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
    • Atypical lymphs – Epstein-Barr Virus
    • Gametocytes – malaria
    • Morula – Ehrlichia, Anaplasma
    • Spirochetes – relapsing fever, Borrelia
    • Trypanosomes – trypanosomiasis
• 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)

• Stroke
• Vasculitis
• Autoimmune disease (most commonly systemic lupus erythematosus)
• Drug overdose
• Severe metabolic derangement (eg, metabolic acidosis, hyperglycemia)
• Malignancy – primary or metastatic

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

• Viral – often initiated by nasopharyngeal colonization or acquisition on another skin or mucous membrane surface
  • HSV, human herpesvirus 6 and 7
  • VZV
  • Epstein-Barr virus
  • CMV
  • Tick-borne viruses
  • Mumps
  • Measles
  • Enterovirus
  • Adenovirus
  • Arboviruses (eg, West Nile virus)
  • Lymphocytic choriomeningitis
  • HIV
  • Rabies
  • Influenza virus
  • Rubella virus
• Bacterial
  • Chlamydia
  • Mycoplasmas
  • Legionella
  • Listeria
  • Mycobacterium tuberculosis
  • Nocardia
  • Actinomyces
  • Bartonella
  • Brucella
  • Borrelia
  • Rickettsia rickettsii
  • Rickettsia typhi
  • Leptospira
  • Tropheryma whippelii (Whipple disease)
  • Treponema pallidum (meningovascular syphilis)
• Parasitic
  • Toxoplasma
  • Naegleria
  • Acanthamoeba
  • Balamuthia
  • Echinococcus
  • Plasmodium falciparum
  • Trypanosoma spp
• Fungal
  • Cryptococcus neoformans
  • Histoplasma capsulatum
  • Blastomyces dermatitidis
  • Candida spp

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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
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 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 & 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 & 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 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 & 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