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Diagnostic Algorithm

Diagnostic Algorithm for Initial Evaluation of Encephalitis in Adultsa [1]

ROUTINE STUDIES

CSF

Collect at least 20 cc fluid, if possible; freeze at least 5–10 cc fluid, if possible

Opening pressure, WBC count with differential, RBC count, protein, glucos

Gram stain and bacterial culture

HSV-1/2 PCR (if test available, consider HSV CSF IgG and IgM in addition)

VZV PCR (sensitivity may be low; if test available, consider VZV CSF IgG and IgM in addition)

Enterovirus PCR

Cryptococcal antigen and/or India Ink staining

Oligoclonal bands and IgG index

VDRL

SERUM

Routine blood cultures

HIV serology (consider RNA)

Treponemal testing (RPR, specific treponemal test)

Hold acute serum and collect convalescent serum 10–14 d later for paired antibody testing

IMAGING

Neuroimaging (MRI preferred to CT, if available)

Chest imaging (Chest x-ray and/or CT)

NEUROPHYSIOLOGY

EEG

OTHER TISSUES/FLUIDS

When clinical features of extra-CNS involvement are present, we recommend additional testing (eg, biopsy of skin lesions; bronchoalveolar lavage and/or endobronchial biopsy in those with pneumonia/pulmonary lesions; throat swab PCR/culture in those with upper respiratory illness; stool culture in those with diarrhea); also see below

CONDITIONAL STUDIES

HOST FACTORS

Immunocompromised—CMV PCR, HHV6/7 PCR, HIV PCR (CSF); Toxoplasma gondii serology and/or PCR; MTB testingb; fungal testingc; WNV testingd

GEOGRAPHIC FACTORS

Africa—malaria (blood smear), trypanosomiasias (blood/CSF smear, serology from serum and CSF); dengue testingd

Asia—Japanese encephalitis virus testingd; dengue testingd; malaria (blood smear); Nipah virus testing (serology from serum and CSF; PCR, immunohistochemistry, and virus isolation in a BSL4 lab can also be used to substantiate diagnosis)

Australia—Murray Valley encephalitis virus testingd, Kunjin virus testingd, Australian Bat Lyssavirus (ABLV) testinge

Europe—Tick-borne encephalitis virus (serology); if Southern Europe, consider WNV testingd, Toscana virus testingd

Central and South America—dengue testingd; malaria (blood smear); WNV, Venezuelan equine encephalitis testingd

North America—Geographically appropriate arboviral testing (eg, WNV, Powassan, LaCrosse, Eastern equine encephalitis virusesd, Lyme (serum ELISA and Western blot)

SEASON AND EXPOSURE

Summer/Fall: Arbovirusd and tick-borne diseasef testing

Cat (particularly if with seizures, paucicellular CSF)—Bartonella antibody (serum), ophthalmologic evaluation

Tick exposure—tick-borne disease testingf

Animal bite/bat exposure—rabies testinge

Swimming or diving in warm freshwater or nasal/sinus irrigation—Naegleria fowleri (CSF wet mount and PCRg)

SPECIFIC SIGNS AND SYMPTOMS

Psychotic features or movement disorder—anti-NMDAR antibody (serum, CSF); rabies testinge; screen for malignancy, Creutzfeld-Jakob disease

Prominent limbic symptoms—Autoimmune limbic encephalitis testingh; HHV6/7 PCR (CSF); screen for malignancy

Rapid decompensation (particularly with animal bite history or prior travel to rabies-endemic areas)—rabies testinge

Respiratory symptoms—Mycoplasma pneumoniae serology and throat PCR (if either positive, then do CSF PCR); respiratory virus testingi

Acute flaccid paralysis—Arbovirus testingd; rabies testinge

Parkinsonism –Arbovirus testingd; Toxoplasma serology

Nonhealing skin lesions—Balamuthia mandrillaris, Acanthamoeba testingg

LABORATORY FEATURES

Elevated transaminases—Rickettsia serology, tick borne diseases testingf

CSF protein >100 mg/dL, or CSF glucose < 2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset—MTB testingb, fungal testingc

CSF protein >100 mg/dL or CSF glucose < 2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and recent antibiotic use—CSF PCR for S. pneumoniae and N. meningiditis

CSF eosinophilia –MTB testingb; fungal testingc; Baylisascaris procyonis antibody (serum); Angiostrongylus cantonensis and Gnathostoma sp. testingj

RBCs in CSF—Naegleria fowleri testingg

Hyponatremia—anti-VGKC antibody (serum); MTB testinga

NEUROIMAGING FEATURES

Frontal lobe—Naegleria fowleri testing (CSF wet mount and PCRg)

Temporal lobe—VGKC antibodies (serum and CSF); HHV 6/7 PCR (CSF)

Basal ganglia and/or thalamus—Arbovirusd testing; MTB testinga

Brainstem—Arbovirus testingd; Listeria PCR(if available); Brucella antibody (serum); MTB testingb

Cerebellum—EBV PCR (CSF) and serology

Diffuse cerebral edema—Respiratory virus testingi

Space occupying and/or ring-enhancing lesions—MTB testingb; fungal testingc; Balamuthia mandrillaris and Acanthamoeba testingg; Toxoplasma serology

Hydrocephalus and/or basilar meningeal enhancement—MTB testingb; fungal testingc

Infarction or hemorrhage—MTB testingb; fungal testingc; respiratory virus testingi

  • Abbreviations: ABLV, Australian bat lyssavirus; BSL4, biosafety level 4; CNS, central nervous system; CSF, cerebral spinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; EEG, electroencephalography; ELISA, enzyme-linked immunosorbent assay; HHV, human herpesvirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; MRI, magnetic resonance imaging; MTB, Mycobacterium tuberculosis; PCR, polymerase chain reaction; VDRL, Venereal Disease Research Laboratory; VGKC, voltage gated potassium channel; VZV, varicella-zoster virus; RBC, red blood cell; WBC, white blood cell; WNV, West Nile virus.
  • a This table is not intended to encompass all causes of encephalitis, nor all epidemiological or laboratory-based risk factors. We recommend using this table as a guideline for initial management of acute encephalitis in adults. For additional information, we recommend consulting Tunkel et al. 2008, Steiner et al. 2010, Solomon et al. 2012 (see references). Consultation with local health authorities is also recommended.
  • b MTB testing includes CSF smear for acid-fast bacilli and CSF mycobacterial culture along with one or more of the number of MTB PCR tests for CSF now commercially available. Sensitivity of smear and culture increases with the volume of CSF analyzed; we recommend consulting with the laboratory regarding optimal volumes of CSF to be analyzed. Given the varying sensitivity of these tests, systemic MTB testing including tuberculin skin test (may be negative) or interferon gamma release assay, stains and cultures from sputum, and tissue from biopsies from any potential systemic sites of infection.
  • c Fungal testing should be tailored to specific geographic region and prior travel history/place of residence, and typically consists of serology, antibody testing from urine and/or CSF, and cultures from blood and CSF.
  • d Arbovirus testing should be tailored to specific geographic region and typically consists of IgG and IgM from serum and CSF; PCR (serum, CSF) can be performed for select arboviruses (ie, WNV, California serogroup viruses), and is particularly useful in immunocompromised patients.
  • e Rabies/ABLV testing includes serologic analysis of serum and CSF; virus isolation or RT-PCR from saliva; tests for viral antigen or histopathology on either a brain biopsy or full-thickness biopsy of the nape of the neck. Testing should be conducted in concert with a local or regional public health department.
  • f Tick borne disease testing should be tailored to specific geographic region and typically consists of serology (ie, Borrelia, Ehrlichia, Rickettsia sp., Anaplasma phagocytophilum, TBEV), and blood PCR (Ehrlichia, Anaplasma).
  • gNaegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp. testing is only available at specialized laboratories (eg, CDC) and includes serum immunofluorescence assay, immunohistochemistry on brain or other tissue and PCR testing on brain or other tissue and CSF. In addition, CSF wet mount is recommended for Naeglaeria fowleri testing. Brain tissue from affected region offers optimal sensitivity and specificity but other specimens can be tested.
  • h Autoimmune limbic encephalitis evaluation includes testing for antibodies to VGKC (most commonly identified cause in adults), GAD, AMPA receptor, GABAb receptor, mgluR5, Hu, CV2, Ma2, and amphiphysin.
  • i Respiratory virus testing includes either culture or respiratory PCR panel from respiratory specimens (eg, nasopharyngeal swab, nasal wash). Respiratory virus testing should include Influenza A and B (during influenza season). Testing for other respiratory viruses such as parainfluenza and adenovirus should be considered although their role in causing CNS illness is controversial.
  • j Limited testing may be available through research laboratories, and includes examination of CSF or other affected tissues (ie, eye, muscle) for presence of parasite, or detection of antibody in serum or CSF.

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Last updated: May 29, 2016