Infectious Encephalitis

Encephalitis is a devastating neurologic syndrome that is characterized by inflammation of the brain parenchyma. While infectious encephalitis is most often identified, the cause remains unknown in up to 50% of cases. An acute clinical presentation may suggest more virulent viruses and bacteria, while a subacute presentation is more often associated with indolent bacteria, fungi, parasites, and autoimmune and paraneoplastic causes. More than 90% of viral encephalitis is caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and enteroviruses (Venkatesan, 2014), with typical bacterial causes of cerebritis and abscesses consisting of polymicrobial streptococci, gram-negative bacilli, and Staphylococcus aureus infections. Early recognition and treatment for HSV, bacterial, Plasmodium falciparum, and rabies infections are critical and potentially life saving. Diagnosis requires a combination of clinical, laboratory, and neuroimaging findings (Venkatesan, 2014).

Diagnosis

Indications for Testing

  • Focal neurologic signs
  • Confusion, altered mental status, or behavioral changes
  • Fever
  • Seizure

Criteria for Diagnosis

International Encephalitis Consortium’s 2013 Diagnostic Criteria for Encephalitis
Major Criterion (required) Minor Criterion (2 required for possible encephalitis, ≥3 required for probable or confirmed encephalitis)

Patient presenting for 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

  • 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/mm3
  • Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onset
  • Abnormality on EEG that is consistent with encephalitis and not attributable to another cause

CSF, cerebrospinal fluid; EEG, electroencephalography; WBC, white blood cell

Source: Venkatesan, 2013

Laboratory Testing

  • Initial, nonspecific testing
    • CBC – usually not helpful
      • Leukocytosis suggests a bacterial etiology
      • Relative lymphocytosis suggests a viral etiology
    • Electrolyte panel, liver function studies – useful to rule out metabolic encephalopathy
      • Elevated transaminases – consider tickborne disease testing if appropriate clinical history
    • C-reactive protein (CRP)
      • Indicated to detect inflammatory process
      • If CRP not available, order erythrocyte sedimentation rate (ESR)
    • Non-CSF cultures – relatively poor sensitivity
      • Blood – two to three sets from separate venipuncture sites prior to the administration of antibiotics
      • Other site cultures may be helpful based on other symptoms suggesting infection – sputum, urine, pleural/peritoneal/synovial fluid, stool, skin lesions
  • Routine studies for encephalitis workup
    • CSF analysis – critical for diagnosis unless contraindicated (Zunt, Infectious Diseases Society of America [IDSA], 2008; Venkatesan, 2014)
      • Glucose – collect concomitantly for comparison
        • Low or normal glucose – suggests bacterial, fungal, or mycobacterial infection
      • Protein
      • Gram stain and bacterial culture
      • Nucleic acid amplification testing (eg, polymerase chain reaction [PCR])
        • HSV 1/2, enterovirus, and VZV
          • Most commonly identified etiologic agents in acute encephalitis (Venkatesan, 2014)
          • HSV – should be performed on all CSF specimens in patients with encephalitis (Zunt, IDSA, 2008)
            • Consider retesting in 3-7 days if signs and symptoms suggest high probability or if temporal lobe localization on neuroimaging (Zunt, IDSA, 2008)
          • Enterovirus – more commonly positive in meningitis
      • Serology – viral IgM antibodies in CSF specimen considered diagnostic for many diseases (eg, primary VZV and many arboviruses) (Zunt, IDSA, 2008)
      • Other tests, if indicated – Cryptococcal antigen or India ink staining
      • Venereal Disease Research Laboratory (VDRL) testing – syphilis
    • Routine blood culture
    • Serum (Venkatesan, 2014)
      • HIV serology (consider RNA)
      • Treponemal testing – rapid plasma reagin (RPR), specific treponemal test
  • Examples of conditional studies – for more comprehensive listing, refer to 2008 IDSA guidelines, or Venkatensan, 2014
    • Host factors (eg, immunocompromised) – CMV or HHV6/7 PCR testing, West Nile virus
    • Geographic factors
      • North America – geographically appropriate arboviruses
      • Africa – malaria, dengue
      • Asia – Japanese encephalitis virus
      • Europe – tickborne encephalitis virus
    • Seasonal factors
      • Tick exposure (consider tickborne disease testing), animal bite (eg, if bat, consider rabies testing), swimming or diving in warm freshwater (consider Naegleria fowleri testing)

Histology

Brain biopsy – not routinely recommended, but may be indicated if patient continues to decline and no etiology has been established (Zunt, IDSA, 2008)

Imaging Studies

  • Magnetic resonance imaging (MRI) – most sensitive neuroimaging test to evaluate patients with encephalitis (Zunt, IDSA, 2008)
    • Evaluate for abscess, tumor, subdural or subarachnoid bleed, other structural lesions, demyelination, and cerebral edema
    • Computed tomography (CT), with and without contrast enhancement, should be used only if MRI is not available (Zunt, IDSA, 2008)

Other Tests

EEG – may demonstrate seizure activity; most useful in HSV

Differential Diagnosis (Noninfectious)

  • Vascular disease
    • Stroke
    • Subarachnoid or subdural hemorrhage
  • Autoimmune or paraneoplastic
  • Toxin-induced disorder
  • Metabolic derangement
  • Malignant disease
    • Primary tumor
    • Metastatic tumors
    • Paraneoplastic syndromes
  • Neurodegenerative disease
    • Frontotemporal dementia
    • Prion disease (eg, Creutzfeldt-Jakob)
  • Demyelinating disease
  • Endocrine disease
    • Addisonian crisis
    • Hyperthyroid storm
  • Psychiatric disorder
    • Psychosis
    • Catatonia

Background

Epidemiology

  • Incidence – 0.7-13.8/100,000 for all ages (Solomon, 2012)
    • Increased incidence (10.5-13.8/100,000) in children
  • Age – peaks at >65 years and <1 year
  • Sex – M>F (minimal)

Organisms

Examples of Typical Viral, Bacterial, Parasitic, Fungal Organisms
Viral Bacterial Parasitic Fungal

Adenovirus

Arbovirus

Cytomegalovirus

Enterovirus

Epstein-Barr virus

Human herpesvirus 6 and 7

Human immunodeficiency virus

Influenza virus

Lymphocytic choriomeningitis

Measles virus

Mumps virus

Rabies virus

Rubella virus

Tickborne viruses

Varicella-Zoster virus

Actinomyces odontolyticus

Bartonella spp

Borrelia burgdorferi, B. miyamotoi

Brucella spp

Chlamydia spp

Legionella spp

Leptospira spp

Listeria monocytogenes

Mycobacterium tuberculosis

Mycoplasma pneumoniae

Nocardia spp

Rickettsia spp

Treponema pallidum

Tropheryma whipplei

Acanthamoeba spp

Balamuthia mandrillaris

Echinococcus multilocularis

Naegleria fowleri

Plasmodium falciparum

Toxoplasma gondii

Trypanosoma spp

Blastomyces dermatitidis

Candida spp

Cryptococcus neoformans

Histoplasma capsulatum

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)

ARUP Laboratory Tests

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

Panel includes Cryptococcus neoformans/gattii, CMV, enterovirus, Escherichia coli K1, Haemophilus influenzae, HSV-1, HSV-2, human herpesvirus 6 (HHV-6), human parechovirus, Listeria monocytogenesNeisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, and VZV

Identify bacteria in CSF

Important informationLimited to the University of Utah Health Sciences Center only

Aid in differentiation of viral from bacterial etiology

Detect presence of bacteria in blood

Important informationLimited to the University of Utah Health Sciences Center only

Identify Cryptococcus as an etiological agent of meningitis

CAP requires confirmation by culture for this test

When test is ordered by the University of Utah Hospital, Huntsman Cancer Hospital, or VA Hospital of SLC, CSF culture will be ordered automatically; other clients should order culture separately

Related Tests

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

Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)

Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases

Gold standard; most sensitive test for diagnosing mycobacteria​

The laboratory should be notified when the presence of Mycobacterium genavense is suspected, as this organism will not grow on media routinely used for Mycobacterium isolation

Susceptibility testing will be performed on organisms isolated from a sterile source and for isolates of M. chelonae, M. abscesses, M. fortuitum complex, M. immunogenum, M. mucogenicum; susceptibility testing will be performed by request only on M. kansaii and M. marinum; susceptibility testing of M. gordonae is inappropriate

Use to detect aerobic actinomycetes (Nocardia and Gordonia spp, etc) in clinical specimens

Diagnose anaerobic bacterial infections

Gold standard test to diagnose fungi as agent of infection

Gold standard test to diagnose fungi as agent of infection in blood

Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy

Panel includes Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo, Tr/DNER); amphiphysin antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; NDMA receptor antibody, IgG with reflex to titer; glutamic acid decarboxylase (GAD) antibody; voltage-gated potassium channel (VGKC) antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; leucine-rich, glioma-inactivated protein 1 antibody, IgG with reflex to titer; contactin-associated protein-2 antibody, IgG with reflex to titer; N-type voltage-gated calcium channel (VGCC) antibody; P/Q type VGCC antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; and striated muscled antibody

Comprehensive panel for the evaluation of paraneoplastic and neuromuscular junction disorders, and/or encephalitis, in the presence or absence of malignancy

Panel includes Purkinje cell (PCCA) antibody and neuronal nuclear (ANNA) antibody IgG by IFA with reflex to titer and immunoblot (Hu, Ri, Yo); amphiphysin antibody IgG; CV2.1 antibody IgG by IFA with reflex to titer; NDMA receptor antibody, IgG with reflex to titer; GAD antibody; VGKC antibody; aquaporin-4 receptor antibody; aquaporin-4 receptor antibody, IgG by IFA with reflex to titer; LGI1 antibody, IgG with reflex to titer; CASPR2 antibody, IgG with reflex to titer; N-type voltage-gated calcium channel (VGCC) antibody; P/Q type VGCC antibody; acetylcholine receptor binding antibody with reflex to acetylcholine receptor modulating antibody; titin antibody; and striated muscled antibody; SOX1 antibody, IgG

Detect Acanthamoeba spp and N. fowleri in various specimen types

Useful if Giemsa stain is negative, but high suspicion of babesiosis exists

Will not detect Babesia duncani or strain MO-1

Detect Bartonella species in blood, CSF, or tissue

Use in conjunction with positive serologic testing for the workup of suspected acute Lyme neuroborreliosis

Do not order in the absence of clinical symptom

Preferred reflex test to detect Lyme disease in individuals with ≤4 weeks of clinical symptoms or exposure to tick

Positive/equivocal screen confirmed by immunoblot

Reflex pattern: if enzyme-linked immunosorbent assay (ELISA) result is 1.00 LIV or greater, then IgG and IgM immunoblot will be added

Not a first-line test for Lyme disease; may be useful if strong suspicion of Lyme disease persists in spite of persistent negative serologic testing

Detect C. pneumoniae in bronchoalveolar lavage (BAL), nasal wash, nasopharyngeal swab, or pleural fluid

Identify Cryptococcus neoformans as the infectious agent of invasive cryptococcal disease

Aid in discriminating between current and past CMV infection in immunocompetent individuals

Detects CMV 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

Adjunct to other diagnostic tests (eg, imaging) for echinococcosis

Patient's travel history is necessary to aid in test interpretation

Diagnose infection from E. chaffeensis

Detect enterovirus in blood, CSF, or nasopharyngeal specimens

Aid in diagnosis of primary EBV infectious mononucleosis after a suspected false-negative heterophile antibody (Monospot) test

Panel includes EBV antibody to viral capsid antigen, IgG and IgM; nuclear antigen, IgG; early D antigen (EA-D), IgG

Aid in determining past or present EBV infection as well as susceptibility to future EBV infection

May be used in conjunction with EBV nuclear antigen to diagnose primary EBV infectious mononucleosis

Panel includes EBV antibody to viral capsid antigen, IgG and IgM

Do not use for diagnosis of infectious mononucleosis

Order to detect EBV in individuals suspected of having EBV-related disease

Preferred test for detecting antibodies during acute or convalescent phase

Convalescent sera may be required for diagnosis

Detect antibodies during convalescent phase

Convalescent sera may be required for diagnosis

Detect antibodies during convalescent phase

Convalescent sera may be required for diagnosis

Traditional gold standard test for identifying acute HSV infection in active lesions (eg, vesicles, ulcers, inflamed mucous membranes)

Molecular testing is generally preferred (refer to HSV by PCR)

Preferred test for detecting HSV infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary

Recommend testing in conjunction with the combined complement fixation and immunodiffusion antibody and urine galactomannan antigen tests

Detect and quantify HHV6 subtypes A and B in immunocompromised patients

A negative result (<3.0 log copies/mL or <1,000 copies/mL) does not rule out the presence of PCR inhibitors in the patient specimen or HHV6 DNA in concentrations below the level of detection of the test

2014 CDC Recommended Algorithm for Laboratory Diagnosis of HIV infection

Fourth generation test screens for HIV-1 p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2

Not available to New York clients; refer to New York HIV combo antigen/antibody (HIV-1/O/2) reflexive panel

Reflex pattern: repeatedly reactive HIV-1, 2 antigen/antibody screening results are confirmed with an HIV-1/ HIV-2 antibody differentiation test; negative or indeterminate results for HIV-1, 2 antibody differentiation are confirmed with a quantitative NAAT test

Detect Legionella species

May provide definitive diagnosis, but sensitivity is low and culture may take several weeks to yield result

Aid in the diagnosis of lymphocytic choriomeningitis (LCM) viral infection

Aid in the diagnosis of LCM viral infection in CNS

Culture test for detecting measles virus in specimens other than CSF

Aid in the diagnosis of measles infection

Test may not be helpful in patients who have recently received an MMR vaccination

Aid in the diagnosis of measles infection

Test may not be helpful in patients who have recently received an MMR vaccination

Not recommended

Detect M. pneumoniae bacteria

Confirm diagnosis of anti-NMDAR encephalitis

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

Reflex pattern: if NMDA antibody IgG is positive, then an NMDA antibody IgG titer is reported

CDC-recommended screening test for syphilis

May use to confirm reactive treponemal test (eg, enzyme immunoassay [EIA], chemiluminescence immunoassay [CIA]) if using so-called reverse algorithm testing

Preferred test for monitoring treatment response in established syphilis

Reflex pattern: if RPR is reactive, then a titer will be added

Confirm toxoplasmosis infection in immunocompromised hosts as well as fetuses and newborns

May be used to confirm equivocal antibody testing

Aid in the diagnosis of nonacute (chronic phase) Chagas disease (T. cruzi)

Generally not recommended for the diagnosis of acute disease/encephalitis

May aid in diagnosing VZV vasculopathy

Detect VZV

Negative or inadequate direct fluorescent antibody (DFA) results are confirmed with culture

DFA sensitivity 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

Detect VZV in blood, CSF, ocular fluid, tissue, or vesicle fluid

Preferred test for diagnosing West Nile encephalitis

Detect presence of IgG and IgM antibodies in individuals with a clinical suspicion of West Nile virus

Medical Experts

Contributor

Fisher

Mark A. Fisher, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Bacteriology, Special Microbiology, and Antimicrobial Susceptibility Testing, ARUP Laboratories
Contributor
Contributor

Klonoski

 

Joshua M. Klonoski, MD, PhD
Former Resident Physician, Department of Pathology, University of Utah
Former Assistant Medical Director of Informatics and Content Editor at ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®