Encephalitis, Infectious

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

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 and risk factors
        • 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 or test results may guide testing
      • Psychotic features/movement disorders – consider testing for anti-NMDA receptor antibody (serum, CSF), rabies virus, limbic encephalitis
      • Limbic symptoms – human herpesvirus 6, PCR of CSF, autoimmune testing
      • Respiratory signs/symptoms prominent – Mycoplasma serology
      • Acute flaccid paralysis – arbovirus, rabies virus​
      • Parkinsonism – arbovirus, Toxoplasma serology
      • Cerebellar lobe involvement on CT/MRI – Epstein-Barr virus, VZV, enterovirus
      • Frontal lobe involvement on CT/MRI – N. fowleri, B. mandrillaris

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 (Bennett, 2014 [in 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
      • Estimates (Glaser, 2003)
        • Confirmed or probable agent
          • Viral – 9%
          • Bacterial – 3%
          • Parasitic – 1%
        • Possible etiology – 12%

Organisms

Clinical Presentation

  • Constitutional – fever, fatigue, myalgias
  • Neurologic – headache, altered consciousness, focal neurologic findings, seizurescoma
  • Dermatologic – skin rashes (eg, Rickettsia spp.), skin lesions (varicella-zoster virus, herpes simplex virus), bite-site paresthesias (rabies virus)
  • Gastroenterologic – nausea, emesis (enterovirus)
  • Pulmonary – cough, dyspnea (Mycobacterium spp., Mycoplasma spp.)
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

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

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]

Britton PN, Eastwood K, Paterson B, Durrheim DN, Dale RC, Cheng AC, Kenedi C, Brew BJ, Burrow J, Nagree Y, Leman P, Smith DW, Read K, Booy R, Jones CA, Australasian Society of Infectious Diseases (ASID), Australasian College of Emergency Medicine (ACEM), Australian and New Zealand Association of Neurologists (ANZAN), Public Health Association of Australia (PHAA). Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand Intern Med J. 2015; 45(5): 563-76. PubMed

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

Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld M, Whitley RJ, 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 AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, Stahl J, Mailles A, Drebot M, Rupprecht CE, Yoder J, Cope JR, Wilson MR, Whitley RJ, Sullivan J, Granerod J, Jones C, Eastwood K, Ward KN, Durrheim DN, Solbrig MV, Guo-Dong L, Glaser CA, 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.

Glaser CA, Gilliam S, Schnurr D, Forghani B, Honarmand S, Khetsuriani N, Fischer M, Cossen CK, Anderson LJ, California Encephalitis Project, 1998-2000. In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000 Clin Infect Dis. 2003; 36(6): 731-42. PubMed

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 SS. 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 SR, Fisher MA, Ryan ME, Khasawneh FA. Rhodococcus erythropolis encephalitis in patient receiving rituximab. Emerg Infect Dis. 2012; 18(8): 1377-9. PubMed

Suh-Lailam BB, Haven TR, Copple SS, Knapp D, Jaskowski TD, Tebo AE. 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: August 2016