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
- PCR of fluids
- Consider meningitis/encephalitis, herpes simplex virus (HSV), varicella-zoster virus (VZV), enterovirus
- Greater sensitivity during first week of symptoms onset when viral agent is present in highest concentrations in CSF
- In undiagnosed, severe cases, PCR should be repeated after 3-7 days
- C-reactive protein (CRP)
- Preferred test to detect inflammatory processes (Choosing Wisely: 15 Things Physicians and Patients Should Question, 2016; American Society for Clinical Pathology)
- If CRP not available, order erythrocyte sedimentation rate (ESR)
- 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)
- Vascular disease
- Stroke
- CNS vasculitis
- Autoimmune CNS disease (most commonly systemic lupus erythematosus)
- Immune mediated (eg, anti-NMDAR syndrome)
- Toxin induced disorder
- Drug overdose
- Alcohol
- Other drugs (eg, cyclosporine)
- Metabolic derangement (eg, metabolic acidosis, hyperglycemia)
- Malignant disease
- Primary
- Metastatic
- Neurodegenerative disease
- Frontotemporal dementia
- Prion disease (eg, Creutzfeldt-Jakob)
- Demyelinating disease
- Endocrine disease
- Addisonian crisis
- Hyperthyroid storm
- Psychiatric disorder
- Psychosis
- Catatonia
Mycoplasma pneumoniae by PCR 0060256
Method: Qualitative Polymerase Chain Reaction
Detect M. pneumoniae bacteria
Chlamydia pneumoniae by PCR 0060715
Method: Qualitative Polymerase Chain Reaction
Detect C. pneumoniae in nasal wash, nasopharyngeal swab, bronchoalveolar lavage (BAL) or pleural fluid
More sensitive than IFA and culture
Legionella Species by Qualitative PCR 2010125
Method: Qualitative Polymerase Chain Reaction
Detect Legionella species
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
Preferred test for diagnosing West Nile encephalitis
N-methyl-D-Aspartate Receptor Antibody, IgG, Serum with Reflex to Titer 2004221
Method: Semi-Quantitative Indirect Fluorescent Antibody
Confirm diagnosis of anti-NMDAR encephalitis
May be used in monitoring treatment response in individuals who are antibody positive
Analytical sensitivity – unknown
Analytical specificity – ~100%
Reflex pattern – if NMDA antibody IgG is positive, then an NMDA antibody IgG titer is reported
West Nile Virus Antibodies, IgG and IgM by ELISA, Serum 0050226
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Detect presence of IgG and IgM antibodies in individuals with a clinical suspicion of West Nile Virus
Superior sensitivity compared to PCR testing
Sensitivity –10% at day 1; increases 10%/day, peaking at 80% by the end of first week of symptoms
Rickettsia rickettsii (Rocky Mountain Spotted Fever) Antibodies, IgG & IgM by IFA 0050371
Method: Semi-Quantitative Indirect Fluorescent Antibody
Preferred test for acute or convalescent phase of disease; acute and convalescent titers often necessary
Fourfold increase in titers from acute to convalescent stage (2-4 weeks) is diagnostic
Cytomegalovirus by Qualitative PCR 0060040
Method: Qualitative Polymerase Chain Reaction
Detect cytomegalovirus 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
Herpes Simplex Virus by PCR 0060041
Method: Qualitative Polymerase Chain Reaction
Preferred test for detecting herpes simplex virus (HSV) infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary
Sensitivity – 96%; when CSF is taken 2-7 days from symptom onset
Specificity – 99%; when CSF is taken 2-7 days from symptom onset
Poor sensitivity during the first 24-48 hours after symptom onset
Viral Meningoencephalitis Panel by PCR, Cerebrospinal Fluid 2007062
Method: Qualitative Polymerase Chain Reaction
Identify CMV, EBV, HSV, or VZV as etiological agents of meningoencephalitis
Panel includes CMV, EBV, HSV, and VZV by PCR
Meningitis/Encephalitis Panel by PCR 2013305
Method: Qualitative Polymerase Chain Reaction
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
Human Herpesvirus 6 (HHV-6A and HHV-6B) by Quantitative PCR 0060071
Method: Quantitative Polymerase Chain Reaction
Detect and quantify HHV6 subtypes A and B in immunocompromised patients
Varicella-Zoster Virus DFA with Reflex to Varicella-Zoster Virus Culture 0060282
Method: Direct Fluorescent Antibody Stain/Cell Culture
Detect varicella-zoster virus (VZV)
Negative or inadequate DFA results are confirmed with culture
Sensitivity of DFA 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
Reflex pattern – If DFA is negative or inadequate, then a VZV culture will be added
Epstein-Barr Virus by PCR 0050246
Method: Qualitative Polymerase Chain Reaction
Do not use for diagnosis of infectious mononucleosis
Order to detect EBV in individuals suspected of having EBV-related disease
Do not use to confirm acute mononucleosis
Blood Culture 0060102
Method: Continuous Monitoring Blood Culture/Identification
Detect presence of bacteria in blood
Limited to the University of Utah Health Sciences Center only
Guidelines
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
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Jun 2017]
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: July 2017