ROUTINE STUDIES

CSF^b

Collect at least 5 cc fluid, if possible; freeze unused fluid for additional testing

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

Gram stain and bacterial culture

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

Enterovirus PCR

SERUM

Routine blood cultures

EBV serology (VCA IgG and IgM and EBNA IgG)

Mycoplasma pneumoniae IgM and IgG

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

IMAGING

Neuroimaging (MRI preferred to CT, if available)

NEUROPHYSIOLOGY

 EEG

OTHER TISSUES/FLUIDS

Mycoplasma pneumoniae PCR from throat sample

Enterovirus PCR and/or culture of throat and stool

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

Age < 3 y—Parechovirus PCR (CSF)

Immunocompromised—CMV PCR, HHV6/7 PCR, HIV PCR (CSF); cryptococcal antigen; Toxoplasma gondii serology and/or PCR; MTB testing^c; fungal testing^d; WNV testing^e

GEOGRAPHIC FACTORS

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

Asia—Japanese encephalitis virus testing^e; dengue testing^e; 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 testing^e; Kunjin virus testing^e, Australian Bat Lyssavirus (ABLV) testing^f

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

Central and South America—dengue testing^e; malaria (blood smear)

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

SEASON AND EXPOSURE

Summer/Fall: Arbovirus^e and tick-borne disease^g testing

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

Tick exposure– Tick borne disease testing^g

Animal bite/bat exposure—rabies testing^f

Swimming or diving in warm freshwater or nasal/sinus irrigation– Naegleria fowleri (CSF wet mount and PCR^h)

SPECIFIC SIGNS AND SYMPTOMS

Abnormal behavior (eg, new onset temper tantrums, agitation, aggression), psychotic features, seizures or movement disorder– NMDAR antibody (serum, CSF), oligoclonal bands, IgG index, rabies testing^f

Behavior changes followed by myoclonic spasms/jerks: measles IgG (CSF and serum)

Vesicular rash—VZV PCR from CSF (sensitivity may be low; if test available, consider CSF IgG and IgM); VZV IgG and IgM from serum

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

Respiratory symptoms—chest imaging (chest X-ray and/or CT scan); respiratory virus testingⁱ; Mycoplasma pneumoniae PCR (CSF)

Acute flaccid paralysis—Arbovirus testing^e; rabies testing^f

Parkinsonism –Arbovirus testing^e; Toxoplasma serology

Nonhealing skin lesions—Balamuthia, Acanthamoeba testing^h

Prominent limbic symptoms—Autoimmune limbic encephalitis testing^j, HHV6/7 PCR (CSF)

LABORATORY FEATURES

If EBV serology is suggestive of acute infection, perform EBV PCR (CSF)

Elevated transaminases—Rickettsia serology, tick-borne diseases testing^g

CSF protein >100 mg/dL, or CSF glucose < 2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset—MTB testing^c, fungal testing^d, Balamuthia mandrillaris testing^h

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 testing^c; fungal testing^d; Baylisascaris procyonis antibody (serum and CSF); Angiostrongylus cantonensis, Gnathostoma sp. testing^k

Hyponatremia—MTB testing^c

Mycoplasma pneumoniae serology or throat PCR positive— Mycoplasma pneumoniae PCR (CSF)

NEUROIMAGING FEATURES

Frontal lobe—Naegleria fowleri (CSF wet mount and PCR^h)

Temporal lobe—HHV 6/7 PCR (CSF)

Basal ganglia and/or thalamus—Respiratory virus testingⁱ; Arbovirus testing^e; MTB testing^c

Brainstem—respiratory virus testingⁱ; Arbovirus testing^e; Listeria PCR (if available); Brucella antibody (serum); MTB testing^c

Cerebellum—VZV PCR from CSF (sensitivity may be low; if test available, consider CSF IgG and IgM); VZV IgG and IgM from serum; EBV PCR (CSF)

Diffuse cerebral edema—respiratory virus testingⁱ

Space occupying and/or ring-enhancing lesions—MTB testing^c; fungal testing^d; Balamuthia mandrillaris and Acanthamoeba testing^h, Toxoplasma gondii serology

Hydrocephalus and/or basilar meningeal enhancement—MTB testing^c; fungal testing^d; Balamuthia mandrillaris testing^h; Infarction or hemorrhage—MTB testing^c; fungal testing^d; respiratory virus testingⁱ;

White matter lesions—Oligoclonal bands, IgG index, Lyme (serum ELISA and Western blot); Brucella (serology or CSF culture)

Measles virus testing for SSPE; Baylisascaris procyonis antibody (serum and CSF); Balamuthia mandrillaris testing^h

• Abbreviations: ABLV, Australian bat lyssavirus; BSL4, biosafety level 4; CNS, central nervous system; CMV, cytomegalovirus; CSF, cerebral spinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; EBNA, Epstein-Barr virus nuclear antigen; 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; RBC, red blood cell; HSV, herpes simplex virus; RBC, red blood cell; NMDAR, N-methyl-D-aspartate receptor; VCA, viral capsid antigen; VDRL, Venereal Disease Research Laboratory; VGKC, voltage gated potassium channel; VZV, varicella-zoster virus; SSPE, subacute sclerosing panencephalitis; 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 utilizing this table as a guideline for initial management of acute encephalitis in children beyond the neonatal period. For additional information, we recommend consulting Tunkel et al. 2008, Steiner et al. 2010, Kneen et al. 2012 (see references). Consultation with local health authorities is also recommended.
• ^b Although some members of the consortium recommended M. pneumoniae CSF PCR as routine testing for all children, a consensus was not reached given the challenges of establishing a diagnosis of encephalitis due to M. pneumoniae (see text).
• ^c 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.
• ^d 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.
• ^e 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.
• ^f 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.
• ^g 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).
• ^hNaegleria 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.
• 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 including Parainfluenza 1–4, Adenovirus, and human metapneumovirus should be considered although their role in causing CNS illness is controversial.
• ^j Autoimmune limbic encephalitis evaluation includes testing for antibodies to VGKC, GAD, AMPA receptor, GABA_b receptor, mgluR5, Hu, CV2, Ma2, and amphiphysin.
• ^k 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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