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Encephalitis, InfectiousClinical 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%), bacter ial (20%), prion (6%), parasitic (3%), fungal (1%)

• Fungal, par asitic or  tuberculosis agents more likely to cause chronic disease

• Host immune function is critical for establishing an infectious differential diagnosis

• Herpes simplex virus (HSV) is a common cause of viral encephalitis• 2,000 cases in the U.S. annually; up to 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 [SLE])

• 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 (EBV)

• CMV

• Tick-bor ne viruses

• Mumps

• Measles

• Enterovirus

• Adenovirus

• Arboviruses (eg, West Nile virus)

• Lymphocytic choriomeningitis

• HIV

• Rabies

• Influenza virus

• Rubella virus

• Bacterial

• Chlamydia

• Mycoplasmas

• Legionella

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The Physician's Guide to Laboratory Test Selection and Interpreta

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• 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)

Treatment

• Pathogen-specific; therapy limited to several viral agents

• Should be instituted as soon as possible if a presumptive diagnosis can be made

DiagnosisIndications for Testing

• Altered state of consciousness in appropriate clinical setting

Laboratory Testing

• CBC – not usually helpful, although leukocytosis may indicate a bacterial etiology and relative

lymphocytosis may suggest a viral etiology

• Peripheral smear 

• Atypical lymphs – EBV

• Gametocytes – malaria

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• 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) should be 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 are 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

• HSV by PCR – standard of care for diagnosis of HSV encephalitis

• Sedimentation rate/C-reactive protein for suspected vasculitis

Imaging Studies• MRI/CT to 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 by patient immune status

Differential Diagnosis (non-infectious)

• Stroke

• Vasculitis• Autoimmune disease (most commonly SLE)

• Drug overdose

• Severe metabolic derangement (eg, metabolic acidosis, hyperglycemia)

• Malignancy – primary or metastatic

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Lab TestsIndications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations. For test-specific information, refer to the

test number in the ARUP Laboratory Test Directory on the ARUP Web site at www.aruplab.com.

Test Name and Number Recommended Use Limitations Follow Up

CBC with Platelet Count &

 Automated Differential

0040003

Method:

 Automated Cell Count with

Flow Cell 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

CSF Bacterial Culture

(Includes Gram Stain

0060101)

0060106

Method:

Standard reference

procedures for bacterial

stain, aerobic culture, and

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

Hepatic Function Panel

0020416

Method:

Refer to individual

components.

Rule out metabolic encephalopathy

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Blood Culture

0060102

Method:

BACTEC® continuous

monitoring system.

Standard referenceprocedures for 

identification of 

aerobic and anaerobic

microorganisms

Identify cause of bacteremia Testing is limited to

the University of Utah

Health Sciences Center 

only

Additional Tests Available

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&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 by ELISA (CSF)

0054444

Method:

Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Superior to PCR VZV test

Epstein-Barr Virus Antibody Panel I

0050600

Method:

Semi-Quantitative Chemiluminescent Immunoassay

Epstein-Barr Virus Antibody Panel II0050602

Method:

Semi-Quantitative Chemiluminescent Immunoassay

Epstein-Barr Virus by PCR

0050246

Method:

Qualitative Polymerase Chain Reaction

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Cytomegalovirus Antibodies, IgG & IgM

0050622

Method:

Refer to individual components.

Cytomegalovirus by PCR

0060040

Method:

Qualitative Polymerase Chain Reaction

West Nile Virus Antibodies, IgG & 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 DNA Detection 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

negativeRickettsia 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

2005353Method:

Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Francisella tularensis Antibody, IgM

2005354

Method:

Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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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

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

0050250

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 & IgM

0050375

Method:

Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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

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 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 AntibodyLymphocytic 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 Human Immunodeficiency Virus

Type 1 (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

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 AFB Culture (Includes AFB Stain 0060151)

0060152

Method:

Standard reference procedures for stain and culture.

Identification tests of AFB are ordered and billed separately.

DNA probes are available for M. tuberculosis complex and M.avium-intracellulare complex as indicated. DNA sequencing

and other molecular techniques are used for identification. For 

drug susceptibilities, refer to Antimicrobial Susceptibility - AFB

Mycobacteria (ARUP test code 0060217).

 Acid Fast Stain, Partial or Modified (for Nocardia sp.)

0060325

Method:

Stain/Microscopic Exam

 Anaerobe Culture (Includes Gram Stain 0060101)

0060143

Method:Standard reference procedures for bacterial stain, anaerobic

culture and identification

Bartonella DNA Detection by PCR

0093057

Method:

Qualitative Polymerase Chain Reaction

Leptospira Culture

0060158

Method:

Standard reference procedures for Leptospira bacterial culture

and exam

Treponema pallidum (Rapid Plasma Reagin) with Reflex to

Titer 

0050471

Method:

Semi-Quantitative Charcoal Agglutination

 Acanthamoeba and Naegleria Culture

0060245

Method:

Qualitative Culture/Microscopic Identification

Trypanosoma cruzi Antibody, IgG

0051076

Method:

Semi-Quantitative Rapid Strip Assay

Cryptococcus Antigen, Serum

0050196

Method:

Semi-quantitative Enzyme Immunoassay

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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:

Standard reference procedures for fungal culture. Standardreference procedures for identification and/or ITS rDNA

Sequencing. DNA probes available for Histoplasma,

Coccidioides, and Blastomyces

Blood Culture, Fungal

0060070

Method:

BACTEC® Continuous Monitoring System.

Standard reference procedures for identification and/or DNA

Sequencing

Sedimentation Rate, Westergren (ESR)

0040325

Method:

Westergren

Determine symptoms involved in vasculitic-like

infections

C-Reactive Protein

0050180

Method:

Quantitative Immunoturbidimetric

Determine symptoms involved in vasculitic-like

infections

General References

Granerod J, Crowcr oft NS. The epidemiology of acute encephalitis.Neuropsychol Rehabil. 2007; 17 (4-5) :406-428.

Hunt WG. Meningitis and encephalitis in adolescents.Adolesc Med State Art Rev. 2010; 21 (2) :287-28x.

Lindquist L, Vapalahti O. Tick-borne encephalitis.Lancet. 2008; 371 (9627) :1861-1871.

Long SS. Encephalitis diagnosis and management in the real world.Adv Exp Med Biol. 2011; 697 :153-173.

Sejvar JJ. The evolving epidemiology of viral encephalitis.Curr Opin Neurol. 2006; 19 (4) :350-357.

Starza-Smith A, Talbot E, Grant C. Encephalitis in children: a clinical neuropsychology perspective.Neuropsychol

Rehabil. 2007; 17 (4-5) :506-527.

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.

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 © 2006–2012 ARUP Laboratories. All Rights Reserved. Encephalitis, Infectious - p. 11 of 1

Stone MJ, Hawkins CP. A medical overview of encephalitis.Neuropsychol Rehabil. 2007; 17 (4-5) :429-449.

Reviewed by

Cook, Joshua B., MD. Digital Publications Assistant Editor at ARUP Laboratories; Anatomic and Clinical Pathology,

University of Utah

Fisher, Mark A., PhD. Medical Director, Bacteriology and Antimicrobials at ARUP Laboratories; Assistant Professor of 

Pathology, University of Utah

Related Content

 Acanthamoeba and Naegleria

 Arboviruses

Bartonella Species

Bordetella pertussis - Whooping Cough

Borrelia burgdorferi - Lyme Disease

Brucella Species

Central Nervous System Tumors - Brain Tumors

Clostridium tetani - Tetanus

Cytomegalovirus - CMV

Dengue Fever Virus

Ehrlichiosis and Colorado Tick Fever 

Enterovirus

Henoch Schönlein Purpura - IgA-Associated Vasculitis

Herpes Simplex Virus - HSV

Herpesvirus 6 - HHV6

Influenza Virus

Measles Virus - Rubeola

Meningitis, Acute

Mumps Virus

N-methyl-D-Aspartate (NMDA) type Glutamate Receptor Autoantibody Disorders - Anti-NMDA-Receptor Encephalitis

Paraneoplastic Neurological Syndromes

Rabies Virus

Rickettsia rickettsii - Rocky Mountain Spotted Fever 

Rickettsia typhi - Typhus Fever 

Rubella Virus

Schistosoma Species - Schistosomiasis

Sepsis in Newborns - Neonatal Sepsis

Staphylococcal Disease

Taenia Solium - Cysticercosis

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