Brain & Development 44 (2022) 122–130

www.elsevier.com/locate/braindev

Original article

Involuntary movements as a prognostic factor for

acute encephalopathy with biphasic seizures
and late reduced diffusion
Yosuke Miyamoto a,b, Tohru Okanishi a,⇑, Masanori Maeda a,c, Tatsuya Kawaguchi a,
Sotaro Kanai a, Yoshiaki Saito a,d, Yoshihiro Maegaki a
a
Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, Tottori
683-8504, Japan
b
Department of Pediatrics, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
c
Department of Pediatrics, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan
d
Division of Child Neurology, Saiseikai Yokohama City Tobu Hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama, Kanagawa 230-8765, Japan

Received 3 July 2021; received in revised form 17 September 2021; accepted 29 September 2021

Abstract

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic sei-
zures and white matter lesions with reduced diffusion, which are often accompanied by involuntary movements. The neurological
outcomes of AESD vary from normal to mild or severe sequelae, including intellectual disability, paralysis, and epilepsy. The pre-
sent study aimed to clarify the prognostic factors of AESD, including involuntary movements.
Methods: We enrolled 29 patients with AESD admitted to Tottori University Hospital from 1991 to 2020 and retrospectively
analyzed their clinical data. Neurological outcomes were assessed by the Pediatric Cerebral Performance Category score and cere-
bral paralysis as neurological sequelae.
Results: Of the 29 patients, 12 had favorable outcomes and 17 had unfavorable outcomes. Univariate analysis revealed that the
presence of underlying diseases, a decline in Glasgow Coma Scale (GCS) score 12–24 h after early seizures, and involuntary move-
ments were associated with unfavorable outcomes. In multivariate analysis, a decline in GCS score and involuntary movements were
associated with unfavorable outcomes. The sensitivities and specificities of underlying diseases, a decline of  3 points in GCS score
12–24 h after early seizures, and involuntary movements for unfavorable outcomes were 53% and 92%, 92% and 65%, and 59% and
92%, respectively.
Conclusions: The appearance of involuntary movements may be associated with unfavorable outcomes of AESD. The prognostic
factors identified herein are comparable with previously known prognostic factors of consciousness disturbances after early seizures.
Ó 2021 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.

Keywords: Acute encephalopathy; Acute encephalopathy with biphasic seizures and late reduced diffusion; Children; Involuntary movement;
Outcome

1. Introduction

⇑ Corresponding author. Acute encephalopathy with biphasic seizures and late

E-mail addresses: okanishipediatrics@gmail.com, t.okanishi@ reduced diffusion (AESD) is one of the most common
tottori-u.ac.jp (T. Okanishi).

https://doi.org/10.1016/j.braindev.2021.09.011
0387-7604/Ó 2021 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.
 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130
childhood acute encephalopathies in East Asia. Unlike
acute necrotic encephalopathy or hemorrhagic shock
and encephalopathy syndrome caused by a cytokine
storm, the mechanism underlying AESD has been pro-
posed to be an excitotoxic injury with delayed neuronal
death [1,2]. AESD is characterized by a prolonged feb-
rile seizure as the initial neurological symptom on day
1 (early seizure phase), followed by a cluster of seizures
associated with deterioration of consciousness on days
4–6 (late seizure phase). Patients often have disturbances
in consciousness between the early and late seizure
phases. Although brain magnetic resonance imaging
(MRI) during the first 2 days shows no abnormality, it
reveals reduced diffusion in the cortical and subcortical
white matter around the late seizure phase (typically
days 3–9); this finding is known as the ‘‘bright tree
appearance” [1–3]. The neurological outcomes of AESD
vary from normal to mild or severe sequelae, including
intellectual disability, paralysis, and epilepsy [1,2].
Impaired awareness 12–24 h after early seizures, early
onset age, prolonged convulsions, the need for mechan-
ical ventilation, and elevated liver transferase, blood glu-
cose, and creatinine levels are early predictive factors for
the development of AESD [4]. In previous analyses of
the prognostic factors for the neurological outcomes of
AESD and other acute encephalopathies with reduced
subcortical diffusion, prolonged seizures at onset, coma,
diffuse lesions with an injury around the perirolandic
region, and basal ganglia or thalamus lesions have been
associated with intellectual disability, cerebral palsy,
and epilepsy [5–8]. In patients with AESD, involuntary
or stereotypic movements are often observed beginning
4–18 days after onset [9]. Only one previous study [7]
has described the association between the outcomes of
AESD and involuntary movements, and it reported that
involuntary movements prior to late seizures were asso-
ciated with unfavorable outcomes.
We encountered patients with AESD who presented
with involuntary movements after late seizures, which
were followed by unfavorable outcomes. Therefore, we
hypothesized that involuntary movements during the
course of AESD are associated with unfavorable out-
comes. We performed a retrospective study in children
with AESD to analyze the prognostic factors of AESD
using clinical data, including information regarding
involuntary movements.
2. Materials and Methods
2.1. Patients and AESD criteria
This study was approved by the Institutional Ethical
Review Board of Tottori University (approval number:
20A151). The requirement for informed consent was
waived owing to the retrospective nature of the study.
The inclusion criteria were as follows: (1) diagnosis of
123
AESD and (2) admission to Tottori University Hospital
from January 1991 to December 2020. The diagnostic
criteria of AESD were based on the Clinical Consensus
and Guidelines for Acute Encephalopathy in Children
advocated by the Japanese Society of Child Neurology
[10]: (1) AESD that developed during the fever stage
of the infection without potential trigger conditions,
such as head trauma, other encephalopathy syndromes,
or encephalitis; (2) convulsive seizures that developed on
the day of or the day following the onset of fever (early
seizure phase); (3) recurrent convulsive seizures or a
deterioration in consciousness 3–7 days after disease
onset (late seizure phase); (4) restricted diffusivity in
the subcortical white matter or cortex on diffusion-
weighted imaging (DWI) 3–14 days after disease onset;
and (5) residual lesions or atrophy confirmed by com-
puted tomography (CT), MRI, or decreased blood flow
on single-photon emission CT (SPECT) in the frontal
region or the frontal and parietal regions 2 weeks after
disease onset. Patients were definitively diagnosed with
AESD if they met criteria (1) and (2) and at least one cri-
terion from (3) to (5).
2.2. Data collection
We retrospectively reviewed the patients’ medical
records and investigated the following clinical data:
age at diagnosis, sex, underlying diseases, infectious
agents, duration of the initial seizure, results of blood
examinations on admission (including the levels of
aspartate aminotransferase [AST], alanine aminotrans-
ferase [ALT], lactate dehydrogenase [LDH], creatinine,
serum glucose, sodium [Na], and ammonia and pH in
venous blood gas analysis), the course of consciousness,
neurological symptoms, treatment options for acute
encephalopathy, brain imaging findings, and neurologi-
cal outcomes. We classified involuntary movements into
chorea, dystonia, ballism, myoclonus, and oral
dyskinesia.
Consciousness level was assessed using the Glasgow
Coma Scale (GCS), and the decline in comparison with
the GCS score before onset was also evaluated. Since
consciousness levels were presumed to fluctuate during
the observation period, we selected the highest levels
for each patient on each day.
We reviewed the brain lesions on images in the acute
phase (within 14 days of onset) using DWI, and those in
the chronic phase (from 28 days onward after disease
onset) using T1/T2-weighted and fluid-attenuated inver-
sion recovery images on MRI and CT. For brain DWI
in the acute phase, we reviewed the subcortical high-
signal lesions for the diagnosis of AESD, and evaluated
the distribution of lesions in the cerebral cortices of the
left or right frontal lobe, cerebral cortices other than the
frontal lobe, basal ganglia or thalamus, and cortices in
the perirolandic region. Using MRI and CT in the
124 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130
chronic phase, we reviewed the atrophic changes in the
cerebrum to diagnose AESD.
Treatment options included anticonvulsant drugs,
high-dose steroids (intravenous methylprednisolone
pulse or high-dose dexamethasone therapy), intravenous
immunoglobulin, vitamins, thermoregulation (therapeu-
tic hypothermia or normothermia), mechanical respira-
tory support with intubation, and edaravone. Vitamin
therapy included vitamins B1, B6, and levocarnitine;
however, the combination and dosage of these compo-
nents varied among patients.
2.3. Neurological outcome assessment
Two pediatricians assessed the medical records of
each patient to evaluate the neurological outcomes at
12 months after the onset of AESD using the Pediatric
Cerebral Performance Category (PCPC) score [11]: 1,
normal performance; 2, mild disability; 3, moderate dis-
ability; 4, severe disability; 5, coma or vegetative state;
and 6, death.
Since the PCPC score = 3 means that the patients
need or are expected to need attending special education
classrooms and/or have learning deficits during their
school ages [11] (Supplementary Table 1), we set PCPC
score = 3 as the boundary of unfavorable/favorable out-
comes: we classified patients with PCPC scores of 1–2
before the onset of AESD as showing ‘‘unfavorable out-
comes” if the PCPC scores became  3 or if the patients
showed cerebral paralysis. When the PCPC scores
were  3 before the onset of AESD, due to underlying
diseases, we judged ‘‘unfavorable outcomes” if the
scores increased, or paralysis was persisted or exacer-
bated 12 months after disease onset. The other patients
were classified as having ‘‘favorable outcomes” in this
study.
2.4. Statistical analysis
First, to examine the differences in clinical findings
and laboratory findings between the favorable and unfa-
vorable groups, Fisher’s exact tests and Mann-Whitney
U tests were used for categorical and numerical vari-
ables, respectively. Second, to analyze the correlations
between neurological outcomes and clinical and labora-
tory findings, we performed univariate and multivariate
logistic regression analyses using variables with p < 0.05.
To examine the differences in treatment options and
neuroimaging between the favorable and unfavorable
groups, Fisher’s exact test was used. Statistical signifi-
cance was set at p < 0.05. Moreover, we analyzed the
accuracy of the sensitivity and specificity for unfavor-
able outcomes in relation to the clinical findings. We
used the Youden index to determine cutoff values. Sta-
tistical analyses were conducted using Excel 2019
(Microsoft, Redmond, WA, USA) with the Bell Curve
for Excel version 3.20 add-in (Social Survey Research
Information Co., Ltd, Tokyo, Japan).
3. Results
3.1. Patient characteristics
We recruited 29 patients (14 men, 15 women) who
fulfilled the diagnostic criteria for AESD, of whom 12
were classified into the ‘‘favorable outcome” group
and 17 were classified into the ‘‘unfavorable outcome”
group. Clinical features and laboratory data are
described in Table 1. The median age of onset in the
favorable outcome group was 22.5 (interquartile range
[IQR]: 21–32.2) months, while that of the unfavorable
outcome group was 23 (IQR: 19–48) months. The iso-
lated viruses in the preceding infection included human
herpesvirus 6 in five patients, influenza virus in four, res-
piratory syncytial virus in one, and rotavirus in one; the
viruses remained unidentified in 18 patients.
Underlying diseases before the onset of AESD were
significantly more frequent in the unfavorable outcome
group (n = 9) than in the favorable outcome group
(n = 1; p = 0.016). The underlying diseases were perina-
tal brain injury in five patients, genetic or chromosomal
syndrome in two patients (tuberous sclerosis complex
and Sotos syndrome in one each), perinatal infectious
disease in one patient (cytomegalovirus), and other dis-
eases in three patients.
The decline in GCS score 12–24 h after early seizures
was significantly larger in the unfavorable outcome
group than in the favorable outcome group
(p = 0.003) (Table 1, Supplementary figure 1 and Sup-
plementary figure 2).
There were no significant differences in the laboratory
data obtained at initial sampling during the early seizure
phase between the two groups.
Involuntary movements were observed in 11 of the 29
patients (38%). All involuntary movements occurred
after the late seizure phase. In the favorable outcome
group, one of the 12 (8.3%) patients showed ballism as
an involuntary movement. In contrast, in the unfavor-
able outcome group, 10 of 17 (58.8%) patients developed
involuntary movements, including chorea in six, dysto-
nia in five, ballism in one, and myoclonus in five
patients. The proportion of patients presenting with
involuntary movements was significantly higher in the
unfavorable outcome group than in the favorable out-
come group (p = 0.007) (Fig. 1). These involuntary
movements started from 7 to 30 (median, 13) days after
disease onset, with a duration ranging from 4 to 72 days.
3.2. Prognostic factors for the outcomes of AESD
We performed univariate logistic regression analysis
of unfavorable outcomes using the explanatory vari-
 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130 125

Table 1
Clinical features and laboratory data in favorable and unfavorable outcome groups.
Favorable outcome total number = 12 Unfavorable outcome total number = 17 p value
Age (months) [median, (IQR)] 22.5 (21–32.2) 23 (19–48) 0.550
Gender (Women) [n, (%)] 8 (66.7) 7 (41.2) 0.165
Underlying diseases [n, (%)] 1 (8.3) 9 (52.9) 0.016*
Perinatal brain injury [n, (%)] 1 (8.3) 4 (23.5)
Genetic/chromosomal syndrome [n, (%)] 0 (0) 2 (11.8)
Perinatal infectious disease [n, (%)] 0 (0) 1 (5.9)
Others [n, (%)] 0 (0) 3 (17.6)
Early seizure duration (min) [median, (IQR)] 45 (23.3–60) 60 (35–100) 0.241
GCS decline at 12–24 h after the early seizure 1 (0–2.5) 4 (2–5.8) 0.003*
[median, (IQR)]
Involuntary movements
Total [n, (%)] 1 (8.3) 10 (58.8) 0.007*
Chorea [n, (%)] 0 (0) 6 (35.3)
Dystonia [n, (%)] 0 (0) 5 (29.4)
Ballism [n, (%)] 1 (8.3) 1 (5.9)
Myoclonus [n, (%)] 0 (0) 4 (23.5)
Laboratory data at initial sampling after
the early seizure
AST (IU/L) [(n*), median, (IQR)] (10) 45.5 (36.3–50) (17) 40 (33–62) 0.841
ALT (IU/L) [(n*), median, (IQR)] (10) 17 (15.3–17) (17) 19 (14–24) 0.467
LDH (IU/L) [(n*), median, (IQR)] (10) 306.5 (291–337) (16) 353.5 (285–413) 0.292
Creatinine (mg/dL) [(n*), median, (10) 0.36 (0.25–0.47) (17) 0.32 (0.22–0.36) 0.880
(IQR)]
Serum glucose (mg/dL) [(n*), median, (9) 221 (147–289) (17) 230 (145–260) 0.936
(IQR)]
Na (mmol/L) [(n*), median, (IQR)] (9) 137 (135–138) (17) 136 (134–137) 0.788
Ammonia (lg/dL) [(n*), median, (IQR)] (8) 90.5 (33.3–151.8) (13) 61 (49–78) 0.772
pH [(n*), median, (IQR)] (8) 7.07 (6.889–7.258) (9) 7.28 (6.910–7.346) 0.501
IQR: interquartile range; n*: number of patients with sampling; We used Fisher’s exact tests and Mann-Whitney U tests for categorical and
numerical variables, respectively. p < 0.05 was set as significance.

ables of underlying diseases, a decline in GCS score 12–
24 h after early seizures, and involuntary movements.
The analysis revealed that each of these variables was
associated with unfavorable outcomes (p = 0.029,
0.010, and 0.017, respectively; Table 2). The sensitivities
and specificities of these variables for unfavorable out-
comes were 53% and 92% for underlying diseases, 92%
and 65% for a decline in GCS score 12–24 h after early
seizures (cutoff value, 3 with Youden index), and 59%
and 92% for involuntary movements, respectively. Mul-
tivariate logistic regression analysis revealed that GCS
decline and involuntary movements were associated
with unfavorable outcomes (p = 0.027 and 0.027,
respectively; Table 2). The odds ratio for unfavorable
outcomes was 2.194 for GCS decline, and 46.566 for
involuntary movements (Table 2).
3.3. Treatment options
We evaluated the prognostic factors for each treatment
option for the early and late seizure phase (Table 3). The
proportion of patients who received vitamin therapy after
the late seizure phase was higher in the favorable than in
the unfavorable outcome group (p = 0.028). There were
no statistically significant differences in other treatment
options, including anticonvulsant drugs, high-dose ster-
oids, intravenous immunoglobulin, thermoregulation,
mechanical respiratory support with intubation, or edar-
avone, between the two groups.
3.4. Neuroimaging
3.4.1. Brain lesions on each neuroimaging examination
Brain MRI was performed in 27 of the 29 patients.
Brain DWI in the acute phase was performed in 20
patients, and MRI in the chronic phase was performed
in 23 patients. Brain CT scans were obtained in 25
patients in the acute phase and three patients in the
chronic phase. SPECT was performed in four patients
in the chronic phase.
For seven patients who did not undergo DWI in the
acute phase, T2-weighted and fluid-attenuated inversion
recovery images showed high-signal intensity in the sub-
cortical white matter 8–24 days after disease onset, and
atrophy of the same lesions in the chronic phase. The
remaining two patients who did not undergo MRI
showed brain edema on head CT 7 and 9 days after dis-
ease onset, respectively. In the chronic phase, brain
126 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130

Fig. 1. The detailed course of involuntary movements in patients with favorable and unfavorable outcomes. Involuntary movements were observed
more frequently in patients with unfavorable outcomes (10/17 [58.8%] patients) than in those with favorable outcomes (1/12 [8.3%] patients). Arrows
indicate the onset of the late seizure phase or the bright tree appearance on diffusion-weighted imaging. The patients indicated by an asterisk (*)
showed no changes in PCPC scores, although cerebral paralysis persisted or exacerbated in the follow-up period. Abbreviations: D, dystonia; C,
chorea; B, ballism; M, myoclonus; OD, oral dyskinesia; PCPC, Pediatric Cerebral Performance Category.

Table 2
Univariate and multivariate analyses of clinical factors predicting unfavorbale outcomes.
Estimate Standard error Odds Ratio for unfavourable outcome p-value
Univariate analyses
Underlying diseases 2.516 1.152 12.376 0.029*
GCS decline at 12–24 h after the early seizure 0.680 0.264 1.974 0.010*
Involuntary movements 2.755 1.155 15.723 0.017*
Multivariate analyses
Underlying diseases 2.332 1.469 10.296 0.112
GCS decline at 12–24 h after the early seizure 0.786 0.354 2.194 0.027*
Involuntary movements 3.841 1.731 46.566 0.027*
GCS: Glasgow Coma Scale; We used univariate and mutivariate logistic regression analyses; p < 0.05 was set as significance.

atrophy was confirmed on CT in two patients, and
decreased blood flow with frontal lobe predominance
was confirmed on SPECT in four patients.
3.4.2. DWI lesions and their associations with outcomes
Of the 20 patients who underwent brain DWI in the
acute phase, 10 patients each were included in the favor-
able and unfavorable outcome groups (Table 4). The
proportion of patients who presented with high-signal
lesions extending to both hemispheres or regions other
than the frontal lobe was higher in the unfavorable out-
come group than in the favorable outcome group,
although this difference did not reach statistical signifi-
cance (p = 0.167 and 0.095, respectively). High-signal
lesions in the basal ganglia, thalamus, or perirolandic
region were more frequently observed in the unfavorable
 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130 127

Table 3
Comparison of treatment between favorable and unfavorable outcome groups.
Favorable outcome total number = 12 Unfavorable outcome total number = 17 p value
Treatment options at early seizure phase
PHT or f-PHT div [n, (%)] 5 (41.7) 5 (29.4) 0.283
MDL div [n, (%)] 2 (16.7) 5 (29.4) 0.369
PB div [n, (%)] 0 (0) 2 (11.8) 0.335
Thiopental div, iv [n, (%)] 1 (8.3) 4 (23.5) 0.293
High-dose steroids [n, (%)] 1 (8.3) 7 (41.2) 0.060
IVIG [n, (%)] 0 (0) 2 (11.8) 0.335
Vitamins [n, (%)] 7 (58.3) 7 (41.2) 0.297
Thermoregulation [n, (%)] 1 (8.3) 3 (17.6) 0.444
Intubation [n, (%)] 1 (8.3) 6 (35.3) 0.108
Edaravone div [n, (%)] 3 (25.0) 4 (23.5) 0.705
Treatment options after late seizure phase
PHT or f-PHT div [n, (%)] 7 (58.3) 6 (35.3) 0.198
MDL div [n, (%)] 6 (50.0) 8 (47.1) 0.587
PB div [n, (%)] 0 (0) 1 (5.9) 0.586
Thiopental div, iv [n, (%)] 3 (25.0) 9 (52.9) 0.131
High-dose steroids [n, (%)] 2 (16.7) 6 (35.3) 0.250
IVIG [n, (%)] 3 (25.0) 1 (5.9) 0.178
Vitamins [n, (%)] 10 (83.3) 7 (41.2) 0.028*
Thermoregulation [n, (%)] 3 (25.0) 3 (17.6) 0.487
Intubation [n, (%)] 4 (33.3) 9 (52.9) 0.253
Edaravone div [n, (%)] 4 (33.3) 6 (35.3) 0.615
div: drip infusion in vein; f-PHT: fos-phenytoin; iv: intravenous; IVIG: intravenous immunoglobulin; MDL: midazolam; PB: phenobarbital; PHT:
phenytoin; We used Fisher’s exact tests. p < 0.05 was set as significance.

Table 4
Comparison of lesion extent on diffusion-weighted imaging between favorable and unfavorable outcome groups.
Favorable outcome total number = 10 Unfavorable outcome total number = 10 p value
Bilateral lesions [n, (%)] 5 (50.0) 9 (90.0) 0.167
Lesions other than frontal lobe [n, (%)] 6 (60.0) 9 (90.0) 0.095
Basal ganglia or thalamus lesion [n, (%)] 1 (10.0) 3 (30.0) 0.291
Perirolandic area lesion [n, (%)] 0 (0) 3 (30.0) 0.105
We used Fisher’s exact tests. p < 0.05 was set as significance.

outcome group, although this difference also showed no
statistical significance (p = 0.291 and 0.105,
respectively).
4. Discussion
4.1. Summary of the results
In this retrospective study, we investigated the clinical
findings, treatment options, and distributions of DWI
lesions to identify prognostic factors for unfavorable
outcomes. A decline in GCS score 12–24 h after early
seizures and involuntary movements were associated
with unfavorable outcomes in the univariate and multi-
variate analyses, and underlying diseases were associ-
ated with unfavorable outcomes in the univariate
analysis. The administration of vitamins after the late
seizure phase was associated with favorable outcomes.
The distribution of DWI lesions was not associated with
the outcomes in this study.
4.2. Impaired consciousness after early seizures
In our study, a decline in GCS score 12–24 h after
early seizures was a prognostic factor for unfavorable
outcomes of AESD in both univariate and multivariate
analyses. This is generally consistent with the findings of
previous studies showing an association between poor
outcomes and coma before the late seizure phase or
decreased consciousness 24 h after disease onset [5,7].
The excitotoxicity induced by the first prolonged seizure
causes dysfunction of the cortices and subcortical white
matter between the early and late seizure phases in
AESD. This dysfunction impairs consciousness after
the early seizure phase [1,7]. Thus, a seriously impaired
consciousness may reflect strong excitotoxicity during
128 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130
early seizures, which may result in profound neuronal
cell death in the late seizure phase.
4.3. Involuntary movements
The appearance of involuntary movements was asso-
ciated with unfavorable outcomes in both univariate
and multivariate analyses. Involuntary movements in
children are likely to result from global dysfunction of
corticobasal ganglia circuits, which are composed of
connections in the cerebral cortex, striatum, globus pal-
lidus, subthalamic nucleus, substantia nigra, and the
ventral nucleus of the thalamus [12]. Cortical insults
sparing the basal ganglia can result in the development
of involuntary movements via interruption of the cir-
cuits [13]; in our study, seven of the 11 patients with
involuntary movements did not have basal ganglia
lesions. In these patients, widespread cortical lesions
may disrupt corticobasal ganglia circuits and cause
involuntary movements.
In this study, involuntary movements were a prog-
nostic factor for unfavorable outcomes (sensitivity,
59%; specificity, 92%), and were as useful as GCS
decline (sensitivity, 92%; specificity, 65%) and underly-
ing diseases (sensitivity, 53%; specificity, 92%). The odds
ratio for unfavorable outcomes in the statistical analysis
was higher for involuntary movements than for GCS
decline (46.566 and 2.194, respectively). This suggests
that involuntary movements may have a larger impact
on outcomes of AESD than GCS decline. Lee et al. [7]
reported 20 patients with AESD and evaluated the
appearance of involuntary movements in the groups
showing unfavorable and favorable outcomes. Unlike
our patients, these patients showed involuntary move-
ments, including dystonia, oral dyskinesia, and chorea,
prior to the late seizure phase. These movements were
frequently observed in five of the eight (63%) patients
with unfavorable outcomes, in comparison with one of
the 12 (8%) patients with favorable outcomes. There
are two possible reasons why no patients in our cohort
showed involuntary movements prior to the late seizure
phase. First, as Lee et al. [7] reported, involuntary move-
ments prior to the late seizure phase are subtle and unre-
markable compared with those after the late seizure
phase, and might have been overlooked in this study.
Second, seven of the 29 (24%) patients required intuba-
tion in the early seizure phase, and the involuntary
movements might be masked by sedation. In patients
with AESD, involuntary movements may reflect severe
dysfunction or insults of cortices, respectively, before
and after the late seizure phase, and are associated with
unfavorable outcomes.
As shown in Fig. 1, the patients who presented with
dystonia had more unfavorable outcomes with PCPC = 4
or cerebral paralysis than those without dystonia. Com-
pared with other involuntary movements, dystonia
occurs in the situations with widespread lesions in cere-
bral cortices, stratum or thalami [14,15]. Dystonia in
AESD may indicate widespread cortical lesions or
involving deep gray matter injuries and might be associ-
ated with the unfavorable outcomes.
In cases showing involuntary movements during the
course of AESD, assessments of and rehabilitation for
intellectual disability or paralysis that can be assumed
to occur subsequently could be started early. Moreover,
post-encephalopathic epilepsy, which tends to be
intractable, has been reported to occur more frequently
in patients with AESD presenting with coma or involun-
tary movements during the disease course [16,17]. There-
fore, cautious observation, including planning for
electroencephalography, should be performed, consider-
ing the development of post-encephalopathic epilepsy in
the follow-up period. On the other hand, involuntary
movements often appear after the late seizure phase
and may have minimal effect on prognosis-altering treat-
ment choices.
4.4. Presence of underlying diseases
Patients with underlying diseases tended to have
unfavorable outcomes in the univariate analysis, but
not in the multivariate analysis. The onset of AESD
has been reported to be more prevalent in children with
underlying neurological disorders [18]. Using data on
the outcomes of AESD, we clarified the associations
between underlying diseases and unfavorable outcomes.
The underlying diseases in the patients assessed in this
study, including neonatal hypoxic-ischemic
encephalopathy, tuberous sclerosis complex, Sotos syn-
drome, and congenital cytomegalovirus infection, tend
to result in the development of epileptic seizures [19–
23]. Neuronal excitability due to these neurological
background factors may cause susceptibility to excito-
toxicity in early seizures and is associated with unfavor-
able outcomes.
4.5. Treatment options
There is no established treatment strategy for AESD
other than the management of the general condition and
termination of status epilepticus as early as possible [10].
Fukui et al. [24] reported that early administration of
vitamins B1 and B6 and levocarnitine within 24 h after
disease onset could prevent the late seizure phase of
AESD, leading to milder clinical manifestations and bet-
ter outcomes. They described that these vitamins may
have mitochondrial rescue functions, neuroprotective
effects, and antioxidant actions. In our study, the favor-
 Y. Miyamoto et al. / Brain & Development 44 (2022) 122–130
able outcome group included more patients who
received vitamins after the late seizure phase. Thus, fur-
ther studies with a standardized vitamin administration
protocol are necessary to demonstrate that vitamin ther-
apy after the late seizure phase also improves outcomes.
4.6. Neuroimaging
The neuroimaging findings that have been previously
associated with unfavorable outcomes are extensive
DWI abnormalities, perirolandic lesions, and basal gan-
glia or thalamus lesions [6,8,25]. In the present study,
high-signal lesions extending to both hemispheres, other
than the frontal lobe, in the basal ganglia or thalamus,
and in the perirolandic region were observed more fre-
quently in the unfavorable outcome group than in the
favorable outcome group, although the difference was
not statistically significant. We consider this lack of sig-
nificance attributable to the small sample size of only 20
subjects in both groups combined.
Our study had some limitations. This was a retro-
spective, single-center study, and the number of patients
was small. The time points of laboratory and MRI eval-
uations and treatments varied according to the clini-
cian’s judgment. Therefore, additional research should
aim to unify examination and treatment plans.
In conclusion, our study revealed that the appearance
of involuntary movements may be associated with the
unfavorable outcomes of AESD, and that these prog-
nostic factors were comparable to the previously known
prognostic factors of consciousness disturbances after
early seizures. Larger sample sizes or prospective studies
in multiple centers are needed to confirm the present
results and clarify the association between prognosis
and neuroimaging findings or treatment options.
Funding
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors.
6. Data statement
All data generated or analysed during this study are
available from the corresponding author on reasonable
request.
Declaration of Competing Interest
The authors declare that they have no known com-
peting financial interests or personal relationships that
could have appeared to influence the work reported in
this paper.
129
Acknowledgments
We thank the doctors who examined and treated the
patients in this study.
Appendix A. Supplementary data
Supplementary data to this article can be found online
at https://doi.org/10.1016/j.braindev.2021.09.011.
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