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).

Tabs Content

Clinical Overview

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
- Autoimmune central nervous system (CNS) disease (most commonly systemic lupus erythematosus [SLE])
- CNS vasculitis
- Anti-NMDA receptor syndrome
- Paraneoplastic neurological syndromes
Toxin-induced disorder
- Drug overdose
- Alcohol
- Adverse drug reactions (eg, cyclosporine)
Metabolic derangement
- Metabolic acidosis
- Hyperglycemia/hypoglycemia
- Hepatic encephalitis
- Renal encephalitis
Malignant disease
- Primary tumor
- Metastatic tumors
- Paraneoplastic syndromes
Neurodegenerative disease
- Frontotemporal dementia
- Prion disease (eg, Creutzfeldt-Jakob)
Demyelinating disease
- Multiple sclerosis
- Neuromyelitis optica
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

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 Lab Tests

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.

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

Recommended Use

Detect cytomegalovirus (CMV), Epstein-Barr virus (EBV), HSV, or VZV as etiological agents of meningoencephalitis

Meningitis/Encephalitis Panel by PCR 2013305
Method: Qualitative Polymerase Chain Reaction

Recommended Use

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

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

Limitations

A negative result does not exclude a diagnosis of meningitis or encephalitis due to infection

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

Recommended Use

Identify bacteria in CSF

Glucose, CSF 0020515
Method: Enzymatic

Recommended Use

Aid in differentiation of viral from bacterial etiology

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Recommended Use

Aid in differentiation of viral from bacterial etiology

Blood Culture 0060102
Method: Continuous Monitoring Blood Culture/Identification

Recommended Use

Detect presence of bacteria in blood

Limitations

Limited to the University of Utah Health Sciences Center only

Cryptococcus Antigen, CSF 0050195
Method: Semi-Quantitative Enzyme Immunoassay

Recommended Use

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

Medical Experts

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

Hillyard, David R., MD, Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Professor of Biology, University of Utah

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

Palmer, Cheryl Ann, MC, Medical Director at ARUP Laboratories; Professor of Anatomic Pathology, University of Utah

References

Guidelines

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
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
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
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Apr 2019]
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

General References

Bennett J, Dolin R, Blaser M. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Elsevier Churchill Livingston, 2014.

Bloch KC, Glaser CA. Encephalitis Surveillance through the Emerging Infections Program, 1997-2010. Emerg Infect Dis. 2015; 21(9): 1562-7. PubMed

Bradshaw MJ, Venkatesan A. Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management. Neurotherapeutics. 2016; 13(3): 493-508. PubMed

George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010. PLoS One. 2014; 9(9): e104169. PubMed

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

Love S, Perry A, Ironside J, Budka H. Greenfield’s Neuropathology, Ninth Edition. Boca Raton: CRC Press. Taylor and Francis Group, 2015.

Perry A, Brat DJ. Practical Surgical Neuropathology A Diagnostic Approach, Second. Philadelphia: Elsevier, 2018.

Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis: A practical approach. Neurol Clin Pract. 2014; 4(3): 206-215. PubMed

Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. Burden of encephalitis-associated hospitalizations in the United States, 1998-2010. Neurology. 2014; 82(5): 443-51. PubMed

Resources 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

Content Review:

April 2018

Last Update: June 2019

Infectious Encephalitis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Imaging Studies

Other Tests

Differential Diagnosis (Noninfectious)

Background

Epidemiology

Organisms

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Infectious Encephalitis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

​Imaging Studies

Other Tests

Differential Diagnosis (Noninfectious)

Background

Epidemiology

Organisms

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult

Imaging Studies