Norimichi Higurashi1, Yukitoshi Takahashi2, Ayako Kashimada3, Yuji Sugawara3, Hiroshi Sakuma4, Yuko Tomonoh5, Takahito Inoue5, Megumi Hoshina6, Ruri Satomi7, Masaharu Ohfu8, Kazuya Itomi9, Kyoko Takano10, Tomoko Kirino11, Shinichi Hirose12. 1. 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. 2. National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan. 3. Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. 4. Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. 5. Department of Pediatrics, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. 6. Department of Pediatrics, Ohara General Hospital, 6-11, Omachi, Fukushima 960-8611, Japan. 7. Department of Pediatrics, JA Toride Medical Center, 2-1-1, Hongo, Toride, Ibaraki 302-0022, Japan. 8. 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. 9. Division of Neurology, Aichi Children's Health and Medical Center, 1-2, Osakada Morioka-cho, Obu, Aichi 474-8710, Japan. 10. Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. 11. Department of Pediatrics, Shikoku Medical Center for Children and Adults, 2-1-1, Senyu-cho, Zentsuji, Kagawa 765-8507, Japan. 12. 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.
Abstract
PURPOSE: 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. CONCLUSION: 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.
PURPOSE: 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. CONCLUSION: 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: Juan A Moncayo; Ivan N Ayala; Jennifer M Argudo; Alex S Aguirre; Jashank Parwani; Ana Pachano; Diego Ojeda; Steven Cordova; Maria Gracia Mora; Christiany M Tapia; Juan Fernando Ortiz Journal: Cureus Date: 2022-06-10
Authors: Andrzej W Cwetsch; Ilias Ziogas; Roberto Narducci; Annalisa Savardi; Maria Bolla; Bruno Pinto; Laura E Perlini; Silvia Bassani; Maria Passafaro; Laura Cancedda Journal: Brain Commun Date: 2022-04-05
Authors: Rosa Chiara Goisis; Angela Chiavegato; Marta Gomez-Gonzalo; Iacopo Marcon; Linda Maria Requie; Petra Scholze; Giorgio Carmignoto; Gabriele Losi Journal: Front Cell Neurosci Date: 2022-07-21 Impact factor: 6.147