Table 7.

Laboratory Diagnosis of Encephalitis

Etiologic Agents	Diagnostic Procedures	Optimum Specimens	Transport Issues and Optimal Transport Time
Viral
Herpes simplex virus	HSV-1 and -2 NAAT	CSF	Sterile container, RT, 2 h
Enteroviruses (nonpolio)	Enterovirus NAAT	CSF	Sterile container, RT, 2 h
Parechoviruses	Parechovirus NAAT	CSF	Sterile container, RT, 2 h
West Nile virus	WNV IgM antibodya	CSF and/or serum	Closed container or clot tube, RT, 2 h
	WNV NAATb	CSF and/or serum	Sterile container, RT, 2 h
Other arbovirusesc	Virus specific antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
Varicella zoster virusd	VZV NAAT	CSF or plasma	Sterile container or EDTA tube, RT, 2 h
	VZV antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
Epstein-Barr virus	EBV NAATe	CSF or plasma	Sterile container or EDTA tube, RT, 2 h
	EBV antibodies, VCA IgG and IgM, EBNA	CSF and/or serum	Closed container or clot tube, RT, 2 h
Cytomegalovirusf	CMV NAATg	CSF or plasma	Sterile container or EDTA tube, RT, 2 h
	CMV antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
Human herpesvirus 6	HHV-6 NAAT	CSF	Sterile container, RT, 2 h
JC virus	JC virus NAAT	CSF	Sterile container, RT, 2 h
Mumps virus	Mumps virus antibodies, IgM and IgG	Serum	Clot tube, RT, 2 h
		CSF	Closed container, RT, 2 h
	Mumps culture and NAAT	CSF	Sterile container, on ice, immediately
		Buccal or oral swab	Viral transport device, on ice, immediately
Measles (rubeola) virus	Measles antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
	Measles culture and NAAT	CSF, urine	Sterile container, RT, 2 h
		Throat swab	Viral transport device, on ice, immediately
Influenza virus	Influenza DFA and culture or NAAT	Nasopharyngeal wash or other respiratory specimen	Viral transport device, on ice, immediately
Adenovirus	Adenovirus DFA and culture or NAAT	Nasopharyngeal wash or other respiratory specimen	Viral transport device, on ice, immediately
	Adenovirus NAAT	CSF or plasma	Sterile container or EDTA, RT, 2 h
Rabies virush	Rabies antigen, DFA	Nuchal skin biopsy	Closed container, RT, immediately
	Rabies NAAT	Saliva	Sterile container, RT, immediately
	Rabies antibody	CSF and serum	Closed container, clot tube, RT, 2 h
Lymphocytic choriomeningitis virus	LCM antibodies, IgM and IgG, IFA	CSF and/or serum	Closed container or clot tube, RT, 2 h
Zika virus (see Table 71)
Bacterial
Mycobacterium tuberculosis	See Table 6, Meningitis
Bartonella spp	Bartonella spp NAAT	CSF or plasma	Sterile container or EDTA, RT, 2 h
	Bartonella spp antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
Mycoplasma pneumoniae	M. pneumoniae NAAT	CSF or respiratory	Sterile container, RT, 2 h
	M. pneumoniae antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
Tropheryma whipplei (Whipple disease)	T. whipplei NAAT	CSF	Sterile container, RT, 2 h
Listeria monocytogenes	Gram stain Aerobic bacterial culture	CSF, blood	Sterile container, aerobic blood culture bottle, RT, 2 h
	Listeria antibody, complement fixation	CSF and/or serum	Closed container or clot tube, RT, 2 h
Coxiella burnetii (Q fever)	C. burnetii antibodies, IgM and IgG	Serum	Clot tube, RT, 2 h
	C. burnetii NAAT	Whole blood	EDTA tube, RT, 2 h
		Tissue	Sterile container, RT, 2 h
Rickettsia rickettsii (RMSF), Rickettsia typhi	Rickettsia spp antibodies, IgG and IgM, IFA	CSF and/or serum	Closed container or clot tube, RT, 2 h
	R. rickettsii DFA or IHC and NAAT	Skin biopsy from rash	Sterile container, RT, 2 h
	R. rickettsii NAAT	Whole blood	EDTA tube, RT, 2 h
Ehrlichia chaffeensis, Anaplasma phagocytophilum	E. chaffeensis and A. phagocytophilum antibodies, IgM and IgG	CSF and/or serum	Closed container or clot tube, RT, 2 h
	E. chaffeensis and A. phagocytophilum NAAT	Whole blood	EDTA tube, RT, 2 h
Other: B. burgdorferi, T. pallidum, Leptospira spp	See Table 6, Meningitis
Fungal
Cryptococcus neoformans	Cryptococcus antigen test	CSF, serum	Closed container, clot tube, RT, 2 h
Cryptococcus gattii	Gram stain Aerobic bacterial culture Fungal culture	CSF	Sterile container, RT, 2 h
Coccidioides spp	Coccidioides antibody, immunodiffusion, and complement fixatione	CSF and/or serum	Closed container or clot tube, RT, 2 h
	Calcofluor stain Fungal culture	CSF, other sites	Sterile container, RT, 2 h
	Histologic examination	Tissue or formalin-fixed tissue	Sterile container, RT, 2 h or formalin, indefinite
Parasitic
Acanthamoeba spp  Naegleria fowleri	Microscopic wet mount Giemsa stain	CSF	Closed container, RT, 2 h
	Histology (trichrome stain)	CSF, brain tissue	Closed container, RT, 2 h
	Culture	CSF, brain tissue	Sterile container, RT, 2 h
	Acanthamoeba antibody IFAi	Serum	Clot tube, RT, 2 h
	Acanthamoeba IIF stainingi	Brain tissue	Closed container, RT, 2 h
	Histology (trichrome stain)	Brain tissue	Closed container, RT, 2 h
Balamuthia mandrillaris	Balamuthia antibody, IFAi	Serum	Clot tube, RT, 2 h
	Balamuthia IIF stainingi	Brain tissue	Closed container, RT, 2 h
Baylisascaris procyonisj	B. procyonis antibodies	CSF and/or serum	Closed container or clot tube, RT, 2 h
Trypanosoma brucei spp	Giemsa stain	CSF, brain tissue	Closed container, RT, 2 h
		Blood	EDTA tube, RT, 2 h
Toxoplasma gondii	Toxoplasma NAAT	CSF, serum, plasma	Sterile container, clot tube, EDTA tube, RT, 2 h
	Toxoplasma antibodies, IgM and IgGk	CSF and/or serum	Closed container or clot tube, RT, 2 h
	Giemsa stain, histology	CSF, brain tissue	Closed container, RT, 2 h
Prion
Creutzfeldt-Jakob diseasel	14-3-3 protein	CSF	Closed container, RT, 2 h
	Neuron-specific enolase	CSF	Closed container, RT, 2 h
	Routine histology, immune stain for prion protein	Formalin-fixed brain tissue	Contact surgical pathologist prior to collection of tissuem
	Western blot for prion protein	Frozen brain tissue	Contact surgical pathologist prior to collection of tissuem
	PrP gene sequencing	Blood, other tissues	EDTA tube, sterile container, RT, 2 h

Abbreviations: CMV, cytomegalovirus; CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; EDTA, ethylenediaminetetraacetic acid; HHV-6, human herpesvirus type 6; HSV, herpes simplex virus; IFA, indirect fluorescent antibody; IgG, immunoglobulin G; IgM, immunoglobulin M; IHC, immunohistochemistry; IIF, indirect immunofluorescent antibody; LCM, lymphocytic choriomeningitis virus; NAAT, nucleic acid amplification testing; RMSF, Rocky Mountain spotted fever; RT, room temperature; VCA, viral capsid antigen; WNV, West Nile virus.

^aWNV IgM antibody may persist for >6 months. False positives may occur with recent immunization (Japanese encephalitis, yellow fever) or other flavivirus infection (dengue, St Louis encephalitis, Zika) [30].

^bSensitivity of WNV NAAT in immunocompetent host is <60% [30]. Testing for IgM in CSF is preferred, but may be falsely negative during first week of symptoms. Persistent viremia in immunocompromised hosts lacking serologic response may improve WNV NAAT sensitivity.

^cEastern equine, Western equine, Lacrosse, St Louis, and California encephalitis viruses.

^dDetection of VZV DNA in CSF (~60% of cases), CSF IgM, or intrathecal antibody synthesis distinguishes meningoencephalitis from postinfectious, immune-mediated process [27].

^eQuantitative EBV NAAT may help distinguish true-positive from latent virus [27].

^fCongenital disease in newborns and reactivation in immunocompromised hosts. False-positive CSF CMV NAAT results have been reported in immunocompetent patients with bacterial meningitis [27].

^gIn human immunodeficiency virus–infected patients, detection of CMV DNA in CSF has 82%–100% sensitivity and 86%–100% specificity for diagnosing central nervous system CMV infection [27].

^hContact state public health department to arrange testing; questions regarding sampling techniques and shipping may be directed to the Rabies section at the Centers for Disease Control and Prevention (CDC), telephone: (404) 639–1050.

ⁱAvailable at the California State Department of Health Services and the CDC [31].

^jConsider if eosinophilia or exposure to raccoon feces [32]. Testing available at the Department of Veterinary Pathobiology, Purdue University (West Lafayette, Indiana), telephone: (765) 494-7558.

^kRefer positive IgM to Toxoplasma Serology Laboratory in Palo Alto, California, for confirmatory testing (http://www.pamf.org/serology/). The absence of serum IgM or IgG does not exclude Toxoplasma infection (22% of AIDS patients with Toxoplasma encephalitis lack IgG; IgM is rarely detected) [33].

^lTesting available at the National Prion Disease Pathology Surveillance Center (http://www.cjdsurveillance.com) [34]. The 14-3-3 protein has limited specificity for prion disease.

^mCompliance with appropriate infection control protocols is essential.