Infectious and Autoimmune Causes of

Encephalitis in Children
Timothy A. Erickson, PhD, MSPH,a,b,f Eyal Muscal, MD, MS,g,f Flor M. Munoz, MD,c Timothy Lotze, MD,d Rodrigo Hasbun, MD,e
Eric Brown, PhD,b Kristy O. Murray, DVM, PhDa,f

Encephalitis can result in neurologic morbidity and mortality in

BACKGROUND AND OBJECTIVES: abstract
children. Newly recognized infectious and noninfectious causes of encephalitis have become
increasingly important over the past decade.
METHODS:We retrospectively reviewed medical records from pediatric patients in Houston
diagnosed with encephalitis in both an urban and rural catchment area between 2010 and
2017. We conducted an investigation to understand the etiology, clinical characteristics, and
diagnostic testing practices in this population.
RESULTS: We evaluated 231 patients who met the case definition of encephalitis, among which
42% had no recognized etiology. Among those with an identified etiology, the most common
were infectious (73; 31%), including viral (n = 51; 22%), with the most frequent being West
Nile virus (WNV; n = 12), and bacterial (n = 19; 8%), with the most frequent being Bartonella
henselae (n = 7). Among cases of autoimmune encephalitis (n = 60; 26%), the most frequent
cause was anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis (n = 31). Autoimmune
causes were seen more commonly in female (P , .01) patients. Testing for herpes simplex
virus and enterovirus was nearly universal; testing for anti-NMDAR encephalitis, WNV, and
Bartonella was less common.
WNV was the most common infectious cause of encephalitis in our pediatric
CONCLUSIONS:
population despite lower testing frequency for WNV than herpes simplex virus or enterovirus.
Increasing testing for anti-NMDAR encephalitis resulted in frequent identification of cases.
Increased awareness and testing for WNV and Bartonella would likely result in more
identified causes of pediatric encephalitis. Earlier etiologic diagnosis of encephalitides may
lead to improve clinical outcomes.

a
Section of Pediatric Tropical Medicine, National School of Tropical Medicine, cSection of Infectious Diseases, WHAT’S KNOWN ON THIS SUBJECT: Pediatric
d
Section of Neurology, Department of Pediatrics, and gSection of Rheumatology, Department of Pediatrics, Baylor encephalitides are often severe and lack an identified
College of Medicine and Texas Children’s Hospital, Houston, Texas; bDepartment of Epidemiology, Human Genetics, etiology. Newly recognized viruses and autoimmune
and Environmental Sciences, School of Public Health, University of Texas Health Science Center, Houston, Texas;
e causes are considered to be important, but no large
Section of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas
Health Science Center, Houston, Texas; and fWilliam T. Shearer Center for Human Immunobiology, Texas Children’s recent studies have been conducted to assess their
Hospital, Houston, Texas exact role in children.
Dr Erickson reviewed all cases and was involved with study design, data analysis, and writing of the WHAT THIS STUDY ADDS: We found more
manuscript; Dr Muscal reviewed cases of autoimmune etiology and was involved with study design encephalitides caused by West Nile virus, Bartonella,
and writing of the manuscript; Dr Munoz reviewed certain cases of infectious etiology and was and autoimmune disease, despite these conditions
involved with study design and writing of the manuscript; Dr Lotze reviewed cases of acute being tested for less frequently. Testing for these
disseminated encephalomyelitis and was involved with study design and writing of the manuscript; conditions will improve our understanding of etiology
Dr Hasbun developed initial study protocol, was involved with study design, consulted for infectious
and pathogenesis and may improve patient outcomes.
cases, and was involved with writing of the manuscript; Dr Brown was involved with study design
and writing of the manuscript; Dr Murray was involved with study design, reviewed cases of
zoonotic etiology, and was involved with writing of the manuscript; (Continued) To cite: Erickson TA, Muscal E, Munoz FM, et al. Infectious
and Autoimmune Causes of Encephalitis in Children.
Pediatrics. 2020;145(6):e20192543

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PEDIATRICS Volume 145, number 6, June 2020:e20192543 ARTICLE
There are .100 different etiologies that
can lead to encephalitis in children;
however, most researchers have found
that the majority (50%– 70%) of
patients lack an identified etiology.1–5
Encephalitis in the pediatric population
may result in substantial morbidity,
disability, and even mortality. Because
a high proportion of encephalitis
patients have an infectious etiology, and
these agents differ with respect to
geography and ecology, etiologies of
encephalitis may have regional
variability. Additionally, a number of
newly discovered causes of encephalitis,
predominantly autoimmune, have been
recognized in the past 2 decades,
leading to the need for contemporary
pediatric prevalence studies.6–8
Inflammatory and autoimmune causes
of encephalitis may be treatable if
identified early in a patient’s course of
illness. To understand the prevalence of
infectious and noninfectious etiologies
of childhood encephalitis, we conducted
an analysis of all pediatric cases at
a large pediatric hospital system in
Houston, Texas.
METHODS
Study Population
We conducted a retrospective chart
review of all patients with an
International Classification of Diseases,
Ninth Revision (ICD-9) or International
Classification of Diseases, 10th Revision
(ICD-10) code associated with
encephalitis or meningoencephalitis
admitted to Texas Children’s Hospital
(TCH) from January 1, 2010, to
December 31, 2017 (Supplemental
Information). The geographic catchment
area for TCH is extensive and includes
both rural and urban settings. Patients
were reviewed and classified as
encephalitis if they met the 2013
definition of the International
Encephalitis Consortium.9 To meet the
definition for encephalitis, patients
needed to have documented altered
mental status lasting at least 24 hours
with no other explainable cause.
Additionally, to be defined as
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2 ERICKSON et al
encephalitis, a patient required at least 2
of the following: (1) fever $38°C within
3 days of presentation, (2) new onset
seizures, (3) new onset of focal
neurologic findings, (4) cerebrospinal
fluid (CSF) white blood cell count $5/
mm3, (5) new onset neuroimaging
abnormality consistent with
encephalitis, or (6) EEG abnormality not
associated with another cause. If
patients did not have an identified
infectious etiology, then their charts
were screened and reviewed by 2 of the
authors (T.A.E., E.M.) using the recently
developed criteria for autoimmune
encephalitis.10 To meet the criteria for
autoimmune encephalitis, patients
required evidence of altered mental
status or neuropsychiatric deficits and
at least 1 objective central nervous
system abnormality: focal neurologic
abnormality, new onset seizures, CSF
pleocytosis, or neuroimaging finding
suggestive of encephalitis.
Patients were excluded if they were
,90 days old at time of admission or
if they were .18 years of age. Only
incident patients were included. We
retained patients who were first seen
at an outside hospital and then
transferred to TCH if they had
medical records from the initial
hospitalization. Patients who were
transferred to our hospital and had
missing information regarding
diagnostic testing or length of stay
from the outside hospital were
excluded from this study (Fig 1).
Data Collection
We acquired data on demographic
factors, immune compromise, tests
ordered and conducted to determine
the cause of encephalitis, and CSF
laboratory values. We created
a variable for admission season
(summer defined as the 6 months with
highest temperature in Houston, May 1
to October 31).11 All patients were
classified as infectious or noninfectious
and further clarified as autoimmune
and immune mediated, infectious
including viral, bacterial, other (eg,
parasitic or fungal), or unknown. Viral
diseases were identified by CSF
polymerase chain reaction (PCR) or
serology (immunoglobulin G [IgG]
and immunoglobulin M [IgM])
identification as relevant; cases were
also identified by blood sample PCR or
serology in the presence of encephalitis
if no CSF result was available. Arboviral
diseases were diagnosed via a panel of
testing that included IgM for West Nile
virus (WNV), St Louis encephalitis
virus, California encephalitis virus,
eastern equine encephalitis virus
(EEEV), and western equine
encephalitis virus (WEEV). Patients
with encephalitis associated with
respiratory viruses (influenza A and B,
parainfluenza 1–3, human
metapneumovirus, adenovirus, and
respiratory syncytial virus) were
identified through nasal wash PCR
detection of a viral agent during the
hospitalization for encephalitis.
Bacterial causes of disease were
identified either through culture or
via relevant serological testing for
Bartonella, Ehrlichia, and Rickettsia.
Patients were considered positive for
an autoimmune condition if the CSF
antibody test was present in an
abnormal range in the absence of any
other identified cause of encephalitis.
Hashimoto’s encephalopathy and
patients with acute disseminated
encephalomyelitis (ADEM) were
included if they met previously
published guidelines and reviewed by
coauthors (T.A.E. and T.L.).10,12 ADEM
was classified as autoimmune or
immune mediated on the basis of
recent literature implicating multiple
white matter disease autoantibodies in
this disease process.13–15 Time to
diagnosis was calculated by subtracting
the first date of admission, at TCH or at
an outside facility, from the date
positive results were obtained that
were used to classify the etiologic cause
of disease.
Statistical Methodology
We conducted comparisons of
categorical variables with x2 testing
with statistical significance set at the
0.05 level. For cells with ,5

FIGURE 1
Patient selection diagram.
observations, we used Fisher exact test.
All statistics were calculated by using
Stata 14.0 (Stata Corp, College Station,
TX). This study was reviewed and
approved by Baylor College of Medicine
Institutional Review Board H-35069.
RESULTS
Through ICD-9 and ICD-10 coding-
based searches of the hospital
database, we identified 409 patients
who were .90 days of age and had
a discharge diagnosis of encephalitis.
After applying the International
Encephalitis Consortium case
definition, 231 patients with
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PEDIATRICS Volume 145, number 6, June 2020
encephalitis were retained (Fig 1).
Half of the patients (133; 58%) had 1
of 29 identified etiologies of
encephalitis, and 42% had no
identified cause. The most common
identified etiologies were infectious
(73 out of 133; 55%) versus
noninfectious or autoimmune (n = 60
out of 133; 45%) (Table 1).
Among the infectious causes of
encephalitis, viral causes were most
incident (n = 51 out of 73; 70%), with
almost one-fifth (n = 13 out of 73;
18%) diagnosed with arboviral
encephalitis, including 12 confirmed
cases of WNV and 1 case of California
encephalitis virus. Although we did
not confirm or include them in our
case numbers, we also identified
IgG–positive probable cases of WNV
(n = 8) and St Louis encephalitis virus
(n = 1). Three patients had positive
IgM for EEEV with low-level antibody
detection. Two of these patients were
subsequently tested by plaque
reduction neutralization using
convalescent sera; both were negative.
With regard to other viral causes,
human herpesvirus (HHV) was also
frequently identified, with herpes
simplex virus 1 (HSV-1) (n = 10),
human herpesvirus 6 (HHV-6) (n = 4),
Varicella Zoster virus (n = 3), Epstein-
Barr virus (n = 2), and herpes simplex
virus 2 (HSV-2) (n = 1) infections
diagnosed. Seven encephalitis cases
were diagnosed with enterovirus.
Respiratory viruses isolated from
nasal wash in patients with
encephalitis were also found, including
influenza (n = 6), parainfluenza (n =
2), and adenovirus (n = 2). One case
was diagnosed with lymphocytic
choriomeningitis virus (LCMV) (n = 1).
Bacterial encephalitis was present at
a lower rate than other causes;
however, it was still responsible for 19
of 133 (14%) patients identified in our
study. The leading identified cause of
bacterial encephalitis was Bartonella
henselae (n = 7). Patients with
antibodies to Rickettsia rickettsii (n =
2) were also present in this group.
Streptococcus pneumoniae (n = 5),
Neisseria meningitidis (n = 1), Serratia
marcescens (n = 1), Bacillus cereus (n =
1), Staphylococcus aureus (n = 1), and
Haemophilus influenzae (n = 1) were
all grown in culture from the CSF of
patients with meningoencephalitis
who met the clinical definition for this
study (Table 2).
In addition to viral and bacterial
causes of encephalitis, we also
identified fungal etiologies associated
with Cryptococcus neoformans (n = 1)
and Candida lusitaniae (n = 1), and 1
patient diagnosed with primary
amebic meningoencephalitis, the
3
TABLE 1 Baseline Characteristics of 231 Children With Encephalitis, Houston, Texas, 2010–2017
Case Characteristics Overall, N = 231 Infectious Causes Noninfectious Causes Unknown,
Viral, Bacterial, Other Infectious,a Autoimmune, n = 98
n = 51 n = 19 n=3 n = 60
Male sex, n (%) 126 (55)b 34 (67) 11 (58) 3 (100) 25 (42) 53 (54)
Mean age in y (range) 8.1 (0–18) 7.2 (0–18) 6.8 (1–16) 3.9 (0–17) 8.4 (0–18) 9.1 (1–18)
Race and ethnicity, n (%)
White, non-Hispanic 76 (33) 22 (43) 8 (42) 1 (33) 16 (27) 29 (30)
White, Hispanic 91 (40) 20 (39) 7 (37) 2 (67) 28 (47) 34 (35)
Black 39 (17) 4 (8) 3 (16) 0 11 (18) 21 (21)
Asian American 11 (5) 3 (6) 0 0 3 (5) 5 (5)
Middle Eastern 5 (2) 0 0 0 1 (2) 4 (4)
Multiple or missing 9 (4) 2 (4) 1 (5) 0 1 (2) 5 (5)
Patient transferred after admission 92 (40) 17 (33) 9 (47) 1 (33) 28 (47) 37 (38)
to an outside hospital, n (%)
Immune compromised, n (%) 23 (10) 9 (18) 1 (5) 2 (67) 2 (3) 9 (9)
Mean Glasgow Coma Scale on 12.3 (3–15) 12.3 (3–15) 11.3 (3–15) 11.7 (8–15) 12.8 (3–15) 12.2 (3–15)
admission (range)
New onset seizure recorded, n (%) 142 (62) 31 (61) 12 (63) 2 (67) 39 (65) 58 (60)
Abnormal MRI findingsc, n (%) 143 out of 219 (65) 35 out of 48 (73) 15 out of 17 (88) 3 out of 3 (100) 33 out of 59 (56) 57 out of 92 (62)
Abnormal EEG findingsc, n (%) 132 out of 159 (83) 29 out of 35 (83) 15 out of 15 (100) 3 out of 3 (100) 33 out of 42 (79) 52 out of 64 (81)
Median No. days hospitalized (range) 12 (3–302) 12 (3–302) 13 (4–83) 69 (3–111) 16.5 (5–101) 10 (3–147)
Fatal cases, n (%) 9 (4) 3 (6) 0 1 (33) 0 5 (5)
a Other includes fungal causes (n = 2) and amoebic infections (n = 1).
b All percentages reflect the number in the cell divided by the n represented in the top of the column.
c The first available MRI and EEG acquired during the admission were used to generate this variable; some patients did not have one or the other test conducted. Denominators include

219 MRI and 159 EEG conducted total, 48 MRI and 35 EEG conducted for viral patients, 17 MRI and 15 EEG conducted for bacterial patients, 3 MRI and 3 EEG conducted for other infectious
patients, 59 MRI and 42 EEG for patients with autoimmune encephalitis, and 92 MRI and 64 EEG conducted for patients with unknown etiology.

result of infection with the parasite including the patient with N. fowleri. had the highest probability of
Naegleria fowleri. Of these, the majority (n = 5) had returning a positive result (27%). The
unknown causes despite each frequency of anti-NMDAR test
Autoimmune and immune-mediated
receiving extensive testing, including administration dramatically increased
causes of encephalitis represented
anti-NMDAR, herpes, Bartonella, WNV throughout the study, from 29% tested
45% (n = 60 out of 133) of all patients
and other arboviruses, and other in 2010 to 76% in 2017 (Fig 2),
with an identified etiology (Table 2).
infectious and noninfectious helping to reduce the percentage of
Anti–N-methyl-D-aspartate receptor
etiologies. The other 3 deaths were unknown etiology from 52% in year
(NMDAR) encephalitis was the most
caused by enterovirus, HSV-1, and 2010 to 2011 to 36% in 2016 to 2017.
frequently identified single cause of
HHV-6, respectively. The patient with
encephalitis (n = 31 out of 60; 52%).
HHV-6 was a recipient of a medically Time to diagnosis of causal agents
Another condition broadly classified as
complex bone marrow transplant, so differed between major causes of
autoimmune, ADEM, was the second
it was unclear as to the influence of encephalitis (Table 2). Zoonotic and
most common identified cause of
HHV-6 in this fatal outcome. autoimmune causes were identified
encephalitis in this population (n = 18
nearly a week (median = 6 days) after
out of 60; 30%); Hashimoto’s
With regard to diagnostic testing presentation, with some taking longer
encephalitis (n = 6) was the seventh
practices, PCR testing for HSV-1 and than one week, whereas more
most common cause of encephalitis.
HSV-2 was common (90%). These test traditionally accepted causes (ie, HSV
We also identified instances of
results were frequently negative, with and enterovirus) were identified in
autoimmune encephalitis related to
only 11 (HSV-1 = 10, HSV-2 = 1) less than half this time (median, 2
anti-voltage-gated potassium channel
positive (11 out of 197; 5.6%). Overall, days). For bacterial pathogens,
(anti-VGKC), anti-glutamic acid
70% of those who had CSF cultures positive results varied between
decarboxylase (anti-GAD), and anti-
negative for bacterial growth had an culture positive (median, 3 days) and
crossveinless 2/collapsin resonse
arboviral panel ordered. There was intracellular (median, 6 days).
mediator protein 5 (anti-CV2/CRMP5)
a trend toward more testing for WNV Autoimmune causes took longer to
antibodies. Cumulatively, non–anti-
in the summer than in winter (76% vs diagnose (median, 6 days) than the
NMDAR causes represented 48% of
62%, P = .03). Of those with no known majority of infectious causes,
identified autoimmune encephalitis.
cause of encephalitis, almost half (n = particularly for those diseases
There were a total of 9 deaths (4%) 42, 43%) were not tested for anti- associated with rarer autoimmune
recorded in this retrospective cohort, NMDAR antibodies; however, this test antibodies (median, 32.5 days).

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4 ERICKSON et al
TABLE 2 Clinical and Laboratory Findings by Cause of Encephalitis
Etiology No. Time From Symptom Onset to Time From Hospitalization to Fever, Rash, CSF CSF
Cases Hospitalization, Diagnosis, n (%) n (%) Pleocytosis, Lymphocyte,
d (range) d (range) n (%) % (range)
Autoimmune
Anti-NMDAR 31 8 (0–90) 6 (1–17) 5 (16) 1 (3) 23 (74) 91 (67–95)
ADEM 18 5 (1–10) 5.5 (0–43) 13 (72) 2 (11) 16 (89) 58.5 (8–93)
Hashimoto’s 6 1 (0–30) 9.5 (0–13) 2 (33) 0 1 (17) —a
Other autoimmuneb 5 10 (0–60) 32.5 (6–53) 2 (40) 0 1 (20) —a
Viral
Herpesvirus 20 2 (0–21) 2 (1–37) 15 (75) 5 (26) 18 (90) 75 (18–92)
Arbovirus 13 0 (4–10) 6 (4–13) 12 (92) 5 (39) 12 (92) 52 (13–91)
Respiratory virusb 10 1 (0–7) 2 (1–24) 9 (90) 1 (10) 5 (50) 74 (2–83)
Enterovirus 7 2 (1–10) 2.5 (1–9) 6 (86) 0 7 (100) 53 (1–96)
Lymphocytic 1 2 8 1 (100) 0 0 —a
choriomeningitis virus
Bacterial
Gram-positive bacteria 7 4 (2–18) 3 (2–9) 6 (86) 0 7 (100) 1 (0–60)
Gram-negative bacteria 3 3 (1–20) 4.5 (3–6) 2 (66) 0 3 (100) 2 (0–4)
B. henselae 7 1 (0–7) 6 (2–8) 5 (71) 2 (29) 3 (43) 48.5 (10–87)
Spotted fever group 2 4.5 (4–5) 30.5 (18–43) 2 (100) 1 (50) 2 (100) 35 (30–40)
rickettsioses
Other infectiousb 3 5 (0–30) 2.5 (1–4) 2 (67) 1 (33) 3 (100) 37 (14–60)
—, not applicable.
a No observations on this variable were available.
b Other autoimmune causes included anti-VGKC (2), anti-GAD (2), and anti-CV2/CRMP5 (1). Respiratory viruses included influenza (n = 6), parainfluenza (n = 2), and adenovirus (n = 2).

Other infectious causes included C. lusitaniae, C. neoformans, and N. fowleri.

No statistically significant temporal
variation was observed related to the
causes of pediatric encephalitis.
Although vector-borne and zoonotic
causes (Bartonella, Rickettsia,
California encephalitis, WNV, and
LCMV) were more frequently
FIGURE 2
Prevalence and efficacy of encephalitis testing. EBV, Epstein-Barr virus; VZV, Varicella Zoster virus.
observed in the summer than in the
winter (13% of all encephalitis and
22% of identified encephalitis versus
6% and 11%, respectively; odds ratio
[OR] = 2.5; P = .06; 95% confidence
interval [CI] = 0.9–8.0), this was not
statistically significant. No
statistically significant trend in
seasonality for anti-NMDAR
encephalitis was identified (25% of
identified encephalitis in summer
versus 21% in winter, OR = 1.3,
P , .59, 95% CI = 0.5–3.1).
We observed some differences in
demographic and clinical findings
between infectious and autoimmune
causes of encephalitis (Table 3). Male
patients were more likely to present
with infectious cause of encephalitis
than autoimmune (66% vs 42%; P =
.005, OR = 2.7, 95% CI = 1.3–5.8),
whereas female patients were more
likely to have an autoimmune etiology
(58% vs 34%). The proportion of
autoimmune encephalitis cases
relative to infectious encephalitides
rose with increasing age (Table 1),
although no significant difference was
seen when dichotomized by the mean
age of the total population of cases
(Table 3). Interestingly, this
prevalence increase paralleled an
increase in autoimmune disease
diagnostic testing practices. As
far as other differences seen,
patients with infectious causes of

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PEDIATRICS Volume 145, number 6, June 2020 5
encephalitis were more likely to be
immunocompromised (16% vs 3%;
P = .02, OR = 5.7, 95% CI = 1.2–54.1)
and have an abnormal brain MRI
(78% vs 56%, P = .008, OR = 2.8, 95%
CI = 1.2–6.5) when compared with
autoimmune encephalitis.
DISCUSSION
This study is one of the largest
investigations of the etiology of
encephalitis in children since the
discovery of anti-NMDAR
encephalitis. Through this study, we
had many intriguing findings,
particularly the prevalence of
autoimmune causes and significant
numbers of patients diagnosed with
vector-borne viral (WNV) and
atypical bacterial (B. henselae and
spotted fever group rickettsioses)
infections. With 42% of all patients
having no etiologic diagnosis, future
research should be focused on
improving use of existing tests as well
as etiologic discoveries by using novel
tools like next-generation sequencing.
Quality improvement and educational
projects should emphasize the
importance of comprehensive and
standardized diagnostic testing in
pediatric cases of encephalitis.
Infections were the most frequently
diagnosed causes of encephalitis. On
the basis of our findings, the
importance of vector-borne and
zoonotic agents as etiologies of
encephalitis in certain regions of the
United States should be emphasized.
Despite being underrepresented in
TABLE 3 Demographic and Clinical Differences Between Infectious and Autoimmune Encephalitis
Etiology
Male sex
Age 8 y or older
Race or ethnicity other
than white, non-Hispanic
Immune compromiseda
New onset seizure
Abnormal MRI
Abnormal EEG
Hospitalized 7 d or longer
a Cell value ,5, so Fisher exact was used to calculate 2-tailed P value.
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6 ERICKSON et al
diagnostic testing, vector-borne and
zoonotic infectious agents were
frequently identified, representing
17% (23 out of 133) of identified
causes of encephalitis in our study
population. We tested for WNV at
a high relative rate compared with
other studies involving both pediatric
and adult populations, and it seems
axiomatic that this increased testing
frequency led to the higher number of
WNV-positive results.16,17 Like most
parts of the United States, Houston is
endemic for WNV and other arboviral
diseases.18 This study contained
2 high-incidence outbreak years in
2012 and 2014 when WNV cases in
Houston were elevated.19–21
We found 3 patients with positive
IgM for EEEV, and 2 were able to be
ruled out by subsequent plaque
reduction neutralization using
convalescent specimens. EEEV is rare
in this region and is associated with
severe course of disease; all 3 of these
patients recovered relatively quickly,
with no neurologic sequelae.22 For
these reasons, these patients were
not considered true EEEV cases and
were classified as unknown. It is
possible these low detectable
antibodies represent cross-reaction
with other alphaviruses. WEEV could
be possible in this population23 and
potentially be cross-reactive with
EEEV; however, only 1 of the 3
patients positive for EEEV was also
positive for WEEV at a low-level titer.
Although we are in a high-risk area
for arboviral disease, it is likely that
arboviruses may be an
Infectious Autoimmune P OR (95% CI)
Encephalitis Encephalitis
(n = 73), /n (%) (n = 60), n (%)
48 (66) 25 (42) .005 2.7 (1.3–5.8)
28 (38) 32 (53) .08 0.54 (0.3–1.2)
42 (58) 44 (73) .06 0.49 (0.2–1.1)
12 (16) 2 (3) .02 5.7 (1.2–54.1)
45 (62) 39 (65) .07 0.87 (0.4–1.9)
53 out of 68 (78) 33 out of 59 (56) .008 2.8 (1.2–6.5)
47 out of 53 (89) 33 out of 42 (79) .18 2.1 (0.6–8.0)
56 (77) 54 (90) .04 0.37 (0.1–1.1)
underrepresented cause of
encephalitis and that they should be
high on the list of differential
diagnoses in certain regions of the
country and particular seasons.
B. henselae (3% of all patients)
represented the fifth most common
cause of encephalitis in our
population. Researchers of one other
study of encephalitis in both pediatric
and adult patients only reported B.
henselae in ,1% of their diagnosed
patients.24 Two patients had
antibodies to spotted fever group
rickettsioses as well. Conventionally,
these bacterial infections (along with
Bartonella and Ehrlichia) would be
considered probable in the absence of
a second convalescent phase test.
Researchers of recent studies have
shown more infections with Rickettsia
as well as confirmed autochthonous
transmission of spotted fever group
rickettsioses in Houston.25,26 In these
studies, relatively few instances of
Rickettsia infections were followed
with convalescent serological testing,
although in every case in which
convalescent testing was conducted,
fourfold conversion confirming
infection occurred.27 For this reason
we chose to include these infections
as causes of encephalitis. One patient
with LCMV was also observed; this
agent, which was once considered
a common cause of encephalitis in the
United States, was rarely tested for in
our population (n = 12) and is
typically thought of in
immunocompromised hosts.28,29
With regard to autoimmune causes of
encephalitis, anti-NMDAR was the
most frequent cause. The prevalent
frequency of anti-NMDAR
encephalitis was expected to be more
common than any other single cause.
In the California Encephalitis Project,
32 of 761 cases (4%) of encephalitis
in patients #30 years of age tested
positive for anti-NMDAR antibodies,
compared with our study, in which 31
of 231 (13%) patients with
encephalitis #18 years were found to
be positive.30 The frequency with which
we identified other autoimmune causes
(29 out of 60; 48%) was somewhat
unexpected. Next to anti-NMDAR
encephalitis, ADEM and Hashimoto’s
encephalitis were among the most
frequently identified autoimmune
causes of encephalitis. Although we
identified encephalitis in the presence
of a positive VGKC assay in 6 patients,
only 1 patient had associated subunit
antibodies (leucine rich glioma
inactivated 1)31 identified;
consequently, those other patients were
classified as unknown. Effective
therapies exist for these autoimmune
conditions, and health care providers
should consider testing for anti-VGKC,
anti-GAD, and anti-CV2/GRMP5
antibodies when attempting to diagnose
the underlying cause of encephalitis.
We observed several trends in
temporality. Zoonotic causes were of
substantial importance in the summer
months and nearly negligible in winter
months, although this was not
significant, most likely because of
sample size considerations. Although
this was expected, the lack of
seasonality in anti-NMDAR and
enterovirus was not. Researchers of
previous studies of these conditions
had indicated some seasonality in anti-
NMDAR encephalitis and enteroviral
meningitis, which were not observed
in our study.32,33 It is possible that the
near-tropical climate of Houston
resulted in an amelioration of
seasonality in these conditions, as has
been previously observed with
enterovirus meningitis.34
Our study had several limitations
worth discussing. One limitation
inherent to retrospective chart
reviews is that clinical data available
for abstraction may have had errors
or omissions at time of
hospitalization. Our unique
geographic location is a strength but
may limit generalizability outside of
the southern region of the United
States; however, many of the causes
identified in our study, especially the
autoimmune conditions, have not
been proven to vary significantly with
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PEDIATRICS Volume 145, number 6, June 2020
geography. Properly separating
meningitis and encephalitis cases can
be difficult, especially with bacterial
meningitis cases, hence our use of
a strict case definition to improve the
rigor and reproducibility of our study.
Despite some limitations, our study
has many strengths. This study
represents a large population of
pediatric encephalitic patients drawn
primarily from a diverse (in terms of
national origin) population in the
United States.35 Houston has
a subtropical climate and is different
from other areas where similar
studies have been conducted. This
ecologic difference is evident in the
higher-than-expected incidence of
vector-borne diseases in our study.
Another strength is that our data are
contemporary, allowing us to examine
the contributions of anti-NMDAR
autoimmune encephalitis, previously
identified as the most common single
cause of encephalitis in pediatric
patients, although only truly
recognized in 2007.6,30 Our hospital
multidisciplinary efforts often led to
comprehensive diagnostic testing for
both traditional and more-novel
causes of encephalitis. Finally, our
strategy of applying the more-
stringent and accepted consensus
case definition for encephalitis
provided rigor by excluding those
patients who did not meet validated
criteria, an important strength in
consideration of recent evidence
suggesting the lack of suitability of
International Classification of Diseases
(ICD) codes without such verification
for identifying encephalitis.36
CONCLUSIONS
This study represents a contemporary
investigation into encephalitis among
a large population of children.
Increased awareness and more
frequent testing for anti-NMDAR
encephalitis, WNV, and Bartonella
would likely result in more identified
causes of pediatric encephalitis.
Pediatric institutions and physicians
should consider immune-mediated
encephalitis etiologies as children
with neurologic dysfunction present
to medical attention. These conditions
may be more effectively treated if
identified early in their course, and
outcomes would be improved.
Further research using innovative
means is needed to promote the
discovery of novel etiologies.
ACKNOWLEDGMENTS
We thank Drs Catherine Troisi, Stacia
DeSantis, Katherine King, Sarah
Gunter, and Shannon Ronca for their
kind input.
ABBREVIATIONS
ADEM: acute disseminated
encephalomyelitis
CI: confidence interval
CSF: cerebrospinal fluid
CV2/CRMP5: crossveinless 2/col-
lapsin response me-
diator protein 5
EEEV: eastern equine encephalitis
virus
GAD: glutamic acid decarboxylase
HHV: human herpesvirus
HHV-6: human herpesvirus 6
HSV-1: herpes simplex virus 1
HSV-2: herpes simplex virus 2
ICD: International Classification of
Diseases
ICD-9: International Classification
of Diseases, Ninth Revision
ICD-10: International Classification
of Diseases, 10th Revision
IgG: immunoglobulin G
IgM: immunoglobulin M
LCMV: lymphocytic choriomenin-
gitis virus
NMDAR: N-methyl-D-aspartate
receptor
OR: odds ratio
PCR: polymerase chain reaction
TCH: Texas Children’s Hospital
VGKC: voltage-gated potassium
channel
WEEV: western equine encephali-
tis virus
WNV: West Nile virus
7
and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
DOI: https://doi.org/10.1542/peds.2019-2543
Accepted for publication Mar 19, 2020
Address correspondence to Kristy O. Murray, DVM, PhD, Professor of Pediatrics and Immunology and Microbiology, Vice Chair for Research, Department of
Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, 1102 Bates Ave, suite 550, Houston, TX 77030. E-mail: kmurray@bcm.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2020 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded in part by the Chao foundation.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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 Infectious and Autoimmune Causes of Encephalitis in Children
Timothy A. Erickson, Eyal Muscal, Flor M. Munoz, Timothy Lotze, Rodrigo Hasbun,
Eric Brown and Kristy O. Murray
Pediatrics 2020;145;
DOI: 10.1542/peds.2019-2543 originally published online May 1, 2020;

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 Infectious and Autoimmune Causes of Encephalitis in Children
Timothy A. Erickson, Eyal Muscal, Flor M. Munoz, Timothy Lotze, Rodrigo Hasbun,
Eric Brown and Kristy O. Murray
Pediatrics 2020;145;
DOI: 10.1542/peds.2019-2543 originally published online May 1, 2020;

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http://pediatrics.aappublications.org/content/145/6/e20192543

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