ARTICLE

Encephalitis in Previously
Healthy Children
Claire E. Fraley, MD,* David R. Pettersson, MD,† Dawn Nolt, MD, MPH‡
*Department of Pediatrics,
†
Department of Diagnostic Radiology,
‡
Division of Pediatric Infectious Diseases, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR

PRACTICE GAP

Children experience a variety of outcomes after encephalitis, with 42% of all

patients having incomplete neurologic and functional recovery. The most
common pediatric encephalitides are reviewed herein, including key
components of their diagnostic evaluation, appropriate empirical
treatments, and anticipated long-term sequelae.

OBJECTIVES After completing this article, readers should be able to:

1. Recognize the most common infectious and autoimmune pediatric

encephalitides.
2. Describe an initial approach to a diagnostic evaluation when there is clinical
concern for encephalitis, including laboratory data and imaging.
3. Understand agents used in empirical antimicrobial treatment and
immunomodulating therapy for infectious and autoimmune
encephalitides, respectively.
4. Appreciate the variable long-term outcomes seen in encephalitis.

ABSTRACT
AUTHOR DISCLOSURE Drs Fraley,
Pettersson, and Nolt have disclosed no
financial relationships relevant to this Encephalitis is defined as altered mental status for more than 24 hours
article. This commentary does not contain a accompanied by 2 or more findings concerning for inflammation of the brain
discussion of an unapproved/investigative
parenchyma: fever, seizures or other focal neurologic disorders, cerebrospinal
use of a commercial product/device.
fluid pleocytosis, and abnormal neuroimaging and electroencephalographic
ABBREVIATIONS findings. Herpes simplex virus causes the most severe form of virus-induced
CSF cerebrospinal fluid encephalitis; the early administration of acyclovir can improve the prognosis of
EEG electroencephalogram
this disease. The rising interest in autoimmune causes of encephalitis, most
EV enterovirus
FDA Food and Drug Administration
notably anti–N-methyl-D-aspartate receptor, should prompt the clinician to
HSV herpes simplex virus consider immunomodulatory treatments, which may improve outcomes. A
IVIG intravenous immunoglobulin broad testing panel may be necessary to detect the etiologic agent; a few
MRI magnetic resonance imaging published pediatric cases suggest that infectious and autoimmune causes
NGS next-generation sequencing may occur concurrently in the same patient with encephalitis. More than 40%
NMDAR N-methyl-D-aspartate receptor
of children diagnosed as having encephalitis will not return to their previous
PCR polymerase chain reaction
WNV West Nile virus level of neurologic function after resolution of their disease, although out-
comes are highly variable depending on the etiologic agent.

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DEFINITION AND PATHOPHYSIOLOGY SPECIFIC ETIOLOGIES
Encephalitis is defined as inflammation of the brain with Herpes Simplex Virus
resultant neurologic dysfunction, often a consequence of HSV should be considered in all children suspected of
direct infection (eg, virus) or a noninfectious process (eg, an having encephalitis given the severe morbidity associated
autoimmune cause). (1)(2) A consensus statement by the with delayed or incorrect treatment of this potentially dev-
International Encephalitis Consortium outlines diagnostic astating viral encephalitis. (1) It is among the most common
criteria for possible and probable/confirmed encephalitis. (2) infectious causes of pediatric encephalitis in the postvaccine
A requirement for this disease is altered mental status for era, (3) although exact numbers are unclear given that it is not
>24 hours without an alternative diagnosis. Additional cri- a nationally reportable infection. Beyond the neonatal period,
teria to support the diagnosis of encephalitis include 2 or the serotype is almost exclusively HSV-1. Pediatric HSV
more of the following: fever (>100°F [>38°C]) within 72 encephalitis may be a manifestation of either primary disease
hours, seizures (new onset or different than preexisting (when virus from an actively shedding individual contacts the
seizure history), new focal neurologic findings, cerebro- oral mucosa or abraded skin of the child) or reactivation
spinal fluid (CSF) pleocytosis (white blood cell count, >5/mL (when the virus emerges from latency in the trigeminal
[>0.01×109/L]), abnormal neuroimaging findings consis- ganglia). The virus has a predilection for the temporal lobes
tent with encephalitis, and/or abnormal electroencepha- of the brain, as found on brain imaging or EEG monitoring.
logram (EEG) readings consistent with encephalitis. (2) Given its sporadic nature, there is no seasonality to HSV
Pediatric encephalitides can be categorized as infectious encephalitis.
or autoimmune. Historically, infectious agents accounted for
most documented etiologies of encephalitis. Before the use Enterovirus
of vaccines, measles, mumps, varicella, and polio were EV is among the top causes of encephalitis in children, most
among the top causes. With the widespread use of vacci- frequently occurring in the first year of life. (11) Incidence
nations, other viral etiologies, such as herpes simplex virus rates are difficult to elicit, again (similar to HSV) because EV
(HSV) and enterovirus (EV), rose to the top of the infectious is not nationally reportable. EV is spread through fecal-oral
etiologies. (3)(4) The pathophysiology of infectious enceph- and respiratory transmission, and subsequent replication
alitis is usually by hematogenous spread of the pathogen into and viremia then seed end organs such as the central nervous
the CSF after systemic infection. (5) system. Seasonality does factor into diagnostic suspicion,
Autoimmune encephalitides are recently described medical given that EV incidence peaks in the summer and fall.
phenomena. Their pathogenesis is attributed to the body’s
immune response to a preceding antigenic stimulus. (1) The West Nile Virus
prototype of these diseases is anti–N-methyl-D-aspartate re- West Nile virus (WNV) is the most common arbovirus in
ceptor (NMDAR) encephalitis. Anti-NMDAR arises when a North America causing neuroinvasive disease (including
patient develops antibodies against the NR1 subunit of the encephalitis). It is so named due to being first discovered in
NMDAR. Increased interest in autoimmune encephalitis has the West Nile area of Uganda in 1937. Analysis of all cases
driven the discovery of other antibodies that may be attributed of WNV-associated neuroinvasive disease shows that less
as possible causative agents for encephalitis. than 4% involve children younger than 18 years, (12) but
The incidence of pediatric encephalitis is unclear given sheer overall numbers of WNV in the population-at-large
the diverse etiologies, inconsistent definitions of encepha- still renders a high case number of pediatric WNV infec-
litis, and denominator populations across studies. Recent tions annually. Encephalitis composes approximately half
reports note that cases of pediatric encephalitis may be in- of all pediatric WNV neuroinvasive disease. (13) Compared
creasing, (6) due in part to recognition of autoimmune with other arboviruses, WNV does not have a clear geo-
etiologies of these causes (1)(7)(8)(9)(10) and improvements graphic specificity, having been reported throughout the
in describing abnormalities in brain parenchyma through United States (except Hawaii and Alaska). WNV is trans-
the use of magnetic resonance imaging (MRI). A large mitted through the bite of infected Culex mosquitos.
proportion (ie, up to 30%) have an undiagnosed etiology. (8) Seasonality is important in diagnostic suspicion given that
This review focuses on encephalitis in the healthy, immu- summer is the major time for its responsible mosquito
nocompetent pediatric patient. vector.

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 La Crosse Virus infectious etiologies. Interestingly, infection itself can be a risk
La Crosse virus is the second most common arbovirus to factor for autoimmune encephalitis because up to 20% of pa-
cause neuroinvasive disease in North America, and it is so tients with HSV develop anti-NMDAR antibodies. (20) There are
named due to it being first discovered and isolated from a 2 published cases of children with anti-NMDAR encephalitis
child who died from fatal meningoencephalitis in La Crosse, attributed as a complication from active HSV and tuberculosis
Wisconsin. Although sheer numbers from the general disease (each with 1 patient). (21)
population lag behind WNV, 88% of all encephalitis attrib- Congenital immune-mediated encephalitis may be of
uted to La Crosse virus occurs in children younger than 18 particular interest to pediatricians. Several publications have
years. (13) There is a clear geographic specificity, with most described cases of infants developing signs from transpla-
cases originating from the Appalachian and Midwestern cental transfer of autoantibodies from both symptomatic and
region of the United States. (13)(14)(15) La Crosse virus is asymptomatic mothers. (22) These signs may include neu-
transmitted through the bite of infected Aedes mosquitos. rologic manifestations, poor feeding, poor respiratory effort,
Similar to WNV, there is a seasonality (late spring through and lethargy at birth. Duration of illness is usually transient
early fall) to this viral disease given its arboviral vector. because the antibodies are eliminated by the infant, although
at least 1 fatality has occurred in a symptomatic infant. (22)
Zika Virus
Zika virus is so named due to discovery of this virus in the PRESENTATION
Zika forest of Uganda in 1947. This pathogen has captured
There is considerable overlap in symptoms between in-
the attention of clinicians due to its causation of infant
fectious and autoimmune encephalitis. As mentioned
microcephaly and neurologic deficits after prenatal exposure.
earlier, altered mental status for longer than 24 hours is
However, children (older than 1 month) may also acquire
necessary. A variety of accompanying clinical features in-
Zika virus encephalitis. Transmission occurs from the bite of
clude fever (67%–80%), seizure (33%–78%), headache
infected Aedes mosquitoes (Aedes aegypti and less commonly
(43%), weakness or pyramidal signs (36%–78%), agitation
Aedes albopictus). The major risk factor is residence in or
(34%), or decreased consciousness (47%). (8)(23) Viral
travel to areas in which these mosquitoes are present and
encephalitis is more likely to cause fever compared with
there are identified ongoing outbreaks. The seasonality of
autoimmune encephalitis. The presentation for autoim-
Zika virus should place it in the differential of a patient with
mune encephalitis tends to be more chronic, with delayed
encephalitis presenting in the summer and early fall.
diagnosis up to several weeks. (5)
Although neurologic deficits are part of the classical
AUTOIMMUNE ENCEPHALITIS presentation, physical examination findings other than those
involving the central nervous system should be sought be-
Autoimmune encephalitis is a collective term for a variety of
cause other findings potentially provide diagnostic clues for
diseases that occur when there is an aberrant response of the
infectious causes. For example, cutaneous lesions involving
immune system against neuronal cells. These diseases may
the hands, feet, and mouth may suggest EV infection,
be organized roughly into 4 groups: those that are neurologic
whereas vesicular lesions on an erythematous base may
manifestations of systemic autoimmune diseases (such as
suggest HSV or varicella as an etiology. (7)
systemic lupus erythematosus), those that are paraneoplastic
manifestations of primary cancers, those with antibodies
against intracellular proteins, and those with antibodies DIAGNOSTIC TESTING
against cell surface proteins (such as anti-NMDAR). (16) The In considering infectious etiologies, a careful history of
oncologic association with the latter 2 autoimmune groups is signs, symptoms, and epidemiologic risk factors is of utmost
not entirely correlated, although anti-NMDAR encephalitis importance to narrow the differential diagnosis. Important
was first described in association with ovarian teratomas in items to identify include geographic areas of travel or resi-
young women. (17)(18) Case numbers of autoimmune en- dence, recreational and occupational exposures, insect or
cephalitis may, ultimately, if not already, outnumber those of animal contact (such as ticks or mosquitoes), and seasonality.
viral encephalitides. At minimum, the incidence of NMDAR Autoimmune encephalitides should be considered in a pa-
encephalitis seems to exceed the rate for a single viral eti- tient who presents with mood, behavior, or personality
ology in pediatric patients in the United States. (19) changes that resemble acute psychosis.
Autoimmune causes of encephalitides have less clear epi- Diagnostic evaluation of a child with suspected encephalitis
demiologic patterns and identifiable risk factors compared with always includes CSF studies, which may be accompanied by

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serum serological testing and neuroimaging. The Table guides For arboviral diagnosis, the clinician needs to rely on virus-
the clinician to organize testing in a tiered manner, focusing specific immunoglobulin M antibodies in the CSF because
on treatable or common conditions, followed by other tests if there is usually no PCR method for common arboviruses. (13)
the patient does not improve and initial testing is unrevealing A promising addition to diagnostic testing for encepha-
for the etiologic agent. These latter tests should be prioritized litis is metagenomic next-generation sequencing (NGS) of
by risk factors (eg, patient age, seasonality of presentation, CSF. A published study of 204 patients (~20% being <18
arbovirus exposure, geography and travel history, and non- years of age) showed that in 58 cases of meningitis and
adherence to the childhood vaccine schedule). encephalitis attributed to infectious etiologies, 22% (n = 13)
In encephalitis, CSF studies often reflect a lymphocytic were detected solely by NGS. (26) Of those detected by NGS
pleocytosis with elevated protein levels and normal glucose alone, 7 of these results guided clinical management. Further
levels. (5)(6) Autoimmune encephalitis tends to have a lower refinement to address concerns about false-negative results, as
level of CSF pleocytosis, (24) followed by higher levels in in- well as optimal timing and appropriate patients for testing, are
fectious encephalitis. HSV encephalitis was historically reported needed before Food and Drug Administration (FDA) approval
to have elevated levels of red blood cells given the hemorrhagic and widespread commercial use. (26)
nature of brain parenchymal lesions; hemorrhagic fluid has When autoimmune encephalitis is suspected, autoanti-
become rare, however, given that diagnosis is made earlier and, bodies in the serum and CSF are sought through indirect
hence, the intracranial lesions have not evolved to the point of immunofluorescence assay and confirmatory Western blot
hemorrhaging. (25) If hemorrhagic fluid is found, it is generally analysis. These tests are available in reference laboratories,
attributed to the lumbar puncture technique. usually as part of a panel for autoimmune testing. Autoim-
Evaluation of any case of pediatric encephalitis should mune evaluation is usually conducted simultaneously with an
include polymerase chain reaction (PCR) of the CSF against infectious evaluation, in the event that any identified infec-
HSV, given the availability of treatment to ameliorate the tions may have a treatment that, when implemented, may
poor prognosis. PCR has become the gold standard to di- speed the recovery of the autoimmune disease.
agnose HSV and EV. Targeted PCR can be developed at MRI of the brain with and without intravenous contrast is
individual institutions rather than using commercially the first-line imaging test for pediatric patients presenting
available PCR kits that involve sending samples to outside with suspected intracranial infection. This test is designated
laboratories, which would prolong the time to results. Al- as “usually appropriate” according to the American College
though “homegrown” PCR testing offers the advantages of of Radiology Appropriateness Criteria® imaging guidelines.
low cost or rapid turnaround time, providers should un- (27) For pediatric patients presenting with suspected auto-
derstand the sensitivity and specificity of their own labo- immune encephalitis, a dedicated epilepsy protocol MRI
ratory’s test, how the test is validated, and how quality control with and without intravenous contrast is recommended
is performed to feel confident in using the test result to direct because this study is tailored for evaluation of the hippo-
clinical management. campi, which are most commonly affected in the autoim-
Multiplex syndromic PCR panels (such as those developed mune encephalitides. Computed tomography of the head
for diarrheal, respiratory, or meningitis/encephalitis pre- without intravenous contrast is recommended as a first-line
sentations) have gained popularity in recent years given their study in pediatric patients presenting with acute mental
effect on turnaround time (4–24 hours for PCR compared status change and suspected intracranial infection because
with days for microbiologic cultures) and broad spectrum of this test can rapidly and accurately exclude all acute neu-
pathogen detection. These panels may test for bacterial, viral, rosurgical emergencies. (27) However, computed tomogra-
and/or fungal etiologies. Although these multiplex PCR phy is not recommended in the evaluation of pediatric
panels, compared with microbiologic cultures, may provide encephalitis (without acute mental status change) because
a timely diagnosis, decreased length of hospital stay, and it has lower diagnostic accuracy than MRI and requires
less need for invasive diagnostic procedures and may help patient exposure to ionizing radiation. Patterns seen on
direct antimicrobial therapy, they are not without limita- neuroimaging may be helpful to differentiate between in-
tions. Limitations include decreased sensitivity compared fectious and autoimmune encephalitis; (5) these patterns are
with targeted PCR assays and confusion about whether by no means universal, however, and should always be
positive results for latent viruses in an immunocompetent interpreted within the clinical context of the patient’s pre-
patient (eg, cytomegalovirus, Epstein-Barr virus, hu- sentation. MRI patterns include autoimmune etiologies lo-
man herpesvirus-6) represent true disease or viral reac- calizing to the limbic system (can be unilateral or bilateral)
tivation in a time of stress. and HSV encephalitis unilaterally affecting the medial

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 temporal lobe. (28)(29)(30) Figure 1 depicts a typical case of diagnostic evaluation should always be in concert with on-
HSV encephalitis from our institution. Unfortunately for going supportive measures. In addition, continued evalua-
diagnostic purposes, most infectious causes of encephalitis tion should be weighed against risks of invasive procedures
are not associated with a typical imaging pattern. and financial costs of additional testing.
Initial experience with anti-NMDAR encephalitis indicated
a strong association of ovarian teratoma in almost 60% of
affected young women. (31)(32) Increasing diagnosis of this DIFFERENTIAL DIAGNOSIS
disorder, in males as well as females, showed that younger Encephalitis can be difficult to distinguish from meningitis
female patients (aged <18 years) had a lower incidence (31%) of because the two often present with the overlapping signs of
associated tumors. (18) Despite a likely low yield, abdominal/ fever, headache, and altered mental status. (1) It is unsur-
pelvic ultrasonography may allow resection of a tumor to al- prising, then, that the term meningoencephalitis may often be
leviate the encephalitis. (33) Figure 2 depicts a typical case of used to describe a child’s presentation. (35) It can be helpful,
anti-NMDAR encephalitis associated with an ovarian tumor. in guiding initial diagnostics and therapeutics, to differen-
The role of EEG in the evaluation of encephalitis is tiate encephalitic or meningitic symptoms based on whether
controversial. The Infectious Diseases Society of America there is evidence of brain parenchymal dysfunction (eg,
guidelines recommend obtaining EEGs in all encephalitic seizures, weakness, focal deficits) or meningeal irritation (eg,
patients. (1) In contrast, the consensus guidelines from of the nuchal rigidity), respectively. (35)
United Kingdom do not routinely recommend EEGs because Because seizures, headaches, and focal neurologic deficits
most patients with encephalitis will have abnormal results. are common presentations for intracranial processes, space-
(7)(34) Consultation with experts in pediatric neurology is occupying lesions such as tumors and abscesses should be
indicated to evaluate the utility of EEG for a particular pa- promptly ruled out given vastly different treatment ventures.
tient. If EEG is performed, most patients with autoimmune Likewise, ischemic and hemorrhagic strokes should be
encephalitis demonstrate interictal and background abnor- considered in the differential diagnosis given the need for
malities. (30) EEG abnormalities are often nonspecific, al- prompt intervention.
though generalized or focal slowing may be seen, particularly Care should be taken to distinguish encephalitis from
in anti-NMDAR encephalitis. (20) encephalopathy as well. Encephalopathy is a disease state
The provider should recognize that a large proportion characterized by disruption of brain function in the absence
of pediatric cases of encephalitis (up to 30%) have no of inflammation of brain parenchyma (1)(2)(7) that lacks the
identifiable etiology. (8) The decision to aggressively pursue additional criteria outlined by the International Encephalitis
an etiology depends on the clinical status of the child. In Consortium. (2) Encephalopathy can occur in the setting of
cases of static or worsening symptoms, continued diag- metabolic disturbances, hypoxia, ischemia, intoxication,
nostic testing may provide a tangible answer that would be medications, organ dysfunction, or even systemic infection
reassuring to both patients and medical providers. Close and is treated quite differently from encephalitis. (1)
attention to new historical details and evolving physical ex- Acute disseminated encephalomyelitis should be in-
amination findings may guide additional testing, although cluded in the differential diagnosis. Acute disseminated

Figure 1. Magnetic resonance

images of herpes simplex virus (HSV)
encephalitis. This 12-year-old boy
presented in status epilepticus after 1
week of fever, headache, and
vomiting. A. Coronal fluid-attenuated
inversion recovery image depicts
abnormal increased signal in the right
amygdala (thin arrow) and right
anterior insula (black asterisk). B. Axial
T2-weighted image depicts abnormal
increased signal in the right insula
(white asterisk) and olfactory portions
of the right frontal lobe (wide arrow).
The asymmetrical distribution of
signal abnormality in the limbic
structures seen here is typical of HSV
encephalitis. Cerebrospinal fluid
qualitative polymerase chain reaction
detected HSV-1.

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Figure 2. Computed tomography (CT) scan and magnetic resonance images (MRIs) of ovarian tumor–associated anti–N-methyl-D-aspartate receptor
(NMDAR) encephalitis. A large pelvic mass was discovered in this 17-year-old female during a routine annual clinic visit. A. CT scan of the pelvis shows a
large pelvic mass (asterisks) with internal coarse calcifications (thin arrow). During treatment planning for the tumor, the patient developed a severe
headache of several days’ duration followed by seizure. B. MRI of the brain was performed and reveled asymmetrical swelling and increased fluid-
attenuated inversion recovery signal in the left amygdala (wide arrow) and left hippocampus. The ovarian tumor, which was a teratoma, was resected. An
elevated cerebrospinal fluid NMDA titer (1:2,560) was found, consistent with anti-NMDAR encephalitis. C. Follow-up MRI 6 months later shows atrophy of
the left amygdala (thin arrow) and hippocampus.

encephalomyelitis is due to postinfectious demyelination. It of a disease without a definitive diagnostic test or therapeutic
is often preceded by a prodromal illness, which is postu- end point.
lated to lead to the development of autoantibodies, causing In otherwise healthy, immunocompetent children, CSF
a multifocal demyelinating process in the central nervous tested with a PCR multiplex panel may detect cytomegalo-
system. (36) virus, Epstein-Barr virus, or human herpesvirus-6. This may
not be clinically significant, but merely reflect bystander
reactivation in the setting of stress. Therefore, these patients
TREATMENT would not require antiviral therapy.
Empirical Antimicrobial Coverage
Given that HSV is the leading cause of severe encephalitis, is Immunomodulators for Infectious and
more frequently associated with poor outcomes than other viral Autoimmune Etiologies
causes, and is treatable, acyclovir therapy should be quickly Corticosteroids may play a role in the treatment of enceph-
initiated in all encephalitic patients until HSV is ruled out. (1)(7) alitis. Among the viral encephalitides, corticosteroids are more
Antibacterial agents are frequently started given the clinical commonly used in varicella zoster encephalitis given the
overlap with acute bacterial meningitis because there are im- vasculitic nature of this infection and may be used in HSV
proved outcomes after swift empirical treatment for bacterial encephalitis if there is concern for cerebral edema. (35)
meningitis. Vancomycin and a third-generation cephalospo- In autoimmune encephalitis such as anti-NMDAR, the
rin (eg, ceftriaxone) are typically used to cover Streptococcus therapeutic goal is inhibition of the immune response. First-
pneumoniae, Haemophilus influenzae serotype b, and Neisseria line therapies include intravenous high-dose corticosteroids,
meningitidis. Providers may consider empirical use of ampi- intravenous immunoglobulin (IVIG), and plasma exchange.
cillin for coverage of Listeria monocytogenes if there is concern The mechanism of action from corticosteroids is a non-
for consumption of contaminated food (eg, deli meats or raw specific damping of the immune system. IVIG seems to act,
dairy products). Antibacterial agents are typically discontinued in part, by decreasing the overall burden of the offending
once bacterial cultures from CSF and blood are negative. autoantibody by dilution. (38) Plasma exchange may be used
A potential role for mycoplasma in pediatric encephalitis in autoimmune encephalitis for its potential to remove the
has intrigued scientists. Confirming the role of mycoplasma disease-causing antibodies. It is difficult to tease out the
has been hampered by difficulty in interpreting various individual contributions of these 3 agents in assessing ther-
microbiologic tests (serological tests may indicate active or apeutic outcomes because some combination is usually used.
previous infection; antigen may be detected in the respiratory (21)(39) A recent systematic review found that plasma ex-
tract long after the acute respiratory infection has resolved). It change tends to be performed if anti-NMDAR encephalitis is
is unclear whether antimicrobial treatment affects recovery refractory to corticosteroids and IVIG. (40)
of encephalitis attributed to mycoplasma. There is no evi- If there is a poor patient response to first-line therapies,
dence suggesting that antimicrobial treatment affects the other aspects of the immune system (eg, B cells and cyto-
disease process, even with PCR detection of mycoplasma in kines) may be targeted. (38)(40) Rituximab is a commonly
the CSF. (37) It is difficult to recommend empirical therapy used second-line agent in autoimmune encephalitis and

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 Table. Diagnostic Evaluation of Pediatric Encephalitis
CSF STUDIES
COMMON AND/OR TREATABLE CONDITIONS RISK FACTORS OR IF PATIENT IS NOT IMPROVING
Autoimmune panel (name and components listed by
Lumbar puncture
commercial laboratory)
Opening pressure Meningoencephalitis multiplex PCR panel
Cell count (white blood cell count + differential count, red CSF immunoglobulin M for specific arboviruses (West Nile
blood cell count) virus, La Crosse virus)
Extra CSF to freeze (eg, for metagenomic next-generation
Protein
sequencing)
Glucose
Gram-stain and bacterial culture
HSV PCR
Enterovirus PCR

NON-CSF STUDIES
COMMON AND/OR TREATABLE CONDITIONS RISK FACTORS OR IF PATIENT IS NOT IMPROVING
Autoimmune panel (name and components listed by
Complete blood cell count with differential count
commercial laboratory)
Complete metabolic panel Respiratory pathogen PCR panel
Abdominal/pelvic ultrasonography to evaluate for
Blood culture
potentially resectable tumors
Extra red-top serum tube to freeze (eg, for pre-IVIG
HSV serum PCR
serological tests, if IVIG is subsequently used)
Enterovirus serum PCR

NEUROIMAGING
Magnetic resonance imaging of the brain
The tests are arranged in order of preference for treatable or common conditions, followed by other tests if the patient does not improve and
initial testing is unrevealing for the etiologic agent. CSF=cerebrospinal fluid, HSV=herpes simplex virus, IVIG=intravenous immunoglobulin,
PCR=polymerase chain reaction.

exerts its effect by binding CD20, thus depleting B cells and outcomes, although it is difficult to separate the natural course
halting the production of antibodies. (41) The published of the encephalitic disease from possible benefit from reha-
literature highlights the variability in timing of administra- bilitation. Enlisting the expertise of therapists in cases of en-
tion during the disease process, making causality between cephalitis may be encouraged, although optimal timing from
treatment and outcomes difficult. (20)(41) In a multicenter, onset of symptoms to initiation of rehabilitation is not clear.
retrospective study of 144 children with autoimmune and
inflammatory central nervous system conditions, initiation
of rituximab ranged from 3 weeks to 9.5 years after diagnosis. OUTCOMES
(41) Rituximab was found to cause infusion reactions, ana- Outcomes are highly variable among the various encephalit-
phylaxis, and infectious complications (including need for ides and depend on the etiologic agent. A retrospective study
hospitalization and intravenous antibiotics). (41) Given the involving 164 children performed in Australia demonstrated
potential for morbidity associated with rituximab treatment, that many children, after being diagnosed as having either
consultation with a pediatric neurologist is recommended. infectious or autoimmune encephalitis, experience an “ab-
normal” outcome, including difficulties in learning (28%),
behavior (24%), and speech (17%). (8) Seventeen percent of
REHABILITATION INTERVENTIONS children ultimately were diagnosed as having epilepsy. (8) One
Data on the impact of rehabilitation after encephalitis are sparse. meta-analysis examining outcomes in patients with infec-
(42)(43) Cognitive therapy, behavioral therapy, and/or physical tious encephalitis demonstrated that 42% experience incom-
therapy seem to have a positive effect on long-term functional plete recovery, 6.7% demonstrate severe sequelae, and 17.5%

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eventually demonstrate a decrease in their intelligence quotient administration of acyclovir may decrease morbidity and
more than 1 SD below the mean. (44) mortality associated with HSV encephalitis.
Of patients with infectious encephalitis, those with HSV
encephalitis tend to be the most severely affected, with up to
64% experiencing late effects; a broad range of deficits, in-
cluding neuropsychological dysfunction, developmental delay, Summary
and focal motor deficits, have been reported. (25)(45) Children
• Based on consensus, the general pediatrician should
with EV encephalitis, on the other hand, have fared better in
recognize enterovirus and herpes simplex virus (HSV)
the long-term. In a prospective study of a large Taiwanese
as causes of the most frequent and the most severe
outbreak of EV-71 (a well-known neuroinvasive EV serotype), 51
forms of infectious encephalitis. Likewise, medical
of 63 children (81%) had no deficits at mean follow-up of 2.8
providers should appreciate anti–N-methyl-D-aspartate
years (range, 1.4–4.9 years). (45) Longitudinal epidemiologic
receptor as the most widely known cause of
studies of acquired Zika virus infection are needed to better
autoimmune encephalitis.
understand neurodevelopmental sequelae, (46) although
• Based on consensus, the initial evaluation of encephalitis
subtle long-term neurologic defects have been reported years
after resolution of primary infection. should focus on the most common and treatable
Of patients with autoimmune encephalitis, approximately causes, guided by epidemiologic factors such as age,
one-third demonstrate full recovery, one-third demonstrate geography, and seasonality.
partial recovery, and one-third show limited recovery with severe • Based on strong evidence, randomized controlled
deficits. This has been demonstrated in both observational trials have consistently shown that early
studies in single institutions and systematic reviews of patients administration of acyclovir is imperative in
diagnosed as having anti-NMDAR encephalitis. (18)(47)(48) decreasing the morbidity and mortality associated
Time to recovery may be prolonged, with one observational with HSV encephalitis. (1)
study citing at least a 6-week interval between presentation and
• Based on strong evidence, prospective studies
signs of initial improvement. (18) Use of immunotherapy
and meta-analyses have demonstrated that
generally correlates with improved outcomes, (48) although
long-term outcomes are highly variable in both
optimal timing for initiation of these therapies is unclear. (41)
infectious and noninfectious encephalitis, with
Several studies have suggested predictors of poor out-
children infected with HSV experiencing worse
comes of encephalitis, including status epilepticus, ICU
outcomes. (44)(45)
admission, presence of a movement disorder, and (with
autoimmune encephalitis) a delay of immunotherapy (al-
though what constitutes a delay is unclear). (8)(48) The
presence of diffusion restriction on MRI, usually repre-
senting cytotoxic edema and irreversible cell death, is also a
poor prognostic indicator in pediatric patients. (8) To view teaching slides that accompany this article,
visit http://pedsinreview.aappublications.org/content/
Disease relapse may be seen. Of an Australian cohort of 42/2/68.
164 pediatric patients with encephalitis (either infectious or
autoimmune), 8 (5%) relapsed. (8) Even higher rates have
been reported in HSV encephalitis and anti-NMDAR en-
cephalitis, with up to 30% and 25% of children, respectively, † ‡
Claire E. Fraley, MD,* David R. Pettersson, MD, Dawn Nolt, MD, MPH
experiencing relapse. (25)(48)

CONCLUSION
A diagnosis of encephalitis in children has the potential to
negatively impact their trajectory of health, development, and
quality of life, although outcomes are highly variable. Swift
recognition, diagnostic evaluation, and treatment is imper-
ative to cover potentially treatable causes within the wide References for this article can be found at
sphere of infectious and autoimmune encephalitides. Prompt http://pedsinreview.aappublications.org/content/42/No. 2/68.

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 PIR QUIZ

Individual CME quizzes are available via the blue CME link under the article title in the online Table of Contents
of any issue. To learn how to claim MOC points, go to: http://www.aappublications.org/content/moc-credit.

1. A pediatric resident in Colorado performs a retrospective study on the

epidemiology and etiology of encephalitis in immunocompetent children older
than six weeks of age over the past 15 years. Which of the following is the most
likely conclusion of the study?
A. Approximately 30% had an undiagnosed etiology.
B. Borrelia burgdorferi was the most common overall etiology.
C. Herpes simplex virus 2 was the most common viral etiology.
D. Powassen virus was the most common arbovirus causing encephalitis.
E. Subjects with enterovirus had the worst prognosis. REQUIREMENTS: Learners can
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2. A previously healthy 17-year-old girl is brought to the emergency department by and claim credit online only at:
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past day she has become much more agitated and seems to be having visual
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hallucinations. Her parents think she felt warm yesterday but there is no
Pediatrics in Review articles for
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following is the most likely etiology for her current symptoms?

This journal-based CME activity
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D. N-methyl-D-aspartate receptor (NMDAR) antibody.
E. Rickettsia rickettsii.
3. A previously healthy and fully immunized 11-year-old boy is brought to the
emergency department (ED) by his parents with a 3-day history of worsening
headache and intermittent fever. Over the past day he is much sleepier and
seems confused and agitated at times. While in the ED he had a brief generalized 2021 Pediatrics in Review is
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tonic-clonic seizure. His temperature is 38.3°C; other vital signs are normal. He is
Maintenance of Certification
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76 Pediatrics in Review
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4. For the patient in question 3, which of the following is the most appropriate
initial empiric antimicrobial therapy?
A. Acyclovir, ampicillin, and doxycycline.
B. Acyclovir, ceftriaxone, and vancomycin.
C. Ampicillin, gentamycin, and doxycycline.
D. Ampicillin, gentamicin, and vancomycin.
E. Ceftriaxone, doxycycline, and vancomycin.
5. A previously healthy 16-month-old girl is admitted to the hospital with a 2-day
history of fever, some fussiness, and mild nasal congestion. One hour prior she
had a 2-3 minute generalized tonic-clonic seizure. She is sleeping but does wake
up with stimulation and recognizes her parents. Her temperature is 39.1°C. She
has no focal findings on physical examination. Lumbar puncture is performed.
CSF cell count shows 0 RBC, 3 WBC, glucose 62 mg/dl, and protein 23 mg/dl. CSF
gram stain shows no organisms. A CSF multiplex PCR panel is only positive for
human herpes virus 6 (HHV-6). Which of the following is the most appropriate
antiviral therapy?
A. Acyclovir.
B. Cidofovir.
C. Foscarnet.
D. Ganciclovir.
E. No antiviral therapy.

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 Encephalitis in Previously Healthy Children
Claire E. Fraley, David R. Pettersson and Dawn Nolt
Pediatrics in Review 2021;42;68
DOI: 10.1542/pir.2018-0175

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References This article cites 46 articles, 6 of which you can access for free at:
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 Encephalitis in Previously Healthy Children
Claire E. Fraley, David R. Pettersson and Dawn Nolt
Pediatrics in Review 2021;42;68
DOI: 10.1542/pir.2018-0175

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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