今日の臨床サポート

多発性硬化症

著者: 深浦彦彰 埼玉医科大学総合医療センター神経内科

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正/監修レビュー済:2021/09/22
患者向け説明資料

概要・推奨   

  1. 多発性硬化症(multiple sclerosis、MS)の急性増悪時には、メチルプレドニゾロンなどのステロイド大量点滴静注療法(パルス療法と呼ぶ)が強く推奨される(推奨度1)
  1. 血液浄化療法(単純血漿交換、血漿吸着療法)は再発寛解型MSの急性増悪期でステロイドパルス治療が効果不十分なときに、おそらく推奨される(推奨度2)
  1. 再発寛解型MSの再発予防にインターフェロンβが強く推奨される(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
深浦彦彰 : 講演料(ノバルティスファーマ,バイオジェン・ジャパン)[2021年]
監修:高橋裕秀 : 特に申告事項無し[2021年]

改訂のポイント:
  1. McDonaldの診断基準が2017年に改定されたので変更した。
  1. 新規に疾患修飾薬が2薬追加となったので追記した〔シポニモド(メーゼント)、オファツマブ(ケシンプタ)〕。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 多発性硬化症(multiple sclerosis、MS)とは、中枢神経の髄鞘と稀突起グリアが障害されることにより、髄鞘破壊型の障害を、空間的(dissemination in space、DIS)、時間的に多発する(dissemination in time)ことを確認する状態である。
  1. 症状の再発と寛解を認め、脳や脊髄のMRI検査で異常信号領域を呈する場合は、MSも鑑別として挙げる。2017年に改訂されたMcDonaldの診断基準に沿って診断することが望ましい。そのためには、丁寧な病歴の聴取、正確な神経学的診察が重要であり、脳/脊髄のMRI検査、自己抗体を含む血液検査、脳脊髄液検査、電気生理学的検査(脳幹誘発電位や視神経誘発電位)など診断を補助する検査が不可欠である。
  1. また、同様な病歴、症状、検査所見等を呈する他疾患(視神経脊髄炎[NMOSD]、シェーグレン症候群、血管炎、リンパ腫、サルコイドーシス、急性散在性脳脊髄炎[ADEM]ほか)は治療方法が異なるため、初診時にしっかりと鑑別しなくてはいけない。
  1. 多発性硬化症/視神経脊髄炎は、指定難病であり、総合障害度(EDSS)に関する評価基準を用いてEDSS4.5以上などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
 
  1. より早期の診断を目的に2017年に改訂されたMcDonaldの診断基準(推奨度1G)(参考文献:[1][2][3][4]
  1. MSの診断基準として国際的に用いられている。2001年にインターナショナルパネルにより発表され、2005年に改訂された。2010年に日本や南米からのパネリストも加わり再度改訂が行われた。2017年にさらなる改訂が加えられた。
 
Clinically isolated syndromeにおけるMRIによる空間的・時間的多発性の基準

筆者訳

出典

img1:  Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
 
 Lancet Neurol. 2018 Feb;17(2):162-173. d・・・
 
  1. 長く日本で視神経脊髄型MS(OSMS)と呼ばれていたMS患者の大部分は、視神経脊髄炎(neuromyelitis optica spectrum disorder、NMOSD)である(推奨度1G)(参考文献:[5][6][7]
  1. Wingerchukらは、NMOに特異性の高いNMO-IgGの発見に基づいて、1999年発表のNMO診断基準を2006年に改訂し、さらに2015年に改訂した。NMO-IgGはアクアポリン抗体(AQP4抗体)と同等と考えられている。<図表>
病歴・診察のポイント  
現病歴と既往歴:
  1. しっかりと診断するためには、丁寧な病歴の聴取が不可欠である。どのような症状がいつから出現したか、進行しているかどうか、日常生活でどのように困っているのかを、じっくりと聞き出す。また、過去に同じ症状や違う症状の出現がなかったかの確認も忘れずに行う。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

著者: W I McDonald, A Compston, G Edan, D Goodkin, H P Hartung, F D Lublin, H F McFarland, D W Paty, C H Polman, S C Reingold, M Sandberg-Wollheim, W Sibley, A Thompson, S van den Noort, B Y Weinshenker, J S Wolinsky
雑誌名: Ann Neurol. 2001 Jul;50(1):121-7.
Abstract/Text The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

PMID 11456302  Ann Neurol. 2001 Jul;50(1):121-7.
著者: Chris H Polman, Stephen C Reingold, Gilles Edan, Massimo Filippi, Hans-Peter Hartung, Ludwig Kappos, Fred D Lublin, Luanne M Metz, Henry F McFarland, Paul W O'Connor, Magnhild Sandberg-Wollheim, Alan J Thompson, Brian G Weinshenker, Jerry S Wolinsky
雑誌名: Ann Neurol. 2005 Dec;58(6):840-6. doi: 10.1002/ana.20703.
Abstract/Text New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

PMID 16283615  Ann Neurol. 2005 Dec;58(6):840-6. doi: 10.1002/ana.2070・・・
著者: Chris H Polman, Stephen C Reingold, Brenda Banwell, Michel Clanet, Jeffrey A Cohen, Massimo Filippi, Kazuo Fujihara, Eva Havrdova, Michael Hutchinson, Ludwig Kappos, Fred D Lublin, Xavier Montalban, Paul O'Connor, Magnhild Sandberg-Wollheim, Alan J Thompson, Emmanuelle Waubant, Brian Weinshenker, Jerry S Wolinsky
雑誌名: Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366.
Abstract/Text New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

Copyright © 2011 American Neurological Association.
PMID 21387374  Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22・・・
著者: Alan J Thompson, Brenda L Banwell, Frederik Barkhof, William M Carroll, Timothy Coetzee, Giancarlo Comi, Jorge Correale, Franz Fazekas, Massimo Filippi, Mark S Freedman, Kazuo Fujihara, Steven L Galetta, Hans Peter Hartung, Ludwig Kappos, Fred D Lublin, Ruth Ann Marrie, Aaron E Miller, David H Miller, Xavier Montalban, Ellen M Mowry, Per Soelberg Sorensen, Mar Tintoré, Anthony L Traboulsee, Maria Trojano, Bernard M J Uitdehaag, Sandra Vukusic, Emmanuelle Waubant, Brian G Weinshenker, Stephen C Reingold, Jeffrey A Cohen
雑誌名: Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2. Epub 2017 Dec 21.
Abstract/Text The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29275977  Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S14・・・
著者: D M Wingerchuk, W F Hogancamp, P C O'Brien, B G Weinshenker
雑誌名: Neurology. 1999 Sep 22;53(5):1107-14.
Abstract/Text OBJECTIVES: To evaluate the spectrum of neuromyelitis optica (NMO), including characteristics of the index events (optic neuritis [ON]) and myelitis), neuroimaging, CSF, and serologic studies, and to evaluate the long-term course.
METHODS: Review of 71 patients with NMO evaluated at the Mayo Clinic between 1950 and 1997.
RESULTS: NMO was either monophasic or relapsing. Patients with a monophasic course (n = 23) usually presented with rapidly sequential index events (median 5 days) with moderate recovery. Most with a relapsing course (n = 48) had an extended interval between index events (median 166 days) followed within 3 years by clusters of severe relapses isolated to the optic nerves and spinal cord. Most relapsing patients developed severe disability in a stepwise manner, and one-third died because of respiratory failure. Features of NMO distinct from "typical" MS included >50 cells/mm3 in CSF (often polymorphonuclear), normal initial brain MRI, and lesions extending over three or more vertebral segments on spinal cord MRI.
CONCLUSIONS: Clinical, laboratory, and imaging features generally distinguish neuromyelitis optica from MS. Patients with relapsing optic neuritis and myelitis may have neuromyelitis optica rather than MS. Patients with a relapsing course of neuromyelitis optica have a poor prognosis and frequently develop respiratory failure during attacks of cervical myelitis.

PMID 10496275  Neurology. 1999 Sep 22;53(5):1107-14.
著者: D M Wingerchuk, V A Lennon, S J Pittock, C F Lucchinetti, B G Weinshenker
雑誌名: Neurology. 2006 May 23;66(10):1485-9. doi: 10.1212/01.wnl.0000216139.44259.74.
Abstract/Text BACKGROUND: The authors previously proposed diagnostic criteria for neuromyelitis optica (NMO) that facilitate its distinction from prototypic multiple sclerosis (MS). However, some patients with otherwise typical NMO have additional symptoms not attributable to optic nerve or spinal cord inflammation or have MS-like brain MRI lesions. Furthermore, some patients are misclassified as NMO by the authors' earlier proposed criteria despite having a subsequent course indistinguishable from prototypic MS. A serum autoantibody marker, NMO-IgG, is highly specific for NMO. The authors propose revised NMO diagnostic criteria that incorporate NMO-IgG status.
METHODS: Using final clinical diagnosis (NMO or MS) as the reference standard, the authors calculated sensitivity and specificity for each criterion and various combinations using a sample of 96 patients with NMO and 33 with MS. The authors used likelihood ratios and logistic regression analysis to develop the most practical and informative diagnostic model.
RESULTS: Fourteen patients with NMO (14.6%) had extra-optic-spinal CNS symptoms. NMO-IgG seropositivity was 76% sensitive and 94% specific for NMO. The best diagnostic combination was 99% sensitive and 90% specific for NMO and consisted of at least two of three elements: longitudinally extensive cord lesion, onset brain MRI nondiagnostic for MS, or NMO-IgG seropositivity.
CONCLUSIONS: The authors propose revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity. CNS involvement beyond the optic nerves and spinal cord is compatible with NMO.

PMID 16717206  Neurology. 2006 May 23;66(10):1485-9. doi: 10.1212/01.w・・・
著者: Dean M Wingerchuk, Brenda Banwell, Jeffrey L Bennett, Philippe Cabre, William Carroll, Tanuja Chitnis, Jérôme de Seze, Kazuo Fujihara, Benjamin Greenberg, Anu Jacob, Sven Jarius, Marco Lana-Peixoto, Michael Levy, Jack H Simon, Silvia Tenembaum, Anthony L Traboulsee, Patrick Waters, Kay E Wellik, Brian G Weinshenker, International Panel for NMO Diagnosis
雑誌名: Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729. Epub 2015 Jun 19.
Abstract/Text Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

© 2015 American Academy of Neurology.
PMID 26092914  Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0・・・
著者: J F Kurtzke
雑誌名: Neurology. 1983 Nov;33(11):1444-52.
Abstract/Text One method of evaluating the degree of neurologic impairment in MS has been the combination of grades (0 = normal to 5 or 6 = maximal impairment) within 8 Functional Systems (FS) and an overall Disability Status Scale (DSS) that had steps from 0 (normal) to 10 (death due to MS). A new Expanded Disability Status Scale (EDSS) is presented, with each of the former steps (1,2,3 . . . 9) now divided into two (1.0, 1.5, 2.0 . . . 9.5). The lower portion is obligatorily defined by Functional System grades. The FS are Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, and Other; the Sensory and Bowel & Bladder Systems have been revised. Patterns of FS and relations of FS by type and grade to the DSS are demonstrated.

PMID 6685237  Neurology. 1983 Nov;33(11):1444-52.
著者: David H Miller, Declan T Chard, Olga Ciccarelli
雑誌名: Lancet Neurol. 2012 Feb;11(2):157-69. doi: 10.1016/S1474-4422(11)70274-5.
Abstract/Text Clinically isolated syndrome (CIS) is a term that describes a first clinical episode with features suggestive of multiple sclerosis (MS). It usually occurs in young adults and affects optic nerves, the brainstem, or the spinal cord. Although patients usually recover from their presenting episode, CIS is often the first manifestation of MS. The most notable risk factors for MS are clinically silent MRI lesions and CSF oligoclonal bands; weak or uncertain risk factors include vitamin D deficiency, Epstein-Barr virus infection, smoking, HLA genes, and miscellaneous immunological abnormalities. Diagnostic investigations including MRI aim to exclude alternative causes and to define the risk for MS. MRI findings incorporated into diagnostic criteria in the past decade enable MS to be diagnosed at or soon after CIS presentation. The course of MS after CIS is variable: after 15-20 years, a third of patients have a benign course with minimal or no disability and a half will have developed secondary progressive MS with increasing disability. Prediction of the long-term course at disease onset is unreliable. Disease-modifying treatments delay the development from CIS to MS. Their use in CIS is limited by uncertain long-term clinical prognosis and treatment benefits and adverse effects, although they have the potential to prevent or delay future tissue damage, including demyelination and axonal loss. Targets for future therapeutic progress are to achieve safe and effective long-term immunomodulation with neuroprotection and repair.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22265211  Lancet Neurol. 2012 Feb;11(2):157-69. doi: 10.1016/S147・・・
著者: Peter A Brex, Olga Ciccarelli, Jonathon I O'Riordan, Michael Sailer, Alan J Thompson, David H Miller
雑誌名: N Engl J Med. 2002 Jan 17;346(3):158-64. doi: 10.1056/NEJMoa011341.
Abstract/Text BACKGROUND: In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability.
METHODS: Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke's Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability).
RESULTS: Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61).
CONCLUSIONS: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment.

PMID 11796849  N Engl J Med. 2002 Jan 17;346(3):158-64. doi: 10.1056/N・・・
著者: E M Frohman, D S Goodin, P A Calabresi, J R Corboy, P K Coyle, M Filippi, J A Frank, S L Galetta, R I Grossman, K Hawker, N J Kachuck, M C Levin, J T Phillips, M K Racke, V M Rivera, W H Stuart, Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
雑誌名: Neurology. 2003 Sep 9;61(5):602-11.
Abstract/Text Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

PMID 12963748  Neurology. 2003 Sep 9;61(5):602-11.
著者: Optic Neuritis Study Group
雑誌名: Arch Neurol. 2008 Jun;65(6):727-32. doi: 10.1001/archneur.65.6.727.
Abstract/Text OBJECTIVE: To assess the risk of developing multiple sclerosis (MS) after optic neuritis and the factors predictive of high and low risk.
DESIGN: Subjects in the Optic Neuritis Treatment Trial, who were enrolled between July 1, 1988, and June 30, 1991, were followed up prospectively for 15 years, with the final examination in 2006.
SETTING: Neurologic and ophthalmologic examinations at 13 clinical sites.
PARTICIPANTS: Three hundred eighty-nine subjects with acute optic neuritis.
MAIN OUTCOME MEASURES: Development of MS and neurologic disability assessment.
RESULTS: The cumulative probability of developing MS by 15 years after onset of optic neuritis was 50% (95% confidence interval, 44%-56%) and strongly related to presence of lesions on a baseline non-contrast-enhanced magnetic resonance imaging (MRI) of the brain. Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with 1 or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without lesions on MRI, baseline factors associated with a substantially lower risk for MS included male sex, optic disc swelling, and certain atypical features of optic neuritis.
CONCLUSIONS: The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of MS. In the absence of MRI-detected lesions, male sex, optic disc swelling, and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a first acute onset of optic neuritis.

PMID 18541792  Arch Neurol. 2008 Jun;65(6):727-32. doi: 10.1001/archne・・・
著者: L K Fisniku, P A Brex, D R Altmann, K A Miszkiel, C E Benton, R Lanyon, A J Thompson, D H Miller
雑誌名: Brain. 2008 Mar;131(Pt 3):808-17. doi: 10.1093/brain/awm329. Epub 2008 Jan 29.
Abstract/Text Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis. However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable. In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability. We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years. CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years. Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 20.2 years (range 18-27.7). Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score. Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI. Multiple sclerosis was still relapsing-remitting in 39 (58%)--including 26 (39%) with a 'benign' course (EDSS < or = 3)--whilst 28 (42%) had developed secondary progression. T2 lesion volume at all time-points correlated moderately with 20-year EDSS (r(s) values 0.48 to 0.67; P < 0.001) and MSFC z-score [r(s) values (-0.50) to (-0.61); P < 0.001]. In those developing multiple sclerosis, a concurrent correlation of change in T2 lesion volume with change in EDSS was most evident in years 0-5 (r(s) = 0.69, P < 0.001). The estimated rate of lesion growth over 20 years was 0.80 cm3/year in those who retained a relapsing remitting multiple sclerosis course, and 2.89 cm3/year in those who developed secondary progressive multiple sclerosis, a difference of 2.09 cm3/year (95% CI: 0.77, 2.96; P < 0.001). This study extends previous follow-up of CIS patients and sheds new light on how the lesions evolve according to the natural history. Baseline MRI findings are predictive for development of clinically definite multiple sclerosis. Lesion volume and its change at earlier time points are correlated with disability after 20 years. Lesion volume increases for at least 20 years in relapse-onset multiple sclerosis and the rate of lesion growth is three times higher in those who develop secondary progressive than in those who remain relapsing remitting multiple sclerosis.

PMID 18234696  Brain. 2008 Mar;131(Pt 3):808-17. doi: 10.1093/brain/aw・・・
著者: M Tintoré, A Rovira, J Río, C Nos, E Grivé, N Téllez, R Pelayo, M Comabella, J Sastre-Garriga, X Montalban
雑誌名: Neurology. 2006 Sep 26;67(6):968-72. doi: 10.1212/01.wnl.0000237354.10144.ec.
Abstract/Text OBJECTIVE: To determine the relation between baseline MRI and both conversion to multiple sclerosis (MS) and development of disability in a cohort of patients with clinically isolated syndromes (CIS).
METHODS: From 1995 to 1998, 175 consecutive patients with CIS underwent brain MRI within 3 months of their first attack and again 12 months and 5 years later. We studied the number and location of lesions at baseline and development of new T2 lesions. We also analyzed conversion to MS and development of disability (Expanded Disability Status Scale [EDSS] > or = 3.0).
RESULTS: We included 156 patients with CIS followed for a median of 7 years. Compared to the reference group with 0 Barkhof criteria at baseline MRI, patients with one or two Barkhof criteria showed an adjusted hazard ratio (HR) of 6.1 (2.2 to 16.6) and patients with three to four Barkhof criteria of 17.0 (6.7 to 43) for conversion to MS and differentiated patients with low, medium, and high conversion risk. EDSS at year 5 correlated with baseline number of Barkhof criteria (r = 0.46, p < 0.0001). When categorizing by number of baseline lesions, similar results were seen. Patients with a baseline MRI with three to four Barkhof criteria had an adjusted HR of 3.9 (1.1 to 13.6) for reaching EDSS > or = 3.0. Only 10% of the latter had disability at year 5, but 40% reached this at 8 years.
CONCLUSIONS: Baseline MRI determines the risk for converting to clinically definite multiple sclerosis and correlates with disability at 5 years. The proportion of patients developing disability is low during the first 5 years but rapidly increases shortly after.

PMID 17000962  Neurology. 2006 Sep 26;67(6):968-72. doi: 10.1212/01.wn・・・
著者: M Clerico, F Faggiano, J Palace, G Rice, M Tintorè, L Durelli
雑誌名: Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005278. doi: 10.1002/14651858.CD005278.pub3. Epub 2008 Apr 16.
Abstract/Text BACKGROUND: Immunomodulatory drugs have been shown to be only modestly effective in clinically definite relapsing remitting multiple sclerosis (RRMS). It has been hypothesized that their efficacy could be higher if used at the first appearance of symptoms, that is in the clinically isolated syndromes (CIS) suggestive of demyelinating events, a pathology which carries a high risk to convert to clinically definite MS (CDMS).
OBJECTIVES: The objective of this review was to assess the effects of immunomodulatory drugs compared to placebo in adults in preventing conversion from CIS to CDMS which means the prevention of a second attack.
SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (June 2007), Cochrane Central Register of Controlled Trials (CENTRAL)The Cochrane Library Issue 3, 2007, MEDLINE (January 1966 to June 2007), EMBASE (January 1974 to June 2007) and reference lists of articles. We also contacted manufacturers and researchers in the field.
SELECTION CRITERIA: The trials selected were double-blind, placebo-controlled, randomised trials of CIS patients treated with immunomodulatory drugs.
DATA COLLECTION AND ANALYSIS: Study selection have been independently done by two reviewers. Two further reviewers independently assessed trial quality and extracted and analysed data. Study authors were contacted for additional informations. Adverse effects information was collected from the trials.
MAIN RESULTS: Only three trials tested the efficacy of interferon (IFN) beta including a total of 1160 participants (639 treatment, 521 placebo); no trial tested the efficacy of glatiramer acetate (GA). The metanalyses showed that the proportion of patients converting to CDMS was significantly lower in IFN beta-treated than in placebo-treated patients both after one year (pooled OR 0.53; 95% CI, 0.40 to 0.71; p <0.0001) as well as after two years of follow-up (pooled OR 0.52; 95% CI, 0.38 to 0.70; p <0.0001). Early treatment with IFN beta was associated with the side effect profile reported by the randomised controlled trials with this drug. Since side effects were reported with some heterogeneity in the three studies the metanalysis was possible only for the frequency of serious adverse events, not significantly different in IFN beta-treated or placebo-treated patients.
AUTHORS' CONCLUSIONS: The efficacy of IFN beta treatment on preventing the conversion from CIS to CDMS was confirmed over two years of follow-up. Since patients had some clinical heterogeneity (length of follow-up, clinical findings of initial attack), it could be useful for the clinical practice to further analyse the efficacy of IFN beta treatment in different patient subgroups.

PMID 18425915  Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005278. d・・・
著者: G Comi, V Martinelli, M Rodegher, L Moiola, O Bajenaru, A Carra, I Elovaara, F Fazekas, H P Hartung, J Hillert, J King, S Komoly, C Lubetzki, X Montalban, K M Myhr, M Ravnborg, P Rieckmann, D Wynn, C Young, M Filippi, PreCISe study group
雑誌名: Lancet. 2009 Oct 31;374(9700):1503-11. doi: 10.1016/S0140-6736(09)61259-9. Epub 2009 Oct 6.
Abstract/Text BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis.
METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224.
FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]).
INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI.
FUNDING: Teva Pharmaceutical Industries, Israel.

PMID 19815268  Lancet. 2009 Oct 31;374(9700):1503-11. doi: 10.1016/S01・・・
著者: Anat Achiron, Irena Kishner, Ida Sarova-Pinhas, Havi Raz, Meir Faibel, Yael Stern, Mor Lavie, M Gurevich, Mark Dolev, David Magalashvili, Yoram Barak
雑誌名: Arch Neurol. 2004 Oct;61(10):1515-20. doi: 10.1001/archneur.61.10.1515.
Abstract/Text BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to reduce disease activity in patients with relapsing-remitting multiple sclerosis. We assessed the effect of IVIg treatment in patients after the first neurological event suggestive of demyelinative disease and evaluated the occurrence of a second attack and dissemination in time demonstrated by brain magnetic resonance imaging within the first year from onset.
METHODS: We conducted a randomized, placebo-controlled, double-blind study in 91 eligible patients enrolled within the first 6 weeks of neurological symptoms. Patients were randomly assigned to receive IVIg treatment (2-g/kg loading dose) or placebo, with boosters (0.4 g/kg) given once every 6 weeks for 1 year. Neurological and clinical assessments were done every 3 months, and brain magnetic resonance imaging was performed at baseline and the end of the study.
RESULTS: The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in the IVIg treatment group compared with the placebo group (rate ratio, 0.36 [95% confidence interval, 0.15-0.88]; P = .03). Patients in the IVIg treatment group had a significant reduction in the volume and number of T2-weighted lesions and in the volume of gadolinium-enhancing lesions as compared with the placebo group (P = .01, P = .01, and P = .03, respectively). Treatment was well tolerated, compliance was high, and incidence of adverse effects did not differ significantly between groups.
CONCLUSIONS: Intravenous immunoglobulin treatment for the first year from onset of the first neurological event suggestive of demyelinative disease significantly lowers the incidence of a second attack and reduces disease activity as measured by brain magnetic resonance imaging.

PMID 15477504  Arch Neurol. 2004 Oct;61(10):1515-20. doi: 10.1001/arch・・・
著者: D H Miller, B G Weinshenker, M Filippi, B L Banwell, J A Cohen, M S Freedman, S L Galetta, M Hutchinson, R T Johnson, L Kappos, J Kira, F D Lublin, H F McFarland, X Montalban, H Panitch, J R Richert, S C Reingold, C H Polman
雑誌名: Mult Scler. 2008 Nov;14(9):1157-74. doi: 10.1177/1352458508096878. Epub 2008 Sep 19.
Abstract/Text BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis.
METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases.
RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system.
CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

PMID 18805839  Mult Scler. 2008 Nov;14(9):1157-74. doi: 10.1177/135245・・・
著者: Catherine M Dalton, Peter A Brex, Katherine A Miszkiel, Simon J Hickman, David G MacManus, Gordon T Plant, Alan J Thompson, David H Miller
雑誌名: Ann Neurol. 2002 Jul;52(1):47-53. doi: 10.1002/ana.10240.
Abstract/Text Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow-up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

PMID 12112046  Ann Neurol. 2002 Jul;52(1):47-53. doi: 10.1002/ana.1024・・・
著者: D T Okuda, E M Mowry, A Beheshtian, E Waubant, S E Baranzini, D S Goodin, S L Hauser, D Pelletier
雑誌名: Neurology. 2009 Mar 3;72(9):800-5. doi: 10.1212/01.wnl.0000335764.14513.1a. Epub 2008 Dec 10.
Abstract/Text BACKGROUND: The discovery and broad application of MRI in medicine has led to an increased awareness in the number of patients with incidental white matter pathology in the CNS. Routinely encountered in clinical practice, the natural history or evolution of such individuals with respect to their risk of developing multiple sclerosis (MS) is unclear.
OBJECTIVE: To investigate the natural history of patients who exhibit incidental imaging findings highly suggestive of MS pathology.
METHODS: Detailed clinical and radiologic data were obtained from asymptomatic patients with MRI anomalies suggestive of MS.
RESULTS: The cohort consisted of 41 female and 3 male subjects (median age = 38.5, range: 16.2-67.1). Clinical evaluations were performed in 44 patients at the time of initial imaging; longitudinal clinical follow-up occurred for 30 patients, and longitudinal MRI data were acquired for 41 patients. Neurologic examination at the time of the initial MRI scans was normal in nearly all cases. While radiologic progression was identified in 59% of cases, only 10 patients converted to either clinically isolated syndrome or definite MS. The presence of contrast-enhancing lesions on the initial MRI was predictive of dissemination in time on repeat imaging of the brain (hazard ratio [HR] = 3.4, 95% confidence interval [1.3, 8.7], p = 0.01).
CONCLUSION: Individuals with MRI anomalies highly suggestive of demyelinating pathology, not better accounted for by another disease process, are very likely to experience subsequent radiologic or clinical events related to multiple sclerosis. Additional studies will be necessary to fully define this risk.

PMID 19073949  Neurology. 2009 Mar 3;72(9):800-5. doi: 10.1212/01.wnl.・・・
著者: Dennis Bourdette, Jack Simon
雑誌名: Neurology. 2009 Mar 3;72(9):780-1. doi: 10.1212/01.wnl.0000337255.89622.ce. Epub 2008 Dec 10.
Abstract/Text
PMID 19073944  Neurology. 2009 Mar 3;72(9):780-1. doi: 10.1212/01.wnl.・・・
著者: F Barkhof, M Filippi, D H Miller, P Scheltens, A Campi, C H Polman, G Comi, H J Adèr, N Losseff, J Valk
雑誌名: Brain. 1997 Nov;120 ( Pt 11):2059-69.
Abstract/Text We compared MRI criteria used to predict conversion of suspected multiple sclerosis to clinically definite multiple sclerosis. Seventy-four patients with clinically isolated neurological symptoms suggestive of multiple sclerosis were studied with MRI. Logistic regression analysis was used to remove redundant information, and a diagnostic model was built after each MRI parameter was dichotomized according to maximum accuracy using receiver operating characteristic analysis. Clinically definite multiple sclerosis developed in 33 patients (prevalence 45%). The optimum cut-off point (number of lesions) was one for most MRI criteria (including gadolinium-enhancement and juxta-cortical lesions), but three for periventricular lesions, and nine for the total number of T2-lesions. Only gadolinium-enhancement and juxta-cortical lesions provided independent information. A final model which, in addition, included infratentorial and periventricular lesions, had an accuracy of 80%, and having more abnormal criteria, predicted conversion to clinically definite multiple sclerosis strongly. The model performed better than the criteria of Paty et al. (Neurology 1988; 38: 180-5) and of Fazekas et al. (Neurology 1988; 38: 1822-5). We concluded that a four-parameter dichotomized MRI model including gadolinium-enhancement, juxtacortical, infratentorial and periventricular lesions best predicts conversion to clinically definite multiple sclerosis.

PMID 9397021  Brain. 1997 Nov;120 ( Pt 11):2059-69.
著者: D M Miller, B Weinstock-Guttman, F Béthoux, J C Lee, G Beck, V Block, L Durelli, L LaMantia, D Barnes, F Sellebjerg, R A Rudick
雑誌名: Mult Scler. 2000 Aug;6(4):267-73.
Abstract/Text Despite recent advances in multiple sclerosis treatment, patients experience relapses for which standard treatment remains glucocorticosteroids (GCS). However, there is limited information comparing doses or routes of administration for different GCS types or the benefit of GCS compared to natural recovery. Currently, high dose (HD) methylprednisolone (MP) is the preferred therapy. We conducted meta-analyses of published studies assessing MP at different doses and in comparison to other steroid products or no treatment. Relevant studies were identified through predetermined processes and five articles met the inclusion criteria. Three studies compared HD MP to placebo; two studies compared the effect of HD MP and low dose (LD) MP; only one accepted report compared HD MP to another GCS. This report could not be included in a meta-analysis. The meta-analysis of HD MP vsplacebo studies indicated a mean treatment difference of 0.76 in Expanded Disability Status Score (EDSS) changes from baseline. The meta-analysis of HD and LD MP demonstrated no difference in EDSS change. Despite these rather obvious findings, these meta-analyses have been valuable in identifying further research questions. We recommend studies to determine optimum benefit related to dosage, timing for starting therapy and the most appropriate GCS type. Given the advances in MS therapeutics, these studies will have to include patients on additional disease modifying therapy. Multiple Sclerosis (2000) 6 267 - 273

PMID 10962547  Mult Scler. 2000 Aug;6(4):267-73.
著者: G Filippini, F Brusaferri, W A Sibley, A Citterio, G Ciucci, R Midgard, L Candelise
雑誌名: Cochrane Database Syst Rev. 2000;(4):CD001331. doi: 10.1002/14651858.CD001331.
Abstract/Text BACKGROUND: Corticosteroids are often used to improve the rate of recovery from acute exacerbation in multiple sclerosis (MS) patients. However, it is still unclear just how relatively effective these agents are and the type of drug, optimal dose, frequency, duration of treatment and route of administration are unknown.
OBJECTIVES: The object of this review was to determine the efficacy and safety of corticosteroids or ACTH in reducing the short and long term morbidity from MS. Moreover, we wished to examine from indirect comparisons if the effect of corticosteroids is different according to different doses and drugs, routes of administration, length of treatment.
SEARCH STRATEGY: A search strategy developed for the Cochrane MS Group (last searched: June 1999) completed with handsearching and personal contacts with trialists and pharmaceutical companies was used.
SELECTION CRITERIA: All randomised, double-blind, unconfounded trials comparing corticosteroids or ACTH to placebo in patients with MS, treated for acute exacerbations, without any age or severity restrictions, were evaluated.
DATA COLLECTION AND ANALYSIS: Two reviewers independently selected articles for inclusion, assessed trials' quality and extracted the data. A third reviewer cross-checked them and disagreements were resolved by a joint discussion.
MAIN RESULTS: Six trials contributed to this review; a total of 377 participants (199 treatment, 178 placebo) were randomised. The drugs analysed were methylprednisolone (MP) (four trials, 140 patients) and ACTH (two trials, 237 patients). Overall, MP or ACTH showed a protective effect against the disease getting worse or stable within the first five weeks of treatment (odds ratio[OR]=0.37, 95% confidence interval [CI] 0.24-0.57) with some but non significant greater effect for MP and intravenous administration. Short (five days) or long (15 days) duration of treatment with MP did not show any significant difference. Only one study (with 51 patients) reported data after one year of follow-up: no difference between oral MP and placebo in the prevention of new exacerbations or improvement in long term disability was detected. No data are available beyond one year of follow-up to indicate whether steroids or ACTH have any effect on long-term progression. One study reported that a short term treatment with high dose intravenous MP was not attended by adverse events. On the contrary, gastrointestinal symptoms and psychic disorders were significantly more common in the oral, high-dose MP than in the placebo group. Weight gain and edema were significantly more frequent in the ACTH group than in controls.
REVIEWER'S CONCLUSIONS: We found evidence favouring the corticosteroid MP for acute exacerbation in MS patients. Data are insufficient to reliably estimate effect of corticosteroids on prevention of new exacerbations and reduction of long-term disability. Studies assessing long term risk/benefit and adverse effects of corticosteroids in MS patients are urgently needed.

PMID 11034713  Cochrane Database Syst Rev. 2000;(4):CD001331. doi: 10.・・・
著者: Jodie M Burton, Paul W O'Connor, Marika Hohol, Joseph Beyene
雑誌名: Cochrane Database Syst Rev. 2012 Dec 12;12:CD006921. doi: 10.1002/14651858.CD006921.pub3. Epub 2012 Dec 12.
Abstract/Text BACKGROUND: This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006921. DOI: 10.1002/14651858.CD006921.pub2).Multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), is characterized by recurrent relapses of CNS inflammation ranging from mild to severely disabling.  Relapses have long been treated with steroids to reduce inflammation and hasten recovery.  However, the commonly used intravenous methylprednisolone (IVMP) requires repeated infusions with the added costs of homecare or hospitalization, and may interfere with daily responsibilities. Oral steroids have been used in place of intravenous steroids, with lower direct and indirect costs.
OBJECTIVES: The primary objective was to compare efficacy of oral versus intravenous steroids in promoting disability recovery in MS relapses <= six weeks.  Secondary objectives included subsequent relapse rate, disability, ambulation, hospitalization, immunological markers, radiological markers, and quality of life.
SEARCH METHODS: A literature search was performed using Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Trials Register (January 2012), abstracts from meetings of the American Academy of Neurology (2008-2012), the European Federation of Neurological Sciences (2008-2012), the European Committee for Treatment and Research in Multiple Sclerosis and American Committee for Treatment and Research in Multiple Sclerosis (2008-2012) handsearching. No language restrictions were applied.
SELECTION CRITERIA: Randomized or quasi-randomized trials comparing oral versus intravenous steroids for acute relapses (<= six weeks) in patients with clinically definite MSover age 16 were eligible.
DATA COLLECTION AND ANALYSIS: Three review authors (JB, PO and MH) participated in the independent assessment of all published articles as potentially relevant to the review. Any disagreement was resolved by discussion among review authors.We contacted study authors for additional information.Methodological quality was assessed by the same three review authors. Relevant data were extracted, and effect size was reported as mean difference (MD), mean difference (MD), odds ratio (OR) and absolute risk difference (ARD).
MAIN RESULTS: With this current update, a total of five eligible studies (215 patients) were identified. Only one outcome, the proportion of patients with Expanded Disability Status Scale (EDSS) improvement at four weeks, was common to three trials, while two trials examined magnetic resonance imaging (MRI) outcomes. The results of this review shows there is no significant difference in relapse recovery at week four (MD -0.22, 95% confidence interval (95% CI), 0.71 to 0.26, P = 0.20) nor differences in magnetic resonance imaging (MRI) gadolinium enhancement activity based on oral versus intravenous steroid treatment. However, only two of the five studies employed more current and rigorous methodological techniques, so these results must be taken with some caution. The Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial and the "Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses" (COPOUSEP) trial, designed to address such limitations, are currently underway.
AUTHORS' CONCLUSIONS: The analysis of the five included trials comparing intravenous versus oral steroid therapy for MS relapses do not demonstrate any significant differences in clinical (benefits and adverse events), radiological or pharmacological outcomes. Based on the evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy in the treatment of MS relapses.

PMID 23235634  Cochrane Database Syst Rev. 2012 Dec 12;12:CD006921. do・・・
著者: Ryo Yamasaki, Takuya Matsushita, Toshiyuki Fukazawa, Kazumasa Yokoyama, Kazuo Fujihara, Mieko Ogino, Takanori Yokota, Katsuichi Miyamoto, Masaaki Niino, Kyoichi Nomura, Ryo Tomioka, Masami Tanaka, Izumi Kawachi, Takashi Ohashi, Ken-Ichi Kaida, Makoto Matsui, Yuji Nakatsuji, Hirofumi Ochi, Hikoaki Fukaura, Takashi Kanda, Akiko Nagaishi, Kanae Togo, Hidehiro Mizusawa, Hiroyuki Murai, Jun-Ichi Kira
雑誌名: Mult Scler. 2016 Sep;22(10):1337-48. doi: 10.1177/1352458515617248. Epub 2015 Nov 12.
Abstract/Text BACKGROUND: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO).
OBJECTIVE: To explain differences in treatment responses of MS and NMO patients to IVMP.
METHODS: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases.
RESULTS: In MS patients, decreased EDSS score was significant after the first (-0.8 ± 0.9), second (-0.7 ± 0.9), and third (-0.7 ± 0.8) courses (p < 0.05), but not after the fourth (-0.3 ± 0.7) and fifth (-0.5 ± 0.6). However, decreased EDSS score was only significant after the first course (-0.5 ± 1.5, p < 0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p < 0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p < 0.05).
CONCLUSION: IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.

© The Author(s), 2015.
PMID 26564994  Mult Scler. 2016 Sep;22(10):1337-48. doi: 10.1177/13524・・・
著者:
雑誌名: Lancet. 1998 Nov 7;352(9139):1491-7.
Abstract/Text BACKGROUND: The beneficial effects of interferon beta have only been shown for patients in the relapsing-remitting phase of multiple sclerosis (MS). The role of interferon beta in the treatment of patients who are in the secondary progressive phase of the disease (SP-MS), and for whom no effective drug treatment is available, has not been assessed.
METHODS: In this multicentre, double-masked, randomised, placebo-controlled trial, outpatients with SP-MS having scores of 3.0-6.5 on the Expanded Disability Status Scale (EDSS) received either 8 million IU interferon beta-1b every other day subcutaneously, or placebo, for up to 3 years. The primary outcome was the time to confirmed progression in disability as measured by a 1.0 point increase on the EDSS, sustained for at least 3 months, or a 0.5 point increase if the baseline EDSS was 6.0 or 6.5. A prospectively planned interim analysis of safety and efficacy of the intention-to-treat population was done after all patients had been in the study for at least 2 years.
FINDINGS: 358 patients with SP-MS were allocated placebo and 360 were allocated interferon beta-1b; 57 patients (31 placebo, 26 interferon beta-1b) were lost to follow-up. There was a highly significant difference in time to confirmed progression of disability in favour of interferon beta-1b (p=0.0008). Interferon beta-1b delayed progression for 9-12 months in a study period of 2-3 years. The odds ratio for confirmed progression was 0.65 (95% CI 0.52-0.83). This beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive deterioration without relapses. Positive results were also obtained regarding time to becoming wheelchair-bound, relapse rate and severity, number of steroid treatments and hospital admissions, as well as on magnetic resonance imaging variables. The drug was safe and side effects were in line with previous experience with interferon beta-1b. The study was stopped after the interim results gave clear evidence of efficacy.
INTERPRETATION: Treatment with interferon beta-1b delays sustained neurological deterioration in patients with SP-MS. Interferon beta-1b is the first treatment to show a therapeutic effect in patients with SP-MS.

PMID 9820296  Lancet. 1998 Nov 7;352(9139):1491-7.
著者: P D Molyneux, G J Barker, F Barkhof, K Beckmann, F Dahlke, M Filippi, M Ghazi, D Hahn, D MacManus, C Polman, C Pozzilli, L Kappos, A J Thompson, K Wagner, T Yousry, D H Miller, European Study Group on Interferon Beta-1b in Secondary Progressive MS
雑誌名: Neurology. 2001 Dec 26;57(12):2191-7.
Abstract/Text BACKGROUND: The recently completed placebo-controlled multicenter randomized trial of interferon beta-1b (Betaferon) in 718 patients with secondary progressive MS shows significant delay of disease progression and reduction of relapse rate. This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with secondary progressive MS.
METHODS: Brain T2-weighted lesion volume was measured annually in all available patients, with visual analysis to identify any new or enlarging (active) T2 lesions at each annual time point. A subgroup of 125 patients had monthly gadolinium-enhanced, T1-weighted imaging at months 0 to 6 and 18 to 24. Relapses were documented and expanded disability status scale (EDSS) was measured every 3 months.
RESULTS: For the annual MRI outcomes, a significant but modest correlation was identified between the change in T2 lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS (r = 0.17, p < 0.0001). There were significant correlations between the cumulative number of active T2 lesions and 1) change in EDSS (r = 0.18, p < 0.0001) and 2) relapse rate (r = 0.24, p < 0.0001). In the subgroup of 125 patients undergoing monthly imaging, MRI lesion activity was correlated with relapse rate over months 0 to 24 (r = 0.24, p = 0.006) but not with change in EDSS.
CONCLUSIONS: These results confirm that the clinical-MRI relationships previously identified in relapsing-remitting MS still are apparent in the secondary progressive phase of the disease and support the use of MRI as a relevant outcome measure. In view of the relatively modest nature of the correlations, it seems unwise to rely on such MRI measures alone as primary efficacy variables in secondary progressive MS trials.

PMID 11756596  Neurology. 2001 Dec 26;57(12):2191-7.
著者: Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group
雑誌名: Neurology. 2001 Jun 12;56(11):1496-504.
Abstract/Text BACKGROUND: The beneficial effect of interferon beta on exacerbations in relapsing-remitting MS has been demonstrated repeatedly, but results concerning disability vary.
OBJECTIVE: This multicenter, randomized, parallel-group, placebo-controlled study tested two doses of interferon beta-1a in patients with secondary progressive MS, which may include relapses but is dominated by accumulating disability.
METHODS: A total of 618 patients received subcutaneous placebo or interferon beta-1a, 22 or 44 microg three times weekly for 3 years. Patients were assessed every 3 months.
RESULTS: The primary outcome, time to confirmed progression in disability, was not significantly affected by treatment (hazard ratio, 0.83; 95% CI, 0.65 to 1.07; p = 0.146 for 44 microg versus placebo). Relapse rate was reduced from 0.71 per year with placebo to 0.50 per year with treatment (p < 0.001 for both doses). Significant treatment effects were seen on other exacerbation-related outcomes and on a composite measure incorporating five separate clinical and MRI outcomes. The hazard ratio for time to progression for the combined interferon beta-1a groups compared with placebo was 0.74 among patients reporting relapses in the 2 years before study (p = 0.055), and 1.01 for those without prestudy relapses (p = 0.934). An unexpected treatment-by-sex interaction favored women. The drug was well tolerated.
CONCLUSIONS: Treatment with interferon beta-1a did not significantly affect disability progression in this cohort, although significant treatment benefit was observed on exacerbation-related outcomes. Exploratory post hoc analyses suggested greater benefit in women and in patients who had reported at least one relapse in the 2 years before the study.

PMID 11402106  Neurology. 2001 Jun 12;56(11):1496-504.
著者: Emmanuelle Leray, Jacqueline Yaouanq, Emmanuelle Le Page, Marc Coustans, David Laplaud, Joël Oger, Gilles Edan
雑誌名: Brain. 2010 Jul;133(Pt 7):1900-13. doi: 10.1093/brain/awq076. Epub 2010 Apr 27.
Abstract/Text It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, 'Phase 1', from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, 'Phase 2', from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan-Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26,273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, >or=15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependent on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis.

PMID 20423930  Brain. 2010 Jul;133(Pt 7):1900-13. doi: 10.1093/brain/a・・・
著者: Michel C Clanet, Jerry S Wolinsky, Raymond J Ashton, Hans-Peter Hartung, Stephen C Reingold
雑誌名: Mult Scler. 2014 Sep;20(10):1306-11. doi: 10.1177/1352458513513207. Epub 2013 Nov 30.
Abstract/Text BACKGROUND: Risk for multiple sclerosis (MS) disease-modifying therapies (DMT) must be assessed on an ongoing basis. Early concerns regarding the first-approved DMTs for MS have been mitigated, but recently licensed therapies have been linked to possibly greater risks.
OBJECTIVES: The objective of this review is to discuss risk assessment in MS therapeutics based on an international workshop and comprehensive literature search and recommend strategies for risk assessment/monitoring.
RESULTS: Assessment and perception of therapeutic risks vary between patients, doctors and regulators. Acceptability of risk depends on the magnitude of risk and the demonstrated clinical benefits of any agent. Safety signals must be distinguishable from chance occurrences in a clinical trial and in long-term use of medications. Post-marketing research is crucial for assessing longer-term safety in large patient cohorts. Reporting of adverse events is becoming more proactive, allowing more rapid identification of risks. Communication about therapeutic risks and their relationship to clinical benefit must involve patients in shared decision making.
CONCLUSIONS: It is difficult to produce a general risk-assessment algorithm for all MS therapies. Specific algorithms are required for each DMT in every treated-patient population. New and evolving risks must be evaluated and communicated rapidly to allow patients and physicians to be well informed and able to share treatment decisions.

© The Author(s) 2013.
PMID 24293456  Mult Scler. 2014 Sep;20(10):1306-11. doi: 10.1177/13524・・・
著者: Jens Ingwersen, Orhan Aktas, Hans-Peter Hartung
雑誌名: Neurotherapeutics. 2016 Jan;13(1):47-57. doi: 10.1007/s13311-015-0412-4.
Abstract/Text Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of disease-modifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult. A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis.

PMID 26701666  Neurotherapeutics. 2016 Jan;13(1):47-57. doi: 10.1007/s・・・
著者: C McGuigan, M Craner, J Guadagno, R Kapoor, G Mazibrada, P Molyneux, R Nicholas, J Palace, O R Pearson, D Rog, C A Young
雑誌名: J Neurol Neurosurg Psychiatry. 2016 Feb;87(2):117-25. doi: 10.1136/jnnp-2015-311100. Epub 2015 Oct 22.
Abstract/Text The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
PMID 26492930  J Neurol Neurosurg Psychiatry. 2016 Feb;87(2):117-25. d・・・
著者: J S Sloka, M Stefanelli
雑誌名: Mult Scler. 2005 Aug;11(4):425-32.
Abstract/Text Methylprednisolone plays an important role in the current treatment of multiple sclerosis (MS), particularly in the acute phase of relapse. It acts in various ways to decrease the inflammatory cycle including: dampening the inflammatory cytokine cascade, inhibiting the activation of T cells, decreasing the extravasation of immune cells into the central nervous system, facilitating the apoptosis of activated immune cells, and indirectly decreasing the cytotoxic effects of nitric oxide and tumor necrosis factor alpha. This paper reviews the most recent observations on these mechanisms both to understand the disease mechanism and its treatment. As more becomes known about these mechanisms, it may become possible to design treatment regimes that are more specific towards both the individual and the disease state.

PMID 16042225  Mult Scler. 2005 Aug;11(4):425-32.
著者: D S Goodin, E M Frohman, G P Garmany, J Halper, W H Likosky, F D Lublin, D H Silberberg, W H Stuart, S van den Noort, Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines
雑誌名: Neurology. 2002 Jan 22;58(2):169-78.
Abstract/Text
PMID 11805241  Neurology. 2002 Jan 22;58(2):169-78.
著者: D E Goodkin, R A Rudick, S VanderBrug Medendorp, M M Daughtry, K M Schwetz, J Fischer, C Van Dyke
雑誌名: Ann Neurol. 1995 Jan;37(1):30-40. doi: 10.1002/ana.410370108.
Abstract/Text A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

PMID 7818255  Ann Neurol. 1995 Jan;37(1):30-40. doi: 10.1002/ana.4103・・・
著者: Eugenio Pucci, Giorgio Giuliani, Alessandra Solari, Silvana Simi, Silvia Minozzi, Carlo Di Pietrantonj, Ian Galea
雑誌名: Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007621. doi: 10.1002/14651858.CD007621.pub2. Epub 2011 Oct 5.
Abstract/Text BACKGROUND: Natalizumab (NTZ) (Tysabri(®)) is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier, thus reducing inflammation in central nervous system, and has been approved worldwide for the treatment of relapsing-remitting multiple sclerosis (RRMS).
OBJECTIVES: To evaluate the efficacy, tolerability and safety of NTZ in the treatment of patients with RRMS.
SEARCH STRATEGY: We searched the Cochrane Multiple Sclerosis Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 1), MEDLINE (PubMed) and EMBASE, all up to 19 February 2010, and bibliographies of papers. Handsearching was carried out. Trialists and pharmaceutical companies were contacted. Furthermore, the websites of US Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMA) and the National Institute for health and Clinical Excellence (NICE) were also checked.
SELECTION CRITERIA: All double-blind, randomised, controlled trials analysing more than a single infusion of NTZ (dosage > 3 mg/kg intravenous infusion every 4 weeks), also including its use as add-on treatment, versus placebo or other drugs in patients with RRMS. No restrictions on the basis of duration of treatment or length of follow up.
DATA COLLECTION AND ANALYSIS: Three reviewers independently selected articles which met the inclusion criteria. Disagreements were solved by discussion. Two reviewers independently extracted the data and assessed the methodological quality of each trial. Missing data was sought by contacting principal authors and Biogen Idec, through Biogen-Dompé Italia.
MAIN RESULTS: Three studies met the inclusion criteria. These included one placebo-controlled trial (942 patients) and two add-on placebo-controlled trials, i.e. one plus glatiramer acetate (110 patients) and the second plus interferon beta-1a (1171 patients).This review assessed the efficacy, tolerability and safety of NTZ in patients with RRMS. Data was conclusive with respect to efficacy and tolerability, but not safety. As far as efficacy is concerned, the results showed statistically significant evidence in favour of NTZ for all the primary outcomes and for the secondary ones where data was available. NTZ reduced the risk of experiencing at least one new exacerbation at 2 years by about 40% and of experiencing progression at 2 years by about 25% as compared to a control group. MRI parameters showed statistical evidence in favour of participants receiving NTZ. Infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis and menstrual disorders were reported as adverse events (AEs) more frequently after NTZ treatment. In this review NTZ was found to be well tolerated over a follow-up period of two years: the number of patients experiencing at least one AE (including severe and serious AEs) during this period did not differ between NTZ-treated patients and controls. Safety concerns have been raised about Progressive Multifocal Leukoencephalopathy (PML). In the trials included in this review, two cases of PML were encountered: one in a patient who had received 29 doses of NTZ and a second fatal case of PML in another patient after 37 doses of NTZ. Our protocol was insufficient to evaluate PML risk as well as other rare and long-term adverse events such as cancers and other opportunistic infections, which are very important issues in considering the risk/benefit ratio of NTZ.
AUTHORS' CONCLUSIONS: Although one trial did not contribute to efficacy results due to its duration, we found robust evidence in favour of a reduction in relapses and disability at 2 years in RRMS patients treated with NTZ. The drug was well tolerated. There are current significant safety concerns due to reporting of an increasing number of PML cases in patients treated with NTZ. This review was unable to provide an up-to-date systematic assessment of the risk due to the maximum 2 year-duration of the trials included. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs.All the data in this review came from trials supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.

PMID 21975773  Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007621. d・・・
著者:
雑誌名: Neurology. 1993 Apr;43(4):655-61.
Abstract/Text We report a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB) in 372 ambulatory patients with relapsing-remitting multiple sclerosis (MS). Entry criteria included an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 and at least two exacerbations in the previous 2 years. One-third of the patients received placebo, one-third 1.6 million international units (MIU) of IFNB, and one-third 8 MIU of IFNB, self-administered by subcutaneous injections every other day. The primary end points were differences in exacerbation rates and proportion of patients remaining exacerbation-free. The annual exacerbation rate for patients receiving placebo was 1.27; for 1.6 MIU IFNB, 1.17; and for 8 MIU IFNB, 0.84 after 2 years. Exacerbation rates were significantly lower in both treatment groups compared with the placebo group (8 MIU versus placebo, p = 0.0001; 1.6 MIU versus placebo, p = 0.0101; and 8 MIU versus 1.6 MIU, p = 0.0086), suggesting a dosage effect. The reduction in exacerbation severity in the 8 MIU group was attributable to a twofold reduction in the frequency of moderate and severe attacks. More patients in the 8 MIU group (n = 36) were exacerbation-free at 2 years compared with the placebo group (n = 18; p = 0.007). EDSS scores changed little from baseline in both the placebo and treatment arms. Accordingly, a significant change in disability could not be discerned in this trial. Finally, in serial MRIs, MS activity was significantly less in the high-dose IFNB group.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 8469318  Neurology. 1993 Apr;43(4):655-61.
著者: G J Zhao, R A Koopmans, D K Li, L Bedell, D W Paty
雑誌名: Neurology. 2000 Jan 11;54(1):200-6.
Abstract/Text OBJECTIVE: To determine whether the efficacy of interferon beta-1b (IFNbeta-1b) on lesion activity could be shown with annual analysis of MRI.
BACKGROUND: Clinical outcomes and MRI burden of disease changes in MS patients in a multicenter double-blind placebo-controlled 5-year trial of IFNbeta-1b have been reported, together with an analysis of 6-weekly MRI activity in a small subgroup during 2 years. MRI activity measurements based on annual scans have not been documented.
METHODS: Patients were randomized into three treatment arms: placebo, 1.6 mIU, and 8 mIU IFNbeta-1b self-administered subcutaneously every other day. Active lesions were identified as new, enlarging, or recurrent on proton density and T2-weighted MRI scans. Gadolinium was not used. An annual accumulation activity index was developed as an additional analysis of lesion activity.
RESULTS: During the 5 years, both high- and low-dose IFNbeta-1b groups showed a striking reduction in lesion annual accumulation activity on the activity index versus placebo (p = 0.001). Thirty-five percent of the high-dose patients and 29% of the low-dose patients were MRI inactive by this method of analysis, whereas only 16% of placebo patients were inactive (p = 0.001, placebo versus 8 mIU).
CONCLUSIONS: This analysis of the annual accumulation of lesion activity shows that the previously reported treatment effect seen on MRI scanning once every 6 weeks in a subcohort of the patients can also be seen on yearly scans. This annual accumulation activity analysis provides an independent MRI confirmation of a treatment and dose effect for IFNbeta-1b.

PMID 10636148  Neurology. 2000 Jan 11;54(1):200-6.
著者: T Saida, K Tashiro, Y Itoyama, T Sato, Y Ohashi, Z Zhao, Interferon Beta-1b Multiple Sclerosis Study Group of Japan
雑誌名: Neurology. 2005 Feb 22;64(4):621-30. doi: 10.1212/01.WNL.0000151856.10387.E2.
Abstract/Text OBJECTIVE: To assess the efficacy of interferon beta-1b (IFNB-1b) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS).
BACKGROUND: The effects of IFNB in RRMS have been assessed in study populations comprised predominantly of white patients. MS in Japanese patients is different from that in white patients in that there are two different presentations--classic MS (C-MS) and optic-spinal MS (OS-MS)--and chronic progressive forms are infrequent.
METHODS: A total of 205 Japanese patients with RRMS were randomized to receive 50 microg or 250 microg (1.6 or 8.0 MIU) IFNB-1b administered SC every other day for up to 2 years. The primary endpoint was annual relapse rate. Secondary endpoints included further relapse-related and MRI outcome measures, as well as changes in Expanded Disability Status Scale and Neurologic Rating Scale. Efficacy was assessed in 188 patients, and safety was assessed in 192 patients. Supplemental ad hoc subgroup analyses were also performed for patients with OS-MS and those with C-MS.
RESULTS: Annual relapse rates were 0.763 in the 250 microg group and 1.069 in the 50 microg group, a relative reduction of 28.6% (p = 0.047). Results for all secondary endpoints favored 250 microg IFNB-1b. Subgroup analyses suggested that the magnitude and direction of treatment effect in patients with OS-MS and C-MS was similar, albeit not significant due to small sample size.
CONCLUSIONS: Interferon beta-1b (IFNB-1b) 250 microg significantly reduced relapse rates and change in MRI lesion area in Japanese patients with relapsing-remitting multiple sclerosis, and seemed to be comparably effective in optic-spinal multiple sclerosis (MS) and classic MS. The response to treatment with IFNB-1b in Japanese patients with MS suggests that a common pathogenesis and underlying genetic characteristics are shared with white patients.

PMID 15728282  Neurology. 2005 Feb 22;64(4):621-30. doi: 10.1212/01.WN・・・
著者: L D Jacobs, D L Cookfair, R A Rudick, R M Herndon, J R Richert, A M Salazar, J S Fischer, D E Goodkin, C V Granger, J H Simon, J J Alam, D M Bartoszak, D N Bourdette, J Braiman, C M Brownscheidle, M E Coats, S L Cohan, D S Dougherty, R P Kinkel, M K Mass, F E Munschauer, R L Priore, P M Pullicino, B J Scherokman, R H Whitham
雑誌名: Ann Neurol. 1996 Mar;39(3):285-94. doi: 10.1002/ana.410390304.
Abstract/Text The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.

PMID 8602746  Ann Neurol. 1996 Mar;39(3):285-94. doi: 10.1002/ana.410・・・
著者: J H Simon, L D Jacobs, M Campion, K Wende, N Simonian, D L Cookfair, R A Rudick, R M Herndon, J R Richert, A M Salazar, J J Alam, J S Fischer, D E Goodkin, C V Granger, M Lajaunie, A L Martens-Davidson, M Meyer, J Sheeder, K Choi, A L Scherzinger, D M Bartoszak, D N Bourdette, J Braiman, C M Brownscheidle, R H Whitham
雑誌名: Ann Neurol. 1998 Jan;43(1):79-87. doi: 10.1002/ana.410430114.
Abstract/Text The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon beta-1a (IFNbeta-1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNbeta-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNbeta-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNbeta-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNbeta-1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.

PMID 9450771  Ann Neurol. 1998 Jan;43(1):79-87. doi: 10.1002/ana.4104・・・
著者: L Kappos, C H Polman, M S Freedman, G Edan, H P Hartung, D H Miller, X Montalban, F Barkhof, L Bauer, P Jakobs, C Pohl, R Sandbrink
雑誌名: Neurology. 2006 Oct 10;67(7):1242-9. doi: 10.1212/01.wnl.0000237641.33768.8d. Epub 2006 Aug 16.
Abstract/Text OBJECTIVE: To assess efficacy, safety, and tolerability of every-other-day interferon beta-1b treatment in patients with a first clinical event suggestive of multiple sclerosis (MS) (clinically isolated syndrome).
METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial. Patients with a first clinical demyelinating event and at least two clinically silent brain MRI lesions were randomized to interferon beta-1b (IFNB-1b) 250 mug subcutaneously (SC) every other day (EOD) (n = 292) or placebo (n = 176), until clinically definite MS (CDMS) was diagnosed or they had been followed for 24 months.
RESULTS: After 2 years, 45% of placebo patients had converted to CDMS (Kaplan-Meier estimate; primary outcome measure) and 85% fulfilled the McDonald criteria (co-primary outcome measure). Overall interferon beta-1b delayed the time to diagnosis of CDMS (p < 0.0001) and McDonald MS (p < 0.00001). Hazard ratios (95% CI) were 0.50 (0.36 to 0.70) for CDMS and 0.54 (0.43 to 0.67) for McDonald MS favoring treatment with IFNB-1b. Treatment was well tolerated, as indicated by the low rate of patients dropping out of the study before CDMS was reached (6.6% overall, 7.2% in the IFNB-1b group).
CONCLUSIONS: Interferon beta-1b 250 mug subcutaneously every other day delayed conversion to clinically definite multiple sclerosis, and should be considered as a therapeutic option in patients presenting with a first clinical event suggestive of multiple sclerosis.

PMID 16914693  Neurology. 2006 Oct 10;67(7):1242-9. doi: 10.1212/01.wn・・・
著者: Ludwig Kappos, Mark S Freedman, Chris H Polman, Gilles Edan, Hans-Peter Hartung, David H Miller, Xavier Montalbán, Frederik Barkhof, Ernst-Wilhelm Radü, Lars Bauer, Susanne Dahms, Vivian Lanius, Christoph Pohl, Rupert Sandbrink, BENEFIT Study Group
雑誌名: Lancet. 2007 Aug 4;370(9585):389-97. doi: 10.1016/S0140-6736(07)61194-5.
Abstract/Text BACKGROUND: Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS.
METHODS: In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 microg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211.
FINDINGS: Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44-0.80; p=0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39-0.92; p=0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0.31).
INTERPRETATION: Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

PMID 17679016  Lancet. 2007 Aug 4;370(9585):389-97. doi: 10.1016/S0140・・・
著者: L D Jacobs, R W Beck, J H Simon, R P Kinkel, C M Brownscheidle, T J Murray, N A Simonian, P J Slasor, A W Sandrock
雑誌名: N Engl J Med. 2000 Sep 28;343(13):898-904. doi: 10.1056/NEJM200009283431301.
Abstract/Text BACKGROUND: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value.
METHODS: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis.
RESULTS: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months.
CONCLUSIONS: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

PMID 11006365  N Engl J Med. 2000 Sep 28;343(13):898-904. doi: 10.1056・・・
著者: Ludwig Kappos, Jack Antel, Giancarlo Comi, Xavier Montalban, Paul O'Connor, Chris H Polman, Tomas Haas, Alexander A Korn, Goeril Karlsson, Ernst W Radue, FTY720 D2201 Study Group
雑誌名: N Engl J Med. 2006 Sep 14;355(11):1124-40. doi: 10.1056/NEJMoa052643.
Abstract/Text BACKGROUND: Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis.
METHODS: We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI) and clinical evaluations (core study, months 0 to 6). The primary end point was the total number of gadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In an extension study in which the investigators and patients remained unaware of the dose assignments (months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimod doses.
RESULTS: A total of 255 patients completed the core study. The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second.
CONCLUSIONS: In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies is warranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov] [extension].).

Copyright 2006 Massachusetts Medical Society.
PMID 16971719  N Engl J Med. 2006 Sep 14;355(11):1124-40. doi: 10.1056・・・
著者: Ludwig Kappos, Ernst-Wilhelm Radue, Paul O'Connor, Chris Polman, Reinhard Hohlfeld, Peter Calabresi, Krzysztof Selmaj, Catherine Agoropoulou, Malgorzata Leyk, Lixin Zhang-Auberson, Pascale Burtin, FREEDOMS Study Group
雑誌名: N Engl J Med. 2010 Feb 4;362(5):387-401. doi: 10.1056/NEJMoa0909494. Epub 2010 Jan 20.
Abstract/Text BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.
METHODS: In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point).
RESULTS: A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension.
CONCLUSIONS: As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)

Copyright 2010 Massachusetts Medical Society
PMID 20089952  N Engl J Med. 2010 Feb 4;362(5):387-401. doi: 10.1056/N・・・
著者: Jeffrey A Cohen, Frederik Barkhof, Giancarlo Comi, Hans-Peter Hartung, Bhupendra O Khatri, Xavier Montalban, Jean Pelletier, Ruggero Capra, Paolo Gallo, Guillermo Izquierdo, Klaus Tiel-Wilck, Ana de Vera, James Jin, Tracy Stites, Stacy Wu, Shreeram Aradhye, Ludwig Kappos, TRANSFORMS Study Group
雑誌名: N Engl J Med. 2010 Feb 4;362(5):402-15. doi: 10.1056/NEJMoa0907839. Epub 2010 Jan 20.
Abstract/Text BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis.
METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months.
RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels.
CONCLUSIONS: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

2010 Massachusetts Medical Society
PMID 20089954  N Engl J Med. 2010 Feb 4;362(5):402-15. doi: 10.1056/NE・・・
著者: H L Weiner, P C Dau, B O Khatri, J H Petajan, G Birnbaum, M P McQuillen, M T Fosburg, M Feldstein, E J Orav
雑誌名: Neurology. 1989 Sep;39(9):1143-9.
Abstract/Text We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.

PMID 2549450  Neurology. 1989 Sep;39(9):1143-9.
著者: B G Weinshenker, P C O'Brien, T M Petterson, J H Noseworthy, C F Lucchinetti, D W Dodick, A A Pineda, L N Stevens, M Rodriguez
雑誌名: Ann Neurol. 1999 Dec;46(6):878-86.
Abstract/Text There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.

PMID 10589540  Ann Neurol. 1999 Dec;46(6):878-86.
著者: M Keegan, A A Pineda, R L McClelland, C H Darby, M Rodriguez, B G Weinshenker
雑誌名: Neurology. 2002 Jan 8;58(1):143-6.
Abstract/Text The authors reviewed 59 consecutive patients treated with plasma exchange (PE) for acute, severe attacks of CNS demyelination at Mayo Clinic from January 1984 through June 2000. Most patients had relapsing-remitting MS (n = 22, 37.3%), neuromyelitis optica (NMO) (n = 10, 16.9%), and acute disseminated encephalomyelitis (n = 10, 16.9%). PE was followed by moderate or marked functional improvement in 44.1% of treated patients. Male sex (p = 0.021), preserved reflexes (p = 0.019), and early initiation of treatment (p = 0.009) were associated with moderate or marked improvement. Successfully treated patients improved rapidly following PE, and improvement was sustained.

PMID 11781423  Neurology. 2002 Jan 8;58(1):143-6.

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