Acute viral encephalitis in children: Clinical

manifestations and diagnosis

Author:
Hordur S Hardarson, MD
Section Editors:
Sheldon L Kaplan, MD
Gary R Fleisher, MD
Douglas R Nordli, Jr, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2019. | This topic last updated: Nov 13, 2018.

INTRODUCTION Encephalitis is inflammation of the brain

parenchyma, manifest by neurologic dysfunction (eg, altered mental status,

behavior, or personality; motor or sensory deficits; speech or movement
disorders; seizure) [1].

The clinical manifestations and diagnosis of viral encephalitis in children will be

discussed here. The pathogenesis, etiology, treatment, and prevention of viral
encephalitis in children are discussed separately. (See "Acute viral encephalitis
in children: Pathogenesis, incidence, and etiology" and "Acute viral encephalitis
in children: Treatment and prevention".)

TERMINOLOGY Central nervous system (CNS) infections are

described according to the site of infection:

●Encephalitis – Encephalitis is inflammation of the brain parenchyma and
is associated with neurologic dysfunction. Characteristic clinical features
include altered mental status (decreased level of consciousness, lethargy,
personality change, unusual behavior), seizures, and/or focal neurologic
signs, often accompanied by fever, headache, nausea, and vomiting [2].
(See 'Clinical features' below.)
●Meningitis – Meningitis is inflammation of the meninges and is typically
manifested by fever, headache, nausea, vomiting, photophobia, and stiff
neck. (See "Viral meningitis: Clinical features and diagnosis in children",
section on 'Clinical features'.)
●Rhombencephalitis – Rhombencephalitis, or brainstem encephalitis, is
characterized by myoclonic jerks, tremor, ataxia, cranial nerve involvement,
respiratory abnormalities, shock, and coma.
●Myelitis – Myelitis is inflammation of the spinal cord and is characterized
by weakness, bladder dysfunction, flaccid paralysis, and reduced or absent
reflexes. (See "Disorders affecting the spinal cord", section on 'Acute viral
myelitis'.)
 ●Radiculitis – Radiculitis is inflammation of the nerve roots and is
characterized by weakness, shooting pain, dysesthesia, and diminished
reflexes.

Some viruses cause less discrete manifestations CNS infection and are
described with broader terms:

●Meningoencephalitis – Meningoencephalitis refers to CNS infection

manifesting signs and symptoms consistent with inflammation of the
meninges and brain parenchyma.
●Encephalomyelitis – Encephalomyelitis refers to CNS infection
manifesting signs and symptoms consistent with inflammation of the brain
parenchyma and spinal cord.

Abnormal brain function distinguishes encephalitis from meningitis. The

distinction between these entities is frequently blurred; however, it is important
to try to distinguish between them because the likely causes differ somewhat
(table 1).

●Encephalopathy – Encephalopathy is a disruption of brain function in the

absence of a direct inflammatory process in brain parenchyma (eg, caused
by metabolic disturbance, hypoxia, ischemia, drugs, intoxications, organ
dysfunction, systemic infection) [3]. (See "Acute toxic-metabolic
encephalopathy in children" and "Clinical features, diagnosis, and
treatment of neonatal encephalopathy".)

CLINICAL FEATURES Encephalitis causes neurologic dysfunction

and has a broad range of presenting symptoms and signs. The clinical
manifestations vary depending upon the viral agent, the affected region(s) of the
brain, the age of the patient, and the patient’s immune status [1].

Neonates and young infants — As with other infections in neonates (0 to 28

days) and young infants, the presentation of encephalitis can be nonspecific.
Encephalitis should be considered in a neonate or young infant who has fever,
seizure, poor feeding, irritability, or lethargy. Decreased perfusion may occur in
infants with encephalitis and concomitant disseminated viral infection (eg,
herpes simplex virus [HSV]). Fever is a variable finding. Neonates who have
viral illness, especially HSV and enterovirus, are at risk for severe central
nervous system and systemic illness. (See "Neonatal herpes simplex virus
infection: Clinical features and diagnosis", section on 'Clinical
manifestations' and "Enterovirus and parechovirus infections: Clinical features,
laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

Children and adolescents — In older children and adolescents, encephalitis

can present with fever, psychiatric symptoms, emotional lability, movement
disorder, ataxia, seizures, stupor, lethargy, coma, or localized neurologic
changes (eg, hemiparesis, cranial nerve defect) [4,5]. In severe cases, status
epilepticus, cerebral edema, inappropriate secretion of antidiuretic hormone
(SIADH), and/or cardiorespiratory failure may occur.
In a prospective series of 50 children (6 weeks to 18 years of age) with
encephalitis, the following manifestations were present at the time of admission
[6]:

●Fever (80 percent)

●Seizure (78 percent; 79 percent of these were focal)
●Other focal neurologic signs (56 percent)
●Decreased consciousness (47 percent)

EVALUATION

Overview — Encephalitis is an acute, life-threatening emergency, and a

systematic approach is necessary for prompt recognition and appropriate
management (table 2). The goals of the evaluation are to define the clinical
syndrome (eg, acute encephalitis, postinfectious encephalitis, autoimmune
encephalitis, meningitis, toxic or metabolic encephalopathy) and to identify a
specific etiology [3]. Some of the causes of encephalitis and encephalopathy
require specific therapy (table 3 and table 4). In addition, identification of a
specific etiology may be useful for prognosis, potential prophylaxis, and public
health interventions [3]. (See "Acute viral encephalitis in children: Treatment
and prevention", section on 'Empiric therapy'.)

The evaluation of encephalitis requires a rapid, comprehensive, and systematic

approach. Early identification of the underlying cause can be crucial for patient
management and prognosis. The approach outlined below is generally
consistent with the diagnostic algorithm suggested by the International
Encephalitis Consortium [2].

The initial step in the evaluation of the child with altered brain function begins
with assessment of the airway, breathing, and circulation. The first priorities are
stabilization of cardiorespiratory status and management of seizures.
(See "Initial assessment and stabilization of children with respiratory or
circulatory compromise" and "Management of convulsive status epilepticus in
children", section on 'Initial treatment'.)

After the child is stabilized, a thorough history, physical examination, initial

laboratory tests, lumbar puncture, and neuroimaging are performed [3].
Electroencephalography (EEG) should be performed as soon as is feasible. In
cases with a clinically suspected focal lesion of the central nervous system
(CNS), neuroimaging should be performed before lumbar puncture (LP) if time
allows. Epidemiologic and historical clues (table 5 and table 6), physical
examination findings (table 7), and data from the initial laboratory and imaging
tests may help direct additional evaluation and/or therapy.

History — The history may provide clues to a particular viral etiology (table
5 and table 6). When evaluating a patient with suspected encephalitis, it is
important to ask specific questions regarding travel and exposures (eg, animals,
insects, toxins, etc), particularly within the two to three weeks before onset.
Immunizations and immune status should also be reviewed [1,3]. (See "Viral
encephalitis in adults", section on 'Historical clues'.)
Physical examination — The physical examination should include careful
neurologic evaluation for focal findings. Neurologic evaluation should include
assessment of the mental status and motor, sensory, cranial nerve, cerebellar,
and reflex function. The Glasgow coma scale (GCS) score (table 8), although
not validated in patients with nontraumatic brain injury, can be helpful in
quantifying the level of consciousness and monitoring neurologic progression.
(See "Detailed neurologic assessment of infants and children".)

Examination findings may suggest a possible etiologic agent (table 7).

Examples include:

●Vesicular rash in neonates with CNS herpes simplex virus (HSV) disease
(picture 1A-C) (see "Neonatal herpes simplex virus infection: Clinical
features and diagnosis", section on 'Neonatal HSV')
●Maculopapular rash in West Nile virus (WNV) disease (picture 2)
(see "Clinical manifestations and diagnosis of West Nile virus infection",
section on 'Clinical manifestations')
●Characteristic lesions of hand, foot, and mouth disease (coxsackieviruses
A and B) (picture 3A-D) (see "Hand, foot, and mouth disease and
herpangina")
●The rash of Rocky Mountain spotted fever (picture 4), which typically does
not appear until several days after the onset of fever (see "Clinical
manifestations and diagnosis of Rocky Mountain spotted fever")

Laboratory evaluation — Laboratory studies are performed to support the

clinical diagnosis of encephalitis and establish an etiology (table 3), to assess
for other conditions in the differential diagnosis (table 4), and to look for
potential complications (eg, inappropriate antidiuretic hormone secretion
[SIADH]).

Routine blood tests — Laboratory tests that should be routinely performed in

all patients with suspected encephalitis include (table 9):

●Complete blood count with differential count and platelets

●Serum electrolytes, glucose, blood urea nitrogen, and creatinine
●Serum aminotransferases (alanine aminotransferase, aspartate
aminotransferase)
●Coagulation studies

Laboratory findings that may provide clues to the etiology include the following
[3]:

●Neutropenia – Colorado tick fever, ehrlichiosis, neonatal HSV, measles,

rickettsiae, rubella
●Thrombocytopenia – Ehrlichiosis, rickettsiae, neonatal HSV [7]
●Eosinophilia – Toxocara, Trichinella, and other parasites
●Hyponatremia/SIADH – Rickettsiae, Eastern equine encephalitis virus, St.
Louis encephalitis virus, HSV, M. tuberculosis

CSF analysis — LP should be performed in all patients with suspected

encephalitis unless there are contraindications (eg, coagulopathy, mass lesion)
[4]. In most cases, neuroimaging is required before LP to exclude
contraindications (mass lesion, midline shift). (See 'Neuroimaging' below.)

Samples of CSF should be sent for cell count and differential, glucose, protein,
Gram stain, bacterial culture, HSV polymerase chain reaction (PCR), and
enterovirus PCR; additional tests should be done as indicated by epidemiology
and clinical findings [3,5]. (See 'Identifying the specific pathogen' below.)

The CSF indices in viral encephalitis are similar to those in viral meningitis and
meningoencephalitis and may overlap with those of bacterial meningitis (table
10). Characteristic findings include:

●CSF pleocytosis – CSF pleocytosis is present in approximately 60 percent

of children with encephalitis [6,8,9]. The CSF white blood cell (WBC) count
typically ranges from 0 to 500 cells/microL with a lymphocytic
predominance; however, a predominance of neutrophils can be seen
during the first 24 to 48 hours of infection. The absence of pleocytosis does
not exclude encephalitis, particularly early in the course and in immune
compromised patients [10-12].
●Red blood cells (RBCs) – RBCs are usually absent (except in traumatic
tap), but their presence can indicate HSV encephalitis, La Crosse virus
encephalitis, or other necrotizing encephalitides (eg, Eastern equine
encephalitis, amebic encephalitis) [13,14]. (See "Herpes simplex virus type
1 encephalitis", section on 'Laboratory abnormalities' and "Free-living
amebas and Prototheca", section on 'Clinical manifestations'.)
●Protein – CSF protein may be normal or moderately elevated (generally
<150 mg/dL).
●Glucose – Glucose is usually normal and >50 percent of blood value.
Moderate reduction in glucose can be seen with HSV and mumps; marked
depression, often <10 mg/dL, occurs with tuberculous meningitis.

In 3 to 5 percent of patients with encephalitis, CSF findings are completely

normal [15].

In a study of >1500 cases of encephalitis, there was a wide range of CSF WBC
counts and protein levels [16]. Patients with infectious encephalitis had
significantly higher CSF WBC compared with patients with noninfectious
encephalitis (median CSF WBC 53.5 versus 9.5 cells/microL), but the difference
in protein levels was not significant (median level 71 versus 67 mg/dL). Among
patients with viral encephalitis, 83 percent had CSF WBC count
≥6 cells/microL, and 32 percent had protein levels ≤45 mg/dL.

Evaluation for other causes of encephalopathy — Additional testing is

performed to exclude other causes of encephalopathy (eg, bacterial sepsis or
meningitis, metabolic disorders, drugs and toxins, autoimmune encephalitis).
This includes (see 'Differential diagnosis' below):

●Blood culture
●CSF Gram stain, acid fast stain, and culture
●Urine and serum toxicology screening (see "Approach to the child with
occult toxic exposure")
 ●Metabolic studies (serum ammonia, lactate, and blood pH) (see "Inborn
errors of metabolism: Identifying the specific disorder")
●Anti-N-methyl-D-aspartate receptor (NMDAR) and anti-voltage-gated
potassium channel (VGKC) antibodies if clinically indicated
(see "Paraneoplastic and autoimmune encephalitis")

Identifying the specific pathogen — Testing for specific pathogens is directed

by the clinical findings, the initial laboratory findings, and other epidemiologic
circumstances (eg, time of year, geographic locale, exposures).

●CSF studies – Tests of the CSF that can help to establish an infectious
etiology for encephalitis include PCR and antibody testing [3]:
•Multiplex PCR testing – Multiplex or panel-based nucleic acid
amplification tests are now available that test for multiple bacterial and
viral pathogens simultaneously in a single CSF sample (eg,
FilmArray meningitis/encephalitis panel [BioFire]) [17-19]. Where
available, these tests can be helpful in evaluating a child with
suspected encephalitis. The FilmArray panel targets 14 pathogens:
cytomegalovirus (CMV), enterovirus, HSV 1 and 2, human herpesvirus
6 (HHV-6), human parechovirus, varicella-zoster virus
(VZV), Escherichia coli K1, Haemophilus
influenzae, Listeriamonocytogenes, Neisseria
meningitidis, Streptococcus agalactiae, Streptococcus
pneumoniae, Cryptococcus neoformans, and Cryptococcus
gattii [20].Multiplex PCR tests are highly sensitive and specific, though
false-positive and false-negative results can occur. If a multiplex panel
is performed, it should be used in conjunction with standard
microbiologic tests (eg, cultures of CSF and blood). Multiplex panels
do not detect all causes of CNS infection, nor do they provide any
information on antimicrobial susceptibility.
•Individual PCR tests – If multiplex testing is not available, enterovirus
and HSV CSF PCR testing should be performed [3]. These tests are
helpful when positive, but negative tests do not necessarily exclude the
pathogen. CSF enterovirus PCR does not permit identification of the
enterovirus serotype. Enterovirus 71, an important cause of
encephalitis in young children, is rarely detected by CSF PCR.
•CSF antibody testing – The detection of virus-specific immunoglobulin
(Ig)M in the CSF usually indicates CNS disease because IgM
antibodies do not readily cross the blood-brain barrier.
•Viral culture – CSF viral cultures are not routinely recommended
[3,21].
●Testing of sites outside the CNS – When the pathogen is identified from
an anatomic site other than the CNS (eg, respiratory tract, skin, stool), the
results must be interpreted in conjunction with epidemiologic and clinical
findings, and other diagnostic studies (table 5 and table 6 and table 7) [3].
The isolated pathogen may play a role in the CNS manifestations, but not
necessarily by direct invasion, or may be present but unrelated to
encephalitis (eg, hepatitis C, rotavirus, Mycoplasma pneumoniae) [3].
● Antibody titers – Acute and convalescent antibody titers may be helpful if
cultures and PCR have not established a diagnosis and the patient remains
ill. Detection of antibodies in acute serum may be helpful in identifying
 some pathogens (arboviruses, HIV, rabies) and may be used as evidence
of causation if the infection is rare or highly fatal (eg, rabies, Eastern equine
encephalitis) [3,5,22].
●Brain biopsy – Brain biopsy is rarely indicated in children with suspected
encephalitis. It can be considered if the etiology remains uncertain after
extensive noninvasive testing in a patient with a severe and/or progressive
disease course despite empiric therapy [3].

It may be helpful to freeze samples of CSF and serum to allow for further testing
later if the diagnosis is not reached initially.

The diagnostic approach for specific pathogens is as follows:

●Enteroviruses – Enteroviral CNS infections are diagnosed by detection of

the virus in the CSF using PCR. Throat and rectal swabs can also be
tested with PCR. In a child with clinical findings consistent with
encephalitis, detection of enterovirus in a non-CSF sample suggests
enterovirus as the etiology, though it is not definitive. (See "Enterovirus and
parechovirus infections: Clinical features, laboratory diagnosis, treatment,
and prevention", section on 'Laboratory diagnosis'.)
●HSV – HSV encephalitis is diagnosed by detection of the virus in the CSF
using PCR. HSV surface cultures and/or direct immunofluorescence assay
(DFA) of skin lesions (if present) can also help in making the diagnosis.
(See "Neonatal herpes simplex virus infection: Clinical features and
diagnosis", section on 'Detection of HSV' and "PCR testing for the
diagnosis of herpes simplex virus in patients with encephalitis or
meningitis".)
●Other herpesviruses (including HHV-6, CMV, VZV, Epstein-Barr virus
[EBV]) – These can be diagnosed with CSF PCR testing. In the case of
VZV, DFA of skin lesions (if present) may be helpful. Note that positive
EBV, CMV, VZV, and HHV-6 CSF PCR does not absolutely indicate CNS
infection because latently infected leukocytes in the CSF can cause a false-
positive result [2,3]. Positive herpesviruses PCR in CSF should be followed
by confirmatory testing. For EBV, CMV, and VZV, this involves measuring
serum antibody titers; for HHV-6, measuring quantitative DNA PCR in
whole blood to exclude HHV-6 chromosomal integration [2,23].
●Arboviruses (LaCrosse virus, West Nile virus, St. Louis encephalitis virus,
Eastern and Western equine encephalitis virus, Japanese encephalitis
virus) – These are diagnosed with appropriate serology and PCR testing.
(See "Arthropod-borne encephalitides".)
●Respiratory viruses (including influenza, adenovirus, human
metapneumovirus, and respiratory syncytial virus) – These can be
identified with respiratory viral panel (PCR) and viral culture of
respiratory secretions/nasopharynx; however, positive results do not
necessarily indicate direct CNS infection.
●HIV. (See "Diagnostic testing for HIV infection in infants and children
younger than 18 months" and "Screening and diagnostic testing for HIV
infection".)
●Nonviral pathogens – Appropriate testing is discussed in separate topic
reviews:
 •M. pneumoniae (see "Mycoplasma pneumoniae infection in children",
section on 'Diagnosis')
•L. monocytogenes (see "Clinical manifestations and diagnosis of
Listeria monocytogenes infection", section on 'Diagnosis')
•Mycobacterium tuberculosis (see "Central nervous system
tuberculosis", section on 'Diagnosis')
•Bartonella henselae (cat scratch disease) (see "Microbiology,
epidemiology, clinical manifestations, and diagnosis of cat scratch
disease", section on 'Diagnostic tests')
•Borrelia burgdorferi (Lyme disease) (see "Nervous system Lyme
disease", section on 'Diagnosis')
•Rickettsia rickettsii (Rocky Mountain spotted fever) (see "Clinical
manifestations and diagnosis of Rocky Mountain spotted fever",
section on 'Diagnosis')

Evaluation for additional pathogens may be warranted in immunocompromised

patients (table 9).

The United States Centers for Disease Control and Prevention (CDC) should be
notified when certain pathogens are isolated from patients in the United States.
An updated list of these pathogens is available at the CDC website.

Neuroimaging — Patients with suspected encephalitis should undergo

neuroimaging [2-5]. Neuroimaging abnormalities are seen in 60 to 70 percent of
patients with encephalitis; findings are present at the time of presentation in 30
to 50 percent [6,24]. Findings may include brain edema and inflammation of the
cerebral cortex, gray-white matter junction, thalamus, or basal ganglia [5,25].
Meningeal enhancement may be seen in children with meningoencephalitis.
Children with HSV encephalitis may have hemorrhagic findings [26-28].

Magnetic resonance imaging (MRI) is the neuroimaging modality of choice

because it is more sensitive and specific for encephalitis than is computed
tomography (CT). In one study, 30 percent of patients with normal initial CT
were subsequently found to have abnormalities on MRI [24]. If MRI is
unavailable or is not feasible, CT, with and without contrast enhancement, is an
acceptable alternative, particularly in the initial evaluation [3]. In practical terms,
because CT is often more readily available in the acute care setting than is MRI,
and because it is faster and generally does not
require sedation/anesthesia, many children undergo initial evaluation with CT
before LP to exclude contraindications (eg, mass lesion, midline shift) and then
subsequently undergo MRI. (See 'CSF analysis' above.)

In addition to standard T1- and T2-weighted images, diffusion-weighted imaging

(DWI) appears to increase the sensitivity of MRI, particularly early in the course
[29-32]. On rare occasions, findings on MRI may lead to presumptive diagnosis
of HSV encephalitis despite an initial negative CSF HSV PCR [10].

MRI findings vary somewhat depending on the viral etiology. However, with the
exception of temporal lobe localization in HSV encephalitis, most findings are
not highly sensitive or specific for a particular pathogen. Typical findings include
[3,5,16,25]:
 ●HSV – Temporal lobe localization (image 1); temporal localization also
may occur with other herpes viruses and syphilis (see "Neonatal herpes
simplex virus infection: Clinical features and diagnosis", section on 'Brain
imaging' and "Herpes simplex virus type 1 encephalitis", section on
'Imaging studies').
●Flavivirus, Eastern equine encephalitis virus – Lesions in the thalamus,
basal ganglia, and midbrain that are of mixed intensity or hypodense on T1
and hyperdense on T2 and fluid-attenuated inversion recovery (FLAIR)
images (see "Arthropod-borne encephalitides").
●Enterovirus 71 encephalitis – Hyperintense T2 and FLAIR lesions in the
midbrain, pons, and medulla (see "Enterovirus and parechovirus infections:
Clinical features, laboratory diagnosis, treatment, and prevention").
●Respiratory virus encephalitis (eg, influenza, parainfluenza, adenovirus,
respiratory syncytial virus) – Abnormalities in the thalamus or basal ganglia
(see "Seasonal influenza in children: Clinical features and diagnosis").

Neuroimaging also may detect other conditions that are in the differential
diagnosis (table 4) (see 'Differential diagnosis' below):

●Postinfectious encephalitis (acute disseminated encephalomyelitis

[ADEM]) – Deep and subcortical white matter lesions are typically multiple
and bilateral but may be asymmetric (image 2). Brainstem and spinal cord
abnormalities are common. Gray matter lesions may be observed in the
thalami and basal ganglia. (See "Acute disseminated encephalomyelitis in
children: Pathogenesis, clinical features, and diagnosis".)
●Head trauma or intracranial hemorrhage – In most cases, CT is the
preferred imaging modality for the initial evaluation of suspected head
trauma or intracranial hemorrhage (image 3). (See "Severe traumatic brain
injury in children: Initial evaluation and management", section on
'Imaging' and "Hemorrhagic stroke in children", section on 'Urgent
neuroimaging'.)
●CNS tumor. (See "Clinical manifestations and diagnosis of central nervous
system tumors in children", section on 'Neuroimaging'.)
●Congenital infection (eg, toxoplasmosis, CMV) – Intracranial calcifications
(better detected with CT) (image 4). (See "Overview of TORCH infections".)
●Balamuthia mandrillaris – Space-occupying lesions or unifocal or
multifocal ring-enhancing lesions (image 5). (See "Free-living amebas and
Prototheca", section on 'Balamuthia mandrillaris'.)

Electroencephalogram — Patients with suspected encephalitis should

undergo EEG as soon as is feasible. For practical reasons, the EEG is typically
performed after the initial evaluation in the emergency department or other
acute care settings [3].

EEG may help to differentiate encephalitis from nonconvulsive seizure activity

(ie partial complex seizures, absence seizures). Continuous EEG may be
helpful in documenting or excluding seizures, nonconvulsive seizure activity,
and seizure-mimic if routine EEG is negative or inconclusive [33]. (See "Clinical
features and complications of status epilepticus in children".)
EEG is abnormal in 87 to 96 percent of children with encephalitis; most findings
are nonspecific [6,8,34]. EEG findings range from generalized slowing to
patterns characteristic of specific etiologies (eg, the temporal focus
of Herpesviridae encephalitis) [2,16,35]. (See "Herpes simplex virus type 1
encephalitis", section on 'Electroencephalogram (EEG)' and "Measles: Clinical
manifestations, diagnosis, treatment, and prevention", section on 'Subacute
sclerosing panencephalitis'.)

DIAGNOSIS Encephalitis is largely a clinical diagnosis based upon the

following criteria [2]:

●Altered mental status (ie, decreased or altered level of consciousness,
lethargy, or personality change) lasting ≥24 hours with no alternative cause
identified, plus
●≥2 of the following for a "possible" diagnosis or ≥3 of the following for a
"probable" diagnosis:
•Documented fever ≥38°C (100.4°F) within 72 hours (before or after)
presentation
•Generalized or partial seizures not fully attributable to preexisting
seizure disorder
•New onset focal neurologic findings
•CSF WBC count ≥5 cells/microL
•Abnormality of brain parenchyma on neuroimaging suggestive of
encephalitis that is new or appears to have acute onset
(see 'Neuroimaging' above)
•Abnormality on EEG that is consistent with encephalitis and not
attributable to another cause (see 'Electroencephalogram' above)

Identification of a pathogen known to cause encephalitis confirms the clinical

diagnosis of viral encephalitis; however, it is important to recognize that in the
majority of cases, a specific etiology is not identified despite extensive testing
[2]. In these cases, a presumptive diagnosis is made on the basis of the clinical
findings and exclusion of other causes of encephalopathy. (See 'Identifying the
specific pathogen' above and 'Differential diagnosis' below and "Acute viral
encephalitis in children: Pathogenesis, incidence, and etiology", section on
'Etiology'.)

DIFFERENTIAL DIAGNOSIS There are numerous mimics of viral

encephalitis (table 4). Many of these conditions require specific therapy, and
prompt initiation of therapy may improve outcome. Information from the history,
examination, laboratory, and radiologic evaluation can help distinguish between
viral encephalitis and other conditions in the differential diagnosis.
(See 'Evaluation' above.)

Other infections — Bacterial, parasitic, fungal, and rickettsial infections of the

central nervous system (CNS) can mimic viral encephalitis (table 3). These
infections usually are diagnosed through culture, serology, nucleic acid
amplification tests (eg, polymerase chain reaction [PCR]), examination of blood
smears, and other microbiologic methods [3]. (See 'Laboratory
evaluation' above.)
●Bacterial meningitis – The clinical manifestations and cerebrospinal fluid
(CSF) indices of bacterial meningitis and viral encephalitis may overlap
(table 10). In such cases, the diagnosis of bacterial meningitis is confirmed
by identification of a bacterial pathogen from the CSF (by culture or other
diagnostic techniques) or isolation of bacteria from the blood in a patient
with CSF pleocytosis. (See "Bacterial meningitis in children older than one
month: Clinical features and diagnosis", section on 'Diagnosis'.)
●CNS tuberculosis – Mycobacterium tuberculosis can present with
encephalitis and can have CSF findings similar to those in patients with
viral encephalitis [16]. An extremely low glucose (<10 mg/dL) and elevated
protein (>200 mg/dL) are characteristic of tuberculous meningitis and occur
rarely with viral encephalitis. Tuberculin skin testing is indicated but can be
nonreactive in up to 40 percent of cases; chest radiographs are normal in
one-half of cases. When tuberculosis is diagnosed in children, it is
important to identify the source of the infection through contact
investigation. (See "Central nervous system
tuberculosis" and "Tuberculosis disease in children".)
●Free-living amebae – Primary amebic meningoencephalitis caused
by Naegleria fowleri and granulomatous amebic meningoencephalitis
caused by Acanthamoeba spp. or Balamuthia mandrillaris are CNS
infections caused by free-living amebae. These infections are rare and
almost always fatal. Of six cases reported in the United States in 2007, all
had exposure to recreational freshwater from July to September, and all
died [36]. Balamuthia mandrillaris encephalitis was diagnosed in 10
patients (five children) among 3500 cases referred to the California
Encephalitis Project (1999 to 2008); all but one patient were of Hispanic
ethnicity, five had a history of contact with soil, nine patients died, and one
was lost to follow-up [37]. Diagnosis was made by polymerase chain
reaction (PCR) for Balamuthia mitochondrial 16S rRNA gene DNA on brain
tissue, other tissue, and/or CSF. (See "Free-living amebas and
Prototheca".)

Postinfectious — Postinfectious encephalitis (ie, acute disseminated

encephalomyelitis [ADEM]), is a monophasic illness that is thought to be an
autoimmune response to a preceding antigenic challenge (eg, a febrile illness or
immunization) [3]. Associated preceding illnesses may include measles,
mumps, rubella, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus,
herpes simplex virus, hepatitis A virus, influenza, and enterovirus. Associated
immunizations may include anthrax, influenza, Japanese encephalitis virus,
measles, rabies, smallpox, and yellow fever.

The onset of postinfectious encephalitis is usually subacute and fever is

typically absent at the time of neurologic manifestations. However, it can be
difficult to distinguish postinfectious from acute encephalitis clinically.
Characteristic magnetic resonance imaging findings of postinfectious
encephalitis include multifocal white-matter lesions. (See "Acute disseminated
encephalomyelitis in children: Pathogenesis, clinical features, and diagnosis".)
Autoimmune encephalitis — Autoimmune encephalitis (including anti-N-
methyl-D-aspartate receptor [NMDAR] and voltage-gated potassium channel
antibodies [VGKC Ab]) are increasingly recognized as causes of encephalitis in
children [34,38-41]. (See "Paraneoplastic and autoimmune encephalitis".)

In a retrospective single-center cohort of 164 children with acute encephalitis,

autoimmune encephalitis was the identified etiology in 13 percent and was the
second most common cause of noninfectious encephalitis (after ADEM) [34].

Anti-NMDAR encephalitis should be considered in children and adolescents

who present with psychiatric symptoms, abnormal movements, seizure,
autonomic instability, and hypoventilation [40,41]. It is important to identify anti-
NMDAR encephalitis because it may be associated with tumors (eg, ovarian
teratomas) and often responds to specific therapeutic interventions.
(See "Paraneoplastic and autoimmune encephalitis", section on 'Anti-NMDA
receptor encephalitis'.)

Toxic-metabolic encephalopathy — Encephalitis must be differentiated from

encephalopathy caused by metabolic disorders, drugs, and toxins (table
4 and table 11). These disorders can usually be distinguished from viral
encephalitis by the lack of acute febrile illness, more gradual onset, lack of CSF
pleocytosis, absence of focal changes on brain imaging, and presence in some
cases of abnormal laboratory findings (eg, electrolyte abnormalities,
hypoglycemia, acidosis, hyperammonemia, elevated blood lead level, positive
toxicology screen). (See "Acute toxic-metabolic encephalopathy in children".)

Intracranial pathology — Brain abscess and other noninfectious intracranial

pathology, such as tumor, intracranial bleed, or thrombosis usually can be
differentiated from encephalitis through neuroimaging. (See "Clinical
manifestations and diagnosis of central nervous system tumors in
children" and "Intracranial epidural hematoma in children: Clinical features,
diagnosis, and management" and "Cerebral venous thrombosis: Etiology,
clinical features, and diagnosis".)

SOCIETY GUIDELINE LINKS Links to society and government-

sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Infectious encephalitis".)

INFORMATION FOR PATIENTS UpToDate offers two types of

patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are
best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or email these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
"patient education" and the keyword[s] of interest.)

●Basics topics (see "Patient education: Encephalitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Encephalitis causes neurologic dysfunction and has a broad range of

presenting symptoms and signs. The clinical manifestations vary
depending upon the viral agent, the affected region(s) of the brain, the age
of the patient, and the patient’s immune status. (See 'Clinical
features' above.)
●In neonates and young infants, encephalitis can present with fever,
seizure, poor feeding, irritability, or lethargy; decreased perfusion may
occur in infants with encephalitis and concomitant disseminated viral
infection. Fever is a variable finding. (See 'Neonates and young
infants' above.)
●In older children and adolescents, encephalitis can present with fever,
psychiatric symptoms, emotional lability, movement disorder, ataxia,
seizures, stupor, lethargy, coma, or localized neurologic changes.
(See 'Children and adolescents' above.)
●The evaluation of the child with suspected encephalitis begins with
assessment of the airway, breathing, and circulation. The first priorities are
stabilization of cardiorespiratory status and management of seizures (table
2). (See "Initial assessment and stabilization of children with respiratory or
circulatory compromise" and "Management of convulsive status epilepticus
in children", section on 'Initial treatment'.)
●After the child is stabilized, the evaluation includes:
•History and physical examination (table 5 and table 6 and table 7)
(see 'History' above and 'Physical examination'above).
•Initial laboratory tests (table 9) (see 'Laboratory evaluation' above).
•Neuroimaging (magnetic resonance imaging [MRI] is the modality of
choice) (see 'Neuroimaging' above).
•Electroencephalography (EEG) (see 'Electroencephalogram' above).
●The goals of the evaluation are to define the clinical syndrome (eg, acute
encephalitis, postinfectious encephalitis, autoimmune encephalitis,
meningitis, toxic or metabolic encephalopathy, etc) and to identify a specific
etiology (table 3 and table 4). It is particularly important to consider
etiologies that require specific therapy. (See 'Overview' above.)
●A clinical diagnosis of encephalitis can be made based on the following
criteria (see 'Diagnosis' above):
•Altered mental status (ie, decreased or altered level of
consciousness, lethargy, or personality change) lasting ≥24 hours with
no alternative cause identified, plus
 •≥2 of the following for a "possible" diagnosis or ≥3 of the following for
a "probable" diagnosis:
-Documented fever ≥38°C (100.4°F) within 72 hours (before or
after) presentation
-Generalized or partial seizures not fully attributable to preexisting
seizure disorder
-New onset focal neurologic findings
-Cerebrospinal fluid pleocytosis (≥5 white blood cells/microL)
-Abnormality of brain parenchyma on neuroimaging suggestive of
encephalitis that is new or appears to have acute onset
-Abnormality on EEG that is consistent with encephalitis and not
attributable to another cause
●Testing for specific pathogens is directed by the clinical findings, the initial
laboratory findings, and other epidemiologic circumstances (eg, time of
year, geographic locale, exposures). The causative pathogen may be
identified through testing of the cerebrospinal fluid (eg, polymerase chain
reaction and/or immunoglobulin M antibodies), serologic
testing, and/or testing of anatomic sites other than the central nervous
system (eg, respiratory tract, skin, stool). Identification of a pathogen
known to cause encephalitis confirms the clinical diagnosis of viral
encephalitis; however, in the majority of cases, no specific etiology is
identified. (See 'Identifying the specific pathogen' above and "Acute viral
encephalitis in children: Pathogenesis, incidence, and etiology", section on
'Etiology'.)
●The differential diagnosis of encephalitis is broad (table 4). It may be
narrowed through history, examination, laboratory, and radiologic
evaluation. Autoimmune encephalitis is an increasingly identified
noninfectious etiology. (See 'Differential diagnosis' above
and "Paraneoplastic and autoimmune encephalitis".)
Use of UpToDate is subject to the Subscription and License Agreement.

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