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Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus
  1. Hiroshi Sakuma1,
  2. Naoyuki Tanuma1,2,
  3. Ichiro Kuki3,
  4. Yukitoshi Takahashi4,
  5. Masashi Shiomi5,
  6. Masaharu Hayashi1
  1. 1 Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
  2. 2 Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for the Disabled, Tokyo, Japan
  3. 3 Department of Child Neurology, Osaka City General Hospital, Osaka, Japan
  4. 4 National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, Shizuoka, Japan
  5. 5 Department of Pediatrics, Aizenbashi Hospital, Osaka, Japan
  1. Correspondence to Dr Hiroshi Sakuma, Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya, Tokyo 1568506, Japan; sakuma-hs{at}

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Status epilepticus is one of the most common neurological emergencies in children and adults. Febrile status epilepticus cases are often associated with inflammatory neurological diseases caused by specific pathogens or antineuronal autoimmunity. In addition, there is a subgroup of super-refractory status epilepticus triggered by fever and having no known cause.1 This condition is designated as either acute encephalitis with refractory, repetitive partial seizures (AERRPS)2 or febrile infection-related epilepsy syndrome (FIRES).3 The pathogenesis of AERRPS/FIRES is currently unknown. A close relationship between febrile illness and status epilepticus suggests deleterious effects of inflammation and autoimmunity on the onset and progression of seizure. However, immune mechanisms in human status epilepticus associated with isolated fever have not been fully elucidated.

We report a comprehensive study of the inflammatory mediators in paediatric cases of AERRPS. We show a marked upregulation of proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of patients with this condition.


We defined AERRPS using the criteria shown in online supplementary table S1. Between April 2010 and July 2013, 14 patients with AERRPS and 14 patients with other inflammatory neurological diseases (OIND) were enrolled in the study. Serum and CSF specimens from patients with AERRPS and OIND were collected between 0 and 39 days from the onset of neurological symptoms. Eighteen patients with non-inflammatory neurological diseases (NIND) served as a control group. Additionally, the Shizuoka Institute of Epilepsy and Neurological Disorders provided us with 13 conserved CSF specimens from patients with AERRPS who fulfilled the same criteria, which we also included in our analysis. …

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  • Contributors HS, YT, MS and MH were involved in conception, design and interpretation of the data. HS, NT and IK were involved in analysis of the data. HS, NT, IK, MS and MH were involved in drafting of the paper. All authors were involved in approval of the final version.

  • Funding This work was supported by Health Labour Sciences Research Grant for Research on Measures for Intractable Diseases from the Japanese Ministry of Health, Labour and Welfare (H22-Nanchi-Ippan-029 and H23-Nanchi-Ippan-107, HS, NT, IK), Research Grant from the Japan Epilepsy Research Foundation (H22–5, HS) and Research Support from Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics (20-Young-3, HS).

  • Competing interests None.

  • Ethics approval Institutional Review Board of the National Center of Neurology and Psychiatry (No. 21-9-2) and the Tokyo Metropolitan Institute of Medical Science (No. 12–34).

  • Provenance and peer review Not commissioned; externally peer reviewed.