalopathy
    • Elevated transaminases – consider tick-borne disease testing if appropriate clinical history
  • Cerebrospinal fluid (CSF) studies – collect at least 20 cc
    • Opening pressure
    • Gram stain or other special stains, if indicated (eg, India ink for Cryptococcus spp, acid-fast for Mycobacterium tuberculosis)
      • Cryptococcus antigen, CSF – generally preferred over India ink
    • Cell count with differential (including RBC count)
    • Protein
    • Glucose levels are low in bacterial, fungal, and mycobacterial infections
    • Oligoclonal bands with IgG index
  • Cultures – relatively poor sensitivity
    • Blood – 2-3 sets from separate venipuncture sites prior to the administration of antibiotics
    • CSF
    • Other site cultures may be helpful based on other organ system involvement (sputum, urine, body fluid, tissue, or gastric aspirate)
  • Other tests to consider based on clinical history
    • Serology
      • Acute and convalescent titers based on clinical presentation
        • Serology should be repeated in 4-6 weeks as convalescent titer
      • HIV testing
      • Rapid plasma reagin (RPR) for syphilis
    • PCR of fluids
    • In undiagnosed, severe cases, PCR should be repeated after 3-7 days
    • C-reactive protein (CRP)
    • Specific symptoms may guide testing

Imaging Studies

  • MRI/CT – rule out structural lesions, demyelination, and cerebral edema
  • Temporal lobe enhancement suggestive of HSV-1

Other Tests

  • EEG – may demonstrate seizure activity; most useful in HSV

Differential Diagnosis (non-infectious)

Encephalitis is an inflammatory process of the brain associated with varying degrees of brain dysfunction. The presentation can be acute or chronic.

Epidemiology

  • Incidence – 2-8/100,000 (Mandell, 2014)
  • Age – peaks at >65 years and <1 year
  • Sex – M>F (minimal)
  • Transmission – inhalational, vector borne (mosquito, tick), blood-borne, gastrointestinal, or genital
    • Etiology confirmation depends on organism
      • California Encephalitis Project, 2003 estimates
        • Confirmed or probable agent
          • Viral – 9%
          • Bacterial – 3%
          • Parasitic – 1%
        • Possible etiology – 12%

More Common Organisms

Clinical Presentation

  • Constitutional – fever, fatigue, myalgias
  • Neurologic – headache, altered consciousness, focal neurologic findings, seizurescoma
  • 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.)

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Mycoplasma pneumoniae by PCR 0060256
Method: Qualitative Polymerase Chain Reaction

Limitations

Throat swab specimens are preferred

Chlamydia pneumoniae by PCR 0060715
Method: Qualitative Polymerase Chain Reaction

Legionella Species by Qualitative PCR 2010125
Method: Qualitative Polymerase Chain Reaction

Limitations

Only for respiratory secretions

Negative result does not rule out the presence of PCR inhibitors in patient specimen or test-specific nucleic acid in concentrations below the level of detection by this test

West Nile Virus Antibody, IgM by ELISA, CSF 0050239
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

N-methyl-D-Aspartate Receptor Antibody, IgG, Serum with Reflex to Titer 2004221
Method: Semi-Quantitative Indirect Fluorescent Antibody

West Nile Virus Antibodies, IgG and IgM by ELISA, Serum 0050226
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Rickettsia rickettsii (Rocky Mountain Spotted Fever) Antibodies, IgG & IgM by IFA 0050371
Method: Semi-Quantitative Indirect Fluorescent Antibody

Cytomegalovirus by Qualitative PCR 0060040
Method: Qualitative Polymerase Chain Reaction

Limitations

May be performed on amniotic fluid

PCR on amniotic fluid should be performed >21 weeks gestation to reduce risk of false negatives

Herpes Simplex Virus by PCR 0060041
Method: Qualitative Polymerase Chain Reaction

Limitations

Poor sensitivity during the first 24-48 hours after symptom onset

Viral Meningoencephalitis Panel by PCR, Cerebrospinal Fluid 2007062
Method: Qualitative Polymerase Chain Reaction

Human Herpesvirus 6 (HHV-6A and HHV-6B) by Quantitative PCR 0060071
Method: Quantitative Polymerase Chain Reaction

Varicella-Zoster Virus DFA with Reflex to Varicella-Zoster Virus Culture 0060282
Method: Direct Fluorescent Antibody Stain/Cell Culture

Epstein-Barr Virus by PCR 0050246
Method: Qualitative Polymerase Chain Reaction

Limitations

Do not use to confirm acute mononucleosis

Blood Culture 0060102
Method: Continuous Monitoring Blood Culture/Identification

Limitations

Limited to the University of Utah Health Sciences Center only

Additional Tests Available

Acid-Fast Bacillus (AFB) Culture and AFB Stain 0060152
Method: Stain/Culture/Identification/Susceptiblity

Listeria Antibody, Serum by CF 0099529
Method: Semi-Quantitative Complement Fixation

Acid Fast Stain, Partial or Modified (for Nocardia spp.) 0060325
Method: Stain/Microscopy

Anaerobe Culture and Gram Stain 0060143
Method: Stain/Culture/Identification

Bartonella Species by PCR 0093057
Method: Qualitative Polymerase Chain Reaction

Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM, CSF 2001628
Method: Semi-Quantitative Indirect Fluorescent Antibody

Measles (Rubeola) Virus Culture 0065055
Method: Cell Culture/Immunofluorescence

Measles (Rubeola) Antibodies, IgG and IgM 0050375
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay

Enterovirus by PCR 0050249
Method: Qualitative Reverse Transcription Polymerase Chain Reaction

Comments

Identify one of the most common causes of viral encephalitis

Sensitivity – 65-75%

Specificity – 99%

Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM 2001635
Method: Semi-Quantitative Indirect Fluorescent Antibody

Leptospira Culture 0060158
Method: Culture

Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471
Method: Semi-Quantitative Charcoal Agglutination

Fungal Culture 0060149
Method: Culture/Identification

Blood Culture, Fungal 0060070
Method: Continuous Monitoring Blood Culture/Identification

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Comments

Preferred test to detect inflammatory processes

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Comments

Determine symptoms involved in vasculitic-like infections

Blastomyces Antibodies by CF and ID 0050626
Method: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion

Histoplasma Antigen by EIA, Serum 0092522
Method: Semi-quantitative Enzyme Immunoassay

Acanthamoeba and Naegleria Culture 0060245
Method: Qualitative Culture/Microscopy

Trypanosoma cruzi Antibody, IgG 0051076
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Cryptococcus Antigen, Serum 0050196
Method: Semi-quantitative Enzyme Immunoassay

Cryptococcus Antigen, CSF 0050195
Method: Semi-Quantitative Enzyme Immunoassay

Comments

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

Mumps Virus Antibody IgM, CSF 0054443
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Mumps Virus Antibody, IgM 0099589
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Herpes Simplex Virus Culture 0065005
Method: Cell Culture/Immunoassay

Comments

Poor sensitivity in CSF

Best to collect specimen soon after onset of symptoms

Varicella-Zoster Virus Antibody, IgG, CSF 0054444
Method: Semi-Quantitative Chemiluminescent Immunoassay

Comments

Superior to PCR VZV test

Epstein-Barr Virus Antibody Panel I 0050600
Method: Semi-Quantitative Chemiluminescent Immunoassay

Epstein-Barr Virus Antibody Panel II 0050602
Method: Semi-Quantitative Chemiluminescent Immunoassay

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Comments

Rule out metabolic encephalopathy

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein, total; bilirubin, total

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

Comments

Rule out metabolic encephalopathy

Panel includes anion gap, carbon dioxide, chloride, potassium, sodium

Cell Count, CSF 0095018
Method: Cell Count/Differential

Comments

Aid in differentiation of viral from bacterial etiology

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

Comments

Aid in differentiation of viral from bacterial etiology

Glucose, CSF 0020515
Method: Enzymatic

Comments

Aid in differentiation of viral from bacterial etiology

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Comments

Evaluate meningeal fluid to rule out meningitis

Cytomegalovirus Antibodies, IgG and IgM 0050622
Method: Semi-Quantitative Chemiluminescent Immunoassay

Borrelia burgdorferi Antibodies, Total by ELISA with Reflex to IgG and IgM by Western Blot (Early Disease) 0050267
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Comments

Antibodies should be measured simultaneously in serum and CSF

IgG and IgM useful if symptoms have been present ≤1 month

Colorado Tick Fever Antibodies, IgG and IgM, IFA 0093167
Method: Immunofluorescence Assay
(Indirect Fluorescent Antibody)

Babesia microti Antibodies, IgG and IgM by IFA 0093048
Method: Semi-Quantitative Indirect Fluorescent Antibody

Toxoplasma gondii by PCR 0055591
Method: Qualitative Polymerase Chain Reaction

Echinococcus Antibody, IgG 2007220
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Ehrlichia chaffeensis Antibodies, IgG & IgM by IFA 0051002
Method: Semi-Quantitative Indirect Fluorescent Antibody

Francisella tularensis Antibody, IgM 2005354
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Borrelia Species by PCR (Lyme Disease) 0055570
Method: Qualitative Polymerase Chain Reaction

Borrelia burgdorferi Antibodies, IgG & IgM by Western Blot (CSF) 0055260
Method: Qualitative Western Blot

Comments

For IgG, positive result reported when ≥5 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93kDA; all other bandings reported as negative

For IgM, positive result reported when ≥2 bands are present: 23, 39, or 41kDa; all others reported as negative

Francisella tularensis Antibodies, IgG and IgM  2005350
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Francisella tularensis Antibody, IgG 2005353
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

Initial screening

Leukocytosis may indicate bacterial etiology; relative lymphocytosis may suggest viral etiology

Guidelines

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, Kennedy P. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2010; 17(8): 999-e57. PubMed

Tunkel A, Glaser C, Bloch K, Sejvar J, Marra C, Roos K, Hartman B, Kaplan S, Scheld M, Whitley R, Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008; 47(3): 303-27. PubMed

Venkatesan A, Tunkel A, Bloch K, Lauring A, Sejvar J, Bitnun A, Stahl J, Mailles A, Drebot M, Rupprecht C, Yoder J, Cope J, Wilson M, Whitley R, Sullivan J, Granerod J, Jones C, Eastwood K, Ward K, Durrheim D, Solbrig M, Guo-Dong L, Glaser C, International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013; 57(8): 1114-28. PubMed

General References

Bennett J, Dolin R, Blaser M. Encephalitis, Myelitis, Neuritis. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th ed. Elsevier: Churchill Livingstone, 2014.

Hunt G. Meningitis and encephalitis in adolescents. Adolesc Med State Art Rev. 2010; 21(2): 287-317, ix-x. PubMed

Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet. 2008; 371(9627): 1861-71. PubMed

Long S. Encephalitis diagnosis and management in the real world. Adv Exp Med Biol. 2011; 697: 153-73. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bagdure S, Fisher M, Ryan M, Khasawneh F. Rhodococcus erythropolis encephalitis in patient receiving rituximab. Emerg Infect Dis. 2012; 18(8): 1377-9. PubMed

Suh-Lailam B, Haven T, Copple S, Knapp D, Jaskowski T, Tebo A. Anti-NMDA-receptor antibody encephalitis: performance evaluation and laboratory experience with the anti-NMDA-receptor IgG assay. Clin Chim Acta. 2013; 421: 1-6. PubMed

Medical Reviewers

Last Update: December 2015