Acute viral encephalitis in children: Clinical manifestations and diagnosis

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) and evidence of central nervous system inflammation (eg, cerebrospinal fluid pleocytosis and/or findings consistent with encephalitis on neuroimaging or electroencephalogram).

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, epidemiology, 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 defined as inflammation of the brain parenchyma and is manifested by signs of neurologic dysfunction. Characteristic clinical features include altered mental status (decreased level of consciousness, lethargy, personality change, unusual behavior) lasting at least 24 hours, seizures, and/or focal neurologic signs, often accompanied by fever, headache, nausea, and vomiting [1]. (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 in children: Clinical features and diagnosis", 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, paralysis, bowel and/or bladder dysfunction, and changes in tone and 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 as both may be present concurrently; however, it is important to try to determine the presence of encephalitis because the likely causes may 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). This is discussed separately.

CLINICAL FEATURES — By definition, encephalitis is manifested by signs of neurologic dysfunction, which can be variable. Common presenting symptoms and signs include [2,3]:

●Fever (75 to 80 percent)

●Seizures (50 to 75 percent)

●Irritability or unusual behavior (55 percent)

●Focal neurologic signs (eg, cranial nerve palsies, abnormal movements, weakness; 50 to 60 percent)

●Decreased consciousness (45 to 55 percent)

Clinical manifestations may vary depending upon the patient's age and immune status, causative virus, and affected region(s) of the brain [3,4].

●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], enteroviruses, and parechoviruses). Fever is a variable finding. Neonates who have viral illness, especially HSV and enterovirus, are at risk for severe central nervous system (CNS) 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, paresis, cranial nerve defect) [5,6]. In severe cases, status epilepticus, cerebral edema, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and/or cardiorespiratory failure may occur.

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 [7]. Identification of a specific etiology can inform treatment decisions (table 3 and table 4) and may be useful for prognosis, potential prophylaxis, and public health interventions [7]. (See "Acute viral encephalitis in children: Treatment and prevention", section on 'Empiric antimicrobial therapy'.)

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 [1].

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 'Emergency antiseizure treatment'.)

After the child is stabilized, a thorough history, physical examination, initial laboratory tests, lumbar puncture (LP), and neuroimaging are performed [7]. 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 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, as summarized in the tables (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, water, toxins, etc), particularly within the two to three weeks before onset. Immunizations and immune status should also be reviewed [4,7].

Physical examination

●Neurologic examination – A careful neurologic examination should be performed, including the following (see "Detailed neurologic assessment of infants and children"):

•Mental status examination

•Assessment of the motor, sensory, cranial nerve, cerebellar, and reflex function

•Fundoscopic examination

•Glasgow coma scale score (table 8), which quantifies the level of consciousness and can be used to monitor neurologic progression, although it has not specifically been validated in patients with encephalitis

●Skin examination – Dermatologic findings may point to a specific etiology (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 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 (enteroviruses, especially EV-A71, CVA16, and CVA6) (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), assess for other conditions in the differential diagnosis (table 4), and look for potential complications (eg, syndrome of 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

●Liver function tests (alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin)

●Coagulation studies

Laboratory findings that may provide clues to the etiology include the following [7]:

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

●Thrombocytopenia – Ehrlichiosis, rickettsiae, neonatal HSV [8]

●Eosinophilia – Toxocara, Trichinella, and other parasites

●Hyponatremia/SIADH – Rickettsiae, Eastern equine encephalitis virus, St. Louis encephalitis virus, HSV, Mycobacterium tuberculosis

Cerebrospinal fluid analysis — LP should be performed in all patients with suspected encephalitis unless there are contraindications (eg, coagulopathy, suspected or known mass lesion) [5]. If there are signs of impending herniation (asymmetric pupils, severe obtundation, decorticate or decerebrate posturing, Cheyne-Stokes breathing), neuroimaging is required before LP to exclude contraindications (mass lesion, midline shift). (See 'Neuroimaging' below.)

Samples of cerebrospinal fluid (CSF) should be sent for cell count and differential, glucose, protein, Gram stain, bacterial culture, HSV polymerase chain reaction (PCR), parechovirus PCR, and enterovirus PCR; additional tests should be done as indicated by epidemiology and clinical findings [6,7]. (See 'Identifying the viral pathogen' below.)

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

●CSF pleocytosis – CSF pleocytosis is present in 60 to 80 percent of children with encephalitis [3,9-11]. 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, and a normal CSF WBC count can be seen early in the course and in infants with encephalitis, particularly with parechovirus and enterovirus infections [12,13]. In addition, immune-compromised patients may not mount a CSF pleocytosis [14,15].

●Red blood cells – Red blood cells are usually absent (except in traumatic tap). The presence of RBCs in a nontraumatic tap is more indicative of the disease process (hemorrhagic or necrotizing encephalitis) rather than a specific etiology per se. Infectious etiologies that may present with hemorrhagic or necrotizing encephalitis include HSV, La Crosse virus, Eastern equine encephalitis, and amebic encephalitis; however, there is considerable variation in the presentation of these encephalitides [16,17]. (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 (ie, >50 percent of blood glucose value). Moderate reduction in glucose can be seen with HSV and mumps; marked hypoglycorrhachia (ie, CSF glucose <10 mg/dL) can be seen in bacterial meningitis, including tuberculous (TB), but is only rarely reported with viral infections of the CNS.

In approximately 10 to 15 percent of cases, initial CSF findings are normal [3,9,11,18].

In a study of >1500 cases of encephalitis, there was a wide range of CSF WBC counts and protein levels [11]. Patients with infectious encephalitis had higher CSF WBC compared with patients with noninfectious encephalitis (median CSF WBC 54 versus 10 cells/microL), but protein levels were similar (median level 71 versus 67 mg/dL). Among patients with viral encephalitis, 83 percent had CSF pleocytosis (defined as WBC count ≥6 cells/microL) and 68 percent had elevated CSF protein (defined as protein level >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), voltage-gated potassium channel (VGKC), and antimyelin oligodendrocyte glycoprotein (MOG) antibodies, if clinically indicated (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Antibody testing')

Identifying the viral pathogen — Testing for specific pathogens is directed by the clinical findings, 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 [7]:

•Multiplex PCR testing – Multiplex 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]) [19-21]. Where available, these PCR panels can be helpful in evaluating a child with suspected encephalitis. The FilmArray panel targets 14 pathogens: cytomegalovirus (CMV), enteroviruses, HSV 1 and 2, human herpesvirus 6 (HHV-6), parechoviruses, varicella-zoster virus (VZV), Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, and Cryptococcus [22].

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.

Multiplex PCR testing is less sensitive for HSV-1 and HSV-2 than standard HSV PCR assays, and, therefore, it may be necessary to test specifically for HSV when clinical suspicion for HSV infection is high [20]. If HSV infection is suspected in an infant <6 weeks old, other specimens in addition to CSF should be tested (eg, surface cultures and blood or plasma HSV PCR). The evaluation of suspected neonatal HSV infection is discussed separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

•Individual PCR tests – If multiplex testing is not available, enterovirus, parechovirus, and HSV CSF PCR testing should be performed [7]. 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 A71, an important cause of encephalitis in young children, is rarely detected by CSF PCR.

•CSF antibody testing – The detection of virus-specific immunoglobulin M (IgM) 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 [7,23].

●Testing of sites outside of 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) [7]. The pathogen detected may play a role in the CNS manifestations (but not necessarily by direct invasion) or may be present but unrelated to encephalitis (eg, rhinoviruses in nasal secretions, Epstein-Barr virus [EBV], or Mycoplasma pneumoniae DNA detected in throat swabs) [7].

●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) [6,7,24]. The presence of antibodies to an enterovirus or parechovirus at a single time point does not provide sufficient proof of recent infection.

●Brain biopsy – Brain biopsy 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 [7].

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

Approach for specific pathogens — 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. This is particularly true of rectal swabs and fecal specimens since fecal shedding often continues for many weeks after an asymptomatic infection. (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. If clinical suspicion for HSV encephalitis is high and initial CSF HSV PCR performed early in the course is negative, testing can be repeated (ie, with repeat LP) three to seven days later [7]. (See "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis".)

If HSV infection is suspected in an infant <6 weeks old, other specimens in addition to CSF should be tested (eg, surface cultures and blood or plasma HSV PCR). The evaluation of suspected neonatal HSV infection is discussed separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

●Other herpesviruses (including HHV-6, CMV, VZV, EBV) – These can be diagnosed with CSF PCR testing. In the case of VZV, direct immunofluorescence assay of skin lesions (if present) may be helpful. Note that for EBV, CMV, VZV, and HHV-6, detection of the DNA in the CSF by PCR does not absolutely indicate CNS infection, because latently infected cells, chromosomal integration, or shedding of DNA into the CSF can cause a clinical false-positive result [1,7]. Positive herpesvirus PCRs 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) [1,25].

●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

•M. tuberculosis (see "Central nervous system tuberculosis: An overview")

•Bartonella henselae (cat scratch disease) (see "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Diagnostic tests')

•Borrelia burgdorferi and other Borrelia species (Lyme disease) (see "Nervous system Lyme disease", section on 'Evaluation')

•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. The list of notifiable conditions is available on the CDC website.

Neuroimaging — All patients with suspected encephalitis should undergo neuroimaging [1,5-7].

●Timing – If there are signs of impending herniation (asymmetric pupils, severe obtundation, decorticate or decerebrate posturing, Cheyne-Stokes breathing), neuroimaging should be performed urgently before performing lumbar puncture. Computed tomography [CT] is typically performed as the initial study in this setting because it is faster and generally does not require sedation/anesthesia. Children with encephalitis who undergo initial imaging with CT should subsequently have magnetic resonance imaging (MRI) performed, as discussed below.

For children without clinical concern for impending herniation, MRI can be performed after completing the initial evaluation.

●Preferred modality – MRI is the neuroimaging modality of choice because it is more sensitive and specific for encephalitis than is CT. In one study, 30 percent of patients with normal initial CT were subsequently found to have abnormalities on MRI [26]. If timely MRI is unavailable or not feasible, CT (with and without contrast enhancement) is an acceptable alternative, particularly in the initial evaluation [7]. (See 'Cerebrospinal fluid analysis' above.)

In addition to standard T1- and T2-weighted images, diffusion-weighted imaging appears to increase the sensitivity of MRI, particularly early in the course [27-30]. On rare occasions, findings on MRI may lead to presumptive diagnosis of HSV encephalitis despite an initial negative CSF HSV PCR [14].

●MRI findings – Abnormal neuroradiologic findings are seen in 60 to 70 percent of patients with encephalitis; findings are present at the time of presentation in 30 to 50 percent [2,26]. Findings may include brain edema and inflammation of the cerebral cortex, gray-white matter junction, thalamus, or basal ganglia [6,31]. Meningeal enhancement may be seen in children with meningoencephalitis. Children with HSV encephalitis may have hemorrhagic findings [32-34].

•Findings according to viral etiology – 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 [6,7,11,31]:

-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'.)

-West Nile virus and 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 images. (See "Arthropod-borne encephalitides".)

-Enterovirus A71 encephalitis – Hyperintense T2 and fluid-attenuated inversion recovery 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".)

•Findings that suggest a nonviral etiology – Neuroimaging also may detect other conditions that are in the differential diagnosis (table 4) (see 'Differential diagnosis' below):

-Acute disseminated encephalomyelitis – 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 (ADEM) 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 (TBI) 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 and Acanthamoeba species – Space-occupying lesions or unifocal or multifocal ring-enhancing lesions are seen with these amoebae (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 [7].

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 [35]. (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 [2,9,36]. EEG findings range from generalized slowing to patterns characteristic of specific etiologies (eg, lateralized periodic discharges or temporal focus of Herpesviridae encephalitis) [1,11,37]. (See "Herpes simplex virus type 1 encephalitis", section on 'Electroencephalogram' 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 [1]:

●Altered mental status (ie, decreased or altered level of consciousness, lethargy, or personality/behavior 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 (CSF) white blood cell (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 electroencephalography (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 most cases, a specific etiology is not identified despite extensive testing [1]. 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 viral pathogen' above and 'Differential diagnosis' below and "Acute viral encephalitis in children: Pathogenesis, epidemiology, 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.)

In a prospective multicenter study of 526 children ≤14 years old who underwent evaluation for suspected encephalitis from 2013 to 2016, 45 percent of patients were ultimately diagnosed with other conditions [3]. The most common alternate diagnoses were bacterial or viral meningitis. Other diagnoses included tuberculous (TB) meningitis, disseminated neonatal herpes simplex virus (HSV), acute cerebellar ataxia, stroke, structural brain disease, epilepsy, genetic/metabolic disorders, Guillain-Barre syndrome, psychiatric disorders, medication side effect/overdose, and other miscellaneous forms of encephalopathy.

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 [7]. (See 'Laboratory evaluation' above.)

●Bacterial meningitis – The clinical manifestations and cerebrospinal fluid (CSF) indices of bacterial meningitis and viral encephalitis may overlap in some cases (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'.)

●TB meningitis – CNS infection with M. tuberculosis can present with similar findings and can have CSF findings similar to viral encephalitis [11]. TB meningitis should be suspected in patients with relevant epidemiologic factors (history of prior TB infection or disease, known or possible TB exposure, and/or past or present residence in or travel to an area where TB is endemic). In addition, extremely low glucose (<10 mg/dL) and elevated protein (>200 mg/dL) are characteristic of TB meningitis and rarely occur with viral encephalitis. The diagnosis of TB meningitis is discussed separately. (See "Tuberculous meningitis: Clinical manifestations and diagnosis" and "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis".)

●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. (See "Free-living amebas and Prototheca".)

Autoimmune and postinfectious causes

●Autoimmune encephalitis – Autoimmune encephalitis due to antibodies against neuronal proteins (eg, N-methyl-D-aspartate receptor [NMDAR], voltage-gated potassium channel [VGKC], myelin oligodendrocyte glycoprotein [MOG], and others) are increasingly recognized as causes of encephalitis in children (table 11) [36,38-41]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

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 acute disseminated encephalomyelitis) [36].

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 "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-NMDA receptor encephalitis'.)

●Acute disseminated encephalomyelitis (ADEM) – ADEM (also known as postinfectious encephalitis) is a monophasic illness that is thought to be an autoimmune response to a preceding antigenic challenge (eg, a febrile illness or immunization) in genetically susceptible individuals [7]. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

The diagnosis of ADEM should be suspected in a child who develops multifocal neurologic abnormalities with encephalopathy. Characteristic MRI findings of ADEM include multifocal white matter lesions; brainstem and spinal cord abnormalities are common. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Neuroimaging'.)

Anti-MOG antibodies can be identified in a large subset of patients with ADEM [42]. Thus, all children with suspected ADEM should have testing performed to detect anti-MOG antibodies in the serum and CSF. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Serum autoantibodies'.)

Toxic-metabolic encephalopathy — Encephalitis must be differentiated from encephalopathy caused by metabolic disorders, drugs, and toxins (table 4 and table 12). 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 tests). (See "Acute toxic-metabolic encephalopathy in children".)

Intracranial pathology — Brain abscess and other noninfectious intracranial pathology, such as tumor, intracranial hemorrhage, 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" 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".)

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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

●Presentation – Encephalitis causes neurologic dysfunction and has a broad range of presenting symptoms and signs. Clinical manifestations may vary depending upon the patient's age and immune status, causative virus, and affected region(s) of the brain. (See 'Clinical features' above.)

•Neonates and young infants – 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.

•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.

●Evaluation – 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 'Emergency antiseizure 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.)

●Clinical diagnosis – 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 (CSF) pleocytosis (≥5 white blood cells [WBCs]/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

●Identifying the pathogen – Testing for specific pathogens is directed by the clinical findings, initial laboratory findings, and other epidemiologic circumstances (eg, time of year, geographic locale, exposures). The causative pathogen may be identified through testing of the CSF (eg, polymerase chain reaction [PCR] and/or CSF immunoglobulin M [IgM] antibodies), serologic testing, and/or testing of anatomic sites other than the central nervous system (CNS; eg, respiratory tract, skin, stool). Identification of a pathogen known to cause encephalitis confirms the clinical diagnosis of viral encephalitis; however, in many cases, no specific etiology is identified. (See 'Identifying the viral pathogen' above and "Acute viral encephalitis in children: Pathogenesis, epidemiology, and etiology", section on 'Etiology'.)

●Differential diagnosis – The differential diagnosis of encephalitis is broad and includes other infections (eg, bacterial, mycobacterial, parasitic, fungal, and rickettsial), postinfectious or autoimmune encephalitis, toxic-metabolic encephalopathy, or other intracranial pathology (eg, abscess, tumor, hemorrhage) (table 4). The diagnostic considerations are narrowed through history, examination, laboratory evaluation, and neuroimaging. Autoimmune encephalitis is an increasingly identified noninfectious etiology. (See 'Differential diagnosis' above and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Krogstad, MD, who contributed to earlier versions of this topic review.