Encephalitis, Infectious

Diagnosis

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
    • Sedimentation rate/C-reactive protein for suspected vasculitis
    • 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)

Clinical Background

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, 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.)

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
Test Name and Number Recommended Use Limitations Follow Up
Blood Culture 0060102
Method: Continuous Monitoring Blood Culture/Identification

Identify cause of bacteremia

Limited to the University of Utah Health Sciences Center only

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

Identifies CMV, EBV, HSV, or VZV as etiological agents of meningoencephalitis

Panel includes CMV, EBV, HSV, and VZV by PCR

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

Rapid diagnostic for

  • CSF in herpes encephalitis – standard of care
  • CSF in unusual CNS syndromes and in AIDS patients
  • Patients with recurrent meningitis
  • Infants with suspected neonatal herpes where cultures have been negative (eg, CSF nasopharyngeal aspirate)
  • Resolving etiology of lesions several days old in situations where cultures are more likely to be negative

 96% sensitive; 99% specific when CSF is taken 2-7 days from symptom onset

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

 
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

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

Confirm VZV, especially in active skin lesions

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

Culture considered gold standard

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

Standard of care for detecting EBV in CSF

Diagnose EBV-related diseases in immunocompromised patients or patients with lymphoproliferative tumors

Do not use to confirm acute mononucleosis

 
Cytomegalovirus by Qualitative PCR 0060040
Method: Qualitative Polymerase Chain Reaction

Standard of care for diagnosing CMV in CSF

Rapid test to diagnose CMV in immunocompromised patients or solid organ donors (not tissue donors)

May be performed on amniotic fluid

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

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

Fourfold increase in titers from acute to convalescent stage (2-4 weeks) is diagnostic

   
Chlamydia pneumoniae by PCR 0060715
Method: Qualitative Polymerase Chain Reaction

Confirm C. pneumoniae as infectious agent in nasal wash, nasopharyngeal aspirate, bronchoalveolar lavage (BAL) or pleural fluid

More sensitive than IFA and culture

   
Mycoplasma pneumoniae by PCR 0060256
Method: Qualitative Polymerase Chain Reaction

Diagnose M. pneumoniae infection

Distinguish M. pneumoniae from other viruses and atypical pathogens (C. pneumoniaeB. pertussisLegionella)

Throat swab specimens are preferred

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

Rapid diagnostic test

Aid in diagnosing etiology of pneumonia when Legionella is suspected

Detects and speciates L. pneumophila; nucleic acid from other Legionella species will be detected by this test but cannot be differentiated

Increases chances for discovery of organism in patient partially treated with empirical antibiotics

Sensitivity – 80%

Specificity – 100%

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

Aid in identifying West Nile virus encephalitis

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

Superior sensitivity compared to PCR testing

10% sensitivity at day 1; increases 10%/day, peaking at 80% sensitivity by the end of first week of symptoms

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

First-line autoimmune serologic test

Confirm diagnosis of anti-NMDAR encephalitis

May be used in monitoring treatment response in individuals who are antibody positive

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Initial screening

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

Cell Count, CSF 0095018
Method: Cell Count/Differential

Aid in differentiation of viral from bacterial etiology

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

Aid in differentiation of viral from bacterial etiology

Glucose, CSF 0020515
Method: Enzymatic

Aid in differentiation of viral from bacterial etiology

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Evaluate meningeal fluid to rule out meningitis

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

Rule out metabolic encephalopathy

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

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Rule out metabolic encephalopathy

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

Herpes Simplex Virus Culture 0065005
Method: Cell Culture/Immunoassay

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

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
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

Antibodies should be measured simultaneously in serum and CSF

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

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

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
Francisella tularensis Antibody, IgM 2005354
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Ehrlichia chaffeensis Antibodies, IgG & IgM by IFA 0051002
Method: Semi-Quantitative Indirect Fluorescent Antibody
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
Mumps Virus Antibody, IgM 0099589
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Mumps Virus Antibody IgM, CSF 0054443
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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 Detection by PCR 0050249
Method: Qualitative Reverse Transcription Polymerase Chain Reaction

Identify one of the most common causes of viral encephalitis

65-75% sensitive; 99% specific

Arbovirus Antibodies, IgM, CSF (INACTIVE as of 10/30/14: See Ordering Recommendations) 2001595
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Arbovirus Antibodies, IgM, Serum (INACTIVE as of 10/30/14: See Ordering Recommendations) 2001592
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM 2001635
Method: Semi-Quantitative Indirect Fluorescent Antibody
Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM, CSF 2001628
Method: Semi-Quantitative Indirect Fluorescent Antibody
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
Listeria Antibody, Serum by CF 0099529
Method: Semi-Quantitative Complement Fixation
Acid-Fast Bacillus (AFB) Culture and AFB Stain 0060152
Method: Stain/Culture/Identification/Susceptiblity
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
Leptospira Culture 0060158
Method: Culture
Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471
Method: Semi-Quantitative Charcoal Agglutination
Acanthamoeba and Naegleria Culture 0060245
Method: Qualitative Culture/Microscopy
Trypanosoma cruzi Antibody, IgG 0051076
Method: Semi-Quantitative Immunoassay
Cryptococcus Antigen, Serum 0050196
Method: Semi-quantitative Enzyme Immunoassay
Cryptococcus Antigen, CSF 0050195
Method: Semi-Quantitative Enzyme Immunoassay
Histoplasma Antigen by EIA, Serum 0092522
Method: Semi-quantitative Enzyme Immunoassay
Blastomyces Antibodies by CF and ID 0050626
Method: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion
Fungal Culture 0060149
Method: Culture/Identification
Blood Culture, Fungal 0060070
Method: Continuous Monitoring Blood Culture/Identification
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Determine symptoms involved in vasculitic-like infections

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Determine symptoms involved in vasculitic-like infections

AMPA-Receptor (GluR1/2) Antibody IgG, Serum (Temporary Delay as of 10/21/14 - no referral available) 2011050
Method: Qualitative Immunofluorescence 

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

AMPA-Receptor (GluR1/2) Antibody IgG, CSF (Temporary Delay as of 10/21/14 - no referral available) 2011048
Method: Qualitative Immunofluorescence 

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

Gamma-Aminobutyric Acid-B (GABA-B) Receptor Antibody, Serum (Temporary Delay as of 10/21/14 - no referral available) 2011023
Method: Qualitative Immunofluorescence

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)

Gamma-Aminobutyric Acid-B (GABA-B) Receptor Antibody, CSF (Temporary Delay as of 10/21/14 - no referral available) 2011021
Method: Qualitative Immunofluorescence

May be useful in evaluation of certain types of new-onset cryptogenic epilepsy (eg, associated with movement disorders, psychiatric manifestations, history of autoimmune diseases)