Abstract

Background. Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research.

Methods. In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study.

Results. We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed.

Conclusions. We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Encephalitis results in substantial morbidity and mortality worldwide. Specific etiologies are identified in <50% of cases, in part due to lack of consensus on case definitions and standardized diagnostic approaches. Advances in encephalitis are hampered by the rarity and heterogeneity of cases, highlighting the need for a collaborative international approach. In March 2012, the International Encephalitis Consortium held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. This consortium is an ad-hoc committee begun in 2010 with members from the Americas, Europe, Australia, Africa, and Asia. The mission of the consortium is to advance knowledge of the causes, diagnostic strategies, treatment, and outcome of encephalitis, and to implement interventions based upon this knowledge. Topics discussed at the meeting included: (1) standardization of a case definition for encephalitis, (2) development of practical diagnostic algorithms for evaluation of patients, (3) the role of host genetics in encephalitis, and (4) priorities for the study of selected emerging infectious diseases. Here we present a consensus document that synthesizes our discussions and recent literature, with the goals of aiding clinicians evaluating patients with suspected encephalitis and of identifying priorities and approaches to advance knowledge of encephalitis.

PRIORITY 1: CASE DEFINITION

Encephalitis is defined as inflammation of the brain parenchyma associated with neurologic dysfunction [1]. Although pathologic examination and testing of brain tissue is considered to be the “gold standard” diagnostic test for this syndrome, this is rarely done premortem due to potential morbidity associated with an invasive neurosurgical procedure. In the absence of pathologic confirmation, encephalitis has previously been defined on the basis of selected clinical, laboratory, electroencephalographic, and neuroimaging features [2–7] (Supplementary Table 1). One of the most widely used case definitions for encephalitis, developed by the Brighton Collaboration Encephalitis Working Group [6], standardizes reporting of post-immunization neurologic events. However, whether this definition is applicable to the diagnosis of infectious or autoimmune encephalitis, as well as the relative sensitivity and specificity of the varying levels of diagnostic accuracy of this definition, is unknown.

Further complicating development of a cohesive case definition for encephalitis is the clinical overlap between encephalitis and encephalopathy, terms often used interchangeably in the literature but that may represent distinctive pathophysiologic processes. Encephalopathy refers to a clinical state of altered mental status, manifesting as confusion, disorientation, behavioral changes, or other cognitive impairments, with or without inflammation of brain tissue. Encephalopathy without inflammation can be triggered by a number of metabolic or toxic conditions but may also be associated with specific infectious agents, such as Bartonella henselae [8–10] or influenza virus [11–14].

In contrast, encephalitis is characterized by brain inflammation as a consequence of direct infection of the brain parenchyma, a post-infectious process such as acute disseminated encephalomyelitis (ADEM) [6, 15], or a noninfectious condition such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis [16, 17]. In the absence of pathologic evidence of brain inflammation, an inflammatory response in the cerebrospinal fluid (CSF) or the presence of parenchymal abnormalities on neuroimaging are often used as surrogate markers of brain inflammation. However, encephalitis can occur without significant CSF pleocytosis or demonstrable neuroimaging abnormalities [18–21].

Development of a standardized case definition for encephalitis and encephalopathy of presumed infectious etiology is important for epidemiological surveillance, clinical research, and outbreak investigations. Implementation of a case definition broadly applicable to regions with substantially different resources and surveillance capacities facilitates investigation of newly recognized or emerging causes of encephalitis. Because of the significant clinical overlap between encephalitis (infectious and noninfectious) and encephalopathy of presumed infectious etiology, the case definition is formulated to capture both syndromes.

Several caveats must be recognized regarding the proposed case definition. First, alteration in mental status is a required component (Major criterion; Table 1). It is recognized that some infections or conditions related to infections may cause central nervous system (CNS) dysfunction without affecting consciousness (eg, post-varicella cerebellar ataxia [22]), and our case definition would not capture these entities. Second, there is no restriction on the maximum duration of altered mental status, and therefore both acute causes of encephalitis as well as more subacute or chronic infectious conditions such as those caused by fungi or mycobacteria would meet the case definition. Third, several additional criteria are required to substantiate a diagnosis of encephalitis (Minor criteria; Table 1). Finally, the syndromic definition is viewed to be complementary to the diagnostic testing algorithm (see Priority 2: Diagnostic Algorithm section and Tables 2 and 3). Thus, while identification of an infection with an organism that is strongly associated with encephalitis from an appropriate biologic sample would confirm a clinical diagnosis of encephalitis, failure to identify a pathogen, as has been reported in >50% of cases of presumed encephalitis in some series [1, 5], would not exclude the diagnosis.

Table 1.

Diagnostic Criteria for Encephalitis and Encephalopathy of Presumed Infectious or Autoimmune Etiology

Major Criterion (required): 
 Patients presenting to medical attention with altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) lasting ≥24 h with no alternative cause identified. 
Minor Criteria (2 required for possible encephalitis; ≥3 required for probable or confirmeda encephalitis): 
 Documented fever ≥38° C (100.4°F) within the 72 h before or after presentationb 
 Generalized or partial seizures not fully attributable to a preexisting seizure disorderc 
 New onset of focal neurologic findings 
 CSF WBC count ≥5/cubic mmd 
 Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onsete 
 Abnormality on electroencephalography that is consistent with encephalitis and not attributable to another cause.f 
Major Criterion (required): 
 Patients presenting to medical attention with altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) lasting ≥24 h with no alternative cause identified. 
Minor Criteria (2 required for possible encephalitis; ≥3 required for probable or confirmeda encephalitis): 
 Documented fever ≥38° C (100.4°F) within the 72 h before or after presentationb 
 Generalized or partial seizures not fully attributable to a preexisting seizure disorderc 
 New onset of focal neurologic findings 
 CSF WBC count ≥5/cubic mmd 
 Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis that is either new from prior studies or appears acute in onsete 
 Abnormality on electroencephalography that is consistent with encephalitis and not attributable to another cause.f 

Abbreviations: CNS, central nervous system; CSF, cerebral spinal fluid; EEG, electroencephalogram; RBC, red blood cell; WBC, white blood cell.

a Confirmed encephalitis requires one of the following: (1) Pathologic confirmation of brain inflammation consistent with encephalitis; (2) Defined pathologic, microbiologic, or serologic evidence of acute infection with a microorganism strongly associated with encephalitis from an appropriate clinical specimen (for examples, see references [1, 2]); or (3) Laboratory evidence of an autoimmune condition strongly associated with encephalitis.

b Fever is a common finding in patients with acute encephalitis but is nonspecific. The requirement for objective documentation of fever within a restricted time frame of ≤72 h after hospitalization was chosen to exclude secondary health-care associated infections. It is recognized that fevers can occur as a result of a number of infections outside of the central nervous system that can cause encephalopathy, as well as with noninfectious entities that mimic encephalitis. It is also recognized that fever may fluctuate and, as such, objective fever may be lacking in patients with infectious encephalitis at the time of clinical assessment. Furthermore, immunosuppressed patients with encephalitis may not mount a fever.

c Seizures associated with encephalitis may be generalized, suggestive of global CNS dysfunction, or focal, indicating a localized process. Subclinical seizures may also occur and can be a cause of altered sensorium. Seizures associated with high temperatures are relatively common in young children and, if occurring in isolation, do not mandate evaluation for encephalitis. The major requirement for at least 24 h of altered mentation was selected to exclude the post-ictal state seen in patients with febrile seizures.

d CSF pleocytosis is suggestive of an inflammatory process of the brain parenchyma, meninges, or both (meningoencephalitis). The absence of CSF pleocytosis, however, does not exclude encephalitis. In particular, it is recognized that the CSF may be devoid of cells in immunocompromised patients (Fodor et al., Neurology 1998 51:554–59) or early in the course of infection (Weil et al, Clin Infect Dis 2002 34:1154–57; Mook-Kanamori et al., J Am Geriatr Soc 57:1514–15; Jakob et al., Crit Care Med 2012 40:1304–8). Conversely, the CSF profile with inflammation limited to the meninges may be indistinguishable from that in patients with encephalitis. In the majority of cases of encephalitis, however, the absolute number of leukocytes is <1000/mm3 and lymphocytes typically predominate. To ensure adequate sensitivity of the definition, the group defined CSF pleocytosis as ≥5 WBC/mm3. In cases where there are large numbers of red blood cells in the CSF, such as with a traumatic lumbar puncture, the following formula may allow correction of the WBC count: True CSF WBC = actual CSF WBC—(WBC in blood X RBC in CSF)/RBC in blood (Tunkel A. In Mandel ed., Principles and Practice of Infectious Diseases, 7th ed., 2010:1183–88; Bonadio Pediatr Infect Dis J 1992 11:423–31). Notably, rules for adjusting leukocytes in blood-contaminated CSF have not been well validated (Bonsu and Harper, Pediatr Infect Dis J 2006 25:8–11).

d Neuroimaging plays a crucial role in the evaluation of patients with suspected encephalitis, as it may support the diagnosis of a specific etiology or identify alternate conditions that mimic encephalitis. Magnetic resonance imaging (MRI) is the radiologic modality of choice for evaluation of patients with suspected encephalitis. Multiple studies have confirmed MRI to be superior to computed tomographic (CT) scanning for demonstration of CNS abnormalities (Tunkel et al. Clin Infect Dis 2008 47:303–27; Glaser et al. Clin Infect Dis 2006 43:1565–77). MRI may aid in defining an etiology, as localization of inflammation may be suggestive of particular pathogens (eg, temporal lobe involvement in patients with herpes simplex virus encephalitis) or of an autoimmune phenomenon (eg, demyelination in patients with acute disseminated encephalomyelitis). A noncontrast CT scan is most useful in evaluating safety in the performance of a lumbar puncture and in excluding alternative diagnoses such as subarachnoid hemorrhage. We recognize that MRI or CT may not be available in resource-limited settings, in which case the diagnosis of encephalitis will need to rely on clinical and laboratory criteria.

f EEG abnormalities reported in cases of encephalitis range from nonspecific generalized slowing to distinctive patterns suggestive of specific entities, including repetitive sharp wave complexes over the temporal lobes or periodic lateralizing epileptiform discharges in HSV-1 (Lai and Gragasin J Clin Neurophysiol 1988 5:87–103) and bilateral synchronous periodic sharp and slow waves associated with subacute sclerosing panencephalitis (Gutierrez et al. Dev Med Child Neurol 2010 52:901–7). EEG abnormalities are frequently nonspecific and may be attributable to medications or metabolic abnormalities. The EEG may identify epileptiform discharges in the absence of clinical evidence of seizure activity (subclinical or nonconvulsive status epilepticus) as a cause of obtundation.

Table 2.

Diagnostic Algorithm for Initial Evaluation of Encephalitis in Adultsa

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, glucose 
 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 
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, glucose 
 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.

Table 3.

Diagnostic Algorithm for Initial Evaluation of Encephalitis in Childrena

ROUTINE STUDIES 
CSFb 
 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  testingc; fungal testingd; WNV testinge 
GEOGRAPHIC FACTORS 
 Africa—malaria (blood smear); trypanosomiasias (blood/CSF smear, serology from serum and CSF); dengue testinge 
 Asia—Japanese Encephalitis Virus testinge; dengue testinge; 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 testinge; Kunjin virus testinge, Australian Bat Lyssavirus (ABLV) testingf 
 Europe—Tick-borne Encephalitis Virus (serology); if Southern Europe, consider WNV testinge, Toscana virus testinge 
 Central and South America—dengue testinge; 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: Arboviruse and tick-borne diseaseg testing 
 Cat (particularly if with seizures, paucicellular CSF)—Bartonella antibody (serum), ophthalmologic evaluation 
 Tick exposure– Tick borne disease testingg 
 Animal bite/bat exposure—rabies testingf 
 Swimming or diving in warm freshwater or nasal/sinus irrigation– Naegleria fowleri (CSF wet mount and PCRh
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 testingf 
 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 testingf 
 Respiratory symptoms—chest imaging (chest X-ray and/or CT scan); respiratory virus testingi; Mycoplasma pneumoniae PCR (CSF) 
 Acute flaccid paralysis—Arbovirus testinge; rabies testingf 
 Parkinsonism –Arbovirus testinge; Toxoplasma serology 
 Nonhealing skin lesions—Balamuthia, Acanthamoeba testingh 
 Prominent limbic symptoms—Autoimmune limbic encephalitis testingj, 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 testingg 
 CSF protein >100 mg/dL, or CSF glucose <2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset—MTB  testingc, fungal testingd, Balamuthia mandrillaris testingh 
 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 testingc; fungal testingd; Baylisascaris procyonis antibody (serum and CSF); Angiostrongylus cantonensis,   Gnathostoma sp. testingk 
 Hyponatremia—MTB testingc 
  Mycoplasma pneumoniae serology or throat PCR positive— Mycoplasma pneumoniae PCR (CSF) 
NEUROIMAGING FEATURES 
 Frontal lobe—Naegleria fowleri (CSF wet mount and PCRh
 Temporal lobe—HHV 6/7 PCR (CSF) 
 Basal ganglia and/or thalamus—Respiratory virus testingi; Arbovirus testinge; MTB testingc 
 Brainstem—respiratory virus testingi; Arbovirus testinge; Listeria PCR (if available); Brucella antibody (serum); MTB testingc 
 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 testingc; fungal testingd; Balamuthia mandrillaris and Acanthamoeba testingh,   Toxoplasma gondii serology 
 Hydrocephalus and/or basilar meningeal enhancement—MTB testingc; fungal testingd; Balamuthia mandrillaris testingh; Infarction or  hemorrhage—MTB testingc; fungal testingd; 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 testingh 
ROUTINE STUDIES 
CSFb 
 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  testingc; fungal testingd; WNV testinge 
GEOGRAPHIC FACTORS 
 Africa—malaria (blood smear); trypanosomiasias (blood/CSF smear, serology from serum and CSF); dengue testinge 
 Asia—Japanese Encephalitis Virus testinge; dengue testinge; 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 testinge; Kunjin virus testinge, Australian Bat Lyssavirus (ABLV) testingf 
 Europe—Tick-borne Encephalitis Virus (serology); if Southern Europe, consider WNV testinge, Toscana virus testinge 
 Central and South America—dengue testinge; 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: Arboviruse and tick-borne diseaseg testing 
 Cat (particularly if with seizures, paucicellular CSF)—Bartonella antibody (serum), ophthalmologic evaluation 
 Tick exposure– Tick borne disease testingg 
 Animal bite/bat exposure—rabies testingf 
 Swimming or diving in warm freshwater or nasal/sinus irrigation– Naegleria fowleri (CSF wet mount and PCRh
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 testingf 
 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 testingf 
 Respiratory symptoms—chest imaging (chest X-ray and/or CT scan); respiratory virus testingi; Mycoplasma pneumoniae PCR (CSF) 
 Acute flaccid paralysis—Arbovirus testinge; rabies testingf 
 Parkinsonism –Arbovirus testinge; Toxoplasma serology 
 Nonhealing skin lesions—Balamuthia, Acanthamoeba testingh 
 Prominent limbic symptoms—Autoimmune limbic encephalitis testingj, 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 testingg 
 CSF protein >100 mg/dL, or CSF glucose <2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset—MTB  testingc, fungal testingd, Balamuthia mandrillaris testingh 
 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 testingc; fungal testingd; Baylisascaris procyonis antibody (serum and CSF); Angiostrongylus cantonensis,   Gnathostoma sp. testingk 
 Hyponatremia—MTB testingc 
  Mycoplasma pneumoniae serology or throat PCR positive— Mycoplasma pneumoniae PCR (CSF) 
NEUROIMAGING FEATURES 
 Frontal lobe—Naegleria fowleri (CSF wet mount and PCRh
 Temporal lobe—HHV 6/7 PCR (CSF) 
 Basal ganglia and/or thalamus—Respiratory virus testingi; Arbovirus testinge; MTB testingc 
 Brainstem—respiratory virus testingi; Arbovirus testinge; Listeria PCR (if available); Brucella antibody (serum); MTB testingc 
 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 testingc; fungal testingd; Balamuthia mandrillaris and Acanthamoeba testingh,   Toxoplasma gondii serology 
 Hydrocephalus and/or basilar meningeal enhancement—MTB testingc; fungal testingd; Balamuthia mandrillaris testingh; Infarction or  hemorrhage—MTB testingc; fungal testingd; 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 testingh 

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, GABAb 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.

Summary

The proposed definition of encephalitis and encephalopathy of presumed infectious etiology was developed based on consensus expert opinion and review of available literature. We anticipate that validation using existing cohorts as well as additional prospective studies will be crucial in refining and improving the case definition for encephalitis.

PRIORITY 2: DIAGNOSTIC ALGORITHM

Scope and Purpose

Algorithms for the diagnosis of encephalitis may serve many purposes, including aiding clinicians in management of patients, standardizing evaluations for research, and facilitating public health disease surveillance. Several groups have recently provided reviews of diagnosis and management of encephalitis, with differing purposes and depth [1, 23–26]. Our primary goal was to develop a practical diagnostic algorithm for use by medical professionals worldwide in the initial evaluation of suspected encephalitis. In addition, we intended the algorithm to provide a standardized approach for use in collaborative, multicenter research studies. Etiologies that we focus on include those that (1) are more commonly identified, (2) may benefit from targeted therapies, or (3) are of particular public health significance. The algorithm is directed toward identification of specific infectious and autoimmune causes of encephalitis and therefore does not include a broad evaluation for mimickers of encephalitis or other causes of encephalopathy.

Description

Relatively few causes account for the vast majority of identified cases of encephalitis [5, 7, 27]. Therefore, we recommend testing for these agents, along with selected, treatable conditions, in all individuals. Obtaining a comprehensive case history, including recent and remote travel, animal contacts and insect exposure, and carefully characterizing presenting symptoms, signs, and laboratory and neuroimaging findings are crucial to inform additional testing (Tables 2 and 3). We developed distinct algorithms for adult and pediatric populations, because the spectrum and frequencies of etiologies differ between the 2 age groups [27]. We recommend neuroimaging (preferably magnetic resonance imaging [MRI]), electroencephalography (EEG), and lumbar puncture (LP) in all individuals unless contraindicated [28], because such testing may confirm the diagnosis of encephalitis and establish the etiology.

If the etiology of encephalitis is not rapidly identified or where unique epidemiologic factors or clinical features are present, we recommend referring to several recent publications as a guide to further evaluation [1, 23–26]. Our recommendations incorporate large-scale geographic considerations; however, specific travel history or geographic information should prompt consultation with regional public health departments. Because our focus is on initial evaluation of patients, modalities such as brain biopsy, typically reserved for refractory cases of encephalitis, are not included. Moreover, our knowledge of autoimmune encephalitis is rapidly changing, with ongoing identification of novel autoantibodies and expansion of clinical spectra of disease. Here, we include well-recognized syndromes and relatively common etiologies [29, 30]. Overall, it should be noted that our recommendations provide general guidance for initial evaluation of encephalitis, but rapid advances in autoimmune encephalitis coupled with the emerging nature of infections warrant ongoing evaluation of testing paradigms.

Selected Etiology-specific Considerations

Herpes Simplex Virus (HSV)

Case series and studies have shown that HSV polymerase chain reaction (PCR) can be falsely negative, especially among children and early in the disease course [18, 21, 31]. If testing from the first LP is negative and herpes simplex encephalitis (HSE) is still of concern (eg, temporal lobe involvement seen on neuroimaging), a second LP should be repeated within 3–7 days with CSF sent for HSV PCR [1]. Testing for intrathecal HSV antibodies may complement molecular testing but is not typically useful for acute patient management [32].

Varicella-zoster Virus (VZV)

VZV is one of the most commonly identified causes of acute encephalitis in adults [5, 7], typically associated with viral reactivation and resulting in a CNS vasculopathy [33]. Notably, CNS reactivation may occur in the absence of skin lesions [34]. In children, on the other hand, most cases occur concurrently with chickenpox or in a post-infectious form [22, 35]. Detection of antibodies to VZV in the CSF appears to have greater sensitivity than detection of viral DNA [36]; therefore, we recommend that both assays be sent when possible.

Enteroviruses (EV)

CSF PCR analysis is crucial to perform but alone may be insufficient for diagnosis. In one report of an EV71 outbreak, EV-PCR of CSF yielded positive results in only 31% of cases, with higher yields from PCR of throat and stool specimens [37]. Because enteroviral shedding from the gastrointestinal tract may persist for weeks following infection [38], we recommend testing of both CNS and extra-CNS samples. Moreover, because standard EV PCR assays do not detect parechoviruses, specific PCR assays for these viruses should be performed in young children.

Epstein-Barr Virus (EBV)

EBV is an important cause of encephalitis in the pediatric population, particularly among adolescents. Although helpful in diagnosis of EBV-associated encephalitis, PCR testing can be associated with false-negative and false-positive results, the latter often occurring due to presence of EBV DNA in peripheral blood mononuclear cells. Therefore, serology, including antiviral capsid antigens (VCA) immunoglobulin M/immunoglobulin G (IgM/IgG) and anti-Epstein-Barr nuclear antigen (EBNA), is recommended in addition to CSF PCR [39].

Human Herpesvirus 6 (HHV-6)

The CNS pathogenic potential of HHV-6 has yet to be defined, although increasing evidence implicates its role in limbic encephalitis in the immunocompromised individual [40]. A positive HHV-6 CSF PCR should prompt corresponding evaluation of blood PCR levels in an effort to distinguish between chromosomal integration and acute infection [41]. Notably, latent disease can also be detected through PCR and may be a confounder [42].

Arboviruses

For most arboviruses, serologic testing of serum and CSF is preferred to molecular testing, since the peak of viremia typically occurs prior to symptom onset. For example, in patients with West Nile virus (WNV) associated with neuroinvasive disease, CSF PCR is relatively insensitive (57%) compared with detection of WNV IgM in CSF [43]. The cumulative percentage of seropositive patients increases by approximately 10% per day during the first week of illness, suggesting the need for repeat testing if the suspicion for disease is strong in those with initially negative results [44, 45]. Notably, arbovirus IgM antibodies may be persistently detectable in the serum and, less commonly, in the CSF, for many months after acute infection, and therefore may not be indicative of a current infection [46, 47]. Therefore, if possible, documentation of acute infection by seroconversion and/or 4-fold or greater rises in titre using paired sera is recommended.

Mycoplasma pneumoniae

Several reports have implicated Mycoplasma pneumoniae as a leading cause of encephalitis, particularly among children [48, 49]. In most such cases an immune-mediated mechanism is hypothesized; a preceding respiratory prodrome and detection of the pathogen in the respiratory tract, but not CSF, is typical of such cases. Direct infection of the brain or CSF is less common but has been observed in both adults and children. Serology alone is unreliable in diagnosing neurologic disease due to M. pneumoniae because of the high background incidence of acute infections and limited specificity of currently available assays [50]. Similarly, because detection of M. pneumoniae DNA in respiratory secretions may reflect acute infection, remote infection or asymptomatic colonization its detection does not establish it as the cause of neurologic disease. We recommend that testing be performed in pediatric patients and include both serology and PCR analysis. Overall, the strength of microbiologic evidence needs to be considered when implicating M. pneumoniae as the cause of encephalitis [51].

Anti-NMDA Receptor (NMDAR) Encephalitis

Affected individuals typically develop prominent psychiatric symptoms, cognitive dysfunction, seizures, orofacial dyskinesias, and autonomic instability [52, 53]. Sensitivity of testing is approximately 15% higher from the CSF than from serum, as determined by comparison of paired serum and CSF samples [54]. Notably, the recent demonstration of serum or CSF antibodies to NMDAR in 30% of individuals during the course of typical HSE suggests that a positive antibody result should be interpreted in the proper clinical context [55].

Autoimmune Limbic Encephalitis (ALE)

ALE, characterized by rapidly progressive short-term memory deficits, psychiatric symptoms, and seizures, is associated with a wide variety of autoantibodies, including onconeuronal antibodies (ie, Hu, CV2, Ma2, amphiphysin) and antibodies to neuronal cell surface/ synaptic antigens (ie, voltage gated potassium channel [VGKC], glutamic acid decarboxylase, AMPA receptor, GABAb receptor, mgluR5). Although the former group is highly associated with underlying tumor, in the latter group the presence of malignancy is variable. In most cases, serum testing is sufficient [56].

Summary

This algorithm represents a practical tool for use by clinicians in initial evaluation of patients with suspected encephalitis and provides the basis for worldwide collaboration to advance diagnosis and management of affected individuals. To maximize the benefits of such an approach for research purposes, the use of standardized case history forms with relevant demographic and laboratory data is critical.

PRIORITY 3: HOST GENETICS

Introduction

Although encephalitis is typically a rare clinical entity, it follows infection with a number of relatively common agents. Reasons for this range of disease severity remain unclear. Several general and disease-specific risk modifiers have been identified, including infectious dose, viral or microbial genotypic variation, and age-related changes in anatomic barriers or global immune function. In addition, an individual's genetic make-up contributes significantly to the variation in infectious disease susceptibility and severity [57]. Preclinical studies have identified host cell factors that modulate the course of infection for a range of microbes. With few exceptions, however, these studies have failed to identify genes in which human variation affects disease outcome. Indeed, risk alleles for infectious encephalitis have only been identified in a handful of cases (Table 4 and references).

Table 4.

Risk Alleles Identified for Infectious Encephalitis

Agent Genes Study Design Findings 
West Nile Virus OASL Candidate gene case control Synonymous single nucleotide polymorphism (SNP) associated with symptomatic infectiona; Result not replicated in several studiesb,c
 OAS1 Candidate gene case control in 5 different cohorts Intronic SNP associated with seropositivity (acquisition)b. A separate study could not replicate the finding, but did identify a second SNP associated with severe diseasec 
 CCR5 Candidate gene case control in 5 different cohorts CCD5del32 associated with symptomatic infection and fatal outcome in one cohortd,e. Not associated with seropositivity (acquisition)f; Result was not replicated by Bigham et alc
 IRF3 Candidate gene case control Autosomal dominant SNP associated with symptomatic cases compared to asymptomatic, seropositive controls. Association not observed with random blood donor controlsc
 MX1 Candidate gene case control Autosomal recessive SNP associated with symptomatic cases compared to asymptomatic, seropositive controls. Association not observed with random blood donor controlsc
Herpes simplex virus UNC93B Functional studies and candidate gene sequencing Autosomal recessive deficiency of functional gene product in two patients leading to impaired interferon-mediated antiviral responseg
 TLR3 Functional studies and candidate gene sequencing Autosomal recessive deficiency in one patient and autosomal dominant variant identified in two patients. Both lead to impaired interferon-mediated antiviral responseh,i
 TRAF3 Functional studies and candidate gene sequencing Autosomal dominant variant that functions as a dominant negative, resulting in impaired tumor necrosis factor (TNF) receptor signaling and interferon inductionj
 TRIF Functional studies and candidate gene sequencing Autosomal dominant and autosomal recessive defects, each in a single patient, resulting in impaired toll-like receptor signaling and antiviral responsesk
 STAT1 Functional studies and candidate gene sequencing Two different autosomal recessive alleles, each identified in a single patient, leading to impaired interferon-mediated signaling and antiviral responsesl
 TBK1 Functional studies and candidate gene sequencing Two different autosomal dominant variants, each identified in a single patient, resulting in impaired toll-like receptor signalingm
Tickborne encephalitis virus CCR5 Candidate gene case control CCD5del32 associated with tickborne encephalitisn
Agent Genes Study Design Findings 
West Nile Virus OASL Candidate gene case control Synonymous single nucleotide polymorphism (SNP) associated with symptomatic infectiona; Result not replicated in several studiesb,c
 OAS1 Candidate gene case control in 5 different cohorts Intronic SNP associated with seropositivity (acquisition)b. A separate study could not replicate the finding, but did identify a second SNP associated with severe diseasec 
 CCR5 Candidate gene case control in 5 different cohorts CCD5del32 associated with symptomatic infection and fatal outcome in one cohortd,e. Not associated with seropositivity (acquisition)f; Result was not replicated by Bigham et alc
 IRF3 Candidate gene case control Autosomal dominant SNP associated with symptomatic cases compared to asymptomatic, seropositive controls. Association not observed with random blood donor controlsc
 MX1 Candidate gene case control Autosomal recessive SNP associated with symptomatic cases compared to asymptomatic, seropositive controls. Association not observed with random blood donor controlsc
Herpes simplex virus UNC93B Functional studies and candidate gene sequencing Autosomal recessive deficiency of functional gene product in two patients leading to impaired interferon-mediated antiviral responseg
 TLR3 Functional studies and candidate gene sequencing Autosomal recessive deficiency in one patient and autosomal dominant variant identified in two patients. Both lead to impaired interferon-mediated antiviral responseh,i
 TRAF3 Functional studies and candidate gene sequencing Autosomal dominant variant that functions as a dominant negative, resulting in impaired tumor necrosis factor (TNF) receptor signaling and interferon inductionj
 TRIF Functional studies and candidate gene sequencing Autosomal dominant and autosomal recessive defects, each in a single patient, resulting in impaired toll-like receptor signaling and antiviral responsesk
 STAT1 Functional studies and candidate gene sequencing Two different autosomal recessive alleles, each identified in a single patient, leading to impaired interferon-mediated signaling and antiviral responsesl
 TBK1 Functional studies and candidate gene sequencing Two different autosomal dominant variants, each identified in a single patient, resulting in impaired toll-like receptor signalingm
Tickborne encephalitis virus CCR5 Candidate gene case control CCD5del32 associated with tickborne encephalitisn

a Yakub et al., J Infect Dis 2005; 192:1741–48.

b Lim et al., PLoS Pathog 2009; 5:e1000321.

c Bigham et al., PLoS ONE 2011; 6:e24745.

d Glass et al. J Exp Med 2006; 203:35–40.

e Lim et al. J Infect Dis 2008’ 197:262–65.

f Lim et al., J Infect Dis 2010; 201:178–85.

g Casrouge et al. Science 2006; 314:308–12.

h Guo et al. J Exp Med 2011; 208:2083–98.

i Zhang et al. Science 2007; 317:1522–27.

j Perez de Diego et al., Immunity 2010; 33:400–411.

k Sancho-Shimizu et al., J Clin Invest 2011; 121:4889–902.

l Dupuis et al., Nat Genet 2003; 33:388–91.

m Herman et al., J Exp Med 2012; 209:2567–1582.

n Kindberg et al. J Infect Dis 2008; 197:266–69.

Challenges and Solutions

The rarity and highly sporadic nature of encephalitis presents certain challenges. The strategy and approach to identifying genotypic determinants of a given phenotype depends largely on its allelic architecture—the number, type, penetrance, and frequency of disease associated variants (Supplementary Table 2) [58]. Mendelian traits, representing one extreme on the allelic spectrum, are determined by variants at a single locus. Because Mendelian variants are associated with a high relative risk of disease, they tend to be very rare in populations. Such traits have typically been dissected through linkage studies of families. While this approach has successfully identified genes involved in primary immunodeficiency, it is difficult to identify large pedigrees with multiple exposed and affected individuals for encephalitis and many other infectious diseases [57]. Genomewide resequencing of unrelated cases has emerged as another promising approach in Mendelian disease genetics. This strategy can identify candidate genes with as few as 10–50 individuals, but the case only design necessitates larger validation studies with appropriate controls [59, 60].

On the other end of the allelic spectrum are common genetic variants, which typically have only a modest effect on a disease phenotype. The common disease-common variant hypothesis predicts that many prevalent diseases are the result of common variants in multiple genetic loci, each with a small relative risk. These loci are typically identified in case-control association studies, although even the best candidate gene studies are prone to confounding and bias. While genomewide association studies circumvent many of these issues, adequate statistical power requires recruitment of hundreds or thousands of affected cases and exposed controls [61]. Even then, current study designs are poorly sensitive for rare alleles.

Given the large number of cases required and the cost of genomewide studies, human genetics has become a highly collaborative enterprise. However, many challenges exist in organizing such a genetics research effort. Above all, a multicenter approach will require a set of standard protocols for prospective subject recruitment, informed consent, biospecimen collection, and storage. While many investigators routinely collect serum and CSF from enrolled patients, protocols would need to be expanded to include snap-frozen whole blood with explicit authorization for future use in genetic studies. Similarly, common case history forms are needed to record demographics and relevant risk factors. Ideally, the biospecimens and clinical metadata would be curated and maintained in a central biobank with a mature informational technology infrastructure. The cost of such efforts would be significant.

The group also discussed how research efforts could impact the diagnosis and management of encephalitis. The rapid pace of gene discovery suggests a future in which genetic testing targets high-risk patients in need of immunization or those who would benefit from specific therapeutic interventions. This approach is now commonplace in oncology. In infectious disease, testing for HLA-B5701 is used to identify patients infected with human immunodeficiency virus (HIV) at risk for abacavir hypersensitivity [62], and IL-28B genotype may predict the clinical efficacy of interferon regimens for hepatitis C [63].

Summary

Overall, the identification of genetic risk factors for encephalitis and other neuroinvasive complications of infection is a priority research area. We expect that a more complete understanding of encephalitis host genetics will elucidate pathogenic mechanisms, define relevant biomarkers, and suggest potential therapeutic approaches. As is the case for clinical risk factors, genetic risk factors for encephalitis will likely include alleles that are pathogen-specific as well as mutations that confer broad susceptibility to encephalitis [64]. More work is clearly needed in this area, and this and other consortia can play a productive role in this movement to personalized medicine.

PRIORITY 4: SELECTED EMERGING AREAS

A discussion of selected emerging areas in encephalitis was held together with colleagues from the Centers for Disease Control and Prevention and Public Health Agency of Canada who attended our consortium meeting. Here, we identify priorities for the study of three pathogen groups: arboviruses, lyssaviruses (including rabies), and free living amoebae (FLA) (Table 5).

Table 5.

Emerging Issues in Encephalitis (Selected Agents)

Agent Challenge Recent Progress Recommendations/Future Directions 
Arboviruses    
 Epidemiology: Re-emergence/ resurgence (WNV); Expansion of geographic range (JEV, LACV); Use of spatial and temporal statistics to impute etiologiesa Enhanced surveillance, data mining, and utilization of a wider panel of arbovirus diagnostic assays 
 Epidemiology: Under-recognition of arboviruses as agents of neurologic disease Increased awareness among physicians to include a variety of arboviruses in differential diagnosis Ongoing research to better understand arbovirus pathogenesis, ecology, and the factors contributing to emergence, activity, and outbreaks 
 Prevention: Vaccines unavailable for many arboviruses Some success with vaccination against JEV and TBEV Improved public health messaging regarding personal preventative measures to decrease risk for exposure; increased use of JEV vaccine for prevention in children in risk areas 
  Four WNV vaccines currently in human trialsb Further development of a vaccine for WNV targeted at vulnerable populations 
  Tetravalent dengue vaccine showed modest efficacy; large scale studies are in progressc Further development and validation of dengue vaccine to induce long-term protective immunity against all 4 dengue serotypes simultaneously 
 Treatment: Lack of specific therapeutics Advances in the study of pathogenesis and informed drug design, with several candidate therapeutic platforms being evaluatedd,e More effective bridging of in vitro and animal studies with translational research/clinical trials 
Rabies (Lyssavirus) Epidemiology: Need for enhanced surveillance Recognition of “milder” forms of disease and broader understanding as a continuum Wider inclusion in the differential diagnosis of encephalitis even without a history of animal exposure 
 Prevention: Optimization of prevention programs Experimentation with abbreviated and lower-dose vaccination schedules to lower cost and improve accessibilityf Improved animal control and more widespread vaccination programs towards human rabies prevention and canine rabies elimination 
 Treatment: Lack of specific therapeutics “Milwaukee protocol” reported to show some promise, though subsequent reports inconclusiveg Evaluation of inhibitors of RNA replication, neuroprotectants and better understanding of pathogenesis 
Free living amoebae Epidemiology: Relatively few cases and low level surveillance impedes our understanding of disease Recognition of nasal irrigation for medical or religious purposes as a risk factor for PAMh Serosurveys to define prevalence of disease; more widespread environmental testing to delineate reservoirs of disease 
 Diagnosis: Limited recognition and availability of diagnostic testing Consistent case definitions agreed upon by CDC and Council of State and Territorial Epidemiologists (CSTE) More rapid diagnostics are critical given short therapeutic window 
 Treatment: Lack of widely available and robust treatments Miltefosine treatment for GAEi; Corifungin for FLA in vitroj Further evaluation of miltefosine, corifungin, and other agents in humans 
Agent Challenge Recent Progress Recommendations/Future Directions 
Arboviruses    
 Epidemiology: Re-emergence/ resurgence (WNV); Expansion of geographic range (JEV, LACV); Use of spatial and temporal statistics to impute etiologiesa Enhanced surveillance, data mining, and utilization of a wider panel of arbovirus diagnostic assays 
 Epidemiology: Under-recognition of arboviruses as agents of neurologic disease Increased awareness among physicians to include a variety of arboviruses in differential diagnosis Ongoing research to better understand arbovirus pathogenesis, ecology, and the factors contributing to emergence, activity, and outbreaks 
 Prevention: Vaccines unavailable for many arboviruses Some success with vaccination against JEV and TBEV Improved public health messaging regarding personal preventative measures to decrease risk for exposure; increased use of JEV vaccine for prevention in children in risk areas 
  Four WNV vaccines currently in human trialsb Further development of a vaccine for WNV targeted at vulnerable populations 
  Tetravalent dengue vaccine showed modest efficacy; large scale studies are in progressc Further development and validation of dengue vaccine to induce long-term protective immunity against all 4 dengue serotypes simultaneously 
 Treatment: Lack of specific therapeutics Advances in the study of pathogenesis and informed drug design, with several candidate therapeutic platforms being evaluatedd,e More effective bridging of in vitro and animal studies with translational research/clinical trials 
Rabies (Lyssavirus) Epidemiology: Need for enhanced surveillance Recognition of “milder” forms of disease and broader understanding as a continuum Wider inclusion in the differential diagnosis of encephalitis even without a history of animal exposure 
 Prevention: Optimization of prevention programs Experimentation with abbreviated and lower-dose vaccination schedules to lower cost and improve accessibilityf Improved animal control and more widespread vaccination programs towards human rabies prevention and canine rabies elimination 
 Treatment: Lack of specific therapeutics “Milwaukee protocol” reported to show some promise, though subsequent reports inconclusiveg Evaluation of inhibitors of RNA replication, neuroprotectants and better understanding of pathogenesis 
Free living amoebae Epidemiology: Relatively few cases and low level surveillance impedes our understanding of disease Recognition of nasal irrigation for medical or religious purposes as a risk factor for PAMh Serosurveys to define prevalence of disease; more widespread environmental testing to delineate reservoirs of disease 
 Diagnosis: Limited recognition and availability of diagnostic testing Consistent case definitions agreed upon by CDC and Council of State and Territorial Epidemiologists (CSTE) More rapid diagnostics are critical given short therapeutic window 
 Treatment: Lack of widely available and robust treatments Miltefosine treatment for GAEi; Corifungin for FLA in vitroj Further evaluation of miltefosine, corifungin, and other agents in humans 

Abbreviations: CDC, Centers for Disease Control and Prevention; FLA, free living amoebae; GAE, granulomatous amoebic encephalitis; JEV, Japanese encephalitis virus; LACV, La Crosse Virus; PAM, primary amoebic meningoencephalitis; TBEV, Tick-borne encephalitis virus; WNV, West Nile virus.

a Kulkarni et al., Epidemiology and Infection 2012 (epub ahead of print).

b De Filette et al., Vet Res 2012; 43:16.

c Sabchareon et al. Lancet 2012; 380:1559–67.

d Lee et al., J Gen Virol 2012; 93:20–26.

e Suthar et al., Nat Rev Microbiol 2013; 11:115–28.

f Wieten et al., Clin Infect Dis 2013; 414–19.

g Jackson AC, Antiviral Res 2013 (epub ahead of print).

h Yoder et al. Clin Infect Dis 2012; 55:e79–85.

i Kim et al., Antimicrob Agents Chemother 2008; 52:4010–16.

j Debnath et al. Antimicrob Agents Chemother 2012; 56:5450–57.

Arboviruses

Most arboviruses of medical importance belong to 3 families: Flaviviridae, Togaviridae, and Bunyaviridae [65, 66]. Japanese encephalitis virus (JEV) is the leading cause of mosquito-borne encephalitis globally and continues to expand its range, Tick-borne encephalitis virus (TBEV) is the most common arthropod transmitted viral infection of humans in Europe, and increasing numbers of cases of neuroinvasive disease have been documented in North America involving tick-transmitted Powassan virus [66–69]. West Nile virus (WNV) has re-emerged as an important cause of encephalitis in the United States and Europe, and there has been increasing recognition of dengue (the most common arboviral infection worldwide) and chikungunya viruses as causes of neurological complications [70–74]. La Crosse virus continues to be a leading cause of pediatric encephalitis in the United States, whereas detection of other members of the California serogroup causing severe disease may be hampered by a lack of commercially available diagnostic assays and low level surveillance [75, 76] (Table 5).

Lyssaviruses

Rabies, an acute progressive viral encephalitis with the highest case fatality known for any agent, is caused by viruses in the family Rhabdoviridae, genus Lyssavirus. Although rabies is one of the oldest infectious diseases, and efficacious human and animal vaccines were developed decades ago, the global public health and veterinary burden remains high. Tens of thousands of human deaths, and millions of exposures, occur annually, mostly in developing countries [77]. Reservoirs predominate among the Carnivora and Chiroptera (bats) [78, 79]. Outcome after exposure likely represents a continuum, defined in part by viral type, dose, route, and poorly understood host attributes [80, 81]. The reduction of exposure to rabid animals and postexposure prophylaxis after an animal bite are the 2 most relevant strategies to prevent additional human cases [82–84]. Elimination of canine rabies by mass vaccination, humane population management, and production of more effective, less costly biologics are solutions to reduce the burden [85, 86] (Table 5).

Free Living Amoebae (FLA)

Several FLA, including Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp. cause CNS infections. N. fowleri causes primary amoebic meningoencephalitis (PAM), whereas B. mandrillaris and Acanthamoeba spp. generally cause a more chronic disease, granulomatous amebic encephalitis (GAE). Although case reports of PAM are rare, many additional cases likely go unrecognized, as suggested by the 75% of US PAM cases that are diagnosed postmortem (CDC unpublished data). Prior to 2010, PAM cases were reported only from southern US states. Recently, however, 4 cases were reported from Northern and Midwestern states (CDC unpublished data). Exposure to FLA is believed to be common; a recent serologic investigation showed 3%–4% of individuals with evidence of B. mandrillaris exposure [87]. It remains unclear why some develop disease while the majority of those exposed do not [88]. B. mandrillaris GAE, previously only reported as isolated cases, has recently been diagnosed in multiple organ transplant recipients where the donor was found to have had B. mandrillaris infection, highlighting this organism as a potentially under-recognized cause of fatal encephalitis [89, 90]. Our knowledge of the contribution of FLA to human disease is limited by the lack of consistent surveillance data and a restricted understanding of the ecology of FLA (Table 5).

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online (http://cid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

Notes

Acknowledgments. We thank members of the International Encephalitis Consortium whose discussions informed this article: Heather Sheriff, David Brown, Eileen Farnon, Sharon Messenger, Beverley Paterson, Ariane Soldatos, Sharon Roy, Govinda Visvesvara, Michael Beach, Roger Nasci, Carol Pertowski, Scott Schmid, Lisa Rascoe, Joel Montgomery, Suxiang Tong, Robert Breiman, Richard Franka, Matt Keuhnert, Fred Angulo, and James Cherry. We are grateful to the Seiler family and friends for their generosity, which helped to support the first International Encephalitis Consortium meeting.

Disclaimer. The findings and conclusions in this report are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention, or any other United States Government agency.

Financial support. This work was supported by the Emerging Infectious Diseases Program of the Centers for Disease Control and Prevention U50/CCU915548–03 to C. A. G. and U50/CCU416123 to K. C. B.; French Institute for Public health Surveillance and French infectious Diseases Society (A. M. and J.-P. S.); National Natural Science Foundation of China [8129034] (L. G.-D.); Hunter Medical Research Institute (K. E. and D. D.); National Institutes of Health K08 AI081754 (A. S. L.); Manitoba Health Research Council (M. V. S.); Public Health England (J. G.).

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

1
Tunkel
AR
Glaser
CA
Bloch
KC
, et al.  . 
The management of encephalitis: Clinical practice guidelines by the Infectious Diseases Society of America
Clin Infect Dis
 , 
2008
, vol. 
47
 (pg. 
303
-
27
)
2
Granerod
J
Ambrose
HE
Davies
NW
, et al.  . 
Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study
Lancet Infect Dis
 , 
2010
, vol. 
10
 (pg. 
835
-
44
)
3
Kolski
H
Ford-Jones
EL
Richardson
S
, et al.  . 
Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994–1995
Clin Infect Dis
 , 
1998
, vol. 
26
 (pg. 
398
-
409
)
4
Ball
R
Halsey
N
Braun
MM
, et al.  . 
Development of case definitions for acute encephalopathy, encephalitis, and multiple sclerosis reports to the vaccine: Adverse Event Reporting System
J Clin Epidemiol
 , 
2002
, vol. 
55
 (pg. 
819
-
24
)
5
Glaser
CA
Honarmand
S
Anderson
LJ
, et al.  . 
Beyond viruses: clinical profiles and etiologies associated with encephalitis
Clin Infect Dis
 , 
2006
, vol. 
43
 (pg. 
1565
-
77
)
6
Sejvar
JJ
Kohl
KS
Bilynsky
R
, et al.  . 
Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data
Vaccine
 , 
2007
, vol. 
25
 (pg. 
5771
-
92
)
7
Mailles
A
Stahl
JP
Infectious encephalitis in france in 2007: a national prospective study
Clin Infect Dis
 , 
2009
, vol. 
49
 (pg. 
1838
-
47
)
8
Noah
DL
Bresee
JS
Gorensek
MJ
, et al.  . 
Cluster of five children with acute encephalopathy associated with cat-scratch disease in south Florida
Pediatr Infect Dis J
 , 
1995
, vol. 
14
 (pg. 
866
-
9
)
9
Armengol
CE
Hendley
JO
Cat-scratch disease encephalopathy: a cause of status epilepticus in school-aged children
J Pediatr
 , 
1999
, vol. 
134
 (pg. 
635
-
8
)
10
Easley
RB
Cooperstock
MS
Tobias
JD
Cat-scratch disease causing status epilepticus in children
South Med J
 , 
1999
, vol. 
92
 (pg. 
73
-
6
)
11
Morishima
T
Togashi
T
Yokota
S
, et al.  . 
Encephalitis and encephalopathy associated with an influenza epidemic in Japan
Clin Infect Dis
 , 
2002
, vol. 
35
 (pg. 
512
-
7
)
12
Newland
JG
Romero
JR
Varman
M
, et al.  . 
Encephalitis associated with influenza B virus infection in 2 children and a review of the literature
Clin Infect Dis
 , 
2003
, vol. 
36
 (pg. 
e87
-
95
)
13
Weitkamp
JH
Spring
MD
Brogan
T
Moses
H
Bloch
KC
Wright
PF
Influenza A virus-associated acute necrotizing encephalopathy in the United States
Pediatr Infect Dis J
 , 
2004
, vol. 
23
 (pg. 
259
-
63
)
14
van Zeijl
JH
Bakkers
J
Wilbrink
B
Melchers
WJ
Mullaart
RA
Galama
JM
Influenza-associated encephalopathy: no evidence for neuroinvasion by influenza virus nor for reactivation of human herpesvirus 6 or 7
Clin Infect Dis
 , 
2005
, vol. 
40
 (pg. 
483
-
5
)
15
Bloch
KC
Glaser
C
Diagnostic approaches for patients with suspected encephalitis
Curr Infect Dis Rep
 , 
2007
, vol. 
9
 (pg. 
315
-
22
)
16
Dalmau
J
Lancaster
E
Martinez-Hernandez
E
Rosenfeld
MR
Balice-Gordon
R
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis
Lancet Neurol
 , 
2011
, vol. 
10
 (pg. 
63
-
74
)
17
Gable
MS
Sheriff
H
Dalmau
J
Tilley
DH
Glaser
CA
The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project
Clin Infect Dis
 , 
2012
, vol. 
54
 (pg. 
899
-
904
)
18
Weil
AA
Glaser
CA
Amad
Z
Forghani
B
Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result
Clin Infect Dis
 , 
2002
, vol. 
34
 (pg. 
1154
-
7
)
19
Mook-Kanamori
B
van de Beek
D
Wijdicks
EF
Herpes simplex encephalitis with normal initial cerebrospinal fluid examination
J Am Geriatr Soc
 , 
2009
, vol. 
57
 (pg. 
1514
-
5
)
20
Jakob
NJ
Lenhard
T
Schnitzler
P
, et al.  . 
Herpes simplex virus encephalitis despite normal cell count in the cerebrospinal fluid
Crit Care Med
 , 
2012
, vol. 
40
 (pg. 
1304
-
8
)
21
Elbers
JM
Bitnun
A
Richardson
SE
, et al.  . 
A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease?
Pediatrics
 , 
2007
, vol. 
119
 (pg. 
e399
-
407
)
22
Puchhammer-Stöckl
E
Popow-Kraupp
T
Heinz
FX
Mandl
CW
Kunz
C
Detection of varicella-zoster virus DNA by polymerase chain reaction in the cerebrospinal fluid of patients suffering from neurological complications associated with chicken pox or herpes zoster
J Clin Microbiol
 , 
1991
, vol. 
29
 (pg. 
1513
-
6
)
23
Steiner
I
Budka
H
Chaudhuri
A
, et al.  . 
Viral encephalitis: a review of diagnostic methods and guidelines for management
Eur J Neurol
 , 
2005
, vol. 
12
 (pg. 
331
-
43
)
24
Steiner
I
Budka
H
Chaudhuri
A
, et al.  . 
Viral meningoencephalitis: a review of diagnostic methods and guidelines for management
Eur J Neurol
 , 
2010
, vol. 
17
 (pg. 
999
-
1009
)
25
Kneen
R
Michael
BD
Menson
E
, et al.  . 
Management of suspected viral encephalitis in children—Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group national guidelines
J Infect
 , 
2012
, vol. 
64
 (pg. 
449
-
77
)
26
Solomon
T
Michael
BD
Smith
PE
, et al.  . 
Management of suspected viral encephalitis in adults–Association of British Neurologists and British Infection Association National Guidelines
J Infect
 , 
2012
, vol. 
64
 (pg. 
347
-
73
)
27
de Ory
F
Avellón
A
Echevarría
JE
, et al.  . 
Viral infections of the central nervous system in Spain: A prospective study
J Med Virol
 , 
2013
, vol. 
85
 (pg. 
554
-
62
)
28
Roos
KL
Lumbar puncture
Semin Neurol
 , 
2003
, vol. 
23
 (pg. 
105
-
14
)
29
Rosenfeld
MR
Dalmau
JO
Paraneoplastic disorders of the CNS and autoimmune synaptic encephalitis
Continuum (Minneap Minn)
 , 
2012
, vol. 
18
 (pg. 
366
-
83
)
30
Zuliani
L
Graus
F
Giometto
B
Bien
C
Vincent
A
Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition
J Neurol Neurosurg Psychiatry
 , 
2012
, vol. 
83
 (pg. 
638
-
45
)
31
De Tiège
X
Héron
B
Lebon
P
Ponsot
G
Rozenberg
F
Limits of early diagnosis of herpes simplex encephalitis in children: a retrospective study of 38 cases
Clin Infect Dis
 , 
2003
, vol. 
36
 (pg. 
1335
-
9
)
32
Klapper
PE
Cleator
GM
European guidelines for diagnosis and management of patients with suspected herpes simplex encephalitis
Clin Microbiol Infect
 , 
1998
, vol. 
4
 (pg. 
178
-
80
)
33
Amlie-Lefond
C
Kleinschmidt-DeMasters
BK
Mahalingam
R
Davis
LE
Gilden
DH
The vasculopathy of varicella-zoster virus encephalitis
Ann Neurol
 , 
1995
, vol. 
37
 (pg. 
784
-
90
)
34
Gregoire
SM
van Pesch
V
Goffette
S
Peeters
A
Sindic
CJ
Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with varicella-zoster virus infection of the nervous system
J Neurol Neurosurg Psychiatry
 , 
2006
, vol. 
77
 (pg. 
938
-
42
)
35
De Broucker
T
Mailles
A
Chabrier
S
Morand
P
Stahl
JP
group scai
Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20 patients
Clin Microbiol Infect
 , 
2012
, vol. 
18
 (pg. 
808
-
19
)
36
Gilden
D
Cohrs
RJ
Mahalingam
R
Nagel
MA
Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment
Lancet Neurol
 , 
2009
, vol. 
8
 (pg. 
731
-
40
)
37
Pérez-Vélez
CM
Anderson
MS
Robinson
CC
, et al.  . 
Outbreak of neurologic enterovirus type 71 disease: A diagnostic challenge
Clin Infect Dis
 , 
2007
, vol. 
45
 (pg. 
950
-
7
)
38
Han
J
Ma
XJ
Wan
JF
, et al.  . 
Long persistence of EV71 specific nucleotides in respiratory and feces samples of the patients with Hand-Foot-Mouth Disease after recovery
BMC Infect Dis
 , 
2010
, vol. 
10
 pg. 
178
 
39
Doja
A
Bitnun
A
Jones
EL
, et al.  . 
Pediatric Epstein-Barr Virus-Associated Encephalitis: 10-Year Review
J Child Neurol
 , 
2006
, vol. 
21
 (pg. 
385
-
91
)
40
Tyler
KL
Emerging viral infections of the central nervous system: part 1
Arch Neurol
 , 
2009
, vol. 
66
 (pg. 
939
-
48
)
41
Ward
KN
Leong
HN
Thiruchelvam
AD
Atkinson
CE
Clark
DA
Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis
J Clin Microbiol
 , 
2007
, vol. 
45
 (pg. 
1298
-
304
)
42
Agut
H
Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections
J Clin Virol
 , 
2011
, vol. 
52
 (pg. 
164
-
71
)
43
Lanciotti
RS
Kerst
AJ
Nasci
RS
, et al.  . 
Rapid detection of West Nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a TaqMan reverse transcriptase-PCR assay
J Clin Microbiol
 , 
2000
, vol. 
38
 (pg. 
4066
-
71
)
44
Tardei
G
Ruta
S
Chitu
V
Rossi
C
Tsai
TF
Cernescu
C
Evaluation of immunoglobulin M (IgM) and IgG enzyme immunoassays in serologic diagnosis of West Nile Virus infection
J Clin Microbiol
 , 
2000
, vol. 
38
 (pg. 
2232
-
9
)
45
Davis
LE
DeBiasi
R
Goade
DE
, et al.  . 
West Nile virus neuroinvasive disease
Ann Neurol
 , 
2006
, vol. 
60
 (pg. 
286
-
300
)
46
Kapoor
H
Signs
K
Somsel
P
Downes
FP
Clark
PA
Massey
JP
Persistence of West Nile Virus (WNV) IgM antibodies in cerebrospinal fluid from patients with CNS disease
J Clin Virol
 , 
2004
, vol. 
31
 (pg. 
289
-
91
)
47
Prince
HE
Tobler
LH
Lapé-Nixon
M
Foster
GA
Stramer
SL
Busch
MP
Development and persistence of West Nile virus-specific immunoglobulin M (IgM), IgA, and IgG in viremic blood donors
J Clin Microbiol
 , 
2005
, vol. 
43
 (pg. 
4316
-
20
)
48
Bitnun
A
Ford-Jones
EL
Petric
M
, et al.  . 
Acute childhood encephalitis and Mycoplasma pneumoniae
Clin Infect Dis
 , 
2001
, vol. 
32
 (pg. 
1674
-
84
)
49
Domenech
C
Leveque
N
Lina
B
Najioullah
F
Floret
D
Role of Mycoplasma pneumoniae in pediatric encephalitis
Eur J Clin Microbiol Infect Dis
 , 
2009
, vol. 
28
 (pg. 
91
-
4
)
50
Beersma
MF
Dirven
K
van Dam
AP
Templeton
KE
Claas
EC
Goossens
H
Evaluation of 12 commercial tests and the complement fixation test for Mycoplasma pneumoniae-specific immunoglobulin G (IgG) and IgM antibodies, with PCR used as the “gold standard”
J Clin Microbiol
 , 
2005
, vol. 
43
 (pg. 
2277
-
85
)
51
Bitnun
A
Richardson
SE
Mycoplasma pneumoniae: Innocent Bystander or a True Cause of Central Nervous System Disease?
Curr Infect Dis Rep
 , 
2010
, vol. 
12
 (pg. 
282
-
90
)
52
Irani
SR
Bera
K
Waters
P
, et al.  . 
N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes
Brain
 , 
2010
, vol. 
133
 
Pt 6
(pg. 
1655
-
67
)
53
Dalmau
J
Gleichman
AJ
Hughes
EG
, et al.  . 
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Lancet Neurol
 , 
2008
, vol. 
7
 (pg. 
1091
-
8
)
54
Titulaer
MJ
McCracken
L
Gabilondo
I
, et al.  . 
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study
Lancet Neurol
 , 
2013
, vol. 
12
 (pg. 
157
-
65
)
55
Prüss
H
Finke
C
Höltje
M
, et al.  . 
N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis
Ann Neurol
 , 
2012
, vol. 
72
 (pg. 
902
-
11
)
56
Graus
F
Dalmau
J
Paraneoplastic neurological syndromes
Curr Opin Neurol
 , 
2012
, vol. 
25
 (pg. 
795
-
801
)
57
Chapman
SJ
Hill
AV
Human genetic susceptibility to infectious disease
Nat Rev Genet
 , 
2012
, vol. 
13
 (pg. 
175
-
88
)
58
Reich
DE
Lander
ES
On the allelic spectrum of human disease
Trends Genet
 , 
2001
, vol. 
17
 (pg. 
502
-
10
)
59
Choi
M
Scholl
UI
Ji
W
, et al.  . 
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing
Proc Natl Acad Sci U S A
 , 
2009
, vol. 
106
 (pg. 
19096
-
101
)
60
Ng
SB
Buckingham
KJ
Lee
C
, et al.  . 
Exome sequencing identifies the cause of a Mendelian disorder
Nat Genet
 , 
2010
, vol. 
42
 (pg. 
30
-
5
)
61
McCarthy
MI
Abecasis
GR
Cardon
LR
, et al.  . 
Genome-wide association studies for complex traits: consensus, uncertainty and challenges
Nat Rev Genet
 , 
2008
, vol. 
9
 (pg. 
356
-
69
)
62
Mallal
S
Phillips
E
Carosi
G
, et al.  . 
HLA-B*5701 screening for hypersensitivity to abacavir
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
568
-
79
)
63
Ge
D
Fellay
J
Thompson
AJ
, et al.  . 
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance
Nature
 , 
2009
, vol. 
461
 (pg. 
399
-
401
)
64
Sancho-Shimizu
V
Perez de Diego
R
Jouanguy
E
Zhang
SY
Casanova
JL
Inborn errors of anti-viral interferon immunity in humans
Curr Opin Virol
 , 
2011
, vol. 
1
 (pg. 
487
-
96
)
65
Hollidge
BS
González-Scarano
F
Soldan
SS
Arboviral encephalitides: transmission, emergence, and pathogenesis
J Neuroimmune Pharmacol
 , 
2010
, vol. 
5
 (pg. 
428
-
42
)
66
Weaver
SC
Reisen
WK
Present and future arboviral threats
Antiviral Res
 , 
2010
, vol. 
85
 (pg. 
328
-
45
)
67
Cleton
N
Koopmans
M
Reimerink
J
Godeke
GJ
Reusken
C
Come fly with me: review of clinically important arboviruses for global travelers
J Clin Virol
 , 
2012
, vol. 
55
 (pg. 
191
-
203
)
68
Heinz
FX
Stiasny
K
Holzmann
H
, et al.  . 
Vaccination and tick-borne encephalitis, central Europe
Emerg Infect Dis
 , 
2013
, vol. 
19
 (pg. 
69
-
76
)
69
West Nile virus disease and other arboviral diseases—United States, 2011
MMWR Morb Mortal Wkly Rep
 , 
2012
, vol. 
61
 (pg. 
510
-
4
Centers for Disease Control and Prevention
70
Arnold
C
West Nile virus bites back
Lancet Neurol
 , 
2012
, vol. 
11
 (pg. 
1023
-
4
)
71
Barzon
L
Pacenti
M
Franchin
E
, et al.  . 
Clinical and virological findings in the ongoing outbreak of West Nile virus Livenza strain in northern Italy, July to September 2012
Euro Surveill
 , 
2012
, vol. 
17
 pg. 
20260
 
72
Petersen
LR
Fischer
M
Unpredictable and difficult to control–the adolescence of West Nile virus
N Engl J Med
 , 
2012
, vol. 
367
 (pg. 
1281
-
4
)
73
Public Health Agency of Canada: West Nile Virus MONITOR
 
74
Bhatt
S
Gething
PW
Brady
OJ
, et al.  . 
The global distribution and burden of dengue
Nature
 , 
2013
, vol. 
496
 (pg. 
504
-
7
)
75
Haddow
AD
Odoi
A
The incidence risk, clustering, and clinical presentation of La Crosse virus infections in the eastern United States, 2003–2007
PLoS One
 , 
2009
, vol. 
4
 pg. 
e6145
 
76
Human Jamestown canyon virus infection—Montana, 2009
MMWR Morb Mortal Wkly Rep.
 , 
2011
, vol. 
60
 (pg. 
652
-
5
Centers for Disease Control and Prevention
77
Suraweera
W
Morris
SK
Kumar
R
, et al.  . 
Deaths from symptomatically identifiable furious rabies in India: a nationally representative mortality survey
PLoS Negl Trop Dis
 , 
2012
, vol. 
6
 pg. 
e1847
 
78
Rupprecht
CE
Turmelle
A
Kuzmin
IV
A perspective on lyssavirus emergence and perpetuation
Curr Opin Virol
 , 
2011
, vol. 
1
 (pg. 
662
-
70
)
79
Kuzmin
IV
Shi
M
Orciari
LA
, et al.  . 
Molecular inferences suggest multiple host shifts of rabies viruses from bats to mesocarnivores in Arizona during 2001–2009
PLoS Pathog
 , 
2012
, vol. 
8
 pg. 
e1002786
 
80
Feder
HM
Petersen
BW
Robertson
KL
Rupprecht
CE
Rabies: still a uniformly fatal disease? Historical occurrence, epidemiological trends, and paradigm shifts
Curr Infect Dis Rep
 , 
2012
, vol. 
14
 (pg. 
408
-
22
)
81
Gilbert
AT
Petersen
BW
Recuenco
S
, et al.  . 
Evidence of rabies virus exposure among humans in the Peruvian Amazon
Am J Trop Med Hyg
 , 
2012
, vol. 
87
 (pg. 
206
-
15
)
82
National Association of State Public Health Veterinarians Ic. Compendium of animal rabies prevention and control, 2011
MMWR Recomm Rep
 , 
2011
, vol. 
60
 
RR-6
(pg. 
1
-
17
)
83
Rupprecht
CE
Briggs
D
Brown
CM
, et al.  . 
Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices
MMWR Recomm Rep
 , 
2010
, vol. 
59
 
RR-2
(pg. 
1
-
9
)
84
Wilde
H
Wacharapluesadee
S
Hemachudha
T
Currently approved post-exposure rabies prophylaxis regimens
Travel Med Infect Dis
 , 
2012
, vol. 
10
 (pg. 
162
-
3
)
85
Lembo
T
Prevention
PFR
The blueprint for rabies prevention and control: a novel operational toolkit for rabies elimination
PLoS Negl Trop Dis
 , 
2012
, vol. 
6
 pg. 
e1388
 
86
Wu
X
Smith
TG
Rupprecht
CE
From brain passage to cell adaptation: the road of human rabies vaccine development
Expert Rev Vaccines
 , 
2011
, vol. 
10
 (pg. 
1597
-
608
)
87
Jackson
BR
Kucerova
Z
Aguirre
G
, et al.  . 
Serologic survey of exposure following fatal Balamuthia madrillaris infection—Southern Arizona, 2010
2012
 
88
Schuster
FL
Yagi
S
Gavali
S
, et al.  . 
Under the radar: Balamuthia amoebic encephalitis
Clin Infect Dis
 , 
2009
, vol. 
48
 (pg. 
879
-
87
)
89
Prevention CfDCa
Notes from the field: transplant-transmitted Balamuthia mandrillaris—Arizona, 2010
MMWR Morb Mortal Wkly Rep
 , 
2010
, vol. 
59
 pg. 
1182
 
90
Centers for Disease C, Prevention
Balamuthia mandrillaris transmitted through organ transplantation—Mississippi, 2009
MMWR Morb Mortal Wkly Rep
 , 
2010
, vol. 
59
 (pg. 
1165
-
70
)

Comments

0 Comments