Elsevier

Brain and Development

Volume 43, Issue 1, January 2021, Pages 2-31
Brain and Development

Review article
Guidelines for the diagnosis and treatment of acute encephalopathy in childhood

https://doi.org/10.1016/j.braindev.2020.08.001Get rights and content

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.

Introduction

Acute encephalopathy (AE) denotes syndromes characterized by acute onset of severe and long-lasting disturbance of consciousness, which typically occur in previously healthy children. AE is the most severe complication of common infectious diseases, such as influenza and exanthem subitum, often leading to death or severe neurological disabilities [1].

To date, many syndromes of AE have been described. Among them, Reye syndrome was originally reported in Australia [2], and hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome [3] and hemorrhagic shock and encephalopathy syndrome (HSES) [4] in Europe. During 1993–2006, child neurologists in Japan established and characterized many new syndromes, including acute necrotizing 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]. Based on this classification, a nationwide epidemiologic study of AE was conducted in 2010, and the results were published in 2012 [8]. The time was ripe for the compilation of new guidelines.

We aimed to provide clinicians treating acute neurologic disorders of children, such as seizures and impairment of consciousness, with guidelines that are useful for the acute stage management of AE.

Since AE is rare and many of the syndromes were recently 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 targeting influenza-associated AE, published in 2005 and revised in 2009 [9]. Therefore, our purpose was to publish new, evidence-based guidelines targeting AE associated with any pathogen and classified into any syndrome [10].

In September 2013, the Japanese Society of Child Neurology (JSCN) decided to establish clinical practice guidelines 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) with minor modifications. Briefly, clinical questions (CQs) were selected, and the system of literature search was determined. Documents in English were retrieved from the 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 the levels of evidence. One of the two members wrote the drafts of recommendations and comments, and then the other reviewed them. For some CQs, additional specialists outside of the WG were invited to critically review the draft: a specialist of electroencephalography (EEG) for CQ 2–4, and intensivists from the Japanese Society 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 and also asked the following organizations to review the drafts: Japanese Pediatric Society, Japanese Society for Pediatric Infectious Diseases, Japanese Society of Emergency Pediatrics and Chiisana-inochi (an association of families of children with influenza encephalopathy). After revision of the drafts based on the opinions and comments from members and organizations, the guidelines were published in August 2016 [10]. The guidelines were uploaded on the Minds homepage in February 2017.

The guidelines consist of seven chapters, each of them including two to four CQs. The first half (three chapters) of the guidelines, corresponding to Sections 2.1–2.3 in this 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 be made at all. To facilitate the use of the guidelines in such cases, we illustrated their structure with a flow chart indicating the relevant CQs according to the patient’s clinical findings [10] (Fig. 1).

Section snippets

(CQ1-1) definition of AE

Recommendations:

  • (1)

    AE is defined as impairment of consciousness of acute onset, with severity of Japan Coma Scale ≥20 or Glasgow Coma Scale (GCS) <11, and with duration of 24 h or longer [10]. (Grading not applicable)

    • 1)

      The onset usually occurs during the course of infectious diseases.

    • 2)

      Brain edema is often visualized by cranial computed tomography (CT) or magnetic resonance imaging (MRI).

    • 3)

      Distinction is made from other diseases, such as encephalitis and meningitis, and from other causes of decreased

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 and treatment 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 are either 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

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, from the National Institute of Public Health, Japan, and by Grant-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.

References (182)

  • J. Takanashi et al.

    Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)

    J Neurol Sci

    (2010)
  • J.J. Lin et al.

    Effect of topiramate, in combination with lidocaine, and phenobarbital, in acute encephalitis with refractory repetitive partial seizures

    Brain Dev

    (2009)
  • C.S. Shyu et al.

    Acute encephalitis with refractory, repetitive partial seizures

    Brain Dev

    (2008)
  • A. Okumura et al.

    The spectrum of acute encephalopathy with reduced diffusion in the unilateral hemisphere

    Eur J Paediatr Neurol

    (2009)
  • A. Okumura et al.

    Delirious behavior in children with influenza: its clinical features and EEG findings

    Brain Dev

    (2005)
  • A. Okumura et al.

    Amplitude-integrated electroencephalography in patients with acute encephalopathy with refractory, repetitive partial seizures

    Brain Dev

    (2011)
  • E.A. Accolla et al.

    Clinical correlates of frontal intermittent rhythmic delta activity (FIRDA)

    Clin Neurophysiol

    (2011)
  • L. Hellström-Westas et al.

    Continuous brain-function monitoring: state of the art in clinical practice

    Semin Fetal Neonatal Med

    (2006)
  • M. Komatsu et al.

    Clustered subclinical seizures in a patient with acute encephalopathy with biphasic seizures and late reduced diffusion

    Brain Dev

    (2010)
  • K.R. Smith et al.

    The cell biology of synaptic inhibition in health and disease

    Curr Opin Neurobiol

    (2010)
  • R.C. Scott et al.

    Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial

    Lancet

    (1999)
  • J. McIntyre et al.

    Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial

    Lancet

    (2005)
  • K. Minagawa et al.

    Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions

    Brain Dev

    (1986)
  • H. Yoshikawa et al.

    Midazolam as a first-line agent for status epilepticus in children

    Brain Dev

    (2000)
  • G. Pearson et al.

    Should paediatric intensive care be centralized? Trent versus Victoria

    Lancet

    (1997)
  • M. Nishiyama et al.

    Targeted temperature management of acute encephalopathy without AST elevation

    Brain Dev

    (2015)
  • M. Mizuguchi et al.

    Acute encephalopathy associated with influenza and other viral infections

    Acta Neurol Scand

    (2007)
  • H. Gastaut et al.

    H.H.E. syndrome; hemiconvulsions, hemiplegia, epilepsy

    Epilepsia Eksp Khirurg

    (1960)
  • M. Mizuguchi et al.

    Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions

    J Neurol Neurosurg Psychiatry

    (1995)
  • J. Takanashi et al.

    Diffusion MRI abnormalities after prolonged febrile seizures with encephalopathy

    Neurology

    (2006)
  • H. Tada et al.

    Clinically mild encephalitis/encephalopathy with a reversible splenial lesion

    Neurology

    (2004)
  • Morishima M, Okabe N, Nakamura Y, Kawaoka Y, Yamaguchi S, Mizuguchi M, et al. Guidelines on influenza encephalopathy,...
  • Committee for the Compilation of Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood,...
  • M. Mizuguchi

    Influenza encephalopathy and related neuropsychiatric syndromes

    Influenza Other Resp Virus

    (2013)
  • M. Hosoya et al.

    Cytochrome c and tumor necrosis factor-alpha values in serum and cerebrospinal fluid of patients with influenza-associated encephalopathy

    Pediatr Infect Dis J

    (2005)
  • T. Shiihara et al.

    Serum and cerebrospinal fluid S100B, neuron-specific enolase, and total tau protein in acute encephalopathy with biphasic seizures and late reduced diffusion: a diagnostic validity

    Pediatr Int

    (2012)
  • H. Nagase et al.

    Therapeutic indicators of acute encephalopathy in patients with complex febrile seizures

    Pediatr Int

    (2013)
  • H. Tsukahara et al.

    Prognostic value of brain injury biomarkers in acute encephalitis/encephalopathy

    Pediatr Int

    (2013)
  • M. Harada et al.

    Differences in water diffusion and lactate production in two different types of postinfectious encephalopathy

    J Magn Reson Imaging

    (2000)
  • A.M. Wong et al.

    Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome

    Am J Neuroradiol

    (2006)
  • J. Takanashi et al.

    Excitotoxicity in acute encephalopathy with biphasic seizures and late reduced diffusion. Report of 3 cases

    Am J Neuroradiol

    (2009)
  • H. Yamanouchi et al.

    Acute infantile encephalopathy predominantly affecting the bilateral frontal lobes (AIEF): a novel clinical category and its tentative diagnostic criteria

    Epilepsy Res

    (2006)
  • H. Sakuma et al.

    Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis

    Acta Neurol Scand

    (2010)
  • Y. Maegaki et al.

    Clinical characteristics of acute encephalopathy of obscure origin: a biphasic clinical course is a common feature

    Neuropediatrics

    (2006)
  • A. Harden et al.

    EEG features and their evolution in the acute phase of haemorrhagic shock and encephalopathy syndrome

    Neuropediatrics

    (1991)
  • J.B. Domachowske et al.

    Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children

    Pediatr Infect Dis J

    (1996)
  • A. Bitnun et al.

    Acute childhood encephalitis and Mycoplasma pneumoniae

    Clin Infect Dis

    (2001)
  • H. Kolski et al.

    Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994–1995

    Clin Infect Dis

    (1998)
  • N. Watemberg et al.

    Clinical correlates of occipital intermittent rhythmic delta activity (OIRDA) in children

    Epilepsia

    (2007)
  • J.M. Schreiber et al.

    Continuous video EEG for patients with acute encephalopathy in a pediatric intensive care unit

    Neurocrit Care

    (2012)
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