Curr Pediatr Rep (2015) 3:201–210
DOI 10.1007/s40124-015-0089-5
INFECTIOUS DISEASES (B MARAIS, SECTION EDITOR)
Paediatric Acute Encephalitis: Infection and Inflammation
Cheryl A. Jones1,2
Published online: 21 July 2015
 Springer Science + Business Media New York 2015
Abstract Encephalitis is a multifaceted syndrome with a
myriad of clinical presentations. It is defined as inflam-
mation of the brain with functional disturbance. Infectious
diseases, particularly viruses, and autoimmune disorders
are the commonest causes in children. Young infants have
the highest burden of disease for most infectious causes.
Recent advances include the publication of international
consensus guidelines, emergence of new aetiologies
including human parechoviruses and better characterisation
of known infectious causes, including enterovirus 71,
which continue to cause large epidemics, death and
impairment in children although a number promising vac-
cines are on the horizon; and neurological syndromes
associated with influenza which occur most commonly in
children who are not immunised against the virus. Under-
standing of childhood autoimmune encephalopathies is
also rapidly expanding including responses to
immunomodulation and prognosis. Future research should
see better understanding of the pathogenesis of all forms of
encephalitis, with hope for advances in therapy and
prevention.
Keywords Encephalitis
Encephalopathy
Infectious
encephalitis
Autoimmune encephalitis
Enterovirus

This article is part of the Topical Collection on Infectious Diseases.
& Cheryl A. Jones
Cheryl.jones@health.nsw.gov.au
1
Discipline of Paediatrics and Child Health and Marie Bashir
Institute, The University of Sydney, Sydney, NSW, Australia
2
Department of Infectious Diseases and Microbiology, The
Children’s Hospital at Westmead Clinical School, Cnr
Hawkesbury Rd and Hainsworth St, Locked Bag 4001,
Westmead, NSW 2145, Australia
Herpes simplex virus
Japanese encephalitis virus

Influenza
Arbovirus
Vaccine
Immunomodulation
Introduction
Acute encephalitis is a syndrome characterised by severe
neurological dysfunction due to inflammation of the brain
parenchyma. The presence of central nervous system
(CNS) inflammation enables differentiation from ‘en-
cephalopathy’ where there is altered cerebral function
alone. The highest attack rate for encephalitis is in chil-
dren, particularly in those less than 1 year of age [1–3].
The commonest causes of acute encephalitis are infections
and autoimmune disorders in children, with viruses being
the most commonly identified pathogens [4, 5••]. The
diagnosis of encephalitis is complex because it is now
recognised that some infectious agents (e.g. influenza
virus) can cause encephalopathic syndromes without
directly infecting the brain [6••, 7], and that infection or
immunisation can trigger autoimmune encephalopathies
[8]. There are also toxic and metabolic syndromes that
cause brain inflammation and can mimic infectious
encephalitis [8], including Mild Encephalopathy with
Reversible Splenial Lesions [9]. It is also well established
that a high proportion of cases (between 30 and 70 %
depending on the population studied) will not have an
aetiology identified despite extensive investigation [1, 4,
5••], although this proportion can be reduced with rigorous
application of consensus guidelines [10, 11].
The incidence and case fatality rate of acute childhood
encephalitis rates varies with geographic location, aetiol-
ogy, age and case definition. The incidence of childhood
encephalitis from all causes in industrialised countries has
been calculated in a systematic review to be 10.5 cases per
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100,000 population \15 years per year [11]. The overall
mortality of encephalitis is approximately 10 % across all
age groups in recent population studies [11], although
mortality in children alone is much lower in most paedi-
atric series, except in some Asian countries where there are
ongoing outbreaks of non-polio enteroviruses, particularly
human enterovirus-type 71 (EV71) and endemic Japanese
Encephalitis Virus (JEV) [12–14]. Mortality rates from
encephalitis have reduced in recent decades, with the
availability of immunisations against measles and JEV in
particular, antiviral agents and better supportive care [15,
16]. Although death rates have reduced, disability in
encephalitis survivors can be high, depending on the
pathogen and age [5••, 17•].
This review will discuss recent advances in paediatric
acute encephalitis over the last few years commencing with
a review of recently published consensus definitions and
clinical guidelines, and of infectious encephalitis in chil-
dren including emerging/re-merging pathogens, therapy
and prevention and outcomes, and of childhood autoim-
mune encephalitides, including characterisation of indi-
vidual syndromes, advances in immunomodulation and
long-term prognosis. Finally, it will then provide summary
of remaining knowledge gaps and suggested directions for
future research.
Encephalitis Case Definitions and Practice
Guidelines
The diagnosis or classification of encephalitis poses chal-
lenges for both clinicians and epidemiologists. A number
of groups have developed consensus definitions for both
brain inflammation and dysfunction for different purposes.
In 2007, the Brighton collaboration Encephalitis Working
group’s developed definitions to provide clarify around
reported of adverse neurological events post immunisation
including acute disseminated encephalomyelitis (ADEM).
These have been widely adapted by many groups who
study the condition [8]. The World Health organisation
(WHO) also developed a clinical case definition for acute
encephalitis syndrome (AES) in resource poor settings,
mainly for the purpose of JEV surveillance [18]. Although
brain biopsy provides a gold standard definition for brain
inflammation, most schemas substitute a combination of
surrogate markers of CNS inflammation and clinical signs
of brain dysfunction. Definitions for CSF pleocytosis need
to be adjusted for age, as the upper limit of normal values
of CSF white cell counts is higher in newborn infants, than
in older infants, children and adults. Recent advances have
incorporated the fact that encephalitis can occur in the
absence of CSF pleocytosis, and without neuroimaging
abnormalities. In 2012, the international encephalitis
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Curr Pediatr Rep (2015) 3:201–210
consortium (IEC) published standardised definitions
(Table 1) and consensus practice guidelines for children
and adults to capture both encephalitis and encephalo-
pathies of presumed infectious aetiologies [19••].
A number of clinical guidelines for the management of
encephalitis in children have been recently been published
[20, 21]. Common features of these have been the emphasis
on early lumbar puncture where not contraindicated to
exclude treatable causes of encephalitis (particularly HSV),
the importance of early neuroimaging (preferably MRI) to
confirm the diagnosis, the need to cease acyclovir where an
alternative cause of encephalitis is found or HSV PCR is
negative, early consultation with specialist neurologists and
infectious diseases for advice re-extended investigations
and diagnosis/management of autoimmune encephalitides.
Key features of a pathognomonic infectious encephalitis,
herpes simplex virus; an infection-associated
encephalopathy, influenza virus; and an autoimmune
encephalitis; N-methyl-D-aspartate receptor, or NMDAR,
antibody mediated encephalitis, are compared in Table 2.
Infectious Encephalitis
Epidemiology, Clinical Characteristics
More than 100 pathogens have been reported to cause
encephalitis, although for most infectious agents, this is
usually a rare complication [16]. Granerod and colleagues
devised a hierarchical relationship of diagnostics tests to
define causality of an infectious agent [22]. In their clas-
sification, a confirmed case of infectious encephalitis is
when an organism is identified in the brain, a highly
probable case is when it is detected in a sterile site, a
probable case is where there is organism carriage with a
specific immune response, and a possible case is where
there is the organism carriage (i.e. it is detected in a non-
sterile site) without evidence of a specific immune
response.
The epidemiology of childhood infectious encephalitis
has been reported in a number of large series from around
the world [3, 4, 12, 23–33]. Recent publications have
provided new information. A hospital-based study of
childhood encephalitis which arose out of the California
Encephalitis project and published in 2013, mostly inclu-
ded children who were older than 12 months of age, were
male and either Hispanic or White [4]. A key finding of this
series was the identification of race/ethnicity as an inde-
pendent predictor of outcomes. Clinical characteristics
were similar to previous published series. Fever was the
commonest presenting symptom (75 %) followed by sei-
zures (50 %), ataxia (42 %), personality change (23 %),
movement disorders (15 %) and hallucinations (6 %).
Curr Pediatr Rep (2015) 3:201–210 203

Table 1 International encephalitis consortium case definition [19••]

Characteristics
Encephalopathic Altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change)
features lasting C24 h with no alternative cause identified
Inflammatory features Documented fever C38 C (100.4 F) within the 72 h before or after presentation; CSF WBC count C 5/mm3;
Neuroimaging suggestive of encephalitis; EEG that is consistent with encephalitis and not attributable to another
cause
Neurological features Generalised or partial seizures not fully attributable to a pre-existing seizure disorder; new onset of focal neurologic
findings
Classification
Confirmed encephalitis Encephalopathic features C3 inflammatory or neurological features
Possible Encephalitis Encephalopathic features plus C2 inflammatory or neurological features

Table 2 Characteristics of common infectious and autoimmune encephalitis disorders of childhood

HSV encephalitis [93] Influenza-associated acute NMDAR [83]
encephalopathy syndromes (AES)
[6••]

Age Highest incidence in neonates, and the Mostly in childhood (median age Any age but usually occurs in young children
elderly 4 years), but can from infancy to to mid adult hood
adulthood
Sex distribution M=F Overall 1:1.15 Predominantly in females 4:1
(F:M)
CNS Neonate: non-specific CNS signs, Varied neurological syndromes Movement disorders psychiatric symptoms,
manifestations apnoea, seizures, lethargyNon associated with fever and behavioural change, speech disturbance,
neonate: t respiratory symptoms agitation
CSF findings HSV DNA usually detected Influenza RNA rarely detected in Usually abnormal
CSF Raised CSF lymphocyte count, and protein.
Elevated lymphocyte count in Oligoclonal bands
20–40 % of children
MRI Brain Neonates: Diffuse T2 Abnormalities in approximately Abnormalities in less than 50 %, particularly
Older children and adults: Typical 50 % overall. Characteristic limbic encephalitis. Changes on T2
frontotemporal changes, often neuroimaging associated with (hyperintensity) common in medial
hemorrhagic specific syndromes temporal lobe, focal cortex
Management Parenteral Acyclovir Largely supportive. Immunotherapy (corticosteroids, IVIG,
Immunotherapy (e.g. rituximab)
corticosteroids for Acute
necrotising encephalopathy)
Relapse Neonates–Non neonates: up to 50 %; Not reported Up to 20 %
may be associated with
autoantibodies (e.g. NMDAR Ab)
and movement disorders

Confirmed, probable or possible infectious causes were
identified in just over 38 % of children, however, almost
50 % of children in this series did not have a defined
aetiology. Enteroviruses were the commonest confirmed or
probable infectious cause, and Mycoplasma pneumoniae
was the commonest possible cause. A recent single-centre,
retrospective case series of over 150 children with
encephalitis from Australia identified infectious
encephalitis in 30 % of cases, most commonly, enterovirus,
M. pneumoniae and herpes simplex virus (HSV), and
infection-associated encephalopathy in a further 8 %.
Almost 30 % of children in this series did not have an
identified aetiology [5••].
Prospective studies of encephalitis have been thought to
provide more accurate estimates of incidence, aetiology
and epidemiology of the syndrome. This notion has
recently been evaluated in a recent French study which
compared data from a prospective population-based study
with national hospital discharge and mortality datasets
[34]. The authors concluded that although misclassification
can underestimate incidence and weaken conclusions from
analysis of large datasets, the method does provide an

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inexpensive surveillance tool and accurate estimates of
case fatality rates. A recent Canadian evaluation of national
hospital morbidity datasets included admissions and deaths
with attributable codes for encephalitis from all age groups
[35]. Similar to other studies, it also identified that infants
less than 12 months of age have highest risk of viral
encephalitis (4.2/100,000 population) compared to other
children (0.36–0.70/100,000 population), and identified
clusters of unknown encephalitis, possibly vector-borne
aetiology in older age groups.
Influenza-Associated Encephalopathies
Influenza RNA is very rarely identified directly in the CSF.
However, influenza virus infection has been increasingly
recognised to be complicated by a variety of encephalopathic
syndromes, many but not all with evidence of CNS inflam-
mation [6••, 7, 36, 37]. These include acute necrotizing
encephalopathy (ANE), acute hemorrhagic shock and
encephalopathy (HSE) and acute hemorrhagic leukoen-
cephalopathy (AHL). Influenza-associated encephalopathies
(IAE) have been reported after both pandemic and seasonal
influenza [6••, 7, 36], affect children more than adults and can
be associated with poor outcomes including death. Case series
from around the world suggest somewhere between 6-20 % of
children hospitalised with Influenza A H1N1 pandemic had
neurological manifestations [7]. Surveillance studies from the
United Kingdom (UK) and Japan have further characterised
IAE in children [6••, 36, 38]. Recent results from UK
surveillance for neurological complications of influenza
(2011–2013) confirmed that children (84 %) were more
commonly affected than adults, and that Influenza A (mostly
H1N1) caused the majority (81 %) of cases [6••]. Of the 21
children in the series, slightly more had encephalopathy than
encephalitis/encephalomyelitis; many had specific
encephalopathy syndromes (ANE, HSE and AHL). Similar to
previous series, many cases required intensive care (80 %)
and had impairment at discharge (68 %), and death was not
uncommon (16 %). Of note, and similar to previous reports
from Australia [7], none of the children or adults had been
previously vaccinated against influenza, including 32 % who
had indications for this reinforcing that these syndromes are
potentially preventable. Japanese surveillance for influenza-
associated encephalopathy (IAE) (2009–2011) noted that
attack rates were approximately 10-fold higher during the
H1N1 Influenza A pandemic than from seasonal influenza,
and again were highest in young children [36]. Case fatality
rates of approximately 5–18 % were reported in this series.
Although clinical features of influenza encephalopathy
syndromes can be similar, neuroimaging features are often
distinct. A revised classification schema for IAE has
recently been published [6••] which distinguishes syn-
dromes associated with acute onset which are thought to
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arise from cytokine storm, from those with subacute onset
which are hypothesised to arise from aberrant adaptive
responses, or those with delayed/late onset where the
pathogenesis is unknown. This classification is supported
by neuroimaging findings from a small Chinese series of 17
children with severe IAE (H1N1) [38]. Treatment of
influenza encephalopathy syndromes is supportive. Corti-
costeroids are often given early for some forms of IAE (e.g.
ANE), but there are limited data of their efficacy [6••].
Herpes Simplex Virus (HSV)
In most series, HSV is one of the commonest confirmed
infectious cause of encephalitis in children in the devel-
oped world together with enteroviruses [5••, 39] (Table 2).
HSV encephalitis (HSE) in the newborn period typically
arises after vertical transmission from active maternal
genital herpes disease during labour and delivery. Sporadic
HSE cases in later infancy and childhood are rare, and have
been associated with specific signalling defects in innate
immunity [40]. Results from 15 years of active surveil-
lance for neonatal HSV disease in Australia (1997–2011)
have recently been published [41•]. Approximately one-
third of infants in this cohort of almost 250 neonates, had
HSE alone or as part of a multiorgan disease. HSV-1 was
the commonest serotype causing all forms of neonatal HSV
disease, reflecting the recent increase in genital herpes due
to HSV-1 disease in many countries including Australia.
There were no deaths from HSE in the absence of dis-
seminated infection, and only half the infants with
encephalitis alone had cutaneous lesions at presentation.
Antiviral resistance is rarely encountered in neonatal
HSV disease, but can occur, as shown by a recent case report
from Japan of a neonate with HSE who developed a viro-
logically confirmed acyclovir-resistant HSV 1 strain during
therapy after initial treatment response [42]. The infant was
successfully treated with vidarabine in the absence of fos-
carnet, but survived with significant neurological sequelae.
Baja and colleagues recently described neuroimaging find-
ings in a series of 29 infants who had neonatal HSE, the
majority of whom had MRIs [43]. In contrast to older infants
and children with HSE, temporal lobe predilection was
uncommon, with most neonates having a diffuse restriction
pattern on T2 images with involvement of thalamus and
internal capsule. MRI abnormalities correlated with adverse
neurological outcomes in this small series.
There have been a number of advances in antiviral
therapy for neonatal or childhood HSE. Kimberlin et al.
[44] have reported results from a randomised controlled
trial of oral antiviral suppressive therapy (acyclovir at
30 mg/m2/dose three times a day) versus placebo at the
cessation of intravenous treatment and found that acyclovir
reduced neurological sequelae after neonatal HSV disease
Curr Pediatr Rep (2015) 3:201–210
(predominantly HSV2 in this series) as shown by higher
scores on developmental assessment at 12 months of age
compared to controls. As HSV is a rare cause of
encephalitis beyond the neonatal period, diagnosis and
treatment can be problematic. Gaensbauer and colleagues
[45] recently reported high rates of empiric acyclovir usage
older infants and children for suspected HSE, and high-
lighted that in most cases the therapy was given in the
absence of clinical characteristics of the condition. Expert
opinion has seen a move towards the use of high dose
acyclovir therapy (20 mg/kg/dose) for HSE not only in
neonates, but in all children up to 12 years of age. The
rarity of HSE makes it difficult to adequately power con-
trolled trials to evaluate the efficacy of this recommenda-
tion [46]. Kendrick et al. has recently reported safety data
from a retrospective cohort of 61 children aged from
1 month to 18 years of age who were given standard versus
high dose acyclovir therapy for HSE. They did not identify
a significant difference in the incidence of renal injury
between the two groups.
Complications after HSE beyond the neonatal period
can include choreiform movement disorders and epileptic
encephalopathies. A number of authors have postulated an
autoimmune basis for these phenomena [47, 48]. This
notion is supported by a recent report of nine children from
Australia where HSE relapse with chorea was associated
with development to NMDAR or Dopamine-2 receptor
antibodies [49•]. The initiation of immune suppression
should be considered early in these conditions.
Non-polio Enterovirus Encephalitis Including
HEV71
Non-polio enteroviruses (HEV) are one of the most com-
mon causes of infectious encephalitis in children [5••, 13,
39, 50]. In the California encephalitis project, HEV
accounted for almost 5 % of all cause encephalitis, and
occurred more commonly in the young and in males [4].
One of the most serious forms of EV encephalitis has been
reported after enterovirus-type 71 infection (HEV71).
HEV71 was first identified late last century during large
epidemics of hand-foot-mouth disease (HFMD) across
Europe and South East Asia [50]. More recently, epidemics
of EV71 HFMD and febrile illnesses have emerged in
eastern Asia, complicated by high rates of severe neuro-
logical disease in children including severe brainstem
encephalitis, with high mortality and frequent permanent
neurological sequelae [51]. HEV71 epidemics are seasonal,
with the highest transmission rates occurring during war-
mer, wetter months [52]. Recent outbreak data from
Malaysia and Australia suggest that epidemics occur in two
to three year cycles corresponding with new, naive birth
cohorts [53, 54]. Characteristic clinical features of HEV
205
CNS disease include myoclonus, tremor, ataxia, nystagmus
and cranial nerve palsies, which may develop with or
without HFMD. Cohort studies have identified that serious
HEV71 neurological disease (encephalomyelitis) is asso-
ciated mortality and morbidly, particularly in the presence
of neurogenic pulmonary oedema [55•, 56]. Characteristics
of severe disease variably include young age (\2 years of
age), male sex, prolonged high fever, high white cell count
on admission, neurological signs at presentation, delayed
medical evaluation and the existence of comorbidities such
as pre-existing developmental retardation [56–58]. Pre-
dictors of neurological sequelae after EV71
encephalomyelitis included CSF pleocytosis and myo-
clonic jerks at disease onset [59].
There has also been considerable interest in identifying
the pathogenesis of EV71 neurological disease. As
encephalitis is a rare manifestation of EV71 disease, a
number of studies have investigated genetic polymor-
phisms associated with EV71 encephalitis compared to
uncomplicated HFMD. Single nucleotide polymorphisms
within the genes encoding interleukin (IL)-17F, CCL2
gene, IL-6, IL-8 [60–62] appear to confer increased sus-
ceptibility to severe EV disease including encephalitis in
Chinese populations. Elevation of human leukocyte anti-
gen-G expression has recently been associated with severe
encephalitis with pulmonary oedema [63].
Given the serious public health concerns from EV71
outbreaks, there have been concerted efforts to develop
improved prevention strategies including infection control
and vaccines. A comprehensive guide for clinical man-
agement of HFMD has recently been published by the
World Health Organization [64]. Infection control practices
consist mainly of hand washing, disinfection and isolation
during epidemics. Over the last two years, results from
three large phase three trials in China of vaccine candidates
(all inactivated vaccines against EV71 C4Agenotype) have
been published [65–67]. All candidates provided protection
against HFMD (vaccine efficacy 80–97 %), but to date the
trialled vaccines have been proven to work only for one
sub-type of the HEV71. There is a need to determine EV
subtypes causing disease around the globe, and to test the
current HEV71 vaccines against other subtypes. There is
also a need to develop potent antiviral treatments for
children and adults who acquire this potentially devastating
infection.
Parechovirus Encephalitis
Human parechoviruses (HPeV) have recently been recog-
nised as causing similar clinical syndromes to EV, partic-
ularly in young infants [68–70]. HPeV like enteroviruses,
are members of the picornavirus family of small, positive
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strand non enveloped RNA viruses, but are not detected by
molecular testing for EV (e.g. polymerase chain reaction)
and so must be specifically requested by clinicians. Only
three HPeV serotypes (serotypes 1, 2 and 3) have been
reported to cause disease in humans to date. HPeV-type 3
has been particularly associated with neurological disease
including encephalitis, which is characterised by the
absence of CSF pleocytosis and a significantly elevated
CSF protein [69], and distinct subcortical white matter
involvement on cerebral MRI [71]. Harvala and colleagues
[68] have recently compared HPeV and EV RNA detec-
tions in the CSF and blood in infants presenting with sepsis
or CNS disease and suggested that presence of either virus
in the CSF alone may not be indicative of CNS disease in
the absence of CSF pleocytosis. Infants with sepsis like
syndromes due to HPeV3 had high viral load in the blood,
but low to undetectable load in the CSF. Neurological
sequelae after HPeV3 meningoencephalitis has been
reported in some but not all infants [69, 71]. Further
research is required to define the pathogenesis and prog-
nostic risk factors after HPeV CNS infection.
Arbovirus Encephalitides
Arboviruses are an uncommon but emerging and possibly
under recognised causes of encephalitis in children. Pop-
ulation studies using hospital datasets from around the
world suggest that diagnostic testing for arboviruses in not
always performed for suspected encephalitis, particularly
in the young. Gaensbauer et al. have recently reported the
epidemiology of paediatric neuroinvasive arboviral infec-
tions in the United States (2003–2013) [72•]. They reported
over 1200 cases in their series, including over 20 deaths
from a variety of viruses each with different seasonal and
environmental triggers, most commonly La Crosse Virus
(particularly in young children) and West Nile Virus
(WNV). Eastern Equine encephalitis was an uncommon
cause of neuroinvasive infection but had the highest case
fatality rate. The study serves to reinforce the need to
utilise personal protection against insect bites in children in
areas of possible exposure.
The epidemiology of meningoencephalitis from tick-
borne encephalitis (TBE) virus in Switzerland from 2005 to
2011 has recently been reported [73]. TBE was uncommon
in children under 6 years of age in this country, but
thereafter occured at the same rate til late adulthood, where
there was a further peak. Males were more commonly
affected than females at all age groups and deaths were
rare. The majority of those infected were not vaccinated.
Large outbreaks of WNV are continuing to occur in Greece
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[74], particularly in rural areas, but neuroinvasive disease
appears to be uncommon in the young.
Japanese Encephalitis Virus
Despite the availability of an effective vaccine against Japa-
nese Encephalitis Virus (JEV), the virus remains the leading
cause of AES in many parts of the Asia and the Western
Pacific, particularly in rural areas [13, 75, 76]. The Centres for
Disease Control in the United States recently provided an
update on JEV surveillance and immunisation [77]. They
estimated that there are almost 70,000 cases of JEV in Asia per
year, and that while surveillance for JE occurred in 75 % of
Asian countries with identified transmission risk, only 46 %
of these countries had immunisation programs. Two recent
reports have highlighted that burden of death and disability
from this infection is in children. Wang et al. [78] have
described characteristics of deaths from JEV in China, and
found that children less than 15 years of age accounted for
almost 80 % of over 1500 deaths from JEV from 2005 to
2010. Griffiths et al. [79•] reported a longitudinal follow-up
study of JEV infection in Nepal, and highlighted that almost
70 % of child survivors of JEV had functional impairment at
follow-up, frequently behavioural, and resulted in significant
adverse economic impact to their families.
Considerable effort to develop new cell culture-derived
JEV vaccines has been driven by theoretical safety concerns
as the current inactivated JEV vaccines were developed in
mouse brains. Results of phase III clinical trials of three cell
culture JEV vaccines suggest that they are safe and with
equivalent immunogenicity to inactivated vaccines [80].
Varicella Zoster Virus Encephalitis
Encephalitis is a known rare complication of varicella
zoster virus (VZV) infection. Introduction of VZV immu-
nisation into national schedules has seen the reduction of
disease in many countries. However, a recent case series
reported over 80 children with CNS complications of VZV
from Canada, the majority of whom were not vaccinated
against VZV, including 17 cases of encephalitis (three of
whom died), and 10 who developed strokes, highlighted
that vaccine preventable encephalitis can occur even in
highly developed countries [81]. This series serves as a
reminder that neurological symptoms associated with VZV
infection can predate the rash. A recent case report of fatal
wild-type VZV encephalitis which developed without a
rash in a young child who had received one dose of VZV
vaccine serves as a further reminder that VZV encephalitis
should be considered even in there is a history of vacci-
nation and the absence of rash at presentation [82].
Curr Pediatr Rep (2015) 3:201–210
Autoimmune Encephalitides
A major advance in encephalitis research in recent years
has been in the recognition, diagnosis and treatment of
immune mediated encephalitides in both children and
adults. There is now clear evidence that these disorders can
lead to significant long-term neurological sequelae. A
recent review by Ramanathan et al. [83], provides a
detailed update of autoimmune encephalitides, and high-
lights differences between neuronal surface antibody syn-
dromes (NSAS) which are caused by antibodies against
surface receptors or synaptic proteins and limbic
encephalitis syndromes (LE), which are typically caused by
antibodies directed against intracellular antigens. NSAS
with onset in childhood include N-methyl-D-aspartate
receptor (NMDAR), glycine receptor and recently descri-
bed anti-dopamine-2 receptor (D2R) basal ganglia
encephalitides [84•]. NMDAR are characterised by a
number of features including behavioural disturbance,
psychosis and movement disorders (Table 2). D2R mani-
fest primarily as extrapyramidal movement disturbances
with psychiatric features. LE are characterised by subacute
onset of memory loss, confusion and agitation often with
sleep disturbance hallucinations and hippocampal and
medial temporal lobe changes on neuroimaging. Many LE
are associated with underlying malignancies and often a
relentlessly progressive clinical course.
The last few years have seen further characterisation of
clinical phenotypes of these disorders in childhood
including long-term outcome and further definition of
treatment. The Spanish NMDAR encephalitis group [85]
have recently highlighted age-associated differences in
initial symptoms of the disorder, whereby children have
more neurological and fewer psychiatric symptoms and
signs at onset than adults. Consistent with previous reports,
females were over-represented in this series, and most
children did not have a tumour. All children in this series
received immunomodulatory therapy (intravenous
immunoglobulin, plasma exchange, steroids and or ritux-
imab/cyclophosphamide) and most were reported to have
responded to this therapy, but as this was an uncontrolled
case series, efficacy data are hard to interpret. The benefits
of rituximab, a monoclonal antibody against CD20 used to
deplete B cells, have been shown in randomised controlled
trials of adults with multiple sclerosis [86], but use in
NMDAR has been limited to European observational
cohort study of NMDAR in all age groups, including 211
children [87, 88•]. In this study, early treatment, and no
admission to ICU were predictors of good outcome in
children and adults. Dale et al. have recently reported
higher quality evidence of the efficacy of rituximab in child
and adolescent NMDAR [89•]. This multicentre case
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control study of 144 children with autoimmune neurolog-
ical disorders, predominantly NMDAR, reported benefit in
87 % of patients with the greatest effect seen in early
treatment. Adverse effects were observed in 7.6 %, most
notably infections.
As mentioned previously, another new area of interest
has been description of autoimmune syndromes, after
infectious encephalitis particularly choreoathetosis post
HSE from autoantibodies to NMDAR or D2R [85, 90].
Other associations include respiratory viruses with basal
ganglia/thalamic encephalitis, influenza A and voltage-
gated potassium channel complex encephalitis [91] and
NMDAR and parvovirus B19 [92].
The field of autoimmune encephalitis is rapidly evolving
with molecular techniques enabling new pathological
antibodies being identified to a wide variety of CNS anti-
gens, and better definition of known syndromes. However,
as highlighted by Ramanathan and colleagues [83], there
remain many gaps in our knowledge of the pathogenesis,
diagnosis and management of these conditions in all age
group including the overlap and role of antecedent infec-
tions, the use of CNS antibodies as biomarkers and the
timing and duration of first line and second line
immunotherapy.
Conclusions
Encephalitis remains a complex disorder to diagnose and
treat, particularly in children. The condition is a well-
recognised sentinel for emerging infectious agents and we
remain without vaccines or therapies for known infectious
causes which cause significant death and disability (e.g.
HEV71). The child health clinician needs to be aware of
the clinical phenotypes of autoimmune encephalitides and
refer early for specialist advice and treatment as there is
clear evidence of the benefits of early immunotherapy.
However, even with advanced diagnostics and practice
guidelines, many children with encephalitis do not have an
aetiology identified. Many survivors of childhood
encephalitis are left with lifelong consequences, the mag-
nitude and character of which is poorly understood
worldwide. Future collaborative international research is
required to address these knowledge gaps, and identify new
diagnosis, vaccines and therapies.
Compliance with Ethics Guidelines
Disclosure Cheryl A Jones has received grants from NHMRC
during the conduct of this study.
Human and Animal Rights and Informed Consent This article
does not contain any studies with human or animal subjects per-
formed by any of the authors.
123
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