Encephalitis, Infectious

Diagnosis

Indications for Testing

  • Altered state of consciousness in appropriate clinical setting

Laboratory Testing

  • CBC – not usually helpful
    • Leukocytosis may indicate a bacterial etiology
    • Relative lymphocytosis may suggest a viral etiology
    • Peripheral smear
  • Electrolyte panel, liver function studies – rule out metabolic encephalopathy
  • Cerebrospinal fluid (CSF) studies
    • Gram stain or other special stains, if indicated (eg, India ink for Cryptococcus, acid fast for TB)
    • Cell count with differential – usually have mononuclear pleocytosis
    • Protein – usually elevated
    • Glucose – low in bacterial, fungal, and mycobacterial infections
    • Head imaging (CT/MRI) – performed in most patients prior to the lumbar puncture to rule out significant cerebral edema
  • Cultures – relatively poor sensitivity
    • CSF fluid
    • Blood – 2-3 sets from separate venipuncture sites prior to the administration of antibiotics
    • 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
    • Antibody titers for viruses – comparison of CSF and serum antibody loads
      • Ratio ≥20 indicates intrathecal production
        • Intrathecal antibodies indicative of viral etiology
    • PCR of fluids
      • Greater sensitivity during first week of symptom onset while viral agent present in CSF – yield decreases rapidly after the first week
        • False negatives most common during the first 2 days of symptoms
      • In undiagnosed, severe cases, PCR should be repeated after 3-7 days
        • Serology should be repeated in 4-6 weeks
      • Herpes simplex virus (HSV) by PCR – standard of care for diagnosis of HSV encephalitis          
    • Sedimentation rate/C-reactive protein for suspected vasculitis

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

Prognosis

  • Determined mainly by pathogen and patient immune status

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 – 1-2/100,000 in U.S.
  • Age – most common in children <12 years
  • Sex – M>F (minimal)
  • Transmission – inhalational, vector borne (mosquito, tick), blood borne, gastrointestinal, or genital
    • Etiology confirmed in ~30% of cases

Classification

  • Infectious – viral (70%), bacterial (20%), prion (6%), parasitic (3%), fungal (1%)
    • Fungal, parasitic, or tuberculosis agents more likely to cause chronic disease
    • Host immune function critical for establishing an infectious differential diagnosis
    • Herpes simplex virus (HSV) – common cause of viral encephalitis
      • 2,000 cases in  U.S. annually – as much as 28% mortality
    • Cytomegalovirus (CMV) and varicella-zoster virus (VZV) – can cause a more aggressive form of encephalitis in immunocompromised hosts
  • Autoimmune (eg, systemic lupus erythematosus)
  • Vasculitis
  • Paraneoplastic infiltration
  • Drug reactions

Organisms

Clinical Presentation

  • Constitutional – fever, fatigue, myalgias
  • Neurologic – headache, altered consciousness, focal neurologic findings, seizures, coma
  • Dermatologic – skin rashes (Lyme disease, typhus, rickettsial disease), skin lesions (VZV, HSV), bite-site paresthesias (rabies)
  • Gastroenterologic – nausea, emesis (enteroviral)
  • Pulmonary – cough, dyspnea (mycobacteria)

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
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

70-80% sensitivity; sensitivity decreases if antibiotics given prior to lumbar punch

 
Glucose, CSF 0020515
Method: Enzymatic

Aid in differentiation of viral from bacterial etiology

Glucose loads are normal in >95% of viral cases  
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

   
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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Herpes Simplex Virus Culture 0065005
Method: Cell Culture/Immunoassay

Poor sensitivity in CSF

Best to sample soon after symptom onset

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

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

Herpesvirus 6 (HHV6) (A and B), 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
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
Epstein-Barr Virus by PCR 0050246
Method: Qualitative Polymerase Chain Reaction
Cytomegalovirus Antibodies, IgG and IgM 0050622
Method: Semi-Quantitative Chemiluminescent Immunoassay
Cytomegalovirus by Qualitative PCR 0060040
Method: Qualitative Polymerase Chain Reaction
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

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

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

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 & 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 RT-PCR 0050249
Method: Qualitative Reverse Transcription Polymerase Chain Reaction

Identify one of the most common causes of viral encephalitis

65-75% sensitive; 99% specific

Adenovirus Antibodies, IgG & IgM 0051077
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Arbovirus Antibodies, IgM, CSF 2001595
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Arbovirus Antibodies, IgM, Serum 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
Chlamydia pneumoniae by PCR 0060715
Method: Qualitative Polymerase Chain Reaction
Mycoplasma pneumoniae by PCR 0060256
Method: Qualitative Polymerase Chain Reaction
Legionella Species by PCR 0056105
Method: Qualitative Polymerase Chain Reaction
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