Article infectious diseases

Encephalitis in the Pediatric Population

Stephen J. Falchek, MD*
Educational Gap
Management of encephalitis, which can be fatal, requires understanding of a broad range
Author Disclosure of causative agents, pathophysiologic mechanisms, clinical syndromes, and outcomes.
Dr Falchek has
disclosed no financial Objectives After completing this article, readers should be able to:
relationships relevant 1. Know the many causes of encephalitis, including infectious, parainfectious, and
to this article. This noninfectious disorders.
commentary does not 2. Recognize the clinical features of encephalitis.
contain a discussion of 3. Be able to conduct a diagnostic investigation of a patient with encephalitis by using
an unapproved/ clinical and laboratory criteria.
investigative use of 4. Know the anticipated clinical course of different types of encephalitis.
a commercial product/ 5. Be familiar with the modalities used to treat encephalitis.
device. 6. Understand the factors that influence the outcome in a patient who has encephalitis.

Introduction
The broad denition of the term encephalitis, that is, inammation of the brain, neces-
sitates acknowledgment of the enormous inclusivity of the topic. The most common in-
terpretation of the term implies a direct invasion of the brain by an infectious pathogen,
most commonly, viral, fungal, or parasitic. The topic also includes examples of meningitis
mediated by bacteria or other agents, which can produce extrameningeal symptoms such as
lethargy or seizures, in which case, the combined term meningoencephalitis is used.
There are also many examples of encephalitis not due to direct central nervous system
(CNS) infections. Inammatory processes due to an acute or chronic illness can result in
an acute immune-mediated encephalitis, such as acute disseminated encephalomyelitis
(ADEM), lupus cerebritis, and paraneoplastic syndromes. Agents or conditions that pro-
duce slowly progressive CNS symptoms, such as tertiary syphilis or slow viruses (the
prion protein encephalopathies), also are considered examples of encephalitis. Table 1 lists
only a limited number of the many pathogens and pathologic conditions that can cause
either acute or subacute encephalitis. In this discussion, we will mainly address examples
of acute encephalitis related to direct CNS infection and para-infectious processes involving
the CNS. These examples embrace the major portion of the
spectrum of disease presentation, course, and recovery, as
well as mechanisms of cerebral injury.
Abbreviations In addition to the taxonomic classication in Table 1,
ADEM: acute disseminated encephalomyelitis causes of infectious encephalitis often are grouped according
CEP: California Encephalitis Project to the most common methods of transmission. Arbovi-
CNS: central nervous system ruses are those spread by insect vectors, such as West Nile
CPP: cerebral perfusion pressure virus (WNV) and the equine encephalitis group (both by
CSF: cerebrospinal uid mosquitoes). Zoonotic causes of encephalitis not spread
HSV: herpes simplex virus by intermediary insect vectors include many of the parasitic
IVIG: intravenous immune globulin infections (larva migrans) and rabies. Community-acquired
MS: multiple sclerosis encephalitides, such as enterovirus, adenovirus, and late-
PCR: polymerase chain reaction childhood herpesvirus infections, generally are spread by
WNV: West Nile virus person-to-person contact. Vertically transmitted pathogens
include neonatal herpes simplex (HSV), rubella virus,

*Division of Pediatric Neurology, Alfred I. duPont Hospital for Children/Thomas Jefferson University, Wilmington, DE, and
Philadelphia, PA.

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 infectious diseases encephalitis

Table 1. Potential Causes of Acute Encephalitis

Agent Subcategory Specific Examples
Virus Herpesviruses Herpes simplex 1
Herpes simplex 2
Human herpes virus 6
Varicella-zoster
Cytomegalovirus
Picornaviruses Coxsackievirus A
(Enteroviruses) Coxsackievirus B
Echovirus
Enterovirus 70
Enterovirus 71
Adenoviruses Various subtypes
Alphaviruses Eastern equine encephalitis
Western equine encephalitis
Venezuelan equine encephalitis
Flaviviruses St Louis encephalitis
West Nile virus
Japanese encephalitis
Tick-borne encephalitis
Powassan encephalitis
Bunyaviruses California encephalitis
Myxoviruses Mumps encephalomyelitis
Rhabdoviruses Rabies
Togaviruses Rubella
Retroviruses Human immunodeficiency virus I and II
Influenza viruses Influenza A
Influenza B
Metapneumoviruses Human metapneumovirus
Bacterium Specific encephalitis Listeria monocytogenes
syndromes Francisella tularensis
Rickettsia species
Mycoplasma pneumoniae
Chlamydia pneumoniae
Other causes of bacterial Meningoencephalitis when
meningitis necrosis and direct brain
invasion or inflammation occur
Fungus Cryptococcus neoformans
Blastomyces dermatitidis
Histoplasma capsulatum
Paracoccidioides brasiliensis
Parasitic infection Primary amebic Naegleria fowleri
meningoencephalitis Balamuthia mandrillaris
Raccoon roundworm Baylisascaris procyonis
encephalitis
Neural larva migrans Toxocara canis
Angiostrongylus cantonensis (Asia)
Parainfectious immune-mediated Acute disseminated encephalomyelitis
response Acute hemorrhagic leukoencephalitis
Bickerstaff brainstem encephalitis
Post-infectious cerebellitis
Mycoplasma encephalitis
Systemic inflammatory Systemic lupus erythematosus
diseases
Malignancies Paraneoplastic syndromes Antineuronal antibodies producing specific
encephalitic syndromes

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infectious diseases encephalitis

and cytomegalovirus, and likely many other viral agents. include encephalopathy or ataxia, plus at least one clinical
Vertical, symptomatic transmission of WNV has been nding (fever, seizures, focal neurologic decits, CSF
well documented. Finally, sexual transmission is the ma- pleocytosis, abnormal neuroimaging, or abnormal EEG).
jor mechanism of infection for adult herpes simplex type By using a combination of CSF PCR, nasopharyngeal/
2 virus and HIV (which can produce an acute, often tran- throat specimen viral isolation, and acute and convalescent
sient, meningoencephalitis in the absence of opportunis- paired sera, all patients receive testing for herpesviruses, ar-
tic infection). boviruses, enteroviruses, respiratory viruses, measles virus,
Iconic examples of parainfectious encephalitis in chil- Chlamydia species, and M pneumoniae. Between 1998
dren include ADEM and acute cerebellar ataxia. Variants and 2005, 1,570 patients were enrolled. A conrmed
of these conditions, such as acute hemorrhagic leukoen- or probable causative agent was identied in only 16%
cephalitis and Bickerstaff brainstem encephalitis, are re- of cases. Of identiable causes, 69% were viral, 20%
ported primarily in adult and older adult populations. bacterial, 8% noninfectious (ie, autoimmune disease),
Parainfectious syndromes are differentiated in practice 7% prion protein, 3% parasitic, and 1% fungal. Exten-
from acute infectious encephalitis based upon clinical his- sive testing procedures still revealed no identiable
tory and a lack of supporting evidence for direct CNS in- cause in 63% of patients. (3) Among the more prom-
vasion. In the case of ADEM, there is usually an antecedent inent causes of viral encephalitis, HSV accounted for
illness or immunization, followed 2 to 30 days later by var- only 2.5% of the CEP cases; in contrast, HSV was iden-
ious focal neurologic symptoms, possibly accompanied by tied in 5% of 322 pediatric patients with acute en-
signs of meningeal irritation. The early presentation may be cephalitis seen in one series between 1994 and
confused with acute infectious encephalitis, and some in- 2005. (4)
stances of each phenomenon may be categorized incor- Epidemics of infectious encephalitis have always at-
rectly. Lumbar puncture ndings can be variable, ranging tracted much media attention, such as the WNV out-
from normal to a mild or moderate lymphocytic pleocy- break rst seen in the United States in New York City
tosis with an elevated protein concentration. Acute cere- in 1999. Between 1999 and 2007, 1,478 pediatric cases
bellar ataxia follows a similar course of antecedent illness, of conrmed WNV infection occurred in the United
but with symptoms limited to the cerebellum (ataxia, nys- States, of which 443 (30%) had neurologic involvement.
tagmus, and cerebellar dysarthria). Of those with neurologic symptoms, there were three fa-
Infectious, parainfectious, and primary inammatory talities. Overall, children accounted for only 4% of re-
causes of encephalitis are typically considered mutually ported WNV infection cases, with an estimated median
exclusive. However, the example of Mycoplasma-related annual incidence of 0.07 per 100,000. The pediatric fa-
encephalitis illustrates some difculty in differentiating tality rate contrasts favorably with the 12% mortality rate
direct versus indirect mechanisms of CNS disease, and from the 1999 epidemic, in which the majority of symp-
the magnitude of the topic. Although widely regarded tomatic cases were elderly people. WNV is now an epide-
as a parainfectious phenomenon with variable pathology, miological risk factor throughout the contiguous United
up to 2% of these patients have Mycoplasma polymerase States and the Caribbean. (5) Although WNV remains
chain reaction (PCR)-positive cerebrospinal uid (CSF), the most commonly encountered arboviral encephalitis
which might indicate some direct CNS invasion. Myco- agent, California encephalitis viruses have the greatest
plasma is a prevalent pediatric illness and cause of enceph- proportion of pediatric symptomatic infections (88% of
alitis. One hundred and eleven of 1988 patients referred to cases), and eastern equine encephalitis has the highest
the California Encephalitis Project (CEP) tested positive overall mortality rate of 42%.
for Mycoplasma pneumoniae; 76% of those affected were The importance of local epidemiological information
pediatric patients. (1)(2) and seasonality cannot be ignored. Many cases of viral en-
cephalitis either occur in epidemics, display a clear sea-
Epidemiology sonal predilection, or both. For example, enteroviruses
Epidemiological data on encephalitis is organized accord- are most often seen in spring and summer; arthropod-
ing to identied agent. The CEP was initiated in 1998 for borne illnesses, in the summer and fall. Respiratory virus-
the collection of epidemiological data and is the most mediated cases often are specic to fall and winter. These
comprehensive database to date. It includes all referred elements of conventional epidemiological wisdom, how-
immunocompetent individuals over 6 months of age ever, should be subordinate to locally observed trends,
and all clinical presentations, including chronic and such as cases of H1N1 inuenza encephalitis observed
slowly progressive encephalitis. Criteria for inclusion during an out-of-season epidemic.

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 infectious diseases encephalitis

In contrast, ADEM tends to be more sporadically ob- (12) Evidence supporting the concept of antibody-medi-
served than many infectious causes, although population ated mechanisms derives mainly from the clinical efcacy
data in the United States have supported a winter-spring of intravenous immune globulin (IVIG) and plasmaphe-
predilection for the condition. Recent data from Canada, resis in the treatment of ADEM. Demonstration of anti-
however, failed to show this seasonality. (6) The inclusion body targeting precise CNS molecules in human ADEM
criteria for ADEM strongly inuences reported inci- and other demyelinating disease cases is scarce, with poor
dence, producing wide variations, with a range of 0.2 concordance, even between individuals who have similar
to 0.8 per 100,000 children in the United States and syndromes. Existing knowledge of autoantibodies target-
Canada, and 0.07 per 100,000 in Germany. Antecedent ing specic CNS molecules is derived mainly from experi-
infectious illness or vaccination typically is identied in ence with paraneoplastic syndromes in adults, eg, anti-Yo,
50% to 75% of patients. Presenting symptoms are highly anti-Hu, and anti-Purkinje cell antibodies. These mecha-
variable, as the range of reported incidences of any one nisms, however, produce subacute encephalitis or cerebel-
neurologic symptom in pooled study data suggest. Out- litis distinct from typical pediatric ADEM. Even in children
comes statistics are similarly scattered, with a 57% to 89% with classic postinfectious cerebellitis, fewer than half dis-
reported rate of full recovery. play anti-Purkinje cell antibodies.
The lack of routinely detectable autoantibody in para-
Mechanisms of Cerebral Injury infectious CNS disease is likely attributable to both the
Infectious agents and parainfectious processes are pre- large number of causative infectious agents and the mul-
sumed to mediate their acute symptoms through any tiplicity of possible targeting mechanisms. The latter may
combination of postulated mechanisms listed in Table include both molecular mimicry and abnormal handling
2. Evidence is best for the causes of fatal cases, in which of normally occurring cellular antigens. For example, an
wholesale parenchymal destruction is usually identiable invading virus may manufacture proteins that share epit-
at necropsy, including direct neuronal and glial invasion opes with normal human myelin (mimicry), or may pro-
with apoptosis, neuronophagia, vascular occlusion lead- duce enzymes that cleave or misfold normal host proteins
ing to infarction, and secondary effects of cerebral edema. into immunologically unrecognized forms. For example,
Evidence supporting largely immune-mediated mech- vaccinia virus core protein kinase cleaves myelin basic
anisms of injury (cytotoxic antibodies, cytokine effects, protein.
etc) is less direct, and more evident in parainfectious/ Even more difcult is the isolation of cytokine effects
inammatory causes of encephalitis. In ADEM fatalities, in producing CNS injury. Interleukins 6 and 8, interferon
perivenular lymphocytic inltration with local myeli- g, and tumor necrosis factor a seem to be among those
nolysis is a hallmark nding on pathology specimens. cytokines most commonly identied as correlating with

Table 2. Proposed Mechanisms of CNS Injury in Encephalitis and Myelitisa

Pathogen-mediated cell death
Direct neuronal invasion and cell lysis
Direct glial cell invasion and cell lysis
Mechanical and vascular injury
Cerebral edema with impairment of capillary integrity
Cerebral edema leading to herniation syndromes
Decreased cerebral perfusion pressure leading to ischemia
Vascular occlusion and infarction
Immune-mediated disease
Cytokine effects, including apoptosis
Cytotoxic antibody causing impaired neuronal function or apoptosis
Demyelination
Immune activation, including microglial cells, with neuronophagia
Neurotransmitter and neurophysiologic disturbances
Alterations in neuronal function leading to seizures and secondary apoptosis (eg, altered membrane potentials, balance of
excitatory and inhibitory neurotransmitters)
a
Italicized items are also proposed mechanisms in parainfectious processes.

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infectious diseases encephalitis

severity of disease course or outcomes across multiple of exclusively white matter abnormalities on MRI (espe-
causes of encephalitis, both infectious and noninfectious cially if monolesional), optic neuritis, isolated myelitis,
(eg, lupus cerebritis), but with high variability between a recurrent or polyphasic disease course, or postadoles-
specic agents. High concentrations of interleukins 6 cent age. In these cases, standard lumbar puncture
and 8 can be found in the CSF of patients with Myco- studies also include myelin basic protein assay and mea-
plasma encephalitis and Japanese encephalitis. Higher surement of CSF immunoglobulins with oligoclonal
titers in a small number of Japanese encephalitis patients banding, and concomitant serum protein electropho-
seemingly correlated with a lower survival rate. It is un- resis. Although the presence of disproportionate oli-
clear if cytokines are causative of further CNS injury or goclonal antibody production within the CSF is more
are active markers of disease severity. suggestive of idiopathic demyelination (eg, MS), this
nding is not sufciently specic to prove a diagnosis
Presentation and Evaluation of MS because ADEM and other CNS inammatory
The typical presentation of acute encephalitis consists of conditions, including CNS infection, can produce sim-
any combination of altered mental status, seizures, other ilar results. The neuromyelitis optica antibody often is
behavioral changes, weakness, sensory disturbances, or present in cases having optic neuritis associated with spi-
nonepileptic movement disorders, in the absence of an nal cord symptoms. Documented neuromyelitis optica
identiable external cause, such as intoxication, traumatic antibody-positive patients also have presented with op-
brain injury, or psychosocial stressors. In the younger child tic neuritis only.
or infant, symptoms may be even less distinct, and can in- In following the standard evaluation of patients with
clude uncharacteristic somnolence, disinterest in feeding, symptoms of encephalitis, the diagnostic testing results
weak suck, irritability, loss of head control, or abnormal most commonly encountered include either unremarkable
eye movements. Further clinical clues may include the or variable leukocytosis or lymphocytosis. Comprehensive
presence of fever (either acutely or in the 14 week interval metabolic panels often fail to demonstrate specic ab-
before the onset of symptoms), or meningeal irritation normalities. Some enteroviral infections can produce
(Table 3). However, these supporting clues may not be a sepsislike syndrome with more remarkable hematologic
apparent upon rst presentation. Because the clinical abnormalities. Neonatal HSV infections sometimes pro-
symptoms of encephalitis include a very broad range in duce hepatic function abnormalities and disseminated
both scope and severity, suspicion should be high in the intravascular coagulation. Inappropriate secretion of anti-
approach to any child presenting with uncharacteristic diuretic hormone can be seen in almost any encephalitic
behavior that is persistent and disproportionate to envi- process, but is reported more commonly in St Louis en-
ronmental and situational factors. cephalitis (primarily a disease of the elderly population)
Upon identication of a suspected case of encephalitis, and WNV infections.
a relatively short but critical series of steps should be ex- Understanding clinical-anatomic correlations may be
ecuted, as summarized in Table 4. Additional facts to helpful in rening the differential diagnosis, because some
consider in the initial evaluation of the patient include causes of encephalitis display tropism for specic CNS tis-
seasonal presentation, history of immunosuppression, sues. Table 3 describes the cardinal symptoms of infection
travel history, recent local epidemiological information, or inammation in major anatomic subdivisions, as well as
and presence of focal neurologic symptoms or decits. commonly used clinical terms. Although the anatomic lo-
Table 5 lists additional specic testing that should be rou- calization is an important part of initial symptom recogni-
tinely considered based upon protocols developed for the tion, neuroimaging plays an indispensable role, whether or
CEP and specic clinical settings. Table 6 lists, according not localizing clinical symptoms are present. In the very
to clinical clues, other viral causes of encephalitis that young child, clinically based neuroanatomic localization
would require agent-specic testing if suspected. also can be notoriously difcult. Table 7 describes some
In patients in whom a parainfectious process is sus- classically cited agent-specic localization-related ndings,
pected, acute testing for demyelinating inammatory identiable by symptoms, neuroimaging, or both. How-
conditions is increasingly popular. This testing is moti- ever, a high degree of variability in clinical presentations
vated by the increasing recognition of pediatric multiple mandates that the search for an etiologic agent cannot
sclerosis (MS) and other demyelinating conditions, be conned strictly to those agents classically injurious
eg, neuromyelitis optica (Devic disease), which may to specic CNS locations.
be mistaken initially for ADEM. Signs that increase sus- Neuroimaging, including MRI, early in the course
picion for MS-related conditions include the presence of disease may sometimes yield false-negative results.

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 infectious diseases encephalitis

Localization of CNS Lesions and Associated Terminology and

Table 3.

Symptoms
Common Clinical Term Anatomic Region Acute Symptoms
Limbic encephalitis Limbic system Agitation, confusion, delirium, seizures, autonomic
changes
Rhombencephalitis Brainstem and/or cerebellum Eye movement and gaze deficits, nystagmus, facial
palsies, ataxia, auditory disturbances, autonomic
disturbances, upper-motor-neuron weakness,
sensory disturbances, hyporeflexia, dysphagia,
dysarthria, lethargy, coma, respiratory failure
Cerebritis or Cerebral hemispheres (cortex, Seizures, upper-motor-neuron weakness, sensory
encephalitis subcortical white matter, or both) disturbances, lethargy, coma
(generically applied) Basal ganglia Weakness, hyperkinetic (dystonia, choreoathetosis) or
parkinsonian movement abnormalities, apathetic or
disinhibited behavior
Hypothalamus (diencephalon) Salt and water disturbances (eg, syndrome of
inappropriate antidiuretic hormone, diabetes
insipidus), adrenal and thyroid failure, paroxysmal
autonomic dysfunction
Thalamus (diencephalon) Sensory disturbances, postural abnormalities,
lethargy, coma
Panencephalitis Two or more distinct regions Symptomatic involvement of two or more distinct
regions
Meningitis Meninges Headache, stiff neck, fever, neck or back pain, malaise
but not formal disturbances of arousal
Meningoencephalitis Meninges plus brain parenchyma Symptoms of meningitis paired with those of any
anatomic subdivision of brain
Myelitis Anterior horn cells or long tracts Poliomyelitis (flaccid paralysis and hyporeflexia with
on the spinal cord preserved sensation), transverse myelitis (long-
tract symptoms including sensory disturbance
below the affected region), or both
Encephalomyelitis Any spinal cord plus any cerebral Spinal symptoms may be inapparent in contrast to
region cortical or brainstem symptoms
Cranial neuritis Cranial nerves I-XII Impairment of any of the modalities of cranial nerve
function attributed to dysfunction of the extra-
axial course of the nerves involved and not damage
to brain parenchyma or cranial nerve nuclei. Can be
indistinguishable from nuclear involvement.

For purposes other than identifying substantial cerebral the disease. Although there are reported variations on this
edema, midline shift or hemorrhage, computed tomogra- theme with certain etiologic agents, such as hemorrhagic
phy imaging generally is not sufcient for the diagnostic pleocytosis with HSV, atypical lymphocytes with Epstein-
workup of encephalitis. Barr virus, or mononuclear leukocytes with echovirus or
The lumbar puncture is the single most utilized test varicella-zoster infection, there are no pathognomonic
for the diagnosis of encephalitis. The primary results, CSF ndings that help to differentiate infectious cases
however, generally lack specicity, and can be normal of encephalitis.
early in the course of the disease. In those patients dis- The ability to obtain PCR amplication of viral DNA
playing abnormal CSF results, the most characteristic fortunately has added new usefulness to the lumbar punc-
ndings are increased opening pressure, normal or ele- ture in encephalitis. This modality, however, requires
vated protein concentration, normal glucose level, and clinical suspicion of a specic diagnostic entity, and is
pleocytosis, which often begins with polymorphonuclear not available as a broad battery of testing. Additionally,
leukocytes and then converts to lymphocytic, or some- viral DNA often is not recovered in certain stages of ill-
times monocytic, predominance with progression of ness. For example, 5% to 10% of adult cases of HSV

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infectious diseases encephalitis

Table 4. Initial Evaluation

1. Clinically stabilize Address symptoms of autonomic instability or septic shock, seizures/
status epilepticus
2. Standard laboratory studies Complete blood count, comprehensive metabolic panel, urinalysis
3. Neuroimaging MRI with and without contrast preferable; emergent computed
tomography if signs/symptoms of critically increased intracranial
pressurea before lumbar puncture
4. Lumbar puncture Opening pressure, cell count, glucose, protein, viral and bacterial
culture, polymerase chain reaction testing for enterovirus, herpes
simplex; other specific studies based upon clinical history (see Table
3 and Table 5)
5. Acute empiric treatment Acyclovir if any suspicion of herpes simplex infection; anticonvulsant
prophylaxis if any suspicion of clinical seizures, or if risk for seizures
deemed high
6. Electroencephalography Used to evaluate for clinically relevant lateralized findings (periodic
lateralized epileptiform discharges), to monitor for occult seizures or
subclinical status epilepticus
a
Signs of acute increased intracranial pressure include vomiting and lethargy, bulging fontanel, pupillary asymmetry or lack of reactivity, gaze palsies,
intermittent or xed involuntary downward gaze (sun-setting eyes), or irregular respirations.

meningitis have negative PCR results upon the rst lum- delirium, autonomic instability, and respiratory irregular-
ber puncture. Furthermore, results often are not imme- ities, treatment of these acute symptoms often takes pri-
diately available, and can take from 1 to 7 days or ority. This stabilization should not, however, delay
longer to be available. Hence, the decision to use specic addressing the suspicion of either an infectious or parain-
antibiotic or antiviral treatments, such as acyclovir for fectious condition and initiating appropriate treatment.
suspected HSV meningitis, is still largely predicated Commonly, such patients are empirically treated with in-
upon clinical suspicion. travenous acyclovir while waiting for lumbar puncture, or
Parainfectious encephalitis such as ADEM or acute while waiting for laboratory results, including HSV PCR.
cerebellar ataxia may manifest many of the same CSF Either because of delays in obtaining these results, or be-
ndings as infectious encephalitis. However, pleocy- cause of the known false-negative rate of PCR testing of
tosis tends to be less dramatic in most, but not all, para- acute CSF specimens, many will complete the required
infectious cases. When pathogen genomic material can be 21-day course of acyclovir without a rmly established
isolated from the CSF, the likelihood of a parainfectious laboratory diagnosis.
or purely inammatory etiology becomes remote. The emphasis on prompt treatment of possible HSV
The most reliable standard for demonstrating causa- encephalitis should not overshadow a thorough search
tion of acute infectious encephalitis remains the pairing for clues to other causative agents. Table 5 lists some al-
of acute and convalescent serum titers. A fourfold rise ternative considerations in the diagnosis of acute infec-
in titer, especially immune globulin M, against a suspected tious encephalitis that might affect treatment options.
agent is most often considered diagnostic. This method is Beyond the primary infectious considerations, ADEM
limited by the adequacy of follow-up and the accuracy of ranks as the most likely cause of an acute encephalitis.
testing selection. Many patients are discharged and lost The constellation of a temporally separate infectious ill-
to close follow-up long before convalescent titers are ness or an immunization before the onset of symptoms,
obtainable. Of those tested, the causative agent may multiple encephalitic symptoms, and multifocal MRI
be missed by clinical suspicion-guided testing targeting abnormalities in both gray and white matter are highly
other organisms erroneously. suggestive (but not pathognomonic) for the diagnosis
of ADEM. Treatment varies substantially from the ap-
Clinical Course and Treatment proach to acute infectious encephalitis in that high-dose
The priority in the treatment of acute encephalitis is the corticosteroids are a rst-line treatment, followed by
duality of clinical stabilization and containment of poten- IVIG or plasmapheresis in cases refractory to corticoste-
tially damaging inammatory processes. Because many roid treatment. The use of both IVIG and plasmaphere-
patients present with any combination of seizures, sis remains unsupported by clinical trials; but IVIG has

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 infectious diseases encephalitis

Additional Testing in Encephalitis, Modeled Upon the California

Table 5.

Encephalitis Project
Source Method Specific Agent Added Criteria
Cerebrospinal fluid Polymerase chain Herpes simplex virus 1
reaction (PCR) Herpes simplex virus 2
Enterovirus
Human herpes virus 6 Immunosuppressed patientsa
Varicella-zoster virus
Antibody assay Measles antibody
Fungal culture; Cryptococcus; other fungal
India-ink agents
microscopy
Nasopharyngeal/throat PCR D virus Mycoplasma pneumoniae
Swab isolation Enterovirus
(Human metapneumovirus)b Routinely tested October-March,
Adenovirus if respiratory symptoms
Respiratory syncytial virus present, or based upon
Influenza A local epidemiology
Influenza B
Acute phase serum Serology Mycoplasma pneumoniae
Epstein-Barr virus
Parvovirus B19
Measles
St. Louis encephalitis As indicated by season
Western equine encephalitis
Eastern equine encephalitis
West Nile virus
Convalescent phase Serology Mycoplasma pneumoniae
serum Epstein-Barr virus
Parvovirus B19
Measles
Influenza A As indicated by season and
Influenza B local epidemiology
Adenovirus
West Nile virus
Systemic lupus erythematosus
Western equine encephalitis
Varicella zoster virus As indicated by clinical
Herpes simplex virus presentation and PCR
(Chlamydia pneumoniae) results
Other agent-specific Various See Table 1 Based upon clinical presentation
testing and epidemiological factors as
described in Table 6
a
The predilection for some agents to affect primarily immunosuppressed patients does not wholly exclude the possibility of CNS disease in otherwise
immunocompetent individuals.
b
Items in parentheses are part of the CEP protocol, but generally not found to be major causes of encephalitis nationwide.

received wider acceptance as an alternative treatment at occurs primarily in severely immunocompromised HIV-
this time. positive patients.
The use of corticosteroids in the setting of nonher- The maintenance of adequate cerebral perfusion pressure
petic infectious encephalitis remains controversial. Out- (CPP) (generally accepted as 70 mm Hg or higher over 2
side of single case reports, the only available supportive years of age) is a critical issue in treating infectious en-
evidence for their use derives from the treatment of pro- cephalitis. Increased intracranial pressure is a variable
gressive multifocal leukoencephalopathy, a subacute/ nding in encephalitis. Preserving CPP by managing in-
chronic encephalitis caused by polyomavirus JC that tracranial pressure is an important element of treatment. In

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infectious diseases encephalitis

Table 6. Alternative Considerations in the Diagnosis of (Viral) Encephalitis

Suggestive Findings Diagnostic Consideration
History of recent nonfebrile cough, serous otitis, community Mycoplasma pneumoniae
epidemic of walking pneumonia
History of arthritis, serositis, uveitis, nephritis, or other Lupus or other autoimmune cerebritis/vasculitis
inflammatory conditions
History of recent unexplained weight loss, anemia, slow- Paraneoplastic syndrome
onset encephalitis symptoms, limbic encephalitis
Fever, chest x-ray or hepatic abnormalities, subacute onset of Fungal infection
encephalitis, multiple enhancing lesions on MRI, meningeal
enhancement, mixed CSF pleocytosis
Fever, chest x-ray or hepatic abnormalities, subacute onset of Tuberculous meningitis
encephalitis/rhombencephalitis, basilar meningeal
enhancement, hypoglycorrachia with mixed pleocytosis
Fever, heart murmur, history of congenital or rheumatic heart Mycotic emboli
disease, multifocal enhancing lesions on MRI
Antecedent infectious illness with complete recovery before Acute disseminated encephalomyelitis
onset of neurologic symptoms, or immunization within the
previous 30 days
Neonate with extramedullary hematopoiesis (blueberry Rubella
muffin baby)
Neonate with symptoms of acute encephalitis Toxoplasmosis, rubella, cytomegalovirus, HSV, parvovirus B19
Tick or biting arthropod exposure Borrelia burgdorferi
Rickettsia species
Ehrlichia species
Coxiella burnetii
Age <45 years, peripheral and/or CSF eosinophilia, discrete Neural larva migrans, including baylisascariasis (Raccoon
MRI lesions with enhancement, pica or extensive exposure encephalitis), toxocariasis (dogs), angiostrongylosis
to soil/locations frequented by animals (rodents),
Rhombencephalitis with hemorrhagic pleocytosis, HSV PCR Listeria monocytogenes
negative, elevated CSF lactate (not routinely tested in
encephalitis)
Fever, exposure to cats, local adenopathy Bartonella henselae
Animal bite, or close exposure to wild animals behaving Rabies
abnormally (including bats), rapidly deteriorating course

a series of 20 children with meningitis or meningoenceph- The treatment of symptomatic seizures often becomes
alitis, 4 of 4 patients with CPP <50 mm Hg died, whereas a focus of management in patients with encephalitis. In
3 of 16 with CPP maintained at >50 mm Hg survived. (7) the CEP, 42% of patients manifested seizures. Of these,
When symptomatic intracranial hypertension exists, 62 patients eventually developed intractable seizures re-
conservative measures (head elevation, hyperventilation, quiring barbiturate coma or anesthesia. This group of pa-
and uid restriction) are the most accepted strategies. tients experienced a 32% mortality rate, compared with
Mannitol is used on a limited basis, as individual case re- an 11% overall mortality rate for the entire cohort. Nearly
ports and small series attest. However, the duration of use every anticonvulsant agent known has been used in the
is limited by the dynamics of inammation-related intra- treatment of patients with encephalitis-related acute
cranial hypertension, with eventual breakdown of the symptomatic seizures. Those agents most easily adminis-
blood-brain barrier and the possible passage of osmoti- tered are available in intravenous formulations and include
cally active agents into the extravascular space. This out- benzodiazepines (midazolam, lorazepam, diazepam), bar-
come may result in the ultimate worsening of cerebral biturates (phenobarbital, pentobarbital), anesthetic agents
edema. If more conservative strategies fail and mannitol (propofol, ketamine, inhalant anesthesia), phenytoin, fos-
is unsuccessful also, isolated reports and small series (34 phenytoin, divalproex sodium, and levetiracetam. The typ-
patients) attest to the successful use of craniectomy for ical approach begins with benzodiazepines upon recognition
decompression. of either recurrent or prolonged seizure activity, followed

130 Pediatrics in Review Vol.33 No.3 March 2012

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 infectious diseases encephalitis

Table 7. Examples of Agent-Specific Findings in Infectious Encephalitis

Agent Location Other Specific Details
HSV I Basal frontal and mesial temporal lobes Hemorrhagic meningoencephalitis; >50% of
with prominent lesions on MRI in older cases in individuals >20 y; causes up to 30%
children and adults; tropism not as of neonatal meningoencephalitis
reliable in neonates
HSV II Neonatal panencephalitis;
Adult aseptic meningitis;
Rhombencephalitis or ascending myelitis in
immunocompromised adults
Enterovirus 71 Brainstem encephalitis; A cause of epidemic hand, foot and mouth
Poliomyelitis syndrome disease; also, epidemics of encephalomyelitis
in Taiwan; acute pulmonary edema
Eastern equine 50% of affected patients with MRI lesions in Summer-fall seasonality; Atlantic and Gulf
encephalitis basal ganglia, thalamus, and brainstem coasts; Great Lakes region
West Nile virus Brainstem encephalitis; myelitis in 10% of Only 4% of cases are pediatric; summer-fall
cases; basal ganglia less commonly involved seasonality
Mumps Ependymal cells (choroid plexus and lining of Late winter-early spring; most patients have
ventricles); secondary neuronal destruction only aseptic meningitis symptoms
and perivascular demyelination

by loading of a more sustainable anticonvulsant, with in- interventions, the poorer the prognosis for full recovery
tent to maintain. Fosphenytoin, phenobarbital, and, in and survival.
some locations, phenytoin are still most commonly used
anticonvulsants, but newer agents such as divalproex or
levetiracetam are gaining acceptance. Outcomes
If either high therapeutic levels or apparently adequate Clinical outcomes of both infectious and inammatory en-
dosing fail to achieve cessation of seizure activity, sedative cephalitis range from full recovery to death. The accurate
or anesthetic agent infusions emerge as the next most prediction of clinical outcome remains elusive. Nonetheless,
likely treatment, including the use of midazolam, pento- several factors can be identied that strongly inuence
barbital, propofol, or ketamine drips. During this phase the potential for recovery: nature of the infectious agent
of treatment, bedside EEG monitoring usually is ob- or process, age of the patient, extent of primary cerebral
tained, motivated both by the prevalence of otherwise and spinal cord involvement, presence of complicated
undetectable subclinical seizures in the comatose patient cerebral edema, extent of cerebral perfusion and vascular
and the desire to achieve a burst-suppression EEG pat- injury, presence of other organ system disease and compli-
tern as a measure of the adequacy of dosing. cations, and response to treatment modalities. The impor-
Often, other anticonvulsants are added to the treat- tance of the nonneurologic aspects of infectious disease in
ment regimen, either as intravenous formulations or via affecting outcome should not be underestimated. This as-
nasogastric or other direct enteral route, during the esca- sociation is especially true in neonatal encephalitis accom-
lation of the therapy with sedative-hypnotic and anes- panied by sepsislike syndromes, infectious pneumonitis,
thetic agents. The use of polypharmacy is intended to or hepatitis, which may produce mortality rates >50%.
achieve both more rapid seizure cessation as well as a Even among older children, pulmonary disease espe-
more stable anticonvulsant conguration, facilitating the cially affects outcome, as in the Taiwanese enterovirus
successful withdrawal of the anesthetic agent without sei- 71 epidemics, in which the worst survival rate was
zure relapse. However, metabolic interactions can frustrate among those experiencing pulmonary edema in the
attempts to obtain therapeutic levels of any or all agents acute phase of illness. (8)
simultaneously in use. The question of future functional capacity is para-
Inhalant anesthetics often are used as a treatment mount for families of encephalitis survivors. In response
of last resort. Isolated use of ketosis or vagus nerve stim- to this question, much depends upon the causative agent.
ulation has produced limited results as well. In gen- As a general principle, agents that produce more extensive
eral, the longer the list of unsuccessful anticonvulsant cerebral necrosis (especially if bilateral hemispheric or

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infectious diseases encephalitis

brainstem injury is abundant) or vascular disease have worse

functional outcomes. Clinical outcome is determined largely by the nature of
the causative agent, but with substantial contribution
Otherwise, available statistics offer little guidance in from factors such as other organ system involvement,
anticipatory counseling. The specic etiologic agent does seizure control, and cerebral perfusion. (7)
play some role; for example, >60% of patients who have
HSV encephalitis develop some identiable neurologic
sequelae in some series. But among Taiwanese children References
affected by enterovirus 71, 80% had no detectable decits 1. Christie LJ, Honarmand S, Talkington DF, et al. Pediatric
when evaluated >2 years after the encephalitis. (8) encephalitis: what is the role of Mycoplasma pneumoniae? Pediat-
The potential for more subtle long-term sequelae, rics. 2007;120(2):305313
even in cases where there are no obvious short-term def- 2. Walter ND, Grant GB, Bandy U, et al. Community outbreak of
Mycoplasma pneumoniae infection: school-based cluster of neuro-
icits, remains a controversial topic. For example, of 86 logic disease associated with household transmission of respiratory
Taiwanese children evaluated 3 to 7 years after enterovirus illness. J Infect Dis. 2008;198(9):13651374
71 meningitis or encephalitis, 20% manifested attention- 3. Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses:
decit/hyperactivity disorderrelated symptoms, com- clinical proles and etiologies associated with encephalitis. Clin
pared with only 3% of matched control subjects. (9) Infect Dis. 2006;43(12):15651577
4. Elbers JM, Bitnun A, Richardson SE, et al. A 12-year prospective
The incidence of similar neurologic complications in other study of childhood herpes simplex encephalitis: is there a broader
causes of encephalitis remains largely undocumented at spectrum of disease? Pediatrics. 2007;119(2):e399e407
this time. 5. Lindsey NP, Hayes EB, Staples JE, Fischer M. West Nile virus
disease in children, United States, 1999-2007. Pediatrics. 2009;123
(6):e1084e1089
6. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired
Summary demyelination of the CNS in Canadian children. Neurology. 2009;
72(3):232239
The topic of encephalitis encompasses an enormous 7. Shetty R, Singhi S, Singhi P, Jayashree M. Cerebral perfusion
range of causative agents, clinical syndromes, and pressuretargeted approach in children with central nervous
outcomes. system infections and raised intracranial pressure: is it feasible?
The treatment options remain largely supportive, J Child Neurol. 2008;23(2):192198
except in a select number of cases in which a possible 8. Huang MC, Wang SM, Hsu YW, Lin HC, Chi CY, Liu CC.
or probable causative agent exists and for which there Long-term cognitive and motor decits after enterovirus 71 brain-
is a specific therapy. stem encephalitis in children. Pediatrics. 2006; 118(6):e1785e1788
The specific cause of encephalitis in both the pediatric 9. Gau SS, Chang LY, Huang LM, Fan TY, Wu YY, Lin TY.
and adult population remains unknown in a majority Attention-decit/hyperactivity-related symptoms among children
of cases, despite extensive diagnostic testing. (1) with enterovirus 71 infection of the central nervous system.
Specific causes of encephalitis often have classically Pediatrics. 2008;122(2):e452e458
reported features, but the extent of overlap in clinical 10. Berger JR, Houff S. Neurological complications of herpes
symptomatology mandates broad consideration of simplex virus type 2 infection. Arch Neurol. 2008;65(5):596600
possible causes. (1) 11. Young NP, Weinshenker BG, Lucchinetti CF. Acute dissem-
Parainfectious and inflammatory causes of inated encephalomyelitis: current understanding and controversies.
encephalitis (acute disseminated encephalomyelitis) Semin Neurol. 2008;28(1):8494
are as prevalent and clinically significant as direct CNS 12. Noorbakhsh F, Johnson RT, Emery D, Power C. Acute
infection. (9)(10)(11) disseminated encephalomyelitis: clinical and pathogenesis features.
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 infectious diseases encephalitis

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1. Mosquito control will most likely reduce the frequency of encephalitis caused by
A. Adenoviruses.
B. Flaviviruses.
C. Herpesviruses.
D. Myxoviruses.
E. Picornaviruses.
2. A 10-year-old child presents with the signs of acute encephalitis. While no pattern of brain involvement is
exclusively produced by a single microbiologic agent, the possibility of herpes simplex being the causative
agent is enhanced substantially by an MRI finding of lesions concentrated in the
A. Basal ganglia.
B. Frontal lobes.
C. Midbrain.
D. Temporal lobes.
E. Thalamus.
3. A 17-year-old boy has acute encephalitis associated with weakness in the right arm. He is clinically stable. He
had experienced a febrile illness 3 weeks before presenting with signs of encephalitis, but had apparently
recovered fully. An MRI demonstrated scattered multifocal abnormalities in both gray and white matter within
the brain. Evaluation of serum and CSF has been unrevealing. His most likely diagnosis is
A. Acute disseminated encephalomyelitis.
B. Enteroviral encephalitis.
C. Herpes simplex encephalitis.
D. Mycoplasma encephalitis.
E. Multiple sclerosis.
4. The form of encephalitis shown to benefit most from the use of high-dose glucocorticosteroids is
A. Acute disseminated encephalomyelitis.
B. Enteroviral encephalitis.
C. Herpes simplex encephalitis.
D. Saint Louis encephalitis.
E. West Nile virus encephalitis.
5. The likelihood of full recovery from encephalitis most depends upon
A. Availability of specific treatment.
B. Causative agent.
C. Duration of fever.
D. Initial CSF findings.
E. Timeliness of specific diagnosis.

Pediatrics in Review Vol.33 No.3 March 2012 133

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 Encephalitis in the Pediatric Population
Stephen J. Falchek
Pediatrics in Review 2012;33;122
DOI: 10.1542/pir.33-3-122

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 Encephalitis in the Pediatric Population
Stephen J. Falchek
Pediatrics in Review 2012;33;122
DOI: 10.1542/pir.33-3-122

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