Review

A Comprehensive Review of Pediatric Acute Encephalopathy
George Imataka 1,*, Shigeko Kuwashima 2 and Shigemi Yoshihara 1
Department of Pediatrics, Dokkyo Medical University, 880 Kitakobayashi, Mibu 321-0293, Shimotsuga,
Tochigi, Japan
2 Department of Radiology, Dokkyo Medical University, 880 Kitakobayashi, Mibu 321-0293, Shimotsuga,
Tochigi, Japan* Correspondence: geo@dokkyomed.ac.jp; Tel.: +81-282-86-1111
1

Citation: Imataka, G.;
Kuwashima, S.; Yoshihara, S. A
Comprehensive Review of PediatricAcute Encephalopathy. J. Clin. Med.
2022, 11, 5921. https://doi.org/
10.3390/jcm11195921

Abstract: Acute encephalopathy typically affects previously healthy children and often results indeath or severe neurological sequelae. Acute encephalopathy is a group of multiple syndromescharacterized by various clinical symptoms, such as loss of consciousness, motor and sensory impairments, and status convulsions. However, there is not only localized encephalopathy but also
progression from localized to secondary extensive encephalopathy and to encephalopathy, resulting in a heterogeneous clinical picture. Acute encephalopathy diagnosis has advanced over theyears as a result of various causes such as infections, epilepsy, cerebrovascular disorders, electrolyte
abnormalities, and medication use, and new types of acute encephalopathies have been identified.
In recent years, various tools, including neuroradiological diagnosis, have been developed as methods for analyzing heterogeneous acute encephalopathy. Encephalopathy caused by genetic abnormalities such as CPT2 and SCN1A is also being studied. Researchers were able not only to classify
acute encephalopathy from image diagnosis to typology by adjusting the diffusion-weighted imaging/ADC value in magnetic resonance imaging diffusion-weighted images but also fully comprehend the pathogenesis of vascular and cellular edema. Acute encephalopathy is known as a very
devastating disease both medically and socially because there are many cases where lifesaving issometimes difficult. The overall picture of childhood acute encephalopathy is becoming clearer withthe emergence of the new acute encephalopathies. Treatment methods such as steroid pulse therapy, immunotherapy, brain hypothermia, and temperature control therapy have also advanced.
Acute encephalopathy in children is the result of our predecessor’s zealous pursuit of knowledge.
It is reasonable to say that it is a field that has advanced dramatically over the years. We would liketo provide a comprehensive review of a pediatric acute encephalopathy, highlighting advancements
in diagnosis and treatment based on changing disease classification scenarios from the most recent
clinical data.

Academic Editor: Francesc Graus
Received: 3 June 2022

Keywords: acute encephalopathy; convulsions; pediatrics; brain hypothermia

Accepted: 1 October 2022
Published: 7 October 2022
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Copyright: © 2022 by the author. Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
Acute encephalopathy in childhood and adolescence refers to a brain pathobiologicalcondition that progresses rapidly. Acute encephalopathy is a syndrome that is characterized by central nervous system dysfunction caused by diffuse or widespread noninflammatory cerebral edema [1]. A task force of experts from ten academic societies recently
developed a consensus-based, uniform nomenclature for acute cognition disturbancesand defined it as a rapidly developing pathophysiological brain process manifesting as
subsyndromal delirium, delirium, or coma [1]. This position statement defines subsyndromal delirium as a state intermediate between normal cognition and delirium in which
none of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
criteria for delirium is met. The Japanese Society of Child Neurology guidelines for acuteencephalopathy in infancy and childhood propose that the impairment of consciousness
in acute encephalopathy persists for at least 24 h with 11 points or less on the Glasgow

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coma scale [2]. Some encephalopathy disorders are multifactorial, whereas others, such asprevious viral infection or hepatic or uremic encephalopathy have a known etiology. In
Japan, influenza virus is the leading cause of mild encephalitis/reversible splenic lesion(MERS) and acute necrotizing encephalopathy (ANE). HHV-6 is the most common causeof AESD (acute encephalopathy with biphasic seizures and reduced diffusion). Bacteria
and mycoplasma each accounted for 2% and 1% of the total. MERS and ANE are the mostcommon syndromes, followed by AESD [3,4]. In recent years, there has been an increasein the number of cases of acute encephalopathy associated with other viruses, such as
human metapneumovirus, rhinovirus, and cytomegalovirus [4].
Acute encephalopathy is fairly common in East Asia. From spring 2007 to spring
2010, Hoshino et al. conducted a pediatric acute encephalopathy survey in Japan, recording 983 cases of pediatric acute encephalopathy over a 3-year period. The questionnaire
collection rate was approximately 50%, and the annual number of pediatric acute encephalopathy cases in Japan is estimated to be 400 to 700. Among acute encephalopathy syndrome, AESD was the most common (29%), MERS was the second most common (16%),and ANE was the least common (4%). Other syndromes that occurred in 2% of cases included hemorrhagic shock encephalopathy syndrome (HSES) [3]. The annual incidence inJapan had increased to 1115 cases by 2017 [4]. Despite the fact that the annual incidence
rate in Japan is about 1000, it is significantly greater than the number of cases of acuteencephalopathy in Western countries. According to a statewide questionnaire survey conducted in Japan in 2012, 56.2% of those who suffered from acute encephalopathy recovered completely, 22.1% had mild to moderate sequelae, 13.5% had severe sequelae, and5.6% died [3]. The total percentage of acute encephalopathy-related deaths in Japan is 6%,
with 36% developing neurologic sequelae. Deaths due to AESD are uncommon, but neurologic complications are common. In ANE and HSES, both fatalities and neurologic sequelae are common [2].
Despite the relatively high morbidity and mortality associated with acute encephalopathy, there is limited evidence for diagnosing and treating acute encephalopathy. Virus
epidemics, regional differences, racial disparities, human leukocyte antigen (HLA) differences, and medical level challenges are all discussed, but the true cause of the high incidence of acute encephalopathy in Japanese children remains unknown. Furthermore, various conditions such as intracranial infections, autoimmune encephalitis, cerebrovasculardiseases, traumatic, metabolic and toxic disorders, and the effects of organ failure manifest
with acute impairment of consciousness and may complicate the diagnosis and management of acute encephalopathy. Assessing and comprehending current clinical practicepatterns and variations is an important first step in promoting future research to develop
evidence-based management and, ultimately, reduce the morbidity and mortality associated with acute encephalopathy. The purpose of this review is to offer an updated summary of the available data and a perspective on the diagnosis and management of pediatric acute encephalopathy. A detailed analysis of the epidemiological, clinical presentation,
diagnosis, and management of pediatric acute encephalopathy was beyond the scope of
the authors.
2. Classification of Acute Encephalopathy and Literature Search
We conducted a literature search from 1 Jan 1966 to 1 September 2022, using the
MEDLINE/PubMed and National Institutes of Health Clinical Trials Registry(http://www.clinicaltrials.gov (accessed on 1 September 2022)) electronic medical databases for the identification of publications on acute encephalopathy articles were included
if they were published in the English language. We excluded conference posters. Keywords included acute encephalopathy, pediatric, children, preschool, newborn, infant,acute febrile encephalopathy, and status epilepticus. Abstracts and full-text articles of randomized clinical trials, reviews, and other study designs were considered from studies

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describing relevant data on pediatric acute encephalopathy. An additional search was carried out via Google Scholar, and relevant articles on prospective and retrospective designs
and real-world data on pediatric acute encephalopathy were considered.
To date, over ten acute encephalopathy syndromes have been identified and described. They are classified into four categories based on their primary pathogenesis: metabolic error, cytokine storm, excitotoxicity, and unknown mechanisms (Table 1). Unclassifiable encephalopathies together with a combination of several pediatric acute encephalopathies such as the co-occurrence of AESD with MARS or ANE with MARS and ANE
are named multiple encephalopathy syndrome (MES) [5–15]. Carnitine transpalmitoyl
transferase II, Toll-like receptor 3 single nucleotide polymorphisms, adenosine A2A receptor, neuronal sodium channel alpha 1 subunit (SCN1A) and SCN2A mutation have all
been identified as risk factors for acute encephalopathy [6–10]. Acute encephalopathy thatdevelops in association with acute adrenal insufficiency (congenital adrenal hyperplasia(CGH]), caused by fever or gastroenteritis, has also been reported [16]. Epileptic encephalopathies are a set of epileptic disorders that manifests itself early in life. Early infantile
epileptic encephalopathy with suppression bursts (EIEE/Ottawa syndrome) and early myoclonic encephalopathy (EME) both occur in early infancy [17]. West syndrome affects
children between the ages of 4 months and 2 years and manifests as infantile spasms [18].
Lennox–Gastaut syndrome develops between the ages of 2 and 6 years [19]. In addition,
infantile epilepsy with migrating focal seizures, EIMFS, which occurs at less than 6months of age, is also significant. Some of these developmental epileptic encephalopathies
are linked to STXBP1, ARX, and other proteins. Some patients have KCNT1, SCN1A,
KCNQ2, SCN2A, SCN8A, TBC1D24, SLC25A22, and SLC12A5 genetic abnormalities [20].
Dravet syndrome (infantile severe myoclonic epilepsy SMEI) is caused by mutations in
SCN1A, SCN1B, SCN2A, and GABRG2. Before the age of one year, the majority of Dravet
syndrome patients experience recurrent or status febrile seizures [21].
Table 1. Classification of Acute Encephalopathy [7–21].

Microbiological classification

Metabolic errors

Cytokine storm• Influenza-associated encephalopathy• Human herpesvirus (HHV)-6/7 encephalopathy• Rotavirus encephalopathy• Respiratory syncytial virus encephalopathy• Herpes simplex virus encephalopathy• Varicella-zoster virus encephalopathy• Progressive multifocal leukoencephalopathies (PML) associated with the HIV
virus such as subacute sclerosing panencephalitis (SSPE) caused by the measles
virus and subacute encephalitis caused by the rubella virus.
Bacterial infection-associated encephalopathy(Acute encephalopathy associated with hemolytic uremic syndrome (HUS)
caused by E. coli O157:H7 and rotavirus infection and salmonella infection) [22]• Encephalopathy caused Bacillus cereulide-producing Bacillus cereus.
• Mycoplasma infection-associated encephalopathy• Acute disseminated encephalomyelitis (ADEM)• Others• Classic Reye syndrome• Encephalopathy secondary to inherited metabolic disorders (acute metabolic
encephalopathy with carbamoyl phosphate synthetase 1 deficiency) [23]• Encephalopathy with diffuse brain swelling Rey-like syndrome, sepsis-like encephalopathy)• Hemorrhagic shock and encephalopathy
syndrome (HSES)• Acute necrotizing encephalopathy (ANE)J. Clin. Med. 2022, 11, 5921

Excitotoxicity

Unknown or others

4 of 21• Non-herpetic limbic encephalitis (NHLE)• Acute encephalopathy with biphasic seizures and late reduced diffusion(AESD)• Acute infantile encephalopathy predominantly affects the frontal lobes (AIEF)• Hemiconvulsion–hemiplegiaepilepsy
syndrome (HHE)• Anti-N-methyl-D-aspartate receptor encephalitis• Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)• Posterior reversible leukoencephalopathy syndrome (PRES or RPLS) [24]• Febrile infection-related epilepsy syndrome (FIRES)
synonym: acute encephalitis with refractory, repetitive partial seizures (AERRPS)• Acute cerebellitis/cerebellopathy [25]• Epileptic encephalopathies with child onset• Acute encephalopathy with a background of genetic abnormalities in the earlyneonatal period (NEXMIF gene abnormality, Biallelic TBCD Mutations, mutations in ARX genes) [20,26]• Dravet syndrome• Acute encephalopathy associated with congenital adrenal hyperplasia (CAH)• Unclassified encephalopathy
3. Clinical Presentation
A pathologic feature of acute encephalopathy is noninflammatory brain edema. This
pathologic feature increases intracranial pressure, which leads to decreased cerebral perfusion pressure and, eventually, herniation syndromes and/or brainstem dysfunction associated with central nervous system-caused respiratory and circulatory failure [19,27].
Seizures are common in many people, and they are often febrile and last for a long time
(febrile status epilepticus). Depending on the child’s age, there may be a change in personality or behavior as well as a decrease in cognitive functioning, developmental regression/stasis, a reduction in conscious level, and specific localizing features such as seizures,
ataxia, tremor, or other focal motor symptoms. Fever, vomiting, lethargy, loss of appetite,and headache are all examples of systemic symptoms. Regardless of the cause of encephalopathy, all cases of acute encephalopathy have at least one symptom, namely an alteredmental state. The altered mental state can be subtle and develop over time, such as
apraxia, or the inability to sketch simple drawings, or it can be obvious and develop
quickly, leading to coma or death within minutes [28].
The clinical course of metabolic errors and inherited metabolic disorders may include
gradually progressive or static features, followed by the emergence of an acute encephalopathic crisis, including lethargy, behavioral changes, or gait disturbances caused by infections or a fasting state. Patients presenting with a cytokine storm may have systematic
inflammatory response syndrome, which includes (1) increased or depressed leukocytes
or 10% immature neutrophils, (2) tachycardia or bradycardia, (3) tachypnea or the needfor mechanical ventilation, and (4) elevated or depressed leukocytes or 10% immatureneutrophils. Acute excitotoxic encephalopathy, a mild encephalopathy caused by excitotoxicity is defined as a loss of consciousness that lasts more than 24 h and is usuallyaccompanied by seizures but does not have a biphasic clinical course. Conversely, AESD
is clinically recognized by biphasic seizures; an early seizure that is a prolonged febrile
seizure on day 1, followed by late seizures that are a cluster of complex partial seizures
on days 4–6 [29].
4. Diagnosis
A coma with obvious consciousness impairment or a convulsive condition is a clinical indicator of acute encephalopathy; however, identifying acute encephalopathy in theseJ. Clin. Med. 2022, 11, 5921

5 of 21circumstances is fairly easy. However, there are various early signs and symptoms as wellas variations in these symptoms. This large range of clinical symptoms mirrors the wide
range of cerebral function abnormalities as provided by the International Encephalitis
Consortium, which recommends the diagnosis of encephalitis and encephalopathy of presumed infectious or autoimmune etiology. An altered mental state is a major criterion.
Additional criteria (minor) to substantiate diagnosis include fever ≥ 38 °C (100.4 °F) within
the 72 h before or after presentation; generalized or partial seizures not fully attributable
to a pre-existing seizure disorder; new onset of focal neurological findings; cerebrospinal
fluid (CSF) white blood count ≥ 5 mm3; and electroencephalographic abnormality that is
consistent with encephalopathy and not caused by another factor or and not caused byanother condition [30].
A clinical examination and a management plan for a child with encephalopathy
should be developed concurrently. As soon as possible, a full history should be obtained.
A thorough neurologic examination should be performed to localize brain damage andevaluate early prognostic indicators as well as to detect systemic symptoms such as rash,lymphadenopathy, and hepatosplenomegaly [31]. During a physical examination, clinicalprocedures such as mental status tests, memory tests, and coordination tests that record
an altered mental state are commonly used to diagnose encephalopathy. Clinical test results are frequently used to diagnose or presumptively diagnose encephalopathy. Whenthe altered mental state occurs associated with another primary disorder, such as chronic
liver disease, kidney failure, anoxia, or a variety of other conditions, the diagnosis is typically made [29,32,33]. Glucose, ammonia, lactate, and ketone body levels in the blood aswell as plasma acid–base status can all be used to help identify the subtype associatedwith genetic metabolic illnesses. The eventual diagnosis is based on certain laboratory
findings at the start and/or during the static periods [2].
The cytokine storm subtype is distinguished by a significant increase in inflammatory tumor necrosis factor and interleukin concentrations in the serum and CSF [34]. Patients with disseminated intravascular coagulation and hemophagocytic syndrome havesignificant increases in ferritin, serum aminotransferase, pancreatic amylases, creatine kinase, creatinine, and uric acid nitrogen as well as ferritin, serum aminotransferase, pancreatic amylases, creatine kinase, creatinine, and uric acid nitrogen [33]. Clinical evidence,such as a biphasic pattern of seizure and varying degrees of altered states of consciousness
as well as characteristic patterns of magnetic resonance imaging (MRI) and cerebral flow
images using single-photon emission computed tomography, should be used to diagnose
the excitotoxic crisis subtype [33].
EEG is a widely used technique for detecting and monitoring children with acuteencephalopathy. Technological advancement has greatly simplified long-term bedside
EEG monitoring. EEG has the advantage of being able to examine real-time brain function
by recording electrical activity in the brain. Some children with acute encephalopathy are
extremely ill and unstable in general. Even under these conditions, EEG monitoring ispossible [2]. Several studies on long-term EEG monitoring among critically ill children
with reduced consciousness, including those with acute encephalopathy, have recently
been published. There have been numerous studies published on conventional EEG findings in children with acute encephalopathy. According to these results, EEG abnormalities
are extremely common among children with acute encephalopathy. As a result, EEG isdeemed to be useful in diagnosing acute encephalopathy. These EEG abnormalities include generalized/unilateral/focal slowness, low voltage, periodic lateralized epileptiformdischarges, and paroxysmal discharges [35–38].
EEG has demonstrated its ability to detect nonconvulsive status epilepticus in AESD
and FIRES/AERRPS (intermittent, latent seizures) [39,40]. EEG data may aid in differentiating AESD from long-term febrile seizures. Children with prolonged seizures and fever,reduced or absent spindles/fast waves as well as continuous or frequent slowing during
sleep are diagnosed with AESD [41]. When combined with the clinical picture in patients

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6 of 21with encephalopathy, EEG and brain imaging may improve diagnosis and have prognostic significance. The most common EEG finding in patients with encephalopathy is isolated persistent slowing of background activity. These patterns are linked to a variety ofstructural and non-structural pathologies.
The analysis of CSF is critical for determining the cause of encephalitis and distinguishing it from other types of encephalopathy. Lumbar puncture (LP) should be performed as soon as possible in suspected cases of encephalitis unless contraindicated. Clinical evaluation rather than cranial computerized tomography (CT) should be used to determine whether or not an LP is safe to perform [42,43]. Increased total protein and CSF/serum albumin quotient levels may be linked to severe edema [44]. Increased levels of cytokines and chemokines in CSF and serum may indicate an overly aggressive immune response [45]. CSF examination may reveal pleocytosis in some disorders [46], whereas pleocytosis may be uncommon in others [44].
Since 2000, imaging technology such as CT, MRI, SPECT, PET, and a variety of otherneuroradiological tools have been used to treat heterogeneous acute encephalopathy syndrome. Acute encephalopathy was first defined using neuroradiographic images and clinical data derived from imaging, and it has since advanced significantly. It was possible tosee fine cerebral edema images in acute encephalopathy. Figures 1–4 illustrate imagining
characteristics of MERS, ANE, AESD, and PRES, respectively. When acute encephalopathy is suspected, CT is usually the first test performed, because it is available in the majority of Japanese regional centers and has a quick imaging time. Acute encephalopathy isidentified by cranial CT abnormalities [2,47], which include: (1) low-density zones spanning the entire brain or possibly the entire cerebral cortex, (2) no clear distinction between
the cerebral cortex and the limbic system medulla, (3) both the surface of the cerebral subarachnoid space and the ventricles becoming narrower, (4) areas of low density: bilateralthalamus (ANE) and unilateral cerebral hemisphere (in some cases of AESD), (5) narrowing of the brain’s surrounding cisterns: swelling of the brainstem.

Figure 1. Imaging Characteristics of MERS. (A,B): A Horizontal/B sagittal section was performed on
an 8-year-old boy who had an MRI on the third day of fever due to impaired consciousness andunable to recognize his own name. DWI showed an abnormal high signal in the cerebral corpus

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callosum: WBC 24800, CRP 7.84, Na 133, CL 95, ferritin 119.9, IL-6 171 EEG showed high amplitude
slow waves in the occipital region. After 3 days of steroid pulse therapy, the fever resolved andconsciousness improved. No sequelae. No causative organism or virus could be identified. (C,D):
On the third day of vomiting and fever, he was hospitalized because he could no longer talk to hismother and could not look at her. He had diarrhea and was positive for rotavirus antigen in stool.
In the bilateral frontal and occipital regions, EEG revealed persistent high amplitude slow waves.
He was diagnosed with MERS on the fifth day after a diffusion-weighted MRI revealed an abnormally high signal in the corpus callosum. mPSL steroid pulse therapy was administered for threedays, his level of consciousness improved, and both EEG and MRI were normalized.

Figure 2. Imaging Characteristics of ANE. (A): An 11-month-old boy was admitted to the hospital
after experiencing fever and vomiting. He was given a cold medicine prescription and sent home,
but the next day, after a 3 min febrile convulsion, his loss of consciousness lasted 12 h, and a second 3 min convulsion was noted, so a CT was performed. He was diagnosed with ANE after a CT
scan of the brain revealed abnormalities in the bilateral thalamus. (B): A 4-year-old boy visited thehospital with a high fever, vomiting, impaired consciousness, and convulsions. The rapid influenza A antigen test was positive, and MRI indicated abnormal signals in the bilateral thalamus not
only on diffusion-weighted but also on T2 images, leading to the diagnosis of ANE. The patient
was admitted to the intensive care unit immediately after being diagnosed with ANE. He wasgiven cerebral sedation with high-dose barbital therapy and cerebral hypothermia at 34.5 °C for 48h, which was followed by TTM as temperature control therapy, IVIG high-dose therapy, andmPSL steroid pulse therapy. Mitochondrial cocktail therapy was used in combination with 2months after onset; the patient was able to walk, and 4 months later, his speech function had recovered to the same level as before the onset. (C): A 1-year and 2-month-old girl was admitted tothe hospital with fever and partial seizures. After an MRI the next day, the T2-weighted image
showed abnormal signals in the bilateral thalamus and diagnosed ANE. She was treated in theintensive care unit with 72 h 34.5 °C brain hypothermia, steroid pulse therapy, IVIG, and mito-

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8 of 21chondrial cocktail therapy. The patient was given cerebral sedation with high-dose barbital therapy and she was treated with dextromethorphan, which saved her life, but she was left with severe neurological sequelae.

Figure 3. Imaging characteristics of AESD. (A) An 11-month-old boy who was admitted to the hospital with a high fever and 15 min seizure congestion of the right upper and lower extremities. The
seizures stopped after the administration of midazolam. Thereafter, there was transient Todd’s
palsy of the right upper and lower extremities. Brain MRI was normal. The fever resolved 3 days
later and a rash appeared, which was clinically diagnosed as HHV-6 infection. The second diffusionweighted brain MRI showed a bright tree appearance sign predominantly on the left side, diagnosing AESD. mPSL 30 mg/kg 3 days pulse therapy was administered. At the age of 6, he entered a
regular elementary school, but his language skills were mildly poor. (B) A 3-year and 3-month-old
girl. She has a 1 h febrile convulsion superimposed on fever. Midazolam brought the convulsions
to a halt. The next day, she remained listless and was monitored with intravenous fluids; on theeighth day, she experienced a cluster of short convulsions in her limbs. Diffusion-weighted brain
MRI revealed bilateral subcortical white matter predominance with bright tree appearance and an
AESD diagnosis. Then, 48 h of mild cerebral hypothermia at 35.5 °C, steroid pulse therapy, andmitochondrial rescue therapy were performed. Six years after onset, she is living a normal fourthgrade elementary school life with no sequelae in terms of motor, language, or academic performance. (C) A 1-year and 7-month-old boy. After 4 days of febrile convulsive seizures, the fever subsided and a rash appeared; he was clinically diagnosed with HHV-6 infection. Multiple convulsive
seizures lasting a few minutes were observed 5 days later. Slow waves were detected in the frontal
and occipital regions of the EEG. Diffusion-weighted brain MRI showed an abnormally high signal
in subcortical white matter and diagnosed AESD. mPSL pulse therapy and vitamin cocktail therapy
were started. Body temperature was maintained at 35.5–36.0 TTM for 5 days The disease has beenpresent for over two and a half years, and the child is now over 4 years old. There are no neurologicalsequelae and both language and motor functions are age-appropriate. (D) A 1-year-old boy with a

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fever of 39 °C and spontaneous convulsions that stopped spontaneously before reaching the hospital; 4 days later, he presents with two 3-min generalized convulsions and is rushed to the emergency
room with no recovery of consciousness. He was admitted directly to the ICU, sedated with
Rabonar, and given 48 h of mild cerebral hypothermia at 35 °C. Steroid pulse therapy was also administered. Thereafter, the temperature was kept at 36 °C, and the patient was transferred from the
ICU to the general ward on the eighth day. On the same day, a brain MRI showed an abnormallyhigh signal on diffusion-weighted images with bilateral frontal lobe predominance, and a diagnosis
of AIEF-type AESD was made. Rehabilitation was continued until he was over 2 years old. After 1
year of onset, both his motor and language functions have recovered to the level of his age.

Figure 4. Imaging Characteristics of PRES. (A,B): A 13-year-old boy underwent skin graft surgery
due to severe burns all over his body. He was on ventilatory management and sedatives for a long
period of time postoperatively. As his generalized sepsis improved, his anesthetic was reduced andhe was awakened; after 50 days, his consciousness improved completely; on day 51, he complainedthat “everything I see is white and I can’t see anything.” He then had a severe headache. His bloodpressure was 150/89 mmHg and he had hypertension. Brain MRI scan showed an abnormal highsignal in bilateral occipital areas on T2-weighted (A) and FLAIR (B) images, and he was diagnosed
with PRES.

In some cases, a CT scan can be used to diagnose severe encephalopathy (for example, HUS encephalopathy), which has more edema in the brain than in mild cases [22].
MRI, in contrast, is a sensitive and non-radiological method for detecting encephalopathy,
with diffusion-weighted imaging (DWI) being especially helpful in detecting early abnormalities. High-intensity lesions were either visible only on b = 3000 DWI for AESD, MERS,
HSE, and unclassifiable encephalopathy or effectively identified on b = 3000 DWI than on
b = 1000 DWI. Table 2 summarizes three infectious encephalopathy disorders for which
neuroimaging is essential for diagnosis. The classifications of acute encephalopathy withfebrile convulsive status epilepticus (AEFCSE), AIEF, and AESD are all part of a single
spectrum and may refer to the same condition. On MRI diffusion-weighted images, a clinical form of AESD that specifically disrupts frontal lobe function in infants has been reported. As a result, the concept of AIEF is intended to be included in AESD: unlike
AEFCSE, which has a biphasic course after a relatively short convulsive overlap, AESD
has a biphasic course after a relatively short convulsive overlap, i.e., an initial febrile convulsive overlap followed days later by an afebrile partial convulsion with abnormal onset
on MRI images. There is no English literature on AEFCSE. In Japan, there was controversy
over whether AEFCSE, AIEF, and AESD were all the same disease; AIEF was a concept
proposed based on cases of frontal lobe dominance with a course similar to AESD,

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whereas AEFCSE was a concept focused on the encephalopathy of the convulsive superimposed form of AESD. Since then, it has been determined that these three concepts arenearly identical to the AESD concept.
Table 2. MRI/CT characteristics of acute encephalopathy.

Acute Encephalopathy Syndrome

Imaging Characteristics
a. No abnormal lesion within 2 days.
b. Subcortical white matter lesions between days 3 and 9, which aremost obvious on DWI (bright tree appearance). The lesions are predominantly frontal or frontoparietal in a location with sparing of theperi-Rolandic region (central sparing).
c. After 9 days, the bright tree appearance on DWI has disappeared,
Acute encephalopathy with biphasic seizures andand T2WI or FLAIR imaging show high-intensity lesions with cenlate reduced diffusion (AESD) [29,48–50]
tral sparing, and cerebral atrophy.
d. MRS shows acute Glu elevation (days 1–4), changing to subacute
Gln elevation (days 4–12).
e. Cranial MRI in the late phase shows cerebral cortical lesions of reduced diffusion, indicating cellular edema of the subcortical whitematter.
a. Postictal edematous changes in the white matter and cortex ofboth frontal lobes.
Acute infantile encephalopathy (AIEF) [51] b. Reduced perfusion in the frontal lobes occasionally persisted andwas linked with increasing bilateral atrophic alterations and prolonged high signal intensity on T2-weighted images.
a. Bright tree appearance of subcortical white matter on MRI/DWI
Acute encephalopathy with febrile convulsive with central sulcus being spared.
status epilepticus (AEFCSE)
b. Residual atrophy in the frontal region, or frontal and parietal
combined region on CT or MR.
a. Concentric structure of the thalamocerebral lesions; diffuse cerebral edema and symmetric and multifocal lesions in the thalamus
and other CNS regions, including the posterior limb of the internal
capsule, posterior putamen, cerebral and cerebellar deep white matAcute necrotizing encephalopathy (ANE) [52,53]
ter, and upper brainstem tegmentum.
b. The thalamic lesions often show hemorrhagic degeneration andcystic change after 3 days, showing a high signal on T1WI and a low
signal on T2WI or T2 star-weighted imaging.
a. MRI-DWI shows abnormal signals in the vast portion of the corClinically mild encephalitis/encephalopathy with pus callosum.
a reversible splenial lesion (MERS) [54,55]
b. Abnormal intensities in the splenium on ADC-map, FLAIR, T1,
and T2-weighted images.
a. Abnormal lesions
in the occipital and parietal lobe areas.
b. Extensive signal abnormality in the bilateral cerebellar hemiPosterior reversible encephalopathy
spheres and within the thalami.
syndrome (PRES) [24,56]
c. T2-FLAIR images show signal abnormality within the midbrain,pons, and superior cerebellar peduncles.
c. Fluid-sensitive MR sequences: parieto-occipital predominant
white matter T2 hyperintensities
ADC: Apparent diffusion coefficient; CNS: Central nervous system; DWI: Diffusion-weighted imaging; FLAIR: Fluid attenuated inversion recovery; MRI: Magnetic resonance imaging; MRS: Magnetic resonance spectroscopy.

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The biomarkers used to diagnose and assess the severity of acute encephalopathy
differ depending on the type of encephalopathy (Table 3) [43,44,57,58].
Table 3. Diagnostic markers for acute encephalopathy.

Acute encephalopathy due to cytokine storm

Acute encephalopathy due to excitotoxicity

Markers Indicating Poor Outcomes
Serum elevated aspartate aminotransferase
Hyperglycemia
Serum elevated TNF-α, cytochrome cSerum elevated IL-6, sTNFR1, ILSerum elevated TIMP-1
Serum elevated soluble CD163
Serum elevated HMGB1
Hematuria or proteinuria
Serum elevated MMP-9
Serum elevated MMP-9/TIMP-1 ratio
CSF tau protein
CSF S100B
CSF VILIP-1
CSF IL-6
hsa-mir-34c
hsa-mir-449b
hsa-mir-449c
serine/threonine kinase 39 gene

CSF: Cerebrospinal fluid; IL: Interleukins; HMGB1: High-mobility group box 1; MMP: Metalloproteinases; TIMP: Tissue inhibitors of MMP; TNF: Tumor necrosis factor.

Acute encephalopathy should be distinguished from other conditions that cause
acute loss of consciousness during infectious diseases, such as intracranial infection (e.g.,viral encephalitis and bacterial meningitis), autoimmune encephalitis, cerebrovasculardiseases, traumatic, metabolic, and toxic disorders, and organ failure effects. The mostrecent Japanese guidelines listed several differential diagnoses of acute encephalopathy[2].
5. Management
The current national pediatric acute encephalopathy guideline [2] is based on expert
consensus and case series and retrospective case-control studies for specific therapies suchas corticosteroids [59], immunoglobulin [60], free-radical scavenger [61], osmotic agents[62], immunosuppressant [63], plasmapheresis, and therapeutic hypothermia [64]. Even
though no drugs or therapeutic practices have been systematically demonstrated to lessen
the sequelae of acute encephalopathy, the use of barbiturates and steroids has increased
over time. This could be due to new research highlighting the importance of early aggressive therapy in the treatment of febrile status epilepticus [65]. Only surrogate markers
such as fever and inflammatory changes in the CSF as well as neuroimaging are used torule in or rule out infections in the early stages of infection. It is important to notice clinicalclues from history and examination when narrowing down the etiology and deciding on
an initial treatment approach. Proper head placement, suctioning of oropharyngeal secretions, and, if necessary, the use of oropharyngeal or nasopharyngeal airways should all
be used to ensure airway patency in patients with diminished consciousness [42]. Children who exhibit signs of poor ventilation and oxygenation, such as irregular respiratory
efforts, insufficient chest movements, poor air entry, central cyanosis, or peripheral oxygen saturation of 92% or less should be given a bag and mask first, which is followed by

J. Clin. Med. 2022, 11, 5921

12 of 21endotracheal intubation and mechanical ventilation. For emergency intubation, rapid sequence intubation is recommended to avoid aspiration and a rapid rise in ICP. Thiopental/midazolam, lidocaine, fentanyl, and a short-acting non-depolarizing neuromuscular
blocking drug are among the induction agents (e.g., vecuronium, atracurium). Hypoglycemia and hyponatremia can accompany derangements in critically ill children, potentially exacerbating the underlying disease’s encephalopathy. When glucose levels of 60
mg/dL are treated promptly with 2 mL/kg of intravenous 25% dextrose, the neurologic
symptoms are frequently reversed. Meanwhile, 5 mL/kg of 3% saline is required to raise
sodium levels to acceptable levels in an asymptomatic child with a plasma sodium of 125
mEq/L [2].
Antimicrobials should be given to children with infectious diseases as soon as possible rather than waiting for laboratory confirmation.
Steroid pulse therapy, particularly cytokine storm therapy, is commonly used to treat
virus-associated acute encephalopathy. The prognosis may be improved by beginningsteroids within 24 h of the onset of ANE. It might be useful for treating encephalopathy
caused by Escherichia coli O111, which produces Shiga toxin. However, in a recent study,
steroid pulse treatment within 24 h did not improve the prognosis in children with suspected acute encephalopathy in the presence of AST. However, the authors noted that if
treatment is started earlier, the neurological consequences of this illness could be avoided [66].
The cornerstone treatment for refractory status epilepticus is intravenous general anesthetics (such as midazolam, propofol, and barbiturates) [67]. General anesthetics, in contrast, can cause cardiovascular instability, respiratory suppression, infections, metabolic
abnormalities, paralytic ileus, ischemic bowel, and thromboembolic events [68]. Whengeneral anesthetic therapy fails, several pharmacologic and nonpharmacologic approaches have been documented. Ketogenic diet can be considered for the treatment of
acute encephalitis with refractory, repetitive partial seizures (FIRES/AERPPS). According
to the findings of various case reports and retrospective studies, targeted temperature
management can significantly improve the neurologic outcomes of acute encephalopathy[69–73]. Brain hypothermia therapy protocol has been established at hospitals for treating
childhood status epilepticus and acute encephalopathy (Table 4) [73]. Hypothermia therapy may be useful in preventing the development of post-encephalopathic epilepsy (PEE)in the long-term consequences of AESD. Hypothermia therapy could help these patientsenhance their quality of life by preventing the development of PEE [74]. Mild brain hypothermia therapy, followed by targeted temperature management, may be an effective way
to improve neurological outcomes in children with HSES [75]. In contrast, there are also
reports of inadequate benefits with brain hypothermia [76]. Classically, brain hypothermia was used to lower the body temperature from 32 to 34 °C. Although the effectivenessof this therapy has been suggested, the solution to side effects such as bradycardia, decreased blood pressure, and abnormal coagulation has been a problem. Therefore, in recent years, treatment for mild brain hypothermia that keeps the body temperature at 34.5
to 35.5 °C has been attracting attention as a new treatment strategy for pediatric acuteencephalopathy. Table 5 summarizes the clinical manifestation, diagnosis, and treatment
for major acute encephalopathy subtypes.
Table 4. Proposed protocol for brain hypothermia therapy (Dokkyo Medical University Hospital
ICU: April 2014) [73].
Anti-seizure medication treatment for status epilepticus(A) Midazolam (0.5 mg/kg) administered via the nasal cavity or cheek mucosa(B) Midazolam (0.15 mg/kg) intravenously (i.v.) administered (up to two doses possible)(C) Between ages 0 and 2 years: intravenous phenobarbital, between 15 and 20 mg/kg (10 min i.v.), ≥2 years: fosphenytoin 22.5
mg/kg (10 min i.v.)(D) Sodium thiopental between 3 and 5 mg/kg (slow i.v.)
Brain hypothermia therapy
This protocol applies to infants weighing ≥ 7.5 kg, and aged ≥ 6 months.

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Introductory period
1. Status epilepticus/acute encephalopathy admission: ICU (request for admission), contact brainwave dept/radiology (brain andchest CT)
2. Check vital signs, establish a peripheral line
3. Establish central venous line: establish double/triple lumen catheter + arterial line
4. Fluid infusion between 80 and 100 mL/kg/day: under whole-body management, fluid control must not be reduced more thannecessary to maintain blood pressure and cerebral circulation. Blood pressure is evaluated using an arterial pressure monitor.
Maintenance fluids comprise an acetic acid preparation maintenance fluid and a lactic acid preparation.
Vitamins are administered. When theophylline is administered, vitamin B6 is measured (light-shielding blood collection tube: administer vitamin B6 for theophylline-related seizures. Take care not to induce cardiac arrest by sudden administration of B6).
5. Management of blood count, electrolytes, blood sugars, albumin, and clotting value. Ferritin, IL-2R, β2MG, procalcitonin, immune globulin, etc. submitted.
6. Mannitol 3–5 mL/kg × 4–6 times/day (administered over 1 h).
7. Harvest spinal fluid (after the first administration of mannitol). General spinal fluid + various cytokines (IL-6, IL-1β, TNF-α), Tauprotein, submitted. Freeze and store the remaining fluid at −80 °C.
8. If possible time-wise, implement MRI (DWI/ADC-map).
9. Intratracheal intubation (if difficult, use muscle relaxant or inhalation anesthetic)
10. Artificial ventilation: PCO2 at 35 to 40 mmHg (do not over-ventilate). PEEP kept slightly low considering brain hypertension.
Raise head by 10°. If brain hypertension occurs: request placement of cerebral pressure monitor by a neurosurgeon.
11. Steroid pulse therapy: methylprednisolone 30 mg/kg for >2 h for 3 days, during which heparin or fragmin therapy is continued≥ APTT 1.5.
12. Administer famotidine 0.5 mg/kg twice, or omeprazole.
13. Brain hypothermia therapy: use a whole-body blanket-cooling method to induce target body temperature (direct intestine/bladder temperature of 34.0 to 35.0 °C) within 6 h of onset. If necessary, cool the head or wash the stomach with a normal saline solution while taking care not to cause electrolyte abnormalities, or use chilled fluid infusion.
14. Anti-seizure medication: sodium thiopental, 5–10 mg/kg/h (if this cannot be used, consider midazolam, 0.3 to 0.9 mg/kg/h).
15. Sedation depth should be confirmed by portable electroencephalograph/paperless electroencephalograph (Makin2) as reaching
suppression burst within 6 h of beginning therapy.
Cooling period
16. Target temperature to be maintained for 48 h (or a maximum of 72 h). Confirm the BIS monitor value at suppression burst (aimfor 40 or below) and adjust the sodium thiopental dose administered based on the BIS value as appropriate. Cases achieving a positive sedation depth should have their sodium thiopental dose reduced prior to rewarming at a BIS value between 60 and 70 and atbody temperature of 35.0 °C.
Caution: If spikes remain with suppression bursts, consider complete suppression (pupils will constrict to mydriasis, and response
to light is lost: BIS value of 20 or lower).
17. Use INVOSTM at an appropriate time to check oxygen saturation at the left and right front scalp to evaluate brain circulation.
18. Blood pressure maintenance: appropriate dose of dopamine hydrochloride (5 µg/kg/min = 0.3 mg/kg/h = 0.015 mL/kg/h), manage electrolyte abnormalities and blood glucose. Heart rate will fall to bradycardia with falling body temperature.
19. Administer antibacterial as appropriate. In applicable conditions, cerebroprotective edaravone, sivelestat Na as a neutrophil
elastase inhibitor, and acyclovir.
Rewarming period
20. Rewarming is implemented at a pace of 0.5 °C per 12 h. Care should be taken to avoid pneumonia in linewith increased sputum secretions. Aim to remove the patient from artificial respiration on the fifth to seventh day. For cases inwhich laryngitis is likely, intravenous dexamethasone or epinephrine should be administered prior to removal of the tube.
21. For cases in which critical complications are envisaged, TRH therapy should be initiated at an early stage.
22. Including rehabilitation, aim to discharge the patient one month after onset.
23. Prior to discharge, evaluate brain waves, implement neuroradiological images/nuclear medicine tests and assess development.
Where necessary, anti-seizure mediation should be periodically administered for preventative purposes.
Table 5. Acute Encephalopathy in Infancy and Childhood.
Subtype Description
Incidence in Japan
Clinical Manifestations
Diagnosis
Treatment
ADEM [2,77]
An immune-mediated inBased on clinical features and Combination of intravenous cortiflammatory demyelinating
Polyfocal neurologic deficits findings on neuroimaging and la- costeroids and IVIG, (2) cyclo0.40 per 100,000
condition that predomiand is typically self-limiting. boratory investigations. ADEM sporin, (3) cyclophosphamide, or (4)nately affects the whitelacks a specific identified biologi- plasma exchange/plasmapheresis

J. Clin. Med. 2022, 11, 5921

matter of the brain and spinal cord.

14 of 21cal marker rendering a reliable laboratory diagnosis, long-term follow-up is important as there are
instances where an illness initially diagnosed as ADEM is ultimately replaced with a diagnosis
of MS

AESD [78,79]
A prolonged febrile seizure is
the first symptom. Brief seizures may be present in mildcases. Involuntary movements may act prognostic factor
AESD prediction score by
Tada et al. [80]Level of consciousness 12–24
h after seizure
GCS 14–13 (JCS
1–3) and GCS 12–9 (JCS 10–30) were scored 2, GCS 8–3
Cyclosporine, methylprednisolone(JCS 100–300)
pulse therapy, intravenous immuscored 3, age below 1.5 years
noglobulin, and other therapies that
Biphasic seizure and al- Incidence is higherscored 1, duration of ES
High signal
suppress inflammatory cytokines.
tered consciousness during in Asian countries,
above 40 min
intensity on DWI for the anterior TTM may be considered but need tothe acute phase, followed especially Japan, scored 1, mechanical intubaarea
differentiate AESD from FSE at theby restricted diffusion inand the genetic tion scored 1, AST on admis- Severe acidosis is the most com- early acute stage.
bilateral cerebral parenbackground maysion above
mon lab finding.
TTM during the prolonged convulchyma on MRI during the be a possible higher 40 mEq/l scored 1, blood glu- EEG may usefully differentiate sive phase, prior to the diagnosis of
subacute stage
incidencecose on admission above 200
AESD from PFS
AESD, could prevent the patient
mg/dl scoredfrom developing a second phase of
1, and Cr on admission above
convulsions and thus prevent the
0.35 scored 1
patient from developing AESD.
AESD prediction score by
Yokochi et al. [81]pH < 7.014 1 point
ALT ≥ 28 2 points
Glu ≥ 228 2 points
Time to awakening ≥ 11 h 2
pointsCre ≥ 0.3 1 point
Ammonia ≥ 125 2 points
4 points or more: High-risk
group for AESD for bothscores [77,78]
AEFCSEEEG findings showed slow waves
predominantly on the right hemisphere and a high signal in theDevelops with prolonged
subcortical white matter as with
Pyrexia followed by partial
febrile convulsion, folthe cerebral lobar distribution
seizureslowed by mild unconpattern. Acute infantile encephaIncidence is higher
and subsequently
sciousness, then subselopathy predominantly affects thein Asian countries,
hemiconvulsions.
TTM
quently provoking a clusfrontal lobes (AIEF).
especially Japan Transient neurological sympter of convulsions (late seiThermolabile genotype of CPT II
toms and Intellectual disabilzures) with a comatose
variations consisting of three sinity, attention deficit
state.
gle nucleotide polymorphisms inexons 4 (1055T > G/F352C and
1102G > A/V368I) and 5 (1939A >G/M647V)
ANE [82–84]
Many cases have
Immunomodulatory therapy such
Multiple bilateral brain leDramatic neurological defi- Associated thalamic, putamina,
been reported inas corticosteroids or intravenous
sions, primarily involving
cits/symptoms.
cerebral, cerebellar, and brainAsia as well as in a
immunoglobulin is often used.

J. Clin. Med. 2022, 11, 5921

15 of 21the thalami, but also in- number of Western Neurological deficits may be stem abnormalities are hypo- TTM has also been used. TTM isvolving the putamina, incountries.
preceded by a viral prodense on CT. Bilateral symmet- critical to the outcome of children
ternal and external capdrome.
rical thalamic involvement. Ab- with ANE, especially if started
sules, cerebellar white matnormal signals on MRI are hy- within 12 h of onset.
ter, and the brainstem tegpointense on T1 and hyperintense
mentum.
on T2. Restricted diffusion of theinvolved regions.
ANE of childhood can be distinguished from ADEM clinically by
the onset of encephalitic features
shortly after the prodromal illness, whereas in ADEM, they
may take 1 to 2 weeks to develop.
MERS [85–87]
serum VCA IgG (+), EBNA-1 IgG
An infection-associated en(−), EBV IgM (−), and inflammacephalitis/encephalopathy
tion in the analysis of CSF
syndrome that is predomiCranial MRI+C showed that thenately caused by a virus or
blood vessels on the surface ofa variety of pathological
Supplementation, steroids andthe brain were increasing andconditions, including MISIVIG, acyclovir, and prescribed oral
Fever, headache, neck rigidthickening, and diffuse slow
C. There have been scatsodium, but some cases improveity, and Kerning sign (+)
waves were detected on the EEG
tered reports of MERS aswith the natural course of the disThe high-signal intensity in thesociated with AFBN andease.
splenium of the corpus callosum
Kawasaki disease. AFBN +on T2W
MERS, a urinary tract inSplenial hyperintensity as afection in children, is par“boomerang sign” on DWI andticularly noteworthy
reduced diffusion on ADC
PRES [56]A clinical–radiological syndrome characterized by aVisual disturbance can varyheadache, seizures, alteredfrom blurred vision and ho- The bilateral occipital, parietal,
mental status, visual loss
monymous hemianopsia tofrontal cortex, and subcortical
Intravenous fluids, antibiotics, anand white matter vasocortical blindness. Altered white matter T2/fluid-attenuatedtiepileptics
genic edema affecting theconsciousness may vary from inversion recovery hyperintensiposterior occipital and pamild confusion or agitation toties
rietal lobes of the braincoma.
predominantly.
FIRES [88,89]
A subtype of NORSE that
Benzodiazepines,
requires a prior febrile inFocal seizures with impaired
Barbiturates,
EEG
fection between 2 weeks
awareness and bilateral
Ketamine,
Very rare, affects
Leptomeningeal enhancement, biand 24 h before the onset
tonic–clonic seizures.
Lidocaine,
approximately 1 in alateral claustrum hyperintensityof refractory status epilepSeizures progress to continuMagnesium,
million children
or progressive mesial temporalticus with or without feverous or nearly continuous seiKetogenic diet,lobe atrophy on MRI.
at the onset of status epizures.
Cannabidiol
lepticus.

ADEM: Acute disseminated encephalomyelitis; ANE: Acute necrotizing encephalopathy; AEFCSE:
Acute encephalopathy with febrile convulsive status epilepticus; AESD: Acute encephalopathy withbiphasic seizures and late reduced diffusion; EEG: Electroencephalogram; CSF: Cerebrospinal fluid;
DWI: Diffusion-weighted imaging; FIRES: Febrile infection-related epilepsy syndrome; FLAIR:
Fluid attenuated inversion recovery; MERS: Mild encephalitis/encephalopathy with a reversible
splenial lesion; MRI: Magnetic resonance imaging; PRES: Posterior reversible leukoencephalopathy
syndrome; TTM: Targeted temperature management.

6. Acute Encephalopathy in the COVID-19 Era
Neurologic issues are common in COVID-19 patients who are hospitalized. Approximately 80% of hospitalized patients will experience neurologic symptoms at some point
during their illness. According to recent studies, COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) can cause cerebrovascular events as well as
abnormal eye movements [90–92]. Neurological manifestations in patients with MIS-C

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were found in 27.1% in a recent study; 27% developed headaches, 17.1% developed meningism/meningitis, and 7.6% developed encephalopathy. Other uncommon neurologicalmanifestations of MIS-C include anosmia, seizures, cerebellar ataxia, global proximal
muscle weakness, and bulbar palsy. Neuroimaging revealed signal changes in the corpus
callosum’s splenium in MIS-C patients with neurological features [93]. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV2 mediated NP-COVID-19 [94]. Electroencephalography revealed slow-wave patterns andnerve conduction studies, while electromyography revealed mild myopathic and neuropathic changes. Children with COVID-19 infection have been diagnosed with encephalitis, ANE, acute disseminated encephalomyelitis, cytotoxic lesion of the callosal splenium,
posterior reversible encephalopathy syndrome, and other neurological illnesses [95]. Two
methods have been postulated to explain how SARS-CoV-2 could cause neurologicaldamage: a direct viral infection of the nervous system via ACE2 receptors and inflammatory harm caused by cytokine production [96]; in the latter instance, neurological symptoms could be a part of the overall picture. Acute encephalopathy research is still in its
early stages. There have been case reports of anti-NMDA receptor encephalitis and ADEM
in COVID-19 patients with severe psychotic symptoms [97–99]. Despite the absence ofsignificant respiratory symptoms, neurological manifestations of COVID-19 infection are
possible. Abnormal signals in the vast areas of the corpus callosum on MRI images havebeen reported in the case of a 5-year-old girl positive for COVID-19 [100]. Atypical manifestations in children, such as altered mental status and seizures as well as a hyperinflammatory shock with multiorgan dysfunction, should be noted by pediatricians. COVID-19
testing may be important in children with encephalopathy, as infected patients require
extra measures to prevent further spread.
7. How to Evaluate Neurological Prognosis
In healthy developing infants, acute encephalopathy appears suddenly. Many cases
necessitate rehabilitation training following a period of acute pediatric neurology or intensive care unit treatment. There have also been numerous cases of serious neurologicalsequelae. The question then becomes how long after the onset of the disease should aneurological prognosis be made and in what manner. According to recent reports, thetiming of the assessment of neurological prognosis varies depending on the study design[66,74,79,101]. The Pediatric Cerebral Performance Category (PCPC) scale is the most commonly used scale for assessing disability in pediatric sequelae. The Pediatric Overall Performance Category (POPC) scale, the Wechsler Intelligence Test, and the Tanaka–Binay
test are also commonly used. The PCPC scale is shown below (Table 6).
Table 6. PCPC Scale [102].

Score
1
2
3
4
5
6

Category
NormalDescription
At an age-appropriate level; school-age children attend regular school
Conscious, alert, able to interact at age-appropriate level; regular school, but grades
Mild disability
perhaps not age-appropriate, possibility of mild neurologic deficit
Conscious, age-appropriate independent activities of daily life; special education
Moderate disability
classroom and/or learning deficit present
Severe disability
Conscious, dependent on others for daily support because of impaired brain function
Any degree of coma, unaware, even if awake in appearance, without interaction with
Coma or vegetative state the environment; no evidence of cortex function; possibility for some reflexive response, spontaneous eye-opening, sleep–wake cycles
Brain death/death
Brain death, death
PCPC: Pediatric Cerebral Performance Category.

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8. Conclusions
This review contains a plethora of current information on pediatric acute encephalopathies and sincerely thanks the efforts of the many outstanding researchers who havedevoted their passion to the study and elucidation of pediatric acute encephalopathy.
Author Contributions: The following authors were involved in the preparation of this paper, conceptualization, methodology, writing—original draft preparation, and writing—review and editing,
G.I.; supervision, S.K. and S.Y. All authors have read and agreed to the published version of themanuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors would like to thank the staff of the Department of Pediatrics andICU of Dokkyo Medical University, as well as many pediatric patients and their guardians, for theircooperation in the treatment of pediatric acute encephalopathy. The authors would also like tothank SreeHarsha Bantu for medical writing assistance and Raghuraj Puthige and Magi Kumar for
editorial assistance from Enago LifeSciences, India in accordance with good publication practices(GPP3) guidelines.
Conflicts of Interest: The authors declare no conflict of interest.

References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

11.

12.
13.
14.

15.

Slooter, A.J.C.; Otte, W.M.; Devlin, J.W.; et al. Updated nomenclature of delirium and acute encephalopathy: Statement of ten
So-cieties. Intensive Care Med. 2020, 46, 1020–1022.
Mizuguchi, M.; Ichiyama, T.; Imataka, G.; et al. Guidelines for the diagnosis and treatment of acute encephalopathy in childhood. Brain Dev. 2021, 43, 2–31. https://doi.org/10.1016/j.braindev.2020.08.001.
Hoshino, A.; Saitoh, M.; Oka, A.; et al. Epidemiology of acute encephalopathy in Japan, with emphasis on the association ofviruses and syndromes. Brain Dev. 2012, 34, 337–343. https://doi.org/10.1016/j.braindev.2011.07.012.
Kasai, M.; Shibata, A.; Hoshino, A.; et al. Epidemiological changes of acute encephalopathy in Japan based on national surveillance for 2014–2017. Brain Dev. 2020, 42, 508–514.
Mizuguchi, M.; Yamanouchi, H.; Ichiyama, T.; et al. Acute encephalopathy associated with influenza and other viral infections.
Acta Neurol. Scand. 2007, 115, 45–56. https://doi.org/10.1111/j.1600-0404.2007.00809.x.
Shibata, A.; Kasai, M.; Hoshino, A.; et al. Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factorof overall acute encephalopathy. Brain Dev. 2019, 41, 862–869.
Shinohara, M.; Saitoh, M.; Nishizawa, D.; et al. ADORA2A polymorphism predisposes children to encephalopathy with febrile
status epilepticus. Neurology 2013, 80, 1571–1576. https://doi.org/10.1212/wnl.0b013e31828f18d8.
Shibata, A.; Kasai, M.; Terashima, H.; et al. Case-control association study of rare nonsynonymous variants of SCN1A andKCNQ2 in acute encephalopathywith biphasic seizures and late reduced diffusion. J. Neurol. Sci. 2020, 414, 116808.
Kubota, M.; Chida, J.; Hoshino, H.; et al. Thermolabile CPT II variants and low blood ATP levels are closely related to severityof acute encephalopathy in Japanese children. Brain Dev. 2012, 34, 20–27. https://doi.org/10.1016/j.braindev.2010.12.012.
Chen, Y.; Mizuguchi, H.; Yao, D.; Ide, M.; Kuroda, Y.; Shigematsu, Y.; Yamaguchi, S.; Kinoshita, M.; Kido, H. Thermolabile
phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy.
FEBS Lett. 2005, 579, 2040–2044. https://doi.org/10.1016/j.febslet.2005.02.050.
Saitoh, M.; Shinohara, M.; Ishii, A.; Ihara, Y.; Hirose, S.; Shiomi, M.; Kawawaki, H.; Kubota, M.; Yamagata, T.; Miyamoto, A.; etal. Clinical and genetic features of acute encephalopathy in children taking theophylline. Brain Dev. 2015, 37, 463–470.
https://doi.org/10.1016/j.braindev.2014.07.010.
Saitoh, M.; Ishii, A.; Ihara, Y.; et al. Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures. Epilepsy Res. 2015, 117, 1–6.
Fujita, Y.; Imataka, G.; Sakuma, H.; et al. Multiple encephalopathy syndrome: A case of a novel radiological subtype of acuteencephalopathy in childhood. Eur. Rev. Med. Pharmacol. Sci. 2022, 1, 11720.
Hoshino, A.; Saitoh, M.; Miyagawa, T.; Kubota, M.; Takanashi, J.-I.; Miyamoto, A.; Tokunaga, K.; Oka, A.; Mizuguchi, M. Specific HLA genotypes confer susceptibility to acute necrotizing encephalopathy. Genes Immun. 2016, 17, 367–369.
https://doi.org/10.1038/gene.2016.32.
Mohseni-Bod, H.; Drake, J.; Kukreti, V. Management of raised intracranial pressure in children with traumatic brain injury. J.
Pediatr. Neurosci. 2014, 9, 207–215. https://doi.org/10.4103/1817-1745.147572.

J. Clin. Med. 2022, 11, 5921

16.
17.
18.

19.
20.
21.

22.
23.

24.

25.
26.

27.
28.
29.
30.

31.

32.
33.
34.
35.

36.

37.

38.
39.

18 of 21

Lee, S.; Sanefuji, M.; Hara, T.; et al. Clinical and MRI characteristic of acute encephalopathy in children in congenital adrenal
hyperplasia. J. Nurol. Sci. 2011, 306, 91–93.
Covanis, A. Epileptic encephalopathies (including severe epilepsy syndromes). Epilepsia 2012, 53, 114–126.
https://doi.org/10.1111/j.1528-1167.2012.03621.x.
Scheffer, I.E.; Berkovic, S.; Capovilla, G.; Connolly, M.B.; French, J.; Guilhoto, L.; Hirsch, E.; Jain, S.; Mathern, G.W.; Moshe, S.;et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia
2017, 58, 512–521. https://doi.org/10.1111/epi.13709.
Markand, O.N. Lennox-Gastaut Syndrome (Childhood Epileptic Encephalopathy). J. Clin. Neurophysiol. 2003, 20, 426–441.
https://doi.org/10.1097/00004691-200311000-00005.
Hwang, S.-K.; Kwon, S. Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes. Korean J.
Pediatr. 2015, 58, 407–414. https://doi.org/10.3345/kjp.2015.58.11.407.
Okumura, A.; Uematsu, M.; Imataka, G.; Tanaka, M.; Okanishi, T.; Kubota, T.; Sudo, A.; Tohyama, J.; Tsuji, M.; Ohmori, I.; et al.
Acute encephalopathy in children with Dravet syndrome. Epilepsia 2012, 53, 79–86. https://doi.org/10.1111/j.15281167.2011.03311.x.
Imataka, G.; Wake, K.; Suzuki, M.; Yamanouchi, H.; Arisaka, O. Acute encephalopathy associated with hemolytic uremic syndrome caused by Escherichia coli O157: H7 and rotavirus infection. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 1842–1844.
Imataka, G.; Ishii, J.; Ando, Y.; Yoshihara, S.; Takagi, Y.; Nitta, A.; Arisaka, O.; Yoshihara, S. Long-term survival of a patientwith acute neonatal-onset metabolic encephalopathy with carbamoyl phosphate synthetase 1 deficiency. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 10051–10053.
Wake, K.; Imataka, G.; Ohnishi, T.; Kikuchi, J.; Hoshiyama, E.; Ono, K.; Yoshihara, S. A Case-Study of a Child with Reversible
Posterior Leukoencephalopathy Syndrome (RPLS) Associated with Severe Burns throughout the Body. Iran. J. Public Health2020, 49, 1390–1391. https://doi.org/10.18502/ijph.v49i7.3600.
Imataka, G.; Wake, K.; Yoshihara, S. A girl with acute encephalitis followed by acute cerebellitis/cerebellopathy. Eur. Rev. Med.
Pharmacol. Sci. 2020, 24, 10708–10711.
Miyake, N.; Fukai, R.; Ohba, C.; Chihara, T.; Miura, M.; Shimizu, H.; Kakita, A.; Imagawa, E.; Shiina, M.; Ogata, K.; et al. Biallelic
TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am. J. Hum. Genet. 2016, 99, 950–961.
https://doi.org/10.1016/j.ajhg.2016.08.005.
Abe, Y.; Sakai, T.; Okumura, A.; et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev. 2016, 38, 638–647.
National Institute of Neurological Disorders and Stroke. Encephalopathy Information Page. Available online:
https://www.ninds.nih.gov/Disorders/All-Disorders/Encephalopathy-Information-Page. (accessed on 27 May 2022).
Takahashi, A.; Kamei, E.; Sato, Y.; et al. A. Infant with right hemiplegia due to acute encephalopathy with biphasic seizures andlate reduced diffusion (AESD): A case report. Medicine 2021, 100, e25468.
Venkatesan, A.; Tunkel, A.R.; Bloch, K.C.; Lauring, A.S.; Sejvar, J.; Bitnun, A.; Stahl, J.-P.; Mailles, A.; Drebot, M.; Rupprecht,
C.E.; et al. Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International
Encephalitis Consortium. Clin. Infect. Dis. 2013, 57, 1114–1128. https://doi.org/10.1093/cid/cit458.
Britton, P.N.; Eastwood, K.; Paterson, B.; Durrheim, D.N.; Dale, R.C.; Cheng, A.; Kenedi, C.; Brew, B.; Burrow, J.; Nagree, Y.; etal. Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New
Zealand. Intern. Med. J. 2015, 45, 563–576. https://doi.org/10.1111/imj.12749.
Lim, J.; Kwek, S.; How, C.; Chan, W. A clinical approach to encephalopathy in children. Singap. Med J. 2020, 61, 626–632.
https://doi.org/10.11622/smedj.2020176.
Erkkinen, M.G.; Berkowitz, A.L. A Clinical Approach to Diagnosing Encephalopathy. Am. J. Med. 2019, 132, 1142–1147.
https://doi.org/10.1016/j.amjmed.2019.07.001.
Barbosa-Silva, M.C.; Lima, M.N.; Battaglini, D.; Robba, C.; Pelosi, P.; Rocco, P.R.M.; Maron-Gutierrez, T. Infectious diseaseassociated encephalopathies. Crit. Care 2021, 25, 236. https://doi.org/10.1186/s13054-021-03659-6.
Mohammad, S.S.; Soe, S.M.; Pillai, S.C.; Nosadini, M.; Barnes, E.H.; Gill, D.; Dale, R.C. Etiological associations and outcome
predictors of acute electroencephalography in childhood encephalitis. Clin. Neurophysiol. 2016, 127, 3217–3224.
https://doi.org/10.1016/j.clinph.2016.07.014.
Maegaki, Y.; Kondo, A.; Okamoto, R.; Inoue, T.; Konishi, K.; Hayashi, A.; Tsuji, Y.; Fujii, S.; Ohno, K. Clinical Characteristics ofAcute Encephalopathy of Obscure Origin: A Biphasic Clinical Course Is a Common Feature. Neuropediatrics 2006, 37, 269–277.
https://doi.org/10.1055/s-2006-955928.
Okumura, A.; Suzuki, M.; Kidokoro, H.; Komatsu, M.; Shono, T.; Hayakawa, F.; Shimizu, T. The spectrum of acute encephalopathy with reduced diffusion in the unilateral hemisphere. Eur. J. Paediatr. Neurol. 2009, 13, 154–159.
https://doi.org/10.1016/j.ejpn.2008.03.003.
Hosoya, M.; Ushiku, H.; Arakawa, H.; Morikawa, A. Low-voltage activity in EEG during acute phase of encephalitis predicts
unfavorable neurological outcome. Brain Dev. 2002, 24, 161–165. https://doi.org/10.1016/s0387-7604(02)00011-6.
Okumura, A.; Komatsu, M.; Abe, S.; Kitamura, T.; Matsui, K.; Ikeno, M.; Shimizu, T. Amplitude-integrated electroencephalography in patients with acute encephalopathy with refractory, repetitive partial seizures. Brain Dev. 2011, 33, 77–82.
https://doi.org/10.1016/j.braindev.2009.12.009.

J. Clin. Med. 2022, 11, 5921

40.
41.

42.
43.
44.
45.

46.
47.
48.
49.

50.
51.

52.
53.
54.
55.
56.

57.

58.
59.

60.
61.
62.

63.
64.
65.

19 of 21

Accolla, E.A.; Kaplan, P.W.; Maeder-Ingvar, M.; Jukopila, S.; Rossetti, A. Clinical correlates of frontal intermittent rhythmic
delta activity (FIRDA). Clin. Neurophysiol. 2011, 122, 27–31. https://doi.org/10.1016/j.clinph.2010.06.005.
Ohno, A.; Okumura, A.; Fukasawa, T.; Nakata, T.; Suzuki, M.; Tanaka, M.; Okaia, Y.; Ito, Y.; Yamamoto, H.; Tsuji, T.; et al. Acuteencephalopathy with biphasic seizures and late reduced diffusion: Predictive EEG findings. Brain Dev. 2022, 44, 221–228.
https://doi.org/10.1016/j.braindev.2021.11.003.
Solomon, T.; Hart, I.J.; Beeching, N.J. Viral encephalitis: A clinician's guide. Pract. Neurol. 2007, 7, 288–305.
https://doi.org/10.1136/jnnp.2007.129098.
Kneen, R.; Solomon, T.; Appleton, R. The role of lumbar puncture in children with suspected central nervous system infection.
BMC Pediatr. 2002, 2, 8. https://doi.org/10.1186/1471-2431-2-8.
Neeb, L.; Hoekstra, J.; Endres, M.; et al. Spectrum of cerebral spinal fluid findings in patients with posterior reversible encephalopathy syndrome. J. Neurol. 2016, 263, 30–34.
Okada, T.; Fujita, Y.; Imataka, G.; Takase, N.; Tada, H.; Sakuma, H.; Takanashi, J.-I. Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated withacute focal bacterial nephritis. Brain Dev. 2022, 44, 30–35. https://doi.org/10.1016/j.braindev.2021.07.008.
Imataka, G.; Yoshihara, S. Immature ovarian teratoma with anti-NMDA-receptor encephalitis in a 13-year-old Japanese female
patient. Med. J. Malays. 2021, 76, 436–437.
Mizuguchi, M. Influenza encephalopathy and related neuropsychiatric syndromes. Influ. Other Respir. Viruses 2013, 7, 67–71.
https://doi.org/10.1111/irv.12177.
Takanashi, J.; Tada, H.; Terada, H.; et al. Excitotoxicity in acute encephalopathy with biphasic seizures and late reduced diffusion. Am. J. Neuroradiol. 2009, 30, 132–135.
Takanashi, J.; Oba, H.; Barkovich, A.J.; Tada, H.; Tanabe, Y.; Yamanouchi, H.; Fujimoto, S.; Kato, M.; Kawatani, M.; Sudo, A.; etal. Diffusion MRI abnormalities after prolonged febrile seizures with encephalopathy. Neurology 2006, 66, 1304–1309.
https://doi.org/10.1212/01.wnl.0000210487.36667.a5.
Takanashi, J.-I.; Mizuguchi, M.; Terai, M.; Barkovich, A.J. Disrupted glutamate-glutamine cycle in acute encephalopathy withbiphasic seizures and late reduced diffusion. Neuroradiology 2015, 57, 1163–1168. https://doi.org/10.1007/s00234-015-1573-x.
Yamanouchi, H.; Mizuguchi, M. Acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF): A novel clinical category and its tentative diagnostic criteria. Epilepsy Res. 2006, 70, S263–S268. https://doi.org/10.1016/j.eplepsyres.2005.11.027.
Mizuguchi, M.; Hayashi, M.; Nakano, I.; et al. Concentric structure of thalamic lesions in acute necrotizing encephalopathy
Neuroradiology 2002, 44, 489–493.
Okumura, A.; Abe, S.; Kidokoro, H.; Mizuguchi, M. Acute necrotizing encephalopathy: A comparison between influenza andnon-influenza cases. Microbiol. Immunol. 2009, 53, 277–280. https://doi.org/10.1111/j.1348-0421.2009.00124.x.
Takanashi, J.; Barkovich, A.; Shiihara, T.; Tada, H.; Kawatani, M.; Tsukahara, H.; Kikuchi, M.; Maeda, M. Widening Spectrumof a Reversible Splenial Lesion with Transiently Reduced Diffusion. Am. J. Neuroradiol. 2006, 27, 836–838.
Imataka, G.; Yoshihara, S. Typical MRI Imaging with Clinically Mild Encephalitis/Encephalopathy of a Reversible Splenial Lesion (MERS) Caused by Influenza A Virus. Iran. J. Public Health 2020, 49, 191–192. https://doi.org/10.18502/ijph.v49i1.3069.
Anderson, R.-C.; Patel, V.; Sheikh-Bahaei, N.; Liu, C.S.J.; Rajamohan, A.G.; Shiroishi, M.S.; Kim, P.E.; Go, J.L.; Lerner, A.;
Acharya, J. Posterior Reversible Encephalopathy Syndrome (PRES): Pathophysiology and Neuro-Imaging. Front. Neurol. 2020,
11, 463. https://doi.org/10.3389/fneur.2020.00463.
Tsukahara, H.; Fujii, Y.; Matsubara, K.; Yamada, M.; Nagaoka, Y.; Saito, Y.; Yashiro, M.; Tsuge, M.; Goto, S.; Kitamura, T.; et al.
Prognostic value of brain injury biomarkers in acute encephalitis/encephalopathy. Pediatr. Int. 2013, 55, 461–464.
https://doi.org/10.1111/ped.12094.
Kasai, M.; Omae, Y.; Kawai, Y.; et al. GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion. Sci. Rep. 2022, 12, 1332.
Okumura, A.; Mizuguchi, M.; Kidokoro, H.; Tanaka, M.; Abe, S.; Hosoya, M.; Aiba, H.; Maegaki, Y.; Yamamoto, H.; Tanabe, T.;et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev.
2009, 31, 221–227. https://doi.org/10.1016/j.braindev.2008.03.005.
Esen, F.; Ozcan, P.E.; Tuzun, E.; Boone, M.D. Mechanisms of action of intravenous immunoglobulin in septic encephalopathy.
Rev. Neurosci. 2018, 29, 417–423. https://doi.org/10.1515/revneuro-2017-0065.
Shima, T.; Okumura, A.; Kurahashi, H.; Numoto, S.; Abe, S.; Ikeno, M.; Shimizu, T. A nationwide survey of norovirus-associatedencephalitis/encephalopathy in Japan. Brain Dev. 2019, 41, 263–270. https://doi.org/10.1016/j.braindev.2018.11.001.
Tanuma, N.; Miyata, R.; Nakajima, K.; Okumura, A.; Kubota, M.; Hamano, S.-I.; Hayashi, M. Changes in Cerebrospinal Fluid
Biomarkers in Human Herpesvirus-6-Associated Acute Encephalopathy/Febrile Seizures. Mediat. Inflamm. 2014, 2014, 564091.
https://doi.org/10.1155/2014/564091.
Gwer, S.; Gatakaa, H.; Mwai, L.; Idro, R.; Newton, C.R. The role for osmotic agents in children with acute encephalopathies: A
systematic review. BMC Pediatr. 2010, 10, 23. https://doi.org/10.1186/1471-2431-10-23.
Nishiyama, M.; Tanaka, T.; Fujita, K.; Maruyama, A.; Nagase, H. Targeted temperature management of acute encephalopathy
without AST elevation. Brain Dev. 2015, 37, 328–333. https://doi.org/10.1016/j.braindev.2014.06.005.
Hayakawa, I.; Okubo, Y.; Nariai, H.; Michihata, N.; Matsui, H.; Fushimi, K.; Yasunaga, H. Recent treatment patterns and variations for pediatric acute encephalopathy in Japan. Brain Dev. 2020, 42, 48–55. https://doi.org/10.1016/j.braindev.2019.08.007.

J. Clin. Med. 2022, 11, 5921

66.

67.
68.

69.
70.
71.
72.

73.
74.

75.
76.
77.
78.

79.
80.

81.

82.
83.

84.
85.

86.
87.

88.
89.
90.

20 of 21Ishida, Y.; Nishiyama, M.; Yamaguchi, H.; Tomioka, K.; Takeda, H.; Tokumoto, S.; Toyoshima, D.; Maruyama, A.; Seino, Y.;
Aoki, K.; et al. Early steroid pulse therapy for children with suspected acute encephalopathy. Medicine 2021, 100, e26660.
https://doi.org/10.1097/md.0000000000026660.
Neal, E.G.; Chaffe, H.M.; Schwartz, R.H.; et al. A randomized controlled trial of classical and medium chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2008, 49, 9.
Brophy, G.M.; Bell, R.; Claassen, J.; Alldredge, B.; Bleck, T.P.; Glauser, T.; Laroche, S.M.; Riviello, J.J.J.; Shutter, L.; Sperling,
M.R.; et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit. Care 2012, 7, 3–23.
https://doi.org/10.1007/s12028-012-9695-z.
Cereda, C.; Berger, M.M.; Rossetti, A.O. Bowel Ischemia: A Rare Complication of Thiopental Treatment for Status Epilepticus.
Neurocritical Care 2009, 10, 355–358. https://doi.org/10.1007/s12028-008-9168-6.
Nakagawa, T.; Fujita, K.; Saji, Y.; et al. Induced hypothermia normothermia with general anesthesia prevents neurological damage in febrile refractory status epilepticus in children. No Hattatsu 2011, 43, 459–463.
Imataka, G.; Osamu, A. Brain hypothermia therapy for childhood acute encephalopathy based on clinical evidence. Exp. Ther.
Med. 2015, 10, 1624–1626.
Imataka, G.; Tsuboi, Y.; Kano, Y.; Ogino, K.; Tsuchioka, T.; Ohnishi, T.; Kaji, Y.; Wake, K.; Ichikawa, G.; Suzumura, H.; et al.
Treatment with mild brain hypothermia for cardiopulmonary resuscitation after myoclonic seizures in infant with robertsonian
type of trisomy 13. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 2852–2855.
Imataka, G.; Wake, K.; Yamanouchi, H.; Ono, K.; Arisaka, O. Brain hypothermia therapy for status epilepticus in childhood.
Eur. Rev. Med Pharmacol. Sci. 2014, 18, 1883–1888.
Hoshide, M.; Yasudo, H.; Inoue, H.; Matsushige, T.; Sakakibara, A.; Nawata, Y.; Hidaka, I.; Kobayashi, H.; Kohno, F.; Ichiyama,T.; et al. Efficacy of hypothermia therapy in patients with acute encephalopathy with biphasic seizures and late reduced diffusion. Brain Dev. 2020, 42, 515–522. https://doi.org/10.1016/j.braindev.2020.03.007.
Fujita, Y.; Imataka, G.; Kikuchi, J.; et al. Successful mild brain hypothermia therapy followed by targeted temperature management for pediatric hemorrhagic shock and encephalopathy syndrome. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 3002–3006.
Krishnan, V.; Kumar, V.; Shankaran, S.; Thayyil, S. Rise and Fall of Therapeutic Hypothermia in Low-Resource Settings: Lessons
from the HELIX Trial. Indian J. Pediatr. 2021, Epub ahead of print; PMID: 34297336. https://doi.org/10.1007/s12098-021-03861-y.
Imataka, G.; Arisaka, O. An infant with steroid-refractory cytomegalovirus-associated ADEM who responded to immuno-globulin therapy. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 2148–2151.
Yamaguchi, H.; Nishiyama, M.; Tokumoto, S.; Ishida, Y.; Tomioka, K.; Aoki, K.; Seino, Y.; Toyoshima, D.; Takeda, H.; Kurosawa,
H.; et al. Detailed characteristics of acute encephalopathy with biphasic seizures and late reduced diffusion: 18-year data of asingle-center consecutive cohort. J. Neurol. Sci. 2020, 411, 116684. https://doi.org/10.1016/j.jns.2020.116684.
Watanabe, Y.; Motoi, H.; Oyama, Y.; et al. Cyclosporine for acute encephalopathy with biphasic seizures and late reduced diffusion. Pediatr. Int. 2014, 56, 577–582.
Tada, H.; Takanashi, J.-I.; Okuno, H.; Kubota, M.; Yamagata, T.; Kawano, G.; Shiihara, T.; Hamano, S.-I.; Hirose, S.; Hayashi, T.;et al. Predictive score for early diagnosis of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). J.
Neurol. Sci. 2015, 358, 62–65. https://doi.org/10.1016/j.jns.2015.08.016.
Yokochi, T.; Takeuchi, T.; Mukai, J.; Akita, Y.; Nagai, K.; Obu, K.; Kakuma, T.; Matsuishi, T. Prediction of acute encephalopathy
with biphasic seizures and late reduced diffusion in patients with febrile status epilepticus. Brain Dev. 2016, 38, 217–224.
https://doi.org/10.1016/j.braindev.2015.07.007.
Wong, A.; Simon, E.; Zimmerman, R.; Wang, H.-S.; Toh, C.-H.; Ng, S.-H. Acute Necrotizing Encephalopathy of Childhood:
Correlation of MR Findings and Clinical Outcome. Am. J. Neuroradiol. 2006, 27, 1919–1923.
Ormitti, F.; Ventura, E.; Summa, A.; Picetti, E.; Crisi, G. Acute Necrotizing Encephalopathy in a Child during the 2009 Influenza
A(H1N1) Pandemia: MR Imaging in Diagnosis and Follow-Up. Am. J. Neuroradiol. 2010, 31, 396–400.
https://doi.org/10.3174/ajnr.a2058.
Vargas, W.S.; Merchant, S.; Solomo, G. Favorable outcomes in acute necrotizing encephalopathy in a child treated with hypothermia. Pediatr. Neurol. 2012, 46, 87–389.
Yoshihara, S.; Fujita, Y.; Miyamoto, K.; Imataka, G.; Yoshihara, S. Kawasaki Disease with Mild Encephalitis/Encephalopathy
with Reversible Splenial Lesion in a 2-Year-Old Girl. Indian J. Pediatr. 2021, 88, 718–718. https://doi.org/10.1007/s12098-02103779-5.
Imataka, G.; Fujita, Y.; Kano, Y.; et al. Abnormal predominantly frontal high voltage and slow EEG findings with acute encephalopathy associated with acute focal bacterial nephritis. J. Biol. Regul. Homeost. Agents 2020, 34, 1131–1133.
Imataka, G.; Yamaguchi, T.; Ishii, J.; Ogino, K.; Okamoto, K.; Tsuchioka, T.; Yoshihara, S. MERS associated with bacterial translocation in a pediatric patient with congenital portal vein hypoplasia: A case report. Exp. Ther. Med. 2018, 16, 2831–2834.
https://doi.org/10.3892/etm.2018.6532.
Serino, D.; Santarone, M.E.; Caputo, D.; Fusco, L. Febrile infection-related epilepsy syndrome (FIRES): Prevalence, impact andmanagement strategies. Neuropsychiatr. Dis. Treat 2019, 15, 1897–1903.
Lee, Y.-J. Febrile Infection-Related Epilepsy Syndrome: Refractory Status Epilepticus and Management Strategies. Ann. Child
Neurol. 2020, 28, 8–15. https://doi.org/10.26815/acn.2019.00283.
Montalvan, V.; Lee, J.; Bueso, T.; De Toledo, J.; Rivas, K. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin. Neurol. Neurosurg. 2020, 194, 105921–105921. https://doi.org/10.1016/j.clineuro.2020.105921.

J. Clin. Med. 2022, 11, 5921

91.

21 of 21

Mun, C.; Wong, A.; Toh, C.H. Spectrum of neuroimaging mimics in children with COVID-19 infection. Biomed. J. 2021, 45, 50–
62.
92. Laçinel Gürlevik, S.; Günbey, C.; Ozsurekci, Y.; et al. Neurologic manifestations in children with COVID-19 from a tertiary
center in Turkey and literature review. Eur. J. Paediatr. Neurol. 2022, 37, 139–154.
93. Nepal, G.; Shrestha, G.S.; Rehrig, J.H.; Gajurel, B.P.; Ojha, R.; Agrawal, A.; Panthi, S.; Khatri, B.; Adhikari, I. Neurological Manifestations of COVID-19 Associated Multi-system Inflammatory Syndrome in Children: A Systematic Review and Meta-analysis. J. Nepal Health Res. Counc. 2021, 19, 10–18. https://doi.org/10.33314/jnhrc.v19i1.3410.
94. Ngo, B.; Lapp, S.A.; Siegel, B.; et al. Cerebrospinal fluid cytokine, chemokine, and SARS-CoV-2 antibody profiles in children
with neuropsychiatric symptoms associated with COVID-19. Mult. Scler. Relat. Disord. 2021, 55, 103169.
95. Lin, J.E.; Asfour, A.; Sewell, T.B.; Hooe, B.; Pryce, P.; Earley, C.; Shen, M.Y.; Kerner-Rossi, M.; Thakur, K.T.; Vargas, W.S.; et al.
Neurologicalissuesinchildrenwith
COVID-19.
Neurosci.
Lett.
2020,
743,
135567–135567.
https://doi.org/10.1016/j.neulet.2020.135567.
96. Toubiana, J.; Poirault, C.; Corsia, A.; Bajolle, F.; Fourgeaud, J.; Angoulvant, F.; Debray, A.; Basmaci, R.; Salvador, E.; Biscardi,S.; et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: Prospective observational study. BMJ 2020, 369, m2094.
97. Panariello, A.; Bassetti, R.; Radice, A.; Rossotti, R.; Puoti, M.; Corradin, M.; Moreno, M.; Percudani, M. Anti-NMDA receptor
encephalitis in a psychiatric Covid-19 patient: A case report. Brain Behav. Immun. 2020, 87, 179–181.
https://doi.org/10.1016/j.bbi.2020.05.054.
98. Monti, G.; Giovannini, G.; Marudi, A.; Bedin, R.; Melegari, A.; Simone, A.M.; Santangelo, M.; Pignatti, A.; Bertellini, E.; Trenti,
T.; et al. Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19. Seizure 2020, 81,
18–20. https://doi.org/10.1016/j.seizure.2020.07.006.
99. Siracusa, L.; Cascio, A.; Giordano, S.; et al. Neurological complications in pediatric patients with SARS-CoV-2 infection: A systematic review of the literature. Ital. J. Pediatr. 2021, 47, 123.
100. Urso, L.; Distefano, M.G.; Cambula, G.; Colomba, A.I.; Nuzzo, D.; Picone, P.; Giacomazza, D.; Sicurella, L. The case of encephalitis in a COVID-19 pediatric patient. Neurol. Sci. 2022, 43, 105–112. https://doi.org/10.1007/s10072-021-05670-9.
101. Nishiyama, M.; Nagase, H.; Tanaka, T.; Fujita, K.; et al. Short and long-term outcomes in children with suspected acute encephalopathy. Brain Dev. 2016, 38, 731–737.
102. Oba, C.; Kashiwagi, M.; Tanabe, T.; et al. Inoue K, Okasora K, Tamai H. Prognostic factors in the early phase of acute encephalopathy. Pediatr. Int. 2018, 60, 270–275.