BRAIN and NERVE－神経研究の進歩72巻5号

2020年05月発行

特集 多発性硬化症の現在と未来

多発性硬化症のMRI—診断ツール，バイオマーカー，副作用モニタリングツールとしての役割

著者： 三木幸雄¹

所属機関： ¹大阪市立大学大学院医学研究科放射線診断学・IVR学教室

ページ範囲：P.493 - P.508

文献概要

多発性硬化症（MS）で用いられる画像診断はMRIであり，国際的に広く用いられているMcDonald診断基準においても非常に重要な位置を占めている。多発性硬化症におけるMRIの重要な役割に，診断，イメージングバイオマーカーおよび疾患修飾薬による副作用のモニタリングがある。本論文では，MSにおけるMRIのこれらの役割について，最近の知見を含めて述べる。

参考文献

1)Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17: 162-173, 2018

2)Miki Y: Magnetic resonance imaging diagnosis of demyelinating diseases: An update. Clin Exp Neuroimmunol 19: 32-48, 2019

3)Rovira A, Wattjes MP, Tintore M, Tur C, Yousry TA, et al: Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol 11: 471-482, 2015

4)「多発性硬化症・視神経脊髄炎診療ガイドライン」作成委員会（編）: 多発性硬化症・視神経脊髄炎診療ガイドライン2017. 医学書院, 東京, 2017

5)Traboulsee A, Simon JH, Stone L, Fisher E, Jones DE, et al: Revised recommendations of the consortium of MS centers task force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-up of multiple sclerosis. AJNR Am J Neuroradiol 37: 394-401, 2016

6)Filippi M, Preziosa P, Banwell BL, Barkhof F, Ciccarelli O, et al: Assessment of lesions on magnetic resonance imaging in multiple sclerosis: practical guidelines. Brain 142: 1858-1875, 2019

7)Hu XY, Rajendran L, Lapointe E, Tam R, Li D, et al: Three-dimensional MRI sequences in MS diagnosis and research. Mult Scler 25: 1700-1709, 2019

8)Loevner LA, Grossman RI, Cohen JA, Lexa FJ, Kessler D, et al: Microscopic disease in normal-appearing white matter on conventional MR images in patients with multiple sclerosis: assessment with magnetization-transfer measurements. Radiology 196: 511-515, 1995

9)Ge Y, Grossman RI, Babb JS, He J, Mannon LJ: Dirty-appearing white matter in multiple sclerosis: volumetric MR imaging and magnetization transfer ratio histogram analysis. AJNR Am J Neuroradiol 24: 1935-1940, 2003

10)Vrenken H, Seewann A, Knol DL, Polman CH, Barkhof F, et al: Diffusely abnormal white matter in progressive multiple sclerosis: in vivo quantitative MR imaging characterization and comparison between disease types. AJNR Am J Neuroradiol 31: 541-548, 2010

11)Filippi M, Rocca MA: MR imaging of multiple sclerosis. Radiology 259: 659-681, 2011

12)Simon JH, Li D, Traboulsee A, Coyle PK, Arnold DL, et al: Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol 27: 455-461, 2006

13)Lovblad KO, Anzalone N, Dorfler A, Essig M, Hurwitz B, et al: MR imaging in multiple sclerosis: review and recommendations for current practice. AJNR Am J Neuroradiol 31: 983-989, 2010

14)Lecler A, El Sanharawi I, El Methni J, Gout O, Koskas P, et al: Improving detection of multiple sclerosis lesions in the posterior fossa using an optimized 3D-FLAIR sequence at 3T. AJNR Am J Neuroradiol 40: 1170-1176, 2019

15)Lecler A, Bouzad C, Deschamps R, Maizeroi F, Sadik JC, et al: Optimizing 3D FLAIR to detect MS lesions: pushing past factory settings for precise results. J Neurol 266: 2786-2795, 2019

16)田岡俊昭: 脳ドック. 三木幸雄（編）: 放射線医学 脳 画像診断. 金芳堂, 京都, 2012, pp103-121

17)脳ドックのガイドライン作成委員会, 日本脳ドック学会（編）: 脳ドックのガイドライン2014. 響文社, 札幌, 2014

18)三木幸雄, 坂本真一: 加齢性白質病変（leukoaraiosis）update. Brain Nerve 65: 789-799, 2013

19)Callen DJ, Shroff MM, Branson HM, Li DK, Lotze T, et al: Role of MRI in the differentiation of ADEM from MS in children. Neurology 72: 968-973, 2009

20)Yousry TA, Pelletier D, Cadavid D, Gass A, Richert ND, et al: Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 72: 779-787, 2012

21)Janardhan V, Suri S, Bakshi R: Multiple sclerosis: hyperintense lesions in the brain on nonenhanced T1-weighted MR images evidenced as areas of T1 shortening. Radiology 244: 823-831, 2007

22)Zhou F, Shiroishi M, Gong H, Zee CS: Multiple sclerosis: hyperintense lesions in the brain on T1-weighted MR images assessed by diffusion tensor imaging. J Magn Reson Imaging 31: 789-795, 2010

23)Sarbu N, Shih RY, Jones RV, Horkayne-Szakaly I, Oleaga L, et al: White matter diseases with radiologic-pathologic correlation. Radiographics 36: 1426-1447, 2016

24)Filippi M, Agosta F: Imaging biomarkers in multiple sclerosis. J Magn Reson Imaging 31: 770-788, 2010

25)Rovaris M, Filippi M: Defining the response to multiple sclerosis treatment: the role of conventional magnetic resonance imaging. Neurol Sci 26(Suppl 4): S204-S208, 2005

26)Saade C, Bou-Fakhredin R, Yousem DM, Asmar K, Naffaa L, et al: Gadolinium and multiple sclerosis: vessels, barriers of the brain, and glymphatics. AJNR Am J Neuroradiol 39: 2168-2176, 2018

27)Sahraian MA, Eshaghi A: Role of MRI in diagnosis and treatment of multiple sclerosis. Clin Neurol Neurosurg 112: 609-615, 2010

28)Cotton F, Weiner HL, Jolesz FA, Guttmann CR: MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly intervals. Neurology 60: 640-646, 2003

29)Bergsland N, Ramasamy D, Tavazzi E, Hojnacki D, Weinstock-Guttman B, et al: Leptomeningeal contrast enhancement is related to focal cortical thinning in relapsing-remitting multiple sclerosis: A cross-sectional MRI study. AJNR Am J Neuroradiol 40: 620-625, 2019

30)Inglese M, Petracca M: MRI in multiple sclerosis: clinical and research update. Curr Opin Neurol 31: 249-255, 2018

31)Mattay RR, Davtyan K, Bilello M, Mamourian AC: Do all patients with multiple sclerosis benefit from the use of contrast on serial follow-up MR imaging? A retrospective analysis. AJNR Am J Neuroradiol 39: 2001-2006, 2018

32)Consortium of MS centers MRI protocol and clinical guidelines for the diagnosis and follow-up of MS: 2018 revised guidelines. Consortium of Multiple Sclerosis Centers, Heckensack, 2018

33)Smith TE, Steven A, Bagert BA: Gadolinium deposition in neurology clinical practice. Ochsner J 19: 17-25, 2019

34)Saindane AM: Is gadolinium-based contrast material needed for MRI follow-up of multiple sclerosis? Radiology 291: 436-437, 2019

35)Sadigh G, Saindane AM, Waldman AD, Lava NS, Hu R: Comparison of unenhanced and gadolinium-enhanced imaging in multiple sclerosis: is contrast needed for routine follow-up MRI? AJNR Am J Neuroradiol 40: 1476-1480, 2019

36)Narayana PA, Coronado I, Sujit SJ, Wolinsky JS, Lublin FD, et al: Deep learning for predicting enhancing lesions in multiple sclerosis from noncontrast MRI. Radiology 294: 398-404, 2020

37)Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D: High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 270: 834-841, 2014

38)Roccatagliata L, Vuolo L, Bonzano L, Pichiecchio A, Mancardi GL: Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype. Radiology 251: 503-510, 2009

39)Kasahara S, Miki Y, Kanagaki M, Yamamoto A, Mori N, et al: Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology 258: 222-228, 2011

40)Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, et al: High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 275: 803-809, 2015

41)厚生労働省医薬安全対策課: ガドリニウム造影剤の使用上の注意の改訂について. 2017　https://www.mhlw.go.jp/file/05-Shingikai-11121000-Iyakushokuhinkyoku-Soumuka/0000183970.pdf（最終閲覧日：2020年2月21日）

42)Dousset V, Brochet B, Deloire MS, Lagoarde L, Barroso B, et al: MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol 27: 1000-1005, 2006

43)Tsuchiya K, Hachiya J, Maehara T: Diffusion-weighted MR imaging in multiple sclerosis: comparison with contrast-enhanced study. Eur J Radiol 31: 165-169, 1999

44)Wattjes MP, Vennegoor A, Steenwijk MD, de Vos M, Killestein J, et al: MRI pattern in asymptomatic natalizumab-associated PML. J Neurol Neurosurg Psychiatry 86: 793-798, 2015

45)Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, et al: Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 236: 254-260, 2005

46)Sethi V, Yousry TA, Muhlert N, Ron M, Golay X, et al: Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI. J Neurol Neurosurg Psychiatry 83: 877-882, 2012

47)Umino M, Maeda M, Ii Y, Tomimoto H, Sakuma H: 3D double inversion recovery MR imaging: Clinical applications and usefulness in a wide spectrum of central nervous system diseases. J Neuroradiol 46: 107-116, 2019

48)Riederer I, Karampinos DC, Settles M, Preibisch C, Bauer JS, et al: Double inversion recovery sequence of the cervical spinal cord in multiple sclerosis and related inflammatory diseases. AJNR Am J Neuroradiol 36: 219-225, 2015

49)van Buchem MA, Grossman RI, Armstrong C, Polansky M, Miki Y, et al: Correlation of volumetric magnetization transfer imaging with clinical data in MS. Neurology 50: 1609-1617, 1998

50)Miki Y, Grossman RI, Udupa JK, van Buchem MA, Wei L, et al: Differences between relapsing-remitting and chronic progressive multiple sclerosis as determined with quantitative MR imaging. Radiology 210: 769-774, 1999

51)Wattjes MP, Steenwijk MD, Stangel M: MRI in the Diagnosis and Monitoring of Multiple Sclerosis: An Update. Clin Neuroradiol 25(Suppl 2): 157-165, 2015

52)Kira JI: q-space Myelin Map imaging: A new imaging technique for treatment evaluation in multiple sclerosis. J Neurol Sci 373: 358-359, 2017

53)Hagiwara A, Kamagata K, Shimoji K, Yokoyama K, Andica C, et al: White matter abnormalities in multiple sclerosis evaluated by quantitative synthetic MRI, Diffusion tensor imaging, and neurite orientation dispersion and density imaging. AJNR Am J Neuroradiol 40: 1642-1648, 2019

54)Hori M, Fukunaga I, Masutani Y, Taoka T, Kamagata K, et al: Visualizing non-Gaussian diffusion: clinical application of q-space imaging and diffusional kurtosis imaging of the brain and spine. Magn Reson Med Sci 11: 221-233, 2012

55)Sartoretti E, Sartoretti T, Wyss M, Becker AS, Schwenk A, et al: Amide proton transfer weighted imaging shows differences in multiple sclerosis lesions and white matter hyperintensities of presumed vascular origin. Front Neurol 10: 1307, 2019

56)Cortese R, Collorone S, Ciccarelli O, Toosy AT: Advances in brain imaging in multiple sclerosis. Ther Adv Neurol Disord 12: 1756286419859722, 2019［doi: 10.1177/1756286419859722］

57)Sati P: Diagnosis of multiple sclerosis through the lens of ultra-high-field MRI. J Magn Reson 291: 101-109, 2018

58)Tatekawa H, Sakamoto S, Hori M, Kaichi Y, Kunimatsu A, et al: Imaging differences between neuromyelitis optica spectrum disorders and multiple sclerosis: a multi-institutional study in Japan. AJNR Am J Neuroradiol 39: 1239-1247, 2018

59)Matthews L, Marasco R, Jenkinson M, Kuker W, Luppe S, et al: Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution. Neurology 80: 1330-1337, 2013

60)Rovira À, Sastre-Garriga J, Auger C, Rovira A: Idiopathic inflammatory demyelinating diseases of the brainstem. Semin Ultrasound CT MR 34: 123-130, 2013

61)Sati P, Oh J, Constable RT, Evangelou N, Guttmann CR, et al: The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol 12: 714-722, 2016

to visualize veins in white matter lesions: A new tool for the diagnosis of multiple sclerosis? Eur Radiol 27: 4257-4263, 2017

63)Maggi P, Absinta M, Grammatico M, Vuolo L, Emmi G, et al: Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies. Ann Neurol 83: 283-294, 2018

64)Maggi P, Absinta M, Sati P, Perrotta G, Massacesi L, et al: The “central vein sign” in patients with diagnostic “red flags” for multiple sclerosis: A prospective multicenter 3T study. Mult Scler: 1352458519876031, 2019 [Epub ahead of print]［doi: 10.1177/1352458519876031］

65)Miki Y, Grossman RI, Udupa JK, Wei L, Kolson DL, et al: Isolated U-fiber involvement in MS: preliminary observations. Neurology 50: 1301-1306, 1998

66)Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, et al: Cortical lesions in multiple sclerosis. Brain 122: 17-26, 1999

67)Filippi M, Rocca MA: MR imaging of gray matter involvement in multiple sclerosis: implications for understanding disease pathophysiology and monitoring treatment efficacy. AJNR Am J Neuroradiol 31: 1171-1177, 2010

68)Filippi M, Rocca MA, Ciccarelli O, De Stefano N, Evangelou N, et al: MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 15: 292-303, 2016

69)Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, et al: Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain 131: 1759-1775, 2008

70)Dutra BG, da Rocha AJ, Nunes RH, Maia ACMJ: Neuromyelitis optica spectrum disorders: spectrum of MR imaging findings and their differential diagnosis. Radiographics 38: 169-193, 2018

71)Pohl D, Alper G, Van Haren K, Kornberg AJ, Lucchinetti CF, et al: Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome. Neurology 87(9 suppl 2): S38-S45, 2016

72)Sanchez P, Meca-Lallana V, Vivancos J: Tumefactive multiple sclerosis lesions associated with fingolimod treatment: Report of 5 cases. Mult Scler Relat Disord 25: 95-98, 2018

73)Sato K, Niino M, Kawashima A, Yamada M, Miyazaki Y, et al: Disease exacerbation after the cessation of fingolimod treatment in japanese patients with multiple sclerosis. Intern Med 57: 2647-2655, 2018

74)Jander S, Turowski B, Kieseier BC, Hartung HP: Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler 18: 1650-1652, 2012

75)Moghadasi AN, Baghbanian SM: Tumefactive demyelinating lesions in a patient with multiple sclerosis receiving natalizumab. Acta Neurol Belg 119: 137-139, 2019

76)Kobayashi M, Shimizu Y, Shibata N, Uchiyama S: Gadolinium enhancement patterns of tumefactive demyelinating lesions: correlations with brain biopsy findings and pathophysiology. J Neurol 261: 1902-1910, 2014

77)岡田 務, 本田茉也, 三木幸雄: 炎症性脱髄疾患. 細矢貴亮, 興梠征典, 三木幸雄, 山田 惠（編）: 脳のMRI. メディカル・サイエンス・インターナショナル, 東京, 2015, pp444-456

78)Karaarslan E, Altintas A, Senol U, Yeni N, Dincer A, et al: Balo's concentric sclerosis: clinical and radiologic features of five cases. AJNR Am J Neuroradiol 22: 1362-1367, 2001

79)Pietroboni AM, Arighi A, De Riz MA, Ghezzi L, Calvi A, et al: Balo's concentric sclerosis: still to be considered as a variant of multiple sclerosis? Neurol Sci 36: 2277-2280, 2015

80)Matsuoka T, Suzuki SO, Iwaki T, Tabira T, Ordinario AT, et al: Aquaporin-4 astrocytopathy in Balo's disease. Acta Neuropathol 120: 651-660, 2010

81)Masuda H, Mori M, Katayama K, Kikkawa Y, Kuwabara S: Anti-aquaporin-4 antibody-seronegative NMO spectrum disorder with Balo's concentric lesions. Intern Med 52: 1517-1521, 2013

82)Jarius S, Wurthwein C, Behrens JR, Wanner J, Haas J, et al: Balo's concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures. J Neuroinflammation 15: 22, 2018［doi: 10.1086/s12974-017-1043-y］

83)Nakamura M, Miyazawa I, Fujihara K, Nakashima I, Misu T, et al: Preferential spinal central gray matter involvement in neuromyelitis optica. An MRI study. J Neurol 255: 163-170, 2008

84)Valsasina P, Aboulwafa M, Preziosa P, Messina R, Falini A, et al: Cervical cord T1-weighted hypointense lesions at MR imaging in multiple sclerosis: relationship to cord atrophy and disability. Radiology 288: 234-244, 2018

85)Hickman SJ, Miszkiel KA, Plant GT, Miller DH: The optic nerve sheath on MRI in acute optic neuritis. Neuroradiology 47: 51-55, 2005

86)Rocca MA, Hickman SJ, Bo L, Agosta F, Miller DH, et al: Imaging the optic nerve in multiple sclerosis. Mult Scler 11: 537-541, 2005

87)Brownlee WJ, Miszkiel KA, Tur C, Barkhof F, Miller DH, et al: Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis. Neurology 91: e1130-e1134, 2018

88)Brownlee WJ, Hardy TA, Fazekas F, Miller DH: Diagnosis of multiple sclerosis: progress and challenges. Lancet 389: 1336-1346, 2017

89)Solomon AJ, Naismith RT, Cross AH: Misdiagnosis of multiple sclerosis: Impact of the 2017 McDonald criteria on clinical practice. Neurology 92: 26-33, 2019

90)Solomon AJ, Klein EP, Bourdette D: “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology 78: 1986-1991, 2012

91)Jarius S, Paul F, Aktas O, Asgari N, Dale RC, et al: MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation 15: 134, 2018［doi: 10.1186/s12974-018-1144-2］

92)Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, et al: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85: 177-189, 2015

93)細矢貴亮, 興梠征典, 三木幸雄, 山田 惠（編）: 脳のMRI. メディカル・サイエンス・インターナショナル, 東京, 2015

94)青木茂樹, 相田典子, 井田正博, 大場 洋（編）: よくわかる脳MRI 第4版. 学研メディカル秀潤社, 東京（in press）

95)Aliaga ES, Barkhof F: MRI mimics of multiple sclerosis. Handb Clin Neurol 122: 291-316, 2014

96)Geraldes R, Ciccarelli O, Barkhof F, De Stefano N, Enzinger C, et al: The current role of MRI in differentiating multiple sclerosis from its imaging mimics. Nat Rev Neurol 14: 199-213, 2018

97)Reich DS, Lucchinetti CF, Calabresi PA: Multiple sclerosis. N Engl J Med 378: 169-180, 2018

98)Miki Y, Grossman RI, Udupa JK, Wei L, Polansky M, et al: Relapsing-remitting multiple sclerosis: longitudinal analysis of MR images--lack of correlation between changes in T2 lesion volume and clinical findings. Radiology 213: 395-399, 1999

99)Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, et al: Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 64: 247-254, 2008

100)Nakamura Y, Gaetano L, Matsushita T, Anna A, Sprenger T, et al: A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression. J Neuroinflammation 15: 255, 2018［doi: 10.1186/s12974-018-1295-1］

101)Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC: The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 129: 584-594, 2006

102)Brex PA, Ciccarelli O, O'Riordan JI, Sailer M, Thompson AJ, et al: A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346: 158-164, 2002

103)Genovese AV, Hagemeier J, Bergsland N, Jakimovski D, Dwyer MG, et al: Atrophied brain T2 lesion volume at MRI is associated with disability progression and conversion to secondary progressive multiple sclerosis. Radiology 293: 424-433, 2019

104)Miki Y, Grossman RI, Udupa JK, Samarasekera S, van Buchem MA, et al: Computer-assisted quantitation of enhancing lesions in multiple sclerosis: correlation with clinical classification. AJNR Am J Neuroradiol 18: 705-710, 1997

105)Ge Y, Grossman RI, Udupa JK, Wei L, Mannon LJ, et al: Brain atrophy in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis: longitudinal quantitative analysis. Radiology 214: 665-670, 2000

106)Fujimori J, Fujihara K, Ogawa R, Baba T, Wattjes M, et al: Patterns of regional brain volume loss in multiple sclerosis: a cluster analysis. J Neurol 267: 395-405, 2019

107)Akaishi T, Nakashima I, Mugikura S, Aoki M, Fujihara K: Whole brain and grey matter volume of Japanese patients with multiple sclerosis. J Neuroimmunol 306: 68-75, 2017

108)Filippi M, Preziosa P, Rocca MA: Magnetic resonance outcome measures in multiple sclerosis trials: time to rethink? Curr Opin Neurol 27: 290-299, 2014

109)Miller DH, Altmann DR, Chard DT: Advances in imaging to support the development of novel therapies for multiple sclerosis. Clin Pharmacol Ther 91: 621-634, 2012

110)Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, et al: A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348: 15-23, 2003

111)Kappos L, Antel J, Comi G, Montalban X, O'Connor P, et al: Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355: 1124-1140, 2006

112)Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, et al: A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Mult Scler 18: 1269-1277, 2012

113)Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354: 899-910, 2006

114)Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, et al: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362: 387-401, 2010

115)Saida T, Yamamura T, Kondo T, Yun J, Yang M, et al: A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries. BMC Neurol 19: 5, 2019［doi: 10.1186/s12883-018-1220-3］

116)Rio J, Comabella M, Montalban X: Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol 5: 553-560, 2009

117)Wattjes MP, Rovira A, Miller D, Yousry TA, Sormani MP, et al: Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis--establishing disease prognosis and monitoring patients. Nat Rev Neurol 11: 597-606, 2015

118)Rojas JI, Patrucco L, Miguez J, Besada C, Cristiano E: Brain atrophy as a non-response predictor to interferon-beta in relapsing-remitting multiple sclerosis. Neurol Res 36: 615-618, 2014

119)Sai A, Shimono T, Sakai K, Takeda A, Shimada H, et al: Diffusion-weighted imaging thermometry in multiple sclerosis. J Magn Reson Imaging 40: 649-654, 2014

120)Zivadinov R, Tavazzi E, Bergsland N, Hagemeier J, Lin F, et al: Brain iron at quantitative MRI is associated with disability in multiple sclerosis. Radiology 289: 487-496, 2018

121)Muftuoglu M, Olson A, Marin D, Ahmed S, Mulanovich V, et al: Allogeneic BK virus-specific t cells for progressive multifocal leukoencephalopathy. N Engl J Med 379: 1443-1451, 2018

122)Nakahara J, Tomaske L, Kume K, Takata T, Kamada M, et al: Three cases of non-carryover fingolimod-PML: Is the risk in Japan increased? Neurol Neuroimmunol Neuroinflamm 6: e559, 2019［doi: 10.1212/NXI.0000000000000559］

123)Nieuwkamp DJ, Murk JL, van Oosten BW, Cremers CH, Killestein J, et al: PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med 372: 1474-1476, 2015

124)Rosenkranz T, Novas M, Terborg C: PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med 372: 1476-1478, 2015

125)Hodel J, Outteryck O, Dubron C, Dutouquet B, Benadjaoud MA, et al: Asymptomatic progressive multifocal leukoencephalopathy associated with natalizumab: diagnostic precision with MR imaging. Radiology 278: 863-872, 2016

126)Wattjes MP, Barkhof F: Diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy using MRI. Curr Opin Neurol 27: 260-270, 2014

127)McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, et al: Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 87: 117-125, 2016

128)Wattjes MP, Warnke C: High-frequency MRI monitoring should be performed in natalizumab-treated MS patients with higher risk of PML - Commentary. Mult Scler 23: 770-771, 2017

129)Hodel J, Darchis C, Outteryck O, Verclytte S, Deramecourt V, et al: Punctate pattern: A promising imaging marker for the diagnosis of natalizumab-associated PML. Neurology 86: 1516-1523, 2016

130)Hodel J, Outteryck O, Verclytte S, Deramecourt V, Lacour A, et al: Brain magnetic susceptibility changes in patients with natalizumab-associated progressive multifocal leukoencephalopathy. AJNR Am J Neuroradiol 36: 2296-2302, 2015

131)Pontillo G, Cocozza S, Lanzillo R, Borrelli P, De Rosa A, et al: Brain susceptibility changes in a patient with natalizumab-related progressive multifocal leukoencephalopathy: a longitudinal quantitative susceptibility mapping and relaxometry study. Front Neurol 8: 294, 2017［doi: 10.3389/fneur.2017.00294］

132)Sakai M, Inoue Y, Aoki S, Sirasaka T, Uehira T, et al: Follow-up magnetic resonance imaging findings in patients with progressive multifocal leukoencephalopathy: evaluation of long-term survivors under highly active antiretroviral therapy. Jpn J Radiol 27: 69-77, 2009

133)Ishii J, Shishido-Hara Y, Kawamoto M, Fujiwara S, Imai Y, et al: A punctate magnetic resonance imaging pattern in a patient with systemic lupus erythematosus is an early sign of progressive multifocal leukoencephalopathy: a clinicopathological study. Intern Med 57: 2727-2734, 2018

134)Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, et al: Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 9: 438-446, 2010

135)Miyagawa M, Maeda M, Umino M, Kagawa K, Nakamichi K, et al: Low signal intensity in U-fiber identified by susceptibility-weighted imaging in two cases of progressive multifocal leukoencephalopathy. J Neurol Sci 344: 198-202, 2014

136)Thurnher MM, Boban J, Rieger A, Gelpi E: Susceptibility-weighted MR imaging hypointense rim in progressive multifocal leukoencephalopathy: the end point of neuroinflammation and a potential outcome predictor. AJNR Am J Neuroradiol 40: 994-1000, 2019

137)Wijburg MT, Witte BI, Vennegoor A, Roosendaal SD, Sanchez E, et al: MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance. J Neurol Neurosurg Psychiatry 87: 1138-1145, 2016

138)Wattjes MP, Wijburg MT, van Eijk J, Frequin S, Uitdehaag BMJ, et al: Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS. J Neurol Neurosurg Psychiatry 89: 535-541, 2018

139)Wattjes MP, Wijburg MT, Vennegoor A, Witte BI, de Vos M, et al: MRI characteristics of early PML-IRIS after natalizumab treatment in patients with MS. J Neurol Neurosurg Psychiatry 87: 879-884, 2016

140)Ueda D, Yamamoto A, Nishimori M, Shimono T, Doishita S, et al: Deep learning for MR angiography: automated detection of cerebral aneurysms. Radiology 290: 187-194, 2019

141)Ueda D, Shimazaki A, Miki Y: Technical and clinical overview of deep learning in radiology. Jpn J Radiol 37: 15-33, 2019

142)Sakai K, Yamada K: Machine learning studies on major brain diseases: 5-year trends of 2014-2018. Jpn J Radiol 37: 34-72, 2019

143)Finck T, Li H, Grundl L, Eichinger P, Bussas M, et al: Deep-learning generated synthetic double inversion recovery images improve multiple sclerosis lesion detection. Invest Radiol, 2020 Jan 21[doi: 10.1097/RLI.0000000000000640]

144)McKinley R, Wepfer R, Grunder L, Aschwanden F, Fischer T, et al: Automatic detection of lesion load change in multiple sclerosis using convolutional neural networks with segmentation confidence. Neuroimage Clin 25: 102104, 2019［doi: 10.1016/j.nicl.2019.102104］

145)Salem M, Valverde S, Cabezas M, Pareto D, Oliver A, et al: A fully convolutional neural network for new T2-w lesion detection in multiple sclerosis. Neuroimage Clin 25: 102149, 2019［doi: 10.1016/j.nicl.2019.102149］