title: Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy.
abstract: OBJECTIVE
  The pathomechanism and treatment of PCDH19 female epilepsy (PCDH19-FE) remain unclear. Here, we report that corticosteroids are effective for control of the seizure clusters or other acute symptoms of PCDH19-FE and argue for the possible involvement of a compromised blood-brain barrier (BBB) in its pathogenesis.
  
  
  METHODS
  The efficacy of corticosteroids was retrospectively reviewed in five Japanese patients with PCDH19-FE. The results of antibody assays against the N-methyl-d-aspartate-type glutamate receptor (abs-NR) in serum/cerebrospinal fluid were also compiled.
  
  
  RESULTS
  Corticosteroid treatments significantly improved the acute symptoms, including seizure clusters, in all cases, most often immediately after the initial administration. However, the effect was transient, and some seizures recurred within a few weeks, especially in association with fever. Serum and/or cerebrospinal fluid abs-NR were detected in all patients. Target sequences of the detected antibodies were multiple, and the titers tended to decrease over time. In one patient, immunohistochemical analysis using rat hippocampal slices also revealed serum antibodies targeting an unknown epitope in neuronal cytoplasm.
  
  
  CONCLUSIONS
  Our findings imply an involvement of inflammatory processes in the pathogenesis of PCDH19-FE and therapeutic utility for corticosteroids as an adjunctive option in acute treatment. PCDH19 is well expressed in brain microvascular endothelial cells and thus its impairment may cause BBB vulnerability, which may be ameliorated by corticosteroids. The abs-NR detected in our patients may not indicate an autoimmune pathomechanism, but may rather represent non-specific sensitization to degraded neuronal components entering the general circulation, the latter process facilitated by the BBB vulnerability.
authors.affiliation: Department of Pediatrics, Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; Central Research Institute for the Pathomechanisms of Epilepsy, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Higurashi
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kashimada
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugawara
authors.affiliation: Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakuma
authors.affiliation: Department of Pediatrics, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tomonoh
authors.affiliation: Department of Pediatrics, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Pediatrics, Ohara General Hospital, 6-11, Omachi, Fukushima 960-8611, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Hoshina
authors.affiliation: Department of Pediatrics, JA Toride Medical Center, 2-1-1, Hongo, Toride, Ibaraki 302-0022, Japan.
authors.forename: Ruri
authors.initials: R
authors.lastname: Satomi
authors.affiliation: Division of Child Neurology, Okinawa Prefectural Southern Medical Center & Children's Medical Center, 118-1, Aza Arakawa, Haebaru-cho, Shimajiri-gun, Okinawa 901-1193, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Ohfu
authors.affiliation: Division of Neurology, Aichi Children's Health and Medical Center, 1-2, Osakada Morioka-cho, Obu, Aichi 474-8710, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Itomi
authors.affiliation: Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takano
authors.affiliation: Department of Pediatrics, Shikoku Medical Center for Children and Adults, 2-1-1, Senyu-cho, Zentsuji, Kagawa 765-8507, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kirino
authors.affiliation: Central Research Institute for the Pathomechanisms of Epilepsy, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; Department of Pediatrics, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Electronic address: hirose@fukuoka-u.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004829:Epilepsy, Generalized / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007564:Japan; D009154:Mutation / Q000235:genetics; D000091363:Protocadherins; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D000305:Adrenal Cortex Hormones; D000906:Antibodies; D015820:Cadherins; C121001:NR2B NMDA receptor; C438605:PCDH19 protein, human; D000091363:Protocadherins; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Blood–brain barrier; Epilepsy and mental retardation limited to females (EFMR); Inflammation; N-methyl-d-aspartate (NMDA)-type glutamate receptor; Neuronal antibody