Brain & Development xxx (2020) xxx–xxx
www.elsevier.com/locate/braindev

Review article

Guidelines for the diagnosis and treatment of acuteencephalopathy in childhood
Masashi Mizuguchi a,b,⇑, Takashi Ichiyama a,c, George Imataka a,d, Akihisa Okumura a,e,
Tomohide Goto a,f, Hiroshi Sakuma a,g, Jun-ichi Takanashi a,h, Kei Murayama a,i,
Takanori Yamagata a,j, Hideo Yamanouchi a,k, Tokiko Fukuda l,m,
Yoshihiro Maegaki m,naCommittee for the Compilation of Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood, Japanese Society ofChild Neurology, Tokyo, Japanb
Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japanc
Division of Pediatrics, Tsudumigaura Medical Center for Children with Disabilities, Yamaguchi, Japand
Department of Pediatrics, Dokkyo Medical University, Tochigi, Japane
Department of Pediatrics, Aichi Medical University, Aichi, Japanf
Division of Neurology, Kanagawa Children’s Medical Center, Kanagawa, Japang
Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japanh
Department of Pediatrics, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japani
Department of Metabolism, Chiba Children’s Hospital, Chiba, Japanj
Department of Pediatrics, Jichi Medical University, Tochigi, Japank
Department of Pediatrics, Comprehensive Epilepsy Center, Saitama Medical University, Saitama, Japanl
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japanm
Committee for the Integration of Guidelines, Japanese Society of Child Neurology, Tokyo, JapannDivision of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
Received 18 June 2020; received in revised form 4 August 2020; accepted 4 August 2020

Abstract
The cardinal symptom of acute encephalopathy is impairment of consciousness of acute onset during the course of an infectious disease, with duration and severity meeting deﬁned criteria. Acute encephalopathy consists of multiple syndromes such as acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late reduced diﬀusion and clinically mild encephalitis/
encephalopathy with reversible splenial lesion. Among these syndromes, there are both similarities and diﬀerences. In 2016, the Japanese Society of Child Neurology published ‘Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood’, which
made recommendations and comments on the general aspects of acute encephalopathy in the ﬁrst half, and on individual syndromes in
the latter half. Since the guidelines were written in Japanese, this review article describes extracts from the recommendations and comments in English, in order to introduce the essence of the guidelines to international clinicians and researchers.
Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Coma; Status epilepticus; Brain edema; Metabolic disorder; Cytokine storm; Excitotoxicity; Neuroimaging; Intensive care; Targeted
temperature management⇑ Corresponding author at: Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
E-mail address: mizuguchi-tky@umin.net (M. Mizuguchi).

https://doi.org/10.1016/j.braindev.2020.08.001
0387-7604/Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Mizuguchi M et al. Guidelines for the diagnosis and treatment of acute encephalopathy in childhood. Brain
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1. Introduction
1.1. Background
Acute encephalopathy (AE) denotes syndromes characterized by acute onset of severe and long-lasting disturbance of consciousness, which typically occur inpreviously healthy children. AE is the most severe complication of common infectious diseases, such as inﬂuenza and exanthem subitum, often leading to death orsevere neurological disabilities [1].
To date, many syndromes of AE have been described.
Among them, Reye syndrome was originally reported inAustralia [2], and hemiconvulsion-hemiplegia-epilepsy(HHE) syndrome [3] and hemorrhagic shock andencephalopathy syndrome (HSES) [4] in Europe. During
1993–2006, child neurologists in Japan established andcharacterized many new syndromes, including acutenecrotizing
encephalopathy
(ANE)
[5],
acute
encephalopathy with biphasic seizures and late reduced
diﬀusion (AESD) [6] and clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)[7], and achieved a general consensus upon the syndromic classiﬁcation of AE by around 2007 [1]. Basedon this classiﬁcation, a nationwide epidemiologic studyof AE was conducted in 2010, and the results were published in 2012 [8]. The time was ripe for the compilationof new guidelines.
1.2. Purpose
We aimed to provide clinicians treating acute neurologic disorders of children, such as seizures and impairment of consciousness, with guidelines that are usefulfor the acute stage management of AE.
Since AE is rare and many of the syndromes wererecently characterized, there is only limited information
about the diagnosis and treatment. On the other hand,most children with AE are critically ill, requiring prompt
and intensive care; thus, there is a great need for guidelines. Until 2013, the only guidelines available for AE
had been consensus guidelines speciﬁcally targetinginﬂuenza-associated AE, published in 2005 and revisedin 2009 [9]. Therefore, our purpose was to publish
new, evidence-based guidelines targeting AE associatedwith any pathogen and classiﬁed into any syndrome [10].
1.3. Formulation
In September 2013, the Japanese Society of Child
Neurology (JSCN) decided to establish clinical practiceguidelines for AE, and formed a working group (WG)
of ten members and two advisors. From March 2014
to August 2016, the WG formulated guidelines using
the methodologies recommended by the Medical Information Network Distribution System (Minds) withminor modiﬁcations. Brieﬂy, clinical questions (CQs)
were selected, and the system of literature search was
determined. Documents in English were retrieved fromthe PubMed database and those in Japanese from the
Ichushi-web were provided by the Japan Medical
Abstracts Society. For each CQ, two WG members systematically reviewed the literature, and evaluated thelevels of evidence. One of the two members wrote thedrafts of recommendations and comments, and thenthe other reviewed them. For some CQs, additional specialists outside of the WG were invited to criticallyreview the draft: a specialist of electroencephalography(EEG) for CQ 2–4, and intensivists from the JapaneseSociety of Intensive Care Medicine for CQs 3–2 and
3–3. At the WG meeting, the levels of recommendations(Table 1) were decided and the guidelines were further
edited. In February 2016, the WG solicited public comments on the website from the other JSCN members andalso asked the following organizations to review thedrafts: Japanese Pediatric Society, Japanese Society for
Pediatric Infectious Diseases, Japanese Society of Emergency Pediatrics and Chiisana-inochi (an association offamilies of children with inﬂuenza encephalopathy).
After revision of the drafts based on the opinions andcomments from members and organizations, the guidelines were published in August 2016 [10]. The guidelines
were uploaded on the Minds homepage in February
2017.
1.4. Contents and ﬂow chart
The guidelines consist of seven chapters, each of themincluding two to four CQs. The ﬁrst half (three chapters)of the guidelines, corresponding to Sections 2.1–2.3 inthis article, describes the general aspects of AE such as
epidemiology and initial management. The second half(four chapters), corresponding to Sections 2.4–2.7,
explains the diagnosis and treatment of individual syndromes. In other words, the ﬁrst and second half deals
with the similarities and diﬀerences, respectively, among
syndromes [10].
Classiﬁcation into any of the known syndromes may
be diﬃcult in some cases, in particular immediately after
onset. In other cases, syndromic diagnosis may not bemade at all. To facilitate the use of the guidelines in suchcases, we illustrated their structure with a ﬂow chartindicating the relevant CQs according to the patient’s
clinical ﬁndings [10] (Fig. 1).
2. Extract of guidelines
2.1. Entity and epidemiology
2.1.1. (CQ1-1) deﬁnition of AE
Recommendations:

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3

Table 1
Grading of recommendations.
Grade

Evidence and recommendation

A
B
C1*
C2*
D

There is good evidence to recommend the clinical action.
There is fair evidence to recommend the clinical action.
There is insuﬃcient data to make a recommendation; however, consideration for the clinical action is acceptable.
There is insuﬃcient data to make a recommendation; however, consideration against the clinical action is acceptable.
There is evidence to recommend against the clinical action.

*Given the low quality of evidence currently available, recommendations of Grade C were expected for most of the clinical questions (CQs).
Therefore, we divided Grade C into two sub-grades: C1 and C2.

(1) AE is deﬁned as impairment of consciousness ofacute onset, with severity of Japan Coma Scale20 or Glasgow Coma Scale (GCS) <11, and withduration of 24 h or longer [10]. (Grading notapplicable)
1) The onset usually occurs during the course of
infectious diseases.
2) Brain edema is often visualized by cranial computed tomography (CT) or magnetic resonanceimaging (MRI).
3) Distinction is made from other diseases, such as
encephalitis and meningitis, and from othercauses of decreased consciousness such as sleep,
adverse eﬀects of anticonvulsants, anesthetics
and other drugs, and psychogenic seizures.

Comments:
AE is pathologically deﬁned as brain dysfunction due
to widespread, non-inﬂammatory brain edema. The clinical picture is dominated by acute disturbance of consciousness, which complicates common infections. AE
may occur in any age groups, but is most frequent ininfants and preschool children, during the febrile periodof an acute infectious disease. The pathogens are virusesin most cases, and are Mycoplasma or bacteria in occasional cases [1]. The cardinal symptom is severe andlong-lasting impairment of consciousness, often accompanied by convulsions or seizures. Signs of increased
intracranial pressure may also be noted.
The pathologic substrate of AE is non-inﬂammatory
brain edema, diﬀuse or widespread in distribution, andvascular or cellular in nature [1]. Neuroimaging techniques, such as cranial CT and MRI, are robust tools
to visualize brain edema. In particular, MRI diﬀusionweighted imaging (DWI) is not only sensitive but also
capable of distinguishing vascular and cellular edema
based on the apparent diﬀusion coeﬃcient.
AE is a heterogenous condition consisting of many
syndromes (Table 2).

2.1.2. (CQ1-2) epidemiology of AE
Recommendations:(1) The annual incidence of AE in Japan is estimatedto be 400–700 cases [8]. (Grading not applicable)
1) The most common pathogen is inﬂuenza virus, followed by human herpesvirus 6 (HHV-6), rotavirus
and respiratory syncytial virus (RSV).
2) The most common syndrome is AESD, followed
by MERS and ANE.
3) Inﬂuenza virus is the most common pathogen for
MERS and ANE.
4) HHV-6 is the most common pathogen for AESD.
Comments:
In 2010, the research committee supported by theJapanese government conducted a nationwide surveyof AE in Japan [8]. To date, this has been the only
country-based study that speciﬁcally focused on the epidemiology of AE. Using a questionnaire, this survey collected clinical data of AE cases with onset occurring
between April 2007 and June 2010. Based on the total
number of cases reported (983) and the response rate(51%), the annual incidence of 400–700 cases was estimated. The common pathogens of preceding infection
were inﬂuenza virus (27% of total cases), HHV-6(17%), rotavirus (4%) and RSV (2%). Bacteria andMycoplasma accounted for 2% and 1%, respectively.
The common syndromes were AESD (29%), MERS
(16%), ANE (4%) and HSES (1%).
2.1.3. (CQ1-3) prognosis of AE
Recommendations:(1) The fatality of overall AE in Japan is 6% and neurologic sequelae in 36%. Prognosis varies among
syndromes [8]. (Grading not applicable)
1) In AESD, deaths are rare whereas neurologic
sequelae are common.
2) In ANE and HSES, both deaths and neurologic
sequelae are common.

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

Pa’s Findings

Diagnosis and Treatment

CQ(s)Treatment of sor prolonged seizure

3-1

Infe
fever
Impaired consciousness and/or convulsion

yesSt

olonged seizurenoyesModerate to severe impairment of consciousness orpoor or unstable systemic

Systemic management

3-2

other disease

Diagnosis and treatmentof other disease

1-1,2,32-1,2,3,4

yes

Diagnosis and treatmentof acute encephalopathy
with metabolic disorder

4-1,2,3Diagnosis and treatment of
acute encephalopathy withnsyst

5-1,2,3,4

noDiagnosis and diﬀere al diagnosisof acute encephalopathy
acute
encephalopathy
Findings sugges

y

no
yes
Findings sugges

storm

no
Refractory sta
seizures, or frequent relapse of seizures

yes

Diagnosis and treatmentof acute encephalopathy
with sta

6-1,2

noDiagnosis and treatmentof acute encephalopathyof other type7-1,2,3,4

Fig. 1. Flow chart of the diagnosis and treatment of acute encephalopathy (AE).

3) In MERS, most cases recover without any
sequelae.
Comments:
According to the Japanese epidemiologic study in2010 [8], the outcome of overall AE was as follows:
recovery in 56% of cases, mild to moderate sequelae in
22%, severe sequelae in 14% and death in 6%. Prognosis
varied markedly among the syndromes and pathogens(Table 3). Prognosis appears to have improved recently,
whereby fatality from inﬂuenza encephalopathy reportedly declined from 30% (1995–1999) to 7–8% (2005) [11].
2.2. Diagnosis and examinations
2.2.1. (CQ2-1) Physical, laboratory and radiologic
examinations required for the diagnosis of AE
Recommendations:

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Table 2
Classiﬁcation of acute encephalopathy (AE).
A. Classiﬁcation based on the pathogen of antecedent infection (microbiologic classiﬁcation)
1. AE associated with viral infections
Inﬂuenza encephalopathy
Exanthem subitum (human herpesvirus [HHV]-6/7) encephalopathy
Rotavirus encephalopathy
Chickenpox (varicella-zoster virus) encephalopathy
Measles encephalopathy
Respiratory syncytial virus (RSV) encephalopathy
Other viral encephalopathy
2. AE associated with bacterial and other infections
Pertussis encephalopathy
Salmonella encephalopathy
Enterohemorrhagic Escherichia coli (EHEC) encephalopathy
Cat scratch fever encephalopathy
Mycoplasma encephalopathy
Other bacterial encephalopathy
3. AE associated with infection of unknown pathogen
B. Classiﬁcation based on the clinicopathologic features of encephalopathy (syndromic classiﬁcation)
1. AE caused by metabolic disorderClassical Reye syndrome
Congenital metabolic disorders
2. Encephalopathy caused by cytokine storm
Acute necrotizing encephalopathy (ANE)
Hemorrhagic shock and encephalopathy syndrome (HSES)
Other cytokine storm encephalopathy
3. Encephalopathy with convulsive status epilepticus (CSE) (possibly due to excitotoxic brain damage)Acute encephalopathy with biphasic seizures and late reduced diﬀusion (AESD)
Acute infantile encephalopathy predominantly aﬀecting the frontal lobes
Hemiconvulsion-hemiplegia (HH) syndrome/Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome
Other AESD
Febrile infection-related epilepsy syndrome (FIRES)/Acute encephalitis with refractory, repetitive partial seizures (AERRPS)
4. Miscellaneous syndromes
Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)
AE associated with Dravet syndrome
AE associated with congenital adrenal hyperplasia
Other/Unclassiﬁed encephalopathy

Table 3
Epidemiology of acute encephalopathy (AE) in relation to pathogens and syndromes.
A. Comparison of two major pathogens
PathogenInﬂuenza virus

HHV-6

Percentage in total cases
Sex (male/female)Age (mean ± SD, median) (y)Syndromes
Outcome27%
58%/42%6.3 ± 3.4, 6
MERS (20%), AESD (10%), ANE (6%)
Recovery (76%), Sequelae (16%), Death (7%)

17%
43%/57%0.8 ± 1.1, 1
AESD (64%), ANE (5%), MERS (2%)
Recovery (50%), Sequelae (45%), Death (2%)

B. Comparison of three major syndromes
Syndrome

AESD

MERS

ANE

Percentage in totalcases
Sex (male/female)Age (mean±SD,
median) (y)Pathogens

29%

16%

4%

41%/59%1.7±2.1, 1

52%/45%3.3±3.4, 2

58%/42%5.6±3.7, 5

HHV-6 (38%), Inﬂuenza (10%), Rotavirus(2%), RSV (2%)
Recovery (29%), Sequelae (66%), Death(1%)

Inﬂuenza (34%), Rotavirus (12%), Mumps(4%), Bacteria (3%)
Recovery (90%), Sequelae (7%), Death (0%)

Inﬂuenza (41%), HHV-6 (20%)

OutcomeRecovery (13%), Sequelae (56%),
Death (28%)

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6

M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx(1) When AE is suspected, clinical ﬁndings, such as
disturbance of consciousness and other neurologic
abnormalities, should be evaluated. Cranial imaging, EEG and blood/urine examinations should
also be performed. (Grade B)(2) When diagnosis remains indeﬁnite, evaluation andexamination should be repeated after a certain
time interval. (Grade C1)
1) In AESD and other syndromes, neurologic andlaboratory abnormalities are often unrecognizable
at onset and become apparent after several days.
2) When it is diﬃcult to conduct laboratory examinations due to a lack of facilities and personnel, a
medical institution should consider transfer ofpatients to another institution where examinations
are feasible.
3) Aliquots of blood/urine specimens should be
stored in a freezer to be used later for speciﬁc tests
for diﬀerential diagnosis.
Comments:
The diagnosis of AE is based on the following
criteria:1) Impairment of consciousness, with severity ofJapan Coma Scale 20 or Glasgow Coma Scale<11, and with duration of 24 h or longer. (See
CQ1-1)
2) Brain edema visualized by cranial CT/MRI.
Immediately after the onset of AE, however, it isoften necessary to make a syndromic diagnosis of AE
in a rapid and tentative way, in order to start intensive
care without delay. Previous studies have elucidated
the usefulness and limitation of various clinical and laboratory ﬁndings in the initial stage of AE for the purpose of (1) diﬀerentiation of AE [12–17], especially
AESD, from febrile seizures, or (2) prediction of the
ﬁnal neurologic outcome [17,18]. Findings reportedly
useful in the early diagnosis of AE include the following:
1) Neurologic examination [15,19]: Prolonged orworsening neurologic symptoms such as impairment of consciousness and seizures.
2) Cranial CT/MRI: Cerebral edema.
3) EEG: Abnormal patterns such as diﬀuse, highvoltage slow wave, electrical storm and absenceof spindle waves.
4) Blood/urine/cerebrospinal ﬂuid (CSF) examinations [12–17,19–21]:(a) General examination (in-hospital; data available
within minutes or hours):
Increased serum aspartate aminotransferase (AST)(>90 or 150 IU/L), lactate dehydrogenase (LDH) andalanine aminotransferase (ALT); metabolic acidosis(for 2 h or longer); increased white blood cell count,blood glucose and serum creatinine; decreased platelet
count; disseminated intravascular coagulation (DIC);
increased CSF protein; proteinuria.
(b) Special examination (outsourced; data available
days or weeks later):
Increased serum cytochrome c and soluble tumor
necrosis factor-alpha; increased CSF tau protein,neuron-speciﬁc enolase, interleukin-6, glial ﬁbrillary
acidic protein and visinin-like protein 1; increased urine
beta2-microglobulin/creatinine ratio.
Patients with suspected AE should be evaluated bythese examinations immediately after arrival. If the definite diagnosis is not initially reached, then the patientsshould be evaluated again several hours or days later,
depending on their individual condition.
2.2.2. (CQ2-2) Diﬀerential diagnosis of AE
Recommendations:(1) AE should be diﬀerentiated from various conditions manifesting with acute impairment of consciousness during the course of infectious
diseases, including intracranial infection (e.g. viral
encephalitis and bacterial meningitis), autoimmune encephalitis, cerebrovascular diseases, traumatic, metabolic and toxic disorders and eﬀects
of organ failure. (Grading not applicable)
1) During the several days immediately after
onset, it is often impossible to distinguish
AESD from complex febrile seizures [6].
2) ANE and other syndromes associated withcytokine storm and multiple organ damage
should be diﬀerentiated from systemic inﬂammatory response syndrome (SIRS) due to severe infection and heat stroke [5].
3) Reye syndrome should be diﬀerentiated fromcongenital metabolic disorders [1]. (See CQ4-2)

Comments:
Symptoms, such as fever, convulsion and impaired
consciousness, are common to all AE syndromes. Making the diagnosis of AE therefore requires diﬀerentiationfrom various diseases showing a combination of these
symptoms [9] (Table 4). The initial diagnostic workup
is typically as follows:a. Prompt physical and neurologic examination.
b. Emergency blood examination.
c. Cranial CT (or MRI).
d. CSF examination.

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Table 4Diﬀerential diagnosis of acute encephalopathy (AE).
1. Encephalitis
Herpes simplex virus 1/2
HHV-6/7
Varicella zoster virus
Cytomegalovirus
Measles virus
Mumps virus
Adenovirus 7
Enteroviruses
Japanese encephalitis virusWest Nile virus
Bacteria/Mycoplasma
Parasites
2. Meningitisa. Purulent meningitis
b. Tuberculous meningitisc. Fungal meningitis
d. Viral meningitis
3. Brain abscess
4. Subdural abscess
5. Demyelination
Acute disseminated encephalomyelitis
Multiple sclerosis
6. Autoimmune disorders
Systemic lupus erythematosus
Intracranial disorders
1. Intracranial hemorrhage
a. Subdural hematoma
b. Epidural hematoma
c. Intracerebral hemorrhage
d. Subarachnoid hemorrhage
e. Shaken baby syndrome
2. Vascular diseases
a. Cerebrovascular diseases
b. Cerebral arterio-venous malformationc. Superior sagittal sinus syndrome
d. Moyamoya disease
3. Brain tumors
Metabolic/Toxic disorders
1. Mitochondrial encephalo-myopathy
Mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes (MELAS)
2. Vitamin deﬁciency
Wernicke encephalopathy
3. Wilson disease
4. Diabetic ketoacidosis
5. Other metabolic disorders
Organ failure
1. Liver failure
2. Kidney failure
3. Respiratory failure
4. Heart failure
Others
1. Febrile seizures
2. Myocarditis/Arrhythmia
3. Heatstroke
4. Sudden infant death syndrome
5. Hypertensive encephalopathy
6. Sleep disorders
Hypersomnia/Periodic somnolenceNight terror/Sleepwalking
7. Other conditions causing hypersomnia
8. Side eﬀects of drugs
Infection/Inﬂammation

7

AnticonvulsantsSedatives/Anesthetics
Psychotropic drugs
Antihistamines
9. Psychogenic seizures

After conﬁrming the absence of ﬁndings of imminent
cerebral herniation, either neurologic (e.g. deep coma,abnormal posture, pupils, respiration and/or circulation) or radiologic (marked swelling of the entire brainor brainstem), spinal tap is performed to rule out
intracranial infections such as herpes simplex virus
encephalitis and bacterial meningitis.
4) Microbiological examination of blood, CSF,
urine, stool and/or nasopharyngeal swab.
2.2.3. (CQ2-3) imaging diagnosis of AE
Recommendations:(1) For the diagnosis of AE, cranial CT or MRI is recommended. (Grade B)(2) Characteristic MRI ﬁndings constitute the diagnostic criteria for ANE (Grade B), AESD (GradeB) and MERS (Grade B).
Comments:
When AE is suspected, CT is usually used as the initial neuroimaging examination because it is available inmost regional centers in Japan and the time required for
imaging is short. The diagnosis of AE is made based on
cranial CT ﬁndings [9,11] such as:1) Diﬀuse low density areas involving the entire brain
or entire cerebral cortex.
2) Unclear boundary between cerebral cortex andmedulla.
3) Narrowing of the subarachnoid space on the cerebral surface and of the ventricles.
4) Focal low density areas: bilateral thalamus (ANE)and unilateral cerebral hemisphere (some cases of
AESD).
5) Brainstem swelling: Narrowing of the surrounding
cerebral cisterns.
CT may depict the characteristic lesions in all cases of
ANE and some cases of AESD, but not in the cases of
MERS.
MRI visualizes the cerebral lesions characteristic ofeach syndrome [6,7,22–27] (Table 5). DWI is importantin the diagnosis of AESD and MERS. Apparent diﬀusion coeﬃcient (ADC) is useful in evaluating the statusof water in lesions. Cytotoxic and intra-myelin edemashow low ADC and high signal on DWI, whereas vascu-

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Table 5
Diagnosis of acute encephalopathy (AE) based on cranial MRI ﬁndings.
ANE
In addition to diﬀuse brain edema, there are bilateral symmetric, edematous/necrotic lesions in speciﬁc brain regions, including the thalamus.
Thalamic lesions are oval in shape.
On days 1–2, the lesions show low T1, high T2 and decreased diﬀusion.
On day 3 and thereafter, the thalamic lesions show concentric appearance due to central T1 high lesion indicating hemorrhagic changes. Diﬀusionweighted imaging (DWI) shows increased diﬀusion (necrosis and perivascular hemorrhage) in the center of thalamic lesion, restricted diﬀusion(edema and loosening of neuropil) in the surrounding zone, and increased diﬀusion (extravasation of plasma) in the periphery.
From the second week, there is progressive cerebral atrophy, and shrinkage or disappearance of thalamic lesions.
AESD
On days 1–2, CT and MRI ﬁndings are normal.
Between 3 and 14 days, DWI shows high signals in the subcortical white matter (bright tree appearance) and/or the cortex. Regions around thecentral sulcus are often spared.
From two weeks, CT and MRI show residual lesions or atrophy of the frontal and/or parietal lesions. Single photon emission computed
tomography (SPECT) shows hypoperfusion. Peri-central regions are again often spared.
MERS
At the acute period, the splenium of corpus callosum shows high signal on DWI. T1 and T2 signal changes are only mild. The lesion(s) may
involve the entire corpus callosum, and bilateral cerebral white matter symmetrically.
Within 2 months, the lesion disappears completely. There is neither residual signal changes nor atrophy.

lar edema shows high ADC and iso- or low signal intensity on DWI.
2.2.4. (CQ2-4) electroencephalographic diagnosis of AE
Recommendations:(1) EEG is recommended because it provides information useful for the diagnosis and treatment of AE.
(Grade B)(2) Both conventional and amplitude-integrated EEG(aEEG) are useful. It is recommended to conduct
either according to availability in each institution.
(Grade B)(3) The majority of AE patients have EEG abnormalities, including generalized, unilateral and localizedslowing of background activity. (Grade B)
Comments:
EEG is an irreplaceable examination for evaluating
function of the cerebral cortex in real time. EEG recording has recently become digitalized, and currently iseasily conducted bedside. Furthermore, the recent
advent of aEEG has enabled long-time, continuous
monitoring.
Previous EEG ﬁndings in AE have observed abnormalities in most patients [4,28–36]. Generalized and unilateral slowing of background activity reﬂects
dysfunction of the cerebral hemisphere. Localized slowing is often occipital dominant, and should be interpreted with caution since similar ﬁndings are also seenin fever-induced, mild alteration of consciousness [37].
Low voltage background activity may suggest poor
prognosis. All these ﬁndings may be noted immediately
after febrile and epileptic seizures.

Periodic lateralized epileptiform discharges (PLEDs)
have been reported in various disorders of acuteencephalitis/encephalopathy [29,35,36]. Electrical storm
denotes the intermittent appearance of spike-waves
and rhythmic activities with waning and waxing, andhas been described not only in HSES but also in febrileinfection-related epilepsy syndrome (FIRES)/acuteencephalitis with refractory, repetitive partial seizures(AERRPS) and other syndromes [33,38]. Frontal andoccipital intermittent rhythmic delta activity (FIRDA/OIRDA) have been linked to acute encephalitis/encephalopathy, but their diagnostic signiﬁcance in AE
remains unclear [39,40].
Since no previous studies systematically evaluated theimpact of EEG on the diagnostic accuracy and outcome,the signiﬁcance of EEG is yet to be established. Future
multicenter, collaborative studies should elucidate therole of EEG in the early diagnosis of AE, diﬀerentiationof AE and febrile stupor, recognition of latent or subclinical seizures, and the association between EEG ﬁndings and outcome.
Continuous, multi-channel video-EEG monitoring
has recently been applied to comatose children in a pediatric intensive care unit (PICU) [41–45]. Continuous
monitoring enables recognition of subclinical seizuresin many children, and may provide useful information
not only in head trauma and cerebrovascular diseases,
but also in AE. On the other hand, continuous monitoring requires a large amount of medical and humanresources, making its immediate introduction unrealistic
in Japan.
aEEG is a long-time, continuous recording using 1–2
channels, and is widely used in neonates to monitor
neonatal encephalopathy and seizures [46–48]. To date,
several groups have studied its application to AE,

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

demonstrating its ability to eﬀectively recognize nonconvulsive status epilepticus (intermittent, latent seizures) in AESD and FIRES/AERRPS [38,49].
2.3. Systemic management and brain hypothermia/
normothermia
2.3.1. (CQ3-1) management of convulsive statusepilepticus (CSE) and prolonged convulsion
Recommendations:(1) For the treatment of CSE and prolonged convulsion, an appropriate anticonvulsant should be chosen according to the duration of convulsion, underproper management of systemic condition (Grade
A). Avoiding the administration of a more thannecessary dose of anticonvulsants should be considered, since the assessment of consciousness levelis important for the early diagnosis of AE (Grade
C1).
(2) For non-intravenous treatment of prolonged convulsion, midazolam is administered by a buccal,
intranasal or intramuscular route (Grade B). On
patient’s arrival at the hospital, rectal administration of diazepam suppository is not recommended(Grade C2).
(3) For intravenous treatment of prolonged convulsion and CSE, ﬁrst-choice drugs, such as midazolam and diazepam (Grade B), and second-choicedrugs, such as fosphenytoin, phenytoin, phenobarbital and levetiracetam (Grade B), are given by
rapid intravenous injection. For refractory CSE,
midazolam is administered by continuous infusion, and either thiopental or thiamylal is administered by rapid or continuous intravenous infusion.
Comments:
In the guidelines, CSE is deﬁned as either convulsion
with duration of 30 min or longer, or repetitive convulsions with an interictal impairment of consciousness for
30 min or longer [50–52]. Prolonged convulsion isdeﬁned as convulsion with duration of 5 min or longer[50,51]. Prolonged convulsions are less likely to ceasespontaneously, and, without adequate treatment within
15 min, often last for more than 30 min [53]. WhenCSE continues after the administration of secondchoice intravenous antiepileptic drugs (AEDs), the diagnosis of refractory CSE is made. Super-refractory CSE,
which persists or recurs despite intensive treatment for
24 h, may cause severe complications and death [54].
Prolonged convulsions require rapid intervention
with AEDs adequately selected according to the duration of seizures [55,56]. If an AED fails to stop the
seizures, further administration of an excessive dose
may cause adverse eﬀects. Over-dosage may also occur

9when postictal twilight states with an abnormal posture (e.g. dystonia) and involuntary movements (e.g.
tremor and chorea) are misinterpreted as recurrent
convulsions.
After initial treatment of CSE, patients should bemonitored for vital signs and the level of consciousness.
AEDs may make it diﬃcult to evaluate consciousness.
Since prolonged impairment of consciousness is an
essential criterion for early diagnosis of AE, it is not recommended to sedate patients unnecessarily by administration of excessive AEDs.
a. Treatment of prolonged convulsion without an
intravenous infusion route [57–63].
On a patient’s arrival at the emergency room, administer midazolam by buccal (0.5 mg/kg), intranasal(0.5 mg/kg) or intramuscular (0.1–0.35 mg/kg) route(maximum, 10 mg). Use midazolam 0.5% solution, not
0.1% solution.
b. Treatment of prolonged convulsion and CSE withan intravenous infusion route [64–75].
1)
First line: Use either midazolam or diazepam. If unsuccessful, proceed immediately
to the second line.
i) Midazolam 0.15 mg/kg iv, at a rate of
1 mg/min. If necessary, add 0.1–0.3 mg/
kg/dose, but the total dose should notexceed 0.6 mg/kg.
ii) Diazepam 0.3–0.5 mg/kg iv.
2)

Second line: Use either fosphenytoin, phenobarbital or levetiracetam.
i) Fosphenytoin 22.5 mg/kg (rate not exceeding 3 mg/kg/min). For maintenance,
administer fosphenytoin 5–7.5 mg/kg/day,either in a single or divided dose, at a rate
not exceeding 1 mg/kg/min. Alternatively,
administer phenytoin 15–20 mg/kg/dose
at a rate not exceeding 1 mg/kg/min (maximum 250 mg/dose).
ii) Phenobarbital 15–20 mg/kg iv, at a rate
not exceeding 1 mg/kg/dose, for more than
10 min.
iii) Levetiracetam 20–30 mg/kg iv (for morethan 15 min).

c. Treatment of refractory CSE with an intravenous
infusion route.
i) Midazolam 0.1 mg/kg/hour initially, increasing
at a rate of 0.05–0.1 mg/kg/hour, up to a maximum of 0.4 mg/kg/hour.

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10

M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxxii) Thiopental of thiamylal 3–5 mg/kg (maximum
in adults, 200 mg) iv, followed by 3–5 mg/kg/
hour div.
2.3.2. (CQ3-2) systemic management of AE
Recommendations(1) For moderate to severe cases of AE, systemic condition should be maintained or improved by using
appropriate monitoring devices and conducting
supportive therapies. (Grade A)
1) Initial resuscitation based on PediatricAdvanced Life Support (PALS) 2010.
2) Transfer to tertiary (or equivalent) emergency
medical facilities [76].
3) Admission to PICUs, if necessary.
4) Systemic management of respiration, circulation, central nervous system, blood sugar/electrolytes and nutrition.

Comments:
The management of respiration requires monitoring
devices, including a pulse oximeter, PaCO2 monitor
and end-tidal CO2 monitor. To avoid secondary brain
damage due to aspiration or apnea, patients with
impaired consciousness (GCS 8) should be intubatedand mechanically ventilated. SaO2 should be kept
>94%. With monitoring of PaO2, concentration of oxygen and condition of ventilator should be adequately
determined. Except for the case of hyperventilation therapy for refractory increased intracranial pressure (ICP),PaCO2 should be kept within normal range since low
PaCO2 decreases cerebral perfusion blood volume.
Sedation is recommended for endotracheal intubation,
and administration of analgesics/sedatives for mechanical ventilation.
The management of circulation requires monitoring
devices, including an electrocardiograph (ECG), bloodpressure monitor and pulse oximeter. If available, monitors for central venous pressure and central venous oxygen saturation are also used. Arterial systolic pressure
should be kept above (70 + 2  age) mmHg in children
aged 1 to 10 years, and above 90 mmHg in those older
than 10 years. In selected cases, cerebral perfusion pressure (CPP, mean arterial pressure minus ICP) is monitored. Adequate hydration, but neither undue water
restriction nor diuretics, is recommended. ECG is useful
in monitoring heart rate and detecting arrhythmia, andcardiac ultrasonography is useful in evaluating cardiac
function and intracardiac blood volume. Blood examination provides useful data such as arterial and venous
blood gas, hemoglobin, hematocrit, glucose, electrolytes, urea nitrogen, creatinine, calcium and lactate.
Hypotension may be caused by administration of
AEDs, sedatives and analgesics. For sustained shock,0.9% saline or an extracellular type solution is infused.
Standard volumes for maintenance infusion are[4  body weight (BW in kg)] mL for children with
BW <10 kg, [40 + 2  (BW-10)] mL for those 10–
20 kg, and (40 + BW) mL for those >20 kg.
The management of the central nervous system(CNS) requires serial observation of the level of consciousness (GCS) and brainstem reﬂexes such as light,
corneal and oculocephalic reﬂexes. Continuous monitoring of EEG may also be useful. In cases of suspected
increased ICP, ICP monitoring is recommended [77–81].
ICP should be maintained below 20 mmHg; CPP above
40 mmHg in infants and young children, and above
50 mmHg in schoolchildren [80–82]. Head may be liftedby 30°. Increased ICP may be treated by intravenous
infusion of either 3% sodium chloride, 6.5–10 mL/kg[83–85], or D-mannitol, 0.5–1 g/kg [86]. Barbiturates
are used for children with increased ICP after headtrauma, and may be attempted in children with AE[80,87]. Hyperventilation therapy with ICP monitoringis used for intractable increased ICP [88]. Continuous
EEG monitoring may be useful for deciding clinicalmanagement [43].
The management of blood electrolytes includes thetreatment of hyponatremia, hypocalcemia and metabolic acidosis. Blood glucose should be kept at 100–
150 mg/dL.
The management of body temperature requires monitoring by thermometers. As antipyretics, either acetaminophen, 10/mg/kg/dose every 4–6 h, or ibuprofen, 10/
mg/kg/dose every 6–8 h, is used. In selected cases, brain
hypothermia/normothermia is attempted.
The management of nutrition lacks evidence. Either
enteral or parenteral feeding is considered to avoid malnutrition in critically ill children [89].

2.3.3. (CQ3-3) brain hypothermia/normothermia:
Indication and methods
Recommendations:(1) There is no clear evidence for the eﬃcacy of brain
hypothermia/normothermia in AE. (No grade)(2) Optimal methods of brain hypothermia/normothermia for AE have not yet been established. (Nograde)
Comments:
High-quality evidence for the eﬃcacy and safety ofbrain hypothermia has been documented for acute,post-resuscitation brain injury of adults [90,91] but not
children [92] with out-of-hospital cardiac arrest, andfor hypoxic-ischemic encephalopathy of neonates withperinatal asphyxia [93–96]. In the treatment of these
conditions, brain hypothermia is recommended as astandard therapy.

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

On the other hand, in children with AE, evidence forthe eﬃcacy of brain hypothermia is limited to casereports or case series. Large-scale clinical studies havenot been conducted. Since AE is a wide spectrum involving various pathogenetic mechanisms, treatment should
be tailored according to the condition and severity ineach patient. Therefore, brain hypothermia is not listed
as a routine therapy for all cases of AE.
Brain hypothermia/normothermia has already been
introduced in the treatment of AE by some PICUs.
For brain hypothermia, however, no standard protocols
or safety guidelines are available, except for the protocols in single institutions [97]. A variety of drugs areused concomitantly, and their eﬀects have not been evaluated separately from those of brain hypothermia alone.
Based on the ﬁndings of a study on adult postresuscitation encephalopathy showing the noninferiority of normothermia compared to hypothermia[98], some institutions are conducting clinical trials for
AE, in particular AESD, of brain normothermia or targeted temperature management [99,100], whose eﬃcacy
remains to be established [101].
Given the possibility of secondary neuronal damage
in the early stage of AE, either metabolic or anoxic/ischemic, the therapeutic time window is considered to
be short. At present, little information is available on
the therapeutic time window and adverse eﬀects of brain
hypothermia/normothermia.
2.4. AE caused by metabolic disorders
2.4.1. (CQ4-1) characteristics of metabolic
encephalopathy
Recommendations:(1) Triggered by various factors, AE often occurs inpatients with inborn errors of metabolism. Metabolic encephalopathy encompasses multiple diseases, which commonly show the following
features. (Grading not applicable)
1) Absence of precursory episodes prior to theonset of AE.
2) Mild respiratory disturbance.
3) Rapid progresses and/or ﬂuctuation.
4) Absence of localized neurological signs.
(2) When AE is accompanied by the following symptoms, inborn errors of metabolism should be suspected, and diagnostic workup should be
performed. (Grade B)
1) Rapid deterioration of general condition following
an infectious disease or fasting.
2) Abnormal facial features/cutaneous ﬁndings;
body/urine odor.
3) Tachypnea associated with metabolic acidosis;
breathing disorder.

114) Growth failure; intellectual disability.
5) Cardiomyopathy.
6) Splenohepatomegaly; hepatomegaly without splenomegaly;
splenomegaly
without
portalhypertension.
7) Symptoms of multiple organs with obscure
relationship.
8) Abnormal imaging ﬁndings suggesting mitochondrial diseases.
9) Family history of inborn errors of metabolism.
Comments:
AE may be induced by certain inborn errors of metabolism, such as hyperammonemia (urea cycle disorders),amino-acid metabolism disorders (maple syrup urine
disease, ketotic hyperglycinemia), organic acid metabolism disorders, fatty acid oxidation disorders and mitochondrial electron transport chain disorders. These
disorders often show clinical features as described above[(1), 1–4]. Children presenting with characteristic signs
or symptoms [(2), 1–9] must be carefully examined considering the presence of underlying, inborn errors of
metabolism [102,103].
Outlines of typical disorders that may cause
encephalopathy are provided below.
a. Diseases associated with hyperammonemia
Typical inborn errors of metabolism with hyperammonemia are urea cycle disorders, organic acid disorders, fatty acid oxidation disorders and mitochondrial
diseases. Of these, urea cycle disorders and organic aciddisorders often show hyperammonemia above 1000 lg/
dL.
b. Amino-acid disorders
Maple syrup urine disease (leucine encephalopathy)[104] is a disease for which newborn mass screening programs are oﬀered in Japan. However, AE may develop
in the neonatal period before obtaining the results.
In maple syrup urine disease, impaired branchedchain keto acid dehydrogenase (BCKDH) activity leads
to a disturbance in the metabolism of branched chainketo acids that are derived from the branched chainamino acids—valine, leucine and isoleucine. BCKDH
is a complex of enzymes coded by four genes—E1a,
E1b, E2 and E3, and a defect in any of them represents
an autosomal recessive genetic disorder.
c. Fatty acid oxidation disorder
AE may be induced by defects of fatty acid oxidation,and is often manifested as Reye syndrome or Reye-like
syndrome. A well-known example is medium-chain
acyl-CoA dehydrogenase (MCAD) deﬁciency, a defectPlease cite this article in press as: Mizuguchi M et al. Guidelines for the diagnosis and treatment of acute encephalopathy in childhood. Brain
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12

M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

of an enzyme that metabolizes acyl CoA with a straightmedium chain (4–10 carbon atoms) fatty acid. Children
aged four years or younger, who have had no characteristic ﬁndings or medical history until an acute episode, start
to develop AE or Reye-like syndrome following infection
or famine. If MCAD deﬁciency is identiﬁed by newborn
mass screening, the onset of AE may be prevented by dietary instruction to avoid starvation. Moreover, patientswith long-chain fatty acid oxidation disorders, such as
mitochondrial trifunctional protein (TFP) deﬁciency
and carnitine palmitoyltransferase-2 (CPT2) deﬁciency,
may also develop as Reye or Reye-like syndrome.
Thermosensitive CPT2 morphisms have recently
been implicated in AE. Some CPT2 polymorphisms
are thermolabile, losing their activity with a rise in bodytemperature by 3 to 4 °C. They are relatively common in
infants in East Asia and are suspected to be a predisposing factor for AE.
d. Mitochondrial diseases [105–107]
AE caused by a mitochondrial disease is often diagnosed as Leigh syndrome, Reye-like syndrome or mitochondrial encephalomyopathy with stroke-like episodes(MELAS). Leigh syndrome has bilateral and symmetrical pathological lesions mainly in the brain stem, basal
ganglia and cerebellum, showing spongiform degeneration, vacuolar degeneration, demyelination and gliosis.
Brain CT reveals low density areas in the basal ganglia
and brain stem, whereas MRI (T2/FLAIR) reveals bilateral and symmetric high intensity areas. MELAS ischaracterized by headache, epilepsy and stroke-like episodes. Stroke-like episodes often give rise to headache,nausea, visual disturbances and disturbance of consciousness. Moreover, brain lesions tend to occur inthe temporal and occipital lobes, giving rise to visual disturbances such as homonymous hemianopia and cortical blindness. On brain CT/MRI during the acutephase, there are edematous lesions in the cerebral cortex
that do not coincide with vascular territories.
2.4.2. (CQ4-2) screening for the diagnosis of inborn
errors of metabolism
Recommendations:(1) On the suspicion of metabolic encephalopathy, aﬁrst-line screening test, including blood sugar,
blood gas, ammonia, lactic and pyruvic acids,
serum/urinary ketone (Grade B) and free fatty
acids (Grade C1), should be initially conducted.
(2) Based on the results, a second-line screening test
should be conducted (Grade B). It is also important to obtain critical samples in the second-line
screening test during the hospital visit. Second line
screening test includes:
1) Serum or plasma: Amino acid analysis, carnitine
two fractions (free/acyl) and acyl carnitine analysis(tandem mass analysis).
2) Urine: Urinary organic acid analysis and urinaryamino acid analysis (as needed).
3) Dried blood spot: Acyl carnitine analysis (tandem
mass analysis).
Comments:
a. General outline [102,103,108]
If an inborn error of metabolism is suspected forcases of AE, a ﬁrst-line screening test should be performed. The targets of the ﬁrst-line screening test are

Table 6
Critical samples for diagnosis of metabolic encephalopathy.
A. Storage of critical samplesi) Serum or plasma: cryopreservation at 20 °C or below, 0.5 mL or greater.
Blood amino acid analysis (possible also with serum)
Serum tandem mass analysis
Blood ketone body factions/free fatty acidsii) Urine: cryopreservation at 20 °C or below, 0.5 mL at minimum, preferably 3–10 mL.
Urinary organic acid analysis
Urinary amino-acid analysis (as needed)iii) Dried blood spots: at least 1 spot, preferably 4 spots. Dry well and cryopreserve at 20 °C or below.
Acyl carnitine analysisiv) Cerebrospinal ﬂuid (optional): cryopreservation at 20 °C or below, using several tubes, 0.5 mL each.
Measurement of lactic and pyruvic acids
B. Metabolic autopsy
The following items should be preserved at autopsy:
 Collection of 5 mL of heparinized blood/Cryopreservation of leukocyte pellets at
Enzyme activity measurement
DNA extraction and preservation/Genetic diagnosis
 Cryopreservation of bile at 20 °C or lower.
Acyl carnitine analysis
 Skin biopsy/Culture of skin ﬁbroblast (if possible)

20 °C or lower.

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

blood sugar, blood gas, ammonia, lactic and pyruvic
acids, blood/urinary ketone bodies and free fatty acids.
The results should be obtained and evaluated as quickly
as possible.
Based on the abnormal results of ﬁrst-line screening,
an inborn error of metabolism is suspected. A clinician
should move on to the second-line screening test. In thisstep, critical samples must be obtained (Table 6). The
second-line screening test includes amino acid analysis
in the blood, urinary organic acid analysis and acyl carnitine analysis.
b. Urea cycle disorders [109–111]
An amino acid analysis must be promptly undertaken
for urea cycle disorders. The results determine, to someextent, the diagnosis and treatment.
1) Amino acid analysis of the blood and urine: Abnormally high or low levels of speciﬁc amino acids.
2) Urinary organic acid analysis: Abnormally highurinary orotic acid levels.
3) Enzyme assay or gene analysis.
4) Genetic analysis.
c. Amino-acid metabolism disorders
1)
Maple syrup urine disease (leucine encephalopathy) [112].
For diagnosis, it is of utmost importance to promptly
conduct a serum amino acid analysis. This analysis
demonstrates an increase in the levels of leucine, isoleucine and valine. The development of alloisoleucine ischaracteristic of this condition. Urinary organic acidanalysis shows an increase in the levels of branchedchain a-keto acids and branched-chain a-hydroxyl acids
with this condition. Enzyme activity of the BCKDHcomplex may be measured using extracts from cultured
cells. Genetic analysis is not used for diagnostic purpose.
d. Fatty acid oxidation disorder [108,113]
The most notable characteristic of this condition in
the ﬁrst-line analysis is nonketotic or hypoketotic hypoglycemia. For the diagnosis of fatty acid metabolism disorders, serum acyl carnitine analysis is conducted using
dried blood spot and serum specimens in the acutephase. Urinary organic acid analysis may show nonketotic or hypoketotic dicarboxylic aciduria in an episodeof hypoglycemia. Enzyme activity may be assayed using
cultured skin ﬁbroblasts in some cases. Genetic analysis
may also be performed.
e. Mitochondrial diseases [114–118]
A mitochondrial disease is comprehensively evaluatedby clinical/imaging ﬁndings and by the following exami-

13

nations. On biochemical tests, blood levels of lactic acidare high in many cases, but normal in others. Growthand diﬀerentiation factor 15 (GDF15) is a useful biomarker for mitochondrial myopathy. An analysis of enzyme
activity of the respiratory chain should be carried out
using aﬀected organs and skin ﬁbroblasts. Pathologicalstudies of the skeletal muscle biopsies, cultured cells orcells/tissues of aﬀected organs show abnormalities in the
mitochondria. Genetic analysis may demonstrate abnormalities in either the nuclear or mitochondrial genes, theformer being more frequent in children.
2.4.3. 2.4.3. (CQ4-3) Treatment for mitochondrial rescue
Recommendations:(1) The eﬃcacy of mitochondrial rescue has been documented in speciﬁc metabolic conditions, but not
in AE without underlying metabolic disorders.
Vitamin B1, carnitine and other drugs may be usedin cases of AE when the diagnosis of metabolic disorder is suspected but not yet established (Gradeshown in Table 7).
Comments:
Mitochondrial rescue drugs may be used when laboratory examination at the onset of AE shows acidosis,
lactic acidemia, hypoglycemia or hyperammonemia.
To prescribe them continuously, a precise diagnosis ofcongenital metabolic disorder as the underlying condition of AE is needed.
Vitamin B1, a coenzyme that activates pyruvate metabolism, TCA cycle and mitochondrial electron transportsystem, may be eﬀective in AE complicating Leighencephalopathy (in particular, cases caused by Vitamin
B1-responsive deﬁciency of pyruvate dehydrogenase
complex) and other mitochondrial disorders. Supplementation of thiamine is essential in rare disorders ofthiamine metabolism and transport [119–121] and in
Wernicke encephalopathy [122], a condition due to vitamin B1 deﬁciency that was recently reported in children

Table 7
Treatment for mitochondrial rescue.
Mitochondrial rescue drugs in Leigh syndrome, lactic acidemia andsuspected mitochondrial disorders (Grade C1)i) Active form of vitamin B1 (fursultiamine)ii) Levocarnitineiii) Coenzyme Q
Other drugs for mitochondrial treatment (No grade)iv) Vitamin B2 (riboﬂavin)v) Vitamin C, Vitamin E, Biotin
Treatment of MELAS (Grade B)vi) L-arginine
Other drugs for metabolic disorders (No grade)vii) Active form of vitamin B6 (pyridoxal phosphate)

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

taking an excessive amount of ionic drinking water. As
an eﬃcacy in AE, a recent study suggested that a combination of vitamin B1, B6 and carnitine may reduce
the risk of AESD [123].
Carnitine binds to long chain acyl CoA and transports it from the cytoplasm to the mitochondria. Carnitine deﬁciency suppresses mitochondrial betaoxidation and impairs energy metabolism. Primary carnitine deﬁciency is occasionally complicated by Reyelike syndrome. Secondary carnitine deﬁciency due tomalnutrition, drugs (valproate sodium and pivalateconjugated antibiotics) and acyl CoA dehydrogenase
deﬁciency may cause AE. Supplementation of carnitine
is eﬃcacious in these conditions. CPT2 deﬁciency is also
associated with the risk of AE and requires treatment
with carnitine supplementation [124]. On the other
hand, in other AE cases with a CPT2 thermolabile polymorphism, there have been no reports demonstrating
the eﬃcacy of carnitine [125,126].
Coenzyme Q, an essential factor of electron transportsystem with an antioxidative eﬀect, is a drug for treating
mitochondrial disorders [127,128]. However, its eﬃcacy
in the nervous system remains unclear and its transition
to the brain across the blood–brain barrier is minimal[129]. Thus, evidence for the use of coenzyme Q in AE
is lacking.
Vitamin B2 (riboﬂavin) is a component of electrontransfer complex II. A case of riboﬂavin-dependent,
transient neonatal-onset glutaric aciduria type II reportedly had encephalopathy with hypoglycemia, acidosis
and hyperammonemia.
Arginine, an amino acid synthesized from citrullinethat promotes ammonia excretion, is used to treat
hyperammonemic encephalopathy in urea cycle disorders, and also used for the treatment and preventionof stroke-like episodes in MELAS [130,131].
Trials with other drugs, such as sodium pyruvate,
EPI-743 [132] and taurine, are in progress.
2.5. AE caused by systemic inﬂammation
2.5.1. (CQ5-1) markers of inﬂammation
Recommendations:(1) Direct and indirect indicators have been proposed.
(Grading not applicable)
1) The diagnostic items of SIRS are indirectindicators.
2) The poor prognostic factors of inﬂuenzaassociated encephalopathy are indirect indicators.
3) Various cytokines and related factors have beenreported.
Note: A direct indicator is a marker of the intensityof inﬂammatory response, whereas an indirect indicator

is a marker of the degree of tissue/organ damage caused
by inﬂammation.
Comments:
AE associated with cytokine storm (hypercytokinemia) type often exhibits SIRS. SIRS, a so-called cytokine storm, is a systemic biological response due tooverproduction of inﬂammatory cytokines elicited in
response to trauma, infection and other factors. The
diagnostic items of SIRS [133] (body temperature, pulse
rate, respiration rate and white blood cell count) may bemarkers of indirect inﬂammation. However, there are nodata for patients with AE. Ferritin is also an indicator of
the severity of SIRS, as a marker of inﬂammation [134],
but there are no data for AE patients.
In inﬂuenza-associated AE, previous studies havepointed out poor prognostic factors: Hb 14 g/dL or
more, platelets less than 100,000/lL, AST/ALT
100 IU/L or more, CK 1000 IU/L or more, blood sugar
less than 50 mg/dL or less than 150 mg/dL, prothrombin time (PT) less than 70%, ammonia 80 lg/dL or
more, hematuria and proteinuria [135]. These are considered indirect markers of inﬂammation.
Cytokines and related factors are important for thepathogenesis of cytokine storm type of AE, and havebeen reported to predict poor prognosis. Among them,
serum interleukin-6 [21,136], serum tumor necrosis
factor-a (TNF-a) [21,137,138], serum soluble TNF
receptor [21,137,138] and serum interlukin-10 [137,138]
are considered to be biomarkers of inﬂammation.

2.5.2. (CQ5-2) corticosteroid therapy: signiﬁcance,
indication and methods
Recommendations:(1) Corticosteroids are recommended for AE of cytokine storm type. (Grade C1)
1) Corticosteroids are expected to improve the prognosis of ANE.
2) Corticosteroids are also recommended in othercases of cytokine storm type.
3) Methylprednisolone pulse therapy is commonly
conducted.
Comments:
For anti-inﬂammatory therapy in children with AE,
corticosteroid preparations are recommended in termsof experience and safety. The use of corticosteroids
within 24 h of onset improves prognosis of inﬂuenzaassociated encephalopathy and ANE [139].
The best indication of corticosteroid is for the cytokine storm type of AE. It is recommended that corticosteroids are used aggressively in cases where the presenceof inﬂammation is suggested by the aforementioned
inﬂammatory markers, for instance, meeting the

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

deﬁnition of SIRS. The presence of hypercytokinemia isalso suggested when MRI shows ANE or diﬀuse brain
edema. Among corticosteroids, methylprednisolone
pulse therapy was described in the inﬂuenza-associatedencephalopathy guidelines [9], and has been widely used.
Methylprednisolone 30 mg/kg/day (maximum amount,
1 g/day) is injected intravenously over 2 h. In principle,
it is administered for 3 days. Heparin 100 to 150 IU/kg/day is administered with continuous infusion until theend of pulse therapy to prevent thrombus formation
due to hypercoagulation. As mentioned above, it is necessary to perform corticosteroids treatment as early as
possible.
2.5.3. (CQ5-3) immunoglobulin and blood puriﬁcation:
signiﬁcance, indication and methods
Recommendations:(1) Theoretically, immunoglobulin and blood puriﬁcation are expected to be eﬀective for AE of cytokine storm type where inﬂammation is involved in
the pathogenesis. However, there is no evidence
for their eﬃcacy. (No grade)
1) Gamma globulin therapy, 1 to 2 g/kg is administered intravenously.
2) Blood puriﬁcation should be performed in experienced hospitals.
Comments:
The immunoglobulin preparation exerts an antiinﬂammatory action by suppressing activation of
immunocompetent cells and suppressing inﬂammatory
cytokine production. The mechanism of action still
remains partly unclear [140,141]. It is theoretically reasonable to use immunoglobulin in AE where inﬂammation is involved in the pathology such as the cytokine
storm type of AE. However, suﬃcient evidence has
not been obtained to date [139]. The method of administration is intravenous drip infusion of immunoglobulin
preparation (1 to 2 g/kg). The dosage will be adjusted
appropriately according to the condition of eachpatient. In particular, as anaphylactic shock may occur
at the beginning of treatment, the infusion rate should

15

follow the instructions in the package insert. It is also
necessary to carefully observe patients and to check vital
signs.
Blood puriﬁcation therapy aims to control inﬂammation by removing inﬂammatory substances such as
cytokines in the blood [142,143]. As with immunoglobulin, it is theoretically considered to be of use for AE inwhich inﬂammation is involved in the pathological condition. However, suﬃcient evidence has not beenobtained. Blood puriﬁcation should be considered inpatients with advanced inﬂammatory conditions thatare considered to be diﬃcult to control with corticosteroids and immunoglobulin, and should be performed
at experienced facilities because the treatment is moreinvasive. The main methods of blood puriﬁcation therapy are continuous hemodiaﬁltration (CHDF) andplasma exchange (PE). Against the overproduction of
inﬂammatory cytokines, CHDF consisting of polymethyl methacrylate (PMMA) ﬁlm is considered to be
excellent in mediator removal [144]. PE uses a 5% albumin solution as a substitution solution. In patients withabnormal coagulation, fresh frozen plasma is used, andanticoagulation therapy is performed with heparin or
nafamostat mesilate. The daily plasma exchange volume
is set as circulating blood volume = body weight (kg) 
1000/13  (1 Ht (%)/100). PE is carried out with one
course of 3 days for total plasma replacement.
2.5.4. (CQ 5–4) diagnosis and treatment of ANE
Recommendations:(1) The diagnosis of ANE is based on a combinationof clinical symptoms, laboratory ﬁndings and neuroimaging ﬁndings. Although bilateral sympathetic thalamic lesions are characteristic, it isnecessary to distinguish ANE from several diseases
presenting similar imaging ﬁndings. (Grade B forneuroimaging)(2) Early steroid pulse therapy is recommended forANE (Grade B). The eﬃcacy of intravenous
immunoglobulin or hypothermia/target body temperature has not been established. (Grading notapplicable)

Table 8Diagnostic criteria of acute necrotizing encephalopathy (ANE).
1. Acute encephalopathy related to a febrile viral infection: rapid reduction of consciousness and seizures.
2. Cerebrospinal ﬂuid examination shows normal cell counts and increased protein concentration.
3. Symmetrical and multiple brain lesions on head CT and/or MRI. Bilateral thalamic lesions are always observed. Lesions are often found also inperiventricular white matter, internal capsule, putamen, upper brainstem tegmentum, and cerebellum. No lesions in the other areas.
4. Elevated serum transaminase levels with no elevation in serum ammonia levels.
5. Exclusion of other diseases:
A. Diﬀerential diagnosis from a clinical view: Severe bacterial and viral infections, fulminant hepatitis, toxic shock, hemolytic uremic syndrome,
Reye syndrome, hemorrhagic shock and encephalopathy syndrome, and heat stroke.
B. Diﬀerential diagnosis from a neuroimaging and neuropathological view: Mitochondrial disorders such as Leigh encephalopathy, glutaricacidemia, methylmalonic acidemia, infantile bilateral striatal necrosis, Wernicke encephalopathy, carbon monoxide poisoning, acute diﬀuse
encephalomyelitis, acute hemorrhagic leukoencephalopathy, angiitis, arterial and venous infarction, hypoxia and traumatic head injury.

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Comments:
ANE was proposed by Mizuguchi et al. in 1995 [5].
Its diagnosis is made comprehensively by combining
clinical symptoms, laboratory ﬁndings and neuroimaging ﬁndings (Table 8). The most frequent trigger of
ANE is inﬂuenza followed by HHV-6 infection [8].
Familial or recurrent ANE related to RANBP2 mutations has been reported in Europe and the United States[145].
Bilateral symmetric thalamic lesions are important in
the diagnosis of ANE. During the acute period, thalamic
lesions show low densities on CT, low intensities on T1weighted images and high intensities on T2-weighted

images on MRI (Fig. 2). During the subacute period,
thalamic lesions may show concentric appearance[146,147]. It should be noted that acute encephalitis/encephalopathy other than ANE, such as acute disseminated encephalomyelitis (ADEM) and AESD, mayalso demonstrate thalamic lesions [148,149]. Other than
the thalamus, brain lesions may be present in the cerebral and/or cerebellar white matter, midbrain, and pons.
White matter lesions are generally localized around thethalamus and in the deep white matter, and do not exhibit a bright tree appearance [6].
Coma and seizures are very frequent symptoms of
ANE, and vomiting and diarrhea are also common

Fig. 2. CT and MRI ﬁndings of acute necrotizing encephalopathy (ANE). A and B: CT ﬁndings. Symmetrical low densities are observed in thebilateral thalamus, dorsal pons and cerebellar white matter. C and D: MRI ﬁndings. Lesions showing low intensities on T1-weighted images and highintensities on T2-weighted images are seen in the bilateral thalami, periventricular white matter and external capsule.

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx[150]. Shock may occur early after the onset in severecases. Delirious behavior sometimes precedes reduced
consciousness [37]. Laboratory examinations often
demonstrate an increase in AST, ALT, LDH and CK
levels [150]. DIC is occasionally observed. Cerebrospinal
ﬂuid analysis shows normal cell counts and an increasein protein concentration in two-thirds of patients [150].
There have been few reports regarding treatment for
ANE [139,151]. In a retrospective study in Japan, corticosteroids (steroid pulse therapy or intravenous dexamethasone) within 24 h after onset were associated with
better outcome in patients without brainstem lesions[139]. Although suﬃcient evidence has not been established, steroid pulse therapy is recommended early after
onset. The eﬃcacy of intravenous immunoglobulin has
not yet been proven. Some authors reported good outcome in cases treated with blood puriﬁcation therapy.
Eﬀective ANE treatment remains to be established.

17

reduced diﬀusion in the subcortical white matter (socalled bright tree appearance) on days 3–9 (Fig. 3)[6,24,25]. The average age of onset is 1.7 years (median

2.6. AE with convulsive status epilepticus (CSE)
2.6.1. (CQ6-1) diagnosis and treatment of AE withbiphasic seizures and late reduced diﬀusion (AESD)
Recommendations:(1) AESD is the most common syndrome of Japanesechildhood AE, accounting for approximately 30%.
(Grading not applicable)(2) Diagnosis is based on the combination of biphasic
clinical courses and characteristic imaging ﬁndings. (Grade B for cranial MRI)
(3) Treatment is based on supportive care. (Grade B)(4) There is currently no evidence for the eﬃcacy ofspeciﬁc or special treatment. (No grade)
Comments:
AESD has been recognized since the late 1990s and is
the most common encephalopathy syndrome in Japan,
accounting for 29% of all AE cases [8]. AESD is clinically characterized by biphasic seizures, i.e., a prolonged
febrile seizure (early seizure) on days 1 to 2, followed by
a cluster of complex partial seizures (late seizures) on
days 3–7; it is radiologically characterized by delayed"

Fig. 3. MRI ﬁndings of acute encephalopathy with biphasic seizures
and late reduced diﬀusion (AESD) [10]. An 11-month-old girlpresented convulsion lasting for 60 min. No abnormality was foundon MRI on day 1 (A, B). Diﬀusion-weighted image (DWI) on day 3(C) showed high signal lesions in the frontal subcortical white matter(bright tree appearance). No lesion was detected on T2-weighted image(D). On day 5, she exhibited skin rash after fever, leading to adiagnosis of exanthema subitum. She also presented a cluster of short
convulsions. MRI on day 9 showed high signal mainly in the cortex on
DWI (E), and in the subcortical white matter on T2 weighted-image(F). SPECT on day 14 (G, H) showed hypoperfusion in the frontal
region. On day 16, the high signal on DWI disappeared (I), andFLAIR image showed mild atrophy and high signal lesions mainly inthe subcortical white matter (J).

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1 year), and 100–200 cases occur annually in Japan. The
most common pathogens associated with AESD are
HHV-6 (38%) and inﬂuenza viruses (10%). Between
the early and late seizures, some patients (20–30%) havenormal, clear consciousness with no neurological symptoms. MRI performed at days 1 and 2 usually show noabnormalities, including DWI. This may lead to an initial misdiagnosis of febrile status epilepticus. From theclinical and laboratory points of view, a scoring system
has been proposed to diﬀerentiate between AESD andfebrile status epilepticus [152,153]; however, clear discrimination remains diﬃcult at present.
Delayed neuronal cell death due to excitotoxicity is
assumed to be the pathomechanism, based on cytokine
proﬁle [16] and MR spectroscopy, showing increased
glutamate followed by increased glutamine [6,24,25].
a. Diagnosis of AESD
Diagnostic criteria for AESD include the combination of clinical and radiological ﬁndings (Table 9).
b. Treatment for AESD
Supportive care should be provided for AESD
patients, as described in Section 2.3.2 (CQ3-2). In particular, it is important to stop status epilepticus as early as
possible. There is no speciﬁc or special treatment for
AESD with suﬃcient evidence. The following is
described on the assumption of this situation.
Speciﬁc treatments, such as methylprednisolone
pulse therapy and high-dose gamma globulin therapy, are currently conducted in many Japanese hospitals. On the other hand, there may be an optionof not taking these therapies with suﬃcient informed
consent. Special treatments, including hypothermia[19,99], administration of cyclosporine, free radical
scavengers and vitamin B6, may be also considered.

In any case, the establishment of eﬀective treatment
for AESD is urgently required.
2.6.2. (CQ6-2) diagnosis and treatment of acuteencephalitis with refractory, repetitive partial seizures(FIRES/AERPPS)
Recommendations:(1) The diagnosis of FIRES/AERRPS is based on theclinical features of status epilepticus following
fever, consisting of extremely intractable and frequent, focal seizures, and on the exclusion of otherknown diseases. CSF, EEG and cranial MRI ﬁndings are non-speciﬁc but helpful for diagnosis.
(Grade C1)(2) FIRES/AERRPS is treated mainly with high-dose
barbiturate and other antiepileptic drugs. The
duration of barbiturate therapy should be shortened, since long-term barbiturate therapy may
worsen the outcome. (Grade C1)(3) Ketogenic diet may be eﬃcacious in some cases.
(Grade C1)
Comments:
Both FIRES [154] and AERRPS [30,155] denote a
condition characterized by newly emerged, superrefractory status epilepticus following a febrile illness.
FIRES/AERRPS is a subcategory of new onset refractory status epilepticus (NORSE) [156–158]. Exclusive
criteria are structural, toxic and metabolic causes, aswell as preexisting neurological disorders.
FIRES/AERRPS occurs in previously healthy children several days after preceding febrile illness. Seizure
is a core and mandatory symptom of FIRES/AERRPS.
Cryptogenic FIRES/AERRPS are characterized byunique seizure types (eye deviation or facial twitch)
and acute repetitive seizures (with an interval of 5–
15 min). Seizures are extremely resistant to conventional

Table 9Diagnostic criteria of acute encephalopathy with biphasic seizures and late reduced diﬀusion (AESD).
A diagnosis of AESD is made if there is any of 3) to 5) in addition to 1) and 2).
Clinical ﬁndings:
1) AESD occurs in children during the course of a febrile infection. Other conditions, such as head trauma, child abuse, hypoxic encephalopathy,
other encephalopathy syndromes and encephalitis, are excluded.
2) The onset is on the day of fever or the next day, with a febrile seizure (early seizure) usually lasting longer than 30 min.
3) On day 3 to 7, secondary seizures (late seizures) most often in a cluster of complex partial seizures) or deterioration of consciousness level.
Image ﬁndings:
4) DWI shows high signal in the subcortical white matter (bright tree appearance) and/or in the cortex at day 3 to 14. Sparing of pre- andpostcentral gyrus (central sparing) is usually observed.
5) After 2 weeks, residual lesions or atrophy on CT/MRI, or decreased blood ﬂow on SPECT are observed in the frontal or fronto-parietal region,
often with central sparing.
Reference ﬁndings:(1) HHV-6 and inﬂuenza virus are the most frequent causative agents.
(2) After an early seizure, consciousness level improves.
(3) CT and MRI performed on days 1 and 2 are normal.
(4) Prognosis varies from mild intellectual disability to severe psychomotor impairment.

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

AEDs and frequently require anesthetic agents, including high-dose barbiturates. Outcome is poor with mostpatients developing residual epilepsy and cognitive deﬁcits. CSF analysis often reveals mild pleocytosis andincreased pro-inﬂammatory cytokines. Other occasional
ﬁndings include periodic discharges on EEG [159] andMRI lesions in the hippocampus, insular cortex, thalamus and basal ganglia.
Diagnostic criteria for cryptogenic AERRPS havebeen proposed (Table 10).
There has been no standardized treatment for
FIRES/AERRPS. Although intravenous anesthetic
agents, including barbiturates, have conventionally beenused to control status epilepticus, the duration anddosage of barbiturate treatment should be minimized
to avoid their adverse eﬀects such as cardiorespiratory
depression and paralytic ileus. A retrospective multicenter study on children with FIRES/AERRPS revealed
that poor cognitive outcome was signiﬁcantly associatedwith longer duration of burst-suppression coma [160].
Ketogenic diet is an alternative therapy for FIRES/
AERRPS and is reported to improve not only seizure
but also cognitive outcomes [161]. Additional therapeutic options include topiramate, potassium bromide andlevetiracetam [162]. Although neuroinﬂammation has
been implicated in the pathomechanism of FIRES/
AERRPS, immunomodulatory treatments, including
corticosteroid and intravenous immunoglobulin, haveyielded disappointing results.

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2.7. Miscellaneous AEs
2.7.1. (CQ7-1) diagnosis and treatment of AE associatedwith Dravet syndrome
Recommendations:(1) Dravet syndrome is an epileptic encephalopathy of
infantile onset characterized by repetitive statusepilepticus induced by fever and hyperthermia.
(Grading not applicable)(2) AE is not uncommon in children with Dravet syndrome and may be fatal. (Grading not applicable)(3) In children with Dravet syndrome, when recoveryof consciousness is insuﬃcient after the cessationof SEC, it is necessary to suspect AE and startintensive treatment. (Grade B)
Comments:
An outstanding feature of Dravet syndrome is seizures triggered by fever often resulting in SEC. Seizures
are highly resistant to antiepileptic drugs, and it is diﬃcult to prevent SEC. Development stagnates after the
onset, which is associated with pyramidal signs. Various
types of seizures, including myoclonic seizures, atypicalabsence seizures and focal onset seizures, appear
between the ages of 1–4 years. Thereafter, the frequencyof seizures decreases to some extent. Mutations in the
SCN1A gene are present in 70–80% of children with
Dravet syndrome [163]. Valproic acid and benzodi-

Table 10
Diagnostic criteria for cryptogenic acute encephalitis with refractory, repetitive partial seizures (AERRPS).
The presence of at least two of the following four criteria, one of which must be #1 or #4:
A. Symptoms#1 Preceding febrile illness.
#2 Focal seizures predominating in face (eye deviation, hemifacial twitch).
#3 Clustering brief seizures (more than 4 times per hour).
#4 Super-refractory status epilepticus (requiring high-dose barbiturates or benzodiazepines).
#5 Chronic residual epilepsy.
B. Laboratory and neuroradiological ﬁndings#1 Cerebrospinal ﬂuid (CSF) pleocytosis.
#2 Increased pro-inﬂammatory biomarkers (neopterin, interleukin 6) in CSF.
#3 Interictal periodic discharges on electroencephalography (EEG).
#4 Recurrent seizure discharges on ictal EEG.
#5 MRI abnormalities on hippocampus, periinsular cortex, claustrum, thalamus or basal ganglia.
#6 Chronic cerebral atrophy.
C. Diﬀerential diagnosis
Viral encephalitis, virus-associated encephalopathy (acute encephalopathy with biphasic clinical course and late reduced diﬀusion), autoimmune
encephalitis (acute limbic encephalitis, NMDA receptor encephalitis), metabolic disorders, angiitis and epilepsy syndrome (Dravet syndrome,
PCDH19-associated epilepsy) need to be excluded.
Deﬁnite: All ﬁve of A, at least two of B, and C.
Probable: At least four of A, at least two of B, and C.
Possible: At least four of A and at least one of B.

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azepines are known to be eﬀective. Stiripentol, bromides
and topiramate are also considered to be eﬀective. However, it is diﬃcult to control seizures completely.
Sakauchi et al. reported that 63 of 623 patients with
Dravet syndrome died from 13 months to 24 years ofage [164,165]. Among them, 21 patients died due to
AE with SEC. The age at death was 3 to 8 years. Furthermore, Okumura et al. reported the clinical manifestations of acute encephalopathy of 15 children with
Drave syndrome [166]. The median age at the onset ofacute encephalopathy was 3 years and 8 months (range,
8 months to 15 years). AE began with SEC in all cases,
followed by deep coma despite seizures being suppressedwith AEDs. Neuroimaging showed cortical dominantlesions in 5 cases and subcortical white matter dominantlesions in 2 cases (Fig. 4). The outcome was poor; 4 children died and 9 had severe neurological sequelae.
It is necessary to suspect AE and to start intensive
treatment when recovery of consciousness is insuﬃcient
after the cessation of SEC in children with Dravet syndrome. At present, no speciﬁc treatment is known for
AE in children with Dravet syndrome. Intensive
antiepileptic treatment and continuous EEG monitoring
will be necessary. The eﬃcacy of corticosteroid pulse
therapy and intravenous immunoglobulin remains
unclear. There have been no reports on neuroprotection
such as hypothermia.
2.7.2. (CQ7-2) diagnosis and treatment of AE associatedwith congenital adrenal hyperplasia
Recommendations:(1) AE may occur in infants and children with congenital
adrenal hyperplasia. Acute brain dysfunction is associated with features of adrenal crisis, such as diarrhea, vomiting and hypovolemic shock, which arecommonly triggered by acute infectious illnesses.
AE is usually irreversible, with neurological sequelae
found in most cases. (Grading not applicable)(2) Initial management to adrenal crisis includes bolus
infusion of saline and glucose as well as high doseof hydrocortisone. High dose of methylprednisolone may be beneﬁcial to AE. (Grade C1)
Comments:
Some patients with congenital adrenal hyperplasia
develop AE in infancy and childhood characterized byacute CNS dysfunctions associated with features ofacute adrenal insuﬃciency. Neurological sequelae ofvarious degrees are encountered in spite of quick andappropriate managements [167,168]
Clinical features (diagnostic criteria) include thefollowing:1) Onset of AE during the course of congenital adrenal hyperplasia.
2) Convulsion and unconsciousness at the onset ofAE, associated with features of adrenal crisis,
including fever, vomiting, diarrhea and/or
hypotension, as well as laboratory data such as
hypoglycemia, hyponatremia, hyperkalemia andmetabolic acidosis.
3) Localized or extensive brain edema detected ashigh signal intensity on DWI.
4) Diﬀuse high-voltage slow wave and/or paroxysmal
discharges on EEG.
5) Poor recovery of AE despite management of adrenal crisis.
Laboratory tests are useful for diagnosis. Prior to theadministration of corticosteroids, initial blood tests
include glucose, electrolytes, cortisol, adrenal steroids(such as aldosterone and 17-hydroxyprogesterone),
adrenocorticotropic hormone (ACTH) and renin activity. Urinary tests for electrolytes and fractional excretion of sodium (FENa) and potassium (FEK) arenecessary.
Diﬀerential
diagnosis
includeshypoglycemic
encephalopathy, hypoxic-ischemic encephalopathy andother acute neurological disorders causing encephalopathy. Endocrinological disorders causing acute adrenal
insuﬃciency are also included for diﬀerential diagnosis.
Speciﬁc management for this AE has not been established. Appropriate treatments for adrenal crisis, as wellas careful management for brain protection, are minimal
requirements.
1) Intramuscular or intravenous injection of 50–
75 mg/m2 of hydrocortisone sodium succinate.
The same dose of hydrocortisone should be given
for over 24 h.
2) Bolus administration of 5% glucose with 0.9% saline, 20 mL/kg for 1 h. When hypoglycemia persists
even after this treatment, administer a bolus injection of glucose 0.5–1 g/kg (10% glucose 5–10 mL/kg). The initial bolus administration of saline
may be repeated up to 60 mL/kg until the disappearance of hypovolemia.

"
Fig. 4. MRI ﬁndings on diﬀusion-weighted images of acute encephalopathy in children with Dravet syndrome [166]. A and B. High intensities areobserved in the entire cerebral cortex, thalamus and cerebellar hemispheres. C. High intensities are observed in the fronto-temporal areas, caudate
nuclei and lentiform nuclei. D. High intensities are observed in the temporo-parieto-occipital areas. E. High intensities are observed in the entire
cerebral cortex. F. High intensities are observed in the frontal and mesial occipital areas.

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Table 11
Diagnostic criteria of clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS).
Clinical ﬁndings:
1) Delirious behavior, consciousness disturbance or seizures within 1 week after fever.
2) Recovery without sequelae within 1 month after onset of neurological symptoms.
3) Exclusion of other neurological diseases such as ADEM, AESD and acute cerebellar inﬂammation.
4) Neurological symptoms persisting for more than 12 h.
Note: Delirious behavior may be intermittent.
Imaging ﬁndings:
5) DWI showing a reversible splenial lesion with homogenously reduced diﬀusion with mild T1 and T2 signal abnormalities.
6) Lesion involving at least the splenium. It may expand to the entire corpus callosum or symmetrical white matter.
7) Disappearance of lesion within 2 months, leaving no abnormal signal or atrophy.

3) Administration of methylprednisolone at a dose of
30 mg/kg for 2 h for three consecutive days may be
beneﬁcial to AE, although there is no suﬃcient evidence for its eﬃcacy.

2.7.3. Diagnosis and treatment of MERS
Recommendations:(1) MERS is the second most common pediatric AE
in Japan, accounting for 16% of cases. (Grading
not applicable)(2) Diagnosis is based on mild neurological symptoms
with a good prognosis, as well as characteristic
imaging ﬁndings such as a reversible splenial lesion
with homogenous reduced diﬀusion. (Grade B for
MRI)(3) Treatment is based on supportive care. (Grade B)(4) There is currently no speciﬁc/special treatment
with supporting evidence. (No grade)(5) Methylprednisolone pulse therapy and high-dose
gamma globulin therapy are not always necessary
for typical cases of MERS. (Grade C2)
Comments:
A reversible splenial lesion in the corpus callosum
with homogenous reduced diﬀusion may be detected invarious conditions such as infection, withdrawal ofantiepileptic drugs, altitude sickness, Kawasaki disease,
electrolyte abnormalities (especially hyponatremia),
hypoglycemia and X-linked Charcot-Marie-Tooth disease. In particular, encephalitis and encephalopathy
with mild neurological symptoms and good prognosis
have been reported as MERS [7,8,24,169–174].
MERS is the second most common childhood AE inJapan, accounting for 16% of all AE cases [9]. There isno clear sex diﬀerence, with boys accounting for 52%.
The mean age of onset is 5.6 years; MERS is also common in schoolchildren and adolescents. The most common pathogen associated with MERS is inﬂuenza
virus (34%), followed by rotavirus (12%) and mumps
virus (4%) [8]. Diagnostic criteria for MERS (Table 11)
are a combination of clinical and radiological ﬁndings.

The most common neurological symptom is delirious
behavior in 54%, followed by consciousness disturbancein 35% and seizures in 33% [7,24]. Patients who do notsatisfy the clinical ﬁnding [169], i.e., those with delirious
behavior or consciousness disturbance less than 12 h,
are also considered to comprise the same spectrum(MERS spectrum). Patients with a callosal lesion only
(at least involving the splenium) are classiﬁed into
MERS type 1, and those with accompanying symmetricwhite matter lesions (from the deep white matter near
the central sulci to the entire white matter) into MERS
type 2 (Fig. 5) [169,170]. On laboratory examination,
hyponatremia is common in MERS [171]. CSF cytokine
proﬁle in patients with MERS shows increased IL-6 andIL-10 in 50% of patients [172]. Steroids and gamma
globulins may be theoretically eﬀective for increased
cytokines in CSF. However, the prognosis for many
MERS patients is good regardless of treatment[7,8,24,169,171]. Methylprednisolone pulse therapy andhigh-dose gamma globulin therapy are not always necessary for typical patients.
2.7.4. Diagnosis and treatment of AE associated withenterohemorrhagic Escherichia coli (EHEC) infection
Recommendations:(1) EHEC infection may cause AE in parallel with theonset of hemolytic-uremic syndrome (HUS). The
most common symptoms are seizures andimpaired consciousness. (Grading not applicable)(2) Diagnosis is based on clinical symptoms and diagnostic imaging. Brain CT or MRI (Grade B) andEEG (Grade C1) are recommended at the stageof suspected encephalopathy.
(3) Treatment is based on supportive care. (Grade B)(4) As speciﬁc treatment, methylprednisolone pulse
therapy may be considered. (Grade C1)
Comments:
Patients with EHEC infection may develop CNS
symptoms slightly later (within 24–48 h) than the onset
of HUS. The frequency of CNS manifestations among
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Table 12
Diagnostic criteria of acute encephalopathy associated with enterohemorrhagic E. coli (EHEC) infection.
Deﬁnite:Any of the following during the course of EHEC infection.
Convulsions or disturbance of consciousness and abnormal ﬁndings (bilateral deep gray matter lesions or diﬀuse brain edema) on brain CT or
MRI.
Consciousness disturbance (Japan Coma Scale II 10, Glasgow Coma Scale 13) persisting for 24 h or longer.
Probable:
Convulsion or disturbance of consciousness occurring during the course of EHEC infection.

Fig. 6. Neuroimages in acute encephalopathy associated with EHEC O111 infection. A–C. Neuroimages in a teenage male on day 1 showed low
density on CT (A, arrow) and high signal on T2-weighted image (B, arrow) in the bilateral antero-lateral thalamus. CT on day 2 revealed marked
cerebral edema (C) with low density areas in the bilateral thalamus and globus pallidus. D–F. T2-weighted image (D) in a schoolgirl on day 2 showed
symmetrical high signal lesions in the putamen (red arrow), external capsule and thalamus (white arrow). ADC map (E) showed increase ADC in thebilateral putamen (red arrow) and external capsule, and decreased ADC in the bilateral antero-lateral thalamus (white arrow). On the same day,symmetric high signal lesions were also recognized in the dorsal midpons (F, arrow). (For interpretation of the references to colour in this ﬁgurelegend, the reader is referred to the web version of this article.)

AE associated with EHEC infection have been proposedby the ‘Diagnosis and Treatment Guidelines for Hemolytic Uremic Syndrome’ (Table 12) [175]. The diagnosis
is based on the degree and duration of consciousness
disturbance; however, in the presence of EHEC infection, treatment may be initiated with an early diagnosis
of probable encephalopathy.
Brain imaging (CT or MRI) and EEG are useful for
diagnosis. CT and MRI often show bilateral deep graymatter lesions (basal ganglia or thalamus) and diﬀuse
brain edema (Fig. 6) [176–179]. EEG shows abnormali-ties of the basic activity (slow wave) even in mild cases,
as well as paroxysmal discharges [180].
The pathophysiology is mainly cerebral vascular dysfunction, especially hyperpermeability (broken blood–
brain barrier), caused by Shiga toxin and inﬂammatory
cytokines [181,182]. Additional factors, such as the
direct action of Shiga toxin that enters the brain, ﬂuid
abnormalities due to acute kidney injury, electrolyte
abnormalities and abnormal circulation (e.g. hypertension), are also involved.
The basic treatment for AE associated with EHEC
infection is supportive therapy. Systemic management

3
Fig. 5. Cranial MRI ﬁndings in clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). A, B. A 7-year-old girl withMERS type 1 associated with inﬂuenza. She presented with consciousness disturbance and hallucination on day 2, and recovered completely on day
4. DWI shows high signal lesions in the splenium of the corpus callosum on day 4 (A). The splenial lesion completely disappeared by day 10 (B). C–E.
An 11-year-old boy with MERS type 2 associated with inﬂuenza. DWI on day 5 shows reduced diﬀusion in the splenium of the corpus callosum andsymmetrical subcortical white matter (C, D), which completely disappeared by day 10 (E).

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M. Mizuguchi et al. / Brain & Development xxx (2020) xxx–xxx

and treatment for brain edema and seizures should
preferably be performed in a PICU. There is no established treatment at present; however, eﬃcacy of
methylprednisolone pulse therapy has been shown
for AE associated with EHEC O111 infection [176].
PE therapy may be considered after conﬁrming safety,
although evidence for its eﬀectiveness has not been
established.
3. Limitations and future direction
These guidelines are not intended to show a stereotype of medical management to which a strict compliance is required. The actual strategy of diagnosis andtreatment should be decided according to each patient’s
condition, the clinician’s experience and the environment of medical care.
In these guidelines, grades of recommendations areeither very weak (grade C1) or absent (no grade) for
most of the CQs, since little evidence of high quality
was available. Thus, even if the diagnosis and treatment
are in line with the guidelines, they are not necessarily
good evidence-based. Studies in the near future should
improve both the quality and quantity of evidence.
Because systematic review of the literature was conducted in 2014–2015, references that were publishedvery recently were not included. Because the recommendations and comments were written by Japanese
researchers in 2015, all the diagnostic tools and therapeutic measures, including medical drugs, are conﬁned
to those available in Japan at that time. In 2018, the
JSCN reorganized the WG for revision of the guidelines.
The WG, together with the Research Committee on
Acute Encephalopathy supported by the Japanese
Government, is currently striving to accumulate evidence of high quality for earlier diagnosis and more eﬃcacious treatment of AE.
Acknowledgements
The authors are grateful to the Committee for the
Integration of Guidelines and Committee for the Support of Collaborative Researches of the JSCN for promoting our studies and activities on AE. This research
was supported by Grant-in-Aid for Policy Research
for Intractable Diseases, H30-Nanchi-Ippan-007, fromthe National Institute of Public Health, Japan, and byGrant-in-aid for Scientiﬁc Research, No. 15H04872,
from the Japan Society for the Promotion of Science.
Disclosure
Compilation cost was covered by JSCN and subsequently covered by sales of the guidelines. The authors
have no ﬁnancial conﬂict of interest to disclose.

25

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