Clinical and Pathophysiological analysis of myelin Oligodendrocyte Glycoprotein antibody-Associated Neurologic Disease

2017 Fiscal Year Annual Research Report

• Project/Area Number: 17H04192
• Research Institution: Tohoku University
• Principal Investigator: 藤原 一男 東北大学, 医学系研究科, 大学院非常勤講師 (70280873)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 多発性硬化症 / 非典型例 / 抗MOG抗体 / 視神経脊髄炎 / 脱髄疾患 / アストロサイトパチー

Outline of Annual Research Achievements

最近注目されている、ミエリンオリゴデンドロサイト糖タンパク(MOG)抗体陽性神経疾患の臨床・病態・治療を解析した。
1.本疾患259例において、男女比はほぼ1:1で、発症年齢は10歳以下から70台まで広く分布していたが、10歳、35歳、55歳あたりでの発症がやや多かった。臨床型は小児では視神経炎とADEMが多く、一部の症例は多発性硬化症(MS)と診断されていた。一方、成人は視神経炎が最も多く、一部の症例は大脳皮質脳炎だった。脊髄炎は成人に多く半数が3椎体以上の長大病変だった。MOGは成熟したミエリンのマーカーであり、本疾患におけるこのような年齢と臨床型との関係はミエリンの成熟と関連していることが推察された。MOG抗体価が低下すると再発は少なく、高値が継続する例では再発が起こりやすかった(欧州MS学会[ECTRIMS]で発表し、1200演題の中から学会最終日のクリニカルハイライトで注目すべき20題の1つとして紹介された)。
2.我々が初めて報告したMOG抗体陽性“てんかん発作を呈する片側性大脳皮質脳炎”及び“対麻痺を呈する両側前頭葉内側皮質脳炎”はそれぞれ39例、10例を集めた。しばしばこの大脳皮質脳炎で初発し、その後視神経炎やADEMなどで再発していたが、非再発例もあった。また急性期にはステロイドパルス療法が有効だった。
3.急性期の髄液における総合的なサイトカイン解析では、Th17を中心とするサイトカインの発現亢進が特徴的で、そのパターンは視神経脊髄炎に類似していたが、MSとは大きく異なっていた(JNNP in press)。これと一致して、MSの治療薬であるインターフェロンßの投与で再発率の低下はみられなかったが、視神経脊髄炎と同様にステロイド長期内服は再発予防に有効であると思われた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

1.本疾患259例の解析は国際的にも最多の症例数であり、その結果は上記のごとく欧州MS学会で発表した際に、注目すべき演題としてクリニカルハイライトで紹介された。
上記の2つのタイプの大脳皮質脳炎は、それぞれｓ39例と10例を集積しておりその特徴を解析し、論文執筆中で間もなく投稿する予定である。
2.急性期の髄液における総合的なサイトカイン解析では、Th17を中心とするサイトカインの発現亢進が特徴的で、MSとは大きく異なっていた。この知見は、最近J Neurol Neurosurg Psychiatry誌にacceptされた。今後本疾患の治療戦略を考えるうえで重要な知見と思われる。
インターフェロンßの投与で再発率の低下はみられなかったことも上記の髄液サイトカインの結果と合わせて重要であり、論文執筆中である。
3.脳生検例における神経病理学的解析も現在進行中である。

Strategy for Future Research Activity

上記の如く、本研究は現在ほぼ順調に進展しておりこのまま研究を継続していきたい。我々割れのグループではMOG抗体検査は年間3000検体程度行っており、今後さらに本疾患の症例数を増加させることができると思われる。また髄液や脳生検の検体などもさらに積極的に収集していきたい。細胞性免疫や分子免疫病態の解析も加えていく予定である。執筆中の論文は早期に投稿していく予定である。

Research Products

• [Int'l Joint Research] University College London/University of Oxford/The Walton Center(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University College London/University of Oxford/The Walton Center
• [Int'l Joint Research] University of Southern Denmark(デンマーク)
  • Country Name: DENMARK
  • Counterpart Institution: University of Southern Denmark
• [Int'l Joint Research] Pontifical Catholic University RG do Sul/University of Sao Paulo(ブラジル)
  • Country Name: BRAZIL
  • Counterpart Institution: Pontifical Catholic University RG do Sul/University of Sao Paulo
• [Int'l Joint Research] Cleveland Clinic/University of Pennsylvania/Mayo Clinic(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Cleveland Clinic/University of Pennsylvania/Mayo Clinic
• [Int'l Joint Research] National Cancer Center/Seoul National University(韓国)
  • Country Name: KOREA (REP. OF KOREA)
  • Counterpart Institution: National Cancer Center/Seoul National University
• [Int'l Joint Research]
  • # of Other Countries: 10
• [Journal Article] Fingolimod-associated PML with mild IRIS in multiple sclerosis: a clinicopathological study (2018)
  • Author(s): Nishiyama S, Misu T, Shishido-Hara Y, Nakamichi K, Saijo M, Takai Y, Takei K, Yamamoto N, Kuroda H, Saito R, Watanabe M, Tominaga T, Nakashima I, Fujihara K, Aoki M
  • Journal Title: Neurol Neuroimmunol Neuroinflamm Volume: 5 Pages: e415
  • DOI: 10.1212/NXI.0000000000000415
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis of Multiple Sclerosis: 2017 Revisions of the McDonald Criteria (2018)
  • Author(s): Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee, et al T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L,
  • Journal Title: Lancet Neurol Volume: 17 Pages: 162-173
  • DOI: 10.1016/S1474-4422(17)30470-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A nationwide epidemiological study of neuromyelitis optica in Japan (2018)
  • Author(s): Miyamoto K, Fujihara K, Kira J, Kuriyama N, Matsui M, Tamakoshi A, Kusunoki S
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: - Pages: -
  • DOI: 10.1136/jnnp-2017-317321
  • Peer Reviewed
• [Journal Article] Severe aquaporin 4-IgG-positive neuromyelitis optica with disseminated herpes zoster in a pregnant woman successfully treated with intravenous immunoglobulins (2018)
  • Author(s): Matsumoto Y. Norshalena S, Tsuchiya M, Kaneko C, Kubo J, Yamamoto T, Takahashi T, Fujihara K
  • Journal Title: Mult Scler J Exp Transl Clin Volume: 4 Pages: -
  • DOI: 10.1177/2055217318758119
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Transient Pulmonary Interstitial Lesions in Aquaporin-4-positive Neuromyelitis Optica Spectrum Disorder (2018)
  • Author(s): AsatoY, Kamitani T, Ootsuka K, Kuramochi M, Nakanishi K, Shimada T, Takahashi T, Misu T, Aoki M, FujiharaK, Kawabata Y
  • Journal Title: ingtern Med Volume: - Pages: -
  • Peer Reviewed
• [Journal Article] CSF cytokine profile in MOG-IgG+neurologic disease is similar to AQP4-IgG+NMOSD but distinct from MS: a cross-sectional study and potential therapeutic implications (2018)
  • Author(s): Kaneko K, Sato DK, Nakashima I, Ogawa R, Akaishi T, Takai Y, Nishiyama S, Takahashi T, Misu T, Kuroda H, MD1), Tanaka S, Nomura K, Yuji Hashimoto Y, Callegaro D, Steinman L, Fujihara K, Aoki M
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: - Pages: -
  • Peer Reviewed / Open Access
• [Journal Article] MOG-IgG-associated disease: an overview (2018)
  • Author(s): Fujihara K, Sato DK, Nakashima I, Takahashi T, Kaneko K, Ogawa R, Akaishi T, Matsumoto Y, Takai Y, Nishiyama S, Kuroda H, Misu T, Aoki M.
  • Journal Title: Clin Exp Neuroimmunol Volume: 9(Suppl.1) Pages: 48-55
  • DOI: org/10.1111/cen3.12434
  • Peer Reviewed
• [Journal Article] MOG-IgG-associated optic neuritis, encephalitis, and myelitis (MONEM): lessons learned from neuromyelitis optica spectrum disorder (2018)
  • Author(s): dos Passos GR, Oliveira LM, da Costa BK, Apostolos-Pereira SL, Callegaro D, Fujihara K, Sato DK
  • Journal Title: Front Neurol Volume: - Pages: -
  • DOI: org/10.3389/fneur.2018.00217
  • Peer Reviewed / Open Access
• [Journal Article] Commentary: Children with myelin oligodendrocyte glycoprotein antibodies-associated disease: relation of phenotypes to central nervous system myelin maturation (2018)
  • Author(s): Kuroda H, Fujihara K
  • Journal Title: Dev Med Child Neurol Volume: 60 Pages: 339-340
  • DOI: 10.1111/dmcn.13691
  • Peer Reviewed
• [Journal Article] 2017 Japanese Guidelines for Multiple Sclerosis and Neuromyelitis Optica: achievements and challenges (2018)
  • Author(s): Fujihara K
  • Journal Title: Clin Exp Neuroimmunol Volume: 9 Pages: 4-6
  • DOI: org/10.1111/cen3.12450
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the Great East Japan Earthquake in 2011 on MS and NMOSD: a study in Sendai, Japan. (2017)
  • Author(s): Kanamori Y, Nakashima I, Takai Y, Misu T, Kuroda H, Nishiyama S, Takahashi T, Sato S, Fujimori J, Higuchi J, Itoyama Y, Aoki M, Fujihara K
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 88 Pages: 362-364
  • DOI: 10.1136/jnnp-2016-313890
  • Peer Reviewed
• [Journal Article] MOG-antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy (2017)
  • Author(s): Ogawa R, Nakashima I, Takahashi T, Kaneko K, Akaishi T, Takai Y, Sato DK, Nishiyama S, Misu T, Kuroda H, Aoki M, Fujihara K
  • Journal Title: Neurol Neuroimmunol Neuroinflamm Volume: 4 Pages: e322
  • DOI: 10.1212/NXI.0000000000000322
  • Peer Reviewed / Open Access
• [Journal Article] Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies (2017)
  • Author(s): Fujimori J, Takai Y, Nakashima I, Sato DK, Takahashi T, Kaneko K, Nishiyama S, Watanabe M, Tanji H, Kobayashi M, Misu T, Aoki M, Fujihara K
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 88 Pages: 534-536
  • DOI: 10.1136/jnnp-2016-315094
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of the leptomeningeal blood barrier in neuromyelitis optica spectrum disorder (2017)
  • Author(s): Asgari N, Flanagan EP, Fujihara K, Kim HJ, Skejoe HPB, Wuerfel J, Kuroda H, Kim SH, Maillart E, Marignier R, Pittock SJ, Paul F, Weinshenker BG
  • Journal Title: Neurol Neuroimmunol Neuroiflamm Volume: 4 Pages: e343
  • DOI: 10.1212/NXI.0000000000000343
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole brain and grey matter volume of Japanese patients with multiple sclerosis (2017)
  • Author(s): Akaishi T, Nakashima I, Mugikura S, Aoki M, Fujihara K
  • Journal Title: J Neuroimmunol Volume: 306 Pages: 68-75
  • DOI: 10.1016/j.jneuroim.2017.03.009
  • Peer Reviewed
• [Journal Article] Cognitive Impairment in Neuromyelitis Optica Spectrum Disorders: A comparison of the Wechsler Adult Intelligence Scale-III and the Wechsler Memory Scale Revised with the Rao Brief Repeatable Neuropsychological Battery (2017)
  • Author(s): Fujimori J, Nakashima I, Baba T, Meguro Y, Ogawa R, Fujihara K
  • Journal Title: eNeurologicalSci Volume: 9 Pages: 3-7
  • DOI: 10.1016/j.ensci.2017.09.001
  • Peer Reviewed / Open Access
• [Journal Article] Neuromyelitis optica spectrum disorders (2017)
  • Author(s): Akaishi T, Nakashima I, Sato DK, Takahashi T, Fujihara K
  • Journal Title: Neuroimaging Clin N Am Volume: 27 Pages: 251-265
  • DOI: 10.1016/j.nic.2016.12.010
  • Peer Reviewed
• [Journal Article] Differential diagnosis of neuromyelitis optica spectrum disorders (2017)
  • Author(s): Kim SM, Kim SJ, Lee HJ, Kuroda H, Palace J, Fujihara K
  • Journal Title: Ther Adv Neurol Disord Volume: 10 Pages: 265-289
  • DOI: 10.1177/1756285617709723
  • Peer Reviewed / Open Access
• [Journal Article] 左眼の奥が痛くて、物が見えづらいんです(左眼痛、左視力低下) (2017)
  • Author(s): 黒田 宙、藤原一男
  • Journal Title: 内科「症候から考える画像診断アトラス」 Volume: 119 Pages: 578-581
• [Presentation] Overview of clinical signs and symptoms of spinal cord pathology in MS and NMOSD: gait, pain, bladder/bowel, sexual function (2017)
  • Author(s): Fujihara K
  • Organizer: International Conference on Spinal Cord Involvement and imaging in MS and NMOSD
  • Int'l Joint Research / Invited
• [Presentation] Evolution of disgnostic criteria and its impact on disease management. in Session 1: advaincing the diagnosis and management in MS (2017)
  • Author(s): Fujihara K
  • Organizer: UCB APAC MS Summit 2017
  • Int'l Joint Research / Invited
• [Presentation] NMOSD: an update (2017)
  • Author(s): Fujihara K
  • Organizer: The 3rd Indian Committee for Treatment and Resarch in Multiple Sclerosis (ICTRIMS)
  • Int'l Joint Research / Invited
• [Presentation] MOG-IgG-associated neurologic disease (2017)
  • Author(s): Fujihara K
  • Organizer: The 3rd Indian Committee for Treatment and Resarch in Multiple Sclerosis (ICTRIMS)
  • Int'l Joint Research / Invited
• [Presentation] Intermediate forms between MS and seronegative NMOSD, How to solve this diagnostic puzzle ? (2017)
  • Author(s): Fujihara K
  • Organizer: The 18th Meeting of Brazilian Committee for Treatment and Resarch in Multiple Sclerosis (BCTRIMS)
  • Int'l Joint Research / Invited
• [Presentation] Is NMO a disease or syndrome with different etiologies ? (2017)
  • Author(s): Fujihara K
  • Organizer: The 18th Meeting of Brazilian Committee for Treatment and Resarch in Multiple Sclerosis (BCTRIMS)
  • Int'l Joint Research / Invited
• [Presentation] Diagnostic criteria of MS: new insights and challenges (2017)
  • Author(s): Fujihara K
  • Organizer: The 18th Meeting of Brazilian Committee for Treatment and Resarch in Multiple Sclerosis (BCTRIMS)
  • Int'l Joint Research / Invited
• [Presentation] Pathogenesis of NMOSD (2017)
  • Author(s): Fujihara K
  • Organizer: The 23rd World Congress of Neurology
  • Int'l Joint Research / Invited
• [Presentation] Rheurmatology and NMO overlap (2017)
  • Author(s): Fujihara K
  • Organizer: The 23rd World Congress of Neurology
  • Int'l Joint Research / Invited
• [Presentation] Update on pathogenesis of NMOSD (2017)
  • Author(s): Fujihara K
  • Organizer: The 7th Joint ECTRIMS-ACTRIMS Meeting (MSParis 2017)
  • Int'l Joint Research / Invited
• [Presentation] Symptomatic treatment in MS, NMOSD (2017)
  • Author(s): Fujihara K
  • Organizer: European Charcot Foundation Symposium in The 10th Pan-Asian Committee for Teratment and Resarch in Multiple Sclerosis (PACTRIMS),
  • Int'l Joint Research / Invited
• [Presentation] Update on pathogenesis of NMOSD (2017)
  • Author(s): Fujihara K
  • Organizer: Istanbul MS Days 2017
  • Int'l Joint Research / Invited
• [Book] 今日の治療指針 2018年版 私はこう治療している (2018)
  • Author(s): 藤原一男
  • Total Pages: 2
  • Publisher: 医学書院
• [Book] Pocket Drugs 2018 (2018)
  • Author(s): 藤原一男
  • Total Pages: 6
  • Publisher: 医学書院
• [Book] 多発性硬化症・視神経脊髄炎診療ガイドライン 2017 (2017)
  • Author(s): 松井 真、新野正明、岡本智子、越智博文、河内 泉、近藤誉之、清水優子、野村恭一、深澤俊行、藤原一男、真崎勝久、宮本勝一
  • Total Pages: 18
  • Publisher: 医学書院
• [Book] 神経救急・集中治療ハンドブック (2017)
  • Author(s): 高橋利幸、藤原一男
  • Total Pages: 6
  • Publisher: 医学書院