Infectious and Autoantibody-Associated

Encephalitis: Clinical Features and

Long-term Outcome
Sekhar C. Pillai, FRACPa,b, Yael Hacohen, MRCPCHc, Esther Tantsis, FRACP, PhDa,b, Kristina Prelog, FRANZCRd, Vera Merheb, BSca,
Alison Kesson, PhDe, Elizabeth Barnes, PhDf,g, Deepak Gill, FRACPb, Richard Webster, FRACPb, Manoj Menezes, FRACPb,
Simone Ardern-Holmes, FRACPb, Sachin Gupta, FRACPb, Peter Procopis, FRACPb, Christopher Troedson, FRACPb,
Jayne Antony, FRACPb, Robert A. Ouvrier, FRACPb, Yann Polfrit, MBBSh, Nicholas W. S. Davies, PhDi, Patrick Waters, PhDc,
Bethan Lang, PhDc, Ming J. Lim, PhDc,j, Fabienne Brilot, PhDa, Angela Vincent, FRCPathc, Russell C. Dale, PhDa,b

abstract Pediatric encephalitis has a wide range of etiologies, clinical

BACKGROUND AND OBJECTIVES:
presentations, and outcomes. This study seeks to classify and characterize infectious, immune-
mediated/autoantibody-associated and unknown forms of encephalitis, including relative
frequencies, clinical and radiologic phenotypes, and long-term outcome.
METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian
children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and
we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated
potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined
outcomes by using the Liverpool Outcome Score (for encephalitis).
RESULTS:An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%,
immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%.
In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis
(21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody
(6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%).
Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid
oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with
autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of
5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our
multivariate analysis, an abnormal outcome was more common in patients with status epilepticus,
magnetic resonance diffusion restriction, and ICU admission.
CONCLUSIONS:We have defined clinical and radiologic phenotypes of infectious and immune-
mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/
autoantibody-associated etiologies are common, and the recognition and treatment of these
entities should be a clinical priority.

WHAT’S KNOWN ON THIS SUBJECT: Encephalitis is
a serious and disabling condition. There are
infectious and immune-mediated causes of
encephalitis, but many cases remain undiagnosed.
WHAT THIS STUDY ADDS: This large single-center
study on childhood encephalitis provides insight
into the relative frequency and clinicoradiologic
phenotypes of infectious, autoantibody-associated,
and unknown encephalitis. Risk factors for an
abnormal outcome are also defined.
a
Neuroimmunology Group, Institute of Neuroscience and Muscle Research at the Kids Research Institute, Children’s
Hospital at Westmead, University of Sydney, Australia; bTY Nelson Department of Neurology and Neurosurgery and
Departments of dMedical Imaging, eInfectious Diseases and Microbiology, and fStatistics, the Children’s Hospital at
Westmead, Sydney, Australia; cNuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford,
Oxford, England; gNational Health Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, New
South Wales, Australia; hCentre Hospitalier Territorial Magenta, Service Pediatric, Nouméa, New Caledonia; iChelsea &
Westminster Hospital, Department of Neurology, Imperial College Healthcare National Health Service Trust, London,
England; and jEvelina Children’s Hospital, London, England
Dr Pillai acquired all clinical data, performed radiological phenotyping, retrieved investigation
data, performed outcome assessments, performed statistical analysis, wrote the first draft, and
edited subsequent drafts; Dr Hacohen, Ms Merheb, and Drs Waters, Lang, Lim, and Brilot
performed and supervised all autoantibody testing and edited drafts; Dr Kesson performed
infectious investigation supervision, edited drafts, and

Downloaded from www.aappublications.org/news by guest on June 5, 2019

ARTICLE PEDIATRICS Volume 135, number 4, April 2015
Encephalitis is inflammation of the
brain parenchyma and has many
infectious and immune-mediated
etiologies.1 Acute encephalitis can be
life threatening and results in
permanent neuropsychiatric and
cognitive impairments in a significant
proportion of survivors.
Inflammatory forms of encephalitis
such as acute disseminated
encephalomyelitis (ADEM) have been
known for some time, but in the past
decade other autoimmune forms of
encephalitis have been recognized,
defined by the presence of
autoantibodies against cell surface
antigens. Autoantibody detection is
important as immune suppression
may improve outcomes, particularly
when given early in the disease.2,3 A
recent study suggested that N-
methyl-D-aspartate receptor antibody
(NMDAR-Ab) encephalitis, the best-
known autoimmune form, is more
common than herpes simplex virus
(HSV) encephalitis in children and
young adults,4 and a prospective
study of adults (n = 134) and children
(n = 69) with encephalitis found that
infectious encephalitis and immune-
mediated forms were identified in
42% and 21% of the cohort,
respectively.5
However, most of the previous larger
studies of encephalitis in children
were undertaken before the advent of
neuronal autoantibody testing.6–8 We
studied clinical and radiologic
features, serum autoantibodies in
acute archived samples, and long-
term outcomes in a large
retrospective cohort of pediatric
encephalitis from a single center.
METHODS
Patients, Definitions, and Clinical
Data
Patients
We report patients with encephalitis
seen between January 1998 and
October 2010 at the Children’s
Hospital at Westmead, the largest
tertiary children’s hospital in New
Downloaded from www.aappublications.org/news by guest on June 5, 2019
PEDIATRICS Volume 135, number 4, April 2015
South Wales, Australia. Patients either
presented directly to the hospital
emergency department or were
referred from district hospitals in
western Sydney and New South Wales
(referral base ∼4.5 million people).
Patients were identified
retrospectively from International
Classification of Diseases, 10th
Revision coding of encephalitis or
encephalomyelitis at discharge, plus
screening of consultant
correspondence from the Department
of Neurology database and review of
cerebrospinal fluid (CSF) polymerase
chain reaction testing from the
Department of Infectious Diseases and
Microbiology. The following patients
were excluded: neonates (,1 month
old), patients .16 years old, known or
suspected cases of immunodeficiency,
and viral or bacterial meningitis
without encephalitis. Infection-
associated encephalopathy (influenza
and rotavirus) cases were included. A
total of 164 patients fulfilled the
diagnostic criteria for acute
encephalitis, according to the following
definitions.
Definitions
We used the Granerod encephalitis
case definitions, with minor
modifications.1 Encephalitis was
defined as an acute encephalopathy
with $2 of the following: fever $38°C,
seizures or focal neurologic signs, CSF
pleocytosis ($5 white blood cells/µL)
or elevated CSF neopterin (.30 nmol/
L), EEG consistent with encephalitis
(presence of slowing in this study), or
MRI findings suggestive of
encephalitis. CSF neopterin, which is
produced secondary to a- or
g-interferon stimulation, was included
as an alternative to CSF pleocytosis
because it has been shown to be
a useful marker of central nervous
system (CNS) inflammation.9
Encephalopathy was defined as an
altered or reduced level of
consciousness and a change in
personality or behavior or confusion
lasting .24 hours. We did not use
lethargy and irritability as sole features
of encephalopathy because of the
nonspecific nature of these features in
sick children unless supported by EEG
features of encephalopathy.
Clinical Data During Acute Encephalitis
In total, 179 clinical or investigation
variables were recorded in every
patient (Supplemental Information).
CSF results were available in 157
(96%) patients, and EEG reports from
the first week of admission were
available in 130 (79%) patients. We
obtained follow-up information by
telephone interview in 144 (88%)
cases in 2011 and 2012 by using the
Liverpool Outcome Score (LOS)
questionnaire,10 supplemented by
clinical records. All patients were
followed up for a minimum of 12
months after encephalitis, and the LOS
was recorded as follows: 1 = death,
2 = severe, 3 = moderate, 4 = mild, and
5 = normal, and specific domains of
abnormal outcome were also recorded.
The outcome score describes the
patient’s abilities compared with peers,
with mild describing impairments
without dependence on carers,
whereas severe describes complete
dependence on carers. Clinical relapses
were recorded separately.
MRI
We had access to 1.5-Tesla MRI brain
scans for review in 149 (91%)
patients. MRI data were reviewed,
blinded to clinical and diagnostic
information, by pediatric neurologists
(R.C.D., S.C.P.) and a pediatric
neuroradiologist (K.P.), and
consensus was reached on
abnormalities. The mean and median
duration of first MRI scan after
admission were 4.8 days and 3 days,
respectively (range 1–70 days).
Etiologic Investigation to Determine
Encephalitis Causation
Infectious Encephalitis and Infection-
Associated Encephalopathy
The CSF, serological, and non-CNS
specimen testing for infectious
etiologies are summarized in
Supplemental Table 3. Testing of up
e975
to 42 different microorganisms was
carried out as clinically indicated. The
mean and median etiologic tests
(including autoantibodies) per
patient were 14 and 13 tests,
respectively (range 0–36).
CSF Testing
A CSF was obtained at a mean and
median admission duration of 2.9
days and 2 days, respectively (range
1–48 days). Bacterial and viral
cultures of the CSF were done on 155
(95%) and 152 (93%) patients,
respectively. CSF polymerase chain
reaction testing was obtained in 131
(80%) of the total cohort, with
patients with ADEM less frequently
tested (63%).
Serology
Serological testing for $1
microorganisms was performed on
139 (85%) patients. Serological
studies for microorganisms used
complement fixation tests and
immunoglobulin M (IgM) enzyme-
linked immunosorbent assays
(Table 1).
Non-CNS Specimens
These tests include blood culture (n =
144, 87.8%), nasopharyngeal aspirate
(n = 69, 42%), stool and rectal swab
(n = 68, 41%), throat swab (n = 47,
29%), and skin swab (n = 5, 3%)
(Supplemental Table 3).
Immune-Mediated/Autoantibody-
Associated Encephalitis
We used Granerod case definition for
confirmed ADEM. Retrospective
autoantibody testing on stored acute
sera was performed in 103 of the 129
patients with non-ADEM encephalitis
(80%). Patients with a preliminary
diagnosis of ADEM were excluded
from autoantibody testing (n = 35).
Antibodies to NMDAR (n = 103),
voltage-gated potassium channel
complex (VGKC-complex) (n = 102),
leucine-rich glioma-inactivated 1
(LGI1) (n = 99), contactin-associated
protein-like 2 (CASPR2) (n = 99),
glycine receptor (n = 102), and
Downloaded from www.aappublications.org/news by guest on June 5, 2019
e976
TABLE 1 Hierarchical Classification for the Etiology of Encephalitis
Etiology of Encephalitisa Confirmed Probable Possible Total N (%)
Infectious (N = 49, 30%)
Enterovirus 17 — 3 20 (12)
Mycoplasma pneumoniae — 11 — 11 (7)
HSVb 4 1 4 9 (5)
Cytomegalovirus — — 3 3 (2)
Other infectionsc — 1 5 6 (4)
Infection-associated encephalopathy (N = 13, 8%)
Influenza virus — — 5 5 (3)
Rotavirus — — 5 5 (3)
ANEd 3 — — 3 (2)
Immune-mediated or autoantibody-associated (N = 56, 34%)e
ADEM 35 — — 35 (21)
NMDAR antibody 5 5 — 10 (6)
VGKC-complex antibody — 7f — 7 (4)
Dopamine D2 receptor antibody — 4 — 4 (2)
Unknown (N = 46, 28%) 46 (28)
Total 64 29 25 164 (100)
ANE, acute necrotizing encephalopathy.
Table adapted from Granerod et al. (2010).1 Serological testing for $1 microorganisms was performed on 139 (85%)
patients. Serological studies for microorganisms used complement fixation tests (CFTs) and IgM enzyme-linked immu-
nosorbent assays. Only 14 patients had paired acute and convalescent serology, and no patients had a diagnosis of
infectious encephalitis based on a fourfold change in titer. A single raised anti-streptolysin O (group A Streptococcus, n =
1) and a positive IgM and IgG (HSV [n = 3] and Epstein–Barr virus, parvovirus B19 [each, n = 1]) result were used to
diagnose probable or possible infectious encephalitis. A positive IgM provided a probable infectious diagnosis for
Mycoplasma pneumoniae (n = 11).
a 11 patients had $2 etiologic associations and are presented in Supplemental Table 4.
b HSV-1 (n = 4, CSF PCR confirmed); HSV-2 (n = 1, skin swab polymerase chain reaction possible); 1 patient with probable
HSV (relapsing) also had positive serum NMDAR and D2R antibodies.
c Group A Streptococcus (n = 1, probable), adenovirus (n = 1, possible), Epstein–Barr virus (n = 1, possible), para-
influenza 3 virus (n = 1, possible), parvovirus B19 (n = 1, possible), varicella zoster virus (n = 1, possible).
d Associated infections (probable/possible) in 2 of 3 patients.
e 22 patients tested positive for $1 of the following antibodies: NMDAR (n = 11), VGKC (n = 7), D2R (n = 6), and glycine
receptor (n = 1). LGI1, CASPR2, and glutamic acid decarboxylase antibodies were negative in all. One patient with a VGKC-
complex antibody titer of 421 pM had positive glycine receptor antibody.
f 5 of the 7 VGKC-positive patients had Mycoplasma pneumoniae IgM detected (see Supplemental Table 4).
glutamic acid decarboxylase (n = 102) diagnosis was based on detection of
were tested as previously the organism from a specimen sample
described.11–14 Only 5 patients had outside the CNS, such as stool or
combined testing of CSF and serum nasopharyngeal aspirate.1 As
for autoantibodies (NMDAR only). accepted in the literature, we used
VGKC-complex antibody positivity the term infection-associated
was based on titers .150 pM, as encephalopathy rather than
suggested in children.15 Dopamine-2 encephalitis to denote encephalitis
receptor antibody testing (n = 103) related to influenza virus or
was undertaken as described.16 rotavirus.17–19 In cases with multiple
etiologies (Supplemental Table 4), the
Etiologic Causation agent with the strongest hierarchical
The final etiologic diagnosis was association (confirmed . probable .
determined by stringent application possible) was designated as the
of the consensus guidelines proposed etiology of encephalitis.
by Granerod et al.1 Cases were
classified as confirmed, probable, or Ethics
possible. Confirmed cases had The study was ethically approved
detection of the organism or (09/CHW/56), and written consent
autoantibody in CSF or brain.1 A was obtained from the families and
probable diagnosis was based on patients for a follow-up telephone
serological evidence of acute infection interview and testing of stored acute
or autoantibody, and a possible samples.
PILLAI et al
Statistical Analysis
For comparison of clinical variables
between the different major etiologic
groups, we used SAS version 9.3 (SAS
Institute, Inc, Cary, NC). Categorical
variables were compared with the
exact x2 test and described in terms
of proportions and Wilson confidence
intervals (CIs); continuous variables
were compared with the
Kruskal–Wallis test and described in
terms of median and range
(Supplemental Tables 5–8). We
assessed the relationship of clinical
variables to outcome by using
univariate and multivariate logistic
regression analyses. All variables with
a univariate P ,.05 were included as
potential predictors in a multivariate
model that used a stepwise backward
selection procedure in SPSS (IBM
SPSS Statistics, IBM Corporation). We
described these associations by using
odds ratios (ORs) and Wald CIs. We
assessed the association between
clinical variables to autoantibody
status by using the x2 test and
described it in terms of ORs and 95%
CIs. We made no adjustment for
multiple statistical testing.
Demographics and Seasonality
The median age at presentation was
5.5 years (range 5 weeks–15.1 years),
and 94 (57%) patients were male.
Figure 1 demonstrates that young
children are more frequently affected.
The majority of encephalitis cases
(n = 57, 35%) presented during the
Australian winter season
(June–August, data not shown).
Clinical Features, CSF, EEG, and MRI
Figure 2 and Supplemental Table 5
compare the clinical features, which
in descending order of frequency
were fever (n = 126, 77%), seizures
(n = 88, 54%), headache (n = 71,
43%), weakness or pyramidal signs
(n = 61, 37%), any respiratory
symptoms (n = 57, 35%), and
agitation (n = 56, 34%).
CSF pleocytosis was present in 110
out of 155 (71%) patients and
elevated CSF protein in 50 out of 154
(33%) patients. CSF neopterin was
elevated in 36/47 (77%) tested
patients. Oligoclonal bands were
measured in 53 (32%), and
intrathecal oligoclonal bands were
detected in only 2 patients (1 with
NMDAR encephalitis, 1 unknown)
and mirrored oligoclonal bands in
another 16 (5 infectious, 10 immune-
mediated [ADEM 4, NMDAR 4,
dopamine receptor D2 {D2R} 2], 1
unknown). Five patients with positive
serum NMDAR antibody also had
CSF testing and were confirmed CSF
NMDAR antibody positive. CSF
findings by subgroup are presented in
Supplemental Table 6. The EEG was
abnormal in 115 out of 130 (88%)
patients; EEG slowing was found in
111 out of 130 (85%) and
epileptiform discharges in 27 out of
130 (21%) patients, respectively.
Figure 3 and Supplemental Table 7
describe the MRI features. The MRI
brain (T2-weighted fluid-attenuated
inversion recovery) was abnormal in
121 out of 149 (81%) of patients.
Duration of Stay, Therapy, and Outcome
The mean and median length of stay
for patients were 27 and 13 days,
respectively (range 1–618 days).
Admission to the ICU was necessary
in 66 (40%) patients, with the
majority needing management of

RESULTS
All Encephalitis (n = 164)
Overview of Etiologies (Table 1)
A total of 164 children were
diagnosed with acute encephalitis. An
etiology was proposed in 118 (72%)
patients, of whom 64 (39%) were
confirmed, 29 (18%) probable, and
25 (15%) possible. In 46 (28%)
patients, the cause was unknown. The
etiologic groups were infectious
encephalitis, n = 49 (30%); infection-
associated encephalopathy, n = 13
(8%); and immune-mediated/
autoantibody-associated encephalitis,
n = 56 (34%). Complete autoantibody
and some infectious serological
findings are presented in Table 1.
Potential dual or multiple etiology
occurred in 11 (7%) patients FIGURE 1
Number of patients with acute encephalitis according to age at presentation and etiologic group.
(Supplemental Table 4), including 8 11% of patients were ,1 year of age, and 54% of patients were #5 years old, with the frequency
with Mycoplasma pneumoniae. descending steadily at later ages.

Downloaded from www.aappublications.org/news by guest on June 5, 2019

PEDIATRICS Volume 135, number 4, April 2015 e977
FIGURE 2
Clinical features at any stage in all encephalitis and major etiologic subgroups (n $ 7). Data including statistical significance is in Supplemental Table 5.
EV, enterovirus; GI, gastrointestinal; MycoP, Mycoplasma pneumoniae; Unk, unknown.

Downloaded from www.aappublications.org/news by guest on June 5, 2019

e978 PILLAI et al
FIGURE 3
MRI features according to neuroanatomical location and sequence characteristics in all encephalitis and the major etiologic subgroups (n $ 7). Data
including statistical significance are in Supplemental Table 7. EV, enterovirus; FLAIR, fluid-attenuated inversion recovery; MycoP, Mycoplasma pneumoniae;
T1-W, T1-weighted; T2-W, T2-weighted; Unk, unknown.

Downloaded from www.aappublications.org/news by guest on June 5, 2019

PEDIATRICS Volume 135, number 4, April 2015 e979
encephalopathy, seizures, or both. Of
the 164 patients, 147 (87%) received
antibiotics or antiviral therapy. The
mean and median duration of follow-
up were 6.6 years and 5.8 years,
respectively (range 1.1–14.4 years).
There were 5 deaths (4 in the
hospital).
Figure 4 compares the LOS measures.
An abnormal outcome (LOS 1–4) was
present in 71 out of 144 (49%)
patients, including LOS 1 (death) (n =
5, 4%), LOS 2 (severe) (n = 11, 8%),
LOS 3 (moderate) (n = 29, 20%), and
LOS 4 (mild) (n = 26, 18%). The most
common abnormal outcomes by
category (Supplemental Table 8)
were learning problems (n = 39,
28%), behavioral problems (n = 33,
24%), epilepsy (n = 25, 18%), and
speech problems (n = 24, 17%).
Clinical relapse occurred in 9 (5%)
patients: HSV encephalitis (n = 1),
ADEM (n = 1), NMDAR-Ab
encephalitis (n = 3), D2R antibody
encephalitis (n = 2), and unknown
(n = 2). Patients with NMDAR and
D2R antibodies were more likely to
relapse (P = .01).
FIGURE 4
Using univariate analysis, we found The LOS (1–5) in all encephalitis (n = 144, 88%) and the major etiologic subgroups (n $ 7). Data
that an abnormal long-term outcome including statistical significance is in Supplemental Table 8.
was associated with status epilepticus
(seizure .30 minutes) (OR 7.74; 95% symptoms (Mycoplasma, VGKC- (any T2-weighted fluid-attenuated
CI, 2.51–23.89), ICU admission (OR complex Ab), gastrointestinal inversion recovery abnormality) in
3.83; 95% CI, 1.91–7.72), diffusion symptoms (enterovirus), seizures NMDAR encephalitis. Abnormalities
restriction on MRI (OR 2.47; 95% CI, (HSV, VGKC-complex Ab), weakness detected with diffusion-weighted
1.03–5.98), and a movement disorder or pyramidal signs (ADEM), agitation sequencing, T1 sequences, contrast
(OR 2.44; 95% CI, 1.10–5.39). and psychiatric symptoms enhancement, hemorrhage, and cystic
Patients with an infectious prodrome (NMDAR), speech dysfunction (NMDAR), necrosis were all more common in
were less likely to have an abnormal movement disorder (NMDAR), HSV (Fig 3 and Supplemental
outcome (OR 0.28; 95% CI, cerebellar (ADEM), sleep disturbance Table 7). HSV and unknown
0.12–0.63). On multivariate analysis, (NMDAR), brainstem (ADEM and encephalitis had the worst outcomes,
status epilepticus (OR 3.78; 95% CI, enterovirus), and autonomic (NMDAR and ADEM had the best outcome
1.07–13.41, P = .04), diffusion and enterovirus). (Fig 4).
restriction (OR 2.47; 95% CI,
0.95–6.46, P = .06), and ICU According to etiology, the following Of the smaller subgroups (Table 1),
admission (OR 2.27; 95% CI, MRI features were more common all 4 patients with D2R
0.92–5.59, P = .08) each predicted an (Fig 3): abnormalities of white matter antibody–associated encephalitis had
abnormal outcome. (HSV, ADEM), cortical gray matter dystonia–Parkinsonism, and 3 out of
(HSV), basal ganglia (Mycoplasma and 4 had localized basal ganglia
ADEM), thalami (ADEM, HSV), involvement on MRI (basal ganglia
Subgroup Analysis cerebellum and brainstem (ADEM), encephalitis).16 Three patients had
According to etiology, the following and limbic encephalitis (NMDAR, acute necrotizing encephalopathy
clinical characteristics were more VGKC-complex, Mycoplasma). The with the typical radiologic
common (Fig 2): Respiratory MRI was least likely to be abnormal features.18,20 There were no other

Downloaded from www.aappublications.org/news by guest on June 5, 2019

e980 PILLAI et al
characteristic clinicoradiologic
features in the other small subgroups.
Clinicoradiologic Correlation With
Autoantibody Positivity
Using univariate analysis in patients
with non-ADEM encephalitis tested
for autoantibody (n = 103), we found
that an autoantibody-associated
encephalitis was more likely (in
descending order) with clinical
relapse (OR 13.5; 95% CI, 2.46–74.04,
P , .0001), movement disorder (OR
11.2; 95% CI, 3.82–32.9, P , .0001),
CSF intrathecal or mirrored
oligoclonal bands (OR 7.89; 95% CI,
1.53–40.5, P = .02), speech
dysfunction (OR 5.92; 95% CI,
2.03–17.2, P , .0001), psychiatric
symptoms (OR 4.79; 95% CI,
1.73–13.2, P = .002), agitation (OR
3.64; 95% CI, 1.34–9.94, P = .009),
and MRI limbic encephalitis
phenotype (OR 5.22; 95% CI,
1.27–21.5, P = .03). Antibody-
associated encephalitis was less
common with headache (OR 0.35;
95% CI, 0.12–0.98, P = .04) or MRI
thalamic involvement (OR 0.21; 95%
CI, 0.05–0.98, P = .03).
Immunotherapy and Outcome
A total of 60 out of 164 patients
(37%) received immunotherapy
(corticosteroids, n = 59; intravenous
immunoglobulin, n = 16; rituximab,
n = 2), most commonly for ADEM (27
out of 35), NMDAR-Ab encephalitis (6
out of 10), enterovirus (6 out of 20),
and unknown (9 out of 46)
subgroups. Abnormal outcome was
not different in the patients who
received immunotherapy compared
with those who did not (OR 1.17;
95% CI, 0.60–2.31, P = .64). The mean
length of stay was longer in patients
who received immune therapy
(41 days vs 19 days, P = .02).
DISCUSSION
This single-center cohort, followed up
for a median of 5.8 years, is the most
comprehensive retrospective analysis
of pediatric encephalitis to date. In
Downloaded from www.aappublications.org/news by guest on June 5, 2019
PEDIATRICS Volume 135, number 4, April 2015
a resource-rich setting, we have
defined the relative frequency of
acute encephalitis syndromes by
etiology, with emphasis on the
emerging treatable autoantibody-
associated encephalitides. Despite
long follow-up, the study confirms the
high morbidity in survivors of
encephalitis, the significant
proportion who lack a diagnosis, the
need to identify the autoantibody-
associated syndromes, and the need
to improve the acute management
and rehabilitation of these patients
with the hope of reducing long-term
residual neurocognitive impairments.
Immune-mediated/autoantibody-
associated encephalitides were the
most common etiologic group.
Although by definition ADEM is an
encephalomyelitis, it is notable that
many previous encephalitis cohorts
do not include ADEM but generally
focus on infectious encephalitis
alone.6–8,21 NMDAR-Ab encephalitis
was diagnosed in 6% of patients, who
had typical clinical features of the
disease, with dominant movement,
psychiatric, sleep, speech, and
autonomic features. The number
could be an underestimate, because
serum testing was performed on only
103 out of 129 (81%) of the patients
without ADEM. Indeed, 4 of the 46
patients with unknown encephalitis
had a phenotype reminiscent of
NMDAR-Ab encephalitis but were
negative for serum antibody. CSF
might have been helpful,14,22
although that is not our experience.
VGKC-complex antibodies were first
reported in adults with limbic
encephalitis.11 Subsequently, it was
found that the VGKC-complex
antibodies bound not to the VGKC
subunits themselves but to proteins,
namely LGI1 and CASPR2,12,23 which
are complexed with the VGKC
subunits in vivo. In this report, 7
(4%) of children had VGKC-complex
antibodies, but only 2 had evidence of
limbic encephalitis on imaging, and
they were not positive for LGI1 or
CASPR2 antibodies, as is often true
for pediatric cases with positive
VGKC-complex Ab.12,23–25 Although
150 pM has been proposed as
a positive result for VGKC-complex Ab
in children, levels .400 pM are more
relevant in adults,15,26 and only 2
children had these levels.
Nevertheless, VGKC-complex
antibodies appear to be associated
with inflammatory disorders
(Hacohen et al in preparation). The
association seen here of positive
VGKC-complex Ab with Mycoplasma
pneumoniae and with respiratory
symptoms (5 out of 7) suggests that
VGKC-complex Ab could be induced
as part of the immune response to
Mycoplasma pneumoniae. Mycoplasma
pneumoniae–associated encephalitis
occurred in 7% of our cohort,
although the diagnostic specificity
of mycoplasma IgM has been
questioned.27
Antibodies to D2R were
found in only 4 patients with
dystonia–Parkinsonism and basal
ganglia lesions, representing a small
subgroup (2%).16 There were no
patients with antibodies to glutamic
acid decarboxylase and only 1 patient
with glycine R antibody (who also
had VGKC-complex antibodies and
Mycoplasma), and reported pediatric
cases with these antibodies are rare.
Nine (20%) of the patients with
unknown encephalitis did not have
serum available for autoantibody
testing, and comprehensive testing
may help to ensure recognition of
known autoantibodies and to define
some of the “unknown” patients in
the future. For example,
g-aminobutyric acid A receptor
antibodies have recently been found
in patients with acute-onset severe
epilepsy and encephalitis,28 and it
will be interesting to test pediatric
patients with encephalitis for this
autoantibody.
Infectious encephalitis was found in
30%, and the most common infection
was enterovirus (12%). Even with
broad testing for HSV (84% of
patients), HSV encephalitis was
e981
diagnosed in only 5%, confirming
recent reports that HSV encephalitis
is less common in children than
adults with encephalitis.4,29,30
Despite early acyclovir therapy (not
described), the outcomes after HSV
encephalitis were poor, as described
in recent pediatric cohorts.30,31
Interestingly, 1 patient with HSV
encephalitis relapsed with chorea and
had NMDAR and D2R antibodies.32
The emerging theme of postviral
autoimmunity is increasingly
recognized, and it emphasizes the
importance of considering
immunotherapies in post-HSV
relapses.32–34 There were some
patients with $2 etiologic
associations (Supplemental Table 4),
and these patients provide
a challenge for diagnosis and
illustrate the overlap between
infectious and autoantibody-
associated syndromes.32,35–38
There were notable etiologic
absences in this cohort, such as no
Mycobacterium tuberculosis
encephalitis. Unlike in the United
Kingdom,5 Mycobacterium
tuberculosis is rare in Australian
children. We also did not observe any
confirmed varicella encephalitis,
a result probably related partly to the
introduction of routine varicella
vaccination during the study period.
As is true for most resource-rich
countries, we no longer observe
measles or mumps encephalitis
because of vaccination. Other
etiologies not seen in our cohort
include arboviruses and Bartonella.
There were small subgroups of
infection-associated encephalopathy
(8%) associated with influenza and
rotavirus, and these were kept as
a separate group, by convention.18,39
Acute necrotizing encephalopathy,
which is an infection-associated
encephalopathy, is observed more
frequently in Japanese and East
Asian children, presumably because
of their differing genetic
vulnerability.18
The main limitation of the study was
the retrospective design and
therefore incomplete investigation
and the potential incomplete
ascertainment of milder or atypical
cases. Despite these limitations, the
study confirms that encephalitis is
a serious disease with an abnormal
outcome in ∼50%, particularly in
cognitive and behavioral domains,
with 3% mortality. In general, the
predictors of poor outcomes were ICU
admission and status epilepticus, as
in previous studies.40–42 In addition,
we found diffusion restriction on MRI,
a marker of cytotoxic injury,
correlated with abnormal outcomes.
The use of immunotherapy was not
associated with better outcomes, but
the patients receiving immune
therapy had longer admissions,
suggesting that these patients had
a more complicated course.
Immunotherapy has only recently
become established in the treatment
of autoantibody-associated
encephalitis (other than ADEM),3 and
prospective studies are needed to
determine the benefit of
immunotherapy in patients with
encephalitis irrespective of whether
an autoantibody is detected. The
percentage of unknown encephalitis
(28%) in this study is the lowest
among substantial pediatric
cohorts,6–8,40,41 but it represents an
important subgroup that is
comparable in size to the prospective
UK cohort in adults and children.5
There were no distinguishing clinical
or radiologic characteristics of the
unknown subgroup, mainly because
of the likely heterogenous etiologies.
The unknown encephalitis group may
contain both encephalitis of viral
origin (untested or unknown) and
autoimmune etiologies. The poor
outcome in this group emphasizes the
importance of future research in this
area.
ACKNOWLEDGMENTS
We thank the patients, their families,
and all health professionals who
contributed to this study. S.C.P. has
funding from the Australian
Postgraduate Award scheme. Y.H. has
funding from Oxford University
Clinical Academic Graduate School
and Oxford National Institute for
Health Research Biomedical Research
Centre. R.C.D. and F.B. have funding
from NHMRC (Australia) for this
work.

was involved in clinical data acquisition and analysis; Dr Davies was involved in study design and edited drafts; Dr Prelog performed radiological phenotyping and
edited drafts; Drs Tantsis, Gill, Webster, Menzes, Ardern-Holmes, Gupta, Procopis, Troedson, Antony, Ouvrier, and Polfrit were involved in clinical data acquisition and
analysis and edited drafts; Dr Barnes performed statistical analysis and edited drafts; Dr Vincent supervised autoantibody testing and edited first and subsequent
drafts; Dr Dale conceived and designed the study, supervised all clinical aspects of the study, performed radiological phenotyping, wrote the first draft, and edited
subsequent drafts; and all authors approved the final manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2014-2702
DOI: 10.1542/peds.2014-2702
Accepted for publication Jan 6, 2015
Address correspondence to Russell C. Dale, PhD, Clinical School, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: russell.
dale@health.nsw.gov.au
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2015 by the American Academy of Pediatrics

Downloaded from www.aappublications.org/news by guest on June 5, 2019

e982 PILLAI et al
FINANCIAL DISCLOSURE: S.C.P., F.B., and R.C.D. are funded by Australian Postgraduate Award, Star Scientific Foundation, Petre Foundation, and National Health and
Medical Research Council. Y.H. has funding from Oxford University Clinical Academic Graduate School and Oxford National Institute for Health Research Biomedical
Research Centre. The other authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Dr Pillai has an Australian Postgraduate Award, and Drs Dale and Brilot have funding from Star Scientific Foundation, Petre Foundation, and National
Health and Medical Research Council. No other authors have funding relevant to this project.
POTENTIAL CONFLICT OF INTEREST: Dr Waters has received speaker honoraria from Euroimmun AG. The other authors have indicated they have no potential conflicts
of interest to disclose.
REFERENCES
1. Granerod J, Cunningham R, Zuckerman
M, et al. Causality in acute encephalitis:
defining aetiologies. Epidemiol Infect.
2010;138(6):783–800
2. Dale RC, Brilot F, Duffy LV, et al. Utility and
safety of rituximab in pediatric
autoimmune and inflammatory CNS
disease. Neurology. 2014;83(2):142–150
3. Titulaer MJ, McCracken L, Gabilondo I,
et al. Treatment and prognostic factors
for long-term outcome in patients with
anti-NMDA receptor encephalitis: an
observational cohort study. Lancet
Neurol. 2013;12(2):157–165
4. Gable MS, Sheriff H, Dalmau J, Tilley DH,
Glaser CA. The frequency of autoimmune
N-methyl-D-aspartate receptor
encephalitis surpasses that of individual
viral etiologies in young individuals
enrolled in the California Encephalitis
Project. Clin Infect Dis. 2012;54(7):
899–904
5. Granerod J, Ambrose HE, Davies NWS,
et al; UK Health Protection Agency (HPA)
Aetiology of Encephalitis Study Group.
Causes of encephalitis and differences in
their clinical presentations in England:
a multicentre, population-based
prospective study. Lancet Infect Dis.
2010;10(12):835–844
6. Koskiniemi M, Korppi M, Mustonen K,
et al. Epidemiology of encephalitis in
children. A prospective multicentre
study. Eur J Pediatr. 1997;156(7):541–545
7. Fowler A, Stödberg T, Eriksson M,
Wickström R. Childhood encephalitis in
Sweden: etiology, clinical presentation
and outcome. Eur J Paediatr Neurol.
2008;12(6):484–490
8. Kolski H, Ford-Jones EL, Richardson S,
et al. Etiology of acute childhood
encephalitis at The Hospital for Sick
Children, Toronto, 1994–1995. Clin Infect
Dis. 1998;26(2):398–409
9. Dale RC, Brilot F, Fagan E, Earl J.
Cerebrospinal fluid neopterin in
Downloaded from www.aappublications.org/news by guest on June 5, 2019
PEDIATRICS Volume 135, number 4, April 2015
paediatric neurology: a marker of active 1994–2002. Virus Res. 2004;103(1–2):
central nervous system inflammation. 75–78
Dev Med Child Neurol. 2009;51(4):
18. Mizuguchi M, Yamanouchi H, Ichiyama T,
317–323
Shiomi M. Acute encephalopathy
10. Lewthwaite P, Begum A, Ooi MH, et al. associated with influenza and other viral
Disability after encephalitis: infections. Acta Neurol Scand. 2007;115(4
development and validation of a new suppl):45–56
outcome score. Bull World Health Organ.
19. Lynch M, Lee B, Azimi P, et al. Rotavirus
2010;88(8):584–592
and central nervous system symptoms:
11. Vincent A, Buckley C, Schott JM, et al. cause or contaminant? Case reports and
Potassium channel antibody-associated review. Clin Infect Dis. 2001;33(7):
encephalopathy: a potentially 932–938
immunotherapy-responsive form of
20. Mizuguchi M. Acute necrotizing
limbic encephalitis. Brain. 2004;127(3):
encephalopathy of childhood: a novel
701–712
form of acute encephalopathy prevalent
12. Irani SR, Alexander S, Waters P, et al. in Japan and Taiwan. Brain Dev. 1997;
Antibodies to Kv1 potassium 19(2):81–92
channel–complex proteins leucine-rich,
21. Glaser CA, Gilliam S, Schnurr D, et al;
glioma inactivated 1 protein and
California Encephalitis Project,
contactin-associated protein-2 in limbic
1998–2000. In search of encephalitis
encephalitis, Morvan’s syndrome and
etiologies: diagnostic challenges in the
acquired neuromyotonia. Brain. 2010;
California Encephalitis Project,
133(9):2734–2748
1998–2000. Clin Infect Dis. 2003;36(6):
13. Hutchinson M, Waters P, McHugh J, et al. 731–742
Progressive encephalomyelitis, rigidity,
22. Gresa-Arribas N, Titulaer MJ, Torrents A,
and myoclonus: a novel glycine receptor
et al. Antibody titres at diagnosis and
antibody. Neurology. 2008;71(16):
during follow-up of anti-NMDA receptor
1291–1292
encephalitis: a retrospective study.
14. Dalmau J, Lancaster E, Martinez- Lancet Neurol. 2014;13(2):167–177
Hernandez E, Rosenfeld MR, Balice-
23. Lai M, Huijbers MGM, Lancaster E, et al.
Gordon R. Clinical experience and
Investigation of LGI1 as the antigen in
laboratory investigations in patients with
limbic encephalitis previously attributed
anti-NMDAR encephalitis. Lancet Neurol.
to potassium channels: a case series.
2011;10(1):63–74
Lancet Neurol. 2010;9(8):776–785
15. Haberlandt E, Bast T, Ebner A, et al.
24. Hacohen Y, Wright S, Waters P, et al.
Limbic encephalitis in children and
Paediatric autoimmune
adolescents. Arch Dis Child. 2011;96(2):
encephalopathies: clinical features,
186–191
laboratory investigations and outcomes
16. Dale RC, Merheb V, Pillai S, et al. in patients with or without antibodies to
Antibodies to surface dopamine-2 known central nervous system
receptor in autoimmune movement and autoantigens. J Neurol Neurosurg
psychiatric disorders. Brain. 2012;135(pt Psychiatry. 2013;84(7):748–755
11):3453–3468
25. Suleiman J, Brenner T, Gill D, et al. VGKC
17. Togashi T, Matsuzono Y, Narita M, antibodies in pediatric encephalitis
Morishima T. Influenza-associated acute presenting with status epilepticus.
encephalopathy in Japanese children in Neurology. 2011;76(14):1252–1255
e983
26. Paterson RW, Zandi MS, Armstrong R,
Vincent A, Schott JM. Clinical relevance
of positive voltage-gated potassium
channel (VGKC)-complex antibodies:
experience from a tertiary referral
centre. J Neurol Neurosurg Psychiatry.
2014;85(6):625–630
27. Christie LJ, Honarmand S, Talkington DF,
et al. Pediatric encephalitis: what is the
role of Mycoplasma pneumoniae?
Pediatrics. 2007;120(2):305–313
28. Petit-Pedrol M, Armangue T, Peng X, et al.
Encephalitis with refractory seizures,
status epilepticus, and antibodies to the
GABAA receptor: a case series,
characterisation of the antigen, and
analysis of the effects of antibodies.
Lancet Neurol. 2014;13(3):276–286
29. Mailles A, Stahl JP; Steering Committee
and Investigators Group. Infectious
encephalitis in France in 2007: a national
prospective study. Clin Infect Dis. 2009;
49(12):1838–1847
30. Elbers JM, Bitnun A, Richardson SE, et al.
A 12-year prospective study of childhood
herpes simplex encephalitis: is there
a broader spectrum of disease?
Pediatrics. 2007;119(2). Available at:
www.pediatrics.org/cgi/content/full/119/
2/e399
31. Schleede L, Bueter W, Baumgartner-Sigl
S, et al. Pediatric herpes simplex virus
Downloaded from www.aappublications.org/news by guest on June 5, 2019
e984
encephalitis: a retrospective multicenter
experience. J Child Neurol. 2013;28(3):
321–331
32. Mohammad SS, Sinclair K, Pillai S, et al.
Herpes simplex encephalitis relapse with
chorea is associated with autoantibodies
to N-methyl-D-aspartate receptor or
dopamine-2 receptor. Mov Disord. 2014;
29(1):117–122
33. Armangue T, Leypoldt F, Málaga I, et al.
Herpes simplex virus encephalitis is
a trigger of brain autoimmunity. Ann
Neurol. 2014;75(2):317–323
34. Hacohen Y, Deiva K, Pettingill P, et al. N-
methyl-D-aspartate receptor antibodies
in post–herpes simplex virus
encephalitis neurological relapse. Mov
Disord. 2014;29(1):90–96
35. Prüss H, Finke C, Höltje M, et al. N-methyl-
D-aspartate receptor antibodies in
herpes simplex encephalitis. Ann Neurol.
2012;72(6):902–911
36. Titulaer MJ, Höftberger R, Iizuka T, et al.
Overlapping demyelinating syndromes
and anti–N-methyl-D-aspartate receptor
encephalitis. Ann Neurol. 2014;75(3):
411–428
37. Hacohen Y, Absoud M, Woodhall M, et al;
UK & Ireland Childhood CNS
Inflammatory Demyelination Working
Group. Autoantibody biomarkers in
childhood-acquired demyelinating
syndromes: results from a national
surveillance cohort. J Neurol Neurosurg
Psychiatry. 2014;85(4):456–461
38. Tsiodras S, Kelesidis I, Kelesidis T,
Stamboulis E, Giamarellou H. Central
nervous system manifestations of
Mycoplasma pneumoniae infections.
J Infect. 2005;51(5):343–354
39. Amin R, Ford-Jones E, Richardson SE,
et al. Acute childhood encephalitis and
encephalopathy associated with
influenza: a prospective 11-year
review. Pediatr Infect Dis J. 2008;27(5):
390–395
40. DuBray K, Anglemyer A, LaBeaud AD,
et al. Epidemiology, outcomes and
predictors of recovery in childhood
encephalitis: a hospital-based study.
Pediatr Infect Dis J. 2013;32(8):839–844
41. Wang IJ, Lee PI, Huang LM, Chen CJ, Chen
CL, Lee WT. The correlation between
neurological evaluations and
neurological outcome in acute
encephalitis: a hospital-based study.
Eur J Paediatr Neurol. 2007;11(2):63–69
42. Fowler A, Stödberg T, Eriksson M,
Wickström R. Long-term outcomes of
acute encephalitis in childhood.
Pediatrics. 2010;126(4). Available at:
www.pediatrics.org/cgi/content/full/126/
4/e828
PILLAI et al
 Infectious and Autoantibody-Associated Encephalitis: Clinical Features and
Long-term Outcome
Sekhar C. Pillai, Yael Hacohen, Esther Tantsis, Kristina Prelog, Vera Merheb, Alison
Kesson, Elizabeth Barnes, Deepak Gill, Richard Webster, Manoj Menezes, Simone
Ardern-Holmes, Sachin Gupta, Peter Procopis, Christopher Troedson, Jayne Antony,
Robert A. Ouvrier, Yann Polfrit, Nicholas W. S. Davies, Patrick Waters, Bethan Lang,
Ming J. Lim, Fabienne Brilot, Angela Vincent and Russell C. Dale
Pediatrics 2015;135;e974
DOI: 10.1542/peds.2014-2702 originally published online March 23, 2015;

Updated Information &
Services
References
Subspecialty Collections
Permissions & Licensing
Reprints
including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/135/4/e974
This article cites 41 articles, 9 of which you can access for free at:
http://pediatrics.aappublications.org/content/135/4/e974#BIBL
This article, along with others on similar topics, appears in the
following collection(s):
Neurology
http://www.aappublications.org/cgi/collection/neurology_sub
Neurologic Disorders
http://www.aappublications.org/cgi/collection/neurologic_disorders_
sub
Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on June 5, 2019

 Infectious and Autoantibody-Associated Encephalitis: Clinical Features and
Long-term Outcome
Sekhar C. Pillai, Yael Hacohen, Esther Tantsis, Kristina Prelog, Vera Merheb, Alison
Kesson, Elizabeth Barnes, Deepak Gill, Richard Webster, Manoj Menezes, Simone
Ardern-Holmes, Sachin Gupta, Peter Procopis, Christopher Troedson, Jayne Antony,
Robert A. Ouvrier, Yann Polfrit, Nicholas W. S. Davies, Patrick Waters, Bethan Lang,
Ming J. Lim, Fabienne Brilot, Angela Vincent and Russell C. Dale
Pediatrics 2015;135;e974
DOI: 10.1542/peds.2014-2702 originally published online March 23, 2015;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/135/4/e974

Data Supplement at:

http://pediatrics.aappublications.org/content/suppl/2015/03/17/peds.2014-2702.DCSupplemental

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on June 5, 2019