Original Article

Yonago Acta medica 2016;59:1–14

Distinguishing Acute Encephalopathy with Biphasic Seizures and Late Reduced
Diffusion from Prolonged Febrile Seizures by Acute Phase EEG Spectrum Analysis
Masayoshi Oguri,* Yoshiaki Saito,* Chisako Fukuda,† Kazuko Kishi,‡ Atsushi Yokoyama,*§ Sooyoung Lee,||¶Hiroyuki Torisu,||** Mitsuo Toyoshima,†† Hitoshi Sejima,‡‡ Shunsaku Kaji,§§ Shin-ichiro Hamano,||||
Toru Okanishi,¶¶ Yutaka Tomita*** and Yoshihiro Maegaki**Department of Child Neurology, Institute of Neurological Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan,†Department of Pathobiological Science and Technology, School of Life Sciences, Tottori University Faculty of Medicine, Yonago 6838503, Japan, ‡Department of Pediatrics, Shimane University Hospital, Izumo 693-8501, Japan, §Department of Pediatrics, Shimane
Prefectural Center Hospital, Izumo 693-8555, Japan, ||Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, ¶Department of Critical care Medicine, Fukuoka Children’s Hospital, Fukuoka 813-0017, Japan, **Section of Pediatrics, Department of Medicine, Fukuoka Dental College, Fukuoka 814-0193, Japan, ††Department of Pediatrics, Graduate
School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan, ‡‡Department of Pediatrics, Matsue RedCross Hospital, Matsue 690-8506, Japan, §§Department of Pediatrics, Tsuyama Chuo Hospital, Tsuyama 708-0841, Japan, ||||Divisionof Neurology, Saitama Children’s Medical Center, Saitama 339-8551, Japan, ¶¶Division of Child Neurology, Seirei-Hamamatsu General Hospital, Hamamatsu 430-8558, Japan and ***Department of Laboratory Medicine, Kyoto Min-iren Central Hostpial, Kyoto 6048453, Japan

ABSTRACT

Conclusion Sequential EEG recording up to 24 hfrom onset appeared to be helpful for distinction of
AESD from FS before emergence of the second phase of
AESD.

BackgroundTo differentiate the features of electroencephalography (EEG) after status epileptics in febrilechildren with final diagnosis of either febrile seizure (FS)or acute encephalopathy for an early diagnosis.
Methods We retrospectively collected data from 68
children who had status epilepticus and for whom EEGs
were recorded within 120 h. These included subjects
with a final diagnosis of FS (n = 20), epileptic status(ES; n = 11), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 18), mild
encephalopathy with a reversible splenial lesion (MERS;n = 7), other febrile encephalopathies (n = 10), hypoxicischemic encephalopathy (n = 1), and intracranial bleeding (n = 1). Initially, all EEGs were visually assessed
and graded, and correlation with outcome was explored.
Representative EEG epochs were then selected for quantitative analyses. Furthermore, data from AESD (n = 7)
and FS (n = 16) patients for whom EEG was recorded
within 24 h were also compared.
Results Although milder and most severe grades of
EEG correlated with neurological outcome, the outcomeof moderate EEG severity group was variable and was
not predictable from usual inspection. Frequency band
analysis revealed that solid delta power was not significantly different among the five groups (AESD, MERS,
FS, ES and control), and that MERS group showed thehighest theta band power. The ratios of delta/alpha and(delta + theta)/(alpha + beta) band powers were significantly higher in the AESD group than in other groups.
The alpha and beta band powers in EEGs within 24 hfrom onset were significantly lower in the AESD group.
The band powers and their ratios showed earlier improvement towards 24 h in FS than in AESD.

Key words

acute encephalopathy; acute encephalopathy with biphasic seizures and late reduced diffusion(AESD); electroencephalography; febrile seizure; spectrum analysis
The term acute encephalopathy (AE) encompasses various etiologies with acute insult to the brain and clinicalmanifestations of seizures, impaired consciousness andother neurological symptoms. This includes bacterial meningitis, viral encephalitis, hypoxic-ischemic
encephalopathy (HIE), head injury, cerebrovasculardisorders, and encephalopathies secondary to hepatic or
renal failure.1, 2 Among others, AE as a complication ofcommon viral (rarely bacterial) infections often affects
young children and causes death or severe neurologicalsequelae. This subgroup of AE is a main cause of acutecerebral injury in Japan.3, 4 Acute encephalopathy withbiphasic seizures and late reduced diffusion (AESD) is
Corresponding author: Yoshihiro Maegaki, MD, PhD
maegaki@med.tottori-u.ac.jp
Received 2015 November 20
Accepted 2015 December 14
Abbreviations: AE, acute encephalopathy; AESD, acute encephalopathy with biphasic seizures and late reduced diffusion; ANE,
acute necrotizing encephalopathy; CNS, central nervous system;
DQ, development quotient; EEG, electroencephalogram; ES, epileptic status; FFT, fast Fourier transform; FS, febrile seizure; HHS,
hemiconvulsion-hemiplegia syndrome; HIE, hypoxic-ischemic
encephalopathy, IQ, intelligence quotient ;MERS, mild encephalitis/
encephalopathy with a reversible splenial lesion; MRI, magnetic
resonance imaging

1

M. Oguri et al.

the most frequent subtype,3, 5 characterized by no abnormalities on magnetic resonance imaging (MRI) at thedisease onset, and evolution of second phase of encephalopathy following 4–7 days of latent period, accompanied by reduced diffusion due to cytotoxic edema.6–8 It
is often difficult to identify which patient represents thefirst phase of AESD, and which just manifests with aprolonged febrile seizure (FS) with favorable outcome.
Given that a sustained increase in excitatory transmittersplay a role in the provocation of second phase in AESD,8
early initiation of treatment may lead to a better outcome. Therefore, early diagnosis of AESD is desirable
for decision of treatment strategy that possibly preventsor ameliorates the second phase of AESD to improve theprognosis of this burden for previously healthy children.
Electroencephalogram (EEG) during the acute phaseof AE shows diffuse slowing and attenuation/ flattening
in encephalopathy due to various etiologies,1, 9 including AESD.10, 11 However, it is not easy to distinguish AE
from prolonged FS or infection-induced epileptic status(ES), because diffuse delta activities are also often seenin these conditions for a few days after seizure onset.10, 11
The aim of this study was to examine whether qualitative analysis of EEGs during acute phase of AEs wasable to predict the prognosis, and specifically to find any
findings that distinguish EEGs of AESD from those ofother disorders including FS and ES, through quantitative EEG analysis by using fast Fourier transform (FFT).

sion-hemiplegia syndrome (HHS), Reye-like syndrome,and clinical mild encephalitis/encephalopathy with areversible splenial lesion (MERS) according to the previous reports.4, 12, 13 Sixty-eight patients (mean age ±SD; 3.5 ± 3.1, 38 males and 30 females) were identified,including 34 patients with AE, 20 with FS, and 11 withES, 1 with hypoxic-ischemic encephalopathy (HIE),
and 1 with intracranial bleeding (Table 1). All of thesepatients underwent EEG recording during acute periods.
A control group (n = 13, aged 4.8 ± 3.2 years, M:F = 8:5)
was also selected whose EEG were recorded in Tottori
University Hospital. They showed normal development
without previous history of AE or other brain injuries;
simple FS in 6, attention deficit hyperactivity disorder in
2, headache in 2, benign infantile convulsion in 1, breath
holding spell in 1, shuddering attack in 1.
The study protocol was approved by institutional
review boards.
EEG recordings

Seventy two EEGs of 20–30 min were recorded in 68
patients during the acute phase, at period of 1–120 h(mean ± SD; 21 ± 25) from the onset of neurological illness. For the 4 patients (2 AESD and 2 FS) with repeated EEG recordings, the initial ones were used for visualand quantitative analyses. EEGs were recorded during
sleep or unconsciousness state after antiepileptic injections; those at later periods up to 120 h were recorded
during sleep induced by sedative agents. Electrodes wereplaced according to the international 10–20 system using at least 13 EEG channels (Fp1, Fp2, F3, F4, Cz, C3,
C4, P3, P4, O1, O2, T3 and T4). Ground electrodes wereattached to the forehead (Fpz). EEG data with bipolar
montages were used for visual assessment and spectrum
analysis to avoid the influence by artifacts due to body
movements involving the scalp and earlobe electrodes.
Recordings were carried out using the Neuropack EEG
system (Nihon-Koden, Tokyo, Japan) and signals were
downsampled at 1 kHz, then EEG was resampled at 200
or 500 Hz and stored on the hard disk for analysis. The
sensitivity was set at 10μV/mm with low-frequency filter of 0.5 Hz, high-frequency filter of 60 Hz. The notch
filter was used at 60 Hz for data from western districtsof Japan and at 50 Hz for data from eastern districts. Patients who had been evaluated for burst suppression andepileptiform activity (periodic or rhythmic spikes, sharp
waves, spike-waves) were excluded in this study.

SUBJECTS AND METHODS
Subjects

This study enrolled children who manifested with acute
symptoms of status epilepticus (SE) and impaired consciousness, who was referred to Tottori University Hospital, Shimane University Hospital, Seirei-Hamamatsu
Hospital, Shimane Prefectural Central Hospital, Kyushu
University Hospital, Kagoshima University Hospital,
Matsue Red-Cross Hospital, Tsuyama Central Hospital,
and Saitama Children’s Medical Center between December 2001 and June 2014. Clinical data including the EEG
tracings were retrospectively collected. SE was defined
as any seizure > 30 min or a series of recurrent seizures
beyond 30 min. In a narrow sense, AE in this study wasdefined according to the previously proposed criteria3–5:i) acute onset of impaired consciousness accompanied
by seizures during a febrile infection; ii) exclusion ofwell-defined central nervous system inflammation, headtrauma, cerebrovascular disease, toxic encephalopathy,
and systemic and metabolic diseases and iii) normal cellcount in CSF and negative viral and bacterial culture of
CSF samples. AE subtypes were classified into AESD,
acute necrotizing encephalopathy (ANE), hemiconvul-

Visual EEG assessment

EEG patterns used for power spectrum analysis wereclassified into five grades by an epileptologist (YM) who
was blind to the clinical information, according to the2EEG analysis in acute encephalopathy
Table 1. Clinical characteristics of the patients
Patient age of onset

Sex

Diagnosis

Accompanying symptoms and/or EEG from Therapy for neurologicalinfectious agents identified
the onset (h) symptom

1

3y7m

M

AESD

–

44

DZP, MDZ

2

5y2m

M

AESD

–

2

MDZ, PB

3

5y4m

F

AESD

Fever, vomiting

33

DZP

Most Severe(in -hospital death)
Most Severe(in -hospital death)
Severe

4

11 m

F

AESD

Exanthema subitum

34

DZP, MDZ

Severe

5

1y5m

F

AESD

Influenza

120

DZP, PB

Severe

6

1y1m

M

AESD

Exanthema subitum

20

DZP, MDZ

Severe71 y 11 m

M

AESD

Bronchitis

1

None

Moderate-mild

8

2 y 11 m

M

AESD

Influenza

2

NoneModerate-mild

9

1 y 10 m

M

AESD

Influenza

20

DZP, MDZ

Moderate-mild

10

1y4m

M

AESD

11–18

8 m–5 y4 M/4 F AESD

Upper respiratory infection 66
fPHT
Exanthema subitum, gastroenDZP, MDZ, PB, fPHT,
teritis (Rotavirus), fever, nasal 1 to 101 propofol or none in 5
discharge, unclassified
Influenza, gastroenteritis(Rotavirus), adenovirus, fever, 3 to 39 DZP, MDZ, fPHT
or noneclouding of consciousness

19–25 1 y 0 m–9 y 0 m 5 M/2 F MERS
26

11 m

F

27

1y8m

M

Reye-like
syndrome
Reye-like
syndrome

28

8m

M

ANE

29

4y

M

Prognosis

Moderate-mild
NormalNormalExanthema subitum

5

DZP

Most Severe(in -hospital death)Upper respiratory infection

3

DZP, MDZ

NormalUpper respiratory
inflammation
Influenza

77

DZP, PB

Normal3

11

fPHT, vitamin compoundsNormal
DZP, MDZ, TPL, PB,
Severeor none in 2
None
Most severe

19

PB

HHS
AE
30–35 2 m–11 y 6 m 3 M/3 F (unclassified) Fever, vomiting
36
1y7m
F
HIE
–
Intracranial
Upper respiratory
37
1y4m
M
bleeding
inflammation
Influenza, upper respiratory
38–57 11 m–9 y 3 m
9 M/11 F FS
inflammation, fever
58–68 1 y 3 m–16 y 11 m6 M/5 F ES–

8 to 34

MDZ, TPL, PB,
1 to 105 DZP,
or none in 4

Most severe
Normal

0.5 to 101 DZP, MDZ, or none in 1 Normal–: symptoms other than fever and neurological manifestations were absent and no infectious agents were identified, AESD, acute encephalopathy with biphasic seizures and late reduced diffusion; DZP, diazepam; ES, epileptic status; F, female; fPHT, fosphenytoin; FS, febrile
seizure; HHS, hemiconvulsion-hemiplegia syndrome; HIE, hypoxic ischemic encephalopathy; M, male; m, month(s); MDZ, midazolam;
MERS, mild encephalitis/encephalopathy with a reversible splenial lesion; PB, phenobarbital; none, no medication; TPL, thiopental; y,year(s).

scale reported by Synek et al.9 : Grade 1; normal or mild
abnormality with alpha activity but little, scattered theta
activity, Grade 2; mild signs of encephalopathy withdominant activity in the theta frequency range, withsome alpha and delta waves, Grade 3; moderate signs ofencephalopathy characterized by dominant widespreaddelta activity, regular or irregular, with little activity inother frequency range, Grade 4; severe signs of encephalopathy with epileptiform discharges or with low-output
EEG, Grade 5; signs of vegetative encephalopathy withfrequent isoelectric EEG. The EEG data with bipolar
montages (Fp1-F3, Fp2-F4, F3-C3, F4-C4, C3-P3, C4P4, P3-O1 and P4-O2) were analyzed.

Quantitative EEG analysis

For the quantitative analyses, EEG power spectrum wascalculated with a fast Fourier transform (FFT) by the
MATLAB software, R2013 student version (The MathWorks, Natick, MA). A representative, artifact-free five5-second epochs were selected from each record andwas averaged before absolute FFT. We excluded sudden
deflection, such as epileptiform discharges and vertex
sharp transients. Subsequently, the power spectrum
was calculated for frequencies between 0.5 and 60 Hzwith frequency step of 0.4 Hz in sampling 200 Hz and
0.2Hz in sampling 500Hz, and then averaged across thefollowing bands: delta (0.5–3.9 Hz), theta (4.0–7.9 Hz),3

M. Oguri et al.

alpha (8.0–12.9 Hz), beta (13.0–19.9 Hz), and gamma(20.0–39.9Hz) frequency bands. The ratios of different
EEG frequency bands reported by Stewart J et al14 : thedelta-alpha ratio (the delta band power divided by thealpha band power) and the (delta + theta)/(alpha + beta)
ratio (the sum of delta plus theta band power divided by
the sum of alpha plus beta band power) were also evaluated to enhance the identification of increased power ofslow waves and decreased power of faster waves. These
power values were averaged in each etiology group,i.e. AESD, FS, MERS, ES and controls, and used foranalysis. We then selected patients with AESD (n = 7)
and FS (n = 16) for whom EEGs were recorded within
24 h from onset, and compared the quantitative data toclarify whether any difference are present between thesegroups. In addition to the aforementioned FFT variables
in average, we illustrated the temporal distribution of thevariables through the 24 h, as well as the evolution in the
4 patients for whom EEGs were re-examined within 24 h.

was most severe in 2 patients, severe in 4 patients,
moderate-mild in 4 patients, and normal in 8 patients.
All 7 patients with MERS had a normal prognosis.
Twenty FS and 11 ES patients all showed a full recovery(Table 1). Regarding the treatment for termination of
initial SE, which may increase fast activity on the EEG,
diazepam was used in 9 AESD, 2 MERS, 2 Reye-like
syndrome, 1 ANE, 10 FS, 7 ES, and 1 unclassified AE.
Midazolam was used in 7 AESD, 1 MERS, 1 Reye-like
syndrome, 8 FS, 4 EP, and 1 unclassified AE. Both ofthese agents were administrated in 5 AESD, 1 MERS,
1 Reye-like syndrome, 4 FS, 1 ES, and 1 unclassified
AE. Phenobarbital was used in 4 AESD, 1 ANE, 1 intracranial bleeding, 3 FS, and 2 unclassified AE. The
proportion of usage of these agents was not statisticallysignificant among the AESD, MERS, FS and ES groups.
Other medications included thiopental in 4, propofol in
1, fosphenytoin in 4, and vitamin compounds in 1. The
medication used in the 5 most severe patients were diazepam in 2, midazolam in 2, phenobarbital in 3, and no
medication in 1. All 5 severe patients were treated withdiazepam in 5, midazolam in 3, and phenobarbital in 1.
Two of 4 moderate-mild patients were treated with diazepam in 1, midazolam in 1, and fosphenytoin in 3.

Neurological sequelae in clinical prognosis

The intellectual (IQ) or development quotient (DQ) laterin the chronic phase was assessed in each patient by the
Enjoji or Tanaka-Binet developmental scales. Neurological sequelae were graded into 4 categories: most severe;
in-hospital death during acute periods, clinical brain
death or vegetative state with brainstem dysfunction, severe; IQ/DQ < 35, moderate-mild; IQ/DQ = 35–69, andnormal; IQ/DQ ≥ 70).

Visual EEG assessment

The severity grades of acute phase EEGs were variablein the AESD, FS, and ES groups, and distinction ofthese etiologies by visual inspection were impossible between EEGs of each grade (Fig. 1, Table 2). The EEGs
in MERS was graded to 1–3, consistent with the favorable outcome of this patient group (Table 2). EEGs insome MERS patients were characterized by high amplitude theta activity with fronto-occipital predominance.
As shown in Table 2, there was a considerable overlap
among AESD, FS and ES groups, particularly in grades
3 and 4.
As for the correlation between the visual EEG grading and the neurological sequelae (Table3), all but 1 patients (18/19, 95.0%) in grades 1 and 2 were normal andone patient had mild-moderate sequelae. In Grades 3,
although most patients were normal, some patients (5/36,
14.0%) had neurological sequelae. In Grade 4, although
5 patients were normal, the other patients (5/10, 50.0%)
had neurological sequelae. In Grade 5, all 3 patientswere suffering from most severe sequelae.

Statistical analysis

The EEG power spectra of each etiology group wereanalyzed using the Tukey way after using Kruskal-Wallis test. The proportion of patients for whom individual
anticonvulsive agents in each etiology group, i.e. AESD,
FS, MERS and ES was analyzed with Chi-square test.
The comparison between AESD and FS was carriedout by the Mann-Whitney U test. Regression lines forthe spectrum data from AESD and FS during 24 h weredrawn by the recording period as the independent variable and the power value as the dependent variable. P
values of < 0.05 were considered statistically significant.
The IBM SPSS Statistics 20 (IBM, Tokyo, Japan) wasused for these statistical tests.
RESULTSClinical characteristics

EEG spectrum analysis of different etiology groups(Fig. 2, Table 4)

Of the 68 participants, 14 resulted in hospital death orneurological sequelae: classified as most severe prognosis in 5 patients (in-hospital deaths in 3 and vegetative
state in 2), severe prognosis in 5 patients, and moderatemild prognosis in 4 patients. The prognosis of AESD

The absolute value of spectrum band powers showed nosignificant difference among the 5 groups in the delta
band (Fig. 2A). In the theta band, the MERS group4

EEG analysis in acute encephalopathyA	 Grade 1	 B	
 Fp1-F3	
Fp2-F4	
F3-C3	
F4-C4	
C3-P3	
C4-P4	
P3-O1	
P4-O2	

1 s	

C	
 

D	
 

100 µV	

Grade 2	 Grade 3	 Grade 4	 Fig. 1. Representative EEG of each severity grade in patients with A: AESD,
B: MERS, C: prolonged FS and D: ES.
AESD, acute encephalopathy with biphasic seizures and late reduced diffusion; EEG, electroencephalogram; ES, epileptic status; FS, febrile seizure;
MERS, mild encephalitis/encephalopathy with a reversible splenial lesion.

Grade 5	 	 Figure 1	

Table 2. Severity grades on visual assessment of EEGs in children after status epilepticus due to each etiology
Grade 1

Grade 2

Grade 3

AESD (n = 18)

1

1

10

MERS (n = 7)

3

2

2

Reye - like syndrome (n = 2)

2

AE (unclassified) (n = 6)

4

HHS (n = 1)

1

ANE (n = 1)

1

Grade 4

Grade 551

2

HIE (n = 1)

1

Intracranial bleeding (n = 1)

1

FS (n = 20)

1

6

11

2

ES (n = 11)

3

2

5

1

AE, acute encephalopathy; AESD, acute encephalopathy with biphasic seizures and late reduced diffusion; ANE, acutenecrotizing encephalopathy; EEG, electroencephalogram; ES, epileptic status, FS, febrile seizure, MERS, mild encephalitis/
encephalopathy with a reversible splenial lesion, HIE, hypoxic-ischemic encephalopathy; HHS, hemiconvulsion-hemiplegia
syndrome.

5M. Oguri et al.
Table 3. Relationship between the EEG severity grades during the acute phase and prognosis
Grade 1

Grade 2

Grade 3

Grade 4

Normal (n = 54)

7

11

31

5

Mild-moderate (n = 4)

1

2

1

Severe (n = 5)

2

3

Most severe (n = 5)1

1

Grade 5

3

EEG, electroencephalogram.

showed a significantly high power value in the frontal
and centro-parietal areas (Fig. 2B). In the alpha band,
the AESD group showed a significantly lower power
value than the FS group in the fronto-central areas (Fig.
2C). In the beta band, the power value in the FS groupwas significantly higher than the AESD group in the F3C3 area (Table 4). The MERS group showed a higher
beta band power with frontal predominance (Fig. 2D).
In the gamma band, the FS group showed a significantly
higher power value than the other groups in the centroparietal areas. Gamma band power in MERS was higher
in the frontal areas compared to other groups (Table 4).
The ratios of delta/alpha and (delta + theta)/(alpha + beta)
in the AESD group were both higher than those in theother groups in the frontal and parietal predominance(Figs. 2E and F). In terms of the correlation between theband power and the prognosis, delta power was lower inthe patients with the most severe outcome and higher inthe patient group with mild—moderate sequelae in thefrontal and right parieto-occipital areas (Table 5).

significantly decreased with time in the FS group (Fig.
3). In the 4 patients [2 AESD (Patients 7 and 8; see Table
1) and 2 FS (Patients 45 and 56)] for whom EEGs wererepeatedly recorded within 24 h from onset, theta, alpha, and beta band powers were higher and/or increased
with time, and the delta/alpha and (delta + theta)/(alpha+ beta) ratios remained lower from the early stage in the
FS patients (Fig. 4).
DISCUSSION
This is the first report that quantitatively analyzed acutephase EEGs in childhood infection-related AEs withband spectrum powers. Significance of usual visual inspection of EEG was limited to the expectation of themost severe or mild outcomes, common to the casesof the AEs in a broad sense: slow and/or low voltage
background, lack of EEG reactivity to external stimuli,
and epileptiform discharges are characteristic in acutecerebral injuries with outcomes of various severities due
to hypoxia-ischemia, bacterial infections, hepatic coma,
and head trauma.1, 2, 9 Among others, isoelectric and/or
discontinuous EEG patterns, which correspond to Grade
5 in this study, have been linked to the poorest outcomein these etiologies.
In previous reports, findings in EEG spectrum analysis from patients with AEs include a decreased (delta +theta)/(alpha + beta) ratio in severe bacterial infections,15
and increased delta power and lower 50% spectral edge
frequency in hepatic coma,14 all of which did not show
significant correlation with prognosis. Although diffuse
asymmetrical slow waves in various AE etiologies,16 andelectrical storm in hemorrhagic shock and encephalopathy syndrome17 are described as useful in outcome prediction, these appear to be applicable to rather specificconditions.
The band power analysis in this study among groupsof different severity in outcomes revealed significant difference only in the delta frequency power bands in thefrontal areas, which was lower in the most severe prognosis group and higher in the mild-moderate prognosis
group. This may represent the low-voltage or isoelectricComparison of EEGs in AESD and FS by spectrum
analyses including temporal evolution

Despite the significant differences revealed in the spectrum analysis among the different etiologies in the patient groups, there was still overlap in the spectra fromeach group. To identify further information for management of individual patient for whom the distinction of
AESD and FS was desired, we compared EEGs within
24 h from onset in AESD (n = 7) and FS (n = 15) patients. The delta power values of these groups were notsignificantly different in any areas. The AESD group
showed lower band powers than the FS group in the F3C3, F4-C4 and P3-O1 areas in the theta band, and in allareas in the alpha, beta, and gamma bands. The ratios ofdelta/alpha and (delta + theta)/(alpha + beta) were higher
in the AESD group in all areas (Table 6).
We then plotted the temporal distribution of spectrum band powers from the 22 patients and found thatabsolute theta and alpha band power tended to increase,and delta/alpha and (delta + theta)/(alpha + beta) ratios
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＊	
 
	
 

	
 	
 
	
  ＊	
 
	
 	
 
	
 

	
 	
 

	
 	
 
	
  ＊	
 
	
 	
 
	
 

100	
10	

10	
100	
1	
10	
1	

Fp2-F4	

F4-C4	

C4-P4	

P4-O2	

Fp2-F4	

F4-C4	

C4-P4	

P4-O2	

10	
1	
1	

Fp2-F4	

F4-C4	

C4-P4	

P4-O2	

Fp2-F4	

F4-C4	

C4-P4	

P4-O2	

Fig. 2. Spectrum analysis of EEGs in different etiologies. Absolute power of A: delta (0.5–3 Hz), B: theta (4–7 Hz), C: alpha (8–12 Hz)
and D: beta (13–19 Hz) frequency bands, as well as the ratio of band powers, E: delta/alpha and F: (delta + theta)/(alpha + beta), areshown. Five vertical bars for each area, e.g. Fp2-F4, represent the groups of AESD, MERS, FS, ES and control from the left to the right.
Vertical squares on each bar show 25, median and 75 percentile values. Dots on the right of the bars represent the values of individual
subject. The dots enclosed by blank signs represent the patients whose EEG tracings are shown in Fig. 1 (○: grade 1, □: grade 2, △ :grade 3, ▽ : grade 4, ☓: grade 5). *P < 0.05, **P < 0.01. AESD, acute encephalopathy with biphasic seizures and late reduced diffusion;
EEG, electroencephalogram; ES, epileptic status; FS, febrile seizure; MERS, mild encephalitis/encephalopathy with a reversible splenial
lesion.

Figure 2	
Figure 2	

7

M. Oguri et al.
Table 4. Power spectrum values of EEGs in children after status epilepticus due to each etiology
Frequency

Patient group

Locations
Fp1-F3

Fp2-F4

F3-C3

AESD
76380 (892–513043)
59377 (1407–319824)
75346 (161–457518)
MERS
80817 (3029–303123)
99577 (4824–378404)
62617 (3098–275621)
delta (µV2)
FS
48315 (3210–171041)
37976 (4550–128664)
60494 (1472–326000)
ES
23169 (7313–56033)
22168 (2994–82100)
28054 (1393–82363)
Control
22200 (3186–69500)
23096 (3638–84100)
20603 (1740–68200)
AESD
1956 (33–14977) **2154 (55–17872)**
1750 (8–7779)*
MERS
8973 (300–28335) **, *9970 (312–29121)**7754 (364–22529)*
FS
2978 (236–19977) *2381 (350–7910)**4253 (139–18426)
theta (µV2)
EP
1939 (426–5804) *1983 (174–4904)**
1687 (258–4554)*
Control
1574 (618–3140) **1984 (630–6770)**
1845 (975–3660)*
AESD
221 (14–965)**242 (12–1203)
308 (4–1380)
MERS
1117 (232–3014)**1233 (170–4453)
776 (87–2291)
alpha (µV2)
FS
506 (41–1902)
502 (74–1640)
672 (47–2016)
ES
433 (98–1431)
453 (104–854)
453 (115–963)
Control
667 (75–3269)
651 (62–2737)
507 (107–1520)
AESD
70 (6–298)**
62 (4–347)**
77 (2–452)*
MERS
677 (32–2927)**, *286 (35–958)**, *177 (23–567)
beta (µV2)
FS
135 (23–586)**134 (34–396)
247 (23–1260)*ES
154 (16–516)*
107 (45–162)*
202 (20–567)
Control
72 (22–212)**81 (17–302)**
134 (25–447)
AESD
29 (1–211)**19 (1–99)**
18 (1–136)*
MERS
500 (2–2346)**, *233 (1–887)**, *32 (1–84)
gamma (µV2)
FS
68 (13–311)**66 (9–193)*
76 (8–309)*ES
67 (5–281)*
51 (9–164)*
79 (5–285)
Control
31 (10–81)**32 (6–78)**
24 (6–67)
Mean and the range of power values are shown in each cell. *P < 0.05, ** P < 0.01.
AESD, acute encephalopathy with biphasic seizures and late reduced diffusion; ES, epileptic status epilepticus; FS, febrile status epilepticus;
MERS, mild encephalitis/encephalopathy with a reversible splenial lesion.
Table 5. Comparison of power spectrum values of EEGs between different severity groups of children after
status epilepticus
Frequency

Prognosis

Locations
Fp2-F4 (µV)

Fp1-F3 (µV)

F3-C3 (µV)

Most severe
27134 (130–127928)*
20164 (135–91042)
11516 (62–56556)*
Severe40583 (2445–120609)*
48629 (1194–179730)
59618 (4309–251536)
delta (µV )Moderate–mild
157172 (2273–513034)**, *113672 (4365–319824)*
137676 (2807–457517)*
Normal42520 (970–303122)**40677 (1406–378404)*
46431 (1392–326000)*
Most severe
770 (15–3532)
592 (22–2471)
584 (7–2860)
Severe1416(133–5236)
1517(86–5554)
1939(267–7779)
theta (µV2)
Moderate–mild
1437 (401–4339)
1437 (670–3830)
1334 (499–3129)
Normal2860 (58–28335)
3064 (55–29121)
3043 (42–22529)
Most severe
172 (6–751)
150 (11–596)
101 (4–481)
Severe252(34–964)313(17–1202)347(58–1380)
alpha (µV2)
Moderate–mild
218 (16–426)
253 (24–742)
343 (34–1073)
Normal509 (8–3270)
529 (7–4453)
508 (6–2292)
Most severe
45 (6–69)
41 (4–88)
46 (14–86)
Severe65 (3–298)
61 (3–256)
35 (2–178)
2
beta (µV )Moderate–mild
36 (9–70)
31 (8–87)
40 (8–92)
Normal192 (4–2928)
143 (3–958)
244 (3–4279)
Most severe
22 (2–88)
23 (2–85)
14 (1–65)
Severe13(0–37)
12(0–40)
12(0–53)
gamma (µV2)
Moderate–mild
6 (1–14)
6 (1–18)
6 (1–19)
Normal113 (2–2347)
80 (1–888)
71 (1–1300)
Mean and the range of power values are shown in each cell. *P < 0.05, ** P < 0.01. EEG, electroencephalogram.
2

8

EEG analysis in acute encephalopathy
Table 4-Continued
Locations
F4-C4

C3-P3

C4-P4

P3-O1

P4-O2

66801 (168–309148)
52807 (1808–283534)
55717 (1218–310697)
18963 (1567–53800)
23757 (2570–77000)
1662 (4–9400)
4520 (198–15201)
3714 (305–16900)
2093 (235–3993)
2044 (912–4750)
269 (2–1257)*
612 (206–1354)
623 (130–1370)*
519 (138–917)
444 (84–1020)
72 (1–247)
82 (26–114)
290 (46–2072)
243 (53–1076)
131 (19–531)
21 (1–111)**17 (1–36)*
84 (21–277)**, *51 (18–162)
24 (6–55)**65870 (71–420264)
68914 (3054–344211)
58728 (2133–291000)
27627 (840–150000)
21398 (1315–75902)
1533 (6–5752)*
5417 (251–22572)*
3189 (387–12800)
1180 (243–2289)*
1635 (679–3950)
220 (3–1293)
770 (167–3132)
429 (126–1099)
277 (44–524)
437 (119–1740)
88 (2–500)
108 (33–305)
121 (37–8326)
84 (7–176)
72 (26–228)
19 (1–94)**
16 (1–30)
59 (8–268)**, *28 (2–60)
22 (5–60)*

92043 (412–472320)
94172 (4492–345928)
41958 (1444–145000)
32622 (1984–177000)
23337 (949–120517)
1493 (11–5150)*
9032 (522–38951)*
2965 (402–18900)*
1448 (289–2937)*
1558 (374–4438)*
188 (6–920)*
1028 (112–4635)*
466 (70–1312)
389 (175–1293)
372 (77–1610)
70 (3–254)
188 (20–645)
166 (26–725)
157 (27–678)
65 (27–164)
20 (1–92)**
30 (1–89)
69 (10–265)**, *63 (6–277)
20 (5–64)*

109876 (122–580641)
53371 (4603–136840)
111192 (4223–423000)
27550 (2083–153000)
48173 (1676–119967)
1835 (10–7307)*
7115 (230–24193)*
3957 (429–21800)
1567 (234–4067)*
2028 (894–5274)
218 (7–1552)
605 (120–1185)
433 (107–1652)
339 (55–1055)
328 (141–903)
90 (3–564)*454 (37–2285)*
132 (44–384)
96 (11–328)
71 (25–150)*
25 (1–110)
252 (1–1611)
76 (6–352)
37 (3–135)
26 (5–73)

113063 (784–601826)
64119 (5122–167628)
78466 (2312–376309)
34188 (148–158000)
59700 (2124–202674)
1570 (22–5944)
5962 (282–14508)
3641 (322–27400)
1351 (331–3408)
2059 (825–5866)
193 (9–457)
616 (143–1962)
444 (78–2198)
304 (129–772)
290 (116–510)
83 (6–529)
116 (40–502)
154 (20–465)
145 (24–493)
68 (36–137)
38 (1–335)
20 (1–72)
87 (10–362)
82 (5–399)
24 (6–69)

F4-C4 (µV)

C3-P3 (µV)

LocationsC4-P4 (µV)

P3-O1 (µV)

P4-O2 (µV)

12285 (43–49985)
59131 (6489–233011)
102912 (4467–309148)
41084 (1217–310697)
387 (4–1530)
1175 (92–3429)
1305 (863–1667)
2709 (45–16900)
102 (2–376)
237 (9–727)
380 (50–1256)
490 (7–1370)
69 (4–139)
36 (1–154)
48 (10–124)
188 (2–2071)
19 (0–73)
7 (0–25)
13 (1–54)
50 (1–277)

23365 (11–114752)
69001 (2825–242085)
105818 (5165–420263)
47111 (839–344211)
928 (2–4469)
1877 (265–5752)
952 (184–2578)
2444 (242–22572)
208 (1–876)
358 (27–1293)
163 (8–407)
394 (29–3132)
68 (15–234)
65 (0–241)
27 (3–63)
229 (7–8775)
22 (0–66)
12 (1–46)
9 (1–41)76 (1–2762)

25319 (32–116038)*
115692 (1739–472320)
165972(6766–464742)*
46940(949–345928)*
812 (9–3725)
1510 (143–5150)
1522 (369–4483)
2913 (182–38951)
199 (6–865)
289 (12–920)
150 (34–280)
443 (21–4635)
75 (9–167)
66 (3–307)
42 (11–126)
135 (3–725)
22 (1–80)
11 (0–35)
21 (2–92)
47 (1–277)

23312 (20–115912)
153993(2278–580641)
165137 (3859–569219)
74752 (1676–479000)
1342 (4–6630)
2487 (180–7307)
1720 (205–6123)
2962 (70–24193)
205 (1–984)
452 (20–1551)
119 (19–241)
364 (11–1652)
30 (5–90)
55 (1–280)
32 (5–60)
148 (7–2285)
19 (1–78)
23 (1–62)
15 (1–56)
70 (1–1611)

33022 (85–163056)
147245 (3383–559450)
185116 (9388–601826)
65355 (1481–376308)
757 (9–3651)
1295 (131–3417)
2042 (338–5943)
2721 (129–27400)
197 (3–899)
216 (20–445)
200 (33–330)
349 (17–2198)
31 (5–80)
64 (1–257)
40 (6–101)
124 (8–529)
27 (1–85)
12 (1–28)
19 (0–68)
58 (0–362)

Table 5-Continued

9M. Oguri et al.

A

2( μV )
500000	
  FS;	  r	  =	
  –0.33	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  P	
  =	
  	
  	
  0.21300000

AESD;	  r	  =	
  –0.34	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  
P	
  =	
  	
  	
  0.45	
  

15000

Power

Power

pow er

20000

AESD;	
  r =	
  –0.13	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  
P	
  =	
  	
  	
  0.78	
  400000B

2( μV )

200000	
  FS;	
  r	
  =	
  	
  	
  0.42	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  P	
  =	
  	
  	
  0.11

10000

5000

100000
0
0

10

20

30

0

(h
o u rs)
(h)	

0

2

C

( μV )

	
  FS;	
  r	
  =	
  	
  	
  0.41	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  P	
  =	
  	
  	
  0.12800

AESD;	
  r =	
  –0.53	
  
P	
  =	
  	
  	
  0.22	
  

600

Power

Power

(h(h)	
o u rs)

D

2

1000

30

Recording	
  Ame	
  from	  onset

AESD;	
  r =	
  –0.59	
  	
  	
  
P	
  =	
  	
  	
  0.17 	
  

1500

20

R e c o rd in g tim e fr o m o n s e t

R e c o rd in g tim e fr o m o n s e t
Recording	  Ame	
  from	  onset	( μV )10	
  FS;	
  r	
  =	
  	
  	
  0.03	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  P	
  =	
  	
  	
  0.90

400

500
200

0
0

10

20

30

(h(h)	
o u rs)00

R e c o rd in g tim e fr o m o n s e t

2500

FS;	
  r =	
  –0.56	
  	
  	
  
P	
  =	
  	
  	
  0.02 	
  

Power

1500
1000

F

(% )

AESD;	
  r = 	  0.73	
  	
  	
  
P	
  =	
  	
  	
  0.06 	
  

2000

(h)	
(h
o u rs)Recording	
  Ame	
  from	  onset

AESD;	
  r = 	  0.69
P	
  =	
  	
  	
  0.09

2500
2000

Power

E

3000

30

20

R e c o rd in g tim e fr o m o n s e t

Recording	
  Ame	
  from	  onset

(% )

10

500

FS;	
  r =	
  –0.56	
  	
  	
  
P	
  =	
  	
  	
  0.02 	
  

1500
1000
500

0
0

10

20

30

(h)	
(h
o u rs)00

R e c o rd in gAtimom oo nsetnset
Recording	  me	
  e ffrrom	
  

10

20

R e c o rd in g tim e fr o m o n s e t
Recording	  Ame	
  from	  onset	

30

(h)	
(h
o u rs)Fig. 3. Temporal distribution of spectrum band powers in AESD and FS within 24 h after the onset of seizures. Corresponding regression lines (the solid line for the AESD group and the dotted line for the FS group) are drawn for each of the 2 groups. The power value
at C4–P4 area was chosen for demonstration. Blank and filled circles represent the FS (n = 15) and AESD (n = 7) patients. A: delta, B:
theta, C: alpha, and D: beta frequency bands, and E: delta/alpha and F: (delta + theta)/(alpha + beta) ratios. Note that alpha power in FS
significantly increases (C), and the ratios of delta/alpha and (delta + theta)/(alpha + beta) in FS decrease (E and F) with time. AESD, acuteencephalopathy with biphasic seizures and late reduced diffusion; FS, febrile seizure.

10

(µV22)	
)	
(µV

A	
A	

2
(µV
)	
(µV2)	B	B	Power	
Power	

A	
A

(h)	
(h)	
recording	  recording	
  ,
,me	
  
me	
  ffrom	
  
rom	
  o
onset	nset	(µV2)	

B	B

Power	(µV2)	

Power	

Power	
Power	

EEG analysis in acute encephalopathy

(h)	
(h)	
recording	  recording	
  ,
,me	
  
me	
  ffrom	
  
rom	
  o
onset	
nset	

(h)	

(h)	

Rrecording	
  ,me	
  from	  onset	Power	

Power	
Power	(h)	(h)	Recording	  Recording	
  ,
,me	
  
me	
  ffrom	
  
rom	
  o
onset	
nset	
(%)	
(%)	

E	
E
E	
Recording	
  ,me	
  from	  onset	

(%)	

E	

(h)	

(h)	
(h)	
Recording	  Recording	
  ,
,me	
  
me	
  ffrom	
  
rom	
  o
onset	
nset	
(h)	

2
(µV
)	
(µV2)	D	D	D(µV2)	

D	Power	C	Power	
Power	

Power	
Power	

Power	(µV2)	

Rrecording	
  ,me	
  from	  onset	C	C	CPower	

Power	
Power	

2(µV(µV2)	
)	

(h)	
(h)	
Recording	  Recording	
  ,
,me	
  
me	
  ffrom	
  
rom	
  o
onset	
nset	
(%)	
(%)	

F	
F
F	
Recording	
  ,me	
  from	  onset	

(%)	

F	

(h)	

(h)	
(h)	
Recording	  Recording	
  ,
,me	
  
me	
  ffrom	
  
rom	
  o
onset	nset	(h)	Fig. 4. Evolution of band powers in individuals for whom EEGs were recorded twice within 24 h after the onset of seizures. The power
values at C4–P4 area are shown. Solid and dotted lines represent the AESD and the FS patients, respectively. and A: delta, B: theta, C:,me	
  onset	
 with biRecording	
  
,me	
  
rom	
  
onset	and F: (delta + theta)/(alpha + beta)Recording	  alpha and D: beta frequency
bands,
andfE:
delta/alpharatios. AESD,
acutefrom	  encephalopathy
phasic seizures and late reduced diffusion; EEG, electroencephalogram; FS, febrile seizure.

11M. Oguri et al.
Table 6. Comparison of AESD and FS power spectrum value in EEGs within 24 h from onset
Frequency

Patient group

Locations
Fp1-F3

Fp2-F4

F3-C3

AESD
139812 (6575–513043)
97891 (6557–319824)
131689 (703–457517)
FS
55493 (3210–171041)
42645 (4550–128664)
69815 (5188–32600)
AESD
3340
(133–14977)
3633(86–17872)
1935 (27–7345)
theta (µV2)*
FS3639 (236–19977)
2894 (417–7910)
4764 (495–18426)
AESD
170 (5–341)
171 (17–524)
200 (10–634)
alpha (µV2)
*
**
**
FS
559 (41–1902)
563 (74–1640)
738 (107–2016)
AESD
36 (7–84)
30 (6–70)
37 (6–92)
beta (µV2)
**
**
**
FS
147 (23–586)
150 (34–396)
275 (46–1259)
AESD
9 (1–35)
8 (1–28)
6 (1–20)
gamma (µV2)
**
**
**
FS
73 (13–310)
73 (9–192)
79 (13–309)
AESD
685 (81–1710)
629 (78–1520)
881 (64–2990)
delta/alpha(%)
*
**
*
FS
144 (12–778)
121 (13–629)
107 (3–359)
577 (59–1586)
515 (55–1192)
743 (46–2744)(delta + theta)/(alpha + beta) AESD
*
**
*
(%)
FS
112 (15–609)
96 (12–492)
82 (6–276)
Mean and the range of power values are shown in each cell. *P < 0.05, **P < 0.01.
AESD, acute encephalopathy with biphasic seizures and late reduced diffusion; EEG, electroencephalogram; ES, epileptic status epilepticus;
FS, febrile status epilepticus; MERS, mild encephalitis/encephalopathy with a reversible splenial lesion.
delta (µV2)

per 3 years in Japan,3 which is presumably higher thanother countries. The prevalence of FSs in Japan18 ishigher than Caucasian countries,19 which may suggest
a link between FS and AESD.5 On the other hand, FS
is more prevalent in boys than girls,18, 20, 21 whereas themale-predominance was not observed in AESD (M:F
= 114:167).3 This is suggestive of certain genetic predisposition factors for AESD other than those for FSs ingeneral. These may include certain genotype of carnitine palmitoyl transferase II,22, 23 SCN1A,24 SCN2A,25
ADORA2A,26 and TLR3.27 These vulnerability factors to
AESD may result in the persistent increase of excitatorytransmitters assumed in the pathogenesis of AESD.8
Subclinical status epilepticus has been identified in an
AESD patient at the onset of the second phase.28 Thisphenomenon was not found in the present patient series;
however, considering the pathogenesis of AESD, early
diagnosis could lead to improve the prognosis throughearly decision of treatment with some agents reported as
potentially effective for AESD. These include fosphenytoin,28, 29 L-carnitine and vitamins,30 and erythropoietin.31 The present study supports that follow-up EEGs
up to 24 h from the onset would be helpful for early
identification of AESD patients. EEG findings of AESD
between 5 and 20 h from the onset, as well as any effectof the aforementioned treatment options, would be worth
for further examination.

EEGs in the most severe group. As for the differencesamong the background conditions, higher theta band
power was characteristic in the MERS group. AESD
group showed higher delta/alpha and (delta + theta)/(alpha + beta) ratios in the frontal and parieto-occpitalareas than the FS group. In contrast, delta band power
was comparable between FS and AESD groups. These
could be interpreted that EEGs in AESD are more monotonous with decreased power of alpha and beta bands
compared to those in FS. Thus, significant difference
was found between AESD and FS but there was someoverlap when focusing on individual patients (Fig. 2)
based on the EEG within 120 h from the onset of first
seizures.
Interestingly, Synek et al.9 found that EEGs at 24–
48 h from onset of anoxic and traumatic cerebral injury
was reliable than those during earlier phases in prediction of outcome. Temporal evolution of EEG may also be
indicative of the etiology and severity of the childhood
infection-related AEs. This prompted us to compare theEEGs in AESD and FS within the first 24 h in terms oftime-dependent changes. Although the number of EEGs
in AESD between 5 and 24 h were limited, increase ofalpha and beta power bands with time was apparent on
EEGs in FS compared to those in AESD (Figs. 3 and 4).
These suggest that serial EEGs up to 24 h after the onset
would enhance the quality in early diagnosis of AESD
before the emergence of second phase. Initial EEG earliest after admission would be also helpful for identification of most severe cases of AESD.
A nationwide survey identified 282 AESD cases

The authors declare no conflict of interest.

12

EEG analysis in acute encephalopathy
Table 6-Continued
Locations
F4-C4

C3-P3

C4-P4

P3-O1

110619 (7152–309148)
62161 (4249–310697)
2181 (92–9399)*
4198 (644–16900)
213 (9–676)**
688 (139–1370)
43 (2–101)**
328 (58–2071)
9 (1–21)**91 (20–276)
900 (117–2836)**
102 (3–450)
727 (91–2586)**
77 (5–337)

99733 (1922–420263)
60333 (4160–291000)
1247 (156–2981)
3392 (421–12800)
120 (27–190)**
428 (126–1099)
39 (12–126)**
123 (37–326)
9 (1–40)**59 (8–268)
898 (12–2531)*
168 (4–829)
734 (7–2376)*
138 (6–727)

127946 (9967–464742)
130996 (122–569219)
43634 (3240–145000)
123128 (4223–423000)
1824 (143–4483)
1668 (28–6123)*
3265 (402–18900)
4385 (759–21800)
151 (13–280)
90 (19–241)***
491 (80–1312)
455 (190–1652)
43 (3–120)
24 (7–52)****
179 (26–724)
140 (60–384)
9 (1–31)
6 (1–12)****71 (11–264)
82 (6–351)
981 (100–2587)
1120 (6–2361)***
138 (3–462)
350 (2–901)
815 (69–2080)
903 (4–2110)***
107 (5–336)
250 (5–637)

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43 (6–101)**
166 (20–464)
11 (1–36)**
91 (10–362)
1212 (15–2610)*
262 (3–990)
991 (7–1888)*
183 (5–589)

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