Brain & Development 40 (2018) 799–806

www.elsevier.com/locate/braindev

Original article

Influenza-associated neurological complications

during 2014–2017 in Taiwan
Li-Wen Chen a, Chao-Ku Teng a, Yi-Shan Tsai b, Jieh-Neng Wang a, Yi-Fang Tu a,
Ching-Fen Shen a, Ching-Chuan Liu a,⇑
a
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
b
Department of Diagnostic Radiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University,
Tainan, Taiwan

Received 17 April 2018; received in revised form 23 May 2018; accepted 30 May 2018

Abstract

Introduction: Seasonal influenza-associated neurological complications had high mortality and morbidity rates in recent studies.
We reported influenza-associated encephalitis/encephalopathy in children during 2014–2017 in Taiwan, focusing on neurological
presentations, neuroimaging correlations, and critical care managements.
Materials/Subjects: During January 1st 2014 to June 30th 2017, pediatric patients reported to the Taiwan Centers for Disease
Control surveillance system for severe complicated influenza infections in the hospital were retrospectively reviewed. Children with
influenza-associated encephalitis/encephalopathy were inspected for clinical presentations, laboratory data, neuroimaging studies,
treatment modalities, and neurological outcomes.
Results: Ten children with median age 5.9 years were enrolled for analysis. Influenza-associated encephalitis/encephalopathy
appeared in the spring and summer, with a delayed peak comparing with the occurrence of pneumonia and septic shock. The neu-
rological symptoms developed rapidly within median 1 day after the first fever episode. All patients had consciousness disturbance.
Seven patients (70%) had seizures at initial presentation, and six of them had status epilepticus. Anti-viral treatments were applied in
all patients, with median door-to-drug time 0.9 h for oseltamivir and 6.0 h for peramivir. Multi-modality treatments also included
steroid pulse therapy, immunoglobulin treatment, and target temperature management, with 85.2% of the major treatments admin-
istered within 12 h after admission. Nine of the ten patients recovered without neurological sequelae. Only one patient had epilepsy
requiring long-term anticonvulsants and concomitant cognitive decline.
Conclusions: In highly prevalent area, influenza-associated encephalitis/encephalopathy should be considered irrespective of sea-
sons. Our study suggested the effects of timely surveillance and multi-modality treatments in influenza-associated encephalitis/
encephalopathy.
Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Influenza; Encephalitis; Encephalopathy; Status epilepticus; Multi-modality treatments

⇑ Corresponding author at: Department of Pediatrics, National
Cheng Kung University Hospital, College of Medicine, National
Cheng Kung University, 138 Sheng-Li Road, Tainan City 70403,
Taiwan.
E-mail address: liucc@mail.ncku.edu.tw (C.-C. Liu).
1. Introduction
Influenza infection is well known for the neurological
complications with high morbidity and mortality rates
[1]. The manifestations are heterogeneous, from simple
febrile seizure to the severe acute necrotizing

https://doi.org/10.1016/j.braindev.2018.05.019
0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
800 L.-W. Chen et al. / Brain & Development 40 (2018) 799–806
encephalopathy (ANE) [1–3]. In contrast to the high
morbidity and mortality rates, previous studies show
that most patients of influenza-associated encephalitis/
encephalopathy do not receive adequate vaccination,
and some of them do not have anti-viral treatments [1].
The epidemiology of influenza-associated encephali-
tis/encephalopathy in East Asia is different from that
in western countries. The fulminant ANE with distinc-
tive thalamic necrosis was first reported in 1979 in
Japan [4,5]. ANE is most prevalent in Taiwan, Japan,
and South Korea, emphasizing the importance of treat-
ment protocol for influenza-associated neurological
complications in high-risk populations and countries
[4,6,7].
In children, encephalitis/encephalopathy associated
with pandemic H1N1 infection in 2009 and neurolog-
ical complications in the post-H1N1 era during 2013–
2015 are described in the literatures [2,8]. However,
only a few studies addressed the emerging influenza-
associated encephalitis/encephalopathy in recent years
[9]. In the observational study, we reported clinical
and neuroimaging characteristics of influenza-
associated encephalitis/encephalopathy in children
during 2014–2017 in Taiwan, emphasizing treatments
during critical care and correlative neurological
outcomes.
2. Materials/Subjects
2.1. Patients
During January 1st 2014 to June 30th 2017, patients
less than 18 years old who were reported to the Taiwan
Centers for Disease Control (CDC, Taiwan) surveillance
system for severe complicated influenza infection in the
hospital were retrospectively reviewed. Severe compli-
cated influenza infection is defined as myocarditis or
pericarditis, pulmonary complications, neurological
complications, and superimposed invasive bacterial
infections [10]. Patients reported for neurological com-
plications were included. The demographic data, clinical
manifestations, laboratory studies, neuroimaging stud-
ies, treatment modalities, and neurological outcomes
were analyzed. The hospital’s institutional review board
approved the study.
2.2. Virology survey
The nasopharyngeal aspirates/throat swabs and cere-
brospinal fluid (CSF) samples were sent for viral isola-
tion and immunofluorescence staining assay. Real-time
transcription polymerase chain reactions (RT-PCR)
for influenza detection were also performed with the air-
way and CSF specimens. Rapid influenza diagnostic
tests (RIDT) for antigen detection were tested with air-
way samples.
2.3. Definition of neurological complications
Encephalitis/encephalopathy was defined as alter-
ation of consciousness due to inflammation [3]. Status
epilepticus was defined according to the consensus of
International League Against Epilepsy in 2015, with
tonic-clonic seizure for more than 5 min, or focal seizure
with consciousness impairment for more than 10 min
[11].
2.4. Neuroimaging studies
Neuroimaging studies included computed tomogra-
phy (CT) and magnetic resonance imaging (MRI) with
T1 and T2-weighted images, fluid-attenuated inversion
recovery (FLAIR), diffusion-weighted imaging (DWI)
and apparent diffusion coefficient (ADC, b = 1000). Neu-
roimaging studies were acquired by 1.5 T or 3 T MR
machines. Gadolinium contrast medium was injected
for better demonstration of inflammation, and post-
contrast T1-weighted 3D images would be obtained.
2.5. Statistical analysis
The clinical data was analyzed with descriptive statis-
tics. Numerical variables were presented in median and
interquartile range (IQR). Fisher’s exact test was per-
formed for categorical variables. The statistical tests were
performed with GraphPad Prism 5 and R version 3.4.2
software. The level of significance was set at p < 0.05.
3. Results
3.1. Epidemiology
During the study period, thirty patients younger than
18 years old were reported to the surveillance system for
complicated influenza infection in the hospital. Among
the thirty patients, fifteen were reported for pneumonia
(including four combined with sepsis), and five for septic
shock. Ten children were reported for neurological com-
plications and fulfilling the definition of encephalitis/
encephalopathy. The distribution of disease-onset
month was shown in Fig. 1. In contrast to pneumonia
and sepsis occurring during the winter to spring,
encephalitis/encephalopathy tended to occur in later
months with a peak in the spring to summer, which is
not the typical flu season in Taiwan.
3.2. Demographic data
Five boys and five girls had influenza-associated
encephalitis/encephalopathy at median age 5.9 years
(range 0.4–17 years, IQR 2.3 years). Although four
patients had past medical history, these diseases were
not complicated (simple febrile convulsion in 1; asthma
 L.-W. Chen et al. / Brain & Development 40 (2018) 799–806
Fig. 1. Distribution of complicated influenza infections by month.
Encephalitis/encephalopathy was shown in black and other complica-
tions (pneumonia and septic shock) in gray. Encephalitis/encephalopa-
thy clustered from April to August, which was not typical flu season in
Taiwan, while pneumonia and septic shock congregated from January
to June.
in 1; Kawasaki disease in 1; and epilepsy underwent
complete anticonvulsants treatment in 1). At the time
of encephalitis/encephalopathy, these patients were not
taking any medication for the underlying diseases. The
past influenza vaccination history was known in nine
patients. Three in the four patients in 2017 had received
influenza vaccine in the 2016–2017 season, while only
one in the five patients during 2014–2016 had adequate
vaccination (75% vs. 20%; p = 0.2).
3.3. Neurological symptoms
The neurological manifestations were summarized in
Table 1. All patients had consciousness disturbance with
median Glasgow coma scale (GCS) 11 (IQR 1.75) at ini-
tial presentation. Neurological symptoms occurred
rapidly within median 1 day (IQR 1.5 days) after the
first fever episode during the illness. Although the initial
course of encephalitis/encephalopathy showed acute
deterioration, consciousness recovered soon after med-
ian 1 day (IQR 0.75 days). However, the associated neu-
rological symptoms could be persistent and of great
variability. High cortical function impairments and
movement disorders were common. Brainstem dysfunc-
tion was the most severe symptom, presented with stra-
bismus, bulbar signs, and bradycardia in two patients.
Seven patients (70%) had seizures at initial presentation,
and six of them had status epilepticus. Most seizures
stopped after acute treatment with benzodiazepine and
phenytoin. Nevertheless, the seizures could be refrac-
tory. In two patients, it required four anticonvulsants
including general anesthesia, and took 5 days to com-
pletely control seizures.
3.4. Laboratory examinations
The viral types were mostly identified by viral isola-
tion or RT-PCR, except for three patients that RIDT
was performed followed by oseltamivir treatment in
801
local clinics. Eight (80%) of them had influenza A infec-
tion while only two had influenza B infection. The labo-
ratory examinations in these patients did not show
typical leukopenia or thrombocytopenia during influ-
enza infection (median white blood cell count 10.4  1
03/lL; median platelet count 244.5  103/lL). Rather,
the white blood cell counts fell within normal range with
neutrophil predominance (median neutrophil percentage
62%). Thrombocytopenia was rare; only one patient had
platelet count less than 150  103/lL. Nine patients
underwent lumbar puncture procedures, however, the
CSF studies were mostly unremarkable. Pleocytosis
could be found only in two patients (22.2%) (white cell
count 6 and 14/mm3 respectively; all lymphocytes).
CSF biochemistry data was normal in glucose and total
protein levels. Elevated lactate in CSF could be found in
one patient; however, the patient also had high blood
lactate. Viral isolation and RT-PCR with CSF samples
could not detect influenza virus in all of the nine
patients.
3.5. Neuroimaging findings
Among the ten patients, six had brain MRI studies
and three had CT images. Brain CT identified diffuse
cerebral swelling in the three patients (Patients 5, 9,
and 10). Brain MRI studies demonstrated cerebral swel-
ling particularly involving cortical gyrus in four patients
presented with status epilepticus (Patients 1, 3, 4, and 6).
The other two patients (Patients 2 and 7) showed multi-
focal lesions, involving deep gray matter, brainstem, and
cerebral/cerebellar white matters. Despite the similarity
in area of involvement, patient 2 was classified as
ANE (Fig. 2) while patient 7 was classified as acute dis-
seminated encephalomyelitis (ADEM; Fig. 3).
3.6. Treatments
The treatments included antiviral medications,
immunomodulation therapies, and target temperature
managements, with 85.2% of the critical treatments
administered within 12 h after admission (Fig. 4). All
of the ten patients received oseltamivir, which started
at local clinics in three. The other seven patients received
oseltamivir at median 0.9 h after admission. Seven
patients (70%) had peramivir at median 6.0 h, usually
when there were laboratory evidences of influenza infec-
tion. Methylprednisolone pulse therapy was applied in
six patients (60%) at median 2.5 h. In addition to steroid
treatment, four patients (40%) also received
immunoglobulin infusion at median 5.8 h due to severe
neurological symptoms, such as brainstem involvements
in patients 2 and 7, generalized status epilepticus for two
hours in patient 4, and status epilepticus plus obvious
movement disorder in patient 6. Target temperature
 802
Table 1
Clinical characteristics of children with influenza-associated encephalitis/encephalopathy during 2014–2017.

L.-W. Chen et al. / Brain & Development 40 (2018) 799–806

Patient Age Past history Disease Vaccine Viral GCS Seizure Associated symptoms in acute stage Neuroimaging Neurological
(years) year type findings Sequela
1 6.7 – 2017 + B 11 +, SEa Mood liability, visual hallucination Gyral swelling Epilepsy, cognitive
deficit
2 6.0 – 2017 + A (swH1) 12 + Ankle clonus, hypertonia, bradycardia, ANE Incoordination,
hypotension dysmetriac
3 9.8 – 2017 + A (H3) 11 +, SE Abnormal Babinski sign, somnolence, Gyral swelling –
hypotension
4 4.2 Febrile 2017 – A (H3) 3 +, SE Respiratory failure, coagulopathy, Gyral swelling –
convulsion rhabdomyolysis
5 7.0 Asthma 2016 + B 6 +, SE Metabolic and respiratory acidosis Cerebral swelling –
6 4.6 Kawasaki 2015 – A (H3) 11 +, SE Rigidity, tremor, increased extensor Gyral swelling –
disease tone, myotonia
7 0.4 – 2015 – A (H1) 13 +, SEb Strabismus, bulbar sign, hemiparesis, ADEM Delayed motor
dystonia milestonesc
8 17 Epilepsy 2014 – A 13 – Athetosis, clumsy movement, – –
personality change
9 4.6 – 2014 – A (swH1) 13 – Unsteady gait, hypotension Cerebral swelling –
10 5.7 – 2014 unknown A (H3) 11 – Mutism, projectile vomiting Cerebral swelling –
ADEM: acute disseminated encephalomyelitis; ANE: acute necrotizing encephalopathy; GCS: Glasgow coma scale; SE: status epilepticus; a. Controlled with midazolam continuous infusion,
phenytoin, oxcarbazepine, and clobazam; b. Controlled with midazolam continuous infusion, phenytoin, phenobarbital, and levetiracetam; c. Complete recovery during follow up.
 L.-W. Chen et al. / Brain & Development 40 (2018) 799–806 803

Fig. 2. Brain MRI of acute necrotizing encephalopathy (ANE). MRI

in Patient 2 at the third day of illness showed symmetric cytotoxic
edema involving (A–C). Cerebellar white matter (arrowheads), (D–F)
Tegmentum (arrows) and cerebellar gray matter (arrowheads), and
(G–I). Thalami (open arrows). Besides T2-weighted images (A, D, G),
cytotoxic edema was illustrated as hyperintensity on diffusion weighted
images (B, E, H) and decreased apparent diffusion coefficient values
(C, F, I).
management was applied in three patients (30%) at med-
ian 0.48 h as an adjunctive therapy for status epilepticus.
3.7. Prognosis
Fig. 3. Brain MRI of acute disseminated encephalomyelitis (ADEM).
T2-weighted MRI in Patient 7 at the fifth day of illness showed
involvements of (A). Ventral pons (arrow) and tegmentum (arrow-
head), (C) Left substantia nigra and red nucleus (arrowhead), and (E).
Thalami (open arrows) and subcortical white matter (open arrow-
head). (B, D, F) There was no restricted diffusion, supporting for the
reversibility of vasogenic edematous lesions. (For interpretation of the
references to colour in this figure legend, the reader is referred to the
web version of this article.)

Most patients (90%) required critical care with med-

ian 4 days of hospitalization in intensive care unites
(IQR 1 day). After discharged from the hospital, the
patients were followed for median 3 months (IQR 9.5
months). Two patients had motor function impairment
such as unsteady gait and delayed motor development,
which improved during follow up. Only one patient
developed epilepsy and required long term anticonvul-
sants treatment (Patient 1). In addition to epilepsy,
regression of behavior and decline in cognitive function Fig. 4. Time-sequence of major treatments for influenza-associated
were found in the same patient. encephalitis/encephalopathy. The time intervals between admission
and treatment were plotted with median and interquartile range (IQR)
(hours). Oseltamivir: median 0.9, IQR 2.9; Peramivir: median 6.0, IQR
4. Discussion 5.5; Steroid pulse therapy: median 2.5, IQR 4.5; Immunoglobulin
(IVIg): median 5.8, IQR 34.3; Target temperature management
Among the heterogeneous etiology of childhood (TTM): median 0.48, IQR 1.9. Of the 27 decisions of major treatments,
encephalitis/encephalopathy, influenza-associated neu- 23 (85.2%) were within 12 h after admission. The three patients who
started oseltamivir before admission to hospital were not analyzed.
rological complications are diagnosed through the virol-
ogy survey and clinical-radiological correlations. As the
second leading cause of identifiable pediatric encephali- not be overemphasized [12]. Although the pandemic
tis in East Asia, the standard managements for outbreak in 2009 brought about several discussions on
influenza-associated neurological complications should neurological complications, encephalitis/encephalopa-
804 L.-W. Chen et al. / Brain & Development 40 (2018) 799–806
thy due to seasonal flu was still devastating during 2013–
2015 [1,3]. Our study reported the clinical-radiological
characteristics of influenza-associated encephalitis/
encephalopathy during 2014–2017, with emphasis on
the clinical managements. The multimodality therapies,
most of which given within 12 h after admission, could
be integrated into the treatment protocol of childhood
encephalitis, especially in countries with high prevalence
rates of influenza-associated encephalitis/
encephalopathy.
In our study, the seasonal distribution of encephali-
tis/encephalopathy is different from that of pneumonia
and septic shock during 2014–2017. Influenza-
associated encephalitis/encephalopathy occurred in the
spring and summer, with a delayed peak when com-
pared with pneumonia and septic shock, which occurred
mostly in the winter and spring. Climatic factors were
related to influenza transmission, but the differences
between neurological and pulmonary complications
were less discussed before [13]. Unusual influenza activ-
ity during inter-seasonal months could be a pitfall for
the empirical managements of pediatric encephalitis/
encephalopathy related to influenza infection, especially
in sentinel cases [14]. Our finding of seasonal distribu-
tion warranted the integration of virology tests and
anti-influenza medications into the encephalitis/
encephalopathy management protocols, even in summer
months that was not the typical flu season in Taiwan.
According to previous studies on neurological symp-
toms following influenza infection in children, seizure
was the most common neurological complication [15].
It was similar in our report, that seizure occurred in
70% of influenza-associated encephalitis/encephalopa-
thy, in which status epilepticus accounted for 85.7%.
All patients in the study had consciousness disturbance,
as well as a variety of neurological symptoms such as
movement disorders and neuropsychiatric symptoms.
Children in the study represented a more severe neuro-
logical condition because only those reported to the Tai-
wan CDC surveillance system for complicated influenza
infection were enrolled for analysis. Nine in the ten
patients were admitted to intensive care unites for med-
ian 4 days. Although critical care was required at acute
stage, most of the seizures could be controlled and the
movement deficits eliminated. Among the seven patients
with acute seizures, only one (14.3%) developed epilepsy
during follow-up visits.
Clinical-neuroimaging correlations identified one
ANE and one ADEM in the study, suggesting the vari-
ability of syndrome classification in influenza-associated
encephalitis/encephalopathy. The differentiation of
ANE from ADEM was discussed in previous literatures
[5]. Lesions of ANE were characterized by cytotoxic
edema mainly over thalamus, brainstem, and sometimes
with white matter involvements. In ADEM, vasogenic
edema mainly occurred over white matter, and occasion-
ally involving gray matter. The nadir of clinical symp-
toms occurred soon within 2–7 days in ADEM,
however, the progression of ANE showed an even more
dramatic course, that the patients could become coma-
tose within hours [5,16]. Children with ADEM generally
had good response to steroid treatment; however, the
prognosis of ANE was devastating [5,16]. Since syn-
drome classification directs to treatments and outcomes,
reviewing the neuroimaging studies and correlation with
clinical symptoms were important for precise differenti-
ation among the heterogeneous neurological complica-
tions of influenza infection [1].
As speed of treatment is related to prognosis, the
favorable neurological outcomes albeit severe acute
symptoms in the study may be the result of prompt diag-
nosis and treatment [17]. The manifestations and neuro-
logical outcomes of influenza-associated encephalitis/
encephalopathy vary across countries [7,15,18]. The
racial factor may alert the clinicians in highly prevalent
areas, leading to early diagnosis and integrative manage-
ments. Currently, there was no recommendation for
standard of care in influenza-associated encephalitis/
encephalopathy, but anti-viral medications against influ-
enza could be beneficial [1,9]. In our study, all patients
received oseltamivir either before hospitalization or at
median 0.9 h after admission, even in summer months.
When the laboratory tests suggested influenza infection,
peramivir was administered in 70% of patients at med-
ian 6 h. In our series, antiviral medications were given
in a higher rate and rapidity when compared with other
large-scale studies [1,9]. Although roles of steroid pulse
therapy and immunoglobulin were still controversial,
they were frequently applied in influenza-associated
encephalitis/encephalopathy because immune-mediated
mechanism may be a major pathogenesis [19]. Some
studies proposed the neuroprotective effects of
hypothermia therapy, with roles on controlling status
epilepticus and increased intracranial pressure [20]. We
also used target temperature management for better sei-
zure control in patients with status epilepticus [21]. In
our study, 85.2% of critical managements including
anti-viral therapies, immune modulation treatments,
and target temperature managements were administered
within 12 h after admission, demonstrating the time-
sequence of critical care in influenza-associated
encephalitis/encephalopathy.
Moderate to severe neurological deficits were
reported in 21–45% of surviving patients, and mortality
was also frequently reported in influenza-associated neu-
rological complications [1,9]. In our series, most patients
had good neurological outcomes with no cases of mor-
tality. Nine of the ten patients had full recovery. Only
one patient had epilepsy and cognitive decline. Our
experiences showed that most patients could have good
neurological outcomes when diagnosed and treated
early. Through the rapid influenza detection and anti-
 L.-W. Chen et al. / Brain & Development 40 (2018) 799–806
viral treatments, the neurological outcome may improve
under the prompt management of encephalitis/
encephalopathy.
The vaccine effectiveness against influenza virus var-
ied according to age and viral types. For example, the
vaccine effectiveness in preventing influenza A H3N2
infection during 2012–2016 was inferior to the effective-
ness against influenza A H1N1 [22]. The circulation of
drifted virus may explain the lack of vaccine protection
for influenza A infection [22]. In our observation, three
in the four patients developed encephalitis/encephalopa-
thy in 2017 had vaccination during 2016–2017 season.
Our experiences in 2017 showed that adequate vaccina-
tion could not exclude the possibility of influenza-
associated encephalitis/encephalopathy in children, thus
initial empiric treatments should still be considered
before the establishment of disease-causing pathogen.
There were several limitations in the study. There was
only one ANE in our series, in which the severity of neu-
rological outcome would be alleviated. The single-center
study would have uniform results on encephalitis/
encephalopathy managements, but the feasibility to the
whole population requires more extensive studies since
pediatric encephalitis/encephalopathy is a heteroge-
neous disease. Although influenza virus is the second
common identifiable cause of pediatric encephalitis in
East Asia, influenza-associated encephalitis/
encephalopathy was still rare that larger cohorts for val-
idation of treatment effectiveness were required.
Nevertheless, our report emphasized that irrespective
of flu season and past vaccination status, surveillance
and multi-modality treatments against influenza virus
should be considered in pediatric encephalitis/
encephalopathy.
5. Study funding
None.
6. Conflicts of interest
None.
Acknowledgement
None.
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