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

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
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)

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count and Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count/Differential

Use:

Initial screening

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

Test name: Cell Count, CSF

ARUP #: 0095018

Methodology: Cell Count/Differential

Use:

Aid in differentiation of viral from bacterial etiology

Test name: Cerebrospinal Fluid (CSF) Culture and Gram Stain

ARUP #: 0060106

Methodology: Stain/Culture/Identification

Use:

Aid in differentiation of viral from bacterial etiology

Limitations:

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

Test name: Glucose, CSF

ARUP #: 0020515

Methodology: Enzymatic

Use:

Aid in differentiation of viral from bacterial etiology

Limitations: Glucose loads are normal in >95% of viral cases

Test name: Protein, Total, CSF

ARUP #: 0020514

Methodology: Reflectance Spectrophotometry

Use:

Evaluate meningeal fluid to rule out meningitis

Test name: Electrolyte Panel

ARUP #: 0020410

Methodology: Quantitative Ion-Selective Electrode/Enzymatic

Use:

Rule out metabolic encephalopathy

Panel includes anion gap, carbon dioxide, chloride, potassium, sodium

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Quantitative Enzymatic/Quantitative Spectrophotometry

Use:

Rule out metabolic encephalopathy

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein, total; bilirubin, total

Test name: Blood Culture

ARUP #: 0060102

Methodology: Continuous Monitoring Blood Culture/Identification

Use:

Identify cause of bacteremia

Limitations:

Limited to the University of Utah Health Sciences Center only

Test name: Viral Meningoencephalitis Panel by PCR, Cerebrospinal Fluid

ARUP #: 2007062

Methodology: Qualitative Polymerase Chain Reaction

Use:

Identifies CMV, EBV, HSV, or VZV as etiological agents of meningoencephalitis

Panel includes CMV, EBV, HSV, and VZV by PCR

Additional Tests Available

Test name: Herpes Simplex Virus Culture

ARUP #: 0065005

Methodology: Cell Culture/Immunoassay

Comments:

Poor sensitivity in CSF

Best to sample soon after symptom onset

Test name: Herpes Simplex Virus by PCR

ARUP #: 0060041

Methodology: Qualitative Polymerase Chain Reaction

Comments:

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

Test name: Herpesvirus 6 (HHV6) (A and B), Quantitative PCR

ARUP #: 0060071

Methodology: Quantitative Polymerase Chain Reaction

Comments:

Test name: Varicella-Zoster Virus DFA with Reflex to Varicella-Zoster Virus Culture

ARUP #: 0060282

Methodology: Direct Fluorescent Antibody Stain

Comments:

Test name: Varicella-Zoster Virus Antibody, IgG, CSF

ARUP #: 0054444

Methodology: Semi-Quantitative Chemiluminescent Immunoassay

Comments:

Superior to PCR VZV test

Test name: Epstein-Barr Virus Antibody Panel I

ARUP #: 0050600

Methodology: Semi-Quantitative Chemiluminescent Immunoassay

Comments:

Test name: Epstein-Barr Virus Antibody Panel II

ARUP #: 0050602

Methodology: Semi-Quantitative Chemiluminescent Immunoassay

Comments:

Test name: Epstein-Barr Virus by PCR

ARUP #: 0050246

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Cytomegalovirus Antibodies, IgG and IgM

ARUP #: 0050622

Methodology: Semi-Quantitative Chemiluminescent Immunoassay

Comments:

Test name: Cytomegalovirus by PCR

ARUP #: 0060040

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: West Nile Virus Antibodies, IgG and IgM by ELISA, Serum

ARUP #: 0050226

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

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

Test name: Borrelia burgdorferi Antibodies, Total by ELISA with Reflex to IgG & IgM by Western Blot (Early Disease)

ARUP #: 0050267

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Comments:

Antibodies should be measured simultaneously in serum and CSF

IgG and IgM useful if symptoms have been present less than or equal to 1 month

Test name: Borrelia Species by PCR (Lyme Disease)

ARUP #: 0055570

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Borrelia burgdorferi Antibodies, IgG & IgM by Western Blot (CSF)

ARUP #: 0055260

Methodology: Qualitative Western Blot

Comments:

For IgG, positive result reported when greater than or equal to 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 greater than or equal to 2 bands are present: 23, 39, or 41kDa; all others reported as negative

Test name: Rickettsia rickettsii (Rocky Mountain Spotted Fever) Antibodies, IgG & IgM by IFA

ARUP #: 0050371

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Fourfold increase in titers from acute to convalescent stage (2-4 weeks) is diagnostic

Test name: Francisella tularensis Antibodies, IgG and IgM

ARUP #: 2005350

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Francisella tularensis Antibody, IgG

ARUP #: 2005353

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Francisella tularensis Antibody, IgM

ARUP #: 2005354

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Ehrlichia chaffeensis Antibodies, IgG & IgM by IFA

ARUP #: 0051002

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Colorado Tick Fever Antibodies, IgG & IgM, IFA

ARUP #: 0093167

Methodology: Immunofluorescence Assay
(Indirect Fluorescent Antibody)

Comments:

Test name: Babesia microti Antibodies, IgG & IgM by IFA

ARUP #: 0093048

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Toxoplasma gondii by PCR

ARUP #: 0055591

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Echinococcus Antibody, IgG

ARUP #: 2007220

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Mumps Virus Antibody, IgM

ARUP #: 0099589

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Mumps Virus Antibody IgM, CSF

ARUP #: 0054443

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Measles (Rubeola) Virus Culture

ARUP #: 0065055

Methodology: Cell Culture/Immunofluorescence

Comments:

Test name: Measles (Rubeola) Antibodies, IgG and IgM

ARUP #: 0050375

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay

Comments:

Test name: Enterovirus Detection by RT-PCR

ARUP #: 0050249

Methodology: Qualitative Reverse Transcription Polymerase Chain Reaction

Comments:

Identify one of the most common causes of viral encephalitis

65-75% sensitive; 99% specific

Test name: Adenovirus Antibodies, IgG & IgM

ARUP #: 0051077

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Arbovirus Antibodies, IgM, CSF

ARUP #: 2001595

Methodology: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Arbovirus Antibodies, IgM, Serum

ARUP #: 2001592

Methodology: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM

ARUP #: 2001635

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM, CSF

ARUP #: 2001628

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies with Reflex to HIV-1 Antibody Confirmation by Western Blot

ARUP #: 2005377

Methodology: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Comments:

Test name: Chlamydia pneumoniae by PCR

ARUP #: 0060715

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Mycoplasma pneumoniae by PCR

ARUP #: 0060256

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Legionella Species by PCR

ARUP #: 0056105

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Listeria Antibody, Serum by CF

ARUP #: 0099529

Methodology: Semi-Quantitative Complement Fixation

Comments:

Test name: Acid-Fast Bacillus (AFB) Culture and AFB Stain

ARUP #: 0060152

Methodology: Stain/Culture/Identification/Susceptiblity

Comments:

Test name: Acid Fast Stain, Partial or Modified (for Nocardia spp.)

ARUP #: 0060325

Methodology: Stain/Microscopy

Comments:

Test name: Anaerobe Culture and Gram Stain

ARUP #: 0060143

Methodology: Stain/Culture/Identification

Comments:

Test name: Bartonella Species by PCR

ARUP #: 0093057

Methodology: Qualitative Polymerase Chain Reaction

Comments:

Test name: Leptospira Culture

ARUP #: 0060158

Methodology: Culture

Comments:

Test name: Rapid Plasma Reagin (RPR) with Reflex to Titer

ARUP #: 0050471

Methodology: Semi-Quantitative Charcoal Agglutination

Comments:

Test name: Acanthamoeba and Naegleria Culture

ARUP #: 0060245

Methodology: Qualitative Culture/Microscopy

Comments:

Test name: Trypanosoma cruzi Antibody, IgG

ARUP #: 0051076

Methodology: Semi-Quantitative Immunoassay

Comments:

Test name: Cryptococcus Antigen, Serum

ARUP #: 0050196

Methodology: Semi-quantitative Enzyme Immunoassay

Comments:

Test name: Cryptococcus Antigen, CSF

ARUP #: 0050195

Methodology: Semi-quantitative Enzyme Immunoassay

Comments:

Test name: Histoplasma Antigen by EIA, Serum

ARUP #: 0092522

Methodology: Semi-quantitative Enzyme Immunoassay

Comments:

Test name: Blastomyces Antibodies by CF & ID

ARUP #: 0050626

Methodology: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion

Comments:

Test name: Fungal Culture

ARUP #: 0060149

Methodology: Culture/Identification

Comments:

Test name: Blood Culture, Fungal

ARUP #: 0060070

Methodology: Continuous Monitoring Blood Culture/Identification

Comments:

Test name: Sedimentation Rate, Westergren (ESR)

ARUP #: 0040325

Methodology: Visual Identification

Comments:

Determine symptoms involved in vasculitic-like infections

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetry

Comments:

Determine symptoms involved in vasculitic-like infections

References

Guidelines

General

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) :1377-1379.PubMed

Medical Reviewers

Comprehensive Review: July 2012
Last Update: March 2013