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急性運動失調

著者: 瀧山嘉久 山梨大学大学院総合研究部 医学域 神経内科学講座

監修: 永山正雄 国際医療福祉大学大学院医学研究科 脳神経内科学

著者校正済:2020/09/24
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 多発性硬化症の急性増悪では副腎皮質ステロイドによる治療を行うことを推奨する(推奨度1)
  1. 視神経脊髄炎においては急性増悪期に副腎皮質ステロイド薬による治療を行うことを推奨する (推奨度1)
  1. 視神経脊髄炎の再発予防に副腎皮質ステロイド薬は有効である (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
  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
  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す。閲覧にはご契約
  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
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:
瀧山嘉久 : 奨学(奨励)寄付など(武田薬品工業,大塚製薬)[2021年]
監修:永山正雄 : 未申告[2021年]

改訂のポイント:
  1. 多発性硬化症・視神経脊髄炎診療ガイドライン2017に基づき改訂を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 急性運動失調とは、急性に起こる協調運動障害を指す。運動失調は障害部位により、小脳性、脊髄性、前庭性、大脳性に分けられる(アルゴリズム[1][2]。発病率は不明である。
  1. 原因疾患は多岐にわたる。小脳性運動失調では、小脳炎、脳幹脳炎(ビッカースタッフ型を含む)、感染後脳症、ウェルニッケ脳症、橋本脳症(参照:橋本病)、HIV感染症、フィッシャー症候群(参照:ギラン・バレー症候群)、多発性硬化症、抗アクアポリン4抗体関連疾患、急性散在性脳脊髄炎、周期性失調症、傍腫瘍性神経症候群、 脳血管障害 、アルコールや抗てんかん薬(参照: てんかん )など薬剤による中毒、Superficial siderosisなどが鑑別疾患となる[2][3][4][5][6][7][8][9]<図表><図表><図表><図表><図表>
  1. 小児の急性小脳性運動失調症は、水痘、ムンプス、ポリオなどの感染症に引き続いて起こることが多い[10]
  1. 脊髄性運動失調では、亜急性連合性脊髄変性症、後脊髄動脈症候群(参照: 脊髄血管障害 、傍腫瘍性神経症候群、シェーグレン症候群などが鑑別疾患となる。
  1. 前庭性では、良性発作性頭位めまい症メニエール病前庭神経炎突発性難聴CO中毒が鑑別疾患となる。良性発作性頭位めまい症の頻度が最も高い[11]
  1. 大脳性では、前頭葉性失調、頭頂葉性失調などが 脳腫瘍 により起こることがある。
 
  1. 小児で突然発症の歩行障害を呈した患者では、急性小脳性運動失調症を疑い、先行感染やワクチン接種の有無を聴取し、頭部MRIと髄液検査を行って診断することが勧められる(推奨度1O)
  1. まとめ、代表事例:急性小脳性運動失調の大半は2~5歳の幼児であり、水痘をはじめとするウイルス感染やワクチン接種の数日~数週後に発症する[12][10][13]。他疾患を除外するために、頭部MRIと髄液検査が勧められる[12]
  1. 結論:頭部MRIは両側小脳半球のびまん性異常信号を呈することがあるが、病的意義や予後との関連はない[14]。また、髄液所見は軽度リンパ球増多を認める[10][15]。したがって急性散在性脳脊髄炎などとの鑑別のためにこれらの検査を行う[12]
  1. 追記:15歳以下の罹患率は、オランダでは10万人あたり0.75人である[13]。予後は良好で、2~3週で軽快する[10][15]
問診・診察のポイント  
  1. 病歴では、鑑別診断に役立つように、先行感染症、アルコール多飲や偏食、抗てんかん薬など薬剤の服用、寛解・再発、めまい(回転性、浮動性)、高血圧症や癌についての既往歴の有無などを聴取する。

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文献 

著者: Yuji Hashimoto, Zen Kobayashi, Minoru Kotera
雑誌名: Intern Med. 2008;47(4):331-2. Epub 2008 Feb 15.
Abstract/Text
PMID 18277044  Intern Med. 2008;47(4):331-2. Epub 2008 Feb 15.
著者: Masaaki Odaka, Nobuhiro Yuki, Mitsunori Yamada, Michiaki Koga, Toshihiko Takemi, Koichi Hirata, Satoshi Kuwabara
雑誌名: Brain. 2003 Oct;126(Pt 10):2279-90. doi: 10.1093/brain/awg233. Epub 2003 Jul 7.
Abstract/Text Bickerstaff reported eight patients who, in addition to acute ophthalmoplegia and ataxia, showed drowsiness, extensor plantar responses or hemisensory loss. This condition has been named Bickerstaff's brainstem encephalitis (BBE). One patient had gross flaccid weakness in the four limbs. Presumably because of the rarity of this disorder, there has been no reported study on a large number of patients with BBE. To clarify its clinical features, we reviewed detailed clinical profiles and laboratory findings for 62 cases of BBE diagnosed by the strict criteria of progressive, relatively symmetrical external ophthalmoplegia and ataxia by 4 weeks, and disturbance of consciousness or hyperreflexia. Ninety-two per cent of the patients involved had had an antecedent illness. Besides ophthalmoplegia and ataxia, disturbance of consciousness was frequent (74%), and facial diplegia (45%), Babinski's sign (40%) and pupillary abnormality and bulbar palsy (34%) were present. Almost all the patients had a monophasic remitting course and generally a good outcome. Serum anti-GQ1b IgG antibody was positive in 66%, and MRI showed brain abnormality in 30% of the patients. Another striking feature was the association with flaccid symmetrical tetraparesis, seen in 60% of the patients. An autopsy study of a BBE patient clearly showed the presence of definite inflammatory changes in the brainstem: there was perivascular lymphocytic infiltration with oedema and glial nodules. Electrodiagnostic study results suggested peripheral motor axonal degeneration. Limb weakness in the BBE cases studied was considered the result of overlap with the axonal subtype of Guillain-Barré syndrome. These findings confirm that BBE constitutes a clinical entity and provide additional clinical and laboratory features of BBE. A considerable number of BBE patients have associated axonal Guillain-Barré syndrome, indicative that the two disorders are closely related and form a continuous spectrum.

PMID 12847079  Brain. 2003 Oct;126(Pt 10):2279-90. doi: 10.1093/brain/・・・
著者: H E DeWARDENER, B LENNOX
雑誌名: Lancet. 1947 Jan 4;1(6436):11-7.
Abstract/Text
PMID 20278697  Lancet. 1947 Jan 4;1(6436):11-7.
著者: Mikie Yamamoto, Kenji Wada-Isoe, Makoto Yoneda, Koji Doi, Hisanori Kowa, Kenji Nakashima
雑誌名: Rinsho Shinkeigaku. 2010 Aug;50(8):581-4.
Abstract/Text We reported a 61-year-old man who had developed acute cerebellar ataxia in the trunk and the lower limbs. His chemical blood analysis showed very mild hypothyroidism and the presence of serum anti-thyroid peroxidase (TPO) antibody and anti-NH2 terminal of alpha-enolase (NAE) antibody. While cerebellar atrophy was not evident on magnetic resonance imaging (MRI) of the brain, 99mTc-ECD SPECT using the easy Z-score imaging system (eZIS) showed decreased regional cerebral blood flow (rCBF) in the vermis of cerebellum. His cerebellar ataxia improved spontaneously within three weeks. The present case is very rare and suggests that anti-NAE autoantibody may be associated with actue cerebellar ataxia.

PMID 20803969  Rinsho Shinkeigaku. 2010 Aug;50(8):581-4.
著者: Seika Nakamura, Reika Wate, Akiyo Shinde, Shinya Asayama, Satoshi Nakano, Hirofumi Kusaka
雑誌名: Rinsho Shinkeigaku. 2009 Oct;49(10):651-5.
Abstract/Text A 36-year-old man was hospitalized because of subacutely progressive gait disturbance. Neurological examination disclosed severe ataxia of gait and trunk and moderate ataxia of the four limbs, without signs of cognitive impairment. There were no manifestations of systemic infections. Brain MRI showed mild atrophy of the cerebellar vermis and hemispheres. Extensive laboratory search failed to disclose the cause of subacute ataxia. Cerebellar ataxia progressed, leading to the patient becoming wheelchair-bound two months after admission, when PCR analysis of the cerebrospinal fluid was positive for Epstein-Barr, JC, and hepatitis B viruses. In addition, the quantity of serum HIV1-RNA was 2.9 x 10(4) copies, the absolute count of CD4+ lymphocyte was 28/mm3, and the CD4/CD8 ratio was 0.04, despite clear denials by both the patient and his wife regarding any apparent infectious opportunities. Accordingly thereafter, highly active antiretroviral therapy was initiated. Several weeks after the initiation of therapy, ataxia stabilized with disappearance of serum HIV and cerebrospinal fluid JCV viral load. He returned to his occupation 20 months after disease onset without progression of ataxia or development of other neurological dysfunctions including dementia. We could not establish the exact pathogenesis of ataxia in this patient It could have been primary cerebellar degeneration caused by HIV, or the other viruses detected (EBV, JCV) or autoimmune mechanisms caused by these viruses. However, HIV infection should be considered as an etiology in clinical setting of subacute ataxia, particularly in a young or immunocompromised patient.

PMID 19999147  Rinsho Shinkeigaku. 2009 Oct;49(10):651-5.
著者: Koji Shinoda, Hiroyuki Murai, Ken-Ichi Shibata, Shoko Samejima, Shuji Kaneto, Nobuyoshi Takashima, Kimihiro Tanaka
雑誌名: Rinsho Shinkeigaku. 2012;52(1):30-3.
Abstract/Text A 29-year-old female developed diplopia, nasal voice and gait disturbance after an upper respiratory infection. On admission, she presented with bilateral external ophthalmoplegia, slight bilateral facial nerve palsy, dysarthria, dysphagia, cervical and brachial muscle weakness, ataxia and areflexia. She had serum anti-GT1a, anti-GQ1b and anti-galactocerebroside IgG antibodies. She was diagnosed with an overlap case of Fisher syndrome and pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Intravenous immunoglobulin therapy was effective for the ophthalmoplegia and ataxia, but did not improve the bilateral facial nerve palsy and brachial muscle weakness. The facial nerve palsy clearly worsened despite improvement in other symptoms, and therefore high-dose intravenous methylprednisolone therapy was added. The distinct response to treatment may be caused by different activity, production, clearance and reactivity to intravenous immunoglobulin of the autoantibodies. The present case suggests that treatment response and patterns of recovery differ according to the causative anti-ganglioside antibodies.

PMID 22260976  Rinsho Shinkeigaku. 2012;52(1):30-3.
著者: A M Connolly, W E Dodson, A L Prensky, R S Rust
雑誌名: Ann Neurol. 1994 Jun;35(6):673-9. doi: 10.1002/ana.410350607.
Abstract/Text We report a study of 73 consecutive children with acute cerebellar ataxia, representing all of the children evaluated at St. Louis Children's Hospital during a 23-year-period to whom this diagnosis could appropriately be assigned. Twenty-six percent had chickenpox, 52% had other illnesses that were presumed to be viral, and in 3% the ataxia was related to immunization. Nineteen percent had no definite prodrome. Sixty children were followed for 4 months or longer after onset of their ataxia (mean, 7.4 +/- 6.0 years). Ninety-one percent (55/60) of these, including all children with chickenpox, recovered completely from ataxia. Eighty-nine percent (39/44) of the children with non-varicella-related ataxia recovered completely from the ataxia, a much better rate of recovery than what was found in prior large studies. One fifth of the children followed for more than 4 months experienced transient behavioral or intellectual difficulties, but only 5 of the 60 children demonstrated sustained learning problems. This study represents the largest reported series of acute cerebellar ataxia and the most complete characterization of the clinical features and outcome of this illness.

PMID 8210223  Ann Neurol. 1994 Jun;35(6):673-9. doi: 10.1002/ana.4103・・・
著者: N A T van der Maas, P E Vermeer-de Bondt, H de Melker, J M Kemmeren
雑誌名: Vaccine. 2009 Mar 18;27(13):1970-3. doi: 10.1016/j.vaccine.2009.01.019. Epub 2009 Jan 30.
Abstract/Text AIM: Acute cerebellar ataxia (ACA, sudden onset of truncal ataxia and gait disturbances) usually follows a benign illness (25% varicella). It is also described after vaccination, like MMR and varicella zoster virus (VZV). We will establish incidence rates of (varicella related) ACA and assess the attributable risk of vaccination to ACA in the Netherlands.
METHOD: Data on ACA in children, following infections, like varicella, and vaccinations, obtained from prospective, active pediatric surveillance and passive surveillance on adverse events following immunizations (AEFI) were compared with hospitalization data for ataxia. Capture-recapture (CRC) method was used to estimate the burden of ACA in the Netherlands.
RESULTS: 45 children with ACA were included (44 and 1 reported by pediatric and AEFI surveillance respectively, 30 were hospitalized). Chickenpox preceded ACA in 15 cases, one case followed MMR. Of the hospitalization reports, 13 fulfilled the criteria for ACA. Using CRC the estimated number of hospitalized ACA cases was 42. For varicella related ACA, this estimate was 10, resulting in an incidence rate of 0.7:100,000 (95%CI 0.52-0.94, all cases) and 0.17:100,000 (95%CI 0.09-0.31, varicella related cases) for children under 15 years of age.
CONCLUSION: The incidence rates were comparable with other studies. We found no association with MMR, but chickenpox was clearly related to ACA. According to age-specific seroprevalence data the incidence rate of ACA was 5:100,000 VZV infections for children up to 5 years, compared to an ACA-reporting rate of 0.15:100,000 doses VZV-vaccine. Therefore, uptake of VZV-vaccine in the immunization programme will diminish the incidence rate of ACA.

PMID 19186201  Vaccine. 2009 Mar 18;27(13):1970-3. doi: 10.1016/j.vacc・・・
著者: Y De Bruecker, F Claus, P Demaerel, F Ballaux, R Sciot, L Lagae, G Buyse, G Wilms
雑誌名: Eur Radiol. 2004 Aug;14(8):1478-83. doi: 10.1007/s00330-004-2247-y. Epub 2004 Feb 13.
Abstract/Text Acute cerebellitis is an inflammatory process involving the cerebellum. We report the clinical, CT and MRI features of four cases and a review of the literature. Bilateral diffuse hemispheric abnormalities represent the most common imaging presentations. Our observations demonstrate the various imaging appearances of acute cerebellitis. Simultaneous involvement of both hemispheres and the vermis has not been reported previously. The development of cerebellar atrophy following an initial normal MR imaging examination is also a new finding. In atypical clinical presentation, MR imaging can lead to the diagnosis. MR imaging findings have, however, no prognostic value.

PMID 14968261  Eur Radiol. 2004 Aug;14(8):1478-83. doi: 10.1007/s00330・・・
著者: Moshe Nussinovitch, Dario Prais, Benjamin Volovitz, Rivka Shapiro, Jacob Amir
雑誌名: Clin Pediatr (Phila). 2003 Sep;42(7):581-4. doi: 10.1177/000992280304200702.
Abstract/Text Acute cerebellar ataxia is a relatively common neurologic disorder among children. Our aim was to characterize the clinical picture, etiology, and prognosis of acute cerebellar ataxia. The medical records of all children with a diagnosis of acute cerebellar ataxia hospitalized in our center and Hasharon Medical Center from 1990 to 2001 were reviewed. The diagnosis of acute cerebellar ataxia was based on the following criteria: acute onset of ataxia with or without nystagmus; absence of known genetic predisposing factors, such as familial degenerative disorders; and absence of drug intoxication, bacterial meningitis, and metabolic disorders. Thirty-nine children were identified; 54% were male; mean age at presentation was 4.8 +/- 3.8 years. All patients were observed for at least 1 year. A prodromal febrile illness was noted in 74.4%: varicella, 31%; mumps, 20%; nonspecific viral infection, 15.4%; mycoplasma, 5%; Epstein Barr virus, 3%. Latency from the prodromal illness to the onset of ataxia was 8.8 +/- 7.4 days. The most common associated neurologic findings were nystagmus and dysmetria. Full gait recovery took less than 2 weeks on average, and the longest duration of neurologic signs was 24 days (mumps-related). Acute cerebellar ataxia in childhood is a self-limited disease. The recovery was faster than that reported in previous publications and was complete in all children without any neurologic sequelae. Imaging studies are needed only in atypical presentation or if there is no spontaneous improvement after 1 to 2 weeks.

PMID 14552515  Clin Pediatr (Phila). 2003 Sep;42(7):581-4. doi: 10.117・・・
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: 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 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: 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: T Saida, S Kikuchi, Y Itoyama, Q Hao, T Kurosawa, K Nagato, D Tang, L Zhang-Auberson, J Kira
雑誌名: Mult Scler. 2012 Sep;18(9):1269-77. doi: 10.1177/1352458511435984. Epub 2012 Feb 21.
Abstract/Text BACKGROUND: Fingolimod (FTY720) has previously shown clinical efficacy in phase II/III studies of predominantly Caucasian populations with multiple sclerosis (MS).
OBJECTIVES: To report six-month efficacy and safety outcomes in Japanese patients with relapsing MS treated with fingolimod.
METHODS: In this double-blind, parallel-group, phase II study, 171 Japanese patients with relapsing MS were randomized to receive once-daily fingolimod 0.5 mg or 1.25 mg, or matching placebo for six months. The primary and secondary endpoints were the percentages of patients free from gadolinium (Gd)-enhanced lesions at months 3 and 6, and relapses over six months, respectively; safety outcomes were also assessed.
RESULTS: 147 patients completed the study. Higher proportions of patients were free from Gd-enhanced lesions at months 3 and 6 with fingolimod (0.5 mg: 70%, p = 0.004; 1.25 mg: 86%, p < 0.001) than with placebo (40%). Odds ratios for the proportions of relapse-free patients over six months favoured fingolimod versus placebo but were not significant. Adverse events related to fingolimod included transient bradycardia and atrioventricular block at treatment initiation, and elevated liver enzyme levels.
CONCLUSIONS: This study demonstrated the clinical efficacy of fingolimod for the first time in Japanese patients with MS, consistent with the established effects of fingolimod in Caucasian patients.

PMID 22354739  Mult Scler. 2012 Sep;18(9):1269-77. doi: 10.1177/135245・・・
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: Kazuhiro Honda, Tatsuhiko Yuasa
雑誌名: Magn Reson Med Sci. 2008;7(1):55-8.
Abstract/Text We present a case of anti-aquaporin-4 antibody-positive myelitis, which suggests the high-risk syndrome of neuromyelitis optica, whose modest clinical signs were in conspicuous contrast to the extensive spinal cord lesions demonstrated on magnetic resonance (MR) imaging. Follow-up MR imaging showed marked improvement of lesions. Interestingly, an anti-glutamate receptor antibody, which has been suggested to cause dysfunction of N-methy-D-aspartate receptor on neuron, was detected in the cerebrospinal fluid of the patient. We discuss the case and related literature.

PMID 18460850  Magn Reson Med Sci. 2008;7(1):55-8.
著者: Rina Takano, Tatsuro Misu, Toshiyuki Takahashi, Masahiro Izumiyama, Kazuo Fujihara, Yasuto Itoyama
雑誌名: Tohoku J Exp Med. 2008 May;215(1):55-9.
Abstract/Text Neuromyelitis optica (NMO) is a neurologic disease characterized by severe optic neuritis, longitudinally extended, transverse myelitis and serum aquaporin-4 (AQP4) antibody. Our recent neuropathological study revealed the extensive loss of AQP4 and glial fibrillary acidic protein (GFAP), an astrocyte-specific protein, in NMO lesions, but not in MS lesions, suggesting that severe astrocytic damage or dysfunction may be related to the pathogenesis of NMO. Here we report a patient of NMO, in which the cerebrospinal fluid (CSF) levels of GFAP were measured both during relapse of myelitis and after high-dose intravenous methylprednisolone (HIMP). The patient was a 34-year old woman with two previous episodes of optic neuritis. She developed myelitis longitudinally extending from C3 to T12 with contrast enhancement, and was AQP4 antibody-positive. In the acute phase, the GFAP level in the cerebrospinal fluid (CSF) was prominently elevated (18,966.7 ng/ml) as compared with controls (0.6 +/- 0.33 ng/ml). However, following HIMP, the clinical and MRI findings improved, and the CSF-GFAP level was near-normal (2.1 ng/ml). The CSF of myelin basic protein was also elevated in relapse (1,016.0 pg/ml), and became lower but still remained high (158.7 pg/ml) after HIMP compared with controls (3.36 +/- 3.83 pg/ml). The prominent elevation of the CSF-GFAP level in relapse of NMO, followed by its sharp decline after therapy, suggests severe astrocytic damage with a temporal profile distinct from that of the demyelinating process in NMO. CSF-GFAP may be useful as a biomarker of NMO.

PMID 18509235  Tohoku J Exp Med. 2008 May;215(1):55-9.
著者: Haruo Shimazaki, Koichi Nakao, Kinya Ishikawa, Yoshihisa Takiyama, Imaharu Nakano
雑誌名: No To Shinkei. 2006 Jan;58(1):63-7.
Abstract/Text We reported a Japanese case of spinocerebellar ataxia type 6 (SCA6) with episodic ataxia type 2 (EA2) phenotype. A 28-year-old woman was admitted to our hospital because of episodic unsteadiness of gait and dysarthria for 4 years. Neurological examination revealed truncal ataxia and dysarthria during attacks, but no abnormal findings in interictal phases. A brain MRI showed no obvious cerebellar atrophy, whereas proton MR spectroscopy (1H-MRS) disclosed decrease of the N-acetylaspartate/ceatine (NAA/Cr) ratio in the cerebellar hemisphere. We identified the expanded 22 CAG repeats without a missense mutation in the CACNA1A gene. After one year from the discharge, her gait ataxia became gradually obvious even in the interictal phase. To our knowledge, although a few foreign papers had reported the SCA6 cases with EA2 phenotype, there is no particular report on such cases in Japan. 1H-MRS, in addition to CAG repeats analysis, might enable us to differentiate SCA6 from EA2, because the latter showed no decrease of NAA/Cr ratio in cerebellar hemisphere according to the previous reports.

PMID 16482924  No To Shinkei. 2006 Jan;58(1):63-7.

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